Aminomethylation of Imidazoheterocycles with Morpholine

Article abstract of DOI:10.1021/acs.orglett.7b01594

A hitherto unreported aminomethylation occurs at C-3 of imidazopyridines with morpholine in the presence of (diacetoxyiodo)benzene at ambient temperature in short reaction times. This methodology is also applicable to indolizine, imidazo[2,1-b]thiazole, benzo[d]imidazo[2,1-b]thiazole, and indole. Interestingly, the aminomethylation involving morpholine as a source of methylene group is a new phenomenon. This protocol is of much potential for the synthesis of aminomethylated derivatives under mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.7b01594

Letter
pubs.acs.org/OrgLett
Aminomethylation of Imidazoheterocycles with Morpholine
Susmita Mondal, Sadhanendu Samanta, Mukta Singsardar, and Alakananda Hajra*
Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India
S
* Supporting Information
ABSTRACT: A hitherto unreported aminomethylation occurs at C-3 of imidazopyridines with morpholine in the presence of
(diacetoxyiodo)benzene at ambient temperature in short reaction times. This methodology is also applicable to indolizine,
imidazo[2,1-b]thiazole, benzo[d]imidazo[2,1-b]thiazole, and indole. Interestingly, the aminomethylation involving morpholine as
a source of methylene group is a new phenomenon. This protocol is of much potential for the synthesis of aminomethylated
derivatives under mild reaction conditions.
Scheme 1. Aminomethylation of Imidazo[1,2-a]pyridine
evelopment of new methods for the formation of C−C
and C−N bonds that avoid prefunctionalization is highly
D
appreciable in modern organic chemistry.1 Aminomethylation
is one of the most important methods for the direct C−C and
C−N bond forming reaction.2 Conventionally aminomethyla-
tion is done by the Mannich reaction using formaldehyde as a
methylene source.3 Aminomethylated compounds are widely
used as analgesics, antioplastics, and antibiotics and also as a
synthetic precursor of many pharmaceutical active compounds.4
Imidazopyridine, a nitrogen containing fused heterocycle,
shows wide range of biological activities.5 These are broadly
applicable in pharmaceutical chemistry as well as in material
science.6 Zolpidem, saripidem, alpidem, zolimidine, olprinone,
and necopidem are some marketed drugs that contain this
scaffold. Although in recent times various functionalization on
imidazopyridines have been made,7 aminomethylation is rare.
Recently, a vanadium-catalyzed aminomethylation at C-3
position of imidazo[1,2-a]pyridine has been reported by
Kumar et al. by using N-methylmorpholine oxide (NMO),
which acts as coupling partner as well as the oxidant at high
temperature in 1,4-dioxane solvent.8 In continuing the
development of new protocols for the functionalization of
imidazoheterocycles,9 herein we report a direct amino-
methylation at C-3 of imidazopyridine with morpholine using
(diacetoxyiodo)benzene (PIDA) under neat conditions
(Scheme 1). To the best of our knowledge, this kind of
transformation is unprecedented where morpholine itself acts
as a source of methylene group.
phenylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine (3a) in
35% yield after 5 min (Table 1, entry 1). Inspired by this result,
we increased the amount of morpholine from 1 equiv to 2
equiv, and yield was also increased to 57% (Table 1, entry 2).
Next we used 2 equiv of PIDA in the presence of 2 equiv of
morpholine, and the desired product was obtained in 92% yield
(Table 1, entry 3). No further improvement of the yield was
obtained with increasing the amount of both morpholine and
PIDA (Table 1, entry 4). In all these cases, only a trace amount
of aminated product 4a was obtained.9j No product was formed
in the presence of other oxidant such as K2S2O8, p-
benzoquinone (BQ), or 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ) (Table 1, entries 5−7). The yield of the reaction
did not improve with increasing both reaction temperature and
reaction time (Table 1, entry 8). Next we checked the effect of
different common solvents such as 1,2-DCE, toluene, ethanol,
1,4-dioxane, and DMF. However, in the presence of solvents,
aminomethylated product was obtained in very poor yields,
whereas direct aminated product was formed as a major
product (Table 1, entries 9−13). Finally, the use of PIDA (2
equiv) under solvent-free conditions was found to be the
optimized reaction conditions (Table 1, entry 3).
We started our investigation by taking 2-phenylimidazo[1,2-
a]pyridine (1a) as model substrate to find out the optimized
reaction conditions as summarized in Table 1. Initially, the
reaction was carried out by employing 1 equiv of morpholine
(2a) and 1 equiv of PIDA at room temperature. Interestingly,
aminomethylation occurred at C-3 of 1a to afford 4-((2-
With the optimized reaction conditions in hand, we showed
the generality of this methodology by examining a variety of
Received: May 26, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01594
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
substituted phenyl ring of imidazo[1,2-a]pyridine also
successively gave the desired product without any difficulties
(3i). Both naphthyl and heteroaryl substituted imidazopyr-
idines also well tolerated (3j and 3k). Next we checked the
effect of substituent at the pyridine ring of imidazo[1,2-
a]pyridine. Presence of both electron-releasing and electron-
withdrawing substituents (−CH3, −Cl, −Br, and −CN) at the
pyridine ring afforded the desired products in excellent to good
yields (3l−3q). Isopropyl substituted (C-2) imidazo[1,2-
a]pyridine also reacted very smoothly (3r). It is noteworthy
to mention that indolizine-1-carbonitrile was also amino-
methylated under the present reaction conditions without any
difficulties (3s).
Table 1. Optimization of Reaction Conditions
2a
oxidant
(equiv)
solvent
(2 mL)
yield of 3a
yield of 4a
b
b
entry (equiv)
(%)
35
57
(%)
1
1
2
2
3
2
2
2
2
2
2
2
2
2
PIDA (1)
PIDA (1)
PIDA (2)
PIDA (3)
K2S2O8 (2)
BQ (2)
trace
trace
trace
trace
2
c
3
92 (93)
89
4
5
To extend the scope of our methodology, we carried out the
reaction with other imidazoheterocycles (5) such as imidazo-
[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazole (Scheme
3). In all cases, aminomethylated products were obtained in
excellent yields (6a−6j) at 50 °C.
6
7
DDQ (2)
PIDA (2)
PIDA (2)
PIDA (2)
PIDA (2)
PIDA (2)
PIDA (2)
d
8
90
trace
32
9
1,2-DCE
toluene
ethanol
1,4-dioxane
DMF
10
10
11
12
13
<5
67
13
25
Scheme 3. Coupling between Imidazobenzothiazole and
trace
trace
76
a b
,
Benzothiazole with Morpholine
trace
a
Reaction conditions: all reactions were carried out on 0.2 mmol scale
b
c
at room temperature for 5 min. Isolated yields. 1 mmol scale.
d
Stirred at 50 °C for 1 h.
imidazo[1,2-a]pyridines as shown in Scheme 2. The presence
of electron-donating substituents (−CH3 and −OCH3) at the
a b
,
Scheme 2. Substrate Scopes
a
Reaction conditions: 0.2 mmol of 5 and 2 equiv of 2a in the presence
b
of 2 equiv PIDA at 50 °C for 15 min. Isolated yields.
Next we checked the practicability of this method on the
indole moiety (Scheme 4). Simple indole did not provide the
desired product under the optimized reaction conditions.
However, 2-substituted indole reacted very smoothly with
morpholine to afford the desired products in good yields (8a−
ab
,
Scheme 4. Substrate Scopes
a
Reaction conditions: 0.2 mmol of 1 and 2 equiv of 2a in the presence
b
of 2 equiv PIDA at room temperature for 5 min. Isolated yields.
phenyl ring of imidazo[1,2-a]pyridines reacted with morpho-
line to give excellent yields of the desired products (3b and 3c).
Electron-withdrawing groups (−F, −CF3, −NO2, and −Cl)
containing imidazo[1,2-a]pyridines also worked well (3d−3g).
It is notable that marketed drug zolimidine also produced the
aminomethylated product in good yield (3h). Hydroxy-
a
Reaction conditions: 0.2 mmol of 7 and 2 equiv of 2a in the presence
b
of 2 equiv of PIDA at room temperature for 5 min. Isolated yields.
B
DOI: 10.1021/acs.orglett.7b01594
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
8c). In case of 3-methylindole, aminomethylation took place at
nitrogen center of the indole moiety (8d).
To get a better understanding of the mechanistic pathway of
the reaction, few mechanistic experiments were carried out
(Scheme 5). The reaction did not hamper in the presence of
Through the ring opening, the intermediate A is converted to
the intermediate B, which is readily coupled with morpholine to
give the intermediate C. Subsequently, the intermediate C is
oxidized by PIDA to the intermediate D, which reacts with
imidazo[1,2-a]pyridine to produce the aminomethylated
product 3a via the formation of E.
Scheme 5. Control Experiments
The single crystal X-ray analysis of 3g was performed to
confirm the structure of the 4-((2-(4-chlorophenyl)-8-
methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine (Figure
1).10
Figure 1. Single crystal XRD structure of compound 3g.
In conclusion, unprecedented aminomethylated derivatives
were obtained by the coupling between imidazoheterocycles
and morpholine using PIDA as an oxidant at ambient
temperature under neat conditions in short reaction times.
Remarkably, this is the first report for the employment of
morpholine as methylene source for aminomethylation
reaction. The reaction exhibits good functional group tolerance
with a variety of heterocycles such as imidazo[1,2-a]pyridine,
indolizine, imidazo[2,1-b]thiazole, benzo[d]imidazo[2,1-b]-
thiazole, and indole. Certainly, the present strategy opens a
new door to synthesize aminomethylated derivatives under the
mild reaction conditions and is of much potential in organic
synthesis.
radical scavengers such as 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO), 2,6-di-tert-butyl-4-methyl phenol (BHT), and BQ
(Scheme 5, eq A). This result suggested that the reaction
probably followed an ionic pathway. In the presence of PIFA,
the reaction also proceeded very smoothly, from which it can
be proposed that PIDA is not source of −CH2 group for
aminomethylation (Scheme 5, eq B). The aminomethylation
was also carried out using 2,6-dimethylmorpholine (2b)
(Scheme 5, eq C). Formation of 2,6-dimethyl-4-((8-methyl-2-
phenylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine (3t) in-
dicated that the source of methylene group is the C-3 of
morpholine. No improvement of the yield was observed with
the addition of paraformaldehyde (1 equiv) in the reaction
mixture (Scheme 5, eq D). This result signified that the
reaction did not proceed through the formation of form-
aldehyde from morpholine.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01594.
Additional data, spectral data of all compounds, scanned
spectra of new compounds (PDF)
CIF information on 3g (CIF)
On the basis of the control experiments and our previous
experiences on the functionalization of imidazo[1,2-a]-
pyridines,9 a proposed reaction mechanism is outlined in
Scheme 6. Probably at the first step N-iodoamido species (A) is
formed by the reaction between morpholine and PIDA.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: alakananda.hajra@visva-bharati.ac.in
ORCID
Scheme 6. Plausible Mechanistic Pathway
Susmita Mondal: 0000-0002-8795-942X
Sadhanendu Samanta: 0000-0003-2215-9189
Alakananda Hajra: 0000-0001-6141-0343
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
A.H. acknowledges the financial support from SERB-DST
(Grant No. EMR/2016/001643). S.M. thanks CSIR-New Delhi
■
C
DOI: 10.1021/acs.orglett.7b01594
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
S.; Samanta, S.; Santra, S.; Bagdi, A. K.; Hajra, A. Adv. Synth. Catal.
2016, 358, 3633. (i) Samanta, S.; Mondal, S.; Santra, S.; Kibriya, G.;
Hajra, A. J. Org. Chem. 2016, 81, 10088. (j) Mondal, S.; Samanta, S.;
Jana, S.; Hajra, A. J. Org. Chem. 2017, 82, 4504.
(10) Further information can be found in the CIF file. This crystal
data were deposited in the Cambridge Crystallographic Data Centre
and assigned as CCDC 1551255.
(CSIR-JRF) and S.S. thanks UGC-New Delhi (UGC-JRF) for
their fellowships.
REFERENCES
■
(1) (a) Amino Group Chemistry, From Synthesis to the Life Sciences;
Ricci, A., Ed.; Wiley-VCH: Weinheim, 2008. (b) Hartwig, J. F. Acc.
Chem. Res. 2008, 41, 1534. (c) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc.
Rev. 2012, 41, 3464. (d) De Meijere, A.; Diederich, F. Metal Catalyzed
Cross-Coupling Reactions, 2nd ed.; Wiley-VCH: Chichester, 2004.
(e) Cho, S. H.; Yoon, J.; Chang, S. J. Am. Chem. Soc. 2011, 133, 5996.
(f) Manna, S.; Serebrennikova, P. O.; Utepova, I. A.; Antonchick, A.
P.; Chupakhin, O. N. Org. Lett. 2015, 17, 4588. (g) Miyasaka, M.;
Hirano, K.; Satoh, T.; Kowalczyk, R.; Bolm, C.; Miura, M. Org. Lett.
2011, 13, 359. (h) Guo, X.; Li, C. Org. Lett. 2011, 13, 4977.
(i) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932.
(j) Bag, S.; Patra, T.; Modak, A.; Deb, A.; Maity, S.; Dutta, U.; Dey, A.;
Kancherla, R.; Maji, A.; Hazra, A.; Bera, M.; Maiti, D. J. Am. Chem. Soc.
2015, 137, 11888.
(2) (a) Hwang, D. R.; Uang, B. J. Org. Lett. 2002, 4, 463. (b) Stowers,
K. J.; Fortner, K. C.; Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 6541.
(c) Wasa, M.; Engle, K. M.; Yu, J. Q. J. Am. Chem. Soc. 2010, 132,
3680. (d) Ibrahem, I.; Casas, J.; Cordova, A. Angew. Chem., Int. Ed.
2004, 43, 6528.
(3) (a) Mannich, C.; Krosche, W. Arch. Pharm. 1912, 250, 647.
(b) Tramontini, M.; Angiolini, L. Mannich Bases: Chemistry and Uses;
CRC: Boca Raton, FL, 1994. (c) Tramontini, M. Synthesis 1973, 1973,
703. (d) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
3817. (e) Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221.
(4) For excellent reviews, see: (a) Kleinmann, E. F. Comprehensive
Organic Synthesis; Trost, B. M., Flemming, I., Eds.; Pergamon Press:
New York, 1991; Chapter 4.1, Vol. 2. (b) Arend, M.; Westermann, B.;
Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044. (c) Denmark, S.;
Nicaise, O. J.-C. Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamomoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, p 93.
(d) Tramontini, M.; Angiolini, L. Tetrahedron 1990, 46, 1791.
(5) (a) Enguehard-Gueiffier, C.; Gueiffier, A. Mini-Rev. Med. Chem.
2007, 7, 888. (b) Baviskar, A. T.; Amrutkar, S. M.; Trivedi, N.;
Chaudhary, V.; Nayak, A.; Guchhait, S. K.; Banerjee, U. C.; Bharatam,
P. V.; Kundu, C. N. ACS Med. Chem. Lett. 2015, 6, 481.
́
(6) (a) Stasyuk, A. J.; Banasiewicz, M.; Cyranski, M. K.; Gryko, D. T.
J. Org. Chem. 2012, 77, 5552. (b) Shao, N.; Pang, G.-X.; Yan, C.-X.;
Shi, G.-F.; Cheng, Y. J. Org. Chem. 2011, 76, 7458.
(7) (a) Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A. Chem. Commun.
2015, 51, 1555. (b) Pericherla, K.; Kaswan, P.; Pandey, K.; Kumar, A.
Synthesis 2015, 47, 887. (c) Koubachi, J.; El Kazzouli, S.; Bousmina,
M.; Guillaumet, G. Eur. J. Org. Chem. 2014, 2014, 5119. (d) Ravi, C.;
Chandra Mohan, D.; Adimurthy, S. Org. Lett. 2014, 16, 2978.
(e) Chernyak, N.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49,
2743. (f) He, C.; Hao, J.; Xu, H.; Mo, Y.; Liu, H.; Han, J.; Lei, A.
Chem. Commun. 2012, 48, 11073. (g) Cao, H.; Liu, X.; Zhao, L.; Cen,
J.; Lin, J.; Zhu, Q.; Fu, M. Org. Lett. 2014, 16, 146. (h) Yang, D.; Yan,
K.; Wei, W.; Li, G.; Lu, S.; Zhao, C.; Tian, L.; Wang, H. J. Org. Chem.
2015, 80, 11073. (i) Lei, S.; Mai, Y.; Yan, C.; Mao, J.; Cao, H. Org.
Lett. 2016, 18, 3582. (j) Wang, H.; Wang, Y.; Liang, D.; Liu, L.; Zhang,
J.; Zhu, Q. Angew. Chem., Int. Ed. 2011, 50, 5678. (k) Zeng, J.; Tan, Y.
J.; Leow, M. L.; Liu, X.-W. Org. Lett. 2012, 14, 4386. (l) Yan, R.-L.;
Yan, H.; Ma, C.; Ren, Z.-Y.; Gao, X.-A.; Huang, G.-S.; Liang, Y.-M. J.
Org. Chem. 2012, 77, 2024. (m) Reddy, K. R.; Reddy, A. S.; Shankar,
R.; Kant, R.; Das, P. Asian J. Org. Chem. 2015, 4, 573.
(8) Kaswan, P.; Porter, A.; Pericherla, K.; Simone, M.; Peters, S.;
Kumar, A.; DeBoef, B. Org. Lett. 2015, 17, 5208.
(9) (a) Bagdi, A. K.; Hajra, A. Chem. Rec. 2016, 16, 1868. (b) Bagdi,
A. K.; Rahman, M.; Santra, S.; Majee, A.; Hajra, A. Adv. Synth. Catal.
2013, 355, 1741. (c) Santra, S.; Bagdi, A. K.; Majee, A.; Hajra, A. Adv.
Synth. Catal. 2013, 355, 1065. (d) Monir, K.; Bagdi, A. K.; Ghosh, M.;
Hajra, A. Org. Lett. 2014, 16, 4630. (e) Monir, K.; Bagdi, A. K.; Ghosh,
M.; Hajra, A. J. Org. Chem. 2015, 80, 1332. (f) Mitra, S.; Ghosh, M.;
Mishra, S.; Hajra, A. J. Org. Chem. 2015, 80, 8275. (g) Mishra, S.;
Monir, K.; Mitra, S.; Hajra, A. Org. Lett. 2014, 16, 6084. (h) Mondal,
D
DOI: 10.1021/acs.orglett.7b01594
Org. Lett. XXXX, XXX, XXX−XXX