Synthesis of α-amino amidines through molecular iodine-catalyzed three-component coupling of isocyanides, aldehydes and amines

Article abstract of DOI:10.3762/bjoc.10.214

A facile and efficient synthetic protocol for the synthesis of a-amino amidines has been developed using a molecular iodinecatalyzed three-component coupling reaction of isocyanides, amines, and aldehydes. The presented strategy offers the advantages of mild reaction conditions, low environmental impact, clean and simple methodology, high atom economy, wide substrate scope and high yields.

Full text of DOI:10.3762/bjoc.10.214

Synthesis of α-amino amidines through molecular
iodine-catalyzed three-component coupling of isocyanides,
aldehydes and amines
Praveen Reddy Adiyala, D. Chandrasekhar, Jeevak Sopanrao Kapure,
Chada Narsimha Reddy and Ram Awatar Maurya*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 2065–2070.
Division of Medicinal Chemistry and Pharmacology, CSIR-Indian
Institute of Chemical Technology, Hyderabad-500007, India
doi:10.3762/bjoc.10.214
Received: 12 May 2014
Email:
Accepted: 14 August 2014
Published: 02 September 2014
Ram Awatar Maurya* - ramaurya@iict.res.in
* Corresponding author
Associate Editor: T. J. J. Müller
Keywords:
© 2014 Adiyala et al; licensee Beilstein-Institut.
License and terms: see end of document.
α-amino amidines; iodine; isocyanide; multicomponent reaction; Ugi
reaction
Abstract
A facile and efficient synthetic protocol for the synthesis of α-amino amidines has been developed using a molecular iodine-
catalyzed three-component coupling reaction of isocyanides, amines, and aldehydes. The presented strategy offers the advantages of
mild reaction conditions, low environmental impact, clean and simple methodology, high atom economy, wide substrate scope and
high yields.
Introduction
Amidines are a class of organic compounds exhibiting a variety the development of multicomponent-coupling strategies for the
of biological activity that makes them potential candidates for synthesis of amidines.
drug development and discovery [1-5]. Simple amidines are
generally synthesized from their corresponding nitriles either by The Ugi reaction is probably one of the best multicomponent
the Pinner reaction [6] or by the thioimidate route [7]. Recently, reactions to provide huge structural diversification of the prod-
much attention was given to the development of new routes for ucts [12]. Thus, several modifications of the Ugi reaction were
the synthesis of substituted amidines [8-11]. Even if these explored recently. As depicted in Figure 1, diamides, α-amino
methods provide amidines in acceptable yields, they suffer from amides, and α-amino amidines can be obtained depending on
limitations such as limited structural diversity of the final prod- the nucleophile used. However, the reaction does not lead to
ucts. Since multicomponent reactions (MCRs) are expected to acceptable product yields of products without using proper cata-
provide a rich structural diversity, much attention was paid on lysts except when the nucleophile is carboxylate. For instance,
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Figure 1: Synthesis of diamides, α-amino amides [13,14] and α-amino amidines [15-19] through Ugi and related MCRs.
among various catalysts screened, only phosphinic acid and Iodine is expected to act as a Lewis acid or Brønsted acid in
boric acid were found suitable for conversion of substrates into methanol [20]. Apart from oxidation, catalytic iodine provides
products when water was used as a nucleophile for amide mild and efficient ways for the formation of C–C and C–N
preparations [13,14]. In the direction of amidine synthesis bonds [20]. As a part of our ongoing interest towards the syn-
using isocyanide MCRs, a few catalysts such as p-toluene- thesis of new molecular libraries [21-24], we were interested in
sulfinic acid [15], metal triflates [16], bromodimethylsulfonium developing a one-pot MCR strategy for the synthesis of
bromide [17], ZnO nanoparticles [18] and BF3·OEt2 [19] were amidines.
reported with varying degrees of success. All these reported
methods for the preparation of α-amino amidines have their
Results and Discussion
own limitations such as long reaction times, high catalyst
loading and use of expensive and hazardous metal catalysts.
Therefore, the development of a mild, inexpensive and
efficient catalytic protocol for the amidine synthesis is highly
needed.
To check the feasibility of the iodine-catalyzed amidine syn-
thesis through the modified Ugi reaction, we carried out a
model reaction of tert-butyl isocyanide (1 mmol), benzalde-
hyde (1 mmol), and aniline (2 mmol) using 5 mol % of molec-
ular iodine in methanol (Table 1). The reaction worked well at
Table 1: Synthesis of α-amino amidine 4a through a three-component coupling of benzaldehyde, aniline, and tert-butyl isocyanide.a
Entry
Catalyst (I2)
Solvent
Time (h)
Yield of 4a (%)b
1
2
5 mol %
2 mol %
1 mol %
0.5 mol %
0.5 mol %
10 mol %
20 mol %
1 mol %
1 mol %
1 mol %
none
methanol
methanol
methanol
methanol
methanol
methanol
methanol
ethanol
2
2
90
91
90
78
88
85
70
85
78
72
0
3
2
4
2
5
6
6
2
7
2
8
2
9
acetonitrile
THF
2
10
11
2
methanol
24
aComposition of reaction mixture: Benzaldehyde (1 mmol), aniline (2 mmol), tert-butyl isocyanide (1 mmol), solvent (5 mL), I2, rt, stirring. bIsolated
yields which are not optimized.
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ambient temperature and led to good yields of 4a. Among Next we studied the substrate compatibility of the reaction to
various solvents screened, methanol was found to be the best generalize the scope of the α-amino amidine synthesis
choice as solvent for the reaction. Furthermore, we observed (Table 2). Aliphatic, aromatic and heteroaromatic aldehydes
that the catalyst loading could be reduced to 1 mol % without were used with similar success leading to high yields of
affecting the product yield. Further decreasing the amount of amidines. It is worth to note here that aldehydes containing an
catalyst (0.5 mol %) still lead to a good yield of 4a, albeit with a alkyne moiety yielded the corresponding amidines with similar
longer reaction time (Table 1, entry 5). It was interesting to success (Table 2, entries 17 and 18). With aromatic amines, the
notice a significant decrease in the product yield when the cata- reaction was good; with aliphatic amines (for instance benzyl-
lyst was overloaded (Table 1, entries 6 and 7). When the amine) the reaction was sluggish and the desired amidine was
reaction was carried out without catalyst (iodine), no not obtained. The reaction worked well with a variety of
product was observed (Table 1, entry 11). This observation isocyanides such as tert-butyl isocyanide, cyclohexyl
confirmed that catalytic iodine is necessary for the success of isocyanide, and more importantly with functional groups
the reaction.
bearing isocyanides such as ethyl isocyanoacetate and
Table 2: Scope of the α-amino amidine synthesis through three-component coupling of aldehyde, amine, and isocyanide.a
Entry
R
R1
R2
Product
Yield of product (%)b
1
2
C6H5
C6H5
C6H5
C6H5
(CH3)3C
c-C6H11
(CH3)3C
c-C6H11
c-C6H11
c-C6H11
(CH3)3C
(CH3)3C
(CH3)3C
(CH3)3C
(CH3)3C
(CH3)3C
(CH3)3C
(CH3)3C
(CH3)3C
(CH3)3C
4a
4b
4c
4d
4e
4f
90
93
85
86
88
88
90
90
87
88
85
90
86
92
91
83
3
2-Br-C6H4
c-C6H11
n-C8H17
4-Cl-C6H4
2-Furyl
C6H5
4
C6H5
5
C6H5
6
C6H5
7
C6H5
4g
4h
4i
8
c-C6H11
n-C8H17
4-F-C6H4
4-Cl-C6H4
4-Cl-C6H4
C6H5
C6H5
9
C6H5
10
11
12
13
14
15
16
C6H5
4j
C6H5
4k
4l
4-CH3O-C6H4
4-CH3-C6H4
4-CH3-C6H4
4-CH3-C6H4
4-CH3-C6H4
4m
4n
4o
4p
4-F-C6H4
n-C3H7
c-C6H11
17
C6H5
(CH3)3C
4q
85
18
C6H5
(CH3)3C
4r
77
19
20
3,4,5-(MeO)3-C6H2
3,4,5-(MeO)3-C6H2
C6H5
C6H5
EtOOCCH2
4s
4t
75
79
p-TolSO2CH2
aAldehyde (1 mmol), amine (2 mmol), isocyanide (1 mmol), iodine 1 mol %, methanol (5 mL), rt, stirring, 2 h. bIsolated yield which is not optimized.
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p-toluenesulfonylmethyl isocyanide (p-TosMIC) (Table 2, [25-27]. Recently, catalytic iodine (10 mol %) was found to
entries 19 and 20). Thus, the diversification of the α-amino give good yields of imidazolopyridine in a three-component
amidine was achieved by varying the aldehyde, aromatic amine reaction of 2-amino-5-chloropyridine, isocyanide, and alde-
and isocyanide components of the reaction. The iodine- hydes under reflux conditions [28]. However, we found that the
catalyzed protocol gave better yields (75–93%) of amidines similar reaction using 2-amonopyridine could be performed at
than a recently reported p-toluenesulfinic acid [15] catalyzed ambient temperature using 1 mol % of iodine as catalyst to
protocol (52–71%). In contrary to the p-toluenesulfinic acid- achieve a satisfactory yield of product (82–85%).
catalyzed protocol, the formation of byproducts (α-amino
amides) was suppressed in our iodine-catalyzed protocol which A probable mechanistic pathway for the formation of α-amino
gave rise to better yields and cleaner products. When compared amidines is outlined in Figure 3 which is analogous to the estab-
with other related reports [16-19], our iodine-catalyzed protocol lished mechanism reported in the literature [28,29]. Iodine can
gave similar yields of α-amino amidines. However, it should be serve as a catalyst for the activation of imine. The attack of
emphasized that our protocol with low catalyst loading nucleophilic isocyanide on the activated imine leads to the for-
(1 mol %) makes it a cleaner and lower environmental impact mation of intermediate 8 or 8’. Subsequently, another molecule
methodology to access α-amino amidines.
of amine attacks the intermediate 8 or 8’ to give α-amino
amidine 9 which undergoes further [1,3]-hydrogen shift to
Then, we tried the three-component reaction using heteroaro- provide the α-amino amidines 4 [17].
matic amines such as 2-aminopyridine, 3-aminopyridine and
4-aminopyridine. The desired products (amidines) were not Conclusion
obtained with 3-aminopyridine and 4-aminopyridine. However, In conclusion, we have developed a simple and clean method-
we found that iodine can efficiently catalyze the three-compo- ology for the synthesis of substituted α-amino amidines using a
nent coupling reaction of 2-aminopyridine, aldehyde and three-component coupling of isocyanide, aldehyde, and
isocyanide (Groebke–Blackburn–Bienaymé reaction) (Figure 2) aromatic amines with molecular iodine as a catalyst. The
Figure 2: Synthesis of imidazolopyridines 7a–d through a three-component coupling reaction of substituted benzaldehydes, 2-aminopyridine, and
tert-butyl isocyanide using 1 mol % iodine as catalyst.
Figure 3: A plausible reaction mechanism for the iodine-catalyzed α-amino amidine synthesis.
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R.A.M. is thankful to DST-India for financial support (GAP
0378). Financial support in part from 12th Five Year Plan
Project “Affordable Cancer Therapeutics (ACT-CSC-0301)” is
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