One-pot Pd-catalyzed hydrostannation/Stille reaction with acid chlorides as the electrophiles

Article abstract of DOI:10.1016/j.jorganchem.2005.11.041

A one-pot hydrostannation/Stille coupling sequence amenable to the employment of acid chloride electrophiles has been developed. In this protocol, palladium mediated alkyne hydrostannations using Me₃SnF/PMHS as an in situ trimethyltin hydride source are followed by the addition of the acid chloride to afford a variety of α,β-unsaturated ketones in a single pot.

Full text of DOI:10.1016/j.jorganchem.2005.11.041

Journal of Organometallic Chemistry 691 (2006) 1462–1465
www.elsevier.com/locate/jorganchem
One-pot Pd-catalyzed hydrostannation/Stille reaction
with acid chlorides as the electrophiles
Kyoungsoo Lee, William P. Gallagher, Elli A. Toskey,
*
Wenzheng Chong, Robert E. Maleczka Jr.
Department of Chemistry, Michigan State University, 540 Chemistry, East Lansing, MI 48824, USA
Received 15 November 2005; accepted 16 November 2005
Available online 28 December 2005
Abstract
A one-pot hydrostannation/Stille coupling sequence amenable to the employment of acid chloride electrophiles has been developed.
In this protocol, palladium mediated alkyne hydrostannations using Me3SnF/PMHS as an in situ trimethyltin hydride source are fol-
lowed by the addition of the acid chloride to afford a variety of a,b-unsaturated ketones in a single pot.
Ó 2005 Elsevier B.V. All rights reserved.
Keywords: Hydrostannation; Stille reaction; Polymethylhydrosiloxane; Tin; Acid chloride; Enone synthesis
Pd-catalyzed cross-couplings of organostannanes and
various electrophiles are convenient and widely used reac-
tions for r-bond construction [1]. Despite the well-estab-
lished power of the Stille reaction, there are negative
issues associated with handling the often unstable and/or
toxic organostannanes used in these couplings [2]. To obvi-
ate direct manipulation of the stannane coupling partners,
our group has developed one-pot Pd-catalyzed hydrostan-
nation/Stille coupling sequences [3] that begin with the
in situ generation of triorganotin hydrides [4]. The hydrides
so formed react in situ with alkynes to form vinylstann-
anes, which without isolation undergo Stille cross-coupling
reactions (Scheme 1). In earlier reports, we showed that
vinyl, aryl, and benzyl halides were all acceptable electro-
philes for this sequence [3]. Noticeably absent from this
group of electrophiles were acid chlorides.
one pot hydrostannation/Stille protocol to include acid
chlorides among the viable electrophiles (Scheme 2).
As it were, the prospect of adopting a straightforward
extension of our existing methodology with acid chlorides
exposed a number of uncertainties. Unlike previously used
electrophiles, reactions with acid chlorides face a host of
potential problems. For example, under our standard con-
ditions the triorganotin hydrides used in the hydrostanna-
tion step are prepared by the reduction of organotin halides
with polymethylhydrosiloxane (PMHS) in the presence of
fluoride. Thus, we were confronted with the possibility of
residual tin hydride or PMHS reducing the acid chloride
[6] or the a,b-unsaturated ketone products [7]. In addition,
while Stille reactions with acid chlorides have been done in
water [5b], we worried about acid chloride hydrolysis. Fur-
thermore, adventitious formation of HCl from the acid
chlorides could promote competitive protiodestannylation
of the vinyltin intermediates [8]. Lastly, decarbonylation
[5a] of the palladium(II) oxidative addition intermediate
was also one of our concerns. Nonetheless, provided these
problems could be defeated, achieving the synthesis of var-
ious a,b-unsaturated ketones from alkynes and acid chlo-
rides in a single pot using an organotin salt as the initial
tin source, a single load of catalyst, and unpurified vinyltin
intermediates would be attractive.
We considered this omission problematic because acid
chlorides represent an important class of Stille electrophiles
[5]. In StilleÕs earliest studies, he showed that reactions with
these compounds could efficiently produce a,b-unsaturated
ketones [5a]. Thus, we sought to expand the scope of the
*
Corresponding author. Tel.: +1 517 355 9715x124; fax: +1 517 353
1793.
E-mail address: maleczka@chemistry.msu.edu (R.E. Maleczka Jr.).
0022-328X/$ - see front matter Ó 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2005.11.041

K. Lee et al. / Journal of Organometallic Chemistry 691 (2006) 1462–1465
1463
Table 1
Bu3SnF, PMHS,
One-pot hydrostannation/Stille with acid chlorides using Bu3SnF
cat. TBAF,
R
O
R
H
1.5 equiv Bu3SnF,
Ph
1 mol% (Ph3P)2PdCl2;
1.6 equiv PMHS,
R'
Cl
1 mol % Pd2dba3,
4 mol % TFP,
Ph
, THF
O
Br
R
(1.3 equiv)
R'
R
Scheme 1.
cat. TBAF
THF, 2 h, rt
65 ˚C
Entry
Yielda
(%)
Stille rxn
time (h)
R
Acid chloride
O
O
cat. Pd
1
2
Bu3SnH
COCl
CH3
R'
Cl
96
84
6
6
R
R
Bu3Sn
R'
R
CH(CO2Me)2
Bu3SnF
COCl
3
4
56
CH3
6
2
Scheme 2.
74b
CH(CO2Me)2
F3C
5
6
CH3
57
63
6
6
In starting our exploration of this putative one-pot
COCl
COCl
S
sequence, we opted to use an ‘‘anhydrous’’ variation for
the in situ generation of tributyltin hydride [4]. Thus,
Bu3SnF, PMHS, and a catalytic amount of TBAF were
reacted in the presence of an alkyne and an acid chloride.
Not surprisingly, this procedure gave little of the desired
a,b-unsaturated ketone as the acid chloride was consumed
by the Bu3SnF/PMHS/TBAF combination in advance of
the cross-coupling. To avoid this trouble, we simply added
the acid chloride (without any additional Pd-catalyst) after
vinylstannane formation was complete (1 mol% Pd2dba3,
4 mol% TFP, 1.5 equiv. Bu3SnF, 2.5 equiv. PMHS, cat.
TBAF, THF, r.t., ca. 2 h or until complete by GC). Under
this two-step one-pot procedure a variety of a,b-unsatu-
rated ketones could be formed (Table 1).
CH3
CH3
O
31
1-Naphthoyl acid
chloride
10
7
8
COCl
10
6
91
58
CH3
9
CH(CO2Me)2
a
Average isolated yield over two runs.
The decarbonylated product was also observed.
b
1.5 equiv Bu3SnF,
2.5 equiv PMHS,
This first generation study only employed alkynes that
were tri-substituted at the propargylic position so that
our evaluation of the process would not be complicated
by the formation of regioisomers. The protocol proved
workable with a variety of acid chlorides. Typically cross-
couplings were achieved after 6–10 h at 65 °C and the
yields could be very high. However, in some cases intrusive
amounts of side products were observed. For example,
reactions with either 4-trifluoromethylbenzoyl chloride
(entry 4) or 2-chlorobenzoyl chloride (Scheme 3) witnessed
the formation of the corresponding benzaldehydes and the
decarbonylated coupling products [5a]. Moreover, despite
our best efforts at reaction optimization some of the prod-
uct yields remained moderate at best.
We attributed some of these problems to the relatively
slow cross-coupling times. In our previously reported tin
catalyzed hydrostannation/Stille sequence with other sp2-
halides, switching from Bu3SnCl to the less sterically
demanding Me3SnCl gave faster reaction times and
decreased byproduct formation [9]. Looking for a similar
outcome for the two-step one-pot acid chloride coupling
sequence, the initial tin species was changed from Bu3SnF
to Me3SnF. In doing so, we were gratified to observe a sig-
nificantly improved process.
1 mol % Pd2dba3,
4 mol % TFP, cat. TBAF,
(71 %)
Cl
THF, 2 h, rt; then
+
CHO
2-chlorobenzoyl chloride
(1.3 equiv), 65 oC, 6 h
(32 %)
Cl
Scheme 3.
to 2 h [10]. More importantly; the observed increases in
reaction rates were generally met with substantially higher
yields and fewer visible side reactions. For example, the
previously failed coupling of 2-chlorobenzoyl chloride
(entry 3) could now be achieved in an over all yield of
86%. Other entries worthy of further comment include
the reaction of 4-bromobenzoyl chloride (entry 6). Despite
its two potential coupling sites (acid chloride and aryl bro-
mide) this substrate chemoselectively reacted with the
in situ generated vinyl stannane at the acid chloride site
to afford the product in near quantitative yield [11]. Fur-
thermore, that product did not suffer from any unwanted
dehalogenation of the aryl bromide [12]. Likewise, cinna-
moyl chloride afforded the 1,4-diene-3-one in 80% yield
without any 1,4-reduction [7] of this activated dienone
(entry 12).
As illustrated in Table 2, using Me3SnF in place of
Bu3SnF typically decreased cross-coupling times from 6

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K. Lee et al. / Journal of Organometallic Chemistry 691 (2006) 1462–1465
Table 2
One-pot hydrostannation/Stille with acid chlorides using Me3SnF [10]
O
(1.3 equiv)
Cl
1.5 eq. Me3SnF, 2.5 eq. PMHS,
1 mol % Pd2dba3, 4 mol % TFP,
O
R
R
Me3Sn
cat. TBAF, THF, 2 h, rt
65 ˚C
Entry Acid
chloride
Product
Yielda Entry Acid chloride
(%)
Product
Yielda
(%)
Stille
rxn
Stille
rxn
time (h)
time (h)
O
COCl
1
2
94
96
7
8
99
95
2
2
2
2
COCl
COCl
S
S
O
O
MeO
MeO
COCl
MeO
MeO
O
O
O
OMe
OMe
O
O
COCl
Cl
COCl
3
4
86
72
9
92
90
2
2
2
2
Cl
O
6
COCl
NO2
COCl
10
6
NO2
O
O
NC
COCl
NC
COCl
5
6
98
98
11
12
92
80
2
4
4
4
O
O
COCl
COCl
Br
Br
a
Average isolated yield over two reactions.
Unfortunately, even under these conditions not all
the Stille reaction time to 8 h to achieve the reported yield.
In an attempt to circumvent the distal/proximal regiochem-
ical matter, we first looked at performing the Pd-catalyzed
hydrostannation step on the 1-bromoalkyne derivative
[3b,8b]. However, for reasons that remain unclear, that
substrate did not work well in the hydrostannation/cross-
coupling sequence. Another option involved running the
hydrostannation step under free radical conditions [4]
and then adding the acid chloride along with a Pd-catalysts
to carry out the second step. Owing to the volatility [2] of
Me3SnH, we chose to run the radical hydrostannation with
Bu3SnH. While, this modified procedure was successful at
eliminating the proximal isomer (at the cost of some Z-
vinylstannane formation), recourse to the tributyltin again
gave the a,b-unsaturated ketone in only modest average
overall yield (42%). Usefully, the TBS ether survived the
fluoride present throughout both successful sequences.
substrates were universally accepted. As shown in entry
4, 2-nitrobenzoyl chloride still gave the decarbonylated
coupling product, even when the reaction was run under
an atmosphere of CO [5a].
Finally, we examined a reaction sequence that started
with an alkyne that was not fully substituted at the propar-
gylic position (Scheme 4). As previously mentioned such
substrates afford measurable levels of the proximal vinylst-
annanes under Pd-catalyzed conditions [4,8b,13]. Such
vinyltins are known to be sluggish Stille partners [1,14].
This is reflected in the slightly diminished yield (71%) of
the cross-coupled product, which arose from the partially
selective cross-coupling of the distal vinyltin intermediate
with the benzoyl chloride [15]. Furthermore, it must be
noted that for this substrate we were also required to add
an additional load of the palladium catalyst and extend

K. Lee et al. / Journal of Organometallic Chemistry 691 (2006) 1462–1465
1465
[2] (a) P.J. Smith (Ed.), Chemistry of Tin, Blackie Academic and
Professional, New York, 1998;
(b) A.G. Davies (Ed.), Organotin Chemistry, VCH, New York, 1997.
[3] (a) W.P. Gallagher, R.E. Maleczka Jr., J. Org. Chem. 70 (2005) 841–
846;
1.5 equiv Me3SnF,
2.5 equiv PMHS,
cat. TBAF,
OTBS
then (1.3 equiv)
benzoyl chloride,
2 mol %
(Ph3P)2PdCl2,
THF, 2 h, rt;
Me3Sn
+ proximal vinyltin
2 mol %
(Ph3P)4Pd ,
65 ˚C, 8 h (71%)
(b) Also see: C.D.J. Boden, G. Pattenden, T. Ye, J. Chem. Soc.,
Perkin Trans. I (1996) 2417–2419.
[4] R.E. Maleczka Jr., L.R. Terrell, D.H. Clark, S.L. Whitehead, W.P.
Gallagher, I. Terstiege, J. Org. Chem. 64 (1999) 5958–5965.
[5] (a) J.W. Labadie, D. Tueting, J.K. Stille, J. Org. Chem. 48 (1983)
4634–4642;
OTBS
TBSO
Ph
O
(b) For selected recent examples, see: R. Lerebours, A. Camacho-
Soto, C. Wolf, J. Org. Chem. 70 (2005) 8601–8604;
(c) T. Ichige, S. Kamimura, K. Mayumi, Y. Sakamoto, S. Terashita,
E. Ohteki, N. Kanoh, M. Nakata, Tetrahedron Lett. 46 (2005) 1263–
1267;
OTBS
then (1.3 equiv)
benzoyl chloride,
1.5 equiv Bu3SnF,
2.5 equiv PMHS,
(d) K.R. Dieter, Tetrahedron 55 (1999) 4177–4236.
[6] J. Lipowitz, S.A. Bowman, J. Org. Chem. 38 (1973) 162–165.
[7] J.A. Muchnij, R.E. Maleczka, Jr. Chemoselective Conjugate reduc-
tion of a,b-unsaturated carbonyl compounds with poly-
methylhydrosiloxane. In: Proceedings of the 37th Organosilicon
Symposium, Philadelphia, PA, 2004; Poster P-34.
[8] (a) S.A. Hitchcock, D.R. Mayhugh, G.S. Gregory, Tetrahedron Lett.
36 (1995) 9085–9088;
Bu3Sn
1 mol %
(Ph3P)2PdCl2,
65 ˚C, 3 h (42%)
cat. AIBN
toluene, 70 ˚C, 2 h;
+ Z-vinyltin
Scheme 4.
´
(b) H.X. Zhang, F. Guibe, G. Balavoine, J. Org. Chem. 15 (1990)
In summary, we have expanded the one-pot hydrostan-
nation/Stille coupling method to allow acid chlorides to
serve as the electrophilic coupling partner. Problems asso-
ciated with the use of these reactive building blocks can be
avoided by adding the acid chloride to the reaction after
the vinylstannane has been produced in situ from
Me3SnF/PMHS generated Me3SnH and a corresponding
alkyne. Both aliphatic and electronically varied aromatic
acid chlorides can be employed in this one-pot synthesis
of a,b-unsaturated ketones.
1857–1867.
[9] R.E. Maleczka Jr., W.P. Gallagher, I. Terstiege, J. Am. Chem. Soc.
122 (2000) 384–385.
[10] Typical reaction procedure: Pd2dba3 (0.01 mmol, 9.2 mg) and TFP
(0.04 mmol, 9.3 mg) were added to THF (5 mL) and the resulting
mixture was stirred at r.t. for 15 min. At that time, 3,3-dimethyl 1-
butyne (1 mmol, 0.125 mL), Me3SnF (1.5 mmol, 274 mg), PMHS
(2.5 mmol, 0.09 mL), and TBAF (1 drop of a 1 M solution in THF
(ꢀ0.008 mmol)) were added successively. The reaction was then
allowed to stirr at r.t. for 2 h, at which time the hydrostannation was
complete by GC. The acid chloride (1.3 mmol) was then added and
the mixture was allowed to stirr at reflux (ꢀ65 °C) until the cross-
coupling was judged complete by TLC (ꢀ2–4 h). At that time, the
reaction was diluted with saturated aq. KF (3 mL) and stirred for 0.5
h. The reaction was extracted with Et2O and H2O and the aqueous
phase was back extracted with Et2O. The combined organics were
dried over MgSO4, filtered, and concentrated. The resulting residue
was purified by silica gel chromatography to afford the corresponding
a,b-unsaturated ketone.
Acknowledgments
We thank the NIH (HL-58114), NSF (CHE-9984644),
and the Yamanouchi USA Foundation for generous sup-
port. E.A.T. thanks the NSF REU Program (NSF
0138932) at MSU for the opportunity granted.
[11] Such chemoselectivity has been previously observed. See: Ref. [5b].
[12] R.E. Maleczka Jr., R.J. Rahaim, R.R. Teixeira, Tetrahedron Lett. 43
(2002) 7087–7090.
[13] (a) N.D. Smith, J. Mancuso, M. Lautens, Chem. Rev. 100 (2000)
3257–3282;
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.jorganchem.
2005.11.041.
(b) M.B. Rice, S.L. Whitehead, C.M. Horvath, J.A. Muchnij, R.E.
Maleczka Jr., Synthesis (2001) 1495–1504, and references cited;
(c) K. Kikukawa, H. Umekawa, F. Wada, T. Matsuda, Chem. Lett.
(1988) 881–884;
´
(d) H.X. Zhang, F. Guibe, G. Balavoine, Tetrahedron Lett. 29 (1988)
619–622;
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sponding a,b-unsaturated ketone in only 33% yield.
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