L-Proline catalyzed stereoselective synthesis of (E)-methyl-α-indol- 2-yl-β-aryl/alkyl acrylates: Easy access to substituted carbazoles, γ-carbolines and prenostodione

Article abstract of DOI:10.1039/c3ob41573b

A simple, mild and robust method for the stereoselective synthesis of (E)-methyl α-(3-formyl-1H-indol-2-yl)-β-aryl/alkyl-substituted acrylates via a condensation reaction of methyl 2-(3-formyl-1H-indol-2-yl) acetate with several alkyl or aryl aldehydes using l-proline (25 mol%) as a catalyst is presented for the first time. In addition, completely metal free based high yielding methods for the syntheses of highly substituted biologically important carbazoles, γ-carbolines and the marine alkaloid prenostodione have been developed through our methodology.

Full text of DOI:10.1039/c3ob41573b

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COMMUNICATION
LꢀProline catalyzed stereoselective synthesis of (E)ꢀmethylꢀαꢀindolꢀ2ꢀylꢀ
βꢀaryl/alkyl acrylates: Easy access of substituted carbazoles, γꢀ
carbolines and prenostodione
,a
Soumen Biswas, Pradeep Kumar Jaiswal, Shivendra Singh, Shaikh M. Mobin and Sampak Samanta
*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
45 required for the stereoselective synthesis of αꢀindolꢀ2ꢀylꢀβꢀ
aryl/alkylꢀsubstituted acrylates. We envisaged that active
methylene protons of 1a are in equilibrium form of enols 1a' and
1b' which may be efficiently involved in the knoevenagel type of
condensation reaction with aldehyde in the presence of a mild
50 acid and base to obtain the compound 3 as shown in retroꢀ
synthetic path (Scheme 1).
A simple, mild and robust method for the stereoselective
synthesis of (E)ꢀmethyl αꢀ(3ꢀformylꢀ1Hꢀindolꢀ2ꢀyl)ꢀβꢀ
aryl/alkylꢀsubstituted acrylates via a condensation reaction
10 of methyl 2ꢀ(3ꢀformylꢀ1Hꢀindolꢀ2ꢀyl)acetate with several
alkyl or aryl aldehydes using Lꢀproline (25 mol%) as catalyst
is presented for the first time. In addition, the completely
metal free based high yielding methods for the syntheses of
highly substituted biologically important carbazoles, γꢀ
15 carbolines and the marine alkaloid prenostodione have been
developed through our methodology.
CHO
CHO
CHO
OH
CO2Me
Acid-Base
RCHO
OH
CO2Me
N
H
OMe
N
H
N
H
N
H
CO2Me
Enol
R
3
1a
1a′
1b′
55
Scheme 1. Retro synthetic path
The development of an efficient protocol for the synthesis of
indole derivatives is a key research topic that has gained interest
in the chemical community. A primary reason would be that this
20 framework is most frequently visible in a variety of natural
products, phamacophores, agrochemicals and materials.1 In view
of the great applications, numerous elegant methods have been
discovered to prepare this important motif.1,2 Even with such
progress, the synthesis of Cꢀ2 substituted indoles remains a
25 challenging task for organic chemists. In particular, we have been
in the hunt for developing the synthetic route for easier access of
Cꢀ2 substituted αꢀindolylꢀβꢀsubstituted acrylate derivatives. They
are frequently exhibited in many bioactive natural products
(Figure 1) in addition to their useful roles as synthetic
30 intermediates.1,3 Literature survey shows that a little progress has
been made for their synthesis, which includes the photoadditionꢀ
oxidationꢀelimination reactions between indolineꢀ2ꢀthiones and
methyl acrylate,3d Michael addition reaction of 4,7ꢀdihydroindole
with dimethylacetylenedicarboxylate3f etc.
In recent years, naturally accessible, cheap Lꢀproline has acted as
a potent biꢀfunctional (acidꢀbase) organocatalyst for various
60 organic conversions.4 As a part of our continuing interest towards
the synthesis of Nꢀheterocycles using organocatalysis,5 we wish
to report a clean, catalytic, mild, high yielding and robust method
for the stereoselective synthesis of (E)ꢀmethyl αꢀ(3ꢀformylꢀ1Hꢀ
indolꢀ2ꢀyl)ꢀβꢀaryl/alkylꢀsubstituted
acrylates
through
a
65 condensation reaction of several aromatic and aliphatic aldehydes
with methyl 2ꢀ(3ꢀformylꢀ1Hꢀindoleꢀ2ꢀyl)acetate using Lꢀproline
as an organocatalyst.
We have performed the model reaction between methyl 2ꢀ(3ꢀ
70 formylꢀ1Hꢀindolꢀ2ꢀyl)acetate (1a) and benzaldehyde (2a) in the
presence of Lꢀproline (25 mol%) in dry DMF (1.0 mL) under
nitrogen atmosphere at room temperature for 72 h. The
condensation product (3aa) was isolated in moderate yield 65%
(entry 1, Table 1) with a single diastereomer. Consequently, this
75 significant result fuelled us to investigate this reaction in detail.
For this catalyst, further screening of solvents revealed that
common organic ones, led to inferior results (17ꢀ37% yields,
35
O
CO2
H
O
N
HO
Me
H
CO2Me
N
HO
N
H
MeO2
N
H
N
N
H
C
Et
OAc
CO2Me
CO2Me
N
MeO
CO2Me
entries 3ꢀ7,
except DMSO medium 83% yield, entry 2).
N
Me
H
HO
Nostodione
HO
Prenostodione
OH
Interestingly, in all these cases, only one single diastereomer was
80 found as determined by their 1H NMR of the crude products.
Thus, DMSO was chosen as the best solvent for this reaction. In
order to find out the best catalyst for this condensation reaction,
we employed a series of catalysts such as glycine, ammonium
acetate and pyrrolidineꢀbenzoic acid salt in DMSO medium.
Kopsidasine
Vinblastine
40
Figure 1 Indole natural products bearing a Cꢀ2 acetate or acrylate
moiety.
Therefore, an efficient, general and high yielding method is
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DOI: 10.1039/C3OB41573B
Among these investigations, Lꢀproline was a superior catalyst for
Consequently, the versatility of the above mentioned functional
groups can be elaborated into suitable therapeutic targets by
synthetic modifications.
Table 1 Optimization studiesa
CHO
CHO
conditions
45
PhCHO
CO2Me
CO2Me
N
H
N
H
5
Table 2 Scope of condensation reactiona
Ph
1a
2a
3aa
Entry
1
Catalyst
Solvent
DMF
T/h
72
Yield (%)b,c
65
50
LꢀProline
2
3
4
5
6
7
8
9
LꢀProline
LꢀProline
LꢀProline
LꢀProline
LꢀProline
LꢀProline
Glycine
PyrrolidineꢀPhCO2H
NH4OAc
DABCO
DMSO
MeCN
THF
MeOH
DCM
72
72
72
72
72
72
72
72
72
48
48
48
72
83
27
32
37
17
33
44
66
14
10
12
NR
NR
Entry
R
X
T/h Product Yield
(%)b,c
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
I
72
72
72
72
72
80
80
80
80
60
60
60
60
60
60
72
72
72
48
48
48
48
72
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
83
75
78
71
74
72
70
76
77
82
85
78
81
68
72
75
76
78
86
81
85
83
55
3ꢀMeC6H4
4ꢀMeC6H4
2ꢀMeOC6H4
4ꢀMeOC6H4
2,5ꢀ(MeO)2C6H3
3ꢀMeOꢀ4ꢀBnOC6H3
4ꢀOHC6H4
3ꢀMeOꢀ4ꢀOHC6H3
2ꢀClC6H4
EtOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
10
11
12
13d
14d
Pyrrolidine
PhCO2H
DABCOꢀPhCO2H
9
10
11
12
13
14
15
16
17
18
19d,e
20d,e
21d,e
22d,e
23
3aj
3ak
3al
aUnless otherwise specified, all the reactions were carried out with
compound 1a (0.25 mmol), 2a (0.3 mmol) and catalyst ( 25 mol%) in
specified dry solvent (1.0 mL) under nitrogen at room temperature.
bIsolated yield after column chromatography. cSingle diastereomer
was observed in all these cases.dNR indicates no reaction.
4ꢀClC6H4
3ꢀBrC6H4
4ꢀBrC6H4
3am
3an
3ao
3ap
3aq
3ar
3as
3at
2ꢀNO2C6H4
2ꢀNHBocC6H4
NꢀBocꢀIndolyl
2ꢀFuryl
2ꢀThiophenyl
(MeO)2CH
MeCH2CH2
Me(CH2)4
this reaction in terms of reactivity (entry 2). It is pertinent to note
10 that only organic acid (PhCO2H) or organic bases (DABCO and
pyrrolidine) or 3º amineꢀacid salt were unable to trigger this
reaction (entries 11ꢀ14).
3au
3av
3ba
PhCH2CH2
Ph
aUnless otherwise mentioned, all the reactions were carried out with
substrates 1aꢀb (0.2 mmol), aldehydes (2aꢀv, 0.3 mmol) and Lꢀ
proline (25 mol%) in dry DMSO (1.0 mL) under nitrogen at room
temperature. bIsolated yield after column chromatography. cSingle
distereomer was observed. dMixture of diasteromer was observed
(4:1). eReactions were performed with aldehydes (0.9 mmol).
After standardizing the reaction conditions, we investigated the
15 generality and scope of this condensation reaction. The results are
compiled in Table 2. As shown in Table 2, aromatic aldehydes
with diverse range of substituents including Me, OMe, OBn,
OH, Cl, Br, NO2, NHBoc on the aromatic nucleous, all produced
exclusively (E)ꢀmethyl αꢀindolꢀ2ꢀylꢀβꢀarylꢀacrylates in good
20 yields (3aaꢀ3ao, 68ꢀ85%, entries 2ꢀ15) irrespective of their
positions when substrate 1a was employed. In order to assign the
stereochemistry of C=C bond, single crystals of 3ah and 3am
were obtained with their structures unanimously confirmed by
single crystal Xꢀray diffraction analysis data (details in ESI)
25 indicating aryl groups in transꢀrelations with CO2Me. Not only
aromatic aldehydes but also heteroꢀaryl aldehydes were witnessed
to be good substrates for this condensation reaction, after 72 h,
providing the desired products (3apꢀ3ar) in good yields (76ꢀ78%,
entries 16ꢀ18). It is meaningful to point that αꢀunsubstituted
30 aldehydes are well known to be incompatible substrates for crossꢀ
aldol reactions. To our delight, in our conditions, aliphatic
aldehydes did not pose any difficulty in condensation reactions
with 1a leading to the desired compounds (3asꢀ3av) in high
yields (81ꢀ86%, entries 19ꢀ22). However, in all these cases,
35 mixtures of inseparable diastereomers were observed in the ratio
of 4:1. Next, by this procedure, a methyl 2ꢀ(4ꢀiodoꢀ3ꢀformylꢀ1Hꢀ
indolꢀ2ꢀyl)acetate 1b also reacted with 2a providing the
corresponding product 3ba in a mediocre yield (55%, entry 23).
Our optimal conditions are mild enough to sustain several
40 sensitive functional groups like CO2Me, CHO, OMe, OBn, OH,
Boc, CH(OMe)2, Cl, Br, I, NO2, furyl, thiophenyl etc.
The development of highly efficient metalꢀfree based catalytic
system for the synthesis of substituted carbazole derivatives is
55 still a difficult job for organic chemist.6 In this connection, we
have realized that (E)ꢀmethyl αꢀ(3ꢀformylꢀ1Hꢀindolꢀ2ꢀyl)ꢀβꢀ
aryl/alkylꢀsubstituted acrylates can be potentially converted into
carbazole derivatives via
a MichaelꢀHenry reaction with
nitromethane and followed by aerial oxidation. In this regard, a
60 wide range of structurally varied βꢀaryl/heteroꢀaryls substituted
acrylates with diverse steric and stereoelectronic environments
underwent facile reactions with nitromethane in THF medium at
MeNO (3.0 equiv),
2
DBU (35 mol%)
CHO
CO2Me
NO2
N
H
N
H
R
65
THF, air, 18-24 h, rt
CO2Me
3aa-3av
R = alkyl, aryl, heteroaryl
R
H
4aa-4av
NO2
NO2
NO2
OMe
R
X
OBn
N
N
N
H
H
H
CO2Me
CO2Me
CO2Me
4ag: 74%
4aa: X = H, 81%
4ac: X = Me, 78%
4ae: X = OMe, 76%
4ah: X = OH, 71%
4ak: X = Cl, 82%
4am: X = Br, 79%
4at: R = Me(CH ) , 90%
70
2 2
4av: R = Ph(CH ) , 92%
NO2
2 2
N
H
X
CO2Me
: X = O, 82%
4aq
4ar: X = S, 84%
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

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DOI: 10.1039/C3OB41573B
Scheme 2 Synthesis of substituted carbazoles
methyl 2ꢀ(3ꢀformylꢀ1Hꢀindolꢀ2ꢀyl)acetate with both enolizable
room temperature using DBU (35 mol%) under air. After 24 h, 60 and nonꢀenolizable aldehydes using naturally available,
high yields of the corresponding 1ꢀmethoxycarbonylꢀ2ꢀaryl/alkylꢀ
3ꢀnitroꢀ9Hꢀcarbazoles (4aaꢀ4ar, 71ꢀ84%, Scheme 2) were
obtained. Importantly, βꢀalkyl substituted acrylates resulted in
nearly perfect yields (4at and 4av, 90ꢀ92%) at our optimal
inexpensive and nonꢀtoxic Lꢀproline as an organocatalyst.
Moreover, this method excels for a variety of functional groups
and their positions. Importantly, the condensation products can be
transformed directly into important class of Nꢀheterocyclic
5
conditions. Several sensitive functional groups can be achieved 65 compounds like carbazoles and γꢀcarbolines by simple
under present conditions. Moreover, this method excludes the use
of acids, highly toxic reagents, toxic metals, stoichiometric
10 amount of strong oxidants, any need for inert atmosphere, multiꢀ
steps etc.
operations, offering efficient and metal free based new synthetic
strategies to access these heterocycles. In addition, the first total
synthesis of the marine alkaloid prenostodione has been
successfully achieved through this methodology. Additional
70 applications of these compounds are in progress.
After successfully developing the method for carbazoles
synthesis, we focused on the synthesis of γꢀcarbolines by
Acknowledgements
The authors thank the CSIR research grant (Project No.
15 performing the reactions between
ammonium acetate with
several (E)ꢀmethyl αꢀ(3ꢀformylꢀ1Hꢀindolꢀ2ꢀylꢀβꢀaryl/alkylꢀ
02(0019)/11/EMRꢀII) for the generous financial support.
substituted acrylates (3aaꢀ3av) in DMSO medium under air at
room temperature for 12ꢀ16 h. Surprisingly, all these reactions
proceeded smoothly, affording the corresponding substituted
75
Notes and references
aIndian Institute of Technology Indore, 452017, Indore, MP, India. Fax:
91-731-2364182; Tel: 91-731-2438742; E-mail: sampaks@iiti.ac.in
† Electronic Supplementary Information (ESI) available: [Experimental
80 procedures and chracterization data of new compounds, CCDC 952076
(3ah) and CCDC 952075 (3am)]]. See DOI: 10.1039/b000000x/
1 (a) R. J. Sundberg, Indoles; Academic: New York, 1996. For review
see: (b) S. Cacchi and G. Fabrizi, Chem. Rev., 2011, 111, PR215; (c)
G. R. Humphery and J. T. Kuethe, Chem. Rev., 2006, 106, 2875; (d)
20 methyl
3ꢀaryl/heteroꢀaryl/alkylꢀ5Hꢀpyrido[4,3ꢀb]indoleꢀ4ꢀ
carboxylates (5aaꢀ5av) in high to excellent yields (86ꢀ96%,
Scheme 3). The latter moiety is known to be an important class of
heterocyclic compound exhibited in various natural products and
biological activities.7
25
30
35
CHO
85
M. Bandini and A. Eichholzer, Angew. Chem., Int. Ed., 2009, 48,
9608.
2 (a) M. Inman and C. J. Moody, Chem. Sci., 2013, 4, 29; (b) D. F. Taber
and P. K. Tirunahari, Tetrahedron, 2011, 67, 7195.
N
NH4OAc (1.5 equiv)
CO2Me
N
H
DMSO, air, rt, 12-16h
N
H
R
3aa-3av
CO2Me
R
H
5aa-5av
R = alkyl, aryl, hetero-aryl
N
X
N
N
3 (a) A. Ploutno and S. Carmeli, J. Nat. Prod. 2001, 64, 544; (b) P.
Magnus, L. Gazzard, L. Hobson, A. H. Payne and V. Lynch,
Tetrahedron Lett., 1999, 40, 5135; (c) P. Magnus, L. Gazzard, L.
Hobson, A. H. Payne, T. J. Rainey, N. Westlund and V. Lynch,
Tetrahydron, 2002, 58, 3423; (d) C. Arazano, J.ꢀL. Fourrey and B.
C. J. Chem. Soc., Chem. Commun., 1981, 24, 37; (e) M. E. Kuehne
and F. Xu, J. Org. Chem., 1997, 62, 7950; (f) H. Çavdar and N.
Saraçoğlu, J. Org. Chem., 2006, 71, 7793; (g) H. Çavdar and N.
Saraçoğlu, Tetrahedron, 2005, 61, 2401; (h) J. C. Badenock, J. A.
Jordan and G. W. Gribble, Tetrahedron Lett., 2013, 54, 2759.
4 (a) B. List, Asymmetric Organocatalysis; Springer, 291, 2009. For
some recent review, see: (b) W. Notz, F. Tanaka and C.F. III.
Barbas, Acc. Chem. Res., 2004, 37, 580; (c) S. Bertelsen and K. A.
Jørgensen, Chem. Soc. Rev., 2009, 38, 2178; (d) R. M. Kellogg,
Angew. Chem., Int. Ed., 2007, 46, 494; (e) B. List, R. A. Lerner and
C. F. III, Barbas, J. Am. Chem. Soc., 2000, 122, 2395.
X
90
N
NBoc
N
H
H
CO2Me
N
H
CO2Me
CO2Me
5aa: X = H, 96%
: X = Me, 93%
: X = MeO, 89%
5ak: X = Cl, 94%
5am: X = Br, 96%
N
5ap: 94%
5an: X = NO , 93%
2
5ac
5ae
5ao
: X = NHBoc, 86%
OMe
N
N
O
95
R
OBn
N
N
H
N
H
H
CO2Me
CO2Me
CO2Me
5aq: 90%
5ag: 86%
5at: R = Me, 91%
5av: R = Ph, 95%
Scheme 3 Synthesis of substituted γꢀcarbolines.
100
Finally, we have used compound 3ah for a novel access to the
40 marine alkaloid prenostodione3a,h 8 which was obtained in
excellent yield 91% from 6 via Boc protections of NH and OH
groups of 3ah, followed by aldehyde to carboxylic acid using a 105
Pinnic oxidation method to form 6 and subsequent deprotection
of Boc groups (Scheme 4). Similar routes were adopted for the
45 synthesis of compound 9 (details in ESI).
5
(a) D. Majee, A. Srivastava and Samanta, S. RSC Adv., 2013, 3,
11502; (b) S. Singh, A. Srivastava and S. Samanta, Tetrahedron
Lett., 2012, 53, 6087; (c) A. Srivastava, S. Singh and S. Samanta,
Tetrahedron Lett., 2013, 54, 1444; (d) P. K. Jaiswal, S. Biswas, S.
Singh, B. Pathak, S. M. Mobin and S. Samanta, RSC Adv., 2013, 3,
10644; (e) P. K. Jaiswal, S. Biswas, S. Singh and S. Samanta,
Green Chem., submitted.
For selected reviews on carbazoles, see: (a) A. W. Schmidt, K. R.
Reddy and H. ꢀJ. Knölker, Chem. Rev., 2012, 112, 3193; (b) I. Bauer
and H.ꢀJ. Knölker, Top. Curr. Chem., 2012, 309, 203; (c) H.ꢀJ.
Knölker, Chem. Lett., 2009, 38, 8; (d) H.ꢀJ. Knölker, Curr. Org.
Synth., 2004, 1, 309; (e) J. Roy, A. K. Jana and D. Mal, Tetrahedron,
2012, 68, 6099; (f) H.ꢀJ. Knölker and K. R. Reddy, In The
Alkaloids, ed. G. A. Cordell, Academic Press, Amsterdam, 2008, vol.
65, p. 1. Oneꢀpot transition metal free mediated carbazole synthesis,
see: (g) F. Xiao, Y. Liao, M. Wu and G.ꢀJ. Deng, Green Chem.,
2012, 14, 3277; (h) A. P. Antonchick, R. Samanta, K. Kulikov and J.
Lategahn, Angew. Chem., Int. Ed., 2011, 50, 8605; (i) S. H. Cho, J.
Yoon and S. Chang, J. Am. Chem. Soc., 2011, 133, 5996.
CHO
CO2
H
CO2
H
110
115
120
125
1) Boc2O, DMAP,
DCM, rt, 3 h
CO2Me
CO2Me
CO2Me
DCM/TFA = 3/1
rt, 8 h
N
N
N
H
Boc
H
6
2) NaClO2, NaH2PO4
2-methyl-2-butene
t-BuOH/H2O = 3/1
RO
RO
RO
8; R = H, 91%
9; R = Me, 95%
3ah; R = H
3ae; R = Me
6; R = Boc, 90% (two steps)
7; R = Me, 93% (two steps)
50
Scheme 4 Stereoselective synthesis of prenostodione (8)
Conclusions
55 In summary, we have reported first, a very simple, mild, high
yielding and new direct protocol for the stereoselective synthesis
of predominantly (E)ꢀmethyl αꢀ(3ꢀformylꢀ1Hꢀindolꢀ2ꢀyl)ꢀβꢀ
aryl/alkylꢀsubstituted acrylates via a condensation reaction of
7
(a) R. S. Alekseyev, A. V. Kurkin and M. A. Yurovskaya, Chem.
Heterocycl. Compd. 2009, 45, 889. Synthetic approaches to γꢀ
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

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DOI: 10.1039/C3OB41573B
carbolines, see: (b) S. Ding, Z. Shi and N. Jiao, Org. Lett., 2010, 12,
1540; (c) S. Chiba, Y.ꢀJ. Xu and Y.ꢀF. Wang, J. Am. Chem. Soc.,
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Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C3OB41573B
Graphical Abstract
LꢀProline catalyzed stereoselective synthesis of (E)ꢀmethyl αꢀindolꢀ2ꢀylꢀ
βꢀaryl/alkyl acrylates: Easy access of substituted carbazoles, γꢀ
carbolines and prenostodione
Soumen Biswas, Pradeep Kumar Jaiswal, Shivendra Singh, Shaikh M. Mobin, and Sampak Samanta
LꢀProline catalyzed condensation reaction of methyl 2ꢀ(3ꢀformylꢀ1Hꢀindolꢀ2ꢀyl)acetate with several aldehydes providing predominantly
(E)ꢀmethyl αꢀ(3ꢀformylꢀ1Hꢀindolꢀ2ꢀyl)ꢀβꢀaryl/alkylꢀsubstituted acrylates in high yields has been presented.