The base-free van Leusen reaction of cyclic imines on water: Synthesis of N-fused imidazo 6,11-dihydro β-carboline derivatives

Article abstract of DOI:10.1039/c9ob00660e

Construction of imidazoles has been demonstrated on water under base-free conditions. The reaction of dihydro β-carboline imines and p-toluenesulfonylmethyl isocyanides furnished the corresponding substituted N-fused imidazo 6,11-dihydro β-carboline derivatives in very good yields under ambient conditions. The use of deuterium oxide (D₂O) as a solvent enabled the incorporation of deuterium isotopes in the imidazole ring.

Full text of DOI:10.1039/c9ob00660e

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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OPrgleanasice&dBoionmotoaledcjuulsatr mChaermgiinsstry
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DOI: 10.1039/C9OB00660E
Journal Name
COMMUNICATION
Base-Free van Leusen Reaction of Cyclic Imines on Water:
Synthesis of N-Fused Imidazo 6,11-Dihydro β-Carboline
Derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
Killari Satyam,ab V. Murugesh,ab and Surisetti Suresh*ab
DOI: 10.1039/x0xx00000x
www.rsc.org/
Construction of imidazoles has been demonstrated on water under in numerous natural products and biologically active molecules.
base-free conditions. The reaction of dihydro β-carboline imines Compounds stem from the fusion of imidazole and
-carboline
COOMe
β
part
dihydro
and p-toluenesulfonylmethyl isocyanides furnished the
corresponding substituted N-fused imidazo 6,11-dihydro β-
carboline derivatives in very good yields using ambient conditions.
The use of deuterium oxide (D2O) as a solvent enabled the
incorporation of deuterium isotopes in the imidazole ring.
Cl
N
Br
N
Me
N
N
N
N
N
N
H
Me
H
C
Me
N
B
and
&
antiproliferative
imidazole
part
A
sedative
antimetastatic activities
hypnotic
OMe
Me
MeO
H2N
O
H
N
OMe
Considerable attention has been devoted to the study and
development of organic transformations in aqueous medium.1
One of the intriguing areas of organic transformations relies on
the construction of heterocycles owing to their importance in
drug discovery and medicinal chemistry.2 Significant attention
has been devoted to the synthesis of heterocycles using water
as a solvent.3
N
N
H
N
N
O
Br
N
NH
D
A
E
Peganumine
cytotoxic
anti-Alzheimer's
agent
Cl
Fig 1 Selected biologically active imidazo fused β-carboline
derivatives.
Imidazoles are among the most important classes of
heterocyclic compounds that play pivotal role in life processes
and imidazole moiety is found in several marketed drugs.2a,4
One of the important methods for the construction of imidazole
ring relies on the van Leusen reaction i.e. essentially the
reaction of imine and p-toluenesulfonylmethyl isocyanide
(TosMIC) in the presence of a base (Scheme 1, eq 1).5,6
Generally, this reaction has been performed in the presence of
stoichiometric/excess amounts of base in the presence of
organic solvents at higher temperatures/longer reaction times.
However, to the best of our knowledge, use of water as a
solvent for van Leusen imidazole synthesis remains hitherto
undisclosed.7 On the other hand, β-carboline skeleton is found
van
reaction
Leusen imidazole
general
R2
R1
R2
Base
N
N
N
1)
(eq
+
Tos
NC
solvent
R1
This Work
organic
(TosMIC)
R2
R2
No
R
N
N
Base
+
R1
2)
R1
(eq
N
Tos
NC
H2 rt, 2 h
O
,
N
N
H
H
R
(substituted
TosMIC)
1
3
2
Scheme 1 General base-mediated van Leusen reaction in
organic solvents and This Work.
β-carboline (Compound
biological activities. For example, compound
shown hypnotic and sedative properties9 while compound
(Figure 1) displayed significant anti-proliferative effects against
human breast cancer cells.10 Peganumine A (compound
Figure 1), comprised of two tetrahydro β-carboline (THBC)
moieties fused with an imidazo core, is a natural alkaloid that
proved to exhibit significant cytotoxic effects to act as a
A
, Figure 1)8 have shown interesting
(Figure 1) has
B
a.K. Satyam, V. Murugesh, Dr. S. Suresh
Organic Synthesis and Process Chemistry
CSIR-Indian Institute of Chemical Technology (CSIR-IICT)
Hyderabad 500 007, India
C
D
,
E-mail: surisetti@iict.res.in; suresh.surisetti@yahoo.in..
b.K. Satyam, V. Murugesh, Dr. S. Suresh
Academy of Scientific and Innovative Research (AcSIR)
Ghaziabad 201 002, India
† Electronic Supplementary Information (ESI) available: Electronic Supplementary
Information (ESI) available: Experimental procedures, spectral data, copies of NMR
spectra for products. See DOI: 10.1039/x0xx00000x
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Journal Name
Table 1 Optimization studya
View Article Online
R
N
N
DOI: 10.1039/C9OB00660E
N
+
Tos
NC
N
base
O
H2 rt, 2 h
,
N
N
N
+
TosMIC
2a
H
R
H
N
TosMIC)
solvent, temp, time
(substituted
2
3
N
N
1a
H
H
3a
Product
(3)
Substrate
Product
1a
Substrate
(2)
(2)
(3)
N
OMe
N
Entry
Solvent
H2Oc
Temp (oC)
Time (h) % yield of 3ab
N
N
Tos
NC
N
H
N
H
2b
1
2
3
4
5
6
7
8
9
RT
40
60
80
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
2
2
2
2
12
2
2
2
2
2
2
2
2
2
2
2
2
2
76
74
71
65
76
74
72
48
40
30
64
76
76
81
81
70
85
51
Tos
NC
3b, 77%
2h
OMe
3h, 75%
H2Oc
N
N
OMe
N
H
N
H2Oc
Tos
NC
N
N
3c,
2c
76%
H
Tos
NC
H2Oc
2i
3i,
80%
MeO
N
N
H2Oc
N
N
H
Tos
NC
OMe
2d
3d,
78%
MeO
OMe
t-BuOH
t-AmOH
DMSO
DMF
N
N
H
N
Tos
NC
MeO
OMe
N
2j
MeO
N
H
73%
Tos
NC
3j,
3e, 71%
2e
F
N
N
N
N
H
10
THF
N
Tos
NC
N
H
2k
Cl
Tos
2f
NC
3k,
75%
F
3f, 77%
11 Toluene
N
12
13
14
15
16
17
18
H2Od
H2Oe
N
N
N
H
N
OMe
NC
N
H
Tos
NC
OMe
Tos
2l
74%
3l,
78%
3g,
2g
Cl
H2Oc,f
H2Oc,g
H2Oc,h
H2Oc,f,i
Neat
Scheme 2
Synthesis of imidazo fused β-carboline
derivatives using different substituted TosMICs.
aReaction conditions: 1a (0.50 mmol),
2 (0.75 mmol); H2O
(2.5 mL, 0.2 M); bYields are of isolated products.
76% yield (Table 1, entry 1). It should be mentioned that this
reaction was heterogeneous in nature. When the reaction
temperature was increased there was a decrease in the yield of
3a (Table 1, entries 2-4). Increasing the reaction time was not
proved to be effective (Table 1, entry 5). It must be mentioned
that this method has the advantages of obviating organic
solvents and base, at ambient temperature, when compared to
the reported methods for van Leusen reaction that use
stoichiometric/excess amounts of base and organic solvent at
higher temperatures.5,6
Among the organic solvents screened, the alcoholic solvents proved
to give better yields of the product 3a (Table 1, entries 6-11). The
quality or source of water did not have an effect on the reaction yield
(Table 1, entries 1, 12 and 13) while better yields were observed at
higher concentration (Table 1, entries 1, 14-16), and it was noted that
the stirring was better at 0.2 M concentration (Table 1, entry 14) of
the reaction.14 It was observed that the product 3a resulted in slightly
higher yield in the presence of K2CO3 (Table 1, entry 17). Under neat
conditions, the product 3a was isolated in lower yield (Table 1, entry
18). We chose the base-free conditions from entry 14, Table 1
to obviate the use of excess amounts of base.
aReaction conditions: 1a (0.50 mmol), 2a (0.75 mmol),
solvent (5 mL, 0.1 M); bYields are of isolated products; cTap
water (pH = 7.85); dDistilled water (pH = 7.34); eHPLC grade
water (pH = 7.65); f2.5 mL (0.2 M); g1.0 mL (0.5 M); h10 mL
(0.05 M); iK2CO3 (0.75 mmol) was used.
potential anticancer lead candidate.11 Compound
E (Figure 1)
was shown to be a bioavailable anti-Alzheimer's agent.12
The reported synthetic approaches to access these skeletons
use multi-step methods or use transition metal compounds and
unfriendly solvents.8 Recently, we have reported transition
metal-catalyzed and base-mediated tandem/sequential
strategies for the synthesis of various fused heterocycles.13
Herein, alternatively, we report a base-free construction of
imidazole nucleus fusion on dihydro β-carboline imine under
aqueous conditions (Scheme 1, eq 2).
We have set out to start our investigations by choosing dihydro
β-carboline imine 1a and TosMIC 2a as model substrates.
Initially, the reaction of 1a and 2a was performed on water at
room temperature. Gratifyingly, the product 3a was isolated in
2 | J. Name., 2012, 00, 1-3
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COMMUNICATION
R2
C
R2
View Article Online
R2
H
R2
Tos
N
R
R2
H
N
DOI: 10.1039/C9OB00660E
N
H
C
N
N
N
N
N
2
+
H
N
R1
N
Tos
NC
R1
N
Tos
R1
H
R1
H
Tos
III
R
R
N
H2 rt, 2 h
O
,
N
N
H
R1
IV
1
H
1
H
(TosMIC)
2a
3
R2
1
-HTos
N
C
Tos
H
Product
Product
F3C
Substrate
Substrate
N
(3)
(3)
R2
(1)
(1)
3
N
H
R
R1
N
F3C
2
+
1
3
N
1
B
N
B
R1
H
R
N
N
3
N
(base)
N
N
N
N
H
Scheme 6 Plausible mechanism.
N
H
N
H
N
H
1b
3m,
70%
65%
1e
3p,
MeO
MeO
N
N
I
CH3I
N
N
Me
N
THF, reflux, 24 h
N
H
N
H
N
90%
4,
N
Br
N
Br
N
N
N
H
N
H
Scheme 7
precursor.
Synthesis of N-heterocyclic carbene (NHC)
N
H
N
H
1c
3n,
69%
1f
70%
3q,
Cl
Cl
Me
N
Me
N
and 1-naphthyl to afford the corresponding imidazo fused β-
carboline derivatives 3e and 3f, respectively, in high yields.
The phenyl substituted TosMICs 2g-i containing electron
donating groups like methoxy on phenyl ring also served as
good substrates in this transformation, irrespective of the
positioning of the methoxy group, to provide good yields of the
corresponding imidazo fused β-carboline derivatives 3g-i. Also
phenyl ring bearing multiple methoxy groups on the TosMIC 2j
was tolerated well to furnish the corresponding imidazo fused
β-carboline derivative 3j in 73% yield. The reactions of dihydro
β-carboline imine 1a with TosMICs 2k and 2l having halogen
substituents on the phenyl group have provided good yields of
the corresponding imidazo fused β-carboline derivatives 3k and
3l, respectively. However, efforts to prepare heteroaryl
substituted, such as 2-furyl/2-thiophenyl, TosMIC derivatives
were not successful in our hands.
N
N
N
N
N
H
N
N
N
H
H
H
1g
1d
3o,
3r,
66%
68%
Scheme 3
Synthesis of imidazo fused β-carboline
derivatives using different dihydro β-carboline imines.
-------------------------------------------------------------------------------
aReaction conditions:
1
(0.50 mmol), 2a (0.75 mmol); H2O
(2.5 mL, 0.2 M); bYields are of isolated products.
mmol scale
10
O
S
N
N
N
+
N
O
H O rt, 2 h
,
2
N
N
H
H
2a
3a 75%
1.58 g
,
1a
Scheme 4
Gram scale synthesis of 6,11-dihydro-5H-
Later we have investigated the scope of the different dihydro β-
carboline imines in the present transformation (Scheme 3).
Dihydro β-carboline imine 1b having phenyl substituent on the
dihydropyridine ring part was reacted with TosMIC 2a to
provide the corresponding imidazo fused β-carboline derivative
3m in 70% yield. Also dihydro β-carboline imines 1c-e
comprising electron donating and electron withdrawing groups
on the phenyl substituent of the dihydropyridine ring part
served as good substrates to furnish the corresponding imidazo
fused β-carboline derivatives 3n-p in good yields. When the
reaction of TosMIC 2a and dihydro β-carboline imine 1f
containing substituents on both the indole benzene ring and
dihydropyridine ring part gave the corresponding imidazo fused
imidazo[1',5':1,2]pyrido[3,4-b]indole 3a
.
87% deuterium
incorporation
D
N
O
S
N
N
+
N
O
D O rt, 2 h
,
2
N
N
H
H
2a
D
1a
3a-D2 57%
,
80% deuterium
incorporation
D
N
N
N
N
D2O
H
Tos
N
N
D
H
H
H
Tos
II
I
Scheme 5 Reaction of 1a and 2a in D2O.
After identifying the conditions for the construction of β-carboline derivative 3q in 70% yield. Aliphatic substituents on
imidazole on water, we turned our focus to investigate the the dihydropyridine ring part of the β-carboline imine 1g also
scope of this transformation. Accordingly, we have performed tolerated well to provide the corresponding imidazo fused β-
the reaction of 1a and differently substituted TosMIC carboline derivative 3r in 66% yield.
derivatives (Scheme 2). Substituted TosMICs 2b-d containing It must be mentioned that the developed method has enabled
aliphatic substituents–including ethyl, benzyl and allyl–gave to scale up the reaction to gram scale for the synthesis of 6,11-
high yields of the corresponding imidazo fused β-carboline dihydro-5H-imidazo[1',5':1,2]pyrido[3,4-b]indole 3a in good
derivatives 3b-d. We have also conducted the reactions of 1a yield (Scheme 4).
with TosMICs 2e and 2f containing aromatic groups like phenyl The reaction of 1a and 2a in D2O resulted in the formation of
the corresponding imidazo fused β-carboline derivative 3a-D2
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with the incorporation of deuterium atoms on the imidazole
Journal Name
We thank the Science and Engineering ResVeieawrcAhrticleBOonalirnde
ring, albeit in lower yield. It was reported that the reaction rates (SERB), Department of Science and TechDnOoIl:o1g0y.10(D39S/TC)9,OInBd00ia66f0oEr
decrease noticeably in D2O in place of water, in particular it was Fast track grant (SB/FT/CS-055/2012 & EMR/2017/002601) and
evident in the case of basic substrates.1g,15 This reaction is CSIR, New Delhi for financial support as part of XII Five Year plan
probably going through the addition followed by cyclization of the under title ORIGIN (CSC-0108). KS thanks CSIR, VM thanks
TosMIC (vide supra) to dihydro β-carboline imine to give the UGC for financial support. We thank the Director, CSIR-IICT for
intermediate
I that can exchange for deuterium atoms to his kind support. We thank Dr. A. V. S. Sarma for his kind support
provide intermediate II, in the presence of D2O, at the α- on NMR.
position of tosyl group and 2nd position of the newly formed
imidazole ring to eventually afford compound 3a-D2 (Scheme 5).
It must be mentioned that we did not observe any N-
deuteration adduct. However, the experiments with deuterated
TosMIC were inconclusive.
This work is dedicated to Late Dr. A. K. Singh.
IICT Communication No. IICT/Pubs/2018/221.
Conflicts of interest
A plausible mechanism for the present metal-, base-free
imidazole formation has been depicted in the Scheme 6.
“There are no conflicts to declare”.
Initially, the precursor dihydro β-carboline imine
act as a base to abstract a proton from TosMIC
nucleophile that would add on to the dihydro β-carboline imine
followed by cyclization resulting in the formation of
intermediate IV via intermediate III. Another molecule of the
starting dihydro β-carboline imine would abstract proton from
intermediate IV followed by removal of tosyl group that could
1
itself would
2
to provide C-
Notes and references
1
For selected reviews on the use of water as a solvent for
organic reactions, see: (a) P. H. Dixneuf and V. Cadierno,
Metal-Catalyzed Reactions in Water, Wiley-VCH, Weinheim,
1
2013; (b) A. Chanda and V. V. Fokin, Chem. Rev., 2009, 109
,
725; (c) U. M. Lindström, Chem. Rev., 2002, 102, 2751; (d) P.
A. Grieco, Organic Synthesis in Water, Blackie, London, 1998;
(e) C.-J. Li and T.-H. Chan, Organic Reactions in Aqueous
Media, Wiley, New York, 1997; (f) C.-J. Li, Chem. Rev., 1993,
93, 2023; (g) R. N. Butler and A. G. Coyne, Org. Biomol.
Chem., 2016, 14, 9945; (h) D. K. Romney, F. H. Arnold, B. H.
Lipshutz and C.-J. Li, J. Org. Chem., 2018, 83, 7319.
(a) E. Vitaku, D. T. Smith and J. T. Njardarson, J. Med. Chem.,
2014, 57, 10257; (b) J. A. Joule and K. Mills, Heterocyclic
Chemistry at a Glance, John Wiley, West Sussex, 2013; (c) Y.-
J. Wu, in Progress in Heterocyclic Chemistry, ed. G. W.
Gribble and J. A. Joule, Elsevier, Amsterdam, 1st edn, 2012,
Vol. 24, ch. 1, pp. 1‒53.
For reviews on the synthesis of heterocycles in aqueous
medium, see: (a) P. Gunasekaran, J. Menéndez and S.
Perumal, in Green Chemistry: Synthesis of Bioactive
Heterocycles, ed. K. Ameta and A. Dandia, Springer, New
Delhi, 2014, Ch. 1, 1‒35; (b) N. R. Candeias, L. C. Branco, P.
M. P. Gois, C. A. M. Afonso and A. F. Trindade, Chem. Rev.,
2009, 109, 2703.
result in the formation of imidazole derivative
alternatively, the product imidazole might also act as a base
3. Later,
3
to follow the plausible reaction mechanism as depicted in the
Scheme 6 (inset).
The synthetic utility of the N-fused imidazo β-carboline was also
explored. We became interested to synthesize N-heterocyclic
carbene (NHC) since these compounds have emerged as
indispensible and potential ligands or catalysts for several
useful organic transformations.13d,16 We have synthesized NHC
2
3
pre-catalyst
4 from 3a, using methyl iodide (Scheme 7). It may
be noted that compounds containing these kind of core NHC
structure have exhibited anti-proliferative and anti-metastatic
activities against human breast cancer cells.10
Conclusions
4
5
(a) Y.-L. Fan, X.-H. Jin, Z.-P. Huang, H.-F. Yu, Z.-G. Zeng, T. Gao
and L.-S. Feng, Eur. J. Med. Chem., 2018, 150, 347; (b) I. Ali,
M. N. Lone and H. Y. Aboul-Enein, Med. Chem. Commun.,
In conclusion, we have successfully developed an efficient and
eco-friendly method for the construction of imidazole ring on
dihydro β-carboline imines on water under base-free
conditions. Various imidazo fused β-carboline derivatives have
been synthesized in high yields. The optimized method enabled
the gram scale synthesis of a representative imidazo fused β-
carboline derivative. This method allowed to the access of a
representative deuterium decorated imidazo fused β-carboline
derivative in D2O. A representative imidazo fused β-carboline
core containing NHC precursor has been synthesized in good
yields. Explorations are underway on the development of
sustainable methods for the construction of imidazole ring
using functionalized cyclic/acyclic imines that would serve as
potential entities for certain biological activity studies.
2017, 8, 1742; (c) L. Zhang, X.-M. Peng, G. L. V. Damu, R.-X.
Geng and C.-H. Zhou, Med. Res. Rev., 2014, 34, 340; (d) X. Y.
Chen, U. Englert, C. Bolm, Chem. ‒Eur. J. 2015, 21, 13221; (e)
S. W. Fox, Chem. Rev., 1943, 32, 47.
(a) A. M. van Leusen, J. Wildeman and O. H. Oldenziel, J. Org.
Chem., 1977, 42, 1153; (b) J. Sisko, A. J. Kassick, M.
Mellinger, J. J. Filan, A. Allen and M. A. Olsen, J. Org. Chem.,
2000, 65, 1516; (c) P. Chen, J. C. Barrish, E. Iwanowicz, J. Lin,
M. S. Bednarz and B.-C. Chen, Tetrahedron Lett., 2001, 42
,
4293; (d) L. G. Bonnet, R. E. Douthwaite and R. Hodgson,
Organometallics, 2003, 22, 4384; (e) V. Gracias, A. F. Gasiecki
and S. W. Djuric, Org. Lett., 2005, 7, 3183. (f) F. De Moliner
and C. Hulme, Org. Lett., 2012, 14, 1354; (g) G. Shigeng, J.
Tang, D. Zhang, Q. Wang, Z. Chen and L. Weng, J.
Organomet. Chem., 2012, 700, 223; (h) T. Kaur, P. Wadhwa,
and A. Sharma, RSC Adv., 2015, 5, 52769.
6
For very recent selected reports on the applications of van
Leusen imidazole synthesis in medicinal chemistry, see: (a) S.
Kondaparla, A. Manhas, V. R. Dola, K. Srivastava, S. K. Puri, S.
B. Katti, Bioorg. Chem., 2018, 80, 204; (b) M. G. Brant, J.
Acknowledgements
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Goodwin-Tindall, K. R. Stover, P. M. Stafford, F. Wu, A. R.
View Article Online
DOI: 10.1039/C9OB00660E
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Organic & Biomolecular Chemistry
Page 6 of 6
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DOI: 10.1039/C9OB00660E
Graphical Abstract
Base-Free van Leusen Reaction of Cyclic Imines on Water:
Synthesis of N-Fused Imidazo 6,11-Dihydro β-Carboline
Derivatives
Killari Satyam,ab V. Murugesh,ab and Surisetti Suresh*ab
a.
Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology (CSIR-IICT),
Hyderabad, 500 007, India. E-mail: surisetti@iict.res.in; suresh.surisetti@yahoo.in
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India.
b.
Abstract:
Construction of imidazoles has been demonstrated on water under base-free conditions. The
reaction of dihydro β-carboline imines and p-toluenesulfonylmethyl isocyanides furnished the
corresponding substituted N-fused imidazo 6,11-dihydro β-carboline derivatives in very good
yields using ambient conditions. The use of deuterium oxide (D2O) as a solvent enabled the
incorporation of deuterium isotopes in the imidazole ring.
R2
R2
No
N
N
Base
R1
R1
N
(substituted) TosMIC
H2O, rt, 2 h
N
N
H
R3
H
Very Mild Conditions
Water as the Solvent
Good Substrate Scope & Yields
Gram Scale Synthesis
Acid/Base-Free Imidazole Construction
Synthesis of NHC Precursor
Construction of imidazole on dihydro β-carboline imines has been disclosed using van Leusen reaction
under base-free conditions on water.