Highly diastereoselective gold- Or copper-catalyzed formal [4+3] cycloaddition of 1-(1-Alkynyl) cyclopropyl ketones and nitrones

Article abstract of DOI:10.1002/chem.200901133

A study was conducted to demonstrate highly diastereoselective gold- or copper-catalyzed formal [4+3] cycloaddition of 1-(1-alkynyl) cyclopropyyl ketones and nitrones. The reaction of ACP ketone and nitrone was carried out in 1,2-dichloroethane (DCE). Sev

Full text of DOI:10.1002/chem.200901133

COMMUNICATION
DOI: 10.1002/chem.200901133
Highly Diastereoselective Gold- or Copper-Catalyzed Formal [4+3]
Cycloaddition of 1-(1-Alkynyl) Cyclopropyl Ketones and Nitrones**
Yu Bai, Jie Fang, Jun Ren, and Zhongwen Wang*[a]
Cyclic skeletons are widespread among bioactive natural
and synthetic molecules. Methodology for the highly effi-
cient construction of complex skeletons, such as cycloaddi-
tions[1] and tandem reactions,[2] is one of the most important
themes in contemporary organic synthesis; the prototypical
example of this concept was provided by Robinson a centu-
ry ago.[3] Cyclopropanes are
tion of ACP ketones with double bonds, by which a furan-
containing 5/6-bicyclic skeleton was efficiently constructed
(Scheme 1)[12]. Inspired by these results and the important
cycloadditions of nitrones,[1b,13,14] we envisioned exploring
the [4+3] cycloaddition between the ACP ketone and ni-
trone (as a 1,3-dipole) (Scheme 1). Herein we report our re-
useful synthons in organic syn-
thesis because of their easy
availability and versatile reac-
tivity.[4] We hope to develop
new cycloadditions and tandem
reactions of functionalized cy-
clopropanes for the efficient
construction of complex skele-
tons. On the other hand, forma-
tion of a furan ring by cycloiso-
merization of a carbonyl group
with allene,[5] alkyne,[6] enyne,[7]
methylenecyclopropane,[8] and
Scheme 1. Tandem ring-opening of ACP ketones. LA=Lewis acid.
cyclopropene[9] units can be cat-
alyzed by transition metals, es-
pecially coinage metals (Cu, Ag, Au), owing to both their s-
and p-Lewis acidities. Schmalz and Zhang[10] introduced the
cyclopropane ring into the alkyne/carbonyl system, and the
designed 1-(1-alkynyl) cyclopropyl (ACP) ketones success-
fully underwent a tandem cycloisomerization/ring-opening
process with nucleophiles. Recently, Zhang et al.[11] reported
a novel tandem cycloisomerization/formal [4+2] cycloaddi-
sults for the highly diastereoselective construction of a new
type of 5/7-bicyclic heterocycle: 1,2,4,5-tetrahydrofuro
d]
[1,2]oxazepine.[15]
In the initial investigation, the reaction of ACP ketone 1a
ACHTUNGTRENNUNG[3,4-
AHCTUNGTRENNUNG
and nitrone 2a was carried out in 1,2-dichloroethane
(DCE). Several Lewis acids successfully promoted the de-
sired tandem cycloisomerization/formal [4+3] cycloaddition
(Table 1), among which Cu
(5 mol%) gave the best results. In most of the following
cases, Cu(OTf)2 was selected as the catalyst because it is rel-
atively cheap and stable. As the nitrone was not completely
stable in the presence of a Lewis acid (e.g. Cu
1.7 equivalents were used in the reaction.
To explore the scope of the tandem cycloisomerization/
formal [4+3] cycloaddition, we investigated the reactions
between ACP ketone 1a and various nitrones. The results
are shown in Table 2. The reaction could tolerate a variety
of N-aryl nitrones (Table 2, entries 1–13). N-benzyl (Table 2,
ACHTUNGTREN(NGNU OTf)2 (20 mol%) and AuCl3
[a] Y. Bai, J. Fang, J. Ren, Prof. Dr. Z. Wang
State Key Laboratory of Elemento-Organic Chemistry
Institute of Elemento-Organic Chemistry
Nankai University, Tianjin 300071 (P. R. China)
Fax : (+86)22-2350-3627
AHCTUNGTRENNUNG
(OTf)2[16]),
ACHTUNGTRENNUNG
E-mail: wzwrj@nankai.edu.cn
[**] We thank the National Natural Science Foundation of China (Nos.
20572045)
and
the
Ministry
of
Education
of
China
(RFDF20070055022) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901133.
Chem. Eur. J. 2009, 15, 8975 – 8978
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8975

Table 1. Screen of the Lewis acids.[a]
owing to its instability, gave lower yields under both Cu-
AHCTUNTGREN(NGUN OTf)2 (20 mol%) and AuCl3 (10 mol%) catalysis. In most
cases, the yields were moderate to excellent. In all cases, the
diastereoselectivities were high: all acyclic nitrones (as the
Z isomer) gave cis products, while the cyclic nitrone 2p (as
the E isomer) gave the trans product. The structures of 3l
and 3p were established by spectroscopic analysis and fur-
ther confirmed by single-crystal X-ray analysis (Figure 1).[17]
Entry
Cat. [mol%]
None
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
7
7
7
7.5
7
7
7
8
0
40
34
17
32
74
19
0
Sc
Yb
Ni(ClO4)2 (20)
Bi(OTf)3 (20)
T
N
R
ACHTUNGTRENNUNG
AuCl3 (5)
AgOTf (10)
Zn
N
9
CuOTf (20)
CuBr (20)
CuI (20)
8
7
8
7
67
0
0
10
11
12
Cu
A
83
[a] Conditions: ACP ketone 1a (0.077 mmol, 1.0 equiv), nitrone 2a
(0.15 mmol, 2.0 equiv), 3 mL DCE, 508C, 4 ꢁ molecular sieves. [b] Esti-
mated by 1H NMR analysis using 1-chloro-2,4-dinitrobenzene as the in-
ternal standard.
Figure 1. X-ray crystal structures of products 3l and 3p. Ellipsoids drawn
at the probability level.
Several ACP ketones (1b–1h) were also examined
entry 14) and N-isopropyl nitrones (Table 2, entry 15) also
furnished [4+3] cycloaddition products under AuCl3 cataly-
sis (10 mol%). The cyclic nitrone 2p (Table 2, entry 16),
(Scheme 2). The desired products were obtained under Cu-
AHCTUNGTRENNUNG
(OTf)2 catalysis. For ACP ketones where R5 =H (1 f–1h),
lower yields were obtained even when the amounts of Cu-
AHCTUNGRTEN(NGUN OTf)2 and nitrone 2a were increased to 60 mol% and
3.0 equiv, respectively. However, when AuCl3 (10 mol%)
was used as the Lewis acid, the yields improved notably, and
the reaction reached completion more quickly. For ACP ke-
tones where R5 =Ph, there was no significant difference be-
Table 2. Reactions of ACP ketone 1a and various nitrones.[a]
tween the yields with CuACHTNUGTRNEUNG(OTf)2 and AuCl3 catalysis
(Table 2, entry 16; 3s and 3t in Scheme 2). For 3s and 3t,
the diastereoselectivities were also high.
To increase the efficiency and convenience of this
method, we developed a one-pot three-component version
of this reaction (Scheme 3). In the presence of AuCl3
(20 mol%)[20] and 3 ꢁ molecular sieves, the reaction of ben-
zaldehyde, phenylhydroxylamine, and the ACP ketone 1a in
acetonitrile successfully furnished the desired product 3a
(67% yield).
Entry R1
R2
Ph
Product (time [h])
Yield [%][b]
1
2
3
4
5
Ph
3a (7)
3b (7.5)
3c (7)
3d (7)
3e (8.5)
3 f (8.5)
91
88
89
49
61
71
59
75
81
55
71
66
92
87
66
p-Cl-C6H4 Ph
m-Cl-C6H4 Ph
p-Br-C6H4 Ph
p-Me-C6H4 Ph
6
7
Ph
Ph
p-Me-C6H4
p-MeO-C6H4 3g (7)
Based on previous experimental results,[6,7,10,12,18] DFT cal-
culations,[19] and the high diastereoselectivity we observed, a
more possible mechanism may involve the opening of the
8
9
p-Cl-C6H4 p-MeO-C6H4 3h (7.5)
p-Br-C6H4 p-MeO-C6H4 3i (7.5)
m-Cl-C6H4 p-MeO-C6H4 3j (7)
p-Cl-C6H4 p-Me-C6H4
p-Me-C6H4 p-Me-C6H4
p-Cl-C6H4 2-furyl
10
11
12
13
14[c]
cyclopropane ring initiated by
a nucleophilic attack
3k (10)
3l (12)
3m (7.5)
3n (3)
(Scheme 4). The high diastereoselectivity may be a result of
the favored conformation of intermediate C. Thus, cis iso-
mers were obtained from the acyclic Z nitrones, and the
cyclic E nitrone 2p gave the trans isomer 3p.
Bn
Ph
Ph
15[c,d] iPr
3o (4)
In summary, we have developed a novel highly diastereo-
selective Au- or Cu-catalyzed tandem cycloisomerization/
formal [4+3] cycloaddition of ACP ketones and nitrones. A
three-component example has also been accomplished suc-
cessfully. This methodology supplied an efficient construc-
tion of a new type of oxazepine-based 5/7-bicyclic heterocy-
cles. Further development and application of this method
are in progress in our laboratory.
20
16
30[c]
[a] Conditions: ACP ketone 1a (0.38 mmol), nitrone (1.7 equiv), DCE
(13 mL), 508C, 4 ꢁ molecular sieves. [b] Yield of isolated product.[c] Ca-
talyzed by AuCl3 (10 mol%). [d] Reaction was carried out at room tem-
perature.
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Chem. Eur. J. 2009, 15, 8975 – 8978

Cycloaddition
COMMUNICATION
1.0 equiv), and 0.6 g of molecular
sieves
in
8 mL
of
anhydrous
CH2ClCH2Cl was treated with a solu-
tion of nitrone 2a (76 mg, 0.38 mmol)
in 3 mL of anhydrous CH2ClCH2Cl
under Ar gas. The mixture was stirred
at 508C for 4 h, and another solution
of nitrone 2a (53 mg, 0.27 mmol) in
2 mL of anhydrous CH2ClCH2Cl was
added. The mixture was allowed to
react for a further 3 h. After filtration
and evaporation, the residue was puri-
fied by column chromatography on
silica gel (hexane/ CH2Cl2 =5:1) to
afford 160 mg (yield 91%) of 3a as a
1
colorless solid, m.p. 75–768C. H NMR
(CDCl3, 400 MHz):
d (ppm)=7.40–
7.38 (m, 2H), 7.36–7.33 (m, 7H), 7.29–
7.24 (m, 4H), 7.19–7.15 (m, 4H), 6.88–
6.86 (m, 3H), 6.14 (s, 1H), 5.11–5.09
(m, 1H), 3.23–3.17 (dd, J=15.2,
11.8 Hz, 1H), 3.05–3.00 (dd, J=15.2,
2.0 Hz, 1H), 2.36 (s, 3H). 13C NMR
(CDCl3, 100 MHz): d (ppm)=149.63,
147.62, 147.32, 141.01, 137.79, 130.93,
129.06, 128.80, 128.61, 128.37, 127.90,
127.80, 127.37, 127.21, 126.34, 125.95,
122.14, 121.09, 118.74, 116.10, 85.62,
66.85, 34.88, 11.86. IR (neat): n˜ =3085,
3058, 3028, 2921, 1596, 1489, 1450,
Scheme 2. Reactions of various ACP ketones with nitrone 2a.[a–c] The catalyst, the yield, and the reaction time
are listed under the products obtained. [a] Conditions: same as in Table 2. [b] Yield of isolated product. [c] For
3q–3r and 3u–3w, cis/trans >20:1; for 3s and 3t, cis/trans >10/1, all of which were determined by 1H NMR
analysis before separation on by silica gel chromatography. [d] 3.0 equiv of nitrone was used.
1222, 751, 696 cmÀ1
. HRMS (ESI)
Calcd. for C32H27NO2Na (M+Na)+:
480.1939; Found: 480.1934.
Keywords: alkynes · cycloaddition · cyclopropanes · domino
reactions · Lewis acids
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[3,4-d][1,2]oxazepine.
N
ACHTUNGTRENNUNG
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Experimental Section
General procedure for the synthesis of 3a: A mixture of Cu
(28 mg, 0.077 mmol, 0.2 equiv), ACP ketone 1a (100 mg, 0.38 mmol,
ACHTUNGERTN(NUNG OTf)2
Chem. Eur. J. 2009, 15, 8975 – 8978
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8977

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[20] Catalysis of Cu
isfied result.
ACHTUNGRTEN(NUNG OTf)2 for this three-component reaction gave dissat-
Received: April 29, 2009
Published online: July 30, 2009
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