Pd-catalyzed addition of organoboronic acids to alkynes at room temperature

Article abstract of DOI:10.1055/s-2005-862362

Combination of Pd(OAc)₂ with 2-bromo-1,3-bis- [diphenylphosphenomethyl)]benzene (1) or 2-bromo-1,3-bis-[di-tert- butylphosphenomethyl)]benzene (3) catalyzed hydroarylations and hydroalkenylations of various alkynes more efficiently in terms of

Full text of DOI:10.1055/s-2005-862362

LETTER
457
Pd-Catalyzed Addition of Organoboronic Acids to Alkynes at Room
Temperature
P
d-Catalyze
d
Add
r
ition of
O
u
rganoboron
n
ic
A
cids to
A
lkyne
s
GOS lab, Department of Chemistry, Hanyang University, Sagundong gu, Seoul 133-791, Korea
Fax +82(2)22990762; E-mail: changho@hanyang.ac.kr
Received 7 November 2004
C3H7
C3H7
Pd catalyst ( 3 mol%)
HOAc (10 mol%)
C3H7
C3H7
Ph
Abstract: Combination of Pd(OAc)2 with 2-bromo-1,3-bis-[diphe-
nylphosphenomethyl)]benzene (1) or 2-bromo-1,3-bis-[di-tert-bu-
tylphosphenomethyl)]benzene (3) catalyzed hydroarylations and
hydroalkenylations of various alkynes more efficiently in terms of
reaction time and temperature.
5a
PhB(OH)2
6a
Equation 1
Key words: palladium, organoboronic acids, alkynes, catalyst, hy-
droarylation, hydroalkenylation
monodentate ligands did still require higher temperatures
(80 °C) and ligand-free palladium acetate did not catalyze
this transformation (entries 5–7). These observations in-
spired us to search for yet more efficient ligands, which
would make the reaction possible at even lower tempera-
tures. It has been postulated that excellent catalytic activ-
ities have arisen from the use of bidentate ligands with an
aromatic ring spacer which were used as precursors in the
synthesis of pincer complexes in variety of reactions.7
Hence, we have prepared three ligands 1–3 and one Pd-
Pd-catalyzed cross-coupling reaction of organoboronic
acids with various aryl halides, called the Suzuki reaction,
has provided a variety of stereodefined biaryls,1 alka-
dienes,2 and trienes.3 Since organoboron compounds be-
come readily available or can be easily prepared, much
attention has been devoted to developing a new aspect of
organoboron chemistry.
Addition reactions of organoboronic acids to alkynes can pincer complex 4 for our study (Figure 1).
also provide a general entry to stereodefined alkadiene or
Table 1 Addition of Phenylboronic Acid (6a) to 4-Octyne (5a)
arylated alkenes. Such hydroarylation and hydroalkenyl-
ation have been attained by palladium-, rhodium-, and
nickel-catalyzed addition of organometallic compounds
to the alkynes,4 or by titanium-catalyzed hydrozincation
of alkynes.5 There is still a continuing need for simple and
versatile synthetic methods for this important class of
compounds. In continuation of our research interest in hy-
droarylation and hydroalkenylation of alkynes and allenes
by organoboron compounds,6 we are very much interested
in finding more efficient catalysts. In this regard, we have
observed that ligands coordinating to palladium could
play a vital role in catalytic activities. At first we started
the present study with 4-octyne (5a) and phenylboronic
acid (6a) under palladium catalysis (Equation 1) and sum-
marized our results in Table 1. Previously, we have re-
ported this reaction catalyzed by [Pd(PPh3)4], where it
required 60–80 °C and a long reaction time (24 h) for
completion (entry 1). During the course of scrutinizing the
reaction conditions by combination of various palladium
compounds with different ligands, it was interesting to ob-
serve that the reaction was complete at lower temperature
and in shorter time when bidentate ligands such as dppe
and dppb were employed in combination with Pd(OAc)2
without much change in reaction efficiency (entries 2–4).
It is noteworthy that palladium acetate combined with
under Various Conditions
No Catalyst
Solvent
Temp (°C)/ Yield
time (h)
60, 48
50, 15
50, 15
50, 15
80, 18
80, 15
100, 24
120, 48
25, 5
(%)
1
2
Pd(Ph3P)4
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
93
Pd(OAc)2dppe
Pd(OAc)2dppb
Pd(OAc)2dppf
Pd(OAc)2, (cy)3P
85
3
78
4
71
5
63
6
Pd(OAc)2, (t-Bu)3P 1,4-Dioxane
67
7
Pd(OAc)2
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Toluene
7
8
Complex 3
Pd(OAc)2, 1
Pd(OAc)2, 1
Pd(OAc)2, 1
Pd (OAc)2, 1
Pd(OAc)2, 1
PdCl2, 1
N.R
95
9
10
11
12
13
14
15
16
25, 24
25, 8
63
CHCl3
75
THF
25, 10
25, 12
100, 24
100, 24
80, 24
82
DMF
71
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
N.r.
Trace
61
Pd2(dba3), 1
Pd(OAc)2, 2
SYNLETT 2005, No. 3, pp 0457–0460
1
6.
0
2.
2
0
0
5
Advanced online publication: 04.02.2005
DOI: 10.1055/s-2005-862362; Art ID: U31004ST
© Georg Thieme Verlag Stuttgart · New York

458
A. K. Gupta et al.
LETTER
R1B(OH)2 (6), "Pd"
R
R
R
R
• 2HBr
1,4-dioxane
R1
5
7
Ph2P
X
PPh2 (t-Bu)2P
Br P(t-Bu)2 Ph2P
Pd PPh2
Br
R = n-propyl, 5a
CH2OH, 5b
CH2OBn, 5c
CO2Et, 5d
Ph, 5e
1 (X = Br)
2 (X = H)
3
4
PhB(OH)2 (6a)
n-C4H9CH=CHB(OH)2 (6b)
PhCH=CHB(OH)2 (6c)
Figure 1
Si(Me)3, 5f
These ligands 1, 2, and 3, and the Pd-pincer complex 4
were prepared according to known methods. First, we
tested the catalytic activity of Pd-pincer complex 4 for the
Equation 2
hydrophenylation of 4-octyne (5a) with phenylboronic (entries 17–19). Finally, the highly electron-dense alkyne
acid. To our surprise, the reaction did not afford the addi- 5f did not undergo an addition reaction even under harsh
tion product 7aa even at higher temperature (entry 8). On conditions (entry 20).
the other hand, the same reaction occurred by mixing the
ligand 1 in combination with Pd(OAc)2 in situ in a 1:1 ra-
Next we have applied this strategy to conjugated alkyne
carboxylates. Once again, we attempted to optimize the
tio. GC analysis showed that the reaction was completed
reaction conditions for addition of phenylboronic acid
at room temperature within five hours. Product 7aa could
(6a) to ethyl-2-butynoate (8a) as shown in Equation 3 and
be isolated in 95% yield (entry 9).
Table 3.
The present reaction was scrutinized in various solvents
such as toluene, chloroform, THF, and DMF, and by other
palladium compounds such as PdCl2 and Pd2(dba)3 (en-
Table 2 Addition of Organoboronic Acids 6a–c to Symmetrical
Alkynes 5a–f
tries 10–15). It was observed that the optimal conditions
to yield product 7aa were a combination of Pd(OAc)2
(3mol%), ligand 1 (3 mol%), and acetic acid (0.10 equiv)
in 1,4-dioxane at room temperature.8 The combination of
Pd(OAc)2 with ligand 2 required higher temperature
(80 °C) and a prolonged reaction time (24 h) to afford the
product 7aa in only 61% yield. It implies that the presence
of a bromide group in ligand 1 on the aromatic ring could
greatly enhance the catalytic activity.
R
R1
Reaction con- Temp (°C)/ Prod- Yield
ditionsa
A
B
time (h)
60, 48
25, 5
uct
(%)
95
93
89
78
82
86
1
2
5a
6a
7aa
7aa
7ab
7ab
7ac
7ba
3
6b
A
B
80, 24
25, 6
4
5
6c
6a
6b
6c
6a
6b
6c
6a
6b
6c
6a
6b
B
25, 6
This experimental protocol was applied to various types
of symmetrical alkynes 5a–f such as a non-polar alkyne
5a, polar alkynes 5b and 5c, an electron deficient alkyne
5d, a sterically hindered alkyne 5e, and an electron-rich
alkyne 5f toward three different types of organoboronic
acids 6a–c (Equation 2). We have compared two catalytic
systems: the previously reported conditions A, catalyzed
by Pd(PPh3)4, and the present conditions B, catalyzed by
Pd(OAc)2 ligand 1. Our results are summarized in
Table 2. Under the present conditions B, 4-octyne (5a)
and 2-butyne-1,4-diol (5b) underwent the reactions very
smoothly with 6a–c at room temperature to give 7aa–ac
and 7ba–bc in good to excellent yields, respectively
(entries 1–8). The reactions of 5c with 6a–c gave products
7ca–7cc in high yields without debenzylation (entries 9–
11), in contrast to our observations during the reaction of
5c with 6a,b under Pd(PPh3)4-catalyzed reaction. As we
expected, diethyl acetylenecarboxylate (5d) with the three
boronic acids 6a–c gave 7da, 7db, and 7dc in 91%, 66%
and 74% yields, respectively (entries 12–14).
6
5b
5c
5d
5e
B
25, 8
7
B
25, 10
25, 10
25, 10
25, 10
25, 10
25, 3
7bb 76
8
B
7bc
7ca
7cb
7cc
7da
79
82
72
74
91
9
B
10
11
12
13
14
15
16
17
18
19
20
B
B
B
B
25, 4
7db 76
B
25, 4
7dc
7ea
7ea
7eb
7eb
7ec
7fa
74
91
85
75
78
76
N.r.
A
B
80, 12
45, 5
A
B
80, 12
45, 7
The reaction of diphenylacetylene (5e) with phenylboron-
ic acid 6a in the presence of Pd(PPh3)4 was completed at
80 °C in 12 hours (entry 15). The same reaction under
conditions B was successfully completed within five
hours at ambient temperature (entry 16). The similar
reactivity was observed with n-hexenylboronic acid (6b)
and phenylvinylboronic acid (6c) to give 7eb and 7ec
6c
B
50, 7
5f
6d
B
100, 24
a Condition A: Pd(PPh3)4 (3 mol%), HOAc (10 mol%) in 1,4-dioxane
at 60–80 °C. Condition B: Pd(OAc)2 (3 mol%), ligand 1 (3 mol%),
HOAc (10 mol%) in 1,4-dioxane at r.t.
Synlett 2005, No. 3, 457–460 © Thieme Stuttgart · New York

LETTER
Pd-Catalyzed Addition of Organoboronic Acids to Alkynes
459
In order to prove the versatility and diversity of the
methodology, we carried out arylation and alkenylation
with five conjugated alkynecarboxylates 8a–e by varying
the size of alkyl groups and two different organoboronic
acids (6a and 6b, Equation 4).
COOEt
Ph 9aa
CO2Et
Pd catalyst ( 5 mol%)
Additive (10 mol %)
8a
COOEt
Ph–B(OH)2 (6a)
Ph
10aa
Equation 3
R
CO2Et
Pd(OAc)2 (5 mol%)
ligand 4( 5 mol%)
R1
R
R1B(OH)2
CO2Et +
R
9
When we employed the previously reported conditions,
the reaction was complete at 50 °C in 15 hours to give a
85:15 mixture of the expected products 9aa and 10aa in
combined 91% yield (entry 1). Compared to Pd(PPh3)4,
Pd(OAc)2 with a phosphine ligand such as PPh3 or tri(n-
butyl)phosphine resulted in better regioselective phenyla-
tion (entries 2 and 3). We were very gratified that an 1:1
mixture of bidentate phosphine ligands and Pd(OAc)2 dra-
matically improved the regioselectivity. While 1,4-
bis(diphenylphosphine)butane (dppb) gave a 97:3 mixture
of 9aa and 10aa in 76% yield, 1,4-bis(diphenyl-phos-
phine)ethane (dppe) gave 9aa along with a trace of 10aa
(2%, entries 4 and 5). When the present phenylation was
tried by simply employing ligand 3 in combination with
Pd(OAc)2, the reaction did not proceed even after 24
hours at 80 °C (entry 6). When a mixture of palladium
acetate and ligand 3 in 1,4-dioxane was treated with 10
mol% of sodium acetate and additional 10% of acetic ac-
id, the reaction occurred very smoothly at room tempera-
ture in three hours to give a 93:7 mixture of 9aa and 10aa
(entry 7). In fact, almost complete regiospecificity was
obtained when a 1:1:2 mixture of Pd(OA)2, ligand 3 and
sodium acetate was treated with a mixture of 8a and 6a in
aqueous ethylene dichloride (EDC–H2O = 20:1; entry 8).9
The same reaction with ligand 1 resulted in moderate re-
gioselectivity (entry 9). The conditions described for entry
8 were used for our further studies.
NaOAc (10 mol%)
EDC:H2O (20:1), r.t.
8
6
CO2Et
R1
R = CH3 (8a)
n-C4H9 (8b)
i-C3H7 (8c)
t-C4H9 (8d)
C6H5 (8e)
10
R
1 = C6H5- (6a)
n-C4H9CH=CH- (6b)
Equation 4
Table 4 Addition Reactions of Organoboronic Acids to Alkyne-
carboxylate
No
Substrates R1B(OH)2 Yields (%) Ratio 9:10
1
2
8a
8b
8c
8d
8e
6a
6b
89
74
Only 9aa
Only 9ab
3
4
6a
6b
85
81
9ba:10ba (98:2)
9bb:10bb (94:6)
5
6
6a
6b
76
77
9ca:10ca (85:15)
9cb:10cb (75:25)
7
8
6a
6b
79
73
Only 10da
Only 10db
9
6a
6b
92
88
9ea:10ea (83:17)
9eb:10eb (85:15)
10
Table 3 Addition of Phenylboronic Acid (6a) to Ethyl 2-Butynoate (8a) under Various Conditions
Catalyst ligand
Pd(PPh3)4
Additives
HOAc
HOAc
HOAc
HOAc
HOAc
–
Solvent
THF
Temp (°C)/time (h)
Yield (%) (9aa:10aa)
91 (85:15)
95 (95:5)
1
2
3
4
5
6
7
50/15
50/15
50/5
Pd(OAc)2PPh3
Pd(OAc)2 n-(Bu)3P
Pd(OAc)2dppe
Pd(OAc)2dppb
Pd(OAc)2, 3
CHCl3
THF
88 (92:8)
CHCl3
CHCl3
Dioxane
Dioxane
50/5
80 (92:8)
50/5
76 (97:3)
80/24
r.t./2–3
Trace
Pd(OAc)2, 3
NaOAc
HOAc
91 (97:3)
8
9
Pd(OAc)2, 3
Pd(OAc)2, 1
NaOAc
EDC–H2O
Dioxane
r.t./12
r.t./24
89
(9aa only)
HOAc
70 (90:10)
Synlett 2005, No. 3, 457–460 © Thieme Stuttgart · New York

460
A. K. Gupta et al.
LETTER
Lett. 2002, 4, 123. (g) Boiteau, J.; Imbos, R.; Minnaard, A.
J.; Feringa, B. L. Org. Lett. 2003, 5, 681. (h) For Ni-
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Urabe, H.; Okamoto, S. Chem. Rev. 2000, 100, 2835.
(b) Gao, Y.; Harada, K.; Hata, T.; Urabe, H.; Sato, F. J. Org.
Chem. 1995, 60, 290.
Our results are summarized in Table 4. Ethyl 2-butynoate
(8a) was reacted with 1-hexenylboronic acid (6b) to give
exclusively products 9ab in 74% yield (entry 2). Although
the alkyne carboxylate 8b is structurally similar to 8a,
there was a little difference in regioselectivity. A small
amount of 1,3-addition product 10ba was observed with
phenylboronic acid (6a) whereas more 10bb was formed
with 1-hexenylboronic acid (6b, entries 3, 4) In order to
find out the effect of the size of alkyl group, we replaced
the methyl group in 8a by an isopropyl group. The result-
ing substrate 8c was then subjected to the same reaction
conditions. While the reaction of 8c with 6a gave products
9ca and 10ca in 85:15 ratio, the reaction with 6b gave
products 9cb and 10cb in 75:25 ratio (entries 5, 6). Sub-
strate 8d, with an introduced bulky t-butyl group at the
alkyne end, gave rise to a complete reversal of regioselec-
tivity with both 6a and 6b to form the 1,3-addition product
10da and 10bd in 79% and 73% yields, respectively. Fi-
nally, the reaction of ethyl phenylpropynoate (8e) also un-
derwent very smooth addition with both 6a and 6b to give
products 9ea and 10ea in a 83:17 ratio and 9eb and 10eb
in a 85:15 ratio, respectively.
(6) (a) Oh, C. H.; Park, S. J. Tetrahedron Lett. 2003, 44, 3785.
(b) Oh, C. H.; Sung, H. R.; Park, S. J.; Ahn, K. H. J. Org.
Chem. 2002, 67, 7155. (c) Oh, C. H.; Young, M. L. Bull.
Korean Chem. Soc. 2002, 23, 663.
(7) (a) Matsumoto, H.; Motegi, T.; Nakamo, T.; Nagai, Y. J.
Organomet. Chem. 1979, 174, 157. (b) Cabri, W. Acc.
Chem. Res. 1995, 28, 2. (c) Suzuki, A. Chem. Rev. 1995, 95,
2457. (d) Gupta, M.; Hagen, C.; Kaska, W. C.; Crammer, R.
E.; Jenson, C. M. J. Am. Chem. Soc. 1997, 119, 840.
(e) Dani, P.; Karlen, T.; Gossage, R. A.; Gladiali, S.; van
Koten, G. Angew. Chem. Int. Ed. 2000, 39, 743. (f) Gorla,
F.; Togni, A.; Venanzi, L. Organometallics 1994, 13, 1607.
(g) Stark, M. A.; Richards, C. J. Tetrahedron Lett. 1997, 38,
5881. (h) Denmark, S.; Stavenger, R. A.; Faucher, A. M.;
Edwards, J. P. J. Org. Chem. 1997, 62, 3375. (i) Hoveyda,
A. H.; Morken, J. P. Angew. Chem., Int. Ed. Engl. 1996, 35,
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1997, 38, 1725. (k) Del Rio, I.; Robert, A. G.; Milja, S.;
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(8) Preparation of Compound 7; General Procedure
A 10 mL round-bottomed flask was charged with an alkyne
5a–f (0.40 mmol), organo boronic acid 6a–c (0.48 mmol),
ligand 1 (3 mol%), Pd(OAc)2 (3 mol%) and then 1,4-dioxane
(1.0 mL) at 0 °C. The reaction mixture was purged with dry
argon gas and was treated with HOAc (0.04 mmol) via a 10
mL gastight syringe at 0 °C. The mixture was stirred at 25 °C
as described in Table 2. On completion of the reaction, the
mixture was cooled to 0 °C, quenched with H2O, and then
extracted with Et2O. The organic portion was washed with
sat. NaCl solution, dried over anhyd MgSO4, and
In conclusion, we have demonstrated that combinations of
Pd(OAc)2 ligand 1 and Pd(OAc)2 ligand 2 catalyzed hy-
droarylations and hydroalkenylations of various alkynes
in a highly efficient manner. Particularly, ligands possess-
ing an aromatic ring as a spacer (1 and 3) enhanced the
rate of the Pd-catalyzed addition reactions of organo-
boronic acids to various alkynes greatly. More studies on
influence of the bromide group in the ligands 1 and 3 are
underway.
Acknowledgment
We thank the Center of Molecular Design and Synthesis (CMDS)
for support of this research. A. K. Gupta is grateful to BK21 project
for the financial support.
concentrated in vacuo. The residue thus obtained was
purified by flash chromatography (EtOAc–hexane = 1:10)
to give product 7. All the isolated products were
References
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(9) Preparation of Compounds 9 and 10; General Procedure
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carboxylate 8a–e, (0.40 mmol), organoboronnic acid 6a–c
(0.48 mmol), Pd(OAc)2 (5 mol%), ligand 3 (5 mol%),
NaOAc (2.1 equiv, 0.48 mmol) and 0.95 mL of ethylene
dichloride and 0.05 mL of H2O. The reaction mixture was
stirred vigorously until the absence of starting material was
observed on TLC. Then the mixture was diluted with Et2O
(10 mL) plus H2O (5 mL) and extracted twice with Et2O
(2 × 10 mL). The combined organic portion was washed with
a sat. brine solution, dried over anhyd MgSO4, and
concentrated in vacuo. Finally, the residue was purified by
flash chromatography (EtOAc–hexane = 1:10) to get 9 and/
or 10. The product structure was assigned by IR, 1H NMR,
13C NMR and HRMS.
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Synlett 2005, No. 3, 457–460 © Thieme Stuttgart · New York