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† Dedicated to Dr. Mirjana Eckert-Maksić on the occasion of her 70th birthday. * Author to whom correspondence should be addressed. (E-mail: [email protected])
CROATICA CHEMICA ACTA CCACAA, ISSN 0011-1643, e-ISSN 1334-417X
Croat. Chem. Acta 87 (4) (2014) 431–446. http://dx.doi.org/10.5562/cca2482
Original Scientific Article
Photodecarboxylation of N-Adamantyl- and N-Phenylphthalimide Dipeptide Derivatives†
Margareta Sohora, Tatjana Šumanovac Ramljak, Kata Mlinarić-Majerski, and Nikola Basarić*
Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
RECEIVED MAY 22, 2014; REVISED SEPTEMBER 8, 2014; ACCEPTED SEPTEMBER 11, 2014
Abstract. New dipeptide derivatives 1 and 3 were synthesized and their reactivity in the photochemical re-action of decarboxylation was investigated. The photodecarboxylation of N-adamantyl derivatives 1a and 1b and N-phenylphthalimide derivatives 3a and 3b probably takes place from the triplet excited state. The triplet excited state of 1a, 3a and 3b was characterized by laser flash photolysis. N-phenylphthalimides 3a and 3b undergo 2−5 times more efficient photodecarboxylation than N-adamantylphthalimides 1a and 1b. The aminoacid residue (Phe or Gly) at the C-terminus of the dipeptide does not influence the photodecar-boxylation efficiency. Product selectivity in the photoreactions is determined by the conformation of the molecules. N-phenylphthalimides with the separated electron donor (carboxylate) and acceptor moiety (phthalimide) give only simple decarboxylation products, whereas N-adamantyl derivatives also give cy-clization products.
Keywords: photodecarboxylation, dipeptides, phthalimides
INTRODUCTION
Photodecarboxylation is an important photochemical reaction with many applications in organic synthesis.1 For example, photodecarboxylation of Barton esters can induce radical chain reactions,2 whereas degradation of some classes of organic compounds can be carried out by photo-Colbe reaction.3 Photodecarboxylation is also important for the chromophores that compose nonstere-oidal non-inflammatory drugs such as ketoprofen, and naproxen. Since these drugs are known to induce pho-toalergy, their photochemistry has been thoroughly investigated.4 Generally, the mechanism of photodecar-boxylation can take place via homolytic cleavage giving radicals.5 The other suggested mechanism includes photoejection of an electron from the carboxylates and formation of radicals.6 A special interest was directed to the photodecarboxylation of ketoprofene and similar derivatives.7 Although some controversy was encoun-tered regarding the reactive excited state of ketoprofen,8 it is generally accepted that the decarboxylation gives carbanionic species.9
Synthesis of phthalimide derivatives attracts organic chemists due to their application in the amine protection,10 as well as their biological activity.11 Furthermore, phthalimide has shown a potential as a useful chromo-phore that can initiate many synthetically applicable pho-
tochemical reactions giving rise to complex hetero-polycyclic derivatives.12 These reactions include photocy-cloadditions,13 cyclizations initiated by H-abstraction,14 or photoinduced electron transfer (PET).15 In the PET reac-tions, the phthalimide is an electron acceptor, whereas a donor of an electron can be carboxylate16 or silyl deriva-tive.17 Using photoinduced decarboxylation initiated by the phthalimide chromophore, Griesbeck et al. developed synthetic methods for the preparation of medium and large-cyclic ethers18 and cyclic peptides,19 and developed novel chiral photocages.20 Later, Oelgemöller et al. used photoinduced decarboxylation for the acetate,21 benzyl,22 or α-amino acid addition to the phthalimide,23 or for the formation of cyclic aryl ethers,24 which was also conduct-ed in the microflow reactors.25 We have recently demon-strated that photoinduced decarboxylation of 3-(N-phthalimi-do)-1-adamantane carboxylic acid initiate addi-tion of the photogenerated radical to electron deficient alkenes.26 The latter photoaddition is feasible only in the systems wherein the phthalimide is separated by a rigid spacer from the electron donor to prevent the cyclization reaction. In the flexible systems, cyclization takes place, and we have recently shown that it takes place with high enantioselectivity due to memory of chirality. Thus, cy-clization of dipeptide 1a containing L-phenylalanine gives 2a as the major product in 65 % yield with the ee > 99 % (Eq. 1).27
432 M. Sohora et al., Photodecarboxylation of Dipeptides
Croat. Chem. Acta 87 (2014) 431.
Herein we investigate further the scope of the pho-todecarboxylation in a series of dipeptide derivatives wherein the N-terminus is activated by phthalimide. The investigated molecules comprise of N-adamantyl-phthalimide derivatives 1a, 1b, and N-phenylphtha-limide derivatives 3a, 3b (Chart 1). The molecules are designed to probe for the efficiency of photode-carboxylation depending on the spacer between the electron donor (carboxylate) and the acceptor (phthali-mide). Although photochemistry of N-alkylphthalimides has been well documented, reports on photochemistry of N-phenylphthalimides are scarce.28 The C-terminus of the dipeptides bears two distinctly different amino acids, glycine and phenylalanine. The anticipated photodecar-boxylation should give rise to two different radical spe-cies, and therefore, it is anticipated to proceed with different efficiency. We performed preparative pho-tolyses and isolated or characterized primary photo-products and determined quantum efficiency of their formation. In addition, to get more information about the mechanism of the photochemical reactions and to characterize the excited states involved, we carried out laser flash photolysis (LFP).
RESULTS AND DISCUSSION
Synthesis
Adamantyl dipeptide derivatives 1a and 1b were syn-thesized from the N-phthalimide derivative of 3-aminoadamantane-1-carboxylic acid, prepared as previ-ously described.26,27 The acid was activated with N,N'-Dicyclohexylcarbodiimide (DCC) and treated with N-hydroxysuccinimide (NHS) to give iminoester deriva-tive27 which was treated with unprotected L-phe-nylalanine or glycine in the presence of a base to afford the desired peptides 1a and 1b in good yields, that were purified by column chromatography.
N-phenylphthalimide dipeptides 3a and 3b were prepared from acid 4.26 Attempts to activate acid 4 by DCC and NHS failed. Therefore, we used a stronger activation reagent, N,N,N′,N′-tetramethyl-O-(1H-benzo-triazol-1-yl)uronium hexafluorophosphate (HBTU).29 The acid was activated in situ and reacted with ethyl or benzyl ester L-phenylalanine or glycine (Scheme 1). The esters 5a and 5b, as well as the corresponding ethyl
N
O
O
3a R= -CH2-C6H53b R = H
1a R= -CH2-C6H51b R = H
N
O
O
OHN COOH
R
O
NH
COOH
R
Chart 1.
1a
N
O
O
OHN
COOK
CH2Ph
(1)h
acetone-H2O
NH
HN
CH2Ph
O
O
O
2a
**
N
O
O
5a R= -CH2-C6H55b R= H
O
NH
COOBn
R
N
O
O
O
OH
-Cl+H3N COOBn
R
HBTU, TEA
DMF
N
O
O
3a R= -CH2-C6H53b R= H
O
NH
COOH
RN
O
6a R= -CH2-C6H56b R= H
O
NH
COOH
R
H2
5 % Pd/C
EtOH/DMF
5 % Pd/C
MeOH/DMFEt3SiH
4
Scheme 1.
M. Sohora et al., Photodecarboxylation of Dipeptides 433
Croat. Chem. Acta 87 (2014) 431.
ester 5bEt, were prepared in good to moderate yields. Using the same activation protocol we also prepared the corresponding ethyl and benzyl gylcine esters of the adamantane derivative (1bEt, 1bBz). However, all attempts to perform basic or acidic hydrolysis of these esters failed, mostly due to the competitive ring-opening of the phthalimide moiety. Therefore, the benzyl protec-tion of the esters was inferred to be more rewarding, enabling the selective deprotection by hydrogenolysis. However, the usual protocol by use of Pd/C, in addition to the cleavage of the esters, gave phthalides 6a and 6b. A successful benzyl ester deprotection was achieved in a reaction of triethylsilane and Pd/C (5 %) with in situ formed H-radicals.30 The deprotection was carried out in methanol-DMF and furnished desired products 3a and 3b in good yields (Scheme 1). Photochemistry
To isolate and characterize photoproducts, preparative irradiations of 1b, 3a, and 3b were carried out. Irradia-tions were carried out in acetone-H2O (3:1) in the presence of 0.5 equivalents of K2CO3 as a base, ac-cording to the previously documented conditions for
efficient intra- or intermolecular electron transfer and photodecarboxylation.18−26 However, under these con-ditions, irradiation of the phenyl derivatives 3a and 3b gave complex mixtures of many products. Chromato-graphic isolation of the photoproducts was problematic due to their poor solubility in most of the commonly used solvents. However, photolyses (10 min, 16 lamps) taken to lower conversion gave photode-carboxylation products 7a and 7b (formed as major products in small amounts, < 20 %) which were de-tected by NMR and HPLC (Eq. 2, Table 1). To fully characterize 7a and 7b, they were prepared by an in-dependent synthetic method, by applying the above-described protocol (HBTU activation, Scheme 1), from acid 4 phenylethylamine and methylamine, respective-ly (see the experimental). Irradiation of the isolated derivatives 7a and 7b, under the same conditions as used in the photolysis of 3a and 3b, lead to a fast for-mation of numerous products and high-weight materi-al. All attempts to isolate some of the secondary pho-toproducts failed due to the problems of solubility, the material was lost on the column chromatography on silica or alumina.
Table 1. Photolysis of phthalimides 1a, 1b, 3a, and 3b under different conditions(a)
Comp. Solvent Conc.
(mg/mL) Time (min)
Reactant (%)(d)
Products(c) Decarboxylation
Product Cyclization
Product Unidentified
Products 1a acetone-H2O
(3:1) 10/20
30 15
(1a) ≈ 10 (8a)
40 (2a)
35
acetone-H2O (3:1)
100/100
20 70 (1a)
Traces (8a)
13 (2a)
17
CH3CN-H2O (3:1)
10/20
30 90 (1a)
Traces (8a)
10 (2a)
-
1b acetone-H2O (3:1)(b)
78/185 21 70 (1b)
Traces (8b)
15 (9b) 8 (2b)
7
acetone-H2O (3:1)
20/20 20 21 (1b)
10 (8b)
Traces (9b+2b)
69
acetone-H2O (3:1)
200/100 15 65 (1b)
5 (8b)
Traces (9b+2b)
30
CH3CN-H2O (3:1)
20/20
20 >90 (1b)
Traces (8b)
Traces (9b+2b)
<10
3a acetone-H2O (3:1)
20/20
3 60 (3a)
20 (7a)
0 20
CH3CN-H2O (3:1)
20/20
3 85 (3a)
10 (7a)
0 5
3b acetone-H2O (3:1)
20/20
10 40 (3b)
15 (7b)
0 45
acetone-H2O (3:1)
100/100
10 10 (3b)
5 (7b)
0 85
CH3CN-H2O (3:1)
20/20
10 60 (3b)
15 (7b)
0 25
(a) Irradiations were carried out in N2-purged solutions in the presence of 0.5 equivalents of K2CO3. Luzchem or Rayonet reactor was equipped with 8 or 16 lamps, respectively, with the irradiation maximum at 300 nm. (b) Irradiation was carried out in Luzchem reactor equipped with 3 lamps (300 nm). (c) The ratio of products determined from the NMR spectra of crude mixture. The number in parenthesis corresponds to the ob-tained cyclization product. (d) The conversion was obtained by the weight of the photoproducts after separation from the unreacted acids 1a,b and 3a,b.
434 M. Sohora et al., Photodecarboxylation of Dipeptides
Croat. Chem. Acta 87 (2014) 431.
Irradiation of the adamantane derivatives 1a and 1b under the same conditions as used for the phenyl derivatives, taken to low conversion, gave cleaner photochemical reactions and furnished two types of products, decarboxylation 8, and cyclization products 9 and 2 (Eq. 3). The photolysis of the glycine deriva-tive 1b taken to a low conversion (30 %) gave the cyclization products (8 % of 2b and 15 % of 9b), and traces of 8b. Irradiation to the conversion of 80 % gave 8b (10 %), along with numerous unidentified products. Attempts to isolate these products failed due to high adsorptivity on silica and alumina. To charac-terize the decarboxylation product 8b which was formed in low yield, it was prepared in the independ-ent synthetic method. The succinimide ester27 was treated with methylamine to afford 8b in good yield. Irradiation of 8b under the same conditions as 1b gave numerous products. Furthermore, the photodecomposi-tion of 8b proceeded ten times slower than the decar-boxylation of 1b. Attempts to isolate some of the sec-ondary products from 8b failed.
Irradiation of the isolated 8a and 8b, similar to the photolysis of 7a and 7b, gave many products. However, photodecomposition was much slower with the adaman-tyl derivatives (conversion 5−10 % after 15 minutes), than with the phenyl derivatives (conversion ≈ 30 % after 10 minutes). The secondary photochemical reac-tion of adamantyl derivatives 8a and 8b are anticipated, probably involving intramolecular H-abstractions from the adamantyl moiety, as previously reported.14 Howev-er, it is not yet clear which photochemical transfor-mations are involved in the photodecomposition of the phenyl derivatives 7a and 7b.
The structures of the cyclization photoproducts 9b and 2b were determined by use of 1D and 2D NMR
techniques (COSY, NOESY, HSQC and HMBC). In the 1H NMR spectrum of the glycine product 9b, a charac-teristic singlet corresponding to the methoxy group was observed at δ 3.88 ppm, whereas in the 13C NMR, the corresponding quartet was observed at 52.80 ppm. Fur-ther, in the aliphatic part of the 13C NMR spectrum, in addition to 7 signals of the adamantane C-atoms, a dou-blet at 44.8 ppm can be seen corresponding to the gly-cine CH2 after the loss of the carboxylate. In the 1H NMR the glycine CH2 appears as a singlet at 3.73 ppm. In the aromatic part of the spectrum four different C-H signals were observed, indicating a loss of the symmetry of the phthalimide moiety. Interactions seen in 2D NMR were fully in agreement with the assigned structure. The methoxy group was probably introduced in the molecule during the chromatographic separation on a thin layer of silica using CH2Cl2/CH3OH/TFA as eluent.
The assignation of the structure to the cyclization product 2b was straightforward from its 1H and 13C NMR spectra. In the 13C NMR spectra three characteris-tic singlets in low magnetic field can be seen corre-sponding to three carbonyl groups; they appear at δ 187.7, 179.1 and 171.7 ppm. In addition, a characteristic singlet at 3.74 ppm in 1H, and a triplet at 43.77 ppm in the 13C NMR correspond to the glycine CH2. All inter-actions seen in the 2D NMR fully corroborate the as-signed structures.
To further investigate the photochemical reactivity of phthalimides 1a, 1b, 3a and 3b irradiations were carried out in different solvents: acetone, CH3CN, ace-tone-H2O (3:1) and CH3CN-H2O (3:1). In all aqueous solvents the irradiation experiments were conducted in the presence of 0.5 equivalents of base (K2CO3) to as-sure deprotonation of the acid moiety. After irradiations, a composition of the photolysates was analyzed by
(2)h
acetone-H2ON
O
O
3a R= -CH2-C6H53b R= H
O
NH
COOK
RN
O
O
7a R= -CH2-C6H57b R= H
O
NH
Runidentifiedproducts+
1a R= CH2-C6H51b R= H
N
O
O
OHN COOK
R
(3)h
acetone-H2O N
O
O
OHN R
+
N
HN RO
O
OR'
NH
HN
R
O
O
O
+
8a R= -CH2-C6H58b R= H
2a R= CH2-C6H52b R= H
9a R= CH2-C6H5, R' = CH39b R= H, R' = CH3
M. Sohora et al., Photodecarboxylation of Dipeptides 435
Croat. Chem. Acta 87 (2014) 431.
HPLC, NMR, and in some cases a chromatographic separation was carried out. Due to the solubility prob-lems, irradiations in the presence of the base could be conducted only in the presence of H2O, since K-salts were not soluble in neat CH3CN or acetone. Neverthe-less, NMR and HPLC analysis after irradiations of the colloidal solutions of the K-salts in CH3CN or acetone indicated formation of the same products as in the aque-ous solvents, but with significantly lower efficiency (100 times). The highest photoreactivity for all deriva-tives was observed in acetone-H2O (3:1) in the presence of K2CO3 which is in agreement with the sensitization mechanism of photoexcitation and anticipated electron transfer from carboxylate to phthalimide.26,27 In addi-tion, for 1a and 1b a difference in the product distribu-tion was observed when the irradiation was performed in acetone-H2O (3:1) and CH3CN-H2O (3:1). In ace-tone-H2O the cyclization products were predominantly formed, whereas in CH3CN-H2O cyclization and simple decarboxylation products were formed in comparable yields. For 3a and 3b we could not observe a difference in the product distribution, but the process was more efficient in acetone. The findings clearly indicate that acetone acts as a triplet sensitizer and induce photo-chemical reactions of 1a, 1b, 3a, and 3b. Moreover, a different ratio between the cyclization and the simple decarboxylation photoproducts obtained from 1a and 1b in CH3CN-H2O and acetone-H2O (Table 1) suggests involvement of singlet and triplet excited states, with the cyclization taking place via the triplet.
It is known that phthalimides are unstable under basic conditions and undergo ring opening. Therefore, the stability of phthalimides 1b and 3b (c = 2.0 ×10−3 M) in CH3CN-H2O was tested in the presence of differ-ent concentrations of K2CO3 (c = 1.0 ×10−3 and 1.0 ×10−2 M). The progress of the reaction was monitored by UV-vis spectroscopy (see the supporting info.) Whereas decomposition of 1b at c(K2CO3) = 1.0 ×10−3 M after 20 h did not take place, a slow decomposition at 10−2 M was observed (pseudounimolecular k ≈ 8×10−5 s−1). On the contrary, a slow decomposition of 3b was observed already at c(K2CO3) = 1.0 ×10−3 M (pseudounimolecular k ≈ 1×10−5 s−1). These results indicate that under the irradiation conditions adamantyl derivatives 1a and 1b probably did not undergo ring opening, whereas for the phenyl derivatives 3a and 3b competitive base promoted ring opening could take place.
To investigate which excited state is involved in the formation of the photoproducts, irradiation of 1b (c = 7 ×10−4 M) was performed in CH3CN-H2O in the presence of K2CO3 and potassium sorbate, an ubiquitous quencher of the triplet excited state (ET = 246 kJ mol−1).31 The quenching of the photoreaction of 1b was accomplished with potassium sorbate in the concentra-
tions 0.1−0.4 M, indicating involvement of the triplet excited state in the photoproducts formation.
Irradiation of 3-(N-phthalimido)-1-adamantane carboxylic acid in the presence of a base and electron deficient alkenes gave rise to photodecarboxylation and radical addition of the adamantane to the alkene double bond.26 We attempted to perform the analogous addition to acrylonitrile with the photogenerated radicals from 1a, 1b, 3a, and 3b. Irradiations were performed in the presence of 100 equivalents of acrylonitrile, but no addition products were detected. Since the adamantyl derivatives 1a and 1b after the initial decarboxylation give the cyclization products, the finding is logical. We have already reported that the separation of the electron donor and the acceptor is essential to enable the addi-tion.26 However it is yet not clear why radical addition cannot take place from the phenyl derivatives 3a and 3b. Probably, the anticipated radicals from 3a and 3b (vide infra), are stabilized by the amino substituent, and therefore, less reactive. Hence, only photodecarboxyla-tion products 7a and 7b can be detected, and the addi-tion does not take place.
On attempts to perform photoaddition to acryloni-trile we observed quenching of the photoreaction of 1a and 1b with acrylonitrile. With the phenyl derivatives 3a and 3b, no quenching was observed. This observa-tion can be rationalized by the quenching of the triplet excited state of N-alkylphthalimides by acrylonitrile. The triplet energy of acrylonitrile is 297 kJ mol−1,32 which is similar to the triplet energy of N-methylphthalimide, 293 kJ mol−1.33 Furthermore, this finding suggests that N-phenylphthalimides have lower triplet energy than the analogous N-alkylphthalimides. The energy transfer to acrylonitrile induces polymeriza-tion consuming the alkene, and therefore, the addition to the double bond does not take place. It is interesting to note that quenching of the triplet state of 3-(N-phthalimido)-1-adamantane carboxylic acid by acryloni-trile was not observed.26
Quantum efficiency for the photodecomposition (Φd) of 1a, 1b, 3a, and 3b was determined in CH3CN-H2O (3:1) and acetone-H2O (3:1) in the presence of K2CO3 as a base. For the determination of Φd in CH3CN-H2O (3:1), a primary actinometer was used, photolysis of valerophenone in aqueous solvent giving acetophenone.34 For the photoreaction in acetone-H2O (3:1) we used a secondary actinometer, photocyclization of 6-[(N-phthalimido)methyl]cyclohexane carboxylic acid.35 The photosensitized reaction (irradiation in ace-tone-H2O) gave mostly the cyclization products in case of 1, or photodecarboxylation products in case of 3. Direct excitation (irradiation in CH3CN-H2O) gave photodecarboxylation products in case of 1 and 3. From the values compiled in Table 2 it is evident that photo-transformation is more efficient in acetone-H2O than in
436 M. Sohora et al., Photodecarboxylation of Dipeptides
Croat. Chem. Acta 87 (2014) 431.
CH3CN-H2O. Lower efficiency of the reaction in CH3CN-H2O is probably due to a low efficiency of intersystem crossing (ISC). Furthermore, it is interesting to note a higher efficiency for the aceton-sensitized reaction for the phenyl, than for the adamantyl deriva-tives. This observation could be rationalized with signif-icantly different photophysical properties of N-phenylphthalimide derivatives36 compared to N-alkyl derivatives.35 The difference in the reactivity of 1a vs 1b, may be explained by an energy transfer from the triplet excited state of phthalimide to phenylalanine, giving rise to non-productive deactivation from the excited state. Such an energy transfer is not feasible with the glycine derivative 1b. Laser Flash Photolysis (LFP)
To get a better insight into the mechanism of the photo-chemical transformations of 1 and 3 and characterize the
triplet excited states we carried out LFP measurements. The measurements were conducted in N2- and O2-purged CH3CN and CH3CN-H2O solutions. For the excitation of samples, a frequency quadrupled Nd:YAG laser with the output at 266 nm was used. LFP for 3b in CH3CN gave transient absorption spectra characterized by two bands, a stronger absorption with a maximum at 330−340 nm, and a weaker broad band at 530 nm, both decaying with the rate constant k = 4.4 × 105 s−1 (Figure 1 right). The observed transient was quenched by O2 with the rate constant kq = 2.8 × 109 M−1 s−1. According to the precedent spectra36 and quenching with O2, the transient was assigned to the triplet state of N-phenylphthalimide. Similarly, L-phenylalanine deriva-tive 3a showed transient spectra with a maximum at 330−340 nm, and a weaker band at 530 nm, both as-signed to the triplet-triplet absorption of N-phenylphthalimide. In N2-purged CH3CN solution the triplet of 3a decayed slower (compared to 3b) with the rate constant k = 1.1 × 105 s−1.
The adamantyl derivative 1a gave rise to distinctly different transient absorption spectra in CH3CN then the phenyl derivatives, with only one maximum at 340 nm. The transient decayed in N2-purged solution with the rate k = 1.5 × 106 s−1, and was quenched by O2 (kq = 1.4 × 109 M−1 s−1). Based on the quenching with O2 and precedent spectra,14f it was assigned to the triplet state of phthalimide. The lifetime of the triplet of 1a is signif-icantly shorter than for 3-(N-phthalimido)-1-adamantane carboxylic acid (Table 3). This observation could be explained by intramolecular energy transfer from the triplet state of phthalimide to the phenylalanine. How-ever, due to the overlapping of the absorption of the phthalimide and phenylalanine triplet,37 we could not resolve the signals. The quenching of the triplet by phe-nylalanine is also in agreement with the observed lower quantum efficiency of decomposition for 1a compared to 1b (vide supra, Table 2).
Table 2. Quantum yields for the decomposition (Φd) of 1a, 1b, 3a and 3b in CH3CN-H2O (3:1) and acetone-H2O (3:1)
Compound acetone-H2O(a) CH3CN-H2O(b)
1a 0.06±0.002 (c) 0.011±0.001 (d)
1b 0.3±0.02 (c) 0.0135±0.0005 (d)
3a 0.28±0.02 (d) 0.015±0.003 (d)
3b 0.38±0.06 (d) 0.005±0.003 (d)
(a) Photocyclization of 6-[(N-phthalimido)methyl]cyclohexane carboxylic acid was used as a secondary actinometer (ΦR = 0.3).35 Photoconversion was determined from 1H NMR spectra of the crude photolysis mixture. (b) Photolysis of valerophenone in aqueous CH3CN was used as an actinometer (formation of acetophenone, = 0.65±0.03).34 Photoconversion was determined by HPLC. (c) Quantum yield for the formation of cyclization products. (d) Quantum yield for the formation of decarboxylation prod-ucts.
Figure 1. Transient absorption spectra of 1a (left) and 3a (right) in N2-purged CH3CN.
M. Sohora et al., Photodecarboxylation of Dipeptides 437
Croat. Chem. Acta 87 (2014) 431.
The addition of K2CO3 to the aqueous solution leads to a change of the observed transient absorption spectrum of 1a (Figure 2) and increase of the lifetime (τ > ms, due to low intensity of the signal and long lifetime we could not determine its decay precisely). The new species is assigned to the radical-anion formed by PET, in accordance with the precedent literature.14f LFP ex-periments for 3a and 3b in the presence of K2CO3 (c = 0.01 M) gave no transient absorption signal, suggesting that triplet and subsequent transient species have very short lifetimes under these conditions. Short lifetime of the N-phenylphthalimide triplets can be rationalized by a fast electron transfer from carboxylate, which is also demonstrated by efficient photodecarboxylation quan-tum yield (vide supra). However, it should be noted that N-phenylphthalimides are very sensitive to basic condi-tions, undergoing ring opening. Thus, absence of signal in the transient absorption is due to competative fast decomposition of the sample.
Photochemical Reaction Mechanism
Based on the preparative photolyses and LFP measure-ments the photochemical reaction mechanisms for the transformations of 1 and 3 can be proposed. On direct excitation, N-alkyl and N-phenylphthalimides undergo ISC with a low quantum efficiency of 10 % and popu-late triplet excited states. Photodecarboxylation and formation of photoproducts from 1 and 3 probably takes place from the triplet excited state, as suggested by the quenching with potassium sorbate and acrylonitile. One of the deactivation channels from the triplet excited state is PET, followed by a rapid irreversible decarboxy-lation. LFP measurement in the presence of K2CO3 strongly indicated presence of the phthalimide radical-anion. The biradical anion 10 can be protonated to bi-radical 11, or undergo ring closure to anion 12 (Scheme 2). Nevertheless, the ring closure to 12 or 9 is enantiose-lective (in case of 1a) due to the memory of chirality.27 Biradical 11 probably undergoes unimolecular or bimo-lecular H-transfer and give simple decarboxylation products 8a or 8b. Although these products are formed in higher yields in CH3CN-H2O than in acetone-H2O, they are probably formed from the triplet excited state via some other low efficient mechanism known in the photochemistry of carboxylic acids.2−8 In addition to PET, the other channel for the deactivation from the triplet excited state is probably energy transfer from the phthalimide to the phenylalanine, not leading to any stable product.
Photophysical properties of N-phenylphthalimides are different from the adamantyl analogues. ISC and population of the triplet excited state takes place with the similar efficiency. However, the deactivation from the triplet by electron transfer probably takes place more efficiently, as suggested by higher quantum efficiency of decarboxylation. It gives biradical-anion 13. Contrary to the adamantane derivatives, 13 cannot undergo in-tramolecular cyclization. Most probably it decays by
Table 3. Properties of triplet excited state of 1a, 3a and 3b obtained by LFP
Compound τ / μs (a) ΦISC (b) kq / M−1s−1 (c)
1a 0.66±0.01 0.11±0.02 1.4×109
3a 8.5±0.3 0.07±0.01 2.1×109
3b 2.27±0.02 0.10±0.01 2.8×109
3-(N-phthalimido)adamantane-1-carboxylic acid (d) 13 0.22 2.0×109
N-PhePhth (e) 11.5 0.03 - (a) Lifetime of the triplet excited state in N2-purged solution. (b) ФISC in CH3CN, determined by comparing intensity of the signal with the optically matched solution of N-methylphthalimide in CH3CN (ФISC = 0.8)35
(c) Rate constant for the quenching of the triplet with O2 in CH3CN. (d) Taken from the Ref. 26. (e) N-phenylphthalimide, the values taken from the Ref. 36.
Figure 2. Transient absorption spectra of 3a in N2-purgedCH3CN-H2O (1:1) at pH 7 and in the presence of K2CO3, c =0.01 M.
438 M. Sohora et al., Photodecarboxylation of Dipeptides
Croat. Chem. Acta 87 (2014) 431.
protonation giving biradical 14 (Scheme 3). Since in-tramolecular H-transfer in 14 is not possible, only bimo-lecular reactions give rise to the decarboxylation prod-uct. Furthermore, biradical probably undergo many competitive intermolecular H-abstractions giving rise to a number of unidentified products. As discussed above, nonreactivity of 13 or 14 in the radical additions to
double bonds could possibly be attributed to lower reac-tivity of the radical due to the presence of N-substituent. The other option for the decay of biradical-anion 13 would be back electron transfer giving carbanion. How-ever the latter pathway is less likely due to poor electron accepting properties and low reduction potential of the acetamido group.
1a R= -CH2-C6H51b R= H
N
O
O
OHN COOK
R
N
HN RO
O
OH
NH
HN
R
O
O
O
9a R= -CH2-C6H59b R= H
2a R= -CH2-C6H52b R= H
*T1
N
O-
O
OHN
R
N
OH
O
OHN
R
H+
10 11
N
HN RO
O
O-H+
12
N
O
O
OHN R
8a R= -CH2-C6H58b R= H
Scheme 2.
N
O
O
3a R= -CH2-C6H53b R= H
O
NH
COOK
R
N
O
O
7a R= -CH2-C6H57b R= H
O
NH
R
*T1
N
O-
O
O
NH
R
N
OH
O
O
NH
Rbimolecularreactions
H+
13
14
Scheme 3.
M. Sohora et al., Photodecarboxylation of Dipeptides 439
Croat. Chem. Acta 87 (2014) 431.
CONCLUSION
We have prepared new dipeptide derivatives activated by the phthalimide chromphore. On irradiation of these dipeptides photoinduced decarboxylation takes place. The efficiency of the process depends on the spacer between the electron donor (carboxylate) and the elec-tron acceptor (phthalimide in the triplet excited state). N-phenylphthalimides undergo 2−5 times more effi-cient photodecarboxylation than N-adamantyl-phthalimides. The photodecarboxylation and cycliza-tion of N-adamantyl derivatives 1a and 1b and photo-decarboxylation of N-phenylphthalimide 3a and 3b probably proceeds from triplet excited state. The ami-no acid residue (Phe or Gly) at the C-terminus of the dipeptide does not influence the photodecarboxylation efficiency. Product selectivity in the photoreactions is mostly determined by the molecular conformation. Due to the rigid geometry N-phenylphthalimide de-rivatives with the separated donor and acceptor moiety gave only simple decarboxylation products. On the contrary, N-adamantyl derivatives wherein the donor and acceptor can get in close contact gave cyclization products. Formation of cyclic products with adaman-tylphenylalanine takes place with the memory of chi-rality and ee > 99 %. Therefore, it is anticipated that this cyclization will have an important impact to the future photochemical synthetic methods for the for-mation of cyclic peptidomimetics.
EXPERIMENTAL
General
1H and 13C NMR spectra were recorded on a on a Bruker Avance Spectrometer at 300 or 600 MHz. All NMR spectra were measured in CDCl3, DMSO-d6 or
CD3OD using tetramethylsilane as a reference. High-resolution mass spectra (HRMS) were measured on an Applied Biosystems 4800 Plus MALDI TOF/TOF in-strument. IR spectra were recorded on FT-IR ABB Bonem MB 102 spectrophotometer. Melting points were obtained using an Original Kofler Mikroheitztisch apparatus (Reichert, Wien) and are uncorrected. Silica gel or alumina was used for the chromatographic purifi-cations. Solvents were purified by distillation. The chemicals for the synthesis were obtained from the usual commercial sources. Photochemical reactions were carried in a Rayonet or a Luzchem reactor in quartz cuvettes. CH3CN used in the irradiation experi-ments was of HPLC purity, whereas acetone was of p.a. purity. They were used as received, and were not further purified. Synthesis and characterization of 1a, 2a, and 9a has been reported.27
2-{[3-(N-phthalimido)-1-adamantyl]carboxamido}ace-tic acid (1b) A round bottom flask was charged with of glycine (5 mmol) and TEA (triethylamine, 0.697 mL, 5 mmol), and dissolved in a mixture of THF-H2O (1:1, 20 mL). To the reaction mixture, a solution of N-succimidyl[3-(N-phthalimido)-1-adamantyl]formiate27 (1.990 g, 4.5 mmol) in THF (15 mL) was added dropvise, and the reaction was stirred at rt for 3 days. When the reaction was finished, 1M HCl (20 mL) was added, and the product was extracted with ethyl acetate (3×20 mL). The extracts were dried over anhydrous MgSO4, the solution was filtered and the solvent removed on a rota-ry evaporator to afford crude products. The product was purified by column chromatography on silica gel with 5−10 % MeOH/CH2Cl2 and 10 % MeOH/EtOAc. The pure product was obtained in the yield of 60−80 %.
Colourless oil; IR (KBr) max/cm−1: 3412 (m), 2917 (m), 2852 (w), 2360 (w), 1707 (s), 1654 (m), 1540 (m), 1458 (w), 1369 (m), 1316 (m), 1078 (w), 875 (w), 720 (m), 668 (w); 1H NMR (300 MHz, CD3OD) δ/ppm: 7.78 (s, 4H), 3.87 (d, J = 4.0 Hz, 2H), 2.62−2.56 (m, 4H), 2.50 (d, J = 12.3 Hz, 2H), 2.31 (s, 2H), 2.05−1.80 (m, 5H), 1.74 (d, J = 12.4 Hz, 1H); 13C NMR (150 MHz, CD3OD) δ/ppm: 170.9 (s, 1C), 135.2 (d, 2C), 133.1 (s, 1C), 123.5 (d, 2C), 61.4 (s, 1C), 44.1 (s, 1C), 42.7 (t, 1C), 42.3 (t, 1C), 40.4 (t, 2C), 38.9 (t, 2C), 36.3 (t, 1C), 31.1 (d, 2C); HRMS calcd. for C21H22N2O5 421.1160, obsd. 421.1161. p-(N-phthalimido)benzoic Acid (4)38 A round bottom flask was charged with phthalic anhy-dride (6.0 g, 0.041 mol) and melted. To the melt p-aminobenzoic acid (4.40 g, 0.032 mol), suspended in DMF (10 mL) was added in several portions. The reac-tion mixture was heated and stirred for 20 minutes without stopper with occasional addition of DMF (~2×2 mL). When the reaction was finished and when all DMF evaporated, the mixture was cooled and suspended in EtOAc (100 mL). The suspension was washed with 10 % HOAc (70 mL), and then with 10 % NaHCO3 (70 mL). During this washing, the product was suspended between the organic and the aqueous layer in a form of colourless solid. The suspended product in EtOAc was filtered through a sinter (D-4) and dried in vacuum oven at 60 °C and 10 mbar. The pure product 7 was obtained (7.1 g, 83 %) in a form of colourless crystals. General Procedure for the Synthesis of Benzyl Esters 5a and 5b
A round bottom flask was charged with 4 (534 mg, 2 mmol), dry DMF (10 mL), TEA (0.557 mL, 4 mmol), and HBTU (796 mg, 2.1 mmol). After stirring at rt for 10 min., 2.1 mmol of benzyl ester of glycine or L-
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Croat. Chem. Acta 87 (2014) 431.
phenylalanine hydrochloride were added, and the reac-tion mixture was stirred for 1 day in the case of 5a and 4 days in the case of glycine derivative 5b. To the reac-tion mixture brine (50 mL) was added and extraction with diethyl ether was carried out (1×50 mL). The prod-uct in a form of colourless solid was suspended between the organic and aqueous layers. After removal of the aqueous layer, the suspension of solid in ether was washed with 1M HCl (50 mL), H2O (50 mL), saturated aqueous NaHCO3 (50 mL), and again with H2O (50 mL). The suspension was filtered through a sinter (D-4) and the solid product was dried in a vacuum oven at 60 °C and 10 mbar to afford the pure products. N-{4-[N-(benzyloxycarbonyl-2-phenylethan-1-yl)carba-moyl]phenyl}phthalimide (5a) 707 mg (75 %); colourless solid; mp, 204−206 °C; IR (KBr) max/cm−1: 3326 (m), 3062 (w), 3029 (w), 1707 (s), 1637 (m), 1506 (m), 1389 (m), 1084 (w), 849 (w), 718 (m), 528 (w); 1H NMR (300 MHz, d6-DMSO) δ/ppm: 8.96 (d, J = 7.7 Hz, 1H, NH), 8.08−7.86 (m, 6H), 7.54 (d, J = 8.6 Hz, 2H), 7.40−7.15 (m, 10H), 5.30−5.00 (m, 2H), 4.76−4.68 (m, 1H), 3.27−3.01 (m, 2H); 13C NMR (75 MHz, d6-DMSO) δ/ppm: 171.5 (s, 1C), 166.7 (s, 1C), 166.0 (s, 2C), 137.6 (s, 1C), 135.9 (s, 1C), 134.8 (d, 2C), 134.6 (s, 1C), 133.1 (s, 1C), 131.5 (s, 2C), 129.1 (d, 2C), 128.4 (d, 2C), 128.3 (d, 2C), 128.0 (d, 1C), 127.9 (d, 2C), 127.7 (d, 2C), 126.9 (d, 2C), 126.5 (d, 1C), 123.5 (d, 2C), 66.0 (t, 1C), 54.5 (d, 1C), 36.2 (t, 1C); HRMS calcd. for C31H24N2O5
527.1577, obsd. 527.1569. N-{4-[N-((benzyloxycarboyl)methyl)carbamoyl]phe-nyl}phthalimide (5b) 503 mg (65 %); colourless solid; mp, 245−247 °C; IR (KBr) max/cm−1: 3337 (w), 1759 (m), 1701 (s), 1647 (m), 1506 (m), 1391 (m), 1312 (w), 1207 (m), 1119 (w), 887 (w), 719 (m), 530 (w); 1H NMR (300 MHz, d6-DMSO) δ/ppm: 9.11 (t, J = 5.7 Hz, 1H, NH), 8.14−7.89 (m, 6H), 7.60 (d, J = 8.5 Hz, 2H), 7.40−7.25 (m, 5H), 5.18 (s, 2H), 4.12 (d, J = 5.7 Hz, 2H); 13C NMR (75 MHz, d6-DMSO) δ/ppm: 169.7 (s, 1C), 166.7 (s, 1C), 166.1 (s, 2C), 134.8 (d, 2C), 134.6 (s, 1/2C), 133.0 (s, 1/2C), 131.5 (s, 2C), 128.4 (d, 2C), 128.1 (d, 1C), 127.9 (d, 2C), 127.8 (d, 2C), 127.0 (d, 2C), 123.5 (d, 2C), 65.9 (t, 1C), 41.4 (t, 1C); HRMS calcd. for C24H18N2O5
437.1108, obsd. 437.1099. N-{4-[N-((ethyloxycarbonyl)methyl)carbamoyl]phe-nyl}phthalimide (5bEt) The compound was prepared according to the general pro-cedure for the preparation of benzyl esters 5a and 5b, but the ethyl ester of glycine was used instead of the benzyl. The reaction furnished pure product (332 mg, 36 %).
Colourless solid; mp, 202−204 °C; IR (KBr)
max/cm−1: 3421 (s), 3315 (s), 2916 (m), 1709 (s), 1639 (m), 1508 (m), 1389 (m), 1097 (w), 856 (w), 719 (m);
1H NMR (300 MHz, CD3OD) δ/ppm: 8.05−7.96 (m, 4H), 7.94−7.88 (m, 2H), 7.65 (d, J = 8.8 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.16 (s, 2H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ/ppm: 169.8 (s, 1C), 166.7 (s, 1/2C), 166.4 (s, 1/2C), 134.9 (s, 1C), 134.5 (d, 2C), 133.0 (s, 1C), 131.6 (s, 2C), 127.8 (d, 2C), 126.2 (d, 2C), 123.8 (d, 2C), 61.6 (t, 1C), 41.9 (t, 1C), 14.1 (q, 1C); HRMS calcd. for C19H16N2O5 375.0951, obsd. 375.0948. Benzyl-2-{[3-(N-phthalimido)-1-adamantyl]carboxa-mido}acetate (1bBz) A round bottom flask was charged with 3-(N-phthalimido)-1-adamantane carboxylic acid (400 mg, 1.23 mmol), HBTU (490 mg, 1.29 mmol), TEA (351 L, 2.52 mmol) and CH2Cl2 (3 mL), and stirred at rt for 10 min. Then, benzyl ester of glycine hydrochloride (231 mg, 1.29 mmol) was added and stirring was con-tinued for 3 days. When the reaction was completed, brine (50 mL) was added, resulting in a white suspen-sion which was extracted with diethyl ether (1×50 mL). The organic layer was washed with 1M HCl (50 mL), H2O (50 mL), saturated NaHCO3 (50 mL), and again with H2O (50 mL), and dried over anhydrous MgSO4. The solution was filtered and the solvent was removed on a rotary evaporator to afford the crude product that was purified by column chromatography on silica gel with 10 % EtOAc/CH2Cl2.
552 mg (95 %); colorless solid; mp, 136−138 °C; IR (KBr) max/cm−1: 3437 (m), 2941 (m), 2854 (m), 1709 (s), 1639 (m), 1522 (m), 1369 (m), 1318 (m), 1221 (m), 1080 (w), 974 (m), 839 (s), 756 (m), 723 (m), 642 (w); 1H NMR (600 MHz, CDCl3) δ/ppm: 7.73−7.70 (m, 2H), 7.66−7.62 (m, 2H), 7.36−7.24 (m, 5H), 6.35 (t, J = 5.0 Hz, 1H), 5.15 (s, 2H), 4.05 (d, J = 5.2 Hz, 2H), 2.60 (s, 2H), 2.54 (d, J = 12.0 Hz, 2H), 2.44 (d, J = 12.0 Hz, 2H), 2.28 (s, 2H), 1.92 (d, J = 12.2 Hz, 2H), 1.85 (d, J = 12.2 Hz, 2H), 1.75 (d, J = 12.6 Hz, 1H), 1.64 (d, J = 12.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ/ppm: 176.4 (s, 1C), 169.8 (s, 1/2C), 169.3 (s, 1/2C), 135.1 (s, 1C), 133.6 (d, 2C), 131.7 (s, 2C), 128.4 (d, 2C), 128.3 (d, 1C), 128.1 (d, 2C), 122.4 (d, 2C), 66.9 (t, 1C), 60.1 (s, 1C), 42.6 (s, 1C), 41.2 (t, 1C), 41.1 (t, 1C), 39.1 (t, 2C), 37.8 (t, 2C), 34.9 (t, 1C), 29.3 (d, 2C); HRMS calcd. for C28H28N2O5 495.1890, obsd. 495.1885. General Procedure for the Hydrogenolysis on Pd/C
In a vessel for hydrogenation was placed 5a (500 mg, 1 mmol) or 5b (500 mg, 1.2 mmol) and dissolved in a mixture of dry DMF (75 mL) and aps. EtOH (40 mL), and 10 % Pd/C (300 mg) was added. The hydrogenation was carried out, for 1 day at 55 psi. The crude reaction mixture was filtered, and the solvent was evaporated on a rotary evaporator. The residue was dissolved in EtOAc (20 mL) and extracted with 10 % NaHCO3
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Croat. Chem. Acta 87 (2014) 431.
(3×15 mL). Combined aqueous layers were acidified to pH 3 with 1M HCl, and then extracted with EtOAC (3×15 mL). The organic layers were dried over anhy-drous MgSO4, filtered and the solvent was removed. The pure product was obtained after crystallization from EtOAc/MeOH in a form of colourless crystals in ≈ 30 % yield. 2-[4-(1-Oxoisoindolin-2-yl)benzamido]-3- phenylpro-panoic Acid (6a)40
Colourless solid; 1H NMR (300 MHz, d6-DMSO) δ/ppm: 12.74 (br s, 1H), 8.66 (d, J = 7.5 Hz, 1H), 8.01 (d, J = 8.7 Hz, 2H), 7.89 (d, J = 8.7 Hz, 2H), 7.81 (d, J = 7.4 Hz, 1H), 7.72−7.67 (m, 2H), 7.57 (t, J = 7.0 Hz, 1H), 7.32−7.09 (m, 5H), 5.07 (s, 2H), 4.64−4.60 (m, 1H), 3.23−3.02 (m, 2H); 13C NMR (75 MHz, d6-DMSO) δ/ppm: 173.2 (s, 1C), 167.0 (s, 1C), 165.6 (s, 1C), 142.1 (s, 1C), 141.1 (s, 1C), 138.2 (s, 1C), 132.6 (d, 1C), 132.2 (s, 1C), 129.1 (d, 2C), 128.3 (d, 3C), 128.2 (d, 2C), 126.3 (d, 1C), 123.4 (d, 2C), 118.1 (d, 2C), 54.2 (d, 2C), 50.4 (t, 1C), 36.3 (t, 1C). 2-[4-(1-Oxoisoindolin-2-yl)benzamido] acetic Acid (6b)39 Colourless solid; 1H NMR (300 MHz, d6-DMSO) δ/ppm: 12.59 (s, 1H), 8.86 (t, J = 5.8 Hz, 1H), 8.07−7.95 (m, 4H), 7.85−7.52 (m, 4H), 3.94 (d, J = 5.8 Hz, 2H); 13C NMR (75 MHz, d6-DMSO) δ/ppm: 171.3 (s, 1C), 166.9 (s, 1C), 165.7 (s, 1C), 142.0 (s, 1C), 141.0 (s, 1C), 132.5 (d, 1C), 132.1 (s, 1C), 128.9 (s, 1C), 128.2 (d, 3/2C), 123.3 (d, 2/3C), 118.2 (d, 2C), 50.4 (t, 1C), 41.2 (t, 1C). General Procedure for the Synthesis of Acids 3a and 3b
A two neck round bottom flask was charged with benzyl ester 5a (500 mg, 1 mmol) or 5b (500 mg, 1.2 mmol), 10 % Pd/C (100 mg) and abs MeOH (30 mL). The flask was closed with a septum and purged with nitrogen in order to remove air. The the suspension 10 equivalents of Et3SiH were added during one hour. The reaction was monitored on TLC. After the reaction was finished, the reaction mixture was filtered, and the solvent was re-moved on a rotary evaporator. To the residue cold MeOH (25 mL) was added to precipitate the product. The product was filtered off through a Hirsch funnel and dried in a vacuum oven at 60 °C and 10 mbar. N-{4-[N-(1-carboxy-2-phenylethan-1-yl)carbamo-yl]phenyl}phthalimide (3a)40 267 mg (65 %); colourless solid; 1H-NMR (600 MHz, d6-DMSO) δ/ppm: 8.36 (d, J = 7.2 Hz, 1H, NH), 7.99−7.96 (m, 2H), 7.93−7.89 (m, 4H), 7.54 (d, J = 8.5 Hz, 2H), 7.32−7.29 (d, J = 7.3 Hz, 2H), 7.25 (t, J = 7.4 Hz, 2H), 7.16 (t, J = 7.3 Hz, 1H), 4.60−4.55 (m, 1H), 3.23 (dd, J = 4.2, 13.3 Hz, 1H), 3.07 (dd, J = 10.3, 13.3
Hz, 1H); 13C NMR (75 MHz, d6-DMSO) δ/ppm: 166.8 (s, 1C), 165.3 (s, 2C), 138.8 (s, 1C), 134.8 (d, 2C), 134.3 (s, 1C), 133.9 (s, 1C), 131.5 (s, 2C), 129.1 (d, 2C), 128.0 (d, 2C), 127.7 (d, 2C), 126.9 (d, 2C), 126.1 (d, 1C), 123.5 (d, 2C), 55.1 (d, 1C), 36.8 (t, 1C). N-{4-[N-(carboxymethyl)carbamoyl]phenyl}phthali-mide (3b)41 301 mg (77 %); colourless solid; 1H NMR (600 MHZ, CD3OD) δ/ppm: 8.00 (d, 2H, J = 8.5 Hz), 7.99−7.96 (m, 2H), 7.91−7.87 (m, 2H), 7.62 (d, 2H, J = 8.5 Hz), 4,12 (s, 2H); 1H NMR (600 MHz, d6-DMSO) δ/ppm: 12.59 (br. s, 1H), 8.92 (t, J = 5.7 Hz, 1H), 8.06−7.90 (m, 6H), 7.59 (d, J = 8.4 Hz, 2H), 3.96 (d, J = 5.8 Hz, 2H); 13C NMR (150 MHz, d6-DMSO) δ/ppm: 171.1 (s, 1C), 166.7 (s, 2C), 165.5 (s, 1C), 134.8 (d, 2C), 134.5 (s, 1C), 133.2 (s, 1C), 131.5 (s, 2C), 127.8 (d, 2C), 126.9 (d, 2C), 123.5 (d, 2C), 41.3 (t, 1C). General Procedure for the Synthesis of Decarboxyla-tion Products 7a and 7b
A round bottom flask was charged with acid 4 (200 mg, 0.748 mmol), HBTU (298 mg, 0.786 mmol), TEA (for 7a 0.104 mL, 0.748 mmol, 1 equivalent, and for 7b 0.208 mL, 1.496 mmol, 2 equivalents) and DMF (10 mL), and stirred for 10 min. After activation of the acid, HCl×NH2CH3 (50 mg, 0.748 mmol) or 2-phenylethylamine (94 L, 0.748 mmol) was added. The reaction mixture was stirred at rt for 4 days. After the reaction was completed, DMF was removed on a rotary evaporator. To the crude reaction mixture brine (30 mL) and EtOAc (50 mL) were added. The product was sus-pended in a form of white solid between the aqueous and organic layer. After filtration of this mixture through a sinter, the precipitate was three times washed with ethyl acetate (3×15 mL) and dried over P2O5. N-{4-[N-(2-phenylethan-1-yl)carbamoyl]phenyl}phtha-limide (7a)40
275 mg (100 %); colourless solid; mp, 322−324°C, sublimation at 268−270 °C; 1H NMR (600 MHz, d6-DMSO) δ/ppm: 8.71 (s, 1H, NH), 8.01−7.91 (m, 6H), 7.55 (d, J = 8.2 Hz, 2H), 7.33−7.25 (m, 4H), 7.21 (t, J = 6.9 Hz, 1H), 3.53−3.51 (m, 2H), 2.88 (t, J = 7.4 Hz, 2H); 13C NMR (150 MHz, d6-DMSO) δ/ppm: 166.8 (s, 1C), 165.5 (s, 2C), 139.5 (s, 1C), 134.8 (d, 2C), 134.2 (s, 1C), 134.0 (s, 1C), 131.5 (s, 2C), 128.6 (d, 2C), 128.3 (d, 2C), 127.7 (d, 2C), 126.9 (d, 2C), 126.1 (d, 1C), 123.5 (d, 2C), 40.9 (t, 1C), 35.0 (t, 1C); HRMS calcd. for C23H18N2O3 393.1209, obsd. 393.1206. N-{4-[(N-methyl)carbamoyl]phenyl}phthalimide (7b)40 182 mg (87 %); colourless solid; mp, 303−305 °C, sub-limation at 238−240°C; 1H NMR (300 MHz, d6-DMSO) δ/ppm: 8.56 (d, J = 4.5 Hz, 1H), 8.04−7.87 (m, 6H), 7.55 (d, J = 8.6 Hz, 2H), 2.81 (d, J = 6.4 Hz, 3H); 1H
442 M. Sohora et al., Photodecarboxylation of Dipeptides
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NMR (300 MHz, MeOD) δ/ppm: 8.01−7.95 (m, 4H), 7.93−7.90 (m, 2H), 7.64−7.60 (m, 2H), 2.94 (s, 3H); 13C NMR (150 MHz, MeOD) δ/ppm: 170.1 (s, 1C), 168.4 (s, 2C), 137.8 (s, 1C), 135.9 (d, 2C), 133.1 (s, 2C), 128.8 (d, 2C), 127.7 (d, 2C), 124.7 (d, 2C), 27.0 (q, 1C), one singlet (1C) is not detected; HRMS calcd. for C16H12N2O3 303.0740, obsd. 303.0744. N-[3-(N-methyl)carbamoyl-1-adamantyl]phthalimide (8b) A round bottom flask was charged with a solution of methylamine hydrochloride (62 mg, 0.922 mmol), TEA (257 L, 1.844 mmol) and THF (5 mL). To the solution succinimide (428 mg, 1.014 mmol) was added during 30 minutes. The reaction was conducted at rt for 2 days. The solvent was removed on a rotary evap-orator and 0.5M HCl (10 mL) was added. The extrac-tion with ethyl acetate (3×10 mL) was carried out, and the extracts were dried over MgSO4. After filtration and removal of the solvent the crude product was ob-tained that was purified by column chromatography on silicagel with CH2Cl2 and 2−5 % MeOH/CH2Cl2 as eluent, and cristallization from hexane/CH2Cl2/MeOH mixture. The pure product was isolated in a form of colourless crystals.
73 mg (23 %); colourless crystals; mp, 205−207 °C; IR (KBr) max/cm−1: 3348 (m), 2914 (m), 2850 (m), 1707 (s), 1635 (m), 1541 (m), 1466 (w), 1364 (m), 1313 (m), 1078 (m), 974 (w), 872 (w), 719 (m), 640 (w), 534 (w); 1H NMR (600 MHz, CD3OD) δ/ppm: 7.73 (s, 4H), 2.85−2.68 (m, 3H), 2.58−2.53 (m, 4H), 2.47 (d, J = 12.2 Hz, 2H), 2.27 (br. s, 2H), 1.91 (d, J = 12.4 Hz, 2H), 1.87−1.78 (m, 3H), 1.70 (d, J = 1.8 Hz, 1H); 13C NMR (75 MHz, d6-DMSO) δ/ppm: 176.1 (s, 1C), 169.0 (s, 2C), 134.3 (d, 2C), 131.2 (s, 2C), 122.5 (d, 2C), 59.8 (s, 1C), 42.0 (s, 1C), 41.2 (t, 1C), 38.8 (t, 2C), 37.6 (t, 2C), 34.8 (t, 1C), 29.0 (q, 1C), 25.9 (d, 2C); HRMS, calcd. for C20H22N2O3 339.1703, obsd. 339.1707. Stability of Phthalimides in the Presence of K2CO3
To the solutions of 1b and 3b in CH3CN-H2O (3:1, c = 1×10−3 M) were added aqueos solutions of K2CO3 to reach the final concentration of K2CO3 c = 1×10−3 M or 1×10−2 M. The UV-vis spectra were recorded prior to the addition of base, and afterwards in the intervals of 1 hour (see the supporting info.). Irradiation Experiments, General
In a quartz vessel a solutions of acids 1a, 1b, 3a, or 3b (c ≈ 5−7 × 10−3 M) and 0.5 equivalents of K2CO3 in acetone-H2O (3:1) or CH3CN-H2O (3:1) were prepared. After purging with N2 for 20 minutes, the solutions were irradiated at 300 nm in a Luzchem reactor with 8 lamps. During the irradiation the solution was cooled with a fan
equipped in the reactor. After irradiation, solvent was removed by evaporation, and crude reaction mixture was chromatographed on column and/or thin layer of silica gel.
Decarboxylation product 8b (5 mg, 5 %) was iso-lated from the crude photoreaction mixture after several column chromatographies on silicagel EtOAc/CH2Cl2 and MeOH/EtOAc as eluent, and rechromatography on TLC with EtOAc/MeOH/CH2Cl2 (5:10:85).
Glycine derivatives 12a and 13a were isolated af-ter preparative thin layer chromatography of the crude photoreaction mixture on silica gel with CH2Cl2/TFA/MeOH (30:0.07:69.93). 2,12-Diaza-10-methoxy-hexacyclo[12.5.1.11,16.114,18. 04,9]doeicosa-4,6,8-trien-3,13-dion (9b) Colourless oil; IR (KBr) max/cm−1: 3421 (s), 2917 (m), 2852 (m), 2361 (m), 1718 (m), 1654 (m), 1399 (w), 1314 (w), 1090 (w), 668 (w); 1H NMR (600 MHz, CD3OD) δ/ppm: 7.89 (dd, J = 0.6, 7.7 Hz, 1H), 7.59 (td, J = 7.6, 1.2 Hz, 1H), 7.50 (td, J = 7.7, 1.2 Hz, 1H), 7.42 (dd, J = 0.6, 7.6 Hz, 1H), 3.88 (s, 3H), 3.73 (s, 2H), 2.26−2.20 (m, 7H), 2.11 (d, J = 11.2 Hz, 2H), 1.91 (d, J = 12.1 Hz, 2H), 1.88 (d, J = 12.1 Hz, 2H), 1.76 (d, J = 12.5 Hz, 1H), 1.71 (d, J = 12.5 Hz, 1H); 13C NMR (150 MHz, CD3OD) δ/ppm: 178.9 (s, 1C), 171.9 (s, 1C), 168.5 (s, 1C), 140.8 (s, 1C), 133.2 (d, 1C), 131.0 (d, 1C), 130.2 (d, 1C), 129.9 (s, 1C), 128.9 (d, 1C), 54.0 (s, 1C), 52.8 (q, 1C), 44.8 (t, 1C), 43.8 (s, 1C), 43.6 (t, 1C), 41.2 (t, 2C), 39.2 (t, 2C), 36.5 (t, 1C), 30.9 (d, 2C). 2,12-Diaza-pentacyclo[12.5.1.11,16.114,18.04,9]doeicosa-4,6,8-trien-3,10,13-trion (2b) Colourless oil; IR (KBr) max/cm−1: 3394 (s), 2916 (s), 2850 (m), 1617 (s), 1593 (s), 1566 (s), 1388 (m), 1321 (w), 718 (w), 608 (w); 1H NMR (300 MHz, CD3OD) δ/ppm: 7.61−7.50 (m, 2H), 7.46−7.33 (m, 2H), 3.74 (s, 2H), 2.32 (s, 2H), 2.27−2.06 (m, 6H), 1.93−1.88 (m, 4H), 1.81−1.68 (m, 2H); 13C NMR (75 MHz, CD3OD) δ/ppm: 187.7 (s, 1C), 179.1 (s, 1C), 171.7 (s, 1C), 140.8 (s, 1C), 136.1 (s, 1C), 130.6 (d, 1C), 129.1 (d, 1C), 129.0 (d, 1C), 128.9 (d, 1C), 53.8 (s, 1C), 44.7 (s, 1C), 43.8 (t, 1C), 43.1 (t, 1C), 41.3 (t, 2C), 39.2 (t, 2C), 36.6 (t, 1C), 30.8 (d, 2C). Irradiation in the Presence of Acrylonitrile
A quartz vessel was charged with a solution of 1a, 1b, 3a or 3b (10 mg/20 mL) in acetone-water (3:1), and 0.5 equivalents of K2CO3 were added. The solution was purged with N2 for 15 minutes. After the purging, acry-lonitrile (100 μL) was added and the solution was irra-diated at 300 nm in Luzchem reactor (8 lamps) for 10−30 min. After the irradiation, the solvent was re-moved on a rotary evaporator and 1H NMR spectrum was recorded.
M. Sohora et al., Photodecarboxylation of Dipeptides 443
Croat. Chem. Acta 87 (2014) 431.
Irradiation in the Presence of Potassium Sorbate
A solution of 1b in CH3CN-water (3:1, 10 mg/20 mL) was placed to three quartz cuvettes (5 mL to the each cuvette. To the cuvettes an aqueous solution of K2CO3 (0.5 equivalents) and potassium sorbate were added, and the solutions were diluted with CH3CN-water (3:1) to reach the final concentrations of 1b, c = 7 × 10−4 M, and the sorbate in the concetrations 0, 0.010 M and 0.035 M. The solutions were purged with N2 for 15 minutes and irradiated at 300 nm in Luzchem reactor (6 lamps) for 30 min. After the irradiation, the solvent was removed on a rotary evaporator and 1H NMR spectra were rec-orded. Determination of the Decarboxylation Quantum Yields in CH3CN-H2O
In four quartz cuvettes (25 mL) was placed a solution of 1a, 1b, 3a, and 3b in CH3CN-H2O (3:1), and K2CO3 (0.5 equivalents) was added. To the fifth cuvette was placed a solution of actinometer, valerophenone in CH3CN-H2O (formation of acetophenone in aqueous solution Φ = 0.65 ± 0.03).33 Concentrations of the solu-tions were adjusted to have absorbance at 254 nm in the range 0.6−0.8. The solutions were purged with nitrogen for 15 min, and irradiated at the same time in a Luzchem reactor (1 or 2 lamps, 254 nm) for 30 s, 1 min, or 20−60 min in the case of 4a,b, and 5a,b. During the irradiations small aliquots of the photoreaction mixture were taken by use of a syringe and analysed by HPLC. Determination of Photoreaction Quantum Yields in Acetone-H2O
In four quartz cuvettes (25 mL) was placed a solution of 1a, 1b (5×10−3 mol/L), 3a, and 3b (2.5×10−3 mol/L) in acetone-H2O (3:1), 0.5 equivalents of K2CO3 was added. To the fifth cuvette was placed a solution of actiometer 6-[(N-phthalimido)methyl]cyclohexane carboxylic acid (5×10−3 mol/L, formation of cyclic product, ΦR = 0.3).34 After 20 minutes of purging with nitrogen, the solutions were irradiated at 300 nm in a Luzchem photoreactor (3 lamps) for 3, 6 and 21 min. After each irradiation, a small aliquot of the photolysis mixture was taken, sol-vent was removed on a rotary evaporator and the residue analyzed by HPLC and 1H NMR. Laser Flash Photolysis (LFP)
LFP facility employing a YAG laser, with a pulse width of 10 ns and excitation wavelength 266 nm. Static cells (0.7 cm) were used and solutions were purged with nitrogen or oxygen for 20 min prior to measurements. Absorbances at 266 nm were ≈ 0.4−0.6.
Supplementary Materials. – Supporting informations to the paper are enclosed to the electronic version of the article.
These data can be found on the website of Croatica Chemica Acta (http://public.carnet.hr/ccacaa).
Acknowledgements. These materials are based on work fi-nanced by the Ministry of Science Education and Sports of the Republic of Croatia (grant No. 098-0982933-2911), National Foundation for Science, (HrZZ grant no. 02.05/25) We thank Professors Peter Wan and Cornelia Bohne, and the University of Victoria (Victoria, Canada, BC) for the use of nanosecond LFP.
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S1
Supporting information
for
Photodecarboxylation of N-Adamantyl- and N-Phenylphthalimide Dipeptide
Derivatives
By
Margareta Sohora, Tatjana Šumanovac Ramljak, Kata Mlinarić-Majerski,
Nikola Basarić*
a Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute,
Bijenička cesta 54, 10 000 Zagreb, Croatia.
Tel: +385 1 4561 141, Fax: + 385 4680 195, E-mail: [email protected],
S2
Table of contents:
1. UV-Vis spectra and laser flash photolysis S3
2. Stability of phthalimides in basic conditions S6
3. 1H and 13C NMR spectra S7
S3
1. UV-vis Spectra and Laser Flash Photolysis
220 240 260 280 300 320 3400
2000
4000
6000
N
O
O
HN
O
COOH
Mo
lar
Ab
sorp
tio
n C
oef
fici
ent
/ M-1 c
m-1
Wavelength / nm
Absorption spectrum of 1a in CH3CN.
300 400 500 600 700
0.00
0.01
0.02
0.03
0.04
Wavelength / nm
A
100 ns 360 ns 770 ns 1.5 s
300 400 500 600 7000.00
0.01
0.02
0.03
A
Wavelength / nm
220 ns 730 ns 1.6 s 3.1 s
Transient absorption spectra of 1a in N2-purged CH3CN (left) and CH3CN-H2O (1:1) (right).
300 400 500 600 7000.000
0.005
0.010
0.015
0.020
A
Wavelength / nm
430 ns 1.8 s 3.9 s 7.7 s
Transient absorption spectra of 1a in N2-purged CH3CN-H2O (1:1) in the presence of K2CO3 c = 0.01 M.
S4
300 400 500 600 7000.00
0.01
0.02
0.03
A
Wavelength / nm
CH3CN-H
2O
CH3CN-H
2O, K
2CO
3
Transient absorption spectra of 1a in N2-purged CH3CN-H2O (1:1) at pH 7 and in the presence of K2CO3 c = 0.01 M.
200 225 250 275 300 3250
5000
10000
15000
20000
25000
30000
N
O
O
O
HNCOOHH
Wavelength / nm
Mo
lar
Ab
sorp
tio
n C
oef
fici
ent
/ M-1cm
-1
Absorption spectrum of 3a in CH3CN.
S5
300 400 500 600 7000.00
0.01
0.02
0.03
A
Wavelength / nm
0.6 s 3.9 s 9.3 s 16 s
300 400 500 600 7000.000
0.005
0.010
0.015
0.020
A
Wavelength / nm
1.5 s 9.8 s 23 s 40 s
Transient absorption spectra of 3a in N2-purged CH3CN (left) and CH3CN-H2O (1:1) (right).
300 400 500 600 7000.00
0.01
0.02
0.03
0.04
A
Wavelength / nm
140 ns 590 ns 1.7 s 3.1 s
300 400 500 600 700-0.04
-0.02
0.00
0.02
A
Wavelength / nm
20 ns 50 ns 130 ns 350 ns
Transient absorption spectra of the 3a in N2-purged CH3CN (left) and O2-purged CH3CN (right).
300 400 500 600 7000.000
0.005
0.010
0.015
0.020
Wavelength / nm
A
100 ns 380 ns 820 ns 1.5 s
Transient absorption spectra of 3a derivative in N2-purged CH3CN-H2O (1:1).
S6
2. Stability of phthalimides in basic conditions
250 300 3500,00
0,25
0,50
0,75
1,00
1,25
1,50
c (1b) = 1 x 10-3 M
c (K2CO
3) = 1 x 10-3 M
A
Wavelength / nm
t0
1h 2h 3h 4h 5h 6h 7h 8h 9h 10h 20h
250 300 3500,00
0,25
0,50
0,75
1,00
1,25
1,50
1,75
0 5 10 15 200,2
0,4
0,6
0,8
1,0
Fit to y0+A1e^(-x/t1):Chi^2 3,03691E-4R^2 0,99517---------------------------------------------y0 0,28885 0,013A1 0,73006 0,01712t1 3,45855 0,20308---------------------------------------------
A
t / h
300 nm
c (1b) = 1 x 10-3 M
c (K2CO
3) = 1 x 10-2 M
AWavelength / nm
t0
1h 2h 3h 4h 5h 6h 7h 8h 9h 10h 20h
Fig. Absorption spectra of 1b in CH3CN-H2O (c = 1×10-3 M) in the presence of K2CO3 (left, c = 1×10-3 M; right c = 1×10-2, inset: dependence of the absorbance at 300 nm)
300 325 3500,0
0,5
1,0
1,5
2,0
2,5
0 5 10 15 20
1,05
1,20
1,35
1,50
Fit to y0+A1e^(-x/t1):Chi^2 1,46411E-4R^2 0,99471---------------------------------------------y0 1,82305 0,07856A1 -0,79066 0,07471t1 19,03382 2,8766---------------------------------------------
A
t / h
310 nm
A
Wavelength / nm
t0
1h 2h 3h 4h 5h 6h 7h 8h 9h 10h 20h
c (3b) = 1 x 10-3 M
c (K2CO
3) = 1 x 10-3 M
300 325 3500,0
0,5
1,0
1,5
2,0
2,5
c (3b) = 1 x 10-3 M
c (K2CO
3) = 1 x 10-2 M
A
Wavelength / nm
t0
15 min 1h
Fig. Absorption spectra of 3b in CH3CN-H2O (c = 1×10-3 M) in the presence of K2CO3 (left, c = 1×10-3 M, inset: dependence of the absorbance at 310 nm; right c = 1×10-2)
S7
1H NMR (300 MHz, CD3OD) of 1b g
PPM 8.0 7.6 7.2 6.8 6.4 6.0 5.6 5.2 4.8 4.4 4.0 3.6 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4 -0.0
3.
999
2.
059
4.
302
2.
105
2.
016
4.
372
2.
179
7.
745
9
4.
832
1
4.830
8
4.803
1
3.
836
9
3.
339
1
3.
305
6
3.
302
9
3.300
2
3.297
6
3.
294
9
2.
602
2
2.
578
0
2.485
5
2.
465
5
2.284
5
1.
962
6
1.943
4
1.886
7
1.866
3
1.
796
4
1.724
7
-0.
0089
N
O
O
HNOC
HOOC
S8
13C NMR (150 MHz, CD3OD) of 1b
PPM 180.0 160.0 140.0 120.0 100.0 80.0 60.0 40.0 20.0 0.0
170
.911
2
135
.225
1
133
.096
5
123
.515
7
61.4
250
49.4
195
49.2
770
49.1
383
48.9
962
48.8
535
48.7
105
48.5
678
44.0
614
42.7
149
42.3
106
40.3
953
38.9
248
36.2
830
31.0
429
N
O
O
HNOC
HOOC
S9
1H NMR (300 MHz, d6-DMSO) of 5b Sp o s 5 o a GyO
PPM 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0
1.
996
4.
814
1.
958
6.
284
1.
000
1.
978
9.
106
0
9.104
9
9.086
8
9.067
1
8.
017
2
8.007
8
7.996
4
7.988
6
7.979
0
7.937
5
7.928
2
7.919
5
7.908
9
7.607
3
7.578
9
7.394
4
7.391
8
7.380
2
7.358
7
7.347
3
5.
177
2
4.
121
7
4.102
3
3.
315
3
2.
502
8
2.497
0
2.491
2
-0.
0040
N
O
CONHCOO
O
S10
13C NMR (75 MHz, d6-DMSO) of 5b p y
PPM 180.0 160.0 140.0 120.0 100.0 80.0 60.0 40.0 20.0 0.0
170.
2130
167.
2094
166.
6034
136.
4108
135.
2985
135.
1193
133.
4730
131.
9896
128.
8989
128.
5421
128.
3874
128.
2885
127.
4763
123.
9964
66.
3695
41.
9140
40.
8317
40.
5536
40.
2751
39.
9962
39.
7182
39.
4396
39.
1621
N
O
CONHCOO
O
S11
1H NMR (300 MHz, d6-DMSO) of 5a g
PPM 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0
2.
250
1.
133
6.
073
2.
001
10
.86
0.
956
2.
155
9.
002
8
9.001
5
8.999
4
8.995
4
8.994
5
8.981
8
7.
994
8
7.989
7
7.985
7
7.980
6
7.931
0
7.927
7
7.923
6
7.916
7
7.572
4
7.558
2
7.358
0
7.345
7
7.323
7
7.318
4
7.315
2
7.312
3
7.305
1
7.298
4
7.286
1
7.273
2
7.207
8
5.
155
6
5.144
4
4.
759
9
4.756
3
4.752
7
4.747
1
4.743
4
4.739
8
3.
317
4
3.234
5
3.225
3
3.211
5
3.202
5
3.168
8
3.152
1
3.145
9
3.129
3
2.506
4
2.503
9
2.500
9
2.498
0
2.495
2
0.
000
1
N
O
CONHCOO
O
S12
13C NMR (75MHz, d6-DMSO) of 5a p
PPM 180.0 160.0 140.0 120.0 100.0 80.0 60.0 40.0 20.0 0.0
171
.940
4
167
.206
0
166
.465
9
138
.033
2 1
36.3
460
135
.305
9
135
.075
7 1
33.5
375
131
.975
3
129
.587
8
128
.856
5 1
28.7
604
128
.476
4
128
.413
5 1
28.2
116
127
.392
0
127
.001
3 1
23.9
945
66.
5226
54.
9998
40.
8317
40.
5566
40.
2787
40.
0000
39.
7223
39.
4446
39.
1631
36.
6895
N
O
CONHCOO
O
S13
1H NMR (300 MHz, CDCl3) of 5bEt
PPM 8.0 7.6 7.2 6.8 6.4 6.0 5.6 5.2 4.8 4.4 4.0 3.6 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4 -0.0 -0.4
3
.995
1
.994
2
.146
1
.084
4
.235
3
.082
7
.9907
7
.9802
7
.9734
7
.9626
7
.9457
7
.8312
7
.8211
7
.8132
7
.8029
7
.6216
7
.5931
7
.2576
6
.6756
6
.6648
6
.6618
4
.3127
4
.2889
4
.2658
4
.2503
1
.5600
1
.3489
1
.3251
1
.3013
-0
.0039
N
O
CONHCOO
O
S14
13C NMR (150 MHz, CDCl3) of 5bEt g ( )
PPM 180.0 160.0 140.0 120.0 100.0 80.0 60.0 40.0 20.0 0.0
169.8
318
166.7
132
166.3
706
134.8
431
134.5
304
132.9
533
131.5
594
127.8
071
126.1
635
123.8
220
77.1
073
76.8
947
76.6
838
61.6
290
41.8
917
14.0
618
N
O
CONHCOO
O
S15
1H NMR (600 MHz, CDCl3) of 5aBz
PPM 8.0 7.6 7.2 6.8 6.4 6.0 5.6 5.2 4.8 4.4 4.0 3.6 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4 -0.0 -0.4 -0.8
1
.990
2
.004
4
.972
0
.939
2
.058
2
.008
2
.034
2
.093
2
.060
2
.125
2
.126
1
.895
0
.948
0
.910
7
.7208
7
.7157
7
.7117
7
.7067
7
.6492
7
.6442
7
.6401
7
.6351
7
.3253
7
.3184
7
.2978
7
.2904
7
.2834
6
.3603
6
.3521
6
.3437
6
.2003
5
.1514
4
.0564
4
.0476
2
.7768
2
.5977
2
.5494
2
.5302
2
.4481
2
.4279
2
.2871
2
.2832
2
.0171
1
.9317
1
.9121
1
.8607
1
.8404
1
.7651
1
.7441
1
.6535
1
.6325
-0
.0148
N
O
O
HNOC
O
O
S16
13C NMR (75 MHz, CDCl3) spectrum of 5aBz
PPM 180.0 160.0 140.0 120.0 100.0 80.0 60.0 40.0 20.0 0.0
176.4
272
169.7
824
169.2
848
135.0
648
133.5
599
131.6
518
128.3
875
128.2
417
128.1
004
122.4
040
77.3
183
76.8
947
76.4
694
66.9
091
60.0
422
47.3
228
42.6
240
41.2
201
41.0
826
39.0
967
38.3
777
37.7
606
34.9
502
29.2
861
N
O
O
HNOC
O
O
S17
1H NMR (600 MHz, d6-DMSO) of 3b
PPM 12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0
0
.999
5
.739
1
.925
0
.995
2
.059
12.6
007
8.
9460
8.
9367
8.
9269
8.
0275
8.
0245
8.
0132
8.
0083
8.
0041
7.
9990
7.
9664
7.
9494
7.
9443
7.
9404
7.
9353
7.
6101
7.
5960
3.
9801
3.
9703
3.
3494
3.
3158
3.
2820
2.
5149
0.
0149
N
O
CONHCOOH
O
S18
13C NMR (150 MHz, d6-DMSO) of 3b
PPM 180.0 160.0 140.0 120.0 100.0 80.0 60.0 40.0 20.0 0.0
171
.630
3
167
.206
0 1
66.0
099
135
.264
1 1
34.8
731
133
.972
0 1
31.9
814
128
.215
1
128
.168
4
127
.387
0
123
.965
9
42
.4554
40
.4183
40
.2780
40
.1394
40
.0964
39
.9998
39
.8609
39
.7209
39
.5822
N
O
CONHCOOH
O
S19
1H NMR (600 MHz, d6-DMSO) of 3a g
PPM 8.4 8.0 7.6 7.2 6.8 6.4 6.0 5.6 5.2 4.8 4.4 4.0 3.6 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4 -0.0 -0.4 -0.8
5
.992
1
.064
2
.044
5
.368
1
.161
1
.083
1
.835
8
.557
3
8
.536
2 7
.997
0
7
.986
5 7
.977
4 7
.968
3 7
.954
4 7
.942
3
7
.929
3
7
.919
9 7
.918
6 7
.910
8 7
.901
1 7
.873
9
7
.550
8 7
.536
2 7
.522
7
7
.295
0 7
.288
3 7
.268
0 7
.243
9 7
.218
8 7
.174
3 7
.159
4 7
.151
6 7
.129
4
4
.517
8 4
.515
9 4
.514
9
3
.331
3 3
.329
4 3
.326
9 3
.324
3 3
.321
6 3
.317
2 3
.206
5
3
.192
7 3
.106
6
3
.105
9 3
.074
3 3
.063
5 3
.061
0 3
.030
0
2
.502
0 2
.496
1 2
.490
2
-0
.005
6 -0
.016
4
N
O
CONHCOOH
O
S20
13C NMR (75 MHz, d6-DMSO) of 3a
PPM 180.0 160.0 140.0 120.0 100.0 80.0 60.0 40.0 20.0 0.0
167
.215
8
165
.787
2
139
.258
0 1
35.2
967
134
.770
3 1
34.3
262
131
.959
7
129
.604
4
128
.507
5 1
28.1
714
127
.373
9 1
26.5
598
123
.967
9
55.
5966
40.
8224
40.
5434
40.
3549
40.
2648
39.
9865
39.
7080
39.
4286
39.
1529
37.
2945
N
O
CONHCOOH
O
S21
1H NMR (300 MHz, d6-DMSO) of 7b
PPM 8.4 8.0 7.6 7.2 6.8 6.4 6.0 5.6 5.2 4.8 4.4 4.0 3.6 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4 -0.0 -0.4
0.
997
6.
079
2.
003
2.
969
8.5
392
8.5
236
8.0
013
7.9
909
7.9
843
7.9
815
7.9
725
7.9
669
7.9
602
7.9
451
7.9
379
7.9
335
7.9
243
7.9
217
7.9
151
7.9
045
7.5
640
7.5
354
3.3
342
2.8
185
2.8
034
2.5
095
2.5
036
2.4
976
2.4
915
2.4
856
-0.
0050
N
O
CONH
O
CH3
S22
13C NMR (150 MHz, CD3OD) of 7b
PPM 160.0 140.0 120.0 100.0 80.0 60.0 40.0 20.0 0.0
169.
9087
168.
4522
135.
9010
128.
8178
127.
7553
124.
6760
49.
4370
49.
2966
49.
1563
49.
0132
48.
8701
48.
7274
48.
5867
40.
1593
26.
9760
N
O
CONH
O
CH3
S23
1H NMR (600 MHz, d6-DMSO) of 7a
PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0
1
.121
5
.757
4
.997
1
.799
2
.314
2
.111
8
.708
9 8
.707
4
7
.984
4
7
.979
3 7
.971
9 7
.957
7
7
.934
5 7
.929
8
7
.556
2
7
.542
4
7
.306
3 7
.269
2
3
.522
4 3
.511
3
3
.302
6 3
.239
8
3
.236
0 3
.234
9
2
.891
7
2
.879
0
2
.501
7
2
.464
8
2
.461
2
2
.456
9
1
.206
8 1
.204
5
-0
.000
0
N
O
CONH
O
S24
3C NMR (150 MHz, d6-DMSO) of 7a
PPM 180.0 160.0 140.0 120.0 100.0 80.0 60.0 40.0 20.0 0.0
167
.2321
165
.9758
140
.0059
135
.3409
135
.2902
134
.6707
134
.4547
131
.9663
129
.1215
128
.7819
128
.1636
127
.3298
126
.5284
123
.9681
41
.377
5 40
.836
3
40
.557
7 40
.421
0 40
.278
8
40
.000
0 39
.721
4
39
.565
2 39
.442
8 39
.306
0 39
.164
0 39
.052
5 39
.024
6
35
.501
5
S25
NMR (600 MHz, CD3OD) of 8b
PPM 8.0 7.6 7.2 6.8 6.4 6.0 5.6 5.2 4.8 4.4 4.0 3.6 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4 -0.0
3.
999
3.
086
4.
078
2.15
9
2.
069
2.
061
3.
163
1.
469
7.
741
4
7.727
0
7.714
0
7.712
5
5.
484
4
5.
480
6
4.
771
1
3.
320
2
3.
317
6
3.314
8
3.312
2
2.
735
1
2.
731
5
2.727
9
2.
561
5
2.
538
3
2.
476
1
2.455
8
2.266
8
2.
262
7
1.
921
4
1.
900
8
1.
862
6
1.856
7
1.834
1
1.812
8
1.
802
1
1.
798
5
1.780
7
1.777
6
1.
705
0
1.
702
0
1.693
8
1.689
2
1.684
0
1.
681
2
N
O
O
HNOC
H3C
S26
13C NMR (75 MHz, d6-DMSO) of 8b p g g
PPM 160.0 140.0 120.0 100.0 80.0 60.0 40.0 20.0 0.0
176
.624
1
169
.521
1
134
.824
1 1
34.7
141
131
.691
2
123
.354
5
122
.939
1
60.2
703
42.4
946
41.6
600
40.8
436
40.5
643
40.2
855
40.0
068
39.7
284
39.4
496
39.3
301
39.1
714
38.0
617
35.3
168
33.8
005
29.4
972
26.3
751
24.9
101
N
O
O
HNOC
H3C
S27
1H NMR (300 MHz, CD3OD) of 8a
PPM 8.0 7.6 7.2 6.8 6.4 6.0 5.6 5.2 4.8 4.4 4.0 3.6 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4 -0.0
3.
999
0.
804
5.
114
2.
044
2.
062
6.
462
2.
206
6.
720
7.
739
6
7.
251
1
7.
248
0
7.227
3
7.200
9
7.195
8
7.172
3
7.
168
6
7.
143
5
4.
785
6
3.
405
4
3.386
0
3.
380
8
3.
307
4
3.
302
3
3.297
0
3.291
8
3.286
7
2.801
6
2.776
6
2.753
1
2.516
1
2.467
1
2.
242
0
1.
780
5
1.
755
2
1.
270
2
N
O
O
HNOC
S28
13C NMR (75 MHz, CDCl3) of 8a
PPM 180.0 160.0 140.0 120.0 100.0 80.0 60.0 40.0 20.0 0.0
176
.158
6
169
.420
1
138
.870
3 1
33.6
486
133
.585
4 1
31.7
241
128
.705
3 1
28.5
309
128
.485
3
126
.331
3
122
.484
9
77
.3190
76
.8957
76
.4716
60
.2213
42
.6787
41
.3161
40
.4633
39
.1939
37
.9108
35
.5751
35
.0339
29
.3730
N
O
O
HNOC
S29
1H NMR (600 MHz, CD3OD) spectrum of 9b
PPM 7.6 7.2 6.8 6.4 6.0 5.6 5.2 4.8 4.4 4.0 3.6 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4 -0.0
0.
997
1.
087
1.
061
0.99
9
2.
774
1.
912
6.
097
2.
105
3.
987
1.
860
7.8
934
7.8
903
7.8
680
7.8
645
7.7
492
7.6
100
7.6
056
7.5
850
7.5
806
7.5
602
7.5
557
7.5
154
7.5
108
7.4
899
7.4
854
7.4
646
7.4
601
7.4
273
7.4
239
7.4
022
7.3
991
5.4
763
4.7
935
3.8
667
3.7
238
3.3
126
3.3
072
3.3
018
3.2
964
3.2
910
2.2
400
2.2
014
2.1
227
2.0
880
1.8
913
1.7
360
1.7
322
1.7
284
1.2
826
-0.0
043
N
OHN
O
OCH3
S30
13C NMR (150 MHz, CD3OD) of 9b j
PPM 180.0 160.0 140.0 120.0 100.0 80.0 60.0 40.0 20.0 0.0
178.9
565
171.9
262
140.8
068
133.1
968
131.0
052
130.2
655
129.9
310
128.9
144
54.0
663
52.8
214
49.4
510
49.3
081
49.1
654
49.0
231
48.8
830
48.7
417
48.5
992
44.7
983
43.8
140
43.6
385
41.2
477
39.2
684
36.5
198
31.1
389
30.8
759
30.7
730
30.7
414
N
OHN
O
OCH3
S31
1H NMR (300 MHz, CD3OD) of 2b
PPM 8.0 7.6 7.2 6.8 6.4 6.0 5.6 5.2 4.8 4.4 4.0 3.6 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4 -0.0
2.
069
1.
995
2.
047
9.
841
4.
227
1.
849
7.5
465
7.5
266
7.5
220
7.5
152
7.5
103
7.4
907
7.4
852
7.3
796
7.3
741
7.3
544
7.3
479
7.3
291
7.3
238
5.4
759
4.7
928
3.7
135
3.3
129
3.3
075
3.3
021
3.2
966
3.2
911
2.2
933
2.2
052
2.1
628
2.0
896
2.0
885
2.0
530
2.0
520
1.8
818
1.8
737
1.7
302
1.7
256
1.7
227
1.7
212
1.7
195
1.7
133
1.7
114
1.2
819
-0.
0048
NH
OHN
O
O
S32
13C NMR (75 MHz, CD3OD) of 2b p
PPM 180.0 160.0 140.0 120.0 100.0 80.0 60.0 40.0 20.0 0.0
187
.730
6
179
.087
0
171
.699
5
140
.795
7
136
.155
1 1
30.6
066
129
.106
2 1
29.0
097
128
.912
9
53.
8234
49.
8634
49.
5796
49.
2958
49.
0119
48.
7281
48.
4444
48.
1606
44.
7388
43.
7854
43.
1201
41.
3538
39.
2732
36.
6046
30.
8421
30.
7481
NH
OHN
O
O
