Bi(OTf)3-catalyzed three-component synthesis of amidomethylarenes and -heteroarenes

Article abstract of DOI:10.1055/s-0033-1339654

A highly efficient Bi(OTf)₃-catalyzed multicomponent synthesis of amidomethylated arenes and heteroarenes from readily available starting materials has been developed. This reaction proceeds under mild conditions, has a broad substrate scope, and in addition water is generated as only side product. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339654

LETTER
▌2057
letter
Bi(OTf)3-Catalyzed Three-Component Synthesis of Amidomethylarenes and
-Heteroarenes
Bismuth-Catalyzed Amidomethylation
Angelika E. Schneider, Georg Manolikakes*
Department of Organic Chemistry and Chemical Biology, Goethe University Frankfurt, Max-von-Laue-Straße 7, 60438 Frankfurt am Main,
Germany
Fax +49(69)79829248; E-mail: g.manolikakes@chemie.uni-frankfurt.de
Received: 26.07.2013; Accepted after revision: 01.08.2013
atom-economical8 synthesis of amidoalkylated (het-
Abstract: A highly efficient Bi(OTf)3-catalyzed multicomponent
ero)arenes (path d). Generating water as only side prod-
synthesis of amidomethylated arenes and heteroarenes from readily
uct, these reactions could meet the requirements of
available starting materials has been developed. This reaction pro-
modern sustainable organic synthesis. However, all com-
mon procedures either employ preformed acylimine pre-
cursors or use stoichiometric amounts of Lewis or
Brønsted acid.9 Hence considerable amounts of waste are
generated in these processes.
ceeds under mild conditions, has a broad substrate scope, and in ad-
dition water is generated as only side product.
Key words: multicomponent reactions, bismuth, green chemistry,
acylimines, amidoalkylation
O
Amidomethyl moieties, in particular amidomethylated
arenes, are frequently found in biologically active mole-
cules (Figure 1).1
O
+
X
Ar
+
X
Ar
BF3K
N
H
R
R
NH2
c
a
OMe
O
alkylation
cross-coupling
O
H
N
N
H
R
N
Ar
H
O
b
d
amido-
alkylation
amidation
lactosamide
antiseizure and
antineuropathic pain
Ar
H
R
O
+
Ar
O
O
+
H2N
O
R
X
NH2
H
H
Me
OH
O
F
N
N
N
Scheme 1 Possible routes to amidomethylated arenes
H
H
N
N
O
N
O
Our interest in developing new multicomponent reactions
for the rapid synthesis of pharmaceutically relevant mole-
cules has led us to closer examination of these three-com-
ponent amidoalkylation reactions. We envisioned, that by
careful choice of the catalyst, the development of a truly
catalytic and general three-component amidoalkylation
should be possible. Herein, preliminary studies towards
this goal are disclosed. Initially, we focused on the identi-
fication of a suitable catalyst using the reaction between
benzamide (1a), paraformaldehyde (2), and m-xylene
(3a), as moderately reactive arene, in dichloroethane
(DCE) as model system (Table 1). From a multitude of
tested Lewis and Brønsted acids only Bi(OTf)3 efficiently
catalyzed this transformation, furnishing the desired ami-
doalkylation product 4a in 61% yield (Table 1, entry 2).
Since Bi(OTf)3 is commercially available, nontoxic, air-
and moisture-stable, it is a very attractive catalyst.10–12
raltegravir
antiretroviral
Figure 1 Amidomethyl moiety in biologically active molecules
Most commonly, these compounds are synthesized by N-
alkylation of amides with benzylic halides2 (Scheme 1,
path a) or amide-bond forming reactions3 (path b). Re-
cently, Molander has developed a complementary route
based on palladium-catalyzed cross-coupling reactions4
(path c). However, a decisive disadvantage of all these
methods is the utilization of prefunctionalized, often not
readily available starting materials. Another disadvantage
is the generation of stoichiometric amounts of waste.5
A different synthetic route is the Mannich-type amidoal-
kylation of arenes with acylimines or acyliminium ions.6,7
Especially the in situ generation of these reactive imine
derivatives from an aldehyde and an amide represents an
Other Bi3+ salts such as BiCl3 and BiBr3, as well as HOTf
showed no comparable catalytic activity for this transfor-
mation (Table 1, entries 3–5). Performing the reaction in
nitromethane as solvent led to an increased yield of 84%
(Table 1, entry 6). By reducing the catalyst loading to 2.5
mol%, an 85% yield of the desired product was obtained
SYNLETT 2013, 24, 2057–2060
Advanced online publication: 09.08.2013
DOI: 10.1055/s-0033-1339654; Art ID: ST-2013-B0702-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2058
A. E. Schneider, G. Manolikakes
LETTER
Table 1 Survey of Catalystsa
Table 2 Variation of Arenes and Heteroarenesa
O
O
H
H
Bi(OTf)3 (5 mol%)
MeNO2
O
H
H
O
+
O
+
(Het)Ar
H
catalyst
solvent
100 °C
+
Ph
NH2
H
H
+
BzHN
(Het)Ar
Ph
N
Ph
1a
NH2
r.t. to 100 °C
H
H
H
1a
2
3
4
4a
2
3a
Entry
Product
Yield (%)b
Entry
1
Catalyst (mol%)
M(OTf)x (5)d
Yield (%)b
<5
1
BzHN
BzHN
4b
4c
73c
M = Cu, Zn, In, Sc, Mg, Yb
2
3
4
5
6
7
8
9
Bi(OTf)3 (5)d
61c
<5
BiBr3 (5)d
2
68 (3:1)d
OMe
X
BiCl3 (5)d
<5
3
4
5
4d X = Br
4e X = Cl
4f X = I
88c
84c
79c
HOTf (5)d
10
BzHN
BzHN
Bi(OTf)3 (5)e
84c
85c
79c
75c
OMe
OMe
Bi(OTf)3 (2.5)e
Bi(OTf)3 (5)e,f
Bi(OTf)3(5) + dbpy (10)e
6
7
8
4g X = Br
4h X = Cl
4i X = I
77c
83c
64c
X
a General reaction conditions: benzamide (1.0 equiv), p-formaldehyde
(1.2 equiv), m-xylene (3.0 equiv), catalyst (x mol%), 100 °C, 18 h.
b Isolated yield of analytical pure product.
c Obtained as a 15:1 mixture of regioisomers.
d Reaction in DCE.
H
N
66c
68c
BzHN
BzHN
9
4j
O
e Reaction in MeNO2.
OH
f Reaction with aqueous formalin.
10
4k
(Table 1, entry 7). It has to be emphasized that this reac-
tion is quite insensitive to air and moisture and therefore
very simple to perform. Switching from paraformalde-
hyde to an aqueous formalin solution as formaldehyde
source gave the product 4a in comparable 79% yield (Ta-
ble 1, entry 8). Performing the reaction in the presence of
the proton scavenger 2,6-di-tert-butylpyridine (dbpy)13
did not led to a significant decrease in yield (Table 1, entry
8).
Br
OMe
BzHN
11
4l
87c
COOEt
12
13
14
4m R = Me 64 (12:1)d,e
4n R = Br
4o R = Cl
BzHN
BzHN
94c
S
69c,e
These results suggest that Bi(OTf)3 is the active catalyst
and no ‘hidden Brønsted acid catalysis’14 occurs. With the
optimized conditions in hand, we investigated the scope
of the reaction. Various electron-rich arenes, such as me-
sitylene (3b), anisole (3c), and its halogenated derivatives
3d–i furnished the desired amidoalkylation products 4b–i
in good to excellent yields (Table 2, entries 1–8). In most
cases, the reactions provide the amidomethylated arenes
with high regioselectivity or as single regioisomer. Only
in the case of anisole (3c) a 3:1 mixture of regioisomers is
obtained. Unprotected phenols or acid-labile ester func-
tionalities were well tolerated under the reaction condi-
R
15
16
4p
4q
70 (24:1)d,e
76 (14:1)d,e
O
BzHN
N
Ts
a General reaction conditions: benzamide (1.0 equiv), p-formaldehyde
(1.2 equiv), m-xylene (3.0 equiv), Bi(OTf)3 (5 mol%).
b Isolated yield of analytical pure product.
tions (Table 2, entries 10 and 11). The reaction with the c Obtained as single regioisomer.
d Obtained as a mixture of regioisomers, ratio of regioisomers given
sterically hindered pivaloyl amide 3j proceeded chemose-
lectively and afforded the amidomethylarene 4j in 66%
yield (Table 2, entry 9). In the case of heteroarenes, lower
reaction temperatures were required to avoid direct addi-
tion of the heteroarene to formaldehyde.15 Several elec-
tron-rich heterocycles, such as different substituted
thiophenes 3m–o, benzofuran (3p), or N-tosylindole
in parentheses.
e Reaction with aqueous formalin.
(3q)16 gave the corresponding amidomethylated products
4m–q in 64–94% yield (Table 2, entries 12–16). For some
of these heteroaromatics (3m,o–q) considerably higher
Synlett 2013, 24, 2057–2060
© Georg Thieme Verlag Stuttgart · New York

LETTER
Bismuth-Catalyzed Amidomethylation
Table 3 Variation of Amidesa (continued)
2059
yields were obtained with aqueous formalin as formalde-
hyde source.
O
O
O
H
H
The scope of the reaction is not limited to benzamide as
amide component. Reaction of paraformaldehyde and
m-xylene with other primary aryl or alkyl amides fur-
nished the desired amidoalkylation products 4r–x in good
to excellent yields and regioselectivities (Table 3, entries
1–7). Acid-sensitive functionalities, such as a cyano
group or an acrylamide were well tolerated (Table 3, en-
tries 6 and 7). Using carbamates as amide component, the
corresponding N-protected aminomethyl arenes 4y und 4z
were obtained in 71% and 45% yield (Table 3, entries 8
and 9). Therefore this method also provides straightfor-
ward access to aminomethylated arenes, which are found
in various bioactive compounds.17 Secondary amides did
not react under our standard conditions, with the excep-
tion of the cyclic carbamate 1aa (Table 3, entry 10).18 Fi-
nally, reaction with the phthalimide-protected valinamide
1ab provided the amino acid derivative 4ab in 63% yield
(Table 3, entry 11).
Bi(OTf)3 (5 mol%)
+
+
H
H
R
N
Ar
R
NH2
MeNO2
H
40–100 °C
1
2
3a
4
Ar = m-xylyl
Entry
9
Product
Yield (%)b
O
4z
45 (14:1)d
Ph
O
O
N
Ar
H
O
10
11
4aa
71c (>25:1)
N
Ar
O
O
4ab
63 (12:1)c,d
N
H
Table 3 Variation of Amidesa
N
Ar
O
O
O
O
H
H
Bi(OTf)3 (5 mol%)
a General reaction conditions: benzamide (1.0 equiv), p-formaldehyde
(1.2 equiv), m-xylene (3.0 equiv), Bi(OTf)3 (5 mol%).
b Isolated yield of analytical pure product.
+
+
H
H
R
NH2
R
N
Ar
MeNO2
40–100 °C
H
c Obtained as single regioisomer.
1
2
3a
4
d Obtained as a mixture of regioisomers, ratio of regioisomers given
in parentheses.
Ar = m-xylyl
Entry
1
Product
Yield (%)b
70 (24:1)d
In summary we have developed an efficient Bi(OTf)3-cat-
alyzed three-component reaction between amides, form-
aldehyde, and arenes.19 This practical and operational
simple method provides straightforward and versatile ac-
cess to amidomethylated arenes or heteroarenes. The
scope of the reaction is quite broad and water is generated
as only side product. Using carbamates as amide compo-
nent different protected amidomethylarenes could be syn-
thesized. Studies to expand the scope of this method and
to investigate the reaction mechanism are currently under
way in our laboratory.
O
4r
N
Ar
H
Br
O
65c
N
H
Ar
2
4s
MeO
O
3
4
5
6
7
8
4t
51 (15:1)d
77 (17:1)d
73 (18:1)d
55 (13:1)d
96 (11:1)d
71c
N
H
Ar
O
Acknowledgment
4u
4v
4w
4x
4y
t-Bu
N
Ar
This work was financially supported by the Fonds der Chemischen
Industrie (Liebig Fellowship to G. M. and A. E. S.) and the Goethe
University (Nachwuchs im Fokus-Programm). We would like to
thank Prof. Michael Göbel (Goethe University Frankfurt) for his
support and Rockwood Lithium (Frankfurt) and Evonik Industries
(Darmstadt) for the generous gift of chemicals.
H
O
Cl
N
Ar
H
O
N
H
Ar
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
O
NC
N
H
Ar
References and Notes
O
(1) (a) French, K. J.; Zhuang, Y.; Maines, L. W.; Gao, P.; Wang,
W.; Beljanski, V.; Upson, J. J.; Green, C. L.; Keller, S. N.;
Smith, C. D. J. Pharmacol. Exp. Ther. 2010, 133, 129.
O
N
Ar
H
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2057–2060

2060
A. E. Schneider, G. Manolikakes
LETTER
(b) Belyk, K. M.; Morrison, H. G.; Jones, P.; Summa, V.
WO 2006060730, 2007. (c) McIntyre, J. A.; Castaner, J.
Drugs Future 2004, 29, 992. (d) Ratti, S.; Quarato, P.;
Casagrande, C.; Fumagalli, R.; Corsini, A. Eur. J.
Pharmacol. 1998, 355, 77.
(12) For Bi(OTf)3-catalyzed Mannich-type amidoalkylation and
Mannich-type reactions with reactive nucleophiles, see:
(a) Pin, F.; Comesse, S.; Garrigues, B.; Marchalin, S.; Daïch,
A. J. Org. Chem. 2007, 72, 1181. (b) Ollevier, T.; Nadeau,
E. Org. Biomol. Chem. 2007, 5, 3126. (c) Ollevier, T.;
Nadeau, E. J. Org. Chem. 2004, 69, 9292. (d) Ollevier, T.;
Ba, T. Tetrahedron Lett. 2003, 44, 9003.
(2) Science of Synthesis; Vol. 21; Weinreb, S. M., Ed.; Thieme:
Stuttgart, 2005.
(3) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61,
10827.
(13) For the use of dbpy as mechanistic probe to determine
between Lewis and Brønsted acid catalysis, see: Wabnitz, T.
C.; Yu, J.-Q.; Spencer, J. B. Chem. Eur. J. 2004, 10, 484.
(14) Dang, T. T.; Boeck, F.; Hintermann, L. J. Org. Chem. 2011,
76, 9353.
(15) See Supporting Information for experimental details.
(16) Reactions with indoles not bearing electron-withdrawing
N-protecting groups or other more reactive heterocycles
such as furan or pyrrole led to the exclusive formation of
bisheteroarylmethane derivatives.
(17) (a) Musher, D. M.; Fainstein, V.; Young, E. J. Antimicrob.
Agents Chemother. 1980, 254. (b) Campoli-Richards, D.;
Lackner, T.; Monk, J. Drug 1987, 34, 411. (c) Kaczanowska,
K.; Wiesmuller, K.-H.; Schaffner, A.-P. ACS Med. Chem.
Lett. 2010, 1, 530.
(4) (a) Molander, G. A.; Shin, I. Org. Lett. 2012, 14, 3138.
(b) Molander, G. A.; Beaumard, F. Org. Lett. 2011, 13,
1242. (c) Molander, G. A.; Shin, I. Org. Lett. 2011, 13, 3956.
(d) Molander, G. A.; Hiebel, M.-A. Org. Lett. 2010, 12,
4876.
(5) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: 2000,.
(6) (a) Yazici, A.; Pyne, S. G. Synthesis 2009, 339. (b) Petrini,
M.; Torregiani, E. Synthesis 2007, 159. (c) Speckamp, W.
N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817.
(d) Zaugg, H. Synthesis 1984, 85.
(7) (a) Salama, T. A. Synlett 2013, 24, 713.
(b) Jaratjaroonphong, J.; Krajangsri, S.; Reutrakul, V.
Tetrahedron Lett. 2012, 53, 2476. (c) Nandi, G. C.; Samai,
S.; Kumar, R.; Singh, M. S. Tetrahedron Lett. 2009, 50,
7220. (d) Shirakawa, S.; Kobayashi, S. Org. Lett. 2006, 8,
4939. (e) Ben-Ishai, D.; Altman, J.; Bernstein, Z.; Peled, N.
Tetrahedron 1977, 34, 467.
(18) This might be due to the decreased sterical shielding of 4ab.
(19) Typical Procedure
A 10 mL screw-cap vial was charged with Bi(OTf)3
(5 mol%), amide (1.0 equiv), formaldehyde (1.2 equiv),
(hetero)arene (3–4 equiv), and nitromethane and closed with
a Teflon lined screw cap. The reaction mixture was stirred at
25–100 °C for the specified time. After cooling to r.t. the
reaction mixture was diluted with EtOAc and filtered over a
short plug of Celite and silica gel. The plug was rinsed with
additional EtOAc. The combined filtrates were concentrated
under reduced pressure. Purification of the crude residue by
column chromatography (hexane–EtOAc) afforded the
analytically pure product.
(8) Trost, B. M. Science 1991, 254, 1471.
(9) Typical procedures use at least 1 equiv of the acid (often >3
equiv). In some cases the acid is used as solvent (see ref. 6
and 7).
(10) Reviews: (a) Bothwell, J. M.; Krabbe, S. W.; Mohan, R. S.
Chem. Soc. Rev. 2011, 40, 4649. (b) Gaspard-Iloughmane,
H.; Le Roux, C. Eur. J. Org. Chem. 2004, 2517.
(11) For some recent applications, see: (a) Zhang, L.; Li, Z.; Fan,
R. Org. Lett. 2013, 15, 2482. (b) Li, Z.; Plancq, B.; Ollevier,
T. Chem. Eur. J. 2012, 18, 3144. (c) Rubenbauer, P.;
Herdtweck, E.; Strassner, T.; Bach, T. Angew. Chem. Int. Ed.
2008, 47, 10106. (d) Rueping, M.; Nachtsheim, B. J.;
Kuenkel, A. Org. Lett. 2007, 9, 825. (e) Qin, H.; Yamagiwa,
N.; Matsunaga, S.; Shibasaki, M. Angew. Chem. Int. Ed.
2007, 46, 409. (f) Rueping, M.; Nachtsheim, B. J.; Scheidt,
T. Org. Lett. 2006, 8, 3717.
Synthesis of N-(2,4,6-Trimethylbenzyl)benzamide (4b,
Table 2 Entry 1)
N-(2,4,6-Trimethylbenzyl)benzamide was synthesized
according to the typical procedure from benzamide (242 mg,
2.0 mmol), paraformaldehyde (72 mg, 2.4 mmol),
mesitylene (0.83 mL, 6.0 mmol, 3 equiv), and Bi(OTf)3 (66
mg, 0.1 mmol) in MeNO2 (4 mL) at 100 °C for 16 h.
Purification by chromatography (hexane–EtOAc, 4:1)
yielded the product as colorless solid (371 mg, 73%).
Synlett 2013, 24, 2057–2060
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.