On the use of boronates in the Petasis reaction

Article abstract of DOI:10.1016/j.tetlet.2005.09.060

Alcohols are solvents of choice to react boronates, aldehydes and either primary or secondary amines. Thus, while the reaction proceeds sluggishly, or not at all, in aprotic solvents, the desired aminoacids are in most cases obtained in high yields when c

Full text of DOI:10.1016/j.tetlet.2005.09.060

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8027–8031
On the use of boronates in the Petasis reaction
a
a
b
H e´ l e` ne Jourdan, G e´ raldine Gouhier, Luc Van Hijfte,
b
a,
*
Patrick Angibaud and Serge R. Piettre
a
Laboratoire des Fonctions Azot e´ es et Oxyg e´ n e´ es Complexes, UMR 6014 CNRS, Universit e´ de Rouen, rue Tesni e` res,
F-76821-Mont Saint Aignan, France
b
Johnson and Johnson Pharmaceutical Research and Development, A division of Janssen-Cilag S.A., Campus de Maigremont,
BP 615, F-27106 Val de Reuil cedex, France
Received 12 July 2005; revised 8 September 2005; accepted 12 September 2005
Available online 28 September 2005
Abstract—Alcohols are solvents of choice to react boronates, aldehydes and either primary or secondary amines. Thus, while the
reaction proceeds sluggishly, or not at all, in aprotic solvents, the desired aminoacids are in most cases obtained in high yields when
conducted in methanol or hexafluoro-iso-propanol. In the case of secondary amines, microwave activation is shown to strongly
accelerate the process without altering the yields.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
of the reaction, involving the use of chiral boronic esters
as auxiliaries. This letter describes our own efforts to
5
One of the most efficient ways to rapidly increase the
molecular complexity of products is represented by the
multicomponent processes (MCP), in which at least
three chemical entities are brought together to produce
improve the use of boronates in the Petasis reaction.
As detailed below, these efforts secured the efficient use
of primary amines, and the original procedure was
greatly improved in the case of secondary amines.
1
a multifunctional compound. An additional feature of
these reactions is the numerous possible reagent combi-
nations, which usually result in a high exploratory
power. Among the various MCP at the disposal of
2
. Results and discussion
2
The Petasis reaction has been reported as being strongly
dependent on the solvent. Screening aprotic solvents at
room temperature or under reflux, when starting from
pinacolyl 2-styrylboronate (2a), glyoxylic acid (3a) and
benzylamine (4a) confirmed the observed lack of any
reaction reported in the original letter (Table 1, entry
the chemists, the borono-Mannich reaction, or Petasis
reaction, has received much attention due to its power
to produce variously substituted aminoacids and hetero-
6
3
cyclic compounds. In most of the reported cases, the
Petasis reaction results from the interaction between a
boronic acid 1, an aldehyde 3 and an amine 4 to form
product 5 and boric acid (6) (Scheme 1).
1
). Alcohols, including electron-poor ones, have been
7
increasingly used to accelerate reactions. Indeed, carry-
ing out the reaction in methanol (0.14 M) at room
temperature resulted in a 65% conversion after 24 h,
and in the isolation of the desired 4-phenyl-1-(N-benzyl-
amino)but-3-enoic acid (5a) in 60% yield (entry 2).
Reflux conditions, high pressures (12 kbar) or addition
of water did not lead to any improvement. Carrying
out the reaction in a more concentrated medium (1 M),
however, resulted in a complete conversion after 72 h,
and in a 67% isolated yield. Microwave activation
proved to be deleterious, leading to tarry materials.
Two isolated examples of the use of boronic esters have
also been described by Petasis and Hall, and, recently,
Scobie has reported a more extensive study on the use
3
d,4
of boronates.
Primary amines were described as
unreactive and only six of the 15 entries involving sec-
ondary amines resulted in isolated yields greater than
2
8%. The main reason behind ScobieÕs efforts was the
possible development of a new diastereoselective variant
Keywords: Boronates; Petasis reaction; Hexafluoropropanol.
*
Corresponding author. Tel.: +33 0235522970; fax: +33
235522971; e-mail: Serge.Piettre@univ-rouen.fr
Alcohols with higher ionizing powers were then consid-
ered. Among these, hexafluoro-iso-propanol (HFIP) was
0
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.060

8028
H. Jourdan et al. / Tetrahedron Letters 46 (2005) 8027–8031
R3
R1
R4
R2
OR5
OR5
O
R3
R4
OR5
OR5
N
R1
B
HO
B
+
+
HN
+
H
R2
5
5
1
2
: R = H
3
4
5
6: R = H
5
5
5
5
: R , R =
7: R , R =
-
C(CH3)2-(CH3)2C-
-C(CH3)2-(CH3)2C-
Scheme 1.
Table 1. Conversion of 2a, 3a and 4a into 5a in various solvents after 4 h at room temperature
HN
Ph
Ph
O
O
O
B
+
+
H2N
Ph
Ph
CO2H
CO2H
2a
3a
4a
5a
Entry
Solvent
Toluene, THF, CH
CH OH
CH
CHOH
% Conversion
0
1
2
3
4
5
6
7
8
2 2
Cl or dioxane
a
3
52 (65)
CF
3
2
OH
74
88
24
34
42
53
3 2
(CF )
CH
CH
CH
CH
2
Cl
Cl
Cl
2
2
2
/CH
/CF
/(CF
3
OH (9:1)
CH OH (9:1)
CHOH (9:1)
CHOH (9:1)
2
2
3
3
2
3 2
)
3 2
OH/(CF )
a
Conversion after 24 h, see text.
introduced by Schleyer more than 30 years ago, and has
received increasing attention during the last decade.
Substituting methanol with HFIP at room temperature
allowed reaction times to be shortened to 4 h, and an
The conditions above were next used to generate a small
library on a semi-automated synthesizer, using either
8
1
0
methanol or HFIP (Table 2). In most of the cases,
the reaction proceeded smoothly and allowed the isola-
tion of the desired product in fair to good yields (entries
1–6 and 9–12). The results indicated that HFIP generates
a more appropriate medium than methanol for the trans-
formation. Of particular note is the observed, improved
diastereoselectivity in the case of (R)-(a-methyl)benzyl-
8
5% isolated yield in 5a was obtained (entry 4). Expect-
edly, trifluoroethanol (TFE) led to intermediate results
entry 3). Attempts to use these alcohols as additives
afforded less effective results than TFE and HFIP
(
9
(
entries 5–8).
11
Table 2. Products 5 and yields of the reaction between boronates 2, aldehydes 3 and primary amines 4 in MeOH, and in HFIP
R3
O
O
NH
R2
R1
B
H2N R3
+
+
H
R2
R1
O
2
3
4
5
a
b
Entry
1
Boronate
Aldehyde
Amine
Product
HN
Yield (%)
Yield (%)
Ph
O
O
O
Ph
CO H
2a
2a
H2N
Ph
5a
67
66
85
B
3
a
4a
4b
CO H
Ph
Ph
2
2
Ph
Ph
O
O
O
O
NH
2
3
B
B
3a
H N
77
92
2
5b
CO H
CO H
2
2
Ph
Ph
O
O
2a
2a
2a
4c
HN
HN
Ph
5c
64
3
a
a
CO H
2
H2N
H2N
Ph
Ph
CO H
2
Ph
Ph
O
O
O
O
5
d
3
4d
Ph
4
5
70 (ed = 33%)
77 (ed = 81%)
B
B
CO H
Ph
2
Ph
Ph
CO H
2
O
O
HN
CO H
5
e
3
a
H N
60
78
2
4e
CO H
2
2

H. Jourdan et al. / Tetrahedron Letters 46 (2005) 8027–8031
8029
Table 2 (continued)
a
b
Entry
Boronate
Aldehyde
Amine
Product
HN
Yield (%)
Yield (%)
Ph
O
O
O
Ph
OH
6
B
2a
H N
Ph
Ph
4a
4a
5f
5
78
46
OH
3b
3c
2
Ph
O
OH
HN
HO
Ph
Ph
O
O
g
7
8
9
B
H N
Ph
0
0
0
2
a
2
Ph
Ph
O
O
O
O
O
O
O
5h
5i
2a
3d
3a
4a
4a
HN
0
B
H N
Ph
Ph
2
Ph
HN
O
2b
2b
Ph
40
68
78
35
90
83
79
75
B
B
B
B
H N
2
CO H
S
S
O
2
CO2H
HN
HN
O
O
1
1
1
0
1
2
H N
4b
5j
3a
3a
2
CO H
S
S
S
S
2
CO2H
Ph
Ph
Ph
O
O
5k
2b
2b
4
c
CO H
H N
2
2
Ph
S
S
CO H
2
O
O
HN
CO H
3
a
5l
H N
4e
2
CO H
2
2
a
Isolated yields; experiments conducted in methanol (1 M).
Isolated yields; experiments conducted in HFIP; see Ref. 12.
b
amine 4d (entry 4). Both o-hydroxybenzaldehyde and
,3-dimethylbutyraldehyde, however, were found to be
inert under these conditions (entries 7 and 8).
instead of methanol, even when microwave activation
was used with the latter. The improvement is best illus-
trated by the case of components 2c, 3a and 4g (entry
3
11). Thus, the yield obtained in methanol under micro-
Secondary amines were next considered. The use of
ScobieÕs optimized conditions (methylene chloride,
room temperature) to react with pinacol boronate 2a,
glyoxylic acid 3a and piperidine 4f allowed us to isolate
the desired product 5m in 62% yield. Conducting the
above reaction in methanol led to a complete conver-
sion in 72 h, which translated into a substantial increase
in yield (92% isolated), while HFIP at room tempera-
ture yielded a 94% conversion after only 4 h, which
led to a 90% isolated yield. The higher cost of HFIP,
when compared to methanol, led us to subject the reac-
tion in the latter to microwave activation (120 °C,
wave activation doubles than that reported by Scobie
for the same substrates, and becomes nearly quantitative
in HFIP. Here again, microwave activation shortened
the reaction time from 4 h to 10 min without altering
the isolated yield (94%). An identical analysis can be
made on entry 12.
The superiority of HFIP over methanol as the solvent
appears quite clearly from Tables 2 and 3. It is probably
due to the effect of its ionizing power on both the forma-
tion of ionic intermediates and the stabilization of polar-
8
a,15
ized or ionic transition states.
In the case of primary
1
3
3
00 W). Under these conditions, the transformation
amines, the increased acidity may also play a role in the
efficacy of the process, although the results cannot be
clearly explained on the basis of this sole parameter:
the use of acidified methylene chloride led to a much
reached completion in only 10 min and resulted in an
essentially identical result (89% isolated yield). Expect-
edly, a reduced, 62% isolated yield was obtained when
activation by microwaves was carried out in dichloro-
methane. The versatility of the reaction was then further
illustrated with other boronates, aldehydes and second-
ary amines (Table 3).
1
6
lower conversion.
3. Conclusion
In most cases, the desired products were obtained in
very good to excellent yields and the process was usually
cleaner and more efficient when conducted in HFIP
HFIP constitutes a very effective solvent to react
aldehydes and amines with boronates. The ground is
now firmly established to study the diastereoselection

8030
H. Jourdan et al. / Tetrahedron Letters 46 (2005) 8027–8031
11
Table 3. Products and yields of the reaction between boronates and secondary amines in MeOH under microwave activation and in HFIP
R3
R1
R4
R2
O
R3
R4
O
N
R1
+
+
B
HN
H
R2
O
2
3
4
5
a
b
Entry
1
Boronate
Aldehyde
Amine
Product
Yield (%)
Yield (%)
Ph
O
O
O
N
2a
HN
Ph
5m
89
90
B
3
a
a
4f
CO H
2
CO H
2
O
Ph
Ph
Ph
Ph
O
O
O
Ph
N
5n
5o
5p
5q
2
3
4
B
B
B
B
2a
2a
HN
Ph
O
85
67
81
97
97
96
3
4g
CO H
2
CO H
2
O
O
O
Ph
Ph
N
Ph
N
Ph
3a
3b
4h
H
CO H
2
CO2H
O
O
O
O
2a
HN
Ph
O
4
g
Ph
N
OH
OH
OH
O
O
O
Ph
Ph
N
5
6
2a
2b
N
4i
75
88
99
85
3
b
OH
H
O
O
N
B
B
HN
3
a
4f
5r
CO H
S
O
2
S
S
S
CO H
2
O
N
O
O
O
7
8
9
HN
HN
O
92
89
89
86
3a
2
b
b
CO H
4g
5s
S
S
2
CO H
2
NBoc
O
O
O
NBoc
N
B
3a
3a
3c
2
CO H
4j
5t
2
CO H
2
Ph
N
Ph
O
O
O
Ph
N
Ph
5u
B
B
2b
2b
4h
78
28
85
65
H
CO H
CO H
2
S
S
2
S
O
N
O
OH
O
O
10
HN
O
4g
4g
5v
OH
S
O
O
O
O
c
d
1
1
2
B
HN
HN
O
O
N
53 (25)
97 (94)
3
a
2
c
CO H
5w
S
O
2
S
CO H
2
O
O
O
c
1
N
21 (12)
81
B
2d
3a
4
g
CO H
5x
2
CO H
2
a
b
c
Isolated yields; experiments conducted in methanol under microwave activation; see Ref. 14.
Isolated yields; experiments conducted in HFIP at room temperature for 4 h.
See Ref. 4c.
d
Experiment conducted in HFIP under microwave activation.

H. Jourdan et al. / Tetrahedron Letters 46 (2005) 8027–8031
8031
resulting from the use of chiral boronates. Work in that
direction is actively pursued.
Eur. J. Org. Chem. 2000, 3402–3410; (f) Magueur, G.;
Crousse, B.; Our e´ vitch, M.; Bonnet-Delpon, D.; B e´ gu e´ ,
J.-P. J. Org. Chem. 2003, 68, 9763–9766.
9
. The accelerating effect of HFIP as additive on the Petasis
reaction has been recently reported in the case of boronic
acid. See: Nanda, K. K.; Trotter, B. W. Tetrahedron Lett.
References and notes
2
005, 46, 2025–2028.
TM
1
2
3
. Zhu, J.; Bienaym e´ , H. Multicomponent Reactions; Wiley-
VCH: Weinheim, 2005.
. Bienaym e´ , H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.
Eur. J. 2000, 6, 3321–3329.
. (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett.
10. A Quest synthesizer was used. Details can be obtained
from Argonaut Technologies at the following web address:
http://www.argotech.com. This synthesizer features verti-
cal magnetic stirring.
11. All new compounds had analytical data in accordance
with the depicted structures.
1
993, 34, 583–586; (b) Harwood, L. M.; Currie, G. S.;
Drew, M. G. B.; Luke, R. W. A. Chem. Commun. 1996,
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12. General procedure for products 5a–l. The requisite
boronic ester (0.5 mmol, 1 equiv) and aldehyde (0.5 mmol,
1 equiv) were dissolved in 1,1,1,3,3,3-hexafluropropan-2-ol
(0.5 mL), and the primary amine (0.5 mmol, 1 equiv) was
then added at room temperature to the resultant solution.
The mixture was stirred for 4 h at room temperature after
which period of time the solvent was evaporated. The
crude residue was purified either by flash chromatography
on silica and eluted with the appropriate eluant (5f: DCM/
MeOH (97:3)), or by crystallization from diethyl ether
(5a–e and 5i–l).
13. For the use of microwave activation of the Petasis reaction
conducted with boronic acids, see: (a) McLean, N. J.; Tye,
H.; Whittaker, M. Tetrahedron Lett. 2004, 45, 993–995; (b)
Follmann, M.; Graul, F.; Sch a¨ fer, T.; Kopec, S.; Hamley,
P. Synlett 2005, 1009–1011.
14. General, microwave-activated procedure for products 5m–
x. The starting boronic ester (0.5 mmol, 1 equiv) and
aldehyde (0.5 mmol, 1 equiv) were dissolved in methanol
(0.5 mL) in a 10 mL microwave vessel. The requisite amine
(0.5 mmol, 1 equiv) was then introduced to the resultant
stirring solution at room temperature. The tube was sealed
with a pressure cap and irradiated for 10 min at 120 °C
(300 W). After cooling to room temperature, the solvent
was evaporated. The crude residue was either purified by
flash chromatography on silica and eluted with the
appropriate eluant (5o–q and 5u: DCM/MeOH (98:2);
5v: cyclohexane/AcOEt (85:15)), or crystallized from
diethyl ether (5m,n,r–t,w and 5x).
1
Soc. 1997, 119, 445–446; (d) Petasis, N. A.; Goodman, A.;
Zavialov, I. A. Tetrahedron 1997, 53, 16463–16470; (e)
Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998,
1
20, 11798–11799; (f) Currie, G. S.; Drew, M. G. B.;
Harwood, L. M.; Hughes, D. J.; Luke, R. W. A.; Vickers,
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2, 2545–2547; (h) Naskar, D.; Roy, A.; Seibel, W. L.;
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Lee, S. H.; Nam, M. H.; Cho, M. Y.; Park, Y. S.; Yoon,
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4
. (a) Petasis, N. A. World Patent 98-00398, 1998; (b)
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5
965–5968.
5
6
. Koolmeister, T.; S o¨ dergren, M.; Scobie, M. Tetrahedron
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. The Petasis reaction proceeds efficiently in a variety of
different solvents. However, cases have been reported in
which a given solvent provides a particularly efficient
medium. See, for instance, Ref. 3h.
. See for instance: (a) Kelly, T. R.; Meghani, P.; Ekkundi,
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(
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2
8
335–2338; (b) Ichikawa, J.; Miyazaki, S.; Fujiwara, M.;
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À1
16. The use of HCl (1% mol ) in CH
Cl
2
led to a 30%
2
conversion of 2a, 3a and 4a after 72 h. This acid
presumably reacts with the amine to generate an ammo-
4
661–4665; (e) Iskra, J.; Bonnet-Delpon, D.; B e´ gu e´ , J.-P.
nium salt, with a pK value lower than that of HFIP.
a