An efficient HCl promoted Petasis reaction of 2-pyridinecarbaldehydes, amines and 1,2-oxborol-2(5H)-ols

Article abstract of DOI:10.1016/j.tetlet.2018.04.013

A Petasis reaction of 2-pyridinecarbaldehydes with various amines and 4-substituted 1,2-oxaborol-2(5H)-ols was developed. In the presence of HCl, the reaction proceeded smoothly under very mild conditions and the corresponding desired products were obtained in medium to excellent yields. This method allows the access a wide range of highly functionalized allylic alcohols, which might be useful compounds in medicinal and material chemistry.

Full text of DOI:10.1016/j.tetlet.2018.04.013

Accepted Manuscript
An Efficient HCl Promoted Petasis Reaction of 2-Pyridinecarbaldehydes,
Amines and 1,2-Oxborol-2(5H)-ols
Tao Ding, Yazhen Duan, Hui Li, Baoguo Zhao, Jun Yang
PII:
S0040-4039(18)30456-8
https://doi.org/10.1016/j.tetlet.2018.04.013
TETL 49876
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
9 February 2018
2 April 2018
8 April 2018
Please cite this article as: Ding, T., Duan, Y., Li, H., Zhao, B., Yang, J., An Efficient HCl Promoted Petasis Reaction
of 2-Pyridinecarbaldehydes, Amines and 1,2-Oxborol-2(5H)-ols, Tetrahedron Letters (2018), doi: https://doi.org/
1
0.1016/j.tetlet.2018.04.013
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An Efficient HCl Promoted Petasis Reaction
of 2-Pyridinecarbaldehydes, Amines and 1,2-
Oxborol-2(5H)-ols
Leave this area blank for abstract info.
a
b
b
,a
,b
Tao Ding , Yazhen Duan , Hui Li ，Baoguo Zhao* , Jun Yang*
R
R1
R
HCl (1.0 equiv)
R2
R3
R1
+
+
N
N
o
H
CH CN, 80 C, 48h
N
CHO
O B
3
N
R2
R3 OH
OH
1
5 examples
yield : 36~98%

1
Tetrahedron Letters
An Efficient HCl Promoted Petasis Reaction of 2-Pyridinecarbaldehydes, Amines and
,2-Oxborol-2(5H)-ols
1
a
b
b
,a
,b
Tao Ding , Yazhen Duan , Hui Li ，Baoguo Zhao* , Jun Yang*
a
The Education Ministry Key Lab of Resources Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University,
Shanghai 200234, China
Key Laboratory of Advanced Propellant Materials, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of
b
Sciences, 345 Lingling Road, Shanghai 200032, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A Petasis Reaction of 2-pyridinecarbaldehydes with various amines and 4-substituted 1, 2-
oxaborol-2(5H)-ols was developed. In the presence of HCl, the reaction proceeded smoothly
under very mild conditions and the corresponding desired products were obtained in medium to
excellent yields. This method allows the access a wide range of highly functionalized allylic
alcohols, which might be useful compounds in medicinal and material chemistry.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Petasis Reaction
2
1
-Pyridinecarbaldehyde
,2-Oxborol-2(5H)-ol
Amine
Iminium
The Petasis borono-Mannich(PBM) reaction involves the
aziridine-aldehyde dimers16 were reported to react successfully
in the PBM reaction. To expand the reaction scope of the unique
1,2-oxabrol-2(5H)-ols, herein we reported the details of an
condensation of amines, aldehydes and boronic acid
1
nucleophiles . This reaction has been proved to be a useful tool to
prepare complex molecules in a single step from readily available
efficient
Petasis
borono-Mannich
reaction
of
2-
2
1b,3
1a,4
5
materials . Amino acids , amino alcohols , amino diols , 2H-
pyridinecarbaldehydes, amines and 4-substituted 1, 2-oxaborol-
2(5H)-ols.
6
7
chromenes , 2,5-dihydrofurans and some other types of
8
heterocycles could be constructed from this versatile reaction.
2
-Pyridinecarbaldehyde, 4-benzyl-1, 2-oxaborol-2(5H)-ol and
Organoboron compounds are stable, non-toxic and
compatible of many functional groups . In 2006, Fang reported
morphine was selected as model substrates for the Petasis
reaction (Table 1). When using 1, 2-dichloroethane as solvent,
the desired compound 4a was obtained in a low yield of 28%
after stirring at 80°C for 48 hrs (Table 1, Entry 1). Reductive
product 5a from 4-benzyl-1, 2-oxaborol-2(5H) was also observed
in the reaction. An elevated temperature of 90°C led to 4a in a
better yield of 54% (Table 1, Entry 2). Considering the acidic
property of glyoxylic acid or salicyladehyde commonly used in
the Petasis reaction, we anticipated that acid might accelerate the
iminium formation step and benefit the Petasis reaction. At the
beginning, some organic acids like acetic acid, benzoic acid and
trifluoromethanesulfonic acid were tested, only acetic acid
afforded 4a in 29% yield (Table 1, Entry 3). While benzoic acid
and trifluoromethanesulfonic acid only led to messy mixtures and
no further effort was given. Lowering the temperature was totally
disfavored when using acetic acid as addictive (Table 1, Entry 4).
Then we turn our attention to inorganic acids, which showed
hydrochloride acid could promote the reaction well and afforded
the desired product in yield of 75% determined by 1H NMR
9
the first preparation of 4-substituted 1,2-oxaborol-2(5H)-ols and
1
0
their Suzuki-Miyaura cross-coupling reaction with aryl halides .
Indeed, substituted allyl alcohols are commonly encountered in
natural products and their syntheses are tedious and usually led to
11
mixtures of E and Z configurations . Allylic alcohols are
necessary intermediates for allylic substitution. Kobayashi etc.
reported that the E and Z configurations of the olefin could
1
2
switch the configuration of the products . By involvement of 4-
substituted 1,2-oxaborol-2(5H)-ols, (Z)-4-aryl-but-2-en-1-ols
were prepared efficiently by Fang’s method. A more delicate
structure, furan, was designed based on the coupling reaction of
13
oxaborol compounds and carboxylic anhydrides . In 2013, we
reported the first amine-promoted Petasis borono-Mannich
reaction of 4-substituted 1,2-oxaborol-2(5H)-ols with
7
salicylaldehydes . This procedure combines a borono-Mannich
reaction and an intramolecular SN
2
cyclization.
The borono-Mannich reaction
was
limited
to
(Table 1, Entry 5). A reaction was carried out under Argon did
salicylaldehydes in the early stage. This allows the activation of
not provide better yield (Table 1, Entry 6). When the reaction
was proceed for a shorter time of 24 hrs, only 41% yield of the
desired production was obtained. However prolonged reaction
time provided 4a in 76% yield (Table 1, Entry 9). A little
boronic acid as an ‘ate’ complex and resulted in the transfer of a
14
vinyl or aryl group to the transient iminium species . Later on, 2-
15
6b
pyridinecarbaldehydes ,
2-sulfamidobenzaldehyde
and

2
Tetrahedron Letters
decrease in yield was observed when utilizing a higher
or just similar to conditions without it. But byproduct 5a was not
detected (Table 1, Entry 7 & 17). A control experiment without
acid was carried out in acetonitrile and the yield of desired
product 4a was decreased (Table 1, Entry 18).
reaction temperature of 90°C (Table 1, Entry 10). Increasing in
the amount of HCl affected the reaction dramatically and led to
low yields. In the following experiments, several solvents were
screened and acetonitrile was proved to be the best solvent and
an excellent yield of 94% was obtained (Table 1, Entry 16).
When 4 Å molecular sieves were added, yield of 4a was higher
a
Table 1: Opitimization of Reaction Conditions
b
b
Entry
Solvent
DCE
Temp(°C)
80
Time(h)
48
Acid(equiv)
none
4a (％)
5a (％)
1
2
3
4
5
28
54
29
15
9
11
24
14
8
DCE
90
48
none
DCE
80
48
AcOH (1.0)
AcOH (1.0)
HCl (1.0)
HCl (1.0)
HCl (1.0)
HCl (1.0)
HCl (1.0)
HCl (1.0)
HCl (1.5)
HCl (2.0)
HCl (1.0)
HCl (1.0)
HCl (1.0)
HCl (1.0)
HCl (1.0)
none
DCE
70
48
c
DCE
80
48
75(59)
d
6
DCE
80
48
75
80
41
76
73
35
20
50
52
68
94
93
86
7
e
7
DCE
80
48
0
8
9
DCE
80
24
4
DCE
80
72
7
1
1
1
1
1
1
1
0
1
2
3
4
5
6
DCE
90
48
9
DCE
80
48
45
24
5
DCE
80
48
i-PrOH
Toluene
80
48
80
48
9
CH
3
CN:H
CH
CH
CH
2
O(4 : 1)
80
48
trace
5
3
CN
CN
CN
80
48
e
1
7
3
80
48
0
1
8
3
80
48
16
a
Reaction conditions: A mixture of 1a (1.0 equiv), 2a (1.5 equiv) and morpholine 3a (1.0 equiv) was stirred in a
sovlent at elevated temperature in a sealed tube.
b
Determined by crude 1H-NMR (400 MHz, CDCl3) with adding 4'-nitro-acetophenon as internal standard. Reaction
yield was based on 1a.
c
Isolated product yield (silica gel chromatography) was showed in parentheses.
Reaction was carried out under Argon.
With 4 Ả molecular sieves.
d
e
Next, the reaction scope was investigated under the optimized
reaction conditions (Table 1, Entry 16). As we can see from
Table 2, both aryl groups (4a-4d) and alkyl group (4e) on 4-
substituted 1,2-oxaborol-2(5H)-ols could tolerate the reaction
well and gave the corresponding Petasis products in good to
excellent yields. A strong electron-donating group of methoxyl
on benzyl ring led to a decreased yield (4c, 61%). However, a
bulky group of naphthalene gave an excellent yield (4d). A yield
of 75% was achieved when 4-phenylehthyl-1, 2-oxaborol-2(5H)-
ol was utilized (4e).
yields (4f-4j). Cyclic amines (4f&4i) led to better results than
acyclic amines (4g&4h). While a steric-hindered amine, 8-oxa-3-
aza-bicyclo [3.2.1] octane, only afforded the desired product in
yield of 42% (4j).
As regard for aldehyde components, both electronic and steric
effects played important roles in the reaction (4k-4o). Electron-
withdrawing groups on 2-pyridinecarbaldehyde could retard the
reaction and only give the desired product in low to medium
yields (4m-4o). It is worth mentioning that when two aldehydes
present on pyridine, only aldehyde at ortho-position took place in
this reaction and para-position aldehyde left intact (4m). A steric
hindered 3-methoxyl-2-pyridinecarbaldehyde could react with 4-
Both cyclic and acyclic amines could be used in the Petasis
reaction, affording the desired product in medium to excellent

3
p-methylphenyl-1, 2-oxaborol-2(5H)-ol and 1-phenylpiperazine
and gave the desired product in a yield of 37% (4o). The
structure of the Petasis reaction products was confirmed by the
X-ray crystallographic analyses of 4a (Figure 1).
a
Table 2. Substrate Scope for Petasis Reaction of 2-Pyridinecarbaldehydes, 1, 2-Oxaborol-2(5H)-ols, and Amines
a
Reaction conditions: A mixture of 1a (0.5 mmol, 1.0 equiv), 2a (0.75mmol, 1.5 equiv), 3a (0.5
mmol, 1.0 equiv) and HCl (2.0 M in dioxane, 0.5 mmol, 1.0 equiv) in a sealed tube was stirred at
8
0°C for 48h.
b
With side reaction. Reaction time was 24h.

4
Tetrahedron
amines adjacent to heteroaromatic rings, which might be useful
compounds in medicinal and material chemistry. Further
exploration of this powerful strategy of Petasis reactions in
establishing new C-N bond formation reactions is underway in
our laboratory.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (NSFC) (grant number 21602241) and Natural Science
Foundation of Shanghai, China (grant number 16ZR1443600) for
financial support.
References
1
.
(a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798-
11799; (b) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron
Figure 1 X-ray Structure of 4a
1
997, 53, 16463-16470; (c) Petasis, N. A.; Zavialov, I. A. J. Am. Chem.
In order to test the generality of this method, a normal boronic
Soc. 1997, 119, 445-446; (d) Petasis, N. A.; Akritopoulou, I. Tetrahedron
Lett. 1993, 34, 583-589.
(a) Graaff, C.; Ruijiter, E.; Orru, R. R. A. Chem. Soc. Rev. 2012, 41,
acid, 4-methoxyphenylboronic acid was used to participate in this
HCl promoted Petasis reaction and a good yield of 86% was
achieved (Scheme 1).
2
3
.
.
3
969-4009; (b) Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois,
P. M. P. Chem. Rev. 2010, 10, 6169-6193; (c) Yu, T.; Li, H.; Wu, X. Y.;
Yang, J. Chin. J. Org. Chem. 2012, 32, 1836-1845.
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2
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Scheme 1 Boronic Acid in Petasis Reaction
(a) Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063-4065; (b) Petasis, N.
A.; Butkevich, A. N. J. Organomet. Chem. 2009, 694, 1747-1753.
Cui, C. –X.; Li, H.; Yang, X. –J.; Yang, Y.; Li, X. –Q. Org. Lett. 2013,
A possible mechanism for the process was depicted in Scheme
2. Initially pyridinecarbaldehyde reacted with secondary amines
1
5, 5944-5947.
(a) Regnier, T.; Berree, F.; Lavastre, O.; Carboni, B. Green Chem. 2007,
, 125-126. (b) Hong, Z.; Liu, L; Hsu, C. –C.; Wong, C. –H. Angew.
and converted to iminium intermediate 6 under the aid of acid.
Next, complexation of 4-substituted 1, 2-oxaborol-2(5H)-ol
yielded an ate complex 7. Subsequent, a C-C bond was formed
by the intermolecular transfer of the vinyl group to give
intermediate 8. Finally hydrolysis of intermediate 8 gave the final
product 4.
9
Chem. Int. Ed. 2006, 45, 7417-7421; (c) Hong, Z.; Liu, L.; Sugiyama, M.;
Fu, Y.; Wong, C. –H. J. Am. Chem. Soc. 2009, 31, 8352-8353.
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9
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1
995, 95, 2457-2483.
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1
1
1
1
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1
1
4. (a) Schlienger, N.; Bryce, M. R.; Hanson, T. K. Tetrahedron Lett. 2000,
4
1, 1303-1305; (b) Petasis, N. A.; Boral, S. Tetrahedron Lett. 2001, 42,
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Scheme 2 Plausible Reaction Mechanism
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8, 11637-11645.
1
In conclusion, we have developed a Petasis reaction of 2-
pyridinecarbaldehydes with various amines and 4-substituted 1,
7
2
-oxaborol-2(5H)-ols. In the presence of HCl, the reaction could
proceed smoothly under very mild conditions and the
corresponding desired products were obtained in medium to
excellent yields. This method allows us to access a wide range of
Click here to remove instruction text...

5
A Petasis reaction of 2-pyridinecarbaldehydes, amines
and 1, 2-oxborol-2(5H)-ols was developed
Medium to excellent yields was achieved in the
presence of HCl
This reaction afforded a wide range of highly
functionalized allylic alcohols