Application of dicyclohexyl-(S)-trimethoxyphenyl phosphine·HBF 4 salt for the highly selective suzuki coupling of the C-Cl bond in β-chlorobutenolides over the more reactive allylic C-O bond

Article abstract of DOI:10.1002/chem.201000169

[Chemical equation presented] Selective coupling: A readily available monophosphine HBF₄ salt, I·HBF₄, was applied to the highly selective coupling of the inert C-Cl bond in optically active β-chlorobutenolides in preference to the more reactive lactonic, allylic C-O bond in the presence of Pd(OAc)₂ as the catalyst.

Full text of DOI:10.1002/chem.201000169

DOI: 10.1002/chem.201000169
Application of Dicyclohexyl-(S)-trimethoxyphenyl Phosphine·HBF4 Salt
À
for the Highly Selective Suzuki Coupling of the C Cl Bond in
À
b-Chlorobutenolides Over the More Reactive Allylic C O Bond
Bo Lꢀ, Chunling Fu, and Shengming Ma*[a]
In memory of Professor Xian Huang
À
À
The reactions of C Cl bonds are currently of interest due
to the cheap, readily available nature of organic chlorides
and the atom economy caused by the low atomic weight of
tonic, allylic C O bond, it is a challenge to couple the rela-
À
tively inert C Cl bond exclusively with the organic boronic
À
acid (4) over the more reactive allylic C O bond also pres-
ent [Eq. (1)].[5] In this paper, we wish to report the applica-
À
the chlorine atom compared with reactions involving C Br
and C I bonds. Much attention has been paid to research
[1]
À
tion of a new ligand 5, prepared in this group, to this reac-
tion (Scheme 1); the C Cl bond is efficiently cleaved in the
presence of Pd, while the more reactive allylic C O bond
remains unchanged.
in this area.[2] It has been well established that electron-rich,
sterically bulky phosphines may serve nicely as ligands in
the Suzuki coupling reactions of organic chlorides. Some of
the most notable ligands (including compounds 1–3; Cy=cy-
clohexyl) in this area are shown here.[3]
À
À
In 2001, we developed an efficient method to synthesize
optically active b-chlorobutenolides from 2,3-allenoic acid–
chiral base salts using CuCl2 as the halogen source.[4] In this
type of compound, due to the presence of the reactive lac-
Scheme 1. Rationale for a new ligand.
[a] B. Lꢀ, Prof. Dr. C. Fu, Prof. Dr. S. Ma
Laboratory of Molecular Recognition and Synthesis
Department of Chemistry, Zhejiang University
Hangzhou 310027 (P. R. China)
Fax : (+86)21-6416-7510
E-mail: masm@sioc.ac.cn
We began by screening reaction conditions using the com-
mercially available and well established ligands PCy3 (1), by
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000169.
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COMMUNICATION
Table 1. Pd
N
Table 2. Pd
PhB(OH)2 to form (R)-(À)-7aa.
A
(R)-(À)-6a with PhB(OH)2 to form (R)-(À)-7aa.
Entry
Ligand
Base
Solvent
Yield
[%]
ee
[%]
Recovery of
6a [%]
Entry
PhB(OH)2
[equiv]
5·HBF4
[%]
Base
[equiv]
t
Yield
[%]
32[a]
65[c]
81
ee
[%]
G
E
A
[a]
[a]
1
2
3
4
5
6
7
8
9
1·HBF4
1·HBF4
1·HBF4
1·HBF4
1·HBF4
1·HBF4
2
K2CO3
K2CO3
K3PO4
Et3N
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Et3N
DMF
trace
38
38
5
68
67
5
18
69
6
17
40
–
42
16
44
88
0
–
–
66
–
92
–
32
25
64
29
9
1
2
1.5
1.5
2.0
2.0
2.0
2.0
1.5
1.5
1.5
5
5
6
10
10
5
5
10
5
K3PO4 (3.5)
K3PO3 (3.5)[b]
K2CO3 (3.5)
K2CO3 (3.5)
K2CO3 (4.5)
K2CO3 (4.5)
K2CO3 (3.5)
K2CO3 (4.5)
K2CO3 (4.5)
5
5
74
60
0
35
88
94
90
85
98
dioxane
toluene
toluene
toluene
toluene
DMF
dioxane
toluene
toluene
toluene
toluene
3[d]
4
30
30
5
100
86
83
[b]
5
6
7
8
[b,c]
5
5
5
5
77[e]
65[f]
75
6
2
2
26
10
86
84
11
9
10
11
12
2
[a] 36% of 6a was recovered. [b] 1.0 equiv of H2O was added. [c] 13% of
6a was recovered. [d] 3 mol% of Pd(OAc)2 was added. [e] 22% of 6a
was recovered. [f] 15% of 6a was recovered.
2[b]
K2CO3
K2CO3
AHCTUNGTRENNUNG
2[b,c]
–
[d]
[a] Reaction time 30 min. [b] 10 mol% of this ligand was used. [c] Re-
action time: 60 min. [d] Low ee. The exact ee value is not available since
the purity was only 83%.
the product in a higher yield but with lower ee (entry 2,
Table 2). Further study led to the observation that by per-
forming the reaction in toluene using 3.5 equivalents of
K2CO3 as the base affords the product (R)-(À)-7aa in 100%
yield, but only 35% ee (entry 4, Table 2). We reasoned that
increasing the loading of K2CO3 might speed up the trans-
metallation process and ensure a faster coupling reaction.[9]
Thus, through further screening, we were able to find a
transformation without racemization that gives (R)-(À)-7aa
in 75% yield and 98% ee by using 1.5 equivalents of
PhB(OH)2 and 5 mol% 5·HBF4 (entry 9, Table 2). As a
Shen et al.[3a] and Fu et al.,[3b,c] and SPhos (2), by Buchwald
et al.[3e] (Table 1). As shown in Table 1, a slow reaction with
considerable racemization is the major challenge we needed
to tackle. By comparing the results of using PCy3 as the
ligand with those of SPhos (entries 3 and 9, Table 1) we con-
cluded that the presence of a methoxy group in SPhos may
À
promote the C Cl coupling reaction through a faster reduc-
tive elimination reaction and retard the oxidative addition
À
of Pd to the allylic C O bond due to the increased steric
hindrance in II compared with I (see Scheme 1).[6] Thus, we
reasoned that removing the phenyl group connecting the
phosphorous atom with the 2,6-dimethoxyphenyl group in II
may create a much better ligand for this transformation due
to the further increase in steric hindrance caused by the
more favorable formation of a five-membered ring coordi-
nation complex in III as compared with the seven-mem-
bered ring coordination in II.[6]
comparison, it should be noted that, if the reaction is per-
[3a–c]
formed with PCy3·HBF4
or SPhos[3e] as the ligand under
the same reaction conditions (entries 6 and 12, Table 1), the
essentially racemized product 7aa is produced with some
(R)-(À)-6a remaining.
Encouraged by these results, we investigated the scope of
this highly selective coupling reaction of optically active b-
chlorobutenolides for our newly developed Suzuki coupling
À
Based on this notion, and in order to use the cheaper S-
trimethoxybenzene as the starting material for the synthesis,
ligand 5 was designed and prepared.[7] Compound 5 was
formed by the lithiation of S-trimethoxybenzene to generate
2,4,6-trimethoxyphenyl lithium, which was then treated with
Cy2PCl, generated in situ from the reaction of cyclohexyl
magnesium chloride with PCl3, to afford dicyclohexyl(2,4,6-
trimethoxyphenyl)phosphine (5). This compound was treat-
ed with aqueous HBF4, as previously reported by Fu et al.,[8]
to afford the air-stable solid salt 5·HBF4 for further study.
conditions (Table 3). In all the cases tried, the C Cl bond
Suzuki coupling reaction afforded the optically active b-sub-
À
stituted butenolides without touching the reactive, allylic C
O bond.
We also performed a control experiment to show that
treating the coupling product (S)-(+)-7aa (98% ee) with
SPhos (2) does not cause racemization; however, under the
standard conditions with 2 as the ligand, not only racemiza-
À
tion occurs, indicating that the allylic C O bond has been
easily cleaved in the presence of Pd and SPhos,[5] but also a
new, unidentified product is formed (Scheme 2).
Luckily, (R)-(À)-4-chloro-5-phenyl-3-propylfuran-2
ACHTUNGTNER(NUNG 5H)-
one, (R)-(À)-6a, did undergo the Pd
U
In conclusion, we have successfully applied the HBF4 salt
of dicyclohexyl(2,4,6-trimethoxyphenyl)phosphine to the
Suzuki coupling reaction with phenylboronic acid (4a) in
toluene, with K3PO4 as the base to give product (R)-7aa in
an improved ee (74%), albeit with low conversion (entry 1,
Table 2); the addition of one equivalent of water afforded
À
highly selective activation of the relatively inert C Cl bond
in b-chlorobutenolides over the more reactive lactonic, allyl-
À
ic C O bond, which may be explained by the electronic and
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www.chemeurj.org
6435

S. Ma et al.
Table 3. Suzuki coupling reactions of (S)-(À)-6 and 4 using 5 as the ligand.
À152.0 (c=0.95, CHCl3); m.p.: 103.8–
104.98C
(n-hexane);
1H NMR
(300 MHz, CDCl3): d=7.37–7.15 (m,
10H), 6.14 (s, 1H), 2.58–2.42 (m, 2H),
1.78–1.60 (m, 2H), 0.98 ppm (t, J=
7.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=174.1, 159.1, 134.9, 131.5,
129.5, 129.1, 128.7, 128.5, 127.8, 127.3,
83.7, 26.3, 21.5, 14.1 ppm; IR (KBr):
n˜ =3057, 3027, 2958, 2939, 2870, 1749,
1734, 1649, 1498, 1455, 1445, 1355,
1340, 1206, 1126, 1090, 1072,
1014 cmÀ1; MS (70 eV, EI): m/z (%):
279 (16.57) [M+1]+, 278 (77.10) [M]+,
173 (100); elemental analysis calcd
(%) for C19H18O2: C 81.99, H 6.52;
found: C 82.00, H 6.53.
Entry
R1
R2
R3
6
R4
4
t
Isolated
yield [%]
Product
ee
[%]
A
1
2
3
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
nC5H11
nC5H11
nC5H11
nC5H11
Ph
Me
Me
Me
Me
Me
Me
Me
Pr
(S)-(+)-6b
(S)-(+)-6b
(S)-(+)-6b
(R)-(+)-6c
(R)-(+)-6c
(R)-(+)-6c
(R)-(+)-6c
(R)-(À)-6a
(R)-(À)-6a
(R)-(À)-6a
H
4a
4b
4c
4a
4b
4c
4d
4d
4a
4a
6
6
5
83
100
72
81
93
81
84
90
75
(S)-(+)-7ba
(S)-(+)-7bb
(S)-(+)-7bc
(R)-(À)-7ca
(R)-(À)-7cb
(R)-(À)-7cc
(R)-(À)-7 cd
(R)-(À)-7ad
(R)-(À)-7aa
(R)-(À)-7aa
99
97
96
97
97
98
98
95
98
98
4-MeO
4-Me
H
4-MeO
4-Me
3-MeO
3-MeO
H
4
10
10
10
10
5
5[a]
6[a]
7[a]
8
9
Ph
Ph
Pr
Pr
5
8
10[b]
H
84
[a] 2.0 equivalents of PhB(OH)2 were used; with 1.5 equivalents of PhB(OH)2 and the reaction did not go to
completion. [b] The reaction was conducted with 0.98 mmol of (R)-(À)-6a.
Acknowledgements
Financial support from the National
Basic Research Program of China
(No. 2009CB825300) is greatly appre-
ciated. Shengming Ma is a Qiu Shi Adjunct Professor at Zhejiang Uni-
versity. We thank Mr. Guangke He for reproducing the results for the
formation of (S)-(+)-7bb in Table 3.
Keywords: chlorine
· palladium · selectivity · Suzuki
coupling reactions
[1] For reviews, see: a) J. Tsuji, T. Mandai, Angew. Chem. 1995, 107,
2830; Angew. Chem. Int. Ed. Engl. 1995, 34, 2589; b) V. V. Grushin,
H. Alper, Chem. Rev. 1994, 94, 1047.
Scheme 2. Reaction of (R)-(À)-7aa and speculation about its racemiza-
À
[2] For comprehensive reviews on Suzuki coupling reactions of C Cl
tion.
bonds with different ligands, see: a) A. F. Littke, G. C. Fu, Angew.
Chem. 2002, 114, 4350; Angew. Chem. Int. Ed. 2002, 41, 4176;
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Weng, S. Teo, T. S. A. Hor, Acc. Chem. Res. 2007, 40, 676; d) R.
Martin, S. L. Buchwald, Acc. Chem. Res. 2008, 41, 1461; e) H.
Doucet, Eur. J. Org. Chem. 2008, 2013.
steric effects shown in Scheme 1. The HBF4 salt of this
ligand is easy to prepare and air stable. Further studies in
this area of this ligand are being conducted in our laborato-
ry.
[3] a) W. Shen, Tetrahedron Lett. 1997, 38, 5575; b) J. H. Kirchhoff, C.
Dai, G. C. Fu, Angew. Chem. 2002, 114, 2025; Angew. Chem. Int. Ed.
2002, 41, 1945; c) N. Kudo, M. Perseghini, G. C. Fu, Angew. Chem.
2006, 118, 1304; Angew. Chem. Int. Ed. 2006, 45, 1282; d) A. F.
Littke, G. C. Fu, Angew. Chem. 1998, 110, 3586; Angew. Chem. Int.
Ed. 1998, 37, 3387; e) S. D. Walker, T. E. Barder, J. R. Martinelli,
S. L. Buchwald Angew. Chem. 2004, 116, 1907; Angew. Chem. Int. Ed.
2004, 43, 1871; f) X. Huang, K. W. Anderson, D. Zim, L. Jiang, A.
Klapars, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125, 6653; g) D. W.
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73, 7803.
Experimental Section
Typical procedure for the preparation of (R)-(À)-4,5-diphenyl-3-propyl-
furan-2
G
ACHTUGNTERN(NUNG OAc)2 (1.2 mg, 0.0054 mmol), 5·HBF4
(2.3 mg, 0.0051 mmol), K2CO3 (63.1 mg, 0.46 mmol), 4a (19.1 mg, 98%
purity, 0.15 mmol) and toluene (0.5 mL) were sequentially added to a
flame-dried, nitrogen filled Schlenk vessel. After being stirred for about
3 min at room temperature, (R)-(À)-6a (22.8 mg, 0.096 mmol, 97% ee)
and toluene (0.5 mL) were added. The resulting mixture was heated at
1108C, by using a preheated oil bath, for 6 min (until complete conversa-
tion, as monitored by TLC) and then quenched with water (10 mL), ex-
tracted with diethyl ether (2ꢂ10 mL), washed with brine (10 mL), and
dried over anhydrous Na2SO4. Filtration, evaporation, and purification by
column chromatography (petroleum ether/ethyl acetate=10:1) on silica
gel afforded (R)-(À)-7aa (20.1 mg, 75%) as a white solid in 98% ee, as
determined by HPLC (Chiralpak OD-H, n-hexane/iPrOH=65:35,
[4] S. Ma, S. Wu, Chem. Commun. 2001, 441.
[5] For reports on the Pd-catalyzed cleavage of such allylic C O bonds
À
in butenolides, see: a) B. M. Trost, F. D. Toste, J. Am. Chem. Soc.
1999, 121, 3543; b) B. M. Trost, F. D. Toste, J. Am. Chem. Soc. 2003,
125, 3090. c) B. M. Trost, M. L. Crawley, J. Am. Chem. Soc. 2002, 124,
9328; d) B. M. Trost, M. L. Crawley, Chem. Eur. J. 2004, 10, 2237.
0.8 mLminÀ1
, =
l=230 nm, tR =8.3 (major), 6.3 min (minor)). [a]D20
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b-Chlorobutenolides
COMMUNICATION
[6] For a discussion of the Pd–OMe interaction in of SPhos ligand for
the coupling reactions by Buchwald et al., see pp. 1464–1465 of
ref. [2d].
[7] China patent Application No. 200910154029.4 for synthesis of the
ligand and applications in simple Suzuki reactions of aryl or 1-alkenyl
chlorides; see: B. Lꢀ, C. Fu, S. Ma, Tetrahedron Lett. 2010, 51, 1284.
[8] M. R. Netherton, G. C. Fu, Org. Lett. 2001, 3, 4295.
[9] For a detailed discussion of the effect of bases for Suzuki couplings,
see: a) A. Suzuki, Pure Appl. Chem. 1985, 57, 1749; b) A. Suzuki,
Pure Appl. Chem. 1991, 63, 419; c) A. Suzuki, Pure Appl. Chem.
1994, 66, 213.
Received: January 21, 2010
Published online: May 5, 2010
Chem. Eur. J. 2010, 16, 6434 – 6437
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6437