Diastereoselective Petasis Mannich reactions accelerated by hexafluoroisopropanol: A pyrrolidine-derived arylglycine synthesis

Article abstract of DOI:10.1016/j.tetlet.2005.01.151

A diastereoselective synthesis of pyrrolidine-derived arylglycines has been developed using the Petasis boronic acid Mannich reaction. High diastereoselectivities in the reactions of chiral amines, aryl boronic acids, and glyoxylic acid monohydrate have been demonstrated for the first time. Key to the implementation of this method is the discovery that hexafluoroisopropanol accelerates the Petasis process, reducing reaction times from multiple days to less than 24 h.

Full text of DOI:10.1016/j.tetlet.2005.01.151

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2025–2028
Diastereoselective Petasis Mannich reactions accelerated by
hexafluoroisopropanol: a pyrrolidine-derived arylglycine synthesis
Kausik K. Nanda* and B. Wesley Trotter
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
Received 4 November 2004; revised 26 January 2005; accepted 27 January 2005
Abstract—A diastereoselective synthesis of pyrrolidine-derived arylglycines has been developed using the Petasis boronic acid
Mannich reaction. High diastereoselectivities in the reactions of chiral amines, aryl boronic acids, and glyoxylic acid monohydrate
have been demonstrated for the first time. Key to the implementation of this method is the discovery that hexafluoroisopropanol
accelerates the Petasis process, reducing reaction times from multiple days to less than 24 h.
Ó 2005 Elsevier Ltd. All rights reserved.
In the course of a recent drug discovery program, we
required a diastereoselective synthesis of pyrrolidine-
derived arylglycines of structure I.
eration of this reaction upon addition of hexafluoroiso-
propanol as a co-solvent.
B(OH)2
+
H
N
O
HO2C
toluene
25 oC
Ph
Me
O
H
HO
+
Me
ð1Þ
N
H2N
I
HO
O
R
OMe
Ar
82% (dr 68:32)
OMe
The Petasis boronic acid Mannich reaction1 provides an
operationally simple route to arylglycines ideally suited
to variation of Ar and R. Diastereoselective Petasis reac-
tions of alkenyl boronic acids and chiral amines have
been reported2 for the synthesis of a-amino acids. Peta-
sis and co-workers have also reported3 high diastereose-
lectivity in the analogous synthesis of b-amino alcohols
from chiral a-hydroxy aldehydes and achiral amines.
However, the only reported attempt at stereoselective
arylglycine synthesis from chiral amines using these
methods proceeds with poor diastereoselectivity (Eq.
1).4 Petasis and co-workers speculated that facile epi-
merization of the a-stereocenter might be responsible
for this result.5,6 In this letter we report the diastereose-
lective synthesis of arylglycines I via a Petasis boronic
acid Mannich reaction and document a significant accel-
Our initial investigations identified refluxing acetoni-
trile7 as an optimal medium for reaction of cyclic sec-
ondary amines in the Petasis process. These conditions
provided useful yields and reasonable reaction times.
Further, we observed that the reaction of 2-methylpyr-
rolidine, phenyl boronic acid, and glyoxylic acid
monohydrate under these conditions and subsequent
esterification8 provided methyl ester 1 in 65% yield with
a diastereomeric ratio of 83:17 (Scheme 1) favoring the
isomer shown (vide infra). Improved diastereoselectivity
was realized by lowering the reaction temperature to
25 °C, resulting in a diastereomeric ratio of 94:6 (Table
1, entry 1). However, long reaction times (ca. 1 week)
O
B(OH)2
HN
i) MeCN
O
N
reflux, 7 h
MeO
H
+
HO
+
Me
ii) TMS-CHN2
Me
Keywords: Petasis; Boronic acid Mannich; Arylglycine; Diastereo-
selective.
O
rac-1
(65%, dr 83:17)
*
Corresponding author. Tel.: +1 215 652 0371; fax: +1 215 652
7310; e-mail: kausik_nanda@merck.com
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.151

2026
K. K. Nanda, B. W. Trotter / Tetrahedron Letters 46 (2005) 2025–2028
Table 1. Effect of solvent on the reaction rate and the diastereoselectivity
O
O
B(OH)2
+ Ph
solvent TMSCHN2
r.t.
N
HN
H
MeO
+
HO
Me
rac-1
Diastereomeric ratioa
Ph
Me
O
Entry
Solvent
Time (days)
Isolated yieldb (%)
1
2
3
4
5
6
7
CH3CN
CH2Cl2
Toluene
8
6
6
6
6
6
1
94:6
>95:5
93:7
64
80
53
53
C2H5OH
CF3CH2OH
(CF3)2CHOH
93:7
>95:5
—
>95:5
78
26% conv.c
80
CH2Cl2–HFIP 90:10
a Determined by 1H NMR of the unpurified reaction mixture.
b Isolated yield of the major diastereomer unless otherwise noted.
c Conversion estimated by LC/MS of the reaction mixture.
proved to be a major limitation of room temperature
processes. Examination of several solvents indicated
that CH2Cl2 provided slightly shorter reaction times
and higher conversion than other aprotic solvents.
Among the protic solvents examined, the more acidic
CF3CH2OH provided better conversion than C2H5OH;
however, use of the even more acidic (CF3)2CHOH
(HFIP) resulted in a much slower reaction (entry 6).
We speculated that the fluorinated alcohols might in-
deed be promoting the desired reaction but exhibiting
undesirable solvent effects. We were thus gratified to find
that use of HFIP as an additive in CH2Cl2 solution dra-
matically accelerated the reaction9,10 while preserving
yield and stereoselectivity.11 This phenomenon appears
to be general for a variety of cyclic and acyclic amines
(Table 2).
The scope of this diastereoselective process with regard
to aryl boronic acids was examined using the improved
reaction conditions (Table 3). In general, both electron-
rich and sterically hindered aryl boronic acids provided
good yields and diastereoselectivities (Table 3, products
1, 2, 3, and 6), whereas electron-deficient aryl boronic
acids such as 3-cyanophenyl boronic acid did not react
under the same conditions. 3-Fluorophenyl and 4-fluoro-
phenyl boronic acids provided good yields and good
diastereoselectivities. A difference in both reactivity
and diastereoselectivity was observed for 2- and 3-thio-
phene boronic acids (Table 3, products 8 and 9).
Table 2. Effect of HFIP on reaction rate
O
R1
N
The scope of the reaction with regard to the amine com-
ponent was also explored. Table 4 summarizes the
results from reactions of different amines with phenyl
boronic acid and glyoxylic acid monohydrate. 2-Substi-
tuted pyrrolidines underwent reaction with excellent dia-
stereoselectivities and good yields (Table 4, products 1,
10, 11, 12). When 2,6-dimethylpyrrolidine was used as
the amine component, it failed to react (Table 4, 13).
Similar behavior was also observed in the case of 2-
methylpiperidine. The lower basicity12 of piperidine in
comparison to pyrrolidine along with greater steric con-
gestion may render it inert under these conditions. No
diastereoselectivity was observed in reactions of 3-
substituted pyrrolidines (Table 4, 15). It should be noted
that the reaction in Eq. 1 was also accelerated under
these conditions but did not show any improvement in
diastereoselectivity.13,14
B(OH)2
O
HO
R2
H
N
solvent
r.t.
H
+
HO
+
R1
R2
O
Entry
HNR1R2
Time (h)
% Conversiona
CH2Cl2–HFIPb
CH2Cl2
H
N
20
86
25
1
H
N
2
3
20
20
68
59
15
42
H
N
H
N
To establish the relative stereochemistry between the
two chiral centers in these arylglycines, a single crystal
X-ray structure of 11aÆHCl was obtained.15 The crystal
structure16 (Fig. 1) shows the relative stereochemistry
between the two chiral centers as R and S. The observed
diastereoselectivity is consistent with addition of the aryl
group to an intermediate iminium ion, where approach
of the aryl group occurs from the face opposite the
4
5
92
20
26
7
0
0
Me Me
NH2
Me
a Determined by LC/MS of the reaction mixture.
b CH2Cl2–HFIP (90:10, v/v).

K. K. Nanda, B. W. Trotter / Tetrahedron Letters 46 (2005) 2025–2028
2027
Table 3. Reactions of 2-methylpyrrolidine and glyoxylic acid mono-
hydrate with different aryl boronic acids
Table 4. Reactions of phenyl boronic acid and glyoxylic acid mono-
hydrate with different amines
CH2Cl2
O
R1
N
O
O
B(OH)2
B(OH)2
CH2Cl2
TMSCHN
10% HFIP
O
2
N
H
HN
H
N
TMSCHN MeO
R2
10% HFIP
Ar
MeO
+
2
HO
+
H
r.t.
+
HO
+
R1
R2
Me
Ar
O
Me
r.t.
O
Ester
product
Ar–B(OH)2
Time Diastereo-
(h)
Isolated
meric ratioa yieldb (%)
Ester
product
HNR1R2
Time Diastereo-
(h)
Isolated
meric ratioa yieldb (%)
B(OH)2
22
rac-1
>95:5
>95:5
80
H
N
Me
22
>95:5
>95:5
80
90
rac-1
B(OH)2
Me
91c
Me
Me
H
N
rac-2
rac-3
24
20
rac-10
19
7
B(OH)2
H
N
rac-11
(S)-12
13
>95:5
>95:5
—
96
Ph
94:6
93
H
N
MeO
24
24
85
B(OH)2
OMe
H
N
rac-4
rac-5
24
22
95:5
95:5
83
No reaction
Me
Me
F
F
H
N
B(OH)2
B(OH)2
Me
14
24
24
—
No reaction
71
H
N
rac-15
50:50
80c
rac-6
rac-7
17
22
87:13
88d
F
NHBoc
BnO
a Determined by 1H NMR of the unpurified reaction mixture.
b Isolated yield of the major diastereomer unless otherwise noted.
c dr = 57:43 in the isolated material.
B(OH)2
—
No
reaction
NC
S
rac-8
rac-9
7
7
57:43
91:9
59e
70d
B(OH)2
B(OH)2
S
a Determined by 1H NMR of the unpurified reaction mixture.
b Isolated yield of the major diastereomer unless otherwise noted.
c dr > 95:5 in the isolated material.
d dr = 86:14 in the isolated material.
e dr = 56:44 in the isolated material.
pyrrolidine 2-substituent. A graphical representation
invoking the mechanism proposed by Hansen and
co-workers is shown in Figure 2.17
Figure 1. ORTEP representation of rac-11aÆHCl. Non-hydrogen
atoms are represented by ellipsoids corresponding to 50% probability.
In summary, a diastereoselective synthesis of pyrrol-
idine-derived arylglycines has been achieved via an
accelerated Petasis boronic acid Mannich reaction.
The use of HFIP as a co-solvent dramatically reduces
reaction times, and this protocol may find application
in other instances of the widely used Petasis synthesis.
R
N
H
O
O
B
HO
HO
Typical reaction procedure: To a suspension of glyoxylic
acid monohydrate (89 mg, 0.968 mmol) in 4.5 mL of
CH2Cl2 and 0.5 mL of hexafluoroisopropanol (HFIP)
was added 2-methylpyrrolidine (82 mg, 0.968 mmol)
Figure 2. Aryl group approach from the face opposite the pyrrolidine
2-substituent.

2028
K. K. Nanda, B. W. Trotter / Tetrahedron Letters 46 (2005) 2025–2028
7. Petasis, N. A.; Patel, Z. D. Tetrahedron Lett. 2000, 41,
9607.
8. Amino acids obtained from the boronic acid Mannich
reactions were converted into the corresponding methyl
esters (TMSCHN2) for ease of purification and
characterization.
9. HFIP has been found to accelerate substitution reactions
of dihydroartemisinin derivatives. Bonnet-Delpon and co-
workers speculated that this is due to the strong hydrogen
bond donor ability of HFIP: Magueur, G.; Crousse, B.;
Ourevitch, M.; Begue, J. P.; Bonnet-Delpon, D. J. Org.
Chem. 2003, 68, 9763.
followed by phenyl boronic acid (118 mg, 0.968 mmol).
The reaction mixture was stirred for 22 h at room
temperature and then concentrated. To a solution of
this crude amino acid in a mixture of MeOH (2 mL)
and CH2Cl2 (4 mL) was added TMS–diazomethane
(2 mmol, 2 M in hexane) solution dropwise. The reac-
tion mixture was stirred at room temperature for 2 h
and concentrated, then purified by flash chromatogra-
phy using a linear gradient of 3–30% EtOAc in hexanes.
Product 1 was obtained as a colorless, viscous oil
(181 mg, 80%).
10. For other HFIP-accelerated reactions see: (a) Iskra, J.;
Bonnet-Delpon, D.; Begue, J. P. Eur. J. Org. Chem. 2002,
3402; (b) Ichikawa, J.; Miyazaki, S.; Fujiwara, M.;
Minami, T. J. Org. Chem. 1995, 60, 2320; (c) Takita, R.;
Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2002, 43,
4661.
11. Use of 10% CF3CH2OH in CH2Cl2 at room temperature
provided 61% conversion by LC/MS after 26 h.
12. (a) Frenna, V.; Vivona, N. J. Chem. Soc., Perkin Trans. 2
1985, 1865; (b) Searles, S.; Tamres, M.; Block, F.;
Quarterman, L. A. J. Am. Chem. Soc. 1956, 78, 4917.
13. Interestingly, the reaction of a-methylbenzylamine with
phenyl boronic acid did not proceed under our conditions
(see Ref. 14) or under the conditions in Eq. 1. The relative
rates of reactions of the more nucleophilic 4-methoxy
phenyl boronic acid, a-methylbenzylamine and glyoxylic
Acknowledgements
We thank Nancy N. Tsou for obtaining the single crys-
tal X-ray structure, Joan Murphy for mass spectral data
and Christopher Dinsmore for helpful discussions.
Supplementary data
1H NMR spectral data and high resolution mass spec-
tral data for all compounds and Table S1 summarizing
results from the reactions of different amines with
phenyl boronic acid. Supplementary data associated
with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2005.01.151.
acid
monohydrate
in
toluene
and
CH2Cl2–
HFIP were estimated by LC/MS as follows: toluene, rt, 1 h,
46% conversion; CH2Cl2–HFIP, rt, 1 h, 96% conversion;
toluene, 0 °C, 5.5 h, 36% conversion; CH2Cl2–HFIP, 0 °C,
5.5 h, 94% conversion, 92% yield, diastereomeric ratio
69:31.
References and notes
14. Reactivities of several other acyclic and cyclic amines were
examined. In general, acyclic amines showed no reaction
or very little conversion to the desired arylglycines. See
Table S1 in the supporting information.
15. The relative stereochemistry of all compounds was
assigned by analogy to 11 and supported by similar
chemical shift patterns in the 1H NMR spectra of the
isolated methyl esters.
16. Crystallographic data (excluding structure factors) for this
structure have been deposited with the Cambridge Crys-
tallographic Data Center as supplementary publication
number CCDC 254668. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
17. Although no detailed mechanism for the Petasis reaction
has been elucidated, Hansen and co-workers have put
forward a speculative proposal supported by 11B NMR
data: Schlienger, N.; Bryce, M. R.; Hansen, T. K.
Tetrahedron 2000, 56, 10023.
1. Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993,
34, 358.
2. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997,
119, 445.
3. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998,
120, 11798.
4. Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron
1997, 53, 16463.
5. Arylglycine epimerization is well documented in the
literature: (a) Mellin-Morliere, C.; Aitken, D. J.; Bull, S.
D.; Davies, S. G.; Husson, H. H. Tetrahedron: Asymmetry
2001, 12, 149; (b) Williams, R. M. Synthesis of Optically
Active a-Amino Acids; Pergamon: Oxford, 1989.
6. Harwood and co-workers have reported a related diaste-
reoselective reaction of 2-furyl boronic acid and formal-
dehyde in a non-epimerizable system: Currie, G. S.; Drew,
M. G. B.; Harwood, L. M.; Hughes, D. J.; Luke, R. W.
A.; Vickers, R. J. J. Chem. Soc., Perkin Trans. 1 2000,
2982.