2 H-Azirine-2-carbonyl Azides: Preparation and Use as N-Heterocyclic Building Blocks

Article abstract of DOI:10.1021/acs.joc.9b03367

2H-Azirine-2-carbonyl azides, new reactive heterocyclic building blocks, were synthesized in high yield by the reaction of sodium azide with 2H-azirine-2-carbonyl chlorides, generated by the Fe(II)-catalyzed isomerization of 5-chloroisoxazoles. 2-(Azidocarbonyl)-1H-pyrroles, prepared by the Ni(II)-catalyzed reaction of 2-(azidocarbonyl)-2H-azirines with 1,3-diketones, easily undergo the Curtius rearrangement in boiling tBuOH to give Boc-protected α-aminopyrroles in high yield. Heating of 2-(azidocarbonyl)-1H-pyrroles for a short time in inert solvents leads to the high-yield formation of benzo- A nd hetero-fused 1H-pyrrolo[2,3-b]pyridin-6(7H)-ones, which are formed via a 6πelectrocyclization involving the vicinal aryl or hetaryl substituent and the Na?C bond of isocyanate, generated by the Curtius rearrangement of the azidocarbonyl group. The Pd-catalyzed cross-coupling reaction of 1-acetyl-2-methyl-3H-pyrrolo[2,3-c]isoquinolin-5-yl triflate, easily prepared from the corresponding pyrroloisoquinolone, leads to variously 5-substituted 3H-pyrrolo[2,3-c]isoquinolines in excellent yields.

Full text of DOI:10.1021/acs.joc.9b03367

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Article
2H-Azirine-2-carbonyl Azides: Preparation
and Use as N-Heterocyclic Building Blocks
Liya D. Funt, Yulia V. Krivolapova, Olesya V. Khoroshilova,
Mikhail Sergeevich Novikov, and Alexander F. Khlebnikov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03367 • Publication Date (Web): 26 Feb 2020
Downloaded from pubs.acs.org on February 27, 2020
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2
H-Azirine-2-carbonyl Azides: Preparation and Use as N-Heterocyclic Building
Blocks
Liya D. Funt, Yulia V. Krivolapova, Olesya V. Khoroshilova, Mikhail S. Novikov, Alexander F.
Khlebnikov*
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Saint Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab.,
St. Petersburg 199034, Russia
*
E-mail: a.khlebnikov@spbu.ru.
ABSTRACT: 2H-Azirine-2-carbonyl azides, new reactive heterocyclic building blocks, were
synthesized in high yield by the reaction of sodium azide with 2H-azirine-2-carbonyl chlorides,
generated by Fe(II)-catalyzed isomerization of 5-chloroisoxazoles. 2-(Azidocarbonyl)-1H-pyrroles,
prepared by the Ni(II)-catalyzed reaction of 2-(azidocarbonyl)-2H-azirines with 1,3-diketones easily
undergo the Curtius rearrangement in boiling tBuOH to give Boc-protected α-aminopyrroles in high
yield. Heating of 2-(azidocarbonyl)-1H-pyrroles for a short time in inert solvents leads to the high
yield formation of benzo- and hetero-fused 1H-pyrrolo[2,3-b]pyridin-6(7H)-ones, which are formed
via a 6π electrocyclization involving the vicinal aryl or hetaryl substituent and the N=C bond of
isocyanate, generated by the Curtius rearrangement of the azidocarbonyl group. The Pd-catalyzed
cross-coupling reaction of 1-acetyl-2-methyl-3H-pyrrolo[2,3-c]isoquinolin-5-yl triflate, easily
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prepared from the corresponding pyrroloisoquinolone, leads to variously 5-substituted 3H-
pyrrolo[2,3-c]isoquinolines in excellent yields.
Introduction
Acyl azides are known as versatile reagents for the synthesis of heterocycles and natural products.1,2
The most important reaction of these acyl azides is the Curtius rearrangement leading to isocyanates.
The latter can be hydrolyzed to the corresponding amines or used in further reactions, in particular in
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various cyclizations leading to azaheterocycles. A combination of the acyl azide group with strained
small rings provides synthetic building blocks with increased potential by utilizing the reactivity of
3
4
both components. Examples of such are azidocarbonylcyclopropanes and azidocarbonyloxiranes.
We speculated that 2H-azirine-2-carbonyl azides 3 could serve as valuable synthetic building blocks
5
1, 2
for the implementation of orthogonal reactivity, since both the azirine and carbonyl azide moieties
can be activated in completely different ways using various catalysts and reaction conditions. Recently
we found conditions for the generation of the unstable 2H-azirine-2-carbonyl chlorides 2 by Fe(II)-
6
catalysed isomerization of 5-chloroisoxazoles 1 and supposed that the use of this isomerization would
allow the synthesis of 2H-azirine-2-carbonyl azides by the reaction of chlorides 2 with sodium azide
7
(
Scheme 1). The aim of this work is, therefore, to develop a synthetic method for the preparation of
2H-azirine-2-carbonyl azides and to investigate their orthogonal reactivity.
Scheme 1. Retrosynthetic Scheme for the Preparation of 2H-Azirine-2-carbonyl Azides 3 via
Isomerization of Chloroisoxazoles 1
Ar
Ar
Ar
N
N
Cl
N
O
O
Cl
O
N3
1
2
3
Results and discussion
-Phenyl-2H-azirine-2-carbonyl chloride 2a, generated by the Fe(II)-catalyzed isomerization of 5-
3
6
c
chloro-3-phenylizoxazole 1a according to the earlier described procedure, was reacted with 1 equiv
of sodium azide in acetone to give target 3-phenyl-2H-azirine-2-carbonyl azide 3a in 56% yield. An
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increase in the amount of NaN to 1.6 equiv improved the yield of azide 3a to 91%. In order to evaluate
3
the scope of the reaction substituted isoxazoles 1a-m were reacted with catalytic amounts of
anhydrous FeCl and then with sodium azide under the optimized conditions mentioned above. We
2
failed to isolate pure samples of azides 3h and 3j due to their low stability, and these compounds were
used in further reactions without prior isolation. Meanwhile azides 3a-g, i, k-m with various p-, m-
and o-substituted aryl and hetaryl groups were prepared mostly in excellent yields (Table 1). An
attempt to perform the reaction with 5-chloro-4-(4-nitrophenyl)isoxazole failed, possibly due to
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specific reactions of the nitro-group, promoted by FeCl , leading to complete tarring of the reaction
2
mixture at the 3-(4-nitrophenyl)-2H-azirine-2-carbonyl chloride preparation step. All new compounds
1
13
were characterized by H, C NMR and HRMS. The structure of azide 3d was confirmed by X-ray
analysis (see the Supporting Information). Azides 3a-g, i, k-m are non-hygroscopic crystalline solids,
which are stable under an air atmosphere for a long time at rt.
Table 1. Synthesis of 3-Aryl/hetaryl-2H-Azirine-2-carbonyl Azides 3a-ma
R
R
R
FeCl2 (anhyd)
20 mol%
N
N
NaN3 (1.6 equiv)
Cl
N
O
acetone, 0°Crt
MeCN, rt, 2 h
O
Cl
a-m
O
N3
1
a-m
1 h
2
3a-m
F
Cl
N
Br
N
N
N
N
Br
O
N3
O
N3
O
N3
O
N3
O
N3
3a 91%
3b 92%
3c 91%
3d 73%
3e 94%
MeO
MeO
MeO
N
N
N
MeO
N
O
N3
O
N3
O
N3
g 89%
O
N3
3
hb
3
3i
94%
3
f 91%
F3C
S
O
N
N
N
N
O
N3
O
N3
0%
O
N3
O
N3
3
jb
3k 77%
3l
7
3m 94%
a
b
Isolated yields. Not isolated in pure form.
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Attempts to carry out the Curtius rearrangement of azides 3 under various conditions to obtain 2-
amino-2H-azirines failed. Heating azide 3a in MeOH or tert-BuOH in order to obtain the
corresponding azirin-2-ylcarbamate led to extensive tarring. On the other hand, the reactions of the
azirine moiety of compounds 3 with the retention of the azidocarbonyl group turned out to be much
more successful. Thus, the Ni(II)-catalyzed reaction of azides 3 with acetyl acetone 4a under the
conditions similar to those used for the reaction of azirine-2-carboxylic acid derivatives6b, 8 provides
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2-(azidocarbonyl)pyrroles 5 in good to excellent yields (Table 2).
Table 2. Synthesis of 4-Acetyl-3-aryl-5-methyl-1H-pyrrole-2-carbonyl Azide 5a-ka
R
O
R
N
O
O
NiCl26H2O
0 mol%
N3
O
1
MeCN, rt, 1-2 d
NH
O
N3
3a-m
4a
5a-k
F
Cl
Br
O
O
O
O
N3
N3
N3
N3
N
N
N
N
H
H
O
H
O
H
O
O
5a 92%
5b 88%
5c 91%
5d 73%
OMe
MeO
O
O Br
O
O
N3
N3
N3
N3
N
N
H
N
H
O
O
N
O
H
H
O
5e 87%
5f 91%
5g 74%
CF3
5h 53%b
MeO
OMe
O
O
O
N3
N3
N3
N
H
N
H
N
H
O
O
O
5j 19%b
5k 85%
5i 90%
a
b
Isolated yields. For 3 step, starting from isoxazole 1.
Pyrroles 5h and 5j were prepared without intermediate isolation of azides 3h and 3j. The structure of
azide 5d was confirmed by X-ray analysis (see the Supporting Information). The Ni(II)-catalyzed
1
reaction of azide 3a with benzoylacetone 4b gave a ca. 1:1 mixture ( H NMR) of regioisomers 5l and
5
m in ca. 92% (Scheme 2). 2-(Azidocarbonyl)pyrrole 5l was isolated in pure form by
chromatography, in contrast to isomer 5m, which turned out to be unstable like other pyrroles 5 with
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an aryl substituent in the 5 position (vide infra). Ethyl acetoacetate did not react with azide 3a under
the same reaction conditions.
Scheme 2. Reaction of Azide 3a with Nonsymmetrical 1,3-Diketone
O
O
Ph
Ph
NiCl 6H O
2
2
Ph
Ph
Ph
N
O
O
20 mol%
1
1
1
1
1
1
1
1
1
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9
0
+
+
N3
N3
MeCN, rt, 2 d
Ph
N
O
N3
N
H
H
O
O
l, 41%
3
a
4b
5
5m
ca. 92%
In contrast to azirine-2-carbonyl azides 3, 1H-pyrrole-2-carbonyl azides 5a-i, k easily undergo the
Curtius rearrangement in boiling tert-BuOH to give Boc-protected α-aminopyrroles 6a-i,k (Table 3).
Table 3. Synthesis of Boc-Protected α-Aminopyrroles 6a-i, ka
O
O
R
N3
O
R
tBuOH
O
reflux
O
NH
N
N
H
5a-i, k
H
6a-i, k
F
Cl
Br
O
O
O
O
Boc
Boc
Boc
Boc
N
N
N
N
N
H
N
N
N
H
H
H
H
H
H
H
6
a 97%
6b
6c 100%
6d 94%
1
00%
OMe
O
Br
O
O
Boc
Boc
N
Boc
N
N
N
H
H
N
H
H
N
H
H
6
e 91%
6f 96%
6g 95%
MeO
OMe MeO
MeO
OMe
O
MeO
O
O
O
O
+
+
NH
NH
Boc
6i 55%
N
H
O
N
H
N
N
N
N
H
H
Boc
H
H
7h 20%
7i 35%
6h 75%
a
Isolated yields.
4
-Benzoyl-substituted azidocarbonylpyrrole 5n was synthesized by the Ni(II)-catalyzed reaction of
azide 3a with dibenzoylmethane 4c, but due to its instability, it was not fully characterized. It easily
decomposed when kept in air at rt to give urea 8a. Heating crude azidocarbonylpyrrole 5n in tert-
BuOH led to Boc-protected α-aminopyrrole 6n in 59% yield (Scheme 3).
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Scheme 3. Synthesis of α-Aminopyrrole 6n
Ph
O
O
Ph
NiCl 6H O
Ph
2
2
Ph
N
O
O
tBuOH
20 mol%
Ph
N3
O
Boc
NH
Ph
+
reflux
MeCN, rt, 2 d
N
O
N3
Ph
N
H
Ph
Ph
H
6n
4
c
5n
3a
(
51% on two steps)
rt, H2O (air)
O
O
Ph
Ph
Ph
Ph Ph
0
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0
O
Ph
N
H
N
N
N
8a
H
H
H
Heating of azide 5a in boiling aq AcOH (v/v, 1:1), in an attempt to prepare unprotected α-
aminopyrrole 9a, led to the quantitative formation of urea 8b (Scheme 3). α-Aminopyrroles 9 can be
prepared, however, by deprotection of N-Boc-aminopyroles 6 using TFA (Scheme 4).
Scheme 4. Synthesis of Urea 8b and Unprotected α-Aminopyrroles 9a and 9f
O
O
O
Ph
N3
O
Ph Ph
O
aq AcOH (v/v, 1:1)
reflux
N
N
H
N
N
N
H
H
5a
H
H
R1
8b, 96%
R1
O
R
O
CF CO H
R
R
3
2
a, R = Me, R1 = H, 80%
9
R
NH
Boc
9f, R = Me, R1 = Me, 82%
N
rt, 15 min
H
NH2 9n, R = Ph, R1 = H, 84%
N
6
a, f, n
H
It was found that azidocarbonylpyrroles 5h and 5i, containing an m-MeO-substituted phenyl group
under Curtius rearrangement conditions, afforded, in addition to Boc-protected α-aminopyrroles 6h
and 6i, 3,4-dihydro-5H-pyrrolo[2,3-c]isoquinolin-5-ones 7h and 7i as byproducts. (Table 3).
Compounds 7 are most likely the products of the electrocyclization of the intermediate isocyanates 10
(Scheme 5).
Scheme 5. Transformations of Intermediate isocyanates
R
R
O
O
NH
O
O
C
O
O
tBuOH
N3
O
N
HN
8
2 o
C
NH
NH
6
1
0
R
5
R = MeO
MeO
O
O
NH
N
H
7
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[6π]-Electrocyclization involving the N=C bond of the isocyanates, generated via the Curtius
rearrangement, with formation of fused pyridin-2(1H)-ones derivatives, occurs normally at high
9
o
10
temperatures: 240 °C in diphenyl ether, 180 °C in o-dichlorobenzene ( DCB), 170 °C in p-
1
1
o
12
o
cymene, 180 °C in DCB in the presence of Hg(OAc) as a catalyst, 170 °C in DCB in the presence
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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of I as a catalyst. The mentioned electrophilic cyclization is characteristic of electron-rich azoles
2
(
Scheme 6).9-11, 13 When a substituted phenyl ring is involved in the cyclization, a donor substituent
accelerates the reaction.12a
Scheme 6. [6π]-Electrocyclization Involving the N=C bond of the Isocyanates
O
O
N3
o
Ph O, 240 C
2
NH
X= NMe, O, S
X
X
2
ref. 9
2-54%
O
H
N
X
O
N3
o
o
X
DCB, 180 C
X= NH, O
ref. 10
N
N
Ar
Ar
O
N3
Bu N
3
NH
o
p-cymene, 170 C
O
ref. 11
I2
S
S
o
o
Br
DCB, 170 C
ref. 13
Br
O
N3
NH
Hg(OAc)2
o
o
O
DCB, 180 C
ref. 12a
R
R
O
N3
R
Hg(OAc)2
R
o
o
DCB, 180 C
ref. 12b
NH
R
O
R
We speculated, therefore, that the electron-donating m-MeO group in the 3-aryl substituent of pyrroles
plays a crucial role in facilitating their electrophilic cyclization into compounds 7 and thus the
5
cyclization of intermediate isocycanates 10h and 10i can occur already at 82 °C.
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3
4
5
6
7
8
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
To check this hypothesis a calculation of model isocyanates 10a and 10i and the transition states (TS)
for their 1,6--cyclization were performed at the DFT B3LYP/6-311+G(d,p) level (PCM model for
oDCB) (Scheme 7, for details of the calculations see the Supporting information).
Scheme 7. Relative Gibbs Free Energies of Isocyanates 10a and 10i and the Transition States
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
(
TS) for Their 1,6--Cyclization at the DFT B3LYP/6-311+G(d,p) level a
O
O
R
TSH
R
28.6
TSMeO 25.4
NH
NH
N
C
H N
O
C
O
10a (R =H)
0.0
11a (R =H)
22.9
10i (R =MeO) 0.0
11i (R =MeO) 19.7
prototropic
shift
O
R
O
R
prototropic
shift
NH
N
NH
O
NH
O
H
1
2a (R = H)
-12.4
7a (R =H)
7i (R =MeO) -15.1
-14.9
12i (R = MeO) -12.5
a
o
In kcal/mol, 298 K, PCM model for DCB.
According to the calculations, the barrier for the cyclization of the MeO-substituted compound 10i is
lower by 3.2 kcal/mol than the barrier for the cyclization of the unsubstituted compound 10a. The
value of the energy barrier for the cyclization of 25.4 kcal/mol indicates why the cyclization of
compound 10i can occur already at 82 °C. The value of the energy barrier for the cyclization of the
unsubstituted analog 10a (28.6 kcal/mol) means that this cyclization would occur at higher
o
temperature, but obviously lower than the boiling point of DCB. One more conclusion follows from
the calculation: the pyridone tautomer of product 7 is much more stable than pyridol tautomer 12.
Based on this analysis, it was decided to search for conditions for the high yield transformation of
acyl azides 5 into 5H-pyrrolo[2,3-c]isoquinolin-5-one derivatives 7, which, to the best of our
knowledge, have not yet been synthesized.
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o
It was found that heating a DCB solution of synthesized azides 5 (Table 2) at 150 °C for 0.5 h without
any catalyst is sufficient to obtain 5H-pyrrolo[2,3-c]isoquinolin-5-ones 7 in high yields (Table 4).
Moreover no chromatographic purification is required to isolate these products from their reaction
mixtures.
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
Table 4. Synthesis of 5H-Pyrrolo[2,3-c]isoquinolin-5-one Derivatives 7a-d, f-ka
R
O
O
R
N3
oDCB, 150 °C, 0.5 h
N
N
H
O
N
H
H
O
5
a-d, f-k
7a-d, f-k
O
O
F
O
Cl
O
Br
N
N
H
N
N
H
c 80%
O
N
N
H
O
N
H
O
N
O
H
H
H
H
7
a 82%
7b 74%
7
7d 69%
OMe
O
OMe
O
O
N
N
N
N
O
N
H
O
N
H
O
H
H
H
H
7f 83%
7g 85%
7h 96%
OMe
O
OMe
O
CF3
O
N
N
N
O
N
H
O
N
H
H
N
H
k 91%
O
H
H
7i 95%
7j 84%
7
a
Isolated yields.
Some unstable azidocarbonylpyrroles 5, without prior isolation from the reaction mixtures of
azidocarbonylazirines 3 with diketones 4, were rearranged to 5H-pyrrolo[2,3-c]isoquinolin-5-one
derivatives 7 (Table 5). The structure of compound 7n was confirmed by X-ray analysis (see the
Supporting Information).
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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
Table 5. Synthesis of 5H-Pyrrolo[2,3-c]isoquinolin-5-one Derivatives 7o-qa
O
O
R
o
R
NiCl 6H O
20 mol%
DCB
2
2
O
O
R
o
N
150 C
0.5 h
+
N3
R
MeCN
R
N
H
5n-q
N
N
H
O
1-2 d
R
H
O
N3
O
rt
4c-f
Me
7n-q
3a
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
MeO
O
S
O
O
O
HN
HN
HN
OMe
HN
HN
HN
S
Me
HN
HN
O
O
O
O
7o 30%
7p 56%
7q 52%
7n 41%
a
Isolated yields on two steps.
The cyclizations of isocyanates, derived from azidocarbonylpyrroles 5r and 5s, involving an electron
rich furan and thiophene ring, proceed so easily that it is possible to perform these transformations in
boiling acetonitrile (Scheme 8).
Scheme 8. Synthesis of Compounds 7l, m
X
O
X
Me
NiCl 6H O
10 mol%
2
2
Me
Me
O
O
N
+
N3
MeCN
rt, 1 d
N
O
l,m
N3 Me
4a
H
O
3
5
r,s
MeCN
reflux
X = O, 1 h
X = S, 5 h
O
Me
X
7l (X = O, 90%)
m (X = S, 90%) Me
7
N
N
O
H
H
Moreover, preparation of these new heterocyclic backbones, 5,6-dihydro-4H-furo[2,3-d]pyrrolo[2,3-
b]pyridin-4-one and 5,6-dihydro-4H-pyrrolo[2,3-b]thieno[2,3-d]pyridin-4-one, can be implemented
as one-pot process in up to 90% yield over two steps. Thus, various 1,2,7,8-substituted 3H-
pyrrolo[2,3-c]isoquinolin-5(4H)-ones and their benzo[g] and hetero-analogs can be prepared from the
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appropriate 2-(azidocarbonyl)-2H-azirines 3. However, 2-aryl-2-(azidocarbonyl)-2H-azirines with
ortho-substituted aryl ring cannot be used for the preparation of 9-substituted derivatives, probably
due to steric hindrance, preventing the isocyanate 10e adopting the conformation required for
cyclization. Thus, heating of azidocarbonylpyrrole 5e does not lead to pyrroloisoquinolinone 7e,
although it is obvious that the formation of isocyanate 10e does occur, since the treatment of the
reaction mixture with wet DCM gave urea 8c (Scheme 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
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
Scheme 9. Transformation of Azidocarbonyl Pyrrole 5e
8
Br
7
Ac
9
1
6
Me
5
2
Br
Ac
N
Br
Ac
3
N
O
H
4
H
O
7e
C
N3
oDCB,
N
Me
N
Me
N

150 C,
H
wet
DCM
Br
Br
H
H
O
0.5 h
H
1
0e
5e
N
N
Ac
Ac
NH
O
HN
Me
Me
8c
It is easy to introduce a substituent into the 5 position of the pyrrolo[2,3-c]isoquinoline skeleton via
O-triflation of 3H-pyrrolo[2,3-c]isoquinolin-5(4H)-one 7, followed by various cross-coupling
reactions. The reaction of compound 7a with triflic anhydride in the presence of DBU afforded triflate
1
3 in 86% yield (Scheme 10). The structure of 13 was confirmed by X-ray analysis (see Supporting
Information). The Stille reaction of triflate 13 with 2-(tributylstannyl)pyridine afforded the modified
,2’-bipyridyl ligand 14 in 94% yield. The Sonogashira reaction of 13 with ethynyltrimethylsilane
2
gave 5-ethynyl-substituted 3H-pyrrolo[2,3-c]isoquinoline 15 in 92% yield. The Heck reaction of
triflate 13 with acrylonitrile led to 5-(2-cyanovinyl)-substituted 3H-pyrrolo[2,3-c]isoquinoline 16 in
9
8% yield and its Suzuki reaction with boronic acids afforded 5-aryl-substituted 3H-pyrrolo[2,3-
c]isoquinolines 17a-c in 77-95% yield.
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8
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
Scheme 10. Synthesis of Triflate 13 and Its Cross-Coupling Reactions
O
O
Tf O
2
DBU
DCM, 0 °C
N
N
N
O
N
OTf
O
H
H
H
1
3, 86%
7a
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
O
N
N
N
H
N
H
14, 94% N
1
5, 92%
TMS
TMS
Pd(PPh ) ,
3
4
Pd(PPh ) Cl ,
3 2 2
N
SnBu3
CuI
CuI, Et N
3
O
O
(
HO) B
OMe
2
N
N
Pd(OAc) , PPh , Et N
N
N
OTf
2
3
3
H
H
13
dioxane/water
0 °C
1
7a, 77%
OMe
6
Et N
3
Pd(PPh ) Cl
2
(HO)2B Ar
3
2
DMF, 100 °C
8 h
Pd(PPh3)4
CN
Et N
O
4
3
dioxane/water
4:1, 85 °C
24 h
O
N
N
Ar
H
1
7b, Ar = 4-FC H , 95%
6
4
N
N
CN
H
17c, Ar = thienyl-2, 96%
1
6, 98%
In conclusion: a synthetic method was developed for the high yielding preparation of 2H-azirine-2-
carbonyl azides through reaction of sodium azide with 2H-azirine-2-carbonyl chlorides, generated by
Fe(II)-catalyzed isomerizationof 5-chloroisoxazoles. Attempts to prepare 2-amino-2H-azirines by the
Curtius rearrangement of 2-(azidocarbonyl)-2H-azirines under various conditions were unsuccessful.
However, 2-(azidocarbonyl)-1H-pyrroles, prepared by the Ni(II)-catalyzed reaction of 2-
(azidocarbonyl)-2H-azirines with 1,3-diketones, easily undergo the Curtius rearrangement in boiling
tBuOH to give Boc-protected α-aminopyrroles in high yield and these could be deprotected by TFA.
Short-term heating of 3-aryl-2-(azidocarbonyl)-1H-pyrroles in o-dichlorobenzene at 150 °C leads to
the high yield formation of substituted 3H-pyrrolo[2,3-c]isoquinolin-5(4H)-ones via a [6π]-
electrocyclization of isocyanates, generated by the Curtius rearrangement. The cyclizations of
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activated 3-methoxyphenyl, furyl and thienyl groups occur already at 82 °C. Thus, various 1,2,7,8-
substituted 3H-pyrrolo[2,3-c]isoquinolin-5(4H)-ones and their benzo[g] and hetero analogs can be
prepared from the appropriate 2-(azidocarbonyl)-2H-azirines. The Pd-catalyzed cross-coupling
reaction of 1-acetyl-2-methyl-3H-pyrrolo[2,3-c]isoquinolin-5-yl triflate, easily prepared from the
corresponding pyrroloisoquinolone, lead to variously 5-substituted 3H-pyrrolo[2,3-c]isoquinolines in
excellent yields.
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
EXPERIMENTAL SECTION
General Information and Methods. Melting points were determined on a melting point apparatus.
1
13
19
H (400 MHz), C (100 and 125 MHz) and F (376 and 470 MHz) NMR spectra were recorded on a
NMR spectrometer in CDCl or DMSO-d . Chemical shifts (δ) are reported in parts per million
3
6
1
downfield from tetramethylsilane (TMS δ = 0.00). H NMR spectra were calibrated to the residual
13
1
13
peak of CHCl (7.26 ppm) or DMSO-d (2.50 ppm). For all new compounds, C{ H} and C DEPT-
3
5
1
35 spectra were recorded and calibrated according to the peak of CDCl (77.00 ppm) or DMSO-d
3 6
1
9
(
39.51 ppm). F NMR spectra were calibrated according to a CFCl external standard (δ = 0 ppm).
3
Electrospray ionization (ESI) mass spectra were recorded on a mass spectrometer, HRMS-ESI-QTOF,
electrospray ionization. Single crystal X-ray data were collected by means of diffractometer.
Crystallographic data for the structures 3d, 5d, 7n and 13 (CCDC 1956380, 1956383, 1956381 and
1956382 correspondingly) have been deposited with the Cambridge Crystallographic Data Centre.
Thin-layer chromatography (TLC) was conducted on aluminum sheets with 0.2 mm silica gel with
fluorescent indicator.
1
4
15
3-Aryl/heteryl-5-chloroimidazoles 1a-d, f-h, k, m, 1e were prepared according to the published
16
17
15
6b
procedures. Physical and spectral data of 5-chloroisoxazoles 1a, c, d, f-h, k, 1b, 1e, 1l, m, were
in agreement with previously reported values.
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1
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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
CAUTION: Although azides 3 and 5 were found to be safe in our hands, they are potentially explosive
and should be handled with care.
5
-Chloro-3-(3,4-dimethoxyphenyl)isoxazole (1i). Compound 1i was prepared following the
6a
published procedure from 3-(3,4-dimethoxyphenyl)isoxazol-5(4H)-one (2.5 g, 11.31 mmol), POCl
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
(
17.36 g, 113.12 mmol, 10 equiv) and Et N (913 mg, 9.04 mmol, 0.6 equiv) in 1.84 g (68% yield,
3
after flash chromatography on silica gel using hexanes/EtOAc (5:1 v/v) as eluent) as a beige solid: mp
1
6
8-70 °C (hexane/ EtOAc). H NMR (CDCl , 400 MHz): δ 3.93 s (2H), 3.94 s (3H), 6.44 s (1H), 6.93
3
1
3
1
d (1H, J = 8.3 Hz), 7.24 dd (1H, J = 8.3, 2.0 Hz), 7.36 d (1H, J = 1.9 Hz). C{ H} NMR (CDCl , 100
3
MHz): δ 55.9 (CH ), 56.0 (CH ), 99.4 (CH), 108.9 (CH), 111.1 (CH), 120.0 (CH), 120.8 (C), 149.4
3
3
+
+
(
C), 151.1 (C), 154.8 (C), 163.9 (C). ). HRMS (ESI) m/z: [M + Na] Calcd for C H ClNNaO
11 10 3
2
62.0241; Found 262.0249.
5-Chloro-3-(4-(trifluoromethyl)phenyl)isoxazole (1j). Compound 1j was prepared following
6
a
the published procedure from 3-(4-(trifluoromethyl)phenyl)isoxazol-5(4H)-one (1.84 g, 8.05 mmol),
POCl (12.35 g, 80.52 mmol, 10 equiv) and Et N (488 mg, 4.83 mmol, 0.6 equiv) in 1.72 g (86%
3
3
yield, after flash chromatography on silica gel using hexanes/EtOAc (5:1 v/v) as eluent) as a beige
1
solid: mp 93-95 °C (hexane/ EtOAc). H NMR (CDCl , 400 MHz): δ 6.53 (s, 1H), 7.68-7.79 (m, 2H),
3
1
3
1
7
.85-7.96 (m, 2H). C{ H} NMR (CDCl , 100 MHz): δ 99.8 (CH), 123.9 (q, J = 270.6 Hz, q),
3 C-F
126.2 (q, JC-F = 3.7 Hz, CH), 127.2 (CH), 131.8 (C), 132.6 (q, JC-F = 33.0 Hz, C), 156.0 (C), 163.2
+
+
(
C). HRMS (ESI) m/z: [M + H] Calcd for C H ClF NO 248.0085; Found 248.0085.
10 6 3
General Procedure A for the Preparation of 2H-Azirine-2-carbonyl azides (3a-m).
Anhydrous iron(II) chloride (1.40 mmol, 20 mol%) was added to a solution of 5-chloroisoxazole 1
(7.00 mmol, 1 equiv) in dry acetonitrile (50 mL) under argon atmosphere and the reaction mixture
was stirred for around 2 h (TLC control). After the reaction was completed, the solvent was
evaporated, the residue was diluted with dry diethyl ether (50 mL) and the precipitated iron chloride
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was filtered off through Celite. The ether was also evaporated, anhydrous acetone (40 mL) was added
and the resulting solution was cooled to 0 °C in an ice bath. Sodium azide (0.011 mol, 1.6 equiv) was
added and the reaction mixture was stirred for additional 20 minutes at 0 °C and then for 1 h at rt.
After the reaction was completed, the solvent was evaporated and the residue was partitioned between
water and dichloromethane, water layer was extracted three times with dichloromethane, the
combined organic phases were washed with water, dried over Na SO , filtered, concentrated in vacuo
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
2
4
and the residue was purified by column chromatography on silica gel (hexanes or petroleum
ether/ethyl acetate, 3:1 v/v).
3
-Phenyl-2H-azirine-2-carbonyl azide (3a). Compound 3a was prepared following general
procedure A from 5-chloro-3-phenylisoxazole 1a (1.26 g, 7.00 mmol), FeCl (178 mg, 1.40 mmol)
2
and NaN (729 mg, 0.011 mol) in 1.19 g (91% yield, after flash chromatography on silica gel using
3
1
hexanes/EtOAc (3:1 v/v) as eluent) as a beige solid: mp 56-58 °C (hexanes/EtOAc). H NMR (CDCl ,
3
1
3
1
400 MHz): δ 2.87 (s, 1H), 7.57-7.63 (m, 2H), 7.65-7.71 (m, 1H), 7.86-7.92 (m, 2H). C{ H} NMR
(CDCl , 100 MHz): δ 32.1 (CH), 121.7 (С), 129.6 (CH), 130.7 (CH), 134.4 (CH), 158.1 (С), 178.7
3
+
+
(
С). HRMS (ESI) m/z: [M + Na] Calcd for C H N NaO 209.0434; Found 209.0435.
9
6
4
3
-(4-Fluorophenyl)-2H-azirine-2-carbonyl azide (3b). Compound 3b was prepared
following general procedure A from 5-chloro-3-(4-fluorophenyl)isoxazole 1b (850 mg, 4.33 mmol),
FeCl (110 mg, 0.87 mmol) and NaN (448 mg, 6.89 mmol) in 810 mg (92% yield, after flash
2
3
chromatography on silica gel using hexanes/EtOAc (3:1 v/v) as eluent) as a beige solid: mp 59-60 ºС
1
(
hexanes/EtOAc). H NMR (CDCl , 400 MHz): δ 2.87 (s, 1H), 7.25-7.34 (m, 2H), 7.86-7.98 (m, 2H).
3
1
9
1
13
1
F{ H} NMR (CDCl , 376 MHz): δ -101.54. C{ H} NMR (CDCl , 100 MHz): δ 32.2 (CH), 117.3
3
3
d (CH, JC-F = 22.9 Hz), 118.2 d (C, JC-F = 3.5 Hz), 133.3 d (CH, JC-F = 9.7 Hz), 157.1 (С), 166.4 d (С,
+
+
JC-F = 258.1 Hz), 178.5 (С). HRMS (ESI) m/z: [M + Na] Calcd for C H FN NaO 227.0340; Found
9
5
4
2
27.0345.
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
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5
5
5
5
5
5
5
5
5
5
6
3
-(4-Chlorophenyl)-2H-azirine-2-carbonyl azide (3c). Compound 3c was prepared
following general procedure A from 5-chloro-3-(4-chlorophenyl)isoxazole 1c (642 mg, 3.00 mmol),
FeCl (76 mg, 0.60 mmol) and NaN (312 mg, 4.80 mmol) in 602 mg (91% yield, after flash
2
3
chromatography on silica gel using hexanes/EtOAc (3:1 v/v) as eluent) as beige solid: mp 96-98 ºС
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
(hexanes/EtOAc). H NMR (CDCl , 400 MHz): δ 2.87 (s, 1H), 7.55-7.63 (m, 2H), 7.80-7.88 (m, 2H).
3
1
3
1
C{ H} NMR (CDCl , 100 MHz): δ 32.2 (CH), 120.3 (C), 130.1 (CH), 131.9 (CH), 141.1 (C), 157.5
3
+
+
(С), 178.4 (С). HRMS (ESI) m/z: [M + Na] Calcd for C H ClN NaO 243.0044; Found 243.0036.
9 5 4
3
-(4-Bromophenyl)-2H-azirine-2-carbonyl azide (3d). Compound 3d was prepared
following general procedure A from 3-(4-bromophenyl)-5-chloroisoxazole 1d (864 mg, 3.34 mmol),
FeCl (85 mg, 0.67 mmol) and NaN (262 mg, 4.02 mmol) in 650 mg (73% yield, after flash
2
3
chromatography on silica gel using hexanes/EtOAc (3:1 v/v) as eluent and recrystallization from
1
benzene) as a beige solid: mp 110-112 ºС (benzene). H NMR (CDCl , 400 MHz): δ 2.88 (s, 1H),
3
1
3
1
7
.72-7.79 (m, 4H). C{ H} NMR (CDCl , 100 MHz): δ 32.2 (CH), 120.7 (C), 129.7 (C), 131.9 (CH),
3
+
79
+
1
33.1 (CH), 157.7 (C), 178.4 (C). HRMS (ESI) m/z: [M + Na] Calcd for C H BrN NaO 286.9539;
9 5 4
Found 286.9548.
3
-(2-Bromophenyl)-2H-azirine-2-carbonyl azide (3e). Compound 3e was prepared following
general procedure A from 3-(2-bromophenyl)-5-chloroisoxazole 1e (1.02 g, 3.94 mmol), FeCl (100
2
mg, 0.79 mmol) and NaN (409 mg, 6.30 mmol) in 977 mg (94% yield, after flash chromatography
3
on silica gel using hexanes/EtOAc (3:1 v/v) as eluent) as a beige solid: mp 68-70 ºС (hexanes/EtOAc).
1
H NMR (CDCl , 400 MHz): δ 2.94 (s, 1H), 7.47-7.58 (m, 2H), 7.74-7.81 (m, 1H), 7.83-7.92 (m, 1H).
3
13
1
C{ H} NMR (CDCl , 100 MHz): δ 33.4 (CH), 122.4 (C), 126.0 (C), 128.2 (CH), 133.6 (CH), 134.4
3
+
79
+
(CH), 135.2 (CH), 158.6 (C), 178.4 (C). HRMS (ESI) m/z: [M + Na] Calcd for C H BrN NaO
9 5 4
2
86.9539; Found 286.9533.
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-(p-Tolyl)-2H-azirine-2-carbonyl azide (3f). Compound 3f was prepared following general
procedure A from 5-chloro-3-(p-tolyl)isoxazole 1f (830 mg, 4.29 mmol), FeCl (109 mg, 0.86 mmol)
2
and NaN (446 mg, 6.87 mmol) in 781 mg (91% yield, after flash chromatography on silica gel using
3
1
hexanes/EtOAc (3:1 v/v) as eluent) as a beige solid: mp 86-87 ºС (hexanes/EtOAc). H NMR (CDCl ,
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
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
3
1
4
00 MHz): δ 2.48 (s, 3H), 2.83 (s, 1H), 7.34-7.44 (m, 2H), 7.74-7.80 (m, 2H). C{ H} NMR (CDCl ,
3
100 MHz): δ 22.1 (CH ), 32.0 (CH), 118.9 (C), 130.4 (CH), 130.8 (CH), 145.7 (С), 157.6 (С), 178.9
3
+
+
(С). HRMS (ESI) m/z: [M + Na] Calcd for C H N NaO 223.0590; Found 223.0591.
10 8 4
3
-(4-Methoxyphenyl)-2H-azirine-2-carbonyl azide (3g). Compound 3g was prepared
following general procedure A from 5-chloro-3-(4-methoxyphenyl)isoxazole 1g (841 mg, 4.02
mmol), FeCl (102 mg, 0.80 mmol) and NaN (418 mg, 6.42 mmol) in 768 mg (89% yield, after flash
2
3
chromatography on silica gel using hexanes/EtOAc (3:1 v/v) as eluent) as a colorless solid: mp 106-
1
1
2
07 ºС (hexanes/EtOAc). H NMR (CDCl , 400 MHz): δ 2.81 (s, 1H), 3.91 (s, 3H), 7.05-7.12 (m,
3
1
3
1
H), 7.79-7.86 (m, 2H). C{ H} NMR (CDCl , 100 MHz): δ 32.0 (CH), 55.8 (CH ), 113.9 (C), 115.2
3
3
+
(CH), 132.9 (CH), 156.6 (С), 164.5 (С), 179.1 (С). HRMS (ESI) m/z: [M + Na] Calcd for
+
C H N NaO 239.0539; Found 239.0532.
1
0
8
4
2
3
-(3,4-Dimethoxyphenyl)-2H-azirine-2-carbonyl azide (3i). Compound 3i was prepared
following general procedure A from 5-chloro-3-(3,4-dimethoxyphenyl)isoxazole 1i (1.745 g, 7.29
mmol), FeCl (185 mg, 1.46 mmol) and NaN (758 mg, 11.66 mmol) in 1.68 g (94% yield, after flash
2
3
chromatography on silica gel using hexanes/EtOAc (3:1 v/v) as eluent) as a colorless solid: mp 84-86
1
ºС (hexanes/EtOAc). H NMR (CDCl , 400 MHz): δ 2.84 (s, 1H), 3.97 (s, 3H), 3.98 (s, 3H), 7.03 (d,
3
13
1
J = 8.2 Hz, 1H), 7.40 (d, J = 1.9 Hz, 1H), 7.43 (dd, J = 8.2, 1.9 Hz, 1H). C{ H} NMR (CDCl , 100
3
MHz): δ 32.3 (CH), 56.3 (CH ), 56.4 (CH ), 111.3 (CH), 111.8 (CH), 114.0 (C), 125.9 (CH), 150.0
3
3
+
107
+
(C), 154.3 (C), 157.0 (C), 179.0 (C). HRMS (ESI) m/z: [M + Ag] Calcd for C H
AgN O
4 3
11 10
3
52.9798; Found 352.9798.
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6
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-(Naphthalen-2-yl)-2H-azirine-2-carbonyl azide (3k). Compound 3k was prepared
following general procedure A from 5-chloro-3-(naphthalen-2-yl)isoxazole 1k (300 mg, 1.31 mmol),
FeCl (33 mg, 0.26 mmol) and NaN (136 mg, 2.09 mmol) in 238 mg (77% yield, after flash
2
3
chromatography on silica gel using hexanes/EtOAc (3:1 v/v) as eluent) as a beige solid: mp 97-99 ºС
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
(hexanes/EtOAc). H NMR (CDCl , 400 MHz): δ 2.96 (s, 1H), 7.57-7.74 (m, 2H), 7.90-8.10 (m, 4H),
3
1
3
1
8.32 (s, 1H). C{ H} NMR (CDCl , 100 MHz): δ 32.4 (CH), 119.0 (C), 124.9 (CH), 127.7 (CH),
3
1
28.3 (CH), 129.4 (CH), 129.5 (CH), 129.8 (CH), 132.8 (C), 133.4 (CH), 136.1 (C), 158.2 (C), 178.8
+
+
(C). HRMS (ESI) m/z: [M + Na] Calcd for C H N NaO 259.0590; Found 259.0588.
13 8 4
3-(Furan-2-yl)-2H-azirine-2-carbonyl azide (3l). Compound 3l was prepared following
general procedure A from 5-chloro-3-(furan-2-yl)isoxazole 1l (267 mg, 1.58 mmol), FeCl (40 mg,
2
0
.32 mmol) and NaN (164 mg, 2.52 mmol) in 194 mg (70% yield, after flash chromatography on
3
1
silica gel using hexanes/EtOAc (3:1 v/v) as eluent) as a beige solid: mp 87-89 ºС (hexane/EtOAc). H
NMR (CDCl , 400 MHz): δ 2.86 (s, 3H), 6.71 (dd, J = 3.6, 1.8 Hz, 1H), 7.30 (dd, J = 3.6, 0.5 Hz, 1H),
3
1
3
1
7
.86 (dd, J = 1.8, 0.5 Hz, 1H). C{ H} NMR (CDCl , 100 MHz): δ 31.7 (CH), 113.3 (CH), 122.5
3
+
(CH), 138.8 (C), 147.9 (C), 149.8 (CH), 178.1 (C). HRMS (ESI) m/z: [M + Na] Calcd for
+
C H N NaO 199.0226; Found 199.0222.
7
4
4
2
3
-(Thiophen-2-yl)-2H-azirine-2-carbonyl azide (3m). Compound 3m (855 mg, 94%) was
prepared following general procedure A from 5-chloro-3-(thiophen-2-yl)isoxazole 1m (884 mg, 4.76
mmol), FeCl (121 mg, 0.95 mmol) and NaN (495 mg, 7.62 mmol) in 855 mg (94% yield, after flash
2
3
chromatography on silica gel using hexanes/EtOAc (3:1 v/v) as eluent) as a brown solid: mp 47-49
1
ºС (hexanes/EtOAc). H NMR (CDCl , 400 MHz): δ 2.89 (s, 1H), 7.30 (dd, J = 5.0, 3.8 Hz, 1H), 7.73
3
1
3
1
(dd, J = 3.8, 1.1 Hz, 1H), 7.92 (dd, J = 5.0, 1.1 Hz, 1H). C{ H} NMR (CDCl , 100 MHz): δ 32.8
3
(CH), 123.9 (C), 128.8 (CH), 136.1 (CH), 136.3 (CH), 151.3 (С), 178.3 (С). HRMS (ESI) m/z: [M +
+
+
Na] Calcd for C H N NaOS 214.9998; Found 214.9990.
7
4
4
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General Procedure B for the Preparation of 1H-Pyrrole-2-carbonyl azides (5a-k).
1
,3-Diketone 4 (1.60 mmol, 1.05 equiv) and NiCl ∙6H O (0.15 mmol, 10 mol%) were added to a
2 2
solution of azirine 3 (1.52 mmol, 1 equiv) in acetonitrile (5 mL) and the resulting mixture was stirred
at rt to the completion of the reaction (monitored by TLC, 1-2 d). After the reaction was over, the
product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 3:1 v/v).
Poorly soluble compounds such as 5d and 5g could be purified by filtration from the reaction mixture
and washing with acetonitrile and water.
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
4
-Acetyl-5-methyl-3-phenyl-1H-pyrrole-2-carbonyl azide (5a). Compound 5a was prepared
following general procedure B from 3-phenyl-2H-azirine-2-carbonyl azide 3a (283 mg, 1.52 mmol),
acetylacetone 4a (160 mg, 1.60 mmol) and NiCl ∙6H O (36 mg, 0.15 mmol) in 375 mg (92% yield,
2
2
after flash chromatography on silica gel using petroleum ether/EtOAc (3:1 v/v) as eluent) as a
1
colorless solid: mp 116-117 ºС (petroleum ether/EtOAc). H NMR (CDCl , 400 MHz): δ 1.78 (s, 3H),
3
1
3
1
2
.59 (s, 3H), 7.27-7.33 (m, 2H), 7.38-7.46 (m, 3H), 9.39 (s, 1H). C{ H} NMR (CDCl , 100 MHz):
3
δ 14.7 (CH ), 30.8 (CH ), 119.3 (C), 124.8 (C), 128.2 (CH), 128.2 (CH), 130.1 (CH), 134.5 (C), 134.7
3
3
-
-
(C), 141.0 (C), 164.9 (C), 196.6 (C). HRMS (ESI) m/z: [M - H] Calcd for C H N O 267.0887;
1
4
11
4
2
Found 267.0874.
4
-Acetyl-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carbonyl azide (5b). Compound 5b
was prepared following general procedure B from 3-(4-fluorophenyl)-2H-azirine-2-carbonyl azide 3b
400 mg, 1.96 mmol), acetylacetone 4a (206 mg, 2.06 mmol) and NiCl ∙6H O (47 mg, 0.20 mmol) in
(
2
2
495 mg (88% yield, after flash chromatography on silica gel using petroleum ether/EtOAc (3:1 v/v)
1
as eluent) as a colorless solid: mp 118-119 ºС (petroleum ether/EtOAc). H NMR (CDCl , 400 MHz):
3
1
9
1
δ 1.81 (s, 3H), 2.59 (s, 3H), 7.06-7.18 (m, 2H), 7.22-7.32 (m, 2H), 9.69 (s, 1H). F{ H} NMR (CDCl ,
3
1
3
1
3
2
76 MHz): δ -113.62. C{ H} NMR (CDCl , 100 MHz): δ 14.7 (CH ), 30.9 (CH ), 115.3 (d, J
=
3
3
3
C-F
1.6 Hz, CH), 119.5 (С), 124.8 (С), 130.4 (d, JC-F = 3.8 Hz, C), 131.8 (d, JC-F = 7.9 Hz, CH), 133.5
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
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5
5
5
5
5
5
5
6
-
(С), 141.2 (С), 162.8 (d, JC-F = 247.8 Hz, C), 164.9 (C), 196.2 (С). HRMS (ESI) m/z: [M - H] Calcd
-
for C H FN O 285.0793; Found 285.0793.
1
4
10
4
2
4
-Acetyl-3-(4-chlorophenyl)-5-methyl-1H-pyrrole-2-carbonyl azide (5c). Compound 5c
was prepared following general procedure B from 3-(4-chlorophenyl)-2H-azirine-2-carbonyl azide 3c
250 mg, 1.13 mmol), acetylacetone 4a (119 mg, 1.19 mmol) and NiCl ∙6H O (27 mg, 0.11 mmol) in
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
2
303 mg (91% yield, after flash chromatography on silica gel using petroleum ether/EtOAc (3:1 v/v)
1
as eluent) as a colorless solid: mp 124-125 ºС (petroleum ether/EtOAc). H NMR (CDCl , 400 MHz):
3
1
3
1
δ 1.82 (s, 3H), 2.58 (s, 3H), 7.20-7.27 (m, 2H), 7.36-7.46 (m, 2H), 9.37 (s, 1H). C{ H} NMR (CDCl ,
3
100 MHz): δ 14.7 (CH ), 31.0 (CH ), 119.4 (C), 124.7 (C), 128.5 (CH), 131.5 (CH), 133.0 (C), 133.2
3
3
+
(
C), 134.4 (C), 141.1 (C), 164.8 (C), 196.1 (C). HRMS (ESI) m/z: [M + Na] Calcd for
+
C H ClN NaO 325.0463; Found 325.0455.
1
4
11
4
2
4-Acetyl-3-(4-bromophenyl)-5-methyl-1H-pyrrole-2-carbonyl azide (5d). Compound 5d
was prepared following general procedure B from 3-(4-bromophenyl)-2H-azirine-2-carbonyl azide
3
d (165 mg, 0.62 mmol), acetylacetone 4a (66 mg, 0.66 mmol) and NiCl ∙6H O (15 mg, 0.06 mmol)
2 2
1
in 158 mg (73% yield) as a colorless solid: mp 129-130 ºС (MeCN). H NMR (CDCl , 400 MHz): δ
3
13
1
1
1
.82 (s, 3H), 2.58 (s, 3H), 7.10-7.23 (m, 2H), 7.47-7.65 (m, 2H), 9.35 (s, 1H). C{ H} NMR (CDCl ,
3
00 MHz): δ 14.7 (CH ), 31.0 (CH ), 119.3 (C), 122.6 (C), 124.7 (C), 131.4 (CH), 131.8 (CH), 133.1
3
3
-
79
-
(C), 133.5 (C), 141.0 (C), 164.7 (C), 196.1 (C). HRMS (ESI) m/z: [M - H] Calcd for C H BrN O
2
1
4
10
4
3
44.9993; Found 344.9994.
4
-Acetyl-3-(2-bromophenyl)-5-methyl-1H-pyrrole-2-carbonyl azide (5e). Compound 5e
was prepared following general procedure B from 3-(2-bromophenyl)-2H-azirine-2-carbonyl azide 3e
(
300 mg, 1.13 mmol), acetylacetone 4a (119 мг, 1.19 mmol) and NiCl ∙6H O (27 mg, 0.11 mmol) in
2 2
3
41 mg (87% yield, after flash chromatography on silica gel using petroleum ether/EtOAc (3:1 v/v)
1
as eluent) as a colorless solid: mp 118-119 ºС (petroleum ether/EtOAc). H NMR (CDCl , 400 MHz):
3
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δ 1.82 (s, 3H), 2.63 (s, 3H), 7.23-7.33 (m, 2H), 7.34-7.43 (m, 1H), 7.64-7.72 (m, 1H), 9.51 (s, 1H).
13
1
C{ H} NMR (CDCl , 100 MHz): δ 15.0 (CH ), 30.1 (CH ), 119.4 (C), 123.8 (C), 124.7 (C), 127.3
3
3
3
(CH), 129.9 (CH), 131.6 (CH), 132.7 (CH), 132.9 (C), 136.1 (C), 141.6 (C), 164.7 (C), 195.6 (C).
+
79
+
HRMS (ESI) m/z: [M + Na] Calcd for C H BrN NaO 368.9958; Found 368.9950.
1
4
11
4
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
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4
-Acetyl-5-methyl-3-(p-tolyl)-1H-pyrrole-2-carbonyl azide (5f). Compound 5f was
prepared following general procedure B from 3-(p-tolyl)-2H-azirine-2-carbonyl azide 3f (150 mg,
.75 mmol), acetylacetone 4a (79 mg, 0.79 mmol) and NiCl ∙6H O (18 mg, 0.08 mmol) in 193 mg
0
2
2
(91% yield, after flash chromatography on silica gel using petroleum ether/EtOAc (3:1 v/v) as eluent)
1
as a colorless solid: mp 119-120 ºС (petroleum ether/EtOAc). H NMR (CDCl , 400 MHz): δ 1.80 (s,
3
13
1
3
H), 2.42 (s, 3H), 2.58 (s, 3H), 7.09-7.19 (m, 2H), 7.20-7.32 (m, 2H), 9.39 (s, 1H). C{ H} NMR
(
(
CDCl , 100 MHz): δ 14.7 (CH ), 21.5 (CH ), 30.8 (CH ), 119.3 (C), 124.9 (C), 128.9 (CH), 130.0
3
3
3
3
CH), 131.3 (C), 134.9 (C), 138.0 (C), 141.0 (C), 164.9 (C), 196.8 (C). HRMS (ESI) m/z: [M + H]-
Calcd for C H N O + 283.1190; Found 283.1201.
1
5
15
4
2
4
-Acetyl-3-(4-methoxyphenyl)-5-methyl-1H-pyrrole-2-carbonyl azide (5g). Compound
5g was prepared following general procedure B from 3-(4-methoxyphenyl)-2H-azirine-2-carbonyl
azide 3g (150 mg, 0.69 mmol), acetylacetone 4a (73 mg, 0.73 mmol) and NiCl ∙6H O (16 mg, 0.07
2
2
1
mmol) in 152 mg (74% yield) as a colorless solid: mp 100-101 ºС (MeCN). H NMR (CDCl , 400
3
MHz): δ 1.81 (s, 3H), 2.57 (s, 3H), 3.87 (s, 3H), 6.92-7.00 (m, 2H), 7.17-7.24 (m, 2H), 9.37 (s, 1H).
13
1
C{ H} NMR (CDCl , 100 MHz): δ 14.7 (CH ), 30.8 (CH ), 55.4 (CH ), 113.7 (CH), 119.3 (C),
3
3
3
3
1
24.9 (C), 126.4 (C), 131.3 (CH), 134.6 (C), 140.9 (C), 159.6 (C), 164.8 (C), 196.8 (C). HRMS (ESI)
+
+
m/z: [M + Na] Calcd for C H N NaO 321.0958; Found 321.0959.
15 14
4
3
4
-Acetyl-3-(3-methoxyphenyl)-5-methyl-1H-pyrrole-2-carbonyl azide (5h). Compound
5
h was prepared following general procedure B from crude 3-(3-methoxyphenyl)-2H-azirine-2-
carbonyl azide 3h (which in its turn was prepared following general procedure A from 350 mg (1.67
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mmol) of 5-chloro-3-(3-methoxyphenyl)isoxazole 1h, 42 mg (0.33 mmol), FeCl and 174 mg (2.67
2
mmol) NaN ), acetylacetone 4a (129 мг, 1.29 mmol) and NiCl ∙6H O (29 mg, 0.12 mmol) in 264 mg
3
2
2
(53% yield for two steps, after flash chromatography on silica gel using petroleum ether/EtOAc (3:1
1
v/v) as eluent) as a colorless solid: mp 118-120 ºС (petroleum ether/EtOAc). H NMR (CDCl , 400
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
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2
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MHz): δ 1.83 (s, 3H), 2.58 (s, 3H), 3.83 (s, 3H), 6.80-6.85 (m, 1H), 6.86-6.91 (m, 1H), 6.92-6.98 (m,
1
3
1
1
H), 7.33 (t, J = 8.0 Hz, 1H), 9.36 (s, 1H). C{ H} NMR (CDCl , 100 MHz): δ 14.7 (CH ), 30.6
3 3
(CH ), 55.4 (CH ), 113.6 (CH), 116.0 (CH), 119.2 (C), 122.7 (CH), 124.7 (C), 129.2 (CH), 134.4 (C),
3
3
+
1
35.8 (C), 141.1 (C), 159.4 (C), 165.0 (C), 196.6 (C). HRMS (ESI) m/z: [M + Na] Calcd for
+
C H N NaO 321.0958; Found 321.0946.
1
5
14
4
3
4-Acetyl-3-(3,4-dimethoxyphenyl)-5-methyl-1H-pyrrole-2-carbonyl
azide
(5i).
Compound 5i was prepared following general procedure B from 3-(3,4-dimethoxyphenyl)-2H-
azirine-2-carbonyl azide 3i (281 mg, 1.14 mmol), acetylacetone 4a (120 mg, 1.20 mmol) and
NiCl ∙6H O(27 mg, 0.11 mmol) in 336 mg (90% yield, after flash chromatography on silica gel using
2
2
petroleum ether/EtOAc (3:1 v/v) as eluent) as a colorless solid: mp 129-131 ºС (petroleum
1
ether/EtOAc). H NMR (CDCl , 400 MHz): δ 1.84 (s, 3H), 2.57 (s, 3H), 3.88 (s, 3H), 3.94 (s, 3H),
3
1
3
1
6.80 (d, J = 1.8 Hz, 1H), 6.85 (dd, J = 8.2, 1.8 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 9.29 (s, 1H). C{ H}
NMR (CDCl , 100 MHz): δ 14.6 (CH ), 30.6 (CH ), 55.9 (CH ), 56.1 (CH ), 110.9 (CH), 113.5 (CH),
3
3
3
3
3
1
19.3 (C), 122.7 (CH), 124.9 (C), 126.6 (C), 134.5 (C), 140.8 (C), 148.7 (C), 149.1 (C), 164.8 (C),
+
+
196.8 (C). HRMS (ESI) m/z: [M + Na] Calcd for C H N NaO + 351.1064; Found 351.1064.
1
6
16
4
4
4
-Acetyl-5-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2-carbonyl azide (5j).
Compound 5j was prepared following general procedure B from crude 3-(4-(trifluoromethyl)phenyl)-
2
4
H-azirine-2-carbonyl azide 3j (which in its turn was prepared following general procedure A from
33 mg (1.75 mmol) of 5-chloro-3-(4-(trifluoromethyl)phenyl)isoxazole 1j, 44 mg (0.35 mmol) FeCl2
and 182 mg (2.80 mmol) NaN ), acetylacetone 4a (55 мг, 0.55 mmol) and NiCl ∙6H O (12 mg, 0.05
3
2
2
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mmol) in 110 mg (19% yield for two steps, after flash chromatography on silica gel using petroleum
1
ether/EtOAc (3:1 v/v) as eluent) as a colorless solid: mp 129-131 ºС (petroleum ether/EtOAc). H
NMR (CDCl , 400 MHz): δ 1.79 (s, 3H), 2.60 (s, 3H), 7.35-7.52 (m, 2H), 7.65-7.77 (m, 2H), 9.42 (s,
3
1
9
1
13
1
1H). F{ H} NMR (DMSO-d , 376 MHz): δ -60.85. C{ H} NMR (DMSO-d , 100 MHz): δ 13.8
6
6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
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2
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3
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3
3
3
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3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
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0
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(
CH ), 30.5 (CH ), 118.7 (C), 123.7 (C), 124.3 (q, J = 270.3 Hz, C), 124.4 (q, JC-F = 3.7 Hz, CH),
3 3 C-F
1
27.9 (q, JC-F = 31.5 Hz, C), 130.9 (CH), 132.2 (C), 139.3 (C), 140.9 (C), 163.1 (C), 194.1 (C). HRMS
-
-
(ESI) m/z: [M - H] Calcd for C H F N O 335.0761; Found 335.0763.
1
5
10
3
4
2
4
-Acetyl-5-methyl-3-(naphthalen-2-yl)-1H-pyrrole-2-carbonyl azide (5k). Compound 5k
was prepared following general procedure B from 3-(naphthalen-2-yl)-2H-azirine-2-carbonyl azide
k (177 mg, 0.75 mmol), acetylacetone 4a (79 mg, 0.79 mmol) and NiCl ∙6H O (18 mg, 0.08 mmol)
3
2
2
in 202 mg (85% yield, after flash chromatography on silica gel using petroleum ether/EtOAc (3:1 v/v)
1
as eluent) as a colorless solid: mp 134-135 ºС (petroleum ether/EtOAc). H NMR (CDCl , 400 MHz):
3
δ 2.14 (s, 3H), 3.00 (s, 3H), 7.77-7.84 (m, 1H), 7.88-7.95 (m, 2H), 8.12-8.18 (m, 1H), 8.20-8.26 (m,
13
1
1
1
H), 8.27-8.33 (m, 2H), 10.35 (s, 1H). C{ H} NMR (CDCl , 100 MHz): δ 14.7 (CH ), 30.9 (CH ),
3 3 3
19.5 (C), 125.0 (C), 126.6 (CH), 126.6 (CH), 127.7 (CH), 128.0 (CH), 128.1 (CH), 128.2 (CH),
129.2 (CH), 132.0 (C), 133.0 (C), 133.1 (C), 134.5 (C), 141.1 (C), 165.0 (C), 196.6 (C). HRMS (ESI)
+
+
m/z: [M + Na] Calcd for C H N NaO 341.1009; Found 341.1010.
1
8
14
4
2
4
-Benzoyl-5-methyl-3-phenyl-1H-pyrrole-2-carbonyl azide (5l). Reaction of 3-phenyl-2H-
azirine-2-carbonyl azide 3a (150 mg, 0.81 mmol), 1-phenylbutane-1,3-dione 4b (137 mg, 0.85 mmol)
and NiCl ∙6H O(19 mg, 0.08 mmol), performed following general procedure B, gave a ca. 1:1 mixture
2
2
(1
H NMR) of regioisomers 5l and 5m 245 mg (ca. 92% yield). 2-(Azidocarbonyl)pyrrole 5l was
isolated in pure form by chromatography on silica gel (eluent a mixture of benzene/DCM, 5:4 v/v) in
1
10 mg (41% yield), in contrast to isomer 5m, which turned out to be unstable. Compound 5l, colorless
1
solid: mp 106-107 ºС (benzene/DCM). H NMR (CDCl , 400 MHz): δ 1.88 s (3H), 7.35-7.40 m (2H),
3
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7.40-7.50 m (6H), 7.52-7.60 m (2H), 9.44 s (1H). C{ H} NMR (CDCl , 100 MHz): δ 31.4 (CH ),
3
3
1
1
20.6 (C), 126.0 (C), 128.1 (CH), 128.3 (CH), 128.9 (CH), 128.9 (CH), 129.7 (CH), 130.3 (CH),
+
30.7 (C), 133.5 (C), 134.1 (C), 139.3 (C), 164.7 (C), 197.2 (C). HRMS (ESI) m/z: [M + Na] Calcd
+
for C H N NaO 353.1009; Found 353.0997.
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9
14
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General Procedure C for the Preparation of Carbamates (6a-i, n). A solution of azide
5 (0.93 mmol) in anhyd t-BuOH (10 mL) was refluxed for 1 h (monitored by TLC) using oil bath.
After the reaction was complete, the solvent was evaporated and the residue was purified by flash
column chromatography on silica gel (eluent a mixture of petroleum ether/EtOAc, 3:1 v/v).
tert-Butyl (4-acetyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)carbamate (6a). Compound 6a
was prepared following general procedure C from 4-acetyl-5-methyl-3-phenyl-1H-pyrrole-2-carbonyl
azide 5a (250 mg, 0.93 mmol) in 283 mg (97% yield, after flash chromatography on silica gel using
petroleum ether/EtOAc (3:1 v/v) as eluent) as a colorless solid: mp 177-178 ºС (petroleum
1
ether/EtOAc). H NMR (DMSO-d , 400 MHz): δ 1.38 (s, 9H), 1.84 (s, 3H), 2.36 (s, 3H), 7.14-7.28
6
1
3
1
(
m, 3H), 7.29-7.39 (m, 2H), 8.36 (s, 1H), 11.39 (s, 1H). C{ H} NMR (DMSO-d , 100 MHz): δ 13.5
6
(CH ), 28.0 (CH ), 30.3 (CH ), 78.6 (C), 118.9 (C), 119.5 (C), 121.3 (C), 126.2 (CH), 127.7 (CH),
3
3
3
+
1
29.9 (CH), 131.0 (C), 135.4 (C), 155.2 (C), 194.3 (C). HRMS (ESI) m/z: [M + H] Calcd for
+
C H N O 315.1703; Found 315.1716.
1
8
23
2
3
tert-Butyl (4-acetyl-3-(4-fluorophenyl)-5-methyl-1H-pyrrol-2-yl)carbamate (6b).
Compound 6b was prepared following general procedure C from 4-acetyl-3-(4-fluorophenyl)-5-
methyl-1H-pyrrole-2-carbonyl azide 5b (323 mg, 1.20 mmol) in 400 mg (100% yield, after flash
chromatography on silica gel using petroleum ether/EtOAc (3:1 v/v) as eluent) as a colorless solid:
1
mp 174-176 ºС (petroleum ether/EtOAc). H NMR (DMSO-d , 400 MHz): δ 1.37 (s, 9H), 1.88 (s,
6
1
3
1
3
H), 2.36 (s, 3H), 7.02-7.20 (m, 2H), 7.21-7.35 (m, 2H), 8.39 (s, 1H), 11.41 (s, 1H). C{ H} NMR
(
DMSO-d , 100 MHz): δ 13.6 (CH ), 28.0 (CH ), 30.4 (CH ), 78.7 (C), 114.4 (d, J = 21.0 Hz, CH),
6
3
3
3
C-F
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117.8 (C), 119.4 (С), 121.6 (C), 131.2 (C), 131.6 (C), 131.7 (d, JC-F = 7.9 Hz, CH), 155.2 (C), 161.0
+
+
(
d, JC-F = 242.6 Hz, C), 194.0 (C). HRMS (ESI) m/z: [M + H] Calcd for C H FN O 333.1609;
18 22 2 3
Found 333.1617.
tert-Butyl (4-acetyl-3-(4-chlorophenyl)-5-methyl-1H-pyrrol-2-yl)carbamate (6c).
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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3
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3
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3
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4
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4
4
4
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5
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5
5
5
5
5
5
5
6
0
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2
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0
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Compound 6c was prepared following general procedure C from 4-acetyl-3-(4-chlorophenyl)-5-
methyl-1H-pyrrole-2-carbonyl azide 5c (300 mg, 0.99 mmol) in 344 mg (100% yield, after flash
chromatography on silica gel using petroleum ether/EtOAc (3:1 v/v) as eluent) as a colorless solid:
1
mp 191-193 ºС (petroleum ether/EtOAc). H NMR (DMSO-d , 400 MHz): δ 1.38 (s, 9H), 1.92 (s,
6
1
3
1
3H), 2.37 (s, 3H), 7.19-7.26 (m, 2H), 7.34-7.43 (m, 2H), 8.43 (s, 1H), 11.44 (s, 1H). C{ H} NMR
(
(
[
DMSO-d , 100 MHz): δ 13.6 (CH ), 28.0 (CH ), 30.4 (CH ), 78.8 (C), 117.5 (C), 119.3 (C), 121.7
6 3 3 3
C), 127.6 (CH), 130.8 (C), 131.3 (C), 131.6 (CH), 134.3 (C), 155.1 (C), 193.9 (C). HRMS (ESI) m/z:
+
+
M + Na] Calcd for C H ClN O Na 371.1133; Found 371.1148.
18 21
2
3
tert-Butyl (4-acetyl-3-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl)carbamate (6d).
Compound 6d was prepared following general procedure C from 4-acetyl-3-(4-bromophenyl)-5-
methyl-1H-pyrrole-2-carbonyl azide 5d (53 mg, 0.15 mmol) in 57 mg (94% yield, after flash
chromatography on silica gel using petroleum ether/EtOAc (3:1 v/v) as eluent) as a colorless solid:
1
mp 199-200 ºС (petroleum ether/EtOAc). H NMR (DMSO-d , 400 MHz): δ 1.38 (s, 9H), 1.93 (s,
6
1
3
1
3H), 2.37 (s, 3H), 7.01-7.30 (m, 2H), 7.36-7.70 (m, 2H), 8.43 (s, 1H), 11.45 (s, 1H). C{ H} NMR
(
(
[
DMSO-d , 100 MHz): δ 13.6 (CH ), 28.0 (CH ), 30.4 (CH ), 78.8 (C), 117.5 (C), 119.3 (C), 119.4
6 3 3 3
C), 121.7 (C), 130.5 (CH), 131.4 (C), 132.0 (CH), 134.6 (C), 155.1 (C), 193.9 (C). HRMS (ESI) m/z:
+
79
+
M + Na] Calcd for C H BrN O Na 415.0628; Found 415.0611.
18 21
2
3
tert-Butyl (4-acetyl-3-(2-bromophenyl)-5-methyl-1H-pyrrol-2-yl)carbamate (6e).
Compound 6e was prepared following general procedure C from 4-acetyl-3-(2-bromophenyl)-5-
methyl-1H-pyrrole-2-carbonyl azide 5e (300 mg, 0.86 mmol) in 310 mg (91% yield, after flash
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6
chromatography on silica gel using petroleum ether/EtOAc (3:1 v/v) as eluent) as a colorless solid:
1
mp 194-196 ºС (petroleum ether/EtOAc). H NMR (DMSO-d , 400 MHz): δ 1.35 (s, 9H), 1.79 (s,
6
3
H), 2.39 (s, 3H), 7.19-7.27 (m, 1H), 7.28-7.40 (m, 2H), 7.60-7.69 (m, 1H), 8.37 (m, 1H), 11.41 (s,
1
3
1
1H). C{ H} NMR (DMSO-d , 100 MHz): δ 13.6 (CH ), 28.0 (CH ), 29.3 (CH ), 78.7 (C), 116.9
6
3
3
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
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(C), 119.2 (C), 121.9 (C), 125.4 (C), 127.1 (CH), 128.8 (CH), 131.0 (C), 132.1 (CH), 132.5 (CH),
+
79
+
1
36.7 (C), 154.7 (C), 193.3 (C). HRMS (ESI) m/z: [M + Na] Calcd for C H BrN NaO 415.0628;
18 21 2 3
Found 415.0632.
tert-Butyl (4-acetyl-5-methyl-3-(p-tolyl)-1H-pyrrol-2-yl)carbamate (6f). Compound 6f
was prepared following general procedure C from 4-acetyl-5-methyl-3-(p-tolyl)-1H-pyrrole-2-
carbonyl azide 5f (320 mg, 1.13 mmol) in 356 mg (96% yield, after flash chromatography on silica
gel using petroleum ether/EtOAc (3:1 v/v) as eluent) as a colorless solid: mp 200-201 ºС (petroleum
1
ether/EtOAc). H NMR (DMSO-d , 400 MHz): δ 1.38 (s, 9H), 1.83 (s, 3H), 2.31 (s, 3H), 2.35 (s, 3H),
6
1
3
1
7.05-7.20 (m, 4H), 8.32 (s, 1H), 11.36 (s, 1H). C{ H} NMR (DMSO-d , 100 MHz): δ 13.5 (CH ),
6
3
2
0.7 (CH ), 28.0 (CH ), 30.3 (CH ), 78.6 (C), 118.7 (C), 119.5 (C), 121.2 (C), 128.3 (CH), 129.8
3 3 3
+
(
CH), 131.0 (C), 132.3 (C), 135.2 (C), 155.3 (C), 194.4 (C). HRMS (ESI) m/z: [M + H] Calcd for
+
C H N O 329.1860; Found 329.1865.
1
9
25
2
3
tert-Butyl (4-acetyl-3-(4-methoxyphenyl)-5-methyl-1H-pyrrol-2-yl)carbamate (6g).
Compound 6g was prepared following general procedure C from 4-acetyl-3-(4-methoxyphenyl)-5-
methyl-1H-pyrrole-2-carbonyl azide 5g (262 mg, 0.88 mmol) in 287 mg (95% yield, after flash
chromatography on silica gel using petroleum ether/EtOAc (3:1 v/v) as eluent) as a colorless solid:
1
mp 194-196 ºС (petroleum ether/EtOAc). H NMR (DMSO-d , 400 MHz): δ 1.38 (s, 9H), 1.83 (s,
6
3
H), 2.35 (s, 3H), 3.76 (s, 3H), 6.84-6.95 (m, 2H), 7.10-7.19 (m, 2H), 8.32 (s, 1H), 11.34 (s, 1H).
1
3
1
C{ H} NMR (DMSO-d , 100 MHz): δ 13.5 (CH ), 28.0 (CH ), 30.3 (CH ), 55.0 (CH ), 78.6 (C),
6
3
3
3
3
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113.2 (CH), 118.5 (C), 119.5 (C), 121.2 (С), 127.4 (C), 130.9 (C), 131.0 (CH), 155.3 (C), 157.9 (C),
+
+
1
94.4 (C). HRMS (ESI) m/z: [M + H] Calcd for C H N O 345.1809; Found 345.1824.
19 25 2 4
tert-Butyl (4-acetyl-3-(3-methoxyphenyl)-5-methyl-1H-pyrrol-2-yl)carbamate (6h).
Compound 6h was prepared following general procedure C from 4-acetyl-3-(3-methoxyphenyl)-5-
methyl-1H-pyrrole-2-carbonyl azide 5h (116 mg, 0.39 mmol) in 100 mg (75% yield, after flash
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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5
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5
5
6
0
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0
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0
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0
chromatography on silica gel using petroleum ether/EtOAc (3:1 v/v) as eluent) as a colorless solid:
1
mp 147-148 ºС (petroleum ether/EtOAc). H NMR (DMSO-d , 400 MHz): δ 1.38 (s, 9H), 1.86 (s,
6
3
H), 2.34 (s, 3H), 3.74 (s, 3H), 6.64-6.94 (m, 3H), 7.24 (t, J = 7.7 Hz, 1H), 8.37 (s, 1H), 11.39 (s, 1H).
1
3
1
C{ H} NMR (DMSO-d , 100 MHz): δ 13.4 (CH ), 28.0 (CH ), 30.2 (CH ), 54.9 (CH ), 78.7 (C),
6
3
3
3
3
1
11.9 (CH), 115.4 (CH), 118.7 (C), 119.5 (C), 121.3 (C), 122.5 (CH), 128.6 (CH), 131.0 (C), 136.7
+
+
(
C), 155.2 (C), 158.8 (C), 194.4 (C). HRMS (ESI) m/z: [M + Na] Calcd for C H N NaO 367.1628;
19 24 2 4
Found 367.1630.
tert-Butyl (4-acetyl-3-(3,4-dimethoxyphenyl)-5-methyl-1H-pyrrol-2-yl)carbamate (6i).
Compound 6i was prepared following general procedure C from 4-acetyl-3-(3,4-dimethoxyphenyl)-
5-methyl-1H-pyrrole-2-carbonyl azide 5i (181 mg, 0.55 mmol) in 113 mg (55% yield, after flash
chromatography on silica gel using petroleum ether/EtOAc (3:1 v/v) as eluent) as a colorless solid:
1
mp 163-165 ºС (petroleum ether/EtOAc). H NMR (DMSO-d , 400 MHz): δ 1.39 (s, 9H), 1.85 (s,
6
3H), 2.34 (s, 3H), 3.72 (s, 3H), 3.76 (s, 3H), 6.68-6.78 (m, 1H), 6.79-6.87 (m, 1H), 6.92 (d, J = 8.2
13
1
Hz, 1H), 8.33 (s, 1H), 11.35 (m, 1H). C{ H} NMR (DMSO-d , 100 MHz): δ 13.5 (CH ), 28.2 (CH ),
6
3
3
3
0.2 (CH ), 55.3 (CH ), 55.5 (CH ), 78.6 (C), 111.4 (CH), 114.0 (CH), 118.7 (C), 119.5 (C), 121.1
3 3 3
(C), 122.3 (CH), 127.8 (C), 130.9 (C), 147.5 (C), 148.0 (C), 155.2 (C), 194.4 (C). HRMS (ESI) m/z:
+
+
[
M + H] Calcd for C H N O 375.1914; Found 375.1905.
2
0
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2
5
tert-Butyl (4-benzoyl-3,5-diphenyl-1H-pyrrol-2-yl)carbamate (6n). Compound 6n was
prepared following general procedure C from 4-benzoyl-3,5-diphenyl-1H-pyrrole-2-carbonyl azide
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(which in its turn was prepared following general procedure B from 3-phenyl-2H-azirine-2-carbonyl
azide 3a (200 mg, 1.08 mmol), 1,3-diphenylpropane-1,3-dione 4b (253 mg, 1.13 mmol) and
NiCl ∙6H O (26 mg, 0.11 mmol)) in 240 mg (yield 51% for 2 steps, after flash chromatography on
2
2
silica gel using petroleum ether/EtOAc (3:1 v/v) as eluent) as a pale green solid: mp 177-178 ºС
0
1
2
3
4
5
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8
9
0
1
2
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0
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0
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8
9
0
1
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9
0
1
(
petroleum ether/EtOAc). H NMR (DMSO-d , 400 MHz): δ 1.44 (s, 9H), 7.03-7.10 (m, 1H), 7.11-
6
7
.19 (m, 5H), 7.20-7.27 (m, 4H), 7.30-7.39 (m, 3H), 7.58-7.64 (m, 2H), 8.69 (s, 1H), 11.88 (s, 1H).
1
3
1
C{ H} NMR (DMSO-d , 100 MHz): δ 28.3 (CH ), 79.1 (C), 118.8 (С), 120.3 (С), 123.9 (С), 125.9
6
3
(CH), 127.2 (CH), 127.7 (CH), 127.9 (CH), 128.3 (CH), 128.4 (CH), 129.0 (CH), 129.4 (CH), 129.9
(
C), 131.7 (C), 132.6 (CH), 134.2 (C), 138.7 (C), 155.5 (C), 194.2 (C). HRMS (ESI) m/z: [M - H]-
-
Calcd for C H N O 437.1871; Found 437.1861.
28 25
2
3
1
,3-Bis(4-benzoyl-3,5-diphenyl-1H-pyrrol-2-yl)urea (8a). Compound 8a was obtained from
crude 4-benzoyl-3,5-diphenyl-1H-pyrrole-2-carbonyl azide 5n (48 mg, 0.12 mmol) while standing on
air for 2 weeks and purified by column chromatography on silica gel (eluent a mixture of
hexanes/EtOAc, 1:1 v/v) to give 22 mg (50% yield) of pure product as a yellow solid: mp 167-169 ºС
1
(
dec., hexanes/EtOAc). H NMR (DMSO-d , 400 MHz): δ 7.07-7.13 (s, 2H), 7.14-7.20 (m, 10H),
6
1
3
1
7.21-7.28 (m, 8H), 7.31-7.40 (m, 6H), 7.62-7.69 (m, 4H), 8.41 (s, 2H), 11.75 (s, 2H). C{ H} NMR
DMSO-d , 100 MHz): δ 118.6 (С), 124.5 (С), 125.7 (CH), 126.9 (CH), 127.5 (CH), 128.0 (CH),
(
6
1
28.0 (CH), 128.2 (CH), 128.2 (C), 129.0 (CH), 129.2 (C), 129.3 (CH), 131.5 (С), 132.4 (CH), 133.7
+
+
(С), 138.5 (C), 155.7 (C), 194.0 (C). HRMS (ESI) m/z: [M + H] Calcd for C H N O 703.2704;
4
7
35
4
3
Found 703.2711.
1
,3-Bis(4-acetyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)urea (8b). 4-Acetyl-5-methyl-3-
phenyl-1H-pyrrole-2-carbonyl azide 5a (70 mg, 0.26 mmol) was dissolved in AcOH/H O mixture
2
(v/v 1:1, 2 mL) and the resulting solution was refluxed for 1 h by using oil bath heating. The reaction
mixture was poured into water (30 mL), neutralized with 5% NaHCO and extracted with EtOAc
3
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(3×20 mL). The combined organic phases were washed with water (30 mL), dried over Na SO ,
2
4
filtered off and concentrated in vacuo. The residue was purified by column chromatography on silica
gel (eluent a mixture of DCM/MeOH, 50:1 v/v) to give 58 mg (96% yield) of pure product as an ochre
1
solid: mp 246-247 ºС (dec., DCM/MeOH). H NMR (DMSO-d , 400 MHz): δ 1.83 (s, 6H), 2.37 (s,
6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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4
4
4
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5
5
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0
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0
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0
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13
1
6
H), 7.10-7.22 (m, 4H), 7.24-7.30 (m, 2H), 7.31-7.38 (m, 4H), 7.84 (s, 2H), 11.30 (s, 2H). C{ H}
NMR (DMSO-d , 100 MHz): δ 13.5 (CH ), 30.3 (CH ), 119.3 (C), 122.2 (C), 126.2 (CH), 128.0 (CH),
6
3
3
+
129.0 (С), 130.1 (CH), 130.8 (С), 135.1 (C), 155.5 (C), 194.2 (C). HRMS (ESI) m/z: [M + H] Calcd
+
for C H N O 455.2078; Found 455.2095.
2
7
27
4
3
1
,3-Bis(4-acetyl-3-(2-bromophenyl)-5-methyl-1H-pyrrol-2-yl)urea (8c). A solution of 4-
acetyl-3-(2-bromophenyl)-5-methyl-1H-pyrrole-2-carbonyl azide 5e (259 mg, 0.75 mmol) in o-DCB
3 mL) was kept at 150 °C for 1 h by using oil bath heating, then the solvent was evaporated and the
(
residue was left overnight. After that it was diluted with DCM containing traces of water, the
precipitate formed was filtered off and washed with Et O to give pure compound 8c in 107 mg (47%
2
1
yield) as an ochre solid: mp > 182 ºС (dec., DCM). H NMR (DMSO-d , 400 MHz): δ 1.75 (s, 6H),
6
2
.40 (s, 6H), 7.16-7.31 (m, 4H), 7.33-7.41 (m, 2H), 7.55-7.70 (m, 2H), 7.75 (s, 2H), 11.32 (m, 2H).
1
3
1
C{ H} NMR (DMSO-d , 100 MHz): δ 13.7 (CH ), 29.4 (CH ), 29.4 (CH ), 118.7 (C), 118.8 (C),
6
3
3
3
1
22.6 (C), 125.6 (C), 127.6 (CH), 129.0 (CH), 130.8 (C), 132.2 (CH), 132.2 (CH), 132.7 (CH), 132.8
(CH), 136.3 (C), 136.3 (C), 154.2 (C), 154.5 (C), 193.1 (C). (Extra peaks in the NMR spectra are
associated with hindered rotation of the o-bromophenyl moiety of the molecule). HRMS (ESI) m/z:
-
79
-
[
M - H] Calcd for C H Br N O 611.0142; Found 611.0119.
27 23 2 4 3
General Procedure D for the Preparation of Aminopyrroles (9a-c). Carbamate 6 (0.45
mmol) was stirred in CF COOH (2-3 mL) at rt for 0.25 h. The reaction mixture was poured into water,
3
neutralized with 5% aq NaHCO and extracted with EtOAc. The combined organic phases were dried
3
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