Rh(II)-catalysed reactions of 2H-azirines with ethyl 2-acyl-2- diazoacetates. Synthesis of novel photochromic oxazines

Article abstract of DOI:10.1016/j.tetlet.2009.09.033

Photochromic non-fused 2H-1,4-oxazines are synthesised by a Rh ₂(OAc)₄-catalysed reaction of 2H-azirines with ethyl 2-acyl-2-diazoacetates. The reaction proceeds via the formation of an azirinium ylide which undergoes ring-opening to

Full text of DOI:10.1016/j.tetlet.2009.09.033

Tetrahedron Letters 50 (2009) 6509–6511
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Rh(II)-Catalysed reactions of 2H-azirines with ethyl 2-acyl-2-diazoacetates.
Synthesis of novel photochromic oxazines
*
Vsevolod A. Khlebnikov, Mikhail S. Novikov , Alexander F. Khlebnikov, Nikolai V. Rostovskii
Department of Chemistry, Saint Petersburg State University, Universitetskii pr. 26, 198504 St. Petersburg, Petrodvorets, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2009
Revised 21 August 2009
Accepted 4 September 2009
Available online 10 September 2009
Photochromic non-fused 2H-1,4-oxazines are synthesised by a Rh2(OAc)4-catalysed reaction of 2H-azi-
rines with ethyl 2-acyl-2-diazoacetates. The reaction proceeds via the formation of an azirinium ylide
which undergoes ring-opening to a 2-azadiene followed by 1,6-electrocyclisation.
Ó 2009 Elsevier Ltd. All rights reserved.
Photochromism is
a
phenomenon involving photoinduced
Earlier we found that 2,3-di- and 2,2,3-trisubstituted 2H-azi-
rines react with dimethyl diazomalonate and methyl 2-diazo-2-
phenylacetate in dichloromethane under reflux in the presence of
Rh2(OAc)4 as catalyst to give substituted 2-azadienes in good yields
(Scheme 2).11f,g
reversible changes in the visible absorption spectrum. An important
and promising class of organic photochromic materials are spiroox-
azines.1 These molecules contain a fused ring-substituted 2H-1,4-
oxazine moiety in which the C-2 atom is involved in a spiro linkage.
Under UV irradiation these molecules undergo C–O bond cleavage to
give merocyanine open-chain isomers, which cyclise back to the
oxazine in the dark (Scheme 1).
Spirooxazines have excellent fatigue resistance and have been
the subject of intense investigations as to their potential applica-
tions. These include light filters and photo-switching devices,2
photochromic liquid crystals,3 photochromic plastics,4 photochro-
mic substances used in lenses,5 metal-complexing agents6 and
erasable optical disks.7 The structural diversity of 2H-1,4-oxazines
is mainly limited to ortho-fused derivatives (Scheme 1) because of
their synthetic availability. A few simple and effective methods for
their preparation from o-hydroxynitroso compounds, 1-amino-2-
naphthols and several other compounds have been elaborated.1a,c
A few examples of the preparation of photochromic non-spiro
ortho-fused 2H-1,4-oxazines are also known.8 The only known
non-fused 2H-1,4-oxazine is the tricyclic 2-acetoxy-3-acetyl-
substituted oxazine with a norpinane fragment which was isolated
as a by-product (14%) in the reaction of the corresponding oxazin-
3-one with acetyl chloride.9 Attempts to synthesise non-fused spi-
rooxazines by standard procedures have failed.10
According to this protocol, slow addition, over several hours, of
the diazo compound to a boiling solution of the azirine and catalyst
was employed in order to avoid the competing reaction of the
intermediate Rh(II)-carbenoid with the diazo compound.11f,g
The investigation of the reactivity of the diazoketo esters under
these conditions was started with the initial Rh2(OAc)4-catalysed
test reaction of ethyl 2-diazoacetoacetate 2a with 2,3-diphenyl-
2H-azirine 1a. It is known that diazo compound 2a decomposes
in the presence of Rh2(OAc)4 or Cu(hfacac)2 at temperatures over
70 °C in benzene or fluorobenzene.12 In fact, under the above men-
tioned conditions, as well as under reflux in CHCl3, reaction with
2,3-diphenyl-2H-azirine does not occur. This process proceeds,
however, in benzene at 80 °C (protocol A) and unexpectedly led
N
N
O
N
h
ν
O
N
Δ
spirooxazine isomer
(colourless)
merocyanine isomer
(coloured)
In the context of our investigations towards the discovery of no-
vel ylide systems as useful synthons for heterocycle design,11 we
have reacted substituted 2H-azirines with different carbenes and
metallocarbenoids. Herein, the first method for the synthesis of
non-fused 2H-1,4-oxazines, including spiro-derivatives based on
the Rh2(OAc)4-catalysed reaction of 2H-azirines with 2-acyl-2-dia-
zoacetates, is described. The ability of the products to display pho-
tochromic activity is demonstrated.
Scheme 1. Photochromism of spiro benzoxazines.
N2
R2
R3
R2
R1
R1
X
CO2Et
R3
N
X
Rh2(OAc)4
N
CO2Et
CH2Cl2, reflux
X = Ph, CO2Et
* Corresponding author. Tel.: +7 812 428 4021; fax: +7 812 428 6939.
E-mail address: Mikhail.Novikov@pobox.spbu.ru (M.S. Novikov).
Scheme 2. The reaction of azirines with diazo esters.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.033

6510
V. A. Khlebnikov et al. / Tetrahedron Letters 50 (2009) 6509–6511
R3
R2
R3
N2
O
R4
R1
3a,b and azadienes 4a,b (Scheme 4). It was found that azadienes
4a,b could be smoothly converted into oxazines 3a,b by heating.
To remove traces of azadiene 4a the reaction mixture derived from
azirine 1a was heated at reflux for an additional five minutes and
then purified by flash chromatography. In the case of azirine 1b,
the mixture of compounds 3b and 4b was purified by chromatog-
Rh2(OAc)4
R4
+
R2
CO2Et
C6H6, reflux
R1
N
CO2Et
N
O
2a-c
1a-d
3a-g
slow addition
Scheme 3. The reaction of azirines 1a–d with 2-acyl-2-diazoacetates 2a–c (proto-
col A).
Table 1
Rh2(OAc)4-catalysed reaction of azirines 1a–d with diazo compounds 2a–c
Azirine
R1
R2
R3
Diazo
compound
R4
Oxazine
Yield of oxazine 3, %
protocol A/protocol B
Ratio of 3:4 in the reaction
mixture (protocol)
a
1a
1b
1c
1d
1a
1a
1c
Ph
Ph
Ph
4-MeC6H4
Ph
Ph
Ph
Ph
H
2a
2a
2a
2a
2b
2c
2c
Me
Me
Me
Me
Ph
3a
3b
3c
3d
3e
3f
37/75
43/75
11/73
16/81
45/39
32/Traces
30/Traces
12:1 (B)
1:1 (B)
2,20-Biphenylene
H
H
Ph
Ph
H
H
H
H
H
H
3c only (A, B)
3d only (A, B)
3:1 (B)
3f only (A)
3e only (A)
CF3
CF3
3g
a
Measured by 1H NMR spectroscopy directly after decomposition of the last portion of diazo compound.
to the formation of 2H-1,4-oxazine 3a, which was isolated in 37%
yield (Scheme 3).
In this case the isomeric 2-azadiene was not observed in the
reaction mixture. Analogously, oxazines 3b–g were synthesised
in 11–45% yield (Table 1, protocol A) from azirines 1a–d and ethyl
2-acyl-2-diazoacetates 2a–c.13
Experiments to optimise the protocol showed that the yields of
oxazines 3a–d derived from ethyl 2-diazoacetoacetate could be
improved by changing the solvent from benzene to 1,2-dichloro-
ethane as well as the rate of addition of the diazo compound: three
equivalents of diazo compound were added, one equivalent was
added every five minutes (protocol B).13 According to the 1H
NMR data, the reaction in 1,2-dichloroethane gave smaller
amounts of by-products. The decrease of product yield over pro-
longed reaction times was attributed to the lability of the starting
azirines and oxazines formed under the reaction conditions. In the
reactions of 2,3-disubstituted azirines 1a,b with diazo compound
2a, according to 1H NMR data, two products were formed: oxazines
raphy, and 4b was dissolved in ethanol and heated under reflux for
five hours. Azadiene 4b cyclised quantitatively into oxazine 3b,
which crystallised from ethanol. According to this procedure oxa-
zines 3a–d were prepared in 73–81% yields from azirines 1a–d
and ethyl 2-diazoacetoacetate 2a.14 In the reaction mixture ob-
tained from 2,3-diphenylazirine 1a and ethyl benzoyldiazoacetate
2b, 2-azadiene 4b was also detected. However, in this case the
modified procedure had no advantage over protocol A.
In contrast to diazo compounds 2a,b, ethyl 2-diazo-4,4,4-triflu-
oroacetoacetate 2c is rarely utilised in catalytic reactions. A major
obstacle to its use is the number of side reactions of the diazo com-
pound itself as well as the intermediate carbenoid.15 The known
reactions of this diazo compound usually failed to proceed in solu-
tions of inert solvent, but provided good results when the substrate
itself was used as the solvent. Nevertheless, using protocol A, we
succeeded in obtaining the corresponding trifluoromethyl-substi-
tuted oxazines 3f,g, albeit in poor yields. All attempts to prepare
these compounds using protocol B were unsuccessful. The yields
of oxazines 3a–g, prepared according to protocols A and B, as well
as the oxazine/azadiene ratio are shown in Table 1.
2a,b
R3
A mechanistic rationale for the formation of oxazines 3a–g is
shown in Scheme 5. The initial reaction involves attack of the
Rh(II)-carbenoid onto the lone pair of electrons on the nitrogen
of azirine 1 giving stereoisomeric azirinium ylides 5 and 50. Ring-
opening of the three-membered ring led to isomeric azadienes
(E)-4 and (Z)-4. Oxazine 3 is formed via 1,6-electrocyclisation of
azadiene (E)-4. None of the cyclisation products of stereoisomeric
ylide (Z)-5, formed with participation of the ester carbonyl, was de-
R3
O
R4
R4
OEt
O
R2
R1
fast addition
R2
+
1a-d
R1
N
CO2Et
Rh2(OAc)4
1,2-dichloroethane
N
O
3a-e
4a,b,e
Δ
Scheme 4. The reaction of azirines 1a–d with 2-acyl-2-diazoacetates 2a,b (protocol
B).
R2
R1
R2
R3
O
OEt R4
R2
R3
R1
O
R1
O
R3
N
1
N2
RhLn
Rh2(OAc)4
N
N
R4
R4
+
O
CO2Et
CO2Et
C6H6, reflux
R4 OEt
O
O
2
5
′
5
R3
O
R3
O
R3
O
R4
CO2Et
R2
R1
OEt
R4
R2
R1
1,6-electrocyclisation
R4
OEt
O
R2
R1
N
N
N
O
3
(E)-4
(Z)-4
Scheme 5. The proposed mechanism for the formation of oxazines 3 and azadienes 4.

V. A. Khlebnikov et al. / Tetrahedron Letters 50 (2009) 6509–6511
6511
R3
R3
O
9. El Achqar, A.; Boumzebra, M.; Roumestant, M.-L.; Viallefont, P. Tetrahedron
1988, 44, 5319–5332.
10. Christie, R. M.; Agyako, C.; Mitchell, K.; Lyèka, A. Dyes Pigments 1996, 31, 155–
170.
R4
OEt
O
R4
R2
R1
h
ν
R2
R1
N
CO2Et
Δ
N
O
11. (a) Khlebnikov, A. F.; Novikov, M. S.; Kostikov, R. R. Russ. Chem. Rev. 2005, 74,
171–192; (b) Khlebnikov, A. F.; Novikov, M. S.; Kostikov, R. R.; Kopf, J. Russ. J.
Org. Chem. 2005, 41, 1341–1348; (c) Voznyi, I. V.; Novikov, M. S.; Khlebnikov, A.
F. Synlett 2005, 1006–1008; (d) Konev, A. S.; Novikov, M. S.; Khlebnikov, A. F.
Tetrahedron Lett. 2005, 46, 8337–8340; (e) Voznyi, I. V.; Novikov, M. S.;
Khlebnikov, A. F.; Kostikov, R. R. Russ. J. Org. Chem. 2006, 42, 689–695; (f)
Khlebnikov, A. F.; Novikov, M. S.; Amer, A. A. Tetrahedron Lett. 2004, 45, 6003–
6006; (g) Khlebnikov, A. F.; Novikov, M. S.; Amer, A. A.; Kostikov, R. R.; Magull,
J.; Vidovic, D. Russ. J. Org. Chem. 2006, 42, 515–526; (h) Novikov, M. S.; Amer, A.
A.; Khlebnikov, A. F. Tetrahedron Lett. 2006, 47, 639–642; (i) Shinkevich, E. Yu.;
Novikov, M. S.; Khlebnikov, A. F. Synthesis 2007, 2, 225–230; (j) Konev, A. S.;
Novikov, M. S.; Khlebnikov, A. F. Russ. J. Org. Chem. 2007, 43, 286–296; (k)
Kadina, A. P.; Novikov, M. S.; Khlebnikov, A. F.; Magull, J. Chem. Heterocycl.
Compd. 2008, 44, 576–584; (l) Shinkevich, E. Yu.; Abbaspour Tehrani, K.;
Khlebnikov, A. F.; Novikov, M. S. Tetrahedron 2008, 64, 7524–7530; (m)
Khistiaev, K. A.; Novikov, M. S.; Khlebnikov, A. F.; Magull, J. Tetrahedron Lett.
2008, 49, 1237–1240; (n) Khlebnikov, A. F.; Novikov, M. S.; Dolgikh, S. A.;
Magull, J. ARKIVOC 2008, 9, 94–115; (o) Konev, A. S.; Khlebnikov, A. F. Collect.
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3
4
Scheme 6. Photochromic activity of oxazines 3a–e.
tected in the reaction mixture. It should be noted that previously,
we never observed the electrocyclisation of 2-azadienes via the
oxygen of the ester group (Scheme 2).11f,g Apparently, the isomeri-
sation (Z)-4 ? (E)-4 occurs under heating. The rate of the process
depends strongly upon the substitution pattern of the C@C bond
in the azadiene and decreases with an increased number of aryl
groups.
It was found that oxazines 3a–e are photochromic compounds.
Thus, according to 1H NMR spectroscopy, a colourless 0.03 M solu-
tion of oxazine 3a in C6D6 is converted into a yellow–orange solu-
tion of azadiene 4a under UV irradiation (Tungsram HGOK 400
lamp) at 45 °C for 2.5 h (93% conversion) (Scheme 6). The half-life
time of the reverse ‘dark’ cyclisation reaction of 4a into 3a is 80 h
at 20 °C. The process of bleaching is accelerated by heating and
proceeds completely after 20 min at reflux in C6D6.
12. (a) Brooks, G.; Howarth, T. T.; Hunt, E. J. Chem. Soc., Chem. Commun. 1981, 642–
643; (b) Maryanoff, B. E. J. Org. Chem. 1982, 47, 3000–3002; (c) Maryanoff, B. E.
J. Org. Chem. 1979, 44, 4410–4419; (d) Alonso, M. E.; Morales, A.; Chitty, A. W. J.
Org. Chem. 1982, 47, 3747–3754.
13. General procedure for the preparation of oxazines 3a–g. Protocol A. A solution of
diazo compounds 2a–c (1 mmol) in anhydrous benzene (1 mL) was added
In conclusion, the Rh2(OAc)4-catalysed reaction of 2H-azirines
with 2-acyl-2-diazoacetates provides a convenient synthetic ap-
proach to non-fused 2H-1,4-oxazines. The process occurs consecu-
tively via an unstable azirinium ylide and 2-azadiene, followed by
electrocyclisation involving the keto group. 1,4-Oxazines obtained
by this method are the first representatives of monocyclic 2H-1,4-
oxazine derivatives which possess photochromic activity. Further
studies on this reaction and the photochromic properties of the
2H-1,4-oxazines formed are currently ongoing in our laboratory.
dropwise over 3 h to
a stirred solution of azirines 1a–d (1 mmol) and
Rh2(OAc)4 (5 mg) in anhydrous benzene (4 mL) at reflux under an argon
atmosphere. The solvent was evaporated under vacuum and the residue was
purified by flash chromatography on silica gel (eluent: hexane–Et2O) to give,
after crystallisation from hexane–Et2O, compounds 3a–g. Protocol B. A solution
of azirines 1a–d (1 mmol) and diazo compounds 2a, b (1 mmol) in anhydrous
dichloroethane (4 mL) was heated to reflux under an argon atmosphere and
then Rh2(OAc)4 (5 mg) was added. The mixture was stirred under reflux until
nitrogen stopped flowing from the outlet (from 5 min for diazo compound 2a
to 15 min for diazo compound 2b), after which the next two equivalents of
diazo compound were added consecutively after 5 min (diazo compound 2a) or
15 min (diazo compound 2b) periods. The resulting mixture was evaporated
under reduced pressure and the residue was purified by flash chromatography
on silica gel using hexane–Et2O followed by recrystallisation from hexane–
Et2O to give oxazines 3a, c, d as colourless solids. In the case of the reaction of
azirine 1b with diazo compound 2a the mixture of compounds 3b and 4b was
separated by flash chromatography, dissolved in ethanol and heated under
reflux for 5 h. Crystallisation from ethanol afforded oxazine 3b as a colourless
solid.
Acknowledgement
We gratefully acknowledge the financial support of the Russian
Foundation for Basic Research (project 08-03-00112).
14. Ethyl 6-methyl-2,3-diphenyl-2H-1,4-oxazine-5-carboxylate (3a), mp 128–129 °C
References and notes
(from hexane–Et2O). IR (CHCl3) m
max: 1725 (CO). 1H NMR (300 MHz, CDCl3):
1.21 (3H, t, J = 7.1 Hz, CH3), 2.13 (3H, s, CH3), 4.15 (2H, q, J = 7.1 Hz, CH2), 6.13
(1H, s, H-2), 7.15–7.25 (8H, m, Ph), 7.65–7.72 (2H, m, Ph). 13C NMR (75 MHz,
CDCl3): d 14.4 (CH3), 18.6 (CH3), 60.5 (OCH2), 72.3 (2-C), 119.8 (5-C), 126.8,
127.8, 128.6, 128.8, 129.3, 130.4, 134.9, 135.6 (Ph), 149.3 (6-C), 155.1 (3-C),
165.7 (C@O). Found: C, 74.73; H, 6.00; N, 4.44. Calcd for C20H19NO3: C, 74.75; H,
5.96; N, 4.36. Ethyl 6-methyl-3-(4-methylphenyl)-2H-1,4-oxazine-5-carboxylate
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(3d), mp 61–62 °C (from hexane–Et2O); IR (CHCl3) m
max: 1720 (CO). 1H NMR
(300 MHz, CDCl3): 1.41 (3H, t, J = 7.1 Hz, CH3), 2.40 (6H, s, 2CH3), 4.36 (2H, q,
J = 7.1 Hz, OCH2), 4.79 (2H, s, CH2), 7.25 (2H, d, J = 8.2 Hz, Ar), 7.77 (2H, d,
J = 8.2 Hz, Ar). 13C NMR (75 MHz, CDCl3): d 14.4 (CH3), 17.9 (CH3), 21.4 (CH3),
60.5 (OCH2), 62.0 (CH2), 120.5 (5-C), 126.5, 129.3, 132.2, 140.9 (Ar), 148.3 (6-C),
157.3 (3-C), 165.8 (C@O). Found: C, 69.36; H, 6.50; N, 5.31. Calcd for
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H), 126.9, 127.3, 128.3, 128.4, 128.5, 129.6, 135.5, 137.2 (Ph), 145.3 (C–N),
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