An Efficient Metal-Free Mono N-Alkylation of Anilines via Reductive Amination Using Hydrosilanes

Article abstract of DOI:10.1002/ejoc.201801288

2-Aminoquinazolin-4-one based efficient organocatalytic eco-friendly reductive amination approach was developed for the mono N-alkylation of anilines using hydrosilane as a reducing agent. This practically easy and sustainable approach works under neat reaction conditions and utilizes non-toxic environmentally benign acetic acid as a dehydrating agent. The developed protocol have several advantages, such as broad substrate scope, wide functional group tolerance, short reaction time, and absence of metal catalyst in the reaction.

Full text of DOI:10.1002/ejoc.201801288

A Journal of
Accepted Article
Title: An Efficient Metal-Free Mono N-Alkylation of Anilines via
Reductive Amination using Hydrosilanes
Authors: Maheshwar S Thakur, Onkar S Nayal, Arti Sharma, Rohit
Rana, Neeraj Kumar, and Sushil K. Maurya
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801288
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801288
Supported by

10.1002/ejoc.201801288
European Journal of Organic Chemistry
COMMUNICATION
An Efficient Metal-Free Mono N-Alkylation of Anilines via
Reductive Amination using Hydrosilanes
Maheshwar S. Thakur,[a,b] Onkar S. Nayal,[a,b] Arti Sharma,[a,b] Rohit Rana,[a,b] Neeraj Kumar[c] and
Sushil K. Maurya*[a,b]
Dedication ((optional))
Abstract: 2-Aminoquinazolin-4-one based efficient organocatalytic
eco-friendly reductive amination approach was developed for the
mono N-alkylation of anilines using hydrosilane as a reducing agent.
This practically easy and sustainable approach works under neat
reaction conditions and utilizes non-toxic environmentally benign
acetic acid as a dehydrating agent. The developed protocol have
several advantages such as broad substrate scope, wide functional
group tolerance, short reaction time and absence of metal catalyst in
the reaction.
amination[4c] and Buchwald-Hartwig amination.[4d] Among them,
the direct reductive amination is one of the most suitable,
versatile and effective approach for the synthesis of N-alkylated
anilines.[5] Previously numerous metal catalyzed direct reductive
amination based strategies have been developed.[6] Despite the
advantages of high yield and high chemo- and regioselectivity,
demanding reaction conditions such as requirement of inert
atmosphere, dry solvents, strong reducing agents, elevated
temperature and utilization of precious and toxic metal based
catalytic systems, turned researchers towards the development
of environment-friendly metal-free catalytic system. In this
respect, few metal-free approaches were also reported that are
mediated by different organic molecules such as hantzsch ester,
hydrosilatrane, boranes etc (Scheme 1).[7]
Introduction
Using environmentally benign solvents or avoiding the
implication of hazardous solvent in the organic transformations
is an ecologically sound and promising alternatives according to
the principles of green chemistry.[1] In this quest, chemists have
done enthusiastic efforts to perform clean, atom-economical and
environmentally safe organic transformations.[2]
Amine moieties are ubiquitous in various bio-active molecules,
natural products, agrochemicals, dyes and pharmaceutical
products (Figure 1).[3] Hence, an efficient, green and economical
route for the preparation of amines is of the paramount active
research area in medicinal chemistry as well as in modern
organic synthesis.
Scheme 1. Different metal free approaches
Recently, we have explored guanine type bicyclic moiety i.e. 2-
aminoquinazolin-4(3H)-one based organocatalytic system
wherein tertiary amines were synthesized from aldehydes and
N-alkylated anilines via the reductive amination in acetonitrile at
100 oC (Scheme 2).[8a]
Figure 1. Secondary amine containing drug molecules.
According to the repertoire, introduction of amine functionality
into organic framework is usually achieved by different methods
viz. alkylation of amines,[4a] reduction of nitriles,[4b,c] reductive
[a]
Natural Product Chemistry & Process Development Division, CSIR-
Institute of Himalayan Bioresource Technology Palampur, Himachal
Pradesh 176061, India.
E-mail:sushilncl@gmail.com, skmaurya@ihbt.res.in.
http://www.ihbt.res.in/en/staff/scientific-
Scheme 2. Previous approach for the synthesis of tertiary amine.
staff?chronoform=sctdetail&task=detail&id=44
:
[b]
Academy of Scientific and Innovative Research, CSIR-HRDC,
Ghaziabad, Uttar Pradesh- 201 002, India.
Deceased on 28th March 2016
In continuation, herein, we successfully perform the synthesis of
N-alkylated anilines at room temperature using 2-
aminoquinazolin-4(3H)-one as an organocatalyst, acetic acid as
a dehydrating agent and phenylsilane as reducing agent under
solvent free reaction conditions.
[c]
Supporting information for this article is given via a link at the end of
the document. ((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801288
European Journal of Organic Chemistry
COMMUNICATION
Results and Discussion
Firstly the screening of solvents were carried out at room
temperature in the presence of acetic acid as additive and
previously explored hydrogen bonding organocatalyst, 2-
aminoquinazolin-4(3H)-one encompasses bronsted acidic and
Lewis basic sites (Figure 2).[8]
For the optimization of reaction conditions, benzaldehyde and p-
anisidine were chosen as model substrate (Table 1).
Different protic and non-protic solvents were tested and
appreciable yield was obtained in all the solvents (Table 1,
entries 1-9). Despite this, reaction was also attempted under
neat reaction condition where highest yield was obtained (Table
1, entry 10). Then reaction was also performed using different
reducing agents under solvent free condition, among different
hydrosilanes used, phenylsilane afforded the highest yield
(Table 1, entries 10-14). Surprisingly no reaction was observed
with formic acid under these reaction conditions (Table 1, entry
15). Further reaction was carried out in the absence of additive
but no reaction was observed, indicating the dehydrating role of
acetic acid which is required for the formation of imine (Table 1,
entry 16). To confirm its dehydrating activity, the amount of
acetic acid is decreased in the reaction mixture which led to
decrease in the yield of desired product (Table 1, entry 17). Next,
temperature effect was perceived and decrease in the yield of
desired amine was observed when temperature was raised to 50
oC, with the increase in by-products i.e. (over-alkylated product)
(Table 1, entry 18).
Figure 2. Various catalytic sites on 2-aminoquinazolin-4(3H)-one
Table 1. Optimization of reaction conditions.
S.No.
1
Solvent
EtOH
MeOH
CHCl3
DCE
Reducing agent
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
Ph2SiH2
Ph3SiH
Et3SiH3
PMHS
Yield(%)a
85
2
89
With the optimized conditions in hand, we explored the substrate
scope (Table 2). Initially aromatic aldehydes were reacted with
different anilines bearing electron donating and withdrawing
functional groups.
3
79
4
68
5
DCM
Toluene
DMSO
DMF
81
Table 2. Substrate Scope for the synthesis of secondary aminesa
6
71
7
67
8
75
9
AcOH
Neat
46
10
11
12
13
14
15
16
17
18
19
99
Neat
51
Neat
trace
trace
12
Neat
Neat
Neat
HCOOH
PhSiH3
PhSiH3
PhSiH3
PhSiH3
n.r.
n.r.b
87c
81d
85
Neat
Neat
Neat
EtOH
a)Reaction conditions: benzaldehyde (1a, 0.1 mmol), p-anisidine (2a, 0.1
mmol), 2-aminoquinazolin-4(3H)-one (20 mol %), acetic acid (10 equiv.),
reducing agent (1 equiv.) and solvent 2 ml at room temperature for 5
hour; yield was obtained by NMR using tetrachloroethane as internal
standard. b)Reaction carried out in the absence of acetic acid. c)Reaction
carried out using 5 equiv. of acetic acid. d)Reaction carried out at 50 °C.
aReaction conditions: aldehyde (1, 1.0 mmol), amine (2, 1.0 mmol), 2-
aminoquinazolin-4(3H)-one (20 mol %), acetic acid (10 equiv.) and
phenylsilane (1 equiv.) at room temperature for 5 hour; isolated yield.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801288
European Journal of Organic Chemistry
COMMUNICATION
equiv.), phenylsilane (2 mmol, 2 equiv.) and acetic acid (10 equiv.). The
reaction mixture was subjected to stirring for 5 hour at room temperature.
After completion (TLC), work up was done using ethylacetate and water
to yield crude which was further purified by column chromatography to
afford desired product and confirmed by NMR.
Reaction proceeds efficiently with anilines bearing electron
donating functional group and provide excellent yield of the
desired products (Table 2, 3a-3f, 3q and 3r). Halogen
substituted anilines also provided excellent yield with
benzaldehydes (Table 2, 3c-3f). Moreover, anilines bearing
electron withdrawing functional group gave good to excellent
yield with benzaldehyde (Table 2, 3h-3j).
Then reaction of halogen substituted benzaldehydes undergo
smoothly with aniline (Table 2, 3k and 3l). Polysubstituted
benzaldehydes also provide excellent yield with anilines (Table 2,
3e, 3m and 3n). Benzaldehydes bearing electron donating
groups were also giving good yield with different anilines (Table
2, 3o-3r).
General procedure for the synthesis of compounds 6a-6f: Aldehyde
(1.0 mmol, 1.0 equiv.) was added to the mixture of aniline (1.0 mmol, 1.0
equiv.), phenylsilane (2 mmol, 2 equiv.) and acetic acid (10 equiv.). The
reaction mixture was subjected to stirring for 5 hour at room temperature.
After completion (TLC), work up was done using ethylacetate and water
to yield crude which was further purified by column chromatography to
afford desired product and confirmed by NMR.
Table 3. Miscellaneous substrate scope for secondary amine synthesisa
Acknowledgments
The authors are grateful to the Director, CSIR-IHBT for financial
support (MLP0203). M.S.T. is thankful to UGC and R. R. is
thankful to CSIR, New Delhi, India for their Fellowships. A. S. is
thankful to DST, New Delhi, India for providing INSPIRE
fellowship. IHBT communication no. for this publication is 4271.
Keywords: Alkylation
• Amination • Green Chemistry •
Organocatalysis • Reduction
[1] S. Kotha, P. Khedkar, Chem. Rev., 2012, 112, 1650-1680.
[2] a) C.-J. Li, B. M. Trost, PNAS, 2008, 105, 13197-13202; b) M.-O.
Simona, C.-J. Li, Chem. Soc. Rev., 2012, 41, 1415-1427.
aReaction conditions: aldehyde (4, 1.0 mmol), amine (5, 1.0 mmol), 2-
aminoquinazolin-4(3H)-one (20 mol %), acetic acid (10 equiv.) and
phenylsilane (1 equiv.) at room temperature for 5 hour; isolated yield.
[3] a) F. D. Klinger, Acc. Chem. Res., 2007, 40, 1367-1376; b) W. P. Hems,
M. Groarke, A. Z. Gerosa, G. A. Grasa, Acc. Chem. Res. 2007, 40,
1340-1347; c) T. C. Nugent, M. E. Shazly, Adv. Synth. Catal., 2010, 352,
753-819; d) N. B. Johnson, I. C. Lennon, P. H. Moran, J. A. Ramsden,
Acc. Chem. Res., 2007, 40, 1291-1299; e) C. Wang, A. Pettman, J.
Basca, J. Xiao, Angew. Chem. Int. Ed. 2010, 49, 7548-7552.
Subsequently cinnamaldehyde and 4-methoxycinnamaldehyde
were reacted under optimized conditions with aniline and good
yield was obtained in both the cases (Table 3, 6a and 6b).
Polycyclic 9-anthraldehyde also provide excellent yield with
aniline (Table 3, 6c). Further few heterocyclic compounds were
also tested under these reaction conditions and high yield of the
desired product was observed (Table 3, 6d-6f).
[4] a) T. Yan, B. L. Feringa, K. Barta, Nat. Commun. 2014, 5, 5602, 1-7; b)
D. B. Bagal, B. M. Bhanage, Adv. Synth. Catal. 2015, 357, 883-900; c) S.
Gomez, J. A. Peters, T. Maschmeyer. Adv. Synth. Catal. 2002, 344, 10,
1037-1057; d) P. R.-Castillo, S. L. Buchwald, Chem. Rev. 2016, 19,
12564-12649.
Conclusions
[5] a) E. W. Baxter, A. B. Reitz, Org. React. 2002, 59, 1-714; b) H.
Alinezhad, H. Yavari, F. Salehian, Curr. Org. Chem. 2015, 19, 1021-
1049.
A new and efficient organocatalytic environmentally friendly
route was developed for the synthesis of N-alkylated anilines via
reductive amination. 2-Aminoquinazolin-4(3H)-one was first time
explored for the mono N-alkylation of anilines using phenylsilane
as a reducing agent. This method is practical and sustainable,
works under neat reaction conditions and utilizes non-toxic
environmentally benign acetic acid as dehydrating agent. Broad
substrate scope, wide functional group tolerance, less reaction
time and absence of metal catalyst are other noticeable features
of this protocol.
[6] a) M. Zhang, H. Yang, Y. Zhang, C. Zhu, W. Li, Y. Cheng, H. Hua, Chem.
Commun., 2011, 47, 6605-6607; b) Y. Yamane, X. Liu, A. Hamasaki, T.
Ishida, M. Haruta, T. Yokoyama, M. Tokunaga, Org. Lett., 2009, 11,
5162-5165; c) M. M. Aghayan, M. M. Tavana, M. Rahimifard, R.
Boukherroub, Appl. Organometal. Chem., 2014, 28, 113-115; d) A.
Cabrera, P. Sharma, F. J. P. Flores, L. Velasco, J. L. Arias, L. R. Perez,
Catal. Sci. Technol., 2014, 4, 2626-2630; e) B. Sreedhar, P. S. Reddy, D.
K. Devi, J. Org. Chem., 2009, 74, 8806-8809; f) L. Hu, X. Cao, D. Ge, H.
Hong, Z. Guo, L. Chen, X. Sun, J. Tang, J. Zheng, J. Lu, H. Gu, Chem.
Eur. J., 2011, 17, 14283-14287; g) F. Qi, L. Hu, S. Lu, X. Cao, H. Gu,
Chem. Commun., 2012, 48, 9631-9633; h) Y. Chi, Y. G. Zhou, X. Zhang,
J. Org. Chem., 2003, 68, 4120-4122; i) P. Mattei, G. Moine, K. Pntener,
Experimental Section
General procedure for the synthesis of compounds 3a-3r: Aldehyde
(1.0 mmol, 1.0 equiv.) was added to the mixture of aniline (1.0 mmol, 1.0
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801288
European Journal of Organic Chemistry
COMMUNICATION
R. Schmid, Org. Process Res. Dev., 2011, 15, 353-359; j) R. Kadyrov,
and T. H. Riermeier, Angew. Chem. Int. Ed., 2003, 42, 5472-5474.
Kutsuma, T. Kataoka, T. Iwakuma, T. Yokomatsu, Synthesis, 2014, 46,
455-464; e) M. Horn, H. Mayer, E. Lacote, E. Merling, J. Deaner, S.
Wells, T. McFadden, D. P. Curran Org. Lett. 2012, 14, 82-85.
[7] a) N. J. A. Martin, B. List, J. Am. Chem. Soc., 2006, 128, 13368-13369;
b) D. Menche, J. Hassfeld, J. Li, G. Menche, A. Ritter, S. Rudolph, Org.
Lett., 2006, 8, 741-744; (c) S. E. Varjosaari, V. Skrypai, P. Suating, J. J.
M. Hurley, A. M. De Lio, T. M. Gilbert, M. J. Adler, Adv. Synth. Catal,
2017, 359, 1872-1878; d) Y. Kawase, T. Yamagishi, J.-y. Kato, T.
[8] a) M. S. Thakur, O. S. Nayal, R. Upadhyay, N. Kumar, S. K. Maurya, Org.
Lett. 2018, 20, 1359-1362; b) M. S. Thakur, O. S. Nayal, R. Rana, M.
Kumar, S. Sharma, N. Kumar, S. K. Maurya, New J. Chem. 2018, 42,
1373-1378.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801288
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Organocatalysis, Green chemistry*
Maheshwar S. Thakur, Onkar S. Nayal,
Arti Sharma, Rohit Rana, Neeraj Kumar
and Sushil K. Maurya*
Page No. – Page No.
A new 2-aminoquinazolin-4-one based organocatalytic eco-friendly reductive
amination approach was developed for the mono N-alkylation of anilines. The
current protocol works under neat reaction conditions, utilizes non-toxic
environmentally benign acetic acid as a dehydrating agent and phenyl silane as
reducing agent.
An Efficient Metal-Free Mono N-
Alkylation of Anilines via Reductive
Amination using Hydrosilanes
This article is protected by copyright. All rights reserved.