General and regioselective synthesis of substituted pyrroles by metal-catalyzed or spontaneous cycloisomerization of (Z)-(2-en-4-ynyl)amines

Article abstract of DOI:10.1021/jo034850j

A general and regioselective synthesis of substituted pyrroles 2 by cycloisomerization of readily available (Z)-(2-en-4-ynyl)amines 1 is reported. Spontaneous cycloisomerization leading to 2 occurred in the course of preparation of enynamines bearing a terminal triple bond or a triple bond substituted with a phenyl or a CH₂OTHP group. When the triple bond was substituted with an alkyl or alkenyl group, enynamines were stable and could be converted into the corresponding pyrroles by metal catalysis. CuCl ₂ was found to be an excellent catalyst for cycloisomerization of substrates substituted at C-3, while PdX₂ in conjunction with KX (X = Cl, I) turned out to be a superior catalyst for the reaction of enynamines unsubstituted at C-3.

Full text of DOI:10.1021/jo034850j

Gen er a l a n d Regioselective Syn th esis of Su bstitu ted P yr r oles by
Meta l-Ca ta lyzed or Sp on ta n eou s Cycloisom er iza tion of
(Z)-(2-En -4-yn yl)a m in es
Bartolo Gabriele,*,† Giuseppe Salerno,‡ and Alessia Fazio‡
Dipartimento di Scienze Farmaceutiche, Universita` della Calabria,
87036 Arcavacata di Rende, Cosenza, Italy, and Dipartimento di Chimica,
Universita` della Calabria, 87036 Arcavacata di Rende, Cosenza, Italy
b.gabriele@unical.it
Received J une 18, 2003
A general and regioselective synthesis of substituted pyrroles 2 by cycloisomerization of readily
available (Z)-(2-en-4-ynyl)amines 1 is reported. Spontaneous cycloisomerization leading to 2 occurred
in the course of preparation of enynamines bearing a terminal triple bond or a triple bond substituted
with a phenyl or a CH2OTHP group. When the triple bond was substituted with an alkyl or alkenyl
group, enynamines were stable and could be converted into the corresponding pyrroles by metal
catalysis. CuCl2 was found to be an excellent catalyst for cycloisomerization of substrates substituted
at C-3, while PdX2 in conjunction with KX (X ) Cl, I) turned out to be a superior catalyst for the
reaction of enynamines unsubstituted at C-3.
In tr od u ction
roles have found broad application in the field of material
chemistry.2
Pyrroles are a very important class of heterocyclic
compounds. The pyrrole ring is present in many natural
products, and a large number of pyrrole derivatives have
displayed interesting biological activity.1 Moreover, pyr-
Recently, there has been considerable interest in the
development of new regioselective methods for the syn-
thesis of substituted pyrroles, either by cyclization or
cycloaddition of suitably functionalized acyclic precursors
or by functionalization of the pyrrole ring.3
† Dipartimento di Scienze Farmaceutiche.
‡ Dipartimento di Chimica.
We recently reported the Pd-catalyzed cycloisomeriza-
tion of (Z)-2-en-4-yn-1-ols, (Z)-2-en-4-yne-1-thiols, and
2-alkynylbenzyl alcohols to substituted furans,4 thio-
phenes,5 and 1-alkylidene-1,3-dihydroisobenzofurans or
1H-isochromenes,6 respectively. On the other hand, the
Pd-catalyzed cycloisomerization of (Z)-(2-en-4-ynyl)-
amines 1 to pyrroles 2 has only been disclosed in a
preliminary communication.7 In this work, we report a
full account on the synthesis of substituted pyrroles 2
by transition-metal-catalyzed (eq 1) or spontaneous (eq
2; square brackets indicate that the compound is un-
stable) cycloisomerization of readily available 1.
(1) (a) Comprehensive Heterocyclic Chemistry; Bird, C. W., Ed.;
Pergamon Press: Oxford, 1996; Vol. 2. For some recent examples on
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10.1021/jo034850j CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/10/2003
J . Org. Chem. 2003, 68, 7853-7861
7853

Gabriele et al.
1, entry 1). The reaction did not occur in the absence of
catalyst, as confirmed by blank experiments. The nature
of alkaline metal cation as well as that of the halide anion
(entries 1-7) did not affect substrate conversion and the
yield of 2a significantly, even though slightly higher
yields were observed with chloride rather than iodide;
modest results were instead obtained by using Pd(OAc)2
(entry 8). Remarkably, a virtually quantitative yield was
achieved by changing the metal catalyst to CuCl2 (entry
9 and eq 3) or CuI + 2KI (entry 10).
Similar results were observed using (Z)-butyl(3-meth-
ylnon-2-en-4-ynyl)amine 1b and (Z)-butyl(3-butylnon-2-
en-4-ynyl)amine 1c, which were somewhat more reactive
than 1a (Table 1, entries 11-16 and eq 3).
Resu lts a n d Discu ssion
En yn a m in es Su bstitu ted a t C-3. En yn a m in es (Z)-
R 4CtCC(R3)dCH CH2NH R . We began our investiga-
tion with enynamines bearing a substituent at C-3 and
C-5 and bearing a secondary amino group, such as (Z)-
benzyl(3-methylnon-2-en-4-ynyl)amine 1a (R ) CH2Ph,
R3 ) Me, R4 ) Bu). The reaction of this substrate was
initially carried out under conditions similar to those
employed for enynols4 and enynethiols,5 i.e., with PdI2
(1 mol %) in conjunction with KI (2 mol %) as catalyst in
anhydrous N,N-dimethylacetamide (DMA) as the solvent
(2 mmol of 1a per mL of DMA) at 100 °C under nitrogen.
After 6 h, GLC analysis revealed the formation of
1-benzyl-3-methyl-2-pentylpyrrole 2a in 53% yield; for-
mation of unidentified heavy products, as showed by TLC
analysis, accounted for substrate conversion (90%, Table
Interestingly, using Cu(II) as catalyst the cycloisomer-
ization reaction could also be effected on substrates
bearing a bulky substituent on nitrogen, such as tert-
butyl, even though the reaction rate was decreased. The
results obtained with (Z)-tert-butyl(3-methylnon-2-en-4-
ynyl)amine 1d are reported in Table 1, entries 17-19.
With 5% CuCl2 at 100 °C, after 26 h the GLC yield of
the corresponding pyrrole 2d reached 72% (63% isolated)
at total substrate conversion (entry 17 and eq 3). Sub-
strate conversion was quantitative after only 8 h working
with 10% CuCl2, with a 66% GLC yield of 2d (entry 19).
No reaction occurred under conditions similar to those
reported in entries 17-19 using PdCl2 + 2KCl or PdI2 +
2KI as catalyst.
The cycloisomerization procedure also worked well
with substrates substituted at C-3 and C-5 with alkyl
groups and bearing a primary amino group. The results
obtained with (Z)-3-methylnon-2-en-4-ynylamine 1e are
shown in Table 1, entries 20-27. As for 1a -d , Cu-based
catalysts ensured a higher yield of pyrrole 2e [93% GLC
yield (88% isolated) using CuCl2, entry 20 and eq 3], with
respect to Pd-based catalysts.
(3) For a review on recent advances in the synthesis of pyrroles,
see: (a) Ferreira, V. F.; de Souza, M. C. V. B.; Cunha, A. C.; Pereira,
L. O. R.; Ferreira, M. L. G. Org. Prep. Proced. Int. 2001, 33, 411-454.
For a recent review on synthesis of aromatic heterocycles, see: (b)
Gilchrist, T. L. J . Chem. Soc., Perkin Trans. 1 2001, 2491-2515. For
some very recent examples on the synthesis of pyrrole derivatives,
see: (c) Trofimov, B. A.; Demenev, A P.; Sobenina, L. N.; Mikhaleva,
A. I.; Tarasova, O. A. Tetrahedron Lett. 2003, 44, 3501-3503. (d) Ranu,
B. C.; Dey, S. S. Tetrahedron Lett. 2003, 44, 2865-2868. (e) Zhang, X.
Q.; Sui, Z. Tetrahedron Lett. 2003, 44, 3071-3073. (f) Quiclet-Sire, B.;
Quintero, L.; Sanchez-J imenez, G.; Zard, S. Z. Synlett 2003, 75-78.
(g) Kim J . T.; Kel’in A. V.; Gevorgyan, V. Angew. Chem., Int. Ed. 2003,
42, 98-101. (h) Okada, H.; Akaki, T.; Oderaotoshi, Y.; Minakata, S.;
Komatsu, M. Tetrahedron 2003, 59, 197-205. (i) Bullington, J . L.;
Wolff, R. R.; J ackson, P. F. J . Org. Chem. 2002, 67, 9439-9442. (j)
Demir, A. S.; Akhmedov, D. M.; Sesenoglu, O. Tetrahedron 2002, 58,
9793-9799. (k) Langer, P.; Freifeld, I. Chem. Commun. 2002, 2268-
2269. (l) Deng, G. S.; J iang, N.; Ma, Z. H.; Wang, J . B. Synlett 2002,
1913-1915. (m) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone,
P.; Mantellini, F.; Santeusanio, S. J . Org. Chem. 2002, 67, 8178-8181.
(n) Bergman, J .; Rehn, S. Tetrahedron 2002, 58, 9175-9185. (o) Smith,
N. D.; Huang, D. H.; Cosford, N. D. P. Org. Lett. 2002, 4, 3537-3539.
(p) Quiclet-Sire, B.; Wendeborn, F.; Zard, S. Z. Chem. Commun. 2002,
2214-2215. (q) Hwang, S. H.; Kurth, M. J . J . Org. Chem. 2002, 67,
6564-6567. (r) Paulus, O.; Alcaraz, G.; Vaultier, M. Eur. J . Org. Chem.
2002, 2565-2572. (s) Pedrosa, R.; Andres, C.; de las Heras, L.; Nieto,
J . Org. Lett. 2002, 4, 2513-2516. (t) Dvornikova, E.; Kamienska-Trela,
K. Synlett 2002, 1152-1154. (u) Airaksinen, A. J .; Ahlgren, M.;
Vepsalainen, J . J . Org. Chem. 2002, 67, 5019-5021. (v) Gabriele, B.;
Salerno, G.; Fazio, A.; Campana, F. B. Chem. Commun. 2002, 1408-
1409. (w) Hewton, C. E.; Kimber, M. C.; Taylor, D. K. Tetrahedron
Lett. 2002, 43, 3199-3201. (x) J ust, P. E.; Chane-Ching, K. I.; Lacaze,
P. C. Tetrahedron 2002, 58, 3467-3472. (y) Hercouet, A.; Neu, A.;
Peyronel, J . F.; Carboni, B. Synlett 2002, 829-831. (z) Alickmann, D.;
Frohlich, R.; Maulitz, A. H.; Wurthwein, E. U. Eur. J . Org. Chem. 2002,
1523-1537.
En yn a m in es (Z)-R4CtCC(R3)dCHCHR1NHR. Ad-
ditional substitution at C-1 with respect to substrates
1a -e resulted in a slight decrease of the substrate
conversion rate, both with Cu(II)- and Pd(II)-based
catalysts, as exemplified by the results obtained with (Z)-
benzyl(1-butyl-3-methylnon-2-en-4-ynyl)amine 1f (Table
2, entries 28-30, to be compared with the results
reported in Table 1 for 1a ). As for 1a -e, the best yield
in the corresponding pyrrole 2f (95% GLC yield, 90%
isolated) was obtained with CuCl2 as catalyst (entry 28
and eq 3), even though an 86% GLC yield (80% isolated)
could also be obtained using PdCl2 + 2KCl (entry 29).
(4) Gabriele, B.; Salerno, G.; Lauria, E. J . Org. Chem. 1999, 64,
7687-7692.
(5) Gabriele, B.; Salerno, G.; Fazio, A. Org. Lett. 2000, 2, 351-352.
(6) Gabriele, B.; Salerno, G.; Fazio, A.; Pittelli, R. Tetrahedron 2003,
59, 6251-6259.
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Lett. 2001, 42, 1339-1341.
7854 J . Org. Chem., Vol. 68, No. 20, 2003

Substituted Pyrroles from (Z)-(2-En-4-ynyl)amines
TABLE 1. Syn th esis of P yr r oles 2a -e by Cu - or P d -Ca ta lyzed Cycloisom er iza tion of En yn a m in es 1a -ea
entry
catalyst
1
R
R1
R2
R3
R4
t (h)
conversion of 1 (%)b
yield of 2 (%)c
1
2
3
4
5
6
7
8
PdI2 + 2KI
PdI2 + 2NaI
PdI2 + 2LiI
PdCl2 + 2KCl
PdCl2 + 2NaCl
PdCl2 + 2LiCl
(PhCN)2PdCl2
Pd(OAc)2
CuCl2
CuI + 2KI
CuCl2
PdCl2 + 2KCl
PdI2 + 2KI
CuCl2
PdCl2 + 2KCl
PdI2 + 2KI
CuCl2
CuI + 2KI
CuCl2
CuCl2
CuI + 2KI
PdCl2 + 2KCl
PdCl2 + 2KCl
(PhCN)2PdCl2
PdI2 + 2KI
PdI2 + 2KI
Pd(OAc)2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1d
1e
1e
1e
1e
1e
1e
1e
1e
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bu
Bu
Bu
Bu
Bu
Bu
t-Bu
t-Bu
t-Bu
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
6
6
6
6
6
6
6
6
6
6
3
14
14
3
3
3
26
26
8
2
2
2
6
2
2
6
2
90
96
99
53 (48)
55
53
65
60
55
57
20
100 (91)
98
85 (80)
49 (43)
52 (47)
81 (75)
25
26
72 (63)
59
66
93 (88)
87
23
75 (69)
36
100
100
100
100
46
100
100
100
100
100
100
45
48
100
61
100
100
100
30
100
42
9
10
11
12
13
14
15
16
17d
18d
19e
20
21
22
23
24
25
26
27
Bu
Bu
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
40
100
80
28
73 (68)
61
a
Unless otherwise noted, all reactions were carried out under nitrogen at 100 °C using 1 mol % of catalyst in anhydrous DMA (2 mmol
of 1/mL DMA, 3-6 mmol scale based on 1). Based on starting 1, by GLC. c GLC yield (isolated yield) based on 1. The reaction was
b
d
carried out using 5 mol % of catalyst. e The reaction was carried out using 10 mol % of catalyst.
TABLE 2. Syn th esis of P yr r oles 2f-h by Cu - or P d -Ca ta lyzed Cycloisom er iza tion of En yn a m in es 1f-h a
entry
catalyst
1
R
R1
R2
R3
R4
t (h)
conversion of 1 (%)b
yield of 2 (%)c
28d
29d
30d
31
32
33
34
35
36
37
38
39
40
41
CuCl2
1f
1f
1f
Bn
Bn
Bn
Bu
Bu
Bu
Bu
Bu
Bu
Bn
Bn
Bn
Bn
Bn
Bu
Bu
Bu
H
H
H
H
H
H
H
H
H
H
Et
Et
Et
Et
Et
Et
H
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
CHdCMe2
CHdCMe2
CHdCMe2
CHdCMe2
CHdCMe2
12
12
12
1.5
1.5
1.5
1.5
1.5
1.5
5
100
100
100
100
100
60
71
85
40
100
99
95 (90)
86 (80)
42 (35)
100 (90)
100
35
40
68
22
92 (83)
48
52
31
18
PdCl2 + 2KCl
PdI2 + 2KI
CuCl2
CuI + 2KI
PdCl2 + 2KCl
(PhCN)2PdCl2
PdI2 + 2KI
Pd(OAc)2
1g
1g
1g
1g
1g
1g
1h
1h
1h
1h
1h
CuCl2
PdCl2 + 2KCl
(PhCN)2PdCl2
PdI2 + 2KI
Pd(OAc)2
H
H
H
H
H
H
H
H
5
5
5
5
100
68
89
a
Unless otherwise noted, all reactions were carried out under nitrogen at 100 °C using 1 mol % of catalyst in anhydrous DMA (2 mmol
of 1/mL DMA, 3-6 mmol scale based on 1). Based on starting 1, by GLC. c GLC yield (isolated yield) based on 1. The reaction was
carried out using 2 mol % of catalyst.
b
d
En yn a m in es (Z)-R4CtCC(R3)dCR2CH2NHR. CuCl2
turned out to be the catalyst of choice also for enynamines
bearing an internal triple bond and a substituent on both
olefinic carbons, as in the case of (Z)-butyl(2-ethyl-3-
phenylnon-2-en-4-ynyl)amine 1g (Table 2, entries 31-
36). A virtually quantitative GLC yield of the correspond-
ing pyrrole 2g was obtained after only 1.5 h using either
CuCl2 (entry 31 and eq 3) or CuI + 2KI (entry 32),
whereas under similar conditions the Pd-based catalysts
were less active (entries 33-36).
yield as high as 92% (83% isolated, Table 2 entry 37 and
eq 3). As before, under analogous conditions, Pd-based
catalysts led to lower yields of 2h (Table 2, entries 38-
41).
En yn a m in es (Z)-P h CtCC(R3)dCHCH2NHR. Inter-
estingly, enynamines bearing a triple bond conjugated
with a phenyl group turned out to be unstable and
underwent spontaneous cyclization to the correspond-
ing pyrroles without need of metal catalysis. Thus,
column chromatography of the crude product deriving
from bromination of 3-methyl-5-phenylpent-1-en-4-yn-3-
ol 3a followed by nucleophilic substitution with benzyl-
amine or butylamine led to the corresponding pyrroles
2i and 2j in 45% and 46% isolated yield based on starting
enynol (Scheme 1; allylic isomerization occurred during
the bromination step, see Experimental Section for
details).
E n y n a m i n e s
( Z ) -R 5 2 C dC H C tC C ( R 3 ) d
CHCHR1NHR. Enynamines with the triple bond con-
jugated with a double bond behaved similarly to the
analogous substrates with the triple bond substituted
with an alkyl group. Thus, (Z)-benzyl(3,7-dimethylocta-
2,6-dien-4-ynyl)amine 1h was smoothly converted into
pyrrole 2h in 5 h using CuCl2 as catalyst, with a GLC
J . Org. Chem, Vol. 68, No. 20, 2003 7855

Gabriele et al.
TABLE 3. Syn th esis of P yr r oles 2m -o by Cu - or P d -Ca ta lyzed Cycloisom er iza tion of En yn a m in es 1m -oa
entry
catalyst
1
R
R1
R2
R3
R4
t (h)
conversion of 1 (%)b
yield of 2 (%)c
42
PdCl2 + 2KCl
PdCl2 + 2KCl
(PhCN)2PdCl2
PdI2 + 2KI
PdI2 + 2KI
Pd(OAc)2
1m
1m
1m
1m
1m
1m
1m
1m
1n
1n
1n
1o
1o
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bn
Bn
Bn
Bu
Bu
Bu
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
7
25
7
7
25
7
7
7
6
5
100
75
62
100
100
58
90 (85)
69
47
87 (80)
89 (83)
52
43d
44
45
46d
47
48
49
50
CuCl2
CuI + 2KI
49
90
45
73
PdCl2 + 2KCl
PdI2 + 2KI
PdI2 + 2KI
PdCl2 + 2KCl
PdI2 + 2KI
PdI2 + 2KI
100
100
100
100
100
100
94 (85)
92 (82)
89 (80)
93 (86)
95 (86)
96 (87)
51
52d
53
15
4
4
54
55d
1o
15
a
Unless otherwise noted, all reactions were carried out under nitrogen at 25 °C using 1 mol % of catalyst in anhydrous DMA (2 mmol
of 1/mL DMA, 3-6 mmol scale based on 1). Based on starting 1, by GLC. c GLC yield (isolated yield) based on 1. The reaction was
carried out using 0.2 mol % of catalyst.
b
d
SCHEME 1
SCHEME 3
faster with PdI2 + 2KI (entry 46) rather than PdCl2 +
2KI (entry 43).
Similar results were obtained with (Z)-benzyl(2-ethyl-
non-2-en-4-ynyl)amine 1n (Table 3, entries 50-52), which
was somewhat more reactive than 1m . Under conditions
analogous to those reported in entry 42 for 1m , substrate
conversion reached 100% after 6 h, with a yield of the
corresponding pyrrole 2n of 94% by GLC (85% isolated,
entry 50 and eq 4). (Z)-Butyl(2-phenylnon-2-en-4-ynyl)-
amine 1o, bearing a phenyl rather than an alkyl sub-
stituent at C-2, was also more reactive than 1m , as
shown by the results reported in Table 3 (entries 53-
55).
SCHEME 2
From these reactions, it has also been possible to
isolate (E)-benzyl(3-methyl-5-phenylpent-2-en-4-ynyl)-
amine 1i′ (13% yield based on 3a ) and (E)-butyl(3-methyl-
5-phenylpent-2-en-4-ynyl)amine 1j′ (10%). Cycloisomer-
ization of these latter compounds did not occur even in
the presence of catalyst.
En yn a m in es (Z)-HCtCC(R3)dCHCH2NHR. Spon-
taneous annulation also occurred in the case of enyn-
amines bearing a terminal triple bond, as shown in
Scheme 2 for the synthesis of pyrroles 2k and 2l. It is
worth noting that cyclization occurred readily even with
a sterically hindered amine such as tert-butylamine.
En yn a m in es Un su bstitu ted a t C-3. En yn a m in es
(Z)-R 4CtCCH dC(R 2)CH 2NH R . Enynamines substi-
tuted at C-2 and C-5 and unsubstituted at C-3 were
considerably more reactive than analogous substrates
substituted at C-3, and cycloisomerization reactions could
be carried out at 25 °C. Moreover, with these substrates,
PdX2 + 2KX (X ) Cl, I) turned out to be more active than
Cu-based catalysts, as exemplified by the results obtained
with (Z)-butyl(2-ethylnon-2-en-4-ynyl)amine 1m , which
are shown in Table 3 (entries 42-49, to be compared with
the results reported above for 1a -c). By using PdCl2 +
2KCl (1 mol % of PdCl2) at 25 °C for 7 h, the yield of
pyrrole 2m reached 90% by GLC (85% isolated, entry 42
and eq 4) at total substrate conversion. Interestingly,
when the substrate to catalyst molar ratio was raised to
500, the cycloisomerization process was appreciably
Interestingly, when R4 was CH2OTHP rather than a
simple alkyl group, spontaneous cycloisomerization to the
corresponding pyrrole occurred. Thus, mesylation of (Z)-
2-ethyl-6-(tetrahydropyran-2-yloxy)hex-2-en-4-yn-1-ol 4a
followed by nucleophilic substitution with butylamine
afforded directly pyrrole 2p ′ in 85% isolated yield. After
deprotection, 1-butyl-4-ethyl-2-(2-hydroxyethyl)pyrrole
2p could be recovered in 90% yield with respect to 2p ′
(Scheme 3).
En yn a m in es (Z)-HCtCCHdCHCH2NHR. As ex-
pected, spontaneous cyclization also took place when the
triple bond was terminal, as exemplified by the direct
formation of 4-ethyl-2-methylpyrrole 2q by deprotection
7856 J . Org. Chem., Vol. 68, No. 20, 2003

Substituted Pyrroles from (Z)-(2-En-4-ynyl)amines
TABLE 4. Syn th esis of P yr r oles 2r ,s by Cu - or P d -Ca ta lyzed Cycloisom er iza tion of En yn a m in es 1r ,sa
entry
catalyst
1
R
R1
R2
R3
R4
t (h)
conversion of 1 (%)b
yield of 2 (%)c
56
57d
58
59
60
61
62
63
64e
65
66
67
68
PdI2 + 2KI
PdI2 + 2KI
PdCl2 + 2KCl
(PhCN)2PdCl2
Pd(OAc)2
1r
1r
1r
1r
1r
1r
1r
1s
1s
1s
1s
1s
1s
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
H
H
H
H
H
H
H
Bu
Bu
Bu
Bu
Bu
Bu
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
15
7
100
100
70
26
44
89 (80)
95 (88)
64
21
40
30
59
91
91 (86)
50
15
15
15
15
15
26
8
26
28
26
26
CuCl2
32
68
CuI + 2KI
PdCl2 + 2KCl
PdCl2 + 2KCl
(PhCN)2PdCl2
PdI2 + 2KI
Pd(OAc)2
100
100
59
100
52
88
43
25
CuCl2
35
a
Unless otherwise noted, all reactions were carried out under nitrogen at 25 °C using 1 mol % of catalyst in anhydrous DMA (2 mmol
of 1/ mL DMA, 3-6 mmol scale based on 1). Based on starting 1, by GLC. c GLC yield (isolated yield) based on 1. The reaction was
b
d
carried out at 50 °C. e The reaction was carried out at 40 °C.
SCHEME 4
SCHEME 5
of (Z)-butyl(2-ethyl-5-trimethylsilanylpent-2-en-4-ynyl)-
amine 1q′ (Scheme 4).
E n yn a m in es (Z)-R4CtCCH dCH CH2NH R . The
cycloisomerization procedure was also successfully ap-
plied to substrates unsubstituted at C-2 and C-3 for the
synthesis of 2-substituted pyrroles. Actually, the present
reaction represents one of the few examples of direct
synthesis of 2-susbtituted pyrroles by metal-catalyzed
annulation of acyclic precursors.8 Enynamines unsubsti-
tuted at C-2 were slightly less reactive than the analo-
gous ones bearing a substituent at C-2 and required a
longer reaction time to achieve complete conversion
under analogous conditions. This is evident, for example,
by comparing the results obtained with (Z)-benzyl(non-
2-en-4-ynyl)amine 1r , reported in Table 4 (entries 56-
62) with those shown in Table 3 for 1m . Using PdI2 +
2KI at 25 °C, substrate conversion was quantitative after
15 h, with formation of pyrrole 2r in 89% GLC yield (80%
isolated, entry 56). By working at 50 °C, reaction time
could be shortened to 7 h with a GLC yield of 2r of 95%
(88% isolated, entry 57 and eq 4).
On the basis of the results obtained above the following
observations can be made on cycloisomerization of (Z)-
(2-en-4-ynyl)amines to substituted pyrroles:
(a) Spontaneous cycloisomerization occurred when the
triple bond of (Z)-(2-en-4-ynyl)amines was either (i)
terminal, (ii) conjugated with a phenyl group, or (iii)
substituted with a CH2OTHP group. This is conceivable,
since uncatalyzed nitrogen attack on the triple bond
becomes possible when the triple bond is less hindered
or made more electrophilic by conjugation to a phenyl
group or substitution with an alkyl group bearing an
electron-withdrawing substituent.
(b) When the triple bond was substituted with an alkyl
or alkenyl group, (Z)-(2-en-4-ynyl)amines were stable and
isolable and could be smoothly converted into the corre-
sponding pyrroles in high yields through catalysis by
copper or palladium.
En yn a m in es (Z)-R4CtCCHdCHCHR1NHR. As ex-
pected, additional substitution at C-1 with respect to 1r
resulted in a slight decrement of reactivity, as in the case
of (Z)-benzyl(1-butylnon-2-en-4-ynyl)amine 1s (Table 4,
entries 63-68). The best results in terms of substrate
conversion rate and product yield were observed by
working with either PdCl2 + 2KCl or PdI2 + 2KI, while
the other Pd-based catalysts tested as well as CuCl2 were
less active. Using PdCl2 + 2KCl, GLC yield of pyrrole 2s
was as high as 91% either after 26 h at 25 °C (entry 63)
or after 8 h at 40 °C, with an isolated yield of 86% (entry
64 and eq 4).
(c) No cycloisomerization occurred in the case of (E)-
(2-en-4-ynyl)amines, either spontaneous or catalyzed.
This means that, analogously to what we have previously
observed for 2-en-4-yn-1-ols,4 no E f Z isomerization
occurred under the reaction conditions.
(d) For stable enynamines requiring metal catalysis for
cycloisomerization to occur, substrate reactivity was
much higher in the absence of a substituent at C-3. This
is in agreement with an anti 5-exo-dig mechanism, with
the triple bond activated by coordination to the metal
cation from the opposite site with respect to the CHR1NHR
moiety (Scheme 5, unreactive ligands are omitted for
clarity). Clearly, such coordination is more favored in the
absence of substitution at C-3 for steric reasons. The
resulting vinylmetal intermediate then undergoes pro-
tonolysis and aromatization or vice versa to give the
pyrrole with regeneration of the catalyst.
(8) CuI-assisted cycloisomerization of alkynyl imines (30 mol % of
CuI with respect to the substrate) to 2-substituted pyrroles, carried
out at 110 °C under basic conditions (1:7 Et3N/DMA), has been recently
reported: Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J . Am. Chem.
Soc. 2001, 123, 2074-2075.
J . Org. Chem, Vol. 68, No. 20, 2003 7857

Gabriele et al.
SCHEME 6
(e) Palladium catalysis was significantly more sensitive
to the steric effects exerted by the substituent at C-3 than
copper catalysis. This can be due to the larger ionic radius
of Pd2+ with respect to both Cu2+ and Cu+,9 although
other effects (such as a different coordination environ-
ment) might also be at work. As a consequence, in the
presence of C-3 substitution, both CuCl2 and CuI + 2KI
turned out to be more active catalysts than Pd-based
catalysts, either neutral (as in the case of (PhCN)2PdCl2
or Pd(OAc)2) or anionic (as in the case of PdX42-, formed
in situ from PdX2 + 2 KX, X ) Cl or I). CuCl2 usually
gave slightly better results than CuI + 2KI, which is in
agreement with the diminished steric requirements of a
complex bearing chlorides rather than iodides as ligands.
This effect is partially counterbalanced by the higher
electron-releasing power of I- as compared with Cl-,
which tends to favor protonolysis when X ) I rather than
Cl.
SCHEME 7
2-
(f) For substrates unsubstituted at C-3, PdX4 (X )
Cl, I) catalysts were more active than CuI + 2KI, which
was in its turn significantly more active than CuCl2. On
the other hand, neutral palladium catalysts (such as
(PhCN)2PdCl2 or Pd(OAc)2) showed low reactivity, com-
parable to that of CuCl2. These results indicate that, in
the absence of a steric hindrance at C-3, active catalytic
species are actually favored by halide ligands. Moreover,
although PdCl2 + 2KCl and PdI2 + 2KI showed a level
activity with a substrate to Pd molar ratio of 100, PdI2
+ 2KI was somewhat more active when this ratio was
raised to 500. The higher electron-releasing power of I-
as compared with Cl-, which tends to favor protonolysis
when X ) I rather than Cl, can be responsible for this
effect.
(g) As expected in view of a mechanism involving
intramolecular nucleophilic attack by the nitrogen of the
NHR moiety to the triple bond, the cycloisomerization
reaction was sensitive to the steric effect exerted by the
substituent on nitrogen. For example, other substituents
and reaction conditions being the same, reactivity de-
creased passing from R ) H to R ) Bu or Bn and even
more to R ) t-Bu. Also, nitrogen nucleophilicity was
affected by R-substitution, as shown by the fact that
slower reactions were usually observed for substrates
bearing an additional substituent at C-1 with respect to
the analogous ones unsubstituted at C-1.
(h) Substitution at C-2 tended to enhance substrate
reactivity. This effect is clearly related to the steric
assistance exerted by the R2 group; in fact, the unfavor-
able steric repulsion between the substituent and the
CHR1NHR moiety is relieved going through the transi-
tion state leading to cyclization.
(i) Phenyl rather than alkyl substitution on olefinic
carbons resulted in higher reactivity. This is apparently
due to the stabilizing effect exerted by the phenyl group
by conjugation in the transition state leading to final
pyrrole.
SCHEME 8
is a powerful technique for the construction of the pyrrole
ring with the desired substitution pattern. The methodol-
ogy is quite general and allows the regioselective syn-
thesis of substituted pyrroles in high yields under mild
conditions. The amino group of the substrate can be
either primary or secondary, and the nitrogen can be
substituted even with a very bulky group such as tert-
butyl. The triple bond can be terminal or internal, and
in the latter case alkyl, aryl, and alkenyl, as well as
functionalyzed groups, can be present as substituents.
Exp er im en ta l Section
Syn th esis of (Z)-(2-en -4-yn yl)a m in es 1. Enynamines 1a -
d , 1g,h , 1m -o, and 1r , bearing a secondary amino group, were
easily prepared by bromination of either 3-methylnon-1-en-4-
yn-3-ol 3c or (Z)-2-en-4-yn-1-ols 4c-h with PBr3 followed by
nucleophilic substitution with RNH2 (Schemes 6 and 7). Allylic
isomerization occurred in the course of bromination of 3c to
give a ca. 20:1 (by GLC and GC-MS) Z:E mixture of the more
stable allylic primary bromide. Following the reaction with
RNH2, (Z)-(2-en-4-ynyl)amine 1a , 1b , or 1d could be easily
isolated in the pure state by column chromatography, as
detailed below.
Enynamine 1e bearing a primary amino group was prepared
from (Z)-3-methylnon-2-en-4-yn-1-ol 4i by reaction with phthal-
imide under Mitsunobu conditions,10 followed by cleavage with
hydrazine (Scheme 8). Enynamines 1f and 1s bearing a
substituent R to the amino group were prepared from 4i or
(Z)-non-2-en-4-yn-1-ol 4h , respectively, through oxidation with
MnO2 to give (Z)-2-en-4-ynals, reaction with RNH2 to the
corresponding imines, and regioselective addition of BuLi in
the presence of LaCl3 (Scheme 9).
Con clu sion s
We have shown that spontaneous or catalyzed cyclo-
isomerization of readily available (Z)-(2-en-4-ynyl)amines
(9) Shannon, R. D.; Prewitt, C. T. Acta Crystallogr. 1969, B25, 925-
946.
(10) Mitsunobu, O. Synthesis 1981, 1-28.
7858 J . Org. Chem., Vol. 68, No. 20, 2003

Substituted Pyrroles from (Z)-(2-En-4-ynyl)amines
purification. The procedure described by Nussbaumer15 was
employed for the amination. To a cooled solution of RNH2 (490
mmol) in EtOH (60 mL) maintained at 0 °C was added
dropwise a solution of the bromide in anhydrous DMF (16 mL).
After being stirred at 0 °C for 1 h, the mixture was allowed to
stir at room temperature overnight. The solvent was evapo-
rated, and the residue was quenched with water and extracted
several times with Et2O. The aqueous layer was basified to
pH 9 with 1 N NaOH and then extracted several times with
Et2O. The basic organic layer was analyzed by TLC and GLC;
in some cases it only contained RNH2 and was discarded,
otherwise it was added to the previously obtained organic
phase. After drying over Na2SO4, the solvent was evaporated,
and crude enynamines were purified by column chromatog-
raphy on silica gel: 1a was a pale yellow oil (hexane-AcOEt
from 9:1 to 8:2, 5.72 g, 79% based on starting 3c); 1b was a
yellow oil (hexane-AcOEt from 9:1 to 7:3, 3.17 g, 51% based
on starting 3c); 1c was a colorless oil (hexane-AcOEt from
9:1 to 8:2, 5.09 g, 68% based on starting 4c); 1d was a yellow
oil (hexane-AcOEt from 9:1 to 7:3, 5.04 g, 81% based on
starting 3c); 1g was a yellow oil (hexane-AcOEt from 9:1 to
7:3, 6.60 g, 74% based on starting 4d ); 1h was a yellow oil
(hexane-AcOEt from 98:2 to 90:10, 4.74 g, 66% based on
starting 4e); 1m was a yellow oil, hexane-AcOEt from 9:1 to
7:3, 4.38 g, 66% based on starting 4f); 1n was a pale yellow
oil (hexane-AcOEt from 9:1 to 7:3, 3.98 g, 52% based on
starting 4f); 1o was a yellow oil (hexane-AcOEt from 9:1 to
7:3, 6.30 g, 78% based on starting 4g); 1r was a pale yellow
oil, 9:1 hexane-AcOEt, 5.05 g, 74% based on starting 4h ).
(Z)-(3-Meth yln on -2-en -4-yn yl)a m in e 1e (Sch em e 8). The
method of Hegedus16 was employed. To a stirred solution of
phthalimide (13.2 g, 90 mmol) and PPh3 (23.6 g, 90 mmol) in
anhydrous THF (382 mL) was added dropwise a mixture of
(Z)-3-methylnon-2-en-4-yn-1-ol 4i4 (11.6 g, 76.2 mmol) and
DEAD (15.7 g, 90 mmol). During the addition, the reaction
flask was suitably cooled so that the reaction temperature
would not exceed 25 °C. The mixture was allowed to stir at
room temperature for 3 days. After elimination of the solvent
in vacuo, a pale yellow semisolid was obtained, which was
dissolved in MeOH (380 mL). Hydrazine monohydrate (7.7 g,
154 mmol) was added slowly, and the resulting mixture was
refluxed overnight. After cooling to room temperature, con-
centrated HCl (11.5 mL) was added, and the mixture refluxed
overnight. The solvent was evaporated to obtain a pale yellow
solid, which was washed several times with 90 mL of a HCl
solution prepared from 13.4 mL of concentrated HCl and 383
mL of water. After filtration, the collected aqueous phases were
collected and washed with CHCl3 (7 × 58 mL) and Et2O (3 ×
58 mL). The aqueous phase was cooled to 0 °C and basified
with saturated NaOH to pH 13. Phases were separated, the
aqueous phase was extracted with Et2O (10 × 60 mL), and
the collected organic layers were washed with brine (4 × 95
mL) and dried (Na2SO4). After evaporation of the solvent, the
brown residue was distilled under reduced pressure (28-29
°C/47 × 10-2 mmHg) to give 1e as a colorless oil (5.9 g, 51%
based on 4i).
SCHEME 9
P r ep a r a tion of En yn ols 3c a n d 4c-h . Enynols 3c, 4e-h
were prepared as we already reported.4 Enynol 4c,d were
prepared by Pd/Cu-catalyzed coupling between (Z)-3-iodohept-
2-en-1-ol11 or (Z)-2-ethyl-3-iodo-3-phenylprop-2-en-1-ol, respec-
tively, and 1-hexyne, as described below. (Z)-2-Ethyl-3-iodo-
3-phenylprop-2-en-1-ol was prepared by addition of EtMgBr
to 3-phenylprop-2-yn-1-ol12 followed by iodolysis according to
Duboudin.13 To a cooled solution (0 °C) of 3-phenylprop-2-yn-
1-ol (10.0 g, 75.8 mmol) and CuI (1.44 g, 7.6 mmol) in Et2O
(100 mL) was added dropwise a solution of EtMgBr [prepared
from 20.6 g (189 mmol) of EtBr, 5.0 g (206 mmol) of Mg and
100 mL of Et2O]. After being stirred at room temperature for
3 h, the reaction mixture was cooled to 0 °C and iodine (25.9
g, 102 mmol) was added in small portions. The mixture was
then allowed to stir at 0 °C for 1 h and then at room
temperature for 1 h. After cooling to 0 °C, the reaction mixture
was quenched with saturated NH4Cl, and phases were sepa-
rated. The aqueous layer was extracted with Et2O, and the
collected organic phases were washed with saturated Na2S2O3
and water and eventually dried over Na2SO4. The solvent was
evaporated, and the crude iodide was used for the next step
without further purification.
The method of Alami14 was employed for the coupling. To a
cooled (0 °C), stirred mixture of Pd(PPh3)4 (2.86 g, 2.5 mmol)
and CuI (950 mg, 5.0 mmol) in pyrrolidine (10 mL) was added
dropwise a solution of the vinyl iodide (12.0 g, 50 mmol of (Z)-
3-iodohept-2-en-1-ol, or crude (Z)-2-ethyl-3-iodo-3-phenylprop-
2-en-1-ol obtained as above) in pyrrolidine (50 mL), followed
by stirring for 5 min. A solution of BuCtCH (8.1 g, 98.6 mmol)
in pyrrolidine (10 mL) was then added dropwise at 0 °C. After
stirring at room temperature for 2 h, the reaction mixture was
diluted with Et2O and quenched at 0 °C with saturated NH4Cl.
The aqueous layer was extracted with Et2O, and the combined
organic layers were washed with brine, dried (Na2SO4), and
evaporated. The residue then was purified by column chro-
matography on silica gel: 4c was a yellow oil (8:2 hexane-
AcOEt, 9.0 g, 93% based on (Z)-3-iodohept-2-en-1-ol); 4d was
a colorless oil (9:1 hexane-AcOEt, 10.4 g, 57% based on
starting 3-phenylprop-2-yn-1-ol).
Gen er a l P r oced u r e for Br om in a tion of 3c or 4c-h
F ollow ed by Rea ction w ith RNH2 (Sch em es 6 a n d 7). To
a cooled (-15 °C) solution of 3c or 4c-h (30.0 mmol) in
anhydrous Et2O (5.2 mL) and pyridine (490 µL) was added
dropwise a solution of PBr3 (3.2 g, 11.8 mmol) in Et2O (18 mL).
After being stirred at room temperature for 0.5 h, the reaction
mixture was quenched with water, and the phases were
separated. The aqueous layer was extracted with Et2O, and
the collected organic phases were washed with saturated
NaHCO3, washed with water to neutral pH, dried over Na2SO4,
and evaporated. The crude allylic primary bromide thus
obtained was then used for the next step without further
(Z)-Ben zyl-(1-bu tyl-3-m eth yln on -2-en -4-yn yl)a m in e 4f
an d (Z)-Ben zyl-(1-bu tyln on -2-en -4-yn yl)am in e 4s (Sch em e
9). The method of Dixneuf17 was employed for the oxidation
of enynols 4h ,i. To a stirred suspension of MnO2 (20.0 g, 230
mmol) in CH2Cl2 (75 mL) was added enynol 4h or 4i (30.0
mmol) in 15 min, and the mixture was allowed to stir at room
temperature for 16 h. After filtration through Celite, the
solvent was evaporated, and the crude aldehyde thus obtained
was used as such for the next step. The method of Martin18
(11) Marshall, J . A.; DuBay, W. J . J . Org. Chem. 1993, 58, 3435-
3443.
(12) Denis, J . N.; Greene, A. E.; Serra, A. A.; Luche, M. J . J . Org.
Chem. 1986, 51, 46-50.
(15) Nussbaumer, P.; Petranyi, G.; Stu¨ltz, A. J . Med. Chem. 1991,
34, 65-73.
(13) (a) Duboudin, J . G.; J ousseaume, B. J . Organomet. Chem. 1979,
168, 1-11. (b) Duboudin, J . G.; J ousseaume, B.; Bonakdar, A. J .
Organomet. Chem. 1979, 168, 227-232.
(16) Hegedus, L. S.; McKearin, J . M. J . Am. Chem. Soc. 1982, 104,
2444-2451.
(17) Seiller, B.; Bruneau, C.; Dixneuf, P. H. Tetrahedron 1995, 51,
13089-13102.
(18) Martin, S. F.; Li, W. J . Org. Chem. 1991, 56, 642-650.
(14) Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993,
34, 6403-6406.
J . Org. Chem, Vol. 68, No. 20, 2003 7859

Gabriele et al.
was used for the formation of imines. To a cooled (0 °C) solution
of MgSO4 (3.30 g, 27.4 mmol) and benzylamine (2.94 g, 27.5
mmol) in anhydrous Et2O (34 mL) was added dropwise the
crude aldehyde. The mixture was allowed to stir for 0.5 h at 0
°C and then at room temperature for 15 h. After filtration,
the solvent was evaporated, and the crude imine thus obtained
was used as such for the next step. The method of Qian19 was
employed for the regioselective addition of BuLi to the imino
group. A mixture of LaCl3 (7.3 g, 29.8 mmol) in anhydrous THF
(60 mL) was allowed to stir at room temperature for 2 h. The
resulting white slurry suspension was then cooled to -78 °C,
and a 1.6 M solution of BuLi in hexane (18.6 mL, 29.8 mmol)
was added dropwise. After stirring for 1 h at -78 °C, a solution
of the imine in THF (15 mL) was added dropwise, and the
resulting mixture was allowed to stir at -78 °C for 4 h. The
reaction was quenched with a saturated solution of NaF (150
mL) and filtered to remove lanthanum fluoride. Phases were
separated, and the aqueous phase was extracted 5 times with
Et2O. The combined organic layers were washed with brine,
dried (Na2SO4), and evaporated. The crude product was then
purified by column chromatography on silica gel: 1f was a
yellow oil (9:1 hexane-AcOEt, 3.30 g, 37% based on 4i); 1s
was a yellow oil (9:1 hexane-AcOEt, 2.89 g, 34% based on 4h ).
Gen er a l P r oced u r e for Cycloisom er iza tion of En yn -
a m in es 1a -h , 1m -o, 1r ,s. Reactions were carried out on a
3-6 mmol scale based on enynamine 1. Catalyst composition,
substrate to catalyst molar ratio, reaction temperature and
time, and yields of pyrroles 2 are indicated in Tables 1-4. In
a typical experiment, the catalyst was added to a solution of
1 (5 mmol) in anhydrous DMA (2.5 mL) in a Schlenk flask.
The resulting mixture was stirred at the temperature and for
the time indicated in Tables 1-4. Solvent was evaporated and
the crude product purified by column chromatography on silica
gel: 2a was a yellow oil (99:1 hexane-AcOEt); 2b was a
colorless oil (pure hexane); 2c was a colorless oil (90:10
hexane-AcOEt); 2d was a colorless oil (97:3 hexane-AcOEt);
2e was a yellow oil (pure Et2O); 2f was a pale yellow oil (97:3
hexane-AcOEt); 2g was a coloress oil (99:1 hexane-AcOEt);
2h was a yellow oil (98:2 hexane-AcOEt); 2m was a colorless
oil (pure hexane); 2n was a yellow oil (pure Et2O); 2o was a
yellow oil (pure hexane); 2r was a pale yellow oil (98:2 hexane-
AcOEt); 2s was a yellow oil (97:3 hexane-AcOEt).
Sp on t a n eou s Cycloisom er iza t ion t o P yr r oles 2i,j
(Sch em e 1). Starting 3-methyl-5-phenylpent-1-en-4-yn-3-ol 3a
was prepared as we already reported.4 Bromination of 3a
followed by reaction with RNH2 was carried out as described
above in the general procedure, starting from 5.17 g (30.0
mmol) of the enynol. As above, bromination occurred with
allylic isomerization to give a ca. 4:1 (by GLC and GC-MS)
mixture of (Z)- and (E)-(5-bromo-3-methylpent-3-en-1-ynyl)-
benzene. The Et2O extracts deriving from amination of the
mixture of bromides with BnNH2 contained a ca. 45:30:25
mixture of 1,2-dibenzyl-3-methylpyrrole (2i)/(Z)-benzyl(3-
methyl-5-phenylpent-2-en-4-ynyl)amine (1i)/(E)-benzyl(3-methyl-
5-phenylpent-2-en-4-ynyl)amine 1i′, as shown by GC-MS
analysis. Column chromatography (SiO2, hexane-AcOEt from
9:1 to 3:7) of the crude mixture afforded 3.53 g of 2i (yellow
oil, 13.51 mmol, 45% yield based on 3a ) and 1.01 g of 1i′ (yellow
oil, 3.86 mmol, 13% based on 3a ). This result clearly shows
that further conversion of 1i into 2i occurred during the
purification procedure.
commercially available; alternatively, it could be prepared as
we already reported.4 Bromination of 3b followed by reaction
with RNH2 was carried out as described above in the general
procedure, starting from 2.88 g (30.0 mmol) of the enynol. The
Et2O extracts, containing a ca. 20:1 (by GLC and GC-MS)
mixture of (Z)- and (E)-5-bromo-3-methylpent-3-en-1-yne, were
distilled at atmospheric pressure rather than in vacuo to
eliminate the solvent. Column chromatography (SiO2, 9:1
hexane-AcOEt) of the reaction crude deriving from amination
with BnNH2 afforded 3.17 g of 1-benzyl-2,3-dimethylpyrrole
2k (17.11 mmol, 57% yield based on 3b) as a low-melting (36-
37 °C) colorless solid. In the case of amination with t-BuNH2,
the Et2O extracts were distilled at atmospheric pressure rather
than in vacuo to eliminate the solvent. Transfer distillation
of the residue finally afforded 2.25 g of 1-tert-butyl-2,3-
dimethylpyrrole 2l as a pale yellow oil (14.88 mmol, 50% based
on 3b).
Syn th esis of 2-(1-Bu tyl-4-eth ylp yr r ol-2-yl)eth a n ol 2p
(Sch em e 3). Starting (Z)-2-ethyl-6-(tetrahydropyran-2-yloxy)-
hex-2-en-4-yn-1-ol 4a was prepared by Pd/Cu-catalyzed cou-
pling between (Z)-2-ethyl-3-iodoprop-2-en-1-ol4 and commer-
cially available 2-prop-2-ynyloxytetrahydropyran employing
the method of Alami.14 To a cooled (0 °C), stirred mixture of
Pd(PPh3)4 (1.32 g, 1.14 mmol) and CuI (435 mg, 2.28 mmol)
in pyrrolidine (4.5 mL) was added dropwise a solution of the
vinyl iodide (4.78 g, 22.6 mmol) in pyrrolidine (18 mL), followed
by stirring for 5 min. A solution of HCtCCH2OTHP (6.41 g,
45.7 mmol) in pyrrolidine (4.0 mL) was then added dropwise
at 0 °C. After being stirred at room temperature for 1 h, the
reaction mixture was quenched with saturated NH4Cl and
extracted several times with CH2Cl2. The combined organic
layers were washed with brine and water, dried (CaCl2), and
evaporated. The residue then was purified by column chro-
matography on silica gel using hexane-AcOEt from 9:1 to 8:2
to give 4a (4.55 g, 20.3 mmol, 90%) as a pale yellow oil.
The method of Marshall20 was used for mesylation of 4a .
To a cooled (-78 °C), stirred solution of 4a (1.84 g, 8.20 mmol)
in anhydrous CH2Cl2 (41 mL) were added Et3N (2.3 mL) and
MsCl (1.41 g, 12.31 mmol). The resulting mixture was allowed
to stir at -78 °C for 1 h to obtain a suspension. The reaction
was quenched at -78 °C with saturated NaHCO3, allowed to
warm to room temperature, stirred at room temperature for
additional 15 min, and finally extracted several times with
Et2O. The combined organic layers were washed with brine,
dried (MgSO4), and evaporated. The crude mesylate thus
obtained was then used as such for the next step. To a cooled
solution of BuNH2 (12.2 g, 166.8 mmol) in EtOH (21 mL)
maintained at 0 °C was added dropwise a solution of the
mesylate in anhydrous DMF (5 mL). After being stirred at 0
°C for 1 h, the mixture was allowed to stir at room temperature
for 1 h. The solvent was evaporated, and the residue was
quenched with water and extracted several times with Et2O.
After drying over Na2SO4, the solvent was evaporated, and
the residue was purified by column chromatography on silica
gel using 8:2 hexane-AcOEt as eluent to give 1.94 g of 1-butyl-
4-ethyl-2-[2-(tetrahydropyran-2-yloxy)ethyl]pyrrole 2p ′ as a
colorless oil (6.94 mmol, 85% based on starting 4a ).
Deprotection of 2p ′ was effected using the method of Ueda.21
To a stirred solution of 2p ′ (1.69 g, 6.05 mmol) in MeOH (100
mL) was added p-toluenesulfonic acid monohydrate (115 mg,
0.60 mmol), and the resulting mixture was allowed to stir at
room temperature for 1 h, then diluted with CH2Cl2, and
washed with brine. After driying over Na2SO4, the solvent was
evaporated, and the residue was purified by column chroma-
tography on silica gel using hexane-AcOEt from 8:2 to 7:3 to
give 1.06 g of 2p as a yellow oil (5.43 mmol, 90% based on
2p ′).
Similar results were obtained from amination of the crude
mixture of the bromides with BuNH2: column chromatography
(SiO2, hexane-AcOEt from 85:15 to 0:100) afforded 3.12 g of
2-benzyl-1-butyl-3-methylpyrrole 2j (pale yellow oil, 13.72
mmol, 46% based on 3a ) and 680 mg of (E)-butyl(3-methyl-5-
phenylpent-2-en-4-ynyl)amine 1j′ (yellow oil, 2.99 mmol, 10%
based on 3a ).
Sp on ta n eou s Cycloisom er iza tion to 1-Bu tyl-4-eth yl-
2-m eth ylp yr r ole 2q (Sch em e 4). Starting (Z)-2-ethyl-5-
Sp on t a n eou s Cycloisom er iza t ion t o P yr r oles 2k ,l
(Sch em e 2). Starting 3-methylpent-1-en-4-yn-3-ol 3b was
(20) Marshall, J . A.; Xie, S. J . Org. Chem. 1995, 60, 7230-7237.
(21) Ueda, Y.; Chuang, J . M.; Crast, L. B.; Partyka, R. A. J . Org.
Chem. 1988, 53, 5107-5113.
(19) Qian, C.; Huang, T. J . Organomet. Chem. 1997, 548, 143-147.
7860 J . Org. Chem., Vol. 68, No. 20, 2003

Substituted Pyrroles from (Z)-(2-En-4-ynyl)amines
trimethylsilanylpent-2-en-4-yn-1-ol 4b was prepared as we
already reported.4 Bromination of 4b followed by reaction with
BuNH2 was carried out as described above in the general
procedure, starting from 5.47 g (30.0 mmol) of the enynol.
Column chromatography (SiO2, hexane-AcOEt from 9:1 to 7:3)
afforded 3.21 g of (Z)-butyl(2-ethyl-5-trimethylsilanylpent-2-
en-4-ynyl)amine 1q′ as a pale yellow oil (13.52 mmol, 45%
based on 4b).
To a stirred solution of 1q′ (622 mg, 2.62 mmol) in MeOH
(4.8 mL) was added KF (228 mg, 3.93 mmol), and the resulting
mixture was allowed to stir at room temperature overnight.
The reaction mixture was diluted with Et2O and quenched
with water. Phases were separated, and the aqueous phase
was extracted several times with Et2O. The combined organic
layers were washed with brine, dried (Na2SO4), and evapo-
rated. Column chromatography (SiO2, 95:5 hexane-AcOEt)
afforded 350 mg of 2q as a yellow oil (2.12 mmol, 81% based
on 1q′).
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal methods and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O034850J
J . Org. Chem, Vol. 68, No. 20, 2003 7861