A Metal-Free Domino Process for Regioselective Synthesis of 1,2,4-Trisubstituted Pyrroles: Application toward the Formal Synthesis of Ningalin B

Article abstract of DOI:10.1021/acs.joc.9b01520

A new one-pot, transition-metal, acid/base-free domino process is developed for the regioselective synthesis of 1,2,4-trisubstituted pyrroles. The process involves 1,3-dipolar cycloaddition of unsymmetrical azomethine ylide resulting from the thermal C-C bond cleavage of unactivated aziridines with β-bromo-β-nitrostyrene, followed by a cascade of elimination and aromatization reaction sequence to preferentially furnish 1,2,4-trisubstituted pyrroles instead of the expected 1,2,3-trisubstituted pyrroles, in good to excellent yields. Further, the application of the methodology for the formal synthesis of ningalin B is delineated.

Full text of DOI:10.1021/acs.joc.9b01520

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Article
A Metal Free Domino Process for Regioselective
Synthesis of 1,2,4-Trisubstituted Pyrroles: Application
towards the Formal Synthesis of Ningalin B
Virendra Kumar, Annapurna Awasthi, Abhisek Metya, and Tabrez Khan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01520 • Publication Date (Web): 21 Aug 2019
Downloaded from pubs.acs.org on August 21, 2019
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A Metal Free Domino Process for Regioselective Synthesis of 1,2,4-
Trisubstituted Pyrroles: Application towards the Formal Synthesis of
Ningalin B
Virendra Kumar, Annapurna Awasthi, Abhisek Metya and Tabrez Khan*
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Organic Synthesis Laboratory, School of Basic Sciences, Indian Institute of Technology
Bhubaneswar, Argul, Khurdha-752050, Odisha, India.
tabrez@iitbbs.ac.in
NO
2
HO
HO
R
O
Br
O
N
R
N
Acid
Base
Metal
X
O
N
Oxidants
COX
∆
OH
HO
OH HO
1
,2,4-trisubstituted pyrrole
Ningalin B
3
6 examples; upto 96% yield
Abstract: A new one-pot transition-metal, acid/base free domino process has been developed
for the regioselective synthesis of 1,2,4-trisubstituted pyrroles. The process involves 1,3-
dipolar cycloaddition of unsymmetrical azomethine ylide resulting from the thermal C-C bond
cleavage of unactivated aziridines with β-bromo-β-nitrostyrene, followed by a cascade of
elimination and aromatization reaction sequence to preferentially furnish 1,2,4-trisubstituted
pyrroles instead of the expected 1,2,3-trisubstituted pyrroles, in good to excellent yields.
Further, the application of the methodology for the formal synthesis of ningalin B is delineated.
Introduction
Pyrroles are one of the most prevalent N-heterocycles which manifests in numerous molecules
1
2
of natural origin and human imagination for diverse applications ranging from pharmaceutics
3
to material science. A few representative examples of biologically interesting and structurally
fascinating pyrrole containing alkaloids and therapeutically potent molecule with a central
pyrrole core are as captured in Figure 1.
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O
HO
HO
O
O
N
N
CO Me
2
HO
N
MeO
MeO
O
O
MeO
HO
OH
OH
HO
OH
HO
OH HO
MeO
Lamellarin D
Lamellarin O
Ningalin B
0
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HO
HO
CO
2
H
O
O
OH
N
OH
N
R
Ph
N
N
O
H
R = H, rhazinilam;
R = CHO, rhazinal
R = CH OH, kopsiyunnanine C3
2
R = CH OMe, kopsiyunnanine C1
2
R = H, lukianol A
R = I, lukianol B
PhHN
HO
O
R
F
Atorvastatin
R = CH OEt, kopsiyunnanine C2
2
Figure 1. Representative natural products and pharmaceutically active molecule with a central
pyrrole core.
4
5
Despite a plethora of classical and recently developed synthetic approaches towards the
construction of polysubstituted pyrroles, highly regioselective synthesis of pyrroles with
precise substituent location constitute a greener pasture for exploration in heterocyclic
chemistry. Among the various substituted pyrroles, we comprehended that in particular, the
approaches towards 1,2,3/1,2,4-trisubstituted pyrroles6,7 are very limited despite interesting
8
bioactivity profile of such pyrroles. Therefore, in view of the scarcity of the methods towards
9
such trisubstituted pyrroles and our ongoing interest towards the synthesis of pyrrole based
alkaloids we were motivated to develop a transition metal as well as acid/base free approach
for the regioselective synthesis of 1,2,3/1,2,4-trisubstituted pyrroles.
Our quest for a versatile starting material culminated on aziridines in view of their inherent
1
0
11
12
reactivity due to the existing ring-strain. Through the seminal work of Padwa, Huisgen,
and Katritzky13 its well-established how the thermal C-C bond cleavage in unactivated
aziridines can be exploited to harness the potential of the resultant azomethine ylides for
annulation with activated dipolarophiles to access dihydropyrroles/pyrroles. However, the
method suffers from the limitation of poor regioselectivity in case of unsymmetrical
dipolarophiles and poor reactivity with unactivated dipolarophiles rendering them unsuitable
1
4
for total synthesis endeavor. Nevertheless, recently independent reports from Wender et al. as
well as Wang and co-workers demonstrated the generation of 1,3-dipolar species from
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a)
i) Wender et al. JACS, 2009;
Wang et al. Chem. Commun. 2009]
ii)Zhang et al. OL, 2011
Tos
N
Tos
N
"C-C cleavage"
Ar
"
C-N cleavage"
Bronsted/
Tos
N
Tos
N
EWG'
EWG'
Ar
Lewis acid
R Ar
EWG
EWG
Lewis acid
Ar
Ar
R
Ar'
3-pyrroline
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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2
3
4
5
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7
8
9
0
R
Ar
R
Ar
EWG = -CO R
2
-pyrroline
2
b) [3+2] annulation of activated aziridines with nitrostyrenes [Wang et al. OBC, 2014]
NO2
"
C-C cleavage"
Cu2+
H
N
O
H
.
H
O
N
Cu(OAc)
2
2
O
Ar
Ar
H
N
Ar
Ar
∆
Ar
Ar
Ar
,3,5-trisubstituted pyrrole
O
Ar
2
c)
a new acetylene equiv.
[3+2] annulation of unactivated aziridines with
[This work]
EWG
Ar
R
N
R
N
EWG
NO2
Br
Unsymmetrical partially
stabilized azomethine ylide
1,2,3-trisubstituted pyrrole
(Not observed)
R
N
∆
Ar
vs
EWG
R
R
N
EWG
N
EWG
Unsymmetrical non-
stabilized azomethine ylide
Ar
1,2,4-trisubstituted pyrrole
Highlights: i) Single regiosmer ii) Metal, Acid/Base free iii) Easy accesible synthons
iv) Broad substrate scope v) Adaptable for pyrrole alkaloid synthesis
Scheme 1. Recent strategies involving [3+2] annulation of aziridines to access dihydro-
pyrrole/pyrrole.
unactivated aziridine using Bronsted/Lewis acid and their subsequent annulation with
unactivated, unsymmetrical dipolarophiles to access 2-pyrrolines in a regioselective manner
(Scheme 1a).15 Similarly, Zhang et al. demonstrated the Lewis acid mediated C-C bond
cleavage of activated donor-acceptor substituted aziridine and subsequent annulation of the
resultant azomethine ylide with unactivated, unsymmetrical dipolarophiles to access 3-
pyrrolines in regioselective manner (Scheme 1b).16 While, very recently Wang et al.
demonstrated the transition metal salt assisted thermal C-C bond cleavage of activated donor-
acceptor aziridine and the subsequent annulation of the resultant azomethine ylide with
1
7
nitrostyrenes to access 2,3,5-substituted pyrroles (Scheme 1c). And, to further demonstrate
the versatility of aziridine we herein, disclose a transition metal as well as acid/base free one
pot domino process for the regioselective synthesis of 1,4-disubstituted-2-carbonylated pyrrole
involving thermal C-C bond cleavage in unactivated aziridines. Interestingly, to the best of our
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knowledge the present case is the first report on the annulation of an unactivated aziridine with
unsymmetrical dipolarophile like β-bromo-β-nitrostyrene, which exclusively offers the
unexpected 1,2,4-trisubstituted pyrroles instead of the expected 1,2,3-trisubstituted isomer, in
a highly regioselective fashion (Scheme 1c). Though such anomalous trapping of the
0
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9
0
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0
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4
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7
8
9
0
1
8
dipolarophiles in 1,3 dipolar cycloadditions is precedented for other coupling partners but the
excellent regioselectivity observed in the present case is something quite noteworthy.
Results and Discussion
Our foray towards the method development commenced with the preparation of
aziridines and β-bromo-β-nitrostyrenes through the protocols highlighted in Scheme 2. With
the desired aziridines and β-bromo-β-nitrostyrenes in hand, we began the reaction optimization
task and for this purpose the aziridine 1a and β-bromo-β-nitrostyrene 2a were chosen as the
coupling partners for exploring the annulation reaction. After examining the thermolysis at
varied temperature, temperature of 150 °C proved to be the ideal reaction temperature while
among the investigated solvents as highlighted in Table 1, toluene proved to be the ideal
solvent for the [3+2] annulation in terms of yield by furnishing 3aa in 96% yield . While,
execution of the reaction in solvent-free condition proved to be an instant method to access 3aa
in decent yield. Further, to our delight the reaction was even feasible in 90% H O-EtOH
2
mixture offering the same product 3aa albeit in modest yield. The decomposition of the
aziridines and recovery of the dipolarophile accounted for the mass balance in case of low
yields.
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a)
Synthetic protocol for accessing N-substituted aziridines
R NH
4
2
°
EtOH, 0 C-rt
vi
For
R4
(
Step I)
(Step II)
R NH
R3
Br R''
R'
R
Br2
4
2
N
R3
R1
X
X
R1
R2
X
= Bn, PhCH
-
,
,
0 °
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
CCl4
C-rt
R4
iPr, t
CH
2 2
O
Br
O
-Bu, Cy, allyl,
-CH
R2
O
=
H; X = -OEt, (i)
= H; X = -Me, (ii)
= Me; R = H; X = -OEt, (iii)
,
,
,
R , R
R , R
R1
R1
R1
R1
1a-j, 8, 9,
12, 12-d
2
3
3
CH OH,
2 2
-,
2,14
2
3,4-(OMe) C H CH CH
2
2
6
3
2
R
2
3
=
H; X = -OBn, (iv)
D; X = -OBn, (v)
H; R3 = Br; X = -OEt, (vi)
, R , R
R , R
2
3
3
=
,
=
R1
2
N
H
Ph; R
=
R1
2
-
bromo- -nitrostyrenes
b) Synthetic protocols for accessing β
β
(
Protocol B)
Py.HBr.Br2
°
Py, DCM, 0 C-rt
(
Protocol A)
NO2
, AcONa
NO2
Br2
,
reflux
CHCl3
Br
R
R
-
nitrostyrene
2a-m
β
Scheme 2: Synthetic strategy for the preparation of starting materials.
O
NO2
solvent, X h
N
+
N
OEt
refer condition table
Br
OEt
2a
3aa
1a
O
b
Entry
Solvent
Temp. (°C)
150
Time (h)
29
Yield (%)
1
2
3
4
5
6
7
8
9
Benzene
Toluene
Xylene
Xylene
DMF
69
96
63
72
54
28
54
58
52
56
30
32
150
150
200
150
16
2
1.5
2.5
1.25
2.5
16
Dioxane
150
1,2 dichlorobenzene
Dichloroethane
THF
150
150
150
2.25
8
1
0
Dimethoxy-ethane
Ethanol
150
11
150
7
1
2
H O:EtOH (9:1)
150
1.25
2
13
Neat
150
0.2
51
a
In a oven-dried sealed tube, under N
dissolved in solvent (2 ml) and placed in preheated oil bath maintained as per the indicated
2
atmosphere, 1a (0.22 mmol) and 2a (0.22 mmol) were
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
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5
5
5
5
5
5
5
6
b
temperature and upto the indicated time in the table. Isolated yield after flash column
chromatography.
Table 1. Reaction condition optimization for the domino process involving [3+2]
annulation/subsequent elimination and aromatization sequence.
Next, the stage was set for demonstrating the generality and broad substrate scope of
the developed domino process. Towards this goal, we first explored the substrate scope with
respect to β-bromo-β-nitrostyrene having diverse substitution pattern on the aryl ring. And the
result of the [3+2] annulation with respect to N-substituted-aziridine-2-carboxylates 1b/c are
as captured in Scheme 3. Gratifyingly, in all the cases, 1,2,4-trisubstituted pyrroles were
exclusively obtained in moderate to good yields. β-bromo-β-nitrostyrene with mono and
polysubstituted electron donating group showed good compatibility and offered the desired
pyrroles in good yields (3bb-3be /3cb-3ce). To our delight, also in case of 3cb the crystalline
nature of compound helped us in unambiguously securing the structure through X-ray
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
19
crystallographic studies. While, β-bromo-β-nitrostyrenes with electron withdrawing group (-
F, -Cl, -Br and NO ) proved to be comparatively more reactive furnishing the desired products
2
(3bf-3bi /3cf-3ci) in comparatively lesser time and with yields ranging from 68-45%. Also, the
annulation process was quite smooth with β-bromo-β-nitrostyrene 2j having two –Cl atoms as
well as with 2k having both electron donating as well withdrawing group on the aryl ring
affording the corresponding pyrrole 3bk/3ck in good yields. Similarly, naphthalene and furan
appendage on the β-bromo-β-nitrostyrene unaffected the domino process as pyrroles (3bl,
3
bm/3cl, 3cm) were obtained in decent yields.
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R
N
R
N
O
+
OEt
NO2
toluenea
Ar
°
OEt
Br
2a-m
X h, 150 C
Ar
ba-bm/3ca-cm
O
1b
3
R = -CH CH Ph,
2
2
b
(
upto 89% yield)
R = iPr, 1c
O
O
O
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
N
N
OEt
OEt
OEt
OEt
3
ba [t =16 h,
3bb [t = 23 h,
3bc [t = 20 h,
3bd
[t = 5 h,
81%]
MeO
MeO
8
1%]
68%]
73%]
MeO
MeO
OMe
N
O
O
N
O
N
,
t = 5 h, 45%);
X = F, (3bf
OEt
OEt
Cl, (
Br, (
, t = 8 h, 62%);
, t = 8 h, 54%)
bh
OEt
MeO
3bg
O N
2
3
3
be [t =12 h,
3bi [t = 7 h,
7
5%]
60%]
X
O
N
O
O
N
O
N
N
OEt
OEt
OEt
OEt
Br
3bj [t = 6 h,
0%]
3bk [t = 13 h,
3bl [t = 9.5 h,
3bm [t = 7 h,
O
Cl
6
82%]
89%]
68%]
MeO
Cl
OMe
O
O
O
N
N
N
OEt
OEt
OEt
3
ca [t =16 h,
3cb t = 23 h,
3cc [t = 20 h,
[
6
0%]
74%]
81%]
MeO
MeO
OMe
Crystal structure of 3cb
O
O
N
O
N
O
N
N
OEt
OEt
OEt
OEt
MeO
O N
2
3
cd [t = 6 h,
3ce [t = 12
3ci [t = 7 h, 62%]
MeO
6
8%]
h, 83%]
X
OMe
,
t = 5 h, 47%);
, t = 8 h, 68%);
, t = 8 h, 59%)
ch
X = F, (3cf
Cl, (
3
cg
Br, (
3
O
O
N
O
N
O
N
N
OEt
OEt
OEt
Br
OEt
3
cj [t = 6 h,
2%]
3ck [t = 13
h, 76%]
3cm [t = 7 h,
Cl
3cl [t = 9.5
h, 73%]
5
O
60%]
Cl
MeO
OMe
a
Reaction condition: 1b/1c (0.5 mmol) and 2a-m (0.5 mmol) were refluxed in toluene under
N atmosphere in a sealed tube for specified time. Isolated yield after column chromatography.
b
2
Scheme 3. Substrate scope of β-bromo-β-nitrostyrene in the domino process.
Subsequently, attention was turned towards demonstrating the generality and broad
substrate scope with respect to aziridines. In this direction as depicted in Scheme 4, diverse N-
substituted aziridine-2-carboxylates 1d –h were subjected to the annulation protocol under the
optimized reaction condition with 2a. To our delight, in all the cases the corresponding pyrroles
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
3da-3ha) were obtained with excellent regioselectivity and in good yields. Also, the N-benzyl-
2
-acetyl-aziridine (1i) and N-benzyl- aziridine-2-carboxamide (1j) were found to be equally
compatible in the domino process offering the corresponding pyrrole 3ia and 3ja respectively
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
in decent yield.
R
N
R
N
O
NO2
toluenea
+
°
X
X
Br
X h, 150 C
b
2a
(76-50% yield)
O
3da-3ha
1d-j
HO
O
O
O
N
O
N
N
N
OEt
OEt
OEt
OEt
[
3
da t = 15 h;
3ea t = 9.5 h;
3fa t = 6.5 h;
3ga t = 4.5 h;
[
[
[
6
1%]
76%]
40%]
70%]
O
N
O
O
N
N
HN
N
OMe
Me
OEt
Me
3
ha [t = 6.5 h;
3ia [t = 10 h;
3ja t = 5 h;
66%]
[
5
9%]
50%]
a
Reaction condition: 1d-1j (0.5 mmol) and 2a (0.5 mmol) were refluxed in toluene under N
2
b
atmosphere in a sealed tube for specified time. Isolated yield after column chromatography.
Scheme 4. Substrate scope of aziridines in the domino process.
Next, in order to demonstrate the superiority and the unexpected regioselectivity
offered by β-bromo-β-nitrostyrene exclusively with the presently used unactivated aziridines
as well as to get some mechanistic insight for the present domino process, several experiments
as highlighted in Scheme 5 were conducted. Execution of the annulation of aziridine 1b in
presence of equimolar quantities of 2b and nitrostyrene (4) under standard condition offered
readily 3bb (64% yield) along with 81% recovery of 4 (Scheme 5a) thereby demonstrating the
superior reactivity of 2b over 4. While the domino process involving annulation of 1b with 520
2
1
as well as 7 (Scheme 5b) failed to deliver 3ba/6 in either case but instead just resulted in the
decomposition of aziridine which further demonstrate the versatility of β- bromo-β-
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7
8
9
NO2
NO2 1b (0.5 mmol)
+
3bb
+
a) 2b
(0.5 mmol)
standard
condition
4
4
(0.5 mmol)
(0.32 mmol, MeO
MeO
64%)
(
0.4 mmol, 81% recovered)
I
Ph
O
1
b
N
1b (0.5 mmol)
standard condition
(
0.5 mmol)
Ph
Br
b)
standard
condition
OEt
7
NO2
(0.5 mmol)
5
Ph
(
0.5 mmol)
3ba/6 (0%)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ph
Ph
(
0.5 mmol)
(0.5 mmol)
2a
N
2a
N
3ba
Decomposition
of SM
c)
e)
d)
,
Me
Me
OEt standard condition
OEt TEMPO
(0.5 mmol) (74%)
standard condition
1b
8
O
(0.5 m mO ol)
Ph
Ph
Ph
O
Ph
OEt
O
2
a,
°
C
i)
toluene, 150
N
N
N
Ph
+
OEt
OEt
ii) Et N
3
Ph
9
10
Ph
Ph 11
(
0.015 mmol, 3%)
O
(0.5 mmol)
(
0.075 mmol, 15%)
normal reactivity product
°
OTBS
N
CO
2
Bn
a) toluene, 150
C
Br
OTBS
OBn
D
52%
f)
NO2
reaction time = 5 h
, 150 °
N
+
96%D
D
Br
MeO
MeO
MeO
25%
D
Br
96%
b) toluene-d8
C
O
OMe
2k
1
2-d2
13-d2
(0.28 mmol, 72%)
(
0.5 mmol)
(0.5 mmol)
Scheme 5. Competitive, comparative and labelling experiments.
nitrostyrene in the present domino process. The formation of 3ba in 74% yield during the
annulation of 1b with 2a in presence of TEMPO (Scheme 5c) under standard condition rules
out the possibility of radical mechanism for the present domino process. Next, annulation of
aziridine 8 with 2a under standard condition resulted in just decomposition of starting materials
(Scheme 5d) thereby indicating the non-tolerance of double substitution at the C position of
3
aziridine in the present domino process. While, the annulation of donor-acceptor aziridine 9
with 2a (Scheme 5e) under standard condition followed by base treatment of the resultant
cycloadducts delivered the expected pyrrole 10 (15% yield) as the predominant product along
with a marginal amount of 11 (3% yield). Also, C
used for annulation with 2k (Scheme 5f) in both toluene and deuterated toluene as solvent to
arrive at 13-d in each case with 25% and 52% of labelling at C and C position respectively.
This indicates the C position of aziridine as the source of H/D for the C position of pyrrole.
D/H scrambling between C and C position during the azomethine ylide generation from 12-
could be attributed to the drop in the labelling percentage observed at C and C position of
13-d
3
labelled aziridine 12-d
2
was prepared and
2
3
5
3
3
3
2
d
2
3
5
2
.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In view of the experiments described in Scheme 5, especially Scheme 5d, 5e it is quite
clear that the regioselectivity of the [3+2] annulation of N-alkyl-2-carboxyl aziridines with β-
bromo-β-nitrostyrene is quite sensitive with respect to the C substituents of the aziridine and
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
is also perhaps responsible for influencing the regioselectivity in the dipolar cycloaddition.
Further, keeping in mind the faster reaction rate of β-bromo-β-nitrostyrene with electron
withdrawing substituents on the aryl ring compared to those having electron donating
substituents, the present annulation is most likely to be associated with the Sustmann’s type I
22
class of 1,3-dipolar cycloadditions with contribution of HOMO from the azomethine ylide
and LUMO of the dipolarophile. While, the experimentally observed regioselectivity in case
of aziridine 8 with β-bromo-β-nitrostyrene is similar to that observed by Wang and coworkers17
(Scheme 1c) which can be satisfactorily accounted through FMO theory treatment. However,
the anomalous regioselectivity observed with the unsymmetrical partially stabilized
azomethine ylides generated in the present methodology from the C
3
nonsubstituted aziridines
18
seems difficult to be accounted through FMO theory. Thus, as demonstrated by others we
look forward for a detail DFT as well as computational transition state energy investigation in
quest for a convincing justification to account for the anomalous regioselectivity observed in
the present domino process.
Nevertheless at this point, a plausible reaction mechanism we wish to propose for the
present domino process is as delineated in Scheme 6. Thermal C-C bond cleavage of aziridine
1 is more likely to furnish azomethine ylide A which on reaction with β-bromo-β-nitrostyrene
2
a initially forms the more sterically crowded cycloadduct B. A spontaneous E2 elimination
of HBr in B results in the formation of C and then through two successive isomerizations C is
anticipated to be converted into E via D. Eventually the elimination of HNO
to offer the pyrrole 3.
2
in E is anticipated
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9
NO2
H
R
R
N
Br
H O
Br
O
2a
N
H
H
R
N
R
N
O
-HBr
X
X
∆
H
H
X
X
O
N
O
N
[
3+2]
n
1
O
A
cycloaddit
O
O
unsymmetrical-partially stabilized
azomethine ylide
B
C
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
isomerizatn
R
N
R
N
O
R
O
N
O
H
-
HNO
isomerizatn
X
H
H
2
X
X
H
N O
H
E
N O
3
O
O
D
Scheme 6. A plausible mechanism for the present domino process.
Next, we were interested to demonstrate the efficacy of the present methodology by
applying it in natural product synthesis. Among several options, marine alkaloid ningalin B23
was chosen as the target for total synthesis. Our synthetic endeavor in this direction as
highlighted in Scheme 7, commenced with the annulation of aziridine ester 14 with β-bromo-
β-nitrostyrene 2c under our optimized condition to access the 1,2,4-trisubstituted pyrrole ester
2
4
15 in good yield which was then subjected to Vilsmeier-Haack formylation followed by
saponification of the ester group to arrive at 16. Also, the crystalline nature of 16 enabled the
1
9
unambiguous structural confirmation through its X-ray crystallographic analysis. Then, the
intermediate 16 was elaborated to acid 17, through a 2-step synthetic manipulation involving
decarboxylation of the acid functionality in 16 and Pinnick oxidation25 of the aldehyde
functionality to acid. In context of ningalin B, the next task was to introduce the lactone fusion
between the central pyrrole core and the C aryl ring. After investigating various conditions,
3
2
6
finally exposure of 17 to Pb(OAc)
4
afforded the desired lactone 18 in moderate yields. At this
27
stage our synthesis intercepts with that of Banwell’s reported synthesis of ningalin B, who
has demonstrated the elaboration of 18 to ningalin B in 3 steps. Thus, in this manner our efforts
culminates in the formal synthesis of ningalin B.
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
MeO
MeO
N
MeO
MeO
MeO
14
O
N
O
COOEt
NO
N
toluene
MeO
i) DMF, POCl3
OEt
O
OH
150 °C, 16 h
80 °C, 2 h,;
ii) NaOH, EtOH: H
MeO
MeO
2
86%
2O
16
MeO
MeO
15
MeO
MeO
Br
(
8
3:1), reflux, 3 h,
2% over 2 steps
2c
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
i) Cu O, quinoline,
2
°
1
,10 phenanthroline, 220 C,
8 min.; ii) NaClO
2,
NaH
2PO
4,
2
-methyl but -2- ene,
°
t
THF: BuOH:H O, 10 C, 12 h,
2
80% over 2 steps
MeO
Crystal structure of 16
HO
HO
MeO
O
O
O
N
N
N
MeO
MeO
Pb(OAc)4
ref. 23
O
O
OH
EtOAc, reflux, 1 h
35%
1
8
17
OH
OMe
OMe
HO
HO
MeO
MeO
OH
Ningalin B
Scheme 7. Formal synthesis of ningalin B.
In summary, we have demonstrated the regioselective synthesis of 1,2,4-trisubstituted
pyrroles via anomalous trapping of the unactivated aziridine derived azomethine ylide with β-
bromo-β-nitrostyrene. The main highlights of the synthesis are i) it is metal, acid as well as
base free; ii) involves cheap and readily accessible starting materials; iii) offers excellent
regioselectivity; iv) broad substrate scope. Also, the efficacy of the method is demonstrated
through its application for the formal synthesis of ningalin B. Further, efforts to demonstrate
the applicability of the present methodology towards the synthesis of several natural and
unnatural lamellarins are nearing completion in our laboratory and the outcome of that study
shall be communicated soon.28
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9
Experimental Section
General Method: All the reagents were purchased from commercial suppliers and used
without further purification. While most of the desired solvents supplied by commercial
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
29
suppliers were dried using the standard drying procedures. All the moisture and air sensitive
reactions were performed under a flow of nitrogen or argon atmosphere using flame-dried or
oven-dried glassware with magnetic stirring. All purifications were done using column
chromatography with 100-200 mesh size SiO
petroleum ether were typically used for column chromatography. The H & C{ H} NMR
spectra were recorded on 400 MHz Bruker spectrometer using CDCl (H: δ = 7.26 and C: δ =
7.0 ppm) or TMS (δ = 0.0) residual solvent peaks as internal standard and DMSO-d ((H: δ =
.50 and C: δ = 39.52±0.06 ppm). The following abbreviations are used for spin multiplicity:
2
-gel as the stationary phase. Distilled EtOAc and
1
13
1
3
7
6
2
s = singlet, d = doublet, t = triplet, q = quartet, p = quintet/pentet, sept. = septet, dd = doublet
of doublet, ddd= doublet of doublet of doublet, td = triplet of doublet, dq = doublet of quartet
and m = multiplet. The chemical shifts are reported as δ values (ppm) and the coupling
constants (J) values are reported in Hz. High Resolution Mass Spectra (HRMS) were obtained
using electron spray ionization (ESI) technique and TOF mass analyzer. IR spectra were
recorded on a Bruker FT/IR-460 Plus spectrometer. Melting points were determined on a Buchi
M-560 apparatus and are uncorrected. Progress of the reactions were monitored using
precoated SiO
using spot developing stains like p-anisaldehyde, ceric ammonium molybdate, ninhydrin or
KMnO
2
-gel GF254 TLC plates while spot visualizations were done under UV light and
4
.
1
) General procedure for the synthesis of N-substituted aziridine-2-carboxy derivatives
1a-1i, 8, 9, 12, 12-d , 14)
(
2
1
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Step I: Except for vi, to the solution of vinyl ester/ketone (10 mmol) in CCl (10 mL) was
4
added liq. Br
rt over 12 h until complete consumption of starting material was indicated by TLC analysis.
The reaction was worked up by quenching it with aq. Na followed by extraction in DCM
4 x 25 mL). The combined organic phase was dried over Na SO and then subjected to solvent
2
(0.77 mL,15 mmol, 1.5 equiv.) at 0 °C and the reaction was allowed to warm to
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
S
2
O
8
(
2
4
removal under reduced pressure to arrive at the crude dibromo residue which was directly used
in the next step.
Step II: Next, in an oven dried round-bottom flask under N atmosphere, dibrominated
2
compound derived from i-v/vi (2.5 mmol) was dissolved in EtOH (5 mL). After stirring the
solution at 0 °C for 10 min. appropriate primary amines (7.5 mmol, 3 equiv.) dissolved in ~2
mL of ethanol were added dropwise to the flask over 10 min. The reaction was then allowed to
warm to rt and continued stirring for another 6-48 h until complete consumption of starting
material was indicated by the TLC analysis. Upon reaction completion, the solvent was
removed under reduced pressure and the resultant residue was subjected to purification using
SiO
2
-gel column chromatography to arrive at the desired aziridines.
3
0
30
31
32
Among the synthesized aziridines, the previously reported ones are 1a, 1b, 1d , 1g and
33
1
i while 1c, 1 e, 1e', 1e'-d
2
, 1f, 1h, 1j, 8, 9 and 14 are new and their spectral data are as
described below:
Ethyl 1-isopropylaziridine-2-carboxylate (1c): Following general procedure 1 using
dibrominated-i30b (0.65 g, 2.5 mmol) and isopropyl amine (0.44 g, 7.5 mmol), 1c was obtained
as pale yellow oil (0.35 g, 90% yield); R
f
= 0.6 (30% EtOAc + pet. ether). IR (neat): νmax 2971,
-1
1
1
743, 1657, 1466, 1414, 1280, 1237, 1186, 1100, 1035, 750 cm ; H NMR (400 MHz,
CDCl
3
):δ 4.23 (dq, J
.16 (dd, J = 0.8 Hz, J
.2 Hz, J
1
= 7.2 Hz, J
2
= 10.8 Hz, 1H), 4.14 (dq, J
1
2
= 7.2 Hz, J
2
= 10.8 Hz, 1H),
2
1
1
2
= 3.4 Hz, 1H), 2.03 (dd, J
1
= 2.8 Hz, J
= 6.4 Hz, 1H), 1.59 (dd, J =
1
2
= 6.4 Hz, 1H), 1.54-1.48 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.17 (d, J = 3.6 Hz, 3H),
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13
1
1
.16 (d, J = 3.6 Hz, 3H); C{ H} NMR (100 MHz, CDCl
3
): δ 171.0, 61.4, 61.0, 37.1, 33.89,
+
2
1.9, 21.7, 14.2. HRMS (ES) m/z calcd for C
8
H15NNaO
2
(M+Na) : 180.0995; found:
180.1004.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ethyl 1-(2-hydroxyethyl)aziridine-2-carboxylate (1e): Following general procedure 1,
using dibrominated-i30b (0.65 g, 2.5 mmol) and ethanolamine (0.46 g, 7.5 mmol), 1e was
obtained as pale yellow oil (0.37 g, 95% yield); R = 0.5 (EtOAc). IR (neat): νmax 2984, 1732,
f
-1
1
1
649, 1446, 1416, 1280, 1243, 1195, 1083, 1035, 748 cm ; H NMR (400 MHz, CDCl
.25-4.12 (m, 2H), 3.77 (t, J = 5.2 Hz, 2H), 2.72 (br s, 1H), 2.60 (dt, J = 5.1 Hz, J = 12.1 Hz,
= 3.2 Hz, J = 6.4 Hz, 1H), 1.67
3
):δ
4
1
2
1H), 2.44-2.38 (m, 1H), 2.19 (d, J = 2.8 Hz, 1H), 2.14 (dd, J
1
2
d, J = 6.4 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H); 113C{ H} NMR (100 MHz, CDCl
1
): δ 170.8, 62.2,
(
3
+
6
1.7, 61.2, 37.0, 34.2, 14.1. HRMS (ES) m/z calcd for C
7
H
13NNaO
3
(M+Na) : 182.0788;
found: 182.0800.
Benzyl 1-(2-hydroxyethyl)aziridine-2-carboxylate (1eʹ): Following general procedure 1,
3
4
using dibrominated-iv (0.80 g, 2.5 mmol) and ethanolamine (0.46 g, 7.5 mmol), 1eʹ was
obtained as colourless oil (0.47 g, 85% yield); R = 0.4 (EtOAc). IR (neat): νmax 2984, 1732,
645, 1454, 1381, 1213, 1068, 739, 698 cm ; H NMR (400 MHz, CDCl ) δ 7.37-7.31 (m,
H), 5.20 (d, J = 12.4 Hz, 1H), 5.14 (d, J = 12.4 Hz, 1H), 3.76 (t, J = 5.2 Hz, 2H), 2.62 (dt, J
= 12.4 Hz, 1H), 2.42-2.37 (m, 1H), 2.22-2.19 (m, 2H), 1.69 (d, J = 6.4 Hz, 1H);
f
-1
1
1
5
3
1
= 5.2 Hz, J
2
13
1
C{ H} NMR (100 MHz, CDCl
3
) δ 170.7, 135.4, 128.6 (2C), 128.4, 128.3 (2C), 67.0, 62.2,
+
6
1.6, 36.9, 34.4. HRMS (ES) m/z calcd for C12
H15NO
3
Na (M+Na) : 244.0944; found:
244.0940.
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2
2
2
2
2
2
2
2
2
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6
Benzyl 1-(2-hydroxyethyl)aziridine-2-carboxylate-3,3-d
2
(1eʹ-d
2
): Following general
procedure 1, using dibrominated-v34,35(0.82 g, 2.5 mmol) and ethanolamine (0.46 g, 7.5
mmol), 1eʹ-d
2
was obtained as colourless oil (0.50 g, 89% yield); R
f
= 0.4 (EtOAc). IR (neat):
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
1
νmax 2984, 1732, 1641, 1454, 1414, 1256, 1190, 1125, 1062, 749, 698 cm ; H NMR (400
MHz, CDCl ) δ 7.37-7.32 (m, 5H), 5.20 (d, J = 12.4 Hz, 1H), 5.14 (d, J = 12.4 Hz, 1H), 3.74
3
(br s, 2H), 2.64-2.58 (m, 1H), 2.39-2.33 (m, 1H), 2.19 (s, 1H), 1.66 (d, J = 6.4 Hz, 0.06H);
1
3
1
C{ H} NMR (100 MHz, CDCl
3
) δ 170.6, 135.3, 128.5 (2C), 128.3, 128.3 (2C), 66.9, 62.1,
+
6
1.5, 36.7. HRMS (ES) m/z calcd for C12
H
14
D
2
NO
3
(M+H) : 224.1250; found: 224.1250.
Ethyl 1-cyclohexylaziridine-2-carboxylate (1f): Following general procedure 1 using
dibrominated-i30b (0.65 g, 2.5 mmol) and cyclohexylamine (0.74 g, 7.5 mmol), 1f was obtained
as pale yellow oil (0.45 g, 92% yield); R
1744, 1450, 1413, 1370, 1282, 1235, 1184, 1089, 1027, 863, 850, 742 cm ; H NMR (400
MHz, CDCl ):δ 4.24-4.11 (m, 2H), 2.12 (d, J = 2.4 Hz, 1H), 2.01 (dd, J = 3.2 Hz, J = 6.4 Hz,
H), 1.84-1.73 (m, 4H), 1.59-1.57 (m, 2H), 1.46-1.40 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H), 1.15-
f
= 0.5 (20% EtOAc + pet. ether). IR (neat): νmax 2930,
-1
1
3
1
2
1
1
2
1
1
3
1
.10 (m, 4H); C{ H} NMR (100 MHz, CDCl
3
): δ 171.1, 69.3, 61.0, 36.4, 33.2, 32.5, 32.3,
+
5.9, 24.8, 24.7, 14.2. HRMS (ES) m/z calcd for C11
H20NO
2
(M+H) : 198.1489; found:
98.1510.
Ethyl 1-(2-(1H-indol-3-yl)ethyl)aziridine-2-carboxylate (1h): Following general procedure
, using dibrominated-i30b (0.65 g, 2.5 mmol) and tryptamine (1.2 g, 7.5 mmol), 1h was
1
obtained as pale yellow oil (0.63 g, 97% yield); R = 0.3 (40% EtOAc + pet. ether). IR (neat):
f
-1 1
νmax 3054, 2986,1714, 1606, 1422, 1326, 1264, 1165, 1123, 895 cm ; H NMR (400 MHz,
CDCl ):δ 8.12 (br s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 8 Hz, 1H), 7.20-7.17 (m, 1H),
3
7
.13-7.09 (m, 1H), 7.01(s, 1H), 4.24-4.10 (m, 2H), 3.16-3.03 (m, 2H), 2.72-2.61 (m, 2H), 2.17
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(
dd, J
1
= 0.9 Hz, J
2
= 3.0 Hz, 1H), 1.99 (dd, J
1
= 3.0 Hz, J
2
= 6.4 Hz, 1H), 1.56 (dd, J
1
= 0.9
13
1
Hz, J
2
=6.4 Hz, 1H), 1.25 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl
3
): δ 171.0,
136.2, 127.3, 121.9, 121.9, 119.2, 118.7, 113.5, 111.1, 61.4, 61.1, 37.4, 34.35, 25.4, 14.2.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
HRMS (ES) m/z calcd for C15
H
19
N
2
O
2
(M+H) : 259.1441; found: 259.1441.
Ethyl 3,3-dimethyl-1-phenethylaziridine-2-carboxylate (8): Following general procedure 1,
3
7
using dibrominated-iii (0.71 g, 2.5 mmol) and phenethylamine (0.91 g, 7.5 mmol), 8 was
obtained as colourless oil (0.40 g, 65% yield); R = 0.3 (15% EtOAc + pet. ether). IR (neat):
f
-1
1
ν
max 1743, 1718, 1650, 1454, 1384, 1305, 1179, 1135, 1030, 750, 700 cm ; H NMR (400
MHz, CDCl
3
) δ 7.28-7.24 (m, 2H), 7.20-7.16 (m, 3H), 4.20-4.11 (m, 2H), 2.93-2.83 (m, 3H),
= 6.0 Hz, J = 8.2 Hz, J = 10.6 Hz 1H), 1.83 (s, 1H), 1.25 (t, J = 7.2 Hz, 3H),
.23 (s, 3H), 1.21 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 170.2, 139.8, 128.8 (2C), 128.3
2
1
.61 (ddd, J
1
2
3
1
3
1
3
(2C), 126.1, 60.6, 54.5, 49.2, 43.9, 36.5, 21.5, 17.5, 14.2. HRMS (ES) m/z calcd for C15
H
22NO
2
+
(M+H) : 248.1645; found: 248.1645.
rel-ethyl (2S,3R)-1-phenethyl-3-phenylaziridine-2-carboxylate (9): Following just step II
3
6
of general procedure 1, using vi (0.63 g, 2.5 mmol) and phenethylamine (0.91 g, 7.5 mmol),
was obtained as a colourless oil (0.40 g, 62% yield); R = 0.3 (10% EtOAc + pet. ether). IR
neat): νmax 3086, 3028, 1714, 1649, 1604, 1495, 1453, 1198, 1030, 858, 740 cm ; H NMR
(400 MHz, CDCl ) δ 7.37 (d, J = 7.2 Hz, 2H), 7.29-7.17 (m, 8H), 3.99 (dq, J = 7.2 Hz, J
0.8 Hz, 1H), 3.88 (dq, J = 7.2 Hz, J = 10.8 Hz, 1H), 3.09-3.04 (m, 1H), 3.00-2.91 (m, 2H),
9
f
-1
1
(
3
1
2
=
1
2
1
2
.86 (d, J = 7.2 Hz, 1H), 2.63-2.58 (m, 1H), 2.43 (d, J = 7.2 Hz, 1H) 0.94 (t, J = 7.2 Hz, 3H);
1
3
1
C{ H} NMR (100 MHz, CDCl
3
): δ 168.1, 139.2, 135.1, 128.7 (2C), 128.3 (2C), 127.8 (2C),
1
27.7 (2C), 127.3, 126.2, 62.2, 60.6, 47.8, 46.0, 35.8, 13.8. HRMS (ES) m/z calcd for
+
C
19
H21NO
2
(M+H) : 296.1645; found: 296.1645.
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6
Ethyl 1-(3,4-dimethoxyphenethyl)aziridine-2-carboxylate (14): Following general
procedure 1 using dibrominated-i30b (0.65 g, 2.5 mmol) and 3,4-dimethoxyphenethylamine
(1.35 g, 7.5 mmol), 1i was obtained as pale yellow oil (0.60 g, 86% yield); R
f
= 0.5 (50%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EtOAc + pet. ether). IR (neat): νmax 2937, 1739, 1516, 1465, 1417, 1262, 1237, 1189, 1157,
-
1
1
1
028, cm ; H NMR (400 MHz, CDCl
m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 2.96-2.84 (m, 2H), 2.62 (ddd, J
11.5 Hz, 1H), 2.50 (ddd, J = 7.0 Hz, J = 8.0 Hz, J = 11.5 Hz, 1H), 2.15 (dd, J
= 3.2 Hz, 1H), 1.94 (dd, J = 3.2 Hz, J = 6.4 Hz, 1H), 1.53 (dd, J = 1.2 Hz, J
H), 1.26 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl ): δ 170.9, 148.8, 147.5, 132.1,
3
) δ 6.82-6.79 (m, 1H), 6.75-6.72 (m, 2H), 4.24-4.12
= 6.2 Hz, J = 8.4 Hz, J
= 0.8 Hz,
= 6.4 Hz,
(
1
2
3
=
1
2
3
1
J
2
1
2
1
2
1
3
1
1
3
120.6, 112.2, 111.3, 62.6, 61.1, 55.9, 55.8, 37.6, 35.7, 34.3, 14.1. HRMS (ES) m/z calcd for
+
C
15
H22NO
4
(M+H) : 280.1543; found: 280.1548.
3
8
1-benzyl-N-methoxy-N-methylaziridine-2-carboxamide (1j) : In an round bottom flask,
30
under N
2
atmosphere to an ice cold solution of 1a (1.0 g, 4.8 mmol, 1 equiv.) and N,O-
dimethyl hydroxylamine hydrochloride (2.38 g, 24 mmol, 5 equiv.) in dry THF (8 mL),
isopropyl magnesium chloride (2M) (9.7 mL, 19.5 mmol, 4 equiv.) was added. The reaction
was allowed to warm to rt over the next 3 h. Upon complete consumption of starting material
the reaction was quenched with sat. aq. NH
of the organic phase over Na SO followed by removal of solvent under reduced pressure gave
a crude residue which was subjected to SiO -gel flash column chromatography to access
aziridine (1j) as colourless oil (0.49 g, 45% yield); R = 0.4 (EtOAc); IR (neat): νmax 1645, 1485,
454, 1396, 1339, 1180, 1153, 1017, 982, 746, 699 cm ; H NMR (400 MHz, CDCl
(d, J = 7.2 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.25-7.22 (m, 1H), 3.73 (d, J = 13.2 Hz, 1H), 3.53
4
Cl and extracted with EtOAc (3 × 20 mL). Drying
2
4
2
f
-1
1
1
3
) δ 7.37
(
s, 3H), 3.41 (d, J = 13.6 Hz, 1H), 3.18 (s, 3H), 2.66 (s, 1H), 2.32 (dd, J
1
= 1.2 Hz, J
2
= 2.8 Hz,
1
3
1
1
H), 1.73 (dd, J
1
= 1.2 Hz, J
2
= 6.2 Hz, 1H); C{ H} NMR (100 MHz, CDCl ): δ 170.0, 138.1,
3
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28.3 (2C), 128.1 (2C), 127.2, 64.3, 61.5, 34.8, 34.4, 32.5. HRMS (ES) m/z calcd for
+
C
12
H
16
N
2
NaO
2
(M+Na) : 243.1104; found: 243.1112.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
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4
4
4
4
4
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Benzyl 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)aziridine-2-carboxylate (12): In an round
bottom flask, under N atmosphere, 1e' (0.22 g, 1 mmol, 1 equiv.) was dissolved in DCM (2.5
2
mL) and cooled to 0 °C. Then, TBSCl (0.30 g, 2 mmol, 2 equiv.) and imidazole (0.14 g, 2
mmol, 2 equiv.) were added over 5 min. followed by DMAP (112.2 mg, 0.1 mmol, 0.1 equiv.)
and reaction was allowed to warm to rt over 5 h. After complete consumption of starting
material, water was added followed by extraction with DCM (3 × 15 mL). Drying of the organic
phase over Na
which was purified by column chromatography to access aziridine (12) as colourless oil (0.31
g, 93% yield); R = 0.2 (15% EtOAc + pet. ether); IR (neat): νmax 2954, 2929, 1745, 1641, 1461,
1280, 1255, 1174, 1007, 941, 811, 777 cm ; H NMR (400 MHz, CDCl
2
SO
4
followed by removal of solvent under reduced pressure gave a crude residue
f
-1 1
3
):δ 7.36-7.31 (m, 5H),
= 3.2 Hz, J = 5.6 Hz, 2H),
= 6.4 Hz, 1H), 2.16 (dd, J
= 6.4 Hz, 1H), 0.88 (s, 9H), 0.04 (s, 3H),
): δ 171.0, 135.6, 128.5 (2C), 128.4 (2C), 128.3,
5
2
0
0
6
.19 (d, J = 12.4 Hz, 1H), 5.13 (d, J = 12.4 Hz, 1H), 3.83 (td, J
.48 (td, J = 2.4 Hz, J = 5.6 Hz, 2H), 2.20 (dd, J = 3.2 Hz, J
.8 Hz, J = 2.8 Hz, 1H), 1.67 (dd, J = 0.8 Hz, J
.03 (s, 3H); C{ H} NMR (100 MHz, CDCl
1
2
1
2
1
2
1
=
2
1
2
1
3
1
3
6.8, 62.7, 62.3, 36.9, 34.1, 25.9 (3C), 18.2, -5.4, -5.5. HRMS (ES) m/z calcd for C18
H
30NO Si
3
+
(M+H) : 336.1989; found: 336.1988.
Benzyl 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)aziridine-2-carboxylate-3,3-d2 (12-d
2
):
Applying above described procedure for 12 on 1e'-d (0.22 g, 1 mmol), aziridine (12-d ) was
2
2
obtained as colourless oil (0.30 g, 90% yield); R
f
= 0.3 (20% EtOAc + pet. ether); IR (neat):
-1 1
νmax 3036, 1728, 1643, 1461, 1256, 1172, 1110, 1006, 939, 829, 697 cm ; H NMR (400 MHz,
CDCl
3
):δ 7.36-7.31 (m, 5H), 5.19 (d, J = 12.4 Hz, 1H), 5.13 (d, J = 12.4 Hz, 1H), 3.83 (td, J
1
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
=
3.2 Hz, J
2
= 5.6 Hz, 2H), 2.47 (td, J
1
= 2 Hz, J = 5.6 Hz, 2H), 2.19 (s, 1H), 2.16 (d, J = 0.8
2
1
3
1
Hz, 0.02H), 1.66 (dd, J
1
3
= 6.4 Hz, 0.04H), 0.87 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); C{ H}
NMR (100 MHz, CDCl
) δ 171.0, 135.6, 128.5 (2C), 128.4 (2C), 128.2, 66.8, 62.7, 62.2, 36.7,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
2
5.9 (3C), 18.2, -5.4, -5.5. HRMS (ES) m/z calcd for C18
H
28
D
2
NO
3
Si (M+H) : 338.2115;
found: 338.2126.
2
) General Procedure for the preparation of β-bromo-β-nitrostyrenes (2a-m).
Protocol A: As described earlier.39
Protocol B: To a cold solution of β-nitrostyrene (2.5 mmol, 1 equiv.) in DCM at 0 °C, pyridine
(0.4 mL, 5 mmol, 2 equiv.) was added followed by pyridinium tribromide ( 0.8 g, 2.5 mmol, 1
equiv.) in two portions. The reaction was then allowed to warm to rt over the next 3-12 h until
complete consumption of starting material. Upon reaction completion, water was added
followed by extraction with DCM. Drying of the organic phase over Na
2
SO followed by
4
removal of solvent under reduced pressure gave a crude residue which was purified by column
chromatography to access β-bromo-β-nitrostyrene.
3
9
Among the synthesized β-bromo-β-nitrostyrene, 2a-c, 2f-i and 2l are known while 2d, 2e,
2
j, 2k and 2m are new and their spectral data are as follows:
(Z)-1-(2-bromo-2-nitrovinyl)-3,5-dimethoxybenzene (2d): Following protocol B, using 3,5-
4
0
dimethoxy-β-nitrostyrene (0.52 g, 2.5 mmol), 2d was obtained as fluorescent green solid
(0.51 g, 71% yield); m.p. 113-114 °C. IR (neat): νmax 1642, 1605, 1524, 1454, 1426, 1297,
-1
1
1
206, 1167, 1155, 946 cm ; H NMR (400 MHz, CDCl
3
):δ 8.55 (s, 1H), 7.01 (d, J = 2.4 Hz,
1
3
1
2
H), 6.61 (t, J = 2 Hz, 1H), 3.84 (s, 6H); C{ H} NMR (100 MHz, CDCl ): δ 160.8 (2C),
3
136.5, 131.7, 128.4, 108.8 (2C), 104.1, 55.6 (2C). HRMS (ES) m/z calcd for C10
H
11BrNO
4
+
(M+H) : 287.9866; found: 287.9866.
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(
Z)-1-(2-bromo-2-nitrovinyl)-3,5-di-tert-butyl-2-methoxybenzene (2e): Following protocol
3
9
41
A, using (E)-1,5-di-tert-butyl-2-methoxy-3-(2-nitrovinyl)benzene (0.73 g, 2.5 mmol), 2e
was obtained as green solid (0.82 g, 88% yield); m.p. 120-124 °C. IR (neat): νmax 2989, 1714,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1 1
1
607, 1479, 1275, 1260, 1017, 163, 750 cm ; H NMR (400 MHz, CDCl
3
) δ 8.83 (s, 1H), 7.83
1
3
1
(d, J = 2.2 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 3.77 (s, 3H), 1.40 (s, 9H), 1.33 (s, 9H); C{ H}
NMR (100 MHz, CDCl
3
): δ 158.1, 145.7, 142.4, 134.6, 128.6, 128.0, 124.8, 123.9, 64.0, 35.3,
+
3
4.8, 31.4 (3C), 30.8 (3C). HRMS (ES) m/z calcd for C17
H
24BrNNaO
3
(M+Na) : 392.0832;
found: 392.0832.
(Z)-4-(2-bromo-2-nitrovinyl)-1,2-dichlorobenzene (2j): Following protocol B, using 3,4-
4
2
dichloro-β-nitrostyrene (0.54 g, 2.5 mmol), 2j was obtained as a pale yellow oil (0.70 g, 95%
-1 1
yield). IR (neat): νmax 1643, 1581, 1469, 1395, 1317, 1207, 1033, 915, 883, 854 cm ; H NMR
(
400 MHz, CDCl
J = 8.4 Hz, 1H), 6.00 (s, 1H); C{ H} NMR (100 MHz, CDCl
30.3, 129.9, 91.8, 56.1. HRMS (ES) m/z calcd for C BrCl
found: 317.8684.
3
):δ 7.84 (d, J = 2.4 Hz, 1H), 7.57 (dd, J = 2.4 Hz, J = 8.4 Hz, 1H), 7.50 (d,
1
2
13
1
3
): δ 134.9, 133.5, 132.7, 132.6,
+
1
8
H
4
2
NNaO
2
(M+Na) : 317.8695;
(Z)-1-bromo-2-(2-bromo-2-nitrovinyl)-4,5-dimethoxybenzene (2k): Following protocol
A,39 using (E)-1-bromo-4,5-dimethoxy-2-(2-nitrovinyl)benzene (0.72 g, 2.5 mmol) 2k was
obtained as yellow solid (0.78 g, 85% yield); m.p. 133-135 °C. IR (neat): νmax1713, 1668, 1488,
-1
1
1
428, 1367, 1258, 1198, 1151, 1017, 749 cm ; H NMR (400 MHz, CDCl
3
):δ 8.90 (s, 1H),
1
3
1
7
.66 (s, 1H), 7.15 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ
3
152.2, 148.0, 135.7, 122.4, 119.3, 115.8, 115.4, 112.2, 56.0, 56.2. HRMS (ES) m/z calcd for
+
C
10
H
9
Br
2
NNaO
4
(M+Na) : 387.8791; found: 387.8791.
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
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5
5
5
5
5
5
5
5
6
3
9
(
Z)-2-(2-bromo-2-nitrovinyl)-5-methylfuran (2m): Following protocol A, using (E)-2-
methyl-5-(2-nitrovinyl)furan 43 (0.38 g, 2.5 mmol), 2m was obtained as pale yellow solid (0.52
g, 91% yield); m.p. 69-70 °C. IR (neat): νmax 3054, 2986, 1714, 1606, 1422, 1326, 1264, 1165,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
1
1
123, 895 cm ; H NMR (400 MHz, CDCl ):δ 8.51 (s, 1H), 7.35 (d, J = 3.2 Hz, 1H), 6.00 (d,
3
1
3
1
J = 3.2 Hz, 1H), 2.42 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
): δ 159.3, 145.2, 125.0, 122.9,
+
1
2
22.4, 110.7, 14.2. HRMS (ES) m/z calcd for C
7
H
7
BrNO
3
(M+H) : 231.9604; found:
31.9604.
3) General procedure for synthesis of 1,2,4-trisubstituted pyrroles:
In an oven-dried seal tube, under nitrogen atmosphere, β-bromo-β-nitrostyrene (0.5 mmol) was
taken. After that aziridine (0.5 mmol, 1 equiv.) dissolved in toluene (2 mL) was added. The
reaction was then sealed while maintaining the N atmosphere and then stirred in a preheated
2
oil bath at 150°C until complete consumption of starting materials was indicated upon reaction
monitoring. After reaction completion, the solvent was removed under reduced pressure and
the crude residue was subjected to purification using SiO
2
-gel flash column chromatography
, 15).
to access 1,2,4-trisubstituted pyrrole (3aa-3ja, 3bb-3bm, 3cb-3cm, 13, 13-d
2
Ethyl 1-benzyl-4-phenyl-1H-pyrrole-2-carboxylate (3aa):44 By following general
procedure , using 1a (102 mg, 0.5 mmol) and 2a (114 mg, 0.5 mmol) with reaction time of 16
h, 3aa was obtained as a yellow oil (146 mg, 96% yield); R = 0.6 (5% EtOAc + pet. ether). IR
f
-1
1
(
neat): νmax 2927, 1700, 1605, 1453, 1397, 1268, 1210, 1094, 758, 724, 694 cm ; H NMR
(400 MHz, CDCl ) δ 7.52 (d, J = 8 Hz, 2H), 7.38-7.31 (m, 5H), 7.29-7.20 (m, 1H), 7.24-7.20
3
(
m, 1H), 7.18-7.16 (m, 3H), 5.61 (s, 2H), 4.29 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H);
1
3
1
C{ H} NMR (100 MHz, CDCl ) δ 161.0, 138.0, 134.3, 128.7 (2C), 128.6 (2C), 127.5, 126.9
3
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(
2C), 126.1, 125.5, 125.1 (2C), 124.4, 123.1, 115.3, 60.0, 52.2, 14.3. HRMS (ES) m/z calcd
+
for C20
H20NO
2
(M+H) : 306.1489; found: 306.1461.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ethyl 1-phenethyl-4-phenyl-1H-pyrrole-2-carboxylate (3ba):- By following general
procedure, using 1b (110 mg, 0.5 mmol)and 2a (114 mg, 0.5 mmol) with reaction time of 16
h, 3ba was obtained as a yellow oil (129 mg, 81% yield); R
neat): νmax 2929, 1700, 1604, 1474, 1453, 1399, 1254, 1199, 758, 697 cm ; H NMR (400
MHz, CDCl ) δ 7.45 (dd, J = 1.2 Hz, J = 8 Hz, 2H), 7.37-7.29 (m, 5H), 7.28-7.19 (m, 4H),
.92 (d, J = 2 Hz, 1H), 4.56 (t, J = 7.6 Hz, 2H), 4.36 (q, J = 7.2 Hz, 2H), 3.11 (t, J = 7.6 Hz,
f
= 0.4 (5% EtOAc + pet. ether). IR
-1
1
(
3
1
2
6
1
3
1
2H), 1.42 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ 161.0, 138.3, 134.5, 128.9
(2C), 128.6 (2C), 128.5 (2C), 126.5, 126.0, 125.5, 125.0 (2C), 123.8, 122.3, 115.3, 59.9, 51.0,
+
3
8.2, 14.4. HRMS (ES) m/z calcd for C21
H
22NO (M+H) : 320.1651; found: 320.1645.
2
Ethyl 1-isopropyl-4-phenyl-1H-pyrrole-2-carboxylate (3ca):- By following general
procedure, using 1c (79 mg, 0.5 mmol) and 2a (114 mg, 0.5 mmol) with reaction time of 16 h,
3
ca was obtained in 16 h as a yellow oil (77 mg, 60% yield) R
IR (neat): νmax 2979, 1700, 1605, 1470, 1408, 1241, 1197, 1102, 1064, 758, 694 cm ; H NMR
400 MHz, CDCl ) δ 7.56 (dd, J = 1.2 Hz, J = 8.0 Hz, 2H), 7.40-7.36 (m, 3H), 7.25 (d, J =
.0 Hz 1H), 7.20 (tt, J = 1.2 Hz, J = 7.2 Hz, 1H), 5.49 (spt, J = 6.8 Hz, 1H), 4.30 (q, J = 7.2
Hz, 2H), 1.49 (d, J = 6.8 Hz, 6H), 1.38 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl
f
= 0.5 (5% EtOAc + pet. ether).
-1 1
(
3
1
2
2
1
2
13
1
3
)
δ 161.1, 134.7, 128.7 (2C), 126.0, 125.0 (2C), 124.2, 122.6, 120.4, 115.0, 59.9, 48.6, 23.8 (2C),
+
1
4.4. HRMS (ES) m/z calcd for C16
H20NO
2
(M+H) : 258.1494; found: 258.1489.
Ethyl 4-(4-methoxyphenyl)-1-phenethyl-1H-pyrrole-2-carboxylate (3bb): By following
general procedure, using 1b (110 mg, 0.5 mmol) and 2b (129 mg, 0.5 mmol) with reaction time
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1
1
1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
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4
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5
5
5
5
5
5
5
6
of 23 h, 3bb was obtained as a yellow oil (118.7 mg, 68% yield); R = 0.2 (3% EtOAc + pet.
f
-1
1
ether). IR (neat): νmax 2932, 1696, 1566, 1511, 1249, 1197, 1094, 1032, 931, 700 cm ; H
NMR (400 MHz, CDCl ) δ 7.37 (d, J = 8.8 Hz, 2H), 7.32-7.28 (m, 2H), 7.26-7.22 (m, 1H),
.21 (d, J = 2 Hz, 1H), 7.19-7.17 (m, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 2 Hz, 1H), 4.54
t, J = 7.2 Hz, 2H), 4.34 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 3.09 (t, J = 7.2 Hz, 2H), 1.40 (t, J
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
(
13
1
=
7.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ 161.1, 158.1, 138.4, 129.0 (2C), 128.5
3
(2C), 127.4, 126.6, 126.3 (2C), 125.0, 123.6, 122.2, 115.1, 114.2 (2C), 60.0, 55.3, 51.1, 38.4,
+
1
4.5. HRMS (ES) m/z calcd for C22
H23NO
3
(M+H) : 350.1756; found: 350.1751
Ethyl 1-isopropyl-4-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (3cb) : By following
general procedure, using 1c (79 mg, 0.5 mmol) and 2b (129 mg, 0.5 mmol) with reaction time
of 23 h, 3cb was obtained as a colourless solid (106 mg, 74% yield); R
f
= 0.3 (3% EtOAc +
pet. ether); m.p. 65-68 °C. IR (neat): νmax 2979, 1697, 1564, 1510, 1469, 1407, 1246, 1197,
-1
1
1
102, 1064, 826, 792 cm ; H NMR (400 MHz, CDCl
3
) δ 7.44 (d, J = 8.8 Hz, 2H), 7.25 (d, J
=
2 Hz, 1H), 7.18 (d, J = 2 Hz, 1H), 6.09 (d, J = 8.8 Hz, 2H), 5.49 (sept, 1H), 4.30 (q, J = 7.2
1
3
1
Hz, 2H), 3.82 (s, 3H), 1.48 (d, J = 6.8 Hz, 6H), 1.38 (t, J = 7.2 Hz, 3H); C{ H} NMR (100
MHz, CDCl
3
) δ 161.2, 158.1, 127.6, 126.2 (2C), 124.0, 122.4, 119.8, 114.8, 114.1 (2C), 59.8,
+
5
2
5.3, 48.6, 23.8 (2C), 14.5. HRMS (ES) m/z calcd for C17
88.1587.
H22NO
3
(M+H) : 288.1594; found:
Ethyl 4-(3,4-dimethoxyphenyl)-1-phenethyl-1H-pyrrole-2-carboxylate (3bc): By
following general procedure, using 1b (110 mg, 0.5 mmol) and 2c (144 mg, 0.5 mmol) with
reaction time of 20 h, 3bc was obtained as a yellow oil (138 mg, 73% yield); R
f
= 0.5 (20%
EtOAc + pet. ether). IR (neat): νmax 2933, 1698, 1564, 1514, 1456, 1249, 1196, 1093, 1026,
-1 1
7
62, 699 cm ; H NMR (400 MHz, CDCl ) δ 7.31-7.27 (m, 2H), 7.25-7.21 (m, 1H), 7.19 (d,
3
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J = 2 Hz, 1H),7.18-7.15 (m, 2H), 6.98 (dd, J
1
= 2 Hz, J
2
= 8.2 Hz, 1H), 6.93 (d, J = 2 Hz, 1H),
6
.85 (d, J = 8 Hz, 1H), 6.82 (d, J = 2 Hz, 1H), 4.54 (t, J = 7.2 Hz, 2H), 4.09 (q, J = 7.2 Hz, 2H),
1
3
1
3.92 (s, 3H), 3.88 (s, 3H), 3.08 (t, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H); C{ H} NMR (100
MHz, CDCl ) δ 161.1, 149.1, 147.6, 138.4, 129.0 (2C), 128.5 (2C), 127.7, 126.6, 125.2, 123.8,
22.2, 117.4, 115.1, 111.6, 108.8, 60.0, 56.0, 55.9, 51.1, 38.3, 14.5. HRMS (ES) m/z calcd for
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
+
C
23
H
26NO (M+H) : 380.1856; found: 380.1856.
4
Ethyl 4-(3,4-dimethoxyphenyl)-1-isopropyl-1H-pyrrole-2-carboxylate (3cc): By following
general procedure, using 1c (79 mg, 0.5 mmol) and 2c (144 mg, 0.5 mmol) with reaction time
of 20 h, 3cc was obtained as a colourless oil (128.5 mg, 81% yield); R
f
= 0.6 (20% EtOAc +
pet. ether). IR (neat): νmax 2978, 1699, 1562, 1513, 1469, 1408, 1242, 1196, 1102, 1064, 1027,
-1 1
7
62, 611 cm ; H NMR (400 MHz, CDCl
7.05 (dd, J = 2 Hz, J = 8 Hz, 1H), 7.01 (d, J = 2 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 5.49 (sept,
J = 6.4 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 1.48 (d, J = 6.4 Hz, 6H),
3
) δ 7.24 (d, J = 2 Hz, 1H), 7.17 (d, J = 2 Hz, 1H),
1
2
1
3
1
1
1
.37 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ 161.1, 149.2, 147.6, 128.0, 124.2,
3
22.4, 120.0, 117.4, 114.8, 111.6, 108.8, 59.9, 56.0, 55.9, 48.6, 23.8 (2C), 14.5. HRMS (ES)
+
m/z calcd for C18
H24NO
4
(M+H) : 318.1700; found: 318.1686.
Ethyl 4-(3,5-dimethoxyphenyl)-1-phenethyl-1H-pyrrole-2-carboxylate (3bd): By
following general procedure, using 1b (110 mg, 0.5 mmol) and 2d (144 mg, 0.5 mmol) with
reaction time of 20 h, 3bc was obtained as a yellow oil (153.5 mg, 81% yield); R
f
= 0.4 (10%
EtOAc + pet. ether). IR (neat): νmax 1694, 1642, 1565, 1514, 1249, 1195, 1093, 1026, 699, 673,
-1 1
663 cm ; H NMR (400 MHz, CDCl
3
) δ 7.31-7.26 (m, 2H), 7.25-7.20 (m, 1H), 7.23 (d, J =
.0 Hz, 1H), 7.16-7.14 (m, 2H), 6.86 (d, J = 2.0 Hz, 1H), 6.58 (d, J = 2.4 Hz, 2H), 6.33 (t, J =
.0 Hz, 1H), 4.53 (t, J = 7.6 Hz, 2H), 4.34 (q, J = 7.2 Hz, 2H), 3.81 (s, 6H), 3.08 (t, J = 7.6 Hz,
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
1
2
1
H), 1.40 (t, J =7.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl
3
): δ 161.0 (2C), 161.0, 138.3,
36.5, 129.0 (2C), 128.6 (2C), 126.6, 125.8, 123.8, 122.3, 115.5, 103.3 (2C), 98.2, 60.1, 55.4,
+
51.1, 38.3, 14.5. HRMS (ES) m/z calcd for C23
H26NO
4
(M+H) : 380.1856; found: 380.1855.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ethyl 4-(3,5-dimethoxyphenyl)-1-isopropyl-1H-pyrrole-2-carboxylate (3cd): By following
general procedure, using 1c (79 mg, 0.5 mmol) and 2d (144 mg, 0.5 mmol) with reaction time
of 20 h, 3cd was obtained as a pale yellow oil (108 mg, 68% yield); R
f
= 0.6 (10% EtOAc +
pet. ether). IR (neat): νmax 2979, 1701, 1596, 1486, 1461, 1403, 1230, 1204, 1174, 1155, 1103,
-1 1
1
065 cm ; H NMR (400 MHz, CDCl
3
) δ 7.29 (d, J = 2 Hz, 1H), 7.21 (d, J = 2 Hz, 1H), 6.67
(d, J = 2.0 Hz, 2H), 6.34 (t, J = 2 Hz, 1H), 5.49 (sept, J = 6.8 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H),
13
1
3
.83 (s, 6H), 1.48 (d, J = 6.8 Hz, 6H), 1.38 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz,
CDCl
3
) δ 161.1 (2C), 161.0, 136.8, 124.2, 122.5, 120.7, 115.2 , 103.3 (2C), 98.2, 59.9, 55.4
+
(2C), 48.7, 23.8 (2C), 14.5. HRMS (ES) m/z calcd for C18
18.1692.
H24NO
4
(M+H) : 318.1700; found:
3
Ethyl
3be):- By following general procedure, using 1b (110 mg, 0.5 mmol) and 2e (185 mg, 0.5
mmol) with reaction time of 12 h, 3be was obtained as a colourless oil (172 mg, 75% yield);
= 0.5 (3% EtOAc + pet. ether). IR (neat): νmax 2959, 1701, 1479, 1382, 1361, 1290, 1251,
4-(3,5-di-tert-butyl-2-methoxyphenyl)-1-phenethyl-1H-pyrrole-2-carboxylate
(
R
f
-
1 1
1231, 1194, 1095, 1008, 699 cm ; H NMR (400 MHz, CDCl
.17 (m, 4H), 7.14 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 2 Hz, 1H), 4.58 (t, J = 7.2 Hz, 2H), 4.36
q, J = 7.2 Hz, 2H), 3.39 (s, 3H), 3.12 (t, J = 7.2 Hz, 2H), 1.43 (s, 9H), 1.41 (t, J = 7.2 Hz, 3H),
3
) δ 7.29-7.26 (m, 3H), 7.24-
7
(
13
1
1.33 (s, 9H); C{ H} NMR (100 MHz, CDCl
3
) δ 161.3, 154.9, 145.4, 142.0, 138.5, 129.0 (2C),
1
28.5 (2C), 128.2, 127.7, 126.6, 125.2, 122.4, 121.4 (2C), 117.8, 60.1, 59.9, 51.0, 38.3, 35.3,
2
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+
3
4.5, 31.6 (3C), 31.1 (3C), 14.6. HRMS (ES) m/z calcd for C30
H
40NO (M+H) : 462.3008;
3
found: 462.3003.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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0
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8
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0
Ethyl
3ce) : By following general procedure, using 1c (79 mg, 0.5 mmol) and 2e (185 mg, 0.5 mmol)
with reaction time of 12 h, 3ce was obtained as a colourless oil (165.6 mg, 83% yield); R
4-(3,5-di-tert-butyl-2-methoxyphenyl)-1-isopropyl-1H-pyrrole-2-carboxylate
(
f
=
0
1
1
.7 (3% EtOAc + pet. ether). IR (neat): νmax 2961, 1702, 1469, 1394, 1361, 1281, 1226, 1200,
-1 1
101, 1064, 1008, 758 cm ; H NMR (400 MHz, CDCl
3
) δ 7.45 (s, 1H), 7.26 (d, J = 2.0 Hz,
H), 7.25 (d, J = 2.0 Hz, 1H), 7.20 (s, 1H), 5.54 (sept, J = 6.4 Hz,1H), 4.33 (q, J = 7.2 Hz, 2H),
3.47 (s, 3H), 1.49 (d, J = 6.4 Hz, 6H), 1.44 (s, 9H), 1.40 (t, J = 7.2 Hz, 3H), 1.34 (s, 9H);
13
1
C{ H} NMR (100 MHz, CDCl ) δ 161.3, 154.8, 145.5, 142.0, 128.0, 125.2, 123.6, 122.4,
3
1
21.8, 121.5, 117.2, 59.9, 59.8, 48.5, 35.3, 34.5, 31.6 (3C), 31.1 (3C), 24.0 (2C), 14.5. HRMS
+
(ES) m/z calcd for C25
H38NO
3
(M+H) : 400.2846; found: 400.2832.
Ethyl 4-(4-fluorophenyl)-1-phenethyl-1H-pyrrole-2-carboxylate (3bf): By following
general procedure, using 1b (110 mg, 0.5 mmol) and 2f (123 mg, 0.5 mmol) with reaction time
of 5 h, 3bf was obtained as a colorless solid (76 mg, 45% yield); R
f
= 0.5 (5% EtOAc + pet.
ether); m.p. 68-70 °C. IR (neat): νmax 2981, 1695, 1566, 1510, 1475, 1424, 1397, 1255, 1227,
-1 1
1
197, 1094, 824 cm ; H NMR (400 MHz, CDCl
3
) δ 7.39-7.36 (m, 2H), 7.32-7.28 (m, 2H),
7.26-7.22 (m, 1H), 7.21 (d, J = 2 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 7.03 (t, J = 8.8 Hz, 2H),
6
.83 (d, J = 2 Hz, 1H), 4.54 (t, J = 7.2 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.09 (t, J = 7.2 Hz,
1
3
1
2
H), 1.41 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ 161.4 (d, J = 243 Hz, 1C),
3
161.0, 138.2, 130.6 (d, J = 3 Hz, 1C) , 128.9 (2C), 128.5 (2C), 126.5 (d, J = 3 Hz, 2C), 126.4,
1
25.2, 122.9, 122.4, 115.4 (d, J = 21 Hz, 2C), 115.1, 60.0, 51.0, 38.2, 14.4. HRMS (ES) m/z
+
calcd for C21
H21FNO
2
(M+H) : 338.1556; found: 338.1551.
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Ethyl 4-(4-fluorophenyl)-1-isopropyl-1H-pyrrole-2-carboxylate (3cf):- By following
general procedure, using 1c (79 mg, 0.5 mmol) and 2f (123 mg, 0.5 mmol) with reaction time
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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8
9
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8
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6
7
8
9
0
of 5 h, 3cf was obtained as a yellow oil (64.6 mg, 47% yield); R = 0.3 (3% EtOAc + pet. ether).
f
-1
IR (neat): νmax 2981, 1699, 1564, 1508, 1473, 1407, 1242, 1196, 1103, 1065, 827, 755 cm ;
1H NMR (400 MHz, CDCl
3
) δ 7.48-7.44 (m, 2H), 7.25 (d, J = 2 Hz, 1H), 7.18 (d, J = 2 Hz,
1
6
1
H), 7.06-7.01 (m, 2H), 5.41 (sept, J = 6.8, 1H), 4.30 (q, J = 7.2 Hz, 2H), 1.48 (d J = 6.8 Hz,
1
3
1
H), 1.38 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ 161.4 (d, J = 242 Hz, 1C),
3
61.0, 130.9 (d, J = 3 Hz, 1C), 126.5 (d, J = 7 Hz, 2C), 123.3, 122.6, 120.1, 115.5 (d, J = 21
(M+H)+ :
Hz, 2C), 114.9, 59.9, 48.6, 23.8 (2C), 14.4. HRMS (ES) m/z calcd for C16
H18FNO
2
2
76.1394; found: 276.1399.
Ethyl 4-(4-chlorophenyl)-1-phenethyl-1H-pyrrole-2-carboxylate (3bg):- By following
general procedure, using 1b (110 mg, 0.5 mmol) and 2g (130 mg, 0.5 mmol) with reaction time
of 8 h, 3bg was obtained as white solid (109.5 mg, 62% yield); R
f
= 0.4 (5% EtOAc + pet.
ether); m.p. 103-104 °C. IR (neat): νmax 2981, 1698, 1646, 1495, 1474, 1453, 1254, 1197, 1091,
-1 1
7
52, 699 cm ; H NMR (400 MHz, CDCl
3
) δ 7.36-7.33 (m, 2H), 7.30-7.27 (m, 4H), 7.25-7.23
(m, 1H), 7.21 (d, J = 2 Hz, 1H), 7.16-7.14 (m, 2H), 6.85 (d, J = 2 Hz, 1H), 4.54 (t, J = 7.2 Hz,
1
3
1
2
H), 4.34 (q, J = 7.2 Hz, 2H), 3.08 (t, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H); C{ H} NMR
) δ 161.0, 138.3, 133.1, 131.6, 129.0 (2C), 128.8 (2C), 128.6 (2C), 126.6,
26.3 (2C), 125.5, 122.6, 122.6, 115.2, 60.1, 51.2, 38.3, 14.5. HRMS (ES) m/z calcd for
(100 MHz, CDCl
3
1
+
C
21
H
21ClNO (M+H) : 354.1261; found: 354.1255.
2
Ethyl 4-(4-chlorophenyl)-1-isopropyl-1H-pyrrole-2-carboxylate (3cg):- By following
general procedure, using 1c (79 mg, 0.5 mmol) and 2g (130 mg, 0.5 mmol) with reaction time
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of 8 h, 3cg was obtained as yellow oil (99 mg, 68% yield); R
IR (neat): νmax 2980, 1700, 1494, 1406, 1242, 1197, 1103, 1064, 823, 792 cm ; H NMR (400
MHz, CDCl ) δ 7.44 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 2 Hz, 1H), 7.20
d, J = 2 Hz, 1H), 5.49 (sept, J = 6.8 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 1.48 (d, J = 6.8 Hz,
f
= 0.5 (5% EtOAc + pet. ether).
-1 1
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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8
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0
1
2
3
4
5
6
7
8
9
0
(
1
3
1
6
H), 1.38 (t, J = 7.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ 161.0, 133.3, 131.5, 128.8
3
(2C), 126.2 (2C), 123.1, 122.8, 120.3, 114.9, 60.0, 48.7, 23.8 (2C), 14.4. HRMS (ES) m/z
+
calcd for C16
H
19ClNO
2
(M+H) : 292.1099; found: 292.1087.
Ethyl 4-(4-bromophenyl)-1-phenethyl-1H-pyrrole-2-carboxylate (3bh):- By following
general procedure, using 1b (110 mg, 0.5 mmol) and 2h (154 mg, 0.5 mmol) with reaction time
of 8 h, 3bh was obtained as a fluorescent green solid (107.2 mg, 54% yield); R
f
= 0.4 (3%
EtOAc + pet. ether); m.p. 115-116 °C. IR (neat): νmax 1699, 1558, 1493, 1473, 1419, 1255,
-1 1
1198, 1095, 1008, 929 cm ; H NMR (400 MHz, CDCl
.20 (m, 4H), 7.20-7.22 (m, 1H), 7.21 (d, J = 2.8 Hz, 1H), 7.16-7.14 (m, 2H), 6.86 (d, J = 2
Hz, 1H), 4.54 (t, J = 7.2 Hz, 2H), 4.34 (q, J = 7.2 Hz, 2H), 3.08 (t, J = 7.2 Hz, 2H), 1.40 (t, J =
3
) δ 7.44 (d, J = 8.8 Hz, 2H), 7.30-
7
1
3
1
7
.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ 161.0, 138.2, 133.5, 131.8 (2C), 129.0 (2C),
3
1
28.6 (2C), 126.65, 126.62 (2C), 125.5, 122.6, 122.6, 119.6, 115.2, 60.1, 51.2, 38.3, 14.5.
+
HRMS (ES) m/z calcd for C21
H
21BrNO
2
(M+H) : 398.0756; found: 398.0747.
Ethyl 4-(4-bromophenyl)-1-isopropyl-1H-pyrrole-2-carboxylate (3ch):- By following
general procedure, using 1c (79 mg, 0.5 mmol) and 2h (154 mg, 0.5 mmol) with reaction time
of 8 h, 3ch was obtained as a yellow oil (98.8 mg, 59% yield); R = 0.5 (3% EtOAc + pet.
f
-1
ether). IR (neat): νmax 1700, 1470, 1406, 1310, 1241, 1195, 1103, 1064, 1008, 930, 791 cm ;
1H NMR (400 MHz, CDCl
3
) δ 7.45 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.29 (d, J =
2
Hz, 1H), 7.20 (d, J = 2 Hz, 1H), 5.49 (sept, J = 6.4 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 1.48 (d
2
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