Highly functionalized 4-alkylidenebicyclo[3.1.0]hex-2-enes by tandem michael addition and annulation of electron-deficient enynes

Article abstract of DOI:10.1002/asia.200900290

Rapid access: Highly functionalized 4-alkylidenebicyclo[3.1.0]hex-2-enes can be rapidly constructed by a tandem Michael addition and formal [3+2] cycloaddition of electron deficient enynes with a crotonate-derived sulfur ylide. The stereochemistry of all

Full text of DOI:10.1002/asia.200900290

DOI: 10.1002/asia.200900290
Highly Functionalized 4-AlkylidenebicycloACTHNUTRGNE[NUG 3.1.0]hex-2-enes by Tandem
Michael Addition and Annulation of Electron-Deficient Enynes
Zuliang Chen[a] and Junliang Zhang*[a, b]
Domino reactions are of high importance in synthetic
chemistry, since they can combine several transformations
into one-step and thus provide a rapid access to architectur-
ally complex molecules from relatively simple starting mate-
rials.[1] Recently, tandem reactions consisting of ylide routes
leading to fused bicyclic compounds have attracted the in-
terest of many chemists.[2,3] In the context of our ongoing ef-
forts to develop novel chemistry of electron-deficient
enynes,[4] we report herein a novel selective tandem Michael
Scheme 1. Previous work on ylide reaction of 1 and 2.
addition and annulation of a crotonate-derived sulfur ylide
with electron-deficient enynes for the rapid construction of
highly functionalized 4-alkylidenebicyclo
[3.1.0]hex-2-enes.[5]
lents of Et3N to furnish the desired product 4a with a 72%
yield of isolated product and a trace amount of unidentified
product (Table 1, entry 1). The structure of 4a was further
Very recently, a tandem reaction of crotonate-derived sul-
fonium salt 1 with a, b-unsaturated ketones for synthesis of
cyclohexadiene epoxides in high efficiency was reported by
Tang (see Scheme 1).[2a] We have just reported that the reac-
tions of conjugated yne-enone 3 with ylide 2 proceeded
smoothly to produce the cyclopropane derivatives via the
cyclopropanation reaction of the C=C double bond. The cy-
cloadducts can be further converted into fused bicyclic
furans under the catalysis of a RhI species under a CO at-
mosphere.[6] To our surprise, we found that the reaction of
conjugated eny-enone 3a with sulfonium salt 1 gave the
Table 1. Screening the reaction conditions of tandem cyclization of 3a
with sulfonium salt 1.
Entry[a]
Base [equiv]
Solvent
Time [h]
Isolated yield [%]
novel bicycloACHTUNGTRENNUNG[3.1.0]hex-2-ene 4a rather than cyclopropanes
1
2
3
4
5
Et3N (4.0)
Et3N (2.4)
Et3N (3.0)
Na2CO3 (4.0)
Et3N (4.0)
EtOH
EtOH
EtOH
EtOH
MeOH
CH3CN
DCM
DCE
0.5
2
1.5
4
0.5
0.8
3.5
7
72
58
69
64
66
54
59
64
and cyclohexadiene epoxides in the presence of base. The
reaction is complete in 0.5 h at 08C in EtOH using 4 equiva-
[a] Z. Chen, 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 (China)
Fax : (+86)21-6223-3213
THF
3.5
25
0.5
0.5
30
10
3
65
toluene
DMF
EtOH
THF
THF
THF
55[c,d]
60[c]
48[c]
trace[d]
57
E-mail: jlzhang@chem.ecnu.edu.cn
13
14
15
16
Li2CO3 (4.0)
Cs2CO3 (4.0)
DBU (4.0)
Et3N (4.0)
[b] Prof. Dr. J. Zhang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
50[c]
58[c]
THF
26
354 Fenglin Road, Shanghai 200032 (China)
[a] Unless otherwise noted, all reactions were carried out at 08C in
0.3 mmol scale. [b] Isolated yield. [c] Yield measured by 1H NMR, with
CH2Br2 as an internal standard. [d] The reactions were carried out at RT.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200900290.
Chem. Asian J. 2009, 4, 1527 – 1529
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1527

COMMUNICATION
confirmed by single crystal X-ray diffraction (Figure 1).[7]
Reducing the equivalents of Et3N resulted in decreasing
slightly the yield (entries 2–3). Further studies showed other
Table 2. Synthesis of multi-functionalized bicycloACTHNUGRTNEUNG[3.1.0]hex-2-ene deriva-
tives.
Entry[a]
Enyne 3
Time [h]
4 Yield [%]
R1/R2/R3
1
Ph/Ph/4-NO2C6H4 (3b)
Ph/Ph/4-MeOC6H4 (3c)
Ph/Ph/n-C4H9 (3d)
Ph/Ph/1-cyclohexenyl (3e)
4-MeOC6H4/Ph/Ph (3 f)
4-ClC6H4/Ph/Ph (3g)
Ph/4-ClC6H4/Ph (3h)
Ph/Me/Ph (3i)
0.5
10
10
3.5
12
0.5
0.5
11
4b (59)
4c (40)
4d (58)
4e (40)
4 f (62)
4g (85)
4h (62)
4i (56)
4j (47)
4k (56)
4l (30)
2[b]
3
4
5
6
7
8
9
10
11
Ph/MeO2C/Ph (3j)
Ph/Me/nC4H9 (3k)
nC4H9/Me/Ph (3l)
0.5
41
3
[a] Unless othewise noted, all reactions were carried out using
3
(0.3 mmol), 1 (0.6 mmol), Et3N (1.2 mmol), EtOH (3 mL) at 08C and
yield is yield of isolated product. [b] K2CO3 and THF were used.
The generality of this transformation was also investigated
using the (E)-2-benzylidene-4-phenylbut-3-ynenitrile 5 and
(E)-enyne 7 (Scheme 2). To our delight, the reaction of 5
Figure 1. ORTEP representation of 4a.
bases such as Na2CO3, K2CO3, Cs2CO3, and DBU are slight-
ly less effective. However, Li2CO3 is ineffective to mediate
this reaction even at elevated temperature. Solvents also
have effects on the reaction. For example, the reaction run
in THF gave the product 4a in a relatively lower yield
(58%, entry 16) than the one in EtOH (72% yield).
Scheme 2. The tandem reactions of 5 and 7 with 1.
With the optimal reaction conditions in hand, we next
study the scope of conjugated yne-enone 3 and the results
are summarized in Table 2. These results showed that all
three substitutents (R1–3) could be not only aryl but also ali-
could give the desired bicyclic product 6 in a yield of isolat-
ed product of 73% after stirring the reaction for 9 h at RT.
The reaction of 7 can also give a moderate yield of bicyclic
cycloadduct 8. In this case, K2CO3 is a better base than Et3N
and gives a slightly better yield, however, the reason for this
increase is not clear.
The preliminary result [Eq. (1)] showed that the camphor-
derived sulfonium salt 9[2a] could react with yne-enone 3a to
give 4a in a yield of isolated product of 69% with 38% ee.
Although the ee value is only moderate, it is still a good ex-
ample for controlling three stereogenic centers including
two all-carbon quaternary ones in a single operation.
phalic to afford the corresponding bicycloACHTNUTRGNEUNG[3.1.0]hex-2-ene
derivatives in moderate to good yields (entries 1–13). Intro-
duction of an electron-donating group to the aryl ring of R1
decreased the reactivity and the reaction furnished the de-
sired product in relatively lower yield. For example, the re-
action of 3 f was complete after 12 h to give 4 f in 62%
yield, whereas the reaction of 3g furnished 4g in 85% yield
after 0.5 h (entries 5 and 6). It is interesting that the reaction
of (E)-methyl 3-benzylidene-2-oxo-5-phenylpent-4-ynoate
(3j) also gave the corresponding 4-alkylidenebicyclo-
ACHTUNGTRENNUNG[3.1.0]hex-2-ene 4j in 47% yield. The yne-enone 3l is not
stable under the reaction conditions and gives the desired
product in 30% yield (entry 11). It is also noteworthy that
all these reactions give the cycloadducts as a single diaste-
reomer, indicating that this tandem transformation is highly
selective.
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Chem. Asian J. 2009, 4, 1527 – 1529

Alkylidenebicyclohexenes by Tandem Michael Addition
A plausible mechanism for this novel tandem transforma-
tion is depicted in Scheme 3. The crotonate-derived sulfoni-
um salt 1 was treated with Et3N to give an allylic ylide with
Acknowledgements
Financial support from NSFC (20702015) and STCSM (07DZ22937,
08dj1400101), Shanghai Shuguang Program (07SG27), Shanghai Pujiang
Program (07pj14039), and Shanghai Leading Academic Discipline Project
(B409) is greatly appreciated.
Keywords: carbocycles · cycloaddition · domino reactions ·
enynes · ylides
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two resonance structures A and B, which undergo a Michael
addition with 3a to produce a new ylide C.[2a] The subse-
quent stereoselective intramolecular Michael addition of C
from the side opposite the phenyl group gave the intermedi-
ate D, which would in turn undergo a stereoselective intra-
molecular SN2’ nucleophilic substitution to furnish the prod-
uct 4a. The two newly formed stereogenic centers are effec-
tively induced by the adjacent phenyl group.
In summary, we have developed a novel tandem Michael
addition and ylide annulation of a crotonate-derived sulfur
ylide with readily available electron-deficient enynes, which
provide a rapid, efficient, and selective route to multi-func-
tionalized 4-alkylidenebicycloACTHNUGRTNEUNG[3.1.0]hex-2-enes. It is note-
worthy that not only the stereochemistry of all three newly
formed carbon stereogenic centers, including two all carbon
quaternary ones, but also the double bond could be con-
trolled in this domino process. Further studies on the syn-
thesis of other chiral sulfur ylides and their applications in
this transformation are ongoing in this laboratory.
Experimental Section
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Typical procedure for the synthesis of 4a (Table 1, entry 1): To a stirred
mixture of sulfonium salt 1 (145 mg, 0.6 mmol) and 3a (93 mg, 0.3 mmol)
in EtOH (3 mL), Et3N (122 mg, 1.2 mmol) was added, and the resulting
solution was stirred at 08C until the reaction was complete (monitored
by TLC). Then the reaction mixture was diluted with water (3 mL), and
extracted with CH2Cl2. The organic layers were combined, washed with
brine (10 mL), and dried over anhydrous MgSO4. After filtration and
concentration under reduced pressure, the crude product was purified by
flash column chromatography on silica gel (hexanes/AcOEt=30:1) to
afford 88 mg (72%) of 4a as a white solid. M.p.: 134–1368C (hexanes/
CH2Cl2); 1H NMR (300 MHz, CDCl3): d=7.34–7.16 (m, 13H), 7.10 (t,
J=7.5 Hz, 2H), 6.50 (s, 1H), 6.36 (d, J=5.4 Hz, 1H), 6.05 (d, J=5.4 Hz,
1H), 4.55 (s, 1H), 3.58 ppm (s, 3H); 13C NMR (75.4 MHz, CDCl3) d
194.11, 168.98, 142.69, 136.26, 135.46, 135.41, 133.44, 132.09, 130.28,
129.98, 128.45, 128.99, 128.05, 128.00, 127.71, 127.59, 127.48, 126.97, 54.62,
53.78, 52.45, 42.95 ppm; MS (EI) m/z (%): 406 [M+] (12.76); HRMS
calcd for C28H22O3: 406.1569, found: 406.1564. For preparative proce-
dures and spectroscopic data for all new compounds, see the Supporting
Information.
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enes have been reported from the cyclopropanation of fulvenes;
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2002, 124, 5948; b) for cyclopropanation with dichloro- and dimethox-
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persen, J. Am. Chem. Soc. 1981, 103, 2413; c) for CuCl-catalyzed cy-
clopropanation with ethyl diazoacetate, please see: B. Decock-le Re-
verend, M. Durand, R. Merenyi, Bull. Soc. Chim. Fr. 1978, 369.
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[7] CCDC 736940 (4a) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre at www.ccdc.cam.ac.uk/da-
ta_request/cif.
Received: July 20, 2009
Published online: August 22, 2009
Chem. Asian J. 2009, 4, 1527 – 1529
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1529