Microwave assisted Petasis boronic-Mannich reactions

Article abstract of DOI:10.1016/j.tetlet.2003.11.092

We have used a design of experiments (DOE) approach to optimise rapidly a set of microwave assisted conditions for the Petasis reaction. The optimal conditions involved the microwave heating of the reaction components in dichloromethane (1M concentration)

Full text of DOI:10.1016/j.tetlet.2003.11.092

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 993–995
Microwave assisted Petasis boronic-Mannich reactions
Neville J. McLean, Heather Tye* and Mark Whittaker
Evotec OAI, 151 Milton Park, Abingdon, Oxfordshire OX14 4SD, UK
Received 15 September 2003; revised 10 November 2003; accepted 21 November 2003
Abstract—We have used a design of experiments (DOE) approach to optimise rapidly a set of microwave assisted conditions for the
Petasis reaction. The optimal conditions involved the microwave heating of the reaction components in dichloromethane (1 M
concentration) at 120 ꢀC for 10 min in a focussed microwave (CEM Explorer). These conditions were successfully applied to a range
of Petasis reactions employing either glyoxylic acid or salicylaldehyde as the carbonyl component along with a number of aryl/
heteroaryl boronic acids and amine components.
ꢁ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
performing best and hindered primary amines per-
forming well in some cases. Anilines and hydrazines
have also been applied to the Petasis reaction to good
effect.9
The Petasis or boronic-Mannich reaction involves the
reaction between an aldehyde, an amine and a boronic
acid (Scheme 1). The reaction is most frequently carried
out with an aldehyde possessing a coordinating group,
which can form a boronate complex and thus facilitate
the carbon–carbon bond forming step. The two alde-
hydes most commonly used are glyoxylic acid 1 and
salicylaldehyde 2 although other hydroxy aldehydes
have also been utilised.1–8 In general the reaction works
well for alkenyl boronic acids and electron neutral or
electron rich aryl and heteroaryl boronic acids. The
range of amines is also varied with secondary amines
In general the reaction conditions employed for the
Petasis reaction involve stirring at room temperature for
periods of 24 h or more. The solvents employed vary
depending on the application and include dichlorome-
thane (DCM), toluene, ethanol and acetonitrile. In some
cases refluxing conditions have been employed but these
cases usually involve a second transformation in addi-
tion to the initial Petasis step.10;11 In our current work to
develop rapid and efficient methods for the synthesis of
compound libraries we have sought to speed up multi-
component reactions using focussed microwave
sources.12 In this communication we describe our results
achieved when applying this approach to the Petasis
reaction of glyoxylic acid and salicylaldehyde, respec-
tively.
R3
OH
B
O
R3
R
N
HN
+
+
OH
R2
R1
X
R
X
R2
R1
O
O
O
OH
O
O
O
or
=
O
O
R
X
a
B
HO
N
OH
+
+
OH
OH
RO
N
H
O
1
2
Scheme 1. The Petasis or boronic-Mannich reaction.
R = H 3a
R = Me 4a
b
Keywords: Petasis; Boronic acid; Mannich; Microwaves; Design of
experiments.
Scheme 2. The Petasis reaction of glyoxylic acid, phenyl boronic acid
and morpholine and subsequent esterification: (a) microwave irradia-
tion; (b) TMS–diazomethane, THF, rt, 3 h.
* Corresponding author. Tel.: +44-01235-441341; fax: +44-01235-44-
1509; e-mail: heather.tye@evotecoai.com
0040-4039/$ - see front matter ꢁ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.092

994
N. J. McLean et al. / Tetrahedron Letters 45 (2004) 993–995
R2
N
O
Ar
O
R2
O
a,b
OH
B
R2
OH
B
R2
HO
HN
HN
R1
a
+
+
OH
N
+
+
R1
MeO
Ar
R1
Ar
OH
R1
O
Ar
4 a-m
OH
OH
5 a-g
Scheme 3. The Petasis reaction of glyoxylic acid under optimised
conditions: (a) microwave irradiation, 120 ꢀC, 10 min, DCM; (b)
TMS–diazomethane, THF, rt, 3 h.
Scheme 4. The Petasis reaction of salicylaldehyde under optimised
conditions: (a) microwave irradiation, 120 ꢀC, 10 min, DCM.
conversions were determined to be 63% and 72%,
respectively, by LC–MS analysis. The crude products
were then esterified and isolated to give the desired
product 4a in 40% and 60% yields, respectively. Al-
though the conversion of the 30 min reaction was mar-
ginally higher we chose to adopt the shorter time of
10 min for further studies to increase the throughput of
the process.17
2. Results and discussion
Initial efforts focussed on the optimisation of the reac-
tion between phenyl boronic acid, glyoxylic acid and
morpholine to give the amino acid derivative 3a (Scheme
2). We used LC–MS to determine the extent of con-
version by comparing the integration of the product
peak with residual boronic acid in the UV trace. Isola-
tion of product 3a proved problematic13 so we opted to
transform the crude product to the corresponding
methyl ester 4a in order to simplify the purification
process.
The optimised reaction conditions were then applied to
a range of aryl boronic acids and amines to assess the
versatility of the microwave assisted reaction (Scheme 3
and Table 1).
In general the reaction gave moderate to good conver-
sion across a range of boronic acids with the electron
poor 4-fluorophenyl boronic acid giving the lowest
result as expected (4d, 53%). The isolated yields of the
ester derivatives were moderate and generally followed
the trends of the conversions with the exception of the
benzofuran derivative (4g, 10%), which was isolated in
low yield due to decomposition during chromatography.
Of the range of amines employed the secondary amines
generally performed best with the exception of diethyl-
Optimisation of the reaction was carried out using a
design of experiments (DOE)14 approach screening
reaction temperature (50–100 ꢀC), time (10–30 min),
concentration (0.1–0.5 M) and solvent (MeOH or DCM)
using a CEM Explorer focussed microwave.15 The
screen determined that DCM was the best solvent, time
was of little importance and the temperature and con-
centration should be high. Two further reactions were
carried out in DCM at 1 M concentration, the first at
120 ꢀC for 10 min and the second for 30 min.16 The
Table 1. Scope of the microwave assisted Petasis reaction with glyoxylic acid
Compound
Boronic acid
Amine
Conversion (%)a
Yield (%)b
4a
4b
4c
4d
4e
4f
Phenyl
Morpholine
Morpholine
63
78
60
53
78
100
66
91
50
54
82
52
40
42
35
34
31
62
10
65
17
18
83
27
3-MeO-phenyl
4-Br-phenyl
4-F-phenyl
4-t-Bu-phenyl
2-Thiophenyl
2-Benzofuranyl
1-Naphthyl
Phenyl
Morpholine
Morpholine
Morpholine
Morpholine
4g
4h
4i
Morpholine
Morpholine
Aminodiphenylmethane
Diethylamine
Dibenzylamine
p-Anisidine
4k
4l
Phenyl
Phenyl
Phenyl
4m
a Conversion to acid assessed by LC–MS.
b Isolated yield of ester after column chromatography.
Table 2. Scope of the microwave assisted Petasis reaction with salicylaldehyde
Compound
Boronic acid
Amine
Conversion (%)
Yield (%)
5a
5b
5c
5d
5e
5f
Phenyl
Phenyl
Morpholine
Aminodiphenylmethane
p-Anisidine
77
––
––
nd
75
57
92
76
Imine
Imine
50
Phenyl
Phenyl
Dibenzylamine
Morpholine
Morpholine
3-MeO-phenyl
4-F-phenyl
2-Benzofuranyl
62
75
5g
Morpholine
23

N. J. McLean et al. / Tetrahedron Letters 45 (2004) 993–995
995
7. Prakash, G. K. S.; Mandal, M.; Schweizer, S.; Petasis,
N. A.; Olah, G. A. Org. Lett. 2000, 2, 3173–3176.
8. Prakash, G. K. S.; Mandal, M.; Schweizer, S.; Petasis,
N. A.; Olah, G. A. J. Org. Chem. 2002, 67, 3718–3723.
9. Portlock, D. E.; Naskar, D.; West, L.; Li, M. Tetrahedron
Lett. 2002, 43, 6845–6847.
10. Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063–4065.
11. Petasis, N. A.; Patel, Z. D. Tetrahedron Lett. 2000, 41,
9607–9611.
amine, which gave only a moderate conversion and the
product being isolated in low yield (4k, 18%). The hin-
dered primary amine and the aniline derivative gave
only moderate conversions as expected.
The microwave assisted protocol was then applied to
reactions involving salicylaldehyde (Scheme 4 and Table
2). In this case the product from the Petasis reaction
could be isolated directly by column chromatography.18
12. Ireland, S. M.; Tye, H.; Whittaker, M. Tetrahedron Lett.
2003, 44, 4369–4371.
13. Ref. 2 above describes the use of ion exchange chroma-
tography but this was not practical in our hands.
14. We used the MODDE 6.0 programme from Umetrics. See
www.umetrics.com.
15. The Explorer microwave is a focussed microwave with a
robotic arm. See www.cem.com.
The reaction proceeded well across the range of boronic
acids employed. Again the yield of the benzofuran
derivative 5g was low due to poor stability. In contrast
to the reaction with glyoxylic acid the range of amines
applicable to this reaction was largely reduced with only
secondary amines giving the desired products. In the
case of the primary amine and the aniline only the
intermediate imine could be detected. This observation
is consistent with results published by Petasis4 who only
achieved a low yield of product when employing a pri-
mary amine in a reaction with a more electron rich
boronic acid in a protic solvent. Attempts to catalyse
our reaction by addition of acetic acid to the reaction
mixture were unsuccessful.
16. The maximum temperature of 120 ꢀC can be achieved in
DCM solvent at 300 W power.
17. Typical procedure: Glyoxylic acid (0.5 mmol) was dis-
solved in DCM (0.5 mL) in a 10 mL microwave tube and
the boronic acid (0.5 mmol) was added with stirring. The
amine (0.5 mmol) was then added at room temperature
and the tube sealed with a pressure cap. The tube was
irradiated in a CEM Explorer microwave for 10 min at
120 ꢀC (300 W). After cooling to room temperature the
solvent was blown off under a stream of nitrogen gas. The
crude residue was dissolved in THF (2 mL) and TMS–
diazomethane (1.0 mmol) added dropwise with stirring.
After 3 h at room temperature the solvent was evaporated
and the product purified by flash column chromatography
on silica gel eluting with an appropriate ethyl acetate/
hexane mixture. Analytical data for compound 4h: yield
65%; 1H NMR (400 MHz, CDCl3) 8.52 (1H, d, J 8.6),
7.89–7.80 (2H, m), 7.68 (1H, dd, J 7.1, 1.0), 7.60–7.42 (3H,
m), 4.77 (1H, s), 3.75–3.68 (4H, m), 3.65 (3H, s), 2.63–2.47
(4H, m); 13C NMR (100 MHz, CDCl3) 183.18 (C@O),
134.39 (C), 132.36 (C), 131.71 (C), 129.52 (CH), 129.04
(CH), 127.8 (CH), 126.79 (CH), 126.26 (CH), 125.71 (CH),
124.56 (CH), 71.37 (CH), 67.43 (CH3), 52.38 (CH2), 51.99
(CH2); MS (ESþ) 286 (M+H)þ.
18. Typical procedure: Salicylaldehyde (0.5 mmol) was dis-
solved in DCM (0.5 mL) in a 10 mL microwave tube. The
boronic acid (0.5 mmol) was added with stirring followed
by the amine (0.5 mmol). The vessel was sealed with a
pressure cap and irradiated in a CEM Explorer microwave
for 10 min at 120 ꢀC (300 W). After cooling to room
temperature the solvent was evaporated and the crude
product purified by column chromatography on silica gel
eluting with an appropriate ethyl acetate/hexane mixture.
Analytical data for compound 5e: yield 62%; 1H NMR
(400 MHz, CDCl3) 11.67 (1H, s), 7.22 (1H, t, J 7.9), 7.15–
7.09 (1H, m), 7.06–6.97 (2H, m), 6.95 (1H, dd, J 7.6, 1.6),
6.85 (1H, dd, J 8.1, 1.2), 6.79 (1H, ddd, J 8.2, 2.6, 0.9),
6.73 (1H, dt, J 7.5, 1.1), 4.36 (1H, s), 3.77 (3H, s), 3.77–
3.74 (4H, m), 2.76–2.40 (4H, m); 13C NMR (100 MHz,
CDCl3) 159.9 (C), 156.06 (CH), 140.93 (CH), 129.97 (C),
129.38 (CH), 128.71 (CH), 124.69 (C), 119.61 (CH), 117.04
(CH), 113.09 (C), 76.84 (CH), 66.92 (2 · CH2), 55.18
(CH3); MS (ESþ) 300 (M+H)þ.
3. Conclusion
We have developed a rapid, microwave assisted protocol
for carrying out Petasis reactions of glyoxylic acid or
salicylaldehyde, which give comparable results to exist-
ing literature methods but only require a 10 min reaction
time as opposed to many hours. The method is appli-
cable to a wide range of aryl boronic acids but generally
only gives good results when secondary amines are
employed. Use of a DOE approach allowed us to rap-
idly screen reaction conditions against a number of
variables and efficiently determine the optimum condi-
tions for the microwave assisted reaction.
References and notes
1. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997,
119, 445–446.
2. Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron
1997, 53, 16463–16470.
3. Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron
2000, 56, 10023–10030.
4. Petasis, N. A.; Boral, S. Tetrahedron Lett. 2001, 42, 539–
542.
5. Berree, F.; Debache, A.; Marsac, Y.; Carboni, B. Tetra-
hedron Lett. 2001, 42, 3591–3594.
6. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1980,
120, 11798–11799.