Synthesis of pyrroles through coupling of enyne-hydrazones with fischer carbene complexes

Article abstract of DOI:10.1021/ol034414j

Matrix presented The coupling of enyne-imines with Fischer carbene complexes leads to the formation of alkenylpyrrole derivatives. Maximum yields of pyrrole adducts were obtained using N,N-dimethylhydrazones. A mechanism involving alkyne insertion followe

Full text of DOI:10.1021/ol034414j

ORGANIC
LETTERS
2003
Vol. 5, No. 12
2043-2045
Synthesis of Pyrroles through Coupling
of Enyne-hydrazones with Fischer
Carbene Complexes
Yanshi Zhang and James W. Herndon*
Department of Chemistry and Biochemistry, New Mexico State UniVersity, MSC 3C,
Las Cruces, New Mexico 88003-8001
jherndon@nmsu.edu
Received March 8, 2003
ABSTRACT
The coupling of enyne-imines with Fischer carbene complexes leads to the formation of alkenylpyrrole derivatives. Maximum yields of pyrrole
adducts were obtained using N,N-dimethylhydrazones. A mechanism involving alkyne insertion followed by nucleophilic attack of the imine
nitrogen at the intermediate alkenylcarbene complex was proposed.
In a recent publication, the coupling of Fischer carbene
complexes (1, Scheme 1) with either enyne-aldehydes (e.g.,
2) or ketones to produce vinylfuran derivatives (e.g., 3) was
reported.1 In a related study, the analogous preparation of
vinylisobenzofurans from the coupling of Fischer carbene
complexes with various o-alkynylbenzaldehyde derivatives
was reported.2 In this manuscript, extension of these studies
to the preparation of pyrroles (e.g., 5) from Fischer carbene
complexes and enyne-imines (e.g., 4) is reported.3,4 In a
process similar to that invoked for furan formation, coupling
of enyne-imines with carbene complexes will afford vinyl-
carbene complex intermediate 6, which can then undergo
nucleophilic attack by nitrogen at the carbene carbon to
afford pyrrole 5 (E-isomer)5 after loss of chromium from
intermediate 7. Synthesis of pyrroles from imine-alkynes has
precedent;6 however, the conversion of 4 to 5 is unique in
Scheme 1
(1) Herndon, J. W.; Wang, H. J. Org. Chem. 1998, 63, 4564-4565.
(2) (a) Ghorai, B. K.; Menon, S.; Johnson, D. L.; Herndon, J. W. Org.
Lett. 2002, 4, 2121-2124. (b) Ghorai, B. K.; Herndon, J. W. Org. Lett.
2001, 3, 3535-3538. (c) Jiang, D.; Herndon, J. W. Org. Lett. 2000, 2,
1267-1269.
(3) Pyrrole syntheses based on the coupling of alkynes and carbene
complexes have precedent; however, nitrogen is attached to the carbene in
all cases. (a) Merlic, C. A.; Baur, A.; Aldrich, C. A. J. Am. Chem. Soc.
2000, 122, 7398-7399. (b) Parlier, A.; Rudler, M.; Rudler, H.; Goumont,
R.; Daran, J. C.; Vaissermann, J. Organometallics 1995, 14, 2760-2774.
(c) Grotjahn, D. B.; Kroll, F. E. K.; Schaefer, T.; Harms, K.; Do¨tz, K. H.
Organometallics 1992, 11, 298-310. (d) Aumann, R.; Heinen, H.; Goddard,
R.; Krueger, C. Chem. Ber. 1991, 124, 2587-2593. (e) Dragisich, V.;
Murray, C. K.; Warner, B. P.; Wulff, W. D.; Yang, D. C. J. Am. Chem.
Soc. 1990, 112, 1251-1253. (f) Dragisich, V.; Wulff, W. D.; Hoogsteen,
K. Organometallics 1990, 9, 2867-2870.
(4) For an extensive listing of references to nitrogen heterocycle synthesis
using carbene complexes, see: Kagoshima, H.; Akiyama, T. J. Am. Chem.
Soc. 2000, 122, 11741-11742.
10.1021/ol034414j CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/13/2003

that formation of an exocyclic carbon-carbon bond occurs
simultaneously with closure of the pyrrole ring.
Scheme 3
Prior to initiation of these studies, a concern was that direct
coupling of the carbene complex and imine functionalities
would interfere with the desired initial alkyne insertion.
Previously reported ground-state reactions for imines and
Fischer carbene complexes include aldol-like processes7 and
nucleophilic attack of the imine nitrogen at the carbene
carbon.8 Use of imines of minimal basicity (R4 is electron-
withdrawing) was initially deemed optimal because these side
reactions would be less likely and these imines are electroni-
cally similar to the aldehyde carbonyl groups successfully
employed in the furan synthesis. These compounds will be
less optimal, however, in the key ring-closure step (conver-
sion of 6 to 7) because nucleophilicity at nitrogen is reduced.
However, related compounds were found to be optimal for
formation of pyrrolidine derivatives by intramolecular cou-
pling of amines and group VI vinylidene complexes.9
General synthetic protocols for the preparation of enyne-
imines are depicted in Scheme 2. The choice of synthetic
14.11 Compounds where R2 ) H and R3 ) alkyl/aryl were
prepared from propargyl alcohol (10).12 Compounds where
R2 and R3 ) H were prepared from ethyl propiolate (12).13
A variety of imines were treated with carbene complex 1;
the results are depicted in Scheme 3 and Table 1. Initial
studies focused on N-sulfonyl imines (entries B and C). The
initially formed enol ether-pyrrole derivatives 5 were unstable
with respect to air oxidation and were hydrolyzed to the
corresponding ketones 16 for characterization purposes.
Coupling of N-tosyl imine 4B with methylcarbene complex
1 led to the desired pyrrole derivative 16B in only 37% yield.
The N-methanesulfonyl imine 4C afforded a similar result.
Electron-rich imines were next investigated as a result of
the limited success using electron-deficient imines. The
simple N-benzyl imine 4D (entry D) was far less efficient
and afforded pyrrole derivative in only 9% yield. No other
identifiable products were obtained from these coupling
reactions.
Scheme 2a
Table 1. Synthesis of Pyrroles through Coupling of
Enyne-imines with Fischer Carbene Complexes
entrya
R1
R2
R3
R4
yield 16b (%)
A
B
C
D
E
F
G
H
I
Bu
Bu
Bu
Bu
Bu
H
Bu
Bu
Bu
Bu
Bu
Ph
Ph
Ph
Ph
Bu
Bu
H
H
H
H
H
H
H
H
Et
allyl
NMe2
Ts
Ms
62
37
35
9
64
59c
70
74
64
36
25c
a (i) PBr3/DMF/CHCl3; (ii) R1CtCH/(PPh3)2PdCl2/CuI/Et3N/
THF; (iii) R4NH2 (/TiCl4 if R4 ) Ts); (iv) R3MgBr/CuI, then I-Cl;
(v) ClCOCOCl/DMF/Et3N/CH2Cl2; (vi) NaI/HOAc; (vii) Br2/
CH2Cl2; (viii) DIBAL-H.
CH2Ph
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
H
H
J
K
-(CH2)4-
-(CH2)3-
route for the preparation of enyne-imines 4 depends primarily
on the identity of the R2 and R3 substituents. Compounds
where R2 and R3 * H or where R2 ) aryl, R3 ) H were
prepared from ketones 8.10 Compounds where R2 ) alkyl
and R3 ) H were prepared from R,â-unsaturated aldehydes
a Table entry letters define substituents for compounds 4-16. b Isolated
yield of material that is pure by NMR and chromatographic analysis. c The
hydrolysis step was omitted; the yield is for compound 5.
(5) This stereochemistry is generally obtained in chromium carbene-
alkyne couplings. McCallum, J. S.; Kunng, F. A.; Gilbertson, S. A.; Wulff,
W. D. Organometallics 1988, 7, 2346-2360.
Enyne-hydrazone derivatives of 4 were prepared so that
imines at both extremes of the basicity scale could be
evaluated.14 Reactions employing this imine were far more
efficient and led to the N-aminopyrrole derivatives. Coupling
enyne-hydrazone with carbene complex 1 led to N-aminopy-
rrole derivative 16A in considerably higher yield (entry A,
(6) (a) Arcadi, A.; Rossi, A. Tetrahedron 1998, 54, 15253-15272. (b)
Knight, D.; Redfern, A. L.; Gilmore, J. Chem. Commun. 1998, 2207-2208.
(c) Kel’in, A.; Sromek, A. W.; Gevorgyan. V. J. Am. Chem. Soc. 2001,
123, 2074-2075.
(7) Hegedus, L. S.; McGuire, M. A.; Schultze, L. M.; Chen, Y.;
Anderson, O. P. J. Am. Chem. Soc. 1984, 106, 2680-2687.
2044
Org. Lett., Vol. 5, No. 12, 2003

62%) than analogous imine derivatives in entries B-D. The
imine nitrogen is far more basic and presumably more
nucleophilic in this system. Stabilization of the carbene
complex intermediate 6 by the amine nitrogen lone pair might
also play a role in the higher yields obtained from the N,N-
dimethylhydrazone.
Scheme 4
Structurally diverse N,N-dimethylhydrazone derivatives of
enyne 4 were prepared, and their subsequent reaction with
carbene complex 1 was examined (entries E-K). The
reaction appears to be quite general with respect to substitu-
tion on the alkene and alkyne and led to monosubstituted
(entry G), 1,2-disubstituted (entries A, E, F), and 1,3-
disubstituted (entries H and I) N-aminopyrrole derivatives
in good yields. The trisubstituted N-aminopyrrole derivatives
in entries J and K were obtained in considerably lower yield.
These highly electron-rich compounds rapidly turned dark
colors upon prolonged exposure to air, and thus the low yield
in these cases might be attributed to product instability.
As a further test of the efficiency of pyrrole formation in
entries J and K, the coupling of enyne-hydrazone 4K with
carbene complex 1715 was tested (Scheme 4). As expected,
the initially formed pyrrole 18K undergoes an intramolecular
Diels-Alder reaction followed by aminonitrene extrusion16
to afford the phenanthrene derivative 20K. The reaction is
quite efficient and affords dehydro-steroid product 20K in
68% yield. The reaction employing the six-membered ring
analogue 4J proceeded similarly; however, the nitrogen
bridge remained intact under the reaction conditions, leading
to compound 19J in 72% yield. The differing stability of
the nitrogen bridge in compounds 19J and 19K is somewhat
surprising. The efficient formation of 19J and 20K suggests
that pyrrole formation in entries J and K is efficient and that
the low yields are likely due to difficulty in isolating the
extremely electron-rich pyrroles produced in these two
examples.
substrates differing in the degree of alkyl substitution on the
alkene and alkyne substituents. Optimal yields have been
obtained using N,N-dimethylhydrazones. These reactions lead
to N-aminopyrrole derivatives, which to date have been
synthesized primarily from either reaction of 1,4-dicarbonyl
derivatives with hydrazines17 or from reaction of RCHdCH-
NdN-COR derivatives with enolates.18 N-Aminopyrrole
derivatives have proven to be highly useful for cycloaroma-
tization reactions16 and can be converted to simple pyrroles
through reduction.19 Further investigation of the scope of this
novel pyrrole-forming reaction and the synthetic potential
of the pyrrole products is currently underway in this
laboratory.
Acknowledgment. The authors thank the National Insti-
tutes of Health (SCORE Program) for financial support of
this research. We thank Yi Zhang, Alejandro Camacho, and
Adrian Rodriquez for experimental assistance.
In conclusion, the conversion of enyne-imines (4) to
pyrroles (5, 16) has been demonstrated for a variety of
(8) (a) Barluenga, J.; Tomas, M.; Rubio, E.; Lopaz-Peligrino, J. A.;
Garcia-Granda, S.; Priede, M. P. J. Am. Chem. Soc. 1999, 121, 3065-
3071. (b) Barluenga, J.; Ballesteros, A.; Santamaria, J.; Tomas, M. J.
Organomet. Chem. 2002, 643-644, 363-368; the reaction under study in
this manuscript affords pyrroles as minor products.
Supporting Information Available: Detailed experi-
mental for synthesis of compounds 4A-K, 5F, 5K, 16A-
E, 16G-J, and 20K and characterization data for compounds
5F, 16A-E, 16G-J, 19J, and 20K. This material is
available free of charge via the Internet at http://pubs.acs.org.
(9) For successful application of this theory in a related reaction, see:
Chen, M. J.; Chung, S. T.; Liu, R. S. Tetrahedron 2000, 56, 5029-5035.
(10) Arnold, Z.; Holy, A. Collect. Czech. Chem. Commun. 1961, 26,
3059-3073.
OL034414J
(11) Severin, T.; Wanninger, G.; Lerche, H. Chem. Ber. 1984, 117,
2875-2885.
(17) Recent examples: (a) Gadaginamath, G. S.; Shyadligeri, A. S. Indian
J. Chem. B 2000, 39B, 31-35. (b) Al-Ashmawy, M. I.; El-Samii, Z. K. A.;
El Feky, S. A.; Osman, N. A. Boll. Chim. Farm. 1998, 137, 110-114. (c)
Hiremath, U. S.; Yelamaggad, C. V.; Badami, B. V.; Puranik, G. S. J. Chem.
Res., Synop. 1994, 502-503. (d) Jacobi, P. A.; Cai, G. Heterocycles 1993,
35, 1103-1120.
(18) Recent examples: (a) Attanasi, O. A.; De Crescentini, L.; Filippone,
P.; Fringuelli, F.; Mantellini, F.; Matteucci, M.; Piermatti, O.; Pizzo, F.
HelV. Chim. Acta 2001, 84, 513-525. (b) Attanasi, O. A.; De Crescentini,
L.; Filippone, P.; Mantellini, F.; Tietze, L. F. Tetrahedron 2001, 57, 5855-
5863. (c) Attanasi, O. A.; Filippone, P.; Perrulli, F. R.; Santeusanio, S.
Tetrahedron 2001, 57, 1387-1394. (d) Attanasi, O. A.; De Crescentini,
L.; Filippone, P.; Mantellini, F. Synlett 2000, 955-958.
(12) Duboudin, J. G.; Jousseaume, B.; Bonakdar, A. J. Organomet. Chem.
1979, 168, 227-232.
(13) Piers, E.; Wong, T.; Coish, P. D.; Rogers, C. Can. J. Chem. 1994,
72, 1816-1819.
(14) (a) The pKa of protonated N,N-dimethylhydrazones is around 10.
Zzerev, V. V.; Pylaeva, T. N.; Stolyarov, A. P.; Kitaev, Y. P. J. Org. Chem.
USSR 1978, 14, 717-720. (b) The pKa of a protonated N-alkylimine is
around 8. Buist, G. J.; Lucas, H. J. J. Am. Chem. Soc. 1957, 79, 6157-
6160.
(15) For previous uses of this carbene complex, see: Hohmann, F.;
Siemoneit, S.; Nieger, M.; Kotila, S.; Do¨tz, K. H. Chem. Eur. J. 1997, 3,
853-859.
(16) (a) Carpino, L. A.; Padykula, R. E.; Lee, S. N.; Han, G. Y.; Kirkley,
R. K. J. Org. Chem. 1988, 53, 6047-6053. (b) Carpino, L. A.; Padykula,
R. E.; Barr, D. E.; Hall, F. H.; Krause, J. G.; Dufresne, R. F.; Thoman, C.
J. J. Org. Chem. 1988, 53, 2565-2572. (c) Schultz, A. G.; Shen, M.
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(19) (a) Enders, D.; Maassen, R.; Han, S. H. Liebigs Ann. 1996, 1565-
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Org. Lett., Vol. 5, No. 12, 2003
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