Synthesis of tertiary arylamines: Lewis acid-catalyzed direct reductive: N -alkylation of secondary amines with ketones through an alternative pathway

Article abstract of DOI:10.1039/c6cc04381j

We report herein a highly efficient, tin(ii)/PMHS catalyzed reductive N-alkylation of arylamines with ketones affording tertiary arylamines. A very wide substrate scope was observed for the current catalytic method as all six permutations of ketones/aldehydes/heterocyclic carbonyls and primary/secondary/heterocyclic amines were well tolerated, enabling access to secondary, tertiary and heterocyclic amines. The method is also convenient for the synthesis of N-substituted isoindolinones and phthalazinones via a tandem amination-amidation sequence. Mechanistic investigations revealed a carbocationic pathway instead of an ordinary direct reductive amination pathway.

Full text of DOI:10.1039/c6cc04381j

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DOI: 10.1039/C6CC04381J
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Synthesis of tertiary arylamines: Lewis acid-catalyzed direct
reductive N-alkylation of secondary amines with ketones through
an alternative pathway**
Received 00th January 20xx,
Accepted 00th January 20xx
Onkar S. Nayal, Maheshwar S. Thakur, Vinod Bhatt, Manoranjan Kumar, Neeraj Kumar,$ Bikram
Singh* and Upendra Sharma*
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report herein
a
highly efficient, tin(II)/PMHS catalyzed with arylamine to generate tin(II) amidinium complex, which
reductive N-alkylation of arylamines with ketones affording restricted the enamine or iminium ion formation.7a Delighted
tertiary arylamines. Very wide substrate scope was observed for with this observation, we questioned whether this strategy
current catalytic method as all six permutations of might be extended for an alternative pathway to DRA.
ketones/aldehydes/heterocyclic
carbonyls
and
primary/
Previous work
secondary/ heterocyclic amines were well tolerated, enabling
access to secondary, tertiary and heterocyclic amines. The method
is also convenient for the synthesis of N-substituted
isoindolinones and phthalazinones via tandem amination–
amidation sequence. Mechanistic investigations revealed
carbocationic pathway instead of ordinary direct reductive
amination pathway.
a) N-Alkylation of amines
b) Direct reductive amination
Tertiary arylamines are one of the most important class of
compounds, widely used in sensor designing,1 catalysis,2
nitrogen group insertion,3 and as synthetic building blocks.4
Among numerous methods used for the synthesis of tertiary
amines, alkylation of amines,5 direct reductive amination
(DRA) of carbonyl compounds6 and reductive hydroamination
of alkynes7 are the most common approaches (Scheme 1).
DRA of easily available and cost effective carbonyl
compounds is a simple and effective approach for the
functionalization of amines. DRA has been mainly used for
synthesizing secondary amines,8 however, the synthesis of
tertiary arylamines via this pathway is still a challenge.9 DRA of
carbonyl compounds with secondary amines disfavours the
formation of iminium ion/enamine product due to steric
hindrance. Nevertheless, few reports of DRA of secondary
arylamines are available,6c,d,f an alternate pathway that can
overcome the above difficulties is needed. In our previous
study, we found that tin(II) triflate showed specific interaction
c) An alternative pathway
Scheme 1. Approaches for synthesis of tertiary amines.
Although, Chisholm group described Brønsted acid catalyzed
N-alkylation of aniline by using trichloroacetimidate
electrophiles via carbenium ion pathway, requirement for pre-
activated substrate limit the scope of thismethod.10 Herein, we
report a tin-catalyzed reductive N-alkylation of unactivated
secondary arylamines with ketones in the presence of
polymethylhydrosiloxane (PMHS). PMHS is an economic and
[**]Natural Product Chemistry and Process Development Division, CSIR-Institute of
Himalayan Bioresource Technology, Palampur, Himachal Pradesh 176 061, INDIA;
Academy of Scientific and Innovative Research, CSIR-IHBT.
Email: upendra@ihbt.res.in (US); bikram_npp@rediffmail.com (BS).
$
This manuscript is dedicated to Dr. Neeraj Kumar, who deceased on 28th March
2016 while compiling the manuscript. He was a great advisor and a brilliant
scientist who is missed by all who knew him.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here. See
DOI: 10.1039/x0xx00000x
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environment friendly reducing agent.11 In addition, it is less air amines which may be due to steric hindrance (TaVbielew A2r,tic3leyO).nlNine-
DOI: 10.1039/C6CC04381J
Methylaniline treated with 1,4-diacetylbenzene to afford both
and moisture sensitive as compared to other silanes.
We initiated the investigation by using 4-acetylbenzonitrile 3aa and 3ab in almost equivalent ratio (Table 2, 3aa-3ab).
(
1g) with N-methylaniline (2a) as a model substrate (Table 1).
Unfortunately, no reaction
Table 2. Direct reductive amination of secondary arylamines.a
Table 1. Optimization of reaction condition.a
Entry
Catalsyt
Sn(OTf)2
Sn(OTf)2
Sn(OTf)2
--
Reducing agent
PMHS
PMHS
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
Yield (%)[b]
89
1
2
3
4
5
6
50c
PMHS
PMHS
--
PMHS
87d
NR
Sn(OTf)2
Sn(OTf)2
NR
35e
aReaction conditions: 1g (2 mmol), 2a (1 mmol), catalyst (10 mol%), reducing
agent (2 mmol), solvent (3 mL), 120 °C, 7h. bGC yield using hexadecane as an
internal standard. c5 mol% of Sn(OTf)2. d15 mol% of Sn(OTf)2. eDry toluene and N2
atm. NR = no reaction.
When the reductive N-alkylation of 2a was carried out with 1g
in presence of 10 mol% tin(II) triflate and 2.0 equivalent PMHS
o
in toluene at 120 C for 7h, 3g was formed in 89% yield (Table
1, entry 1). Decreasing the catalyst loading led to low yield
whereas no effect was observed on increasing the catalyst
loading (Table 1, entries 2-3). Product was not detected in the
absence of either tin(II) triflate or reducing agent PMHS (Table
1, entries 4-5).12 To improve the reaction efficiency a range of
Lewis acid catalysts, reducing agents and solvents were
examined (for details, see the Supporting Information, Table
S1). Surprisingly, when the reaction was carried out in
substantially anhydrous condition under N2 atmosphere,
comparatively low yield was observed (Table 1, entry 6). This
observation suggested that traces of water are crucial for the
success of the reaction.13
aReaction conditions: Sn(OTf)2 (10 mol%), 1 (2 mmol), 2 (1 mmol), PMHS (2
mmol), Toluene (3 mL), 120 °C. NR = no reaction. Np=naphthyl.
Table 3. Direct reductive N-alylation of anilines.a
With the optimized reaction conditions substrate scope of
the developed method was explored. A wide range of tertiary
amines has been prepared in moderate to excellent yields
(Table 2). Aromatic ketones bearing halogens and electron
withdrawing groups such as cyano at different positions
coupled smoothly with N-alkylaniline as well as electron
aReaction conditions: Sn(OTf)2 (10 mol%), 4 (2 mmol), 5 (1 mmol), PMHS (2
mmol), Toluene (3 mL), 120 °C.
deficient aniline (Table 2, 3a
of N-methylaniline with
naphthylmethylketone proceeded well to afford the
corresponding amines (Table 2, 3j 3w). Alkyl substituents
-
3i
&
3x). The reductive alkylation
acetophenone and 2-
was observed with secondary aliphatic amines (not shown).
Anilines possessing electron donating or electron withdrawing
substituents reacted efficiently with ketones to afford the
corresponding secondary amines in good yields (Table 3).
Next, amination of aldehydes with secondary arylamines
was studied (Table 4). Polysubstituted aldehydes were well
tolerated with N-methylaniline and gave excellent yield of
desired amines (Table 4, 9a-9c). Excellent chemoselectivity
(>99%) and yield was observed for the reaction of
cinnamaldehyde with N-methylaniline (Table 4, 9d).
Cinnamaldehyde was also well compatible with N-allyl aniline
(Table 4, 9e). Furthermore, reductive amination of
benzaldehyde proceeded smoothly with electron deficient
&
bearing acetophenone were well compatible with electron
deficient as well as electron rich anilines providing the desired
product in good to excellent yields (Table 2, 3k-3p).
Propiophenone derivatives and 4-Benzo[1,3]dioxol-5-yl-butan-
2-one reacted smoothly with aniline moieties, providing good
yields of corresponding amines (Table 2, 3q-3r). Switching
from N-methylaniline to N-ethylaniline and from
acetophenone to aliphatic or cyclic ketones did not affect the
outcome of the reaction (Table 2, amines 3s-3v & 3z). 4-
Fluorobenzophenone gave the moderate yield of the desired
2 | J. Name., 2012, 00, 1-3
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aniline to give products in good yields (Table 4, 9f-9g). the synthesis of biologically important18 N-substituted
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Heteroaromatic amines are common building blocks in the isoindolinones via tandem amination–amidation of
DOI: 10.1039/C6CC043821J-
synthesis of drugs and agrochemicals 14 and also an important carboxybenzaldehyde (Table 6). N-Substituted isoindolinones
structural motif in many biologically active compounds, such
have demonstrated
a
remarkably wide variety of
pharmacological activities, including antiinflammatory,
Table 4. Direct reductive N-alkylation of secondary arylamines with aldehydes.a
antihypertensive,
antipsychotic,
vasodilatory
and
anticanceretc.19 Interestingly, both electron rich and electron
deficient anilines delivered the corresponding isoindolinones
in excellent yields (Table 6, entries 15a-15b).
Table 6. Synthesis of N-substituted isoindolinones and phthalazinones via
tandem amination–amidation of 2-carboxybenzaldehyde.a
aReaction conditions: Sn(OTf)2 (10 mol%), 7 (2 mmol), 8 (1 mmol), PMHS (2
mmol), Toluene (3 mL), 120 °C.
Table 5. Synthesis of heterocyclic amines via direct reductive N-alkylation of
amines with carbonyl compounds.a
aReaction conditions: Sn(OTf)2 (10 mol%), 13 (1 mmol), 14 (1 mmol), PMHS (2
mmol), Toluene (3 mL), 120 °C.
Heteroaromatic amines such as halogen substituted
aminopyridine
isoindolinones in good yields (Table 6, entries 15c
provided
corresponding
N-substituted
15d).
-
Aliphatic amine also afforded excellent yield of the desired
product (15e). Phthalazinones were obtained in excellent
yields when phenyl hydrazine or substituted phenylhydrazine
is used as the nitrogen source instead of amines under
standard reaction conditions (15f-15g).
For understanding the reaction pathway various
experiments were carried out, where we rule out the
possibility of DRA (See SI). Standard reaction in the absence of
N-methylaniline gave corresponding alcohol in 41% yield
(Scheme 2a). When 1-phenylethanol was reacted in absence
of N-methylaniline, styrene and stilbene derivate were
detected, which indicates that reaction might involve
carbocation intermediate (Scheme 2b).20 The formation of 12K
in case of 2-acetylfuran under current reaction condition
through Aza-Piancatelli rearrgement also supported the
carbocation involvment.17
aReaction conditions: Sn(OTf)2 (10 mol%), 10 (2 mmol), 11 (1 mmol), PMHS (2
mmol), Toluene (3 mL), 120 °C.
as UDP-galactopyranose mutase inhibitor, fanetizole (anti-
inflammatory agent) and small molecule somatostatin
receptor subtype 5 (SST5R) antagonists.15 Owing to the
immense importance of these amines, synthesis ofheterocyclic
amines was attempted (Table 5). The heterocyclic carbonyl
compounds such as 3-acetylpyridine, furfural and 2-chloro-3-
quinolinecarboxaldehyde reacted well with amine 2a affording
the corresponding products in good yields (Table 5, 12a-12c). A
heteroaryl substrate such as 5-amino-2-chloropyridine was
also compatible with aliphatic as well as aromatic ketones
providing the desired amines in excellent yields (Table 5, 12d-
12g). 2-Aminothiazole and its derivatives also reacted
smoothly with benzaldehyde and 3-acetylpyridine to afford
desired amines with excellent yields. These compounds are
highly demandable in medicinal chemistry due to their
antitumor, anticancer and antimicrobial activities (Table 5,
12h-12j).16 Surprisingly, the reaction carried out between 2-
furylmethylketone and N-methylaniline, yielded the
unexpected product 12k (Table 5, 12k). The formation of 12k
in this case might be proceeding through Aza-Piancatelli
rearrgement involving ketone reduction to alcohol which
reacted with amine in the presence of Lewis acid.17
Furthermore, the scope of the reaction was extended for
Scheme 2. Control experiments.
To trap carbocation intermediates upon reaction with
suitable nucleophiles, substrates 16 and 19 were reacted
under the optimized reaction conditions with nucleophiles
such as thiol and alkyne (Scheme 3).21,22 The formation of
corresponding products in these cases clearly suggests that the
current reaction is proceeding via a carbocationic pathway.
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2
3
4
F. Yang, Y. Zhang, R. Zheng, J. Tang and M. He, J. Organomet.
On the basis of above various control experiments and our
previous study on the unique interaction between tin salts and
aniline,7a we proposed a possible reaction pathway as depicted
in scheme 4. Initially, ketone is reduced to corresponding
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Scheme 4. Proposed reaction mechanism.
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Soc. Perkin Trans., 1999, 3381-3391;
12 No iminium ion or enamine product was observerd in the
absence of reducing agent (PMHS).
13 Water act as proton source in ketone reduction see SI,
scheme S2.
14 S. A. Lawrence, Amines: Synthesis, Properties and
Applications; Cambridge University Press: Cambridge, U.K.
2004.
15 (a) S. N. Manjula, N. M. Noolvi, K. V. Parihar, S. A. M. Reddy,
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D. Strobaek, P. Christophersen, C. Hougaard, M. L. Jensen, E.
alcohol
Subsequently the alcohol undergoes silylation with PMHS to
form O-silylated product ( ). Meanwhile, insertion of N-
methylaniline into Sn(II) triflate would form tin(II) amidinium
complex ( ) which protonate to form the benzylic cation (
. Further tin(II) amide ( ) attacks the
to form . Demetalation of complex
(C) in the presence of Sn(OTf)2 and PMHS.
D
A
D
F)
via desilylation of
E
B
cationic centre of
F
G
G,
resulted in the formation of product 3j along with the
regeneration of tin(II) triflate.
In conclusion, a novel Sn(OTf)2 catalyzed method with wide
substrate scope has been developed for the synthesis of
tertiary as well as secondary amines by using PMHS as a
reducing agent. Furthermore, the generality of the current
catalytic method was demonstrated by the synthesis of
biologically important isoindolinones and phthalazinones in
good to excellent yields.
The authors are grateful to The Director, CSIR-IHBT for
support. M.S.T, V.B. and M.K. thanks UGC for granting research
fellowship. This work is inacially supported by CSIR-New Delhi
(CSC-0108).
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DOI: 10.1039/C6CC04381J
Table of contents
Synthesis of tertiary arylamines: Lewis acid-catalyzed direct reductive N-
alkylation of secondary amines with ketones through an alternative pathway
Onkar S. Nayal, Maheshwar S. Thakur, Vinod Bhatt, Manoranjan Kumar, Neeraj Kumar, Bikram Singh and
Upendra Sharma
Reductive N-alkylation through carbocation pathway