Azirinium ylides from α-diazoketones and 2H-azirines on the route to 2H-1,4-oxazines: Three-membered ring opening vs 1,5-cyclization

Article abstract of DOI:10.3762/bjoc.11.35

Strained azirinium ylides derived from 2H-azirines and α-diazoketones under Rh(II)-catalysis can undergo either irreversible ring opening across the N-C2 bond to 2-azabuta-1,3-dienes that further cyclize to 2H-1,4-oxazines or reversibly undergo a 1,5-cycl

Full text of DOI:10.3762/bjoc.11.35

Azirinium ylides from α-diazoketones and 2H-azirines
on the route to 2H-1,4-oxazines: three-membered
ring opening vs 1,5-cyclization
Nikolai V. Rostovskii1, Mikhail S. Novikov*1, Alexander F. Khlebnikov1, Galina L. Starova1
and Margarita S. Avdontseva2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 302–312.
1Institute of Chemistry, Saint-Petersburg State University,
Universitetskii pr. 26, 198504 St. Petersburg, Russia and 2Institute of
Earth Science, Saint-Petersburg State University, Universitetskaya
nab. 7–9, 199034 St. Petersburg, Russia
doi:10.3762/bjoc.11.35
Received: 22 November 2014
Accepted: 13 February 2015
Published: 02 March 2015
Email:
Mikhail S. Novikov* - m.s.novikov@chem.spbu.ru
Associate Editor: J. A. Murphy
* Corresponding author
© 2015 Rostovskii et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
2-azabuta-1,3-dienes; azirines; diazo compounds; nitrogen ylides;
2H-1,4-oxazines
Abstract
Strained azirinium ylides derived from 2H-azirines and α-diazoketones under Rh(II)-catalysis can undergo either irreversible ring
opening across the N–C2 bond to 2-azabuta-1,3-dienes that further cyclize to 2H-1,4-oxazines or reversibly undergo a 1,5-cycliza-
tion to dihydroazireno[2,1-b]oxazoles. Dihydroazireno[2,1-b]oxazoles derived from 3-aryl-2H-azirines and 3-diazoacetylacetone or
ethyl diazoacetoacetate are able to cycloadd to acetyl(methyl)ketene generated from 3-diazoacetylacetone under Rh(II) catalysis to
give 4,6-dioxa-1-azabicyclo[3.2.1]oct-2-ene and/or 5,7-dioxa-1-azabicyclo[4.3.1]deca-3,8-diene-2-one derivatives. According to
DFT calculations (B3LYP/6-31+G(d,p)), the cycloaddition can involve two modes of nucleophilic attack of the dihydroazireno[2,1-
b]oxazole intermediate on acetyl(methyl)ketene followed by aziridine ring opening into atropoisomeric oxazolium betaines and
cyclization. Azirinium ylides generated from 2,3-di- and 2,2,3-triaryl-substituted azirines give rise to only 2-azabuta-1,3-dienes
and/or 2H-1,4-oxazines.
Introduction
2H-Azirines are unique strained compounds which have found applications of these compounds imply cleavage of either the
various applications in organic synthesis due to their ability to N–C2 or N–C3 bond. In these syntheses 2H-azirines serve as
react both with retention and opening of the three-membered C–C–N three-atomic building blocks for the construction of
ring. Even though each of the three bonds in the azirine ring can both acyclic compounds, such as nonproteinogenic amino acids
be cleaved under certain conditions, the majority of synthetic and peptides [1-3], and various 4–7-membered heterocycles
302

Beilstein J. Org. Chem. 2015, 11, 302–312.
[4-11]. The reactions of azirines with acylketenes [12,13], competition between ring opening and 1,5-cyclization in
carboxylic acids [14] and amino acids [1] proceed via N–C3 azirinium ylides, as well as the mechanism of trapping of dihy-
bond cleavage to afford 5,7-dioxa-1-azabicyclo[4.4.1]undeca- droazireno[2,1-b]oxazole intermediates by acetyl(methyl)ketene
3,8-diene derivatives, ketamides, and aminoamides, respective- were investigated by the DFT method.
ly. On the other hand, rhodium carbenoids derived from
α-diazocarbonyl compounds transform 2H-azirines 1 to Results and Discussion
azirinium ylides 5 (Scheme 1) which undergo facile N–C2 bond Rhodium(II) carbenoids generated from α-diazoketones or
cleavage to give 2-azabuta-1,3-dienes 3. Recently we showed 2-diazo-1,3-diketones react with various nitrogen-containing
that the use of α-diazo-β-ketoesters 2 in these reactions, which compounds, such as amines [16], amides [17-19], and nitriles
are finished by 1,6-cyclization of azadienes onto the keto group, [20,21], to give N–H insertion products or N- or N,O-hetero-
provides a rapid access to non-fused 2H-1,4-oxazine-5-carboxy- cyclic systems. The reactivity of acyl- or diacyl-substituted
lates 4, a new type of non-spirocyclic 1,4-oxazine photo- Rh(II) carbenoids toward an sp2-hybridized nitrogen [22-24] is
chromes [15].
much less studied, while examples of their reactions with
2H-azirines are unknown at all. Our study of the chemical
behavior of 2H-azirines under Rh(II)-catalyzed decomposition
of diazoketones was started with searching for optimal condi-
tions for the catalytic reaction of 2,3-diphenyl-2H-azirine (1a)
with 1-diazo-1-phenylpropan-2-one (2a), leading to oxazine 4a.
The most successful procedure involving addition of
Rh2(OAc)4 to a boiling 1:1.25 mixture of azirine 1a and diazo
compound 2a in 1,2-dichloroethane (DCE) (procedure A) gave
rise to oxazine 4a and azadiene Z-3a in 60 and 7% yields, res-
pectively (Scheme 2, Table 1, entry 1). It was also shown that
azadiene Z-3a did not cyclize into oxazine 4a under the reac-
tion conditions. According to our previous computational and
experimental results for transformations of 3,4-diphenyl-substi-
tuted 2-azabuta-1,3-dienes derived from α-diazo-β-ketoesters,
oxazine 4a formed via rapid cyclization of azadiene E-3a [15],
whereas 2-azabuta-1,3-dienes with the C=C bond in Z-configur-
ation have a sufficiently high activation barrier for cyclization
and are usually stable up to 90–100 °C.
Scheme 1: Rh(II)-catalyzed synthesis of photochromic 2H-1,4-
oxazines from 2H-azirines and α-diazo-β-ketoesters.
Oxazine 4b was synthesized in a similar way from azirine 1b
and diazo compound 2a (Table 1, entry 2), but in this case no
traces of azadiene Z-3b were detected. 4,4-Dimethyl- and 4,4-
In the search for new compounds with useful photochromic diphenyl-2-azabuta-1,3-dienes 3c,d derived from azirines 1c,d
characteristics and a high fatigue resistance we focused on (Table 1, entries 3 and 4) showed a different behavior. The
5-unsubstituted, 5-aryl-, and 5-acyl-substituted 2H-1,4- former rapidly cyclized into oxazine 4c, isolated in 58% yield.
oxazines. They could, in principle, be prepared from azirines On the contrary, oxazine 4d was obtained in as low as 7% yield,
and α-diazo ketones or 2-diazo-1,3-diketones via ring opening while the main reaction product was azadiene 3d. Moreover,
across the N–C2 bond in the intermediate azirinium ylides to when dissolved separately in CDCl3, compounds 3d and 4d
form 2-azabuta-1,3-dienes and subsequent cyclization of the both converted into 4.5:1 3d + 4d equilibrium mixtures after a
latter into 2H-1,4-oxazines. In the work reported herein we week at room temperature.
studied Rh(II)-catalyzed reactions of alkyl-, aryl-, and hetaryl-
substituted 2Н-azirines with α-diazo-α-phenylacetone (2a), To prepare a C5-unsubstituted 1,4-oxazine derivative, we
α-diazo-4-chloroacetophenone (2b), and 3-diazoacetylacetone synthesized α-diazo-4-chloroacetophenone (2b) according to
(2c). A new type of transformation of azirinium ylides, specifi- the published procedure [25]. Diazo compound 2b slowly
cally 1,5-cyclization into dihydroazireno[2,1-b]oxazoles decomposes in the presence of Rh2(OAc)4 and 2,2-dimethyl-3-
capable of cycloadding to acyl ketenes, was discovered in the phenylazirine (1c) even at room temperature, but no conversion
study on the reactivity of 3-monosubstituted azirines toward of the latter was observed according to 1H NMR spectroscopy.
3-diazoacetylacetone (2c) under catalytic conditions. The A satisfactory result was obtained, when the reaction was
303

Beilstein J. Org. Chem. 2015, 11, 302–312.
Scheme 2: Rh(II)-catalyzed reaction of azirines 1a−g with diazo compounds 2a–c.
Table 1: Rh(II)-catalyzed reaction of azirines 1a–g with diazo compounds 2a–c (method A, DCE, 84 °C).
Entry
1
Ar
R1
R2
R3
R4
2
Catalyst
Isolated yields, %
3
4
6
7
8
1
2
3
4
5
6
7
8
9
10
1a
1b
1c
1d
1c
1e
1e
1f
Ph
Me
Ph
H
Ph
2a Rh2(OAc)4 7 (Z-a)a 60 (a)
Ph
Me
Ph
H
1-Btb 2a Rh2(OAc)4
55 (b)
58 (c)
Ph
Me
Ph
Me
Ph
Me
H
Me
Ph
Me
H
2a Rh2(OAc)4
Ph
Me
Ph
2a Rh2(OAc)4 75 (d)c 7 (d)
2b Rh2(OAc)4 43 (e)d 67 (e)e
Ph
4-ClC6H4
Me
H
4-MeC6H4
4-MeC6H4
MeCO
MeCO
MeCO
MeCO
MeCO
2c Rh2(OAc)4
2c Rh2(Oct)4
2c Rh2(Oct)4
2c Rh2(Oct)4
2c Rh2(OAc)4
17 (f)
–f
–f
–f
Me
H
H
22 (f)g 23 (f)
7 (f)
4 (f)
4-MeOC6H4 Me
4-NO2C6H4 Me
H
H
18 (g)
58 (h)
47 (i)i
26 (g)h 6 (g) 4 (g)h
13 (h)
1g
1a
H
H
Ph
Me
H
Ph
aCompound Z-3a is a 1.1:1 mixture of isomers across C=N bond. b1H-Benzotriazol-1-yl. cCompound 3d is a 1.2:1 mixture of isomers across C=N
bond. dReaction temperature 60 °C. eObtained from azadiene 3e at 84 °C. fNot isolated. gEt3N-doped eluent for chromatography was used. hThe
yield was determined by 1H NMR spectroscopy with acenaphtene as internal standard. The compound decomposes on silica gel. iThe reaction was
carried out according to method B.
carried out at 60 °С: azirine 1c was completely consumed to enough at room temperature to be isolated by column chroma-
give azadiene 3e isolated by column chromatography in 43% tography (Table 1, entry 5).
yield (Table 1, entry 5). The structure of azadiene 3e was
confirmed by X-ray diffraction analysis (Figure 1). It should be When 3-(p-tolyl)azirine 1e was reacted with diazoacetylacetone
noted that azadiene 3e in crystal exists in the s-trans-con- 2c under similar conditions (Rh2(OAc)4, 60 °C, DCE), four
formation across the single С–N bond (the С2–N1–С3–C4 dihe- products were detected by 1H NMR spectroscopy (Scheme 2,
dral angle is 4.3°, Figure 1), unlike its C4-aryl-substituted Table 1, entry 6). However, chromatography of the reaction
analogs with the angle of 73–75° [26]. The Е-configuration of mixture on silica gel gave only oxazine 4f in 17% yield,
the С=N bond, unfavorable for cyclization into 1,4-oxazine, whereas other compounds completely decomposed. The use of
explains the enhanced thermal stability of compound 3e.
dirhodium tetraoctanoate Rh2(Oct)4 as a catalyst in refluxing
DCE, as well as an Et3N-doped eluent gave a slightly higher
Heating azadiene 3e in DCE under reflux (84 °C) for 3.5 h gave yield of 4f (Table 1, entry 7) and allowed isolation of three
a 6:1 equilibrium mixture of 1,4-oxazine 4e and azadiene 3e byproducts formed via cleavage of the azirine N–C3 bond:
(according to 1Н NMR spectroscopy). Oxazine 4e is stable bicycle 6f (hereinafter referred to as the [3.2.1] adduct), bicycle
304

Beilstein J. Org. Chem. 2015, 11, 302–312.
Figure 1: X-ray crystal structure of azadiene 3e.
7f (hereinafter referred to as the [4.3.1] adduct), and 5,7-dioxa- adduct 7h, which were isolated in 58 and 13% yields, respect-
1-azabicyclo[4.4.1]undeca-3,8-diene derivative 8f. The same ively (Table 1, entry 9). Compounds 6–8 were characterized by
catalyst and the same reaction and purification conditions were standard spectral methods and the structures of adducts 6f and
used in further experiments. Analogous reaction of 4-methoxy- 7h were additionally confirmed by X-ray diffraction analysis
phenyl-substituted azirine 1f yielded the same set of products (Figure 2). The reaction of diazoacetylacetone 2c with 2,3-
(Scheme 2, Table 1, entry 8). Unfortunately, [3.2.1] adduct 6g diphenyl-2H-azirine (1a) provides oxazine 4i as a sole product
and imide 8g were too unstable to be isolated by chromatog- (Table 1, entry 10). It was isolated with the highest yield of
raphy on silica gel, even using Et3N-doped eluents. Their pres- 47% by slow addition of a solution of the diazo compound to a
ence in the reaction mixture was unambiguously confirmed by solution of the azirine and Rh2(OAc)4 in DCE at 60 °С (proce-
1H NMR spectroscopy (Table 1, entry 8). At the same time, dure B).
oxazine 4g and adduct 7g are stable on silica and were isolated
in a pure form. The reaction of azirine 1g containing a 4-nitro- To the best of our knowledge, neither heterocyclic systems
phenyl substituent on C3 produces only oxazine 4h and [4.3.1] with a 4,6-dioxa-1-azabicyclo[3.2.1]oct-2-ene backbone
Figure 2: X-ray crystal structures of compounds 6f and 7h.
305

Beilstein J. Org. Chem. 2015, 11, 302–312.
(compounds 6) nor systems with a 5,7-dioxa-1-azabi- N-benzylideneanisidine and diazoacetylacetone under
cylo[4.4.1]undec-8-ene backbone (compounds 7) have ever Rh2(OAc)4-catalysis undergoes 1,3-cyclization to an aziridine
been reported. On the contrary, bicyclic compounds 8f,g are derivative in high yield, rather than 1,5-cyclization [22].
representatives of a known class of 5,7-dioxa-1-azabi- However, no cyclizations of azirinium ylides, cyclic analogs of
cylo[4.4.1]undeca-3,8-diene-2,10-dione derivatives formed by azomethine ylides, are known. This is not surprising in view of
the recently reported reaction of 3-arylazirines with acyl ketenes the high strain of the azirinium system, and until now ring
generated by thermolysis of 2-diazo-1,3-diketones [12] or opening in these systems seemed much more preferable than
5-arylfuran-2,3-diones [13]. Therefore, the presence of com- annelation of a new cycle. Nevertheless, we decided to study
pounds 8f,g among the reaction products provides evidence for two competing pathways for isomerization of the model
the formation of some amounts of acetyl(methyl)ketene (12) azirinium ylide 9j: ring opening into azadiene 3j and 1,5-
under the reaction conditions, which, in turn, gives us insight to cyclization into azirenooxazole 10j (Scheme 4), by means of
the mechanism of formation of adducts 6 and 7 (Scheme 3). A DFT calculations (B3LYP/6-31+G(d,p)). In addition, two rea-
separate experiment was performed to show that these com- sonable pathways for the formation of adducts 6j and 7j formed
pounds are formed via independent pathways, as they do not from azirenooxazole 10j and ketene 12 were studied at the same
interconvert under the reaction conditions (Rh2(Oct)4, 84 °C, level of theory (Scheme 4).
DCE).
According to the calculations, the barrier to the 1,5-cyclization
We assumed that the reaction sequence leading to bicycles 6 of ylide 9j to compound 10j was found to be even slightly lower
and 7 involves the 1,5-cyclization of azirinium ylide 9f–h to (7.9 kcal/mol) than the barrier to the ring opening across the
dihydroazireno[2,1-b]oxazole 10f–h followed by cycloaddition N–С2 bond to azadiene 3j (10.1 kcal/mol) (Figure 3).
of the latter to ketene 12 to give two regioisomeric adducts 6f,g Azirenooxazole 10j is thermodynamically more stable than
and 7f–h (Scheme 3).
ylide 9j, by ca. 15 kcal/mol, but the barrier to the reverse reac-
tion 10j→9j is not too high (22.6 kcal/mol). The ring opening
Several examples of the 1,5-cyclization of azomethine ylides in azirinium ylide 9j into azadiene 3j, too, has a low activation
bearing an α-keto group into oxazole derivatives were reported barrier but occurs irreversibly. Therefore, azirenooxazole 10j
[27-29]. As also known, the azomethine ylide derived from might form in this reaction, and, moreover, its formation from
Scheme 3: General scheme for the formation of compounds 4,6 and 7.
306

Beilstein J. Org. Chem. 2015, 11, 302–312.
Scheme 4: Possible pathways for the formation of 6j and 7j from azirenooxazole 10j and ketene 12.
Figure 3: Energy profiles [DFT B3LYP/6-31+G(d,p), 357 K, 1,2-dichloroethane (PCM)] for the transformation of ylide 9j into azadiene 3j and dihy-
droazireno[2,1-b]oxazole 10j and for the transformation of 10j to adducts 6j,7j.
307

Beilstein J. Org. Chem. 2015, 11, 302–312.
ylide 9j is kinetically preferred over the formation of azadiene TS8 for alternative betaine 14j formation pathways are very
3j. However, in view of the reversibility of the 1,5-cyclization close in energy, the reaction sequence 10j→13j→14j leading to
9j →10j and in the absence of an active trap for azirenooxazole [3.2.1] adduct 6j seems to be more reasonable than
10j in the reaction mixture, it isomerizes via ylide 9j to a much 10j→15j→14j due to the much higher concentrations of the
more thermodynamically stable open-chain form 3j.
reacting species. Actually, the activation barrier to the bicyclic
C–N bond cleavage in 10j is very low, but the equilibrium
Curiously, the same energy profile (see Supporting Information between 10j and 15j is strongly shifted toward bicyclic isomer
File 1, Scheme S1) was obtained for isomerization of azirinium 10j, and, therefore, carbonyl ylide 15j should be formed in an
ylide 5 (Scheme 1, R1 = Me, R3 = R4 = H, R5 = Ph, Alk = Me) extremely low concentration.
which contains one acyl group and one ester group at the
carbanion center. From these results it follows that 1,5-cycliza- Thus, the computations predict: a) two competing pathways for
tion of azirinium ylides is a general stabilization route for ylides transformation of azirinium ylides derived both from 2-diazo-
derived from diazo compounds containing an α-keto group. 1,3-diketons and α-diazo-β-ketoesters; b) a high reactivity of
However, azirenooxazoles 10 reversibly formed in these reac- azirenooxazole 10j toward acetyl(methyl)ketene (12); c) two
tions could not be detected in the absence of an active electro- competing modes of the attack of 10j on ketene 12, leading to
philic trap in the reaction mixture. 3-Diazoacetylacetone under adducts 6j,7j via two short-lived betaine intermediates 13j,13′j
Rh(II)-catalysis gives, along with a Rh(II) carbenoid, a highly and 14j,14′j.
electrophilic acetyl(methyl)ketene (12) via Wolff rearrange-
ment (Scheme 3).
It is worthy to notice that the distribution of products 6,7
strongly depends on the electronic effects of the para
The nucleophilic attack of the azirenooxazole 10j nitrogen on substituents in the aryl group of 3-aryl-2H-azirine 1. The [3.2.1]
the ketene sp-carbon followed by cyclization provides two adduct is preferably formed from azirines 1e,f with electron-
isomeric adducts 6j and 7j. There are two reasonable pathways donating substituents (Table 1, entries 7 and 8), while 3-(4-
to these unexpected products. The first pathway involves the nitrophenyl)-2H-azirine (1g) provides the [4.3.1] adduct only
addition of bicycle 10j to ketene 12 to form atropoisomeric (Table 1, entry 9).
azirenooxazolium betains 13j,13′j (Scheme 4) which can
further undergo aziridine ring opening to give atropoisomeric It is known that the Rh(II)-catalyzed reaction of 3-aryl-2H-
oxazinium betaines 14j,14′j and their cyclization into adducts azirines with ethyl diazoacetoacetate (2d) gives rise to 2H-1,4-
6j and 7j, respectively. Besides, betaines 14j,14′j can result oxazines as a single product [15]. The absence of products like
from aziridine ring opening in azirenooxazole 10j into carbonyl 6 or 7 may be caused by a decreased propensity of the
ylide 15j and its addition to ketene 12 (Scheme 4).
carbenoid derived from 2d to undergo a Wolff rearrangement
into a ketene derivative. To obtain experimental evidence for
The energy profiles for both the cycloaddition pathways of 10j the formation of azirenooxazole intermediates 10 in the reac-
to 12 are represented in Figure 3 with the use of relative scale tions of azirines 1 with α-diazo-β-ketoesters, we reacted azirine
for total energy ΔΔE. According to the calculations, the two 1g with a mixture of two diazo compounds, ethyl diazoacetoac-
attack modes of azirenooxazole 10j to ketene 12 (red and blue etate (2d) and diazoacetylacetone (2c), in the presence of
lines on the plot) give rise to atropoisomeric azirenooxazolium Rh2(Oct)4 (Scheme 5). We suggested that the azirenooxazole
betains 13j,13′j (not shown in the plot) which undergo a virtu- formed from the azirine and diazo compound 2d will be trapped
ally barrierless aziridine ring opening to give oxazinium by ketene 12 generated from diazoacetylacetone 2c via Wolff
betaines 14j,14′j. The activation barriers to both the transforma- rearrangement. The 1H NMR and TLC analysis of the reaction
tion pathways of 10j to 13 are close to each other (10.5 and mixture revealed, along with oxazines 4k, 4h and adduct 7h,
11.6 kcal/mol, respectively) but much lower than that to the ring one compound. The latter was not detected among the products
opening of azirenooxazole 10j to azirinium ylide 9j. The of the reactions of azirine 1g separately with each of the diazo
cyclizations of betaines 14j,14′j into bicycles 6j,7j proceed with compounds. This product was isolated by column chromatog-
extremely low activation barriers (1.1 and 4.7 kcal/mol). The raphy on silica gel, and its structure corresponding to the [4.3.1]
alternative pathway to compounds 6j,7j, involving reversible adduct 7k formed by cycloaddition of ketene 12 to azirenoxa-
formation of carbonyl ylide 15j, can result in exclusive forma- zole 10k was assigned on the basis of the 1H and 13C NMR and
tion of [3.2.1] adduct 6j, because the transition state TS9 mass spectra. According to the 1H NMR spectrum of the reac-
leading to betaine 14′j, a precursor of [4.3.1] adduct 7j, has a tion mixture, the 4k:4h:7k:7h ratio was 16:7:1:2. In the analo-
higher energy than the transition state TS5 for the competitive gous reaction of 3-(p-tolyl)azirine (1e) with a mixture of diazo
pathway. In spite of the fact that the transition states TS3 and compounds 2c,d, no other products than [3.2.1] adduct 6l (see
308

Beilstein J. Org. Chem. 2015, 11, 302–312.
Scheme 5: Rh2(Oct)4-catalyzed reaction of azirine 1g with diazo compound 2d in the presence of diazo compound 2c.
Supporting Information File 1, Scheme S1) formed from the from cycloaddition of acyl ketene 12 derived from 2c under the
ethoxycarbonyl-substituted azirenooxazole derivative and reaction conditions to the carbonyl group of oxazine 16. Actu-
ketene 12 were detected.
ally, compound 17 formed in the reaction of a pure oxazine 16
with diazo compound 2c in the presence of Rh2(OAc)4. Its
Obviously, the bridgehead nitrogen in azirenooxazoles 10 must structure was assigned by standard spectral methods and
be sterically accessible for smooth addition of 10 to ketene 12. confirmed by X-ray diffraction analysis (Figure 4). It was found
For example, methyl or phenyl substitution in the one-atom that, when kept for a week in a CDCl3 solution in the dark at
bridge in the related 5-oxa-1-azabicyclo[4.1.0]hept-3-ene room temperature, oxazine 17 undergoes reversible ring
system completely suppresses the reactivity of the latter toward opening to form a 1:2.3 equilibrium mixture of 17 and 18.
acylketenes [12]. This is a possible reason for the formation of Azadiene 18 was isolated by chromatography and characterized
neither 6 nor 7 adduct in the reaction of diazoacetylacetone (2c) by standard spectral methods.
with 2,3-diphenyl-2H-azirine (1a, Table 1, entry 10). The
moderate yield of compound 4i is explained by the formation of The synthesized 5-phenyl- (4a–d) and 5-unsubstituted (4e)
an unstable by-product of the transformation of the acetyl group 2H-1,4-oxazines proved to be stable in the dark but undergo an
in target oxazine 4i under the reaction conditions. We irreversible ring opening to azadienes 3 under UV irradiation.
succeeded in isolating a by-product of this type in the analo- Thus, irradiation of oxazine 4a for 1.5 h gives quantitatively
gous reaction of spiroazirine 1h with diazo compound 2c azadiene Z-3a which was also obtained by the reaction of
(Scheme 6). Along with oxazine 16 (57%), small amount of azirine 1a and α-diazo-α-phenylacetone (2a, Table 1, entry 1).
1,4-oxazine 17 with a modified acetyl group at С5 was isolated By contrast, 5-acetyl-substituted oxazines 4f–i are photo-
by column chromatography. Compound 17 obviously resulted chromic compounds. Being pale yellow colored, under UV ir-
309

Beilstein J. Org. Chem. 2015, 11, 302–312.
Scheme 6: Rh2(OAc)4-catalyzed reaction of azirine 1h with diazo compound 2c.
Scheme 7: Effect of the C5-substituent in the 2H-1,4-oxazine system
Figure 4: X-ray crystal structure of compound 17.
on its photochromic activity.
radiation in a CDCl3 solution at room temperature they undergo Conclusion
a ring opening to yellow–orange azadienes 3f–i which cyclize 5-Unsubstituted and 5-aryl-substituted 2H-1,4-oxazines can be
back to oxazines 4f–i in the dark. The effect of the readily prepared by the Rh(II)-catalyzed reaction of 2H-azirines
C5-substituent in 2H-1,4-oxazine on its photochromic activity with α-diazo ketones. The reaction involves intermediate forma-
can be tracked by changes in the half-life times of open-chain tion of azirinium ylides and their irreversible ring opening
isomers Z-3a,Z-3i and 19 (Scheme 7). It was found that the across the N–C2 bond to 2-azabuta-1,3-diene followed by 1,6-
azadiene cyclization rate strongly depends on the electron-with- cyclization. Along with ring opening, transient azirinium ylides
drawing ability of substituent R and increases as it changes more readily undergo reversible 1,5-cyclization to dihy-
from Ph or H to CO2Et or COMe.
droazireno[2,1-b]oxazoles which can be trapped with such
310

Beilstein J. Org. Chem. 2015, 11, 302–312.
3. Brun, K. A.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 2002, 85,
3422–3443.
active electrophiles as acylketenes to give 4,6-dioxa-1-azabi-
cyclo[3.2.1]oct-2-ene and/or 5,7-dioxa-1-azabicyclo[4.3.1]deca-
3,8-diene-2-one derivatives. This reaction sequence partly
occurs, when 3-aryl-2H-azirines and 3-diazoacetylacetone,
which is able to produce acetyl(methyl)ketenes via Rh(II)-
catalyzed Wolff rearrangement, are used as starting materials.
According to DFT B3LYP/6-31+G(d,p) calculations, the cyclo-
addition of dihydroazireno[2,1-b]oxazoles to acetyl(methyl)-
ketene, leading to the final bicyclic products, proceeds via
consecutive low barrier formation of two pairs of atropoiso-
meric betaine intermediates followed by their cyclization.
doi:10.1002/1522-2675(200210)85:10<3422::AID-HLCA3422>3.0.CO;
2-N
4. Huang, C.-Y.; Doyle, A. G. Chem. Rev. 2014, 114, 8153–8198.
doi:10.1021/cr500036t
5. Khlebnikov, A. F.; Novikov, M. S. Tetrahedron 2013, 69, 3363–3401.
doi:10.1016/j.tet.2013.02.020
6. Rostovskii, N. V.; Novikov, M. S.; Khlebnikov, A. F.; Korneev, S. M.;
Yufit, D. S. Org. Biomol. Chem. 2013, 11, 5535–5545.
doi:10.1039/c3ob40708j
7. Teixeira Costa, F. In Heterocyclic Targets in Advanced Organic
Synthesis; do Carmo Carreiras, M.; Marco-Contelles, J., Eds.;
Research Signpost: Trivandrum, India, 2011; p 145.
8. Padwa, A. Adv. Heterocycl. Chem. 2010, 99, 1–31.
doi:10.1016/S0065-2725(10)09901-0
The reaction of 2,3-di- and 2,2,3-triaryl-2H-azirines with both
α-diazo-α-phenylacetone and 3-diazoacetylacetone gives rise to
2-azabuta-1,3-dienes and/or 2H-1,4-oxazines. The alternative
reaction pathway via N–C3 azirine bond cleavage does not take
place in this case because of the steric shielding of the nitrogen
atom in the dihydroazireno[2,1-b]oxazole intermediate. Under
UV irradiation 5-unsubstituted and 5-aryl-substituted 2H-1,4-
oxazines produce stable 2-azabuta-1,3-dienes. In contrast,
5-acyl-substituted 2H-1,4-oxazines are photochromic com-
pounds, i.e., under UV irradiation they undergo ring opening to
2-azabuta-1,3-dienes which transform back to the oxazines in
the dark at room temperature. The rate of the reverse cycliza-
tion reaction increases with increasing electron-withdrawing
ability of C1-substituent in 2-azabuta-1,3-diene.
9. Lemos, A. Molecules 2009, 14, 4098–4119.
doi:10.3390/molecules14104098
10.Palacios, F.; Ochoa de Retana, A. M.; Martínez de Marigorta, E.;
de los Santos, J. M. In Recent Developments in Heterocyclic
Chemistry; Pinho e Melo, T. M. V. D.; d'A Rocha-Gonsalves, A. M.,
Eds.; Research Signpost: Trivandrum, India, 2007; p 27.
11.Palacios, F.; Ochoa de Retana, A. M.; Martínez de Marigorta, E.;
de los Santos, J. M. Eur. J. Org. Chem. 2001, 2401–2414.
doi:10.1002/1099-0690(200107)2001:13<2401::AID-EJOC2401>3.0.C
O;2-U
12.Khlebnikov, A. F.; Novikov, M. S.; Pakalnis, V. V.; Yufit, D. S.
J. Org. Chem. 2011, 76, 9344–9352. doi:10.1021/jo201563b
13.Khlebnikov, A. F.; Novikov, M. S.; Pakalnis, V. V.; Iakovenko, R. O.;
Yufit, D. S. Beilstein J. Org. Chem. 2014, 10, 784–793.
doi:10.3762/bjoc.10.74
14.Palacios, F.; Aparicio, D.; Ochoa de Retana, A. M.;
de los Santos, J. M.; Gil, J. I.; Alonso, J. M. J. Org. Chem. 2002, 67,
7283–7288. doi:10.1021/jo025995d
Supporting Information
15.Rostovskii, N. V.; Novikov, M. S.; Khlebnikov, A. F.; Khlebnikov, V. A.;
Korneev, S. M. Tetrahedron 2013, 69, 4292–4301.
doi:10.1016/j.tet.2013.03.106
Supporting Information File 1
Experimental part, computational details and copies of 1H
and 13C NMR spectra.
16.Livant, P.; Jie, Y.; Wang, X. Tetrahedron Lett. 2005, 46, 2113–2116.
doi:10.1016/j.tetlet.2005.01.131
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-35-S1.pdf]
17.Bréhu, L.; Fernandes, A.-C.; Lavergne, O. Tetrahedron Lett. 2005, 46,
1437–1440. doi:10.1016/j.tetlet.2005.01.045
18.Lee, S.-H.; Yoshida, K.; Matsushita, H.; Clapham, B.; Koch, G.;
Zimmermann, J.; Janda, K. D. J. Org. Chem. 2004, 69, 8829–8835.
doi:10.1021/jo048353u
Acknowledgements
We gratefully acknowledge the financial support of the Russian
Foundation for Basic Research (grant no. 14-03-00187, 14-03-
31117) and Saint Petersburg State University (grant no.
12.38.239.2014, 12.38.217.2015). This research used resources
of the resource center ‘Computer Center’, ‘Research resource
center for Magnetic Resonance’, ‘Center for Chemical Analysis
and Material Research’, and ‘Research resource Centre for
X-ray Diffraction Studies’ of Saint Petersburg State University.
19.Zhang, X.; Sui, Z. Tetrahedron Lett. 2006, 47, 5953–5955.
doi:10.1016/j.tetlet.2006.06.053
20.Lee, Y. R.; Suk, J. Y. Tetrahedron Lett. 2000, 41, 4795–4799.
doi:10.1016/S0040-4039(00)00716-4
21.Lee, Y. R.; Suk, J. Y. Heterocycles 1998, 48, 875–883.
doi:10.3987/COM-97-7881
22.Zhang, X.-J.; Yan, M.; Huang, D. Org. Biomol. Chem. 2009, 7,
187–192. doi:10.1039/b813763c
23.Dong, C.; Deng, G.; Wang, J. J. Org. Chem. 2006, 71, 5560–5564.
doi:10.1021/jo0605039
24.Padwa, A.; Dean, D. C. J. Org. Chem. 1990, 55, 405–406.
doi:10.1021/jo00289a001
References
1. Heimgartner, H. Angew. Chem., Int. Ed. Engl. 1991, 30, 238–264.
25.Wilds, A. L.; Mearder, A. L., Jr. J. Org. Chem. 1948, 13, 763–769.
doi:10.1021/jo01163a024
doi:10.1002/anie.199102381
2. Koch, K. N.; Linden, A.; Heimgartner, H. Tetrahedron 2001, 57,
2311–2326. doi:10.1016/S0040-4020(01)00091-6
311

Beilstein J. Org. Chem. 2015, 11, 302–312.
26.Khlebnikov, A. F.; Novikov, M. S.; Amer, A. A.; Kostikov, R. R.;
Magull, J.; Vidovic, D. Russ. J. Org. Chem. 2006, 42, 515–526.
doi:10.1134/S1070428006040075
27.Shimoharada, H.; Ikeda, S.; Kajigaeshi, S.; Kanemasa, S. Chem. Lett.
1977, 6, 1237–1238. doi:10.1246/cl.1977.1237
28.Beletskii, E. V.; Kuznetsov, M. A. Russ. J. Org. Chem. 2009, 45,
1229–1240. doi:10.1134/S107042800908020X
29.Kuznetsov, M. A.; Voronin, V. V. Chem. Heterocycl. Compd. 2011, 47,
173–181. doi:10.1007/s10593-011-0738-8
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.11.35
312