Reaction of α-(N-carbamoyl)alkylcuprates with enantioenriched propargyl electrophiles: Synthesis of enantioenriched 3-pyrrolines

Article abstract of DOI:10.1021/jo061442h

Enantioenriched propargyl mesylates or perfluorobenzoates react with α-(N-carbamoyl)alkylcuprates to afford scalemic α-(N-carbamoyl) allenes which undergo N-Boc deprotection and AgNO₃-promoted cyclization to afford N-alkyl-3-pyrrolines. The syn

Full text of DOI:10.1021/jo061442h

Reaction of r-(N-Carbamoyl)alkylcuprates with Enantioenriched
Propargyl Electrophiles: Synthesis of Enantioenriched 3-Pyrrolines
R. Karl Dieter,* Ningyi Chen, and Vinayak K. Gore
Howard L. Hunter Chemistry Laboratory, Clemson UniVersity, Clemson, South Carolina 29634-0973
dieterr@clemson.edu
ReceiVed July 11, 2006
Enantioenriched propargyl mesylates or perfluorobenzoates react with R-(N-carbamoyl)alkylcuprates to
afford scalemic R-(N-carbamoyl) allenes which undergo N-Boc deprotection and AgNO3-promoted
cyclization to afford N-alkyl-3-pyrrolines. The synthetic sequence proceeds under optimal conditions
with no loss of enantiopurity relative to the starting propargyl alcohols prepared by asymmetric addition
of terminal alkynes to aldehydes.
Introduction
included reaction of R-(N-carbamoyl)alkyl6a and R-iminoalkyl-
cuprates6b with scalemic propargyl substrates, alkylidene carbene
1,5-CH insertion reactions,7 addition of 1-lithio-1-methoxy
allene to SAMP or RAMP hydrazones8a-c or chiral imines,8d
cyclization of (Z)-amino allylic mesylates,9 reaction of scalemic
R-amino ketones with vinyl phosphonium salts,10 and asym-
metric arylation11 of 2-pyrrolines. More recently, the base12a
and AuCl3-catalyzed5c cyclization of R-allenylsulfonamides has
been reported.
∆3-Pyrrolines are a synthetically useful1,2 and biologically3
interesting class of N-containing compounds. They serve as
inhibitors of monoamine oxidase (MAO)3a-d which plays an
important role in psychopharmacology.4 A variety of synthetic
routes to racemic 3-pyrrolines have been reported,5 and some
of these approaches are amenable to the synthesis of enantioen-
riched (i.e., scalemic) products. Asymmetric syntheses have
Although proof of concept for the R-(N-carbamoyl)alkylcu-
prate route was demonstrated with a single example,6a the
enantioselectivity appeared to degrade at some point along the
synthetic sequence. We now report an efficient enantioselective
synthesis of 3-pyrrolines wherein the enantiomeric purity of the
(1) Garcia, A. L. L.; Carpes, M. J. S.; de Oca, A. C. B. M.; dos Santos,
M. A. G.; Santana, C. C.; Correia, C. R. D. J. Org. Chem. 2005, 70, 1050-
1053.
(2) For use of pyrrolines in aza sugar synthesis, see: (a) Chang, D.;
Heringa, M. F.; Witholt, B.; Li, Z. J. Org. Chem. 2003, 68, 8599-8606.
(b) Huwe, C. M.; Blechert, S. Tetrahedron Lett. 1995, 36, 1621-1624.
(3) For pyrrolines as monoamine oxidase inhibitors, see: (a) Lee, Y.;
Ling, K.-Q.; Lu, X.; Silverman, R. B.; Shepard, E. M.; Dooly, D. M.; Sayre,
L. M. J. Am. Chem. Soc. 2002, 124, 12135-12143. (b) Williams, C. H.;
Lawson, J. Neurobiology 1999, 7, 225-233. (c) Williams, C. H.; Lawson,
J. Biochem. J. 1998, 336, 63-67. (d) Lee, Y.; Huang, H.; Sayre, L. M. J.
Am. Chem. Soc. 1996, 118, 7241-7242. As NMDA receptor agonists see:
(e) Rondeau, D.; Gill, P.; Chan, M.; Curry, K.; Lubell, W. D. Bioorg. Med.
Chem. Lett. 2000, 10, 771-773. As k-agonists see: (f) Mou, Q.-Y.; Chen,
J.; Zhu, Y.-C.; Zhou, D.-H.; Chi, Z.-Q.; Long, Y.-Q. Bioorg. Med. Chem.
Lett. 2002, 12, 2287-2290. As tumor inhibitors see: (g) Anderson, W. K.;
Milowsky, A. S. J. Med. Chem. 1987, 30, 2144-2147.
(4) (a) Sahlberg, C.; Ross, S. B.; Fagervall, I.; Ask, A.-L.; Claesson, A.
J. Med. Chem. 1983, 26, 1036-1042. (b) Smith, R. A.; White, R. L.; Krantz,
A. J. Med. Chem. 1988, 31, 1558-1566 and references therein.
(5) (a) Dieter, R. K.; Chen, N.; Yu, H.; Nice, L. E.; Gore, V. K. J. Org.
Chem. 2005, 70, 2109-2119 and references therein. (b) Zhu, X.-F.; Henry,
C. E.; Kwon, O. Tetrahedron 2005, 61, 6276-6282. (c) Morita, N.; Krause,
N. Org. Lett. 2004, 6, 4121-4123. (d) Jayaprakash, K.; Venkatachalam,
C. S.; Balasubramanian, K. K. Tetrahedron Lett. 1999, 40, 6493-6496.
(6) (a) Dieter, R. K.; Yu, H. Org. Lett. 2001, 3, 3855-3858. (b) Horva´th,
A.; Benner, J.; Ba¨ckvall, J.-E. Eur. J. Org. Chem. 2004, 3240-3243.
(7) (a) Green, M. P.; Prodger, J. C.; Hayes, C. J. Tetrahedron Lett. 2002,
43, 2649-2652. (b) Green, M. P.; Prodger, J. C.; Sherlock, A. E.; Hayes,
C. J. Org. Lett. 2001, 3, 3377-3379.
(8) (a) Breuil-Desvergnes, V.; Gore´, J. Tetrahedron 2001, 57, 1939-
1950. (b) Breuil-Desvergnes, V.; Gore´, J. Tetrahedron 2001, 57, 1951-
1960. (c) Breuil-Desvergnes, V.; Compain, P.; Vate`le, J. M.; Gore´, J.
Tetrahedron Lett. 1999, 40, 5009-5012. (d) Amombo, M. O.; Hausherr,
A.; Ressig, H.-U. Synlett 1999, 1871-1874.
(9) (a) Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.;
Takemoto, Y.; Ibuka, T. J. Org. Chem. 2001, 66, 4904-4914. (b) Ishii,
K.; Ohno, H.; Takemoto, Y.; Ibuka, T. Synlett 1999, 228-230.
(10) Burley, I.; Hewson, A. T. Tetrahedron Lett. 1994, 35, 7099-7102.
(11) Ozawa, F.; Hayashi, T. J. Organomet. Chem. 1992, 428, 267-277.
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950.
10.1021/jo061442h CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/13/2006
J. Org. Chem. 2006, 71, 8755-8760
8755

Dieter et al.
SCHEME 1
SCHEME 2a
3-pyrroline reflects the enantiomeric ratio of the starting
propargyl alcohol. The synthetic sequence involves asymmetric
1,2-addition of metalated 1-alkynes to aldehydes,13,14 mesylate
or perfluorobenzoate15 formation, cuprate SN2′ substitution on
propargyl substrates,16 N-Boc deprotection, and AgNO3-
promoted cyclization (Scheme 1).5a The near quantitative yields
in mesylate formation and N-Boc deprotection provide for an
efficient process. Although the R-(N-carbamoyl)alkylcuprates
provide for variation in substitution pattern, the focus of this
study was on controlling the enantioselectivity throughout the
synthetic sequence.
a Conditions: (a) RCHO (1.0 equiv), Zn(OTf)2 (0.22 equiv), (1S,2R) or
(1R,2S)-3-(tert-butyldimethylsilyloxy)-2-N,N-(dimethylamino)-1-(p-nitro-
phenyl)propan-1-ol (0.22 equiv), alkyne (3.0 equiv), Et3N (0.3 equiv), 25
°C, 2 h, 70 °C, 48 h; (b) MeSO2Cl, Et3N, CH2Cl2, -40 °C, 2 h (93-95%);
(c) F5C6COCl (1.2 equiv), CH2Cl2, pyridine (1.5 equiv), DMAP (0.05 equiv),
0 to 25 °C, 2 h (82%).
coupled with slow addition of the aldehyde,13c gave modest
yields with octanal (entries 11 and 16), although the procedure
could not be extended to shorter chain aldehydes, such as butanal
or 3-phenylpropanal. For straight chain aldehydes, stoichiometric
amounts of the chiral ligand (+)-N-methylephedrine could be
employed since it gave the same enantiomeric excess as (1S,2R)-
3-(tert-butyldimethylsilyloxy)-2-N,N-(dimethylamino)-1-(p-ni-
trophenyl)propan-1-ol (entry 11). Similarly, benzaldehyde gave
only trace amounts of propargyl alcohols under solvent-free
conditions, and modest yields could be achieved using toluene
as solvent and stoichiometric amounts of chiral ligand (entries
10 and 15). In all instances where modest to excellent chemical
yields could be achieved, excellent enantioselectivity (81-99%
ee) was observed. Although our chemical yields and enantio-
selectivities were comparable to those reported by Jiang14 and
Carreira,13c,d it should be noted that difficulties have been
reported in the literature, and these appear to revolve around
the source and particle size of the Zn(OTf)2 and its dryness.13e,f
The monoconjugated propargyl sulfonate esters were readily
prepared (MeSO2Cl, Et3N, CH2Cl2, -40 °C) in excellent yields
(93-95%) at low temperatures and were isolated and used
without purification. When the alcohol was both benzylic and
propargylic, attempts to prepare the mesylate were unsuccessful,
resulting in formation of the corresponding chloride.18 These
propargyl benzyl alcohols could be readily converted into the
perfluorobenzoates which were stable to chromatography.15
Carbamate deprotonation (s-BuLi, THF, TMEDA, -78 °C,
1 h),19 cuprate formation, and reaction with the propargyl
mesylates proceeded as previously described for the racemic
analogues.5a Good chemical yields and enantiomeric excesses
were obtained (Table 2). Although formation of metallic copper
is known to isomerize scalemic allenes,20 the enantiomeric
excesses of the R-N-carbamoyl allenes were identical to the
values measured for the starting propargyl alcohols (i.e., Table
1 entries reproduced in Table 2 vs Table 2 product entries,
respectively). Although the use of tri-n-butylphoshine to sup-
press allene isomerization20 can be quite dramatic,20b its use in
Results and Discussion
Although scalemic propargyl alcohols can be prepared by
asymmetric reduction of R,â-ynones,17 we utilized Jiang’s14
modification of Carreira’s13 strategy for the asymmetric addition
of 1-alkynylzinc reagents to aldehydes in the presence of chiral
amino alcohols (Scheme 2, Table 1.). Heating (70 °C, 48 h) a
mixture of aldehyde (1.0 equiv), 1-alkyne (3.0 equiv), and
catalytic amounts of reagents [Zn(OTf)2, Et3N, (1S,2R), or
(1R,2S)-3-(tert-butyldimethylsilyloxy)-2-N,N-(dimethylamino)-
1-(p-nitrophenyl)propan-1-ol]14c under solvent-free conditions
gave good yields of propargyl alcohols with excellent enantio-
meric excesses with R-branched aldehydes (Table 1, entries 1-9
and 14). The reaction tolerated alkynyl alcohols protected as
esters or silyl ethers (entries 3, 4 and 7, 8). Utilization of butanal
or 3-phenylpropanal afforded only traces of product (entries 12,
13 and 17, 18) under solvent-free conditions. The diminished
yields with straight chain aldehydes13c,d or n-alkyl-substituted
glyoxylates14a have been attributed to enolization followed by
aldol condensation reactions. Utilization of toluene as solvent,
(13) (a) Pu, L.; Yu, H. B. Chem. ReV. 2001, 101, 757-824. (b) Frantz,
D. E.; Fa¨ssler, R.; Tomoka, C. S.; Carreira, E. M. Acc. Chem. Res. 2000,
33, 373-381. (c) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001,
123, 9687-9688. (d) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem.
Soc. 2000, 122, 1806-1807. (e) Kirkham, J. E. D.; Courtney, T. D. L.;
Lee, V.; Baldwin, J. E. Tetrahedron 2005, 61, 7219-7232. (f) Recent efforts
to effect these alkyne additions failed with old bottles of Zn(OTf)2 and
with newly purchased Zn(OTf)2. The chemical yields could be reproduced
when the Zn(OTf)2 was heated at 120 °C for 48 h under vacuum. Dieter,
R. K.; Huang, Y. Unpublished results.
(14) (a) Jiang, B.; Chen, Z.; Tang, X. Org. Lett. 2002, 4, 3451-3453.
(b) Jiang, B.; Chen, Z.; Xiong, W. Chem. Commun. 2002, 1524-1525. (c)
The chiral ligand (1S,2R)-3-(tert-butyldimethylsilyloxy)-2-N,N-(dimethyl-
amino)-1-(p-nitrophenyl)propan-1-ol], derived from the (1S,2S) alcohol, is
incorrectly labeled as the (1S,2S) silyl ether isomer in these papers.
(15) Harrington-Frost, N.; Leuser, H. M.; Calaza, I.; Kneisel, F. F.;
Knochel, P. Org. Lett. 2003, 5, 2111-2114.
(18) The downfield absorptions for the carbinol methine proton [δ 6.76
(t, J ) 2.1 Hz, 1H)] and carbinol carbon [δ ) 64.9] were shifted upfield,
δ 4.03 and δ 46.2, respectively, as expected for the less electronegative
chlorine substituent.
(19) Beak, P.; Lee, W. K. J. Org. Chem. 1990, 55, 2578-2580.
(20) (a) Alexakis, A. Pure Appl. Chem. 1992, 64, 387-392. (b) Krause,
N.; Purpura, M. Angew. Chem., Int. Ed. 2000, 39, 4355-4356.
(16) (a) Ohno, H.; Nagaoka, Y.; Tomioka, K. In Modern Allene
Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim,
Germany, 2004; Chapter 4, pp 141-181. (b) Jansen, A.; Krause, N. Inorg.
Chim. Acta 2006, 359, 1761-1766 and references therein.
(17) (a) Tombo, G. M. R.; Didier, E.; Loubinoux, B. Synlett 1990, 547-
548. (b) Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990, 937-943.
8756 J. Org. Chem., Vol. 71, No. 23, 2006

Synthesis of Enantioenriched 3-Pyrrolines
TABLE 1. Asymmetric Addition of Terminal Alkynes to Aldehydes
a (1S,2R) or (1R,2S)-3-(tert-butyldimethylsilyloxy)-2-N,N-(dimethylamino)-1-(p-nitrophenyl)propan-1-ol. b Catalytic procedure was used unless otherwise
noted. (i) Zn(OTf)2 (0.22 equiv), chiral ligand (0.22 equiv), alkyne (3.0 equiv), Et3N (0.3 equiv), 25 °C, 2 h; (ii) aldehyde (1.0 equiv), 70 °C, 48 h. c Yields
are based upon isolated products purified by column chromatography. d Enantiomeric ratios were determined by chiral stationary phase HPLC on a CHIRALCEL
OD column [cellulose tris(3,5-dimethylphenylcarbamate) on silica gel] on the benzoate derivatives of chiral alcohols 3-9. e PhMe was used as solvent with
a stoichiometric amount of chiral ligand. f A stoichiometric amount of (+)-N-methylephedrine (NME) was employed. g Stoichiometric amount of the (1R,2S)
ligand was employed.
TABLE 2. Reactions of the Cuprate (RCuCNLi) Reagent Derived from N-Boc-N,N-Dimethylamine with Scalemic Propargyl Electrophiles
a Prepared from the alcohols with methanesulfonyl chloride or pentafluorobenzoyl chloride. b Enantiomeric ratios were determined by chiral stationary
phase HPLC on a CHIRALCEL OD column [cellulose tris(3,5-dimethylphenylcarbamate) on silica gel] on the benzoate esters of the enantiomerically
enriched propargyl alcohols and are assumed to be the same for the mesylate or perfluorobenzoate esters. c Yield of crude propargyl mesylate which was
used without purification. d N-Boc deprotonation [s-BuLi, THF, TMEDA, -78 °C, 1 h], cuprate formation [-78 °C, 45 min] followed by reaction with
scalemic propargyl substrate [-78 to 25 °C, 12 h]. e Average yields of 2-3 reactions based upon isolated material purified by column chromatography.
f Enantiomeric ratios were determined by chiral stationary phase HPLC on a CHIRALCEL OD column [cellulose tris(3,5-dimethylphenylcarbamate) on
silica gel]. g n-Bu3P (1.0 equiv) was added to the cuprate solution prior to addition of the propargyl mesylate 3bR (81% ee). h The perfluorobenzoate propargyl
ester was employed.
the present cuprate substitution reaction was examined and did
not give higher enantiomeric purities in the product R-N-
carbamoyl allenes (entry 2).
N-Boc deprotection of R-(N-carbamoyl)alkylcuprates was
initially achieved with trimethylsilyltriflate [TMSOTf (1.1
equiv), CH2Cl2, -40 to 0 °C] followed by neutralization with
K2CO3 (Scheme 3). Variation among several experiments
revealed that the free amine 18S underwent cyclization to
pyrroline 24S in the CH2Cl2/K2CO3 biphasic medium with loss
of enantiomeric purity as a function of time (Scheme 3). When
aqueous K2CO3 was added to the reaction mixture and stirred
for 2-3 min followed by separation of the layers, only 18S
was isolated. If the CH2Cl2/K2CO3 biphasic medium containing
18S was allowed to stir for longer periods of time, increasing
amounts of 24S were present in the product mixture reaching a
33:66 ratio of 18S:24S after 12 h. Treatment of sample (a)
containing only 18S with AgNO3 gave pyrroline 24S of the same
enantiomeric purity as the starting N-Boc allene 12S. In contrast,
J. Org. Chem, Vol. 71, No. 23, 2006 8757

Dieter et al.
SCHEME 3
tion. Minimum motion after SET and slow geometrical
isomerization22d of the allyl radical are necessary for maintaining
stereochemical integrity. Although the effect of allene and
N-atom substituents on substrate reactivity and stereochemical
outcome was not examined, it is expected that these would play
significant roles.
Treatment of the N-Boc carbamates with MeOH/TMSCl
effected cleavage of the N-Boc protecting group without
concomitant cyclization to 3-pyrrolines and without isomeriza-
tion of the scalemic allenes. Under this deprotection protocol,
nearly quantitative yields of the free R-amino allenes could be
obtained (eq 1, Table 3), although when the solution was
allowed to stir for longer than 48 h, some amino allene
decomposition occurred.
SCHEME 4
Treatment of the free R-amino allenes with a catalytic amount
of AgNO3 afforded the 3-pyrrolines in good chemical yields
and with excellent enantiomeric purities that reflected the
enantiomeric purities of the starting propargyl alcohols (eq 1,
Table 3). The assignment of absolute configuration is predicated
upon the observed high degree of enantioselectivity, the
assumption of anti-SN2′ stereochemistry in the cuprate-mediated
propargyl substitution reaction,16 and the orthogonal arrangement
of substituents at the end of an allene moiety. Approach of silver
nitrate occurs on the π-face opposite that of the aminomethyl
substituent leading to the 3-pyrroline derivatives with the
predicted absolute stereochemistry. This predicted stereoselec-
tivity for R-heteroatom allene cyclizations has been assumed6,25
and found to agree with product stereochemistry determined
by X-ray analysis26 and by synthesis of both stereoisomers12a
in the diastereoselective reactions. The stereoselective cycliza-
tion of R-heteroatom allenes has been mediated by acids,25b Cu-
(II) salts,26 AgNO3,6a,25a AuCl3,5c,25b N-bromosuccinimide,6b and
bases12a for both oxygen25,26 and nitrogen6,12 heteroatoms and
in all cases gave the predicted stereochemistry (i.e., anti-addition
of proton or transition metal ion and heteroatom to the allene
double bond).27
Although the base-promoted cyclization of R-allenyl alcohols22d
and R-allenyl hydrazines8a,b sometimes affords vinyl epoxides
and azetidines, respectively, 3-pyrrolines are obtained exclu-
sively with AgNO3, AuCl3, or NBS. The absence of aziridines
suggests that the 3-pyrrolines are kinetically favored, although
it is unclear whether the rate-determining step involves silver
ion complexation or heteroatom cyclization.28
The resulting N-methyl-3-pyrrolines are relatively stable to
silica gel chromatography and storage. Although the present
study focused only on the integrity of the chirality transfer
treatment of sample (b) containing a 33:66 mixture of 18S:24S
with AgNO3 gave 24S with diminished enantiomeric purity
relative to that measured for the starting N-Boc allene 12S.
Precedent for this base-induced cyclization is found in the
reported cyclization of ortho-allenyl phenoxides21 and R-allenyl
alkoxides,22 sulfonamide anions,8d,12 and hydrazides.8a-c In
contrast to the formal 5-endo-trig intramolecular cyclizations,
oxime23 and thiolate24 anions (as well as the ortho-substituted
phenoxide) add to the central carbon atom of allene. The latter
reactions occur in the presence of allene-propyne isomerization
events and may well involve nucleophilic addition to propyne.
It has been suggested that nucleophilic additions to allene do
not occur.24 Mechanistic studies of R-allenyl alkoxide22d and
hydrazide8b cyclizations implicate a SET pathway generating a
heteroatom radical and an allyl radical anion that collapse to
the heterocyclic product. Although many of these cyclizations
are conducted between 50 and 180 °C,8d,12,22a,d several R-allenyl
hydrazide anions8a,b with favorable substitution patterns undergo
cyclization at -25 °C. The K2CO3-promoted cyclization of
R-allenyl sulfonamides was conducted between 80 and 180 °C12
and was reported to be stereospecific, affording single diaster-
eomers. This is in contrast to the low temperatures, small loss
of stereospecificity, and participation of a neutral aliphatic amine
observed in our experiments. SET from the aliphatic amine to
the allene moiety in 18S would afford a zwitterionic diradical
intermediate (Scheme 4) that under the basic aqueous conditions
could undergo the necessary proton transfer events and cycliza-
(21) Gaertner, R. J. Am. Chem. Soc. 1951, 73, 4400-4404.
(26) Ma, S.; Wu, S. J. Chem. Soc., Chem. Commun. 2001, 441-442.
(27) For reviews, see: (a) Ma, S. In Modern Allene Chemistry; Krause,
N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2004;
Chapter 10, Vol. 2, pp 595-699. (b) Tius, M. A. In Modern Allene
Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim,
Germany, 2004; Chapter 13, Vol. 2, pp 817-845. (c) Nakamura, I.;
Yamamoto, Y. Chem. ReV. 2004, 104, 2127-2198. (d) Hatem, J. Targets
Heterocycl. Syst. 2002, 6, 399-417. (e) Ma, S. Acc. Chem. Res. 2003, 36,
701-712.
(22) (a) Hoff, S.; Brandsma, L.; Arens, J. F. Recl. TraV. Chim. Pays-
Bas 1969, 88, 609-619. (b) Gange, D.; Magnus, P. J. Am. Chem. Soc.
1978, 100, 7746-7747. (c) Gange, D.; Magnus, P.; Bass, L.; Arnold, E.
V.; Clardy, J. J. Am. Chem. Soc. 1980, 102, 2134-2135. (d) Magnus, P.;
Albaugh-Robertson, P. J. Chem. Soc., Chem. Commun. 1984, 804-806.
(23) Trofimov, B. A.; Tarasova, O. A.; Mikhaleva, A. I.; Kalinina, N.
A.; Sinegovskaya, L. M.; Henkelmann, J. Synthesis 2000, 1585-1590.
(24) Mueller, W. H.; Griesbaum, K. J. Org. Chem. 1967, 32, 856-858.
(25) (a) Marshall, J. A.; Wang, X. J. Org. Chem. 1991, 56, 4913-4918.
(b) Hoffmann-Roder, A.; Krause, N. Org. Lett. 2001, 3, 2537-2538.
(28) Linn, W. S.; Waters, W. L.; Caserio, M. C. J. Am. Chem. Soc. 1970,
92, 4018-4025.
8758 J. Org. Chem., Vol. 71, No. 23, 2006

Synthesis of Enantioenriched 3-Pyrrolines
TABLE 3. Preparation and Conversion of Scalemic r-Amino Allenes to 3-Pyrrolines (eq 1)
a N-Boc deprotection [MeOH, TMSCl (5.0 equiv), 25 °C, 12 h]. b Yields based upon crude weight of amino allenes, which were used without further
purification. c Enantiomeric ratios were determined by chiral stationary phase HPLC on a CHIRALCEL OD column [cellulose tris(3,5-dimethylphenylcarbamate)
on silica gel] on the N-Boc-protected allenes. The enantiomeric ratios were assumed to be the same for the deprotected amines, which was confirmed by
determinations on the pyrroline products. d Average yield of 2-3 reactions based upon isolated products purified by column chromatography. e Enantiomeric
ratios were determined by chiral stationary phase HPLC on a CHIRALCEL OD column [cellulose tris(3,5-dimethylphenylcarbamate) on silica gel].
through Celite; the organic phase separated, and the aqueous phase
was extracted three times with Et2O. The combined organic phases
were washed one time with saturated brine and dried over MgSO4.
Evaporation of the solvent in vacuo afforded the products. Purifica-
tion was accomplished using flash column chromatography eluting
with 5% EtOAc/95% petroleum ether (v/v) to give pure adduct.
Carbamic acid, Methyl[2-(3-phenyl-5,5-dimethyl-2,3-hexadi-
enyl], 1,1-Dimethylethyl ester (15S). Employing General Proce-
dure G with N-Boc-N,N-dimethylamine (0.145 g, 1.0 mmol) and
7bR (0.308 g, 1.0 mmol) afforded 15S (0.256 g, 85%) as a colorless
oil after purification by flash column chromatography (silica gel,
ether/petroleum ether, 1:5, v/v): IR (neat) 2954 (vs), 2921 (vs),
2855 (s), 1956, 1693 (vs), 1448 (vs), 1382 (vs), 1354 (vs), 1241,
operations, the procedure should be amenable to the synthesis
of a wide range of N-alkyl- or N-aryl 3-pyrrolines.
Summary
In summary, a rapid synthesis of enantioenriched 3-substituted
pyrrolines is available by reaction of R-(N-carbamoyl)alkyl-
cuprates with scalemic propargyl mesylates or perfluoroben-
zoates. The perfluorobenzoates are used when the carbinol center
is in conjugation with two unsaturated functional groups (e.g.,
aryl or propargyl) since the corresponding mesylates are easily
converted to the chlorides when methanesulfonyl chloride is
used for mesylate preparation. The synthetic sequence can be
carried out to afford 3-pyrrolines that have the same enantio-
purity as that of the starting propargyl alcohols. The procedure
should be amenable to the synthesis of a wide variety of N-alkyl-
or N-aryl-substituted 3-pyrrolines.
1
1161 (vs), 879, 737, 690 (vs) cm-1; H NMR (CDCl3) δ 1.08 (s,
9H), 1.48 (s, 9 H), 1.80 (quint, J ) 7.1 Hz, 2H), 1.94-1.99 (m,
2H), 2.68 (t, J ) 7.1 Hz, 2H), 2.85 (s, 3H), 3.73 (dd, J ) 15.1, 2.6
Hz, 1H), 3.87-3.99 (m, 1H), 5.27 (t, J ) 2.6 Hz, 1H), 7.16-7.31
(m, 5H); 13C NMR (CDCl3) δ 22.7, 28.5, 29.3 (29.4), 30.3, 32.2,
33.7 (34.1), 35.6, (50.9) 51.63, (79.1) 79.3, 102.8 (103.0), 105.6
(105.7), 125.7, 128.3, 128.4, 142.3, 155.6, (197.8) 198.2; mass
spectrum m/z (relative intensity) EI 301 (55), 284 (10), 244 (8),
197 (10), 170 (11), 122 (20), 88 (35), 57 (100).
The enantiomeric purity of 15S was determined by chiral HPLC
analysis on a CHIRACEL OD column [cellulose tris(3,5-dimeth-
ylphenylcarbamate) on silica gel] to be 93% ee (hexane/iPrOH, 99.8:
0.2 (v/v), flow rate ) 0.5 mL/min, detection at λ ) 210 nm. The
(S)-enantiomer eluted first with a retention time of 30.6 min
followed by the (R)-isomer (minor) at 32.8 min.
Experimental Section
General Procedure B: Propargylic Mesylate Preparation.
Under argon, a solution of propargylic alcohol (5.0 mmol) in CH2-
Cl2 (20 mL) was treated with redistilled Et3N (0.76 g, 7.5 mmol)
and methanesulfonyl chloride (0.69 g, 6.0 mmol) at -40 °C. The
stirring was continued under argon for 1 h at -40 °C, and the
reaction mixture was then warmed to room temperature, quenched
with saturated NaHCO3 (aq), and extracted with CH2Cl2 (3 × 10
mL). The combined organic layer was dried over MgSO4 and
concentrated under vacuum to afford neat crude product, which
General Procedure H: Deprotection of N-Boc Carbamates
with Chlorotrimethylsilane (TMSCl) in Methanol. To a solution
of N-Boc-protected amino allene (1.0 mmol) in MeOH (5.0 mL)
was added TMSCl (0.540 g, 5.0 mmol) via syringe at 25 °C. The
reaction mixture was stirred at room temperature for 12 h. The
reaction mixture was quenched with saturated NaHCO3 (aq) and
diluted with CH2Cl2. The organic phase was separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The
combined organic extractions were dried over MgSO4 and con-
centrated under vacuum to afford crude product, which was pure
1
was clean by both H and 13C NMR analysis. The mesylate was
used for the next reaction without purification.
General Procedure G: Reaction of RCuCNLi with Propargyl
Mesylates. To N-Boc-N,N-dimethylamine (1.0 mmol) in THF (2.0
mL) cooled to -78 °C was added TMEDA (0.16 mL, 1.2 mmol).
sec-BuLi (1.0 mmol) was added by syringe, and the mixture was
allowed to stir for 1 h at -78 °C. A THF soluble CuCN•2LiCl
complex [prepared by dissolving CuCN (0.0895 g, 1.0 mmol) and
LiCl (0.0840 g, 2.0 mmol); LiCl was flamed dried under vacuum
prior to use and purged with argon] in THF (2 mL) at room
temperature was added via syringe to the 2-lithio-N-Boc amine at
-78 °C. The mixture was allowed to stir at -78 °C for 45 min to
generate a clear homogeneous solution. A solution of the propargyl
substrate (1.0 mmol) dissolved in THF (1.0 mL) was added, and
the reaction mixture was allowed to warm to room temperature
over 3 h. The reaction mixture was quenched with saturated NH4-
Cl (aq). The mixture was diluted with Et2O and filtered by vacuum
1
(>95%) by both H and 13C NMR analysis.
N-Methyl-2-(3-phenylpropyl)-5,5-dimethyl-2,3-hexadienyl-1-
amine (21S). General Procedure H was employed on 15S (0.357
g, 1.0 mmol) to afford 21S (0.244 g, 95%) which was pure by
1
both H and 13C NMR analysis: IR (neat) 3322 (br s), 2957 (vs),
1
2358, 2335, 1960, 1450, 1357, 739, 692 cm-1; H NMR (CDCl3)
δ 1.09 (s, 9H), 1.82 (quint, J ) 7.4 Hz, 2H), 2.02-2.06 (m, 2H),
2.20-2.80 (br s, 4H), 2.70 (t, J ) 7.2 Hz, 2H), 2.90-3.50 (br s,
2H), 5.31 (s, 1H), 7.17-7.32 (m, 5H); 13C NMR (CDCl3) δ 22.8,
J. Org. Chem, Vol. 71, No. 23, 2006 8759

Dieter et al.
29.4, 30.3, 32.0, 32.2, 35.7, 53.9, 105.1, 105.8, 125.7, 128.3, 128.4,
142.4, 197.4; mass spectrum m/z (relative intensity) 257 (6, M+),
242 (10), 201 (21), 91 (100), 77 (49), 57 (48).
spectrum m/z (relative intensity) 257 (1, M+), 255 (3), 200 (100),
151 (12), 91 (51). High-resolution mass spectrum m/z 257.2143
(M+) (calcd for C18H27N 257.2143).
General Procedure I: AgNO3-Catalyzed Cyclization of
Amino Allenes. Crude amino allene (e.g., 18-23) (0.67 mmol),
prepared by General Procedure I or J, was dissolved in acetone
(from drum, without further purification), followed by the addition
of a catalytic amount of AgNO3 (0.023 g, 0.14 mmol). The reaction
mixture was stirred at room temperature under nitrogen in the dark
(flask was wrapped with aluminum foil). The reaction was
monitored by TLC until starting material was consumed (Rf ) 0.2-
0.5 on silica gel, 100% ether as eluent). Then the reaction mixture
was diluted with diethyl ether, filtered through a thin layer of Celite,
and concentrated under vacuum to afford crude product, which was
purified by flash column chromatography (silica gel, 100% diethyl
ether as eluent) to give colorless oils.
The enantiomeric purity of 27R was determined by chiral HPLC
analysis on a CHIRACEL OD column [cellulose tris(3,5-dimeth-
ylphenylcarbamate) on silica gel] to be 93% ee (hexane/iPrOH/
diethylamine, 99:0.5:0.5 (v/v), flow rate ) 1.0 mL/min, detection
at λ ) 210 nm). The (R)-enantiomer eluted first with a retention
time of 22.8 min followed by the (S)-isomer at 27.7 min. The
enantiomer, 27S, gave a specific rotation [R]22D ) -47.3 (c 0.002,
CHCl3).
Acknowledgment. This work was generously supported by
the National Science Foundation (CHE-0132539). Support of
the NSF Chemical Instrumentation Program for purchase of a
JEOL 500 MHz NMR instrument is gratefully acknowledged
(CHE-9700278).
1-Methyl-2-(1,1-dimethylethyl)-4-(3-phenylpropyl)-3-pyrro-
line (27R). General Procedure I was employed on 21S (0.172 g,
0.6 mmol) to afford 27R (94 mg, 61%) after purification by flash
column chromatography (silica gel, ether/petroleum ether, 1/1
Supporting Information Available: General experimental
information, materials, data reduction for 3aR-9aR, 3bR-5bR,
7bR, 8cR, 9bR, 12S-14S, 18S, 19S-23S, 24S, 25S-26S, 28R,
(v/v)): [R]22 ) +40.4 (c 0.0025, CHCl3); IR (neat) 2942 (vs),
D
2852, 2831, 2774, 1444, 1387 (vs), 1350, 861, 745, 693 (vs) cm-1
;
1H NMR (CDCl3) δ 0.83 (s, 9H), 1.80 (quint, J ) 6.8 Hz, 2H),
2.13 (t, J ) 7.4 Hz, 2H), 2.51 (s, 3H), 2.65 (t, J ) 7.4 Hz, 2H),
3.11 (br s, 2H), 3.86-3.90 (m, 1H), 5.33-5.34 (m, 1H), 7.19-
7.35 (m, 5H); 13C NMR (CDCl3) δ 26.5, 28.3, 29.6, 35.6, 35.9,
47.1, 66.7, 77.2, 84.6, 121.6, 125.8, 128.4, 140.5, 142.3; mass
1
29S, isomerization studies for 18S, and H and 13C NMR spectra
for 13S-17S and 19S-23S. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO061442H
8760 J. Org. Chem., Vol. 71, No. 23, 2006