Direct β-C(sp3)-H Functionalization of Aliphatic Amines to α,β-Unsaturated Imines, Aldehydes, and Chromenes

Article abstract of DOI:10.1021/acs.orglett.5b01744

A metal-free method for direct β-C(sp³)-H functionalization of aliphatic amine was developed. The method is based on a reaction that yields enamine directly from the corresponding aliphatic amine, which otherwise requires the aid of metallic reagent and/or external oxidant. The reaction is operationally simple, general, and highly efficient in functionalizing both cyclic and acyclic amines. Structurally diverse unsaturated imines were obtained from N-heterocycles, while acyclic amines provided 2-alkyl cinnamaldehyde and benzopyran derivatives with excellent E/Z-selectivity.

Full text of DOI:10.1021/acs.orglett.5b01744

Letter
pubs.acs.org/OrgLett
Direct β‑C(sp3)−H Functionalization of Aliphatic Amines to α,β-
Unsaturated Imines, Aldehydes, and Chromenes
Sumana Mandal,† Sujit Mahato,† and Chandan K. Jana*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
S
* Supporting Information
ABSTRACT: A metal-free method for direct β-C(sp3)−H
functionalization of aliphatic amine was developed. The method
is based on a reaction that yields enamine directly from the
corresponding aliphatic amine, which otherwise requires the aid
of metallic reagent and/or external oxidant. The reaction is
operationally simple, general, and highly efficient in function-
alizing both cyclic and acyclic amines. Structurally diverse
unsaturated imines were obtained from N-heterocycles, while acyclic amines provided 2-alkyl cinnamaldehyde and benzopyran
derivatives with excellent E/Z-selectivity.
synthase inhibitor.3 A similar structural motif was found in the
liphatic amines with varied functionalization are key
Astructural motifs of many biologically important molecules alkaloid isolated from the venom of the Costa Rican ant.4
of natural and synthetic origin.1 In this regard, α,β-unsaturated
Further, α,β-unsaturated pyrrolines are direct precursors of the
β-substituted pyrrole derivatives, and thus, these can be used
for the syntheses of pyrrole-based natural products.5 In addition
to biological significance, the α,β-unsaturated pyrroline moiety
is also very important in material chemistry in the context of
the development of biomimetic molecular photoswitches.6
Various synthetic methodologies were developed for the
preparation of functionalized aliphatic amines.7 Direct C−H
functionalization of suitable saturated amines has become the
method of choice in synthesis.8 This strategy provides products
with desired complexity, in a single step, avoiding the additional
step(s) to preactivate or prefunctionalize the substrates. In this
context, α-C−H functionalization of amine has dominated the
field.7,8 On the other hand, although indirect pathways are
known for the preparation of β-functionalized amine,9 reports
on direct functionalization of more challenging β-C(sp3)−H
bonds are very few.10 Reactions primarily using metal- and/or
oxidant-based reagent/catalyst were employed to achieve direct
β-C(sp3)−H functionalization of amines (Scheme 1B). More-
over, removal of the N-protecting group, which is essential in
metal-mediated C−H functionalization, is required for further
application of functionalized amines. The known reaction on β-
C−H functionalization without metal and oxidant necessitates
the use of suitably prefunctionalized amine as substrate.11
Development of novel methodology that operates under metal-
and oxidant-free conditions for direct β-functionalization of
aliphatic amine is desirable. Herein, we report a metal- and
oxidant-free novel method for direct β-C(sp3)−H functional-
ization of aliphatic amines. Cyclic aliphatic secondary amines
produced α,β-unsaturated imines, while α,β-unsaturated
aldehydes and chromenes were obtained from acyclic amines.
imines are of particular interest because they can participate in
different reactions, producing various functionalized amines.2
Moreover, different bioactive molecules are decorated with this
moiety (Scheme 1A). The relevant examples include a class of
natural products having an α,β-unsaturated pyrroline unit,
lanopylin B1 and their derivatives, acting as a human lanosterol
Scheme 1. (A) Natural and Synthetic α,β-Unsaturated
Imines; (B) β-C(sp3)−H Functionalization of Aliphatic
Amine; (C) First Result for Metal- and Oxidant-Free β-
C(sp3)−H Functionalization
Received: June 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01744
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Organic Letters
Letter
During the development of direct α-C−H arylation of
amine,12 we reacted pyrrolidine in the presence of 9-fluorenone
and p-nitrophenol in refluxing benzene (Scheme 1C).
However, we observed that, instead of the desired C−H
arylated product, compound 1 was formed with 26% yield. We
realized that the reaction will provide the opportunity to
achieve direct β-C−H functionalization of aliphatic amines
under simple reaction conditions without using metal- or
oxidant-based reagents or catalyst. Furthermore, the method
will have potential to provide privileged structures in a single
step without using preoxidized or prefunctionalized substrates.
Therefore, we investigated the reaction further. Reaction
conditions varying the additives, solvents, reaction times, and
temperatures were examined to optimize the reaction of p-
chlorobenzaldehyde with pyrrolidine (see the Supporting
Information, Table S1). The best yield (94%) of desired
product 2a was obtained in a reaction of aldehyde with
pyrrolidine (4 equiv) in the presence of 3,5-dinitrobenzoic acid
(DNBA, 0.6 equiv) in refluxing xylene. The isolated product
was found to have the double bond exclusively with E-
configuration.
2m with 76% yield, while cinnamaldehyde was reacted with
pyrrolidine under the standard reaction conditions (Scheme 3).
Scheme 3. Unusual Reactivity of Cinnamaldehyde and
Reaction of 2-Methylpyrrolidine
Retro-aldol reaction is proposed to rationalize this observa-
tion.14 In the presence of excess pyrrolidine, cinnamaldehyde
probably participated in conjugate addition to provide β-amino
iminium ion derivative 3. Subsequently, 3 underwent retro-
aldol reaction forming benzaldehyde or its corresponding
iminium ion, which reacted with pyrrolidine under standard
reaction conditions providing pyrroline 2m.
The reaction with 2-substituted pyrrolidine was investigated
next. Accordingly, L-proline was reacted with p-chlorobenzal-
dehyde under optimized reaction conditions. However,
decarboxylation occurred and compound 2a (10%) was isolated
along with other undesired derivatives (Scheme S1, eq 1). On
the other hand, two regioisomeric conjugated imines 4a and 4b
were obtained from 2-methyl pyrrolidine (Scheme 3).
The optimized reaction conditions were employed to
investigate the substrate scope of the reaction. Various
aldehydes containing a wide range of functional groups were
reacted with different N-heterocycles providing structurally
diverse α,β-unsaturated imines 2a−t (Scheme 2). Aldehydes
Scheme 2. Scope in Synthesis of α,β-Unsaturated Imines
With the success in functionalizing aliphatic N-heterocycles,
we turned our attention to acyclic saturated secondary amines
as the potential substrates for β-C−H functionalization. We set
the first reaction of N,N-dibutylamine with p-chlorobenzalde-
hyde under the reaction conditions optimized for N-hetero-
cycles. However, the homologated unsaturated aldehyde 6a was
isolated with 50% yield instead of desired unsaturated imine 5
(Scheme 4 and Scheme S2). Unsaturated aldehydes were
widely used in organic synthesis for the preparation of bioactive
natural and unnatural compounds.15 Specially, 2- alkyl-
substituted cinnamaldehyde derivatives find direct application
in the perfume and cosmetic industry.16 Syntheses of these
compounds, primarily via cross-aldol reaction, remained
inefficient due to the associated undesired self-condensation
and polymerization reaction.17 These complications could be
potentially avoided during their syntheses via this operationally
simple method utilizing amine as the formal aldol donor.
Therefore, we looked further to optimize (Table S2) and
investigate the scope of the reaction. Different dialkylamines
were reacted with various aldehydes providing structurally
diverse 2-alkylated cinnamaldehyde derivatives 6a−q (Scheme
4). Many of them can be considered as potential aroma
substances for use in the fragrance industry. In particular, hexyl
cinnamal (6l) is a natural aroma found in the essential oil of
chamomile and used in perfume. This compound was prepared
from benzaldehyde and dioctylamine in a single step without
using metal- or oxidant-based reagents. Conjugated aldehydes
were found to have thermodynamically more stable E-geometry
in the double bond. However, mixtures of E- and Z-isomers
were found for aldehyde 6g and dienals 6p and 6q.
Interestingly, coumarin and/or chromene-2-ol derivatives
with or without an electron-donating or electron-withdrawing
substituent in the aryl moiety were equally efficient in providing
corresponding β-functionalized amines. Moreover, the reac-
tions worked well with aryl aldehydes having substituents
irrespective of their position ortho, meta, and para to aldehyde
moiety. Heteroaromatic aldehyde also provided the desired
imine 2p with excellent yield (88%). Lower yields of imine
derivatives (2q−s) were obtained by functionalizing piper-
idine.13 Similarly, cinnamaldehyde derivative was also employed
successfully to obtain conjugated imine 2t with very good yield.
To our surprise, dehomologation occurred, producing pyrroline
B
DOI: 10.1021/acs.orglett.5b01744
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Organic Letters
Letter
went subsequent oxidation to coumarin derivatives 7. Ring
closing occurred either via thermal 6π-electrocyclization of o-
quinone methide 15 or through intramolecular hemiacetaliza-
tion (Scheme S2).19 Attempts were made to isolate benzyl
amine 13 as the support for the mechanistic proposal. Tertiary
amine 6aa corresponding to 13 was isolated along with the
conjugated aldehyde 6a (see Table S2). We thought that benzyl
pyrrolidine 13 and benzyl alcohol 12, which were not detected,
probably reacted further, giving desired imine 2. As a test for
this, we found that, under the same reaction conditions, benzyl
alcohol and benzyl pyrrolidine reacted separately in the
presence of pyrrolidine to provide the desired imine 2m
(Scheme S1, eq 2 and 4). A considerable reduction of yield (to
46%) of 2a was observed in a reaction performed under argon
atmosphere (Table S1, entry 17). Therefore, the direct reaction
of imine 11, formed via aerial oxidation of pyrrolidine,20 with
aldehyde also contributed to the yield of 2 (Scheme S2).
However, the experiment in the presence of radical inhibitor
(BHT) did not show significant decrease in the yields of the
desired product (Table S1).
Scheme 4. Scope in Synthesis of 2-Alkylated
Cinnamaldehyde
Functionalized heterocycles obtained via this method can be
further derivatized in a varied way to provide valuable products.
For example, the imine functionality of 2 was reduced to afford
allylic amines 16a and16b (Scheme 6). Addition of
Scheme 6. Further Reactions of β-Functionalized
Pyrrolidines
(7a−d) with a Z-double bond were obtained on reaction with
2-hydroxyaryl aldehydes. As these compounds belong to an
important class of heterocycles having biological importance,18
salicylaldehyde derivatives were reacted with different dialkyl
amines to obtain structurally diverse benzopyran derivatives
(7a−d). 2-Alkylcoumarins were obtained from the reaction of
salicylaldehyde, while o-vanillin gave chromene-2-ol as the
major product.
On the basis of the experimental findings, a mechanistic
proposal for the metal- and oxidant-free direct β-C−H
functionalization of secondary amine is presented in Scheme
5. Aldehyde 8 condensed with secondary aliphatic amine
benzylmagnesium chloride furnished α,β-difunctionalized
amines 17a and 17b with very good yields. Furthermore,
valuable 3-substituted pyrrole derivatives 18a and 18b were
obtained via base-mediated aromatization of the corresponding
β-functionalized imines.
Scheme 5. Mechanistic Proposal for Direct β-C(sp3)−H
Functionalization
We have discovered a novel method for the direct β-C−H
functionalization of aliphatic amines. Enamines were formed in
situ directly from corresponding aliphatic amines without the
aid of metal-based reagents and external oxidant. The method is
general as it functionalizes both cyclic and acyclic saturated
amines. Cyclic aliphatic amines provided biologically as well as
synthetically important α,β-unsaturated imines with good to
excellent yields and excellent E-selectivity. As the formal aldol
donor, acyclic amine reacted with aldehyde under simple
reaction conditions producing a series of 2-alkylcinnamalde-
hyde and chromen-2-ol/-one derivatives including natural
aromas.
providing iminium ion 9, which then rearranged to isomeric
iminium ion 10. Nucleophilic substitution reaction occurred at
the benzylic or allylic position of 10 to release imine 11 and
benzyl alcohol 12 or benzyl amine 13. Subsequent reaction of
enamine, formed from imine 11, with aldehyde 8 provided the
desired α,β-unsaturated imine 2 via intermediate alcohol 14.
For acyclic amine, the corresponding unstable imine 5
underwent hydrolysis providing conjugated aldehyde 6. For
salicylaldehyde-based substrates, the hydroxy group promoted
intramolecular cyclization providing chromene-2-ol that under-
ASSOCIATED CONTENT
■
S
* Supporting Information
Tables, additional schemes, experimental details, spectral data
of all compounds, and X-ray data for compound 1 (CIF). The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01744.
C
DOI: 10.1021/acs.orglett.5b01744
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
F.; Han, Z.-Y.; He, Y.-P.; Yu, J.; Gong, L.-Z. Angew. Chem., Int. Ed.
AUTHOR INFORMATION
Corresponding Author
■
2012, 51, 12307. (o) Jurberg, I. D.; Peng, B.; Wostefeld, E.;
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18, 5160 and reports cited in ref 7.
*E-mail: ckjana@iitg.ernet.in.
Author Contributions
†S.M. and S.M. contributed equally.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
C.K.J. acknowledges SERB, New Delhi, for funding.
■
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