Rhodium-catalyzed transannulation of N-sulfonyl-1,2,3-triazoles and epoxides: Regioselective synthesis of substituted 3,4-dihydro-2 H-1,4-oxazines

Article abstract of DOI:10.1021/ol5021042

Rhodium-catalyzed transannulation of 1,2,3-triazoles and ring-opening reactions of epoxides is described. A number of 3,4-dihydro-2H-1,4-oxazines are obtained in moderate yields probably involving generation of α-imino rhodium(II) carbene species.

Full text of DOI:10.1021/ol5021042

Letter
pubs.acs.org/OrgLett
Rhodium-Catalyzed Transannulation of N‑Sulfonyl-1,2,3-triazoles
and Epoxides: Regioselective Synthesis of Substituted 3,4-
Dihydro‑2H‑1,4-oxazines
Xueji Ma,† Shanfei Pan,† Hangxiang Wang,*,‡ and Wanzhi Chen*,†
†Department of Chemistry, Zhejiang University, Hangzhou 310028, People’s Republic of China
‡First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, People’s Republic of China
S
* Supporting Information
ABSTRACT: Rhodium-catalyzed transannulation of 1,2,3-tri-
azoles and ring-opening reactions of epoxides is described. A
number of 3,4-dihydro-2H-1,4-oxazines are obtained in moder-
ate yields probably involving generation of α-imino rhodium(II)
carbene species.
1,4-Oxazine derivatives show interesting photochromic proper-
ties1 and are biologically active compounds as herbicides,
fungicides, and other therapeutically useful drugs.2 Aromatic
ring-fused 1,4-oxazine derivatives are generally prepared via
cyclocondensation of aminophenols with appropriate dihalo
compounds,3a copper-catalyzed intramolecular O-arylation of β-
amino alcohols,3b and silver-promoted sequential C−N and C−
O formation reactions between 2,5-dihydroxybenzaldehyde and
amino acid precursors.3c Nonfused 1,4-oxazines have been less
studied. A typical approach to 1,4-oxazine derivatives involves
the condensation of β-amino alcohols and α-halo ketones
(Scheme 1a). These methods suffered from tedious synthetic
catalyzed intermolecular annulation of N-sulfonyl-1,2,3-triazoles
with styrene oxide derivatives.
Recently, the metal-catalyzed denitrogenative transannula-
tion converting 1,2,3-triazoles to other heterocyclic compounds
via α-imino rhodium(II) carbene complexes received consid-
erable attention.4 Various interesting and useful cyclic
compounds include cyclopropanes,5 and heterocyclic com-
pounds, pyrroles,6 pyrroloindoline,7 imidazoles,8 oxazoles,8a
indole,9 imidazolones, and thiazoles10 have been prepared
through cycloaddtion of unsaturated compounds. The in situ
generated α-imino rhodium(II) carbene complexes are also able
to react with 1,3-dioxolanes and 1,3-dioxanes, leading to eight-
and nine-membered dioxazocine and dioxazonine adducts,
respectively,11 while the rhodium-catalyzed reactions of
tetrahydrofuran and triazoles were also reported to give 1,4-
oxazocines in poor yields.9,11 Moreover, the ring expansion and
rearrangement reactions of triazole derivatives under rhodium-
(II)-catalyzed conditions have been utilized to synthesize
various enaminones.12 Very recently, α-ketone carbenes derived
from triazoles were reported to be able to insert into epoxides
to give 1,4-dioxene motifs with excellent stereochemistry.13 The
α-imino rhodium(II) carbene species bear both an electrophilic
carbenoid carbon and a nucleophilic α-amino nitrogen;
therefore, we envisioned that the nucleophilic oxygen of
epoxides could interact with the carbenoid to generate oxonium
species. After ring opening and the subsequent intramolecular
attack of α-imino nitrogen toward the epoxides, the oxonium
species would afford substituted 3,4-dihydro-2H-1,4-oxazine
derivatives. Here we describe the rhodium-catalyzed ring-
opening reactions of triazoles and epoxide leading to 3,4-
dihydro-2H-1,4-dioxazines.
Scheme 1. Synthesis of 1,4-Oxazine Derivatives
We initially attempted the reactions of N-tosyl-4-phenyl-
1,2,3-triazoles with styrene oxide. Triazole 1a was allowed to
react with 1,2-epoxyethylbenzene in the presence of Rh2(OAc)4
procedures and limited substrate scope. Recently, metal-
catalyzed addition of alkene or alkyne with amines or alcohols
emerged as an attractive alternative for 1,4-oxazine derivatives
(Scheme 1a).3d−f However, only very limited examples were
reported. Herein, we describe a novel approach to the synthesis
of highly substituted 1,4-oxazine derivatives via a rhodium(II)-
Received: July 17, 2014
© XXXX American Chemical Society
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Letter
(1.0 mol %) in dichloroethane (DCE) at 120 °C. After 1 h,
triazole 1a was completely consumed; however, the desired
product 3a was obtained in only 16% yield together with
detosylated product 4-phenyl-1H-1,2,3-triazole (5−10%) and
other unidentified mixtures (Table 1, entry 1). For comparison,
a
Table 1. Optimization of Reaction Conditions
b
entry
Rh2L4 (mol %)
temp (°C)
solvent
yield (%)
1
Rh2(OAc)4 (1)
120
120
120
120
120
120
120
120
120
120
120
110
130
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CHCl3
toluene
PhF
16
19
20
38
44
41
46
52
41
36
43
0
2
Rh2(Oct)4 (1)
Figure 1. . Anisotropic displacement ellipsoids plot of 3a.
3
Rh2(Piv)4 (1)
4
Rh2(S-PTV)4 (1)
Rh2(S-NTV)4 (1)
Rh2(S-PTTL)4 (1)
Rh2(S-NTTL)4 (1)
Rh2(S-NTTL)4 (1.5)
Rh2(S-NTTL)4 (1.5)
Rh2(S-NTTL)4 (1.5)
Rh2(S-NTTL)4 (1.5)
Rh2(S-NTTL)4 (1.5)
Rh2(S-NTTL)4 (1.5)
Scheme 2. Reactions of Styrene Oxide with Various
5
a
Triazoles
6
7
8
9
10
11
12
13
DCE
DCE
20
a
Reaction were carried out with 1 (0.20 mmol) and styrene oxide
b
1
(0.60 mmol) in DCE (0.5 mL). All yields were determined by H
NMR of the crude products.
in the absence of rhodium catalyst no desired product was
observed. To optimize the reaction, the influence of a few other
dirhodium tetracarboxylate catalysts was examined. The results
are summarized in Table 1. When 1 mol % of rhodium catalysts
were employed, Rh2(Oct)4 and Rh2(Piv)4 were nearly identical
for the annulation reaction to give 3a in less than 20% yields
(entries 2 and 3). We found that the yields could be
significantly improved when Hashimoto-type catalysts were
used. The yields of 3a could be raised to more than 40% in the
presence of Rh2(S-NTV)4, Rh2(S-PTTL)4, and Rh2(S-NTTL)4
(entries 5−7). Rh2(S-NTTL)4 was found to be the most
efficient catalyst furnishing the product in 46% yield (entry 7).
An increase in catalyst loading to 1.5 mol % can further
improve the reaction yield to 52% (entry 8). The solvent
optimization showed that among toluene, fluorobenzene,
chloroform, and DCE tested (entries 9−11), DCE was the
best solvent for this rhodium-catalyzed reaction. Temperature
screening showed that the reaction was totally suppressed at
110 °C and only the starting material was recovered. Higher
temperature was also found to be detrimental (entries 12 and
13). No product 3a′ was detected regardless of rhodium
catalysts. X-ray crystallographic analysis confirmed the molec-
ular structure of 3a. The diffraction also shows that two
enantiomers in equal amounts cocrystallize, and only one is
shown in Figure 1.
a
Reactions were carried out with 1 (0.20 mmol), Rh2(S-NTTL)4 (1.5
mol %), and styrene oxide (0.60 mmol) in DCE (0.5 mL); all are
isolated yields.
electron-donating methyl group at the para-position on the
phenyl ring gave product 3b in moderate yields. In the case of
1-sulfonyl-4-(2-methylphenyl)-1,2,3-triazole only a trace
amount of the product was obtained, suggesting the significant
steric encumbrance of the ortho substituent. However, 1-
sulfonyl-4-naphthyl-1,2,3-triazole reacted smoothly with styrene
oxide affording 3c in a comparable yield as 3a. The reaction of
the triazole bearing a m-methoxy group on the phenyl ring
reacted with styrene oxide affording 3d in moderate yield.
Unfortunately, the triazole bearing a p-methoxy group on the
phenyl ring is nearly inactive, and the corresponding product
was isolated in less than 5% yield, probably due to the
The generality of the reaction was investigated with a diverse
variety of triazoles under the optimized conditions. As
illustrated in Scheme 2, the reactions of triazoles bearing an
B
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Letter
decreased electrophilicity of the α-imino rhodium carbenoid
carbon center. It was expected that the electron-deficient
triazoles would be more active for the annulation reaction.
Indeed, the reactions of triazoles having electron-withdrawing
substitutents such as fluoride, chloride, acetyl, cyanide, and
carboxylate gave the corresponding products 3e−j in enhanced
yields. The triazoles derived from alphatic alkynes were also
compatible under the optimized reaction conditions, producing
3l and 3m in yields of 51% and 34%, respectively. Furan-
substituted triazole could also be transformed to 1,4-oxazine
product 3n in a comparable yield compared to other aromatic
triazoles.
within 1 h. These results clearly demonstrated the important
role of steric effect in the cycloaddition reaction. 4-tert-
Butylphenyl ethylene oxide and 1-naphthyl ethylene oxide also
gave desired products 4g and 4h successfully when the reaction
temperature was raised to 130 °C. 1-Tosyl-4-fluorophenyl-
1,2,3-triazoles gave an identical result. 1-Methyl-1-phenyl-
ethylene oxide was also compatible to the reaction, giving 4l
in 46% yield. Unfortunately, nonaromatic epoxides such as
cyclohexene oxide and propylene oxide are not effective
probably because the ring-opening to intermediate 6 is more
difficult, and only decomposed mixtures were observed. trans-
Stilbene oxide was also examined. Unfortunately, no desired
product was detected, probably due to larger steric hindrance.
A possible mechanism is proposed in Scheme 4. Reaction of
triazole 1 with dirhodium tetracarboxylate would generate α-
The scope of epoxides for the reaction was also explored, and
the results are listed in Scheme 3. The transannulation,
Scheme 3. Synthesis of 1,4-Oxazines with Various Styrene
Oxides
a
Scheme 4. Proposed Mechanism
imino rhodium(II) carbene species 2 upon reaction with
rhodium catalyst by extrusion of one molecule of dinitrogen.
The nucleophilic attack of epoxide oxygen to the electrophilic
carbenoid carbon center would lead to the formation of
oxonium species 6. Driven by the electrophilic activation and
ring strain of epoxide, the C−O cleavage would occur to give
carbocationic intermediate 7 and 7′. The intermediate 7 is
highly preferred due to the stabilizing effect of phenyl ring. The
nucleophilic attack of the imino group toward the carbocation
would result in the formation of the final product along with
the releasing of the dirhodium complex. The bulky rhodium
catalysts favor the reaction probably because the steric
repulsion would accelerate the elimination of rhodium species.
The electronic effect of the catalysts should also be responsible
for the reaction since electronic deficient rhodium center would
promote the formation of oxonium species 6 and facilitate the
ring-opening of epoxides.
In summary, we have described a novel and efficient protocol
for the preparation of a library of substituted 3,4-dihydro-2H-
1,4-oxazine derivatives via the reaction of epoxides and
triazoles. A number of 3,4-dihydro-2H-1,4-oxazines with diverse
substituents were obtained in moderate yields. The proposed
mechanism involves generation of α-imino rhodium(II)
carbene species through denitrogenative transannulation of
triazoles and ring-opening of epoxides. Although the efficiency
needs to be improved, the present reaction offers an option for
the preparation of 3,4-dihydro-2H-1,4-oxazines which are not
easily available from the known synthetic routes.
a
Reactions were carried out with 1 (0.20 mmol), 5 (0.60 mmol),
Rh2(S-PTV)4 (1.5 mol %), and DCE (0.5 mL, 0.4 M); all are isolated
yields. 2 h. 130 °C.
b
c
however, proceeded sluggishly in the presence of Rh2(S-
NTTL)4. In contrast, the reactions of N-tosyl-4-acetylphenyl-
1,2,3-triazole and styrene oxide having substituents such as
methoxy, methyl, tert-butyl, and fluoride proceeded smoothly in
the presence of less sterically demanding Rh2(S-PTV)4 complex
to generate products 4a−g in 37−51% yields. The variation of
substituents did not show any significant influence on the
reactivity of epoxides. Product 4e was obtained in a slightly
lower yield even the reaction time was prolonged to 2 h, which
may be due to the steric hindrance of the ortho substituent. As a
comparison, 2-fluorophenylethylene oxide did not show any
steric effect giving the F-containing product 4f in 47% yield
C
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Letter
(9) Miura, T.; Funakoshi, Y.; Murakami, M. J. Am. Chem. Soc. 2014,
136, 2272−2275.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
(10) Chuprakov, S.; Kwok, S. W.; Fokin, V. V. J. Am. Chem. Soc.
2013, 135, 4652−4655.
(11) Medina, F.; Besnard, C.; Lacour, J. Org. Lett. 2014, 16, 3232−
3235.
(12) (a) Selander, N.; Worrell, B. T.; Fokin, V. V. Angew. Chem., Int.
Ed. 2012, 51, 13054−13057. (b) Miura, T.; Funakoshi, Y.; Morimoto,
M.; Biyajima, T.; Murakami, M. J. Am. Chem. Soc. 2012, 134, 17440−
17443. (c) Liu, R. H.; Zhang, M.; Winston-McPherson, G.; Tang, W.
P. Chem. Commun. 2013, 49, 4376−4378.
(13) Achard, T.; Tortoreto, C. T.; Lacour, J. Angew. Chem., Int. Ed.
2014, 53, 6140−6144.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wanghx@zju.edu.cn.
*E-mail: chenwzz@zju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Science Foundation of China for
financial support (Nos. 21352002 and 21202147).
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REFERENCES
(1) Minkin, V. I. Chem. Rev. 2004, 104, 2751−2776.
■
(2) (a) Jabeen, I.; Wetwitayaklung, P.; Klepsch, F.; Parveen, Z.;
Chiba, P.; Ecker, G. F. Chem. Commun. 2011, 47, 2586−2588. (b) Li,
W. P.; Duan, X. W.; Yan, H.; Xin, H. X. Org. Biomol. Chem. 2013, 11,
4546−4550. (c) Baraldi, P. G.; Saponaro, G.; Moorman, A. R.;
Romagnoli, R.; Preti, D.; Baraldi, S.; Ruggiero, E.; Varani, K.; Targa,
M.; Vincenzi, F.; Borea, P. A.; Tabrizi, M. A. J. Med. Chem. 2012, 55,
6608−6623. (d) Fox, B. M.; et al. J. Med. Chem. 2014, 57, 3464−3483.
(e) Matralis, A. N.; Kourounakis, A. P. J. Med. Chem. 2014, 57, 2568−
2581. (f) Kourounakis, A. P.; Charitos, C.; Rekka, E. A.; Kourounakis,
P. N. J. Med. Chem. 2008, 51, 5861−5865.
(3) (a) Kuroita, T.; Sakamori, M.; Kawakita, T. Chem. Pharm. Bull.
1996, 44, 756−764. (b) Zhangqin Liu, Z.; Chen, Y. Tetrahedron Lett.
2009, 50, 3790−3793. (c) Iqbal, J.; Tangellamudi, N. D.; Dulla, B.;
Balasubramanian, S. Org. Lett. 2012, 14, 552−555. (d) Lai, J. Y.; Shi, X.
X.; Gong, Y. S.; Dai, L. X. J. Org. Chem. 1993, 58, 4775−4777.
(e) Zulys, A.; Dochnahl, M.; Hollmann, D.; Lohnwitz, K.; Herrmann,
J. S.; Roesky, P. W.; Blechert, S. Angew. Chem., Int. Ed. 2005, 44,
7794−7798. (f) Fukudome, Y.; Naito, H.; Hata, T.; Urabe, H. J. Am.
Chem. Soc. 2008, 130, 1820−1821.
(4) For leading reviews, see: (a) Chattopadhyay, B.; Gevorgyan, V.
Angew. Chem., Int. Ed. 2012, 51, 862−872. (b) Gulevich, A. V.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2013, 52, 1371−1373. (c) Davies,
H. M. L.; Alford, J. S. Chem. Soc. Rev. 2014, 43, 5151−5162.
(5) (a) Chuprakov, S.; Kwok, S. W.; Zhang, L.; Lercher, L.; Fokin, V.
V. J. Am. Chem. Soc. 2009, 131, 18034−18035. (b) Grimster, N.;
Zhang, L.; Fokin, V. V. J. Am. Chem. Soc. 2010, 132, 2510−2511.
(c) Alford, J. S.; Davies, H. M. L. Org. Lett. 2012, 14, 6020−6023.
(d) Zibinsky, M.; Fokin, V. V. Org. Lett. 2011, 13, 4870−4872.
(6) (a) Parr, B. T.; Green, S. A.; Davies, H. M. L. J. Am. Chem. Soc.
2013, 135, 4716−4718. (b) Alford, J. S.; Spangler, J. E.; Davies, H. M.
L. J. Am. Chem. Soc. 2013, 135, 11712−11715. (c) Kwok, S. W.;
Zhang, L.; Grimster, N. P.; Fokin, V. V. Angew. Chem., Int. Ed. 2014,
53, 3452−3456. (d) Chattopadhyay, B.; Gevorgyan, V. Org. Lett. 2011,
13, 3746−3749. (e) Shi, Y.; Gevorgyan, V. Org. Lett. 2013, 15, 5394−
5396. (f) Miura, T.; Yamauchi, M.; Murakami, M. Chem. Commun.
2009, 1470−1471. (g) Miura, T.; Hiraga, K.; Biyajima, T.; Nakamuro,
T.; Murakami, M. Org. Lett. 2013, 15, 3298−3301. (h) Schultz, E. E.;
Sarpong, R. J. Am. Chem. Soc. 2013, 135, 4696−4699. (i) Kim, C. E.;
Park, S.; Eom, D.; Seo, B.; Lee, P. H. Org. Lett. 2014, 16, 1900−1903.
(j) Ran, R. Q.; He, J.; Xiu, S. D.; Wang, K. B.; Li, C. Y. Org. Lett. 2014,
16, 3704−3707.
(7) Spangler, J. E.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135,
6802−6805.
(8) (a) Zibinsky, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2013, 52,
1507−1510. (b) Horneff, T.; Chuprakov, S.; Chernyak, N.;
Gevorgyan, V.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 14972−
14974.
D
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