A new access to 2-(alkylamino)- and 2-(arylamino)pyrroles by addition of isocyanides to protonated 1-azabutadienes

Article abstract of DOI:10.1002/(SICI)1099-0690(199907)1999:7<1729::AID-EJOC1729>3.0.CO;2-S

A number of 5-(alkylamino)- or 5-(arylamino)-2H-pyrrolium salts 3 or 5 have been obtained by treating the 1-aza-1,3-diene hydrochlorides 2 with isocyanides R⁴NC in refluxing acetonitrile or chloroform for a few hours. Depending on the experimental conditions, deprotonation of these species can occur in the reaction medium to furnish the corresponding 2-aminopyrroles 4 and 6. Insertion of isocyanide into a carbonhydrogen bond of the pyrrolium salts can also lead to the generation of the (pyrrol-2-yl)methyleneiminium chlorides 79. Under similar conditions, treatment with an excess of tert- butyl isocyanide converts the protonated α-chlorocinnamaldimines 2j,k into the 5-(tert-butylamino)-pyrrole-2-carbonitriles 13. Structural assignments of all the cycloadducts have been made on the basis of their NMR-spectroscopic properties, particularly the effects observed in NOEDIFF experiments. Mechanisms are suggested to account for the ring-closure reactions and autoxidation of pyrroles 4 and 6 under atmospheric oxygen to give the 5- imino-2-pyrrolinones 17 and 18.

Full text of DOI:10.1002/(SICI)1099-0690(199907)1999:7<1729::AID-EJOC1729>3.0.CO;2-S

FULL PAPER
A New Access to 2-(Alkylamino)- and 2-(Arylamino)pyrroles by Addition
of Isocyanides to Protonated 1-Azabutadienes
Evelyne Marchand,[a] Georges Morel,*[a] and Sourisak Sinbandhit[b]
Keywords: Azabutadienes / Isocyanides / Cycloadditions / 1H-Pyrroles / Autoxidation
A number of 5-(alkylamino)- or 5-(arylamino)-2H-pyrrolium
salts 3 or 5 have been obtained by treating the 1-aza-1,3-
diene hydrochlorides 2 with isocyanides R4NC in refluxing
acetonitrile or chloroform for a few hours. Depending on the
experimental conditions, deprotonation of these species can
occur in the reaction medium to furnish the corresponding 2-
aminopyrroles 4 and 6. Insertion of isocyanide into a carbon–
hydrogen bond of the pyrrolium salts can also lead to the
generation of the (pyrrol-2-yl)methyleneiminium chlorides 7–
9. Under similar conditions, treatment with an excess of tert-
butyl isocyanide converts the protonated α-chloro-
cinnamaldimines 2j,k into the 5-(tert-butylamino)-pyrrole-2-
carbonitriles 13. Structural assignments of all the
cycloadducts have been made on the basis of their NMR-
spectroscopic properties, particularly the effects observed in
NOEDIFF experiments. Mechanisms are suggested to
account for the ring-closure reactions and autoxidation of
pyrroles 4 and 6 under atmospheric oxygen to give the 5-
imino-2-pyrrolinones 17 and 18.
Substituted pyrroles are a class of heterocycles of con- roles or related compounds,[5,11,12] can be classified as
siderable interest owing to their wide distribution in nature C2ϩC2 methods.
and the remarkable diversity of their biological activities.
They form part of the molecular structure of many alka-
loids and natural macrocycles (hemes, bile pigments,
chlorophylls, etc.) and are used in constructing attractive
materials such as porphyrins,[1] expanded porphyrins and
their heterologs,[2] porphyrazines,[3] and open-chain polyp-
yrroles.[4]
Scheme 1. Straightforward route to 2-aminopyrroles
Consequently, it is not surprising that a vast amount of
work has and is still being devoted to the development of
Despite the large number of published methods for the
practical methods for the synthesis of pyrroles bearing ap-
propriate substitution patterns.[5][6] In connection with our
ongoing interest in the chemistry of isocyanides and es-
pecially in their formal [1ϩ4] cycloadditions to conjugated
diaza and azathiadienes[7] or related iminium salts,[8Ϫ10] we
wondered whether it might be possible, under suitable con-
ditions, to utilize the 1-azabutadiene system 1 in a similar
procedure. If successful, this reaction with subsequent aro-
matization could provide a useful and straightforward route
to N-substituted 2-aminopyrroles (Scheme 1). The main
characteristic of this method is clearly the construction of
the ring by formation of both the N(1)ϪC(2) and the
C(2)ϪC(3) bonds. This is a rather new and scarcely applied
approach in pyrrole synthesis. It can be classified as C3ϩC1
in terms of the number of carbon atoms supplied to the
heterocycle by the starting reagents.[5] In this way, the base-
catalyzed reactions of acidic isocyanides with Michael ac-
ceptors, that have been known for many years to give pyr-
elaboration of various pyrroles, relatively few examples have
been reported for the preparation of simple 2-amino deriva-
tives. Most compounds of this type have been obtained by
reaction of a nitrogen-two-carbon compound with an ap-
propriate two-carbon unit (C2ϩC2), e.g. base-promoted
condensation of an α-amino ketone[13] or a conjugated
azoalkene[14] with a nitrile containing an active methylene
group; 1,3-dipolar cycloaddition of conjugated azoalkenes
with 1-propynyldiethylamine;[15] or base-induced 1,3-di-
polar cycloaddition of 4,5-diaminothiazolium salts with
electrophilic alkynes.[16] Other miscellaneous and limited
methods were also described in the review by Trofimov et
al.[5b] In particular, nickel- and palladium-catalyzed reac-
tions of alkynes with a large excess of either tert-butyl isocy-
anide[17] or trimethylsilyl cyanide[18] led to the generation
of the corresponding 5-aminopyrrole-2-carbonitriles ac-
cording to unexplained processes.
Our assumption that α,β-unsaturated aldimines might be
involved in the route depicted in Scheme 1 was supported
by the known nucleophilic behaviour of isocyanides[19] as
well as numerous precedents in analogous reactions with
electron-deficient heterodienes.[11] Notably, there have been
several literature studies dealing with the addition of isocy-
anides to 2-azabutadiene and 1,3-diazabutadiene systems.
For instance, it has been shown that a protic acid induces
[a]
`
`
Laboratoire de Synthese et Electrosynthese organiques, UMR
´
6510, Universite de Rennes I,
Campus de Beaulieu, F-35042 Rennes Cedex, France
Fax: (internat.) ϩ 33-2/99286738
E-mail: Georges.Morel@univ-rennes1.fr
[b]
´
´
Centre Regional de Mesures Physiques de lЈOuest, Universite de
Rennes I,
Campus de Beaulieu, F-35042 Rennes Cedex, France
Eur. J. Org. Chem. 1999, 1729Ϫ1738
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0707Ϫ1729 $ 17.50ϩ.50/0
1729

E. Marchand, G. Morel, S. Sinbandhit
FULL PAPER
the reaction of tert-butyl isocyanide with arylideneanilines
to afford 2-aryl-3-(tert-butylamino)indoles.[20] The uncata-
lyzed [1ϩ4] cycloadditions of N-arylketene imines,[21] vinyl
carbodiimides,[22] and vinyl isocyanates[23] are also known
to produce highly functionalized dihydroindoles and di-
hydropyrroles. About ten years ago, we found that the pro-
tonation of 1,3-diazabutadienes markedly increases their re-
activity towards isocyanides.[8] By similar reasoning, we
have explored the treatment of chloro imino sulfides or
phenyl chlorodithioformate with aldimines, azines, or di-
methylthioformamide in the presence of isocyanides as new
routes to 4-aminoimidazolium[9] or 5-aminothiazolium[10]
salts. Such useful synthetic methodologies involve imidoyl-
or (thiocarbonyl)iminium chlorides as transient intermedi-
ates, which readily undergo cycloaddition reactions.
In contrast, only isolated efforts have been made to carry
out similar transformations of 1-azabutadiene. To the best
of our knowledge, [1ϩ4] cycloadditions of this type have
been limited to the preparation of diiminopyrroles from im-
idoylketene imines[22] and the preparation of 1-aminoisoin-
dole derivatives from 1,4-benzoquinone or naphthoqui-
none[24] and 5,8-quinoxalinediones.[25] In the latter reac-
tions, the authors assumed the first step of the sequence to
be a formal insertion of isocyanide into a carbonϪhydrogen
bond. The 1-azadiene species was formed as an intermedi-
ate and addition of a second isocyanide molecule led to the
observed 1:2 adduct.[24][25]
Scheme 2. Protonation of α-methylenaldimines
overnight, the 2H-pyrrolium salt 3a was isolated in 47%
yield after purification. Conversion of 3a to unprotonated
pyrrole 4a was readily carried out in CHCl3 solution by
treatment with triethylamine or aluminium oxide. Struc-
tural assignments of products 3a, 4a will be rationalized
below. It is interesting to note at this point that they are at
variance with the related stuctures 5, 6, which may be ex-
pected considering the common cycloaddition process
(Scheme 3).
The purpose of the present study is to develop the scope
of the novel one-step procedure outlined in Scheme 1 and
to report our observations on the stability of α-aminopyr-
roles and pyrrolium salts.
Results and Discussion
Preparation of 2-Aminopyrrole Derivatives
The starting α-methylenaldimines 1 were readily access-
ible from the corresponding aldehydes by condensation
with appropriate primary amines.[26] Most of our examples
were based on trans-cinnamaldimines and α-methyl- or α-
chloro-trans-cinnamaldimines. Attempts to prepare 2-amin-
opyrroles by treatment of heterodienes 1 with isocyanides
were generally unsuccessful, the starting dienes 1 being
completely recovered even after prolonged heating at reflux
in acetonitrile containing a large excess of tert-butyl isocy-
anide.
Scheme 3. Reactions of 1-azabutadiene hydrochlorides with iso-
cyanides
Consequently, and according to the procedure mentioned
above, we decided to examine the HCl-catalyzed modifi-
cation of this cycloaddition reaction. The hydrochloride
Various 1-azabutadiene hydrochlorides 2 and isocyanides
salts 2 were quantitatively obtained from the Schiff bases 1 have been tested in this reaction, under a range of exper-
by treatment with gaseous HCl in anhydrous Et2O, and imental conditions; the results are collected in Table 1. They
were easily isolated as crystalline materials (Scheme 2).
are consistent with the following interpretations:
Studies of the reactions of the iminium chlorides 2 with
1. Depending on the nature of starting compounds, either
isocyanides were undertaken in MeCN and CHCl3 solu- the anticipated cycloadducts 5, 6 or the rearranged counter-
tions. Extended reflux times were frequently required. Thus, parts 3, 4 are obtained. A significant example is the forma-
when a twofold excess of tert-butyl isocyanide was added to tion of the same isomeric 3-methyl-2H-pyrrolium salt 3f,
2a in dry acetonitrile and the resulting mixture was refluxed using the N-protonated azadienes 2e and 2f derived from
1730
Eur. J. Org. Chem. 1999, 1729Ϫ1738

A New Access to 2-(Alkylamino)- and 2-(Arylamino)pyrroles
FULL PAPER
reported previously.[27] We have verified that the salt 3a re-
adily adds tert-butyl isocyanide in dry refluxing MeCN
solution, giving the corresponding hydrochloride 7a in good
yield. The compounds 9j,k were characterized as their un-
protonated species 10 after treatment with Al2O3 (entries
14Ϫ16).
2. As expected, the cycloaddition was clearly faster and
higher yields of the unprotonated pyrrole were obtained
when the concentration of the isocyanide was increased.
However, these conditions also promoted the insertion reac-
tion (entries 1, 2).
3. CH3CN proved to be more effective as the solvent than
CHCl3 (see, for instance, entries 7, 8), but also increased the
proportion of insertion products (compare entry 10 with
entry 11 and entry 14 with entry 15).
4. N-Tosyl α,β-unsaturated aldimines show higher reac-
tivity in such cyclizations, owing to the enhancement of
their electrophilic properties. Thus, satisfactory efficiencies
were observed even upon reaction of unprotonated deriva-
tives 1d,i with tert-butyl isocyanide (entries 6, 17).
The formation of pyrrolium salts 3, 5 from N-protonated
1-azabutadienes 2 can be rationalized in terms of the ad-
dition of isocyanide to the electrophilic terminal C-4,
thereby giving a transient nitrilium chloride in the initial
step (Scheme 5). Straightforward ring-closure reaction takes
Scheme 4. Insertion reaction of isocyanides into pyrrolium salts
trans-crotonaldehyde and methacrolein (entries 7, 8, 9). place by nucleophilic attack of the amino nitrogen atom on
Some reactions also provided small quantities of the (pyr- the nitrilium carbon atom (path a). Subsequent tautome-
rol-2-yl)methyleniminium chlorides 7, 8, 9, which requires rism yields the anticipated salt 5. Protonation of pyr-
a formal insertion of isocyanide into a carbonϪhydrogen roles,[28] especially of 2-aminopyrroles[13], is known to occur
bond of the pyrrolium salts 3, 5 (Scheme 4). Insertion reac- at the 5-position rather than at the heteroatom, thereby pro-
tions of isocyanides into pyrroles in acidic media have been ducing a cyclic amidinium species.
Table 1. Reactions of 1-azabutadiene systems with isocyanides
Entry
Reactants
Diene
Reaction conditions[a]
Solvent
Products [yield (%)][c]
Isocyanide (R4)
R4NC/2
Time[b] (h)
1
2
3
4
5
6
7
8
9
10
2a
2a
2a
2b
2c
1d
2e
2e
2f
tBu
2
MeCN
MeCN
CHCl3
CHCl3
CHCl3
MeCN
MeCN
CHCl3
MeCN
MeCN
15
24[d]
120
20
15
90
0.5
6
3a (47); 7a (13)
4a (25); 7a (37)
6b (45)
tBu
3
2,6-Me2C6H3
tBu
2
2.5
2
6c (44)
tBu
6d (40)
tBu
2
6e (71)
tBu
2
3f (55)
tBu
2
3f (40)
tBu
2
0.5
2
3f (50)
2g
tBu
3
4g ϩ 6g[e] (30);
7g (17); 8 (17)
4g ϩ 6g[e] (35);
7g (14); 8 (14)
5h (45)
11
2g
tBu
3
CHCl3
5
12
13
14
15
16
17
18
19
20
21
2g
2g
2h
2h
2h
1i
Et
2.5
2
CHCl3
CHCl3
MeCN
CHCl3
MeCN
MeCN
CHCl3
MeCN
CHCl3
CHCl3
17
36
3
2,6-Me2C6H3
5i (65)
tBu
tBu
3
6j (30); 10j (37)
6j (37); 10j (31)
5k (35); 10k (10)
6l (63)
3
7
2,6-Me2C6H3
2
70
96
2
tBu
tBu
tBu
tBu
tBu
2
2j
3
13a (55)
2k
2k
15
3
0.5
2
120
13b (45)
3
13b (40)
3
16 (35)
[a] The reactions were performed in refluxing solvents, starting from a 0.4  solution of salt 2. Ϫ [b] Times required for complete conversion
[c]
of the azabutadiene system. Ϫ Yields of purified products after flash chromatography on silica gel and/or crystallization. Ϫ [d] 1H-
NMR analysis of the mixture obtained after a shorter reaction time (5 h) revealed complete cyclization of 2a and the formation of the
[e]
1
salts 3a and 7a (60:40). Ϫ 4g/6g ഠ 75:25 (by H-NMR estimated composition of the crude mixture).
Eur. J. Org. Chem. 1999, 1729Ϫ1738
1731

E. Marchand, G. Morel, S. Sinbandhit
FULL PAPER
Another possibility (path b) is rearrangement of the ini-
tially generated nitrilium salt by a 1,2-proton transfer, as
reported in analogous examples.[24][25] The resulting inser-
tion product 11 or 12 furnishes the 2-aminopyrrolium salt
3 or 5 through an intramolecular attack of the imino nitro-
gen atom on the iminium moiety.
Scheme 6. Reaction of protonated α-chlorocinnamaldimines with
tert-butyl isocyanide
Scheme 7. Reaction of protonated 2-(formimidoyl)thiophene with
tert-butyl isocyanide
Air-Induced Oxidation of 2-Aminopyrroles
Autoxidation of monocyclic pyrroles to form various car-
bonyl compounds and peroxidic polymers has some pre-
cedence in the literature.[30][31] The pyrroles 4, 6 proved to
be less stable than the corresponding pyrrolium salts 3, 5,
being oxidized to complex mixtures on leaving them to
stand exposed to atmospheric oxygen at room temperature.
The major product of the reactions starting from 4a or
6i؊k was identified as the 5-imino-2-pyrrolinone 17 or 18,
generated by addition of O2 and loss of H2O. This conver-
sion may be rationalized in terms of the addition of triplet
oxygen to the electron-rich 2-aminopyrrole and spon-
taneous dehydration of the transient peroxide (see Scheme
8 for the representative formation of pyrrolinone 17). Simi-
lar air-induced oxidations have recently been mentioned in
related studies.[9a,10b,32]
The 2-cyanopyrroles 13 exhibit good stability upon expo-
sure to air. Likewise, the pyrrole hydrochlorides 7, 8, 9 do
not show any sensitivity to oxygen. On the contrary, the
unprotonated 2-(formimidoyl)pyrrole 10k was readily con-
verted into the 5-imino-2-pyrrolinol 19. The related com-
pound 10j was hydrolyzed in the course of silica gel chro-
matography to afford the 2-pyrrolecarboxaldehyde 20.
Scheme 5. Postulated mechanisms for the formation of pyrrolium
salts
In order to extend the scope of this method, the pro-
tonated α-chlorocinnamaldimines 2j,k were treated under
similar conditions with excess tert-butyl isocyanide. The 5-
aminopyrroles 13, bearing a cyano group at the 2-position,
were the somewhat surprising products of this reaction
(Table 1, entries 18Ϫ20). Their formation certainly involves
the 2-cyano-1-azabutadiene hydrochlorides 14 as reactive
intermediates, which cyclize according to the aforemen-
tioned route a. The formation of azadienes 14 presumably
proceeds by the addition of isocyanide at the 2-position of
the 3-chloro-1-azabutadiene systems 2j,k, followed by elim-
ination of isobutene and HCl as seen in the overall mecha-
nism outlined in Scheme 6.
Imines derived from 2-thiophenecarboxaldehyde are
interesting substrates in similar reactions as they can lead
to the formation of fused pyrrole derivatives. However, the
addition of tBuNC to the iminium salt 15 required pro-
longed reflux under standard conditions and provided
mainly the 2,3-bis(tert-butylimino)azetidine 16 (Table 1, en-
try 21). This reaction involves a [1ϩ1ϩ2] cycloaddition of
Structural Assignments
All structures were supported by NMR-spectroscopic
two isocyanide molecules across the CϪN double bond evidence, high-resolution mass-spectral data, and satisfac-
(Scheme 7). Similar 2:1 addition patterns giving rise to four- tory elemental analyses (see Experimental Section). Where
membered heterocyclic compounds have been reported pre- necessary, unambiguous 1H- and 13C-NMR assignments
viously in the literature.[11,20,29]
were derived from decoupling experiments, either by selec-
1732
Eur. J. Org. Chem. 1999, 1729Ϫ1738

A New Access to 2-(Alkylamino)- and 2-(Arylamino)pyrroles
FULL PAPER
on similar 4- and 5-unsubstituted 1H-pyrroles (3J ϭ
2.4Ϫ3.1 Hz).[33][34] The protons 3-H and 5-H in cycload-
ducts 4a and 4f couple only with 2.1Ϫ2.4 Hz, in agreement
with the lower values of long-range coupling constants
found for structurally related pyrroles (4J
ϭ
1.4Ϫ2.5 Hz).[33][34] The isomeric assignment of compounds
6g؊l (R2 ϭ CH3) was also deduced from a very low coup-
ling constant between the methyl protons on C-4 and the
proton on C-5 (4J ϭ 0.7Ϫ1 Hz).[34]
Selected 13C-NMR data are given in Tables 2 and 3.
Spectra of 2-aminopyrroles 4, 6 feature a large doublet for
carbon atom C-5 (δ ഠ 115, 1J ϭ 180Ϫ194 Hz) and another
doublet at about δ ϭ 106 for carbon atom C-3 or C-4 when
R2 ϭ H (1J ϭ 166Ϫ173 Hz). These values compare favour-
1
ably with chemical shifts and typical JCH values for a pyr-
role nucleus.[35] The multiplicity of the signal attributed to
C-5 conclusively establishes the structure 4 or 6. For ex-
ample, this carbon atom gives rise to a doublet in the case
of 4g and a doublet of quadruplets in the case of 6g as a
result of an additional long-range coupling with the three
protons of R2 (3JCCCH ϭ 4.5 Hz). The multiplicity of the
methyl carbon atom on C-3 or C-4 (R2) confirms these as-
signments.
Scheme 8. Air-induced oxidation of 2-aminopyrroles
tive irradiations or by addition of D2O in the case of com-
pounds 7, 8.
In particular, accurate determination of the coupling con-
stants between the protons on endocyclic carbon atoms al-
lows the isomers 4a؊f and 6a؊f to be distinguished. Thus,
The 2-cyanopyrroles 13a,b have been fully characterized
the protons 4-H and 5-H in cycloadducts 6b؊e couple with by their IR- and 13C-NMR-spectroscopic properties and by
1
values between 3.1Ϫ3.8 Hz, consistent with literature data comparing the H-NMR-spectral data of the known com-
Table 2. NMR chemical shifts and multiplicities for the main carbon atoms of 2-aminopyrroles[a,b]
No. C-2
C-3
C-4
C-5
CH3 (R2 or R3)
CHϭNR4,
CϵN or CHϭO
(1J ϭ 126 Hz)
4a
137.1 (t, 2J ϭ 3J ϭ 7) 100.1 (dd, 1J ϭ 167,
3J ϭ 6)
120.2 (m)
110.1 (dd, 1J ϭ
182, 3J ϭ 6)
4f[c] 135.9 (t, 2J ϭ 3J ϭ 7) 103.1 (dm, 1J ϭ 166) 114.3 (m)
110.7 (dm, 1J ϭ 181) 12.4 (qt, 3J ϭ 2.1)
112.9 (d, 1J ϭ 181) 13.3 (q)
4g[d] 133.7 (m)
112.9 (qd, 2J ϭ
121.2 (m)
3J ϭ 6)
120.5 (m)
6b
6c
6d
6e
128.0 (t, 3J ϭ 7.2)
104.8 (dd, 1J ϭ
170, 2J ϭ 6.5)
107.2 (dd, 1J ϭ
169, 2J ϭ 6)
115.4 (dd, 1J ϭ 184,
2J ϭ 7.5)
130.0 (td, 3J ϭ
7 and 2)
118.5 (m)
120.0 (m)
124.4 (m)
122.2 (m)
119.0 (m)
112.5 (ddd, 1J ϭ 182,
2J ϭ 7.5, 3J ϭ 4.5)
117.0 (ddd, 1J ϭ 186,
2J ϭ 7.5, 3J ϭ 4.5)
119.5 (dd, 1J ϭ
131.6 (br. t, 3J ϭ
7.5)
107.1 (dd, 1J ϭ
170, 2J ϭ 6)
134.2 (dd, 3J ϭ
7.3 and 4.6)
113.6 (dd, 1J ϭ
173, 2J ϭ 7.7)
113.7 (qd, 2J ϭ 6)
194, 2J ϭ 6.6)
6g[d] 132.3 (d, 3J ϭ 6.8)
112.8 (dq, 1J ϭ 181, 11.5 (qd, 3J ϭ 2.8)
3J ϭ 4.5)
6i[c]
6j
128.7 (d, 3J ϭ
113.5 (qd, 2J ϭ 6.2) 112.7 (dq, 1J ϭ 182, 11.6 (qd, 3J ϭ 1.9)
3J ϭ 5.6)
7.4)
130.6 (dd, 3J ϭ 6.9 and 118.2 (m)
115.4 (qd, 2J ϭ 6.2) 110.2 (dm, 1J ϭ 180) 11.6 (qd, 3J ϭ 2)
1)
6k[c] 128.3 (dd, 3J ϭ
117.0 (m)
123.1 (m)
115.6 (qd, 2J ϭ 6)
110.0 (dm, 1J ϭ 181) 11.9 (qd, 3J ϭ 1.9)
8 and 4.8)
6l
134.9 (d, 3J ϭ 4.9)
122.2 (qd, 2J ϭ 6.5) 116.0 (dq, 1J ϭ 192, 11.7 (qd, 3J ϭ 3)
3J ϭ 6.4)
10j
123.3 (m)
121.7 (qd, 2J ϭ
6.3, 3J ϭ 3.7)
120.3 (m)
134.3 (d, 3J ϭ 3.6)
11.7 (q)
10.5 (q)
147.4 (d, 1J ϭ 152)
13a
13b
99.3 (d, 2J ϭ 7.5)
122.8 (d, 1J ϭ 175)
120.9 (d, 1J ϭ 175)
122.6 (m)
120.3 (m)
138.4 (d, 3J ϭ 7.9)
135.6 (dd, 3J ϭ
8 and 3)
117.4 (d, 3J ϭ 2.5)
115.7 (d, 3J ϭ 2.3)
96.5 (t, 2J ϭ 3J ϭ 6)
20
124.6 (dm, 2J ϭ 27.6) 134.4 (q, 2J ϭ 6.2)
121.2 (m)
141.5 (d, 3J ϭ 3.4)
175.8 (d, 1J ϭ 170)
[a]
[b]
δ (ppm) and J (Hz) in CDCl3 solutions at 75.5 MHz. Ϫ The endocyclic carbon atoms are numbered in such a way that the amino
group is at C-2 in pyrroles 4, 6 and at C-5 in pyrroles 10, 13, 20. The multiplicities of signals attributed to ring-connected exocyclic car-
[c]
bon atoms can unequivocally establish the isomeric structure. Ϫ From a CDCl3 solution of pyrrolium salt in the presence of Al2O3.
Ϫ
[d]
In a 75:25 mixture of the isomers 4g, 6g.
Eur. J. Org. Chem. 1999, 1729Ϫ1738
1733

E. Marchand, G. Morel, S. Sinbandhit
FULL PAPER
Table 3. Selected 13C-NMR data for 2H-pyrrolium salts 3, 5 and other pyrrole derivatives[a,b]
No.
C-2
C-3
C-4
C-5
CH3 (R2 or R3)
CHϭNR4
(1J ϭ 128 Hz)
(1J ϭ 164Ϫ171 Hz)
3a
3f
58.0 (td, 1J ϭ
145, 3J ϭ 7.1)
60.3 (tm, 1J ϭ
144)
161.2 (m)
163.3 (m)
157.9 (m)
159.4 (m)
159.3 (m)
148.2 (m)
113.3 (dm, 1J ϭ 178) 162.9 (d, 2J ϭ 7.9)
116.7 (dm, 1J ϭ 179) 162.6 (d, 2J ϭ 9)
15.1 (qd, 3J ϭ 2.9)
13.2 (q)
5h
5i
59.4 (tq, 1J ϭ
144, 3J ϭ 4.3)
59.9 (tq, 1J ϭ
144, 3J ϭ 4)
55.6 (tm, 1J ϭ
143)
131.0 (m)
131.7 (m)
131.2 (m)
161.4 (s)
161.2 (s)
161.4 (s)
13.3 (q)
5k
7a
13.7 (q)
114.4 (m)
101.2 (dt, 1J ϭ 176, 151.7 (dd, 2J ϭ
135.9 (d)
3J ϭ 5.3)
109.6 (m)
116.3 (m)
6.7 and 1.2)
150.3 (br)
149.5 (br)
7g
8
17
18i
18j
19
115.5 (m)
144.6 (m)
9.0 (q)
10.1 (q)
135.0 (d)
132.6 (d)
115.8 (m)
139.6 (m)
169.7 (d, 3J ϭ 10)
171.5 (q, 3J ϭ 4)
170.2 (m)
140.2 (t, 3J ϭ 4)
139.0 (q, 2J ϭ 7.2)
141.3 (q, 2J ϭ 7.3)
147.4 (q, 2J ϭ 7.4)
119.0 (d, 1J ϭ 175) 152.8 (d, 2J ϭ 8)
137.1 (m)
136.1 (m)
137.0 (m)
152.6 (s)
9.0 (q)
9.5 (q)
10.8 (q)
146.0 (d, 3J ϭ 2.5)
152.6 (d, 3J ϭ 5.4)
92.3 (dq, 2J ϭ
14.3, 3J ϭ 3)
164.3 (dd, 3J ϭ 2)
[a]
[b]
δ (ppm) and multiplicities [J (Hz)] in CDCl3 solutions at 75.5 MHz. Ϫ The ring carbon atoms are numbered in such a way that the
amino group or imino nitrogen atom is at C-5.
Table 4. NOEDIFF experiments for some 2-aminopyrroles 4, 6 and 5-amino-2-(formimidoyl)pyrrole hydrochlorides 7, 8[a]
Compound
Selective irradiation
δ
Enhancement
δ
NOE (%)
Protons
Protons
4a
1.31
1.66
6.17
6.88
0.94
2-(NtBu)
1-tBu
6.17
6.88
7.50
7.50
7.54
7.65
7.03
7.54
7.65
7.00
5.97
6.11
7.35
7.35
4.78
7.24
6.74
7.07
11.06
4.95
11.81
7.07
7.22
4.95
3-H
11
7
5-H
3-H
4-Ph[b]
9
5-H
2-(NtBu)
4-Ph[b]
10
4
6e
7a
3-Ph[b]
1-Tos[b]
5-H
3
6.34
4-H
11
5
3-Ph[b]
7.03
1.40
1.46
5-H
1-Tos[b]
2-(CHϭNϩ)
4-H
3
2-(CϭNϩtBu)
5-(NtBu)
16
23
14
5
5-(NH)
5.97
7.00
1.85
4-H
3-Ph[b]
2-(CHϭNϩ)
4-Me
3-Ph[b]
6
7g
8
5-(NH)
7
3-Ph[b]
4
7.24
1.48
3-Ph[b]
2-(CHϭNϩ)
2-(CHϭNϩ)
2-(CϭNϩH)
5-(NH)
1-H
10
15
5
2-(CϭNϩtBu)
1.57
2.13
7.22
5-(NtBu)
3-Me
20
11
19
6
2-(CHϭNϩ)
4-Ph[b]
4-Ph[b]
5-(NH)
5
[a]
[b]
δ (ppm) in CDCl3 solutions at 300 MHz. Ϫ Aromatic ortho protons.
pound 13a with those reported in the literature.[17] The mul- stituents (Table 4). These explicit NOE perturbations also
tiplicity of the cyano carbon atom signal is significant as it corroborate the chemical shift assignments collected in the
shows coupling to the proton on C-3 (3JCCCH ഠ 2.4 Hz).
The structures of the 2-aminopyrroles 10, 20, the 2H-
pyrrolium salts 3, 5, and other pyrrole derivatives were de-
termined by similar carbon resonance observations, as indi-
cated in Tables 2 and 3. Additionally, the substitution pat-
terns of the pyrrole hydrochlorides 7, 8 and representative
Experimental Section.
Conclusion
We have shown that nucleophilic attack by isocyanides
2-aminopyrroles 4a, 6e were unequivocally established by on acyclic 1-aza-1,3-dienes and subsequent ring-closure re-
NOEDIFF experiments. Significant enhancements were ob- action require initial protonation at the nitrogen atom. The
served, which revealed the relative positions of various sub- novelty of our methodology lies in the generation and for-
1734
Eur. J. Org. Chem. 1999, 1729Ϫ1738

A New Access to 2-(Alkylamino)- and 2-(Arylamino)pyrroles
FULL PAPER
1-Isopropyl-4-phenyl-1-aza-1,3-butadiene Hydrochloride (2b): M.p.
125°C (1.9 g, 60% yield). Ϫ 1H NMR (200 MHz): δ ϭ 1.54 (d, J ϭ
6.7 Hz, 6 H), 4.30 (m, 1 H), 7.30Ϫ8.20 (m, 7 H), 9.20 (d, J ϭ 9 Hz,
1 H, 2-H), 14.20 (br., NH).
mal [1ϩ4] cycloaddition of C-vinyliminium ions. This ap-
proach opens an unprecedented and useful route to 2-
(alkyl- or arylamino)pyrroles that are not easily accessible
by other methods. A mechanism is suggested to account
for the unexpected rearrangement that was observed in the
course of some sequences. Although synthetic application
might appear to be limited by modest yields, owing princi-
pally to the insertion reaction of isocyanide into the pyr-
rolium salts, this is offset by the ready availability of the
starting materials and the simplicity of process.
1-(Diphenylmethyl)-4-phenyl-1-aza-1,3-butadiene Hydrochloride (2c):
M.p. 189°C (MeCN/CHCl3) (3.0 g, 70% yield). Ϫ 1H NMR
(200 MHz): δ ϭ 6.40 (s, 1 H), 7.25Ϫ7.60 (m, 15 H), 7.65 (d, J ϭ
15.5 Hz, 1 H, 4-H), 8.18 (dd, J ϭ 15.5 and 10.2 Hz, 1 H, 3-H),
8.82 (d, J ϭ 10.2 Hz, 1 H, 2-H), 14.95 (br., NH). Ϫ C22H20ClN
(333.86): calcd. C 79.15, H 6.04, Cl 10.62, N 4.20; found C 79.27,
H 6.01, Cl 10.98, N 4.06.
1-tert-Butyl-1-aza-1,3-pentadiene Hydrochloride (2e): M.p. 128°C
(1.45 g, 65% yield). Ϫ 1H NMR (200 MHz): δ ϭ 1.58 (s, 9 H), 2.11
(d, J ϭ 6.8 Hz, 3 H), 7.22 (dd, J ϭ 15.3 and 9.8 Hz, 1 H, 3-H),
7.61 (dq, J ϭ 15.3 and 6.8 Hz, 1 H, 4-H), 8.88 (dd, J ϭ 16.3 and
9.8 Hz, 1 H, 2-H).
Experimental Section
General: NMR: Bruker ARX 200 spectrometer (200 MHz for H)
1
1
or Bruker AM 300 WB spectrometer (300 MHz for H, 75.5 MHz
for 13C, and 30.4 MHz for 15N) in CDCl3 (internal standard: Me4Si
1-tert-Butyl-3-methyl-1-aza-1,3-butadiene Hydrochloride (2f): Amor-
for 1H and 13C; external reference: MeNO2 for 15N). Ϫ HRMS:
1
phous semi-solid (1.45 g, 65% yield). Ϫ H NMR (200 MHz): δ ϭ
´
Centre Regional de Mesures Physiques de lЈOuest; Varian MAT
1.67 (s, 9 H), 2.35 (s, 3 H), 6.35 (br., 1 H), 6.87 (br., 1 H), 8.95 (d,
J ϭ 17 Hz, 1 H, 2-H).
311 spectrometer, EI mode using a potential of 70 eV; with the
exception of molecular-ion peaks, only mass-spectral fragments
with relative intensities of 10% or more are reported. Ϫ IR:
PerkinϪElmer 1420 spectrophotometer; suspensions in Nujol. Ϫ
Elemental analyses: Analytical laboratory CNRS.
1-tert-Butyl-3-methyl-4-phenyl-1-aza-1,3-butadiene Hydrochloride
1
(2g): M.p. 188°C (2.15 g, 85% yield). Ϫ H NMR (200 MHz): δ ϭ
1.71 (s, 9 H), 2.59 (s, 3 H), 7.40Ϫ7.60 (m, 5 H), 8.25 (s, 1 H, 4-H),
8.85 (br. d, J ϭ 12.8 Hz, 1 H, 2-H).
Starting Materials: tert-Butyl isocyanide and ethyl isocyanide were
prepared as described previously[36] employing the customary Hof-
mann carbylamine method. 2,6-Dimethylphenyl isocyanide was
purchased from Fluka. N-Tosylaldimines 1d,i were readily access-
ible from the condensation of p-toluenesulfonamide (4.3 g,
25 mmol) with commercially available trans-cinnamaldehyde and α-
methyl-trans-cinnamaldehyde (25 mmol). The reactions were car-
ried out at room temp. in CH2Cl2 solution using TiCl4/NEt3 as
catalyst, according to a known procedure.[37] Other α,β-unsaturated
aldimines 1 and 2-(N-tert-butylformimidoyl)thiophene were con-
veniently generated by condensing the corresponding aldehydes
with appropriate primary amines on alumina over a period of a
few hours. Such conditions have been reported several times in the
literature.[9a,10,38] Crude 1-aza-1,3-dienes were converted directly to
the hydrochlorides 2 and 15 without prior purification. Thus, a
solution of the imine (10 mmol) in anhydrous diethyl ether (50 mL)
was saturated with dry HCl, resulting in the immediate separation
of a white solid. This was collected by filtration, washed with Et2O,
and recrystallized from Et2O/CH2Cl2 (1:1), except where otherwise
indicated. The salts 2 and 15 belong to a rather stable class of
compounds, which can be stored for several years under dry con-
ditions without any decomposition. They were found to melt with
decomposition (Kofler apparatus; instantaneous melting points).
Overall yields are based on starting aldehydes.
1-Isopropyl-3-methyl-4-phenyl-1-aza-1,3-butadiene Hydrochloride (2h):
M.p. 142°C (2.0 g, 80% yield). Ϫ H NMR (200 MHz): δ ϭ 1.62
(d, J ϭ 6.6 Hz, 6 H), 2.49 (s, 3 H), 4.46 (m, 1 H), 7.40Ϫ7.60 (m, 5
H), 8.12 (s, 1 H, 4-H), 9.25 (d, J ϭ 16.7 Hz, 1 H, 2-H).
1
1-tert-Butyl-3-chloro-4-phenyl-1-aza-1,3-butadiene Hydrochloride (2j):
Undetermined melting point (2.3 g, 55% yield). Ϫ 1H NMR
(200 MHz): δ ϭ 1.77 (s, 9 H), 7.40Ϫ7.50 (m, 3 H), 8.03 (d, J ϭ
7 Hz, 2 H), 9.30 (br., 1 H, 4-H), 9.88 (br., 1 H, 2-H), 13.00 (br.,
NH).
3-Chloro-1-isopropyl-4-phenyl-1-aza-1,3-butadiene Hydrochloride (2k):
Undetermined melting point (2.2 g, 55% yield). Ϫ 1H NMR
(200 MHz): δ ϭ 1.65 (d, J ϭ 6.7 Hz, 6 H), 4.57 (m, 1 H), 7.40Ϫ8.05
(m, 5 H), 8.85 (s, 1 H, 4-H), 10.10 (s, 1 H, 2-H), 12.50 (br., NH).
2-(N-tert-Butylformimidoyl)thiophene Hydrochloride (15): M.p.
175°C (55% yield). Ϫ 1H NMR (200 MHz): δ ϭ 1.69 (s, 9 H), 7.29
(t, J ϭ 4.5 Hz, 1 H), 8.08 (d, J ϭ 4.5 Hz, 1 H), 9.02 (br., 1 H), 9.05
(d, J ϭ 4.5 Hz, 1 H), 14.60 (br., NH).
Cycloaddition Reactions of N-Tosyl Cinnamaldimines: A solution
of 1-azabutadiene 1d,i (10 mmol) and tert-butyl isocyanide (1.7 g,
20 mmol) in anhydrous MeCN (25 mL) was refluxed for about 4
d. Removal of the solvent under reduced pressure left a brownish
residue, which was purified by column chromatography on Merck
silica gel 60 using petroleum ether/diethyl ether (3:2) as eluent. The
cycloadducts 6e,l were recrystallized from MeOH (selected 13C-
NMR data: see Table 2).
4-Phenyl-1-tosyl-1-aza-1,3-butadiene (1d): M.p. 123°C (Et2O/
1
CH2Cl2) (5.6 g, 78% yield). Ϫ H NMR (200 MHz): δ ϭ 2.37 (s, 3
H), 6.90 (dd, J ϭ 16 and 9 Hz, 1 H, 3-H), 7.25Ϫ7.55 (m, 8 H),
7.85 (d, J ϭ 8 Hz, 2 H), 8.75 (d, J ϭ 9 Hz, 1 H, 2-H).
2-(tert-Butylamino)-3-phenyl-1-tosyl-1H-pyrrole (6e): M.p. 94°C
(2.61 g, 71% yield). Ϫ 1H NMR (300 MHz): δ ϭ 0.94 (s, 9 H), 2.37
(s, 3 H), 3.45 (br., NH), 6.34 (d, J ϭ 3.8 Hz, 1 H, 4-H), 7.03 (d,
J ϭ 3.8 Hz, 1 H, 5-H), 7.15Ϫ7.36 (m, 5 H), 7.54 (m, 2 H), 7.65 (d,
J ϭ 8.4 Hz, 2 H). Ϫ C21H24N2O2S (368.49): calcd. C 68.45, H 6.56,
N 7.60, S 8.70; found C 68.36, H 6.59, N 7.53, S 8.65.
3-Methyl-4-phenyl-1-tosyl-1-aza-1,3-butadiene (1i): M.p. 116°C
(Et2O/CH2Cl2) (5.95 g, 79% yield). Ϫ 1H NMR (200 MHz): δ ϭ
2.16 (s, 3 H), 2.43 (s, 3 H), 7.24Ϫ7.50 (m, 8 H), 7.87 (d, J ϭ 8.3 Hz,
2 H), 8.71 (s, 1 H, 2-H).
1-tert-Butyl-4-phenyl-1-aza-1,3-butadiene Hydrochloride (2a): M.p.
185°C (2.0 g, 93% yield). Ϫ 1H NMR (200 MHz): δ ϭ 1.62 (s, 9 2-(tert-Butylamino)-4-methyl-3-phenyl-1-tosyl-1H-pyrrole (6l): M.p.
H), 7.30Ϫ7.70 (m, 5 H), 7.95 (dd, J ϭ 15.6 and 9.5 Hz, 1 H, 3-H),
8.20 (d, J ϭ 15.6 Hz, 1 H, 4-H), 9.03 (dd, J ϭ 15.4 and 9.5 Hz, 1
H, 2-H).
99°C (2.41 g, 63% yield). Ϫ IR: ν˜ ϭ 3360 cmϪ1 (NH), 1590 (Cϭ
1
C). Ϫ H NMR (200 MHz): δ ϭ 0.84 (s, 9 H), 1.90 (d, J ϭ 1 Hz,
3 H), 2.37 (s, 3 H), 3.37 (br., NH), 6.85 (q, J ϭ 1 Hz, 1 H, 5-H),
Eur. J. Org. Chem. 1999, 1729Ϫ1738
1735

E. Marchand, G. Morel, S. Sinbandhit
7.19Ϫ7.35 (m, 7 H), 7.69 (d, J ϭ 8.4 Hz, 2 H). Ϫ C22H26N2O2S (CϭC). Ϫ H NMR (200 MHz): δ ϭ 1.78 (s, 3 H), 1.83 (s, 9 H),
FULL PAPER
1
(382.52): calcd. C 69.08, H 6.85, N 7.32, S 8.38; found C 69.35, H
6.86, N 7.14, S 8.47.
2.11 (s, 6 H), 4.62 (s, 2 H, 2-H), 6.56 (m, 3 H), 6.90 (m, 2 H), 10.74
(br., NH). Ϫ MS: calcd. for C23H28N2 m/z ϭ 332.2252 [M Ϫ
HCl]ϩ·; found 332.2251; m/z (%): 332 (70), 276 (100).
Reactions of N-Protonated 1-Azabutadienes with Isocyanides. ؊
General Procedure: A solution of salt 2 or 15 (10 mmol) and the
appropriate isocyanide was prepared in dry MeCN or CHCl3 (25
mL). The excess of isocyanide used and the requisite reflux time are
indicated in Table 1. The progress of the reaction was monitored by
1H NMR. The solvent was subsequently evaporated in vacuo, the
residual syrup was triturated with anhydrous Et2O, and then slowly
decanted. Concentration of the ethereal solution afforded the pyr-
roles 4a, 6b,c,d,j and 13a,b, which were purified by flash chroma-
tography on silica gel using petroleum ether/diethyl ether (3:1) as
eluent. In some cases, the products were recrystallized. The mate-
rial insoluble in Et2O was worked-up with dry THF to give the
pyrrolium salts 3a,f, 5h,i,k or the 2-(formimidoyl)pyrrole hydro-
chlorides 7a, 9j,k. The crude products obtained in entry 1 (3a, 7a)
and entry 16 (5k, 9k) were separated by repeated crystallizations
from THF. Ϫ In the case of entries 10, 11 and 21, the reaction
mixture was concentrated to a viscous material, which was treated
with diethyl ether and washed with H2O. After decantation, the
organic phase was dried with Na2SO4 and the solvent was evapo-
rated to furnish a mixture of isomeric adducts 4g and 6g (75:25)
or the crystalline azetidine 16. The aqueous solution was extracted
with CH2Cl2 to provide the salts 7g and 8, which were isolated by
fractional crystallization from Et2O. Ϫ Conversion of pyrrolium
salts 3a,f, 5h,i,k and 2-(imidoyl)pyrrole hydrochlorides 9j,k to the
corresponding pyrroles 4, 6 and 10 was quantitatively achieved by
treatment with Al2O3/CHCl3 or NEt3/CHCl3 at room temperature
for 30 min. according to standard procedures.[8,9a] The pyrrole hy-
drochlorides 7a,g, 8 remained unaltered under the same conditions.
The pyrroles 10 were purified by flash chromatography on alumina
using petroleum ether/Et2O (3:1) as eluent. The pyrroles 4f, 6h,i,k
were very susceptible to oxidation and were only characterized by
NMR spectroscopy of CDCl3 solutions of the corresponding salts
in the presence of Al2O3. Ϫ Selected 13C-NMR data: see Tables 2
and 3.
5-[(2,6-Dimethylphenyl)amino]-1-isopropyl-3-methyl-4-phenyl-2H-
pyrrolium Chloride (5k): M.p. 240°C (dec.) (CHCl3/Et2O); yield
1.24 g (35%). Ϫ H NMR (200 MHz): δ ϭ 1.45 (d, J ϭ 6.5 Hz, 6
H), 1.90 (s, 3 H), 2.15 (s, 6 H), 4.50 (s, 2 H, 2-H), 5.63 (m, 1 H),
6.62 (m, 3 H), 6.96 (m, 2 H). Ϫ C22H27ClN2 (354.92): calcd. C
74.45, H 7.67, N 7.89; found C 74.26, H 7.88, N 7.86.
1
1-tert-Butyl-2-(tert-butylamino)-4-phenyl-1H-pyrrole (4a): M.p.
112°C (MeOH); yield 0.68 g (25%). Ϫ IR: ν˜ ϭ 3280 cmϪ1 (NH),
1
1610 (CϭC). Ϫ H NMR (300 MHz): δ ϭ 1.31 (s, 9 H), 1.66 (s, 9
H), 6.17 (d, J ϭ 2 Hz, 1 H, 3-H), 6.88 (d, J ϭ 2 Hz, 1 H, 5-H),
7.11 (t, J ϭ 7 Hz, 1 H), 7.30 (t, J ϭ 7 Hz, 2 H), 7.50 (d, J ϭ 7 Hz,
2 H). Ϫ MS: calcd. for C18H26N2 m/z ϭ 270.2096 [Mϩ·]; found
270.2092; m/z (%): 270 (44), 214 (12), 213 (13), 158 (95), 157 (100),
130 (18).
1-tert-Butyl-2-(tert-butylamino)-4-methyl-1H-pyrrole (4f): 1H NMR
(300 MHz): δ ϭ 1.24 (s, 9 H), 1.57 (s, 9 H), 2.04 (dd, J ϭ 0.9 and
0.4 Hz, 3 H), 5.65 (br. d, J ϭ 2.1 Hz, 1 H, 3-H; sharp doublet by
selective irradiation of the methyl group on C-4), 6.29 (dq, J ϭ 2.1
and 0.9 Hz, 1 H, 5-H).
1-tert-Butyl-2-(tert-butylamino)-3-methyl-4-phenyl-1H-pyrrole (4g):
1H NMR (300 MHz) of an oily mixture of the isomers 4g and 6g
(0.99 g, 35% yield): δ ϭ 1.26 (s, 9 H), 1.64 (s, 9 H), 2.16 (s, 3 H),
6.74 (s, 1 H, 5-H), 7.10Ϫ7.40 (m, 5 H). Ϫ MS: calcd. for C19H28N2
m/z ϭ 284.2252 [Mϩ·]; found 284.2254; m/z (%): 284 (40), 227 (60),
171 (100), 116 (20).
1-tert-Butyl-2-[(2,6-dimethylphenyl)amino]-3-phenyl-1H-pyrrole
(6b): M.p. 110°C (pentane); yield 1.43 g (45%). Ϫ IR: ν˜ ϭ 3380
1
cmϪ1 (NH), 1620 (CϭC). Ϫ H NMR (300 MHz): δ ϭ 1.62 (s, 9
H), 1.96 (s, 6 H), 5.08 (br., NH), 6.24 (d, J ϭ 3.5 Hz, 1 H, 4-H),
6.52 (t, J ϭ 7.5 Hz, 1 H), 6.75 (d, J ϭ 3.5 Hz, 1 H, 5-H), 6.77 (d,
J ϭ 7.5 Hz, 2 H), 6.93Ϫ7.28 (m, 5 H). Ϫ MS: calcd. for C22H26N2
m/z ϭ 318.2096 [Mϩ·]; found 318.2095.
1-tert-Butyl-5-(tert-butylamino)-3-phenyl-2H-pyrrolium Chloride (3a):
M.p. 200°C (dec.) (CH2Cl2/Et2O); yield 1.44 g (47%). Ϫ IR: ν˜ ϭ
3500 cmϪ1 (NH), 1608 (CϭNϩ), 1568 (CϭC). Ϫ 1H NMR
(200 MHz): δ ϭ 1.64 (s, 9 H), 1.77 (s, 9 H), 5.40 (s, 2 H, 2-H), 6.72
(s, NH), 6.95 (s, 1 H, 4-H), 7.47 (m, 3 H), 7.80 (m, 2 H). Ϫ MS:
calcd. for C18H26N2 m/z ϭ 270.2096 [M Ϫ HCl]ϩ·; found 270.2092.
2-(tert-Butylamino)-1-isopropyl-3-phenyl-1H-pyrrole
(6c):
Oily
crude product; yield 1.13 g (44%). Ϫ 1H NMR (200 MHz): δ ϭ
0.91 (s, 9 H), 1.37 (d, J ϭ 7 Hz, 6 H), 2.78 (br., NH), 4.76 (m, 1
H), 6.24 (d, J ϭ 3.4 Hz, 1 H, 4-H), 6.61 (d, J ϭ 3.4 Hz, 1 H, 5-H),
7.10Ϫ7.40 (m, 5 H).
2-(tert-Butylamino)-1-(diphenylmethyl)-3-phenyl-1H-pyrrole
(6d):
1-tert-Butyl-5-(tert-butylamino)-3-methyl-2H-pyrrolium Chloride (3f):
M.p. 200°C (dec.) (CH2Cl2/Et2O); yield 1.34 g (55%). Ϫ IR: ν˜ ϭ
1
M.p. 93°C (MeOH); yield 1.52 g (40%). Ϫ H NMR (200 MHz):
δ ϭ 0.97 (s, 9 H), 2.42 (br., NH), 6.21 (d, J ϭ 3.1 Hz, 1 H, 4-H),
6.32 (d, J ϭ 3.1 Hz, 1 H, 5-H), 6.92 (s, 1 H), 7.00Ϫ7.50 (m, 15 H).
1
3235, 3080 cmϪ1 (NH), 1623 (CϭNϩ), 1572 (CϭC). Ϫ H NMR
(300 MHz): δ ϭ 1.58 (s, 9 H), 1.69 (s, 9 H), 2.34 (d, J ϭ 1.4 Hz, 3
H), 4.89 (s, 2 H, 2-H), 6.55 (q, J ϭ 1.4 Hz, 1 H, 4-H), 6.59 (br.,
1-tert-Butyl-2-(tert-butylamino)-4-methyl-3-phenyl-1H-pyrrole (6g):
1H NMR (300 MHz) of an oily mixture of the isomers 4g and 6g:
δ ϭ 0.78 (s, 9 H), 1.65 (s, 9 H), 1.96 (d, J ϭ 0.9 Hz, 3 H), 6.48 (q,
J ϭ 0.9 Hz, 1 H, 5-H), 7.10Ϫ7.40 (m, 5-H).
NH). Ϫ MS: calcd. for C13H24N2 m/z ϭ 208.1939 [M Ϫ HCl]ϩ·
found 208.1948; m/z (%): 208 (50), 151 (10), 96 (100), 95 (75).
;
1-tert-Butyl-5-(ethylamino)-3-methyl-4-phenyl-2H-pyrrolium Chlo-
ride (5h): M.p. 200°C (dec.) (CH2Cl2/Et2O); yield 1.32 g (45%). Ϫ
IR: ν˜ ϭ 3100 cmϪ1 (NH), 1630 (CϭNϩ), 1595 (CϭC). Ϫ 1H NMR
(300 MHz): δ ϭ 0.83 (t, J ϭ 6.9 Hz, 3 H), 1.64 (s, 9 H), 1.82 (s, 3
H), 3.14 (m, 2 H), 4.60 (s, 2 H, 2-H), 7.12 (m, 2 H), 7.33 (m, 3 H),
8.77 (br. t, J ϭ 6.1 Hz, NH). Ϫ MS: calcd. for C17H25N2 m/z ϭ
257.2018 [M Ϫ Cl]ϩ; found 257.2025; m/z (%): 257 (65), 200 (100),
171 (50), 154 (15), 144 (10). Ϫ C17H25ClN2 (292.85): calcd. C 69.72,
H 8.60, Cl 12.11, N 9.57; found C 69.10, H 8.81, Cl 12.40, N 9.62.
1-tert-Butyl-2-(ethylamino)-4-methyl-3-phenyl-1H-pyrrole (6h): 1H
NMR (300 MHz): δ ϭ 0.92 (t, J ϭ 7.1 Hz, 3 H), 1.64 (s, 9 H), 2.02
(d, J ϭ 0.7 Hz, 3 H), 2.58 (q, J ϭ 7.1 Hz, 2 H), 6.32 (q, J ϭ 0.7 Hz,
1 H, 5-H), 7.28 (m, 5 H).
1-tert-Butyl-2-[(2,6-dimethylphenyl)amino]-4-methyl-3-phenyl-1H-
1
pyrrole (6i): H NMR (300 MHz): δ ϭ 1.67 (s, 9 H), 1.96 (s, 6 H),
2.04 (d, J ϭ 0.7 Hz, 3 H), 6.41 (t, J ϭ 7.2 Hz, 1 H), 6.56 (br., 1 H,
5-H), 6.62 (d, J ϭ 7.2 Hz, 2 H), 7.03 (m, 5 H).
1-tert-Butyl-5-[(2,6-dimethylphenyl)amino]-3-methyl-4-phenyl-2H-
pyrrolium Chloride (5i): M.p. 210°C (dec.) (CHCl3/Et2O); yield
2-(tert-Butylamino)-1-isopropyl-4-methyl-3-phenyl-1H-pyrrole (6j):
2.4 g (65%). Ϫ IR: ν˜ ϭ 3050 cmϪ1 (NH), 1625 (CϭNϩ), 1585, 1567 Oily crude product; yield 1.0 g (37%). Ϫ IR: ν˜ ϭ 3350 cmϪ1 (NH),
1736
Eur. J. Org. Chem. 1999, 1729Ϫ1738

A New Access to 2-(Alkylamino)- and 2-(Arylamino)pyrroles
FULL PAPER
1
1630, 1585 (CϭC). Ϫ 1H NMR (200 MHz): δ ϭ 0.81 (s, 9 H), 1.35 product; yield 0.45 g (10%). Ϫ H NMR (200 MHz): δ ϭ 1.66 (d,
(d, J ϭ 6.8 Hz, 6 H), 2.06 (d, J ϭ 0.7 Hz, 3 H), 2.94 (br., NH), J ϭ 7 Hz, 6 H), 2.34 (s, 6 H), 2.13 (s, 3 H), 2.23 (s, 6 H), 5.17 (br.,
4.73 (m, 1 H), 6.42 (q, J ϭ 0.7 Hz, 1 H, 5-H), 7.13Ϫ7.37 (m, 5 H).
Ϫ MS: calcd. for C18H26N2 m/z ϭ 270.2096 [Mϩ·]; found 270.2092;
m/z (%): 270 (100), 213 (90), 171 (30).
1 H), 6.55Ϫ7.10 (m, 12 H), 8.17 (s, 1 H).
1-tert-Butyl-2,3-bis(tert-butylimino)-4-(2-thienyl)azetidine
(16):
M.p. 97°C (MeOH); yield 1.17 g (35%). Ϫ IR: ν˜ ϭ 1696, 1661
1
2-[(2,6-Dimethylphenyl)amino]-1-isopropyl-4-methyl-3-phenyl-1H-
cmϪ1 (CϭN). Ϫ H NMR (300 MHz): δ ϭ 1.07 (s, 9 H), 1.27 (s,
1
pyrrole (6k): H NMR (300 MHz): δ ϭ 1.32 (d, J ϭ 6.7 Hz, 6 H), 9 H), 1.34 (s, 9 H), 5.27 (s, 1 H), 6.92 (dd, J ϭ 5 and 3.5 Hz, 1 H),
1.97 (s, 6 H), 2.10 (br., 3 H), 4.32 (m, 1 H), 6.44 (br., 1 H, 5-H),
6.56 (t, J ϭ 7.2 Hz, 1 H), 6.77 (d, J ϭ 7.2 Hz, 2 H), 7.16 (m, 5 H).
6.99 (dd, J ϭ 3.5 and 1 Hz, 1 H), 7.23 (dd, J ϭ 5 and 1 Hz, 1 H).
Ϫ
13C NMR (75.5 MHz): δ ϭ 27.3, 29.9, 30.8 (3 qm, 1J ϭ 126 Hz),
1
3
53.0, 54.0, 57.5 (3 m), 63.9 (dd, J ϭ 148 Hz, J ϭ 2.6 Hz), 125.3
(dd, 1J ϭ 184 Hz, 3J ϭ 10 Hz), 125.5 (dm, 1J ϭ 171 Hz), 126.4 (dt,
1J ϭ 167 Hz, 2J ϭ 4.9 Hz), 146.8 (m), 153.4 (d, 3J ϭ 2.6 Hz), 155.5
(d, 2J ϭ 4.2 Hz). Ϫ C19H31N3S (333.54): calcd. C 68.42, H 9.37, N
12.60, S 9.61; found C 68.58, H 9.60, N 12.48, S 9.71.
1-tert-Butyl-5-(tert-butylamino)-2-cyano-4-phenyl-1H-pyrrole (13a):
M.p. 85°C (Et2O/petroleum ether); yield 1.62 g (55%). Ϫ IR: ν˜ ϭ
3380 cmϪ1 (NH), 2186 (CϵN), 1595 (CϭC). Ϫ 1H NMR
(300 MHz): δ ϭ 0.82 (s, 9 H), 1.86 (s, 9 H), 2.85 (br., NH), 6.92 (s,
1 H, 3-H), 7.18Ϫ7.33 (m, 5 H). Ϫ C19H25N3 (295.43): calcd. C
77.25, H 8.53, N 14.22; found C 77.26, H 8.40, N 14.38.
Insertion Reaction of tert-Butyl Isocyanide into Pyrrolium Chloride
3a: A solution of salt 3a (1.5 g, 5 mmol) and the isocyanide (1.25 g,
15 mmol) in dry MeCN (25 mL) was refluxed for 45 h. The solvent
was subsequently removed in vacuo and the hydrochloride 7a was
precipitated by the addition of THF as described above (1.15 g,
69% yield).
5-(tert-Butylamino)-2-cyano-1-isopropyl-4-phenyl-1H-pyrrole (13b):
M.p. 119°C (Et2O/petroleum ether); yield 1.26 g (45%). Ϫ IR: ν˜ ϭ
3323 cmϪ1 (NH), 2189 (CϵN), 1590 (CϭC). Ϫ 1H NMR
(300 MHz): δ ϭ 0.90 (s, 9 H), 1.59 (d, J ϭ 7 Hz, 6 H), 3.08 (br.,
NH), 5.00 (m, 1 H), 6.87 (s, 1 H, 3-H), 7.19Ϫ7.36 (m, 5 H). Ϫ
C18H23N3 (281.40): calcd. C 76.83, H 8.24, N 14.93; found C 76.56,
H 8.23, N 15.07.
Autoxidation of Pyrroles: The reaction was studied with a few selec-
ted 2-aminopyrroles as examples. A sample of 4a or 6j was main-
tained at room temp. under atmospheric O2 for 3 or 12 d. The
pyrrolinone 17 thus produced was suspended in MeOH and fil-
tered, while pyrrolinone 18j was purified by flash chromatography
on silica gel using diethyl ether/petroleum ether (1:3) as eluent. A
CH2Cl2 solution of in situ generated 6i or 6k was concentrated to
give the corresponding pyrrolinone 18i,k, which was worked up by
column chromatography using CH2Cl2/hexane (2:1) as eluent. Ϫ
The 2-(formimidoyl)pyrroles 10k,j were quantitatively converted
into their derivatives 19, 20 in the course of chromatography on
SiO2 using Et2O as eluent. Ϫ Selected 13C-NMR data: see Tables
2 and 3.
tert-Butyl-{[5-(tert-butylamino)-3-phenylpyrrol-2-yl]meth-
ylene}ammonium Chloride (7a): M.p. 260°C (CH2Cl2/Et2O); yield
1.23 g (37%). Ϫ IR: ν˜ ϭ 3178, 3040 cmϪ1 (NH), 1652 (CϭNϩ),
1
1583 (CϭC). Ϫ H NMR (300 MHz): δ ϭ 1.40 (s, 9 H), 1.46 (s, 9
H), 5.97 (d, J ϭ 1.4 Hz, 1 H, 4-H), 6.11 (s, 5-NH), 7.00 (d, J ϭ
14.9 Hz, 1 H), 7.35 (m, 2 H), 7.48 (m, 3 H), 10.2 (br. d, J ϭ
14.9 Hz, ϭNHϩ), 12.36 (br., NH). Ϫ 15N NMR: δ ϭ Ϫ230.52,
Ϫ243.56, Ϫ282.30 (NH). Ϫ MS: calcd. for C19H27N3 m/z ϭ
297.2205 [M Ϫ HCl]ϩ·; found 297.2220; m/z (%): 297 (85), 282 (50),
241 (15), 226 (50), 184 (100). Ϫ C19H28ClN3 (333.90): calcd. C
68.35, H 8.45, Cl 10.62, N 12.58; found C 68.26, H 8.33, Cl 10.85,
N 12.60.
1-tert-Butyl-5-(tert-butylimino)-3-phenyl-3-pyrrolin-2-one (17): M.p.
1
86°C (MeOH). Ϫ IR: ν˜ ϭ 1690 cmϪ1 (CϭO), 1626 (CϭN). Ϫ H
tert-Butyl-{[5-(tert-butylamino)-4-methyl-3-phenylpyrrol-2-yl]meth-
ylene}ammonium Chloride (7g): M.p. 160°C then 220°C (CH2Cl2/
petroleum ether); yield 0.59 g (17%). Ϫ IR: ν˜ ϭ 3240 (br), 3115,
3060 cmϪ1 (NH), 1660 (CϭNϩ), 1575 (CϭC). Ϫ 1H NMR
(300 MHz): δ ϭ 1.35 (s, 9 H), 1.65 (s, 9 H), 1.85 (s, 3 H), 4.78 (s,
5-NH), 6.74 (d, J ϭ 14.7 Hz, 1 H), 7.24 (m, 2 H), 7.48 (m, 3 H),
NMR (200 MHz): δ ϭ 1.42 (s, 9 H), 1.69 (s, 9 H), 6.95 (s, 1 H, 4-
H), 7.40 (m, 3 H), 7.84 (m, 2 H). Ϫ MS: calcd. for C18H24N2O
m/z ϭ 284.1888 [Mϩ·]; found 284.1884; m/z (%): 284 (70), 227 (100),
213 (55), 173 (50), 171 (50). Ϫ C18H24N2O (284.40): calcd. C 76.02,
H 8.51, N 9.85; found C 75.86, H 8.50, N 9.80.
10.89 (br. d, J ϭ 14.7 Hz, ϭNHϩ), 11.84 (br., NH). Ϫ C20H30ClN3 1-tert-Butyl-5-[(2,6-dimethylphenyl)imino]-3-methyl-4-phenyl-3-
(347.93): calcd. C 69.04, H 8.69, N 12.08; found C 68.87, H 8.82,
N 12.02.
pyrrolin-2-one (18i): M.p. 148°C (MeOH). Ϫ IR: ν˜ ϭ 1701 cmϪ1
(CϭO), 1631 (CϭN), 1580 (CϭC). Ϫ 1H NMR (300 MHz): δ ϭ
1.77 (s, 3 H), 1.82 (s, 9 H), 1.99 (s, 6 H), 6.43Ϫ7.00 (m, 8 H). Ϫ
C23H26N2O (346.47): calcd. C 79.73, H 7.56, N 8.09; found C
79.56, H 7.54, N 8.37.
tert-Butyl-{[5-(tert-butylamino)-3-methyl-4-phenylpyrrol-2-yl]meth-
ylene}ammonium Chloride (8): M.p. 262°C (CH2Cl2/petroleum
ether); yield 0.59 g (17%). Ϫ IR: ν˜ ϭ 3377, 3040 cmϪ1 (NH), 1650
1
(CϭNϩ), 1568 (CϭC). Ϫ H NMR (300 MHz): δ ϭ 1.48 (s, 9 H),
5-(tert-Butylimino)-1-isopropyl-3-methyl-4-phenyl-3-pyrrolin-2-one
1.57 (s, 9 H), 2.13 (s, 3 H), 4.95 (br., 5-NH), 7.07 (d, J ϭ 14.6 Hz, (18j): M.p. 98°C (pentane). Ϫ IR: ν˜ ϭ 1693 cmϪ1 (CϭO), 1640
1 H), 7.22 (d, J ϭ 7 Hz, 2 H), 7.30Ϫ7.55 (m, 3 H), 11.06 (br. d, (CϭN). Ϫ 1H NMR (300 MHz): δ ϭ 1.02 (s, 9 H), 1.41 (d, J ϭ
J ϭ 14.6 Hz, ϭNHϩ), 11.81 (br., NH). Ϫ C20H30ClN3 (347.93): 6.9 Hz, 6 H), 1.70 (s, 3 H), 4.61 (m, 1 H), 7.12 (m, 2 H), 7.39 (m,
calcd. C 69.04, H 8.69, Cl 10.19, N 12.08; found C 68.94, H 8.88,
Cl 10.13, N 12.14.
3 H). Ϫ MS: calcd. for C18H24N2O m/z ϭ 284.1889 [Mϩ·]; found
284.1896. Ϫ C18H24N2O (284.40): calcd. C 76.02, H 8.51; found C
75.79, H 8.44.
5-(tert-Butylamino)-2-(N-tert-butylformimidoyl)-1-isopropyl-3-
methyl-4-phenyl-1H-pyrrole (10j): Oily crude product; yield 1.31 g
5-[(2,6-Dimethylphenyl)imino]-1-isopropyl-3-methyl-4-phenyl-3-
(37%). Ϫ IR: ν˜ ϭ 3340 cmϪ1 (NH), 1620 (CϭN), 1585 (CϭC). Ϫ pyrrolin-2-one (18k): M.p. 120°C (Et2O/petroleum ether). Ϫ IR:
1H NMR (300 MHz): δ ϭ 0.82 (s, 9 H), 1.30 (s, 9 H), 1.52 (d, J ϭ ν˜ ϭ 1700 cmϪ1 (CϭO), 1640 (CϭN), 1580 (CϭC). Ϫ 1H NMR
7.1 Hz, 6 H), 2.24 (s, 3 H), 5.18 (m, 1 H), 7.20Ϫ7.50 (m, 6 H), 8.52 (300 MHz): δ ϭ 1.54 (d, J ϭ 6.2 Hz, 6 H), 1.86 (s, 3 H), 1.98 (s, 6
(s, 1 H). Ϫ MS: calcd. for C23H35N3 m/z ϭ 353.2831 [Mϩ·]; found
353.2822; m/z (%): 353 (85), 338 (50), 296 (100), 282 (65).
H), 4.73 (br., 1 H), 6.53Ϫ7.00 (m, 8 H). Ϫ C22H24N2O (332.45):
calcd. C 79.47, H 7.28, N 8.43; found C 79.58, H 7.19, N 8.53.
5-[(2,6-Dimethylphenyl)amino]-2-[N-(2,6-dimethylphenyl)form- 2-[N-(2,6-Dimethylphenyl)formimidoyl]-5-[(2,6-dimethylphenyl)-
imidoyl]-1-isopropyl-3-methyl-4-phenyl-1H-pyrrole (10k): Oily crude
imino]-2,5-dihydro-2-hydroxy-1-isopropyl-3-methyl-4-phenyl-1H-
Eur. J. Org. Chem. 1999, 1729Ϫ1738
1737

E. Marchand, G. Morel, S. Sinbandhit
FULL PAPER
[12]
[13]
pyrrole (19): M.p. 125°C (petroleum ether). Ϫ IR: ν˜ ϭ 3384 cmϪ1
(OH), 1637 (CϭN), 1580 (CϭC). Ϫ 1H NMR (200 MHz): δ ϭ 1.60
(d, J ϭ 6.8 Hz, 3 H), 1.67 (d, J ϭ 6.8 Hz, 3 H), 1.73 (s, 3 H), 1.95
(s, 3 H), 2.08 (s, 3 H), 2.17 (s, 6 H), 3.84 (m, 1 H), 5.63 (s, OH),
6.35Ϫ6.60 (m, 3 H), 6.80Ϫ7.15 (m, 8 H), 7.55 (s, 1 H). Ϫ
C31H35N3O (465.64): calcd. C 79.96, H 7.58, N 9.02; found C
80.13, H 8.01, N 8.71.
Another example: T. D. Lash, J. R. Bellettini, J. A. Bastian, K.
B. Couch, Synthesis 1994, 170Ϫ172.
H. Wamhoff, B. Wehling, Synthesis 1976, 51; J. A. S. Laks, J.
R. Ross, S. M. Bayomi, J. W. Sowell, Sr., Synthesis 1985,
291Ϫ293; H. Pichler, G. Folkers, H. J. Roth, K. Eger, Liebigs
Ann. Chem. 1986, 1485Ϫ1505; J. R. Ross, L. C. Vishwakarma,
J. W. Sowell, Sr., J. Heterocycl. Chem. 1987, 24, 661Ϫ665 and
references therein.
[14]
O. A. Attanasi, Z. Liao, A. McKillop, S. Santeusanio, F. Serra-
Zanetti, J. Chem. Soc., Perkin Trans. 1 1993, 315Ϫ320; O. A.
Attanasi, P. Filippone, D. Giovagnoli, A. Mei, Synthesis 1994,
181Ϫ184 and references therein.
K. Burger, S. Rottegger, Tetrahedron Lett. 1984, 25, 4091Ϫ4094.
F. Berree, G. Morel, Tetrahedron 1995, 51, 7019Ϫ7034.
M. Jautelat, K. Ley, Synthesis 1970, 593Ϫ594.
T. Kusumoto, T. Hiyama, K. Ogata, Tetrahedron Lett. 1986, 27,
4197Ϫ4200; N. Chatani, T. Hanafusa, Tetrahedron Lett. 1986,
27, 4201Ϫ4204.
5-(tert-Butylamino)-1-isopropyl-3-methyl-4-phenyl-1H-pyrrole-2-
carboxaldehyde (20): M.p. 78°C (petroleum ether). Ϫ IR: ν˜ ϭ 3340
[15]
[16]
[17]
[18]
cmϪ1 (NH), 1635 (CϭO). Ϫ H NMR (300 MHz): δ ϭ 0.88 (s, 9
1
´
H), 1.57 (d, J ϭ 7 Hz, 6 H), 2.29 (s, 3 H), 3.15 (br., NH), 5.05 (m,
1 H), 7.18Ϫ7.42 (m, 5 H), 9.72 (s, 1 H). Ϫ MS: calcd. for
C19H26N2O m/z ϭ 298.2045 [Mϩ·]; found 298.2042; m/z (%): 298
(40), 242 (65), 213 (10), 200 (100), 171 (15). Ϫ C19H26N2O (298.43):
calcd. C 76.47, H 8.78, N 9.39; found C 76.34, H 8.85, N 9.31.
[19]
Reviews: H. M. Walborsky, M. P. Periasamy, Recent Advances
in Isocyanide Chemistry in The Chemistry of Triple-Bonded
Functional Groups (Eds.: S. Pata¨ı, Z. Rappoport), J. Wiley, New
York, 1983, chapter 20, pp. 835Ϫ837; I. Ugi, S. Lohberger, R.
Karl, The Passerini and Ugi Reactions in Comprehensive Organic
Chemistry, vol. 2 (Ed.: B. M. Trost), Pergamon Press, Oxford,
1991, pp. 1083Ϫ1109.
[1]
Recent reviews: A. Vicek, Jr., Chemtracts: Org. Chem. 1996, 9,
322Ϫ326; H. Ogoshi, Y. Kuroda, T. Mizutani, T. Hayashi, Pure
Appl. Chem. 1996, 68, 1411Ϫ1415.
[2]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
Reviews: B. Franck, A. Nonn, Angew. Chem. 1995, 107,
J. A. Deyrup, M. M. Vestling, W. V. Hagan, H. Y. Yun, Tetra-
hedron 1969, 25, 1467Ϫ1478.
1941Ϫ1957; Angew. Chem. Int. Ed. Engl. 1995, 34, 1795Ϫ1811;
J. L. Sessler, V. Kral, M. C. Hoehner, K. O. Aileen Chin, R. M.
Davila, Pure Appl. Chem. 1996, 68, 1291Ϫ1295; A. Jasat, D.
Dolphin, Chem. Rev. 1997, 97, 2267Ϫ2340.
N. Obata, H. Mizuno, T. Koitabashi, T. Takizawa, Bull. Chem.
Soc. Jpn. 1975, 48, 2287Ϫ2293.
L. Capuano, B. Dahm, V. Port, R. Schnur, V. Schramm, Chem.
Ber. 1988, 121, 271Ϫ274.
[3]
Recent reviews: P. A. Stuzhin, O. G. Khelevina, Coord. Chem.
Rev. 1996, 147, 41Ϫ86; F. Fernandez-Lazaro, T. Torres, Chem.
Rev. 1998, 98, 563Ϫ575.
J. H. Rigby, M. Qabar, G. Ahmed, R. C. Hughes, Tetrahedron
1993, 49, 10219Ϫ10228.
[4]
Recent reviews: S. J. Higgins, Chem. Soc. Rev. 1997, 26,
W. Ott, V. Formacek, H. M. Seidenspinner, Liebigs Ann. Chem.
1984, 1003Ϫ1012.
247Ϫ257; T. V. Vernitskaya, O. N. Efimov, Russ. Chem. Rev.
1997, 66, 443Ϫ457.
B. Venugopalan, S. S. Iyer, P. J. Karnik, N. J. De Souza, Hetero-
cycles 1987, 26, 3173Ϫ3180.
[5]
Reviews of methods for preparing 1H-pyrroles can be found in:
[5a]
[5b]
J. M. Patterson, Synthesis 1976, 281Ϫ304. Ϫ
L. N. Sob-
G. R. Kieczykowski, R. H. Schlessinger, R. B. Sulsky, Tetra-
hedron Lett. 1976, 597Ϫ600; K. G. Morris, S. E. Thomas, J.
Chem. Soc., Perkin Trans. 1 1991, 97Ϫ101.
enina, A. I. Mikhaleva, B. A. Trofimov, Russ. Chem. Rev. 1989,
58, 163Ϫ180. Ϫ [5c] G. P. Bean, The Synthesis of 1H-Pyrroles in
The Chemistry of Heterocyclic Compounds, vol. 48, part 1 (Ed.:
R. A. Jones), J. Wiley, New York, 1990, chapter 2, pp. 105Ϫ294.
See general procedures and references for obtaining 1H-pyrroles
in the following examples: A. Rohrer, R. Ocampo, H. J. Callot,
Synthesis 1994, 923Ϫ925; B. Oussaid, B. Garrigues, Can. J.
Chem. 1994, 72, 2483Ϫ2485.
[27]
[28]
A. Treibs, A. Diettl, Chem. Ber. 1961, 94, 298Ϫ299.
Y. Chiang, E. B. Whipple, J. Am. Chem. Soc. 1963, 85,
2763Ϫ2767.
[6]
[29]
[30]
[31]
[32]
Review: D. Moderhack, Synthesis 1985, 1083Ϫ1096.
E. B. Smith, H. B. Jensen, J. Org. Chem. 1967, 32, 3330Ϫ3334.
Review: G. P. Gardini, Adv. Heterocycl. Chem. 1973, 15, 67Ϫ98.
E. Marchand, G. Morel, Bull. Soc. Chim. Fr. 1997, 134,
623Ϫ634 and references therein.
G. A. Cordell, J. Org. Chem. 1975, 40, 3161Ϫ3169.
P. Dalla Croce, C. La Rosa, Heterocycles 1988, 27, 2825Ϫ2832.
J. B. Stothers, Carbon-13 NMR Spectroscopy (Eds.: A. T.
Blomquist, H. Wasserman), Academic Press, New York, 1972,
pp. 253 and 343.
[7]
[8]
G. Morel, E. Marchand, A. Foucaud, J. Org. Chem. 1985, 50,
771Ϫ778; G. Morel, E. Marchand, A. Foucaud, L. Toupet, J.
Org. Chem. 1990, 55, 1721Ϫ1727.
[33]
[34]
[35]
G. Morel, E. Marchand, A. Foucaud, L. Toupet, J. Org. Chem.
1989, 54, 1185Ϫ1195.
[9] [9a]
Y. Malvaut, E. Marchand, G. Morel, J. Org. Chem. 1992,
[9b]
57, 2121Ϫ2127. Ϫ
E. Marchand, G. Morel, Tetrahedron
[36]
[37]
[38]
Lett. 1993, 34, 2319Ϫ2322.
W. P. Weber, G. W. Gokel, I. K. Ugi, Angew. Chem. 1972, 84,
587Ϫ588; Angew. Chem. Int. Ed. Engl. 1972, 11, 530Ϫ531.
W. B. Jennings, C. J. Lovely, Tetrahedron Lett. 1988, 29,
3725Ϫ3728.
[10] [10a]
´
F. Berree, Y. Malvaut, E. Marchand, G. Morel, J. Org.
[10b]
Chem. 1993, 58, 6022Ϫ6029. Ϫ
G. Morel, E. Marchand,
A. Touimi Benjelloun, S. Sinbandhit, O. Guillou, P. Gall, Eur.
J. Org. Chem. 1998, 2631Ϫ2639.
F. Texier-Boullet, Synthesis 1985, 679Ϫ681.
[11]
Review: S. Marcaccini, T. Torroba, Org. Prep. Proc. Int. 1993,
25, 143Ϫ208.
Received December 14, 1998
[O98557]
1738
Eur. J. Org. Chem. 1999, 1729Ϫ1738