Tetrahedron Letters 54 (2013) 2140–2142

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Tetrahedron Letters

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Synthesis of nitrogen-containing heterocyclic compounds by photooxidationof aromatic azides

Ekaterina Chainikova ⇑, Rustam Safiullin, Leonid Spirikhin, Alexey ErastovInstitute of Organic Chemistry, Ufa Scientific Center, The Russian Academy of Sciences, 71 Prosp. Oktyabrya, 450054 Ufa, Russian Federation

a r t i c l e i n f o

Article history:Received 9 October 2012Revised 23 January 2013Accepted 13 February 2013Available online 20 February 2013

Keywords:Aromatic azidesArylnitroso oxidesNitrile oxidesNitrogen-containing heterocycliccompounds

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⇑ Corresponding author. Tel.: +7 347 235 5496; faxE-mail address: kinetic@anrb.ru (E. Chainikova).

a b s t r a c t

It is shown that the photolysis of certain aromatic azides in the presence of oxygen leads to the formationof nitrogen-containing heterocyclic compounds via a domino reaction sequence.

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N3

R

hν

-N2

1N

R

3N

R

O2

O2

N

R

OO

NOO

OON

O

Δ

Δ ΔNO

On photolysis of aromatic azides under aerobic conditions theinteraction of triplet nitrenes with molecular oxygen leads to nitro-so oxides as labile intermediates:1

ArN3hν

- N21ArN 3ArN

O2ArNOO

As the N–O bond in the NOO group has a bond order of 1.5,2 ni-troso oxides exist as cis and trans isomers:

Ar NOO

Ar NO O

cis trans

Both isomeric forms are consumed by a first-order law.3 For a longtime the corresponding nitro- and nitrosobenzenes were consideredto be the main products of transformations of nitroso oxides.4 How-ever, using 4-methoxyphenyl azide as an example, we have shownthat photolysis of aromatic azides in the presence of oxygen proceedsvia a sequence of domino transformations consisting of six steps(Scheme 1).5 According to this scheme, unimolecular decay of thetrans form of nitroso oxides occurs through isomerization into thecis form. Transformations of the cis form lead to the final product—

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a conjugated diene with nitrile oxide and aldehyde groups at the ter-mini of the molecule. It should be noted, that these reactions involv-ing consumption of isomeric forms of nitroso oxides are thermal.5

Nitrile oxides are important synthetic intermediates, which areusually rather unstable compounds. Nitrile oxide formed from 4-methoxyphenylnitroso oxide (Scheme 1, R = CH3O), was stable en-ough that we were able to obtain it in an amount sufficient to beidentified.5 Nitrile oxides with a favorable structure undergo intra-molecular cyclization to form stable heterocyclic products. This per-mits nitrogen-containing heterocyclic compounds to be obtainedfrom some aromatic azides. In addition, the task of the accumulationand identification of the final products of the transformations of ni-troso oxides is simplified, because we are dealing with stable com-pounds. This facilitates the verification of the proposed mechanism(Scheme 1) for nitroso oxides of different structures.

R R R

Scheme 1. Mechanism of the photooxidation of aromatic azides.

ON

ON

ON

CH3CH3HO

O

CH3H CH3 CH3 CH3

H

4a 4b 4c

O

Figure 1. Stereoisomeric forms of benzisoxazole 4.

E. Chainikova et al. / Tetrahedron Letters 54 (2013) 2140–2142 2141

The present communication is devoted to a study of the mech-anism of the photooxidation of 4-[(2E)-1-methylbut-2-en-1-yl]-phenyl azide (1) and 6-azidoquinoline (2). The products ofphotolysis of 1 and 2 in the presence of oxygen at 293 K wereinvestigated. The possibility of the synthesis of benzisoxazole andindolizine derivatives from aromatic azides is also presented.

N3

CH3 CH31

N

N3

2

On the basis of the results obtained earlier for 4-methoxyphenyl-nitroso oxide as an example5 (Scheme 1), and taking into accountthe ability of nitrile oxides to undergo intramolecular cycloadditionto the double bond,6 we expected that photooxidation of azide 1would occur in accordance with Scheme 2.

Photolysis of a solution of azide 1 (1 � 10�3 M) in acetonitrilesaturated with oxygen was performed with a filtered xenon lamp(k = 300–380 nm) at 293 K. The irradiation wavelength range waschosen to minimize possible photolytic reactions of the nitrosooxide. The progress of the reaction was monitored by reverse-phase HPLC.7 Judging from the chromatogram of the reaction mix-ture, the photooxidation of azide 1 yielded a single product, whichwas isolated and identified as (3,4-dimethyl-3a,4-dihydro-2,1-ben-zisoxazol-5(3H)-ylidene)acetaldehyde (4) (Scheme 2). Benzisoxaz-ole 4 is formed as a mixture of three stereoisomers 4a, 4b, and 4c inthe ratio 52:30:18 (Fig. 1).8

The parent azide was used as a racemic mixture, so the isomer-ism of compound 4 is caused by cis/trans orientation of the methylsubstituent at C(4). In addition, the isomers differ in the position ofthe aldehyde group with respect to the double bond C(5)@C(10). Inaccordance with Scheme 2, the location of the substituents must bemaintained during the formation of nitrile oxide 3 from thearomatic ring. In this case, the formation of benzisoxazole 4 witha trans aldehyde group, as in the isomers 4b and 4c, would beexpected. However, the conformer 4a prevails in the mixture(52%), possibly due to trans–cis isomerization of the nitrile oxide3 via keto–enol tautomerism:

N3hν

-N2

CH3 CH3

1N

CH3 CH3

3N

CH3 CH3

O2

O2

N

CH3 CH3

N

CH3 CH3

OO

OO

CH3 CH3

OON

CH3 CH3

OON

CH3CH3

O

Δ

Δ

ΔΔ

3

12

34

56

7

9

3a

8

11

7a

10

4

NO

1

Scheme 2. Proposed mechanism for the photooxidation of azide 1.

CH3 CH3

O

CH3 CH3

OH

CH3 CH3

O

N

ON

ON

O

Based on the results of Albini,9 who studied the products of pho-tolysis of phenazines in the presence of oxygen, and on the basisof our results, it is expected that the mechanism shown in Scheme3, takes place during the photooxidation of azide 2.

Indeed, we have identified 3-nitrosoindolizine-8-carbaldehyde(5) as the major product. It is formed in monomeric 5a and di-meric form 5b, which is typical for nitroso compounds.10 The ra-tio of 5a and 5b in the NMR solution was �50:50. In addition, asmall amount of 6-nitroquinoline (6) was isolated.11

To elucidate the effect of the irradiation wavelength range ofthe photolytic source on the yield of the photooxidation productsof azide 2, we performed a quantitative analysis of reactionmixtures using HPLC without isolation of the products (Table 1).In this case, there was no loss of reaction products as is inevitablefor preparative separation, and the results of the analysis reflectthe mechanism of the process studied more adequately. Thereaction was carried out by irradiation of solutions of azide 2(�1 � 10�4 M) in acetonitrile saturated with oxygen using afiltered xenon lamp until consumption of the azide was complete.The data in Table 1 shows that narrowing the wavelength rangedecreased the yield of 6-nitroquinoline (6) and led to anincreased yield of nitroso compound 5.

It is known that the absorption maximum of aromatic nitrosooxides is usually located in the long-wavelength spectral region(kmax >400 nm).3 Therefore, our results demonstrate the photo-chemical nature of the isomerization of ArNOO into ArNO2:

N

OON

N

NOO

6

hν

This reaction is likely to proceed through the formation of anintermediate cyclic isomer of nitroso oxide—a dioxaziridine.

In conclusion, we have demonstrated that the main product ofthe photooxidation of an aromatic azide containing an allyl sub-stituent at the para-position as in 1 is benzisoxazole 4. 6-Azido-quinoline (2) is transformed into indolizine-type compound 5.The reaction proceeds at room temperature via a sequence ofdomino transformations involving the formation of the corre-sponding intermediate nitroso oxide. The latter is isomerizedwith opening of the aromatic ring to form a nitrile oxide, intra-molecular cyclization of which leads to the final product. The ni-troso oxide is transformed into a nitro compound by thephotochemical route only.

N

N3 hν-N2

O2

O2Δ

Δ

Δ

N

1N

N

3N N

NOO

N

NOO

N

OON

NN

O

NO

Δ

ONO

1

2

4

3

6

5

7

910 8

N NN NO

O

O O

5a5b

2

Scheme 3. Proposed mechanism for the photooxidation of azide 2.

Table 1The yields of the products of photooxidation of 6-azidoquinoline (2) in acetonitrile at293 K

Photolytic source wavelength range (nm) [2]0 (M) Yielda (%)

5 6

>300 1.07 � 10�4 70 14270–380 1.09 � 10�4 84 4300–380 1.03 � 10�4 86 3300–380 1.06 � 10�4 95 4300–380 1.08 � 10�4 87 4

a Per consumed azide.

2142 E. Chainikova et al. / Tetrahedron Letters 54 (2013) 2140–2142

Acknowledgments

This work was supported by the Russian Academy of Sciences(Department of Chemistry and Material Sciences program ‘Chemi-cal Reaction Intermediates: Their Detection, Stabilization, andDetermination of Structural Parameters’) and by the Russian Foun-dation for BasicResearch, Project No. 13-03-00201. The authors aregrateful to Dr. Rail R. Gataullin for the development of the methodfor the synthesis of 4-[(2E)-1-methylbut-2-en-1-yl]aniline.

Supplementary data

Supplementary data (experimental procedure, characterizationdata of compounds and copies of 1H NMR, 13C NMR spectra andHPLC chromatograms) associated with this article can be found,in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.02.036.

References and notes

1. (a) Gritsan, N. P.; Pritchina, E. A. Russ. Chem. Rev. 1992, 61, 500–516; (b) Gritsan,N. P. Russ. Chem. Rev. 2007, 76, 1139–1160; (c) Ishiguro, K.; Sawaki, Y. Bull.Chem. Soc. Jpn. 2000, 73, 535–552; (d) Sawwan, N.; Greer, A. Chem. Rev. 2007,107, 3247–3285.

2. Talipov, M. R.; Ryzhkov, A. B.; Khursan, S. L.; Safiullin, R. L. J. Struct. Chem. 2006,47, 1051–1057.

3. Chainikova, E. M.; Khursan, S. L.; Safiullin, R. L. Kinet. Catal. 2006, 47, 549–554.4. (a) Abramovitch, R. A.; Challand, S. R. J. Chem. Soc., Chem. Commun. 1972, 964–

966; (b) Go, C. L.; Waddel, W. H. J. Org. Chem. 1983, 48, 2897–2900; (c)Pritchina, E. A.; Gritsan, N. P. Photochem. Photobiol., A 1988, 43, 165–182; (d)Gritsan, N. P.; Pritchina, E. A. J. Inf. Rec. Mater. 1989, 17, 391–404; (e) Safiullin, R.L.; Khursan, S. L.; Chainikova, E. M.; Danilov, V. T. Kinet. Catal. 2004, 45, 640–648.

5. Chainikova, E. M.; Safiullin, R. L.; Spirikhin, L. V.; Abdullin, M. F. J. Phys. Chem. A2012, 116, 8142–8147.

6. (a) Annuziata, R.; Cinquini, M.; Cozzi, F.; Gennari, C.; Raimondi, L. J. Org. Chem.1987, 52, 4674–4681; (b) Hassner, A.; Amarasekara, A.; Padwa, A.; Bullock, W.H. . Tetrahedron Lett. 1988, 29, 715–718; (c) Gothelf, K. V.; Jørgensen, K. A. Chem.Rev. 1998, 98, 863–910.

7. Photooxidation of 4-[(2E)-1-methylbut-2-en-1-yl]phenyl azide (1): azide 1(6.5 mg, 0.035 mmol) was dissolved in 35 mL of MeCN and placed in a

thermostatically controlled (20 �C) quartz reactor. To saturate the solution withoxygen, O2 was bubbled through it for 5 min. The resulting solution was furtherpurged with O2 and irradiated by means of a xenon lamp through BS-4 andUFS-2 filters (300–380 nm) until the starting material had disappeared. Thereaction mixture was concentrated to about 0.5 mL and separatedchromatographically [Luna 10 lm C18 10 � 250 mm column (Phenomenex),eluent: MeCN].

8. Benzisoxazole 4 was obtained in amount of 4.7 mg (70% per consumed azide).Spectral data for the stereoisomers of (3,4-dimethyl-3a,4-dihydro-2,1-benzisoxazol-5(3H)-ylidene)acetaldehyde (4): Compound 4a—1H NMR(500 MHz, CD3CN): d (ppm) = 10.06 (d, J = 7.9 Hz, 1H, CHO), 6.72 (d,J = 9.7 Hz, 1H, H6), 6.57 (d, J = 9.7 Hz, 1H, H7), 5.96 (d, J = 7.9 Hz, 1H, H10),4.52 (m, 1H, H3), 3.95 (m, 1H, H4), 3.18 (dd, J = 12.6 Hz, J = 6.3 Hz, 1H, H3a),1.46 (d, J = 6.3 Hz, 3H, H8), 1.12 (d, J = 6.9 Hz, 3H, H9). 13C NMR (125 MHz,CD3CN): d (ppm) = 192.01 (C11), 159.01 (C7a), 156.88 (C5), 136.35 (C6), 128.42(C7), 123.96 (C10), 80.25 (C3), 54.42 (C3a), 30.40 (C4), 18.85 (C8), 16.53 (C9).Compound 4b—1H NMR (500 MHz, CD3CN): d (ppm) = 10.15 (d, J = 7.7, 1H,CHO), 7.46 (d, J = 9.9 Hz, 1H, H6), 6.78 (d, J = 9.9 Hz, 1H, H7), 5.92 (d, J = 7.7 Hz,1H, H10), 4.47 (m, 1H, H3), 3.20 (dd, J = 12.6 Hz, J = 6.3 Hz, 1H, H3a), 2.97 (m,1H, H4), 1.44 (d, J = 6.1 Hz, 3H, H8), 1.05 (d, J = 6.3 Hz, 3H, H9). 13C NMR(125 MHz, CD3CN): d (ppm) = 191.90 (C11), 158.72 (C7a), 156.75 (C5), 128.97(C6), 128.54 (C7), 123.75 (C10), 80.37 (C3), 54.60 (C3a), 37.96 (C4), 18.72 (C8),16.23 (C9). Compound 4c—1H NMR (500 MHz, CD3CN): d (ppm) = 10.20 (d,J = 7.5 Hz, 1H, CHO); 7.62 (d, J = 10.0 Hz, 1H, H6), 6.76 (d, J = 10.0 Hz, 1H, H7),5.91 (d, J = 7.5 Hz, 1H, H10), 4.34 (m, 1H, H3), 2.75 (m, J = 6.3 Hz, J = 6.3 Hz, 1H,H4), 2.72 (dd, J = 12.0 Hz, J = 6.3 Hz, 1H, H3a), 1.52 (d, J = 6.3 Hz, 3H, H8), 1.20(d, J = 6.9 Hz, 3H, H9). 13C NMR (125 MHz, CD3CN): d (ppm) = 191.88 (C11),158.25 (C7a), 156.92 (C5), 131.96 (C6), 126.66 (C7), 123.52 (C10), 84.46 (C3),56.41 (C3a), 39.87 (C4), 19.97 (C8), 14.95 (C9). MS (EI, 70 eV), m/z (%): 191 [M]+�

(100), 176 [M�CH3]+ (33.9), 165 [M�C2H2]+� (4.6), 162 [M�CHO]+ (10.0), 149[M�CHCHO] +� (20.0), 147 [M�C2H4O] +� (49.8), 132 [M�C2H5NO] +� (24.6). HR-MS (EI) Calcd for C11H13NO2 [M]+: 191.0941. Found: 191.0932. UV–vis (MeCN):kmax = 313 nm (e = 1.55 � 104 M�1 cm�1).

9. Albini, A.; Bettinetti, G.; Minoli, G. J. Org. Chem. 1987, 52, 1245–1251.10. The Chemistry of the Nitro and Nitroso Groups; Feuer, H., Ed.; John Wiley & Sons:

New York, 1969. Part 1.11. Photooxidation of 6-azidoquinoline (2): azide 2 (13.5 mg, 0.079 mmol) was

dissolved in 80 mL of MeCN. The experimental conditions were the same asthose for the corresponding experiment with azide 1. 3-Nitrosoindolizine-8-carbaldehyde (5) (8.3 mg, 60%) and 6-nitroquinoline (6) (1.3 mg, 9%) wereobtained. Compound 5 is a green solid. Selected physical and spectral data for 3-nitrosoindolizine-8-carbaldehyde (5): UV–vis (MeCN): kmax (nm) = 300, 416,677; mp 200–202 �C. Compound 5a—1H NMR (500 MHz, CD3CN): d(ppm) = 10.19 (s, 1H, CHO); 10.01 (dd, J = 7.1 Hz, J = 1.1 Hz, 1H, H5), 8.26 (dd,J = 7.1 Hz, J = 1.1 Hz, 1H, H7), 7.47 (d, J = 5.1 Hz, 1H, H1), 7.45 (t, J = 7.1 Hz, 1H,H6), 6.86 (d, J = 5.1 Hz, 1H, H2). 13C NMR (125 MHz, CD3CN): d (ppm) = 191.87(C10), 162.01 (C3), 139.52 (C7), 135.84 (C9), 128.94 (C5), 126.50 (C8), 117.36(C6), 109.70 (C1), 104.35 (C2). Compound 5b—1H NMR (500 MHz, CD3CN): d(ppm) = 10.23 (s, 2H, CHO), 10.17 (dd, J = 7.1 Hz, J = 1.1 Hz, 2H, H5, 50), 8.42 (d,J = 5.1 Hz, 2H, H1, 10), 8.27 (dd, J = 7.1 Hz, J = 1.1 Hz, 2H, H7, 70), 7.66 (d,J = 5.1 Hz, 2H, H2, 20), 7.48 (t, J = 7.1 Hz, 2H, H6, 60). 13C NMR (125 MHz,CD3CN): d (ppm) = 192.03 (2C, C10, 100), 156.31 (2C, C3, 30), 140.00 (2C, C7, 70),135.40 (2C, C1, 10), 131.68 (2C, C5, 50), 128.25 (2C, C9, 90), 126.50 (2C, C8, 80),120.45 (2C, C6, 60), 110.69 (2C, C2, 20). MS (EI, 70 eV), m/z (%): 174 [M]+� (100),144 [M�NO]+ (32.5), 130 [M�CH2NO]+ (13.2), 116 [M�NO–CO]+ (36.1), 89[M�NO–CO–HCN]+ (26.5). HR-MS (EI) Calcd for C9H6N2O2 [M]+: 174.0424.Found: 174.0420. 6-Nitroquinoline (6) (CAS 613503) was identified by massspectrometry. The similarity index for the library and recorded spectra was93%. Selected spectral data for 6-nitroquinoline: MS (EI, 70 eV), m/z (%): 174 [M]+

(100), 144 [M�NO]+ (6.0), 128 [M�NO2]+ (82.0). HRMS (EI) Calcd for C9H6N2O2

[M]+: 174.0424. Found: 174.0418. 1H NMR (500 MHz, CD3CN): d (ppm) = 9.09(dd, J = 4.2 Hz, J = 1.5 Hz, 1H), 8.91 (d, J = 2.5 Hz, 1H), 8.53 (d, J = 8.3 Hz, 1H),8.46 (dd, J = 9.3 Hz, J = 2.5 Hz, 1H), 8.21 (d, J = 9.3 Hz, 1H), 7.68 (dd, J = 8.3 Hz,J = 4.2 Hz, 1H).