Synthesis of 3-pyrrolines, annulated 3-pyrrolines, and pyrroles from alpha-amino allenes.

Article abstract of DOI:10.1021/ol016654+

Alpha-amino allenes, readily prepared from reaction of alpha-(N-carbamoyl)alkylcuprates with propargyl substrates followed by N-Boc deprotection, are converted in high yields to pyrrolines with AgNO(3). Palladium-catalyzed cyclization of amino allenes aff

Full text of DOI:10.1021/ol016654+

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3855-3858
Synthesis of 3-Pyrrolines, Annulated
3-Pyrrolines, and Pyrroles from r-Amino
Allenes
R. Karl Dieter* and Huayun Yu
Howard L. Hunter Chemistry Laboratory, Clemson UniVersity,
Clemson, South Carolina 29634-0973
dieterr@clemson.edu
Received August 27, 2001
ABSTRACT
r-Amino allenes, readily prepared from reaction of r-(N-carbamoyl)alkylcuprates with propargyl substrates followed by N-Boc deprotection,
are converted in high yields to pyrrolines with AgNO . Palladium-catalyzed cyclization of amino allenes affords either the pyrroline or the
3
pyrrole depending on reaction conditions and provides for introduction of an aryl substituent at the C-3 position of the pyrroline or pyrrole.
Enantioenriched pyrrolines are readily prepared from scalemic propargyl alcohols.
Pyrroles1 and pyrrolines2 are important classes of heterocyclic
compounds, and many synthetic routes are available for their
preparation.3 Many procedures, however, are limited in terms
of substituents and substitution patterns. With increasing
frequency, the transition-metal-promoted cyclization of a
heteroatom onto an allene moiety provides a powerful
strategy for heterocyclic synthesis.4 Furan formation via silver
ion-catalyzed cyclization of R-hydroxy allenes occurs in a
highly regio- and stereoselective manner.5 Silver ion-
catalyzed cyclization of a nitrogen functionality onto a
proximate olefinic site has been employed for the synthesis
of nitrogen heterocycles. Although these cyclizations pro-
ceeded cleanly for a range of nitrogen-containing function-
alities, many of the cyclizations proceeded in an exocyclic
fashion to afford 2-vinyl-substituted ring systems.6 Neverthe-
less, several recent reports describe silver nitrate-promoted
endo cyclization processes involving either a benzylamine
functionality,7a sulfonamides,7b or acyclic amino allenes.7c
Similarly, the vast majority of palladium-promoted cycliza-
tions of nitrogen functionalities onto adjacent double bonds
involve nitrogen centers containing electron-withdrawing
(1) For biologically important pyrroles, see: (a) Lainton, J. A. H.;
Huffman, J. W.; Martin, B. R.; Compton, D. R. Tetrahedron Lett. 1995,
36, 1401. (b) De Leon, C. Y.; Ganem, B. Tetrahedron 1997, 53, 7731. (c)
Jacobi, P. A.; Coutts, L. D.; Guo, J. S.; Hauck, S. I.; Leung, S. H. J. Org.
Chem. 2000, 65, 205. (d) Gupton, J. T.; Krumpe, K. E.; Burnham, B. C.;
Dwornik, K. A.; Petrich, S. A.; Du, K. X.; Bruce, M. A.; Vu, P.; Vargas,
M.; Keertikar, K. M.; Hosein, K. N.; Jones, C. R.; Sikorski, J. A.
Tetrahedron 1998, 54, 5075. (e) Anderson, W. K.; Milowsky, A. S. J. Med.
Chem. 1987, 30, 2144. For the chemistry of macrocycles containing pyrrole
units, see: (f) Sessler, J. L.; Weghorn, S. J. Expanded, Contracted &
Isomeric Porphyrins; Elsevier Science, Ltd.: Oxford, 1997. For pyrrole-
based dyes, see: (g) Thoresen, L. H.; Kim, H.; Welch, M. B.; Burghart,
A.; Burgess, K. Synlett 1998, 1276.
(4) For reviews, see: (a) Frederickson, M.; Grigg, R. Org. Prep. Proced.
Int. 1997, 29, 63. (b) Tamaru, Y.; Kimura, M. Synlett 1997, 749. (c) Ojima,
I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96, 635.
(d) Zimmer, R.; Dinesh, Cu.; Nandanan, E.; Khan, F. A. Chem. ReV. 2000,
100, 3067.
(2) For use of pyrrolines in aza sugar synthesis see: Huwe, C. M.;
Blechert, S. Tetrahedron Lett. 1995, 36, 1621.
(3) (a) Bean, G. P. In The Chemistry of Heterocyclic Compounds; Jones,
A. R., Ed.; Wiley: New York, 1990; Vol. 48, Part 1, Chapter 2, p 105. (b)
Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1998, 615. For the syntheses
of 3-pyrrolines, see: (c) Breuil-Desvergnes, V.; Compain, P.; Vate`le, J.-
M.; Gore´, J. Tetrahedron Lett. 1999, 40, 5009. (d) Jayaprakash, K.;
Venkatachalam, C. S.; Balasubramanian, K. K. Tetrahedron Lett. 1999, 40,
6493. (e) Burley, I.; Hewson, A. T. Tetrahedron Lett. 1994, 38, 7099. (f)
Kinder, F. R., Jr.; Jarosinski, M. A.; Anderson, W. K. J. Org. Chem. 1991,
56, 6475. (g) Padwa, A.; Norman, B. H. Tetrahedron Lett. 1988, 29, 3041.
(h) Anderson, W. K.; Milowsky, A. S. J. Org. Chem. 1985, 50, 5423.
(5) (a) Marshall, J. A.; Pinney, K. G. J. Org. Chem. 1993, 58, 7180. (b)
Walkup, R. D.; Guan, L. G.; Mosher, M. D.; Kim, S. W.; Kim, Y. S. Synlett
1993, 88. (c) Marshall, J. A. Chem. ReV. 1996, 96, 31. (d) Muller, T. E.;
Beller, M. Chem. ReV. 1998, 98, 693.
(6) (a) Gallagher, T. J. Chem. Soc., Chem. Commun. 1986, 114. (b) Fox,
D. N. A.; Gallagher, T. Tetrahedron 1990, 46, 4697.
(7) (a) Amombo, M. O.; Hausherr, A.; Reissig, H.-U. Synlett 1999, 1871.
(b) Ohno, H.; Toda, A.; Miwa, Y.; Taga, T.; Osawa, E.; Yamaoka, Y.;
Fujii, N.; Ibuka, T. J. Org. Chem. 1999, 64, 2992. (c) Claesson, A.; Sahlberg,
C.; Luthman, K. Acta Chem. Scand. Ser. B 1979, B33, 309.
10.1021/ol016654+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/31/2001

substituents,7b,8 although examples of amine participation
have been reported.4 This is significant since strongly basic
amines can function as ligands for the palladium catalyst
and potentially interfere with the cyclization reaction.
Although some 5-endo-trig cyclizations have been reported,7,8
most of these procedures also involve exo cyclizations,9
raising questions about the generality of the endo cyclization
process particulary for annulated 3-pyrrolines and pyrroles.
With these questions in mind, we have explored the use of
R-amino allenes, available via reaction of R-(N-carbamoyl)-
alkylcuprates with propargyl substrates,10 in these cyclization
reactions.
Table 1. AgNO3-Promoted Cyclization of R-Amino Allenes to
Pyrrolines
Treatment of the N-Boc-protected amino allenes with
trimethylsilyltriflate (CH2Cl2, from -30 to 25 °C) gave the
free amino allenes (Scheme 1) in good to excellent yields
Scheme 1
a Obtained from 2 (TMSOTf, CH2Cl2, from -30 to 25 °C, 2 h). b Yields
based upon isolated products purified by chromatography. c Obtained from
3 (AgNO3, acetone, 25 °C). d Diastereomeric ratio determined from 1H NMR
integration values and/or 13C NMR peak heights.
tion during the cuprate-mediated allylic substitution reaction.
The requisite scalemic propargyl alcohols are readily avail-
able from the zinc triflate-catalyzed 1,2-addition of terminal
alkynes to aldehydes.11 Reaction of phenyl acetylene with
isobutyryl aldehyde afforded the propargyl alchohol, in good
yield (Scheme 2) and with excellent enantioselectivity (ee,
Scheme 2
(Table 1, 62-99%).10 Reaction of the amino allenes with a
catalytic amount of AgNO3 in acetone (25 °C, in the dark)
gave 3-pyrrolines in good to excellent yields. The reaction
readily formed both simple (Table 1, entries 1-5) and
annulated 3-pyrrolines (entries 6-10). The procedure is very
reliable and appears to be capable of tolerating a wide range
of substitution patterns (e.g., 2,3-disubstitution in 4e, entry
5). As expected, utilization of racemic propargyl mesylates
and racemic R-(N-carbamoyl)alkylcuprates afforded mixtures
of diastereomers with little or no diastereoselectivity.
The C-2 substitution pattern in pyrrolines 4a-d and 4g-j
and the C-5 pattern in 4e derive from the terminal position
of the allene providing opportunities for asymmetric induc-
99%), which could be mesylated in quantitative yield.
Reaction of 5 with the cyanocuprate derived from 1a afforded
(8) (a) Prasad, J. S.; Liebeskind, L. S. Tetrahedron Lett. 1988, 29, 4253.
(b) Prasad, J. S.; Liebeskind, L. S. Tetrahedron Lett. 1988, 29, 4257.
(9) (a) Davis, I. W.; Scopes, D. I. C.; Gallagher, T. Synlett 1993, 85. (b)
Johasson, C.; Horvath, A.; Backvall, J.-E. J. Am. Chem. Soc. 2000, 122,
9600. (c) Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 5421.
(10) Dieter, R. K.; Nice, L. E. Tetrahedron Lett. 1999, 40, 4293.
(11) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806.
3856
Org. Lett., Vol. 3, No. 24, 2001

the N-Boc amino allene in 80% yield and 83% ee (91.5:8.5
enantiomeric ratio (er)), which gave 6 after Boc deprotection
with trimethylsilyl triflate. Cyclization with AgNO3 gave
pyrroline 7 in good yield and with good enantioselectivity
(ee g 70%) The er (85:15) of 7 was measured by chiral
stationary-phase HPLC on a CHIRALCEL OD column
(cellulose tris(3,5-dimethylphenylcarbamate) on silica gel)
and was difficult to determine precisely because of extensive
tailing of the peaks with the major isomer eluting first. The
reaction is assumed to proceed with anti selectivity, and on
this basis, the (S)-configuration is assigned to C-2.12 The syn-
selective SN2′ substitution on propargyl substrates appears
to be largely limited to cuprates derived from RMgCl (i.e.,
the halogen effect) reacting with propargyl ethers.13 Conse-
quently, 2,4-disubstituted 3-pyrrolines of high enantiomeric
purity are readily available by a five-step sequence in a
roughly 50% overall yield, although the generality of the
synthesis remains to be examined.
This cyclization protocol, however, does not allow for the
introduction of substituents at the C-3 position. To overcome
this limitation, palladium(II)-promoted cyclizations were
examined. The catalytic cycle involving oxidative addition,
palladium(II)-promoted nucleophilic cyclization, and reduc-
tive elimination has been achieved in a variety of allenes
containing weakly basic nitrogen nucleophiles with electron-
withdrawing substituents on the nitrogen atom.4,7b,8 Although
examples of amine participation have been reported,4,8a
failures of the reaction have been attributed to Pd(II)
deactivation via nitrogen chelation.8a
Table 2. Palladium-Catalyzed [Pd(PPh3)4] Cyclization of
Amino Allenes to Arylated Pyrrolines and Pyrroles
% yield
entry base
equiv additivea solvent T (°C)/t (h)
8
9
1
2
3
4
5
6
7
8
Et3N
1.5
2.0
2.0
4.0
4.0
4.0
4.0
4.0
THF
THF
THF
DMF
DMF
DMF
DMF
DMF
25/14
70/20
25/14
25/20
25/20
25/20
70/14
80/20
31
Et3N
10 10
Et3N
A
B
C
D
5
50
40
37
71
57
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
B
a A ) CuCN (10 mol %). B ) n-Bu4NCl (1.0). C ) n-Bu4NBr (1.0). D
) n-Bu4NCl (1.0), CuCN‚2LiCl (10 mol %).
softer ligands (e.g., SbPh3 and AsPh3) did not succeed, and
greater yields of cyclization products were not obtained when
active Pd(0) obtained by potassium metal reduction of PdCl2
was used.16
Initial treatment of allene 2a with Pd[PPh3]4 in the presence
of triethylamine gave the pyrroline in a low yield of 31%
(Table 2, entry 1). Increasing the amount of triethylamine
resulted in diminished yield of pyrroline 8 and formation of
the pyrrole 9, confirming the concern of amine ligands
interfering with the palladium-promoted catalytic cycle (entry
1 vs entries 2-3). Efforts to facilitate ligand exchange in
the catalytic cycle by addition of 10 mol % CuCN14 resulted
only in reduced yields of cyclization products (entry 3). The
effect of solvent and base was examined in an effort to
improve the yields of these tandem cyclization-coupling
reactions. Employing potassium carbonate as a base, DMF
as a solvent,8a and tetrabutylammonium chloride as an
additive resulted in a modest yield of pyrroline 8 (entry 4).
Phase-transfer catalysts may facilitate oxidative addition,
carbopalladation of the allene, and intramolecular nucleo-
philic substitution while not changing the regioselectivity of
the transformation.15 Modification of this procedure using
tetrabutylammonium bromide or tetrabutylammonium chlo-
ride with soluble CuN‚2LiCl resulted in diminished yields
of 8 (entries 5-6). Efforts to increase the yields by utilizing
When the reaction was conducted at elevated temperatures
in DMF, pyrrole derivative 9 was formed in good yields.
Presumably, formation of pyrroles involves initial formation
of the 3-pyrrolines followed by palladium-promoted dehy-
drogenation. Treatment of 8 under the reaction conditions
(PhI, DMF, Pd(PPh3)4, K2CO3, 70 °C, 12 h) gave recovered
8 (20%) and 9 (60%). Treatment of 8 with Pd(OAc)2/K2-
CO3/DMF (70-80 °C, 12 h) in the absence of PhI also gave
8 (26%) and 9 (36%). These control experiments implicate
Pd(II) species in the conversion of 8 to 9 observed at higher
temperatures. Neither procedure, however, could be extended
to amino allene 3i. Cyclization of 3i and subsequent arylation
gave either the tetrahydropyrrolizine (K2CO3/n-Bu4NCl/PhI/
Pd(PPh3)4/DMF/25 °C, 5%) or the dihydropyrrolizine (K2-
CO3/n-Bu4NCl/PhI/Pd(PPh3)4/DMF/80 °C, 18%) in low
yields.17
The palladium-catalyzed cyclization of amino allenes to
pyrroles, employing the optimal conditions cited in Table 2,
displays some generality as evidenced by the formation of
10 and 11 in modest yields (Table 3). Good yields of
pyrrolines appear to require the absence of electron-donating
substituents on the aromatic ring (Table 3, 12 vs 13).
(12) (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135 and
references therein. (b) Ohno, H.; Toda, A.; Fujii, N.; Takemoto, Y.; Tanaka,
T.; Ibuka, T. Tetrahedron 2000, 56, 2811 and references therein. (c) Tadema,
G.; Everhardus, R. H.; Westmijze, H.; Vermeer, P. V. Tetrahedron Lett.
1978, 41, 3935.
(13) Alexakis, A.; Marek, I.; Mangeney, P.; Normant, J. F. Tetrahedron
1991, 47, 1677.
In summary, R-amino allenes readily available by coupling
of R-(N-carbamoyl)alkylcuprates with propargyl mesylates
(14) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebskind, L. S.
J. Org. Chem. 1994, 59, 5905.
(15) (a) Jeffery, T. Synthesis 1987, 70. (b) Jeffery, T. Tetrahedron Lett.
1985, 26, 2667. (c) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287.
(16) Dieter, R. K.; Li, S. J. Org. Chem. 1997, 62, 7726.
(17) Products formed from 3i were 5-methyl-6,7-diphenyl-2,3,5,7a-
tetrahydro-1H-pyrrolizine and 5-methyl-6,7-diphenyl-2,3-dihydro-1H-pyr-
rolizinine, respectively.
Org. Lett., Vol. 3, No. 24, 2001
3857

peratures in the palladium-catalyzed reactions provides good
yields of the corresponding pyrroles providing for the
introduction of aryl groups at the C-3 position. This protocol
complements a synthetic route to polysubstituted pyrroles
involving the conjugate addition of R-(N-carbamoyl)alkyl-
cuprates to R,â-alkynyl ketones followed by Boc deprotection
and cyclization.18 Finally, reaction of R-(N-carbamoyl)-
alkylcuprates with scalemic propargyl mesylates followed
by N-Boc deprotection provides an alternative route to the
reaction of scalemic proparyl aziridines with cuprate reagents
to produce scalemic R-amino allenes.12b The scalemic amino
allenes can be converted into scalemic 3-pyrrolines with
configurational integrity through the N-Boc deprotection and
AgNO3 sequence.
Table 3. Palladium-Catalyzed [Pd(PPh3)4] Cyclization of
Amino Allenes to Arylated Pyrrolines and Pyrroles Employing
Conditions Shown in Table 2
Acknowledgment. This work was generously supported
by the National Institutes of Health (GM-60300-01). Support
of the NSF Chemical Instrumentation Program for purchase
of a JEOL 500 MHz NMR instrument is gratefully acknowl-
edged.
followed by carbamate deprotection can be cyclized to either
3-pyrrolines or pyrroles. Treatment of the R-amino allenes
with AgNO3 effects cyclization to 1,2,4-tri-substituted 3-pyr-
rolines, while palladium-promoted tandem cyclization and
coupling with aryl iodides in DMF at 25 °C can afford
1,2,3,4-tetra-substituted 3-pyrrolines (e.g., 8). The latter
reaction appears to be limited to aryl iodides that undergo
facile oxidative addition to Pd(0), given the low yields
observed for 12. Additional substitution on the carbamate
moiety can, in principle, afford 1,2,3,5-tetra-substituted and
1,2,3,4,5-penta-substituted 3-pyrrolines for the AgNO3 cy-
clizations and the palladium-induced cyclization and coupling
processes, respectively. Utilization of higher reaction tem-
Supporting Information Available: 1H and 13C NMR
spectra for compounds 2d, 4j, 8, and 7 and data reduction
and experimental procedures for 2d, 5 (and the precursor
alcohol), and 6-9. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL016654+
(18) Dieter, R. K.; Yu, H. Org. Lett. 2000, 2, 2283.
3858
Org. Lett., Vol. 3, No. 24, 2001