Synthesis of tetrasubstituted olefins by Pd-catalyzed addition of arylboronic acids to internal alkynes

Article abstract of DOI:10.1021/ol047759q

(Chemical Equation Presented) Tetrasubstituted olefins are readily prepared by the Pd-catalyzed cis addition of two aryl groups from an arylboronic acid to opposite ends of the triple bond of internal alkynes. The synthesis proceeds under very mild reaction conditions and tolerates a wide variety of functional groups, including alcohol, aldehyde, ester, TMS, and acetal groups.

Full text of DOI:10.1021/ol047759q

ORGANIC
LETTERS
2
005
Vol. 7, No. 2
59-262
Synthesis of Tetrasubstituted Olefins by
Pd-Catalyzed Addition of Arylboronic
Acids to Internal Alkynes
2
Chengxiang Zhou and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received November 2, 2004
ABSTRACT
Tetrasubstituted olefins are readily prepared by the Pd-catalyzed cis addition of two aryl groups from an arylboronic acid to opposite ends
of the triple bond of internal alkynes. The synthesis proceeds under very mild reaction conditions and tolerates a wide variety of functional
groups, including alcohol, aldehyde, ester, TMS, and acetal groups.
The expeditious regio- and stereoselective synthesis of
tetrasubstituted olefins has been of interest to organic
addition of two aryl groups from an arylboronic acid to
internal alkynes under very mild reaction conditions (eq 1).
1
chemists for years. The carbopalladation of alkynes has been
2
widely applied in the synthesis of highly substituted olefins.
For example, some specific tetrasubstituted olefins have been
prepared by the intramolecular carbopalladation of internal
alkynes, followed by cross-coupling with organoboron or
3
organostannane reagents. Recently, we reported an efficient
We first examined the reaction of phenylboronic acid and
1-phenyl-1-butyne in THF in the presence of 5% of Pd(OAc)
2
(eq 2). However, only a trace of the desired tetrasubstituted
olefin was obtained (entry 1, Table 1). To our delight, using
DMSO as a cosolvent greatly increased the yield. For
regio- and stereoselective synthesis of tetrasubstituted olefins
by the Pd-catalyzed intermolecular three-component coupling
of an aryl (or vinylic) iodide, an internal alkyne, and an
4
5
6
7
arylboronic acid. The Rh-, Ni-, or Pd-catalyzed additions
of arylboronic acids to alkynes have been reported to produce
highly substituted olefins. Herein, we wish to report the
synthesis of tetrasubstituted olefins by the Pd-catalyzed
2
example, in the presence of 5% Pd(OAc) , the tetrasubstituted
olefin was obtained in a 51% yield when 5 equiv of
phenylboronic acid and 1 equiv of 1-phenyl-1-butyne were
employed in 50:50 DMSO/THF using air as an oxidant at
room temperature for 48 h (entry 2). The yield was increased
to 60 % using only DMSO as the solvent (entry 3). This
(1) For recent representative examples, see: (a) Itami, K.; Mineno, M.;
Muraoka, N.; Yoshida, J. J. Am. Chem. Soc. 2004, 126, 11778. (b) Liu, X.;
Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2004, 43, 879. (c) Zhu,
N.; Hall, D. G. J. Org. Chem. 2003, 68, 6066. (d) Itami, K.; Kamei, T.;
Yoshida, J. J. Am. Chem. Soc. 2003, 125, 14670. (e) Shindo, M.; Matsumoto,
K.; Mori, S.; Shishido, K. J. Am. Chem. Soc. 2002, 124, 6840.
(5) (a) Oguma, K.; Miura, M.; Satoh, T.; Nomura, M. J. Am. Chem.
Soc. 2000, 122, 10464. (b) Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou,
K.; Martin-Matute, B. J. Am. Chem. Soc. 2001, 123, 5358. (c) Hayashi, T.;
Inoue, K.; Taniguchi, N.; Ogasawara, M. J. Am. Chem. Soc. 2001, 123,
9918. (d) Lautens, M.; Yoshida, M. Org. Lett. 2002, 4, 123.
(6) Shirakawa, E.; Takahashi, G.; Tsuchimoto, T.; Kawakami, Y. Chem.
Commun. 2001, 2688.
(
2) (a) Tsuji, J. Palladium Reagents and Catalysis: New PerspectiVes
for the 21st Century; John Wiley & Sons: New York, 2004. (b) Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; John
Wiley & Sons: New York, 2002.
(3) (a) Grigg, R.; Sridharan, V. Pure Appl. Chem. 1998, 70, 1047. (b)
Grigg, R.; Sridharan, V. J. Organomet. Chem. 1999, 576, 65. (c) Poli, G.;
Giambastiani, G.; Heumann, A. Tetrahedron 2000, 56, 5959. (d) Fretwell,
P.; Grigg, R.; Sansano, J. M.; Sridharan, V.; Sukirthalingam, S.; Wilson,
D.; Redpath, J. Tetrahedron 2000, 56, 7525.
(7) (a) Satoh, T.; Ogino, S.; Miura, M.; Nomura, M. Angew. Chem., Int.
Ed. 2004, 43, 5063. (b) Oh, C.; Jung H.; Kim, K.; Kim, N. Angew. Chem.,
Int. Ed. 2003, 42, 805. (c) Oh, C.; Ryu, J. Bull. Korean Chem. Soc. 2003,
24, 1563. For an example involving the formation of a highly substituted
cyclopentadiene, see: (d) Du, X.; Suguro, M.; Hirabayashi, K.; Mori A.
Org. Lett. 2001, 3, 3313.
(4) (a) Zhou, C.; Emrich, D. E.; Larock, R. C. Org. Lett. 2003, 5, 1579.
(
b) Zhang, X.; Larock, R. C. Org. Lett. 2003, 5, 2993.
1
0.1021/ol047759q CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/30/2004

Table 1. Optimization Studiesa
Scheme 1
4
Å
time
(h)
yield
(%)b
biphenyl
(mmol)c
entry DMSO/THF oxidant MS
1
2
3
4
5
6
7
8
9
0/100
50/50
100/0
100/0
100/0
100/0
100/0
100/0
100/0
air
air
air
O2
O2
O2
no
O2
O2
no
no
no
no
yes
yes
yes
yes
yes
48
48
48
24
24
24
24
24
24
trace
51
60 (55)
65 (59)
80 (73)
42
25
30
trace
trace
0.15
0.25
0.32
0.33
0.35
0.10
0.12
trace
d
e
f
g
a
Unless otherwise indicated, the reaction was run employing 1.25 mmol
was obtained using Pd
and only a trace of the desired product is obtained when
PdCl is used as the catalyst (entry 9). Similar observations
2 3 2
(dba) instead of Pd(OAc) (entry 8),
of phenylboronic acid and 0.25 mmol of 1-phenyl-1-butyne in the presence
of 5 mol % of Pd(OAc)2 in 2 mL of solvent. GC yields based on the
limiting reagent (alkyne); yields of products obtained by column chroma-
tography are reported in parentheses. GC yield. 1 equiv of KOAc was
employed. The reaction was run under N2. 5 mol % of Pd(dba)2 was
used. 5 mol % of PdCl2 was used.
b
2
c
d
have been made in other Pd(II)-catalyzed aerobic oxidation
e
f
g
8
reactions run in DMSO. Thus, the optimal, very simple,
“baseless” procedure described in entry 5 has been employed
for the synthesis of a wide variety of tetrasubstituted olefins.
As indicated in Table 2, this approach to tetrasubstituted
olefins is quite versatile. The reaction of p-tolylboronic acid
and 1-phenyl-1-butyne provides a yield slightly higher than
that of phenylboronic acid (compare entries 1 and 2). Using
p-tolylboronic acid, a wide variety of internal alkynes has
been screened (entries 3-8). Diphenylacetylene works quite
well, although the reaction needs to be run at 50 °C (entry
2
Pd(OAc) /DMSO system has proven to be quite useful in
8
aerobic oxidation reactions. Presumably the presence of
DMSO facilitates the reoxidation of Pd(0) to Pd(II) by air,
thus completing the catalytic cycle (see the latter mechanistic
2
discussion). The reaction proceeds faster using O as the
oxidant, and a 65% yield is obtained in 24 h (entry 4).
Adding 4 Å molecular sieves (4 Å MS, 0.2 g for the 0.25
mmol reaction scale) to the reaction system further increases
the yield. Thus, an 80% yield of tetrasubstituted olefin has
been obtained in DMSO in the presence of 4 Å MS at room
temperature (entry 5). The role of the molecular sieves is
not clear. Possibly the presence of molecular sieves facilitates
3). Aldehyde-, alcohol-, ester-, and TMS-containing alkynes
have also been successfully employed without protection,
and the chemistry provides the desired tetrasubstituted olefins
in good yields (entries 4-7). Unfortunately, electron-rich
dialkylacetylenes, such as 4-octyne, have been unsuccessful
in producing the desired tetrasubstituted olefins in good yield.
A higher yield of the desired product is obtained with the
introduction of an electron-withdrawing nitro group into the
aromatic ring of 1-phenyl-1-butyne, which is consistent with
our previous work on the synthesis of tetrasubstituted
9
heterogeneous Pd catalysis on the molecular sieve surface,
or the molecular sieves absorb the water in the system, which
facilitates the catalytic cycle (see Scheme 1). The presence
of base suppresses the formation of the tetrasubstituted olefin.
Only a 42% yield was obtained when 1 equiv of KOAc was
employed as a base (entry 6). Without the oxidant, the
reaction is sluggish. Only a 25% yield of the tetrasubstituted
4
olefins. Thus, an excellent 90% yield is obtained when 1-(4-
nitrophenyl)-1-butyne is allowed to react with p-tolylboronic
acid (entry 8). The reaction involves cis-addition to the
alkyne of two aryl groups from the arylboronic acid. The
structure of product 8 has been determined by investigating
its NOESY H-H interactions (see Supporting Information).
Using 1-(4-nitrophenyl)-1-butyne as the alkyne, a wide
variety of arylboronic acids have been successfully employed
in this process in good yields (entries 9-12). For example,
an 88% yield of the desired product is obtained when
p-methoxyphenylboronic acid is used (entry 9). Electron-
rich acetal-containing arylboronic acids work quite well in
this chemistry (entries 10 and 11). However, electron-poor
olefin is obtained when the reaction is run under N
). It is noteworthy that trisubstituted olefins are not observed
in our process, despite the fact that trisubstituted olefins have
been reported as the major products in the Rh-, Ni-, or
Pd-catalyzed7 addition of arylboronic acids to internal
alkynes. Interestingly, the Pd source is critical for the success
2
(entry
7
5
6
2
of this chemistry. Pd(OAc) is superior to any other Pd
catalyst so far tested. Only a 30% yield of the desired product
(
8) (a) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400 and references
therein. (b) Andappan, M. M. S.; Nilsson, P.; Larhed, M. Chem. Commun.
004, 2, 218. (c) Steinhoff, B. A.; Fix, S. R.; Stahl, S. S. J. Am. Chem.
Soc. 2002, 124, 766. (d) Peterson, K. P.; Larock, R. C. J. Org. Chem. 1998,
2
3
,5-difluorophenylboronic acid gave a significantly lower
yield of tetrasubstituted olefin (entry 12). Because the mild
baseless” reaction conditions tolerate many functional
6
3, 3185. (e) Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58,
5
298.
(
9) For a review covering the use of molecular sieves in organic synthesis,
see: De Vos, D. E.; Dams, M.; Sels, B. F.; Jacobs, P. A. Chem. ReV. 2002,
02, 3615.
“
1
groups, including aldehyde, ketone, alcohol, ester, acetal, and
260
Org. Lett., Vol. 7, No. 2, 2005

Table 2. Synthesis of Tetrasubstituted Olefins (eq 1)a
a
The reaction employs 0.0125 mmol of Pd(OAc)2, 1.25 mmol of arylboronic acid, 0.25 mmol of alkyne, and 0.2 g of 4 Å MS under an O2 balloon in
b
2
mL of DMSO at the indicated temperature for 24 h. The yields are based on products isolated by column chromatography.
TMS groups, this chemistry should be quite useful in the
synthesis of highly functionalized tetrasubstituted olefins.
A possible mechanism for this process is illustrated in
Scheme 1. It involves the following key steps: (1) trans-
Org. Lett., Vol. 7, No. 2, 2005
261

metalation of the arylboronic acid by the Pd(OAc)
2
catalyst;
(2) cis-carbopalladation of the internal alkyne by the resulting
Scheme 2
arylpalladium intermediate to generate a vinylic palladium
intermediate; (3) transmetalation with another molecule of
arylboronic acid; (4) reductive elimination producing the
tetrasubstituted olefin with simultaneous generation of Pd-
(
0); (5) DMSO-promoted formation of a peroxopalladium-
8c
2
(II) species; and (6) regeneration of the Pd(OAc) catalyst
8c
by protonation of the peroxo species. Regeneration of the
Pd(II) catalyst by aerobic oxidation of Pd(0) is critical for
completion of the catalytic cycle. The unique coordinating
ability of DMSO could play an important role in facilitating
the aerobic oxidation of Pd(0) to Pd(II).8 Thus, the presence
a,c
2
of DMSO and molecular O facilitates the reaction. Alter-
10
natively, the Pd-promoted homocoupling of two molecules
of boronic acid could occur, which would produce the biaryl
side product observed.
Alternatively, a Pd(0)-catalyzed mechanism is also pos-
sible, as shown in Scheme 2. The key steps here would be
In summary, a novel Pd-catalyzed reaction between an
arylboronic acid and an internal alkyne has been successfully
developed. A wide variety of tetrasubstituted olefins have
been obtained in good to excellent yields by this simple
process. The mild, “baseless” reaction conditions tolerate
many functional groups, including aldehyde, ketone, alcohol,
ester, TMS, and acetal groups. We believe this chemistry
should be quite useful in the synthesis of highly function-
alized tetrasubstituted olefins.
(
1) oxidative addition of the arylboronic acid to Pd(0), which
10e,11
generates an arylpalladium(II) species;
(2) carbopalla-
dation; (3) transmetalation to produce a B-B or perhaps a
B-O bond; and (4) reductive elimination that might then
occur in a fashion similar to that shown previously in Scheme
1. This would produce the tetrasubstituted olefin and
regenerate the Pd(0) catalyst. The mechanism shown in
Scheme 1 would appear to be more favorable since there
appears to be no precedent for the formation of such B-B
or B-O bonds and the fact that the presence of DMSO and
O greatly facilitates the reaction. However, we cannot
2
completely rule out the mechanism shown in Scheme 2,
especially when a fair amount of the desired product is
observed even under an N atmosphere (entry 7, Table 1). It
2
is possible that both mechanisms operate in this reaction
system.
Acknowledgment. Partial financial support from the
National Science Foundation and the Petroleum Research
Fund administered by American Chemical Society are
gratefully acknowledged. We also acknowledge Johnson
Matthey, Inc. and Kawaken Fine Chemicals Co. Ltd. for
providing the palladium compounds and Frontier Scientific
Co. for the arylboronic acids.
(
10) (a) Miyaura, N.; Suzuki, A. Main Group Met. Chem. 1987, 10, 295.
(
b) Campi, E. M.; Jackson, W. R.; Marcuccio, S. M.; Naeslund, C. G. M.
J. Chem. Soc., Chem. Commun. 1994, 2393. (c) Gillmann, T.; Weeber, T.
Synlett 1994, 649. (d) Song, Z. Z.; Wong, H. N. C. J. Org. Chem. 1994,
Supporting Information Available: Reaction procedures,
1
13
product characterization data, H and C NMR spectra for
compounds 1-12, and COSEY and NOESY spectra for
compound 8. This material is available free of charge via
the Internet at http://pubs.acs.org.
5
6
9, 33. (e) Moreno-Ma n˜ as, M.; P e´ rez, M.; Pleixats, R. J. Org. Chem. 1996,
1, 2346. (f) Wong, M. S.; Zhang, X. L. Tetrahedron Lett. 2001, 42, 4087.
(
g) Koza, D. J.; Carita, E. Synthesis 2002, 2183. (h) Falck, J. R.; Mohapatra,
S.; Bondlela, M.; Venkataraman, S. K. Tetrahedron Lett. 2002, 43, 8149.
i) Lei, A.; Zhang, X. Tetrahedron Lett. 2002, 43, 2525. (j) Yoshida, H.;
Yamaryo, Y.; Ohshita, J.; Kunai, A. Tetrahedron Lett. 2003, 44, 1541.
11) Cho, C.; Uemura, S. J. Organomet. Chem. 1994, 465, 85.
(
(
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