Page S1

Electronic Supporting Information

Facile access to amides and hydroxamic acids

directly from nitroarenes

Shreyans K. Jain,ab K.A. Aravinda Kumar,c Sandip B. Bharatebc* and Ram A.

Vishwakarmaabc*

aNatural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine , Canal

Road, Jammu-180001, India.

bAcademy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Integrative

Medicine , Canal Road, Jammu-180001, India

c Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road,

Jammu-180001, India.

* sbharate@iiim.res.in (S.B.B.); ram@iiim.res.in (R.A.V.)

Fax: (+) 91-191-2569333; Tel. (+) 91-191-2569111

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2014

Page S2

CONTENTS

Section S1. Observations from investigation on rohitukineSection S2. Monomer-dimer equilibrium of nitroso compoundsSection S3. LCMS analysis of reaction mixture (for entry 3, 12, 13and 14 of Table 1) to

determine ratio of compound 1a and 2aSection S4. NMR data scans

S4.a. 1H NMR of mixture of 1a and 2a (obtained from entry 3 of Table 1) in CDCl3

S4.b. 1H NMR of 4-chloro-N-phenylbenzamide 1a S4.c. 1H NMR spectrum of N-phenylbenzamide (1b)S4.d. 13C NMR spectrum of N-phenylbenzamide (1b)S4.e. 1H NMR Spectrum of 2,6-dichloro-N-phenylbenzamide (1c)S4.f. 13C NMR Spectrum of 2,6-dichloro-N-phenylbenzamide (1c)S4.g. 1H NMR Spectrum of 2,4,5-trimethoxy-N-phenylbenzamide (1d)S4.h. 13C NMR Spectrum of 2,4,5-trimethoxy-N-phenylbenzamide (1d)S4.i. 1H NMR Spectrum of 3-bromo-4-fluoro-N-phenylbenzamide (1e)S4.j. 13C NMR Spectrum of 3-bromo-4-fluoro-N-phenylbenzamide (1e)S4.k. 1H NMR Spectrum of 4-fluoro-N-phenylbenzamide (1f)S4.l. 13 C NMR Spectrum of 4-fluoro-N-phenylbenzamide (1f)S4.m. 1H NMR Spectrum of 3,5-dimethoxy-N-phenylbenzamide (1g)S4.n. 13C NMR Spectrum of 3,5-dimethoxy-N-phenylbenzamide (1g)S4.o. 1H NMR Spectrum of 2-chloro-N-phenylbenzamide (1h)S4.p. 13C NMR Spectrum of 2-chloro-N-phenylbenzamide (1h)S4.q. 1H NMR Spectrum of 5-methyl-N-phenylpyrazine-2-carboxamide (1i)S4.r. 13C NMR Spectrum of 5-methyl-N-phenylpyrazine-2-carboxamide (1i)S4.s. 1H NMR Spectrum of 2-methyl-N-phenylbenzamide (1j)S4.t. 13C NMR Spectrum of 2-methyl-N-phenylbenzamide (1j)S4.u. 1H NMR Spectrum of 3-hydroxy-4-methoxy-N-phenylbenzamide (1k)S4.v. 13C NMR Spectrum of 3-hydroxy-4-methoxy-N-phenylbenzamide (1k)S4.w. 1H NMR Spectrum 2,4,5-trimethoxy-N-(pyridin-2-yl)benzamide (1l)S4.x. 13C NMR Spectrum of 2,4,5-trimethoxy-N-(pyridin-2-yl)benzamide (1l)S4.y. 1H NMR spectrum of 4-chloro-N-hydroxy-N-phenylbenzamide (2a) in

CDCl3S4.z. 13C NMR spectrum of 4-chloro-N-hydroxy-N-phenylbenzamide (2a) in

CDCl3

Section S5. References associated with supporting information

Page S3

Section S1. Observations from investigation on rohitukine

Rohitukine is a chromone alkaloid isolated from barks of Dysoxylum binectariferum. This

natural product led to the discovery of two anticancer clinical candidates viz. flavopiridol and P-

276-00.

O

OOH

HO

N

HO

Cl

O

OOH

Cl

NOH

O

OOH

HO

N

HO

Rohitukine Flavopiridol P-276-00

During our efforts on medicinal chemistry of rohitukine,1 present synthetic method was

discovered. One of the targeted modification was conversion of allylic methyl group into –CHO

functionality, for which we used N,N-dimethylnitrosoanilin2 which produced hydroxamic acid as

a major product along with traces of desired 2-formyl product (Scheme 1).

O

OOH

HO

N

HO

Rohitukine

ON N

KOH, EtOHO

OOH

HO

N

HO

N

O

OH

N

Desired product (minor) Major

Scheme 1

O

O

CHO

OH

HO

N

HO

+

Byproduct(Hydroxamic acid)

ON N

Then, in order to get desired formyl product in good yield, we attempted to generate in situ

‘nitroso’ from nitrobenzene and Mn-oxide.3 However, again the desired formyl product was

obtained only in traces and hydroxamic acid and amide products (revealed by LCMS) were the

major side products (Scheme 2).

O

OOH

HO

N

HO

Rohitukine

O2NO

OOH

HO

N

HO

N

O

R

Desired product (minor) Major

Scheme 2

O

O

CHO

OH

HO

N

HO

+

Byproducts(Hydroxamic acid and amide)

MnO2150 oC, 25 h R = H

R = OH

Page S4

These results led to assumption that the 2-formyl product must have been formed, however it

undergoes further reaction with N,N-dimethylnitrosoanilin to produce corresponding hydroxamic

acid. This unexpected result was then implemented to establish a facile methodology for

synthesis amides and hydroxamic acid from benzaldehydes and nitroarenes in presence of MnO2.

Page S5

Section S2. Monomer-dimer equilibrium of nitroso compounds

Dimerized product was observed as main product (Table 2, entries 13, 14) in case of 2-bromo-

nitrobenzene and 2-iodo-nitrobenzene. These nitroarenes failed to give desired product in

significant amount because the corresponding nitroso favoured dimerization.

Nitroso compounds are usually reactive intermediate and stabilized either by dimerization or

resonance: noteworthy feature of nitroso compounds is their tendency to get stabilized by

dimerization to azodioxy dimer, as a consequence of their low HOMO-LUMO energy gap and

thus promotes high reactivity at low excitation energy.4 It was observed that o-iodo-nitrobenzene

(4m) and o-bromo-nitrobenzene (4n) were failed to give desired amide in significant yield (yield:

7-8%; Table 2). The major product was characteristic colorless crystalline, oraganic solvent

insoluble dimeric azodioxy compound which displayed characteristic IR spectrum. It is again

important to discuss that yield of product in these cases depends on the equilibrium between

monomer and dimer of nitroso. A controlled equilibrium can be translated to product yield. It is

known from previous work that unhindered aromatics favor monomer formation, while o-

substituted and hindered aromatics favor dimer formation. Low temperature with UV λmax 254-

350 nm favor monomer while high temperature and visible wavelength favors dimer.5 Monomer-

dimer interchange depends on the availability of electrons on the N of nitroso, to form dimeric

bond and would therefore decrease with increasing electronegativity of the R2 (here Ph or

substituted Ph). If R2 is sufficient electron-donating, it favours dimerization and if the R2 is

electron-deficient or electron-withdrawing, it favors monomer and gets stabilized by resonance.

NX

NX

O

O

XN

O

X XN NO O

Trans CisX= I, Br

Page S6

Section S3. LCMS analysis of reaction mixture (for entry 3, 12, 13 and 14 of Table 1) to

determine ratio of compound 1a and 2a

Reaction was carried out using condition mentioned in entries 3, 12, 13 and 14 of Table 1. The

LCMS analysis was done after the time point which is mentioned in Table 1.

Method: Chromolith column (50 mm x 4.6 mm, RP-18), Mobile phase: Acetonitrile/water (1%

acetic acid), gradient elution over 25 min (0 min: 0/100, 15 min: 50/50, 20 min: 50/50, 22 min:

0/100, 25 min: 0/100), flow rate: 0.5 ml/min.

Page S7

(a). LCMS analysis for reaction performed as per entry no 3 (LCMS spectra and MS spectras are shown)

(b) LCMS analysis for reaction performed as per entry no 12.

(c) LCMS analysis for reaction performed as per entry no 13.

Page S8

(d) LCMS analysis for reaction performed as per entry no 14.

Page S9

Section S4. NMR data scans

S4a. 1H NMR of mixture of 1a and 2a (obtained from entry 3 of Table 1) in CDCl3

S4.b. 1H NMR of 4-chloro-N-phenylbenzamide 1a

S4.c. 1H NMR spectrum of N-phenylbenzamide (1b)

Page S10

S4.d. 13C NMR spectrum of N-phenylbenzamide (1b)

Page S11

S4.e. 1H NMR Spectrum of 2,6-dichloro-N-phenylbenzamide (1c)

S4.f. 13C NMR Spectrum of 2,6-dichloro-N-phenylbenzamide (1c)

Page S12

S4.g. 1HNMR Spectrum of 2,4,5-trimethoxy-N-phenylbenzamide (1d)

S4.h. 13C NMR Spectrum of 2,4,5-trimethoxy-N-phenylbenzamide (1d)

Page S13

S4.i. 1HNMR Spectrum of 3-bromo-4-fluoro-N-phenylbenzamide (1e)

S4.j. 13C NMR Spectrum of 3-bromo-4-fluoro-N-phenylbenzamide (1e)

0102030405060708090100110120130140150160170f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

c13-aravindSR4BR 29

.70

109.

6710

9.88

116.

7211

6.94

120.

3712

5.01

128.

0612

8.14

129.

1913

2.47

132.

8613

7.45

159.

9816

2.50

163.

39

Parameter Value

1 Data FileName

E:/ NMR-NPC-P/ProcessedNMR Data/SHREYANSNMR Data/Methodoloy/Amide/#Amide 5(3Br4F BA)/c13-aravind/26/ fid

2 Title c13-aravind

3 Comment SR4BR

4 Origin BrukerBioSpinGmbH

5 Owner IIIM

6 Site

7 Spectrometer

spect

8 Author

9 Solvent CDCl3

10 Temperature 300.0

11 PulseSequence

zgpg30

12 Number ofScans

1600

13 ReceiverGain

128

14 RelaxationDelay

1.0000

15 Pulse Width 9.2000

16 AcquisitionTime

1.2976

17 AcquisitionDate

2013-12-30T13:33:05

18 ModificationDate

2013-12-30T13:40:00

19 Spectrometer Frequency

100.61

20 SpectralWidth

25252.5

21 LowestFrequency

-2565.6

22 Nucleus 13C

23 Acquired Size 32768

24 Spectral Size 65536

1

2

3

4

5

6 7

O8

NH9

10

11

12

13

14

15

F16

Br17

Page S14

S4.k.1HNMR Spectrum of 4-fluoro-N-phenylbenzamide (1f)

S4.l.13 CNMR Spectrum of 4-fluoro-N-phenylbenzamide (1f)

405060708090100110120130140150160170f1 (ppm)

-50

0

50

100

150

200

250

300

350

400

450

500c13-shreyansAM-4F 76

.79

77.0

477

.30

115.

8411

6.01

120.

26

124.

7612

9.18

129.

3912

9.46

131.

13

137.

32

163.

8616

4.67

165.

85

Parameter Value

1 Data File Name E:/ NMR-NPC-P/01-jan-c13-mcd-2a/ c13-shreyans/ 8/ fid

2 Title c13-shreyans

3 Comment AM-4F

4 Origin Bruker BioSpinGmbH

5 Owner IIIM

6 Site

7 Spectrometer spect

8 Author

9 Solvent CDCl3

10 Temperature 290.9

11 Pulse Sequence zgpg30

12 Number of Scans 1200

13 Receiver Gain 1825

14 Relaxation Delay 1.0000

15 Pulse Width 8.4500

16 Acquisition Time 1.0420

17 Acquisition Date 2014-01-01T16:22:07

18 Modification Date 2014-01-01T17:03:36

19 SpectrometerFrequency

125.76

20 Spectral Width 31446.5

21 LowestFrequency

-3148.0

22 Nucleus 13C

23 Acquired Size 32768

24 Spectral Size 65536

Page S15

S4.m.1HNMR Spectrum of 3,5-dimethoxy-N-phenylbenzamide (1g)

S4.n.13C NMR Spectrum of 3,5-dimethoxy-N-phenylbenzamide (1g)

Page S16

S4.o.1HNMR Spectrum of 2-chloro-N-phenylbenzamide (1h)

S4.p. 13CNMR Spectrum of 2-chloro-N-phenylbenzamide (1h)

102030405060708090100110120130140150160170180f1 (ppm)

0

500

1000

1500

2000

2500

3000

c13-venketSRLS 12

1.56

125.

7612

8.23

129.

9013

1.07

132.

0713

2.29

138.

1313

9.67

168.

21

Parameter Value

1 Data File Name E:/ NMR-NPC-P/ ProcessedNMR Data/SHREYANSNMR Data/Methodoloy/Amide/#Amide (2-chloro BA-NB)/02-jan-mcd-2b/ c13-venket/ 35/fid

2 Title c13-venket

3 Comment SRLS

4 Origin Bruker BioSpinGmbH

5 Owner IIIM

6 Site

7 Spectrometer spect

8 Author

9 Solvent MeOD

10 Temperature 300.0

11 PulseSequence

zgpg30

12 Number ofScans

1600

13 Receiver Gain 128

14 RelaxationDelay

1.0000

15 Pulse Width 9.2000

16 AcquisitionTime

1.2976

17 AcquisitionDate

2014-01-02T16:52:34

18 ModificationDate

2014-01-02T17:16:34

19 SpectrometerFrequency

100.61

20 Spectral Width 25252.5

21 LowestFrequency

-2422.6

22 Nucleus 13C

23 Acquired Size 32768

24 Spectral Size 65536

Page S17

S4.q. 1HNMR Spectrum of 5-methyl-N-phenylpyrazine-2-carboxamide (1i)

S4.r. 13CNMR Spectrum of 5-methyl-N-phenylpyrazine-2-carboxamide (1i)

2030405060708090100110120130140150160f1 (ppm)

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

c13-aravindBZPY 21

.91

119.

78

124.

68

129.

17

137.

41

141.

7714

2.07

143.

76

157.

46

161.

13 Parameter Value

1 Data FileName

E:/ NMR-NPC-P/ProcessedNMR Data/SHREYANSNMR Data/Methodoloy/Amide/##Amide (5-Me-2-Pyrazine BA,NB)/ c13-aravind/ 58/fid

2 Title c13-aravind

3 Comment BZPY

4 Origin BrukerBioSpinGmbH

5 Owner IIIM

6 Site

7 Spectrometer

spect

8 Author

9 Solvent CDCl3

10 Temperature 300.0

11 PulseSequence

zgpg30

12 Number ofScans

10240

13 ReceiverGain

128

14 RelaxationDelay

1.0000

15 Pulse Width 9.2000

16 AcquisitionTime

1.2976

17 AcquisitionDate

2013-11-12T00:16:49

18 ModificationDate

2013-11-12T00:16:52

19 Spectrometer Frequency

100.61

20 SpectralWidth

25252.5

21 LowestFrequency

-2564.6

22 Nucleus 13C

23 Acquired Size 32768

24 Spectral Size 65536

Page S18

S4.s. 1HNMR Spectrum of 2-methyl-N-phenylbenzamide (1j)

S4.t. 13C NMR Spectrum of 2-methyl-N-phenylbenzamide (1j)

Page S19

S4.u. 1HNMR Spectrum of 3-hydroxy-4-methoxy-N-phenylbenzamide (1k)

S4.v. 13C NMR Spectrum of 3-hydroxy-4-methoxy-N-phenylbenzamide (1k)

S4.w. 1HNMR Spectrum 2,4,5-trimethoxy-N-(pyridin-2-yl)benzamide (1l)

Page S20

S4.x. 13C-NMR Spectrum of 2,4,5-trimethoxy-N-(pyridin-2-yl)benzamide (1l)

405060708090100110120130140150160170f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

c13-shreyansAM-9 56

.20

56.3

056

.35

56.4

960

.96

60.9

9

76.7

676

.78

77.0

277

.04

77.2

777

.29

104.

9210

4.98

107.

43

119.

89

129.

16

139.

33

146.

63

151.

7215

3.28

165.

67

Parameter Value

1 Data File Name E:/ NMR-NPC-P/ 13-jan-c13-mcd-2a/ c13-shreyans/ 13/ fid

2 Title c13-shreyans

3 Comment AM-9

4 Origin Bruker BioSpin GmbH

5 Owner IIIM

6 Site

7 Spectrometer spect

8 Author

9 Solvent CDCl3

10 Temperature 682.0

11 PulseSequence

zgpg30

12 Number ofScans

10240

13 Receiver Gain 1825

14 RelaxationDelay

1.0000

15 Pulse Width 8.4500

16 AcquisitionTime

1.0420

17 AcquisitionDate

2014-01-13T22:55:42

18 ModificationDate

2014-01-13T22:55:48

19 SpectrometerFrequency

125.76

20 Spectral Width 31446.5

21 LowestFrequency

-3148.0

22 Nucleus 13C

23 Acquired Size 32768

24 Spectral Size 65536

Page S21

S4.y. 1H NMR spectrum of 4-chloro-N-hydroxy-N-phenylbenzamide (2a) in CDCl3

6.16.26.36.46.56.66.76.86.97.07.17.27.37.47.57.67.77.87.98.08.1f1 (ppm)

-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

7500#Amide 3 (4-Cl BA NB)Amide-3

1.03

2.32

2.07

2.35

1.00

2.05

7.16

7.18

7.19

7.26

7.32

7.37

7.39

7.41

7.47

7.49

7.62

7.64

7.75

7.81

7.84

S4.z. 13C NMR spectrum of 4-chloro-N-hydroxy-N-phenylbenzamide (2a) in CDCl3

0102030405060708090100110120130140150f1 (ppm)

-200

-100

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

1900

2000

2100

2200

2300

240016-jan-c13-aravindAM3 12

0.22

124.

8212

8.45

129.

0912

9.17

137.

6413

8.08

150.

35

Parameter Value

1 Data FileName

E:/ NMR-NPC-P/ProcessedNMR Data/SHREYANSNMR Data/Methodoloy/Amide/#Amide 3 (4-Cl BA NB)/16-jan-c13-aravind/ 7/fid

2 Title 16-jan-c13-aravind

3 Comment AM3

4 Origin BrukerBioSpin GmbH

5 Owner IIIM

6 Site

7 Spectrometer spect

8 Author

9 Solvent CDCl3

10 Temperature 681.5

11 PulseSequence

zgpg30

12 Number ofScans

1600

13 Receiver Gain 1626

14 RelaxationDelay

1.0000

15 Pulse Width 8.4500

16 AcquisitionTime

1.0420

17 AcquisitionDate

2014-01-16T14:55:34

18 ModificationDate

2014-01-16T16:08:10

19 SpectrometerFrequency

125.76

20 SpectralWidth

31446.5

21 LowestFrequency

-3151.0

22 Nucleus 13C

23 Acquired Size 32768

24 Spectral Size 65536

1

2

3

4

5

6 7

N8

O9

10

11

12

13

14

15

Cl16

OH17

121123125127129131133135137139f1 (ppm)

0

100

200

300

400

500

16-jan-c13-aravindAM3 12

0.22

124.

82

128.

4512

9.09

129.

17

137.

6413

8.08

Page S22

Section S5. References associated with ESI

1. (a) S. K. Jain, S. B. Bharate and R. A. Vishwakarma, Mini-Rev. Med. Chem., 2012, 12, 632-649; (b) S. K. Jain, S. Meena, B. Singh, J. B. Bharate, P. Joshi, V. P. Singh, R. A. Vishwakarma and S. B. Bharate, RSC Adv., 2012, 2, 8929-8933.

2. M. A. Ibrahim, T. E. Ali, Y. A. Alnamer and Y. A. Gabr, ARKIVOC, 2010, 1, 98-135.3. A. Maltha, T. L. F. Favre, H. F. Kist, A. P. Zuur and V. Ponec, J. Catal., 1994, 149, 364-

374.4. (a) A. G. Leach and K. N. Houk, J. Am. Chem. Soc., 2002, 124, 14820-14821; (b) H.

Yamamoto and N. Momiyama, Chem. Comm., 2005, 3514-3525.5. (a) J. C. Stowell, J. Org. Chem., 1971, 6, 3055-3056; (b) I. V. Semin, V. A. Sokolenko and

M. S. Tovbis, Russ. J. Org. Chem., 2007, 43, 544-547; (c) H. Vancik, V. Simunic-Meznaric, I. Caleta, E. Mestrovic, S. Milovac, K. Mlinaric-Majerski and J. Veljkovic, J. Phy. Chem. B, 2002, 106, 1576-1580.