Effect of ligands and additives on the palladium-promoted carbonylative coupling of vinyl stannanes and electron-poor enol triflates

Full text of DOI:10.1021/jo0004310

6254
J . Org. Chem. 2000, 65, 6254-6256
might be synthesized with an unprecedented Stille car-
Effect of Liga n d s a n d Ad d itives on th e
bonylative coupling reaction, i.e., by combining a vinyl
stannane with an electron-poor (carboalkoxy-substituted)
unsaturated halide or triflate in the presence of carbon
monoxide.
P a lla d iu m -P r om oted Ca r bon yla tive
Cou p lin g of Vin yl Sta n n a n es a n d
Electr on -P oor En ol Tr ifla tes
The palladium-catalyzed cross coupling (non-carbon-
ylative) reaction of electron-poor enol triflates or vinyl
halides with vinyl stannanes has been recognized as a
difficult case and shown to require special reaction
conditions.8 These generally include the use of soft
ligands at palladium, such as triphenylarsine or trifuryl-
phosphine (TFP), and the presence of cocatalytic copper-
(I) iodide. Both these expedients, as well as the use of
polar aprotic solvents [N-methylpyrrolidinone (NMP),
dimethylformamide (DMF)], have been shown by Farina
et al. to accelerate the rate-determining transmetalation
step in the direct coupling,9 but nothing is known on the
effect of these modifications on the carbonylative version
of the Stille reaction, where the species involved at the
transmetalation level is an acyl- rather than an alken-
yl-palladium complex.10 Here we demonstrate that the
use of a soft ligand (AsPh3) and of CuI strongly affects
the rate of the palladium-catalyzed carbonylative cou-
pling reaction. In particular, acceleration of the carbon
monoxide insertion over the transmetalation step is
obtained, thus allowing to perform the carbonylative
coupling at room temperature and atmospheric pressure
of carbon monoxide even on electron-poor systems, with-
out formation of the direct coupling products.
Simona Ceccarelli,† Umberto Piarulli,‡ and
Cesare Gennari*,†
Dipartimento di Chimica Organica e Industriale,
Universita` di Milano, Centro CNR (Sost. Org. Nat.),
via Venezian 21, 20133 Milano, Italy, and Dipartimento di
Scienze Mat. Fis. e Chimiche, Universita` degli Studi
dell’Insubria, via Lucini 3, 22100 Como, Italy
cesare@iumchx.chimorg.unimi.it
Received March 22, 2000
The presence of a substituted R-carboalkoxy-R,R′-
dienone substructural element of type 2 can be recognized
within the skeleton of important cytotoxic natural prod-
ucts of the eleutheside family, such as sarcodictyin A (1).1
Our interest in the development of a practical synthetic
route to 12 led us to examine a possible approach to these
extensively conjugated systems, which could be incorpo-
rated in the synthetic strategy at the crucial macrocy-
clization step. Although R-carboalkoxy-R,R′-dienones have
been studied in the past as precursors of substituted
cyclopentenones via the Nazarov cyclization reaction,3 not
many synthetic methods are known for their preparation.
These generally involve titanium catalyzed Knoevenagel-
type condensations4 or reaction of organometallics with
R,â-unsaturated acyl chlorides,3,5 both unpractical meth-
ods for highly functionalized systems and suffering from
limitations in scope.
For this study, we selected enol triflate 6, whose
substitution pattern is similar to that of the desired
substructure present in 1. This can easily be accessed
from cyclohexanecarboxyaldehyde 3 through Horner-
Emmons reaction with a protected R-alkoxyphospho-
nate,11 followed by desilylation and stereoselective tri-
flation with 2-[(N,N-bistrifluoromethanesulfonyl)amino]-
pyridine under thermodynamic control (Scheme 1).12 The
resulting enol triflate 6 was coupled with both the
commercially available tributyl vinyl stannane (7a ) and
the cis-substituted stannane 7b, prepared in turn from
(R)-cyclohexylidene glyceraldheyde 8 by applying Stork’s
methodology for the stereoselective synthesis of Z vinyl
iodides13 followed by tin-iodine exchange14 (Scheme 1).
The presence of a doubly unsaturated ketone in
compounds of type 2 suggests application of the Stille
carbonylative coupling reaction,6 which is a mild and
efficient process generally requiring a moderate pressure
of carbon monoxide (3-5 atm), tolerant of a wide range
of functionalities, and well applicable to the synthesis of
complex natural products.7 The desired substructure 2
(7) See for an example: Gyorkos, A. C.; Stille, J . K.; Hegedus, L. S.
J . Am. Chem. Soc. 1990, 112, 8465.
(8) (a) Go¨rth, F. C.; Umland, A.; Bru¨ckner, R. Eur. J . Org. Chem.
1998, 1055, 5. (b) Beccalli, E. M.; Gelmi, M. L.; Marchesini, A.
Tetrahedron 1998, 54, 6909. (c) Farina, V.; Baker, S. R.; Benigni, D.
A.; Hauck, S. I.; Sapino, C., J r. J . Org. Chem. 1990, 55, 5833. (d) Farina,
V.; Hauck, S. I. Synlett 1991, 157. (e) Maier, M. E.; Bosse, F.; Niestro,
A. J . Eur. J . Org. Chem. 1999, 1. (f) J ohnson, C. R.; Adams, J . P.;
Braun, M. P.; Senanayake, C. B. W. Tetrahedron Lett. 1992, 33, 919.
(g) Bellina, F.; Carpita, A.; Ciucci, D.; De Santis, M.; Rossi, R.
Tetrahedron 1993, 49, 4677. (h) Bellina, F.; Carpita, A.; De Santis,
M.; Rossi, R. Tetrahedron 1994, 50, 12029. (i) Liebeskind, L. S.; Fengl,
R. W. J . Org. Chem. 1990, 55, 5359.
(9) (a) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585.
(b) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S.
J . Org. Chem. 1994, 59, 5905.
(10) For an example of carbonylative coupling involving the use of
AsPh3, see: J eannaret, V.; Meerpoel, L.; Vogel, P. Tetrahedron Lett.
1997, 38, 543.
* To whom correspondence should be addressed. Tel: ++39-02-
2367593; Fax: ++39-02-2364369.
† Universita` di Milano.
‡ Universita` degli Studi dell’Insubria.
(1) For a comprehensive review on the chemistry and biology of the
sarcodictyins, see: Nicolaou, K. C.; Pfefferkorn, J .; Xu, J .; Winssinger,
N.; Ohshima, T.; Kim, S.; Hosokawa, S.; Vourloumis, D.; van Delft,
F.; Li, T. Chem. Pharm. Bull. 1999, 47, 1199.
(2) Ceccarelli, S.; Piarulli, U.; Gennari, C. Tetrahedron Lett. 1999,
40, 153.
(3) Marino, P. M.; Linderman, R. J . J . Org. Chem. 1981, 46, 3696.
(4) Andrews, J . F. P.; Regan, A. C. Tetrahedron Lett. 1991, 32, 7731.
(5) Acuna, C.; Zapata, A. Synth. Commun. 1988, 18, 1133.
(6) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(11) For analogous phosphonate reagents, see: Horne, D.; Gaudino,
J .; Thompson, W. J . Tetrahedron Lett. 1984, 33, 3529.
(12) (a) Fataftah, Z. A.; Kopka, I. E.; Rathke, M. W. J . Am. Chem.
Soc. 1980, 102, 3959. (b) Comins, D. L.; Dehghani, A. Tetrahedron Lett.
1992, 33, 6299.
10.1021/jo0004310 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/26/2000

Notes
J . Org. Chem., Vol. 65, No. 19, 2000 6255
Ta ble 1. P a lla d iu m Ca ta lyzed Cou p lin g of Vin yl Tr ifla te 6 a n d Tr ibu tylvin ylsta n n a n e 7a in th e P r esen ce of Ca r bon
Mon oxid e a t Atm osp h er ic P r essu r e
yield, %
entry
solvent, T, time
catalyst
Pd(PPh3)4 (5%)
Pd(PPh3)4 (5%)
Pd(PPh3)4 (5%)
Pd2dba3 (5%); As(Ph)3 (20%)
Pd2dba3 (5%); As(Ph)3 (20%)
Pd(PPh3)4 (5%)
additives
LiCl (3 equiv)
LiCl (3 equiv)
LiCl (3 equiv), CuI (10%)
LiCl (3 equiv)
LiCl (3 equiv), CuI (10%)
CuI (10%)
CuI (10%)
10a
11a + 12a
1
2
3
4
5
6
7
THF, 55 °C, 7 h
NMP, RT, 5 h
NMP, RT, 4 h
NMP, RT, 35 min
NMP, RT, 6 min
NMP, RT, 15 h
NMP, RT, 17 h
15
39
17
19
<1
-
13a (73:27)b
60 (79:21)b
79 (72:28)b
81 (82:17)b
74c (80:20)b
d
-
-
d
Pd2dba3 (5%); As(Ph)3 (20%)
-
Plus 71% recovered starting material. Ratio determined by integration of the methyl signals in the 1H NMR spectrum. c Plus 25%
a
b
d
recovered starting material. Pd black precipitates immediately after addition of substrates.
Sch em e 1a
reported by Bru¨ckner in ref 8a, the minor isomer 12a is
slowly converted to 11a when exposed to a solution of
LiCl in NMP. An attempt was made to limit the isomer-
ization by eliminating LiCl, but in these cases the
reaction is completely suppressed (Table 1, entries 6, 7).
a
Reagents and conditions: (a) (MeO)2P(O)CH(OTES)CO2Me,
LiN(TMS)2, then 3, THF, 100%; (b) HF‚Py, THF, 98%; (c) 2-[(N,N-
bistrifluoromethanesulfonyl)amino]pyridine, NaN(TMS)2, THF,
46% (+26% recovered starting material); (d) (Ph3PCH2I)I, NaN-
(TMS)2, THF, 75%; (e) Me6Sn2, Pd2dba3, NMP, 78%.
Since a reduced reactivity was to be expected for cis-
substituted stannanes, the more stable catalytic system
obtained combining Pd(PPh3)4 and CuI was first applied
to the reaction of stannane 7b with triflate 6. In this case,
heating is required for the reaction to occur, and only a
modest yield of the carbonylated products 11b and 12b
is obtained, accompanied by 18% of the direct coupling
product 10b and by a significative amount of products
13 where the ∆4,5 double bond has isomerized (Table 2,
entry 1). Use of the softer ligand As(Ph)3 in combination
with CuI (Pd:L:CuI ) 1:4:2) leads to a considerable
improvement: the reaction can be conducted at room
temperature, and only the desired carbonylated adducts
are obtained in 80% yield (Table 2, entry 2), although
with substantial isomerization (11b:12b ) 50:50). Re-
course to the less oxophilic ZnCl28c instead of LiCl failed
to give any product (Table 2, entry 3), and the use of
trifurylphosphine (reported to give more stereospecific
reactions)9a instead of triphenylarsine (Table 2, entry 4)
did not prevent the isomerization.
This drawback should not discourage application of
this method to an intramolecular carbonylative coupling
leading to the medium sized ring of 1, where a marked
control of the ring size over the position of the E:Z
equilibrium is expected. In conclusion, the use of CuI and
of the soft ligand AsPh3 was demonstrated to promote
the carbonylative coupling between substituted vinyl
stannanes 7 and electron-poor enol triflates of type 6.
Acceleration of the carbon monoxide insertion over trans-
metalation is achieved, allowing only the carbonylated
adducts to be obtained at room temperature and atmo-
spheric pressure of carbon monoxide.
While in THF the reaction between 6 and tributylvi-
nylstannane 7a suffers from a low conversion (Table 1,
entry 1), reproducibly high yields are obtained using
NMP (Table 1, entries 2-5). Using Pd(Ph3)4 as catalyst,
coupling in the presence of carbon monoxide at room
temperature and atmospheric pressure affords 39% of the
direct coupling product 10a together with the products
resulting from carbonyl insertion 11a and 12a (Table 1,
entry 2). A better outcome is obtained by adding 0.1 equiv
of Cu(I) iodide to the reaction mixture, which brings the
carbonylative coupling product to 79%, compared to 17%
of direct coupling (Table 1, entry 3). The same result is
obtained employing the soft ligand As(Ph)3, and the rate
of the reaction is notably increased (Table 1, entry 4).
By performing the reaction in the presence of CuI with
As(Ph)3 as ligand and Pd2dba3 as a source of Pd(0) (Pd:
L:CuI ) 1:2:1), only the carbonylated products are
obtained at atmospheric pressure and room temperature
(Table 1, entry 5). Although the reaction is almost
immediate, rapid precipitation of this unstable catalyst
system prevents complete conversion. In all the cases
examined, isomerization of the strongly electrophilic
double bond (doubly conjugated) of 11a is observed, and
17-28% of the isomeric product 12a is obtained. The very
similar ratio 11a /12a (ca. 80:20) obtained under the
various reaction conditions suggests that the mixture is
thermodynamically controlled. In fact, in accord to what
(13) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
(14) Farina, V. Hauck, S. I. J . Org. Chem. 1991, 56, 4317.

6256 J . Org. Chem., Vol. 65, No. 19, 2000
Notes
Ta ble 2. P a lla d iu m -Ca ta lyzed Cou p lin g of Vin yl Tr ifla te 6 a n d Vin ylsta n n a n e 7b in th e P r esen ce of Ca r bon Mon oxid e
a t Atm osp h er ic P r essu r e
yield, %
entry
solvent, T, time
catalyst
Pd(PPh3)4 (7%)
Pd2dba3 (5%); As(Ph)3 (40%)
Pd2dba3 (5%); As(Ph)3 (40%)
Pd2dba3 (5%); TFP (40%)
additives
10b
11b + 12b
13
1
2
3
4
NMP, 60 °C, 3.5 h
NMP, RT, 55 min
NMP, RT
LiCl (3 equiv), CuI (14%)
LiCl (3 equiv), CuI (20%)
ZnCl2 (3 equiv), CuI (20%)
LiCl (3 equiv), CuI (20%)
18
-
-
-
37 (35:65)a
80 (50:50)a
-
14
-
-
b
NMP, RT, 5h
(50:50)c
Ratio determined by integration of the methyl signals in the 1H NMR spectrum. Pd black precipitates immediately after addition
a
b
of substrates. c Ratio based on crude 1H NMR; yield not determined.
2.30 (1H, m); 1.70-1.14 (20H,m). 13C NMR (50 MHz, CDCl3): δ
Exp er im en ta l Section
154.66; 148.94; 127.32; 73.95; 69.04; 52.07; 38.28; 36.10; 35.15;
31.76; 24.95; 24.94; 23.77; 23.72. IR (CDCl3): ν(cm-1) 2931; 2842;
Gen er a l P r oced u r e for th e P a lla d iu m -Ca ta lyzed Ca r -
bon yla tive Cou p lin g of 6 a n d 7b. A flame-dried Schlenck tube
is flushed with argon and charged with Pd2dba3 (0.05 equiv),
AsPh3 (0.40 equiv), and NMP. The mixture is stirred for 5 min,
and then LiCl (3 equiv), CuI (0.20 equiv), and a solution of
methyl (Z)-3-cyclohexyl-2-(trifluoromethanesulfonyloxy)propenoate
(6) (1.0 equiv) and stannane (7b) (1.0 equiv) in NMP are added
(final concentration: 0.05 M). The tube is sealed, purged, and
filled with carbon monoxide. The mixture is stirred at room
temperature until the reaction is judged complete by TLC
analysis or the catalyst precipitates. The tube is then vented
and the mixture diluted with Et2O and washed with water,
saturated NH4Cl, and brine. The ethereal layer is dried (Na2-
SO4) and evaporated, and the residue is purified by flash
chromatography, yielding the carbonylated products 11b and
12b (80%). The ratio 11b/12b (50:50) was determined by
integration of the methyl signals in the 1H NMR spectrum.
Analytically pure samples of 11b and 12b were obtained by
chromatographic separation of the two isomers with DCM/Et2O
99:1. 11b: 1H NMR (200 MHz, CDCl3): δ 6.85 (1H, d, J ) 10.59
Hz); 6.45-6.28 (2H, m); 5.42 (1H, m); 4.49 (1H, dd, J ) 7.74
Hz); 3.77 (3H, s); 3.65 (1H, dd, J ) 6.52 Hz, J ) 7.74 Hz); 2.45-
1720; 1672; 1271; 1228. Anal. Calcd for C21H30O5: C, 69.59; H,
8.34. Found: C, 69.71; H, 8.54. 12b: 1H NMR (200 MHz,
CDCl3): δ 6.68 (1H, d, J ) 10.20 Hz); 6.50 (1H, d, J ) 11.80
Hz); 6.39 (1H, dd, J ) 6.00 Hz, 11.80 Hz); 5.32-5.23 (1H, m);
4.45 (1H, dd, J ) 7.29 Hz, 8.24 Hz); 3.86 (3H, s); 3.63 (1H, dd,
J ) 6.71 Hz, 8.24 Hz); 2.45 (1H, m); 1.74-1.23 (20H, m). 13C
NMR (50 MHz, C6D6): δ 154.15; 150.34; 125.16; 75.30; 70.27;
52.25; 40.11; 37.54; 35.90; 32.53; 26.48; 26.25; 26.08; 25.04; 24.86.
IR (CDCl3): ν(cm-1) 2930; 2852; 1724; 1667. Anal. Calcd for
C
21H30O5: C, 69.59; H, 8.34. Found: C, 69.65; H, 8.58.
Ack n ow led gm en t. We thank Pharmacia & Upjohn
(Nerviano, Milano, Italy) for a graduate fellowship to
S. Ceccarelli.
Su p p or tin g In for m a tion Ava ila ble: Full characteriza-
tion data for compounds 6, 7b, 10a ,b, 11a , 12a , and 13 and
representative experimental procedures are available free of
charge via the Internet at http://www.pubs.acs.org.
J O0004310