Access to α-functionalized glycine derivatives with arylboronic acid via imino amides

Article abstract of DOI:10.1055/s-0029-1218266

An efficient approach was developed for the α-arylation of imino amides with arylboronic acids. Different substrates were examined for this arylation reaction. For the α-arylation of N-phenylimino amide, due to the electron-withdrawing properties of the phenyl group, the tautomerization between the amide and the iminol is more difficult. Thus, low reaction rate and low conversion were observed. This phenomenon supported our previously proposed mechanism for the arylation of -amino acid derivatives. Meanwhile, this method provides an alternative approach for the synthesis of α-functionalized glycine derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218266

LETTER
2953
Access to a-Functionalized Glycine Derivatives with Arylboronic Acid via
Imino Amides
Access to
a
-Fun
i
c
tiona
a
lized
G
lycin
n
e
Derivative
g
s
Zhao, Xiaohong Liao, Chao-Jun Li*
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 2K6, Canada
Fax +1(514)3983797; E-mail: cj.li@McGill.ca
Received 4 August 2009
will occur to afford the arylation product 5. Inspired by
the iminoamide intermediate 2 and in pursuit of a method
which is complementary to, but also beyond the scope of
the oxidative coupling reaction, we herein report an alter-
Abstract: An efficient approach was developed for the a-arylation
of imino amides with arylboronic acids. Different substrates were
examined for this arylation reaction. For the a-arylation of N-phe-
nylimino amide, due to the electron-withdrawing properties of the
phenyl group, the tautomerization between the amide and the iminol native synthetic method by utilizing imino amides and nu-
is more difficult. Thus, low reaction rate and low conversion were
observed. This phenomenon supported our previously proposed
mechanism for the arylation of a-amino acid derivatives. Mean-
while, this method provides an alternative approach for the synthe-
cleophiles such as arylboronic acids to synthesize the a-
arylated product (Scheme 2).
To generate the imine precursor for the arylation and to
demonstrate proof-of-concept, diethyl tartrate was first
converted into dibenzyl tartaric amide by reacting with
benzylamine.10 Oxidative cleavage of the diol by periodic
acid11 generated the glyoxylic amide in situ, which was ef-
ficiently transformed into imino amide (Scheme 2).
sis of a-functionalized glycine derivatives.
Key words: a-functionalization, arylation, iminol, imino amide,
glycine derivatives
For decades, a-arylation of amino acids and their deriva-
tives has attracted much attention due to their high impor-
tance in pharmaceutical compounds (e.g., Ampicillin and
Cefachlor) and natural products (such as Vancomycin).1
The most widely used methods to access these unnatural
amino acids are the Strecker reaction,2 the Ugi reaction,3
and the Petasis reaction,4 which are all based on imine
chemistry.5 Arylations of imines with or without a transi-
tion-metal catalyst have been extensively studied during
the past two decades. Activated imines such as N-tosyl
imine6 and even unactivated imines such as PhN=CHPh
could be arylated with the ArM7 (M = Pd, Rh) species
which are generated via transmetalation. The Petasis reac-
tion (either with an imine or an iminium precursor4d,8) is
one of the most well-known catalyst-free approaches.
However, arylation of an imino amide (a prototype struc-
ture for peptides) has not been explored so far.
We have optimized this procedure so that it may be easily
carried out on multigram scale to make this special imine,
with isolation of the reagent accomplished by simple sili-
ca gel column filtration followed by recrystallization.
With this imino amide in hand, we examined the coupling
reaction with arylboronic acids.
Electron-rich arylboronic acids (entries 2, 5, 7, 9, 13–15,
Table 1) are generally more reactive than their electron-
deficient (entries 3, 8, 16, Table 1) or sterically hindered
(entries 4, 12, Table 1) counterparts. The imine substrate
with an extra glycine moiety affords good yields as well
(entries 11–16, Table 1).
Ar
H
N
[O]
H
PMP
PMP
ArB(OH)2
ArB(OH)2
(a)
(b)
+
+
PMP
N
R1
N
H
R1
N
H
O
O
O
[O]
Recently, we developed a new approach to achieve the
direct a-arylation of glycine and peptide derivatives
(Scheme 1, a) under oxidative conditions via functional-
ization of a C–H bond.9 During the course of studying the
substrate scope, we found that neither the glycine ester nor
the tertiary glycine amide undergo the arylation reaction
(Scheme 1, b and c). This led us to investigate the mecha-
nism of this novel type of arylation reaction (Scheme 1).
We proposed that after formation from glycine derivative
1, the imino amide 2 will tautomerize to its iminol form 3.
Then, the newly formed hydroxyl group will coordinate
with the phenylboronic acid to give intermediate 4. Sub-
sequently, an intramolecular delivery of the phenyl group
O
no coupling
no coupling
N
H
R2
R3
N
[O]
PMP
PMP
ArB(OH)2
(c)
+
N
H
R4
R
O
O
O
H
N
N
R
N
H
PMP
N
H
1
2
proposed
mechanism
PhB(OH)2
R
OH
B
O
OH
H
N
O
Ph
R
N
N
PMP
R
N
PMP
N
H
PMP
N
Ph
SYNLETT 2009, No. 18, pp 2953–2956
x
x
.x
x
.2
0
0
9
3
4
5
Advanced online publication: 08.10.2009
DOI: 10.1055/s-0029-1218266; Art ID: U08009ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Mechanistic studies of the arylation reaction

2954
L. Zhao et al.
LETTER
O
OH
O
OH
O
H5IO6
cat. K2CO3
NHR
OEt
RNH2
+
RHN
EtO
RHN
CHO
MeOH, reflux
THF, r.t.
OH
O
OH
O
R = Bn, Me
O
O
H
PMPNH2
N
N
RHN
PMP
RHN
PMP
CH2Cl2, r.t.
Ar
2a R = Bn
2b R = Me
Scheme 2 Synthesis of imino amide reagent
Table 1 Scope of the Arylation Reactiona
Table 1 Scope of the Arylation Reactiona (continued)
O
O
O
O
H
H
R1
DCE
N
R1
N
R1
DCE
N
N
R1
ArB(OH)2
+
PMP
N
ArB(OH)2
+
PMP
N
H
PMP
N
PMP
N
100 °C
H
100 °C
H
H
Ar
Ar
6
7
8
6
7
8
Entry
Product
Yield (%)
Entry
Product
Yield (%)
O
O
H
N
H
N
Bn
Me
PMP
N
H
PMP
N
H
1
2
65
6
7
96
8a
8f
O
O
H
N
H
N
Bn
Me
Me
Me
PMP
N
H
PMP
N
H
97
81
OMe
O
OMe
O
8b
8g
H
N
H
N
Bn
PMP
N
H
PMP
N
H
3
4
78
56
8
82
Cl
O
Br
O
8c
8h
H
N
H
N
Bn
PMP
N
H
PMP
N
H
Me
9
94
17
8d
O
H
N
8i
Bn
PMP
N
H
O
H
N
Ph
5
99
PMP
N
H
10
8e
8j
Synlett 2009, No. 18, 2953–2956 © Thieme Stuttgart · New York

LETTER
Access to a-Functionalized Glycine Derivatives
2955
Table 1 Scope of the Arylation Reactiona (continued)
It is interesting to note that for the imino amide substrate,
N-alkyl amides (entries 1–9, and entries 11–16, Table 1)
are much more reactive than the N-phenyl amide (entry
10, Table 1). This may be due to the fact that the phenyl
group of N-phenyl amide will withdraw electrons from
amide, making the tautomerization to the iminol more dif-
ficult compared with N-alkyl amides in the current reac-
tion conditions (Figure 1). This reduced activity is
consistent with our previously proposed reaction mecha-
nism.
O
O
H
R1
DCE
N
R1
N
ArB(OH)2
+
PMP
N
PMP
N
100 °C
H
H
Ar
6
7
8
Entry
Product
Yield (%)
O
O
O
H
N
OEt
PMP
N
H
11
12
81
In summary, an alternative route for the synthesis of a-
arylated glycine derivatives and dipeptides was described
via the a-arylation of imino amides with arylboronic ac-
ids. Furthermore, the study supported the mechanism of
our previously reported oxidative coupling reaction of
glycine amide with arylboronic acids. Further studies on
the application of the reaction are in progress.
O
8k
H
N
OEt
PMP
N
H
64
O
Me
General Procedure for the Arylation Reaction of Imino Amide
The N-PMP imine amide (0.10 mmol) and arylboronic acid (0.15
mmol) were added to DCE (0.5 mL) in a test tube. The test tube was
sealed and heated at 100 °C for 5 h. After the reaction was complet-
ed, DCE was removed in vacuo. Flash chromatography using
EtOAc–hexanes (1:4 to 1:2) afforded the arylated product.
8l
H
N
OEt
OEt
OEt
PMP
N
H
13
14
73
41
O
O
O
O
O
Isolation and Characterization of Compound 8a12
8m
1H NMR (300 MHz, CD3Cl): d = 7.46–7.36 (m, 5 H), 7.28–7.13 (m,
5 H), 6.77 (d, 2 H, J = 9.0 Hz), 6.59 (d, 2 H, J = 9.0 Hz), 4.73 (s, 1
H), 4.55 (dd, 1 H, J = 14.7, 6.3 Hz), 4.40 (dd, 1 H, J = 14.7, 6.3 Hz),
3.75 (s, 3 H) ppm. 13C NMR (75 MHz, CD3Cl): d = 171.4, 153.2,
140.6, 138.8, 138.0, 129.2, 128.6, 127.6, 127.4, 127.3, 127.3, 115.1,
114.8, 65.2, 55.7, 43.4 ppm.
H
N
PMP
N
H
S
8n
O
H
N
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
PMP
N
H
15
82
Acknowledgment
OMe
O
We are grateful to the Canada Research Chair (Tier I) foundation (to
C.-J. Li), NSERC, CFI, ACS-Green Chemistry Pharmaceutical
Roundtable and McGill University for their support of our research.
8o
H
N
OEt
PMP
N
H
References
O
16
50
(1) (a) Nagarajan, R. Antimicrob. Agents Chemother. 1991, 35,
605. (b) Perkins, H. R. Pharmacol. Ther. 1982, 16, 181.
(c) Williams, D. H. Acc. Chem. Res. 1984, 17, 364.
(2) (a) Connon, S. J. Angew. Chem. Int. Ed. 2008, 47, 1176.
(b) Groger, H. Chem. Rev. 2003, 103, 2795. (c) Yet, L.
Angew. Chem. Int. Ed. 2001, 40, 875.
(3) (a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3169. (b) Ugi, I. Angew. Chem. 1959, 71, 386. (c) Ugi, I.
Angew. Chem., Int. Ed. Engl. 1962, 1, 8. (d) Ugi, I.;
Steinbruckner, C. Angew. Chem. 1960, 72, 267.
(4) (a) For a comprehensive review on Petasis reaction, see:
Batey, R. A. In Boronic Acids; Hall, D. G., Ed.; Wiley-
VCH: Weinheim, 2005, 279–304. (b) Petasis, N. A.;
Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583.
Cl
8p
a Reaction conditions: imino amide (0.10 mmol), arylboronic acid
(0.15 mmol), DCE (0.5 mL), 5 h at 100 °C.
OH
O
N
R
N
R
N
N
H
O
O
Figure 1 Tautomerization between the amide and the iminol
(c) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997,
119, 445. (d) Petasis, N. A.; Zavialov, I. A. J. Am. Chem.
Soc. 1998, 120, 11798. (e) Petasis, N. A.; Goodman, A.;
Synlett 2009, No. 18, 2953–2956 © Thieme Stuttgart · New York

2956
L. Zhao et al.
LETTER
Zavialov, I. A. Tetrahedron Lett. 1997, 53, 16463.
(f) Naskar, D.; Roy, A.; Seibel, W. L. Tetrahedron Lett.
2003, 44, 8861. (g) Koolmeister, T.; Sodergren, M.
Tetrahedron Lett. 2002, 43, 5969.
Bhanthumnavin, W.; Sritana-Anant, Y. Curr. Org. Chem.
2005, 9, 1315. (e) Youn, S. W.; Song, J.-H.; Jung, D.-I.
J. Org. Chem. 2008, 73, 5658. (f) Yu, A.; Wu, Y.; Cheng,
B.; Wei, K.; Li, J. Adv. Synth. Catal. 2009, 351, 767.
(g) Ding, R.; Zhao, C. H.; Chen, Y. J.; Liu, L.; Wang, D.; Li,
C.-J. Tetrahedron Lett. 2004, 45, 2995.
(5) For other methods to access arylation/allylation of a-amino
acids from our laboratory, see: (a) Huang, T.; Li, C.-J.
Tetrahedron Lett. 2000, 41, 6715. (b) Huang, T.; Li, C.-J.
Tetrahedron Lett. 2000, 41, 9747. (c) Huang, T. S.; Li, C.-J.
Org. Lett. 2001, 3, 2037. (d) Huang, T. S.; Keh, C. C. K.; Li,
C.-J. Chem. Commun. 2002, 2440.
(6) (a) Wei, D. J.; Shi, Y. L.; Ellman, J. A. J. Am. Chem. Soc.
2005, 127, 1092. (b) Dai, H. X.; Lu, X. Y. Org. Lett. 2007,
9, 3077. (c) Kuriyama, M.; Soeta, T.; Hao, X. Y.; Chen, O.;
Tomioka, K. J. Am. Chem. Soc. 2004, 126, 8128.
(d) Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169.
(7) (a) Krug, C.; Hartwig, J. F. Organometallics 2004, 23,
4594. (b) Krug, C.; Hartwig, J. F. J. Am. Chem. Soc. 2004,
126, 2694. (c) Ueura, K.; Miyamura, S.; Satoh, T.; Miura,
M. J. Organomet. Chem. 2006, 691, 2821. (d) Vilaivan, T.;
(8) (a) Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130,
6922. (b) Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am.
Chem. Soc. 2007, 129, 6686. (c) Basle, O.; Li, C.-J. Org.
Lett. 2008, 10, 3661. (d) Selander, N.; Kipke, A.; Sebelius,
S.; Szabo, K. J. J. Am. Chem. Soc. 2007, 129, 13723.
(9) Zhao, L.; Basle, O.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A.
2009, 106, 4106.
(10) Chen, W.; Liu, Y.; Chen, Z. Eur. J. Org. Chem. 2005, 1665.
(11) Bolton, G. L.; Bowles, D. M.; Doyles, D. C.; Howard, W. A.
J.; Hutchings, R. H.; Kennedy, R. M.; Park, W. K.-C.; Poel,
T.-J.; Song, Y. US 2005239857, 2005.
(12) Pan, S. C.; List, B. Angew. Chem. Int. Ed. 2008, 47, 3622.
Synlett 2009, No. 18, 2953–2956 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.