A novel pyrrole synthesis

Article abstract of DOI:10.1039/b412206b

The silver(I)-promoted oxidative cyclization of homopropargylamines at room temperature provides a novel access to pyrroles. Homopropargylamines are readily available by the addition of a propargyl Grignard reagent to Schiff bases.

Full text of DOI:10.1039/b412206b

View Article Online / Journal Homepage / Table of Contents for this issue
C O M M U N I C A T I O N
A novel pyrrole synthesis
Sameer Agarwal and Hans-Joachim Knölker*
Institut für Organische Chemie, Technische Universität Dresden, Bergstrasse 66,
01069 Dresden, Germany. E-mail: hans-joachim.knoelker@chemie.tu-dresden.de;
Fax: +49 351 463 37030
Received 9th August 2004, Accepted 9th September 2004
First published as an Advance Article on the web 21st September 2004
Table 1 Variation of metal salt and stoichiometry for cyclization of the
homopropargylamine 3a to the dihydropyrrolo[2,1-a]isoquinoline 4aa
The silver(I)-promoted oxidative cyclization of homo-
propargylamines at room temperature provides a novel access
to pyrroles. Homopropargylamines are readily available by the
addition of a propargyl Grignard reagent to Schiff bases.
Entry
Metal salt
Equivalents
4a, Yield (%)
1
2
3
4
5
6
7
8
AgOAc
AgOAc
AgOAc
CuOAc
Cu(OAc)2
Pd(OAc)2
PtCl2
1.1
2.1
0.1
1.1
1.1
1.1
1.1
1.1
72
66
5
56
—
18
—
Trace
The pyrrole ring is a basic substructure of numerous biologi-
cally active alkaloids and pharmaceutical products.1 Therefore,
in addition to the classical Hantzsch, Knorr and Paal–Knorr
syntheses many alternative syntheses of pyrroles by cyclization,
multicomponent condensation and coupling reactions have been
reported.2 Herein, we describe a novel procedure for pyrrole
annelation by silver(I)-promoted oxidative cyclization of homo-
propargylamines. Since the homopropargylamines are easily
prepared by addition of a propargyl Grignard reagent to the
appropriate Schiff base, our method consists of only two simple
steps. The procedure is demonstrated for the oxidative annela-
tion of a pyrrole ring at 3,4-dihydroisoquinoline (1) (Scheme 1).
b
AuCl
a Reaction conditions: dry dichloromethane, room temperature, 14 h.
b Complete recovery of starting material.
contrast to cupric acetate which led only to recovery of starting
material (entries 4 and 5). Palladium(II) acetate gave a moderate
yield of the anellated pyrrole 4a (entry 6), while salts of more
noble metals (PtCl2, AuCl) were not useful (entries 7 and 8).
It was demonstrated that the oxidative cyclization of homo-
propargylamines to pyrroles works also for terminally unpro-
tected alkynes (Scheme 1). Protodesilylation of compound
3a provided 1-propargyl-1,2,3,4-tetrahydroisoquinoline (3b),
which on treatment with silver acetate using the same reaction
conditions gave the dihydropyrrolo[2,1-a]isoquinoline 4a in
71% yield. Thus, it is concluded that on cyclization of 3a, the
trimethylsilyl group is removed by protodesilylation following
the aromatization.
We tentatively propose the following mechanism for the
silver(I)-promoted oxidative cyclization of homopropargyl-
amines to pyrroles (Scheme 2). The coordination of the alkyne
to the silver cation (5) initiates a nucleophilic attack of the amine
at the alkyne, leading to intermediate 6. Protonation of 6 affords
the iminium ion 7 which on subsequent b-hydride elimination
generates the pyrrylium ion 8 and metallic silver. Finally, proton
loss of 8 provides the pyrrole 9. For trimethylsilyl-substituted
homopropargylamines 5 (R3 = SiMe3), the 1,2,5-trisubstituted
pyrroles 9 (R3 = SiMe3) formed initially are protodesilylated by
acetic acid to 1,2-disubstituted pyrroles 9 (R3 = H). Preliminary
experiments with internal alkynes 3 (R = Me, Ph) led to the
corresponding 1,2,5-trisubstituted pyrroles 4 (R = Me, Ph).
Scheme 1 Synthesis of the dihydropyrrolo[2,1-a]isoquinoline 4a.
Reagents and conditions: (i) 1. BF3–Et2O, THF, −23 °C, 30 min; 2. 2,
Et2O, −23 °C, 15 h, 80%; (ii) 1.1 eq. AgOAc, CH2Cl2, rt, 14 h, 72% from
3a, 71% from 3b; (iii) TBAF, THF, rt, 3 h, 87%.
The addition of 3-trimethylsilylpropargylmagnesium
bromide (2) to 3,4-dihydroisoquinoline (1)3 using Nakagawa’s
procedure (formation of a BF3–imine complex prior to
Grignard addition)4 afforded 1-(3-trimethylsilylpropargyl)-
1,2,3,4-tetrahydroisoquinoline (3a). Silver(I) salts form stable
p-complexes with terminal acetylenes.5 Therefore, we expected
that the observed activation of the acetylene may be utilized
for cyclization reactions by intramolecular nucleophilic attack
onto the acetylene. Silver(I)-promoted cyclizations of substi-
tuted allenes to heterocyclic rings including 2,5-dihydropyrroles
were reported previously.6 Treatment of compound 3a with
silver acetate in dichloromethane solution at room temperature
overnight resulted in a smooth oxidative cyclization forming the
dihydropyrrolo[2,1-a]isoquinoline 4a in 72% yield along with
metallic silver. An extensive variation of the metal salt and its
stoichiometry demonstrated that the reaction works best using
1.1 equivalents of silver acetate in dichloromethane or acetone
at room temperature (Table 1). Application of a larger excess
of the silver(I) salt does not improve the yield (entry 2) and
since the reaction represents an oxidative cyclization, it is not
catalytic in silver (entry 3). The results presented in Table 1 indi-
cate the important role of the oxidation potential of the metal
ion. Remarkably, cuprous acetate afforded a 56% yield of 4a, in
Scheme 2 Proposed mechanism for the silver(I)-promoted oxidative
cyclization of homopropargylamines to pyrroles.
3 0 6 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 6 0 – 3 0 6 2
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

View Article Online
This method was applied to the annelation of pyrrole at 3,4-
dihydro-b-carboline (10)7 (Scheme 3). Addition of the propargyl
Grignard reagent 2 to 10 afforded 1-(3-trimethylsilylpropargyl)-
1,2,3,4-tetrahydro-b-carboline (11), which was used as a pre-
cursor in our iron-mediated total synthesis of the yohimbane
alkaloid (±)-demethoxycarbonyldihydrogambirtannine.8 The
silver(I)-promoted oxidative cyclization of 11 afforded the di-
hydroindolizino[8,7-b]indole 12, which represents a synthetic
precursor for the indolizidino[8,7-b]indole alkaloid harmicine.9
Experimental
General procedure for the silver(I)-promoted oxidative cyclization
of homopropargylamines
Silver(I) acetate (1.1 eq.) was added to a solution of the homo-
propargylamine 3, 11, or 14 (1.0 eq.) in anhydrous CH2Cl2. In
the absence of light, the solution was stirred at room tempera-
ture under an argon atmosphere for 14 h (compounds 3a, 3b
and 11) or 4 d (compounds 14a–c). Filtration over a short path
of neutral alumina (hexane–EtOAc) and removal of the solvent
provided the pyrroles 4a, 12, or 15a–c.
4a: Light yellow oil. UV (MeOH): k = 293, 303 (sh) nm. IR
(ATR): m = 2927, 2879, 1689, 1606, 1577, 1550, 1494, 1460, 1427,
1413, 1334, 1316, 1245, 1230, 1200, 1167, 1102, 1070, 1045, 751,
706, 689, 673, 605 cm−1. 1H NMR (500 MHz, CDCl3): d = 3.08
(t, J = 6.6 Hz, 2 H), 4.09 (t, J = 6.6 Hz, 2 H), 6.24 (dd, J = 3.5,
2.7 Hz, 1 H), 6.53 (dd, J = 3.5, 1.5 Hz, 1 H), 6.69 (m, 1 H), 7.11
(dt, J = 1.1, 7.4 Hz, 1 H), 7.18 (dd, J = 7.4, 0.4 Hz, 1 H), 7.24
(m, 1 H), 7.54 (dd, J = 7.4, 0.4 Hz, 1 H). 13C NMR and DEPT
(125 MHz, CDCl3): d = 29.45 (CH2), 44.08 (CH2), 103.59 (CH),
108.53 (CH), 120.79 (CH), 122.36 (CH), 125.49 (CH), 127.07
(CH), 127.90 (CH), 129.56 (C), 129.79 (C), 130.27 (C). MS (EI):
m/z (%) = 169 (100) [M+], 168 (67), 167 (25), 166 (5), 154 (5),
141 (5), 84 (9). HRMS: m/z calcd for C12H11N [M+]: 169.0891;
found: 169.0888.
Scheme 3 Synthesis of the dihydroindolizino[8,7-b]indole 12. Reagents
and conditions: (i) 1. BF3–Et2O, THF, −23 °C, 10 min; 2. 2, Et2O, −23 °C,
15 h, 68%; (ii) AgOAc, CH2Cl2, rt, 14 h, 77%.
12: Light green powder; mp: 161–163 °C. UV (MeOH):
k = 224, 281, 290 nm. IR (DRIFT): m = 3425, 3383, 1624, 1603,
1480, 1438, 1369, 1353, 1332, 1320, 1307, 1272, 1244, 1234,
1070, 844, 747, 712 cm−1. 1H NMR (500 MHz, CDCl3): d = 3.18
(t, J = 7.0 Hz, 2 H), 4.22 (t, J = 7.0 Hz, 2 H), 6.26 (dd, J = 3.4,
2.7 Hz, 1 H), 6.33 (dd, J = 3.4, 1.4 Hz, 1 H), 6.80 (dd, J = 2.7,
1.4 Hz, 1 H), 7.18 (m, 2 H), 7.39 (m, 1 H), 7.54 (m, 1 H), 8.10
(br s, 1 H). 13C NMR and DEPT (125 MHz, CDCl3): d = 21.25
(CH2), 45.36 (CH2), 101.87 (CH), 105.17 (C), 108.14 (CH),
110.93 (CH), 117.81 (CH), 119.94 (CH), 121.44 (CH), 121.77
(CH), 124.62 (C), 127.13 (C), 128.96 (C), 136.38 (C). MS (EI):
m/z (%) = 208 (100) [M+], 207 (68), 206 (18), 205 (3), 115 (4),
104 (3). HRMS: m/z calcd for C14H12N2 [M+]: 208.1000; found:
208.0994.
Application of our procedure to Schiff bases generated from
simple arylaldehydes afforded monocyclic pyrroles (Scheme 4,
Table 2). An optimization of the reaction conditions has not
been carried out for each case. However, the following result
demonstrates that almost quantitative yields are feasible for
the oxidative cyclization. Addition of the propargyl Grignard
2 to benzylidene-p-anisidine (13a) gave the homopropargyl-
amine 14a, which on silver(I)-promoted oxidative cyclization
afforded almost quantitatively 1-(p-anisyl)-2-phenylpyrrole
(15a). Analogously a broad variety of pyrroles can be prepared.
It is noteworthy that conjugated double bonds of a,b-unsatu-
rated imines are tolerated in this reaction. Thus, the imine 13c,
easily prepared from cinnamaldehyde and p-anisidine,10 was
transformed to the homopropargylamine 14c and subsequently
to 1-(p-anisyl)-2-cinnamylpyrrole (15c).
15a: Yellow oil. UV (MeOH): k = 225, 277 nm. IR (ATR):
m = 1603, 1511, 1493, 1464, 1442, 1299, 1245, 1180, 1169, 1105,
1073, 1060, 1039, 946, 907, 884, 833, 798, 757, 725, 696, 664, 646,
1
617, 607 cm−1. H NMR (500 MHz, CDCl3): d = 3.82 (s, 3 H),
6.38 (m, 1 H), 6.47 (dd, J = 3.5, 1.8 Hz, 1 H), 6.87 (d, J = 8.9 Hz,
2 H), 6.92 (m, 1 H), 7.13 (d, J = 8.9 Hz, 2 H), 7.16–7.19 (m, 3 H),
7.22–7.25 (m, 2 H). 13C NMR and DEPT (125 MHz, CDCl3):
d = 55.34 (CH3), 108.81 (CH), 110.05 (CH), 114.06 (2 CH),
124.47 (CH), 126.08 (CH), 126.87 (2 CH), 127.97 (2 CH),
128.15 (2 CH), 132.98 (C), 133.66 (C), 133.82 (C), 158.13 (C).
MS (EI): m/z (%) = 249 (100) [M+], 234 (47), 206 (5), 204 (5),
179 (6). HRMS: m/z calcd for C17H15NO [M+]: 249.1154; found:
249.1182.
15b: Yellow oil. UV (MeOH): k = 226 (sh), 270 nm. IR (ATR):
Scheme 4 Synthesis of the pyrroles 15. Reagents and conditions: (i) 1.
BF3–Et2O, THF, −23 °C, 30 min; 2. 2, Et2O, −23 °C, 15 h (conditions for
14c: 1. 0 °C, 30 min; 2. 0 °C, 15 h); (ii) 1.1 eq. AgOAc, CH2Cl2, rt, 4 d.
m = 2924, 1675, 1598, 1510, 1460, 1420, 1366, 1304, 1246, 1168,
1
1109, 1024, 965, 902, 814, 714, 693, 632, 604 cm−1. H NMR
(500 MHz, CDCl3): d = 2.35 (s, 3 H), 3.77 (s, 3 H), 6.33 (m, 1 H),
6.34 (dd, J = 3.5, 1.9 Hz, 1 H), 6.76 (d, J = 8.8 Hz, 2 H), 6.88 (dd,
J = 2.6, 1.9 Hz, 1 H), 7.03–7.08 (m, 4 H), 7.11 (d, J = 8.4 Hz,
2 H). 13C NMR and DEPT (125 MHz, CDCl3): d = 20.99 (CH3),
55.15 (CH3), 108.79 (CH), 109.52 (CH), 113.48 (2 CH), 123.72
(CH), 125.52 (2 CH), 125.78 (C), 129.52 (2 CH), 129.56 (2 CH),
133.60 (C), 136.24 (C), 138.10 (C), 158.13 (C). MS (EI): m/z
(%) = 263 (100) [M+], 248 (57), 220 (5), 189 (8), 135 (12). HRMS:
m/z calcd for C18H17NO [M+]: 263.1310; found: 263.1313.
Table 2 Synthesis of the monocyclic pyrroles 15a–c
R1
R2
14, Yield (%)
15, Yield (%)
a
b
c
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
C6H5
4-MeOC6H4
C6H5CHCH
78
80
88
99
85a
78
a 8% of starting material (14b) was recovered.
15c: Orange oil. UV (MeOH): k = 228, 334 nm. IR (ATR):
m = 1629, 1598, 1512, 1459, 1418, 1298, 1248, 1180, 1147, 1106,
1040, 956, 893, 835, 801, 784, 747, 714, 692, 634, 613 cm−1. 1H
NMR (500 MHz, CDCl3): d = 3.88 (s, 3 H), 6.32 (m, 1 H),
6.64 (dd, J = 3.5, 1.6 Hz, 1 H), 6.78 (d, J = 16.3 Hz, 1 H),
6.84 (dd, J = 2.7, 1.6 Hz, 1 H), 6.86 (d, J = 16.3 Hz, 1 H), 6.99
In conclusion, we have developed a novel two-step procedure
for the synthesis of pyrroles by addition of a propargyl Grignard
reagent to a Schiff base and subsequent silver(I)-promoted
oxidative cyclization of the resulting homopropargylamine.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 6 0 – 3 0 6 2
3 0 6 1

View Article Online
(f) B. Lagu, M. Pan and M. P. Wachter, Tetrahedron Lett., 2001,
42, 6027; (g) B. Quiclet-Sire, F. Wendeborn and S. Z. Zard, Chem.
Commun., 2002, 2214; (h) P. Langer and I. Freifeld, Chem. Com-
mun., 2002, 2668; (i) M. Yoshida, M. Kitamura and K. Narasaka,
Bull. Chem. Soc. Jpn., 2003, 76, 2003; (j) D. W. Knight and C. M.
Sharland, Synlett, 2003, 2258; (k) M. Yu and B. L. Pagenkopf,
Org. Lett., 2003, 5, 5099; (l) R. Dhawan and B. A. Arndtsen, J.
Am. Chem. Soc., 2004, 126, 468; (m) O. Flögel and H.-U. Reissig,
Synlett, 2004, 895; (n) Z. Song, J. Reiner and K. Zhao, Tetrahedron
Lett., 2004, 45, 3953.
3 J. C. Pelletier and M. P. Cava, J. Org. Chem., 1987, 52, 616.
4 T. Kawate, M. Nakagawa, H. Yamazaki, M. Hirayama and T. Hino,
Chem. Pharm. Bull., 1993, 41, 287.
5 J. P. Ginnebaugh, J. W. Maki and G. S. Lewandos, J. Organomet.
Chem., 1980, 190, 403.
6 (a) A. Claesson, C. Sahlberg and K. Luthman, Acta Chem. Scand.,
1979, 33, 309; (b) J. S. Prasad and L. S. Liebeskind, Tetrahedron
Lett., 1988, 29, 4253; (c) M. Kimura, S. Tanaka and Y. Tamaru,
Bull. Chem. Soc. Jpn., 1995, 68, 1689; (d) H. Ohno, A. Toda,
Y. Miwa, T. Taga, E. Osawa, Y. Yamaoka, N. Fujii and T. Ibuka, J.
Org. Chem., 1999, 64, 2992; (e) M. O. Amombo, A. Hausherr and
H.-U. Reissig, Synlett, 1999, 1871.
(d, J = 8.9 Hz, 2 H), 7.17 (tt, J = 7.2, 1.2 Hz, 1 H), 7.25–7.29
(m, 2 H), 7.28 (d, J = 8.9 Hz, 2 H), 7.33 (m, 2 H). 13C NMR
and DEPT (125 MHz, CDCl3): d = 55.54 (CH3), 106.91 (CH),
109.29 (CH), 114.29 (2 CH), 118.04 (CH), 123.68 (CH), 125.94
(3 CH), 126.88 (CH), 127.49 (2 CH), 128.53 (2 CH), 132.47 (C),
132.66 (C), 137.78 (C), 158.75 (C). MS (EI): m/z (%) = 275 (76)
[M+], 274 (26), 260 (14), 201 (49), 167 (13), 158 (12), 108 (56),
106 (85), 105 (89), 78 (27), 77 (100). HRMS: m/z calcd for
C19H17NO [M+]: 275.1310; found: 275.1310.
Acknowledgements
This work was supported by the Deutsche Forschungsgemein-
schaft (Graduiertenkolleg “Struktur-Eigenschafts-Beziehungen
bei Heterocyclen”) and the Fonds der Chemischen Industrie.
Notes and references
1 (a) R. J. Sundberg, Comprehensive Heterocyclic Chemistry, ed.
A. R. Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984,
vol. 4, p. 313; (b) G. P. Bean, Pyrroles, ed. R. A. Jones, Wiley, New
York, 1990, p. 105; (c) R. J. Sundberg, Comprehensive Heterocyclic
Chemistry II, ed. A. R. Katritzky, C. W. Rees and E. F. V. Scriven,
Elsevier, Oxford, 1996, vol. 2, p. 119; (d) G. W. Gribble, Compre-
hensive Heterocyclic Chemistry II, ed. A. R. Katritzky, C. W. Rees
and E. F. V. Scriven, Elsevier, Oxford, 1996, vol. 2, p. 207.
2 For selected examples, see: (a) E. J. Roskamp, P. S. Dragovich,
J. B. Hartung and S. F. Pederson, J. Org. Chem., 1989, 54,
4736; (b) J. Tang and J. G. Verkade, J. Org. Chem., 1994, 59,
7793; (c) R. Grigg and V. Savic, Chem. Commun., 2000, 873;
(d) V. Nair, A. U. Vinod and C. Rajesh, J. Org. Chem., 2001, 66,
4427; (e) B. C. Ranu and A. Hajra, Tetrahedron, 2001, 57, 4767;
7 N. Whittaker, J. Chem. Soc. C, 1969, 85.
8 (a) N. Peube-Locou, M. Plat and M. Koch, Phytochemistry, 1973,
12, 199; (b) L. Angenot, C. Coune and M. Tits, J. Pharm. Belg.,
1978, 33, 284; (c) H.-J. Knölker and S. Cämmerer, Tetrahedron Lett.,
2000, 41, 5035.
9 (a) T.-S. Kam and K.-M. Sim, Phytochemistry, 1998, 47, 145;
(b) T. Itoh, M. Miyazaki, K. Nagata, M. Yokoya, S. Nakamura and
A. Ohsawa, Heterocycles, 2002, 58, 115; (c) T. Itoh, M. Miyazaki,
K. Nagata, S. Nakamura and A. Ohsawa, Heterocycles, 2004, 63,
655; (d) H.-J. Knölker and S. Agarwal, Synlett, 2004, 1767.
10 H.-J. Knölker, G. Baum, N. Foitzik, H. Goesmann, P. Gonser, P. G.
Jones and H. Röttele, Eur. J. Inorg. Chem., 1998, 993.
3 0 6 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 6 0 – 3 0 6 2