Stereospecific Suzuki-Miyaura coupling of chiral α-(Acylamino) benzylboronic esters with inversion of configuration

Article abstract of DOI:10.1021/ja106632j

The first invertive B-alkyl Suzuki-Miyaura coupling has been achieved. The coupling of enantioenriched α-(acylamino)benzylboronic esters with aryl bromides and chlorides took place efficiently in toluene at 80 °C in the presence of Pd(dba)₂ (5 mol %), XPhos (10 mol %), K ₂CO₃ (3 equiv), and H₂O (2 equiv). The reaction proceeded with inversion of configuration to give diarylmethanamine derivatives in high yields with high conservation of enantiomeric excesses.

Full text of DOI:10.1021/ja106632j

Published on Web 09/07/2010
Stereospecific Suzuki-Miyaura Coupling of Chiral
r-(Acylamino)benzylboronic Esters with Inversion of Configuration
Toshimichi Ohmura,* Tomotsugu Awano, and Michinori Suginome*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Katsura, Kyoto 615-8510, Japan
Received July 26, 2010; E-mail: ohmura@sbchem.kyoto-u.ac.jp; suginome@sbchem.kyoto-u.ac.jp
Table 1. Effects of Ligands and Basesa
Abstract: The first invertive B-alkyl Suzuki-Miyaura coupling has
been achieved. The coupling of enantioenriched R-(acylami-
no)benzylboronic esters with aryl bromides and chlorides took
place efficiently in toluene at 80 °C in the presence of Pd(dba)2
(5 mol %), XPhos (10 mol %), K2CO3 (3 equiv), and H2O (2 equiv).
The reaction proceeded with inversion of configuration to give
diarylmethanamine derivatives in high yields with high conserva-
base: KF
% yieldb
base: K2CO3
tion of enantiomeric excesses.
entry
ligand
time (h)
% esc
time (h)
% yieldb
% esc
1
2
3
4
5
P(t-Bu)3
Q-phos
SPhos
RuPhos
XPhos
18
60
18
18
48
78 (8)
85 (8)
34 (44)
88 (9)
73 (27)
19
19
35
6
3
3
3
3
18
28 (38)
83 (4)
75 (17)
46 (45)
95 (<1)
21
47
35
8
The Suzuki-Miyaura coupling utilizing alkylboron compounds
has become a powerful tool in organic synthesis.1 Cross-coupling
of deuterated, configurationally defined primary alkyl-9-BBN
derivatives with alkenyl and aryl iodides proceeds with complete
retention of configuration.2 Retention of configuration was also
established in the coupling of diastereomerically pure cyclopropy-
lboron compounds with organic halides and triflates.3 Quite recently,
Crudden and co-workers demonstrated the first stereospecific cross-
coupling of acyclic secondary alkylboron compounds, in which
enantioenriched 1-arylethylboronic esters produced the coupling
product with retention of configuration.4 There seems to be great
potential in the development of the stereospecific coupling of
R-branched alkylboron compounds not only for greater utilization
of cross-coupling in asymmetric synthesis but also for clarifying
the mechanism of the coupling reaction.5
28
59
a 1 (0.10 mmol), 2a (0.12 mmol), Pd(dba)2 (5.0 µmol), ligand (10
µmol), base (0.30 mmol), and H2O (0.20 mmol) were stirred in toluene
(0.2 mL) at 110 °C. b Isolated yield of 3. GC yield of 4 in parentheses.
c See ref 10.
Table 2. Effects of Acyl Groupsa
We have recently developed the Suzuki-Miyaura coupling of
R-(acetylamino)benzylboronic esters with aryl and alkenyl halides.6
Because the reaction is expected to be a useful method for synthesis
of enantioenriched benzylamines, our interest was then focused on
the establishment of a stereospecific coupling system using enan-
tioenriched organoboron reagents. Herein, we describe the highly
stereospecific cross-coupling of enantioenriched R-(acylamino)ben-
zylboronic esters, which proceeds with inVersion of configuration.
Reaction of enantioenriched R-(acetylamino)benzylboronic ester
17 with 4-bromotoluene (2a, 1.2 equiv) was carried out in toluene
at 110 °C in the presence of Pd(dba)2 (5 mol %), ligand (10 mol
%), base (3 equiv), and H2O (2 equiv) (Table 1).8,9 The yield of
coupling product 3 and enantiospecificity (es)10 of the reaction
strongly depended on the ligands and bases. For example, a Pd/
P(t-Bu)3 catalyst gave 3 in good yield using KF as a base, whereas
a significant amount of protodeborylation product 4 was formed
with K2CO3 (entry 1). The es values were low under both conditions
(19 and 21% es, entry 1). Among several other combinations of
ligands (Q-phos,5c SPhos,11 RuPhos,12 and XPhos13) and bases (KF
and K2CO3) (entries 2-5), use of XPhos and K2CO3 gave the best
yield along with the highest es (59%) (entry 5, right).
entry
substrate
temp (°C)
% yieldb
% eec % esd config
1
2
3
4
1 (R ) Me, 87% ee)
5 (R ) Et, 95% ee)
7 (R ) Ph, 87% ee)
9a (R ) t-Bu, 96% ee)
110
110
110
110
80
95 (3)
85 (6)
65 (8)
51
65
77
59
68
89
inV
inV
inV
80 (10a) 92.7 96.5 inV
84 (10a) 93.4 97.3 inV
5e 9a (R ) t-Bu, 96% ee)
a Organoboronic ester (0.10 mmol), 2a (0.12 mmol), Pd(dba)2 (5.0
µmol), XPhos (10 µmol), K2CO3 (0.30 mmol), and H2O (0.20 mmol)
were stirred in toluene (0.2 mL) at 80-110 °C for 12-18 h. b Isolated
yield. c Determined by HPLC with a chiral stationary phase column.
d See ref 10. e 0.20 mmol scale reaction.
derivatives gave the coupling products 6 and 8 with higher es’s
than the reaction of the acetyl derivatives 1 (entries 2 and 3). We
finally found that a highly stereospecific coupling could be achieved
using boronic ester 9a bearing a sterically more demanding pivaloyl
group (96.5% es, entry 4). The optimized conditions using XPhos
Further improvement of the es was achieved by modification of
the acyl group on the nitrogen atom of the starting boron compounds
(Table 2). Reactions of 2a with propionyl (5) and benzoyl (7)
9
10.1021/ja106632j  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 13191–13193 13191

C O M M U N I C A T I O N S
Table 3. Suzuki-Miyaura Coupling of Enantioenriched 9 with 2a
(S)-9
(% ee)
time
(h)
entry
Ar2Br
% yieldb
% eec % esd
A mechanism involving transmetalation via transition state TS1
is proposed as the rationale for the stereochemical outcome (path
a, Scheme 1).18,19 We assume that backside attack of the palladium
complex on the benzylic carbon atom of R-(acylamino)benzylbo-
ronic ester is preferred because of strong intramolecular coordination
of the carbonyl group to boron,20 which prevents an approach from
the boron side by occupation of the vacant p-orbital of boron.
Competitive transmetalation via conventional transition state TS2,
which would lead to a stereoretentive transformation (path b), may
lower the es as observed in some of the reactions.21
1
2
3
4
5
6
7
8
9
9a (96) 2b (Ar2 ) 4-MeOC6H4) 12 76 [(S)-10b] 93
9a (96) 2c (Ar2 ) 4-EtO2CC6H4) 12 87 [(S)-10c] 93
97
97
96
96
98
97
96
95
96
92
98
95
82
9a (96) 2d (Ar2 ) 4-CF3C6H4)
9a (96) 2e (Ar2 ) 4-AcC6H4)
12 85 [(S)-10d] 92
12 71 [(S)-10e] 92
9a (96) 2f (Ar2 ) 4-CHOC6H4) 12 84 [(S)-10f] 94
9a (96) 2g (Ar2 ) 3-MeC6H4)
9a (96) 2h (Ar2 ) 2-naphthyl)
9a (96) 2i (Ar2 ) 2-MeC6H4)
9a (96) 2j (Ar2 ) 3-thienyl)
12 89 [(S)-10g] 93
12 76 [(S)-10h] 92
18 79 [(S)-10i]
12 80 [(S)-10j] 92
72 83 [(S)-10k] 88
12 79 [(R)-10b] 98
12 68 [(R)-10h] 95
18 55 [(R)-10i] 74
91
10e 9a (96) 2k (Ar2 ) 3-pyridyl)
11 9b (>99) 2l (Ar2 ) Ph)
12 9c (>99) 2l
Scheme 1. Possible Mechanism
13 9d (90) 2l
a 9 (0.20 mmol), 2 (0.24 mmol), Pd(dba)2 (10 µmol), XPhos (20
µmol), K2CO3 (0.60 mmol), and H2O (0.40 mmol) were stirred in
toluene (0.4 mL) at 80 °C. b Isolated yield. c Determined by HPLC with
a chiral stationary phase column. d See ref 10. e 9a (0.30 mmol) and 2k
(0.20 mmol) were used.
and K2CO3 were effective for the reaction of 9a even at 80 °C to
give 10a in 84% yield with 97.3% es (entry 5).14,15
Absolute configurations of the major enantiomers of 3, 6, 8, and
10a were determined to be S by comparison with the specific
rotation of the authentic samples, which were prepared by N-
acylation of (S)-phenyl(p-tolyl)methanamine.16 The stereochemical
assignment clearly indicated that the C-C bond formation took
place with inversion of configuration. The stereochemical course
was also confirmed by our independent determination of the
absolute configurations of the starting material and the product by
X-ray crystallographic analysis.16
Various aryl bromides were subjected to Suzuki-Miyaura
coupling with 9a under the optimized conditions (entries 1-10,
Table 3). The reactions of electron-rich 2b and electron-deficient
2c-f took place efficiently to give the corresponding amides
10b-f in high yields (entries 1-5). The es’s of the reactions
were 98-96%, indicating that the electronic nature of the aryl
bromides does not affect the stereospecificity. Sterically more
demanding 2g-i also reacted with high es’s (entries 6-8).
3-Bromothiophene (2j) reacted efficiently with a high es (entry
9), whereas a slow reaction with a slightly lower es was observed
in the reaction of 3-bromopyridine (2k) (entry 10). Enantioen-
riched 9b and 9c also reacted with bromobenzene (2l) with high
es’s to give 10b and 10h in good yields, respectively (entries
11 and 12). However, inefficient coupling was observed in the
reaction of sterically demanding 9d, which gave 10i in moderate
yield with a lower es (entry 13). It should be noted that 10i
could be obtained from the coupling of 9a with 2i with a better
es (entry 8).
ArylchloridescouldalsobeusedfortheinvertiveSuzuki-Miyaura
coupling under the optimized conditions (eq 1). 4-Chlorotoluene
(11a) and 4-chlorobenzaldehyde (11b) reacted smoothly with
9a at 80 °C to give amides 10a and 10f, respectively, in high
yields with remarkably high es’s. The 1:1 coupling of 9a with
1,4-dichlorobenzene (11c, 1.2 equiv) was also successfully
achieved. The absolute configuration of 10l was assigned to be
S,17 indicating again that the coupling proceeded with inversion
of configuration.
In conclusion, we reported the first highly stereospecific
Suzuki-Miyaura coupling of acyclic R-heteroatom substituted
benzylboron compounds. The stereochemical course of the reaction,
inversion of configuration, is particularly notable.22 Mechanistic
details are now under investigation in our laboratory.
Acknowledgment. The authors thank Dr. Yuuya Nagata for
helping X-ray crystallographic analysis. T.A. acknowledges JSPS
for fellowship support.
Supporting Information Available: Experimental details and
characterization data of the products. This material is available free of
charge via Internet at http://pubs.acs.org.
References
(1) (a) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2001, 40, 4544. (b) Doucet, H. Eur. J. Org. Chem. 2008, 2013. (c) Crudden,
C. M.; Glasspoole, B. W.; Lata, C. J. Chem. Commun. 2009, 6704.
(2) (a) Ridgway, B. H.; Woerpel, K. A. J. Org. Chem. 1998, 63, 458. (b) Matos,
K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461.
(3) (a) Hildebrand, J. P.; Marsden, S. P. Synlett 1996, 893. (b) Wang, X.-Z.;
Deng, M.-Z. J. Chem. Soc., Perkin Trans. 1 1996, 2663. (c) Charette, A. B.;
De Freitas-Gil, R. P. Tetrahedron Lett. 1997, 38, 2809. (d) Rubina, M.;
Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2003, 125, 7198. (e) Fang,
G.-H.; Yan, Z.-J.; Deng, M.-Z. Org. Lett. 2004, 6, 357. (f) Charette, A. B.;
Mathieu, S.; Fournier, J.-F. Synlett 2005, 1779.
(4) Imao, D.; Glasspoole, B. W.; Laberge, V. S.; Crudden, C. M. J. Am. Chem.
Soc. 2009, 131, 5024.
(5) Suzuki-Miyaura coupling of sec-alkylboron compounds other than cy-
clopropylboron compounds: (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.;
9
13192 J. AM. CHEM. SOC. VOL. 132, NO. 38, 2010

C O M M U N I C A T I O N S
Ishikawa, M.; Satoh, M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314.
(b) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.
(c) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem.
2002, 67, 5553. (d) van den Hoogenband, A.; Lange, J. H. M.; Terpstra,
J. W.; Koch, M.; Visser, G. M.; Visser, M.; Korstanje, T. J.; Jastrzebski,
J. T. B. H. Tetrahedron Lett. 2008, 49, 4122. (e) Dreher, S. D.; Dormer,
P. G.; Sandrock, D. L.; Molander, G. A. J. Am. Chem. Soc. 2008, 130,
9257.
(10) The term enantiospecificity [% es ) (product ee/starting material ee) ×
100] has been used to describe the conservation of optical purity over the
course of stereospecific reactions: (a) Denmark, S. E.; Vogler, T.
Chem.sEur. J. 2009, 15, 11737. (b) Denmark, S. E.; Burk, M. T.; Hoover,
A. J. J. Am. Chem. Soc. 2010, 132, 1232. (c) Roggen, M.; Carreira, E. M.
J. Am. Chem. Soc. 2010, 132, 11917.
(11) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2004, 43, 1871.
(12) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028.
(13) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(14) Larger scale reaction of 9a (317 mg, 1.0 mmol) with 2a (205 mg, 1.2 mmol)
was also successfully achieved under the optimized conditions to give 10a
in 80% yield (225 mg) with 97% es.
(6) Ohmura, T.; Awano, T.; Suginome, M. Chem. Lett. 2009, 38, 664.
(7) Enantioenriched 1, 5, 7, 9a, and 9d were prepared in 10 mmol scale via
Matteson’s asymmetric homologation starting from (-)-pinanediol deriva-
tive 12 as shown in the scheme below. (a) Matteson, D. S. In Boronic
Acids; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2005; p 305. (b) Caselli,
E.; Danieli, C.; Morandi, S.; Bonfiglio, B.; Forni, A.; Prati, F. Org. Lett.
2003, 5, 4863. (c) Morandi, S.; Caselli, E.; Forni, A.; Bucciarelli, M.; Torre,
G.; Prati, F. Tetrahedron: Asymmetry 2005, 16, 2918. Enantioenriched 9b-
c were obtained by optical resolution of the corresponding racemates.
(15) Water (2 equiv) was used in all reactions according to our previous study
(ref 6), in which addition of water was crucial in gaining coupling product
in high yields. We eventually found that water had no critical effect on the
yield or es in the present coupling system.
(16) For details, see Supporting Information.
(17) Absolute configuration of 10l was determined by comparison of specific
rotation of the authentic sample that was prepared by N-acylation of (S)-
(Ph)(4-ClC6H4)CHNH2. For details, see Supporting Information.
(18) The mechanism has been proposed for coupling of chiral benzylic stannanes
and silanes, which proceed with full or partial inversion of configuration. (a)
Labadie, J. W.; Stille, J. K. J. Am. Chem. Soc. 1983, 105, 6129. (b)
Hatanaka, Y.; Hiyama, T. J. Am. Chem. Soc. 1990, 112, 7793. (c) Kells,
K. W.; Chong, J. M. J. Am. Chem. Soc. 2004, 126, 15666. For related
reviews, see: (d) Espinet, P.; Echavarren, A. M. Angew. Chem., Int. Ed.
2004, 43, 4704. (e) Malinakova, H. C. Chem.sEur. J. 2004, 10, 2636. (f)
Wendt, O. F. Curr. Org. Chem. 2007, 11, 1417.
(19) Conversion of the C-B bond in trialkylboranes with inversion of configuration: (a)
Bergbreiter, D. E.; Rainville, D. P. J. Organomet. Chem. 1976, 121, 19. (b)
Kabalka, G. W.; Gooch, E. E., III. J. Org. Chem. 1980, 45, 3578.
(20) 11B NMR chemical shifts of R-(acylamino)benzylboronic esters (δ 14-16
ppm) indicate intramolecular coordination of the carbonyl groups to the
boron atoms. Biedrzycki, M.; Scouten, W. H.; Biedrzycka, Z. J. Organomet.
Chem. 1992, 431, 255.
(21) Racemization of R-(acylamino)benzylboronic esters under the coupling
conditions is another possible factor in the lowering of the es. The
racemization took place slowly with base even in the absence of the
palladium catalyst, and the rate was decreased in the order 1 > 5 > 9a. Es
values after treatment with K2CO3 (1 equiv) in toluene at 110 °C for 6 h
were as follows: 1 (86% es), 5 (94% es), and 9a (96% es). On the other
hand, we confirmed that no racemization of the coupling products,
diarylmethanamines, took place under the coupling conditions reported.
(22) Inversion of configuration at the oxidative addition step has been reported
in the Suzuki-Miyaura coupling of chiral alkyl triflates with aryl boronic
acids. He, A.; Falck, J. R. J. Am. Chem. Soc. 2010, 132, 2524.
(8) Initial attempts applying the conditions established previously (in 1,4-
dioxane at 110 °C in the presence of Pd/P(t-Bu)3 catalyst, H2O, and KF)
gave poor results: reaction of 1 with 2a gave 3 in 55% yield with only 6%
es.
(9) Preliminary screening indicated that protodeborylation of 1 was slower in
toluene than in 1,4-dioxane.
JA106632J
9
J. AM. CHEM. SOC. VOL. 132, NO. 38, 2010 13193