Ligand effects on the stereochemistry of Stille couplings, as manifested in reactions of Z-alkenyl halides

Article abstract of DOI:10.1039/c2cc33294a

Unexpected losses in stereochemistry from Stille reactions involving Z-alkenyl halides have been shown to be ligand dependent. A new set of reaction conditions has been developed that, in most cases, leads to highly stereoselective cross-couplings under mild conditions, along with improved yields.

Full text of DOI:10.1039/c2cc33294a

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COMMUNICATION
Ligand effects on the stereochemistry of Stille couplings, as manifested in
reactions of Z-alkenyl halidesw
Guo-ping Lu,ab Karl R. Voigtritter,a Chun Caib and Bruce H. Lipshutz*a
Received 8th May 2012, Accepted 4th July 2012
DOI: 10.1039/c2cc33294a
Unexpected losses in stereochemistry from Stille reactions
involving Z-alkenyl halides have been shown to be ligand
dependent. A new set of reaction conditions has been developed
that, in most cases, leads to highly stereoselective cross-
couplings under mild conditions, along with improved yields.
Table 1 Ligand effects on Stille couplings of Z-b-bromostyrenea,b
Entry Catalyst
Conditions Yield of Zc (%) Z/Ec
1
2
3
4
5
6
7
8
Pd(PPh3)2Cl2
Pd(PPh3)4
A
A
A
A
A
A
A
A
A
A
A
B
45
19
2
86/14
36/64
4/96
Stille couplings are among the most useful and powerful tools
for the synthesis of complex molecules.1 The attractiveness of
organostananes likely derives from their high chemoselectivity
and tolerance towards most functional groups.2 There has been
much effort over the last two decades towards optimization of
reaction conditions, which has resulted in enhanced yields and
broad substrate tolerance.3 However, there are few investiga-
tions that focus on the stereochemistry of Stille couplings with
alkenyl halides, in particular, Z-alkenyl halides. Thus, while the
literature is rich with studies on the effects of external additives
(e.g., the copper effect4a), the prevailing assumption insofar as
the mechanism is concerned remains that the overall sequence
takes place with net double bond retention of substrate geo-
metry and is independent of catalyst.4
Pd(P(o-Tol)3)2
Pd(P(o-Tol)3)2
Pd(P(t-Bu)3)2
Pd(dba)2 + 2P(2-Furyl)3
Pd(dppf)Cl2
PEPPSI
PEPPSI
PEPPSI
PEPPSI
96(83)d,e
26
4/96
36/64
57/43
83/17
93/7
92/8
92/8
92/8
48/52
70/30
22
33
38
40
54
92(77)d,h
48
6
9f
10g
11g
12
13
1/2Pd2(dba)3 + 2P(o-Tol)3
PdCl2(MeCN)2
B
14
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
PEPPSI
1/2Pd2(dba)3 + 2P(o-Tol)3
1/2Pd2(dba)3 + 2P(o-Tol)3
Pd(P(o-Tol)3)2
A
B
A
B
B
B
20
48
9
86
85/15
85/15
90/10
96/4
96/4
95/5
15i
16g
17i
18
Scattered reports have appeared over time, each noting that
erosion of stereochemistry during a Stille coupling of a Z-alkenyl
halide had occurred, albeit under varying conditions.5 Thus, we set
out to determine if the stereoselectivity of Stille couplings, as with
Negishi6 and Suzuki–Miyaura7 reactions, is also ligand-dependent.
If so, could a new set of conditions be found that would allow for
the yield and extent of Z-stereoretention to be maximized
(Scheme 1)? In this report we describe our findings on both fronts.
96(87)h
95(84)h
19
a
A: b-bromostyrene (0.250 mmol), organostannane (0.275 mmol),
Pd catalyst (0.005 mmol; 2 mol % for entries 1–11, or 0.010 mmol,
4 mol %, for entries 14, 16), THF (1.0 mL), rt, 24 h. B: b-bromostyrene
(0.250 mmol), organostannane (0.275 mmol), Pd catalyst (0.010 mmol),
b
K2CO3 (0.500 mmol), DMF (1.0 mL), rt. The Z/E ratio of 1 is 96/4.
c
The yield of Z-product and Z/E ratio determined by GC/MS and
d
1H NMR on crude products. At 45 1C. Isolated yield of E-product.
2.0 equiv. of LiCl is used. 2.0 of equiv. K2CO3 is used. Isolated yield
e
f
g
h
i
of Z-product. No K2CO3.
Scheme 1 Stille couplings of Z-alkenyl halides.
An initial test reaction between mostly Z-b-bromostyrene 1
(Z : E = 96 : 4) and vinyltributylstannane 2, catalyzed by
Pd(PPh3)2Cl2, was carried out in THF at room temperature
(Table 1, entry 1). While a modest yield (45%) was obtained,
more interesting was the noticeable loss of >10% Z-olefin geo-
metry. A series of commercially available ligands was subsequently
screened to determine if this phenomenon is general, and to look
for an alternative combination of catalyst and conditions that
prevent such isomerization. Remarkably, almost complete
inversion from Z- to E-diene 3 took place under the influence of
a Department of Chemistry & Biochemistry, University of California,
Santa Barbara, California 93106, USA.
E-mail: lipshutz@chem.ucsb.edu
b Chemical Engineering College, Nanjing University of Science &
Technology, Nanjing, Jiangsu 210094, P. R. China
w Electronic supplementary information (ESI) available: Experimental
details and characterization data of all products. See DOI: 10.1039/
c2cc33294a
8
Pd(P(o-Tol)3)2 as catalyst, although mild heating to 45 1C was
needed to achieve full conversion (entries 3, 4). Although both
Pd(P(t-Bu)3)2 and Pd2(dba)3/P(o-Tol)3 also led to full consumption
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 8661–8663 8661

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of bromide, poor yields of Z-3 were obtained due to significant
isomerization to E-3 (entries 5, 12) and homecoupling (entry 5).
PEPPSI9 was an effective ligand for maintaining most of the initial
Z-olefin geometry. The yield could be further improved by addition
of K2CO3, along with gentle heating (entries 8–11).
Table 2 Ligand effects on Stille couplings of various Z-alkenyl
halidesa
Yield of Zc (%) Z/Ec
b
Entry X PdLn Conditions Product
In reactions of the corresponding 2-furylstannane 4, chan-
ging the solvent from THF to DMF gave better results (entries
14, 15).5a,b Again, K2CO3 (2 equiv.) appeared to enhance
yields (compare entries 17 vs. 18), although its use with
catalyst system Pd2(dba)3/P(o-Tol)310 led to better results than
did PEPPSI using this stannane (compare entries 16 vs. 18).
Based on the results above, selected ligands on palladium were
used as catalyst systems in a variety of Stille couplings (Table 2).
These additional data are in line with those obtained in the model
study (vide supra); i.e., that the level of erosion of stereochemical
integrity in couplings of Z-alkenyl halides is dependent upon the
ligand. In most cases, Pd2(dba)3/P(o-Tol)3 (III) in DMF led to
the desired products in high yields, with little-to-no isomerization
being observed during these reactions; unexpectedly, however,
the combination of b-bromostyrene and a vinylstannane did not
follow this trend (see Table 1, entry 12). Using catalyst
Pd(PPh3)2Cl2 (I), Z-olefin geometry can be compromised
depending upon educt (entries 1, 9, 13, 16). Surprisingly,
Z-1-iodooctene was converted almost entirely to E-6 in the
presence of Pd(P(t-Bu)3)2 (IV) (entry 6). Couplings under the
influence of commonly used catalyst PdCl2(MeCN)2 (II) dis-
played variable extents of both conversion, and maintenance of
Z-stereochemistry. As examples, products 5 and 9 showed signi-
ficant losses in Z-olefin geometry (entries 2, 17). Only in the case
of entry 18 did Pd2(dba)3/P(o-Tol)3 (III) fail to cleanly yield Z-9.
Further optimization of reaction conditions by applying mild
heat (45 1C) enhanced reaction rates such that complete conver-
sion could be achieved in two hours in the presence of less
catalyst (2 mol %), and without isomerization (entries 4, 12).
When cat. Pd2(dba)3/P(o-Tol)3/K2CO3 was applied to couplings
of b-bromostyrene with both phenyltributyltin and tetrabutyltin in
DMF at room temperature, only a trace of the desired product
was formed in the latter case. Raising the temperature to 100 1C
improved the yield (Table 2, entries 22–27, conditions D). The
combination of Pd2(dba)3/P(o-Tol)3 (III) also proved to be the
best choice for maintenance of Z-stereochemistry. However,
although all b-bromostyrene was consumed, homocoupling was
extensive in both cases, leading to modest yields of Z-11 and Z-12.
Reactions between Z-alkenyl halides and E-alkenylstannanes
were also conducted using several common catalysts
(entries 28–31). Remarkably, ligand effects with respect to
stereochemistry were virtually nonexistent. Best results were
obtained using Pd(MeCN)2Cl2/K2CO3 at 45 1C to afford the
desired product 13 (entry 30).11 Cross-coupling of (Z)-((6-
iodohex-5-enyloxy)-methyl)benzene with (E)-3-(tributylstannyl)-
allyl acetate catalyzed by Pd(PPh3)2Cl2 led to a 24% loss of
Z-stereochemistry (entry 32), while use of either Pd(MeCN)2Cl2
(II) or Pd2(dba)3/P(o-Tol)3 (III), respectively, provided the
stereoisomerically pure Z-product, Z-14 (entries 33, 34).
1d
2d
3d
4d
Br I
A
B
B
C
29
20
30/70
29/71
96/4
Br II
Br III
Br III
96(87)e
96(85)e
96/4
5
6
7
8
I
I
I
I
I
IV
V
A
A
A
B
97(89)e
91(76)e,f
71
98/2
9/91
93/7
99/1
III
99(92)e
9g
I
I
I
I
I
II
III
III
A
B
B
C
42
95
86/14
95/5
96/4
96/4
10g
11g
12g
96(86)e
96(88)e
13
14
15
I
I
I
I
II
III
A
B
B
68
95
89/11
95/5
99/1
99(95)e
16h
17h
18h
I
I
I
I
II
III
A
B
B
36
68
48/52
68/32
80/20
80(69)e
19
20
21
I
I
I
I
II
III
A
B
B
99
99
99/1
99/1
99/1
99(84)e
22d Br I
23d Br II
24d Br III
Di
D
D
24
52
46/54
81/19
96/4
64(55)e
25d Br I
26d Br II
27d Br III
Di
D
D
2
68
41/59
89/11
95/5
44(39)e
28
29
30
31
I
I
I
I
I
A
B
42
99/1
99/1
99/1
99/1
II
II
III
82(73)e
93(84)e
73
Cj
B
32
33
34
I
I
I
I
II
III
A
B
B
64
99(93)e
99(90)e
75/25
99/1
99/1
a
A: alkenyl halide (0.250 mmol), organotin reagent (0.275 mmol), Pd
catalyst (0.01 mmol), THF (1.0 mL), reflux, 24 h. B: alkenyl halide
(0.250 mmol), organotin reagent (0.275 mmol), Pd catalyst (0.01 mmol),
K2CO3 (0.500 mmol), DMF (1.0 mL), rt, 24 h. C: alkenyl halide
(0.250 mmol), organotin reagent (0.275 mmol), Pd2(dba)3 (0.0025 mmol),
P(o-Tol)3 (0.01 mmol), K2CO3 (0.500 mmol), DMF (1.0 mL), 45 1C, 2 h.
D: b-bromostyrene (0.25 mmol), organostannane (0.30 mmol), Pd catalyst
(0.010 mmol), DMF (1.0 mL), K2CO3 (0.500 mmol), 100 1C, 24 h.
b
I: Pd(PPh3)2Cl2, II: Pd(MeCN)2Cl2, III: Pd2(dba)3/P(o-Tol)3, IV:
c
Pd(P(t-Bu)3)2, V: PEPPSI. The yield of Z-product and Z/E ratio
determined by GC/MS and 1H NMR on crude products. The Z/E ratio
d
e
f
of b-bromostyrene is 96/4. Isolated yield. The yield of E-product.
The Z/E ratio of ethyl 3-iodoacrylate is 96/4. The Z/E ratio of 1-(2-
g
h
i
iodovinyl)cyclohex-1-ene is 97/3. No K2CO3. The reaction time is 8 h.
j
As reported by Farina,12 the reaction between Z-triflate 15
(G = OTf) and arylstannane 16 is a particularly challenging
example, as this coupling led to almost complete isomerization
to E-product 17 using Pd2(dba)3/AsPh3 (Table 3, entry 1). By
switching to Pd2(dba)3/P(o-Tol)3/K2CO3 in DMF at 100 1C,
the Z-olefinic product remained highly favored (89 : 11).
Essentially complete retention of Z-geometry was observed
when the iodo-analog 18 (G = I) was coupled with the same
stannane, in this case at room temperature (entry 3).
c
8662 Chem. Commun., 2012, 48, 8661–8663
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Table 3 Ligand effects on the couplings of 15 and 18, with stannane 16a
Notes and references
1 (a) C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot
and V. Snieckus, Angew. Chem., Int. Ed., 2012, 51, 5062;
(b) K. C. Nicolaou and E. J. Sorensen, Classics in
Total Synthesis, VCH, Weinheim, 1996, pp. 591–631;
(c) J. H. Chang, H.-U. Kang, I.-H. Jung and C.-G. Cho, Org.
Lett., 2010, 12, 2016; (d) H. Fuwa, N. Kainuma, K. Tachibana and
M. Sasaki, J. Am. Chem. Soc., 2002, 124, 14983.
Entry Conditions
Yield (%) Z/Eb
2 (a) M. D. Shair, T. Y. Yoon, K. K. Mosny, T. C. Chou and
S. J. Danishefsky, J. Am. Chem. Soc., 1996, 118, 9509;
(b) K. C. Nicolaou and S. A. Snyder, Classics in Total Synthesis
II, Wiley-VCH, Weinheim, 2003, pp. 533–549; (c) N. T. Tam and
C.-G. Cho, Org. Lett., 2008, 10, 601.
3 (a) A. F. Littke, L. Schwarz and G. C. Fu, J. Am. Chem. Soc.,
2002, 124, 6343; (b) K. Menzel and G. C. Fu, J. Am. Chem. Soc.,
2003, 125, 3718; (c) S. R. Dubbaka and P. Vogel, J. Am. Chem.
Soc., 2003, 125, 15292; (d) C. Wolf and R. Lerebours, J. Org.
Chem., 2003, 68, 7551; (e) D.-H. Lee, A. Taher, W.-S. Ahn and
M.-J. Jin, Chem. Commun., 2010, 46, 478.
1 (15) Pd2(dba)3 + 8AsPh3, NMP, overnight12
72c
5/95
89/11
99/1
2 (15) Pd2(dba)3 + 4P(o-Tol)3, K2CO3, DMF, 8 h 76d,e
3 (18) Pd2(dba)3 + 4P(o-Tol)3, K2CO3, DMF, 16 h 86d,f
a
Catalyst (0.0025 mmol), 15 or 18 (0.25 mmol), 16 (0.30 mmol),
b
K2CO3 (0.50 mmol), solvent (1.0 mL), rt. The ratio of Z/E deter-
mined by GC/MS and 1H NMR on crude products. Isolated yield of
c
d
e
E-product. Isolated yield of Z-product. The reaction is performed
at 100 1C. f (Z)-Ethyl 3-iodobut-2-enoate 18 is the substrate in place of 15.
4 (a) X. Han, B. M. Stoltz and E. J. Corey, J. Am. Chem. Soc., 1999,
121, 7600; (b) C. Amatore, A. A. Bahsoun, A. Jutand, G. Meyer,
N. Ndedi and L. Ricard, J. Am. Chem. Soc., 2003, 125, 4212;
(c) P. Espinet and A. M. Echavarren, Angew. Chem., Int. Ed., 2004,
43, 4704; (d) R. Alvarez, O. N. Faza, C. S. Lopez and A. R. de
Lera, Org. Lett., 2006, 8, 35; (e) M. H. Perez-Temprano,
A. M. Gallego, J. A. Casares and P. Espinet, Organometallics,
2011, 30, 611.
5 (a) J. K. Stille and B. L. Groh, J. Am. Chem. Soc., 1987, 109, 813;
(b) J. K. Stille and J. H. Simpson, J. Am. Chem. Soc., 1987,
109, 2138; (c) G. Palmisano and M. Santagostino, Tetrahedron,
1993, 49, 2533; (d) A. Abarbri, J.-L. Parrain, J.-C. Cintrat and
A. Duchene, Synthesis, 1996, 82; (e) J. C. Conway, C. J. Urch,
P. Quayle and J. Xu, Synlett, 2006, 776.
6 A. Krasovskiy and B. H. Lipshutz, Org. Lett., 2011, 13, 3818.
7 G. P. Lu, K. R. Voigtritter, C. Cai and B. H. Lipshutz, J. Org.
Chem., 2012, 77, 3700.
8 F. Paul, J. Patt and J. F. Hartwig, Organometallics, 1995, 14, 3030.
9 S. Calimsiz and M. G. Organ, Chem. Commun., 2011, 47, 5181
Scheme 2 Potential pathways for isomerisation in Stille couplings.
A plausible mechanism for ligand-related isomerization
during Stille couplings of Z-alkenyl halides is illustrated in
Scheme 2. The loss of Z-olefinic geometry may follow from a
pathway involving either an anionic13 or cationic14 carbon as
part of a zwitterionic-metal carbene (e.g. 20) formed from an
initial (likely stereospecific) oxidative addition to 19. The Z/E
ratio of products could also arise via prolonged reaction times
in some cases, which may occur via reversible Pd–H elimina-
tion/re-addition.15 Heating of reaction mixtures (compare
Table 1, entry 14 with Table 2, entry 1) may contribute to
both isomerization of intermediate 19 and/or formation of,
and participation by, Pd–H, although Stille reactions in gen-
eral oftentimes require some degree of heating.
10 T. Hosoya, K. Sumi, H. Doi, M. Wakao and M. Suzuki, Org.
Biomol. Chem., 2006, 4, 410.
11 The reduced yields obtained in these couplings are due to compe-
titive formation of products of rearrangement; e.g., product I is
obtained in addition to product 13 in Table 2
12 V. Farina and G. P. Roth, Tetrahedron Lett., 1991, 32, 4243.
13 (a) J. M. Huggins and R. G. Bergman, J. Am. Chem. Soc., 1981,
103, 3002; (b) C. Amatore, S. Bensalem, S. Ghalem and A. Jutand,
J. Organometal. Chem., 2004, 689, 4642.
14 (a) T. Blackmore, M. I. Bruce and F. G. A. Stone, J. Chem. Soc.,
Dalton Trans., 1974, 106; (b) D. W. Hart and J. Schwartz,
J. Organometal. Chem., 1975, 87, C11; (c) D. Zargarian and
H. Alper, Organometallics, 1993, 12, 712.
15 (a) D. Gauthier, A. T. Lindhardt, E. P. K. Olsen, J. Overgaard and
T. Skrydstrup, J. Am. Chem. Soc., 2010, 132, 7998;
(b) M. E. Limmert, A. H. Roy and J. F. Hartwig, J. Org. Chem.,
2005, 70, 9364; (c) J.-P. Ebran, A. L. Hansen, T. M. Gøgsig and
T. Skrydstrup, J. Am. Chem. Soc., 2007, 129, 6931.
In summary, the stereochemical outcome of Stille couplings
involving Z-alkenyl halides and organostannanes has been
shown to be highly variable, contrary to expectations,
although fully consistent with related observations on Negishi6
and Suzuki–Miyaura7 couplings. In most cases, both
Pd2(dba)3/P(o-Tol)3 and Pd(MeCN)2Cl2 are the preferred
catalysts for maintenance of Z-stereochemistry, as well as
for their effectiveness in mediating highly efficient cross-
couplings in DMF.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 8661–8663 8663