Concise synthesis of aromatic tertiary amines via a double Petasis-borono Mannich reaction of aromatic amines, formaldehyde, and organoboronic acids

Article abstract of DOI:10.1016/j.tetlet.2014.03.131

A simple and efficient strategy to construct aromatic tertiary amines via a double Petasis-borono Mannich reaction of aromatic amines, formaldehyde, and organoboronic acids has been developed. The transformation provides a useful method for the synthesis of amine derivatives.

Full text of DOI:10.1016/j.tetlet.2014.03.131

Accepted Manuscript
Concise synthesis of aromatic tertiary amines via a double Petasis-borono Man-
nich reaction of aromatic amines, formaldehyde and organoboronic acids
Jiayi Wang, Pinzhen Li, Qiaoying Shen, Gonghua Song
PII:
S0040-4039(14)00563-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.03.131
TETL 44453
Reference:
Tetrahedron Letters
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21 March 2014
28 March 2014
Please cite this article as: Wang, J., Li, P., Shen, Q., Song, G., Concise synthesis of aromatic tertiary amines via a
double Petasis-borono Mannich reaction of aromatic amines, formaldehyde and organoboronic acids, Tetrahedron
Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.03.131
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Jiayi Wang, Pinzhen Li, Qiaoying Shen and Gonghua Song*

1
Tetrahedron Letters
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Concise synthesis of aromatic tertiary amines via a double Petasis-borono Mannich
reaction of aromatic amines, formaldehyde and organoboronic acids
Jiayi Wang, Pinzhen Li, Qiaoying Shen and Gonghua Song∗
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, 200237, P. R. China.
1
ARTICLE INFO
ABSTRACT
Article history:
Received
A simple and efficient strategy to construct aromatic tertiary amines via a double Petasis-borono
Mannich reaction of aromatic amines, formaldehyde and organoboronic acids has been
developed. The transformation provides a useful method for the synthesis of amine derivatives.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Petasis-borono Mannich reaction
Organoboronic acids
Aromatic amines
Formaldehyde
Multi-component reaction
Aromatic amines and their derivatives are present in many
bioactive natural products and pharmaceuticals. Therefore, the
formation of C-N bonds, which has attracted more and more
5 attention, is one of the most important transformations in organic
reactions. For the synthesis of aromatic tertiary amines, a number
of synthetic methodologies have been developed (Scheme 1).1
Among these synthetic methods, nucleophilic substitution of
alkyl halides with amines under bases,2 as well as reductive
simple and efficient approach to the synthesis of aromatic tertiary
amines has attracted special attention.
H
N
Ar NH2
a.
a. Ar
X = I, Br, Cl
cat. Cu or Pd
X
R
X
R
R'
X = Cl, Br, I
Base
35
40
b.
ArB(OH)2 or ArB(OR)2
cat. Cu, [O]
b. RCH2OH
cat. Ni, Cu, Pt,
Ru, Pd, etc.
R = R'
A
10 amination between aldehydes and amines under reductants,3 has
been widely used and well documented (Scheme 1, path A (a)
and path B (a, b)). The metal catalyzed alkylation of amines with
alcohols by a hydrogen autotransfer process has also gained
considerable attention (Scheme 1, path A (b) and path B (c)).4,5
15 On the other hand, since Ullmann reported the condensation of
aryl halides and amines by Cu powder in 1903,various Cu or Pd
catalysts have been applied in this type of cross coupling reaction
(Scheme 1, path C (a)).6,7 And the Cu-mediated oxidative
coupling of arylboronic acids or esters with amines, developed
20 independently by the groups of Chan, Lam, and Evans, named
Chan-Lam reaction, provides a complementary approach to
amine derivatives (Scheme 1, path C (b)).8 Besides the
commonly used primary and secondary amines, N,N-dialkyl-O-
acyl hydroxylamine derivatives and N,N-dialkyl-N-chloramines
25 can also be the sources for the synthesis of tertiary amines via Cu
or Ni catalyzed electrophilic amination of
C
Zn
Ar
Ar
Ar
N
ArMgBr
ArB(OR)2
(ArBO)3
or
or
or
R'
X
a.
b.
B
D
X = Cl, Br, I
Base
R
R'
X
N
R
cat. Ni or Cu
Ar NH
R'CHO
[H]: NaBH3CN
or H2, etc
E
R
R'
This study
X = Cl, OBz
cat., [O], [H], base -free!
R = R'
c. R'CH2OH
cat. Ni, Cu, Pt,
Ru, Pd, etc.
Ar NH2
HCHO
2
2 RB(OH)2
via double PBM Reaction
45 Scheme 1 Strategies toward the synthesis of aromatic tertiary
amines.
In addition to high flexibility, selectivity and atom economy,
multicomponent reactions have been one of the most powerful
organometallic 50 and convenient synthetic routes for building large libraries of
reagents with R2N+ synthons (Scheme 1, path D).9 Although the
small molecule compounds.11 In 1993, Petasis et al. reported the
synthesis tertiary allylamines via a three-component reaction of
vinyl boronic acids, secondary amines and paraformaldehyde,
described methods above are usually very efficient, a metal
catalyst, base, oxidant or reductant is necessary to fulfill the
30 reaction, which makes these methods either less friendly to the
environment or less economic.10
which was then named as Petasis-borono Mannich reaction
12
Therefore, the development of a 55 (PBM). So far, PBM reaction has been applied as an efficient
———
∗ Corresponding author. Tel.: +86 21 64253140; fax: +86 21 6425 2603; e-mail: ghsong@ecust.edu.cn

2
Tetrahedron
method in the construction of diverse α-amino acids, α-
the three-component reaction was applicable in a variety of aryl
amines and aryl boronic acids with both electron-donating and -
hydroxyl amines and nitrogen-containing heterocycles.13,14
However, to the best of our knowledge, there is no report of 50 withdrawing groups (-MeO, -Me, -Cl and -F). For the boronic
synthesis of aromatic tertiary amines via a double PBM reaction.
5 Herein we reported a convenient and efficient synthesis of
aromatic tertiary amines via a double Petasis-borono Mannich
reaction of aromatic amines, formaldehyde and organoboronic
acid component, electron-donating substituents on the aromatic
ring led to higher yields than electron-withdrawing groups (4ab,
96% vs. 4ad, 80%; 4bb, 92% vs. 4bd, 62%; 4db, 93% vs. 4dd,
75%; 4eb, 94% vs. 4ed, 87%). As to the amine component, both
acids (Scheme 1, path E). The starting materials are easily 55 electron efficient and weakly electron deficient aryl amines could
available, and there is no need of using any metal catalyst, base,
10 oxidant or reductant. Thus, the protocol presented provides a
useful complementary approach to amine derivatives.
deliver corresponding products in moderate to good yields (4aa-
4ag, 4ba-4bd, 4ca-4cc, 4db-4dg, 4eb and 4ed). Unfortunately,
the highly electron deficient 4-(trifluoromethyl)phenylboronic
acid 3h or 4-nitroaniline 1f was ineffective to produce the
60 product (4ah and 4fa-4fb). While naphthalen-1-amine reacted
well affording the product 4ib in 92% yield, the heteroaryl
amines, pyridin-2-amine 4j and pyrazin-2-amine 4k, resulted
lower yields (34% and 27% yield, respectively).
The optimization study was initiated with model reaction of
aniline 1a, formaldehyde 2 and phenylboronic acid 3a. As shown
in Table 1, the three-component reaction was ineffective in
15 ethanol, acetonitrile or THF with a yield of less than 5% (Table 1,
entries 1-3), and only trace of products was observed with H2O or
DMSO as solvent (Table 1, entries 4-5). The reaction went
Interestingly, steric selectivity was observed according to the
anilines
smoothly in 1,2-dichloroethane, dichloromethane and toluene 65 reaction
results
of
different
with
2-
with moderate yields of 55%, 70% and 67%, respectively (Table
20 1, entries 6-8). A decreased yield of 53% was obtained with
dichloromethane as solvent under reflux, while the yield can be
methoxyphenylboronic acids 3g. As shown in Scheme 2, aniline
1a reacted with 2-methoxyphenylboronic acid 3g to produce
tertiary amine 4ag with a good yield of 82%, while the secondary
amine product 5ag was rarely produced. With increased sterical
o
improved to 89% in toluene at 60 C (Table 1, entries 9-10).
Further elevating the reaction temperature to 80 or 100 oC led to 70 hindrance from aniline 1a to 2-fluoroaniline 1l, the yield of
decrease in yield (Table 1, entries 11-12). When the reaction was
a
dramatically decreased yield of 11% was obtained (Table 1, entry
13). A low yield of 7% was afforded when paraformaldehyde
corresponding tertiary amines 4lg decreased from 82% to 31%,
while the yield of secondary amines 5lg increased to 43%. With
more sterically hindered o-toluidine 1g and 2-methoxyaniline 1m,
only secondary amine 5gg and 5mg were produced in yields of
25 performed under air instead of nitrogen atmosphere,
was adopted instead of formaldehyde (Table 1, entry 14). The 75 49% and 59%, respectively.
three-component reaction went smoothly with 2,4,6-
Table 2 Substrate scope a
30 triphenylboroxin 3ab (73% in yield), while phenylboronic acid
pinacol ester 3ac and potassium phenyltrifluoroborate 3ad failed
to generate the product (Table 1, entries 15-17).
Table 1 Optimization studiesa
80
85
90
95
NH2
35
solvent, T
1a
O
N
B
H
H
2
4aa
3
Entry
1
solvent
EtOH
3, Ph-B
T/oC
25
25
25
25
25
25
25
25
40
60
80
100
60
60
60
60
60
Yieldb (%)
3a, PhB(OH)2
3a, PhB(OH)2
3a, PhB(OH)2
3a, PhB(OH)2
3a, PhB(OH)2
3a, PhB(OH)2
3a, PhB(OH)2
3a, PhB(OH)2
3a, PhB(OH)2
3a, PhB(OH)2
3a, PhB(OH)2
3a, PhB(OH)2
3a, PhB(OH)2
3a, PhB(OH)2
<5
<5
<5
trace
trace
55
70
67
53
89
69
41
11c
7d
2
MeCN
THF
H2O
3
4
5
DMSO
DCE
DCM
6
7
8
toluene
DCM
9
10
11
12
13
14
15
16
17
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
e
3ab, (PhBO)3
3ac, PhBpinf
3ad, PhBF3K
73
0
0
a Reaction conditions: 1a (1 mmol), 2 (40% aqueous solution ) (2.2 mmol)
and 3 (2.2 mmol) in solvent (2 mL) were stirred in a sealed tube under
40 nitrogen atmosphere for 24 h.
b Yields were determined by GC using an internal standard.
c Under air atmosphere.
d Paraformaldehyde was used instead of formaldehyde.
e (PhBO)3: 2,4,6-triphenylboroxin (0.78 mmol) was used.
45 f PhBpin: phenylboronic acid pinacol ester.
With the optimized conditions in hand (Table 1, entry 10), the
a The reaction conditions were the same as entry 10 in Table 1.
scope of this transformation was explored. As shown in Table 21, 00

3
In conclusion, we have developed a simple and efficient
synthetic pathway toward the aromatic tertiary amines via a
double Petasis-borono Mannich reaction of aromatic amines,
formaldehyde and organoboronic acids. The reaction proceeds
55 smoothly under catalyst-, base-, oxidant- and reductant-free
conditions, and the starting materials are readily available.
Therefore, this transformation provides a useful complementary
method for the synthesis of amine derivatives.
5
Scheme 2 Steric effects on the formation of products.
Acknowledgments
To further extend the application of this reaction process, a few
aliphatic and secondary amines, as well as alkenyl-substituted
60 The financial support for this work from the National Basic
Research Program of China (973 Program) (Grant
2010CB126101) and NSFC (Grant 20972052) are gratefully
acknowledged.
10 boronic acid have also been investigated (Scheme 3).
Phenylmethanamine 1n and 1-butanamine 1o produced
corresponding tertiary amines 4nb and 4ob with the yields of
88% and 31%, respectively. Diphenylamine 1p was also effective
to afford 6pb in 84% yield. And the use of (E)-styrylboronic acid
15 3i afforded N,N-dicinnamylaniline 4ai in 78% yield. However,
Supplementary Material
and 65 Experimental procedures, characterization data of products,
and copies of 1H and 13C NMR can be found, in the online
version, at http://....
aliphatic boronic acids, such as butylboronic acid
hexylboronic acid, were ineffective in this reaction.
References and notes
20
25
1. (a) Amino Group Chemistry, From Synthesis to the Life Sciences;
70
75
80
85
Ricci, A., Ed.; Wiley-VCH: Weinheim, 2007. (b) Amines:
Synthesis, Properties and Applications; Lawrence, S. A.;
Cambridge University, Cambridge, 2004.
2.
(a) Rossi, R. A.; Pierini, A. B.; Peñéñory, A. B. Chem. Rev. 2003,
103, 71. (b) Sazonov, P. K.; Artamkina, G. A.; Beletskaya, I. P.
Russ. Chem. Rev. 2012, 81, 317. (c) Sigh, C. B.; Kavala, V.;
Samal, A. K.; Patelm B. K. Eur. J. Org. Chem. 2007, 1369. (d)
Kayser-Bricker, K. J.; Glenn, M. P.; Lee, S. H.; Sebti, S. M.;
Cheng, J. Q.; Hamilton, A. D. Bioorg. Med. Chem. 2009, 17,
1764. (e) Basu, B.; Paul, S.; Nanda, A. K. Green Chem. 2009, 11,
1115. (f) Monopoli, A.; Cotugno, P.; Cortese, M.; Calvano, C. D.;
Ciminale, F.; Nacci, A. Eur. J. Org. Chem. 2012, 3105.
For selected reviews, see: (a) Nugent, T. C.; El-Shazly, M. Adv.
Synth. Catal. 2010, 352, 753. (b) Tripathi, R. P.; Verma, S. S.;
Pandey, J.; Tiwari, V. K. Curr. Org. Chem. 2008, 12, 1093. (c)
Gomez, S.; Peters, J. A.; Maschmeyer, T. Adv. Synth. Catal. 2002,
344, 1037.
3.
4.
5.
For selected reviews, see: (a) Hamid, M. H. S. A.; Slatford, P. A.;
Williams, J. M. J. Adv. Synth. Catal. 2007, 349, 1555. (b) Dixon,
T. D.; Whittlesry, M. K.; Williams, J. M. J. Dalton Trans. 2009,
753. (c) Guillena, G.; Ramón, D. J.; Yus, M. Chem. Rev. 2010,
110, 1611.
30 Scheme 3 Substrate scope.
Based on the experimental results and previous literature 90
reports,12-14 a plausible mechanism for this three-component
reaction was proposed (Scheme 4). The amine 1 reacted with
35 formaldehyde 2 to form an adduct intermediate A, which might
further react with organoboronic acid 3 to produce imunium 95
intermediate B and [R2B(OH)3]−. Secondary amine 5 was
produced by the reaction of [R2B(OH)3]− with the intermediate B.
And the final desired product 4 was obtained by the reaction
For selected examples, see: (a) Saidi, O.; Blacker, A. J.; Farah, M.
M.; Marsden, S. P.; Williams, J. M. J. Angew. Chem. Int. Ed.
2009, 48, 7375. (b) Hamid, M. H. S. A.; Allen, C. L.; Lamb, G.
W.; Maxwell, A. C.; Mayturn, H. C.; Watson, A. J. A.; Williams,
J. M. J. J. Am. Chem. Soc. 2009, 131, 1766. (c) Yamaguchi, K.;
He, J.; Oishi, T.; Mizuno, N. Chem. Eur. J. 2010, 16, 7199. (d)
Sundararaju, B.; Tang, Z.; Achard, M.; Sharma, G. V. M.; Toupet,
L.; Bruneau, C. Adv. Synth. Catal. 2010, 352, 3141. (e) Watson,
A. J. A.; Maxwell, A. C.; Williams, J. M. J. J. Org. Chem. 2011,
76, 2328. (f) Cano, R.; Ramón, D. J.; Yus, M. J. Org. Chem. 2011,
76, 5547. (g) Liu, H.; Chuah, G. K.; Jaenicke, S. J. Catal. 2012,
292, 130.
40 between [R2B(OH)3]− and the intermediate D. Thus, a double
100
Petasis-borono Mannich reaction is involved in this three-
component reaction.
6.
Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382.
105
7. For selected reviews, see: (a) Hartwig. J. F. Angew. Chem. Int. Ed.
1998, 37, 2046. (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (c) Hartwig. J. F.
Acc. Chem. Res. 1998, 31, 852. (d) Hartwig. J. F. Acc. Chem. Res.
2008, 41, 1534. (e) Aubin, Y.; Fischmeister, C.; Thomas, C. M.;
Renaud, J.-L. Chem. Soc. Rev., 2010, 39, 4130.
45
110
8. (a) Chan, D. M. T.; Monaco, K. L.; Wang R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933. (b) Evans, D. A.; Katz, J. L.;
West, T. R. Tetrahedron Lett. 1998, 39, 2937. (c) Lam, P. Y. S.;
Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M.
T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941. (d) Antilla, J. C.;
Buchwald, S. L. Org. Lett. 2001, 3, 2077.
115
Scheme 4 A Plausible mechanism.
50
9.
For selected examples, see: (a) Berman, A. M.; Johnson, J. S. J.
Am. Chem. Soc. 2004, 126, 5680. (b) erman, A. M.; Johnson, J. S.

4
Tetrahedron
J. Org. Chem. 2006, 71, 219. (c) Campbell, M. J.; Johnson, J. S.
Org. Lett. 2007, 9, 1521. (d) He, C.; Chen, C.; Cheng, J.; Liu, C.;
Liu, W.; Li, Q.; Lei, A. Angew. Chem. Int. Ed. 2008, 47, 6414. (e)
Barker, T. J.; Jarvo, E. R. J. Am. Chem. Soc. 2009, 131, 15598. (f)
Hatakeyama, T.; Yoshimoto, Y.; Ghorai, S. K.; Nakamura, M.
Org. Lett. 2010, 12, 1516. (g) Matsuda, N.; Hirano, K.; Satoh, T.;
Miura, M. Angew. Chem. Int. Ed. 2012, 51, 11827. (h) Rucker, R.
P.; Whittaker, A. M.; Dang, H.; Latic, G. Angew. Chem. Int. Ed.
2012, 51, 3953. (i) Yan, X.; Chen, C.; Zhou, Y.; Xi, C. Org. Lett.
2012, 14, 4750. (j) Xiao, Q.; Tian, L.; Tan, R.; Xia, Y.; Qiu, D.;
Zhang, Y.; Wang, J. Org. Lett. 2012, 14, 4230. (k) Qian, X.; Yu,
Z.; Auffrant, A.; Gosmini, C. Chem. Eur. J. 2013, 19, 6225.
10. (a) Green Chemistry: Theory and Practice; Anastas, P. T.; Warner,
J. C.; Oxford University Press, Oxford, 1998. (b) Introduction to
Green Chemistry; Matlack. A. S.; Marcel Dekker, Inc., New York,
2001.
5
10
15
20
25
30
35
40
45
11. For recent reviews, see: (a) Biggs-Houck, J. E.; Younai, A.; Shaw,
J. T. Curr. Opin. Chem. Biol. 2010, 14, 371. (b) Ruijter, E.;
Scheffelaar, R.; Orru, R. V. A. Angew. Chem. Int. Ed. 2011, 50,
6234. (c) Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012,
112, 3083. (d) Marson, C. M. Chem. Soc. Rev. 2012, 41, 7712. (e)
Slobbe, P.; Ruijter, E.; Orru, R. V. A. Med. Chem. Commun. 2012,
3, 1189. (f) Brauch, S.; van Berkel, S. S.; Westermann, B. Chem.
Soc. Rev. 2013, 42, 4948.
12. (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34,
583. (b) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron
1997, 53, 16463. (c) Petasis, N. A.; Zavialov, I. A. J. Am. Chem.
Soc. 1997, 119, 445.
13. Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois, P. M. P.
Chem. Rev. 2010, 110, 6169; and references therein.
14. For selected recent examples, see: (a) Muncipinto, G.; Moquist, P.
N.; Schreiber, S. L.; Schaus, S. E. Angew. Chem. Int. Ed. 2011, 50,
8172. (b) Le Quement, S. T.; Flagstad, T.; Mikkelsen, R. J. T.;
Hansen, M. R.; Givskov, M. C.; Nielsen, T. E. Org. Lett. 2012, 14,
640. (c) Han, W. Y.; Wu, Z. J.; Zhang, X.; Yuan, W. C. Org. Lett.
2012, 14, 976. (d) Morin, M. S. T.; Lu, Y.; Black, D. A.; Arndtsen,
B. A. J. Org. Chem. 2012, 77, 2013. (e) Ascic, E.; Le Quement, S.
T.; Ishoey, M.; Daugaard, M.; Nielsen, T. E. ACS Comb. Sci. 2012,
14, 253. (f) Mundal, D. A.; Lutz, K. E.; Thomson, R. J. J. Am.
Chem. Soc. 2012, 134, 5782. (g) Li, Y.; Xu, M. H. Org. Lett. 2012,
14, 2062. (h) Frauenlob, R.; García, C.; Bradshaw, G. A.; Burke,
H. M.; Bergin, E. J. Org. Chem. 2012, 77, 4445. (i) Ghosal, P.;
Shaw, A. K. J. Org. Chem. 2012, 77, 7627. (j) Shi, X.; Hebrault,
D.; Humora, M.; Kiesman W. F.; Peng, H.; Talreja, T.; Wang, Z.;
Xin, Z. J. Org. Chem. 2012, 77, 1154.