Diastereoselective synthesis of arylglycine derivatives by cationic palladium(ll)-catalyzed addition of arylboronic acids to N-tert-butanesulfinyl imino esters

Article abstract of DOI:10.1021/ol0711220

A cationic palladium-complex-catalyzed addition of arylboronic acids to N-tert-butanesulfinyl iminoacetates to yield the optically active arylglycine derivatives with moderate to good yield and high diastereoselectivity was developed. This reaction provid

Full text of DOI:10.1021/ol0711220

ORGANIC
LETTERS
2007
Vol. 9, No. 16
3077-3080
Diastereoselective Synthesis of
Arylglycine Derivatives by Cationic
Palladium(II)-Catalyzed Addition of
Arylboronic Acids to
N-tert-Butanesulfinyl Imino Esters
Huixiong Dai and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai, Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
xylu@mail.sioc.ac.cn
Received May 15, 2007
ABSTRACT
A cationic palladium-complex-catalyzed addition of arylboronic acids to N-tert-butanesulfinyl iminoacetates to yield the optically active arylglycine
derivatives with moderate to good yield and high diastereoselectivity was developed. This reaction provides a convenient and efficient method
for the synthesis of arylglycine derivatives.
The insertion of carbon-carbon multiple bonds into carbon
transition-metal bonds is an important fundamental reaction
in organo transition-metal chemistry.1 However, direct inser-
tion of the carbon-heteroatom multiple bonds, such as
carbonyl, imino, and cyano groups, without using stoichio-
metric organometallic reagents, has received scant attention.2
Among the reactions of carbon-heteroatom multiple bonds,
the stereoselective addition of organometallic reagents to
imines attracts much attention from chemists because it
provides a powerful method to afford optically active amines
that are important in biological and pharmaceutical fields.3
However, difficulties arise in the addition of imines because
of the poor electrophilicity of the azomethine carbon and
the tendency of enolizable imines to undergo deprotonation.3a
Recently, some progress has been achieved, especially in
the catalytic arylation of imines. The most well-known
examples are the addition of arylboron reagents to imines
mediated by rhodium complexes.4 In palladium chemistry,
only examples of the allylation of imines have been reported.5
To the best of our knowledge, there is no report concerning
the addition of aryl groups to aldimines catalyzed by
palladium. The reason may be that the arylpalladium species
are more electrophilic6 and are commonly used in carbon-
carbon coupling reactions or in the reactions with alcohols
(1) (a) Yamamoto, A. Organotransition Metal Chemistry; John Wiley
& Sons: New York, 1986. (b) Collman, J. P.; Hegedus, L. S.; Norton, J.
R.; Finke, R. G. Principles and Applications of Organotransition Metal
Chemistry, 2nd ed.; University Science Books: Mill Valley, CA, 1987.
(2) (a) Tsuji, J. Palladium Reagents and CatalystssNew PerspectiVes
for th 21st Century; John Wiley & Sons: Chichester, 2004. (b) de Meijere,
A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; John
Wiley-VCH Verlag GmbH: Weinheim, 2004.
(3) (a) Bloch, R. Chem. ReV. 1998, 98, 1407. (b) Calderon, S. N.;
Rothman, R. B.; Porreca, F.; Flippen-Anderson, J. L.; McNutt, R. W.; Xu,
H.; Smith, L. E.; Bilsky, E. J.; Davis, P.; Rice, K. C. J. Med. Chem. 1994,
37, 2125.
10.1021/ol0711220 CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/03/2007

and amines.1 Thus, it is worth studying the nucleophilic
addition of the arylpalladium species to the carbon-
heteroatom multiple bonds especially that of aldimines.
As far as we know, the N-tert-butanesulfinyl group is an
excellent auxiliary that not only activates the CdN bond for
nucleophilic addition but also exerts a powerful enantio-
selective induction. In addition, the N-tert-butanesulfinyl
group is easily deprotected,3a,7 making the N-sulfinyl imine
a versatile intermediate8 in the asymmetric synthesis of chiral
amines. Herein we report the cationic palladium-complex-
catalyzed diastereoselective addition of arylboronic acids to
N-sulfinyl iminoacetates for the efficient asymmetric syn-
thesis of arylglycine derivatives.
reaction under our conditions. To improve the electrophilicity
and the reactivity of the imine, N-tert-butanesulfinyl imino
esters were chosen as our substrate. The addition of aryl-
boronic acids to imino esters under the catalysis of rhodium
has been reported to yield arylglycine derivatives.4i
We first investigated the reaction of ethyl ((RS)-N-tert-
butanesulfinyl) iminoacetate (6) (0.25 mmol) with phenyl-
boronic acid (2a) (0.50 mmol) in the presence of Pd(OAc)2
(5 mol %) and bpy (6 mol %) in dioxane (1 mL) at 60 °C;
the addition product was obtained in only 17% yield after
24 h (Table 1, entry 1). The low yield showed that a more
Our group has recently reported the Pd(II)-catalyzed
conjugate addition of arylboronic acid to R,â-unsaturated
carbonyl compounds9 and the addition of arylboronic acids
to nitriles.10 We found that the ligand 2,2′-bipyridine (bpy)
is crucial in these reactions. The presence of the bpy ligand
in these reactions may cause the arylpalladium species to
become more nucleophilic, making the above addition
reactions possible. It occurred to us that bpy may also be
useful in the addition reaction of arylboronic acids to imines
catalyzed by palladium(II) species.
Table 1. Optimization of Reaction Conditions for the Addition
of Phenylboronic Acid (2a) to Ethyl ((RS)-N-tert-Butanesulfinyl)
Iminoacetate (6)a
Initially, we investigated the reaction of (()-N-tert-
butanesulfinyl imine (1) (0.25 mmol) with phenylboronic
acid (2a) (0.50 mmol) in the presence of Pd(OAc)2 (5 mol
%) and bpy (20 mol %) in dioxane (1 mL) at 95 °C; no
addition product was formed. While the N-tosylbenzaldimine
4 was used as the substrate under the same conditions, the
reaction proceeded smoothly, yielding the addition product
5 in 53% yield after 2 days (Scheme 1).
entry
catalyst/L
yield (%)b
1
2
3
4
5
Pd(OAc)2/bpy
Pd(CF3CO2)2/bpy
cat A
cat B
none
17
51
NR
86
NR
a Reaction conditions: phenylboronic acid (2a, 0.5 mmol), ethyl ((RS)-
N-tert-butanesulfinyl) iminoacetate (6, 0.25 mmol), catalyst (5 mol %), L
(6 mol %) in dioxane (1 mL) at 60 °C for 24 h. b Isolated yields.
Scheme 1
reactive catalyst system is necessary for this reaction. As
compared with the neutral palladium species, such as
Pd(OAc)2, the cationic palladium(II) species has vacant
coordination sites and shows a harder metal property.11 Also,
in our group’s study on the addition of arylboronic acids to
nitriles,10a the cationic palladium catalyst was found to exhibit
higher activity than the neutral palladium species. It occurred
to us that the cationic palladium complexes may be useful
in catalyzing the addition of arylboronic acids to aldimines.
(6) (a) Tamaru, Y. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E.-i., Ed.; Wiley: New York, 2002; Vol. 2, pp
1917-1943 and references therein. (b) Miura, M.; Nomura, M. Top. Curr.
Chem. 2002, 219, 211. (c) Hassen, J.; Sevignon, M.; Gozzi, C.; Schulz, E.;
Lemaire, M. Chem. ReV. 2002, 102, 1359. (d) Culkin, D. A.; Hartwig, J. F.
Acc. Chem. Res. 2003, 36, 234. (e) Ueura, K.; Satoh, T.; Miura, M. Org.
Lett. 2005, 7, 2229. (f) Kamijo, S.; Sasaki, Y.; Kanazawa, C.; Schu¨sseler,
T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44, 7718.
(7) (a) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895.
(b) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. ReV. 1998, 27, 13.
(8) (a) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A.
J. Org. Chem. 1999, 64, 1278. (b) Davis, F. A.; McCoull, W. J. Org. Chem.
1999, 64, 3396. (c) Jayathilaka, L. P.; Deb, M.; Standaert, R. F. Org. Lett.
2004, 6, 3659.
(9) (a) Lu, X.; Lin, S. J. Org. Chem. 2005, 70, 9651. (b) Lin, S.; Lu, X.
Tetrahedron Lett. 2006, 47, 7167.
(10) (a) Zhao, B.; Lu, X. Org. Lett. 2006, 8, 5987. (b) Zhao, B.; Lu, X.
Tetrahedron Lett. 2006, 47, 6765.
(11) Mikami, K.; Hatano, M.; Akiyama, K. Top. Organomet. Chem. 2005,
14, 279 and references therein.
These results imply that the electrophilicity of N-tert-
butanesulfinyl imine 1 is not sufficient to promote the
(4) (a) Ueda, M.; Saito, A.; Miyaura, N. Synlett 2000, 1637. (b) Ueda,
M.; Miyaura, N. J. Organomet. Chem. 2000, 595, 31. (c) Kuriyama, M.;
Soeta, T.; Hao, X. Y.; Chen, O.; Tomioka, K. J. Am. Chem. Soc. 2004,
126, 8128. (d) Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.;
Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584. (e) Otomaru,
Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 307. (f)
Duan, H.-F.; Jia, Y.-X.; W, L.-X.; Zhou, Q.-L. Org. Lett. 2006, 8, 2567.
(g) Weix, D. J.; Shi, Y.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 1092.
(h) Bolshan, Y.; Batey, R. A. Org. Lett. 2005, 7, 1481. (i) Beenen, M. A.;
Weix, D. J.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 6304.
(5) (a) Nakamura, H.; Nakamura, K.; Yamamoto, Y. J. Am. Chem. Soc.
1998, 120, 4242. (b) Shimizu, M.; Kimura, M.; Watanabe, T.; Tamaru, Y.
Org. Lett. 2005, 7, 637. (c) Solin, N.; Wallner, O.; Szabo´, K. Org. Lett.
2005, 7, 689.
3078
Org. Lett., Vol. 9, No. 16, 2007

Then, we tried to use cationic Pd(CF3CO2)2/bpy as the
catalyst system. As expected, the yield increased to 53%
(Table 1, entry 2). However, when palladium diaquo catalyst
A was used as the catalyst, the imines disappeared after 3 h
at 60 °C but no addition product was formed (Table 1, entry
3). We next used the binuclear palladium µ-hydroxo catalyst
B instead of catalyst A; to our delight, the yield dramatically
increased to 86% with the diastereoselectivity of the arylation
product up to 95.5% de (Table 1, entry 4). No addition
product was obtained in the absence of the palladium catalyst
(Table 1, entry 5). The difference in the reactivity between
catalysts A and B might be due to their difference in
equilibrium with the active species C. As reported in the
literature,12 1 equiv of TfOH and H2O will be generated
during the change from catalyst A to C, while there is no
formation of TfOH and H2O from catalyst B to C (Scheme
2). The N-tert-butanesulfinyl group might be cleaved from
The addition of different kinds of arylboronic acids to ethyl
((RS)-N-tert-butanesulfinyl) iminoacetate (6) was studied as
shown in Table 2. This reaction is tolerant of many functional
groups. Arylboronic acids with either electron-neutral groups
or electron-donating groups could add to the imino esters
with moderate to good yields and high diastereoselectivity
(Table 2, entries 1-3 and 5), even if the sterically hindered
2-tolyl- and R-naphthylboronic acid also successfully gave
the arylglycine products (Table 2, entries 4 and 6). Both the
diastereoselectivity and yield were higher for the â-naphthyl-
boronic acid than for the R-naphthylboronic acid (Table 2,
entries 6 and 7). Interestingly, electron-withdrawing groups
substituted arylboronic acids could also proceed successfully
in this reaction with high diastereoselectivity (Table 2, entries
8 and 9). However, no reaction occurred for 4-pyridylboronic
acid (Table 2, entry 10). The diastereoselectivity of all
products was determined by measuring the enantiomeric
excess of their acetyl derivatives, which were obtained by
first removing the sulfinyl group and then by acetylation (see
Supporting Information).
Scheme 2
The possible mechanism for the [(bpy)Pd+(µ-OH)]2-
(-OTf)2 (catalyst B) catalyzed addition reaction of aryl-
boronic acids to the imino esters is proposed as shown in
Scheme 3. First, the dimeric catalyst B dissociates to the
Scheme 3. Proposed Mechanism for the Addition of
Arylboronic Acids to Ethyl ((RS)-N-tert-Butanesulfinyl)
Iminoacetate (6) Catalyzed by Catalyst B
the imino ester by the generated TfOH making the reaction
impossible.8
Table 2. [(Bpy)Pd+(µ-OH)]2(-OTf)2-Catalyzed Addition of
Arylboronic Acids (2) to Ethyl ((RS)-N-tert-Butanesulfinyl)
Iminoacetate (6)a
entry
Ar
product
yield (%)b
de (%)c
1
2
3
4
5
6
7
8
9
Phd
7a
7b
7c
7d
7e
7f
7g
7h
7i
86
90
65
69
73
66
84
57
62
0
95.5(-)d
94.8(-)
96.9(-)
93.3(-)
89.4(-)
87.3(-)
93.7(-)
90.8(-)
88.0(-)
4-MeOC6H4
4-CH3C6H4
2-CH3C6H4
3-CH3C6H4
R-naphthyl
â-naphthyl
4-CF3C6H4
3-NO2C6H4
4-pyridyl
10
7j
active species C in the presence of the solvent or the substrate
imino ester 6.12,13 Due to the high oxophilicity of boron, the
coordination of the hydroxyl group of the active species C
a Reaction conditions: ArB(OH)2 (0.50 mmol), ethyl ((RS)-N-tert-
butanesulfinyl) iminoacetate (6, 0.25 mmol), [(bpy)Pd+(µ-OH)]2(-OTf)2 (cat
B, 5 mol %) in dioxane (1 mL) at 60 °C for 24 h. b Isolated yields. c The
diastereoselectivity of the products was determined by measuring the
enantiomeric excess of their acetyl derivatives; see Supporting Information.
d The absolute configuration was determined to be (RS,2R) (see Supporting
Information).
(12) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002,
124, 11240.
(13) Kina, A.; Iwamura, H.; Hayashi, T. J. Am. Chem. Soc. 2006, 128,
3904.
Org. Lett., Vol. 9, No. 16, 2007
3079

with boronic acid facilitates the transmetalation step to form
the intermediate D.14 Because of the vacant coordination site
on the palladium, both the imino group and the sulfinyl group
could coordinate with it15 very easily to generate intermediate
E. The imino group can be activated by the cationic
palladium species due to its higher Lewis acidity. In addition,
because of the 1,3-binding mode of the coordination of the
nitrogen atom of the imine and the oxygen atom of the
sulfinyl group to the palladium center, the aryl group
preferred to add to imines from the Re face in a highly
selective manner to produce the addition product F (RS,2R),
which yielded product 7 upon hydrolysis and regenerated
the catalytic active intermediate C.
In summary, we have developed a cationic palladium-
complex-catalyzed addition of arylboronic acids to N-tert-
butanesulfinyl iminoacetates to yield the optically active
arylglycine derivatives with moderate to good yield and high
diastereoselectivity, which provides a convenient and ef-
ficient method for the synthesis of arylglycines. Further
studies on probing the detailed mechanism and the trans-
formations of the addition products are currently underway.
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (20423001) and Chinese Academy
of Sciences for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Organometallics 2004,
23, 4317.
(15) (a) Annibale, G.; Cattalini, L. J. Chem. Soc., Dalton Trans. 1989,
1265. (b) Cogan, D. A.; Liu, G.-C.; Ellman, J. Tetrahedron 1999, 55, 8883.
(c) Foubelo, F.; Yus, M. Tetrahedron: Asymmetry 2004, 15, 3823.
OL0711220
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