Reaction of vinyl epoxides with palladium-switchable bisnucleophiles: Synthesis of carbocycles

Article abstract of DOI:10.1021/jo0056850

The selective activation of substrates I, potential bisnucleophiles, was achieved by using different palladium catalysts. The synthetic potential of this strategy has been demonstrated in the regiodivergent synthesis of carbocycles from substrates of type

Full text of DOI:10.1021/jo0056850

J . Org. Chem. 2001, 66, 589-593
589
Rea ction of Vin yl Ep oxid es w ith P a lla d iu m -Sw itch a ble
Bisn u cleop h iles: Syn th esis of Ca r bocycles
Ana M. Castan˜o,† Mar´ıa Me´ndez, Mar´ıa Ruano, and Antonio M. Echavarren*
Departamento de Quı´mica Orga´nica, Universidad Auto´noma de Madrid,
Cantoblanco, 28049 Madrid, Spain
anton.echavarren@uam.es
Received October 17, 2000
The selective activation of substrates I, potential bisnucleophiles, was achieved by using different
palladium catalysts. The synthetic potential of this strategy has been demonstrated in the
regiodivergent synthesis of carbocycles from substrates of type I, bearing malonate-type pronu-
cleophiles and an alkenyl stannane, with vinyl epoxides. A selective palladium-catalyzed reaction
of I with the vinyl epoxide gives rise to an allylic alcohol, which, after activation as a carbonate,
led to the cyclization product by a second palladium-catalyzed reaction. The transmetalation process
is favored with palladium catalysts without phosphines or arsines as the ligands. On the other
hand, the use of palladium complexes with PPh3 as the ligand inhibits the transmetalation pathway
and promotes the nucleophilic attack of the malonate-type anions on the intermediate (η3-allyl)-
palladium complexes.
In tr od u ction
dppe in THF as the solvent.1,3 On the other hand,
coupling of vinyl epoxides with organostannanes was
carried out with Pd(MeCN)2Cl2 in DMF-H2O.5 Under the
reaction conditions, the Pd(II) precatalyst is immediately
reduced by the stannane to form the reactive “ligandless”
Pd(0) species. Thus, in principle, bisnucleophiles of type
I bearing a malonate (Z ) CO2R) or a related C-H
activating group and an organostannane (M ) SnR3)
could transmetalate with the intermediate (η3-allyl)-
palladium complex derived from vinyl epoxide II to give
III (X ) H) (Scheme 1). Alternatively, alkylation of the
(η3-allyl)palladium complex derived from the vinyl ep-
oxide II would form the allylic alcohol IV (X ) H). The
desired chemoselective activation of the palladium-swit-
chable bisnucleophiles I was expected to be achieved by
using palladium catalysts with the appropriate ligands.
In any case, capture of the intermediate (η3-allyl)-
palladium complexes by the nucleophile should be faster
than potentially competitive rearrangement of these
complexes to form the corresponding carbonyl compound.9
Allylic alcohols III and IV could be activated by acylation
(X ) COR or CO2R) and then subjected to a second
palladium-catalyzed alkylation or transmetalation.10
Herein, we describe the scope and limitation of the
concept outlined in Scheme 1.11,12
The Pd(0)-catalyzed allylic alkylation is a very useful
reaction that allows for the formation of C-C bonds in a
general way under very mild conditions.1 Although a
number of allylic electrophiles have been used in this
transformation, vinyl epoxides2 are of main interest since
the product of the palladium-catalyzed allylic alkylation
is an allylic alcohol which can be used as the substrate
for a second palladium-catalyzed C-C bond formation.
Although several carbon nucleophiles have been utilized
in reactions with diene epoxides, more general results
have been obtained with stabilized enolates,1,3,4 and
organostannanes.5,6,7,8 The reaction of stabilized enolates
requires the presence of palladium complexes with phos-
phine ligands such as Pd(PPh3)4 and Pd2(dba)3‚CHCl3/
† Present address: Lilly, S. A., Avda. de la Industria, 30, 28108
Alcobendas, Madrid, Spain.
(1) (a) Tsuji, J . Palladium Reagents and Catalysts; Wiley: Chich-
ester, 1995. (b) Heumann, A.; Re´glier, M. Tetrahedron 1995, 51, 975.
(c) Godleski S. A. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, Chapter 3.3. (d)
Harrington P. J . In Comprehensive Organometallic Chemistry; Abel,
E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, 1995;
Vol. 12, pp 797-904.
(2) For a recent lead reference on the synthesis of vinyl epoxides.
Ma, S.; Zhao, S. J . Am. Chem. Soc. 1999, 121, 7943.
(3) (a) Tsuji, J .; Kataoka, H.; Kobayashi, Y. Tetrahedron Lett. 1981,
22, 2575. (b) Trost, B. M.; Molander, G. A. J . Am. Chem. Soc. 1981,
103, 5969. (c) Trost, B. M.; Granja, J . R. J . Am. Chem. Soc. 1991, 113,
1044. (d) Trost, B. M.; Warner, R. W. J . Am. Chem. Soc. 1983, 105,
5940. (e) Safi, M.; Sinou, D. Tetrahedron Lett. 1991, 32, 2025. (f) Blart,
E.; Geˆnet, J . P.; Safi, M.; Savignac, M.; Sinou, D. I. Tetrahedron 1994,
50, 505.
(4) Synthetic applications: (a) Trost, B. M.; Hane, J . T.; Metz, P.
Tetrahedron Lett. 1986, 27, 5695. (b) Trost, B. M.; Scanlan, T. S. J .
Am. Chem. Soc. 1989, 111, 4988. (c) Larock, R. C.; Lee, N. H.
Tetrahedron Lett. 1991, 32, 5911. (d) Trost, B. M.; Ceschi, M. A.; Ko¨nig,
B. Angew. Chem., Int. Ed. Engl. 1997, 36, 1486. (e) Trost, B. M.; Bunt,
R. C.; Lemoine, R. C.; Calkins, T. L: J . Am. Chem. Soc. 2000, 122,
5968.
(5) (a) Echavarren, A. M.; Tueting, D. R.; Stille, J . K. J . Am. Chem
Soc. 1988, 110, 4039. (b) Tueting, D. R.; Echavarren, A. M.; Stille, J .
K. Tetrahedron 1989, 45, 979.
(6) Application in natural product synthesis: (a) White, J . D.;
J ensen, M. S. J . Am. Chem. Soc. 1993, 115, 2970. (b) White, J . D.;
J ensen, M. S. J . Am. Chem. Soc. 1995, 117, 6224.
(7) (a) Palladium-catalyzed reaction of diene epoxides with organo-
mercurials: Larock, R. C.; Ilkka, S. J . Tetrahedron Lett. 1986, 27, 2211.
(b) Reaction with organoboranes: Miyaura, N.; Tanabe, Y.; Suginome,
H. J . Organomet. Chem. 1982, 233, C13. (c) Reaction with organosi-
lanes: Matsuhashi, H.; Asai, S.; Hirabayashi, K.; Hatanaka, Y.; Mori,
A.; Hiyama, T. Bull. Chem. Soc. J pn. 1997, 70, 1943.
(8) Nickel-catalyzed reaction of diene epoxides with arylborates:
Kobayashi, Y.; Takahisa, E.; Usmani, S. B. Tetrahedron Lett. 1998,
39, 597.
(9) (a) Suzuki, M.; Oda, Y.; Noyori, R. J . Am. Chem. Soc. 1979, 101,
1623. (b) Suzuki, M.; Watanabe, A.; Noyori, R. J . Am. Chem. Soc. 1980,
102, 2, 2095. See also: (c) Kulasegaram, S.; Kulawiec, R. J . J . Org.
Chem. 1997, 62, 6547. (d) Kulasegaram, S.; Kulawiec, R. J . Tetrahedron
1998, 54, 1361 and references therein.
(10) Castan˜o, A. M.; Echavarren, A. M. Tetrahedron Lett. 1996, 37,
6587.
(11) Preliminary results by using malonate-stannane 1: Castan˜o,
A. M.; Ruano, M.; Echavarren, A. M. Tetrahedron Lett. 1996, 37, 6591.
10.1021/jo0056850 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/28/2000

590 J . Org. Chem., Vol. 66, No. 2, 2001
Castan˜o et al.
Sch em e 1
Sch em e 2
Ch a r t 1
between 1 and isoprene oxide (5) in the presence of
different palladium complexes (Scheme 2 and Table 1).
In analogy with that found for the palladium-catalyzed
coupling of allyl carbonates with stannanes,10 we ex-
pected that palladium complexes without strongly coor-
dinating ligands would favor Pd/Sn transmetalation.
Thus, employment of palladium complexes bearing MeCN,
COD, or dba as the ligands led selectively to transmeta-
lation-based cross coupled product 6a in moderate to good
yields with E/Z selectivities ranging between 1.1:1 to 3:1
favoring the E isomer (Table 1, entries 1-3). Best results
were obtained by using DMF as the solvent containing
2-5 equiv of water.5 Strong σ-donating ligands such as
bipyridine (bpy) also favored formation of alcohols 6a
(Table 1, entry 4). The optimum conditions were obtained
by using Pd(MeCN)2Cl2 as the catalyst which furnished
6 as a 3:1 mixture of E and Z isomers (Table 1, entry 1).
In this case, the active Pd(0) species probably is a Pd-
(DMF)n (n e 4) or a palladium cluster.16
On the other hand, while the reaction of malonate
anion with epoxide 5 was unsuccessful, direct reaction
of 1 with 5 using Pd(PPh3)4 in THF in the presence or
absence of water gave 7a as the only characterizable
product, contaminated with impurities that could not be
easily removed by flash chromatography. Better results
were obtained in DMF, although allylic alcohol 7a was
obtained as a 1.4:1 mixture of E and Z stereoisomers in
moderate yield (Table 1, entry 5). It is important to note
that none of the alternative product 6a was detected in
these experiments. A similar yield was obtained by using
Pd(OAc)2 and PPh3, although the reaction was faster
(Table 1, entry 6). The best result was obtained by using
Pd2(dba)3‚dba and 2 equiv of PPh3 as the catalyst (Table
1, entry 7). Under these conditions, 7a was obtained as
a 1.6:1 Z/E mixture), which suggest that full syn-anti
equilibration of the intermediate (η3-allyl)palladium com-
plex does not takes place in this case. The active catalyst
formed under these conditions has been demonstrated
to be Pd(dba)(PPh3)2.17 A catalyst prepared with PBu3
Resu lts a n d Discu ssion
Syn th esis of Sta n n a n es 1-4. The required bisnu-
cleophiles 1-4 (Chart 1) were prepared by the hy-
drostannylation of the corresponding terminal alkynes
with Bu3SnH in the presence of Pd(PPh3)2Cl2 as the
catalyst.13 Besides the desired 2-tributylstannylalkenes
which were obtained after column chromatography on
silica gel in 50-55% yield, the hydrostannylation also
furnished significant amounts of the 1-tributylstannyl
derivatives as mixtures of E and Z isomers, as well as
some 1,2-(bis)tributylstannyl alkenes. Nevertheless, pu-
rification of these stannanes was simplified by brief
treatment of the crude mixtures with p-TsOH, which led
to the selective cleavage of the 1-stannyl derivatives. The
selectivity of these hydrostannylation reactions were
highly dependent on the source and quality of the tin
hydride used, best results being obtained with freshly
prepared Bu3SnH.14 The use of Pd(PPh3)4 as the catalyst
instead of Pd(PPh3)2Cl2 gave similar results.15
Ch em oselectivity Stu d ies. Crucial for the success
of the strategy outlined in Scheme 1 was the question of
the chemoselective reaction of the intermediate (η3-allyl)-
palladium complex with bisnucleophiles 1-4. To deter-
mine the optimum conditions we examined the reactions
(12) For lead references on the synthesis of five-membered ring
heterocycles by palladium-catalyzed 3 + 2 processes: Shim, J .-G.;
Yamamoto, Y. J . Org. Chem. 1998, 63, 3067.
(13) Zhang, H. X.; Guibe´, F.; Balavoine, G. J . Org. Chem. 1990, 55,
1857.
(14) Hayashi, K.; Iyoda, J .; Shiihara, I. J . Organomet. Chem. 1967,
10, 81.
(15) Bussaca, C. A.; Swestock, J .; J ohnson, R. E.; Bailey, T. R.;
Musza, L.; Rodger, C. A. J . Org. Chem. 1994, 59, 7553.
(16) For lead references on Pd clusters: (a) Reetz, M. T.; Wester-
mann, E. Angew. Chem., Int. Ed. 2000, 39, 165. (b) Reetz, M. T.; Maase,
M. Adv. Mater. 1999, 11, 773.

Palladium-Switchable Bisnucleophiles
J . Org. Chem., Vol. 66, No. 2, 2001 591
Ta ble 1. In flu en ce of th e Ca ta lyst System on th e Ch em oselectivity of th e Rea ction betw een 1 a n d Ep oxid e 5a
entry
catalyst system (mol %)
H2O (mol equiv)
reaction time (h)
product
yield (%)
1
2
3
4
5
6
7
8
9
Pd(MeCN)2Cl2 (5)
Pd(COD)2Cl2 (10)
Pd2(dba)3‚dba (5)
Pd(bpy)2Cl2 (10)
1
19
3
23
17
3
2
1
6.5
6a
6a
6a
6a
7a
7a
7a
7a
7a
93
75
69
63
51
53
92
65
57
7
5
6
8
2
8
4
4
Pd(PPh3)4 (5)
Pd(OAc)2 (10)/PPh3 (20)
Pd2(dba)3‚dba (5)/PPh3 (20)
Pd2(dba)3‚dba (2.5)/AsPh3 (10)
Pd2(dba)3‚dba (5)/dppf (10)
a
The reactions were run in DMF at 23 °C in a 0.01-2 mmol scale.
Ch a r t 2
was less efficient. Interestingly, P(OPh)3 led to a pal-
ladium catalyst that gave coupled product 6a as the
major product. On the other hand, the reaction in the
presence of Pd(dba)(AsPh3)2 as the catalyst in dry DMF
was rather sluggish leading to a mixture of 6a and 7a in
low yield.18 However, when the reaction was performed
in the presence of 4-5 equiv of H2O, 7a was cleanly
obtained as a 1.3:1 mixture of E and Z isomers (Table 1,
entry 8). Similar results were obtained with Pd(dba)-
(dppf) as the catalyst (Table 1, entry 9).17b,19
From these results it is clear that phosphine or arsine
ligands do not promote the Pd(II)/Sn transmetalation,
presumably as a consequence of the by reduced electro-
philicity of the (η3-allyl)palladium complex, thus leading
to the nucleophilic attack of the malonate-type anion.1,3
On the other hand, intermediate (η3-allyl)palladium
complexes with MeCN, DMF, COD, dba, or bpy as ligands
are more electrophilic and therefore undergo clean trans-
metalation with the organostannane to yield coupled
product 6a .20 The role of water in the mechanism of the
nucleophilic attack of the malonate and the transmeta-
lation of the organostannane is not clear yet since it
improves the performance of both reaction pathways of
Scheme 2.
The chemoselectivity observed in the reaction of 1 and
epoxide 5 is general (Chart 2 and Table 2). Thus, 1,3-
butadiene epoxide (8) reacts with Pd(MeCN)2Cl2 (method
A) as the catalyst to give 10a (69%) (Table 2, entry 1),
while Pd2(dba)3‚dba/ PPh3 (method B) gave 11a in 69%
yield (Table 2, entry 2). Similarly, 2-phenyl-3-vinylox-
irane (9) (3:1 trans/cis) afforded 12a (Table 2, entry 3)
or 13a (Table 2, entry 4) chemoselectively. Alcohols 12
were obtained as a ca. 4:1 mixture of E and Z stereoiso-
mers. However, when the reaction was realized with
diastereoisomerically pure trans-9, alcohol E-12a was
obtained stereoselectively. â-Ketoester 2, as well as
malonates 3-4 also react selectively under conditions A
or B to afford, respectively, cross coupled products (Table
2, entries 5, 7, and 9) or nucleophilic opening derivatives
(Table 2, entries 6, 8, and 10).
Ta ble 2. Rea ction of Sta n n a n es 1-4 w ith Ep oxid es 5, 8,
a n d 9a
yield
(%)
entry
substrate
epoxide
catalystb
product
1
2
3
4
5
6
7
8
9
1
1
1
1
2
2
3
3
4
4
8
8
9
9
5
5
5
5
5
5
A
B
A
B
A
B
A
B
A
B
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
69
60
75
64
66
94
71
66
72
81
Syn th esis of Ca r bocycles V by Cycliza tion of
Su bstr a tes of Typ e III. Allyl carbonates have been
commonly used as reactive substrates in palladium-
catalyzed allylic alkylations by malonate-type nucleo-
10
a
The reactions were run in DMF at 23 °C in the presence of
10-20 molar equiv of H2O at ca. 0.1 M in substrate for 12-24 h.
b
Method A: Pd(MeCN)2Cl2 (5 mol %). Method B: Pd2(dba)3‚dba
(17) (a) Review of palladium-dba complexes: Amatore, C.; J utand,
A. Coord. Chem. Rev. 1998, 178-180, 511. See also: (b) Amatore, C.;
Broeker, G.; J utand, A.; Fhalil, F. J . Am. Chem. Soc. 1997, 119, 5176.
(c) Amatore, C.; Fuxa, A.; J utand, A. Chem. Eur. J . 2000, 6, 1474. (d)
Amatore, C.; Gamez, S.; J utand, A.; Meyer, G.; Moreno-Man˜as, M.;
Morral, L.; Pleixats, R. Chem. Eur. J . 2000, 6, 3372.
(18) For the use of this catalyst in cross coupling reactions: (a)
Farina, V.; Roth, G.; Krishnan, B.; Marshall, D. R. J . Org. Chem. 1993,
58, 5434. (b) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113,
9585.
(2.5mol %)/PPh3 (10 mol %).
philes.1,3,21 These reactions can be carried out under
neutral conditions, since the leaving group decarboxylates
to generate in situ the alkoxide which acts as the base
(20) For a new mechanistic interpretation of the transmetalation
step in the Stille cross-coupling reaction see: Casado, A. L.; Espinet,
P. J . Am. Chem. Soc. 1989, 111, 8979.
(19) Alcazar-Roman, L. M.; Hartwig, J . F.; Rheingold, A. L.; Liable-
Snads, L. M.; Guzei, I. A. J . Am. Chem. Soc. 2000, 122, 4618.

592 J . Org. Chem., Vol. 66, No. 2, 2001
Castan˜o et al.
Sch em e 3
Sch em e 4
Ta ble 3. P a lla d iu m -Ca ta lyzed Cycliza tion of Allyl
Ca r bon a tes of Sch em e 3a
entry
substrate
reaction time (h)
product
yield (%)
1
2
3
4
5
6
6b
10bb
12b
14bb
16c
24
20
24
24
14
14c
20
21
22
23
24
24
63
62
65
59
31
54
16c
a
The reactions were run in DMF at 23 °C in the presence of 2
molar equiv of H2O at ca. 0.1 M in substrate with Pd2(dba)3‚dba
b
(2.5 mol %)/PPh3 (10 mol %). 0.01 M in substrate. c The enolate
was preformed by reaction with NaH.
outlined in Scheme 1 could in principle be achieved by
the Stille coupling of the acetates of allylic alcohols 7a ,
11a -15a , 17a , and 19a under the described conditions.23
However, when the acetate of 7a was treated with Pd2-
(dba)3‚(dba) as the catalyst in the presence of LiCl (3
equiv) in THF as the solvent, carbocycle 25 was obtained
in only 40% yield. Best results were obtained by using
the intramolecular version of the Stille coupling of allyl
carbonates with stannanes.10 Thus, ethyl carbonates 7b,
11b, 13b, and 15b gave five-membered ring carbocycles
25-28 in good yields by using Pd(MeCN)2Cl2 as the
catalyst in DMF at 23 °C (Scheme 4 and Table 4, entries
1-4).
Again, formation of six- and seven-membered ring
carbocycles proved to be a more difficult task. Thus,
cyclization of ethyl carbonate 17b failed to give 29. The
use of TROC derivative 17c allowed for the cyclization
to proceed, giving rise to 29 in 42% yield (Table 4, entry
5). Since destannylation of the starting material was
observed under these conditions, the reaction was carried
out in the presence of i-Pr2NEt as the base, which lead
to a modest increase in the yield (Table 4, entries 6 and
7). Formation of a seven-member ring compound was
possible by palladium-catalyzed cyclization of the TROC
derivative 19b. Thus, cyclization of 19c furnished car-
bocycle 30 (Table 4, entries 8-10). The best results were
again obtained by performing the cyclization at 45 °C in
the presence of i-Pr2NEt (Table 4, entry 10).
to form the desired enolate from the malonate-type
substrate.1 Therefore, for the synthesis of carbocycles V
(Scheme 1), substrates III (i.e., allylic alcohols 6a , 10a ,
12a , 14a , 16a , and 18a ) were first activated by formation
of the corresponding ethyl carbonates or trichloroethyl
(TROC) carbonates under standard conditions.
Cyclization of ethyl carbonates 6b, 10b, 12b, and 14b
was best carried out by using in situ prepared Pd(dba)-
17
(PPh3)2 as the catalyst at room temperature in DMF
containing 2 equiv of water (Scheme 3 and Table 3).
Carbocycles 20 and 22 were obtained in satisfactory yield
by the cyclization of ethyl carbonates 6b and 12b (Table
3, entries 1 and 3). However, cyclization of 10b and 14b
under these conditions (ca. 0.1 M) gave cyclopentene
derivatives 21 and 23 in 19% and 22% yield, respectively.
Satisfactory results were obtained by performing the
reaction at lower concentration (10-2 M) (Table 3, entries
2 and 4). Carbocycle 23 was obtained as an inseparable
mixture of isomers.
Cyclization of 16b failed to proceed under the standard
conditions. Using TROC derivative 16c allowed for the
preparation of the six-membered ring carbocycle 24 in
low yield (Table 3, entry 5). A better yield was obtained
in this case by preforming the malonate enolate with
NaH (Table 3, entry 6). However, neither ethyl- nor
TROC carbonates of alcohol 18 afforded the expected
seven-membered ring carbocycle and gave instead elimi-
nation products.22
(22) (a) Takahasi, T.; Nakagawa, N.; Minoshima, T.; Yamada, H.;
Tsuji, J . Tetrahedron Lett. 1980, 31, 4333. (b) Mandai, T.; Matsumoto,
T.; Tsuji, J .; Saito, S. Tetrahedron Lett. 1993, 34, 2513. (c) Keinan, S.;
Kumar, S.; Dangur, V.; Vaya, J . J . Am. Chem. Soc. 1994, 116, 11151.
(d) Anderson, P. G.; Schab, S. Organometallics 1995, 14, 1. (e) Takacs,
J . M.; Lawson, E. C.; Clement, F. J . Am. Chem. Soc. 1997, 119, 5956.
(f) Braun, M.; Mross, S. Synthesis 1998, 83. (h) Schwarz, I.; Braun, M.
Chem. Eur. J . 1999, 5, 2300.
Syn th esis of Ca r bocycles VI by Cycliza tion of
Su bstr a tes of Typ e IV. The alternative cyclization
(21) (a) Tsuji, J .; Shimizu, I.; Minami, I.; Ohashi, Y. Tetrahedron
Lett. 1982, 23, 4809. (b) Tsuji, J .; Shimizu, I.; Minami, I.; Ohashi, Y.;
Sugiura, T.; Takahashi, K. J . Org. Chem. 1985, 42, 1523. (c) Minami,
I.; Ohashi, Y.; Shimizu, I.; Tsuji, J . Tetrahedron Lett. 1985, 26, 2449.
(d) Geneˆt, J . P.; Ferroud, D. Tetrahedron Lett. 1984, 25, 3579. (e) Safi,
M.; Sinou, D. Tetrahedron Lett. 1991, 32, 2025.
(23) Del Valle, L.; Stille, J . K.; Hegedus, L. S. J . Org. Chem. 1990,
55, 5, 3019.

Palladium-Switchable Bisnucleophiles
J . Org. Chem., Vol. 66, No. 2, 2001 593
Ta ble 4. P a lla d iu m -Ca ta lyzed Cycliza tion of Allyl
Ca r bon a tes of Sch em e 4a
stannane 1 contaminated with the terminal isomers. Treat-
ment of the crude mixture with 0.3-0.4 equiv of p-TsOH in
CH2Cl2 followed by chromatography gave 113 as an oil in 65%
yield.
Gen er a l P r oced u r e for Cou p lin g betw een Vin yl Ep -
oxid es a n d Sta n n a n es (I + II f III, Sch em e 1). To a
solution of Pd(MeCN)2Cl2 (0.05 mol %) in DMF (1 mL) and
H2O (2-5 equiv) were added the vinyl epoxide (0.22 mmol)
and the stannane (0.22 mmol). The reaction mixture was
stirred at 23 °C until TLC showed full conversion of stannane.
Then H2O and Et2O were added. After extractive workup and
chromatography (hexanes-EtOAc 2:1) the desired alcohols
were obtained as oils.
entry
substrate
reaction time (h)
product
yield(%)
1
2
3
4
5
6
7
8
9
7b
11b
13b
15b
17c
17c
17c
19b
19b
19b
1.5
24
8
25
26
27
28
29
29
29
30
30
30
81
62
69
95
42
52
58
27
37
55
24
17b
18b,c
19b-d
17b
17b,d
17b-d
10
Gen er a l P r oced u r e for Nu cleop h ilic Op en in g of Vin yl
Ep oxid es by th e En ola tes of 1-4 (I + II f IV, Sch em e
1). A solution of stannane (0.21 mmol), Pd2(dba)3‚dba (0.025
mol %), and PPh3 (0.1 equiv) in DMF (1 mL) was stirred for a
few minutes (change from red to yellow), and then H2O (2-5
equiv) was added, followed by the epoxide (0.21 mmol) (change
to pale yellow). The reaction mixture was stirred at 23 °C until
TLC showed full conversion. Then Et2O and H2O were added.
After extractive workup and chromatography (4:1 hexanes-
EtOAc), the allylic alcohols were obtained as oils.
Gen er a l P r oced u r e for th e F or m a tion of Ca r bon a tes.
To a solution of allyl alcohol (0.25 mmol) and DMAP (0.02
mmol) in CH2Cl2 (4 mL) at 0 °C were added successively
pyridine (1.1 equiv) and EtOCOCl (1.1 equiv). The reaction
was stirred at 0 °C for 15 min and then 2 h at 23 °C. The
solvent was evaporated and the residue taken up in Et2O,
filtered through silica gel (hexanes-EtOAc 4:1 as eluent) and
evaporation yields the corresponding carbonate. Alternatively,
the reaction mixture was diluted with CH2Cl2 and treated with
1.2 M HCl. Extractive workup and evaporation gave the crude
carbonates. Usually carbonates were used in the cyclization
reaction without further purification.
Cycliza tion Rea ction s of Sch em e 3 (Ta ble 3). A solution
of Pd2(dba)3‚dba (2.5 mol %) and PPh3 (10 mol %) in DMF (1
mL) was stirred for a few minutes (the color changes from red
to yellow), and then H2O (2 equiv) was added, followed by the
allyl carbonate. The reaction mixture was stirred at 23 °C until
TLC showed full conversion and then Et2O and H2O were
added. Extractive workup and chromatography (15:1 hexanes-
EtOAc) gave cyclized compounds.
Cycliza tion Rea ction s of Sch em e 4 (Ta ble 4). To a
solution of the allyl carbonate in DMF (1 mL) was added
Pd2(dba)3‚dba or Pd(MeCN)2Cl2 as the catalyst. For the reac-
tions of 17c and 19b i-Pr2NEt (1 equiv) was added to minimize
destannylation of the starting material. The reaction mixture
was stirred at 23or 45 °C until TLC showed full conversion
and then the mixture was washed with saturated aqueous
solution of KF. Extractive workup and chromatography (15:1
hexanes-EtOAc) gave cyclized compounds.
a
The reactions were run in DMF at 23 °C in the presence of 2
molar equiv of H2O at ca. 0.1 M in substrate with Pd(MeCN)2Cl2
b
(5 mol %) or Pd2(dba)3‚dba (2.5 mol %).
c Pd2(dba)3‚dba (10 mol
%) in anhydrous DMF. 1 equiv of i-Pr2NEt was added. e Reaction
d
carried out at 45 °C.
Con clu sion s
Transmetalation of organostannanes with allyl carbon-
ates and vinylepoxides is favored with palladium cata-
lysts without phosphines or arsines as the ligands. Best
results were obtained by using Pd(MeCN)2Cl2 as the
catalyst in wet DMF as the solvent. On the other hand,
the use of palladium complexes such as Pd(dba)(PPh3)2
inhibits the transmetalation pathway and promotes the
nucleophilic attack of the malonate-type anions on the
intermediate (η3-allyl)palladium complexes. Again, the
use of wet DMF as the solvent gave the best results in
most cases.
By using malonates or acetoacetates bearing alkenyl-
stannanes functions as binucleophiles and diene monoe-
poxides as the electrophiles a regiodivergent synthesis
of carbocycles has been achieved. In these carbocycliza-
tions, two carbon-carbon bonds are formed chemospe-
cifically between the bisnucleophile and the alkenyl
function of the diene monoepoxide. These carbocycliza-
tions proceed under mild conditions and are general for
the formation of five-membered ring compounds. Lower
yields were obtained for the preparation of six- and seven-
membered ring carbocycles. In all cases, the carbon-
carbon formations take place with complete regioselec-
tivity.
Beyond the synthetic interest of this carbocyclization
methodology, these results demonstrate that stannanes
and soft nucleophiles such as malonate enolates can be
orthogonally activated toward allylic electrophiles by
using the appropriate palladium complexes as catalysts.
Ack n ow led gm en t. We are grateful to the DGES
(Project PB97-0020C2-01) for support of this research
and to the MEC for predoctoral fellowships to M.M. and
a contract to A.M.C. We also acknowledge J ohnson
Matthey PLC for a generous loan of PdCl2.
Exp er im en ta l Section
Syn th esis of Alk en ylsta n n a n es 1-4 by Hyd r osta n n y-
la tion of Alk yn es. Typ ica l P r oced u r e. Dimethyl propar-
gylmalonate (7.90 mmol) was added to a solution of palladium
catalyst [1-2 mol % of Pd(PPh3)4 or Pd(PPh3)2Cl2] in THF (50
mL), followed by addition of Bu3SnH (7.90 mmol). The reaction
mixture was stirred at 23 °C for 2-3 h and then the solvent
was evaporated. Chromatography (12:1 hexanes-EtOAc) gave
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0056850