A p-toluenesulfinic acid-catalyzed three-component Ugi-type reaction and its application for the synthesis of α-amino amides and amidines

Article abstract of DOI:10.1016/j.tetlet.2013.02.055

A mild, cost-effective, and simple three-component Ugi-type reaction using p-toluenesulfinic acid (pTSIA) as the acid catalyst has been developed to synthesize α-amino amides and α-amino amidines. Employing 1 equiv of amine used in the reaction generated α-amino amides exclusively, while 2 equiv of amines, especially with more nucleophilic aniline such as p-anisidine, yielded the α-amino amidines as the major product. This methodology would be suitable for the synthesis of natural or unnatural amino acids and drug-like amidine analogues.

Full text of DOI:10.1016/j.tetlet.2013.02.055

Tetrahedron Letters 54 (2013) 2340–2343
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A p-toluenesulfinic acid-catalyzed three-component Ugi-type reaction
and its application for the synthesis of
a-amino amides and amidines
⇑
Biswajit Saha, Brendan Frett, Yuanxiang Wang, Hong-yu Li
College of Pharmacy, Department of Pharmacoloy and Toxicology, The University of Arizona, Tucson, USA
BIO5 Oro Valley, The University of Arizona, Oro Valley, AZ 85737, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild, cost-effective, and simple three-component Ugi-type reaction using p-toluenesulfinic acid (pTSIA)
Received 3 December 2012
Revised 14 February 2013
Accepted 19 February 2013
Available online 26 February 2013
as the acid catalyst has been developed to synthesize
1 equiv of amine used in the reaction generated -amino amides exclusively, while 2 equiv of amines,
especially with more nucleophilic aniline such as p-anisidine, yielded the -amino amidines as the major
a-amino amides and a-amino amidines. Employing
a
a
product. This methodology would be suitable for the synthesis of natural or unnatural amino acids and
drug-like amidine analogues.
Published by Elsevier Ltd.
Keywords:
Three-component Ugi reaction
MCR
Amide
Amidine
p-Toluenesulfinic acid
Multicomponent reactions (MCRs) are powerful tools for the
synthesis of complex, biologically relevant heterocyclic mole-
cules.1 The atom economy of MCRs, their convergent character,
operational simplicity, and the structural diversity and complexity
of the resulting molecules make this chemistry exceptionally use-
ful for discovery and optimization processes in the pharmaceutical
industry.2 Recently MCRs for the synthesis of heterocyclic mole-
cules have emerged as valuable tools for both academic and indus-
trial research.3 Among MCRs, the Ugi reaction4 is the most widely
used methodology for the synthesis of diverse molecules.5 In re-
cent years, several modifications of the classical four-component
Ugi reaction have been reported, in particular the Zhu and Dömling
groups6 have contributed significantly to the advancement of this
transformation.7 Another important modification is the three-com-
ponent Ugi-type reaction (Scheme 1), where an aldehyde, a pri-
mary amine, and an isocyanide are used for various
transformations.8 The three-component Ugi reaction was first dis-
covered by Weber et al. in 2000 during the synthesis of library
compounds.9 Later List et al. reported this reaction using phosphi-
nic acid as the acid catalyst in toluene at high temperature.10 In
2012, Khan reported a three-component Ugi-type condensation
reaction for the synthesis of amidines in high yields with bro-
modimethylsulfonium bromide.7f
but we obtained a three-component Ugi-type product 4a and a
minor compound 5a (Fig. 1). Herein we report the first pTSIA cata-
lyzed three-component (aldehyde, amine, and isocyanide) Ugi-
type reaction for the synthesis of
amidines.
a-amino amides and a-amino
The advantage of this methodology is that the reaction requires
mild reaction conditions at room temperature, an inexpensive cat-
alyst, and simple methanol as a solvent. Even if water is used as a
solvent, moderate yields can be obtained (40–45%). We have pre-
pared pTSIA from the sodium salt of pTSIA, which is commercially
available, by acidification with 2 N HCl just before a reaction.
First, we carried out a reaction with benzaldehyde (1 equiv), p-
anisidine (1 equiv), t-butyl isocyanide (1 equiv), and pTSIA
(1 equiv) in methanol at rt for 12 h. The progress of the reaction
was monitored by TLC and LCMS, and two new products were
identified in the reaction by LCMS. These products were further
separated by column chromatography and characterized by LCMS,
NMR analysis, and X-ray diffraction crystallographic studies. One
of the products, with a lower Rf on TLC, was obtained in 64%
isolated yield and was determined to be the three-component
Ugi-type product 4a (Scheme 1). The second component, with a
higher Rf, was obtained in 12% isolated yield and was identified
by X-ray diffraction crystallographic studies as the
a-amino ami-
In view of our continued interest in the synthesis of drug-like
molecules through MCRs,11 we initially intended to perform a
four-component Ugi reaction with pTSIA as the acid component,
dine 5a. The X-ray structure of 5a is shown in Figure 1.
Next we optimized the conditions of catalyst loading, reaction
time, and solvent to maximize the yield for the synthesis of com-
pound 4i with 4-fluoro benzaldehyde (1i, 1 equiv), p-anisidine
(2i, 1 equiv), and pentyl-2-isocyanide (3i, 1 equiv). It was found
that the reaction with 20 mol % of pTSIA catalyst for 24 h was
⇑
Corresponding author. Tel.: +1 520 626 0794.
E-mail address: hongyuli@pharmacy.arizona.edu (H. Li).
0040-4039/$ - see front matter Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.02.055

B. Saha et al. / Tetrahedron Letters 54 (2013) 2340–2343
2341
R3
Interestingly, when p-anisidine was used in excess (1.5 equiv),
compound 5a (Table 3) was obtained as the major product
(ꢀ50%). Subsequently, we carried out reactions using 2 equiv,
3 equiv, 5 equiv, and 10 equiv of p-anisidine with 20 mol % of pTSIA
to optimize the yield for the synthesis of amidine analogues.
Although 5 equiv of p-anisidine (5 equiv) afforded the best yield
(70%), further increasing the p-anisidine concentration beyond
2 equiv did not drastically improve the overall yield of the amidine
analogues. Amidine yields using excess p-anisidine generally ran-
ged from 60% to 70%.
HN HN R2
O
R1
O
R1
4
20 mol% pTSIA
1
+
R2 NH2
R3
NC
HN HN
OMe
2
3
O
4a
We next investigated the scope and the mechanism of this
reaction with 2 equiv of different anilines (Table 3). In the case with
p-nitro aniline, the formation of 4.5 is slightly favored. The nucleo-
philicity of aniline is completely diminished generating mechanis-
tic difficulty to produce compound 5.5 (Scheme 2). Anilines that
contained ortho and para deactivating bromines also displayed a
tendency to generate compounds 4.3 and 4.4 in higher yields than
seen with activated anilines. With activated anilines, and choice of
aldehyde (1) and isocyanide (3), the reaction scope is broadly open
to generate a variety of amidine analogues (5) in good yield (ꢀ60%).
From the studies of Table 3, a plausible mechanism for the
formation of 4 and 5 could be assumed to be similar to the Ugi
reaction and proceeds via the formation of 6 from the amine and
the aldehyde. Subsequent formation of the iminium ion 9 in the
presence of pTSIA, followed by the nucleophilic addition of isocya-
nides 3 with its terminal carbon atom produces the nitrilium 10.12
The second nucleophilic addition takes place at this intermediate
with the acid anion 8 to the in situ generation of intermediate 11
(Scheme 2). Since the p-toluenesulfinate is a good leaving group, it
can be replaced by a nucleophile of either a water molecule,
generated in the course of imine formation, or an amine molecule.
The nucleophilic replacements also depend on the concentration
of water and amine molecules, and the nucleophilicity of the amine.
This can be easily understood, because when 1 equiv of amine is
used, most of the amine molecule is consumed in the first step
Scheme 1. Three-component Ugi-type reaction.
H3CO
HN
N
N
H
5a
OCH3
Figure 1. X-ray structure of 5a.
optimal (Table 1, entry 8). Different solvents such as dichlorometh-
ane, water, and ethanol were tested, but methanol generally gave
best yields.
Using pTSIA as the acid catalyst and methanol as a solvent, we
initiated a study to explore the scope of this three-component
reaction by synthesizing 25 compounds (Table 2) with a variety
of different aldehydes (1 equiv), amines (1 equiv), and isocyanides
(1 equiv) with moderate to good yields (Table 2).13
and the resulting water molecule acts predominantly as
a
Table 1
Optimization of the three-component Ugi-type reaction
OCH3
O
H
HN HN
4i
F
O
1i
mol % TSIA
F
NH2
p
OCH3
NC
+
+
HN HN
N
OCH3
+
3i
2i
F
5i
OCH3
Entry
Mol % of catalyst
Time (h)
4i, Yield (%)
5i, Yield (%)
1
2
3
4
5
6
7
8
0
5
12
12
12
12
12
12
16
24
0
30
45
47
52
57
65
71
0
5
7
10
15
20
25
20
20
9
12
18
17
22

2342
B. Saha et al. / Tetrahedron Letters 54 (2013) 2340–2343
Table 2
Synthesis of
a
-amino amides
R3
HN
O
TSIA
20 mol %
p
HN R2
+
R2 NH2
+
R3
N
C
R1
O
R1
2
3
1
4
Entry
R1
C6H5–
R2
R3
P
Yield (%)
1
2
3
4
5
6
7
8
4-CH3OC6H4–
4-CH3OC6H4–
4-CH3OC6H4–
4-CH3OC6H4–
4-CH3OC6H4–
4-CH3OC6H4–
4-CH3OC6H4–
4-CH3OC6H4–
4-CH3OC6H4–
4-(CH3)3CC6H4–
2-(CH3)3CC6H4–
4-CF3OC6H4–
2-CF3OC6H4–
4-BrC6H4–
t-Butyl
n-Butyl
Benzyl
Cyclopentyl
t-Butyl
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
70
70
67
62
71
65
63
59
71
65
63
69
67
59
56
64
58
67
59
62
65
52
55
58
62
4-FC6H4–
4-FC6H4–
4-FC6H4–
4-FC6H4–
4-FC6H4–
4-FC6H4–
4-FC6H4–
4-FC6H4–
4-FC6H4–
4-FC6H4–
4-FC6H4–
4-FC6H4–
4-FC6H4–
4-FC6H4–
4-FC6H4–
4-FC6H4–
4-FC6H4–
4-FC6H4–
C6H5–
4-CH3OC6H4–
2,3-Dihydrobenzodioxine
2-(2,4-Dimethylpentyl)
2-Pentyl
2-Pentyl
2-Pentyl
2-Pentyl
2-Pentyl
2-Pentyl
2-Pentyl
2-Pentyl
2-Pentyl
2-Pentyl
2-Pentyl
2-Pentyl
2-Pentyl
2-Pentyl
2-Pentyl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
2-BrC6H4–
3-CF3C6H4–
4-FC6H4–
4-(CH3)2CHC6H4–
2-CH3-4-NO2C6H3–
4-CH3OC6H4–
4-CH3OC6H4–
4-CH3OC6H4–
4-CH3OC6H4–
4-CH3OC6H4–
4-CH3OC6H4–
4s
4t
(CH3)2CHCH2–
4-NO2C6H4–
C6H5C2H4–
2-Benzofuran
4-CH3OC6H4–
4u
4v
4w
4x
4y
2-Pentyl
2-Pentyl
Table 3
Synthesis of
a
-amino amidines
O
R3 NH HN R2
R2 R1
R3 NH HN R2
R2
NH2
R3
N
C
pTSIA
R1
O
R1
N
20 mol %
3
4
2
5
1
Entry
R1
R2
R3
4, Yield%
5, Yield%
1
2
3
4
5
6
7
8
9
C6H5–
C6H5–
C6H5–
C6H5–
4-CH3OC6H4–
4-(CH3)3CC6H4–
4-Br-C6H4–
t-Butyl
t-Butyl
t-Butyl
t-Butyl
t-Butyl
n-Butyl
2-Pentyl
2-Pentyl
t-Butyl
(4a) 20
(4.2) 13
(4.3) 17
(4.4) 23
(4.5) 9
(4b) 16
(4i) 18
(4t) 17
(4.9) 20
(5a) 60
(5.2) 56
(5.3) 28
(5.4) 25
(5.5) 7
(5b) 57
(5i) 57
(5t) 59
(5.9) 62
3-Br-C6H4–
C6H5–
4-NO2C6H4–
4-CH3OC6H4–
4-CH3OC6H4–
4-CH3OC6H4–
4-CH3OC6H4–
4-FC6H4–
4-FC6H4–
C6H4–
C6H5CH2CH2–
nucleophile (path A) generating compound 4 as the major product.
However, when 2 equiv of amine is used, the concentration of amine
is higher and the amine molecule competes with the water molecule
for the nucleophilic addition reaction (path B). In this case, if the
nucleophilicity of the amine is high, such as p-anisidine, we obtain
compound 5 as the major product (Scheme 2).14 However, if the
nucleophilicity of the amine is low, such as p-nitro aniline, we obtain
compound 4 as the major product even with excess amine.
Interestingly, p-toluenesulfonic acid (pTSA) yielded no product
using the same reaction conditions. This is likely due to instability
of the sulfonate version of intermediate 11 (Scheme 2). PTSIA has
rarely been used in organic synthesis as a catalyst. This work
suggests that p-toluenesulfinic acid may be useful in many other
reactions that require an acid catalyst.
generate a-amino amides and amidines. Product 4 is formed in
good yield with readily available substrates and catalyst. When
2 equiv of p-anisidine is used, compound 5 is obtained in good
yield. The broad scope of the reaction is operational simplicity,
practicability, and mild reaction conditions rendering it an attrac-
tive approach for the generation of different
a-amino amides and
a-amino amidines. Further studies are in progress to use the func-
tionalized amino amides for the synthesis of natural and unnatural
amino acids.
Acknowledgments
We would like to thank College of Pharmacy, the University of
Arizona for providing a start-up fund and Dr. Sue A. Roberts in
Department of Chemistry, the University of Arizona, for obtaining
single crystal X-ray structure of 5a.
In summary, we have developed a mild and efficient method
(the pTSIA-catalyzed three-component Ugi-type reaction) to

B. Saha et al. / Tetrahedron Letters 54 (2013) 2340–2343
2343
HO
O
O
O
S
S
OCH 3
OCH3
N
N
NH2
CHO
7
8
OCH3
N
3
N
NH
H
+
OCH3
1
6
2
9
HO
10
O
O
S
O
S
H2O
N
HN
O
HN
OCH3
O
S
HN
O
OCH3
Path A
8
4a
N
HO
O
HN
O
OCH3
12
O
S
S
OCH3
OCH3
H2N
HN
N
N
11
HN
O
Path B
S
HN
O
OCH3
H3CO
5a
13
Scheme 2. Plausible reaction mechanism
Patron, A. P.; Rogers, D.; Priest, C. D.; Darmohusodo, V. Tetrahedron Lett. 2004,
45, 733; (d) Weber, L.; Wallbaum, S.; Broger, C.; Gubernator, K. Angew. Chem.,
Int. Ed. 1995, 34, 2280; Shaabani, A.; Maleki, A.; Moghimi-Rad, J. J. Org. Chem.
2007, 72, 6309; (f) McFarland, J. W. J. Org. Chem. 1963, 28, 2179.
References and notes
1. (a) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168; (b) Ugi, I. J. Prakt.
Chem. 1997, 339, 499. and references therein; (c) Armstrong, R. W.; Combs, A.
P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123; (d)
Ugi, I. Proc. Estonian Acad. Sci. Chem. 1998, 47, 107; (e) Bienayme, H.; Hulme, C.;
Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321; (f) Lee, D.; Sello, J. K.;
Schreiber, S. L. Org. Lett. 2000, 2, 709.
2. Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011, 50, 6234.
3. (a) Dömling, A. Curr. Opin. Chem. Biol. 2002, 6, 306; (b) Dömling, A. Chem. Rev.
2006, 106, 17; (c) Heravi, M. M.; Moghim, S. J. Iran. Chem. Soc. 2011, 8, 306.
4. Ugi, I. Angew. Chem., Int. Ed. 1962, 1, 8.
9. Illgen, K.; Enderle, T.; Broger, C.; Weber, L. Chem. Biol. 2000, 7, 433.
10. Pan, S. C.; List, B. Angew. Chem., Int. Ed. 2008, 47, 3622.
11. (a) Sharma, A.; Li, H. Synlett 2011, 1407; (b) Saha, B.; Sharma, S.; Sawant, D.;
Kundu, B. Synlett 2007, 1591.
12. Baidya, M.; Kobayashi, S.; Mayr, H. J. Am. Chem. Soc. 2010, 132, 4796.
13. General experimental procedure for the synthesis of 4: To a solution of aldehyde 1
(1 mmol) in methanol, amine 2 (1 mmol), isocyanide 3 (1 mmol), and catalyst
pTSIA (20 mol %) were added into a flask. Then the reaction mixture was stirred
for 12–24 h at rt (monitored by TLC and LCMS until no further increase in the
ratio of the desired product vs starting materials). After completion of reaction
the solvent was removed under vacuum to get a crude residue. The crude
residue was purified by silica gel column chromatography using (10–30%)
ethylacetate–hexane to get the pure product 4.
5. (a) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. Engl. 1993, 32, 563; (b) Ugi, I.;
Demharter, A.; Horl, W.; Schmid, T. Tetrahedron 1996, 52, 11657; (c) Portlock,
D. E.; Naskar, D.; West, L.; Ostaszewski, R.; Chen, J. J. Tetrahedron Lett. 2003, 44,
5121; (d) Portlock, D. E.; Ostaszewski, R.; Naskar, D.; West, L. Tetrahedron Lett.
2003, 44, 603; (e) Harriman, G. C. B. Tetrahedron Lett. 1997, 38, 5591; (f) El
Kaim, L.; Gizolme, M.; Grimaud, L.; Oble, J. J. Org. Chem. 2007, 72, 4169.
6. (a) Grassot, J.-M.; Masson, G.; Zhu, J. Angew. Chem., Int. Ed. 2008, 47, 947; (b)
Pirali, T.; Tron, G. C.; Zhu, J. Org. Lett. 2006, 8, 4145; (c) Housseman, C.; Zhu, J.
Synlett 2006, 1777; (d) Sun, X.; Janvier, P.; Zhao, G.; Bienayme, H.; Zhu, J. Org.
Lett. 2001, 3, 877; (e) Ngouansavanh, T.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46,
5775; (f) Zhao, G.; Sun, X.; Bienayme, H.; Zhu, J. J. Am. Chem. Soc. 2001, 123,
6700; (g) Dömling, A.; Beck, B.; Eichelberger, U.; Sakamuri, S.; Menon, S.; Chen,
Q.-Z.; Lu, Y.; Wessjohann, L. A. Angew. Chem., Int. Ed. 2006, 45, 7235; (h)
Dömling, A.; Illgen, K. Synthesis 2005, 662; (i) Kolb, J.; Beck, B.; Almstetter, M.;
Heck, S.; Herdtweck, E.; Dömling, A. Mol. Divers. 2000, 6, 297; (j) Beck, B.;
Larbig, G.; Mejat, B.; Magnin-Lachaux, M.; Picard, A.; Herdtweck, E.; Dömling, A.
Org. Lett. 2003, 1047, 5.
7. (a) Patil, N. T.; Mutyala, A. K.; Lakshmi, P. G. V. V.; Raju, P. V. K.; Sridhar, B. Eur. J.
Org. Chem. 2010, 1999; (b) El Kaim, L.; Gageat, M.; Gaultier, L.; Grimaud, L.
Synlett 2007, 500; (c) Masdeu, C.; Gomez, E.; Williams, N. A. O.; Lavilla, R. Angew.
Chem., Int. Ed. 2007, 46, 3043; (d) Dai, W.-M.; Li, H. Tetrahedron 2007, 63, 12866;
(e) El Kaim, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005, 44, 7961; (f)
Khan, A. T.; Basha, R. S.; Lal, M.; Mohammad, M. RCS Advances 2012, 2, 5506.
8. (a) Mullen, L. B.; Sutherland, J. D. Angew. Chem., Int. Ed. 2007, 46, 8063; (b)
Tanaka, Y.; Hasui, T.; Suginome, M. Org. Lett. 2007, 9, 4407; Keung, W.; Bakir, F.;
Example 4a: 1H NMR (400 MHz, CDCl3) d 7.47–7.29 (m, 5H), 6.84–6.73 (m, 2H),
6.68 (s, 1H), 6.63–6.54 (m, 2H), 4.52 (s, 1H), 4.18 (s, 1H), 3.75 (s, 3H), 1.32 (s,
9H). 13C NMR (101 MHz, CDCl3) d 170.4, 153.2, 140.9, 139.4, 129.1, 128.4,
127.3, 115.1, 114.8, 65.8, 55.7, 51.0, 28.6. HRMS-ESI (M+1)+: m/z calcd for
C19H25N2O2 313.19105, found 313.19083.
14. General experimental procedure for the synthesis of 5: To a solution of aldehyde 1
(1 mmol) in methanol, amine 2 (2 mmol), isocyanide 3 (1 mmol), and pTSIA
(20 mol %) were added into a flask. Then the reaction mixture was stirred for
12–24 h at rt (monitored by TLC and LCMS until no further increase in the ratio
of the desired product vs starting materials). After the completion of reaction
the solvent was removed under vacuum to get a crude residue. The crude
residue was purified by silica gel column chromatography using (10–30%)
ethylacetate–hexane to get the pure product 5.
Example 5a: 1H NMR (400 MHz, CDCl3) d 7.34–7.21 (m, 3H), 7.15 (dd, J = 6.5,
2.9 Hz, 2H), 6.88–6.77 (m, 2H), 6.68–6.54 (m, 4H), 6.46–6.32 (m, 2H), 6.00 (s,
1H), 4.86 (s, 1H), 3.77 (s, 3H), 3.71 (s, 3H), 3.51 (s,1H), 1.46 (s, 9H). 13C NMR
(101 MHz, CDCl3) d 154.8, 154.4, 153.2, 144.0, 141.3, 140.1, 128.7, 128.1, 128.0,
122.9, 114.9, 114.7, 113.9, 60.5, 55.7, 55.5, 50.8, 28.4. HRMS-ESI (M+1)+: m/z
calcd for C26H32N3O2 418.24890, found 418.24861. The detailed information on
X-ray analysis of compound 5a will be reported in Acta Crystallogr. E.