Rhodium-catalyzed asymmetric 1,4-addition of heteroaryl cyclic triolborate to α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1055/s-0028-1088198

Rhodium-catalyzed asymmetric 1,4-additions of electron-deficient heteroaryl groups to α,β-unsaturated carbonyl compounds were established. The reaction resulted in very low yields due to competitive C-B bond cleavage when arylboronic acids, their pinacol

Full text of DOI:10.1055/s-0028-1088198

994
LETTER
Rhodium-Catalyzed Asymmetric 1,4-Addition of Heteroaryl Cyclic
Triolborate to a,b-Unsaturated Carbonyl Compounds
A
symmetric 1, 4-A
i
ddition
a
of
H
eteroa
o
rylborates -Qiang Yu, Yasunori Yamamoto,* Norio Miyaura*
Division of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Fax +81(11)7066561; E-mail: yasuyama@eng.hokudai.ac.jp; E-mail: miyaura@eng.hokudai.ac.jp
Received 16 December 2008
and Figure 1). Addition of triolborates possessing a donat-
ing substituent such as a methoxy group gave 1,4-addition
products with high enantioselectivities at 95 °C in non-
aqueous 1,4-dioxane.
Abstract: Rhodium-catalyzed asymmetric 1,4-additions of elec-
tron-deficient heteroaryl groups to a,b-unsaturated carbonyl com-
pounds were established. The reaction resulted in very low yields
due to competitive C–B bond cleavage when arylboronic acids,
their pinacol esters, or potassium trifluoroborates were used. How-
ever, the corresponding lithium heteroaryl(triol)borates afforded
1,4-adducts with high enantioselectivities up to 97% in the presence
of a rhodium(I) catalyst chelated with a chiral BINAP or BIPAM
ligand.
Lithium triolborates 2 were synthesized by alkylation of
B(Oi-Pr)3 with RLi, followed by ester exchange with triol
by evaporating 2-propanol in vacuo (Scheme 2).
By this protocol, heteroarylborates sensitive to hydrolytic
B–C bond cleavage were synthesized in high yields. The
1H NMR analysis in DMSO-d6 showed the presence of
some water of crystallization (ca. 2 molar amounts) which
was not removable in vacuo (1.33·10–5 bar) at room tem-
perature. They are white solids stable in air and moisture.
Key words: heteroaryl cyclic triolborate, rhodium catalyst, asym-
metric reaction, conjugate addition
The transition-metal-catalyzed asymmetric 1,4-addition
to a,b-unsaturated carbonyl compounds is a powerful
method for producing stereodefined C–C bonds, particu-
larly in the enantioselective synthesis of biologically im-
portant molecules in natural products and drug
candidates.1 Copper complexes have been successfully
used for organolithium, -magnesium, or -zinc reagents,2,3
rhodium complexes have been successfully used for orga-
noboranes, -silicones, or -stannanes,4 and palladium(II)
complexes have been successfully used for arylboron,
-silicone, and -bismuth compounds.4c,5 Among these ex-
tensive studies on asymmetric C–C bond formation, 1,4-
addition of arylboronic acids has attracted much attention
due to their low toxicity, compatibility to a broad range of
functional groups, and high stability in water and air. Al-
though excellent yields and selectivities have been
achieved by using typical arylboronic acids possessing no
heteroatoms, there has been little use of pyridine and
thiophene analogues6–8 due to the high coordination abili-
ty of heteroatoms to catalysts and slow transmetalation
and insertion of electron-deficient heteroaryl rings, thus
facilitating C–B bond cleavage with water relative to 1,4-
addition to unsaturated carbonyl compounds. Recognition
of the importance of heteroaryl groups in biologically ac-
tive compounds recently prompted us to develop novel
cyclic triolborates for C–C and C–N bond formation via
coupling reactions catalyzed by palladium or copper com-
plexes.9,10 We herein report asymmetric 1,4-additions of
pyridyl- and thienyl(triol)borates (2) catalyzed by rhodi-
um(I) complexes ligated by a (S)- BINAP,11 (S,S)-
CHIRAPHOS,12 or (R)-Me-BIPAM13 ligand (Scheme 1
1,4-Addition of lithium p-tolyl(triol)borate (2g, 1.5 equiv)
to 2-cyclohexenone smoothly proceeded at 50 °C in diox-
ane or in aqueous dioxane in the presence of a Rh(I)/(S)-
BINAP catalyst (3 mol%, Table 1). The reaction was fast-
er in aqueous dioxane than in dry dioxane and was further
accelerated in the presence of 1 equivalent of triethyl-
amine.14 The enantioselectivities (higher than 97% ee)
were comparable to those achieved by a rhodium/BINAP
catalyst and p-tolylboronic acid or potassium p-tolyl(tri-
fluoro)borate.11,15
O
PPh2
PPh2
O
O
P
P
O
O
Me2N
NMe2
(S)-BINAP
(R)-Me-BIPAM
Me
Me
PPh2
PPh2
(S,S)-CHIRAPHOS
Figure 1 Chiral ligands
Although typical aryl(triol)borates possessing no hetero-
atom smoothly undergo 1,4-addition under mild condi-
tions, heteroarylborates suffered from low yields due to
competitive hydrolytic B–C bond cleavage. Thus, boron
reagents, catalysts, and solvents were re-optimized by us-
ing 6-methoxy-3-pyridylboron derivatives (1.5 equiv of
4–6 or 2c) for 2-cyclohexenone (Table 2, entries 1–9).
The reactions were carried out at 95 °C in dioxane–H2O
SYNLETT 2009, No. 6, pp 0994–0998
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x.
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Advanced online publication: 16.03.2009
DOI: 10.1055/s-0028-1088198; Art ID: U12708ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric 1,4-Addition of Heteroarylborates
995
O
B
Li
R1
R2
Ar
R1
R2
O
O
2
Ar
O
O
R3
Rh catalyst
1,4-dioxane
R3
Me
1
3
C5H11
Me
1a:
1b:
O
1d:
1f:
Me
N
O
O
H
Me
O
1e:
O
O
1c:
O
2a: Ar =
2b: Ar =
2c: Ar =
OMe
OMe
N
S
N
S
N
S
Ar =
2d:
2e: Ar =
2f: Ar =
OMe
2g: Ar =
Me
Scheme 1 1,4-Addition of heteroaryl(triol)borates
B(Oi-Pr)3
n-BuLi
boronic acid (4) and pinacol ester derivative (5) even in
nonaqueous solvent (entries 2 and 4), but quaternary po-
tassium trifluoroborate (6) gave 3a in 13% yield (entry 6).
The yield was further increased to 83% with 97% ee when
triolborate 2c was used (entry 8). Although a preliminary
experiment at 50 °C shown in Table 1 revealed an accel-
erating effect of triethylamine, it was not significant at 95
°C (entry 9). Finally, an almost quantitative yield was ob-
tained by increasing the catalyst loading to 5 mol% in di-
oxane (entry 10).
ArBr or ArH
r.t.
HO
HO
O
Li
B
O
HO
– 3 i-PrOH
O
Ar
2
2a (82%), 2b (88%), 2c (99%)
2d (99%), 2e (96%), 2f (60%)
Scheme 2 Synthesis of cyclic triolborates
A combination of [Rh(nbd)2]BF4 and BINAP was found
to be the best catalyst for 2-cyclohexenone among the rep-
resentative chiral rhodium(I) complexes (entries 11–15).
Rhodium-cod complexes such as [Rh(cod)2]BF4 and
[Rh(OH)(cod)]2 (entry 11 and 13) resulted in lower enantio-
selectivities than those of coe and nbd complexes due to
slow exchange of the cod ligand with chiral BINAP.
CHIRAPHOS and Me-BIPAM were less efficient than
BINAP (entries 14 and 15).
Table 1 1,4-Addition of p-Tolyl(triol)borate
O
O
2g
[Rh(nbd)2]BF4 (3 mol%)
(S)-BINAP (3.3 mol%)
50 °C
Me
ee (%)
97
Solvent/base
Yield (%)
Lithium 6-methoxy-3-pyridylborate (2c) underwent 1,4-
addition to five-, six-, and seven-membered enones in
good yields and with high enantiomeric excess under op-
timized conditions shown in Table 2 (Table 3, entries 1–
3). The conditions also worked well for acyclic ketone and
ester substrates (3d and 3e, entries 4 and 5), whereas all
attempts at increasing the yield of unsaturated amide (3f)
were unsuccessful (entry 6).
dioxane
68
87
96
dioxane–H2O (10:1)
dioxane–H2O (10:1), Et3N
98
98
(10:1) or dried dioxane in the presence of [Rh(nbd)2]BF4
(3 mol%), (S)-BINAP (3.3 mol%), and triethylamine (1
equiv). 2-Methoxypyridine resulting from hydrolytic B–C
bond cleavage was a major product for all boron deriva-
tives when aqueous dioxane was used as the solvent (en-
tries 1, 3, 5, and 7). No desired product was obtained by
Among them, 3e and 3f resulted in ca. 10% lower selec-
tivities than those reported in 1,4-addition of arylboronic
acids to these substrates with a Rh(I)/(S)-BINAP cata-
lyst.16 Addition of unsubstituted 2-pyridylborate 2a failed
Synlett 2009, No. 6, 994–998 © Thieme Stuttgart · New York

996
X.-Q. Yu et al.
LETTER
Table 2 Reaction Conditionsa
O
O
MeO
BX
N
2c, 4, 6
[Rh(nbd)2] BF4/(S)-BINAP
95 °C, 16 h
N
OMe
1b
3a
O
4: BX = B(OH) ,
, 6: BX = BF3K
5: BX =
B
2
O
Entry
1
ArBX
4
Catalyst
Solvent additive
dioxane–H2O, Et3N
dioxane, Et3N
dioxane–H2O, Et3N
dioxane, Et3N
dioxane–H2O, Et3N
dioxane, Et3N
dioxane–H2O, Et3N
dioxane, Et3N
dioxane
Yield (%)b
ee (%)c
–
[Rh(nbd)2]BF4/BINAP
[Rh(nbd)2]BF4/BINAP
[Rh(nbd)2]BF4/BINAP
[Rh(nbd)2]BF4/BINAP
[Rh(nbd)2]BF4/BINAP
[Rh(nbd)2]BF4/BINAP
[Rh(nbd)2]BF4/BINAP
[Rh(nbd)2]BF4/BINAP
[Rh(nbd)2]BF4/BINAP
[Rh(nbd)2]BF4/BINAPd
[Rh(cod)2]BF4/BINAP
[RhCl(coe)2]2/BINAP
[Rh(OH)(cod)]2/BINAP
0
trace
0
2
4
–
3
5
–
4
5
trace
5
–
5
6
–
6
6
13
10
83
80
94
46
33
95
91
63
91
–
7
2c
2c
2c
2c
2c
2c
2c
2c
2c
8
97
97
97
55
73
91
94
67
9
10
11
12
13
14
15
dioxane
dioxane
dioxane
dioxane
[Rh(nbd)2]BF4/CHIRAPHOS
[Rh(nbd)2]BF4/Me-BIPAM
dioxane
dioxane
a A mixture of 2-cyclohexenone (0.5 mmol), boron compound 4–6, 2c (1 mmol), and Et3N (if used, 0.5 mmol) in dioxane or dioxane–H2O (10:1)
was stirred in the presence of rhodium(I) complex (3 mol%) and chiral ligand (3.3 mol%).
b Isolated yields by chromatography.
c The ee was determined by chiral stationary columns.
d Rh catalyst (5 mol%) was used.
(entry 7), but an electron-rich 6-methoxy derivative 2b ee. However, the corresponding reaction of a 2-thienyl an-
gave a 1,4-addition product 3h in 56% yield and 55% ee alogue failed to give a 1,4-addition product (entry 4). This
(entry 8). Thus, the presence of a donating methoxy group effect of heteroatoms might be due to the higher sensitiv-
was effective for increasing the reaction rate by accelerat- ity of 2-thienylborate 2f with water than 3-thienyl deriva-
ing the insertion of the enone into the C–Rh bond. The tive 2d and lower nucleophilicity of the 2-position in the
presence of a substituent at the position adjacent to the ni- thienyl ring rather than that of the 3-position.
trogen will also work to block coordination to the catalyst.
The enantioselectivity was very low when a BINAP or
Indeed, the reaction proceeded smoothly when electron-
rich 5-methoxy-2-thienylborate 2e was used for cyclic
and acyclic substrates (entries 5 and 6).
CHIRAPHOS catalyst was used (ca. 60% ee), but 93% ee
was finally achieved when (R)-Me-BIPAM13 was used as
In conclusion, we have demonstrated the efficiency of
the chiral auxiliary in the presence of 20 mol% of pow-
lithium triolborates for the first 1,4-addition of 2-pyridyl
dered KOH (entry 9). Me-BIPAM was also good for an
and 2-thienyl groups to a,b-unsaturated carbonyl com-
acyclic substrate, 63% yield and 81% ee being achieved
pounds. Triolborates showed several advantages over
(entry 10).
their boronic acids or related quaternary metal trifluoro-
Thienylation of cyclic and acyclic enones with 3-thienyl-
borates: 1) high nucleophilicity of aryl rings attached to
borate 2f proceeded without any difficulties in the pres-
the boron atom for smooth transmetalation to metal cata-
lysts and 2) high solubility in organic solvents, allowing
ence of a rhodium/(S)-BINAP catalyst (Table 4, entries 1–
3). The enantioselectivities were in the range of 84–95%
the use of water-free solvents for preventing hydrolytic
Synlett 2009, No. 6, 994–998 © Thieme Stuttgart · New York

LETTER
Asymmetric 1,4-Addition of Heteroarylborates
997
Table 3 1,4-Addition of Cyclic Pyridylboratesa
Table 4 1,4-Addition of Cyclic Thienylboratesa
Entry 1
2
Product 3
Yield ee
Entry 1
2
Product 3
Yield ee
(%)b (%)c
(%)b (%)c
O
O
1
2
1a 2f
1b 2f
3j
90
90
88
90
S
N
1
2
1a 2c
1b 2c
3a
96
92
97
92
OMe
O
O
N
3k
3b
S
OMe
O
S
3
4
5
1d 2f
3l
93
84
–
3
4
1c
2c
3c
9,
93
91
N
O
OMe
O
OMe
N
1b 2d 3m
trace
63
1d 2c
3d
97
S
S
O
O
1b 2e
3n
3o
90
OMe
OMe
O
N
5
1e
1f
2c
2c
3e
3f
83
23
82
76
MeO
O
6
1d 2e
63
88
S
O
OMe
N
a A mixture of carbonyl compound 1 (0.5 mmol) and boron compound
2 (1 mmol) in dioxane was stirred in the presence of [Rh(nbd)2]BF4
(3.0 mol%) and (S)-BINAP (3.3 mol%).
6
7
O
b Isolated yields by chromatography.
N
H
c The ee values were determined on chiral stationary columns.
O
O
O
B–C bond cleavage. Since enantiomerically enriched
compounds substituted with a heteroaryl ring at the ste-
reogenic carbon center are expected to be versatile syn-
thetic intermediates of biologically active compounds,
further investigations into the applications of these cyclic
triolborates are under way.
N
1b 2a 3g
0
–
OMe
OMe
8d 1b 2b 3h
56
67
55
93
N
N
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
9e 1b 2b 3h
Acknowledgment
MeO
10e 1d 2b 3i
63
81
This work was supported by a Grand-in-Aid for Science Research
on Priority Areas (No. 18064001, Synergy of Elements), and the
global COE program (No. B01, Catalysis as the Basis for the Inno-
vation in Materials Science) from the Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan.
N
O
a A mixture of carbonyl compound 1 (0.5 mmol) and boron compound
2 (1 mmol) in dioxane was stirred in the presence of [Rh(nbd)2]BF4
(3.0 mol%) and (S)-BINAP (3.3 mol%).
References and Notes
b Isolated yields by chromatography.
c The ee was determined by chiral stationary columns.
d KOH (powder, 0.1 mmol) was used.
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Synlett 2009, No. 6, 994–998 © Thieme Stuttgart · New York

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LETTER
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