Highly substituted furo[3, 4-d][1, 2]oxazines: Gold-catalyzed regiospecific and diastereoselective 1, 3-dipolar cycloaddition of 2-(1-alkynyl)-2-alken-1- ones with nitrones

Full text of DOI:10.1002/anie.200901299

Angewandte
Chemie
DOI: 10.1002/anie.200901299
Synthetic Methods
Highly Substituted Furo[3,4-d][1,2]oxazines: Gold-Catalyzed
Regiospecific and Diastereoselective 1,3-Dipolar Cycloaddition of
2-(1-Alkynyl)-2-alken-1-ones with Nitrones**
Feng Liu, Yihua Yu, and Junliang Zhang*
Dedicated to Professor Li-Xin Dai on the occasion of his 85th birthday
Heterocyclic structures are core components of many natural
products and man-made synthetic drugs. The design and
synthesis of novel heterocyclic compounds with high effi-
ciency is, therefore, highly desirable. 1,3-Dipolar cycloaddi-
tion reactions, which can provide rapid access to heterocyclic
compounds in a convergent and efficient manner, have
attracted the interest of many chemists.
report a gold(I)-catalyzed[13] 1,3-dipolar cycloaddition of 2-(1-
alkynyl)-2-alken-1-ones with nitrones, which provides a
practical, efficient, regiospecific, and highly diastereoselective
route to novel heterobicyclic highly substituted furo[3,4-d]-
[1,2]-oxazines.
During our research on the synthesis and reactivity of 2-
(1-alkynyl)-2-alken-1-ones 1,[10,11] we became interested in the
metal-catalyzed 1,3-dipolar cycloaddition reaction of 1 with
the nitrones 2. We envisaged that this reaction might provide
three different types of adducts (Figure 1): 1) isoxazolidines 3
by a 1,3-dipolar [3+2] cycloaddition of nitrones with the
olefin moiety of 1;[12] 2) 2,3-dihydroisoxazoles 4 by a 1,3-
dipolar [3+2] cycloaddition of nitrones with the alkyne
moiety of 1; and 3) novel heterobicyclic furo[3,4-d]-
[1,2]oxazines 5 by a 1,3-dipolar [3+3] cycloaddition (tandem
double cyclizations) of nitrone with 1.
We began by examining the cycloaddition reaction of
ketone 1a with nitrone 2a in the presence of different metal
catalysts (see Table 1 in the Supporting Information). After
many attempts, we found that the reaction proceeded very
well in CH2Cl2 at room temperature in the presence of
2.5 mol% of Ph3PAuOTf; after a reaction time of 20 minutes
(3S*,8aR*)-furo[3,4-d,e][1,2]oxazine 5aa was isolated in 93%
yield with a greater than 99:1 diastereoselectivity, which was
determined by the 1H NMR analysis of the crude product. In
addition, the reaction was very clean and a [3+2] cycloadduct
was not formed, indicating that this transformation is
regiospecific and chemospecific. The configuration of 5aa
was confirmed by the single-crystal X-ray diffraction analy-
sis.[14] Surprisingly, other commonly used metal catalysts such
as Sc(OTf)3, Sn(OTf)2, Cu(OTf)2, Yb(OTf)3, Y(OTf)3, In-
(OTf)3, and Ni(ClO4)2·6H2O showed almost no catalytic
activity, even at elevated reaction temperatures (408C).
AgOTf and AuCl3 also catalyzed this transformation but
gave lower product yields. Changing to solvents such as
MeCN, THF, or toluene failed to improve the reaction.
To determine the scope of this transformation, various
ketones 1 were examined (Scheme 1). The reactions of both
the cyclic substrates 1a–c and acyclic substrates 1d–i with
various nitrones 2a–f proceeded to afford the corresponding
highly substituted furo[3,4-d][1,2]oxazines 5 in good to
excellent yields with up to > 99:1 diastereoselectivity (reac-
tion time 30 min). The olefinic and cyclopropyl substitutents
on 1b and 1c, respectively, did not affect the reaction. The R1
and R2 substitutents of 1 have larger effects on the diaste-
reoselectivity of the reaction than the R3 group of 1. The
configuration of the cycloadducts derived from acyclic
Despite various metal-catalyzed methods developed for
the synthesis of highly substituted furan compounds from
various cyclic or acyclic precursors in past years,[1] it is still a
challenge to efficiently assemble novel 3,4-fused bicyclic
furans,[1j,2] especially from acyclic precursors. Furthermore,
1,2-oxazines are frequently found as structural skeletons in
biologically active compounds[3] and as valuable synthetic
building blocks in organic synthesis.[4] Among the many
methods developed in past years to construct 1,2-oxazines,[5]
the 1,3-dipolar [3+3] cycloaddition of nitrones[6] is a partic-
ularly effective one. For example, Kerr and co-workers[7]
reported an efficient [3+3] cycloaddition of donor–acceptor
cyclopropanes with nitrones leading to tetrahydro-1,2-oxa-
zines under Lewis acid catalysis. The enantioselective version
of this transformation was later accomplished by Sibi et al.[8a]
and Tang and co-workers.[8b] Recently, Shintani, Hayashi, and
co-workers[9] described an asymmetric and efficient palla-
dium-catalyzed [3+3] cycloaddition of trimethylene methane
derivatives with nitrones leading to 1,2-oxazines. Herein we
[*] F. Liu, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry
East China Normal University
3663 N. Zhongshan Road, Shanghai 200062 (P.R. China)
Fax: (+86)21-6223-5039
E-mail: jlzhang@chem.ecnu.edu.cn
Prof. Y. Yu
Shanghai Key Laboratory of Magnetic Resonance
Department of Physics, East China Normal University (P.R. China)
Prof. Dr. J. Zhang
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (P.R. China)
[**] Financial support from the National Natural Science Foundation of
China (20702015), the Science and Technology Commission of
Shanghai Municipality (07DZ22937), Shanghai Shuguang Program
(07SG27), Shanghai Pujiang Program (07pj14039), and Shanghai
Leading Academic Discipline Project (B409) is greatly appreciated.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901299.
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Scheme 1. Proposed metal-catalyzed cycloaddition of 2-(1-alkynyl)-2-
alken-1-ones 1 with nitrones 2.
Scheme 2. Cyclization of 1a and 1d with 2a on a 5 mmol scale using
only 0.2 mol% of the catalyst. Reaction conditions: a) Ph3PAuOTf
(0.20 mol%), CH2Cl2, RT, 20 min.
Our preliminary results (Scheme 3) showed that chiral the
(R)-MeO-biphep-derived gold complex could be used as the
asymmetric catalyst. The [3+3] cycloaddition reaction of 1a
with 2a proceeded rapidly at room temperature to give the
tricyclic product cis-5aa in 86% yield and 58% ee (71% ee at
Figure 1. Gold(I)-catalyzed 1,3-dipolar [3+3] cycloaddition of 2-(1-
alkynyl)-2-alken-1-ones 1 with nitrones 2. The respective yields and
diastereomeric ratios are given. Reaction conditions: 1 (0.4 mmol),
nitrone 2 (0.44 mmol, 1.1 equiv), catalyst (2.5 mol%), CH2Cl2 (4 mL),
RT, 10–30 min.
ketones 1d–i, which may be different from cyclic ketones, was
also confirmed by the X-ray crystallographic analysis of
5da.[14]
Notably, the catalyst loading could be reduced to
0.2 mol% without any loss in the yield and diastereoselectiv-
ity on a 5 mmol scale reaction (Scheme 2). For example, the
reactions of 2a (5.5 mmol) with 1a (5.15 mmol) or 1d
(5.0 mmol) was complete within 20 minutes to yield
1.97 grams of 5aa (97% yield upon isolation; turnover
number is about 500) or 2.01 grams of 5da (91% yield upon
isolation), respectively. Furthermore, a 75% yield of 5aa
could be obtained through only one simple recrystallization
(CH2Cl2/hexanes) of the crude product, thereby making this
transformation practical.
Scheme 3. Asymmetric gold-catalyzed [3+3] cycloaddition. DCE=1,2-
dichloroethane, Tf=trifluoromethanesulfonyl.
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À308C; after one recrystallization: 98% ee). Furthermore,
heterobicycle cis-5da could also be attained in 95% yield and
50% ee from the corresponding acyclic substrate 1d and
nitrone 2a after reaction for five minutes at room temper-
ature.
The synthetic utility of furo[3,4-d][1,2]oxazines was show-
cased by the selective additional transformations of the two
representative products cis-5aa and cis-5da (Scheme 4). The
molecular cyclization would then yield product 5 as well as
regenerate the gold catalyst.
In summary, a gold(I)-catalyzed 1,3-dipolar [3+3] cyclo-
addition of 2-(1-alkynyl)-2-alken-1-ones with nitrones has
been developed, providing a practical, regiospecific, and
diastereoselective access to highly substituted fused hetero-
bicyclic furo[3,4-d][1,2]oxazines under mild reaction condi-
tions. The cycloadducts were obtained with moderate ee val-
ues by using (R)-MeO-biphep as the chiral ligand. Further-
more, the heterobicyclic products could be easily converted
into furans or 3,6-dihydro-2H-1,2-oxazines in a chemoselec-
tive fashion.
Experimental Section
Typical procedure for furo[3,4-d][1,2]oxazine synthesis (see Table S1,
entry 10 in the Supporting Information): A solution of Ph3PAuOTf
(1 mL, 0.01m in CH2Cl2, 2.5 mol%) was added to a solution of 2-(1-
alkynyl)-2-alken-1-one 1a (78.5 mg, 0.40 mmol) and nitrone 2a
(86.7 mg, 0.44 mmol, 1.1 equiv) in CH2Cl2 (3 mL) at room temper-
ature. The resulting mixture was stirred for 20 min and the reaction
was complete as determined by TLC analysis. The reaction mixture
was passed through a short silica gel column and then concentrated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (hexanes/ethyl acetate 20:1) to afford
the pure product 5aa (146.4 mg) in 93% yield as a white solid.
1H NMR (300 MHz, CDCl3): d = 7.37 (d, J = 7.5 Hz, 2H), 7.24–7.16
(m, 4H), 7.11–6.89 (m, 9H), 5.95 (s, 1H), 5.16–5.09 (m, 1H), 2.86–2.78
(m, 2H), 2.30–2.23 (m, 2H), 1.97–1.98 (m, 1H), 1.64–1.50 ppm (m,
1H); 13C NMR (75 MHz, CDCl3): d = 148.62, 147.00, 146.70, 137.06,
130.93, 129.39, 128.42, 128.28, 127.57, 127.39, 126.30, 123.90, 123.21,
122.39, 118.07, 117.59, 75.26, 66.01, 27.81, 23.14, 20.37 ppm; MS(EI):
m/z (%): 393.3(M+, 13.11); 43.1 (100), HRMS calcd for C27H23NO2:
393.1729, found: 393.1730. For preparative procedures and spectro-
scopic data for all new compounds, see the Supporting Information.
Scheme 4. Chemoselective ring-opening of furo[3,4-d][1,2]oxazines pro-
vides efficient access to highly functionalized furans or 1,2-oxazines.
Reaction conditions: a) SmI2, THF, 408C; b) CAN, CH3CN/H2O 1:1,
RT.
compounds cis-5aa and cis-5da were converted into function-
alized tetrasubstituted amino alcohol containing furans 6 and
8, respectively, by SmI2-mediated reductive cleavage of the
N O bond.[15] Alternatively, the functionalized 1,2-oxazines 7
À
and 9 were obtained in moderate yields by treatment of cis-
5aa and cis-5da, respectively, with cerium(IV) ammonium
nitrate (CAN).[16]
Received: March 9, 2009
Revised: May 15, 2009
Published online: June 24, 2009
A plausible stepwise reaction pathway for this gold(I)-
catalyzed transformation is depicted in Scheme 5. The
cationic gold(I) species first coordinates to ketone 1, with
subsequent cyclization to generate the furanyl gold complex
10, which is rapidly trapped by the nucleophilc oxygen atom
of the nitrone to afford intermediate 11. Subsequent intra-
Keywords: chemoselectivity · cyclization · gold · regioselectivity ·
.
stereoselectivity
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Supporting Information. CCDC 716897(5aa) and 716897(5da)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
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