Polymethylhydrosiloxane (PMHS) as an additive in Sonogashira reactions

Article abstract of DOI:10.1055/s-2003-37522

Polymethylhydrosiloxane (PMHS) in combination with CsF facilitates the Sonogashira reaction of a variety of alkynes and electrophiles. These couplings appear to involve the in situ formation and reaction of an alkynylsiloxane. Such couplings can be run am

Full text of DOI:10.1055/s-2003-37522

LETTER
537
Polymethylhydrosiloxane (PMHS) as an Additive in Sonogashira Reactions
P
W
MH
S
as an
A
dditive in
i
Sonog
l
ashira
l
Reactio
i
ns am P. Gallagher, Robert E. Maleczka Jr.*
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
Fax +1(517)3531793; E-mail: maleczka@cem.msu.edu
Received 24 January 2003
sence of PMHS or CsF. In addition, substituting KF for
CsF resulted in no observable coupling reaction.
Abstract: Polymethylhydrosiloxane (PMHS) in combination with
CsF facilitates the Sonogashira reaction of a variety of alkynes and
electrophiles. These couplings appear to involve the in situ forma- As shown in Table 1, the choice and quantity of copper
tion and reaction of an alkynylsiloxane. Such couplings can be run
salt employed were crucial. The reaction failed in the ab-
amine free at room temperature, reaction times are short, workup is
sence of copper (or palladium). With stoichiometric
easy, and product purification is straightforward. Thus, the advan-
amounts of 2-thiophenecarboxylate (CuTC)7 or CuCl
tages (and disadvantages) of running Sonogashira couplings with
,8
(
entries 1 or 3) the reaction proceed efficiently, but little
1
-silylalkynes are realized, without the need to preform the alkynyl
coupling occured when catalytic quantities of these cop-
per(I) reagents were used (entries 2 or 4). Furthermore,
the use of either catalytic or stoichiometric amounts of
CuI, CuBr, or CuCN afforded only trace amounts of
enyne (entries 4–7). Mori et al. observed similar copper
effects in the coupling of 1-silylalkynes3 and concluded
that copper(I) chloride or a ‘CuO’ can affect transmetala-
tion between silicon and copper, whereas the correspond-
ing bromides or iodides can not. Thus, our data suggested
the possible involvement of a silicon bearing alkyne.
silane.
Key words: Sonogashira reaction, enynes, alkynes, palladium,
copper, cross-coupling
i,l
During the course of our studies on palladium mediated
one-pot hydrostannation/Stille reactions, enyne produc-
tion was occasionally observed. Probing this side product
formation further revealed that adding polymethylhy-
drosiloxane (PMHS) and CsF to a mixture of alkyne, elec-
trophile, CuX and Pd-catalyst facilitates Sonogashira
1
Table 1 Effect of Cu(I) Salts on Equation 1a
2
,3
coupling.
Because these conditions are relatively
4
5
neutral and amine free, and because PMHS is easily han- Entry
CuX (equiv)
CuTC (2.0)
Time (h)
Yield
99%
2%
6
dled, inexpensive, non-toxic, and mild, we deemed this
reaction worthy of additional study. The objectives of this
study would be to establish the best conditions for PMHS
mediated Sonogashira reactions and determine the role of
PMHS.
1
2
24
2
2
3
4
5
6
CuTC (0.02)
CuCl (1.5)
95%
2%
CuCl (0.02)
24
24
24
24
Br
Ph
CuI (0.02–1.5)
CuBr (0.02–1.5)
CuCN (0.02–1.5)
<1%
<1%
<1%
PMHS (2 equiv),
OH
CuX, CsF (5 equiv)
OH
Ph
1
PdCl2(PPh3)2 (2 mol%)
NMP, r.t.
2
7
a
See Equation 1 for reaction conditions.
Equation 1
Based on this hypothesis, the employment of nonaflates or
triflates as electrophiles should produce the necessary
Preliminary experiments carried out on the coupling of 2-
methyl-3-butyn-2-ol (1) with (E)-β-bromostyrene
‘
CuO’ species and allow CuTC or CuCl to be used cata-
(
(
Equation 1) revealed that treatment of alkyne 1 with CsF
5 equiv) and PMHS (2 equiv) in NMP followed by addi-
lytically. With aryl nonaflates prepared from their corre-
sponding phenols by treatment with NfF and NEt in
3
tion of PdCl (PPh ) (2 mol%), CuX and (E)-β-bromosty-
9
2
3 2
CH Cl , Sonogashira couplings were investigated
2
2
rene, afforded the corresponding enyne (2) (Sonogashira
product) after stirring for 2 hours at room temperature
(
Equation 2). After some experimentation, we found that
room temperature reactions run with 1.5 equivalents of
nonaflate along with the alkyne, PMHS, CsF, catalytic
PdCl (PPh ) , and catalytic CuCl (or CuTC) (5 mol %) in
(
Table 1, entry 1). Use of less CsF (2 equiv) resulted in a
slower reaction, while no reaction was observed in the ab-
2
3 2
NMP afforded the corresponding cross-coupled products
10
in good to excellent yields (Table 2). In the absence of
PMHS, CsF, Pd, or Cu no Sonogashira reaction was ob-
served.
Synlett 2003, No. 4, Print: 12 03 2003.
Art Id.1437-2096,E;2003,0,04,0537,0541,ftx,en;S10303ST.pdf.
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

5
38
W. P. Gallagher, R. E. Maleczka, Jr.
LETTER
Ar–ONf (1.5 equiv)
be coupled with an aryl nonaflate (Scheme 1). Treatment
of the product with base leads to an elimination of acetone
to furnish the corresponding aryl alkyne. Subjecting the
newly formed aryl alkyne a second coupling afforded
internal aryl alkyne 27 in 68% yield from 2-methyl-3-bu-
tyn-2-ol (1).
PMHS (2 equiv), CsF (5 equiv)
R
H
R
Ar
CuCl or CuTc (5 mol%)
PdCl2(PPh3)2 (5 mol%)
NMP, r.t.
Equation 2
For coupling aryl or vinyl bromides or iodides
(
Equation 3, Table 3), we found 2 equivalents of CuTC11
This protocol was amenable to the reaction of alkynes that
were mono-, di-, or tri-substituted at the propargylic posi-
tion. Free hydroxyls were tolerated and an aryl nonaflate
was selectively reacted in the presence of an aryl bromide
along with the PMHS and CsF in THF/NMP (1:1) worked
12
best. Unfortunately, these conditions are not universally
effective as bromobenzene, p-bromoanisole, and an aryl
chloride could not be made to couple. Reaction occured
with CuCl, but in slightly lower yields. The need for at
least stoichiometric amounts of copper(I) is again presum-
ably due to the aforementioned involvement of a putative
alkynylsiloxane intermediate. The CuBr or CuI formed
(
entry 7). Vinyl nonaflates (21) and aryl triflates (23) cou-
pled with similar levels of efficiency (entries 9, 10) and a
bisnonaflate could be reacted at both positions in high
yield (entry 11).
Iterative application of the coupling method could be used with each coupling is unable to efficiently undergo trans-
to synthesize disubstituted alkynes. For example, a metalation with such a species3 and therefore cannot cy-
masked acetylene such as 2-methyl-3-butyn-2-ol (1) can cle catalytically.
i,l
Table 2 PMHS-Mediated Couplings of 1-Alkynes with Nonaflatesa
Entry
1
Alkyne (R = )
Ar–NOf
Time (h)
4
Product (Yield)b
Ph (3)
5 (96%)
Ac
ONf
(
4)
2
3
4
5
6
7
HO(Me) C-
4
4
4
4
4
4
5
6
8
8
6
6 (96%)
8 (82%)
2
(
1)
HO(Me)CH-
(
7)
HO(CH ) -
10 (86%)
12 (73%)
14 (95%)
17 (73%)
2
4
(
9)
CH (CH ) -
3
2 2
(
11)
CH (CH ) -
3
2 15
(
13)
HO(Me)(Et)C-
15)
(
Br
ONf
(
16)
8
9
HO(Me)(Ph)C-
18)
7
5
5
6
20 (52%)
22 (82%)
6 (86%)
(
MeO
ONf
(
19)
HO(Me)CH-
7)
(
ONf
(
(
21)
1
1
0
1
HO(Me) C-
2
(
1)
Ac
OTf
23)
HO(Me)(Et)C-
15)
R′-Ar-R′
25 (76%)
R′ = RC≡C-
(
NfO
ONf
(
24)
a
See Equation 2 for reaction conditions.
Average isolated yield of two runs.
b
Synlett 2003, No. 4, 537–541 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
PMHS as an Additive in Sonogashira Reactions
539
1
. 4 (1.5 equiv), PMHS (2 equiv),
CuCl (5 mol %), CsF (5 equiv)
PdCl2(PPh3)2 (5 mol%)
NMP, r.t., 6 h
C16H33
PMHS, CsF
TBAF,
NMP,
13
Ac
( )15
THF, 12 h
(100%)
OH
TMSO
Si
O
TMS
r.t., 5 h
2. K2CO3, 18-c-6, PhCH3
reflux, 8 h
13
1
26
Me
n
(
75% 2 steps)
32
PMHS, CsF,
PdCl2(PPh3)2
CuCl, NMP, r.t., 6 h
4
, CuCl, PMHS, CsF
(cat.) PdCl2(PPh3)2
Ac
OMe
NMP, r.t., 2 h (46%)
2
7
NfO
OMe
(
91%)
C16H33
Ac
19
14
Scheme 1
Scheme 2
R'–X (1.5 equiv)
was obtained. PMHS was then added slowly via a
PMHS (2 eq.), CsF (5 equiv)
13
syringe over which time the alkyne C–H stretch at ν =
R
H
R
Ar
3
231 cm–1 diminished (Figure 1). In contrast, mixing 13
CuTC (2 equiv)
PdCl2(PPh3)2 (5 mol%)
NMP/THF (1:1), r.t.
and CsF alone over the same period of time witnessed lit-
tle change in the C–H stretch. Further studies are under-
way to access more evidence for an alkynylsiloxane
intermediate.
Equation 3
While our observations on the copper(I) requirements of
these reactions and the lack of coupling in absence of
PMHS argue for the intermediacy of a silicon bearing
alkyne, we sought further proof of such an intermediate.
Reacting octadecyne (13), PMHS, and CsF produced a
1
solid material (32). H NMR of the substance showed fea-
tures of the starting alkyne and PMHS except that the
alkynyl proton (δ = 2.42 ppm) and the Si-H from PMHS
(
δ = 4.85 ppm) were absent (Scheme 2). Subjecting this
new product to our coupling conditions produced the de-
sired cross-coupled product in 44–49% yield. Treatment
with TBAF regenerated the original alkyne.
Figure 1 ReactIR™ analysis of the alkyne C–H stretch at
ν = 3231 cm
–1
To complement these reactivity studies, we followed the
reaction of the alkyne, PMHS, and CsF by ReactIR™. Oc-
tadecyne (13) and CsF were mixed and an initial reading
In summary, PMHS in combination with CsF facilitates
room temperature Sonogashira couplings of alkynes with
various electrophiles. These reactions can be run amine
free, which among other things eases reaction workup.
The involvement of an in situ generated alkynyl siloxane
intermediate appears likely. Thus, some of the advantages
of using silylakynes in Sonogashira couplings can be real-
ized without having to preform such a species in a sepa-
rate step (usually by deprotonation with an alkyl lithium
followed by trapping with TMSCl). For example, the use
of 1-silylalkynes can limit unwanted homocoupling of
the parent alkyne (Equation 4).14 As shown in Table 4,
attempted couplings of 2-methyl-3-butyn-2-ol (1) or 2-
phenyl-3-butyn-2-ol (18) under traditional Sonogashira
conditions gives a significant amount of homocoupled
products (entries 1 and 3). This problem is particularly
acute if the reactions were not run under an Ar atmo-
Table 3 PMHS-Mediated Couplings of 1-Alkynes with Halidesa
Entry Alkyne (R = ) R′–X
Time Product
b
(
h)
(Yield)
1
2
HO(Me) C-
E-(β)-bromostyrene
2
2 (99%)
2
(
1)
HO(Me)CH-
7)
I
5
29 (82%)
(
)8
(
(
28)
3
4
5
HO(Me) C-
p-iodoacetophenone
5
5
7
6 (87%)
6 (80%)
2
(
1)
HO(Me) C-
p-bromoacetophenone
2
(
1)
HO(Me)CH-
7)
I
31 (88%)
(
)11
(
15
sphere. In contrast, employment of our protocol in air
(
30)
(
Table 4, entries 2 and 4) only afforded the cross-coupled
products, albeit in modest 52% yield for the coupling of
8 to 19.
a
See Equation 3 for reaction conditions.
Average isolated yield of two runs.
b
1
Synlett 2003, No. 4, 537–541 ISSN 0936-5214 © Thieme Stuttgart · New York

5
40
W. P. Gallagher, R. E. Maleczka, Jr.
LETTER
Table 4 Traditional vs. PMHS Mediated Sonogashira Couplings
Entry
Alkyne
Ar–ONf
Methoda
Cross-Coupled
Product
Homocoupled
Product
33 (39%)
33 (0%)
34 (92%)
34 (0%)
1
2
3
4
1
1
4
4
Aa
Ba
Aa
Ba
6 (48%)
6 (85%)
20 (0%)
20 (52%)
18
18
19
19
a
See Equation 4 for reaction conditions
H
Ar
(3) For recent advances see: (a) Fukuyama, T.; Shinmen, M.;
Nishitani, S.; Sato, M.; Ryu, I. Org. Lett. 2002, 4, 1691.
(b) Mori, A.; Ahmed, M. S. M.; Sekiguchi, A.; Masui, K.;
Koike, T. Chem. Lett. 2002, 756. (c) Heidenreich, R. G.;
Köhler, K.; Krauter, J. G. E.; Pietsch, J. Synlett 2002, 1118.
method A or B
+
R
R
R
R
(
d) Tzschucke, C. C.; Markert, C.; Glatz, H.; Bannwarth, W.
Equation 4 Method A: Et N (2.0 equiv), PdCl (PPh ) (0.05 equiv),
3
2
3 2
Angew. Chem. Int. Ed. 2002, 41, 4500. (e) Choudary, B.
M.; Madhi, S.; Chowdari, N. S.; Kantam, M. L.; Sreedhar, B.
J. Am. Chem. Soc. 2002, 124, 14127. (f) Liao, Y.; Fathi, R.;
Reitman, M.; Zhang, Y.; Yang, Z. Tetrahedron Lett. 2001,
CuI (0.05 equiv), ArONf (1.5 equiv), THF, r.t. Method B: PMHS (2.0
equiv), PdCl (PPh ) (0.05 equiv), CuCl (0.05 equiv), ArONf (1.5
2
3 2
equiv), NMP, r.t.
42, 1815. (g) Marshall, J. A.; Chobanian, H. R.; Yanik, M.
It must also be acknowledged that some of the disadvan-
tages of employing 1-silylalkynes in Sonogashira cou-
plings remain under these conditions. Namely,
stoichiometric amounts of copper are necessary in the
coupling of halides. Furthermore, fluoride is required.
With respect to this last point, while most of our reactions
were run with a five-fold excess of CsF, the fluoride load
M. Org. Lett. 2000, 3, 4107. (h) Erdelyi, M.; Gogoll, A. J.
Org. Chem. 2001, 66, 4165. (i) Nishihara, Y.; Ando, J.-i.;
Kato, T.; Mori, A.; Hiyama, T. Macromolecules 2000, 33,
2779. (j) Alami, M.; Crousse, B.; Ferri, F. J. Organomet.
Chem. 2001, 624, 114. (k) Hundertmark, T.; Littke, A. L.;
Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729.
1
6
(
l) Nishihara, Y.; Ikegashira, K.; Hirabayashi, K.; Ando, J.-
i.; Mori, A.; Hiyama, T. J. Org. Chem. 2000, 65, 1780.
(m) Böhm, V. P. W.; Herrmann, W. A. Eur. J. Org. Chem.
2000, 3679. (n) Nishihara, Y.; Ikegashira, K.; Mori, A.;
Hiyama, T. Chem. Lett. 1997, 1233.
could be reduced to 1.5 equivalents with no loss of effi-
ciency by using fused CsF/CsOH (2:1).17
Currently we aim to increase our mechanistic understand-
ing of this reaction and broaden its scope. Of particular in-
terest is the application of this new method to target
synthesis and the coupling of other species. New develop-
ments in these areas will be reported in due course.
3i,l
(
(
4) Mori et al. (ref. ) have found that using 1-silylalkynes in
place of their parent 1-alkynes allows one to perform a
Sonogashira reaction under neutral conditions with catalytic
3
g
amounts of Pd(0) and Cu(I). Marshall et al. (ref. ) also
reported a similar procedure, utilizing stoichiometric
amounts of CuCl and 2 equiv of Bu N.
3
5) For other examples of amine free Sonogashira-type
reactions see (a) Alonso, D. A.; Nájera, C.; Pacheco, C.
Tetrahedron Lett. 2002, 43, 9365. (b) Mori, A.; Shimada,
T.; Kondo, T.; Sekiguchi, A. Synlett 2001, 649.
(6) (a) Lawrence, N. J.; Drew, M. D.; Bushell, S. M. J. Chem.
Soc., Perkin Trans. 1 1999, 3381. (b) Lipowitz, J.;
Bowman, S. A. Aldrichimica Acta 1973, 6, 1. (c) Fieser,
M.; Fieser, L. F. Reagents for Organic Synthesis, Vol. 4;
Wiley: New York, 1974, 393.
7) CuTC = Copper(I) thiophene carboxylate. CuTC can be
easily made or purchased from Frontier Scientific. This
compound is sufficiently stable and does not require any
special handling when dry. CuCl must be kept and used
Acknowledgment
We thank the Yamanouchi USA Foundation and NSF (CHE-
9
984644), for their generous support. W.P.G. thanks Pfizer and
Dow Chemical for sponsorship of ACS Division of Organic and
MSU graduate fellowships, respectively.
References
(
(
1) Maleczka, R. E. Jr.; Gallagher, W. P. Org. Lett. 2001, 3,
173; and references cited.
2) For reviews see: (a) Sonogashira, K. J. Organomet. Chem.
002, 653, 46. (b) Sonogashira, K. In Metal-Catalyzed
4
(
under N to work efficiently. For other examples of CuTC in
2
2
coupling reactions see: (a) Savarin, C.; Srogl, J.;
Liebeskind, L. S. Org. Lett. 2001, 3, 91. (b) Liebeskind, L.
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(c) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996,
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(
(
8) Couplings of 1 and 2 with 1.0 or 1.5 equiv of CuTC were
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9) (a) Rottländer, M.; Knochel, P. J. Org. Chem. 1998, 63, 203.
(
e) Sonogashira, K. In Comprehensive Organic Synthesis,
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(
b) For a review of the preparation of alkenyl triflates see:
2
Lyapkalo, I. M.; Webel, M.; Reißig, H.-U. Eur. J. Org.
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Synlett 2003, No. 4, 537–541 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
PMHS as an Additive in Sonogashira Reactions
541
(
10) Representative Procedure for PMHS–Sonogashira
Coupling of Aryl- and Vinyl Nonaflates/Triflates.
Preparation of 1-(4-Phenylethynyl-phenyl)-ethanone (5)
(11) CuCl could also be used, but the reaction yields tended to be
slightly lower.
(12) For the coupling of aryl or vinyl halides. The general
1
0
(
Table 2, Entry 1). To 30 mL of NMP was added
phenylacetylene(3) (0.11 mL, 1.0 mmol), PMHS (0.12 mL,
mmol), CsF (0.7595 g, 5.0 mmol), CuCl (0.0050 g, 0.05
mmol), 1,1,2,2,3,3,4,4,4-nonafluoro-butane-1-sulfonic acid
-acetyl-phenyl ester (4) (0.6273 g, 1.5 mmol) and
PdCl (PPh ) (0.0350 g, 0.05 mmol). This mixture was
procedure noted above (ref. ) was followed except that 2
equiv of CuTC were used and the solvent was THF/NMP
(1:1, 15 mL at 1.0 mmol scale).
2
(13) Adding the alkyne, CsF, and PMHS at once caused rapid
foaming that made monitoring by ReactIR™ difficult.
(14) Yang, C.; Nolan, S. P. Organometallics 2002, 21, 1020.
(15) Austin, W. B.; Bilow, N.; Kelleghan, W. J.; Lau, K. S. Y. J.
Org. Chem. 1981, 46, 2280.
4
2
3 2
stirred at r.t. until complete by TLC analysis (90/10 hexanes/
EtOAc). Once complete (4 h), the reaction was diluted with
Et O and then washed with sat. aq NH Cl. The phases were
(16) 1-TMS acetylenes have been coupled with triflates or
iodides under copper free conditions using a combination of
catalytic Pd(0) and Ag(I) salts in the presence of K CO or
2
4
then separated and the combined organics were washed with
H O (2×), brine (2×), dried (MgSO ), filtered and
2
4
2
3
concentrated. The resulting residue was purified by column
chromatography (silica gel; hexane/EtOAc 90:10) to afford
TBAF. See: (a) Halbes, U.; Pale, P. Tetrahedron Lett. 2002,
43, 2039. (b) Halbes, U.; Bertus, P.; Pale, P. Tetrahedron
Lett. 2001, 42, 8641. (c) Bertus, P.; Halbes, U.; Pale, P. Eur.
J. Org. Chem. 2001, 4391.
1-(4-phenylethynyl-phenyl)-ethanone(5) (212 mg, 96%) as a
light yellow solid (mp 95 °C). For spectroscopic data and a
prior preparation see the following: Kabalka, G. W.; Wang,
L.; Pagni, R. M. Tetrahedron 2001, 57, 8017.
(17) Edelson, B. S.; Stoltz, B. M.; Corey, E. J. Tetrahedron Lett.
1999, 40, 6729.
Synlett 2003, No. 4, 537–541 ISSN 0936-5214 © Thieme Stuttgart · New York