Oligosubstituted pyrroles directly from substituted methyl isocyanides and acetylenes

Article abstract of DOI:10.1002/chem.200801395

The formal cycloaddition of α-metallated methyl isocyanides 1 onto the triple bond of electron-deficient acetylenes 2 represents a direct and convenient approach to oligosubstituted pyrroles 3. The scope and limitations of this reaction (24 examples, 2597 % yield) are reported along with an optimization of the reaction conditions and a rationalization of the mechanism. In addition, a related newly developed Cu^I-mediated synthesis of 2,3-disubstituted pyrroles by the reaction of copper acetylides derived from unactivated terminal alkynes with substituted methyl isocyanides is described (11 examples, 5-88% yield).

Full text of DOI:10.1002/chem.200801395

FULL PAPER
DOI: 10.1002/chem.200801395
Oligosubstituted Pyrroles Directly from Substituted Methyl Isocyanides and
Acetylenes
Alexander V. Lygin, Oleg V. Larionov, Vadim S. Korotkov, and Armin de Meijere*[a]
Dedicated to Professor Alan R. Katritzky on the occasion of his 80th birthday
Abstract: The formal cycloaddition of
a-metallated methyl isocyanides 1 onto
the triple bond of electron-deficient
acetylenes 2 represents a direct and
convenient approach to oligosubstitut-
ed pyrroles 3. The scope and limita-
tions of this reaction (24 examples, 25–
97% yield) are reported along with an
optimization of the reaction conditions
and a rationalization of the mechanism.
In addition, a related newly developed
CuI-mediated synthesis of 2,3-disubsti-
tuted pyrroles by the reaction of
copper acetylides derived from unacti-
vated terminal alkynes with substituted
methyl isocyanides is described (11 ex-
amples, 5–88%yield).
Keywords: catalysis · copper · cy-
cloaddition · isocyanides · pyrroles
Introduction
triple bond of electron-deficient alkynes has been reported
independently by de Meijere et al.[13] and by Yamamoto
et al.[14] It has been shown, that a base-mediated as well as a
copper-catalyzed reaction of substituted methyl isocyanides
with electron-deficient acetylenes afforded 2,3,4-trisubstitut-
ed pyrroles in good to excellent yields. Herein we present a
more detailed study of this reaction and a novel copper(I)-
mediated synthesis of 2,3-disubstituted pyrroles from isocya-
nides and unactivated terminal acetylenes.
Oligofunctional pyrroles play a pivotal role among five-
membered heterocycles, being basic constituents of numer-
ous natural products,[1] potent pharmaceuticals,[2] molecular
sensors and other devices.[3] Therefore, considerable atten-
tion has been paid to develop efficient general methods for
the synthesis of pyrroles,[4,5] and in recent years, a large
number of new pyrrole syntheses has indeed been report-
ed.[6] Among them, the addition of isocyanides onto the
triple bond of acetylenes is one of the most promising. Due
to their formally divalent terminal carbon atom, isocyanides
are unique organic nitrogen derivatives. Consequently, they
have found wide use in organic synthesis,[7] especially in
multicomponent reactions,[8] different types of insertions[9,10]
and cycloadditions,[11] giving rise to a large variety of nitro-
gen-containing compounds. Cycloadditions are possible due
to the ability of substituted methyl isocyanides to be metal-
lated in the a-position, as first observed by Schçllkopf and
Gerhart.[12] Recently, the synthesis of oligosubstituted pyr-
roles by the formal cycloaddition of isocyanides across the
Results and Discussion
Synthesis of 2,3,4-trisubstituted pyrroles: Scope and limita-
tions of both the base-mediated and the copper-catalyzed
synthesis of pyrroles 3 were tested with a series of different
acetylenes 2 and various acceptor-substituted methyl isocya-
nides 1 (Scheme 1, Table 1). Apparently, quite a number of
different 2,3,4-trisubstituted pyrroles, bearing sulfonyl, di-
alkoxyphosphoryl, trifluoromethyl, cyano and secondary
amino groups are easily accessible in one step from readily
available acetylenes and commercial acceptor-substituted
methyl isocyanides.
Some of the prepared pyrroles can be employed in the
synthesis of biologically active compounds. For example, the
pyrrole 3eg is a possible precursor for a potent inhibitor of
HMG-CoA reductase.[8] Apart from that, it also exhibits a
notable anti-inflammatory activity.[15]
[a] Dipl.-Chem. A. V. Lygin, Dr. O. V. Larionov,
Dipl.-Chem. V. S. Korotkov, Prof. Dr. A. de Meijere
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen, Tammannstrasse 2
37077 Gçttingen (Germany)
Fax : (+49)551-399-475
E-mail: ameijer1@gwdg.de
Interestingly, the steric and electronic effects of the sub-
stituents may significantly influence the reaction efficiency
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801395.
Chem. Eur. J. 2009, 15, 227 – 236
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
227

CuSPh-catalyzed reactions of isocyanides 1 with methyl pro-
piolate 2p gave the corresponding pyrroles 3 in only 25–
44% yields, and in the presence of KOtBu the yields of pyr-
roles 3 were also low (Table 1, entries 21–24). It is known,
that methyl propiolate 2p easily dimerizes forming dimethyl
hex-2-en-4-ynedioate both under base[16] and copper(I)[17]
catalysis, complicating this reaction. Even with an excess of
2p, the yields of pyrroles 3 were not any better.
Scheme 1. Preparation of 2,3,4-trisubstituted pyrroles by formal cycload-
dition of acceptor-substituted methyl isocyanides to acetylenes. For de-
tails see Table 1.
The copper(I)-catalyzed variant of the reaction is of great
interest, because it may bring along certain advantages in
cost efficiency and compatibility with base-sensitive sub-
strates. Different solvents were tested in the copper-cata-
lyzed cycloaddition of p-toluenesulfonylmethyl isocyanide
(TosMIC, 1b) to methyl cyclopropylacetylenecarboxylate
(2a). Dimethylformamide (DMF) turned out to be the sol-
vent of choice giving a better yield of pyrrole 3ba than any
other tested solvent (toluene, ethanol, ethyl acetate, acetoni-
trile, 1,2-dichloroethane, dioxane). Although higher conver-
sions of TosMIC were achieved, when the reaction was car-
ried out in toluene, ethanol, ethyl acetate or dioxane, the
yields of 3ba were lower than in DMF. In a screening of var-
ious copper catalysts, copper(I) thiophenolate and preacti-
vated nanosize metallic copper powder in DMF at 908C
turned out to be the most efficient, providing the pyrrole
3aa in 93 and 92% yield, respectively (Table 2, entries 1 and
and the nature of the product. Thus, the phenyl substituent
in acetylene 2g was expected to cause reduced reactivity to-
wards nucleophiles. Indeed, the reaction of 2g with 1e was
quite sluggish at 808C, but readily furnished the pyrrole 3eg
at higher temperature (1208C). Other acetylenes with aryl
(2h–j) and heteroaryl substituents (2k, l) were also efficient-
ly converted into the respective pyrroles 3ah–3al using this
method (entries 12–16). The reaction of the diacetylene 2m
with an excess of the isocyanide 1a at prolonged reaction
times yielded the monocycloadduct 3am as the sole product
and no trace of the twofold cycloadduct. This may arise
from the considerable steric encumbrance of the pyrrole
3am. On the other hand, reactive acetylenes bearing addi-
tional electron-withdrawing substituents, as for example,
ethyl trifluoromethylpropiolate 2e, tend to overreact and
undergo a second addition with the intermediate 11 (see
Scheme 3), eventually leading
to oligomerization. This may
cause a significant decrease of
the yields.
Table 1. Various 2,3,4-trisubstituted pyrroles 3 prepared by the formal cycloaddition of substituted methyl iso-
cyanides 1 to acetylenes 2.
Entry
Isocyanide 1
Acetylene 2
Product
Method[a–c]
Yield [%][d]
Therefore, the initial proce-
dure, utilizing potassium tert-
butoxide (KOtBu) (method A),
was modified to avoid any
excess of the acetylene in the
reaction mixture. Thus, the re-
active acetylene 2e was added
simultaneously with the base
[potassium bis(trimethylsilyl)-
amide (KHMDS) proved to be
the base of choice in this case]
from two separate syringes at
À788C (method B) to give the
desired pyrrole 3be in 76%
yield. Similarly, the highly reac-
tive cyanomethyl isocyanide 1d
was employed under the condi-
tions of Method B to give the
2-cyanopyrrole 3db in 83%
yield, whereas with potassium
tert-butoxide (method A) the
product was obtained with a
R1
R2
EWG
1
2
3
4
5
6
7
8
9
a
b
c
b
b
a
d
a
b
CO2Me
SO2Tol
Ph
SO2Tol
SO2Tol
CO2Me
CN
a
a
b
b
c
b
b
d
e
cPr
cPr
cPr
cPr
Me
cPr
cPr
CH2OMe
CF3
CO2Me
CO2Me
CO2tBu
CO2tBu
CO2Me
CO2tBu
CO2tBu
3aa
3ba
3cb
3bb
3bc
3ab
3db
3ad
3be
A, 91
A, 93 C, 64
C,[e] 87
A, 93 C, 91
A, 76 C, 83
A, 97 C, 94
B,[f] 83
A, 53 C, 47
B, 76
CO2Me
SO2Tol
PO
N
CO2Et
10
b
SO2Tol
f
CO2Me
3bf
A,[f] 45
11
12
13
14
15
16
e
a
a
a
a
a
CO2tBu
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
g
h
i
j
k
l
Ph
CO2Et
3eg
3ah
3ai
3aj
3ak
3al
C,[g] 78
C,[g] 75
C,[g] 78
C,[g] 70
C,[g] 68
C,[g] 94
4-EtO-C6H4
4-F-C6H4
4-CF3-C6H4
2-pyridyl
2-thienyl
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
17
a
CO2Me
m
CO2Me
3am
C, 91 h]
18
19
20
21
22
23
24
a
a
f
CO2Me
CO2Me
CO2Et
CO2Et
SO2Tol
Ph
n
o
a
p
p
p
p
CH
CO2Me
cPr
H
H
(OMe)Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
3an
3ao
3 fa
3 fp
3bp
3cp
3gp
C, 54
B, 81
A, 89
f
A, 35 C,[i] 37
A, 38 C,[i] 30
A, 7 C,[i] 25
C,[I] 44
b
c
g
H
H
4-O2NC6H4
lower purity and in
yield.
a poor
[a] Method A: Addition of KOtBu (1.2 equiv), 1 h, then 1 h at 208C, THF. [b] Method B: Simultaneous addi-
tion of KHMDS (1.2 equiv) and the respective acetylene 2 to a solution of the respective isocyanide 1 in THF
at À788C within 1 h, then 3 h at À788C. [c] Method C: Cu catalyst, DMF, 858C, 12 h. [d] Yield of isolated
product. [e] CsOtBu was used instead of KOtBu. [f] Method C was not employed in view of the instability of
the acetylene and/or the substituted isocyanide. [g] The reaction was carried out at 1208C. [h] Only the mono-
With electron-acceptor sub-
stituted terminal acetylenes, the
yields of pyrroles 3 were dra-
matically lower. Thus, the cycloaddition product was obtained. [i] The reaction was carried out at 608C.
228
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Chem. Eur. J. 2009, 15, 227 – 236

Oligosubstituted Pyrroles
FULL PAPER
Table 2. Optimization of the copper catalyst for the synthesis of 3aa.[a]
catalyst in the reaction of 1 f with both terminal and internal
acetylenes without acceptor substituents, failed. Under the
catalysis of CpCuPACTHNUTRGNEUNG(OMe)3 (5 mol%), the isocyanide 1 f di-
merized to the imidazole 4[22] in 85% yield at 208C within
16 h.
All catalysts (except nanosize-copper powder), which
demonstrated moderate and good activity in the pyrrole for-
mation (CuSPh, CuSePh, CuPPh2, Cu2O, Cu2S), have one
common feature, namely a s-donating character of the coun-
terion. Saegusa et al.[23] reported that copper(I) tert-butoxide
with similar electronic properties, reveals a strong affinity
toward p-accepting ligands like isocyanides, and this has not
been observed for common cuprous salts. This feature of
copper(I) compounds with s-donating ligands may be ascri-
bed to the enhancement of back-donation from the copper
to p-accepting ligands, such as isocyanides. Enhanced affini-
ty of copper(I) compounds with s-donating counterions to
isocyanides appears to be crucial for the pyrrole formation.
CuI isocyanide complexes are known to abstract hydrogen
from so-called active hydrogen compounds and to produce
organocopper(I) isocyanide complexes,[24] which can under-
go cycloadditions to form various heterocycles. In view of
this, it is an open question, how copper(0) can be an active
catalyst for the pyrrole formation. Metallic copper powder
is known to dissolve in cyclohexyl isocyanide under an at-
mosphere of nitrogen to form a zero-valent copper–isocya-
Entry
Cu catalyst
Yield 3aa [%][b]
1
2
3
4
5
6
7
8
CuSPh
Cu0-NP[c]
CuSePh
CuSHex
CuPPh2
Cu2O
Cu2S
CuCl
CuBr
CuI
93
92
45
52
39
78
37
6
10
3
24
24
19
89[d]
9
10
11
12
13
14
CuCN
Cu
Cu
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
CpCuPACHTNUGTRENNUNG
[a] Reagents and conditions: 1a (1.1 mmol), 2a (1.0 mmol), copper salt
(5 mol%), DMF (2 mL). [b] Determined by 1H NMR with hexamethyl-
benzene as an internal standard. [c] The abbreviation Cu0-NP stands for
preactivated nanosize copper powder. [d] The reaction was carried out at
208C with 10 mol% of catalyst and, according to TLC, was completed
within 2 h.
nide complex, which can undergo an oxidative addition of a
[25]
À
carbon halogen bond. Apart from the catalytic activity of
metallic copper in the pyrrole synthesis demonstrated by us,
Yamamoto et al.[11b] later reported, that metallic copper effi-
ciently catalyzes the formation of imidazoles from two dif-
ferent isocyanides. These results indicate, that copper(0) iso-
cyanide, like copper(I) isocya-
2). With copper(I) oxide as a catalyst, 3aa was obtained in a
slightly lower yield of 78%, whereas other copper com-
pounds gave inferior results. Surprisingly, some copper(II)
compounds (copper(II) acetylacetonate, copper(II) acetate,
entries 12, 13, respectively) catalyzed the formation of 3aa
as well, and gave even better results than CuI and other
copper(I) halides. Copper(II) compounds are supposed to
be (fully or partly) reduced by isocyanides to the corre-
sponding CuI salts, which actually catalyze the reaction.
It is conceivable, that this reaction could be used for
many other applications, for example, in biological systems,
if it fulfilled the demands of Sharplessꢃ so-called “click”
chemistry“,[18] that is, provided good yields and could be car-
ried out at low temperatures. With the intention to achieve
this kind of pyrrole formation at temperatures lower than
708C, it was attempted to prepare a copper(I) compound,
that would decompose to metallic copper at low tempera-
tures. It is known, that cyclopentadienylcopper com-
pounds[19] show interesting catalytic properties and serve as
sources for copper of high purity,[20] as they decompose at
relatively low temperatures. Thus, Saegusa, Ito et al.[21] re-
ported that the cyclopentadienylcopper(I) tert-butylisocya-
nide complex catalyzes Michael-type additions of com-
pounds containing active hydrogen, to acrylates and acrylo-
nitrile. Indeed, h5-(cyclopentadienyl)trimethylphosphite–
copper(I) at 208C efficiently catalyzes the reaction of 1a
with 2a providing the pyrrole 3aa in 89% yield within 2 h
(Table 2, entry 14). However, all attempts to use this copper
nide complexes, are able to de-
protonate compounds with
active hydrogen. To prove this
hypothesis, the enantiomerically
pure isocyanide 5[26] was synthe-
sized from l-isoleucine. Indeed, 5 underwent complete race-
mization upon heating at 858C for three hours in DMF in
the presence of pre-activated copper nanoparticles.
Synthesis of 2,3-disubstituted pyrroles: Although acetylenes
without electron-withdrawing substituents have not been
used earlier as cycloaddition partners for isocyanides in pyr-
role syntheses[13,14] under usual conditions, an attempted re-
action of 3-hexyne (2q) with ethyl isocyanoacetate (1 f) at
elevated temperature (1208C) in the presence of 1 equiv of
copper(I) iodide as a mediator and 5 equiv of cesium car-
bonate as a base, gave a trace of the pyrrole 6 fq after 16 h
(Scheme 2).
Terminal acetylenes turned out to be more reactive under
these conditions. Thus, ethyl 3-butylpyrrolecarboxylate (6 fr)
was obtained in 29% yield from 1-hexyne and ethyl isocya-
noacetate (1 f) (Table 3, entry 1). The best yield of 6 fr in
this reaction was achieved at 1208C, being almost the same
as at 1408C, while at 1008C it was significantly lower (en-
Chem. Eur. J. 2009, 15, 227 – 236
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
229

A. de Meijere et al.
Table 4. Further optimization of conditions for the synthesis of 6 fr.[a,b]
Entry 1 f
2r
Mediator
Base (equiv) Yield[c] 6 fr
(equiv) (equiv) (equiv)
[%]
1
2
3
1
5
1
1
1
1
CuI (1)
CuBr·SMe2 (1) Cs2CO3 (5)
CuBr·SMe2
(0.1)
Cs2CO3 (5)
36[a]
64[a]
Cs2CO3 (5)
trace[a]
4
5
6
7
8
9
10
11
1
1
3
2
1.5
1
2
2
2
1
1
1
1
1
1
CuBr (1)
CuCl (1)
Cs2CO3 (3)
Cs2CO3 (3)
64[b]
64[b]
70[a]
70[a]
48[a]
43[a]
63[a]
CuBr·SMe2 (1) Cs2CO3 (1)
CuBr·SMe2 (1) Cs2CO3 (1)
CuBr·SMe2 (1) Cs2CO3 (1)
CuBr·SMe2 (1) Cs2CO3 (5)
CuBr·SMe2 (1) Cs2CO3 (1)
Scheme 2. Formation of pyrroles 6 from unactivated acetylenes and sub-
stituted methyl isocyanides. For details see Tables 3 and 4.
tries 3, 2, respectively). Different bases were tested, yet lithi-
um and potassium carbonate were less effective than cesium
carbonate, giving rise to 15 and 19% yield of 6 fr respective-
ly, under the same conditions (entries 4, 5). Tertiary amines
(Et3N, EtNiPr2, DBU, DABCO) were less effective than
alkali carbonates, giving less than 10% yield of 6 fr under
the same conditions. Although DMF was used as a solvent
in most cases, N,N-dimethylacetamide worked as well
(entry 6), in toluene 6 fr was obtained in a lower yield of
only 23% (entry 9). With catalytic quantities of CuI, only
traces of 6 fr were isolated, while 1.3 equiv of CuI did not
provide an improvement compared to an equimolar quanti-
ty. Among the mediators used, CuOTf·0.5C6H6 was com-
2
CuBr·SMe2 (1) Cs2CO3 (0.5) trace[a]
[a] Method A: A solution of the isocyanide 1 f (1–5 mmol) in 5 mL of
DMF was added dropwise at 1208C within 2 h to a mixture of Cs2CO3,
the copper acetylenide generated in situ from the acetylene 2r and the
copper(I) salt in 5 mL of DMF, and the mixture was stirred at 1208C for
12 h. [b] Method B: A solution of the isocyanide 1 f (1 mmol) and the
acetylene 2r (1 mmol) in 5 mL of DMF was added dropwise within 2 h at
1208C to a mixture of Cs2CO3, the copper acetylenide generated in situ
from the acetylene 2r (1 mmol) and the copper(I) salt in 5 mL of DMF,
and the mixture was stirred at 1208C for 12 h. [c] Yields of isolated prod-
uct.
big influence on the yield as well. The yields of 6 fr were
best, when two and more equivalents of isocyanide were
used, whereas with the ratio of 1.5:1 and 1:1 of 1 f to 2r, the
yields of 6 fr were 48 and 43%, respectively (entries 8, 9).
Interestingly, with an excess of the acetylene 2r (2 equiv),
6 fr was obtained in 63% yield based on the isocyanide, in-
dicating that the use of either an excess of the acetylene 2
or an excess of the isocyanide 1 are equally effective.
pletely ineffective as well as Cu2O, while CuI·PACHTUNTGRNENG(U OMe)3 gave
6 fr in 10% yield. AgOAc was slightly worse (27% yield of
6 fr, entry 8) than CuI, and in view of the significantly lower
prices of copper salts, no further silver mediators were
tested. Surprisingly, copper(II) trifluoromethanesulfonate
also achieved the formation of 6 fr in 21% yield (entry 7).
With the optimal conditions for the CuI-mediated cycload-
dition in hand, the reactions of ethyl isocyanoacetate (1 f)
with various terminal alkynes without acceptor substituents
were carried out (see Table 5). 1-Hexyne (2r) afforded the
pyrrole 6 fr in 70 and 64% yield, respectively (entry 1), ac-
cording to methods A and B (for details see footnotes under
Table 5). 3-Methoxy-1-propyne (2s) with its donating me-
thoxymethyl substituent, gave a lower yield of the pyrrole
6 fs (48%, entry 2). Bulky substituents R attached to the
triple bond in 2 also led to decreased yields of the corre-
sponding pyrroles 6. Thus, 2y with a sec-butyl group gave
the pyrrole 6 fy in 58% yield (entry 8) compared to 70% of
6 fr (R=n-butyl). Phenylacetylene (2u), 2-pyridylacetylene
(2x) and tert-butylacetylene (2w) afforded the correspond-
ing pyrroles 6 fu, 6 fx, 6 fw/iso-6 fw in 40, 16 and 5% yields,
respectively (entries 4, 7, 6). In the latter case, a 5:1 mixture
of the 2,3- 6 fw and the regioisomeric 2,4-disubstituted pyr-
role iso-6 fw was formed. The yields of pyrroles from cyclo-
propylacetylene (2v, entry 5) and from 3-methoxy-1-butyne
(2t, entry 3) were the highest, although both of these acety-
lenes contain a-branched substituents. The cycloaddition of
1 f to 3-butyn-1-ol (2z) was accompanied by intramolecular
transesterification of the ethoxycarbonyl group in the initial
product, leading to the lactone-annelated pyrrole 7 in 44%
(method A) and 37% yield (method B, entry 9).
Table 3. Optimization of conditions for the synthesis of 6 fr (see
Scheme 2).[a]
Entry Mediator (equiv) Base (equiv) Solvent T [8C] Yield[b] [%]
1
2
3
4
5
6
7
8
9
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuACHTUNGTRENNUNG(OTf)2 (1)
AgOAc(1)
CuI (1)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Li2CO3 (5)
K2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
Cs2CO3 (5)
DMF
DMF
DMF
DMF
DMF
DMA
DMF
DMF
120
100
140
120
120
120
120
120
29
10
28
15
19
30
21
27
23
toluene 120
[a] All reactions were carried out with 1 mmol of the isocyanide 1 f and
5 mmol of the acetylene 2r in 10 mL of solvent in a sealed vessel with
stirring and heating for 12 h. [b] Yields of isolated product.
The yield of 6 fr could be further improved by gradually
adding the isocyanide 1 f to a mixture of the copper media-
tor, cesium carbonate and the acetylene 2r in DMF kept at
1208C (Table 4). This procedure with a stoichiometric quan-
tity of CuI provided the pyrrole 6 fr in 36% yield (entry 1).
CuBr·SMe2, CuBr and CuCl were equally effective, and all
three of them were better than CuI (entries 2, 4, 5). But
with a substoichiometric quantity (0.1 equiv) of CuBr·SMe2,
only a trace of 6 fr was formed. The ratio of reagents had a
230
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Chem. Eur. J. 2009, 15, 227 – 236

Oligosubstituted Pyrroles
FULL PAPER
Table 5. Synthesis of 2,3-disubstituted pyrroles 6 from the isocyanide 1 f
and terminal acetylenes 2.[a,b]
other known 2-(4-nitrophenyl)-substituted pyrroles: 3,4-di-
methyl-2-(4-nitrophenyl)-5-phenyl-1H-pyrrole and 2-(4-ni-
trophenyl)-3,4,5-triphenyl-1H-pyrrole,[27a]
2,5-bis-(4-nitro-
phenyl)-1H-pyrrole,[27b] 5-methyl-2-(4-nitrophenyl)-1H-pyr-
role,[27c] 5-phenyl-2-(4-nitrophenyl)-1H-pyrrole.[27d]
All experimental data of some preliminary kinetic investi-
gations (see Supporting Information) are in agreement with
an overall second order of the reaction, that is, first order
with the respect to both, the acetylene and the isocyanide.
Thus, a plausible mechanism of both the base-mediated and
the copper(I)-catalyzed[14] pyrrole formation from substitut-
ed methyl isocyanides 1 and electron-acceptor substituted
alkynes 2 can be proposed (see Scheme 3). The initiating
Entry
Acetylene
R
Product
Yield [%][c]
1
2
3
4
5
6
7
8
9
2r
2s
2t
2u
2v
2w
2x
2y
2z
nBu
CH2OMe
CH
Ph
cPr
tBu
2-Py
sec-Bu
CH2CH2OH
6 fr
6 fs
6 ft
6 fu
6 fv
6 fw/iso-6 fw
6 fx
6 fy
7
70[a], 64[b]
48[a], 45[b]
74[a]
(CH3)OMe
40[a]
88[a]
5[b]
16[a]
58[a]
44[a], 37[b]
[a] Method A: A solution of the isocyanide 1 f (1–5 mmol) in 5 mL of
DMF was added dropwise at 1208C within 2 h to a mixture of Cs2CO3,
the copper acetylenide generated in situ from the acetylene 2 and the
copper(I) salt in 5 mL of DMF, and the mixture was stirred at 1208C for
1 h. [b] Method B: A solution of the isocyanide 1 f (1 mmol) and the
acetylene 2 (1 mmol) in 5 mL of DMF was added dropwise within 2 h at
1208C to a mixture of Cs2CO3, the copper acetylenide generated in situ
from the acetylene 2 (1 mmol) and the copper(I) salt in 5 mL of DMF,
and the mixture was stirred at 1208C for 1 h. [c] Yields of isolated prod-
uct.
Various other acceptor-substituted isocyanides 1 were
compared with 1 f in their CuBr-mediated formal cycloaddi-
tions to 1-hexyne (2r) (Table 6). With its bulky tert-butyl
ester moiety, 1e, gave a lower yield of 6er (47%, entry 2)
than the ethyl ester 1 f gave 6 fr (70%, entry 1). p-Nitrophe-
nylmethyl isocyanide (1g) afforded the corresponding pyr-
role 6gr in 20% yield only (entry 3). The methyl isocyanide
with a diethylaminocarbonyl (1h), a dimethoxyphosphonyl
(1j) and a p-toluenesulfonyl group (1c) did not give any of
the respective pyrroles at all, although the consumption of
the isocyanide was complete in all these cases (entries 4–6).
All 2,3-disubstituted pyrroles 6 obtained in this way were
colorless solids or oils except for pyrrole 6gr, which was iso-
lated as red crystals. Indeed, a red color is typical for many
Scheme 3. Proposed mechanism for the formal cycloaddition of an a-met-
allated isocyanide 1 across the C,C-triple bond in an electron-deficient
acetylene 2.
step is the formation of an a-metallated isocyanide 8. Not
only CuI compounds, but also metallic copper powder and
CuII salts (to some extent) must lead to the formation of
such a species. Subsequent Michael-type addition onto the
triple bond of an activated acetylene 2 furnishes an unstable
vinyl-organometallic compound 11, which readily undergoes
cyclization to the 2H-pyrroleninemetallic species 12. The
latter then experiences a 1,5-hydrogen shift to yield 10, and
protonation of the latter by the isocyanide 1 gives the pyr-
role 3, completing the catalytic cycle for M = Cu. The inter-
mediate 12 could also first be protonated, and then undergo
a 1,5-hydrogen shift. There is no experimental evidence fa-
voring either one of the two possibilities. In the base-medi-
ated pyrrole formation, counterions like K+ and Cs+, which
are harder than Cu+, presumably lead to the N-metallated
pyrrole 9, which does not deprotonate to any significant
extent a new molecule of isocyanide 1, and this therefore re-
quires a stoichiometric quantity of base for the pyrrole for-
mation in good yields.
Table 6. Synthesis of 2,3-disubstituted pyrroles 6 from various isocya-
nides 1 and 1-hexyne (2r).[a]
Entry
Isocyanide
R
Product
Yield[b] [%]
1
2
3
4
5
6
1 f
1e
1g
1h
1j
CO2Et
6 fr
6er
6gr
6hr
6jr
70
47
20
0
0
0
CO2tBu
4-O2NC6H4
CONEt2
PO
N
1b
SO2Tol
6br
The pyrrole formation in the copper(I)-mediated reaction
between substituted methyl isocyanides 1 and unactivated
[a] A solution of the isocyanide 1 (2 mmol) in 5 mL of DMF was added
dropwise at 1208C within 2 h to a mixture of Cs2CO3, the copper acetyle-
nide generated in situ from the acetylene 2r and CuBr in 5 mL of DMF,
and the mixture was stirred at 1208C for 1 h. [b] Yield of isolated prod-
uct.
terminal acetylenes
2 can be rationalized as follows
(Scheme 4). Carbocupration[28] of the copper acetylenide 13
by the deprotonated isocyanide 8 followed by cyclization of
Chem. Eur. J. 2009, 15, 227 – 236
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www.chemeurj.org
231

A. de Meijere et al.
Experimental Section
General methods: NMR (1H, 13C, 19F and 31P) spectra were recorded at
300 (1H), 75.5 [13C, APT (Attached Proton Test)], 282.4 (19F), and 121.7
(31P) MHz on Varian Unity-300 and AMX 300 instruments with CDCl3
solutions if not otherwise specified. TLC: Macherey-Nagel, TLC plates
Alugram Sil G/UV254. Detection under UV light at 254 nm or develop-
ment with MOPS (10% molybdophosphoric acid, solution in ethanol).
Chromatography: Separations were carried out on Merck Silica 60
(0.063–0.200 mm, 70–230 mesh ASTM). IR: measured as KBr pellets or
as films between KBr plates. MS: EI-MS: Finnigan MAT 95, 70 eV, DCI-
MS: Finnigan MAT 95, 200 eV, reactant gas NH3; ESI-MS: Finnigan
LCQ. High resolution mass spectrometry (HRMS): APEX IV 7T
FTICR, Bruker Daltonic. M.p.: Bꢀchi 540 capillary melting point appara-
tus, values are uncorrected. Elemental analyses: Mikroanalytisches Labo-
ratorium des Instituts fꢀr Organische und Biomolekulare Chemie der
Universitꢁt Gçttingen.
Scheme 4. Mechanistic rationalization of the copper(I)-mediated reaction
of isocyanides 1 with a terminal acetylene 2 to yield a 2,3-disubstituted
pyrrole 6.
the thus formed intermediate 14 would yield the 2H-pyrro-
lenline-4,5-dicopper derivative 15, which by 1,5-hydrogen
shift and twofold protonation would give the pyrrole 6.
To support this hypothesis, hexynylcopper[29] (13, R=
nBu) was prepared separately and treated with methyl iso-
cyanoacetate (1a) in DMF at 1208C, both in the presence of
base and without it, to furnish the pyrrole 6ar in 28 and
30% yield, respectively. In addition, a reaction of 1a with a
twofold excess of 1-deutero-1-hexyne ([D]2r) employing
method B was carried out (Scheme 5).
Starting materials: Methyl cyclopropylpropiolate (2a),[32] tert-butyl cyclo-
propylpropiolate (2b),[33] 4-nitrophenylmethyl isocyanide (1g),[34] cyano-
methyl isocyanide (1d),[35] diethyl (3-methoxyprop-1-ynyl)phosphonate
(2d),[36] ethyl trifluoromethylpropiolate (2e),[37] methyl morpholin-4-yl-
propiolate (2 f),[38] methyl 3-(4-fluorophenyl)propiolate (2i),[39] methyl 3-
(4-trifluoromethylphenyl)propiolate (2j),[40] methyl 3-(thiophen-2-yl)pro-
piolate (2l),[41] methyl 3-(pyridin-2-yl)propiolate (2k),[42] methyl (1-me-
thoxycarbonylethynylcyclopropyl)propiolate (2m),[43] cyclopropylacety-
ACTHNUTRGNEUNG
lene (2v),[44] CpCuP(OMe)3,[19] 1-deuterohex-1-yne ([D]2r)[45] were pre-
pared according to literature procedures. Commercial nanosize-copper
powder (Aldrich) was preactivated by heating in vacuo (0.05 mbar) at
1508C overnight, and it was then stored under Ar. All other chemicals
were used as commercially available.
Cesium tert-butoxide (CsOtBu): tert-Butyl alcohol (6 mL) was added in
three portions within 1 h to cesium metal (1.0 g, 7.52 mmol) under anhy-
drous toluene (30 mL) at 208C with gentle stirring under an atmosphere
of Ar, and the mixture was stirred until the cesium metal had completely
dissolved (ꢀ1 h). The resulting solution was concentrated under reduced
pressure and dried in vacuo (0.05 mbar) at 708C for 7 h to give cesium
tert-butoxide (1.44 g, 93%) as a colorless solid.
Scheme 5. Formation of the partly deuterated pyrrole [D]6ar.
General procedure for the formal cycloaddition of substituted methyl iso-
cyanides to acetylenes mediated by potassium tert-butoxide (GP 1, meth-
od A): To a solution of the respective acetylene 2 (5.0 mmol) and the re-
spective substituted methyl isocyanide 1 (5.5 mmol) in THF (60 mL) was
This reaction, after work-up with H2O, furnished a mix-
ture of pyrroles [D]6ar with approximately equal deuterium
incorporation (43%) at positions 4 and 5, as evidenced by
added dropwise at 208C within 1 h
a solution of KOtBu (616 mg,
5.5 mmol) in THF (35 mL). The mixture was stirred at 208C for 1 h, the
reaction was then quenched with glacial AcOH (1 mL), and the solution
concentrated under reduced pressure. The residue was triturated with
CH2Cl2 (3ꢄ30 mL) at 208C to extract the crude product, which was puri-
fied by column chromatography.
1
an H NMR spectrum. This fact proves the intermediate for-
mation of a 2H-pyrrolenline-4,5-dicopper species 15, which
is deuterated or protonated by [D]2r or 1a, respectively to
give pyrrole [D]6ar or [H]6ar, respectively.
General procedure for the formal cycloaddition of substituted methyl iso-
cyanides to acetylenes mediated by KHMDS (GP 2, method B): To a so-
lution of the respective substituted methyl isocyanide 1 (5.5 mmol) in
THF (60 mL) were added dropwise and simultaneously from two sepa-
rate syringes by means of a syringe pump at À788C within 1 h a solution
of KHMDS (5.5 mmol) in THF (10 mL) and a solution of the respective
acetylene 2 (5.0 mmol) in THF (10 mL). The mixture was stirred at
À788C for 3 h, then the reaction was quenched with glacial AcOH
(1 mL), and the solution concentrated under reduced pressure. The resi-
due was triturated with CH2Cl2 (3ꢄ30 mL) at 208C to extract the crude
product, which was purified by column chromatography.
Conclusion
The direct formation of pyrroles from substituted methyl
isocyanides 1 and acceptor-substituted acetylenes 2 under
copper(I) catalysis represents a convenient route to 2,3,4-tri-
substituted pyrroles and 3,4-disubstituted pyrroles 3 with
sufficient functionality for further elaboration. The newly
found route to 2,3-disubstituted pyrroles 6 from substituted
methyl isocyanides 1 and non-activated terminal acetylenes
mediated by copper(I) compounds further enhances the ver-
satility of these pyrrole syntheses. The prepared derivatives
can also be easily transformed into pyrroles of higher or
lower order of substitution according to established proto-
cols.[30,31]
General procedure for the copper-catalyzed formal cycloaddition of sub-
stituted methyl isocyanides to acetylenes (GP 3, method C): The copper
catalyst [preferably preactivated nanosize copper powder (3 mg,
0.05 mmol, 5 mol%), or copper thiophenolate (9 mg, 0.05 mmol,
5 mol%)] was added to a solution of the respective substituted methyl
isocyanide 1 (1.1 mmol) and the respective acetylene 2 (1.0 mmol) in
DMF (2 mL), and the mixture was vigorously stirred at 708C (preacti-
vated nanosize-copper powder) or 858C (CuSPh) for 16 h. The solvent
232
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Chem. Eur. J. 2009, 15, 227 – 236

Oligosubstituted Pyrroles
FULL PAPER
was removed in vacuo (0.05 mbar), and the residue was purified by
column chromatography to give the corresponding pyrrole.
5 mol%) at 1208C, after column chromatography (hexane/ethyl acetate
2:1, Rf =0.20) as a yellow solid. M.p. 1468C; 1H NMR (300 MHz, CDCl3,
258C, TMS): d=9.50 (brs, 1H, NH), 7.56 (d, J=3.3 Hz, 1H, NCH), 7.38
(t, J=3.3 Hz, 1H, thienyl-5H), 7.05 (d, J=3.0 Hz, 2H, thienyl-3,4H),
3.73 (s, 3H, CH3), 3.70 ppm (s, 3H, CH3); 13C NMR (75.5 MHz, CDCl3,
258C): d=163.7 (C), 160.9 (C), 132.9 (C), 128.5 (CH), 126.9 (CH), 126.2
(CH), 126.0 (CH), 124.1 (C), 121.9 (C), 117.8 (C), 51.8 (CH3), 51.2 ppm
(CH3); IR (KBr): n˜ =2954, 1731, 1703, 1524, 1439, 1386, 1264, 1197, 1015,
921, 784, 689 cmÀ1; MS (EI): m/z (%): 265.2 (90) [M]+, 233.1 (78), 202.1
(62), 43.1 (100); elemental analysis calcd (%) for C12H11NO4S: C 54.33,
H 4.18, N 5.28; found: C 54.05, H 4.10, N 5.38.
Trimethyl 1H-pyrrole-2,3,4-tricarboxylate (3ai):[46] The pyrrole 3ai
(489 mg, 81%) was obtained from dimethyl acetylenedicarboxylate (2i)
(355 mg, 2.5 mmol) and methyl isocyanoacetate (1a) (327 mg, 3.3 mmol)
following GP 2 (Method B), after column chromatography (cyclohexane/
ethyl acetate 4:1) as a colorless solid. M.p. 878C; 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=10.12 (brs, 1H, NH), 7.45 (d, J=3.3 Hz, 1H,
NCH), 3.91 (s, 3H, CH3), 3.81 (s, 3H, CH3), 3.78 ppm (s, 3H, CH3);
13C NMR (75.5 MHz, CDCl3, 258C): d=165.9 (C), 163.1 (C), 160.1 (C),
126.5 (CH), 123.0 (C), 120.9 (C), 115.8 (C), 52.9 (CH3), 52.4 (CH3),
51.7 ppm (CH3); IR (KBr): n˜ =3298, 3300, 3124, 3016, 2960, 2920, 2854,
1707, 1567, 1520, 1469, 1444, 1393, 1370, 1290, 1197, 1172, 1070, 1016,
959, 935, 817, 785, 682, 618, 578, 531 cmÀ1; MS (EI): m/z (%): 241.2 (100)
[M]+.
Dimethyl 3-cyclopropyl-1H-pyrrole-2,4-dicarboxylate (3aa): Following
GP 1 (method A), the pyrrole 3aa (1.01 g, 91%) was obtained from
methyl cyclopropylpropiolate (2a) (620 mg, 5.0 mmol) and methyl isocya-
noacetate (1a) (545 mg, 5.5 mmol), after column chromatography (cyclo-
hexane/ethyl acetate 4:1) as a colorless solid. M.p. 1238C; 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=9.78 (brs, 1H, NH), 7.43 (d, J=
3.6 Hz, 1H, NCH), 3.82 (s, 3H, CH3), 3.76 (s, 3H, CH3), 2.27–2.17 (m,
1H, cPr-H), 0.96–0.83 ppm (m, 4H, CH2); 13C NMR (75.5 MHz, CDCl3,
258C): d=164.5 (C), 161.4 (C), 135.4 (C), 127.5 (CH), 121.3 (C), 116.9
(C), 51.5 (CH3), 51.0 (CH3), 8.2 (CH2), 7.3 ppm (CH); IR (KBr): n˜ =
3325, 3146, 3010, 2951, 1719, 1696, 1541, 1437, 1276, 1199, 1059, 785 cmÀ1
;
+
MS (EI): m/z (%): 223.1 [M]+; HRMS (ESI): m/z: calcd for C11H14NO4
[M+H]+: 224.0923; found: 224.0917.
tert-Butyl 2-(4-toluenesulfonyl)-3-cyclopropyl-1H-pyrrole-4-carboxylate
(3bb): The pyrrole 3bb (1.65 g, 91%) was obtained from tert-butyl cyclo-
propylpropiolate (2b) (830 mg, 5.0 mmol) and p-toluenesulfonylmethyl
isocyanide (1b) (997 mg, 5.5 mmol) with CuSPh as a catalyst following
GP3 (method C), after column chromatography (cyclohexane/ethyl ace-
tate 4:1) as a colorless solid. M.p. 1658C. Alternatively, it was prepared
following GP 1 (method A) with KOtBu as
a base (1.69 g, 93%).
1H NMR (300 MHz, CDCl3, 258C, TMS): d=9.93 (brs, 1H, NH), 7.75 (d,
J=8.4 Hz, 2H, Ts-CH), 7.38 (d, J=3.5 Hz, 1H, NCH), 7.26 (d, J=
8.4 Hz, 2H, Ts-CH), 2.38 (s, 3H, Ts-CH3), 1.78 (dddd, J=6.0, 6.0, 8.6,
8.6 Hz, 1H, CH), 1.48 (s, 9H, tBu), 0.85–0.74 ppm (m, 4H, cPr-CH2);
13C NMR (75.5 MHz, CDCl3, 258C): d=163.0 (C), 144.1 (C), 138.9 (C),
132.0 (C), 129.7 (CH), 127.0 (2 CH), 126.9 (C), 120.0 (C), 80.4 (C), 28.2
(CH3), 21.6 (CH3), 7.9 (CH2), 6.9 ppm (CH); IR (KBr): n˜ =3314, 3092,
3006, 2973, 2934, 1932, 1713, 1594, 1532, 1503, 1448, 1392, 1372, 1353,
1305, 1238, 1198, 1137, 1101, 1080, 1036, 1018, 967, 891, 813, 738, 677,
607, 532 cmÀ1; MS (EI): m/z (%): 361.1 (10) [M]+, 305.1 (100), 288.1
(18), 261.0 (39), 196.1 (30); HRMS (ESI): m/z: calcd for C19H24NO4S+
[M+H]+: 362.1421; found: 362.4626.
General procedure for the synthesis of 2,4-disubstituted pyrroles
3
(GP 4): Preactivated nanosize-copper powder (3.2 mg, 5 mol%) was
added to a mixture of methyl propiolate (2p) (84 mg, 1.0 mmol) and the
respective isocyanide 1 (1.0 mmol) in DMF (2 mL). The mixture was
stirred at 608C for 16 h, then the solvent was evaporated in vacuo, and
the residue was purified by column chromatography.
Methyl 2-(ethoxycarbonyl)-1H-pyrrole-4-carboxylate (3 fp):[47] The pyr-
role 3 fp (73 mg, 37%) was obtained from methyl propiolate (2p; 84 mg,
1.0 mmol) and ethyl isocyanoacetate (1 f; 113 mg, 1.0 mmol) following
GP4, after column chromatography (hexane/ethyl acetate 4:1, Rf =0.17)
as a colorless solid. M.p. 98–998C; 1H NMR (300 MHz, CDCl3, 258C,
TMS) d=9.98–9.76 (brs, 1H, NH), 7.55 (dd, J=3.2, 1.5 Hz, 1H, CH),
7.31 (dd, J=2.4, 1.6 Hz, 1H, NCH), 4.35 (q, J=7.0 Hz, 2H, CH2), 3.84 (s,
3H, CO2CH3), 1.37 ppm (t, J=7.2 Hz, 3H, Et-CH3); 13C NMR
(75.5 MHz, CDCl3, 258C): d=164.4 (C), 161.0 (C), 127.0 (C), 123.8 (CH),
117.8 (C), 115.8 (CH), 60.9 (CH2), 51.3 (CH3), 14.3 ppm (CH3); IR
(KBr):n˜ =3293, 2981, 1690, 1562, 1499, 1441, 1403, 1280, 1216, 1122, 1085,
1022, 989, 964, 927, 853, 762, 604, 504 cmÀ1; MS (EI) m/z (%): 197.0 (76)
[M]+, 166.1 (53), 152.1 (44), 120.1 (100); elemental analysis calcd (%) for
C9H11NO4: C 54.82, H 5.62, N 7.10; found: C 54.92, H 5.82, N 6.98.
Methyl 2-(4-toluenesulfonyl)-1H-pyrrole-4-carboxylate (3bp):[48] The pyr-
role 3bp (83 mg, 30%) was obtained from methyl propiolate (2p; 84 mg,
1.0 mmol) and tosylmethyl isocyanide (1b; 195 mg, 1.0 mmol) following
GP 4, after column chromatography (hexane/ethyl acetate 2:1, Rf =0.22)
as a colorless solid. M.p. 157–1588C. Alternatively, it was prepared with
KOtBu as a mediator (105 mg, 38%). 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=9.95 (brs, 1H, NH), 7.81 (d, J=8.1 Hz, 2H, Ts-CH), 7.53 (dd,
J=3.1, 1.6 Hz, 1H, CH), 7.30 (d, J=8.1 Hz, 2H, Ts-CH), 7.21 (dd, J=
3.1, 1.6 Hz, 1H, NCH), 3.80 (s, 3H, CO2CH3), 2.41 ppm (s, 3H, CH3);
13C NMR (75.5 MHz, CDCl3, 258C): d=163.8 (C), 144.6 (CH), 138.4 (C),
130.2 (C), 130.0 (2 CH), 127.3 (C), 127.1 (2 CH), 118.5 (C), 115.7 (CH),
51.6 (CH3), 21.6 ppm (CH3); IR (KBr): n˜ =3250, 2950, 1691, 1595, 1546,
1473, 1433, 1392, 1319, 1228, 1183, 1145, 1116, 1076, 1017, 988, 930, 857,
813, 766, 744, 706, 676, 623, 604, 535, 492 cmÀ1; MS (ESI): m/z (%): 302.0
[M+Na]+, 278.3 [MÀH]À; HRMS (ESI): m/z: calcd for C13H14NO4S+
[M+H]+: 280.06381; found: 280.06403.
tert-Butyl 2-cyano-3-cyclopropyl-1H-pyrrole-4-carboxylate (3db): The
pyrrole 3db (687 mg, 83%) was obtained from tert-butyl cyclopropylpro-
piolate (2b) (416 mg, 2.5 mmol) and cyanomethyl isocyanide (1d)
(198 mg, 3 mmol) following GP 2 (method B), after column chromatogra-
phy (cyclohexane/ethyl acetate 4:1) as a colorless solid. M.p. 1128C;
1H NMR (300 MHz, CDCl3, 258C, TMS): d=9.48 (brs, 1H, NH), 7.39 (d,
J=3.3 Hz, 1H, NHCH), 2.34–2.18 (m, 1H, CH), 1.05–0.89 (m, 4H, CH2),
1.56 ppm (s, 9H, tBu); 13C NMR (75.5 MHz, CDCl3, 258C): d=163.3 (C),
139.1 (C), 128.5 (CH), 118.7 (C), 114.1 (C), 99.4 (C), 80.8 (C), 29.7 (CH),
28.3 (CH3), 7.7 ppm (CH2); IR (film): n˜ =3232, 3012, 2977, 2931, 2220,
1683, 1668, 1560, 1379, 1264, 1155, 747 cmÀ1; MS (EI): m/z (%): 232.2
(15) [M]+, 176.2 (100), 158.1 (75), 130.1 (30), 104.1 (12), 57.1 (36); ele-
mental analysis calcd (%) for C13H16N2O2: C 67.22, H 6.94, N 12.06;
found: C 66.96, H 6.71, N 12.11.
Ethyl 2-(tert-butoxycarbonyl)-3-phenyl-1H-pyrrole-4-carboxylate (3eg):
The pyrrole 3eg (246 mg, 78%) was obtained from ethyl phenylpropio-
late 2g (174 mg, 1.0 mmol) and tert-butyl isocyanoacetate 1e (155 mg,
1.1 mmol) following GP 3 (method C) with Cu0-NP (3 mg, 0.05 mmol,
5 mol%) at 1208C, after column chromatography (cyclohexane/ethyl ace-
tate 4:1) as a colorless solid. M.p. 1258C; 1H NMR (300 MHz, CDCl3,
258C, TMS): d=10.18 (brs, 1H, NH), 7.53 (d, J=3.4 Hz, 1H, NCH),
7.38–7.20 (m, 5H, Ph), 4.08 (q, J=7.1 Hz, 2H, CH2), 1.25 (s, 9H, tBu),
1.07 ppm (t, J=7.1 Hz, 3H, CH3); 13C NMR (75.5 MHz, CDCl3, 258C):
d=164.0 (C), 161.1 (C), 134.6 (C), 131.7 (C), 130.0 (CH), 126.9 (CH),
126.7 (CH), 126.5 (CH), 122.4 (C), 117.0 (C), 81.5 (C), 27.9 (CH3),
13.9 ppm (CH3); IR (KBr): n˜ =3289, 3126, 3057, 2977, 2933, 1687, 1552,
1517, 1400, 1367, 1285, 1175, 1115, 1021, 840, 761, 695 cmÀ1; MS (EI): m/z
(%): 315.3 (43) [M]+, 259.2 (100), 241.1 (17), 214.2 (24), 196.2 (61); ele-
mental analysis calcd (%) for C18H21NO4: 68.55, H 6.71, N 4.44; found:
68.31, 6.50, 4.38.
GP A for the synthesis of 2,3-disubstituted pyrroles 6 (GP 5): An oven-
dried Schlenk flask equipped with magnetic stirrer and rubber septum,
was charged with CuBr (143.5 mg, 1.0 mmol), Cs2CO3 (326 mg, 1 mmol)
and DMF (5 mL), evacuated and refilled with nitrogen. The respective
acetylene 2 (1.0 mmol) was added from a syringe with stirring, and the
mixture was heated at 1208C for 10 min, then a solution of the respective
isocyanide 1 (2.0 mmol) in DMF (5 mL) was injected over a period of
2 h, after that the reaction mixture was stirred at 1208C for another 1 h.
Dimethyl 3-(thiophen-2-yl)-1H-pyrrole-2,4-dicarboxylate (3al): The pyr-
role 3al (250 mg, 94%) was obtained from methyl (thiophen-2-yl)propio-
late (2l) (166 mg, 1.0 mmol) and methyl isocyanoacetate (1a) (149 mg,
1.5 mmol) following GP 3 (method C) with Cu0-NP (3 mg, 0.05 mmol,
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233

A. de Meijere et al.
After cooling and evaporation of the solvent in vacuo, the residue was
purified by column chromatography on silica gel (eluting with 5:1 to 1:1
hexane/ethyl acetate) to provide the desired product.
109.8 (CH), 109.2 (C), 60.0 (CH2), 31.6 (CH3), 30.2 (CH3), 22.6 ppm (C);
iso-6 fw: 1H NMR (300 MHz, CDCl3, 258C, TMS): d=8.95 (brs, 1H,
NH), 6.83 (t, J=2.6 Hz, 1H, CH), 6.12 (t, J=2.6 Hz, 1H, CH), 4.31 (q,
J=7.2 Hz, 2H, CH2), 1.37 (t, J=7.2 Hz, 9H, tBu), 0.93 ppm (t, J=
7.2 Hz, 3H, CH3); 13C NMR (75.5 MHz, CDCl3, 258C): d=160.4 (C),
142.6 (C), 121.4 (C), 117.9 (CH), 111.4 (CH), 59.9 (CH2), 33.0 (CH3),
29.7 (CH3), 26.6 ppm (C); MS (EI) m/z (%): 195.2 (26) [M]+, 180.2 (28),
134.2 (100).
GP B for the synthesis of 2,3-disubstituted pyrroles 6 (GP 6): An oven-
dried Schlenk flask equipped with magnetic stirrer and rubber septum
was charged with CuBr (143.5 mg, 1.0 mmol), Cs2CO3 (326 mg, 1 mmol)
and DMF (5 mL), evacuated and refilled with nitrogen. The respective
acetylene 2 (1.0 mmol) was added from a syringe with stirring, and the
mixture was heated at 1208C for 10 min, then solutions of the respective
isocyanide 1 (1.0 mmol) and the respective acetylene 2 (1.0 mmol) in
DMF (5 mL) were injected over a period of 2 h, after that the reaction
mixture was stirred at 1208C for another 1 h. After cooling and evapora-
tion of the solvent in vacuo, the residue was purified by column chroma-
tography on silica gel (eluting with 5:1 to 1:1 hexane/ethyl acetate) to
provide the desired product.
4,5-Dihydro-1H-pyranoACTHNUTRGNE[UNG 3,4-b]pyrrol-7-one (7): The d-lactone-annelated
pyrrole 7 (51 mg, 37%) was obtained from ethyl isocyanoacetate (1 f;
113 mg, 1.0 mmol) and but-3-yn-1-ol (2z; 140 mg, 2.0 mmol) following
GP 6, as a colorless solid. M.p. 123–1248C. Alternatively, 7 was prepared
following GP 5 (61 mg, 44%). Rf =0.45 (hexane/ethyl acetate 1:1);
1H NMR (300 MHz, CDCl3, 258C, TMS): d=10.68 (brs, 1H, NH), 7.08
(t, J=2.8 Hz, 1H), 6.13 (t, J=2.8 Hz, 1H, CH), 4.56 (t, J=6.2 Hz, 2H,
CH2), 2.93 ppm (t, J=6.2 Hz, 2H, CH2); 13C NMR (75.5 MHz, CDCl3,
258C): d=161.2 (C), 130.8 (C), 126.4 (CH), 117.9 (C), 107.2 (CH), 69.5
(CH2), 23.0 ppm (CH2); IR (KBr): n˜ =3274, 1686, 1400, 1308, 1274, 1209,
1185, 1123, 1078, 1049, 1013, 773, 739, 599, 496, 460 cmÀ1; MS (EI) m/z
(%):137.1 (100) [M]+, 107.1 (42), 79.1 (78); elemental analysis calcd (%)
for C7H7NO2: C 61.31, H 5.14, N 10.21; found: C 61.51, H 4.98, N 10.18.
Ethyl 3-butyl-1H-pyrrol-2-carboxylate (6 fr): The pyrrole 6 fr (250 mg,
64%) was obtained from 1-hexyne (2r) (328 mg, 4 mmol), ethyl isocya-
noacetate (1 f) (226 mg, 2 mmol) following GP 6, after column chroma-
tography (hexane/ethyl acetate 4:1, Rf =0.45) as a colorless oil. Alterna-
tively it was obtained following GP 5 (273 mg, 70%). 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=9.10–8.89 (brm, 1H, NH), 6.81 (t, J=
3 Hz, 1H, CH), 6.10 (t, J=3 Hz, 1H, CH), 4.29 (q, J=7 Hz, 2H, Et-
CH2), 2.77 (t, J=8 Hz, 2H, CH2), 1.60–1.20 (m, 7H), 0.91 ppm (t, J=
8 Hz, 3H, Et-CH3); 13C NMR (75.5 MHz, CDCl3, 258C): d=161.7 (C),
133.3 (C), 121.5 (CH), 118.8 (C), 111.4 (CH), 59.9 (CH2), 33.0 (CH2),
26.6 (CH2), 22.6 (CH2), 14.4 (CH3), 13.9 ppm (CH3); IR (film): n˜ =3322,
2957, 2860, 1672, 1561, 1420, 1318, 1262, 1188, 1133, 1044, 783 cmÀ1; MS
(EI): m/z (%): 195 (72) [M]+, 153 (40), 124 (100), 106 (56), 80 (40); ele-
mental analysis calcd (%) for C11H17NO2: C 67.66, H 8.78, N 7.17; found:
C 67.71, H 8.51, N 7.02.
Acknowledgements
This work was supported by the Land of Niedersachsen and the Fonds
der Chemischen Industrie. A.V.L., V.S.K. and O.V.L. are indebted to the
Degussa-Stiftung (Degussa AG) for graduate student fellowships.
Ethyl 3-(methoxymethyl)-1H-pyrrole-2-carboxylate (6 fs): The pyrrole
6 fs (88 mg, 48%) was obtained from ethyl isocyanoacetate (1 f; 226 mg,
2.0 mmol) and 3-methoxypropyne (2s; 70 mg, 1.0 mmol) following GP 5
as a colorless solid. M.p. 748C; Rf =0.27 (hexane/ethylacetate 4:1). Alter-
natively, it was prepared following GP 6 (83 mg, 45%). 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=9.39 (brs, 1H, NH), 6.88 (t, J=
2.6 Hz, 1H, CH), 6.34 (t, J=2.6 Hz, 1H, CH), 4.69 (s, 2H, CH2), 4.34 (q,
J=7.2 Hz, 2H, Et-CH2), 3.43 (s, 3H, OCH3), 1.37 ppm (t, J=7.2 Hz, 3H,
CH3); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=161.2 (C), 128.4 (C),
121.9 (CH), 119.1 (C), 111.1 (CH), 67.2 (CH2), 60.3 (CH3), 58.1 (CH2),
14.4 ppm (CH3); MS (EI): m/z (%): 183.2 (40) [M+], 168.1 (52), 154.2
(45), 122.1 (100); IR (KBr): n˜ =3288, 1671, 1490, 1426, 1373, 1326, 1271,
1222, 1193, 1139, 1111, 963, 782, 751, 601 cmÀ1; elemental analysis calcd
(%) for C9H13NO3: C 59.00, H 7.15, N 7.65; found: C 59.06, H 6.80, N
7.35.
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Ethyl 3-cyclopropyl-1H-pyrrole-2-carboxylate (6 fv): The pyrrole 6 fv
(157 mg, 88%) was obtained following GP 5 from ethyl isocyanoacetate
(1 f; 226 mg, 2.0 mmol) and cyclopropylacetylene (2v; 66 mg, 1.0 mmol)
as a colorless solid. M.p. 51–528C; Rf =0.37 (hexane/ethyl acetate 5:1);
1H NMR (300 MHz, CDCl3, 258C, TMS): d=8.92 (brs, 1H, NH), 6.79 (t,
J=2.9 Hz, 1H, CH), 5.78 (t, J=2.9 Hz, 1H, CH), 4.35 (q, J=7.2 Hz, 2H,
CH2), 2.57–2.48 (m, 1H, cPr-CH), 1.37 (t, J=7.2 Hz, 3H, CH3), 0.99–0.93
(m, 2H, cPr-CH2), 0.64–0.59 ppm (m, 2H, cPr-CH2); 13C NMR
(75.5 MHz, CDCl3, 258C): d=161.7 (C), 135.5 (C), 121.9 (CH), 119.7 (C),
106.2 (CH), 60.0 (CH2), 14.5 (CH), 9.3 (CH2), 7.9 ppm (CH2); IR (KBr):
n˜ =3299, 1673, 1422, 1391, 1322, 1279, 1218, 1185, 1141, 1036, 907, 781,
745, 602 cmÀ1; MS (EI) m/z (%): 179.2 (100) [M]+, 150.2 (45), 133.2 (39),
106.2 (62); elemental analysis calcd (%) for C10H13NO2: C 67.02, H 7.31,
N 7.82; found: C 67.66, H 6.80, N 7.36.
Ethyl 3-tert-butyl-1H-pyrrole-2-carboxylate (9 fq) and ethyl 4-tert-butyl-
1H-pyrrole-2-carboxylate (iso-6 fw):[49] A 5:1 mixture of the regioisomeric
pyrroles 6 fw and iso-6 fw (10 mg, 5%) was obtained following GP 6
from ethyl isocyanoacetate (1 f; 113 mg, 1.0 mmol) and tert-butylacety-
lene (2w; 164 mg, 2.0 mmol) as a colorless oil, Rf =0.43 (hexane/ethyl
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1
acetate 4:1). 6 fw: H NMR (300 MHz, CDCl3, 258C, TMS): d=9.16 (brs,
1H, NH), 6.78 (t, J=2.6 Hz, 1H, CH), 6.21 (t, J=2.6 Hz, 1H, CH), 4.32
(q, J=7.2 Hz, 2H, CH2), 1.40 (s, 9H, tBu), 1.25 ppm (s, 3H, CH3);
13C NMR (75.5 MHz, CDCl3, 258C): d=160.4 (C), 142.6 (C), 120.0 (CH),
234
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Chem. Eur. J. 2009, 15, 227 – 236

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