Regioselective formation of 1,1-disubstituted allenylsilanes via cross-coupling reactions of 3-tri-n-butylstannyl-1-trimethylsilyl-1-propyne

Article abstract of DOI:10.1039/c0cc00679c

The regioselective Stille cross-coupling reactions of 3-tri-n-butylstannyl- 1-trimethylsilyl-1-propyne demonstrate isomerization following the initial transmetalation step resulting in allenyl palladium intermediates for reductive coupling to yield conjug

Full text of DOI:10.1039/c0cc00679c

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Regioselective formation of 1,1-disubstituted allenylsilanes via cross-coupling
reactions of 3-tri-n-butylstannyl-1-trimethylsilyl-1-propynew
David R. Williams* and Akshay A. Shah
Received 30th March 2010, Accepted 22nd April 2010
First published as an Advance Article on the web 19th May 2010
DOI: 10.1039/c0cc00679c
The regioselective Stille cross-coupling reactions of 3-tri-n-
butylstannyl-1-trimethylsilyl-1-propyne demonstrate isomerization
following the initial transmetalation step resulting in allenyl
palladium intermediates for reductive coupling to yield conjugated
1,1-disubstituted allenylsilanes.
Recent studies in our laboratories have examined the
development of bifunctionalized reagents which provide for
0
sequential execution of SE reactions and cross-coupling
processes. Conceptually, the linkage of stereocontrolled
allylations for asymmetric induction in tandem with the
Scheme 1 Stille reactions of propyne (2).
versatility of cross-coupling reactions provides a powerful
3-trimethylsilylpropargyl bromide with an alkenylstannane
demonstrates regioselective production of the skipped enyne.5
In fact, Ma and Zhang6 have reported analogous Negishi
couplings of allenic/propargylic zinc species with aryl and
alkenyl iodides resulting in major adducts corresponding to
enynes 4, and related studies by Jamison et al.7 have described
similar results for cross-coupling reactions of alkenyl iodides
with propargyl copper intermediates. In these studies, trans-
metalations of propargyllithium reagents are assumed to
provide access to an equilibration of allenic and propargylic
copper and zinc species, respectively. On the other hand,
site-selective Stille reactions of tri-n-butylallenylstannanes
have afforded an effective route to substituted allenes.8
Alternatively, Nakamura and coworkers have recently reported
palladium-catalyzed hydrogen-transfer reactions of N,N-dialkyl
propargyl amines for the synthesis of allenes.9
strategy for the rapid assembly of molecular complexity. In
this fashion, we have described the use of bis-tri-n-butyl-
0
stannyl reagents for an initial asymmetric SE reaction resulting
in the production of an alkenylstannane for subsequent Stille
reactions.1 We have also recently explored the SE0 chemistry of
3,3-bis(trimethylsilyl)-2-methyl-1-propene and related alkenes
for the stereocontrolled formation of the 3,4-anti-(E)-1-
trimethylsilyl-3-methyl-4-penten-4-ol motif as a convenient
precursor to the corresponding (E)-alkenyl iodides to advance
cross-coupling processes.2
In this communication, recent studies of Stille cross-
coupling reactions of alkenyl iodides 1 with bifunctional
3-tri-n-butylstannyl-1-trimethylsilyl-1-propyne (2) are described.
In this process, two outcomes may be realized since allylic
bond formation with respect to the propargylic stannane 2
could deliver the TMS–allene 3 via sp2–sp2 coupling whereas a
direct replacement of tin in the usual fashion features the
sp2–sp3 cross-coupling leading to the nonconjugated enyne 4
(Scheme 1).
Our initial cross-coupling experiments of iodobenzene (1a)
with 3-tri-n-butylstannyl-1-trimethylsilyl-1-propyne (2) cleanly
produced the allenylsilane 3a in 76% isolated yield.10 The
observation of an allylic transposition which affords selective
coupling to give 3a is unprecedented based on the results of the
prior art. Further efforts have examined the generality of this
reaction, and our results are compiled in Table 1.
Our plans sought the production of the trimethylsilyl allene
0
3 to be employed in subsequent Sakurai SE reactions
as a strategy toward the selective preparation of (E)- and
(Z)-conjugated enynes. Rationale for the formation of 3 is
based on literature precedents which have recognized the
interconversions of Z1-propargyl and Z1-allenylpalladium
complexes as well as Z3-propargylpalladium(II) species.3,4
However, these studies have generally utilized propargyl
chlorides and bromides for initial insertion reactions with
palladium catalysts followed by transmetalations of organo-
stannanes leading primarily to nonconjugated enyne products
4. The specific example of the Stille cross-coupling of
A convenient preparation of the starting stannane 2 utilized
1-trimethylsilyl-1-propyne for deprotonation at ꢀ78 1C in
THF solution with tert-butyllithium (1.7 M in Hexanes)
followed by addition of tri-n-butylstannyl chloride. Nearly
quantitative yields of 2 were isolated after flash silica gel
chromatography using pentane. Alkyne 2 was stored in
the freezer under N2 without evidence of decomposition or
Department of Chemistry, Indiana University, 800 E Kirkwood Ave,
Bloomington, IN 47405-7102, USA. E-mail: williamd@indiana.edu;
Fax: +1 812-855-8300; Tel: +1 812-855-6629
w Electronic supplementary information (ESI) available: Experimental
details and NMR data. See DOI: 10.1039/c0cc00679c
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Table 1 Allenylsilanes via Pd-catalyzed Stille reactions
isomerization. Subsequent cross-coupling reactions of 2 have
been optimized using Pd2(dba)3 in dry DMF containing
triphenylarsine and purified cuprous iodide. Examples of
alkenyl iodides, aryl iodides and heteroaromatic iodides
(entries 1–12) are generally consumed within eight to fifteen
hours under the reaction conditions. Attempts using the
corresponding alkenyl and aryl bromides proceed to allene
products with much slower reaction rates. The reactions of
Table 1 (entries 1–12) are standardized using 20 mol%
Pd2(dba)3 based on starting iodide. Efforts utilizing 10 mol%
catalyst and 5 mol% catalyst led to incomplete (50–70%)
consumption of 1 after 24 h, and subsequent sequential
additions of catalyst in small quantities provided only modest
improvement. We examined several ligands and found that
AsPh3 provided the most effective reaction rates. Some success
was achieved with the addition of tri-2-furylphosphine,
whereas triphenylphosphine led to very slow rates of
consumption of 1, and Fu et al. conditions11 using P(tBu)3
and caesium fluoride afforded similar results. Finally, we have
found that the addition of small amounts of CuI produced
further enhancement of the rates of our reactions without
altering the observed regioselectivity.12 Aryl iodides (entries 1,
7 and 12) have efficiently produced good yields of allenes 3.
The thiophene and furan examples (entries 8 and 10) also
proceeded readily to give 3i and 3k, respectively, although the
isolated yields are somewhat diminished by the volatility of
these products. Slower reactions are observed in the case of
entries 5, 6 and 11, and small amounts of unreacted alkenyl
iodides (approximately 10%) are recovered after 15 hours.
Isomerization to the more stable E-unsaturated ester 3g occurs
after the cross-coupling event since the corresponding E-iodide
of 1g demonstrates a very slow rate of coupling with 2. On the
other hand, the progress of reactions with 1g was monitored
Entry Iodide
Producta
Yieldb (%)
82
1
2
1b
1c
3b
3c
3d
61
46
3c
1d
4
5
1e
1f
3e
3f
64
51
6
1g
3g
50
7
8
9
1h
1i
1j
3h
3i
3j
77
65
62
1
by H NMR studies using DMF(d6) and clearly indicated the
production of the trans-ester 3g prior to isolation by flash
chromatography.
Preliminary investigations have been undertaken to gain
mechanistic insight into these processes. For example, the
Stille coupling of 1-tri-n-butylstannyl-2-octyne (5) with aryl
iodide 1b gave allene 7 in high yield (95%) (Scheme 2). Under
identical reaction conditions, an enriched mixture of stannane
isomers 6 and 5 (60 : 40 ratio) exclusively led to the production
of 7 (72%). Thus, the allylic transposition observed for reactions
of 5 is not apparent in the reactions of allenylstannane 6. In
10
11
1k
1l
3k
3l
72
54
12
1m
3m
71
a
Reaction conditions: starting iodides 1 (1.0 eq.) were combined with
propargyl stannane 2 (1.3 eq.) and AsPh3 (0.8 eq.) followed by addition of
Pd2(dba)3 (20 mol%) and CuI (0.8 eq.). Stirring under N2 at 22 1C for
8–15 h led to the complete consumption of 1. For entry 1, iodide 1b was
reacted at 45 1C, and for entry 11, iodide 1l was reacted at 70 1C. For
entry 2, we have found that tri-(2-furyl)phosphine (0.8 eq.) is effectively
b
used in place of AsPh3. Yields are given for purified products isolated
c
via flash silica gel chromatography. Iodide 1d is somewhat unstable and
slowly leads to decomposition at room temperature.
Scheme 2 Stille reactions of propargyl and allenylstannanes 5 and 6.
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alkenyl iodides is well tolerated, and this variant of the Stille
reaction may have potential for applications in complex
molecule synthesis.
We acknowledge the financial support of Indiana University
and partial support by the National Institutes of Health
(GM042897).
Scheme 3 Mechanistic considerations.
Notes and references
1 (a) D. R. Williams and K. G. Meyer, J. Am. Chem. Soc., 2001, 123,
765; (b) D. R. Williams and M. W. Fultz, J. Am. Chem. Soc., 2005,
127, 14550.
2 D. R. Williams, A. I. Morales-Ramos and C. M. Williams, Org.
Lett., 2006, 8, 4393.
addition, the formation of 7 precludes specific electronic or
steric considerations due to the presence of TMS substitution
in 2, and suggests substrate generality for our reaction
conditions.
3 (a) C. J. Elsevier, H. Kleijn, J. Boersma and P. Vermeer, Organo-
metallics, 1986, 5, 716; (b) K. Tsutsumi, T. Kawase, K. Kakiuchi,
S. Ogoshi, Y. Okada and H. Kurosawa, Bull. Chem. Soc. Jpn.,
1999, 72, 2687.
4 K. Tsutsumi, S. Ogoshi, K. Kakiuchi, S. Nishiguchi and
H. Kurosawa, Inorg. Chim. Acta, 1999, 296, 37.
5 M. Tsubuki, K. Takahashi, K. Sakata and T. Honda, Hetero-
cycles, 2005, 65, 531.
6 S. Ma and A. Zhang, J. Org. Chem., 2002, 67, 2287.
7 T. P. Heffron, J. D. Trenkle and T. F. Jamison, Tetrahedron, 2003,
59, 8913.
8 (a) C.-W. Huang, M. Shanmugasundaram, H.-M. Chang and
C.-H. Cheng, Tetrahedron, 2003, 59, 3635; (b) C. Mukai and
Y. Takahashi, Org. Lett., 2005, 7, 5793.
Finally, reaction mixtures lacking alkenyl iodide were con-
1
stituted in anhydrous DMF(d6). Under these conditions, H
NMR spectroscopy documented the stability of 2 with no
evidence of isomerization to the corresponding allenylstannane
over 24 hours at 22 1C. These observations suggest intriguing
possibilities that initial transmetalation following the oxidative
insertion of alkenyl iodide 1 may lead to the propargylic
Z1-palladium species 8 which undergoes isomerization to the
Z1-allenyl complex 9 via an Z3-Pd intermediate (Scheme 3).
Formation of the allene product 3 indicates a dynamic
equilibration favoring the more stable palladium(II) complex
9 prior to reductive elimination. Alternatively, the mechanism
for transmetalation of 2 may directly produce the Z1-allenyl
complex 9. In view of prior art leading to skipped enynes, we
postulate that the transmetalation of propargylstannanes may
be an important factor leading to the production of allenes 3.
In summary, our studies of Stille reactions, involving 3-tri-n-
butylstannyl-1-trimethylsilyl-1-propyne with aryl and alkenyl
iodides, lead to the regioselective formation of allenylsilanes.
This novel cross-coupling event generates useful reactive
functionality which may be generally applicable. The examples
of Table 1 have shown that preexisting functionality in starting
9 H. Nakamura, T. Kamakura, M. Ishikura and J.-F. Biellmann,
J. Am. Chem. Soc., 2004, 126, 5958.
10 For leading references that describe the formation of allene 3a:
(a) J. Kjellgren, H. Sunden and K. J. Szabo, J. Am. Chem. Soc.,
´ ´
2005, 127, 1787; (b) H. Westmuze and P. Vermeer, Synthesis, 1979,
390.
11 A. F. Littke, L. Schwarz and G. C. Fu, J. Am. Chem. Soc., 2002,
124, 6343.
12 For background on Stille coupling, including Cu(I)-mediated
reactions, see: (a) V. Farina, V. Krishnamurthy and W. J. Scott,
Org. React., 1997, 50, 1; (b) L. S. Liebeskind and R. Fengl, J. Org.
Chem., 1990, 55, 5359; (c) X. Han, B. M. Stoltz and E. J. Corey,
J. Am. Chem. Soc., 1999, 121, 7600; (d) F. Bellina, A. Carpita,
M. De Santis and R. Rossi, Tetrahedron, 1994, 50, 12029.
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