Rhodium-catalyzed synthesis of 2,3 – Disubstituted N-methoxy pyrroles and furans via [3+2] cycloaddition between metal carbenoids and activated olefins

Article abstract of DOI:10.1016/j.tet.2017.04.007

For the first time, we report the synthesis of 2-substituted N-alkoxy pyrrole 3-carboxylate and furan 3-carboxylate via Rh-catalyzed [3+2] cycloaddition between α-diazo oxime ether or α-diazo carbonyl compounds with vinyl equivalents in a one-pot process. We have demonstrated ethyl vinyl ether as well as vinyl acetate as vinyl equivalents and both were found to give excellent yields. We have also demonstrated the synthesis of N-alkoxy dihydropyrrole derivatives by carrying out the reaction at low temperature.

Full text of DOI:10.1016/j.tet.2017.04.007

Accepted Manuscript
Rhodium-catalyzed synthesis of 2,3 – Disubstituted N-methoxy pyrroles and furans
via [3+2] cycloaddition between metal carbenoids and activated olefins
Bharath Kumar Kuruba, Samuel Vasanthkumar, Lourdusamy Emmanuvel
PII:
S0040-4020(17)30370-8
10.1016/j.tet.2017.04.007
TET 28608
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 November 2016
Revised Date: 4 April 2017
Accepted Date: 5 April 2017
Please cite this article as: Kuruba BK, Vasanthkumar S, Emmanuvel L, Rhodium-catalyzed synthesis of
2,3 – Disubstituted N-methoxy pyrroles and furans via [3+2] cycloaddition between metal carbenoids and
activated olefins, Tetrahedron (2017), doi: 10.1016/j.tet.2017.04.007.
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ACCEPTED MANUSCRIPT
Rhodium-catalyzed synthesis of 2,3 – disubstituted N-methoxy pyrroles and furans via
[3+2] cycloaddition between metal carbenoids and activated olefins
Bharath Kumar Kuruba, Samuel Vasanthkumar, Lourdusamy Emmanuvel*
aSchool of Science & Humanities, Department of Chemistry, Karunya University,
Coimbatore (TN) – 641114, INDIA.
O
O
X
O
R1
X = O
80 oC
X = NOMe
80 oC
R1
R
R1
OR2
N
O
R
N2
R
OMe
Rh2(OAc)4 + DCE
8 - N - alkoxy pyrroles
2 - Vinyl equivalents
8 - Furans
2 - Vinyl equivalents
R = alkyl, aryl
R1 = O-alkyl, O-aryl
R2 = OEt, COCH3
One - pot process
For the first time, we report the synthesis of 2-substituted N-alkoxy pyrrole 3-carboxylate and
furan 3-carboxylate via Rh-catalyzed [3+2] cycloaddition between α-diazo oxime ether or α-
diazo carbonyl compounds with vinyl equivalents in a one-pot process. We have
demonstrated ethyl vinyl ether as well as vinyl acetate as vinyl equivalents and both were
found to give excellent yields. We have also demonstrated the synthesis of N-alkoxy
dihydropyrrole derivatives by carrying out the reaction at low temperature.
Keywords: N-alkoxy pyrrole, [3+2] cycloaddition, imino carbenoids, 2,3-disubstituted furan,
diazo carbonyl compounds.
1

ACCEPTED MANUSCRIPT
Rhodium-catalyzed synthesis of 2,3 – disubstituted N-methoxy pyrroles and furans via
[3+2] cycloaddition between metal carbenoids and activated olefins
Bharath Kumar Kuruba, Samuel Vasanthkumar, Lourdusamy Emmanuvel*
aSchool of Science & Humanities, Department of Chemistry, Karunya University, Coimbatore (TN) – 641114,
INDIA.
*Corresponding address:
Dr. L. Emmanuvel,
Assistant professor, Department of Chemistry, Karunya University, Coimbatore – 641 114 (IN)
Corresponding email: emmanuvel@karunya.edu
Ph No: 0422-2614105, Fax: 0422-2615615
Pyrroles are the basic nitrogen containing heterocycles,1 which have attracted the
synthetic chemists throughout the world. Pyrrole derivatives find application2 in several
fields such as medicinal, agrochemical, dyes, flavouring agents, pesticides, solar cells,
organic functional molecules etc. They exhibit several biological activities3 such as
antifungal, antibacterial, antitumor, antimalarial, antibiotic, antipsychotic and used for
the treatment of diseases such as Alzheimer, neoplastic etc. Owing to the potential
applications of pyrrole derivatives, several methods have been reported to obtain them.
In addition to the classical methods such as Paal-Knorr,4 Huisgen5 and Hantzsch,6
several other methods7 had been developed in recent years. Generally, the synthesis
involves intramolecular cyclization or cycloaddition in the presence of metal catalysts.
In recent years, imino carbenoids have gained much attention in synthetic organic chemistry
as they react with a variety of functional groups including highly unreactive aromatic
hydrocarbon. 1 – Sulfonyl – 1, 2, 3 triazole derivatives have been demonstrated as the stable
precursor for imino carbenoids8 and successfully subjected to transannulation with alkyne,
alkene, vinyl ether to get pyrroles. Since, 1 – sulfonyl – 1, 2, 3-triazole is generally prepared
from terminal alkyne and tosyl azide in the presence of Cu catalyst to avoid regioisomers
whereas, 2 – substituted heterocycles cannot be synthesized by this approach. Further, the
sulfonyl group is deprotected under harsh reaction conditions to obtain N- heterocycles.
Recently, Xu et. al. have reported9 Cu(hfacac)2 catalyzed synthesis of highly
substituted/fused pyrroles via carbene cascade reaction of α-imino diazo compounds.
We have reported10 that α-diazo oxime ether could also serve as a precursor for imino
carbenoids. Unlike 1,2,3-triazole derivatives as precursors for imino carbenoids, highly
2

ACCEPTED MANUSCRIPT
substituted derivatives could be prepared regioselectively with α-diazo oxime ether. In this
communication, we report for the first time, synthesis of 2, 3-disubstituted N-alkoxy pyrrole
via 3+2 cycloaddition between α-diazo oxime ether and ethyl vinyl ether (Fig. 1).
N
Rh2(OAc)4
R
R
N
OEt
Reported by Anbarasan et al.
DCE, 90 oC
16-20 h
N
N
Ts
Ts
Rh2(OAc)4
(2 mol%)
DCE, 80 oC
R1
R1
N2
N
Our work
OEt
N
OMe
OMe
R
R
Fig. 1
Recently, we reported11 a two-step one-pot process for the synthesis of α-diazo oxime ether
directly from the β-keto ester. During the investigation of its ability to serve as potential
building block in the synthesis of N-heterocycles, we found that, the α-diazo oxime ether 1a
undergoes [3+2] cycloaddition with ethyl vinyl ether in the presence of Cu(OTf)2 (5 mol%),
o
in dichloroethane (DCE) at 80 C to give N-methoxy pyrrole 2a in poor yield of 21%
(Scheme 1).
EtO2C
EtO2C
N2
N
Cu(OTf)2
OMe
OEt
N
DCE, reflux
OMe
2a
1a
Scheme 1: Synthesis of 2,3-disubstituted N-alkoxy pyrrole
In order to improve the yield of N-methoxy pyrrole 2a, we screened several transition metal
catalysts that are known to form metal carbenoids in different solvents and the results are
tabulated (Table 1).
Table 1: Optimization of reaction conditionsa
EtO2C
EtO2C
N2
Catalyst
OEt
Solvent, 80 oC
8 h
N
OMe
N
OMe
2a
1a
3

ACCEPTED MANUSCRIPT
Entry Catalyst (mol %) Solvent Yieldb (%)
1
2
3
4
5
6
7
8
9
Cu(OTf)2 (2.0)
Cu(OTf)2 (5.0)
DCE
DCE
DCE
DCE
DCE
DCE
21
38
Tracec
Cu(hfacac)2 (2.0)
Cu(hfacac)2 (5.0)
Rh2(OAc)4 (1.0)
Rh2(OAc)4 (2.0)
25
73
87 (90)e
68d
Rh2(OAc)4 (2.0) CHCl3
Rh2(OAc)4 (2.0) THF
Rh2(OAc)4 (2.0) Toluene
65d
69
aReaction conditions: α-diazo Oxime ether 1a (2 mmol),
o
ethyl vinyl ether (3 mmol), Solvent (3 mL/mmol), 80 C, 8
b
h. Yield corresponds to the isolated product by column
chromatography, cObserved by HPLC. dReaction was
carried out in sealed tube. eYield with 3 mol% Rh2(OAc)4.
In contrast to our earlier reports,12 in which copper salts were found to be a better catalyt than
Rhodium complexes to promote [3+2] cycloaddition between imino carbenoids and enamino
esters or nitriles, Rh2(OAc)4 was found to give better yield of [3+2] cycloaddition product
than copper catalysts. The optimal catalyst loading was found to be 2 mol%. Increasing the
catalyst loading (3 mol%) did not improve the yield considerably while decreasing the
catalyst loading to 1 mol% diminished the yield (Entry 5, Table 1). Among the solvents,
dichloroethane gave the maximum yield, while the reaction in THF or CHCl3 resulted in poor
yields of pyrrole 2a. It is noteworthy to observe that we obtained pyrrole directly without any
acid treatment.10a
Table 2: Synthesis of N-alkoxy pyrroles via [3+2] cycloadditiona
Yieldb
Diazo carbonyl compound
Product
Entry
a
With Ethyl With Vinyl
1
2
vinyl ether
acetate
O
EtO2C
N2
EtO
87
85
N
OMe
OMe
N
4

ACCEPTED MANUSCRIPT
O
O
MeO2C
N2
N
MeO
BnO
b
c
86
81
86
82
N
OMe
OMe
BnO2C
EtO2C
N2
N
N
OMe
OMe
O
O
EtO
EtO
N2
OMe
d
e
79
80
81
80
N
OMe
N
EtO2C
N2
OMe
N
OMe
N
EtO2C
O
EtO
N
OMe
N2
OMe
f
83
81
82
80
N
O2N
O2N
EtO2C
O
EtO
N2
N
OMe
N
OMe
g
NO2
O2N
aReaction conditions: α-diazo oxime ether (2 mmol), vinyl equivalents (3 mmol), DCE (3
mL/mmol), 80 oC, 8 h. bYield corresponds to the isolated product by column
chromatography.
After optimizing the reaction conditions, we treated several α-diazo oxime ethers with vinyl
ether (1.5 equivalent) in the presence of Rh2(OAc)4 and the results are tabulated (Table 2).
2-aryl or 2-alkyl substituted N-methoxy pyrrole 3-carboxylates were conveniently
synthesized following this route in good yields. The bulkiness in the diazo compound had
negligible effect on the yield of the corresponding cyclized product.
5

ACCEPTED MANUSCRIPT
Pirrung et.al13 have successfully employed vinyl acetate to couple with diazo carbonyl
compounds to get the corresponding 3+2 cycloaddition product which was further converted
into furans. Considering the availability of vinyl acetate we believed that vinyl acetate could
serve as a better alternate for ethyl vinyl ether. As expected, under the same reaction
condition, we got the N-alkoxy pyrrole by replacing ethyl vinyl ether with vinyl acetate.
To our surprise, a similar [3+2] cycloaddition with α-diazo carbonyl compounds to get furan
derivatives in a one-step has not been reported. In all the earlier reports,13, 14 the dihydrofuran
derivatives obtained are treated either with an acid like p-TSA or subjected to thermal
elimination to get substituted furans.
O
Rh2(OAc)4
(2 mol%)
N2
EtO2C
R
EtO
DCE, 80 oC
OR'
O
O
R
3
4
R' = Et or COCH3
Scheme 2: Synthesis of 2,3-disubstituted furan
Excited by our observation of direct conversion into heterocycles, presumably due to thermal
elimination, we attempted the synthesis of furan 3-carboxylates 4 by taking α-diazo carbonyl
compounds 3 in place of α-diazo oxime ethers. Indeed, we obtained the desired product not
only with vinyl ether but also with vinyl acetate under the same reaction conditions (Scheme
2). Several diazo carbonyl compounds had been screened and the result is given in Table 3.
Table 3: Synthesis of Furan 3- carboxylate derivativesa,b
EtO2C
MeO2C
BnO2C
O
86 (87)
O
85 (86)
O
4a
4b
4c
83 (82)
EtO2C
EtO2C
EtO2C
O
EtO2C
O
O
O
O2N
NO2
4g
80 (81)
79 (77)
4e
4d
77 (76)
83 (81)
4f
aReaction conditions: α-diazo carbonyl ester (2 mmol), vinyl equivalents (3 mmol), DCE
(3 mL/1 mmol), refluxed for 8 h, bYield with vinyl acetate has been given in parenthesis.
6

ACCEPTED MANUSCRIPT
Since, both α-diazo ketones and imines underwent [3+2] cycloaddition, we were curious to
study the relative reactivity of these two groups. We chose α-diazo mono oxime ether of
acetylacetone 1h as the substrate of study and carried out [3+2] cycloaddition with ethyl vinyl
ether under the same reaction condition (Scheme 3). As expected, we observed the
intermediate A to delocalize over the carbonyl due to higher electro negativity of oxygen than
imine to give furan 3-carboxylate 4h in 68% and N-methoxy pyrrole in 21% yields. This may
be attributed to the high electronegativity of oxygen atom than amine. A similar behaviour
was observed by C. –M. Park et al.15
OMe
N
4h
Major
O
O
O
OEt
OEt
N2
N
Rh
N OMe
A
O
OMe
2h
Traces
1h
N
OMe
Scheme 3: Relative reactivity study of α-diazo ketones and imines
Further, we were surprised to observe the reaction to eliminate acetic acid or ethanol to give
directly pyrrole and furan carboxylates while the earlier reports on this [3+2] cycloaddition
resulted in dihydrofuran which upon treatment with acid or heating furnished furan. In order
to confirm the formation of dihydropyrrole as the intermediate, we carried out this reaction at
o
50 C and obtained dihydropyrrole 2d’ in 52% isolated yield (Scheme 4). This observation
o
strongly supports our prediction that the high temperature (80 C) lead to the thermal
elimination to give pyrrole.
O
EtO2C
Rh2(OAc)4
2 mol%
DCE, 50 oC
EtO
OAc
OMe
52%
N2
OMe
N
OAc
N
1d
2d'
Scheme 4: N-methoxy dihydropyrrole formation at low temperature
Based on the above observation, we strongly believe that the metal carbenoids formed from
α-diazo carbonyl compound undergo [3+2] cycloaddition with vinyl ether or vinyl acetate to
give dihydropyrrole derivative C, which upon extended heating eliminates ethanol or acetic
7

ACCEPTED MANUSCRIPT
acid to give N-alkoxy pyrrole D (Fig. 2).
X
O
R1
R2
RhII
N2
N2
O
R1
O
X
EtOH
X
R1
O
X
X
OEt
Rh
R2
R1
R2
OEt
R2
R1
R2
Rh
O
A
D
C
B
OEt
Fig. 2: Proposed catalytic cycle for the (3+2) cycloaddition
Conclusion
In conclusion, we have described a direct synthesis of N-alkoxy pyrroles and furan 3-
carboxylates from α-diazo oxime ethers and α-diazo carbonyl compounds, respectively via
[3+2] cycloaddition with vinyl ether or vinyl acetate. Thermal elimination of ethanol or acetic
acid to give N-alkoxy pyrrole or furan 3-carboxylates, directly, was confirmed by carrying
out the reaction at low temperature. Thus, the method can also be employed to obtain
N-methoxy dihydropyrrole derivative by simply carrying out the reaction at low temperature.
2, 3-disubstituted N-alkoxy pyrrole derivatives are expected to have interesting biological
activities, which needs further investigation.
Experimental section:
All reagents and solvents were obtained from Merck and Aldrich is used without any
purification. 1H- and 13C- NMR spectra were recorded on Bruker FT- 500 or 400 using
tetramethylsilane (TMS) as an internal standard. The IR spectra were recorded on
Shimadzu FT-IR spectrophotometer (in KBr).The compounds were purified by column
chromatography using silica gel (100-200 mesh) and pet ether: ethyl acetate. TLC was
performed using silica gel 60 F254 pre-coated on aluminium sheets, obtained from
Merck. Visualization of spots on TLC plate was done with UV light (254 nm).
8

ACCEPTED MANUSCRIPT
General procedure
To a solution α-diazo oxime ether (2 mmol) and Rh2(OAc)4 (2 mol %) in DCE (4 mL) under
nitrogen atmosphere and at room temperature was added a solution of ethyl vinyl ether (216
mg, 0.288 mL, 3 mmol) in DCE (2 mL) was added through a syringe. The reaction mixture
was heated at 80 oC for 8 h. After the completion of the reaction as indicated by the TLC, the
reaction mixture was cooled to room temperature and purified by column chromatography
using a pet ether/ethyl acetate 19:1 mixture as eluent to afford the pyrrole 2a.
Synthesis of Ethyl 1-methoxy-2-methyl-1H-pyrrole-3-carboxylate (2a): The title
compound was prepared according to the general procedure and the product was
obtained as colorless viscous oil; Yield: 87% (318.4 mg); Rf (5 % Pet ether/ethyl acetate)
0.33; 1H NMR (400 MHz, CDCl3): δ 7.21 (d, 1H, J = 7.2 Hz), 6.80 (d, 1H, J = 7.2 Hz), 4.31
13
(q, 2H, J = 3.2 & 6 Hz), 3.98 (s, 3H), 2.41 (s, 3H), 1.32 (t, 3H, J = 3.6 Hz); C NMR (125
MHz, CDCl3): δ 164.81, 138.06, 130.13, 129.87, 107.96, 60.69, 57.21, 15.62, 14.68; MS-EI
(m/z) Calcd. for C9H13NO3: 183.0895; found: 183.0899.
Methyl 1-methoxy-2-methyl-1H-pyrrole-3-carboxylate (2b): Yield: 86% (290.68 mg);
1
obtained as a colorless gum; Rf (5 % Pet ether/ethyl acetate) 0.35; H NMR (400 MHz,
CDCl3): δ 6.91 (d, 1H, J = 7.6 Hz), 6.75 (d, 1H, J = 7.6 Hz), 3.91 (s, 3H), 3.87 (s, 3H), 2.31
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 164.85, 139.69, 128.56, 127.96, 107.09, 58.13,
51.74, 15.66; MS-EI (m/z) Calcd. for C8H11NO3: 169.0739; found: 169.0732.
Benzyl 1-methoxy-2-methyl-1H-pyrrole-3-carboxylate (2c): Yield: 81% (477.9 mg);
obtained as a reddish brown gum; Rf (5 % Pet ether/ethyl acetate) 0.31; 1H NMR (400
MHz, CDCl3): δ 7.44 – 7.33(m, 5H), 6.89 (d, 1H, J = 7.2 Hz), 6.69 (d, 1H, J = 6.8 Hz), 5.13
13
(s, 2H), 3.87 (s, 3H), 2.32 (s, 3H); C NMR (125 MHz, CDCl3): δ 165.08, 137.51, 135.11,
129.43, 129.38, 128.90, 128.55, 128.50, 127.81, 127.77, 109.42, 65.97, 57.21, 15.51; MS-EI
(m/z) Calcd. for C14H15NO3: 245.1052; found: 245.1055.
Ethyl 1-methoxy-2-phenyl-1H-pyrrole-3-carboxylate (2d): Yield: 79% (387.52 mg);
obtained as dark yellow oil; Rf (5 % Pet ether/ethyl acetate) 0.32; IR (cm-1) 2978, 1705,
1238, 1062, 975, 752, 696; 1H NMR (400 MHz, CDCl3): δ 7.67 (d, 1H, J = 7.7 Hz), 7.48 –
7.25 (m, 4H), 6.884 (d, 1H, J = 4.4 Hz), 6.694 (d, 1H, J = 4.0 Hz), 4.210 (q, 2H, J = 7.2 Hz &
13
14.4 Hz), 3.961 (s, 3H), 1.320 (t, 3H, J = 7.2 Hz); C NMR (125 MHz, CDCl3): δ 163.39,
138,66 131.46, 129.52, 129.17, 127.12, 126.46, 126.18, 125.89, 125.86, 108.34, 60.11, 57.86,
14.34; MS-EI (m/z) Calcd. for C14H15NO3: 245.1052; found: 245.1052.
9

ACCEPTED MANUSCRIPT
Ethyl 5-acetoxy-1-methoxy-2-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylate (2d’): Yield
52% (317.5 mg); Obtained as dark yellow oil; Rf (5 % Pet ether/ethyl acetate) 0.35; 1H
NMR (400 MHz, CDCl3): δ 7.65-7.27 (m, 5H), 6.31 (t, 1H, J = 7.6 Hz), 4.19 (q, 2H, J
= 7.6 Hz), 3.84 (s, 3H), 2.75 (d, 2H, J = 8 Hz), 2.15 (s, 3H), 1.22 (t, 3H, J = 7.2 Hz);
13C NMR (125 MHz, CDCl3): δ 180.16, 168.66, 151.14, 135.16, 129.14, 129.14,
128.343, 126.01, 106.21, 80.09, 62.04, 60.89, 33.04, 20.13, 13.87; MS-EI (m/z) Calcd.
for C15H16N2O5: 305.1263; found: 305.1266.
Ethyl 2-benzyl-1-methoxy-1H-pyrrole-3-carboxylate (2e): Yield: 80% (414.88 mg);
1
obtained as yellow oil; Rf (5 % Pet ether/ethyl acetate) 0.32; H NMR (400 MHz, CDCl3):
δ 7.50 – 7.38 (m, 5H), 7.25 (d, 1H, J = 7.2 Hz), 6.73 (d, 1H, J = 7.2 Hz), 4.52 (q, 2H, J = 7.2
13
Hz), 4.05 (s, 3H), 1.52 (t, 3H, J = 7.6 Hz); C NMR (125 MHz, CDCl3): δ 164.95, 138.98,
137.76, 129.52, 129.17, 128.98, 128.70, 128.69, 128.11, 128.10, 108.78, 60.75, 57.26, 30.23,
14.13; MS-EI (m/z) Calcd. for C15H17NO3: 259.1208; found: 259.1208.
Ethyl 1-methoxy-2-(4-nitrophenyl)-1H-pyrrole-3-carboxylate (2f): Yield: 83% (481.8
1
mg); obtained as yellow oil; Rf (5 % Pet ether/ethyl acetate) 0.31; H NMR (400 MHz,
CDCl3): δ 8.232 – 8.198 (m, 2H), 7.459 – 7.243 (m, 2H), 7.254 (d, 1H, J = 3.6 Hz), 6.728 (d,
1H, J = 4.4 Hz), 4.210 (q, 2H, J = 4.8 Hz & 14.4 Hz), 4.004 (s, 3H), 1.320 (t, 3H, J = 7.2
Hz); 13C NMR (125 MHz, CDCl3): δ 165.00, 147.84, 138.98, 129.52, 129.17, 128.14, 128.04,
125.95, 125.82, 108.37, 60.76, 57.91, 14.77; MS-EI (m/z) Calcd. for C14H14N2O5: 290.0903;
found: 290.0905.
Ethyl 2-(4-nitrobenzyl)-1-methoxy-1H-pyrrole-3-carboxylate (2g): Yield: 81% (492.9
1
mg); obtained as brown gum; Rf (5 % Pet ether/ethyl acetate) 0.36; H NMR (400 MHz,
CDCl3): δ 8.22 (d, 1H, J = 8 Hz), 8.19 (d, 1H, J = 8 Hz), 7.53 (d, 1H, J = 7.6 Hz), 7.50 (d,
1H, J = 7.6 Hz), 7.18 (d, 1H, J = 8.4 Hz), 7.09 (d, 1H, J = 8.8 Hz), 4.52 (q, 2H, J = 7.2 Hz),
13
4.31 (s, 2H), 4.04 (s, 3H), 1.51 (t, 2H, J = 7.6 Hz); C NMR (125 MHz, CDCl3): δ 164.95,
147.98, 138.98, 137.26, 129.52, 129.17, 128.14, 128.04, 122.11, 122.09, 108.28, 60.85,
57.26, 32.54, 14.23; MS-EI (m/z) Calcd. for C15H16N2O5: 304.1059; found: 304.1056.
General procedure for the synthesis of furan 3-carboxylate derivatives: To a solution α-
diazo ester 3a (318 mg, 2 mmol) and Rh2(OAc)4 (2 mol %) in DCE (4 mL) under nitrogen
atmosphere and at room temperature was added a solution of ethyl vinyl ether (216 mg, 0.288
mL, 3 mmol) in DCE (2 mL) was added through a syringe. The reaction mixture was heated
o
at 80 C for 8 h. After the completion of the reaction as indicated by the TLC, the reaction
10

ACCEPTED MANUSCRIPT
mixture was cooled to room temperature and purified by column chromatography using a pet
ether/ethyl acetate 19:1 mixture as eluent to afford the pyrrole 4a.
Synthesis of ethyl 2-methylfuran-3-carboxylate (4a): The title compound was prepared
following the general procedure and obtained as pale yellow oil; Yield: 86% (265 mg); Rf
1
(5 % Pet ether/ethyl acetate) 0.42; H NMR (400 MHz, CDCl3): δ 7.126 (d, 1H, J = 4.8
Hz), 6.741 (d, 1H, J = 5.2 Hz), 4.998 (q, 2H, J = 7.6 Hz & 13.6 Hz), 2.037 (s, 3H), 1.325 (t,
3H, J = 4.4 Hz; 13C NMR (125 MHz, CDCl3): δ 165.19, 154.15, 138.63, 115.54, 109.89,
60.91, 14.95, 13.11; MS-EI (m/z) Calcd. for C8H10O3: 154.0630; Found: 154.0633.
Methyl 2-methylfuran-3-carboxylate (4b): Yield: 85% (238.07 mg); obtained as pale
1
yellow oil; Rf (5 % Pet ether/ethyl acetate) 0.40; H NMR (400 MHz, CDCl3): δ 7.525 (d,
13
1H, J = 2 Hz), 6.723 (d, 1H, J = 2 Hz), 3.766 (s, 3H), 2.586 (s, 3H); C NMR (125 MHz,
CDCl3): δ 165.09, 154.37, 139.54, 114.42, 109.79, 51.12, 13.23; MS-EI (m/z) Calcd. for
C7H8O3: 140.0473; Found: 140.0477.
Benzyl 2-methylfuran-3-carboxylate (4c): Yield: 83% (358.9 mg); obtained as yellow oil;
1
Rf (5 % Pet ether/ethyl acetate) 0.39; H NMR (400 MHz, CDCl3): δ 7.526 (d, 1H, J = 2
13
Hz), 7.375 – 7.190 (m, 5H), 6.730 (d, 1H, J = 2 Hz), 5.136 (s, 2H), 2.593 (s, 3H); C NMR
(125 MHz, CDCl3): δ 165.00, 154.54, 140.10, 135.15, 129.52, 128.75, 128.63, 127.95,
127.73, 112.48, 64.97, 13.15; MS-EI (m/z) Calcd. for C13H12O3: 216.0786; Found: 216.0782.
Ethyl 2-phenylfuran-3-carboxylate (4d): Yield: 77% (358.9 mg); obtained as dark yellow
oil; Rf (5 % Pet ether/ethyl acetate) 0.42; 1H NMR (400 MHz, CDCl3): δ 7.903 (d, 1H, J =
2 Hz), 7.545 (m, 5H), 6.989 (d, 1H, J = 2 Hz), 4.193 (q, 2H, J = 7.2 Hz & 14.4 Hz), 1.343 (t,
3H, J = 7.2 Hz); 13C NMR (125 MHz, CDCl3): δ 164.93, 151.11, 138.77, 131.01, 127.96,
127.66, 127.04, 125.19, 124.95, 114.75, 109.60, 51.01, 14.24; MS-EI (m/z) Calcd. for
C13H12O3: 216.0786; Found: 216.0785.
Ethyl 2-benzylfuran-3-carboxylate (4e): Yield: 79% (363.8 mg); obtained as dark yellow
oil; Rf (5 % Pet ether/ethyl acetate) 0.44; IR (cm-1) 2956, 1714, 1234, 1209, 1081, 774,
1
697, 665; H NMR (400 MHz, CDCl3): δ 7.545 (s, 1H, J = 2 Hz), 7.367 (m, 5H), 6.747 (d,
1H, J = 2.4 Hz), 4.184 (q, 2H, J = 6.8 Hz & 14 Hz), 3.766 (s, 2H), 1.300 (t, 3H, J = 6.8 Hz);
13C NMR (125 MHz, CDCl3): δ 165.04, 156.16, 139.54, 133.64, 131.60, 128.92, 128.78,
128.47, 128.27, 114.42, 108.40, 60.75, 32.78, 14.24; MS-EI (m/z) Calcd. for C14H14O3:
230.0943; Found: 230.0941.
Ethyl 2-(4-nitrophenyl) furan-3-carboxylate (4f): Yield: 83% (433.6 mg); obtained as
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1
reddish brown oil; Rf (5 % Pet ether/ethyl acetate) 0.46; H NMR (400 MHz, CDCl3): δ
8.285 – 8.256 (m, 2H), 8.081 (d, 1H, J = 2 Hz), 7.673 – 7.264 (m, 2H), 6.816 (d, 1H, J = 2
13
Hz), 4.183 (q, 2H, J = 7.2 Hz & 14 Hz), 1.344 (t, 3H , J = 7.2 Hz); C NMR (125 MHz,
CDCl3): δ 165.04, 150.66, 140.60, 130.25, 125.16, 125.15, 124.54, 124.51, 113.52, 109.42,
60.78, 14.94; MS-EI (m/z) Calcd. for C13H11NO5: 261.0637; Found: 261.0633.
Ethyl 2-(4-nitrobenzyl) furan-3-carboxylate (4g): Yield: 80% (440.0 mg); obtained as
1
reddish brown oil; Rf (5 % Pet ether/ethyl acetate) 0.45; H NMR (400 MHz, CDCl3): δ
7.508 (d, 2H, J = 8.4 Hz), 6.927 (d, 2H, J = 8 Hz), 6.460 (d, 1H, J = 7.2 Hz), 5.288 (d, 1H, J
= 7.2 Hz), 4.352 (q, 2H, J = 7.2 Hz & 14.4 Hz), 4.148 (s, 2H), 1.705 (t, 3H, J = 6.8 Hz); 13C
NMR (125 MHz, CDCl3): δ 163.74, 156.00, 147.97, 140.89, 134.26, 129.59, 129.57, 123.22,
123.19, 114.23, 109.86, 60.57, 32.55, 14.13; MS-EI (m/z) Calcd. for C14H13NO5: 275.0794;
Found: 275.0799.
(E)-1-(2-methylfuran-3-yl) ethanone O-methyl oxime (4h): Yield 68% (208.1 mg);
Obtained as pale yellow gum; Rf (5 % Pet ether/ethyl acetate) 0.43; 1H NMR (400 MHz,
CDCl3): δ 7.213 (d, 1H, J = 1.6 Hz), 6.623 (d, 1H, J = 1.6 Hz), 3.781 (s, 3H), 2.355 (s, 3H),
2.056 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 156.54, 154.35, 138.63, 128.86, 109.90,
61.18, 17.95, 13.13; MS-EI (m/z) Calcd. for C8H11NO2: 153.0790; Found: 153.0794.
Associated content
Supporting Information:
Supporting Information containing 1H and 13C NMR spectra of all the compounds.
AUTHOR INFORMATION
Corresponding address:
Dr L. Emmanuvel,
Assistant professor, Department of Chemistry, Karunya University, Coimbatore – 641 114 (IN)
Corresponding email: emmanuvel@karunya.edu
Ph no.: 0422-2614105, Fax: 0422-2615615
Acknowledgement
The authors thank DST/SERB, New Delhi, for the financial support to carry out this research
work. The authors also thank the administration and the management of Karunya University
for their constant support and encouragement.
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