Ugi three-component reaction of alcohols, amines and isocyanides: A new approach to the synthesis of cyclic amidines

Article abstract of DOI:10.1016/j.tetlet.2017.02.021

We have developed a novel, simple, efficient and one pot synthetic protocol for the synthesis of cyclic amidines via Ugi three-component reaction of alcohols, amines, and isocyanides.

Full text of DOI:10.1016/j.tetlet.2017.02.021

Accepted Manuscript
Ugi three-component reaction of alcohols, amines and isocyanides: A new ap-
proach to the synthesis of cyclic amidines
Kapil Dev, E. Ramakrishna, Saransh Wales Maurya, Ibadur Rahman Siddiqui,
Ruchir Kant, Rakesh Maurya
PII:
S0040-4039(17)30192-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.021
TETL 48632
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 January 2017
6 February 2017
8 February 2017
Please cite this article as: Dev, K., Ramakrishna, E., Maurya, S.W., Siddiqui, I.R., Kant, R., Maurya, R., Ugi three-
component reaction of alcohols, amines and isocyanides: A new approach to the synthesis of cyclic amidines,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.021
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Ugi three-component reaction of alcohols,
amines and isocyanides: A new approach to
the synthesis of cyclic amidines
Leave this area blank for abstract info.
Kapil Dev, E. Ramakrishna, Saransh Wales Maurya, Ibadur Rahman Siddiqui and Rakesh Maurya

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Ugi three-component reaction of alcohols, amines and isocyanides: A new
approach to the synthesis of cyclic amidines
Kapil Deva,b,#, E. Ramakrishnaa,#, Saransh Wales Mauryaa,c, Ibadur Rahman Siddiquic, Ruchir Kantd and
Rakesh Mauryaa,b,
∗
aMedicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow-226031, India
bAcademy of Scientific and Innovative Research, CSIR-Central Drug Research Institute, Lucknow-226031, India.
cDepartment of Chemistry, University of Allahabad, Allahabad-211001, India.
dMolecular and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow-226031, India
ARTICLE INFO
ABSTRACT
Article history:
Received
We have developed a novel, simple, efficient and one pot synthetic protocol for the synthesis of
cyclic amidines via Ugi three-component reaction of alcohols, amines, and isocyanides.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved
.
Available online
Keywords:
Ugi reaction
Amidines
Isocyanide
Amino alcohol
Aminoindoles
———
# Authors contributed equally

2
Tetrahedron Letters
1. Introduction
bromodimethylsulphonium bromide, molecular iodine and silica
gel catalyzed reactions.20 Besides, these successful methods,
some other routes like Pinner reaction21 and thioimidate22 are also
used for the synthesis of simple amidines from their
corresponding nitriles. However, all these reported methods are
only capable in the synthesis of acyclic amidines by utilization of
expensive and unstable aldehydes and also 2.0 equiv. of amine is
needed for the synthesis of α-amino amidines (Scheme 1).
Multicomponent reactions (MCRs) are one pot process during
which three or more substrates react in a single chemical step to
yield a product that incorporates all of the substrates. Since
MCRs represent one of the most powerful approaches for
combinatorial chemistry and diversity-oriented synthesis due to
the generation of an adduct in a single operation from three or
more reactants with high atom economy and bond-forming
efficacy.1 Among many variants of multi-component
transformations, Ugi reactions are the most powerful tool in the
creation of molecular diversity.2 In Ugi reaction, Mumm
rearrangement is the key step for the synthesis of amide
prototype compounds whereas several reactions of isocyanides
with amines and aldehydes/ketones have been reported which do
not involve Mumm rearrangement and lead to the biologically
active molecules.3
Therefore, we were interested in developing a novel protocol
for the synthesis of cyclic amidines by the utilization of
economical 2-aminobenzyl alcohols via Ugi three component
reactions.
Scheme 1: Comparison of classical Ugi and our approach to the
synthesis of amidines
Indole is a ubiquitous scaffold frequently found in numerous
natural products and pharmaceutical agents.4 Among widely
existing indole derivatives 3-iminoindole, 2-aminoindole and 2,3-
diaminoindoles are much more attractive due to their interesting
biological activities like anti-Alzheimer, antibacterial, anti-
inflammatory, antifungal and anticancer activities.5-6 These
prototypes are also important core structure of several natural
products and some clinical candidates such as psychotrimine I
(1)7, kapakahine E (2)8, kapakahine F (3)8, chetomine (4)9,
chaetocochin I (5)10 (Figure 1). 2,3-Diimino indoles exhibited
antioxidant properties for lubricating oils.11
For the synthesis of cyclic amidines, analogous to 2,3-
diaminated indoles, we started from commercially available 2-
aminobenzyl alcohol. Initially, 2-aminobenzyl alcohol was
treated with MnO2 (3.0 equiv.) in dichloromethane for 18 hrs to
oxidize alcohol into their corresponding 2-aminobenzaldehyde
based on earlier work.23 This was further (without purification)
treated with aryl amines and isocyanides in methanol for 12-15
hrs to get desired compound α-imino cyclic amidines. We began
our scouting experiments to optimize the reaction conditions for
the second step, with one pot synthesized starting material 2-
aminobenzaldehyde. This was treated with aniline (1.0 equiv.),
tert-butyl isocyanide (1.0 equiv.) and p-toluene sulphonic acid
(pTSA, 100 mol%) as reaction promoter in dichloromethane (50
mL) solvent for 12h at room temperature, failed to deliver the
desired product (2a) (Table 1, entry 1). In spite of the desired
compound, it was yielded oligomeric mixture of side products.
This was not surprising because the tendency of 2-
aminobenzaldehyde to form polymers is well documented.24 To
prevent the formation of oligomers of 2-aminobenzaldehyde, we
took N-Boc-2-aminobenzyl alcohol, but the reaction failed to
produce the desired product (Table 1, entry 2). Our observations
and possible mechanism of the formation of desired product 2a
revealed that the unprotected amine group is necessary for the
substrate 1a. Presumably, it may be happened due to the weak
nucleophilicity of protected substrate and lesser extent of
rearrangement at final step. With this analysis, again we started
the reaction with same substrate 1a and decreased the amount of
pTSA to 50 mol%, and delighted with 10% yield of the desired
product 2a (Table 1, entry 3). The product 2a was purified by
column chromatography and characterized with the help of 1D,
2D-NMR, and mass spectrometric analysis. Now, the literature
survey of multi-component reactions helped to choose methanol
as a choice of solvent. Further optimizations were carried out by
varying amount of pTSA and solvent.25 Again, the use of pTSA
(20 mol%) and methanol as solvent, afforded increased yield of
the desired product 2a (Table 1, entry 4).
Figure 1: Representative examples of 2,3-diaminoindoles and
amidines containing natural products, clinical candidates, and
common bases.
Due to the easy conversion from imino to amino group and
backward, it plays an interesting role in electrochemical
reactions.12 Similarly, azaindole another privileged structure and
bioisostere of indole have attracted chemists, due to its
interesting physiochemical13 and pharmacological properties.14 In
recent years, several bioactive azaindoles have been reported,
including the synthetic analogues of the natural variolin B (6),15
for their CDK (cyclin dependent kinase) inhibitory activity.16
Amidines are valuable building blocks of various bioactive
molecules17 and have versatile application in organic reactions as
superbases18 (Figure 1). They have been utilized in the synthesis
of heteroaromatic compounds such as benzimidazoles and
quinazolines and acyl group transfer reactions for the synthesis of
antimuscarinic compounds with improved pharmacokinetic and
pharmacodynamic profile.19 As per wide application of amidines
in synthetic organic chemistry and medicinal chemistry, different
methodologies have been developed for their synthesis, by
employing various reagents such as p-toluenesulphinic acid,
Table 1: Optimization of reaction conditionsa
metal
triflates,
BF3.OEt2,
ZnO
nanoparticles,

3
Scheme 2: Substrate scope of the reaction for the synthesis of
α-imino cyclic amidinesa,b
Yield
(%)b
0c
equiv.
(mol%)
Entry
Acid
Solvent
1
2d
3
pTSA
pTSA
pTSA
pTSA
pTSA
pTSA
pTSA
pTSA
pTSA
pTSA
pTSA
BF3.OEt2
TiCl4
100
100
50
20
15
10
15
10
15
15
15
15
15
15
15
15
DCM
DCM
0c,e
10c
40c
79
DCM
4
MeOH
MeOH
MeOH
MeCN
MeOH
THF
5
6
55
7
63
8f
56
9
40
10
11
12
13
14
15
16
PhMe
DMF
45
30
MeOH
MeOH
MeOH
MeOH
MeOH
0c
52
SnCl4
48
AlCl3
35
Ti(OiPr)4
Trace
aReaction conditions: 1a (1.0 mmol), Solvent (50 mL), bIsolated
yields, cOligomeric mixture, d2-N-Boc-aminobenzyl alcohol (1.0
e
mmol), Undesired side products, f4.0 eq. MnO2 was used.
Further, decreasing the amount of pTSA (15 mol%) in
methanol, provided improved yield (79%) of the desired product
2a (Table 1, entry 5). Though, there was no further improvement
in yield of 2a observed, on decreasing the amount of pTSA (10
mol%) and changing the choice of solvent (Table 1, entries 6-11).
Besides, pTSA as an acid component, other Lewis acids were
also screened and none of them were suitable for this multi-
component reaction (Table 1, entries 12-16).
aReaction conditions: (1). 1a (1.0 mmol), MnO2 (3.0 eq.), CH2Cl2 (20 mL),
18h. (2). ArNH2 (1.0 eq.), R3NC (1.0 eq.), pTSA (15 mol%), MeOH (50 ml),
rt, 12-15h, bIsolated yields.
The formation of Schiff bases 2k and 2l instead of desired
products from aliphatic amines i.e. N-benzylamine (1ak) and 4-
methoxy N-benzylamine (1al), restricted us to choose only aryl
amines. Again, this strategy was successfully applied for
substituted 2-aminobenzyl alcohols like 3-methyl (1m) and 4,6-
dibromo (1n), provided their corresponding products 2m (72%)
and 2n (74%) in good yields. The substrate methyl 4-
aminobenzoate (1ao) having strong electron-withdrawing group
i.e p-COOMe (1ao) provided the product 2o in poor yield.
Similarly, the other isocyanides like cyclohexyl isocyanide (1ap)
and p-methoxyphenyl isocyanide (1aq), also showed better
compatibility and yielded their respective product 2p and 2q in
moderate to good yield (Scheme 2).
With a set of suitable reaction conditions developed, next, we
investigated the scope of substrates and the generality of the
methodology (Schemes
2 & 3). The optimized reaction
conditions successfully applied to synthesize compounds 2b and
2c in very good yields, by using 4-methyl aniline and 2,4-
dimethyl aniline respectively. One pot reaction of 2-
aminobenzaldehyde generated from 2-aminobenzyl alcohol, 2,5-
dimethyl aniline (1ad) and tert-butyl isocyanide (1ab) yielded
compound 2d in 72% yield. Fortunately, we got the crystals of
the compound 2d, and further X-ray analysis confirmed the
structure and the trans-geometry of 3-imino group in the
molecule (Figure 2). Again, the reaction of 2-
aminobenzyldehydes with aryl amines having weak electron-
withdrawing substituents like 4-chloroaniline (1ah) and tert-butyl
isocyanide (1ab) provided better yield of product 2h (74%)
whereas other halogen containing substrates 2-bromoaniline (1ai)
and 2-iodoaniline (1aj) provided moderate yields 56% and 48%
of the products 2i and 2j, respectively. Presumably, this decrease
in yield of the products 2i and 2j due to steric hindrance at
reaction centre.
For more generalization of the protocol and the interest to the
synthesis of α-imino cyclic amidines more similar to
azaindoles, we again investigated the methodology by taking (2-
aminopyridin-3-yl)-methanol as a substrate (Scheme 3). The one
pot reaction of the substrate 1r with MnO2 (3.0 equiv.) in DCM
(20 mL) as solvent to produce corresponding o-aminoaldehyde
followed by the evaporation of dichloromethane and then treated
with aryl anilines (1.0 equiv.), alkyl isocyanides (1.0 equiv.) and

4
Tetrahedron Letters
pTSA (15 mol%) in methanol (50 mL) for 12-15h to yield the
corresponding desired products 2r-2t at room temperature in
good yields.
In summary, we have developed one pot novel, simple, and
efficient protocol for the synthesis of α-imino cyclic amidines.
Likewise, we have developed a novel methodology for the
synthesis of aminoindoles. In addition, we discussed the
utilization of economical and readily available o-aminobenzyl
alcohols instead of o-amino benzaldehydes which is quite
expensive and have the stability problem. The operational
simplicity, easy availability of starting materials and mild
reaction conditions of this novel method, could be useful
applications in organic chemistry and medicinal chemistry for the
synthesis of substituted indoles.
Figure 2: ORTEP diagram drawn with 30% ellipsoid probability for non-H
atoms of the crystal structure of compound 2d determined at 293 K.
Similarly, the compound 2u was prepared in moderate yield
from its corresponding commercially available (4-aminopyridin-
3-yl)-methanol (1u) at optimized reaction conditions.
Scheme 3: Substrate scope of the methodology and the synthesis
of α-imino cyclic amidinesa,b
Acknowledgments
The author Kapil Dev is thankful to CSIR, New Delhi, India,
E. Ramakrishna to UGC, New Delhi, India, Saransh Wales
Maurya to Allahabad University, Allahabad, India, for providing
fellowship and Director CSIR-CDRI for providing opportunity of
academic training in CDRI, Lucknow, India. Rakesh Maurya is
grateful to CSIR, New Delhi, India, for providing emeritus
scientist scheme with reference no. 21(1019)/16/EMR-II. We are
thankful to Dr. Tejender S. Thakur of Molecular and Structural
Biology Division, CSIR-Central Drug Research Institute for
supervising the X-ray Data collection and structure determination
of our compound/s reported in this paper. Authors are also
thankful to SAIF of CSIR-CDRI for providing spectral data.
Supplementary data
Supplementary data is associated with this manuscript. It contains
general experimental procedures, compounds characterization
data, X-ray Crystallographic information for compound 2d and
copies of 1H and 13C-NMR spectra of all synthesized compounds.
aReaction conditions: (1). 1r (1.0 mmol), MnO2 (3.0 eq.), CH2Cl2 (20 mL),
18h. (2). ArNH2 (1.0 eq.), R2NC (1.0 eq.), pTSA (15 mol%), MeOH (50 ml),
rt, 12-15h, bIsolated yields.
The mechanism for this three component Ugi reaction can be
depicted as shown in Scheme 4. Initially, MnO2 reacted with the
substrate 2-aminobenzyl alcohol 1a to give 2-aminobenzaldehyde
A which reacted with aryl amine to provide Schiff base B. The
Schiff base B undergoes acid promoted electrophilic reaction
with isocyanide component and generated an electron deficient
species C. The species C undergo intramolecular electrophilic
reaction to yield intermediate D. The species D undergoes
intramolecular rearrangement followed by oxidation26 to yield the
final product 2a.
References
1.
(a) Orru, R. V. A.; Ruijter, E. Editors. Synthesis of
Heterocycles Via Multicomponent Reactions II. [In: Top.
Heterocycl. Chem., 2010; 25]. Springer GmbH: 2010; p
292; (b) J. Zhu and H. Bienayme, Editors. Multicomponent
Reactions. Wiley-VCH Verlag GmbH & Co. KGaA: 2005;
p 468; (c) Dömling, A. Chem. Rev. 2006, 106, 17-89; (d)
Dömling A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168-
3210.
Scheme 4: Proposed mechanism of the reaction
2.
Selected references on the Ugi reaction: (a) Akritopoulou-
Zanze, I. Curr. Opin. Chem. Biol. 2008, 12, 324-331; (b)
Kaim, L. El.; Grimaud, L. Tetrahedron 2009, 65, 2153-
2171; (c) Dömling, A.; Wang, W.; Wang, K. Chem. Rev.
2012, 112, 3083-3135; (d) Sharma, U. K.; Sharma, N.;
Vachhani, D. D.; Van Der Eycken, E. V. Chem. Soc. Rev.
2015, 44, 1836-1860; (e) Hulme, C.; Akritopoulou-Zanze,

5
I.; Dai, W.-M.; Beck, B.; Srivastava, S.; Wang, W.; Wang,
K.; Czarna, A.; Holak, T. A.; Meireles, L. et. al. Multi-
Component Reactions in Drug Discovery. In MCR 2009,
Springer: 2011; pp 75. (f) Dömling, A. Curr. Opin. Chem.
Biol. 2000, 4, 318-323.
15. Pauletti, P. M.; Cintra, L. S.; Braguine, C. G.; Filho, A. A.
S.; Silva, M. L.; Cunha, W. R.; Januario, A. H. Mar. Drugs
2010, 8, 1526-1549.
16. (a) Echalier, A.; Bettayeb, K.; Ferandin, Y.; Lozach, O.;
Clément, M.; Valette, A.; Liger, F.; Marquet, B.; Morris J.
C.; Endicott, J. A. J. Med. Chem. 2008, 51, 737-751; (b)
Walker, S. R.; Carter, E. J.; Huff B. C.; Morris, J. C. Chem.
Rev. 2009, 109, 3080-3098.
3.
4.
(a) Tron, G. C. Eur. J. Org. Chem. 2013, 2013, 1849-1859.
(b) Schneekloth, J. S.; Kim, J. J.; Sorensen, E. J.
Tetrahedron 2009, 65, 3096-3101.
(a) Taylor, E. C.; Saxton, J E. The Chemistry of
Heterocyclic Compounds. Wiley-Interscience: New York,
1983; Vol. 25; (b) Saxton, J. E. Nat. Prod. Rep. 1984, 1,
21-51; (c) Saxton, J. E. Nat. Prod. Rep., 1985, 2, 49-80; (d)
Zhang, M.-Z.; Chen, Q.; Yang, G.-F. Eur. J. Med. Chem.
2015, 89, 421-441; (e) Alves, F. R. S.; Barreiro, E. J.;
Fraga, C. A. M. Mini. Rev. Med. Chem. 2009, 9, 782-793.
17. (a) Rauws, T. R. M.; Maes, B. U. W. Chem. Soc. Rev.
2012, 41, 2463-2497. (b) Berlinck, R. G. S.; and Kossuga,
M. H. Modern Alkaloids, Wiley-VCH Verlag GmbH & Co.
KGaA, 2007, pp. 305-337.
18. Ishikawa, T. Superbases for Organic Synthesis:
Guanidines, Amidines, Phosphazenes and Related
Organocatalysts, Wiley, Chippenham, 2009.
5.
6.
Shaw, K. P.; Aracava, Y.; Akaike, A.; Daly, J. W.; Rickett,
D. L.; Albuquerque E. X. Mol. Pharmacol. 1985, 28, 527-
538.
19. (a) Grimmett, M. R. Imidazole and Benzimidazole
Synthesis, Academic Press, San Diego, 1997. (b) Connolly,
D. J.; Cusack, D.; O'Sullivan, T. P.; Guiry, P. J.
Tetrahedron, 2005, 61, 10153-10202. (c) Ghosh, N.
Synlett, 2004, 3, 574-575.
(a) Repka, L. M.; Reisman, S. E. J. Org. Chem. 2013, 78,
12314-12320; (b) Gupta, S.; Kumar, B.; Kundu B. J. Org.
Chem. 2011, 76, 10154-10162; (c) Staab, A.; Loeffler, J.;
Said, H. M.; Diehlmann, D.; Katzer, A.; Beyer, M.;
Fleischer, M.; Schwab, F.; Baier, K.; Einsele, H.; Flentje,
M.; Vordermark, D. BMC Cancer 2007, 7, 213-219; (d)
Darbu, S.; Kumar, N.; Munirajan, S. Asian J. Chem. 2007,
19, 4124-4126; (e) Darbu, S.; Kumar, N.; Munirajan, S.
Indian J. Heterocyl. Chem. 2005, 15, 195; (g) Velezheva,
V. S.; Tomchin, A. B.; Mel’man, A. I.; Marysheva, V. V.
Russ. J. Org. Chem. 1998, 34, 570.
20. (a) Saha, B.; Frett, B.; Wang, Y.; Li, H.-y. Tetrahedron
Lett. 2013, 54, 2340-2343. (b) Keung, W.; Bakir, F.;
Patron, A. P.; Rogers, D.; Priest, C. D.; Darmohusodo, V.
Tetrahedron Lett. 2004, 45, 733-737. (c) Khan, A. T.;
Siddick, B. R.; Lal, M.; Mir, M. H. RSC Adv. 2012, 2,
5506-5509. (d) Kumar, A.; Saxena, D.; Gupta, M. K. Green
Chem. 2013, 15, 2699-2703. (e) Sharma, S.; Maurya, R. A.;
Min, K.-I.; Jeong, G.-Y.; Kim, D.-P. Angew. Chem., Int.
Ed. 2013, 52, 7564–7568. (f) Adiyala, P. R.;
Chandrasekhar, D.; Kapure, J. S.; Reddy, C. N.; Maurya, R.
M. Beilstein J. Org. Chem. 2014, 10, 2065-2070. (g) Sagar,
A.; Babu, V. N.; Sharada, D. S. RSC Adv., 2015, 5, 29066-
29071.
7.
8.
9.
Takayama, H.; Mori, I.; Kitajima, M.; Aimi, N.; Lajis, N.
H. Org. Lett. 2004, 6, 2945-2948.
Nakao, Y.; Kuo, J.; Yoshida, W. Y.; Kelly, M.; Scheuer, P.
J. Org Lett. 2003, 5, 1387-1390.
21. Barber, H. J.; Slack, R. J. Am. Chem. Soc. 1944, 66, 1607.
Tveit, M. Acta Agric. Scand 1956, 6, 13-16.
22. Zablocki, J. A.; Miyano, M.; Garland, R. B.; Pireh, D.;
Schretzman, L.; Rao, S. N.; Lindmark, R. J.; Panzer-
Knodle, S. G.; Nicholson, N. S.; Taite, B. B.; Salyers, A.
K.; King, L. W.; Campion, J. G.; Feigen, L. P. J. Med.
Chem. 1993, 36, 1811-1819.
10. Xu, G. B.; He, G.; Bai, H. H.; Yang, T.; Zhang, G. L.; Wu,
L. W.; Li, G. Y. J. Nat. Prod. 2015, 78, 1479-1485.
11. (a) Safonova, N. E.; Babel, V. G.; Antropyanskaya, E. A.;
Romanenko, G. N.; Proskuryakov, V. A.; Lubricating
composition. SU556171A1, 1977; (b) Safonova, N. E.;
Babel, V. G.; Bairamukov, M. D.; Proskuryakov, V. A.;
Romanenko, G. N.; Suslov, P. G. Lubricating composition.
SU808527A1, 1981; (c) Mironov, M. A.; Tokareva M. I.;
Mokrushin, V. S. Mendeleev Commun. 2007, 17, 354-356.
23. Chiurato, M.; Boulahjar, R.; Routier, S.; Troin, Y.;
Guillaumet, G. Tetrahedron 2010, 66, 4647-4653.
24. (a) Opie, J. W.; Smith, L. I. Organic Synthesis; Wiley: New
York, 1955; Vol. III, pp 56-58; (b) Li, J.-F.; Zhao, Y.; Cai,
M.-M.; Li, X.-F.; Li, J.-X. Eur. J. Med. Chem. 2009, 44,
2796-2806.
12. Berti, C.; Greci, L.; Andruzzi, R.; Trazza, A. J. Chem. Soc.,
Perkin Trans. 1 1986, 607-610.
13. (a) Twine, S. M.; Murphy, L.; Phillips, R. S.; Callis, P.;
Cash M. T.; Szabo, A. G. J. Phys. Chem. B, 2003, 107,
637-645; (b) Zhao S.-B.; Wang, S.; Chem. Soc. Rev. 2010,
39, 3142-3156.
25. 50 mL solvent is indispensible for the reaction, as we
reduced the amount of solvent, yield of the product got
decreased (observations not shown in the optimization
table) and promoted the formation of oligomeric mixture.
14. (a) Mérour, J.-Y.; Buron, F.; Plé, K.; Bonnet P.; Routier, S.
Molecules 2014, 19, 19935-19979; (b) Prokopov A.;
Yakhontov, L. Pharm. Chem. J. 1994, 28, 471-506.
26. (a) Fei, N.; Yin, H.; Wang, S.; Wang, H.; Yao, Z.-J. Org.
Lett. 2011, 13, 4208-4211; (b) Yin, H.; Kong, F.; Wang, S.;
Yao, Z.-J. Tetrahedron Lett. 2012, 53, 7078-7082.

Highlights
 One pot synthesis of cyclic amidines
 Application of alcohols in multi-component reactions.
 Structural determination and conformational analysis by X-ray.
 Wide range of functional group tolerability.
 Good yield of the products.