PtCl2-catalyzed cycloisomerization of 1,6-enynes for the synthesis of substituted bicyclo[3.1.0]hexanes

Article abstract of DOI:10.1021/jo902083r

(Chemical Equation Presented) The mild and efficient PtCl ₂-catalyzed cycloisomerization of 1,6-enynes containing a heteroatom substituent at the propargylic position is described. The reactions led to the formation of 1-alkenylbicyclo[3.1.0]he

Full text of DOI:10.1021/jo902083r

pubs.acs.org/joc
SCHEME 1
PtCl2-Catalyzed Cycloisomerization of 1,6-Enynes
for the Synthesis of Substituted Bicyclo[3.1.0]hexanes
Liu Ye,† Qian Chen,*,† Jiancun Zhang,*,†,‡ and
,§
ꢀ
Veronique Michelet*
†Guangzhou Institutes of Biomedicine and Health, Chinese
Academy of Sciences, International Business Incubator,
Guangzhou Science Park, Guangzhou 510663, P. R. China,
‡State Key Laboratory of Respiratory Diseases, Guangzhou
§
510120, P. R. China, and Laboratoire Charles Friedel, UMR
ꢀ
7223, Ecole Nationale Superieure de Chimie de Paris, 11, rue
P. et M. Curie, 75231 Paris Cedex 05, France
under mild conditions.3 For example, the 5-exo-dig cycliza-
tion of carbon-tethered 1,6-enynes afforded the 1-alkenylcy-
clopentene products II or III via the cyclopropyl metal
carbene intermediates (Scheme 1).4 Depending on the sub-
stituents on the alkene part, the cyclopropyl metal carbene
may undergo a 1,2-alkyl migration or fragmentation steps
leading to dienes II or III, the latter being generally observed
in the case of monosubstituted alkenes.1,4 On the other hand,
the O- or N-tethered 1,6-enynes underwent 6-endo-dig cycli-
zation to generate the metal carbenes, which led to the
corresponding bicyclo[4.1.0]heptenes IV via 1,2-hydride mi-
gration (Scheme 1).5 The difference in these two types of
cyclic products revealed that the presence of a heteroatom in
the tether might facilitate the 1,2-hydride migration of the
cyclopropyl metal carbenes.5
ustc_chenqian@hotmail.com; veronique-michelet@
chimie-paristech.fr
Received October 1, 2009
The mild and efficient PtCl2-catalyzed cycloisomeriza-
tion of 1,6-enynes containing a heteroatom substituent at
the propargylic position is described. The reactions led to
the formation of 1-alkenylbicyclo[3.1.0]hexanes in good
to excellent yields or 2-(bicyclo[3.1.0]hex-1-yl)acetalde-
hydes in moderate yields.
We have been interested in studying the heteroatom effect
when introduced into the cycloisomerization of carbon-
tethered 1,6-enynes. With the above background and keep-
ing in mind some recent reports,6,7 we envisioned that the
(4) (a) Trost, B. M.; Chang, V. K. Synthesis 1993, 824. (b) Chatani, N.;
Furukawa, N.; Sakurai, H.; Murai, S. Organometallics 1996, 15, 901.
(c) Trost, B. M.; Doherty, G. A. J. Am. Chem. Soc. 2000, 122, 3801.
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~
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(e) Nieto-Oberhuber, C.; Lopez, S.; Munoz, M. P.; Cardenas, D. J.; Bunuel,
E.; Nevado, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2005, 44, 6146.
(5) (a) Blum, J.; Beer-Kraft, H.; Badrieh, Y. J. Org. Chem. 1995, 60, 5567.
Transition-metal-catalyzed cycloisomerization reactions
of enynes provide a rapid access to functionalized cyclic
structures.1 Such reactions are perfectly suited to meet the
high demands for atom economy2 in newly developed meth-
ods. It was well documented that the gold and platinum
complexes catalyzed the cycloisomerization reactions of 1,6-
enynes to allow the generation of a variety of cyclic products
€
(b) Furtsner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122, 6785.
€
(c) Furtsner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2001, 123, 11863.
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D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 2402. (f) Brissy, D.;
Skander, M.; Retailleau, P.; Marinetti, A. Organometallics 2007, 26, 5782.
(g) Ferrer, C.; Raducan, M.; Nevado, C.; Claverie, C. K.; Echavarren, A. M.
Tetrahedron 2007, 63, 6306. (h) Brissy, D.; Skander, M.; Retailleau, P.;
Frison, G.; Marinetti, A. Organometallics 2009, 28, 140. (i) Brissy, D.;
Skander, M.; Jullien, H.; Retailleau, P.; Marinetti, A. Org. Lett. 2009, 11,
2137. (j) Chao, C.-M.; Beltrami, D.; Toullec, P. Y.; Michelet, V. Chem.
Commun. 2009, 6988.
(1) For selected reviews on metal-catalyzed cycloisomerization reactions,
see: (a) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239. (b) Michelet,
^
V.; Toullec, P. Y.; Genet, J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268.
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(c) Nieto-Oberhuber, C.; Lopez, S.; Jimenez-Nunez, E.; Echavarren, A. M.
Chem.-Eur. J. 2006, 12, 5916. (d) Zhang, L.; Sun, J.; Kozmin, S. A. Adv.
Synth. Catal. 2006, 348, 2271. (e) Diver, S. T.; Giessert, A. J. Chem. Rev.
2004, 104, 1317. (f) Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 1, 215.
(2) (a) Trost, B. M. Angew. Chem., Int. Ed. 1995, 34, 259. (b) Trost, B. M.
Acc. Chem. Res. 2002, 35, 695.
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(b) Horino, Y.; Yamamoto, T.; Ueda, K.; Kuroda, S.; Toste, F. D. J. Am.
Chem. Soc. 2009, 131, 2809. (c) Chao, C.-M.; Vitale, M.; Toullec, P. Y.;
^
Genet, J.-P.; Michelet, V. Chem.;Eur. J. 2009, 15, 1319. (d) Leseurre, L.;
Chao, C.-M.; Seki, T.; Genin, E.; Toullec, P. Y.; Genet, J.-P.; Michelet, V.
^
Tetrahedron 2009, 65, 1911. (e) Lu, L.; Liu, X.-Y.; Shu, X.-Z.; Yang, K.; Ji,
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Fujiwara, S.; Shin-ike, T.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc.
2008, 130, 10504. (g) Yeh, M. C. P.; Tsao, W. C.; Cheng, S. T. J. Org. Chem.
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(3) For selected reviews on Au and/or Pt catalysis, see: (a) Jimenez-
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Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326. (b) Muzart, J.
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Tetrahedron 2008, 64, 5815. (c) Chianese, A. R.; Lee, S. J.; Gagne, M. R.
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2008, 73, 2902. (h) Toullec, P. Y.; Chao, C.-M.; Chen, Q.; Genet, J.-P.;
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Michelet, V. Adv. Synth. Catal. 2008, 250, 2401. (i) Barluenga, J.; Fernandez-
107, 3180. (e) Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46,
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´
guez, M. A.; Garcıa-Garcıa, P.; Aguilar, E. J. Am. Chem. Soc. 2008,
ꢀ
´
´
ꢀ
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9550 J. Org. Chem. 2009, 74, 9550–9553
Published on Web 11/19/2009
DOI: 10.1021/jo902083r
r
2009 American Chemical Society

Ye et al.
JOCNote
SCHEME 2
TABLE 1. Cycloisomerization of 1,6-Enyne 1aa
entry catalyst [cat]
conditions
yieldb (%) ratio Z/Ec
1
2
3
4
5
6
7f
8
9
PPh3AuSbF6 CH2Cl2, rt, 10 min
traced
NR
n/a
n/a
n/a
n/a
2/1
2/1
3/1
2/1
n/a
PPh3AuCl
AgSbF6
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
CH2Cl2, rt, 12 h
CH2Cl2, rt, 2 h
toluene, rt, 12 h
toluene, 80 °C, 1 h
d
-
NR
99e
toluene, 80 °C, 12 h 88
toluene, 80 °C, 1 h
dioxane, 80 °C, 1 h
PhH, 80 °C, 12 h
96
35g
traceh
aThe reaction of 1a (0.2 mmol) was carried out in the presence of 5 mol
% of catalysts in solvents (2 mL). bYield based on 1a was determined by
1H NMR using an internal standard; NR = no reaction. Ratio was
c
1
d
determined by H NMR; n/a = not applicable. Most of the material
was decomposed. e95% isolated yield. fA stoichiometric amount of
CH3CN was introduced. g85% conversion. h<5% conversion.
SCHEME 3. Murai’s Cycloisomerization Reaction
carbon-tethered 1,6-enyne A with a heteroatom substituent
at the propargylic position might undergo 5-exo-dig cyclo-
propanation to produce the cyclopropyl metal carbene B,
which might undergo facile 1,2-hydride migration to give
zwitterion C.7 Subsequent elimination of the metal fragment
might produce 1-alkenylbicyclo[3.1.0]hexane D probably as
a mixture of Z- and E-isomers (Scheme 2). A 1,2-alkyl
migration step would be competitive and would give dienes
E or F according to a similar process for the formations of II
and III. Herein, we report that the utilization of PtCl2 as the
catalyst for the cyclization of 1,6-enynes provides a conve-
nient and general approach to substituted bicyclo[3.1.0]-
hexanes under mild conditions.
To test the hypothesis in Scheme 2, we prepared diethyl 2-
allyl-2-(4-(benzyloxy)but-2-yn-1-yl)malonate 1a8 as the
model substrate for the optimization of reaction conditions
(Table 1). We first examined the reaction of 1a under the
conventional PPh3AuCl/AgSbF6 catalysis5e (entry 1). When
the mixture was stirred at room temperature (rt) for 10 min,
the starting material was consumed, leading to a complex
mixture of products including only a trace amount of the
expected product 2a. Substrate 1a also underwent decom-
position with only AgSbF6 as the catalyst, while no reaction
occurred under the catalysis of PPh3AuCl alone (entries 2
and 3). We then turned to PtCl2. The reaction of 1a with
5 mol % of PtCl2 in toluene did not occur at rt (entry 4).
To our delight, when the reaction temperature was raised
to 80 °C, the reaction proceeded smoothly, the bicyclic
product 2a was achieved in 99% yield (95% isolated yield)
within 1 h, and the ratio of Z-alkene and E-alkene was about
2:1 (entry 5). When this reaction was conducted for 12 h, the
yield was slightly decreased to 88% due to the hydrolysis of
the enol ether 2a, where an aldehyde product was detected by
1H NMR (entry 6). A stoichiometric amount of CH3CN as
an additive was also introduced,9 and the expected product
was obtained in 96% yield with a slight increase of the ratio
of two isomers (entry 7). Switching the solvent from toluene
to dioxane decreased the yield to 35% (85% conversion), and
the use of benzene as the solvent led to a very low conversion
(entries 8 and 9). The very low conversion observed in
benzene may be due to a lower solubilization of PtCl2.
The formation of bicyclo[3.1.0]hexane 2a strongly indicates
that the cyclopropyl metal carbene intermediate B generated
from the above reaction may undergo facile 1,2-hydride migra-
tion to produce the intermediate C (Scheme 2). As a compar-
ison, the reaction of the 1,6-enyne with a methyl substituent at
the alkyne terminus under the same conditions reported by
Murai4b afforded 1-alkenyl-1-cyclopentene products, while no
bicyclo[3.1.0]hexanes were observed (Scheme 3). Therefore, the
heteroatom effect is proved to be indispensable in the forma-
tion of bicyclo[3.1.0]hexanes such as 2a.
(7) For selected analogous 1,2-hydride shifts on 1,5-enynes, see: (a)
Mainetti, E.; Mouries, V.; Fensterbank, L.; Malacria, M.; Marco- Contelles,
J. Angew. Chem., Int. Ed. 2002, 41, 2132. (b) Mamane, V.; Gress, T.; Krause,
€
H.; Furstner, A. J. Am. Chem. Soc. 2004, 126, 8654. (c) Harrak, Y.;
Blazykowski, C.; Bernard, M.; Cariou, K.; Mainetti, E.; Mouries, V.;
ꢁ
Dhimane, A.-L.; Fensterbank, L.; Malacria, M. J. Am. Chem. Soc. 2004,
126, 8656. (d) Luzung, M. R.; Markham, J. P.; Toste, F. D. J. Am. Chem. Soc.
2004, 126, 10858. (e) Gagosz, F. Org. Lett. 2005, 7, 4129. (f) Blazykowski, C.;
Harrak, Y.; Brancour, C.; Nakama, K.; Dhimane, A.-L.; Fensterbank, L.;
Malacria, M. Synthesis 2007, 2037. (g) Marco-Contelles, J.; Arroyo, N.;
With the optimized conditions in hand (entry 5, Table 1),
we then set out to explore the generality of this method. The
results are summarized in Table 2. A number of heteroatom
substituents at the propargylic position of substrates 1 were
ꢁ
ꢁ
Anjum, S.; Mainetti, E.; Marion, N.; Cariou, K.; Lemiere, G.; Mouries, V.;
Fensterbank, L.; Malacria, M. Eur. J. Org. Chem. 2006, 4618. (h) Couty, S.;
Meyer, C.; Cossy, J. Tetrahedron 2009, 65, 1809.
(8) Shibata, T.; Toshida, N.; Yamasaki, M.; Maekawa, S.; Takagi, K.
Tetrahedron 2005, 61, 9974.
(9) Sun, J.; Conley, M. P.; Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc.
2006, 128, 9705.
J. Org. Chem. Vol. 74, No. 24, 2009 9551

Ye et al.
JOCNote
TABLE 2. PtCl2-Catalyzed Cycloisomerization of 1,6-Enynes 1a
SCHEME 4. PtCl2-Catalyzed Reactions of 1,6-Enynes 4a
and 4b
containing a sulfonamidyl substituent in which the expected
products were achieved as single E-isomers (entries 9 and 10).
The reactivities of substrates with a terminal vinylic sub-
stituent were also investigated. The cyclization reactions of
methyl substituted E-alkenes afforded the desired products
in good to excellent yields with higher ratios of two isomers
due to the possible steric effect (entries 2, 6, and 8). Surpris-
ingly, the reaction of phenyl-substituted E-alkene 1c did not
occur (entry 3). Trisubstituted alkene 1d did not afford the
corresponding bicyclic product. Instead, alkenylmethylene-
cyclopentane 3 was isolated in 68% yield13 (entry 4).
To further expand the scope of this method, we also
carried out the cycloisomerization of O-tethered 1,6-enyne
4a and N-tethered 1,6-enyne 4b. As anticipated,5 only 6-endo
dig cyclization was observed leading to the formation of
bicyclo[4.1.0]heptenes 5a and 5b in 56% and 87% yields,
respectively (Scheme 4).
In summary, we have extended and developed an efficient
PtCl2-catalyzed method for the synthesis of substituted
bicyclo[3.1.0]hexanes from carbon-tethered 1,6-enynes with
heteroatom substituents at the propargylic position. Further
studies will be focused on applications of this methodology.
aAll reactions were carried out with 1 (0.2 mmol) in the presence of
5 mol % of PtCl2 in toluene (2 mL) at 80 °C. bIsolated yield based on 1.
cRatio was determined by 1H NMR.
Experimental Section
well tolerated, including benzyloxy (entries 1 and 2), meth-
oxy (entries 5 and 6), siloxy (entries 7 and 8), sulfonamidyl
(entries 9 and 10), and hydroxyl (entries 11 and 12) groups,
leading to the corresponding substituted bicyclo[3.1.0]-
hexanes products in 42-95% yields.
General Procedure for Pt-Catalyzed Cyclization Reaction. To
the solution of diethyl 2-allyl-2-(4-(benzyloxy)but-2-ynyl)-
malonate (1a) (72 mg, 0.2 mmol) in dry toluene (2 mL) was
added PtCl2 (2.7 mg, 0.01 mmol) under nitrogen atmosphere.
The mixture was stirred at 80 °C for 1 h. After removal of the
solvent, the residue was then purified by flash chromatography
on silica gel using hexane-ethyl acetate (15:1) as the eluent to
give bicyclo[3.1.0]hexane 2a (68.5 mg, 95% yield) as a colorless
oil.
The range of heteroatoms used and their corresponding
substituents (Bn, H, TBS) leads one to preclude the idea of a
heteroatom chelation effect.10 In all the cases tested, no
corresponding 6-endo-dig cyclization products could be de-
tected. The stereoselectivity was based on the proposed
mechanism for the Pt-catalyzed reaction.5,11 It is worth
mentioning that alcohols 1k and 1l produced aldehydes 2k
and 2l, respectively, via enol intermediates in moderate
yields, while no products resulting from the intramolecular
attack of the hydroxyl group on the cyclopropyl metal
carbene intermediates were observed.12 Such behavior had
been already observed on an analogous 1,6-enyne derivative
of 1k.7b Also noteworthy is the cyclization of substrates
1
Two isomers in 2:1 ratio: H NMR (400 MHz, CDCl3) Z-
isomer δ 7.29-7.38 (5H, m), 5.92-5.94 (1H, d, J = 6.8 Hz), 4.77
(2H, s), 4.32-4.33 (1H, d, J = 6.8 Hz), 4.11-4.21 (4H, m), 2.80
(1H, d, J = 14.0 Hz), 2.45-2.63 (3H, m), 1.43-1.48 (1H, m),
1.22-1.28 (6H, m), 0.78 (1H, t, J = 7.6 Hz), 0.44 (1H, dd, J =
5.6, 4.4 Hz); E-isomer δ 7.29-7.38 (5H, m), 6.34-6.37 (1H, d,
J = 12.4 Hz), 4.97-5.00 (1H, d, J = 12.4 Hz), 4.70 (2H, s),
4.11-4.21 (4H, m), 2.80 (1H, d, J = 14.0 Hz), 2.45-2.63 (3H,
m), 1.18-1.28 (7H, m), 0.60 (1H, t, J = 7.6 Hz), 0.40 (1H, dd,
J = 5.6, 4.4 Hz); 13C NMR (100 MHz, CDCl3) Z-isomer δ
(10) Even if the heteroatom substitution effect seems to be the governing
element, an agostic hydrogen interaction in the cyclopropanation step
cannot be ruled out.
(13) The reaction of 1d under the standard reaction conditions resulted in
the complete consumption of the starting material. However, the only
product isolated was 3 (68% yield). Similar results were reported by
ꢀ
~
Echavarren et al. See: Mendez, M.; Munoz, M. P.; Nevado, C.; Cardenas,
D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2001, 123, 10511.
ꢀ
(11) (a) Nevado, C.; Cardenas, D. J.; Echavarren, A. M. Chem.;Eur. J.
2003, 9, 2627. (b) Soriano, E.; Ballesteros, P.; Marco-Contelles, J. Organo-
metallics 2005, 24, 3172. (c) Soriano, E.; Marco-Contelles, J. J. Org. Chem.
2005, 70, 9345. (d) Soriano, E.; Ballesteros, P.; Marco-Contelles, J. J. Org.
Chem. 2004, 69, 8018.
~
(12) Nieto-Oberhuber, C.; Munoz, M. P.; Lopez, S.; Jimenez-Nunez, E.;
Nevado, C.; Herrero-Gomez, E.; Raducan, M.; Echavarren, A. M. Chem.;
ꢀ
ꢀ
ꢀ~
ꢀ
Eur. J. 2006, 12, 1677.
9552 J. Org. Chem. Vol. 74, No. 24, 2009

Ye et al.
JOCNote
173.0, 172.0, 144.9, 137.7, 128.4, 127.8, 127.2, 109.3, 73.9, 61.6,
61.4, 59.8, 40.5, 35.9, 26.4, 26.0, 17.1, 14.0; E-isomer δ 172.7,
171.9, 146.1, 137.1, 128.5, 127. 9, 127.6, 108.7, 71.5, 61.7, 61.4,
59.7, 39.7, 36.0, 27.3, 25.2, 15.7, 14.0; ESI-MS m/z = 359.1
(Mþ þ H), 381.1 (Mþ þ Na); HRMS-EI calcd for C21H26O5
(Mþ) 358.1780, found 358.1772.
Sciences (KSCX1-YW-10). We thank Prof. Chaozhong Li
(Shanghai Institute of Organic Chemistry, Shanghai, P. R.
China) for valuable discussions on this project.
Supporting Information Available: Typical experimental
procedures and characterizations of compounds 1-5. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. This project was supported by the
Knowledge Innovation Project of the Chinese Academy of
J. Org. Chem. Vol. 74, No. 24, 2009 9553