An improved protocol for Petasis reaction of 2-pyridinecarbaldehydes

Article abstract of DOI:10.1016/j.tetlet.2010.07.039

A highly efficient and improved method has been developed for Petasis reactions of various 2-pyridinecarbaldehydes with secondary amines and boronic acids under catalyst-free conditions. The desired products are obtained in up to 96% yield in refluxed acetonitrile.

Full text of DOI:10.1016/j.tetlet.2010.07.039

Tetrahedron Letters 51 (2010) 4779–4782
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An improved protocol for Petasis reaction of 2-pyridinecarbaldehydes
*
Hiroki Mandai , Kyouta Murota, Takashi Sakai
Division of Chemistry and Biochemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient and improved method has been developed for Petasis reactions of various 2-pyridine-
carbaldehydes with secondary amines and boronic acids under catalyst-free conditions. The desired
products are obtained in up to 96% yield in refluxed acetonitrile.
Received 2 June 2010
Revised 3 July 2010
Accepted 8 July 2010
Available online 11 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Multicomponent reactions are highly efficient and atom eco-
nomical transformations in synthetic organic chemistry.1 They
can be used for constructing an array of compound libraries in
the medicinal chemistry field. In the course of our research pro-
gram, we have been showing interest in the boron Mannich reac-
tion disclosed by Petasis.2 Three substrates (aldehyde, amine, and
boronic acid) react sequentially to afford a Mannich adduct with-
out any catalyst. However, only a few aldehydes (e.g., glyoxylic
conversion than that in 0.5 M which caused solubility issue of vinyl
boronic acid (entries 1–3). In addition, reaction at refluxed temper-
ature in 0.2 M of MeCN gave the product in >98% conversion after
15 h (entry5), and laterTLC analysisof the reaction mixturerevealed
that full consumption of aldehyde was observed after 3 h under the
same conditions (entry 6). Accordingly, the Petasis reaction of 2-pyr-
idinecarbaldehyde 1 with dibenzylamine 2 and vinyl boronic acid 3
proceeded smoothly in MeCN at refluxed temperature within 3 h,
affording the Mannich adduct 4 in >98% conversion (96% isolated
yield after silica gel column chromatography).9
acid3 and -hydroxyl aldehyde4) have been employed in this reac-
a
tion, and successful examples of aromatic aldehydes have been
limited to salicyl aldehydes.5 In 2000, Bryce and Hansen reported
Petasis Mannich reactions of 2-pyridinecarbaldehyde with mor-
pholine and vinyl boronic acid under catalyst-free conditions,
affording the desired products in 10% yield.6 They finally found
that using the more reactive alkenyl trifluoroborate salt and chlo-
rotrimethylsilane as activators improved the yield of the desired
product up to 54% yield. Thus, there are no efficient methods for
Petasis Mannich reactions of 2-pyridinecarbaldehydes with amine
and boronic acid under catalyst-free conditions. In this Letter, we
would like to report on an improved method for Petasis reaction
of 2-pyridinecarbaldehydes with various amines and boronic acids
under catalyst-free conditions.
Table 1
Solvent effect on Petasis reactiona
N
CHO
NBn2
HNBn2
+
N
Ph
1
2
Solvent
rt, 15 h
4
Ph
+
(HO)2B
3
Initially, we examined various solvents for the Petasis reaction
of 2-pyridinecarbaldehyde 1 with dibenzylamine 2 and vinyl boro-
nic acid 3 at room temperature. As illustrated in Table 1, CH2Cl2,
dichloroethane, MeCN, and hexafluoroisopropanol (HFIP)7 under-
went Petasis reactions in 55–78% conversion; however, other
solvents, such as MeOH, H2O,5d and 1-butyl-2,3-dimethylimidazo-
lium tetrafluoroborate ([bdmim]BF4),8 which were often utilized in
Petasis reactions, resulted in <10% conversion. Although the effect
of the solvent is unclear, MeCN clearly enhanced the reaction rate
and was found to be the optimal solvent.
Entry
Solvent
CH2Cl2
Dichloroethane
MeCN
Conv.b (%)
1
2
3
4
5
6
7
8
9
55
46
73
58
<10
<10
<2
HFIP
MeOH
Toluene
THF
Et2O
DMF
<2
<10
<10
<2
10
11
H2O
[bdmim]BF4
Next, to improve the conversion of the desired product, we
screened the substrate concentration and reaction temperature (Ta-
ble 2). Reaction in 0.1 or 0.2 M of the solvent gave a slightly better
a
Reactions performed under an atmosphere of N2 with 1.0 equiv of aldehyde 1
and amine 2 in the presence of 1.0 equiv of vinyl boronic acid at room temperature
for 15 h.
b
* Corresponding author. Tel.: +81 86 251 8604; fax: +81 86 251 8082.
E-mail address: mandai@cc.okayama-u.ac.jp (H. Mandai).
Conversions were determined by analysis of 1H NMR spectra of the unpurified
reaction mixtures.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.039

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H. Mandai et al. / Tetrahedron Letters 51 (2010) 4779–4782
Table 2
sis reaction, affording the desired products in 72–96% yields (en-
Effect of concentration and reaction temperaturea
tries 1–5).10 In contrast, the structure of an aldehyde component
had a great influence on the yield of the product (entries 6–12).
For example, reactions of 6-methoxy- and 6-bromo-2-pyridinecar-
baldehydes with dibenzylamine and vinyl boronic acid dramati-
cally decreased the reaction efficiency under the optimized
conditions (16% for 9 and 11% for 10, respectively; entries 6 and
8), and use of excess vinyl boronic acid (1.5 equiv) slightly in-
creased the yield of the products (31% and 23%, respectively, en-
tries 7 and 9). Whereas 5-bromo-2-pyridinecarbaldehyde with
1.0 equiv of dibenzylamine and vinyl boronic acid reacted
smoothly to deliver the Petasis adduct 11 in 91% yield (entry 10).
These results clearly indicate that steric hinderance adjacent to
pyridine nitrogen dominates the reactivity of the aldehyde compo-
nent. For this reason, 6-bromo-2-pyridinecarbaldehyde suffered
reactivity and resulted in a low yield (entry 8 vs 10). It might be
Entry
Concn (M)
Temp (°C)
Conv.b (%)
1
2
3
4
5
6c
0.1
0.2
0.5
0.2
0.2
0.2
rt
rt
rt
50
Reflux
Reflux
73
73
59
84
>98 (96)d
>98 (96)d
a
Reactions performed under an atmosphere of N2 with 1.0 equiv of aldehyde 1
and amine 2 in the presence of 1.0 equiv of vinyl boronic acid 3 for 15 h except
entry 6.
b
Conversions were determined by analysis of 1H NMR spectra of the unpurified
reaction mixtures.
c
The reaction time was 3 h.
Isolated yield of the product.
d
considered that an a-heteroatom moiety played an important role
Various amines, aldehydes, and boronic acids were examined
under optimized conditions (Table 3). As alternative nitrogen
sources, both acyclic- and cyclic amines could be used in the Peta-
in taking boronic acid close to the reaction site and/or in intramo-
lecular activation of boronic acid (e.g., ate complex formation by
nitrogen atom).1 Reaction of 4-chloro- and 4-dimethylamino-2-
Table 3
Scope of the substrate for Petasis reactiona
NR1R2
+
R1R2NH
+
R3B(OH)2
ArCHO
MeCN, reflux, 3−15h
Ar
R3
Entry
1c
ArCHO
Amine
Boronic acid
Product
Yieldb (%)
NBn2
Ph
Ph
N
CHO
CHO
(HO)2B
N
HNBn2
96
Ph
4
Me
Me
N
N
N
Ph
N
Ph
(HO)2B
(HO)2B
N
H
2
77
72
Ph
5
N(Allyl)2
Ph
Ph
CHO
CHO
N
3d
HN(Allyl)2
Ph
6
O
O
N
N
(HO)2B
4
95
N
Ph
Ph
N
H
7
Ph
Ph
N
CHO
N
N
5
75
(HO)2B
(HO)2B
N
N
H
8
NBn2
MeO
CHO
MeO
N
6
16
31
HNBn2
7e
Ph
9

H. Mandai et al. / Tetrahedron Letters 51 (2010) 4779–4782
4781
Table 3 (continued)
Entry
ArCHO
Amine
HNBn2
Boronic acid
Product
Yieldb (%)
NBn2
Ph
Ph
Br
Br
N
N
CHO
CHO
Br
N
N
8
11
23
(HO)2B
9e
Ph
Ph
10
NBn2
(HO)2B
(HO)2B
10
11
HNBn2
HNBn2
91
74
11
NBn2
Br
N
N
CHO
Ph
Ph
Ph
Ph
12
Cl
Cl
N
NBn2
N
CHO
(HO)2B
(HO)2B
12
HNBn2
35
13
NMe2
N
NMe2
N
NBn2
O
CHO
CHO
O
O
13
14
HNBn2
90
70
O
14
NBn2
N
N
N
N
(HO)2B
(HO)2B
HNBn2
HNBn2
HNBn2
HNBn2
OMe
OMe
15
NBn2
CHO
15
27
46
16e
OMe
OMe
16
NBn2
N
N
N
N
CHO
CHO
(HO)2B
(HO)2B
O
O
S
17
80
17
NBn2
S
18
32
78
19e
18
a
b
c
Reactions performed under an atmosphere of N2 with 1.0 equiv of aldehyde and amine in the presence of 1.0 equiv of boronic acid in refluxed MeCN for 15 h.
Isolated yield of the product after silica gel column chromatography.
The reaction time was 3 h.
The reaction time was 12 h.
1.5 equiv of boronic acid was used.
d
e
pyridinecarbaldehyde proceeded to afford the products 12 and 13
in 74% and 35%11 yields, respectively. Other heteroaromatic alde-
hydes involving 3-pyridinecarbaldehyde, pyrrole-2-carboxalde-
hyde, imidazole-2-carboxaldehyde, and 2-quinolinecarboxalde-
hyde resulted in no conversion or a complex mixture (data not
shown), and the reasons for these results remained obscure. As a

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H. Mandai et al. / Tetrahedron Letters 51 (2010) 4779–4782
result, Petasis reactions of various 2-pyridinecarbaldehyde analogs
took place, and these phenomena were consistent with previous
observations.6
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.039.
With regard to the boronic acid component, a variety of aro-
matic boronic acids could be used in this reaction, delivering the
desired products 14–18 in 46–90% yields (entries 13–17). In some
cases, 1.5 equiv of boronic acid was required to obtain a reasonable
yield (entry 15 vs 16 and 18 vs 19). However, no desirable products
were obtained when the reactions were performed with electron-
deficient phenylboronic acid and 3,5-bis(trifluoromethyl)phenyl-
boronic acid (data not shown). It seems that the boronic acid com-
ponent should have enough nucleophilicity to react with the
iminium intermediate.
In conclusion, we have developed Petasis reactions of various 2-
pyridinecarbaldehydes with various amines and boronic acids
without any catalyst. Our method allows us to access a wide range
of amines adjacent to heteroaromatic rings, which may be useful
compounds for medicinal and material chemistry. Further investi-
gations regarding Petasis reactions of heteroaromatic aldehydes
References and notes
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N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463–16470; (c)
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Butkevich, A. N. J. Organomet. Chem. 2009, 694, 1747–1753; (f) Candeias, N. R.;
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with or without an a-heteroatom are now in progress.
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7. It was reported that use of HFIP as solvent accelerates the Petasis reaction, see:
Acknowledgments
Ref.3c
.
8. Yadav, J. S.; Reddy, B. V. S.; Lakshmi, P. N. J. Mol. Catal. A: Chem. 2007, 274, 101–
104.
9. See Supplementary data for detail.
10. No desired products were obtained when diisopropylamine, pyrrolidine, and
benzylamine were used.
11. Undesirable side reaction was observed.
The financial support was provided by Grant-in-Aid for Young
Scientists (Start-up, No. 21850020) from Japan Society for the Pro-
motion of Science (JSPS), Okayama Foundation for Science and
Technology, Wesco Scientific Promotion, and Okayama University.
We are grateful to the SC-NMR Laboratory of Okayama University
for the measurement of NMR spectra.