5. Results and Discussion

5.1. Nitroketene-NJ-acctals: Introduction

Thc two-carbon synthon, N-methyl-N-[(El)-l-(metl1ylsulfanyl)-2-nitro-l-

ethenyllanline (1~-mcthyl-1~-methyl-2-nitroethylene, NMSM) 76s (Figure 1.6), a

nitroketene-N,S-acetiil, is a versatile molccu~e.~" It is embodied with threc functional

groups on ethylene motif, viz., alkylamine, methylsulfanyl and nitro, each one of

which is amenable for synthetic exploitation and functional group manipulation. With

an excellent electron-withdrawing nitro group in place, the nitro-ethylene substructure

in 76a is a guod Michael acceptor. The methylsulfanyl group is an electron donor and

is also a good leaving group. Utilizing well established methods, the methylsulfanyl

group in 76a can be replaced with a varicty of nucleophiles, by substitution

nucleophilic vinyl (SNV) mechanism.

NMSM Ranitidine

76a 77

Figure 1.6

The ethylene moiety in NMSM 76a is a polarized push-pull alkene with

electron flow cmanating from methylamino I methylsulfanyl to nitro group. Due to

polarization, the C1 in NMSM 76a exhibits electrophilic characteristics and the C2

exhibits nucleophilic charactcristics. Molecules of the type NMSM 76a are synthetic

equivalents of nitroacetic acid where the ester is masked as ketene-N,S-acetal. Also,

NMSM 76a is a synthetic equivalent of the amino acid glycine, which can be realized

by reduction of nitro group and release of masked acid. Above qualities make NMSM

768 a multi-faceted building block ready to be exploited to build organic molecules of

diverse structures." As an example, NMSM 7611 is a starting material in the

manufacture of anti-ulcer (histamine H2 receptor antagonists) bulk drugs ranitidine

7782 and nizatidine."

We reasoned that since nitroketene dithioacetals have electrophilic and

nucleophilic carbons at adjacent (CI and C2) positions they can be condensed with

bifunctional molecules having nucleophilic and electrophilic centres in 1 -4-position so

that a six-membcr ring can be generated. In the present thesis, we describe realization

of this concept for a convenient combinatorial synthesis of several 2-alkylamino-3-

nitro-4H-chromenes and their further transformation to 2-alkylamino-4-aryl-3-nitro-

411-chromenes, non-natural hybrid amino acids as well as four DOPA isomers. The

4H-chromencs and 4-aryl-4H-chromencs are heterocyclic molecules of current

interest as they exhibit cytotoxic properties and thus evaluated as anticancer

5.2. Synthesis of nitroketene SJ-acetal81

Thc starting material for our work is nitroketene N,S-acetals, e.g. 76. The N,S-

acetals were prepared from the S,S-acetal, ],I-bis(methy1thio)-2-nitroethene 81. The

S.S-acetal, 81 was prepared in bulk scale in two stcps following thc procedure

described by Rao and ~akthikumar.'~

KOH Me2S0, MeOH CHINO2 + CJ, _ /=iS 2 K+ benzene - OoC, 3 h 02N S 02N SMe 45%

rt, 2 h, 85%

78 79 80 81

Scheme 1.27

Condensation of nitromethane 78 with carbon disulfide 79 in presencc of

concentrated potassium hydroxide in dry methanol resulted in the formation of

dipotassium salt of nitroketene dithioacetate 80 in moderate yield. The unstable salt

needed storage at 0-5 "C in dark. Methylation of the salt 80 with dimethyl sulfate in

benzene: furnished 1,l-bis(methy1thio)-2-nitroethene 81 in excellent yield (Scheme

1.27). The dimethyl nitroketene dithioacetal 81 exhibited physical (mp -. 127 "C) and

spectral (IR, 'H NMR, "C NMR) properties, matching those of thc authentic sample.

The methyl groups in 81 appeared as two singlets at 2.53 and 2.54 ppm indicating

restricted rotation around the double bond at room temperature even though the bond

between C1 and C2 has single bond character due to push-pull characteristics of the

molecule. This feature of 81 is similar to the one found in Nfl-dimethylfomamide

(DMF), where in two singlets for NMe group are observed in the NMR spectrum

recorded at room temperature."

5.3. Synthesis of nitroketene NJ-acetals 76a-g

MeCN

SMe 3-28 h SMe

82a, 76s: R = Me

82b, 76h: R = 11-Bu

82c, 76c: R = Ph

82d, 76d:R = Bn

82e, 76c: R = (CH2)2Ph

82f,76f: R = (CH2)2CbH40Me-p

82g, 76g: R = CH(CII3)Ph

Scheme 1.28

NMSM 76s is cornmemially available. Other N,S-acetals 76b-g were to bc

prepared in the laboratory. We have convened the nitroketene S,S-acetal 81 into

various nitroketene N,S-acctals 76b-g in good yield by trcating with primary amines

82b-g in acetonitrile reflux (Scheme 1.28, Tablc 1. All the Ar,S-acetals 76b-g

prepared in this study were assigned E-configuration based on the literature

precedence, wherein it was found by X-ray crystallographic studies that E-

configuration is preferred over ~ - c o n f i ~ r a t i o n . ~ ~ The hydrogen bonding interactions

between hydrogen of the NH and negatively charged oxygen of the NOZ dictate the

stable E-geometry. Due to polarized nature of the molecules, thcre is some single

bond character between C1 and C2 of 76a-g, which makes free rotation around C1

and C2 possible.

Table 1.1: Synthesis of nitroketenc N,S-acetal 76a-g from S.S-acetal 81 and primary amines 82b-g in acetonitrile reflux.

Entry Primary am,ne Product nilroketene T~me Yleld N,S acetal (hl 1%)

PhNH, 0,N NHPh

62c 76c

SMe BnNH, 02NANHBn

82d 76d

SMe

SMe 5 MeOC,H,(CH,),NH, 3.5 87

SMe 6 C6H,CH(CH3)NH2 5 50

Among the N,S-acetals prepared in the present study (Tilble 1.1) 76f, having

methoxyphenylethylarnine moiety is a new compound. We present below spectral

characterization details of this compound as a representative example.

5.3.1. Characterization of A'-(4-mcth0xyphenethyI)-N-I(0-1-(methylsny1)-2-

nitro-1-ethenyllamine 76f

Figure 1.7

Thc N,S-acctal 76f (Figure 1.7) was obtained as a yellow colored solid, mp

107 "C. Thc UV spectrum of 76f showed two absorptions at 354 nm (log & = 4.2) and

275 nm (log r: = 3.6). The i,,,,, at Iongcr wavelength was due to the push-pull system

involving NHCH2CH2Ph, C=C and the nitro group. The h,,,,, at 275 nm was due to the

nitroethylcne moiety. The IR spectrum displayed a band at 3187 cm" for the olefinic

C-H strctching. 1571 cm" and 1342 cm" fbr thc nitro group. The ' H NMR spectrum

(Figure 1.8) displayed singlets for SMc, OMe and olefinic hydrogens at 6 2.41, 3.66

and 6.55 ppm respcctively. The aromatic hydrogens appeared as two broad AB tqpc

doublcts at 6 6.8 and 7.1 ppm; CH: protons attached to the aromatic ring appeared as

a triplet at 2.9 ppm and CH2 attached to N H group appeared as a quartet at 3.62 ppm.

The NH proton appearcd downfield at 6 10.5 pprn as a broad singlet, indicating the

hydrogen bonding interaction between NH and NO2 group, which confirms the

assigned E-stercochemistry for the double bond. The ')c NMR spectrum (Figure 1.9)

displayed four signals in the aliphatic region out of which two were for SMe (6 14.2)

and OMe (6 55.2) and rest were for two methylenes (6 34.5 and 55.2). Two olefinic

carbons Cl and C2 appeared at 6 158.6 and 8 106.2 respectively.

Literature study reveals that molecules containing arylethylamine moiety

exhibit profound biological activity because they mimic dopamine. Some molecules

with phenylethylamine core are used for the treatment of Parkinson's disease." In the

light of this background nitroketene N,S-acetals 76e and 76f having phenylethylamine

moiety could show significant biological activity. However, due to lack of facilities

we did not carryout biological evaluation.

Figure 1.9 75 MHz (CDCI,) ')c NMR spectrum of N-(4-methoxyphenethyl). N-[(E)-l-(methylsulfanyl)-2-nitro-I-ethenyl]amine 76f.

I

E I

!! I

-

- - L ,. 1 -- Figure 1.8 300 MHz (CDCI3) 'H NMR spectrum of N-(4-methoxyphenethyl)- N-[(a- I -(mcthylsulfanyl)-2-nitro- I -ethcnyl]am~ne 76f

5.4. Synthesis of amino acid containing nitroketcne NS-acetals 86a-g

With the experience gained from the preparation of the N,S-acctals, we

ventured into the synthesis of the amino acid substituted nitroketenc N,S-acetals. Such

amino acids could become starting materials for the synthesis of Ranitidine like

molecules and increase water solubility of the drug molccule.

SOCI, - +

H N COOH MeOH, rt CI H,N yCOOMe Et,N H,NyCOOMe v - R 12-17 h k R

-

Scheme 1.29

The amino actd esters 85a-g nccdcd for this work were prepared by treating

corresponding commercially available amino acids 83a-g with thionyl chloride,

methanol according according to the procedure described by Meyers and coworkers

(Scheme 1.29)." All the amino acid esters 85a-g were characterized by spectral data,

which matched with thc reported values." Specific rotation for each amino acid ester

was detemined to check if racemization occurred during esterification. The a~ values

matched with the reported values indicating that raceimizatior, did not occur at this

stage.

COOMe COOMe 2:;

02N\=/Me + H,N< - SMe R 4-24 h SMe

50-88%

81 85a-g 86a-g

85a, 86s: R = H

85b, 86h: R =Me

85c, 86c: R = CH2Ph

85d, R6d: R = CH(CHJ)~

85e, 86e: R = CH~CH(CIII)I

85f, 86f: R = CH(CHJ)CHICHJ

85g, 86g: R = CH~(CRH~N)

Scheme 1.30

Ncxt we reacted S,S-acctal 81 with amino acid methyl esters 85a-g in

acetonitrile reflux to furnish corresponding nitroketene N,S-acetals 86a-g (Schcme

1.30). Yields of the product, reaction time, enantiomeric excess (ce) determined on

the basis of chiral HPLC and the optical rotation values obtained in each reaction is

given in Table 1.2.

,a98 [e1aos-s'~ pahuap au!analjo uo!letua)oeaeqo aql uo uo!ssnJs!p molaq a ~ ! 9 am aldruexa aa!)e)uasa~da~ e

s v ~umouy !ou am sl!un Ssg mqdo~dCI~ pm jsg au!bna[os! 'as8 aulonal uroy panpap

P98 PSB

d l Y

sanlen uo!la)o~ lea!$do pun ssaaxa Juauo!iueua Jpyl '8-BSX sJaisa p ! ~ o ou!me pug 18 IIQ~~B-S'S woy 8-698 [BI~JE-S'N aualayoJl!u pa~ni!lsqns p!Je ou!uV :Z'L a l q U

5.4.1. Characterization of methyl (ZS)-4-methyl-2-[(E)-I-(rnethylrulfanyl)-Z-

nltro-1-ethenyl]amlnopentanoate 86c

j N 0 2 MeS NH

f l O M e H,C CH,

86e

Figure 1,10

The UV spectrum of the nitroketcne N,S-acetal 86e (F iy r c 1.10) showed

characteristic A,,,,, at 354 nm (log c = 4.1) assignable to the N,S-acetal moiety. The IR

spectrum displayed bands at 3153 em" for the olefinic CH stretching, 1563 cm" and

1336 cm" for the nitro group. The 'H NMR spectrum (Figure 1.1 1) displayed a signal

at S 0.99 ppm as doublet for six mcthyl hydrogens. The CH proton belonging to the

amino acid portion appearcd as AB quartet at S 4.45 and 4.46 ppm. The SMe and estcr

Me appeared as singlets at S 2.48 and 3.76 ppm respectively. The olefinic proton

displayed u signal at 6 6.6 ppm as a singlet and thc NH proton appeared at 10.5 pprn

as a broad singlet. The "C NMR spectrum (Figure 1.12) displayed signals for the

SMe (8 14.2), ivopropyl (6 21.4, 22.1 and 41.2), methylene (6 24.1), methine (6 55.3),

OMe (6 52.4) and CO (6 170.6) groups. In addition, characteristic signals for the C1

and C2 of olefin appeared at 6 163.4 and 106.9 ppm respectively.

KG-11-44 - 8 9

- PRI

? 5 C C m m--

Figure 1.11. 300 MHz (CDC13) 'H NMR spectrum of methyl 4-methyl-2-[4- (methylsulfanyl)-3-nitro-4H-2-chromenyl]aminopentanoate 86e.

(methylsulfanyl)-3-nitro-4H-2-chromenyl]aminopentanoate 86e.

B y carrying out the chiral HPLC analysis using Daicel A D - H column (4.6 x

250mm) and using acetonitrile (ACN) and isopropyl alcohol (IPA) as the eluent we

found ee of the nitroketene N,S-acetals 86b-e, 86g and dc of 86f. In all the cases 1.0

mg of the sample was dissolved in 1.0 mL of 1:l ACN: IPA (95:s) mixture, out of

whichW.0 pL was injected into HPLC having a flow rate 0.5 mL I min. Betentton time

at which the minor and the major enantiomer separated was calculated by maintaining

the pressure max 14 Kgf 1 cm2 and at column temperature of 25 "C. As an example,

retention times for diasteromers of 86b were found to be 6.6 rnin (minor isomer) and

7.0 rnin (major isomer; Figure 1 . I 3).

Preparation of isolcucine substituted nitroketcne N,S-acetal 86f is interesting

because of the gcneration of diastereomers. There exists one chiral center in the amino

acid which does not get disturbed in the process of N,S-acetal preparation. The "C

NMR spcctrutn of the isolated product 86f showed that it is a single product.

Howcver, both normal and chiral HPLC (Figure 1.14) analysis showed that

diatereomcric excess was 89%. The rctention times for two diastereomers were found

to be 6.9 min (minor enantiomer) and 6.6 rnin (major enantiolncr).

Thc optical rotations of the product N,S-acetals 86b-f were measured and they

are given in Table 1.2. Since HPLC analysis revealed the presence of two enantiomers

in each case, we conclude that raceimization to ccrtain extent has taken place during

SNV substitution of SMe with amino group of amino acid esters. Reported optical

rotation values are for the samples obtained from thc reaction.

Sincc raceimization took place in acetonitrile, we tried thc SsV reaction of

leucine ester and N,S-acetal 86c in polar protic solvent MeOH and polar aprotic

solvent like DMF. In the carlier case reaction was not going to completion cvcn after

48 h reflux. In the later casc yield was low and there was complete raceimization.

In conclusion, we described synthesis and characterization of N,S-acctals 869-

g incorporating amino acid esters. Further experiments are required to find

experimental conditions where raceimization during the SNV reaction can be arrested.

1 Run RrpoH I -A 0 7 o a )

11.M W 49447.19 17Y57 UJZ W

Tmk

Figure 1.13: HPLC diagram for alanine substituted nitroketene N,S-acetal 86b.

Dala Graph - -. .- -

lo IT Mm ,,. -wfun Anr I

O ' 1

00

/. .____ , -- , - ~ , 8 l 4 6 6 7 ~ , , ~

Mln*

Run Report D*IPtDIA OYnm)

R L WatlmTLnr M HliLhl lnUPqlon I 6.617 4 I 7 2 6 S I W W

m" 2 6.m) 2 i l359 66920 1.13 81

w.47 81

T d

Figure 1.14: HPLC diagram for isoleucine substituted nitroketene N,S-acetal 86f.

m8624 1131924 IW.W

5.5. Synthesis and characterizatlon of 3-nitro-4H-chromenes 87

DBU (10 mol%) aCHO + g N 0 2 MeOH - /

OH MeS NHMe " l7 93% NHMe

Schemc 1.31

As noted earlier, nitroketcne N,S-acetals 76a-g possess nucleophilic CI and

electrophilic C2 carbons. We reasoned that nitroketenc N.S-ace~als 76a-g would react

with 2-hydroxybenzaldehyde 18a (salicylaldehyde), which possesses a nucleophilic

phenolic hydroxyl and an electrophilic aldehyde, located in 1.4 positions. Thus

condensation of nitroketene N,S-acetal 76a with salicylaldehyde 18a would provide

henzpyrans 87s (Schemc 1.3 1 ).

We conducted the rcaction of 2-hydroxybenzaldehyde 18a with NMSM 76a in

THF using piperidine (I .0 mol equiv) as a base (entry I, Table 1.3). After stimng at 8

h at rt, a faintly yellow color solid separated from the reaction medium in 85% yield.

However, the reaction was not clean. Same reaction was tried with catalytic amount

(10 mol%) of pipcridine (entry 2, Table 1.3), which provided clean product 87a.

cventhough it took 72 h for completion. The solid was filtcred and recrystallized from

dichloromethane and hexane to generate crystalline product (mp 152-153 'C). The

micro analysis and mass spectra showed that the molecular formula of compound 87a

was Cl lH12N203S The UV spectrum showed absorption A,, at 352 nm (log E = 4.0)

and 279 nm (log c = 3.0), which indicated the presence of nitroketene acetal moiety.

Absorption at longer wavelengh was due to conjugation running from lone pair of

electrons on the oxygen of the pyran ring to the nitro group. The IR spectrum showed

intense bands at 161 I (C=C), 1470 and I372 cm" (N02). The 'H NMR spectrum

(Figure I. IS) displayed a singlet for SMe at 1.8 pprn, a doublet at 3.24 pprn (J = 5.1

Hz) for NMe, a singlet at 5.49 ppm for CH and well defined peaks between 7.1 and

7.5 ppm for I,2-disubstituted benzene and a broad singlet for NH at 10.3 pprn

assignable for the structure of N-methyl-N-[4-(methyIsulfanyl)-3-nitro-4H-2-

chromenyllamine 87a. The "C NMR spectrum (Figure 1.16) exhibited three signals

at b 12.2, 28.0, and 40.3 ppm for three aliphatic carbons. Four quaternary carbons and

four aromatic CH type carbons in the aromatic region supported thc structure.

---1O. . - I pL.I

!igurc 1.15 3 0 0 M H 1 (CDCh) 'H NMR rpatrum of V-mcthy~-A'-[C (rnethylsulfanyl)-3-n1tro-4H-2-chromenyl]am1ne 87a

- 7 - 7 - - 7 - . - - I I% 101 $4 d

Figure 1.16 75 MHz (CDCI,) "C NMR spectrum of N-methyl-N-[4- (methylsulfanyl)-3-nitro-4H-2-chromenyl]amn 87a.

Thc structure of the product 87a was confirmed unambiguously from the

analysis of single crystal X-ray (Figurc 1.17) diffraction datil (depos~ted with

Cambridge Crystallographic Data Centre. CCDC; deposition No. 261071). The X-ray

structure showed that SMe goup takes pseudo axial orientation and the pyan ring

adapts an envelope conformation. Thc nitro group is coplanar with the chromenc

system.

Figure 1.17: The single ctrystal X-ray structure of N-me thy^. N-[4-(methylsulfanyl)-3-nitro-1H-2-chromcnyl]amine 87s.

Condensation of salicylaldehyde 18a with NMSM 76a is a highly atom

economic reaction formed by click, spl~t and add routc (CSA) (vide infia). 3-Nitro-

4H-chromene 87a incorporates functional groups NHMe, NO2, SMe, en01 ether and

an enamine, each one of which is amenable for further functional group

transformations.

Having found a facile synthesis of pharmacologically relevant 4H-chromene

87a, we next attempted various reaction conditions to optimize yields and to find

facile reaction conditions by taking CSA condensation of 2-hydroxybenzaldehyde 18a

and NMSM 76a to form 4H-chromene 87a as a test case. Details of optimization of

base 1 solvents 1 conditions for 3-nitro-4H-chromene 87a formation from nitrokctene

N,S.acetal76a and 2-hydroxybenzaldehyde 18s are gathered in Table 1.3.

Table 1.3: Synthesis of 3-nitro-4H-chromene 87a from NMSM 76a and 2-hydroxybenzaldchyde 18a using different bases f conditions, ;;;;vz;; E F 7 7 ! T ; ) 7

Pipcridine (I .O)

Reactions were conducted at reflux temperature of the solvent used, The reaction was conducted under microwave irradiation (2.45 GHz; 400 W, 2 min).' No reaction.: extensive decomposition of 76 took place. d ~ ~ e l d with respect to recovered NMSM.

2

3

4

5

6

7

8

9

I :p

We attempted CSA condensation with secondary amine like pyrolidine (entry

4) and morpholine (entry 5) in THF or teniary amine like DBU ( I , %

diazabicyclo[5.4.0]undec-7-ene; entry 6), Et3N (entry 7) and DABCO (1,4-

diazabicyclo[2.2.2]octane; entry 8) in THF only to find that the yields were lower and

longer reaction time in each case. The reaction with pyridine (entry 3) in THF at rt or

Piperidinc (0. 1)

Pyridine ( I .0)

Pyrrolidine (0.1) .-

Morpholine (I .O)

THF

THF

-- 72

72

DBU (0.1) ; THI:

90

. 3"

15 ! 20

EtlN (1.0)

DABCO (I .O)

NaH(I.O)

NaH (1.0)

K ~ C O I ( I .O)

54

43

T H I : , 48

144

96

9

5

7

THF

THF

THF

DMF

Acetone

THF

38

70

75'

71

45 ,

192

at reflux temperature did not yield 87a. The abovc experiments revcaled that CSA

reaction worked well with DBU (0.1 equiv)-in MeOH (entry 17) to provide desircd

product in 93% yield and the reaction was also clean. With inorganic bases like NaH

(1.0 equiv) 1 THF (entry 9 ) or NaH (1.0 equiv) in DMF (entry 10). K2C03 1 acetonc

(entry 18) or two-phase reaction with aqueous K2C03. TBAB, DCM (entry 13), the

reaction yields were moderate. Howevcr the condensation was facile with K2C03 (0.1

equiv) in water to provide the 4JI-chromenc 87a in 85% yield (entry 18). The reaction

was slow or did not take place in KF I neutral alumina (entry 15) under microwave

condition or with besic alumina (entry 14) under neat condition. Since the product has

a chiral ccntre, we attempted the condensation with proline (entry 16), proline methyl

ester (entry 17) and proline benzylester (entry 18) in MeOH. Though the product

formation took place in all these cases in moderate to good yield and there was no

chiral induction in the product.

In summary, wc found that the condensation reaction worked well with 0.1

equiv. of piperidine in THF (entry 2) or DBU in MeOH (entry 19) or K2CO1 in water

(entry 20) in each case at room temperature. An yellow solid precipitated and was

obtained by simple filtration. Out of the above reagents and solvents, use of 0.1

equivalent of DBU in McOH (entry 17) appeared to be most appropriate to generalize

the transformation. Employing K?COI-H?O (entry 18) combination needs further fine

tuning when substituted 2-hydroxybenzaldehydcs or substituted NMSM employed.

To generalize CSA condensation, we needed a variety of 2-

hydroxybenzaldehydes, which were prepared by following the published procedures

(Scheme 1.32). Among them, the 2-hydroxybcnzaldehydes 18b, 18f-j were prepared

from corresponding phenols ~ d a Reimer-Tiemann rea~t ion . '~ 2,4-

Dihydroxybenzaldehyde required for the preparation of 18k. 18m, 181 was made from

resorcinol by employing Vilsmeir Hack f o r m y ~ a t i o n . ~ ~ Selective benzylation of C4

hydroxy group in 2,4-dihydraxybcnzaldehyde with benzyl chloride in presence of

NaHCO, (1.1 equiv) and K1 (1.0 equiv) in CH3CN reflux furnished 4-benzyloxy-2-

hydroxybenzaldehyde 18k.~' 2,4-Dihydroxybenzaldehyde was treated with dimethyl

sulfate, NaOH to get 4-methoxy-2-hydroxybenzaldehyde 18m.'~ In the same manner

4-allyloxy-2-hydroxybenzaldehyde 181 was prepared by reacting 2 4 -

dihydr~x~benzaldehyde with allylbromide in presence of K2CO3 in acetone under

reflux."' 2-~~d~~xy-6-methoxybenzaldehyde I8d was prepard in two steps starting

from resorcinol dimethylether.Yv In the first step, resorcinol dimethylether was

transformed into 2,6-dimcthoxybenzaldehyde using n-BuLi and DMF. In the second

step, monodemcthylation with EtSH in the presence Nall in DMF furnished the 2-

hydroxy-6-rnethoxybenzaldehydc 18d.""'

18a.k 78a 87a-k

Ma, 87a: R1= R2 =R3 -R4 = 11

18b. 87b: R1 = R3 = R4 = H, R2 = Br

18c, 87c: RI = R2 = R3 = H, R4 = OMe

18d, 87d: R1 = OMe, R2 = R3 = R4 = H

18e, 87e: R1 = R3 = R4 = H, R2 =Me

18f, 87f: R1 = R3 = R4 = H, R2 = Et

18g, 87g: RI = R3 = R4 = H, R2 = r-Bu

18h, 87h: RI = R3 = R4 = H, R2 = OMe

18i, 87i: RI = R3 = R4 = H, R2 = C1

18j, 87j: RI = Mc, R2 = CI, R3 = R4 = H

18k, 87k: R1 = R? = R4 = H, R3 = OCH2Ph

Scheme 1.32

Above ten different 2-hydroxybenzaldehydes 18b-k were smoothly condensed

with NMSM 76a under optimized condition to furnish 4II-chromenes 87b-k in 75-

93% yield (Scheme 1.32; Table 1.4).

Table 1.4: Synthesis of 3-nitro-4H-chromenes 87a-k from substituted salicylaldehydes 18a-k.

a,' &NO> NHMe

I11 17, (17 h 83%)

& &NO2

NHMe

1 Ld 87d (12h 88%)

"a:"u&No> I I

NHHe

18, 1171 112 h, 89%)

OH

NHMe

l a b 87b (18 h 78%)

CH, 3Ms

cl&cHo c l ~ N O p \ I I

' OH NHMe

1 01 VJ (17 n 78%)

10 PnCH20 PhCH>O NHMI

1Ik 87k (18 h 82%)

11

NHMe NHMe

lam atm (O %I

13

PhCOO PhCOO NHMB

cl&No, 1 1

NHMs

Spectral data of 4H-chromenes 87a-k matched well with the parent

compound, Complete 'k NMR spectral assignments for the above 4H-chromenes

87a-k are given in Table 1.5. The structure of 87e'" was also confirmed

unambiguously by single crystal X-ray analysis and the X-ray crystal structure is

given in Figure 1.18.

--. 1

Figure 1.18: The single crystal X-ray structure of .V- methyl-N-[6-methyl-4-(methylsulfanyl)-3-nitro.4H-2- chromenyllamine 87c.

Table 1.5: Comparison of "C NMR spectral 6 valucs of 3-nitro-4H-chromenes.

--'r- 3-Nitro-lH-Chromenes

34.5 (c);' 55.8 (OMe); 15.9 (Me); 70.5 (CH*), 136.1 (C), 127.4 (2 x CH), 128.7 (2 x CH), 128.3 (CH).

Condensations of 3-methoxy, 4-methoxy, 5-methoxy and 6-methoxy-2-

hydroxybenzaldehydes lac, 18k, 18h, 18d with NMSM 76a to provide corresponding

4H-chromenes 87c, 87k, 87h, 87d were of interest, because they could eventually

lead to dihydroxphenyl alanine (DOPA) isomers. While the CSA reaction of three 2-

hydroxybenzaldehyde namely 18c, lad, 18h worked well, condensation of 4-

methoxy-2-hydroxybenzaldehyde 18m and 4-benzoyloxy-2-hydroxybenzaldehyde

with NMSM 76a did not take place. Only product isolated in low yield appeared to be

that of a polymer derived from KMSM 76a. It is understandable that 4-methoxy-2-

hydroxybenzaldehyde 18m did not participate in the condensation because of the low

electrophilic nature of the carbonyl carbon. To circumvent the difficulty 4-allyloxy-2-

hydroxybenzaldehyde 181 was treated with NMSM 76s. The CSA reaction provided

corresponding 4H-chromene 871 in low yield 59%. Moreover subsequent

desulfurization reaction did not take place at rt and the chromenc 871 charred when

the reaction was conducted at higher temperature. So, we nccdcd to find an alternative

for this condensation. We were happy to find that the condensation of 4-benzyloxy-2-

hydroxybenzaldehyde worked well to yield 82% of N-[7-(benzyloxy)-4-

(methylsulfanyl)-3-nitro-4H-2-chromcnyl]-A1-mcthylamine 18k. From this study it has

been concluded that subtle changes in electronic nature of the aromatic ring gets

reflected in the 4H-chromene formations.

5.5.1. Mechanism for the formation of 3-nitroJH-chromenes

O,N-NHMe + aCHO - aoqNO, C

SMe OH MeOH, rt s N M e

87s

Scheme 1.33

Plausible mechanism for the formation of 411-chromene 870 from NMSM 760

and 2-hydroxybenzaldehyde I8a is given in Scheme 1.33. Thc conversion appears to

follow four major steps namely i. Michael addition, where the anion gencrated from

2-hydroxyhenzaldchyde 180 adds to NMSM 76a in conjugate manner (rate

determining step, rds). ii, nitroaldol condensation to provide the pyran ring (steps 1

and 2: click; rds in the case of 2-hydroxy benzaldehydes with C4-OMe), iii.

dehydration and dethiomethylation (split) to generate intermediate benzpyrilium

cation. iv. thiomethyl anion present in the solution adds on to the benzpyrilium cation

forming 3-nitro-411-chromene 87a (add). Thus thc mechanism of the reaction follows

click, split and add (CSA) route.

The yield of the 4/f-chromene was relatively high for 2-hydroxybenzaldehyde

having electron donating substituent present on C5 carbon (para to hydroxy) 87e-h

compared to those with electron withdrawing substitucnt 87b, 871. This result

indicates that nucleophilic attack of the phenolate anion on C1 of the NMSM 760

could be the rate-determining step. Methoxy group para to aldehyde retards thc

intramolecular nitroaldol condensation. thereby allowing the intermediate to react

with NMSM 76a ugain to generate polymeric product. Quenching of the benzpyilium

cation with methylthiolate anion augers wcll for the replacement of SMe with other

nucleophiles.

5.6. Synthesis of 3-nitro-4H-chromenes 88a-f from dlfferent nitroketene NJ-

acctal76b-g

SMe

59-83% NHR

l e a 76b-g 88a.f

76b, 88s: R = n-Bu

76c, 88b: R = Ph

76d, 88c: R = Bn

76e, 88d: R = (CH2)zPh

76f, 88e: R = (CH2)2C6H40Me-p

76g, 88f: R = CH(CH3)Ph

Scheme 1.34

In continuation of thc studies on CSA reaction, wc ncxt focused on changing

substitution on the amino goup from methyl to alkyl aryl groups (Schemc 1.34).

The condensation reaction of all worked well under optimized conditions (DBU in

MeOH) at rt to generate a combinntorial library of 4H-chromenes 87a-f in good yields

(Tablc 1.6).

Table 1.6: Synthesis of 3-nitro-411-chromencs 88a-f from diffcrcnt nitroketene N,S- acctals 76b-g and 2-hydroxybcnzaldehyde 18%

E~~~ Nnmketna 3.Nllrc-4H.

6"tly Nltmkelsna 3.Nnm4H.

N S.as~lal chmmene

N,S.BCBUI chmmene

(Ilme yield) illme, yleldj

3

NHBn Ma*,,

2 MeS AND' NHPh NO' NHPh

By achieving the synthesis of 4H-chromenes 88d and 88e we have now

incorporated physiologically active arylcthylaminc unit into 4H-chromene (Table 1.6,

entry 4 and S), The spectral values (IR, 'H, I3c NMR spectra) of above 4H-chromene

88a-88f matched well with the parent compound 87% The structure of 88c was

confirmed unambiguously by single crystal X-ray analysis (Figure 1 . 1 9 ) . ' ~ ~

NO

McS ~ N ; ~ ~ H 2 ) , c s H , o M e &NO'

NHICHJ2C.H.0Me

S,Me

6654a/4x3,N02 I II I / 708,8a.0.2\

NHR

Table 1.7: Comparison of "C NMR spectral chemical shift ( 8 ) value of 3- nitc*H-chromencs

Carbon atom

number

2

3 - 4

4a

5

6

7

8

I 8a

I SMe

PEA = Phenylethylamine: PMPEA = p-Methoxy phenylethylamine ' 41.2 (CH!), 3 1.5 (CHI), 19.9 (CH2). 12.2 (CHI); 134.7 (C), 126.3 (2 x CH), 129.4 (2 x CH), 123.1 (CH); ' 45.5 (CH2), 136.0 (C), 127.3 (2 x CH), 129.2 (2 x CH), 126.2 (CH); 43.0 (C'HI), 40.3 (CH*), 137.4 (C), 128.6 (2 x CH), 128.9 (2 x CH), 126.1 (CH): " 43.2 (CHI), 40.3 (CH2), 129.3 (C), 129.7 (2 x CH), 114.3 (2 x CH), 158.6 (CH), 55.2 (OMe).

88a @Sf. 3-Nitro-4H-Chromenes

R - Bu" 88a

159.4

105.5

40.3

122.4

129.1

R-

88b

156.9

106.6'

40.1

122.1

129.0

88e 159.3

105.9 I

40.3

122.4

129.1 ".

128.2

128.7

115.6

127.1

128.2

I 15.6

148.8--

12.2

126.1 126.6

159.3

105.6

36.1 .

126.1

128.6

115.6

148.8

12.2

128.7

115.6

159.4

105.6 -- - . . . -

35.2 -- --

128.8

115.7

148.8

13.6

122.4

129.1

148.7 148.8

122.4

129.1

12.1 12.2

1

./\ 1 I Figure 1.19. Thc s~ngle crystal X-ray structure of A'-bcnzyl-N- [4-(methylsulfanyl)-3-n1tro-4H-2-chromcnyl]m1ne 86c.

5.7. Synthesis of 3-nitro-4H-chromenes 89b-g having amino acid unit

SMe NH 41 -62%

88b-g 18a 89b-g

86h, 89b: R = Me

86c, 89c: R = CH2Ph

86d, 89d: R = CH(CHa)2

86e, 89e: R = CH2CH(CH1)2

86f, 89f: R = CH(CH))CH2CH,

86g, 898: R = CHI(CIH~N)

Scheme 1.35

After realizing the synthesis of n-nlkyllaryl 2-amino-411-chromcne, we

focused on the synthesis and characterization of amino acid substituted 4H-chromenes

89b-g with an objective to determine if there is any chiral induction arising from

amino acid portion to the newly generated stereogenic centre at C4. Thus, the

nitroketene N,S-acetals possessing amino acid residues of alanine 86b, phenylalanine

86c, valine 86d, leucine 86e, isoleucine 86f and tryptophan 86g, on treatment with 2-

hydroxybenzaldehyde 18a under optimized conditions yielded the CSA products 89b-

g as inseparable mixture of diastereomers (Scheme 1.35). The glycine substituted

nitroketene N,S-acetal X6a. howcvcr failed tn undcrgo this condensation reaction,

possibly, becausc of the acidic nature of thc active methylene proton in the glycinc

unit. The chiral HPLC analysis showed the presencc of four products - two pairs of

enantiomers - for each compound. The yiclds of the product and the diastereomer~c

cxcess of the major isomer are given in the form of Table 1.8.

Table 1.8: Synthesis of 3-n1tro-4H-chromcncs 89b-g from amino acid containing nitrokctenc N,S-acetal 86b-g.

All thc six amino acid substitu~ed 3-nitro-4H-chromenes 89b-g were

5-nltro.4H. Enlw chromene de(%)

(t~me, y~eld)

characterized by physical, analytical and spectroscopic data. From thc "C NMR

3-n~tro-4K En'ry chrornene de(%)

(time yleld)

spectra, it was found that the product formed was a diastereomeric mixture. The

diastereomeric ratio and diastcreomeric excess was calculated from the 'k NMR

spectra. The diastereomeric excess was found to be maximum for phenylalanine

substituted 3-nitro-4H-chromene 89c. The yield of the 4H-chromenes 89b-g and

diasterwmeric excess are presented (Table 1.8). The I3c NMR spectral peaks due to

the major product were extracted from the spectra and the data is given in the form of

Table 1.9. As a representative example 'H and "C NMR spectra of 89e are given in

Figure 1.20 and Figure I .21.

Table 1.9: Comparison of "C NMR 6 value of amino acid substituted 3-nitro-4H-

22.7 (CH1); "0.2 (CH), 15.5 (CHI), 24.7 (CHI), 11.2 (CHI); 51.1 (CHl), 106.7 (C), 122.6 (CH), 116.5 (CH), I2O.O(CH), 117.5 (CH), 110.3 (CH).

gbff $URkf#RRE&AWREE8ia I=== .:::: ,,,,,,,,,.,,. $ 139 "! m ... m

I

I

I

BI

.. . - , - - - - -- -

~ i ~ u r i 1-20 300 MH: (CDCI~) 'H R M R spectrum (methylsulfanyl)-3-n1tro-4H-2-chromenyl]am~nopentanoate 89e

I s rn n L Figure 1.21 75 MHz (CDCla) "C NMR spectrum of methyl 4-methyl-2-[4- (methylsulfanyl)-3-nitro-4H-2-chromenyl]aminopentanoate 89e.

5.8. Synthesis of 2:1 adducts 90a-f

aCHO+ ~ ~ ' 2 N a z H F

OH MeS N H R reflux, 800C

76a, 87a. 90a: R = Mc

76b, 88a, 90b: R = n-Bu

76c, 88b, 90c: R = Ph

76d, 88c, 90d: R - CH2Ph

76c, 88d, 90e: R = 11-(CH2)2Ph

76f, 88e, 901: R = (CH2)2CbH40Me-p

Scheme 1.36

When we conducted the CSA reaction of 2-hydroxybenzaldehyde 18a with

NMSM 768 in NaH-THF reflux, we isolated a minor amount of the adduct 90a (4%

yield) along with the major product 87a in 75% yicld (Scheme 1.36). Thc 'H NMR

spectrum of the minor product indicated its formation by the reaction of two

molecules of NMSM 768 and one molecule of 2-hydroxybenzaldehyde 18a. The

product however could not he cleaned from contaminants. On the other hand, in the

reaction of N.5-acetal possessing N-benzyl group 76d, the minor product 90d was

formed in 24% yield (Scheme 1.36). The UV spectrum of 90d showed ),,,, 378 nm

(log E = 4.5), 354 run (log c = 4.7) and a shoulder at 280 nm. Two longer wavelength

bands indicated the presence of two nitroketerie acetal moieties. The IR spectrum

exhibited bands at 1556 and 1370 cm", which are assignable for nitro group. 'H NMR

spectrum (Figure 1.22) displayed a singlet at 6 2.69 ppm assignable to SMe. One of

the two methylenes occurred as doublet at 6 4.8 ppm with a coupling constant of 5.7

Hz and the other occurred at 6 4.9 ppm as doublet of doublet with a coupling constant

of 15.0 Hz and 5.4 Hz assignable to diastereotopic benzylic hydrogens. A singlet at 6

6.55 ppm for benzylic hydrogen and broad singlets at 6 11.0 and 11.5 ppm for two

NH protons indicated the formation of 2:l adduct. The "C NMR spectrum (Figure

1.23) showed signals in the aliphatic region for one SMe, one methine and two

benzylic methylene carbons. Based on HMBC correlations we assigned that the signal

at 161.57 ppm is due to the quaternary carbon of side chain N,S-acetal and 160.32

ppm is due to the quaternary carbon preqcnt in pyran ring where NH-benzyl g o u p is

attached.

-. .,-- . 1. ,. , . , --"".'T' I 8 8 ? , , ,

10 s I a 6 4 a z ~ p p m

'It< 74 Figure 1.22 300 MHz (CDCln) 'H N M R spectrum of M-benzyl-4-[(a-2- (benzy1amino)-2-(methylsulfany1)-I -nitro-I-ethenyl]-3-nitro-4H-2- chromenamine 90d.

80 $0 IW IW m m m w o p

Flgure 1.23 75 MHz (CDCI3) "C NMR spectrum of M-benzyl-4-[(m-2. (benzy1amino)-2-(methy1sulfanyl)-l -nitro- l -ethenyl]-3-nitro-4H-2- chromenamine 90d.

Similar to 1 :l CSA udduct, (see Scheme 1.33) 2: 1 adducl 90 could be formed

through bcnzpyrilium cation (Schemc 1.37). This intermediate is quenched by one or

more unit of N,S-acctal 76. This was confirmed by treating parent 4H-chromene X7a

with nitroketene N,S-acetal 76a in presence of NaH in THF and the reaction yielded

thc 2: 1 adduct 9Ua. Wc found that 2:l adduct formation betwccn NMSM derivatives

76a-f and 2-hydroxyhenzaldehyde 18a is quite general. when conducted in NaH I

THF rcflux. Four more NMSM derivatives were reacted w ~ t h I8a to provide the 2:1

adducts in 4-24% yield formed in each case as minor pr~~ducts (Table 1.10).

Spectroscopic analysis confirmed the assigned structure of the adducts and they

matchcd well with the parent compound 90a (Table 1.1 1).

O N N H R + acHO SMe OH -

76a.f 18a

O Z N y N H R SMe

NO, - W N O 2 NHR

NHR s d H R +

Scheme 1.37

Table 1.10: Synthesis of 3-nitro-4/f-chromenes (2:l adduct) 90a-f ffom different substituted nitroketcne N,S-acetal 76a-f.

3 NO,

@

NHPh

Enlry 2 1 adducl Y'e'd in) IS)

Table 1.11: Comparison of "C FJMR 8 value of 3-nitro-4H-chromenes

Entry I llducl Time yield ih) 1%)

NHCH, I NHCH>Ph

5.9. Reaction of 3-nitro-4H-chromene 87a with high boiling thiols 91s-e

EtOH

+ RSH - NHMe

9-18 h 75-93%

87a Ola-e Q2a-e

91a, 92a: R = ChHs

91 b, 92b: R = 4-CH3ChH4

91c, 92c: R = 4-CICoH4

91d, 92d: R - ~- (CH~) ICHI

91e, 92e: R = n-(CHj)7Ctl1

Scheme 1.38

According to the proposed mechanism for the formation of 4H-chromenes 87

(Scheme 1.33) the benzpyilium cation is the key intermediate. We reasoned that it

should be possible to quench this intermediate with different nucleophiles to prepare

products of structural diversity. Accordingly, 3-nitro-411-chromene 87a was treated

with three-equivalents of high boiling aromatic thiols like thiophcnol 91% 4-methyl

thiophenol 91b, 4-chloro thiophenol 91c and aliphatic thiols like butane 91d and

octane thiols 91e in ethanol retlux to provide C4-substituted 411-chromenes 92a-e in

excellent yield (Scheme 1.38, Table 1.12). Before concluding ethanol as solvent, we

tried the reaction of 87a with butane thiol 91d in THF. However, the reaction

provided 92d as the only product in 62% yield. For efficient conversion of 87a into

92d, the reaction needed three equivalents of thiols 91d. With one or two equivalents,

the reaction was slow, cven after 24 h in EtOH reflux as starting material 87a was

only partly converted to product 92d.

Table 1,12: Synthesis of 3-nitro-4/{-cliromene 87s from high boiling thiols 91a-c

2

NHMe

3

NHCH,

4

NHMe

5 19 93

NHMe

920

A!! the five thiol substituted 3-citro-41f-chromenes 9211-e were characterized

by analytical and spectra! data which matched well with the parent 4fI-chromene 87a.

The I3c NMR spectral data for the fivc compounds arc given in the form of Table

1.13. Apart from the characteristic singlet for benzylic proton at about 6 5.6 ppm in

'H NMR spectra, the newly made 4H-chromenes 92a-e displayed appropriate signals

due to C4 side chain. As a representative example 'H and "C NMR Spectra of 92d

are given in Figure 1.24 and Figure 1.25.

From this study we have shown that C4 SMe group can be readily replaced

with soft nucleophiles. Since thiopheno! replaced SMe group readily, it was of interest

to study the reaction of patent 4Ij-chromene 87a with phenols.

I J Figure 1.24 300 MHz (CDCI1) ' H NMR spectrum of N-[4-(hutylsulfany1)-3- nitro-4H-2-chromenyll-N-methylaminc 92d.

"i30.7(C),128.3 (2 x CH), 137.2 (2 x CH), 128.5 (CH); 127.1 (C), 128.5 (2 x CH), 137.0 (2 x CH), 119.3 (C-CHI), 21.2 (CHI); 135.8 (C), 128.5 (2 x CH), 138.4 (2 x CH), 129.7 (C); 21.4 (CH?), 29.9 (CH?), 22.0 (CHI), 13.5 (CH3); ' 31.7 (CHz), 30.2 (CHz), 29.4 (CH?), 29.1 (CHz), 29.0 (2 x CH); 28.0 (CH?), 22.5 (CHz), 14.1 (CH3).

Tablc 1.13: Comparison of "C NMR 6 value of thiol substituted 3-nitro- 4//-chromenes Carbon

atom

No

2

3

4

. 4a

5

6

i: Xa

NHMe

92a-c. - 3-Nitro-4H-chromenes

R = Pha

92a

159.9 -

105.4

45.6

122.7

129.2

125.9

129.2

148.5

R = P ~ C H ?

92b

159.9

166.1

45.5

1 2 2 . ~ -

129.2

125.8.

129.1

1 1 ~ ~

y78f 27.6

R = PhCI'

92c

159.7

l 0 i 5

45.9

122.7

129.2

126.0

128.8

115.5

148.6

27.7

R - (cH~),

C ~ 1 " 9 2 d

159.9

106.8

39.8 --

123.3

129.0 --

, 126.0

128.6

R = (CH?),

CHqr92e

160.0

106.2

39.9

123.3

129.1

126.1

148.6

28.0

- 148.6

28.0

5.10. Treatment of 3-nitro-4H-chromene 87a with phenols

path c

NHMe

93 87a 140 95a 1,4-sub$tItut1on 1,2-substitut~on

path a

Q

94

(ether)

Scheme 1.39

Three reaction products are possible from the rcaction of phenol 14e and 4H-

chromcnc 87a. i. SNI substitution provides 94, an ether; ii. C2 electrophilic aromatic

substitution product 95a; iii. C4 electrophilic substitution product 93 (Scheme 1.39).

In contrast to the reaction of 3-nitro-411-chromene 87a with thiophenol 91a, which

yielded substitution product 92a, the reaction wi:h phenol 14e in EtOH medium

yielded the regio-selective electrophilic ring substitution product 95a exclusively

(Scheme 1.39). Employing bases like NaH 1 THF or KzC03 I CH,COCHJ or NaOMe I

MeOH provided only lower yield of 95a, but there was no trace of substitution

product 93. When the reaction was carried out with sodium acetate, the reaction was

fast but it was not clean and the overall yield was poor. Thus, best yield of the product

95a was obtained with three equivalent of phenol 14e in ethanol reflux. In all cases,

the product crystallized out from the reaction mixture.

NHR X

87a, 88a-c 14e. i 95a-n

87a: R = Me: 14e: X = Y = Z = H; 95a: R = Me, X = Y = Z - II 87a: R = Me; 14f: X = CH3. Y = Z = H; 95b: R = Me, X -Me. Y = Z = H

R7a: R = Me; 14g, 9%: X = C1, Y = Z = H; 9%: R = Me, X = CI, Y 2 = H

87a: R = Me: 14h, 95d: Y =CHI, X = Z = H; 95d: R = Me, Y =CHI, X = Z = H

87a: R = Me; 14i. 95e: Z = CIIJ, X - Y = H; 95e : R Me, Z = CHI, X = Y = H

88a: R = n-Bu; 14e, 95f: X = Y = Z = H; 95C: R - n-Bu, X - Y = Z = I f

88a: R = n-Bu; 14f, 95g: X =- CH,, Y = Z = H; 95g: n-Bu, X = CHI, Y = Z = H

88s: R = n-Bu; 14g, 95h: X = CI, Y = Z = H; 95h: R = n-Bu, X = C1, Y = Z = H

88b: R - Ph; 14e. 95i: X = Y = Z = H; 95i: R = Ph, X = Y =I, = H

8Xh: R = Ph; 14f, 95j: X = CHI, Y = Z = H; 95j: R = Ph, X = CH3, Y = Z = I f

88b: R - Ph: 14g, 95k: X = Cl, Y = Z = H; 95k: R - Ph, X = CI, Y = Z = H

88c: R = Bn; 14e, 951: X = Y = Z = H; 951: R = Bn, X = Y = Z - H

88c: R = Bn; 14f. 95m: X = CHI, Y = 2 = H; 95m: R = Bn, X = CH3, Y = Z = H

88c: R = Bn; 14g, 9511: X = CI, Y = Z = H; 9%: R = Bn, X = C1, Y = Z = H

Scheme 1.40

The product formation was ascertained by the analysis of 'H and "C NMR

spectra. The 'H NMR spectrum (Figure 1.26) showed a doublet at 6.8 ppm for IH

assignable to aromatic hydrogen next to phenolic hydroxyl group. Similarly, the I3c NMR spectrum (Figure 1.27) displayed a quaternary carbon at 124.7 pprn. As a

comparison the C2 quaternary carbon in 2-methylphenol 14i occurs at 124.0 pprn. If

the substitution were para to hydroxyl as in 93, the 'k NMR spectrum should have

displayed four peaks instead of six as observed. The fact that all the six carbons arc

observed rules out the possibility of ether 94 as a structure of the product.

Substitution of phenol 14e in ortho-carbon shows that electrophilic aromatic

substitution at C2 has taken place exclusively. Hydrogen bonding interaction with

nitro group could be responsible for generating single regioisomer. Such substitution

reaction did not take place with anisole or catechol dimethylether, pointing out the

dccisive role of phenolic hydroxyl g o u p in the product formation.

Present 4-aryl-4H-chromsne synthesis is by two high yielding steps tiom

commercially available 2-hydro~ybenzaldeh~de 18a, nitroketene N,S-acetuls 76 and

phenols 14. In both the steps product crystallized out of the rcaction mixture making

thc reaction attractivc in terms of scale up. As noted in the earlier section 4-aryl-4H-

chromenes 17 are prepared from electron rich phenols 14, reactive aryl aldehydes 15

and malononitrile 16. Eventhough earlier method is a single step process it could not

bc extended to generate 2-hydroxyaryl substituted 4H-chromenes.

To tcst thc gcncrality of electrophilic ring substitution, we prepared a library

of 4-aryl-3-nitro-4H-chromenes 9Sa-n by taking three different phcnols 14e-g. Each

one of them wcre treated with four different NH-substituted 3-nitro-411-chromenes

87a, 88a-c to furnish twelve 4-aryl-3-nitro-4H-chromencs 95a-c and 95f-n in good

yields (Scheme 1.40). In cach case, the substitution was exclusive to C2 position of

phenol. Othcr than these three phenols, we canicd out reactions using ortho and mcta-

cresol 14h & 14i with the parent 3-nitro-4H-chromcncs 87a to yield two isomeric 4-

aryl-3-nitro-411-chromenes 95d, 9Se. The yield of the products arc givcn in the form

of Table 1.14.

Some of the phenol substituted compounds exhibit atropisomcrism due to

restricted rotation around C-C single bond possibly due to strong hydrogen bonding

stabilization between the hydroxyl and the nitro g o u p of the chromene moiety. The

operation of atropisomerism was evidenced by observation of two sets of pcaks from

' H and "C spectra. The 'H NMR spectra of each one of the 4-aryl-3-nitro-4H-

chromenn displayed a characteristic singlet for the brnzylic proton at about 5.4 ppm.

The "C values assigned for the 4H-chromene 95s-n are given in Table 1 . I 5.

We conducted a reaction where two steps namely CSA condensation of 2-

hydroxybenzaldehyde 18s with NMSM 76a followed by electrophilic substitution to

generate 4-aryl-4H-chromene 95a, can be combined in one-pot reaction. Towards this

objective we conducted the reaction by taking one equivalent of 2-

hydroxybenzaldehyde 188, one equivalent of NMSM 76a and 1 . 1 equivalent of

phenol 14e in the presence of 0.1 equivalent of NaOAc in water. This reaction

furnished 4-aryl-4H-chromene 95a in 81% yield after recrystallization using EtOH

Table 1.14: Various 4-aryl-3-nitro-4H-chromcnes 95a-n prcparcd from phenols 14e-g and 87s.

951 (14 h. 45%)

10

NHPh

95j (17 h 64%)

E~~~~ 4.A'yl-3.n1lro.4H. chromene

Entry 4 . ~ , ~ ~ . 3 . ~ , ~ ~ ~ . ~ ~ . chromene

En,ry 4-An/1.3-nlro-4H. chromrns

NHMe

951 (12 h. 88%) 95f(12 h, 63%) 96k (16 h 40%)

\ NHMe \

QSb(19h 73%) 95% (12 h. 73%) 951 112 h 87%)

' OH OH OH

, NO, , NO,

NHCH,Ph

95c (29 h. 51%) e l h ( l 3 h 43%) vsm (16 n. 46%)

I - ... I Figure 1.26: 300 MHz (DMSO-d6) 'H NMR spectrum of 2-[2-(methy1amtno)- 3-nitro-411-4-chromenyl]phenol 9%.

I . * " . , , Z2PEOP:kL% 8 5 5 5 E$E3%g$leE " I

I m 'd

Figure 1.27. 75 MHz (DMSO-d6) "C NMR spectrum of 2-[2-(methylam~no)- m

3-nttro-41f-4-chromenyl]phenol95a.

Tal r-

le 1.15: Comparison of "C NMR 6 value of 4-aryl-3-nitro-4H-chromenes.

1

- R-CH>

X = H 9Sa

I SO S

llK>X

371

I311 2

12'1 ll

I!?!

I 2 7 7

1158

147 4

- 1545

1247

129 I

1188

1279

1156

4.Aryl-3.n~tro4il.c111~~m~1ic, ,.

37 U

R=CHI X-CHt 951,

15'44

1596

1169

372 8

125.2

124 7

R-Bu X-CI 95h

ISYO

llih.2

I 376

R=CHI X-CI 9%

159 1

11163

370 374 j

' R-Ph X-H 951

ISh9

If lR! '

374

' R-Ph X-CHI 95,

I 5 6 9

15'0

l l lX3

37 4

2 4

R-Bu X-H 9Sf

37 h

RrPli X=CI PSk

lShh

1117.7

- - .. R-Bu

X=CII1 9

1289 ' 1 2 q 3 1 I 2 8 4

374

R=B, X z t l 951

158.5

1589

107 1

1082

3

127 1

127 0

127 K

l l X R

145 1 1474

I 5 2 3

1546

1243

I30 I

1303

1343

128 0

I28 4

I 1 5 6

1 15 8

2 9 1 I

1

1 I I 13011

I 5 9 9 / 159 1

I202

l ? b 4

I284

1181

1483

l S 3 b i

1250

1299

1212

I 2 8 4

1157

1249

I2701

1 1 7 0 ,

1473

1514

1217

1288

1318

1277

1154

372

R-ll, X-CH3 95m

IS90

107 1

1072

..-- l i lh8

4 1 s

2

R-0, X-CI 95"

1587

, 1067

1592

I l l6 8

l i ib 9

372

I!X I I I!9!!4

I2Y l I 1291 i 129 I

1 1277

125 !

1259

1169

147 1

153 3

1229

1290

130.9

1272

1169

36 8

37.2

1 ~ x 4

125?

I27 I

127 7

I I X ' I

I455

1474

IS23

IS4.h

124 1

124 7

1290

1294

1343

127 7

1279

l l S 5

1157

1!6!

I 2 7 9

1218

1473

1547

1244

I29 S

1245

1280

1188

3

37 1

. 1252

? ? 4

1172

i475 /

IS37

123 h

129 0

1319

I282

1157

I25 5

I 2 6 2

1280

1189

1454

1472

1524

1517

124.0

129 6

1298

127.2

1283

12R h

111.4

1156

1289

I 2 5 2

I25 7 - 127 X

1 2 7 0 1

1157

11611

1474

1546

IS62

124.7

I29 I

12Y?

1188

I28 I

1152

115.6

24 .9 I 2 2 5

1291

5

1277

127.9

111.7

1188

1454

147.3

1522

1546

I 2 4 3

I 2 9 9

1300

1344

l ? & I

128 4

1154

1156

1288 1 I 2 5 0

I?'?

1169

118.7

1472

153.3

1236

I:8 8

1314

117 7

I 1 5 3

1156

A z i n e gOAc rt, 16 h, 57%

NO2

,' 0' NHMe /

0 NHMe

Scheme 1.41

The parent 4-aryl-4H-chromcnc 95a was converted to its acetylatcd derivative

96 with acetic anhydride and pyridine (Scheme 1.41). The 'H and "C NMR spectra of

the acetylated product 96 showed two sets of signals confirming atropisomerisrn due

lo restricted rotation around C-C single bond. X-ray crystal structure of the acetylated

derivative 96 ( F i p r c I .28) further conf ined the assigned structurc. The X-ray crystal

structurc displayed cxistence of stabilizing hydrogen bond interaction between

oxygen of NO2 and NH of N H M ~ . " " The X-ray crystal structure also showed that thc

aryl ring occupies pseudo-axial orientation with acetyl group projecting into the space

above the plane of 4H-chromene moiety.

I 1

Figure 1.28: The single crystal X-ray structure of 2-[2- (mefhylamino)-3-nitro-4H-4-chromenyl]phenyl acetate 96.

Atler demonstrating facile aromatic substitution of phenols to provide 4-aryl-

4H-chromene, we turned our attention towards the synthesis of bis-chromene by

reaction with 1,2-, 1,3- and 1,4-dihydroxybenzene derivatives.

OH

NaOAc NHMe EtOH, reflux

8 h 82% 97 87a 98

Scheme 1.42

Reactlon of 1,3-dihydroxybcnzene, 1,4-dihydroxybenzcnc in presence or

absence of NaOAc provided only a no no substitution product 97 and 98 respectively

(Scheme 1.42). Eventhough TLC and column chromatography indicated presence of

bis-chromene in minor quantities, they could not bc isolated and characterized (less

than 3%). The 'H and "C NMR spectra of 98 are given in Figure 1.29 and Figure

1.30.

:-c r m m . !!E!Eif3iig ?

? I

Figure 1.29 300 MHz (DMSO-d6) 'H NMR spectrum of 2-[2-(methy1amlno)-3- nltro-4/~-4-chromeny1]-1,4-ben~ened10l 98

OH

87a 90 100

Scheme 1.43

The reaction of parent 4H-chromcnc 87a (2.0 equiv), 1,2-dihydroxybcnzene

( I .O equiv) provided two products (Scheme 1.43). A major product (30%; higher R,

value in silica gel TLC) is the monosubstitution product 99 and the minor (25%)

being bis-chromene 100. Formation of his-chromene 100 was confirmed on the basis

of ESI-MS, which exhibited MtH signal at 519.1526. The 'H and "C NMR spectra

of 99 matched well with 4-aryl-4H-chromene 95a. Several attempts to increase yields

of bis-chromenc by changing reaction conditions like usc of higher boiling solvents

like isopropanol or using NaOAc did not help.

HO

EtOH NHMe NHMe

reflux

87a 101

Scheme 1.44

The reaction of 4/f-chromene 87a with phloroglucinol (1,3,5-

trihydroxyhcnzene) did not yield desirable tris-4-aryl-4fI-chromene 101 (Scheme

1.44) and the starting matcrial was recovered even after 24 h reflux in EtOti with or

without NaOAc.

- 12 h, 92% 8 h, 74%

NHMe

EtOH. reflux 12 h, 89%

103 Scheme 1.45

Reaction of parent 4H-chromene 87a with I-naphthol, 2-naphthol and 8-

hydroxy quinoline in ethanol reflux leads to the formation of 4-aryl-3-nitro-4H-

chrornenes 102-104 respectively in quantitative yields (Scheme 1.45). In each case,

only one regioselectivc product was formed. Thc structure of the product was

confirmed by HMBC correlations between C4H and quaternary carbon next to aryl

OH. It is intercsting to note the regiochemical outcvmc of the reaction of 87a with I -

naphthol. Both C2 and C4 substituted products are possible from this reaction.

Isolation of single regioisomer 102 shows that the substitution is highly influenced by

hydrogen bonding interaction of CH with NO2. The ' H and "C NMR spectra of 103

arc given in Figure 1.31 and Figure 1.32.

8

:a ,, WF SCW461PPR%BRtEi$~@% 1. ----l..--..O.....l*l

I

I

E 8 I 1 n

Figure 1.31 300 MH7 (DMSO-dh) 'H NMR spectrum of I-[2-(meth~l~mlno)-3- n1tro-4il-4-chrornenyI]-2-naphthol 103

l

a E 8 f i iR0Im:Z2Y3ZP:U 5 5 i jafiggac&ggm:snp

/ I

I T I ' ' "

Figure 1.32 75 MHz (DMSO-d6) "C NMR spectrum of 1-[2-(methylam~no)- 3-n1tro-4H-4-chromenyl]-2-naphthol 103

5.1 1 . Reaction of 4H-chromene with electron rich aromatic compounds

Having succeeded in displacing thiomethyl group in 4H-chromene with

phenols. it was our next endeavor to rcplace thiomethyl group with electron rich

aromatic compounds to preparc different 4-aryl-411-chromcnc dcrivatives.

NHMe 10 h, 92%

87a 105 108

Scheme 1.46

As a part of this effort we reacted the 4H-chromene 87a (1.0 cquiv) with NJ-

dimethylaniline 105 (1.0 equiv) and the reaction provided 4-aryl-4H-chromene 106 in

near quantitative yield (Scheme 1.46). The regiochemistry in the substitution of NJ-

dimethylaniline was ascertained from ' H NMR spectmrn (Figure 1.33), which showed

AA'BB' quartet for hydrogens on N,N-dimethylanilino ring. The "C NMR spectrum

(Figure 1.34) displayed signals for four aromatic carhons of NJ-dimethylaniline

portion, confirming assigncd structure.

H,C.N.CH,

0 NHMe

- .-L' . I . . . - -- - - . - . f.

Figure 1.33 300 \{Hz (CDCI! - DSlSO-d,) H SMR spcctrum of .I?-methyl-4-

r- .--,-- - ? ,- -- _ _ _ _ ,. ? --- 7 Flgure 1.34 75 MHz (CDCI3 + DMSO-db) "C NMR spectrum of hZ-methyl-4- [4-(dimethylam1no)phenyl]-3-nltro-4H-2-chromenam1ne 106.

EtOH - reflux 6 h, 93% &""' 0 NHMe

Scheme 1.47

Reaction of 4H-chromene 87a with indole 107 was facile and provided indole

substituted 411-chromenc 108 (Scheme 1.47). Substitution on indole took place, as

anticipated, at C3 position. This fact was ascertained by the presence of quaternary

carbon signals st 111.7 ppni in the "C NMR spcctrum (Figure 1.36) of 108. In

addition the 'H NMR spectrum (Figure 1.35) did not show a signal at 6.5 ppm, which

would have appeared if there was a hydrogen on C3 of indole.

I I

Figure 1.35 400 MHz (DMSO-db) 'H NMR spectrum of N-[4-(llf-3-indoly1)-3- nitro-4H-2-chromenyll-N-methylamine 108.

F' 0 NHMe

$*,

A h I .

, , ; , L I 1 O * I 1 6 1 1 L P P

kl W

I

I - 7 , I- 11. >.. ,.. 1.1 1.0 LI. 1.0 10 'I . 20 0 -

Figure 1.36 100 MHz (DMSO-d(,) "C NMR spectrum of N-[4-(1 H-3-indolyl)- 3-nitro-4H-2-chromenyI]-N-n1cthylamine 108.

reflux

87a 109 110

Scheme 1.48

The reaction of 4H-chromene (1.0 equiv) 87a with pyrole (3.0 equiv) 109

provided C2 substituted product 110 (Scheme 1.48) and this fact was ascertained from

'H NMR, which exhibited three broad and one sharp singlet between 5.2 and 6.8 ppm.

In addition "C spectra showed a quaternary carbon at 134.5 ppm assignable for C2' in

pyrole ring.

mNo2 NHMe

113

CX- NHMe -+ NHMe E~OH, refux EtOH, reflux NHMe

87a

Scheme 1.49

Reaction with other electron rich heterocyclic aromatic compound like

thiophene (3.0 equiv), furan (3.0 equiv) or imidazole (3.0 equiv) did not provide any

substitution product 111-113 (Scheme 1.49). In all the cases the starting material was

rccovered as such

NHMe 115

NHMe

87r

Scheme 1.50

Similarly the reaction with marginally electron rich aromatic compounds like

anisole, 1,3-dimethoxy benzene and o, p-directing chlorobenzene also did not provide

substitution products 114-116 (Scheme 1.50), indicating that electron rich nature of

aromdtlL nng and thc hydrogen bondlng ~nterdct~on of Ot-l with nltlo group dre

rcqulrementr tor the arnmat~c elcctroph~l~c suhst~tut~on redct~on

5.12. Attempted substitution reaction with nucleophiles like alkoxide, prinlarj

amine, azidc and cyanide

NaCN EtOH or NaCN MeOH or

NaCN THF+DMF ' rl NaN, DMFor NaN, DMSO or

-X--

NHMe

118 87a 117

Scheme 1.51

Slnce benzpynl~um catlon IS generated from 4H-chromene 87a by ellrn~ndtlon

of methylth~oldte anlon, we reasoned that t h ~ s lntermcd~ate ~ o u l d be quenched w~!h

products 117-119 (Schcmc 1 51) Rcact~on In each cdsc was conducted both under

S h l and ShZ cond~t~ons only to find that thc reartlon d ~ d not take place, to prov~de

mean~ngful productr In all the ca$er there was an extens~ve decompos~tlon of 4H-

chromene 87a and no lsolahle product could be reallzed S ~ n c e thc nucleoph~les llke

cyan~de, a z ~ d e and alkox~de cdn behave ds bases, ahstract~ng NH proton to generate

anlon IS a competing reactlon Once the anlon gets generated the ~ntermed~dte could

undergo heterocyclic nng opening and d~s~ntegratc the molecule

C,H,NH, EtOH or Benzene or

A A THF, r t

EtOH or Benzene

C,H,CH,NH, EtOH or Benzene or THF, rt

120

Scheme 1.52

When the reaction of 87a was conducted with a primary amine namely.

benzylamine only product isolated was the imine 120, which got generated i ~ ~ s i t u

from 2-hydroxybenzaldehyde and benzylamine (Scheme I . 5 2 ) . In this case the 4H-

chromene 87a possibly undergoes retro-CSA reaction to salicylaldehyde which

condenses with benzylamine. Alternatively it is also possible that the initial

substitution leads to amino product which undergoes decomposition. This reaction

was found to be general for other primary amines like butylamine and aniline. In both

the cases the only isolable products were bidentate ligands 121 & 122 (Scheme 1.52).

Reaction with secondary amine like piperidine leads to undetectable products.

5.13. Substitution of SMc in 4H-chromene 87a with hydride

Next attempt on synthetic modification of 4H-chromene 87a was SMe group

replacement with hydrogen so that thc latent amino acid component can be revcalcd.

In this quest we treated 4H-chromene with various reducing agents. Reduction of 4H-

chromene with Raney Nickel proved to be most difficult reaction to encounter in

present rcscarch.

- reflux, 15 h, 11% NHMe

87a 124

Scheme 1.53

Upfront we thought reductive removal of SMe group is a facile reaction with

Kancy nickel. This reaction, however was most dimcult to handle. Not only reaction

was dependent on the batch of Raney nickel, it also did not yield desired product.

Rancy nickel reaction was conducted in EtOH, EtOH-THF, THF and iPrOH-THF at

rt. Only in one case we isolated a dimeric product 124 in I I% yield (Scheme 1.53).

The NMR spectrum of this molecule was remarkably similar to the parent 4H-

chromene 87a, the signal due to SMc was missing. A singlet at 4.84 ppm for two

hydrogens, two doublets and two triplets in the aromatic region for eight hydrogens

and a broad quartet at 10.27 ppm for two hydrogens along with a doublet at 2.85 ppm

for two hydrogen's endorsed the proposed structure. The "C NMR spectrum

exhibited two signals at 27.52 ppm and 38.94 ppm along with eight signals in the

aromatic region.

dNo2 a:-';. NHMe

rt, 2 h, 12%

87a 125

Scheme 1.54

In one of the runs, thc reaction provided M-methyl-2H-2.3-chromenediaminc

125 in 12% yield (Scheme 1.54). The product however. could not bc isolated in pure

form. The ' H NMR spectrum showed a singlet at 6 3.1 ppm for NHMe, a singlet at 6

6.2 ppm for C2H and multiplct for aromatic hydrogens. "C NMR spectrum displayed

a sibmal for CH, group at 6 33.2 ppm and for CH at 6 102.2 ppm apari from the

aromatic and olefinic carbon signals. In thc abscncc of complete spectral data the

structure assigned is tentative.

mN02 0 0

127

t BF,. Et,O MeOH, fl

NHMe

871 Scheme 1.55

Reductive removal of SMe in 4H-chromene 878 did not take place with H2.

5% Pd-C in presence or absence of acetic acid. Similarly hydride reducing agents like

NaBH4 in MeOH, NaBH4 in EtOH, NaBH4, BF3.Et20 in THF (BH,), LAH in dry

diethyl ether at -78 'C or at room temperature did not yield any tangible products

(Scheme 1.55).

HgCI,, EtOH &No2 or M 4

NHMe reflux, 1 h, 44%

871 127

Scheme 1.56

As a part of our studies on reductive removal of SMe group from 87a, we

e~nployed HgCl2 in EtOH or catalytic amount of HC1 in dry MeOH to remove SMe

group (Scheme 1.56).In4 Only product isolated in low yield was known 3-nitro-

coumarin 127. Spectral data of 3-nitro-coumarin matched well with that of reported

data. "I5

i-HF XNo2+ aHrzi 0 O C , 0.5 h

127 128 129

Scheme 1.57

The NaBH4-BFj.Et20 rcaction provided two products in low yield. One of

which was 2-(2-nitroethy1)phcnol 128"'~ and other one was 2-(3-hydroxy-2-

nitropropy1)phenol 129, which is unknown (Scheme 1.57). From above experiments

we concluded that elimination of MeSH takes plclce to producc nitmstyrene motif

initially. If reduction of double bond follows in preference to reduction of the NO2

group, decarboxylation occurs to provide 2-phenyl-l -nitroethane 128.

The failure of hydrogcnation (metal bound hydrogen) as well as reduction

with hydride donors (both nucleophilic and electrophilic) prompted us to rethink on

the ways to reductively remove C4-SMe. We reasoned that if the SMe was removed

reductively undcr acidic or basic condition, concomitant decarboxylation was a clear

possibility. Therefore we came to an understanding that the SMe removal must be

carried under radical or neutral reaction conditions. As a first choice we employed,

tri-n-butyltin hydride (TBTH) in the presence of 2.2'-azobisisobutyronitrile

(AIBN) ."~ This reaction proved to be inconsistent and not reproducible: when it

worked, a maximum of 82% yield of 126 could be generated. Afier enormous amount

of synthetic effort employed for this seemingly simple transformation, we were elated

to find that SMe removal did takes place when 4H-chromene was heated with

thiophenol in a sealed tube at 163 'C in a pre-heated oil bath. If the reaction was

conducted in open vessel at least five times more thiophenol was required for

complete conversion to 126a (88%) (Scheme 1 S8).

TBTH, AIBN benzene, reflux dNO2 0,s h, 82Oh or

CBH6SH, 163 0C NHMe 2.5 h, 88%

878 126a

Scheme 1.58

The U V spectrum of 1269 showed a A,,,, at 351 nm (log c = 4.5) indicating the

intact nature of nitroketene N,O-acetal moiety. Thc IR spectrum cxhibitcd bands for

the nitro goup at 1475 ern.', 1373 cm'l and olefinic C=C stretching at 1658 cm.'.

Besides, ' H NMR spectrum (Figure 1.37) showed a doublet for NHMe at 3.22 ppm (J

= 5.1 Hz) and a s in~le t for C4 methylene at 2.98 ppm, two doublets and four triplets

between 7.2-7.4 ppm for aromatic hydrogens and a singlet at 10.5 ppm for NH. The

"C NMR spectrum (Figure 1.38) showed two signals at 25.0 ppm (CH2) and 27.0

pprn (CHI). In addition, four methine and four quaternary carbon rcsonancc in the

aromatic region confirmed the structure.

1

: l a ' ? I R e B ..-*h*.b- ! Eii: s i ! % - -

a

--,,d Figure 1.37 300 MHz (CCb CDCI,) 'H NMR spectrum of N-methyl-N-(3- n1tro-4H-2-chromenyl)am1ne 126r

- - - - - - -. - m . -5- - . 2 - -> I#

Figure 1.38 75 MHz (CCI4.CDCI,) "C NMR spectrum of N-methyl-N-(3-nttro- 4H-2-chromenyl)am1nc 126a.

R1 SMe

H,C

R3 NHMe MeOH

R3 R4 reflux, 7-9 h R4

7242% 87a, 87c, 87d, 87h, 87k 126a-e

87a, 126a: R1 = R2 = R3 = R4 = H

87d, 126b: RI = OMc, R2 = R3 = R4 = H

87h, 126c: RI = R3 = R4 = H, R2 = OMe

87k, 126d: R1 = R2 = R4 = H, R3 = OCHzCbHS

87c, 126e: R1 = R2 = R3 =H, R4 = OMe

Scheme 1.59

Mechanistically this transformation could go through the formation of methyl

phenyl sulfide to generate a carbanion intermediate, which gets quenched by the

protic solvent. Employment of thiophenol for the above transformation required

stringent condition of heating the reaction mixture in obnoxiously smelling thiophenol

rcflux. Therefore, there was a requirement to find an alternative for this

transfonation.

As an option, the biornirnetic hydride donor, Hantzsch diester appeared to be a

suitable reagent to this tran~fonnation.'"~ Hantzsch diester prepared over a century

ago, mimics biological hydride donors like NADH and NADPH. It is acquiring

increased attention in recent ycars as a selective and mild reducing agent operating at

neutral conditions.""

Table 1.16: Displacement SMc in 3-nitro-4H-chrornenes 87a, 87c, 87d, 87h, 87k using Hantzsch dicster.

Entry Substrate Product Time yield (h) (%)

SMe

OMe SMe

2

3 Me0&N02 NHMe

87h

SMe

&NO_ 7 74

0 NHMe

126b

phAO mNo2 0 NHMe 1 82

pNO\ 0 NHMe 72

OMe

We were happy to find that Hantzsch dicstcr in MeOH rcflux, converted 87a

to 126a in 4 h and in 82% yield (Scheme 1.59). Reductive removal of SMe from 4H-

chromene 87a by this method was proved to be general. We conductcd this

transformation on five different substrates and in cach case 4H-chromenes were

obtained in good yield (Tablc 1.16). The "C NMR spectral values for all five

compounds are given in the form of Table 1.17.

SMe . ,- C,H,SH

-0 -0 NHMe "-

163OC

871 126f

Scheme 1.60

At this point it is worth noting an experiment conducted on the benzyl ether

87k with thiophenol reflux (Scheme 1.60). Surprisingly this reaction did not yield any

tangible product. Moreover, similar to corresponding benzyl ether 87k, ally1 ether 871

also did not work indicating labile nature of the substrate. Reductive removal of SMe,

however, worked with Hantzsci diester (entry 4; Table 1.16).

5.14. Synthesis of lactones of ortho-tyrosine 1328 and DOPA isomers 132b-e

pNH2 a N H 2

COOH OH 0 0

ortho-Tyrosine ortho-Tyosine lactone N-Acetyl-ortho-tyrosine lactone

130 131 132a

Figure 1.39

ortho-Tyrosine 130 (Figure 1.39) is a natural amino acid synthesized in the

body from phenylalanine."O Sometimes it is formed through non-enzymatic free

radical hydroxylation of phenylalanine under conditions of oxidative stress.'" ortho-

Tyrosine is also formed during radiolytic oxidation of proteins. During limited

radiolysis, its cancentration increases gradually in proteins as a function of absorbed

dose."2 So ortho-tyrosine is proposed as marker for the identification irradiated

protein-rich food."' Patients affected with Diabetes mellitus and chronic kidney

diseases produce ortho-tyosinc in larger quantities, level of which in urine is uscd for

detection of these diseases.22 A few synthetic procedures for ortho-tyrosine are known

but are tedious to conduct.l14 In view of'the difficult~es In literature methods and due

to the fact that scarce amount of ortho-tyrosine available from natural sources design

we embarked to convert 4H-chromene 87a into ortho-tyosine lactone. For this

purpose we needed to reduce the nitro g o u p to the amino g o u p and hydrolyse the

enamine to the lactone carbonyl."' It should be noted that owing to push-pull nature,

reduction of the nitro g o u p in nitroketene dithioacetal 81 is generally difficult.

Previously Rajappa and coworkers tried Zn- Ac20 i AcOH for reduction of the

nitro group to N-acetylamino group enroute to the synthesis of N-acetyldipeptides

derivatives."' Basavaiah and coworkers employed the Pe 1 AcOH for this type of

reduction."' When we employed Fe-AcOH for reduction of 4H-chromene 87a the

reaction was not clean at room temperature or at reflux. Then, we switched over Zn-

AcOH, however. this reaction was also not clean and no meaningful product could bc

Isolated

dNO2 Z z

NHMe AcOH. ri, h Ol"rNH2 0 0 42%

u O A N H M e AcOH, 110 1 h, 69%

126a

Scheme 1.61

When we employed Fe or Zn and AcOH on parent 4If-chromene 871, the

reaction provided known enamine 133 as the only isolable product (Scheme 1 .61) . "~

We were gratified to find that Zn- AczO 1 AcOH reduction on 4H-chromene 126a at

110 "C (oil bath temperature) provided 68% of N-acetyl orrho-tyrosine lactone 132a

(Figure 1.38, Scheme 1.61). It is possible that, with Zn-AcOH as a reducing agent at

certain stage of reduction of nitro group, enamino styrene double bond gets generated

which is stabilired by conjugation with aromatic p u p and carbonyl goup . However

in Ac20 medium, the reaction gets diverted by acetylation which does not allow

enamine to he generated, instead acetyl amino group gets generated. The Fe-AcOH /

Ac2O did not provide amino ac~d in good yield and also the reaction was not clean.

Therefore we adopted Zn-AcOH 1 Ac20 as a general reducing reagent for this

transfetmation.

The ortho-tyrosinc derivative 132a was characterized on the basis of analytical

and spectroscopic data. The IR spectrum showed a lactone carbonyl band at 1765 cm"

and thc secondary amide stretching band at 3290 cm'l. In addition, bands due to the

nitro group were absent. The ' H NMR spectrum (Figure 1.40) showed a singlet at 6

2.1 1 ppm for acetyl, a triplet and a doublet of doublet at 2.02 and 3.49 ppm for

prochiral hydrogens and doublet of triplet at 4.7 ppm for C3H. A broad singlet for NH

was present at 6.6 ppm. "C NMR spcctrum (Figure 1.41) in conjugation with DEPT-

135 spcctrum revealed the presence of one methylene, one methyl, four methines and

Sour quaternary carbons. The two carbonyl groups for lactone and amide appeared at

168.6 and 170.2 ppm respectively.

1 I 1 .I Figure 1.40 300 MHz (CDCI3) 'H NMR spectrum of NI-(2-0x0-3,4-dihydro- 2H-3-chromenyl)acetamide 132a.

1 I Figure 1.41 75 MHz (CDC13) IJC NMR spectrum of NI-(2-0x0-3,4-dihydro- 2ff-3-chromenyl)acctamide 132a.

Figure 1.42

It was our next task to extcnd the newly discovered procedure for conversion

of nitroketene 0,s-acetals 126 to the conespondicg amino acids, towards the

synthesis of dihydroxphcnylalanine (DOPA) isomers.

DOPA is an essential amino acid. It has a role in neur~transmittance."~

Dopamine generated from DOPA act at synapse when the communication is required.

Natural levodopa is used as a prodrug to increase dopamine levels for the treatment of

Parkinson's disease since it is able to cross blood brain barrier whereas dopamine

itself cannot.'20 During Parkinson's disease dopamine producing nerve cells in the

basal ganglia degenerate, which causes tremor, rigidity and akinesia. L-DOPA, which

is converted to dopamine in the brain, compensates for the lack of doparnine and

normalizes motor behavior.'*' Lactones of DOPA isomers, of which we identified

four (Figure 1.42; 133~-d) as synthetic targets, have not been characterized fully.

Literature survey on DOPA isomcrs revealed few reports on their syntl~csis."~ In

1954, Lamhooy reported thc synthesis of four isomers of DOPA.'^' In 1970 Ueno and

coworkers reported an enzymatic synthesis of DOPA isomer 133c from resorcinol and

5-methyl-L-cysteine using P-tyrosinasc c n ~ y n e . ' * ~ The structure was assigned based

on 60 MHz NMR spectrum and mass spectral date. The isomer 133b is known in

patent literaturc. It was synthesized starting from 2,3-dimethoxy bcnzaldehyde,

nitroethane and butyl arnine.''s

Zn, Ac,O R 2 ~ N 0 2 Ac%

R3 0 N H M ~ l lO°C, 0.5-1 h 61-68% R3 0 0

R4 R2@NHAc R4

126b-e 132b-e

126b, 132b: RI = OMe, R2 = R3 = R4 = H

126c, 132c: RI = R3 = R4 = H, R2 = OMe

126d, 132d: R1 = R2 = R4 = H. R3 = OCH2C6Hs

126e, 132e: R1 = R2 = R3 =H, R4 = OMe

Scheme 1.62

Zn-AcOH 1 Ac20 reduction of the isomeric methoxy 1 benzyloxy-4-

(methylsulfanyl)-3-nitro-4H-2-chromenyl]--methylami1e 126b-c provided

corresponding lactones of DOPA isomers 132b-e in the protected form (Scheme 1.62;

Table 1.18). Each one of them exhibited spectral data characteristic of the amino acid

and also in tandem with the lactone of ortho-tyrosine. Presence of OMe group at peri-

position, not surprisingly, influenced the diastercotopic C4 hydrogen in 132b. The 'H

NMR spectrum displayed a chemical shift difference of 1.2 ppm between two C4-

hydrogcns. Large chemical shift difference between diastereotopic C4 hydrogen

indicates the interaction of one of the two with lone pair of electrons on OMe through

hydrogen bonding interaction. The I3c NMR spectral values for all four compounds

are given in the form of Table 1.19.

Table 1.18: Treatment o f 126b-g with xinc, AczO and AcOH to get 132b-g.

Entry Subsrate Product T~me Yleld (h) ( % I

1 hNo2 hNHAc 68

0 NHMe 0 0

126b 132b

M e O m N O , M e O m N H A c 2 1 62

0 NHMe 0 0

3 mNo2 0.5 61 PhCH,O 0 NHMe PhCH20

4 1 68

OMe OMe

126e I320

Table 1.19: Cornpanson of "C NMR spectral values for DOPA

128.7 (2 r CH), 128.2 (CH); 55.6 (OMe).

5.15. Synthesis of novel non-natural hybrid amino acids 135 & 137

108

Scheme 1.63

AAer establishing a facile synthesis of ortho-tyrosine 132a and DOPA isomers

132b-e, our next task was to convert 4H-chromene 108 into hybrid non-natural amino

acids (Scheme 1.63). For example, the compound 135 has both tryptophan and

tyrosine units incorporated into the structure. Initially, the 4H-chromene having indole

substituent 108 was subjected to reduction with Zn-AcOH or Fe-AcOH and we found

that the reaction was more clean wit11 Zn-AcOH. The Zn-AcOH reduction provided

thc enamine 134 in 32% yield (Figure 1.43 and Figure 1.44). On the other hand, the

Zn-AcOH I AczO reduction prov~ded required hybrid acctylated amino acid 135 in

65% yield.

The NMR spectroscopy of the N-acetyl amino acid 135 (Figure 1.45 and

Figure 1.46) shows signals due lo both indole as well as coumarin. Interestingly from

this reaction a single isomer was isolated to which we assigned trans stercochemistry

based upon the largc coupling constant of 13.2 Hz between C3H and C4H. The C3

NH appeurcd as doublet with a coupling constant of 8.7 Hz due to coupling with C3H

- - .- -, - - - * - - - -_._- __ _ Figure 1.43 300 MHz (CDCI, + DMSO-4) 'H NMR spectrum of 3-amino-4- (1K3-indolyl)-2H-2-chromenonc 134.

Figure 1.44 75 MH7. (CDCI, + DMSO-d6) "C NMR spectrum of 3-am1no-4- ( 1 H-3-indolyI)-2H-2-chromenone 134.

1 - 8 1 -- 1 0 * 1 7 * 6 4 1 PP

Flgure 1.45 300 MHz (CDCI,) 'H NMR spectrum of N1-[4-(lH-3-lndolyl)-2- oxo-3,4-dihydro-2H-3-chmrnenyl]acetamide 135.

-.-. - -T- r 7-7-

r o im rm i w ro .o .D 10 ppm

Figure 1.46 75 MHz (CDCI?) " C NMR spectrum of NI-[4-(1H-3-1ndolyl)-2- oxo-3,4-dihydro-2H-3-chromenyl]acetamide 135.

l l D D C , 1 h llOGC, 1 h NHAc 40% 62'K

\ 0 0

95a

Scheme 1.64

As a next effort we converted C4 phenol substituted 4H-chromene 958 to the

cr~rresponding amino acid 137 or the enamine 136. Like in previous case, the Zn-

AcOH reduction provided enamine 136 (Scheme 1.64, Figures 1.47 and 1.48) and Zn-

Ac20 I AcOH reduction provided N-acetyl amino acid 137 (Scheme 1.64, Figures

1.49 and 1.50). From "C NMR spectrum (Figure 1.50) we concluded both cis- and

trans- isomer were formed in 6:5 ratio. Interestingly, the cis- isomer crystallized as a

white solid during fractional crystallization and its structure was confirmed by single

crystal X-ray (Figure 1.51) analysis (Deposited with CCDC; deposition No. 698176).

e -. 6 I - _ ---- .. C-.A

Figure 1.47 300 MHz (DMSO-d6) ' H NMR spectrum of 3-ammo-4-(2- hydroxypheny1)-211-2-chromenone 136.

I .d II Figure 1.48 75 MHz (DMSO-d6) I3c NMR spectrum of 3-amino-4-(2- hydroxypheny1)-2H-2-chromenone 136.

I II I 4 2 rl Figure 1.49 300 MHz (CDCI3) 'H NMR spectrum of NI-[4-(2-hydroxypheny1)- 2-oxo-3,4-dihydro-2H-3-chromenyl]acetamide 137.

I

- - - 1 L - _ . - Figure 1.50 75 MHz (CDCI,) C NMR spectrum of NI-[4-(2-hydroxypheny1)- 2-oxo-3,4-dihydro-2H-3-chromenyl]acetam1de 137.

Figure 1.51: Single crystal XRD structure of N1- [4-(2. hydrox~hcnyl)-2-ox0-3.4-dihydro-2H-3-chromenyl] ucctarnide 137.

5.16. Reduction of enamino double bonds in 134 & 136 by high pressure

hydrogenation

q H,, 10% Pd-C - q MeOH, 80 PI mN~e2 48 h, 82%

0 0 0 0

Scheme 1.65

Scheme 1.66

We attempted to reduce the endo double bond in compound 134 or in 136 by

high pressure hydrogenation using Hz, 10% Pd-C in MeOH. The reduction of the

double bond did not take place, Instead the reaction provided a good yield of N,N-