Reaction of α-(N-carbamoyl)alkylcuprates with propargyl substrates: Synthetic route to α-amino allenes and Δ3-pyrrolines

Article abstract of DOI:10.1021/jo0481405

(Chemical Equation Presented) Carbamate deprotonation followed by treatment with CuCN·2LiCl affords α-(N-carbamoyl)-alkylcuprates which react with propargyl halides, mesylates, tosylates, phosphates, acetates, and epoxides to give α-(N-carbamoyl) allenes via an anti-S_N2′ substitution process. Propargyl halides, sulfonates, and phosphates give good yields of carbamoyl allenes, while the acetates afford low yields. Propargyl substrates undergo regiospecific S_N2′ substitution in the absence of severe steric hindrance. The α-(N-carbamoyl) allenes can be cyclized to 2-oxazolidinones or deprotected to afford the free amines which can be cyclized to Δ³-pyrrolines with either AgNO₃ or Ru₃(CO)₁₂.

Full text of DOI:10.1021/jo0481405

Reaction of r-(N-Carbamoyl)alkylcuprates with Propargyl
Substrates: Synthetic Route to r-Amino Allenes and ∆3-Pyrrolines
R. Karl Dieter,* Ningyi Chen, Huayun Yu, Lois E. Nice, and Vinayak K. Gore
Department of Chemistry, Howard L. Hunter Laboratory, Clemson University,
Clemson, South Carolina 29634-0973
dieterr@clemson.edu
Received October 20, 2004
Carbamate deprotonation followed by treatment with CuCN‚2LiCl affords R-(N-carbamoyl)-
alkylcuprates which react with propargyl halides, mesylates, tosylates, phosphates, acetates, and
epoxides to give R-(N-carbamoyl) allenes via an anti-SN2′ substitution process. Propargyl halides,
sulfonates, and phosphates give good yields of carbamoyl allenes, while the acetates afford low
yields. Propargyl substrates undergo regiospecific SN2′ substitution in the absence of severe steric
hindrance. The R-(N-carbamoyl) allenes can be cyclized to 2-oxazolidinones or deprotected to afford
the free amines which can be cyclized to ∆3-pyrrolines with either AgNO3 or Ru3(CO)12.
Introduction
useful synthetic routes involve conversion of a propargyl
substrate into the allene functionality via either an SN2′-
or an SE2′-substitution event. The amine moiety may be
incorporated in the propargyl substrate2,7 or be part of
the nucleophile (SN2′) or electrophile (SE2′) participating
in the substitution reaction. Propargyl silanes8a-c (eq 2)
and stannanes8d undergo SE2′-substitution reactions with
imines and/or imminium ions to afford R-amino allenes.
The SE2-reaction of imines or iminium ions with prop-
argyl organometallic reagents may afford either the
R-amino allene or the homo propargylamine.9-11 Although
R-methoxy allenyllithium10 reagents add directly to hy-
R-Amino allenes and ∆3-pyrrolines are synthetically
useful1 and biologically2,3 interesting classes of N-con-
taining compounds. Monoamine oxidase which plays an
important role in psychopharmacology2 is inactivated by
R-amino allenes, while ∆3-pyrrolines also function
as MAO inhibitors,3a-c NMDA receptor agonists,3d
k-agonists,3e and tumor inhibitors.3f Mitochondrial mono-
amine oxidase exists in two forms (i.e., A and B) and
effects the oxidative deamination of transmitter amines
(e.g., serotonin, noradrenaline, â-phenylethylamine, and
dopamine).2a MAO-A inhibitors can function as anti-
depressant agents, while MAO-B inhibitors are selective
toward Parkinson’s disease. Although R-amino allenes
have been prepared4 via cyclopropyl carbene5a fragmen-
tation, retro Diels-Alder reactions,5b and nitrogen alkyl-
ation with R-mesyloxy2 (eq 1) or R-halo allenes,6 the most
(4) Landor, P. D. In The Chemistry of the Allenes; Landor, S. R.,
Ed.; Academic: New York, 1982; pp 165-191.
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10.1021/jo0481405 CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/11/2005
J. Org. Chem. 2005, 70, 2109-2119
2109

Dieter et al.
SCHEME 1
drazones (eq 3), the corresponding R-alkyl or silylmetal
reagents (e.g., Zn, Ti, B, Al, Li) react with rearrangement
to afford homo propargylamines.11 The propargyl borane
and allenylborane are in rapid equilibrium and generally
favor formation of the R-amino allene upon reaction with
imines.11c Allyllic SN2′-substitution is also involved in the
palladium-promoted addition of amide anions to 2-bromo-
1,3-dienes,12 (eq 4) and ester enolate Claisen rearrange-
ments on R-amino propargyl esters incorporates both pro-
pargyl rearrangement and R-amino carbanion synthons
(eq 5).6 Reaction of cuprates with δ-amino propargyl
ethers,2a,7d δ-amino propargyl mesylates,7c or alkynyl
azirdines13 also affords R-amino allenes. An early report
and our preliminary study suggested that SN2′-substitu-
tion reactions of propargyl substrates with R-amino-
alkyl-14a or R-(N-carbamoyl)alkylcuprates14b could provide
a general route to R-amino allenes.
onto an allene moiety remains a powerful strategy for
heterocyclic synthesis.16 Furan formation via silver ion-
catalyzed cyclization of R-hydroxy allenes occurs in a
highly regio- and stereoselective manner.17 Silver ion-
catalyzed cyclization of a nitrogen functionality onto a
proximate olefinic site has been employed for the syn-
thesis of nitrogen heterocycles. Although these cycliza-
tions proceeded cleanly for a range of nitrogen-containing
functionality, many of the cyclizations proceeded in an
exo-cyclic fashion to afford 2-vinyl substituted ring sys-
tems.18 Nevertheless, several recent reports describe
silver nitrate-promoted endo-cyclization processes involv-
ing either a benzyl or an alkylamine functionality,19a
sulfonamides,19b or acyclic amino allenes.19c In a prelimi-
nary report, we demonstrated that unprotected secondary
R-amino allenes undergo AgNO3-promoted cyclization to
∆3-pyrrolines in good to excellent yields (Scheme 1).20
Similarly, the vast majority of palladium-promoted cy-
clizations of nitrogen functionalities onto adjacent double
bonds involve nitrogen centers containing electron-
withdrawing substituents,7c,19b,21 although examples of
amine participation have been reported.16 This is signifi-
cant because strongly basic amines can function as
ligands for the palladium catalyst and potentially inter-
fere with the cyclization reaction. Although some 5-endo-
trig-cyclizations have been reported,19,21 most of these
procedures also involve exo-cyclizations,22 raising ques-
(15) For recent examples of pyrroline syntheses, see: (a) Fejes, I.;
To´ke, L.; Blasko´, G.; Nyerges, M.; Pak, C. S. Tetrahedron 2000, 56,
8545-8553. (b) Weeresakare, G. M.; Xu, Q.; Rainier, J. D. Tetrahedron
Lett. 2002, 43, 8913-8915. (c) Grigg, R.; Martin, W.; Morris, J.;
Sridharan, V. Tetrahedron Lett. 2003, 44, 4899-4901. (d) Clique, B.;
Vassiliou, S.; Monteiro, N.; Balme, G. Eur. J. Org. Chem. 2002, 1493-
1499.
(16) For reviews, see: (a) Frederickson, M.; Grigg, R. Org. Prep.
Proced. Int. 1997, 29, 63-116. (b) Tamaru, Y.; Kimura, M. Synlett
1997, 749-757. (c) Zimmer, R.; Dinesh, Cu.; Nandanan, E.; Khan, F.
A. Chem. Rev. 2000, 100, 3067-3126.
(17) (a) Marshall, J. A.; Pinney, K. G. J. Org. Chem. 1993, 58, 7180-
7184. (b) Marshall, J. A.; Wang, X.-j. J. Org. Chem. 1990, 55, 2995-
2996. (c) Marshall, J. A.; Bartley, G. S. J. Org. Chem. 1994, 59, 7169-
7171.
(18) (a) Lathbury, D.; Gallagher, T. J. Chem. Soc., Chem. Commun.
1986, 114-115. (b) Fox, D. N. A.; Gallagher, T. Tetrahedron 1990, 46,
4697-4710. For a review, see: (c) Muller, T. E.; Beller, M. Chem. Rev.
1998, 98, 675-704.
(19) (a) Amombo, M. O.; Hausherr, A.; Reissig, H.-U. Synlett 1999,
1871-1874. (b) Ohno, H.; Toda, A.; Miwa, Y.; Taga, T.; Osawa, E.;
Yamaoka, Y.; Fujii, N.; Ibuka, T. J. Org. Chem. 1999, 64, 2992-2993.
(c) Claesson, A.; Sahlberg, C.; Luthman, K. Acta Chem. Scand. B 1979,
B33, 309-310.
(20) Dieter, R. K.; Yu, H. Org. Lett. 2001, 3, 3855-3858.
(21) (a) Prasad, J. S.; Liebeskind, L. S. Tetrahedron Lett. 1988, 29,
4253-4256. (b) Prasad, J. S.; Liebeskind, L. S. Tetrahedron Lett. 1988,
29, 4257-4260.
Although recently described synthetic routes to ∆3-
pyrrolines provide versatile opportunities for substitution
patterns3d,10,15a-c and multiple-component coupling,15d
transition metal-promoted cyclization of a heteroatom
(10) (a) Breuil-Desvergnes, V.; Compain, P.; Vate`le, J. M.; Gore´, J.
Tetrahedron Lett. 1999, 40, 5009-5012. (b) Breuil-Desvergnes, V.;
Gore´, J. Tetrahedron 2001, 57, 1939-1950.
(11) (a) Poisson, J.-F.; Normant, J. F. J. Org. Chem. 2000, 65, 6553-
6560. (b) Poisson, J.-F.; Chemla, F.; Normant, J. F. Synlett 2001, 305-
307. (c) Nikam, S. S.; Wang, K. K. J. Org. Chem. 1985, 50, 2193-
2195.
(12) (a) Ogasawara, M.; Ikeda, H.; Hayashi, T. Angew. Chem., Int.
Ed. 2000, 39, 1042-1044. (b) Ogasawara, M.; Ueyama, K.; Nagano,
T.; Mizuhata, Y.; Hayashi, T. Org. Lett. 2003, 5, 217-219.
(13) Ohno, H.; Toda, A.; Fujii, N.; Takemoto, Y.; Tanaka, T.; Ibuka,
T. Tetrahedron 2000, 56, 2811-2820.
(14) (a) Claesson, A.; Sahlberg, C. Tetrahedron 1982, 38, 363-368.
(b) Dieter, R. K.; Nice, L. E. Tetrahedron Lett. 1999, 40, 4293-4296.
2110 J. Org. Chem., Vol. 70, No. 6, 2005

Route to R-Amino Allenes and ∆3-Pyrrolines
SCHEME 2
SCHEME 3a
a (a) (i) nBuLi, THF, -20 °C, (ii) cyclohexanone (90%); (b) CaCl,
CuCl, copper powder, concentrated HCl (87%) for 13b; (c) (i) LDA,
THF, -78 °C, (ii) (PhO)2POCl for 13c; (d) pyridine, POCl3, 0 °C 1
h, 25 °C 16 h, 70 °C 2 h (86%); (e) m-ClC6H4CO3H, CH2Cl2, 0-25
°C, 16 h (75%); (f) (i) nBuLi, THF, -20 °C, (ii) CH3COCH2Cl (52%);
t
(g) BuOK, THF (93%).
can be prepared by the addition of lithium or magnesium
acetylides to aldehydes.23 Mesylates containing combina-
tions of alkene, alkyne, or arene functionality on both
sides of the carbinol carbon were prone to rearrange-
ments and nucleophilic substitution reactions and proved
difficult to prepare. Mesylates could not be prepared from
secondary alcohols that were both propargylic and ben-
zylic. Phosphates 10c,l-n, although unstable to purifica-
tion, could be used as crude materials in the substitution
reaction. Similarly, although the proparyl mesylate 13a
or phosphate 13c could not be isolated (Scheme 3),
phosphate 13c could be generated in situ [(i) LDA, THF,
-78 °C, (ii) (PhO)2POCl, -78 to 25 °C] and used in the
cuprate substitution reaction (Scheme 3).
The alkynyl epoxides 14 and 15 were also easily
prepared according to established procedures. Dehy-
dration24 of alcohol 12 followed by chemoselective
epoxidation24b of the enyne afforded propargyl epoxide
14 (Scheme 3), while addition of 1-lithiohexyne to R-chlo-
ro acetone25a followed by treatment with base25b afforded
15. The asymmetric epoxidation of conjugated enynes
provides a convenient access to scalemic (i.e., enantio-
enriched) propargyl epoxides necessary for asymmetric
variations of the synthetic method.26
The R-(N-carbamoyl)alkylcuprate reagents were pre-
pared from N-Boc (i.e., tert-butoxycarbonyl)-protected
amines 1A-D by sequential deprotonation [s-BuLi, THF,
sparteine, or TMEDA, -78 °C (-20 °C for piperidine)]27
and treatment with solid CuCN in the early studies.
tions about the generality of the endo-cyclization process
particularly for annulated ∆3-pyrrolines. In this full
report, we provide a detailed examination of the scope
and limitations of a synthetic route to ∆3-pyrrolines via
R-amino allenes available by reaction of R-(N-carbamoyl)-
alkylcuprates with propargyl substrates (Scheme 1).
Results and Discussion
The key three-step synthetic sequence to ∆3-pyrrolines
involves reaction of R-(N-carbamoyl)alkylcuprates with
propargyl substrates [i.e., mesylates (2), tosylates (7),
phosphates (10 and 13c), halides (6 and 9), and acetates
(8)] in an anti-SN2′ fashion, followed by N-Boc deprotec-
tion and cyclization of the amino moiety onto the allene
functionality (Schemes 1 and 2). Convenient and rapid
access to the propargyl substrates is essential for the
utility of the method. The propargyl mesylates 2b-k and
2o, tosylate 7c, acetate 8f, chloride 9c,n, and phosphates
10c,l-n (Scheme 2) are readily available from the
corresponding propargyl alcohols 11b-o, which in turn
(23) Brandsma, L. Synthesis of Acetylenes, Allenes and Cumulenes;
Elsevier Academic Press: London, 2004; Chapter 5, pp 119-134.
(24) Alaxakis, A.; Marek, I.; Mangeney, P.; Normant, J. F. Tetra-
hedron 1991, 47, 1677-1696.
(25) (a) Doutheau, A.; Sartoretti, J.; Gore, J. Tetrahedron 1983, 39,
3059-3065. (b) Brandsma, L. Synthesis of Acetylenes, Allenes and
Cumulenes; Elsevier Academic Press: London, 2004; Chapter 20, p
410.
(26) (a) Hamada, T.; Daikai, K.; Irie, R.; Katsuki, T. Tetrahedron:
Asymmetry 1995, 6, 2441-2451. (b) Cao, G.-A.; Wang, Z.-X.; Tu, Y.;
Shi, Y. Tetrahedron Lett. 1998, 39, 4425-4428.
(22) (a) Davies, I. W.; Scopes, D. I. C.; Gallagher, T. Synlett 1993,
85-87. (b) Johasson, C.; Horvath, A.; Backvall, J.-E. J. Am. Chem.
Soc. 2000, 122, 9600-9609. (c) Meguro, M.; Yamamoto, Y. Tetrahedron
Lett. 1998, 39, 5421-5424.
(27) (a) Beak, P.; Lee, W.-K. Tetrahedron Lett. 1989, 30, 1197-1200.
(b) Beak, P.; Lee, W.-K. J. Org. Chem. 1993, 58, 1109-1117. (c) For a
review, see: Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.;
Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552-560.
J. Org. Chem, Vol. 70, No. 6, 2005 2111

Dieter et al.
TABLE 1. Reaction of Propargylic Acetates, Bromides, Mesylates, and Phosphates with Acyclic
r-(N-Carbamoyl)alkylcuprates
a Cuprates were prepared from the carbamates by sequential deprotonation (s-BuLi, TMEDA, or sparteine, THF, -78 °C) and addition
of CuCN‚2LiCl (-55 °C, 45 min). b Equivalents of Cu(I) salt per equivalent of RLi (R ) R-aminoalkyl ligand). c Yields based upon isolated
products purified by column chromatography. Yields in brackets refer to yields obtained from the diphenyl phosphate generated in situ.
d Insoluble CuCN was employed. e Yields determined by NMR.
Although these reaction conditions gave modest yields
of substitution products (Table 1, entry 9), the chemical
yields were often capricious with varying amounts of
starting carbamate recovered from experiment to experi-
ment. Reliable and reproducible yields of R-(N-carbamoyl)
allenes could be obtained via an SN2′-substitution process
when the cuprate reagents were prepared from THF-
soluble CuCN‚2LiCl. The thermal stability of the R-lithio
carbamates and the temperature at which the cuprate
reagent is formed play major roles in the efficiency of
R-(N-carbamoyl)alkylcuprate chemistry.28 Utilization of
soluble forms of Cu(I) salts allows formation of the
cuprate reagent to occur rapidly at -78 °C where the
R-lithio carbamates are thermally stable. When solid
CuCN was employed, a warming-cooling protocol (e.g.,
warming to -50 to -40 °C, stirring for 0.5-1.0 h, and
then cooling to -78 °C before addition of the electrophile)
was used to ensure complete cuprate formation, and
variations in time and temperature from experiment to
experiment gave considerable variation in the chemical
yields of coupled products.
Optimization efforts probed several parameters includ-
ing cuprate composition (e.g., RCuCNLi and R2CuLi‚LiX),
copper(I) salt (e.g., CuX, X ) CN, Cl), leaving group (e.g.,
bromide, mesylate, tosylate, phosphate, acetate), and
R-(N-carbamoyl)alkyl ligands [e.g., acyclic (Table 1) and
cyclic (Table 2) carbamoyl ligands]. A number of general
patterns emerged. Good yields of allenes were obtained
from cuprates prepared from 1 equiv of N-lithiomethyl-
N-methyl carbamate (i.e., 1A-Li) and either CuCl‚2LiCl
(28) (a) Dieter, R. K.; Topping, C. M.; Nice, L. E. J. Org. Chem. 2001,
66, 2302-2311. (b) For a review, see: Dieter, R. K. Heteroatomcuprates
and R-Heteroatomalkylcuprates in Organic Synthesis. In Modern
Organocopper Chemistry; Krause, N., Ed.; John Wiley & Sons: New
York, 2002; pp 79-144.
2112 J. Org. Chem., Vol. 70, No. 6, 2005

Route to R-Amino Allenes and ∆3-Pyrrolines
TABLE 2. Reaction of Propargylic Acetates, Halides, Sulfonates, and Phosphates with Cyclic
r-(N-Carbamoyl)alkylcuprates
a Cuprates were prepared from the carbamates by sequential deprotonation (s-BuLi, TMEDA, or sparteine, THF, -78 °C) and addition
of CuCN‚2LiCl (-55 °C, 45 min). b Equivalents of Cu(I) salt per equivalent of RLi (R ) R-aminoalkyl ligand). c Yields based upon isolated
products purified by column chromatography. d A mixture of regioisomers. e Ratio of SN2:SN2′ (55:45). f In-situ generation and use of the
phosphate was employed.
or CuCN‚2LiCl. The latter reagent gave comparable or
slightly better results (Table 1, entries 1 vs 2-3 and 6
vs 5). Although the reaction of 1 equiv of RLi with CuCl
implies formation of an organocopper(I) reagent (i.e., RCu
+ LiCl) based on stoichiometry, the effectiveness of the
reaction suggests formation of a cuprate reagent (e.g.,
RCuClLi). Because CuCl is significantly more air and
moisture sensitive than CuCN, the latter reagent was
employed throughout the study. Both of these cuprate
reagents (i.e., RCuXLi, X ) CN, Cl) contain only one
R-(N-carbamoyl)alkyl ligand and are more efficient than
the reagent prepared from 2 equiv of RLi and 1 equiv of
CuCN‚2LiCl even though similar chemical yields are
sometimes obtained (Table 1, entry 12 vs 13, Table 2,
entry 1 vs 2). More commonly, however, the dialkylcu-
prate reagent R2CuLi gave yields that were about 10-
30% lower than the RCuCNLi reagent (Table 1 entries 4
vs 5, 7 vs 8, 21 vs 22) when the carbamoylalkyl ligand
was acyclic. Although this was also true for phosphate
10l and the cuprates derived from N,N-dimethyl car-
bamate 1A when the reactions were performed on the
isolated phosphate, reaction of in-situ-generated phos-
phate 10l gave a significantly better yield of allenyl
carbamate 3Al (entry 20). This proved to be a general
phenomenon (Table 1, entries 16, 20, 22, and 23 vs 24;
Table 2, entry 30) reflecting the instability of the isolated
propargyl phosphates. Mixed results were obtained when
the carbamoylalkyl ligand was cyclic. Comparable yields
were obtained when the RCuCNLi and R2CuLi‚LiX
reagents derived from N-Boc pyrrolidine (1B) reacted
J. Org. Chem, Vol. 70, No. 6, 2005 2113

Dieter et al.
with propargyl substrate 6a (Table 2, entries 1 vs 2), and
higher yields were obtained with R2CuLi when substrate
2c was employed (entries 11 vs 12). Significantly lower
yields were obtained with the lithium bis-pyrrolidinyl
cuprate when propargyl substrates 2f, 2i, or 2k (Table
2, entries 16 vs 17, 22 vs 21, and 25 vs 24) were employed.
Although the origin of this effect is unclear, the R2CuLi
reagents become less effective for the pyrrolidinyl cu-
prates as the proparagyl substrate becomes sterically
encumbered (e.g., 2i, k) or electronically modified (e.g.,
2f).
The nature of the leaving group also played a signifi-
cant role in the effectiveness of these substitution reac-
tions. Propargyl bromides and mesylates gave compa-
rable yields (Table 1, entries 2-3 vs 5, Table 2, entries 2
vs 4), while the acetate leaving group gave very poor
yields in all instances (Table 1, entries 14-15, Table 2,
entry 6). With the ineffective acetate leaving group,
significantly lower yields were obtained with R2CuLi than
with RCuCNLi (Table 1, entries 14-15). In one experi-
ment, the tosylate 7a gave a better yield with the bis-
pyrrolidinyl cuprate than bromide 6a or the mesylate 2a
with the pyrrolidinylcyanocuprate reagent (Table 2,
entries 5 vs 1, 4). Reaction of mesylate 2c, tosylate 7c,
chloride 9c, and phosphate 10c with the alkylcyanocu-
prate (i.e., RCuCNLi) derived from the N,N-dimethyl
carbamate 1A gave comparable yields (76%, 67%, 81%,
69%, respectively) of carbamoyl allene 3Ac, suggesting
that all four leaving groups display comparable efficacy
in this substitution reaction.
mic propargyl substrates were employed in these reac-
tions, poor diastereomeric ratios were anticipated. Efforts
are currently underway to effect enantio- and diastereo-
control using enantioenriched stereogenic cuprates and
propargyl substrates where synthetically useful diaster-
eomeric ratios are more likely to be achieved.29
The cuprate reagents generated from N,N-dimethyl
carbamate 1A and N-Boc-pyrrolidine 1B gave the car-
bamoyl allenes regiospecifically for all propargyl sub-
strates except 2d where the 1B-derived cuprate gave a
nearly 1:1 mixture of regioisomers resulting from R-(SN2)
and γ-(SN2′) substitution (Table 2, entry 13). The cuprate
reagent prepared from N-Boc-protected piperidine (1C)
also gave a mixture of regioisomers resulting from attack
at both the R- and the γ-positions of the starting prop-
argyl bromide (6a) (Table 2, entry 3). The piperidinyl-
cuprates did give clean SN2′-substitution with propargyl
substrates 2b,c and 2e,f, although diminished chemical
yields were obtained (Table 2, entries 9, 10, 15, and 18).
Because the cuprate derived from 1A reacted with
propargyl mesylate 2d with clean SN2′-regioselectivity,
formation of propargylamines (SN2-substitution) reflects
steric hindrance in the cuprate reagent or the propargyl
substrate. The overwhelming tendency in the propargyl
systems is for substitution with rearrangement (SN2′) in
contrast to the allylic systems where mixtures are often
encountered.29
In the initial studies, tertiary mesylate 13a as well as
the corresponding chloride 13b (Scheme 3) failed to
undergo any substitution reaction with the cuprate
reagents prepared from either 1A or 1B, reflecting the
difficulty of preparing the mesylate and perhaps the
reactivity of the chloride. Generation of the phosphate
13c in situ and immediate use gave reasonably good
yields of the carbamoyl allenes 16 and 17, respectively,
upon reaction with cuprates derived from 1A,B (Table
1, entry 24; Table 2, entry 30). Similarly, the mesylates
2l-n could not be prepared and isolated, and the isolated
phosphates 10l-n or chloride 9n reacted with the 1A,B-
derived cuprates to give R-carbamoyl allenes in moderate
yields (Table 1, entries 20-22; Table 2, entries 26-28).
The in-situ-generated phosphates thus provide a solution
to tertiary propargyl phosphates and those phosphates
flanked by two unsaturated moieties and hence chemi-
cally unstable to solvolysis.
The variation in chemical yield from experiment to
experiment for the same reaction is difficult to under-
stand. In most instances, the propargyl substrates were
not purified and were used as crude materials. Consider-
ing the possibility that the yields of the cuprate substitu-
tion reactions reflected impurities in the crude mesylates,
a series of control experiments were performed on me-
sylate 2i, which was stable to column chromatography.
Reaction of crude 2i, column purified 2i, and crude 2i
washed several times with NaHCO3 with the RCuCNLi
reagent derived from N-Boc pyrrolidine 1B gave 3Bi in
yields of 61%, 67%, and 67%, respectively. In a number
of instances, the starting mesylate and N-Boc carbamate
were present in the crude product mixtures (30-35%
1
yields) as a 1:1 ratio as determined by H NMR spec-
Propargyl epoxides 14 and 15 also participated in the
substitution reaction but with widely varying yields
(Table 3). Initial experiments employed 5 equiv of TMSCl
(entries 1, 3, 5, and 8), although later experiments
suggested that this was unnecessary (entries 4 and 6).
While the use of Lewis acids30 such as Sc(OTf)3 appeared
to increase the yields of substitution products (entries 2,
7, 9, and 11), good yields were obtained in the reaction
of 14 with both the R2CuLi and the RCuCNLi reagents
derived from 1A (entries 4 and 6) in the absence of Lewis
Acids. Reexamination of 14 with bis-pyrrolidinylcuprate
indicated that good yields of carbamoyl allene 20 could
be obtained without the use of TMSCl or Lewis acids
(entry 10). These allenyl alcohols were acid sensitive but
could be purified on neutral alumina.
troscopy. In some experiments, participation of the sec-
butyl ligand was observed, indicating the presence of
excess sec-BuLi in the initial deprotonation procedure.
As noted before, utilization of in-situ-generated phos-
phates always gave higher yields of carbamoyl allenes
than when isolated phosphates were used, and in one
instance the yield obtained with the isolated mesylate
(40%) was nearly doubled by using the in-situ-generated
phosphate (Table 1, entry 16). Collectively, these results
suggest that better yields will generally be obtained by
utilization of in-situ-generated propargyl phosphates.
Reactions between stereogenic cuprates derived from
N-Boc-pyrrolidine 1B (Table 2, entries 11-14, 16-17,
19-29), N-Boc-piperidine 1C (Table 2, entries 10, 15, 18),
or N-ethyl-N-benzyl carbamate 1D (Table 1, entries 25-
26) and propargyl substrates [2c-k,o, 9n, and 10l,n],
2c,e,f, and 2c,f, respectively, gave mixtures of diaster-
eomers ranging between 50:50 and 60:40 mixtures.
Because racemic stereogenic cuprate reagents and race-
(29) Dieter, R. K.; Gore, V. K.; Chen, N. Org. Lett. 2004, 6, 763-
766.
(30) Lipshutz, B. H.; Sclafani, J. A.; Takanami, T. J. Am. Chem.
Soc. 1998, 120, 4021-4022.
2114 J. Org. Chem., Vol. 70, No. 6, 2005

Route to R-Amino Allenes and ∆3-Pyrrolines
TABLE 3. Reaction of Propargylic Epoxides with
SCHEME 5
r-(N-Carbamoyl)alkylcuprate Reagents
ucts. Treatment of the N-Boc-protected amino allenes
with trimethylsilyltriflate [CH2Cl2, -30 to 25 °C] gave
the free amino allenes in good to excellent yields (Table
4, entries 1-3, 5-7, 10-17, 20, and 21, 62-99%).34
Methanolic HCl generated by addition of TMSCl to
methanol proved to be far more convenient and economi-
cal, affording the amino allenes in nearly quantitative
yields (Scheme 4, Table 4, entries 4-9, 15-20, and 22,
83-95%).35 The tetrasubstituted allene 16 gave oxazoli-
dinones 24 as the major product arising from protonation
of the allene and neighboring group participation of the
carbamate carbonyl (Scheme 5).
a Cuprates were prepared from the carbamates by sequential
deprotonation (s-BuLi, TMEDA, or sparteine, THF, -78 °C) and
addition of CuCN‚2LiCl (-55 °C, 45 min). b Equivalents of CuCN
salt per equivalent of RLi [R ) R-(N-carbamoyl)alkyl ligand].
c Yields based upon isolated products purified by column chroma-
tography. e TMSCl (5 equiv) was employed. f Sc(OTf)3 (5 mol %)
was employed.
SCHEME 4a
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 4, entries 1-12) and annulated
(entries 13-24) pyrrolines. The procedure is very reliable
and appears capable of tolerating a wide range of
substitution patterns (e.g., 2,3-disubstitution in 5Dc and
5Df, entries 10-11). As expected, utilization of racemic
propargyl mesylates and racemic R-(N-carbamoyl)alky-
lcuprates afforded mixtures of diastereomers with little
or no diastereoselectivity. The formation of spiro-fused
pyrrolines (entries 23-24) proved problematic involving
difficulty in the N-Boc deprotection step. The minor free
amino allene from 16 could be cyclized to the spiro
pyrroline 26 (Scheme 5).
Although precedented, the 5-endo-trig-cyclizations of
O-17 and N-heteroatoms16,18c,19 onto allenes is dependent
upon the metal catalyst and reaction conditions. AgNO3
is particularly effective for 5-endo-trig-cyclizations of
R-hydroxy allenes17 and R-amino or protected amino
allenes.19,20 Similar palladium-promoted cyclizations16,20,7b
show greater variations that often depend on the solvent
employed and the functional group containing the het-
eroatom participating in the cyclization. This appears to
reflect the ability of palladium catalysts to form π-allyl
complexes from allenes as well as ligand effects (i.e.,
heteroatom functionality and solvent effects)7b not present
in AgNO3 catalysis. The scope and limitations of these
5-endo-trig-cyclizations is not fully established.
a (a) PhOH, TMSCl, CH2Cl2; (b) I2 (3.0 equiv), CH2Cl2, 0 °C; (c)
Me3SiOTf, CH2Cl2, -30 to 25 °C; (d) MeOH, TMSCl, 25 °C.
Considerable difficulty was encountered in initial ef-
forts to effect N-Boc deprotection of the R-(N-carbamoyl)
allenes. Treatment of these allenyl carbamates with
PhOH/TMSCl31 promoted a 5-exo-trig cyclization of the
tert-butoxycarbonyl moiety onto the allene to afford an
oxazolidinone (Scheme 4, 22). A similar reaction occurred
with I2, affording an oxazolidinone containing a vinyl
iodide moiety (i.e., 23). Cyclization and addition of I2
across the terminal double bond of 3Aa (40-72%) oc-
curred when I2/KI/NaHCO3/H2O/CH2Cl2 was employed.32
33b
The reagents tBuMe2SiOTf33a and Ce(NH4)2(NO3)6
failed to effect N-Boc deprotection, while catechol boron
bromide33c and AlCl333d gave a complex mixture of prod-
Free amino allene 4Ah was employed in an effort to
effect ruthenium-catalyzed carbonylation and cyclization
to afford pyrrolin-2-one 30 (eq 6).36 Treatment of 4Ah
with Ru3(CO)12 at 100 °C and bubbling in carbon mon-
(31) Kaiser, E., Sr.; Picart, F.; Kubiak, T.; Tam, J. P.; Merrifield, R.
B. J. Org. Chem. 1993, 58, 5167-5175.
(32) Wang, Y.-F.; Izawa, T.; Kobayashi, S.; Ohno, M. J. Am. Chem.
Soc. 1982, 104, 6465-6466.
(33) (a) Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870-
876. (b) Hwu, J. R.; Jain, M. L.; Tsay, S.-C.; Hakimelahi, G. H.
Tetrahedron Lett. 1996, 37, 2035-2038. (c) Boeckman, R. K., Jr.;
Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411-1414. (d) Bose, D. S.;
Lakshminarayana, V. Synthesis 1999, 66-68.
(34) Hamada, Y.; Kato, S.; Shioiri, T. Tetrahedron Lett. 1985, 26,
3223-3226.
(35) Bechor, Y.; Falb, E.; Fischer, B.; Wexler, B. A.; Nudelman, A.
Synth. Commun. 1998, 28, 471-474.
J. Org. Chem, Vol. 70, No. 6, 2005 2115

Dieter et al.
TABLE 4. AgNO3 or Ru3(CO)12 Promoted Cyclization of r-Amino Allenes (from N-Boc Deprotection) to ∆3-Pyrrolines
a R-Carbamoyl allene derived from cuprate substitution reaction. b Free R-amino allenes 4 were obtained by N-Boc deprotection of 3
with TMSOTf [CH2Cl2, -30 to 25 °C, 2 h] or with MeOH/TMSCl (yields in parentheses). c Yields are based upon crude products homogeneous
by 1H and 13C NMR measurements. d Yields based upon isolated products purified by flash column chromatography. Yields are for the
AgNO3-mediated cyclization, and those in parentheses are for the Ru3(CO)12 catalyzed cyclization reaction. e Diastereomeric ratios
determined from 1H NMR integration values and/or from 13C NMR peak heights.
oxide gave a good yield of pyrroline 5Ah. Simple treat-
ment of 4Ah with the ruthenium catalyst gave an
excellent yield of pyrroline 5Ah, and modest to good
yields of pyrrolines could be obtained from the R-amino
allenes 4Ac, 4Df, 4Bc, 4Cc, and 4Bf (Table 4, entries 1,
11, 14-16). In general, the AgNO3 method gave better
yields of pyrrolines than the ruthenium-catalyzed pro-
tocol with the exception of amino allene 4Bf. Utilization
of an autoclave with an approximately 1 psi atmosphere
of CO afforded pyrrole 29 again with no incorporation of
CO. Increasing the CO pressure to approximately 50 psi
afforded a mixture of pyrrole 29 and pyrrolin-2-one 30
in a 57:43 ratio in 70% yield. The similar carbonylation
reactions of Takahashi were carried out at a CO pressure
of 150 psi, and these results suggest that the ruthenium-
catalyzed reaction conditions can be adjusted to afford
either pyrroline, pyrrole, or pyrolinone derivatives from
R-amino allenes.
(36) (a) Yoneda, E.; Kaneko, T.; Zhang, S. W.; Onitsuka, K.;
Takahashi, S. Org. Lett. 2000, 2, 441-443. (b) Yoneda, E.; Zhang, S.
W.; Onitsuka, K.; Takahashi, S. Tetrahedron Lett. 2001, 42, 5459-
5461.
2116 J. Org. Chem., Vol. 70, No. 6, 2005

Route to R-Amino Allenes and ∆3-Pyrrolines
dried over MgSO4. Evaporation of the solvent in vacuo afforded
the crude products. Purification was accomplished using flash
column chromatography eluting with 5% EtOAc-95% petro-
leum ether (v/v) to give pure pruduct 3Aa as a colorless oil
(0.352 g, 96%): IR (neat) 2982 (s), 2933 (s), 2254 (w), 1956 (s),
1
1697 (s), 1486 (s), 1387 (s), 1154 (s), 876 (s), 847 (s) cm-1; H
NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.80 (s, 3H), 3.78 (s,
2H), 4.72-4.80 (m, 2H), 4.97-5.09 (m, 1H); 13C NMR (CDCl3,
75 MHz) δ 28.4, 33.8, 47.5, 76.6, 79.4, 86.8, 155.6, 208.8. Anal.
Calcd for C10H17NO2: C, 65.57; H, 9.29; N, 7.65. Found: C,
65.54; H, 9.40; N, 7.57.
2-[(1-Propenylidene)pentyl]-1-pyrrolidinecarboxylic
Acid, 1,1-Dimethylethyl Ester (3Bc). To N-tert-butoxycar-
bonylpyrrolidine (0.342 g, 2.0 mmol) in THF (4 mL) cooled to
-78 °C was added TMEDA (0.33 mL, 2.2 mmol). sec-BuLi (1
M, 2.2 mL, 2.2 mmol) was added by syringe, and the reaction
mixture was allowed to stir for 1 h at -78 °C. A solution of
THF-soluble CuCN‚2LiCl complex [prepared by dissolving
CuCN (0.090 g, 1.0 mmol) and LiCl (0.084 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 slowly
via syringe to the 2-lithio-N-tert-butoxycarbonylpyrrolidine at
-78 °C to form the R2CuLi‚LiCN reagent. The mixture was
allowed to stir for 45 min at -78 °C to generate the cuprate
as a homogeneous solution. A solution of the propargyl
mesylate 2c (0.204 g, 1.0 mmol) [prepared from alcohol 11c
(1.260 g, 10.0 mmol) in dry CH2Cl2 (20 mL) added with Et3N
(1.52 g, 15.0 mmol) and methanesulfonyl chloride (1.38 g, 12.0
mmol) at -40 °C. The reaction mixture was stirred under
nitrogen from -40 °C to room temperature over 2 h, quenched
with saturated NaHCO3 (aq), and extracted by CH2Cl2 (3 ×
10 mL). The combined organic layer was dried over MgSO4
and concentrated under vacuum to afford crude mesylate 2c
(1.99 g, 98%) which was used without further purification]
dissolved in THF (1 mL) was added, and the reaction mixture
was allowed to warm to room temperature over 3 h. The
reaction was quenched with saturated NH4Cl (aq). The mix-
ture was diluted with Et2O, filtered by vacuum through Celite,
the organic phase was separated, and the aqueous phase was
extracted three times with Et2O (10 mL). The combined
organic phases were washed one time with brine and dried
over MgSO4. Evaporation of the solvent in vacuo afforded the
crude product. Purification was accomplished using flash
column chromatography eluting with 5% EtOAc-95% petro-
leum ether (v/v) to give pure 3Bc (0.218 g, 78.0%) as a colorless
oil: IR (neat) 2979 (s), 2877 (shoulder), 1966 (w), 1710 (s), 1470
(s), 1387 (s), 1260 (s), 1174 (s), 1115 (s), 928 (m), 885 (s), 783
Summary
In summary, R-(N-carbamoyl)alkylcuprates undergo a
regioselective SN2′-substitution reaction with propargyl
mesylates and phosphates, and SN2-substitution products
only arise when there is steric hindrance in the cuprate
reagent or the propargyl substrate. The R-[(N-carbamoyl)-
alkyl]cyanocuprates (RCuCNLi) are generally more ef-
fective than the lithium bis-R-(N-carbamoyl)alkylcuprates
(R2CuLi), although the latter reagents occasionally pro-
vide better results with sterically hindered substrates.
Formation of the proparyl phosphate in situ affords a
useful protocol for preparation of tertiary and allylic or
benzylic propargyl phosphates, which are often unstable
to isolation and purification, and this is likely to be a
general procedure that will give higher yields even for
those cases where the mesylate can be isolated. The
resulting carbamoyl allenes can be easily deprotected to
the free R-amino allenes in all cases except the tetra-
substituted allenes where formation of oxazolidinones
occurs via participation of the carbamate moiety. Cy-
clization to pyrrolines is achieved in good to excellent
yields with AgNO3, and a wide array of substituted
pyrrolines is available via this three-step procedure. The
ready availability of enantioenriched propargyl alcohols
should afford a convenient route to enantioenriched
pyrrolines, and this methodology is currently under
investigation. Preliminary results with ruthenium cata-
lysts suggest that reaction conditions may be adjusted
to afford synthetic routes to pyrrolines, pyrroles, or
pyrrolinones from R-amino allenes.
1
(s) cm-1; H NMR (CDCl3, 300 MHz) δ 0.85 (t, J ) 6.70-6.87
Hz, 3H), 1.20-1.50 (m, 4H), 1.41 (s, 9H) (1.40), 1.57 (d, J )
6.85 Hz, 3H), 1.68-2.00 (m, 6H), 3.17-3.41 (m, 2H), 3.96-
4.24 (m, 1H), 5.00-5.21 (m, 1H) (rotamer and/or diastereomer);
13C NMR (CDCl3, 75 MHz) δ 13.9, 14.6, 22.4, 23.2, 28.5, 29.2,
29.8, 31.1, 45.8, 58.8 (59.3), 78.7, 88.8 (88.6), 106.3, 154.3, 200.1
(rotamer and/or diastereomer); mass spectrum m/z (relative
intensity) EI 223 (18, M+ - C4H8), 222 (5, M+ - C4H9), 194
(10), 170 (7, M+ - C8H13), 114 (100), 70 (81, C4H8N+), 57 (69,
C4H9+). Anal. Calcd for C17H29NO2: C, 73.07; H, 10.46; N, 5.01.
Found: C, 73.30; H, 10.57; N, 5.15.
Experimental Section
Carbamic Acid, [2,3-Butadienyl]methyl, 1,1-Dimeth-
ylethyl Ester (3Aa). To the solution of N-tert-butoxycarbonyl
N,N-dimethylamine (0.290 g, 2.0 mmol) in THF (4 mL) was
added TMEDA (0.330 mL, 2.2 mmol) at -78 °C under argon.
sec-BuLi (1 M, 2.2 mL, 2.2 mmol) was added dropwise by
syringe, and the reaction mixture was allowed to stir for 1 h
at -78 °C. A solution of THF-soluble CuCN‚2LiCl complex
[prepared by dissolving CuCN (0.180 g, 2.0 mmol) and LiCl
(0.168 g, 4.0 mmol); LiCl was flamed dried under vacuum prior
to use and purged with argon] in THF (2 mL) at room
temperature was added slowly via syringe to the 2-lithio-N-
Boc N,N-dimethylamine at -78 °C to form the RCuCNLi
reagent. The mixture was allowed to stir for 45 min at -78
°C to generate the cuprate as a homogeneous solution. A
solution of propargyl bromide (0.238 g, 2.0 mmol) dissolved in
THF (1 mL) was added, and the reaction mixture was allowed
to warm to room temperature over 3 h. The reaction mixture
was quenched with saturated NH4Cl (aq). The mixture was
diluted with Et2O, filtered by vacuum through a thin layer of
Celite, the organic phase was separated, and the aqueous
phase was extracted three times with Et2O (5 mL). The
combined organic phases were washed one time with brine and
2-(1-Phenyl-1,2-butadienyl)pyrrolidine (4Bf). To a solu-
tion of N-Boc-protected amino allene 3Bf (0.301 g, 1.0 mmol)
in MeOH (5.0 mL) was added TMSCl (0.540 g, 5.0 mmol) via
syringe at 25 ïC. Stirring was continued at room temperature
for 12 h. The reaction mixture was then 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, concentrated under vacuum to afford
crude product 4Bf (0.190 g, 95%), which was pure by both 1H
and 13C NMR analysis: IR (neat) 3058 (m), 3024 (m), 2962
(s), 2968 (s), 1949 (m), 1587 (m), 1450 (s), 1287 (s), 1259 (s),
1
732 (s), 639 (s); H NMR (CDCl3, 300 MHz) δ 1.52-2.01 (m,
6H), 2.73-3.02 (m, 3H), 4.05 (s, 1H), 5.11-5.21 (m, 1H), 5.46-
J. Org. Chem, Vol. 70, No. 6, 2005 2117

Dieter et al.
5.63 (m, 1H), 7.12-7.49 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ
14.4 (14.6), 25.2 (25.3), 31.7 (31.9), 46.4 (46.5), 57.1 (57.3), 91.8
(92.0), 109.3 (109.5), 126.6 (126.7), 126.8 (126.9), 128.5, 136.2
(136.3), 202.2 (202.4) (diasteromers, 39/61); mass spectrum m/z
(relative intensity), EI 200 (7, M+ + 1), 199 (41, M+), 184 (100),
170 (44), 156 (28), 128 (17), 115 (16), 77 (10), 51 (7).
Alternatively, to a solution of N-Boc-protected amino allene
3Bf (0.939 g, 3.14 mmol) in CH2Cl2 (10 mL) was added
TMSOTf (0.74 mL, 4.07 mmol) via syringe at -40 °C. The
reaction mixture was slowly warmed to room temperature over
3 h. The reaction mixture was washed with saturated K2CO3
(aq). The organic phase was separated, and the aqueous phase
was extracted with CH2Cl2 (3 × 10 mL). The combined organic
extractions were dried over MgSO4, concentrated under vacuum
to afford crude product 4Bf (0.570 g, 91%).
1-Methyl-3-isopropyl-4-phenyl-2,5-dihydro-1H-pyr-
role (5Ah). Crude amino allene 4Ah (0.135 g, 0.67 mmol) was
dissolved in technical grade acetone (from drum, without
further purification), followed by 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 for
12 h (flask was wrapped with aluminum foil). The reaction
mixture was then diluted with Et2O, filtered through a thin
layer of Celite, and concentrated under vacuum to afford crude
product 5Ah which was purified by flash chromatography
(silica gel, 100% diethyl ether as eluent) to give a colorless oil
(0.094 g, 70%): IR 2960 (s), 2868 (s), 2774 (s), 1496 (s), 1467
(s), 1452 (s), 1387 (s), 1357 (m), 912 (s), 740 (s); 1H NMR
(CDCl3, 300 MHz) δ 0.93 (d, J ) 6.7 Hz, 3H), 1.03 (d, J ) 6.9
Hz, 3H), 1.72-1.88 (m, 1H), 2.54 (s, 3H), 3.31-3.42 (m, 1H),
3.57-3.65 (m, 1H), 4.21-4.32 (m, 1H), 6.08 (d, J ) 1.5 Hz,
1H), 7.24-7.44 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 18.0,
19.9, 31.9, 43.0, 63.4, 79.6, 123.6, 125.4, 127.4, 128.4, 134.4,
138.9; mass spectrum m/z (relative intensity) EI 201 (2, M+),
200 (6, M+ - 1), 199 (32, M+ - 2), 184 (97), 158 (100), 143
(19), 128 (11), 115 (17), 91 (99), 77 (98), 51 (7). Anal. Calcd for
C14H19N: C, 83.58; H, 9.45. Found: C, 83.31; H, 9.65.
(CDCl3, 75 MHz) δ 14.0, 22.2, 26.2, 27.7, 28.4, 29.7, 29.8, 31.9,
33.5, 51.5 (51.0), 79.0, 98.1, 104.6, 155.7, 195.2; mass spectrum
m/z (relative intensity) EI 307 (M+, 0.05), 251 (30), 234 (8),
206 (6), 178 (9), 163 (13), 134 (35), 88 (22), 57 (100).
2-[1-[(2-Hydroxycyclohexylidene)methylene]pentyl]-
1-pyrrolidinecarboxylic Acid, 1,1-Dimethylethyl Ester
(20). To N-tert-butoxycarbonylpyrrolidine (0.171 g, 1.0 mmol)
in THF (2 mL) cooled to -78 °C was added (-)-sparteine (0.280
g, 1.2 mmol). sec-BuLi (1 M, 1.1 mmol) was added by syringe,
and the mixture was allowed to stir for 1 h at -78 °C. A light-
green solution of THF-soluble CuCN‚2LiCl complex [prepared
by dissolving CuCN (0.090 g, 1 mmol) and LiCl (0.084 g, 2
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-pyrrolidine (clear to
pale yellow) at -78 °C. The mixture was stirred at -78 °C for
0.5 to 1 h to generate the RCuCNLi cuprate as a clear to light-
yellow homogeneous solution. Next, 0.049 g, 0.10 mmol of Sc-
(OTf)3 was added to the resultant cuprate, and the solution
was stirred at -50 °C for 10 min. A solution of 1-hexynyl-7-
oxabicyclo [4.1.0] heptane (0.178 g, 1.0 mmol) dissolved in
ether (1 mL) was added, and the reaction mixture was stirred
at -50 °C for 1 h. The reaction was quenched with saturated
NH4Cl (aq). The mixture was further diluted with Et2O and
filtered by vacuum through Celite. The organic phase was
separated, and the aqueous phase was extracted three times
with Et2O. The crude product was obtained, and purification
by column chromatography eluting with 10% EtOAc-90%
petroleum ether (v/v) solvent mixture gave pure 20 (0.161 g,
46 % yield): IR (neat) 3437 (broad), 2939 (s), 2867 (shoulder),
1966 (w), 1685 (s), 1411 (s), 1267 (s), 1186 (s), 1114 (s), 1043
1
(s), 1018 (s), 921 (m), 849 (s), 737 (s) cm-1; H NMR (CDCl3,
300 MHz) δ 0.82 (t, J ) 7.1 Hz, 3H), 1.09-1.55 (m, 8H), 1.38
(s, 9H), 1.57-1.98 (m, 9H), 2.00-2.14 (m, 1H), 2.15-2.32 (m,
1H), 3.10-3.35 (m, 2H), 3.71-3.85 (m, 1H) (3.85-3.96), 4.07
(br d, J ) 4.07 Hz, 1H) (rotamers and/or diastereomer); 13C
NMR (CDCl3, 75 MHz) δ 13.9 (13.8), 22.3 (22.1), 22.9 (23.7),
24.5, 27.1 (26.9), 28.3, 29.3 (29.5), 29.8 (2C) (29.9), 30.3 (30.9),
35.5, 46.3 (45.8), 59.1 (59.5), 69.0 (68.6), 79.2 (79.9), 109.3,
112.2 (112.0), 154.9 (154.0), 189.7 (rotamer and/or diastere-
omer); mass spectrum m/z (relative intensity) EI 293 (1, M+
- C4H8), 275 (10), 258 (2), 218 (30), 188 (4), 162 (9), 114 (86),
91 (12), 70 (100), 57 (62, C4H9+).
Carbamic Acid, [2-[(Cyclohexylidene)methylene]hexyl]-
methyl-, 1,1-Dimethylethyl Ester (16). To N-tert-butoxy-
carbonyl-N,N-dimethylamine (0.145 g, 1.0 mmol) in THF (2
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
mmol) and LiCl (0.0840 g, 2 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-pyrrolidine at -78 °C. The mixture was allowed to stir
at -78 °C for 45 min to generate a clear homogeneous solution
of the RCuCNLi reagent. A crude sample of propargyl phos-
phate 13c was added dropwise [prepared in situ from alcohol
12 (0.180 g, 1 mmol) in 3 mL of THF at -78 °C by addition of
LDA (prepared from diisopropylamine 0.202 g, 2.0 mmol) and
n-BuLi (2 M, 0.75 mL, 1.5 mmol) in THF at -40 °C for 1 h) or
alternatively n-BuLi (2 M, 0.6 mL, 1.2 mmol) followed by the
addition of diphenyl chlorophosphate (0.403 g, 1.5 mmol) and
stirring for 1 h at -40 °C, and then at 0 °C for another hour]
whereupon the reaction mixture was allowed to warm to room
temperature over a 3 h period. The reaction was quenched with
saturated NH4Cl (aq). The mixture was diluted with Et2O,
filtered by vacuum through Celite, the organic phase was
separated, and the aqueous phase was extracted three times
with 10 mL of Et2O. The combined organic phases were
washed one time with brine and dried over MgSO4. Evapora-
tion of the solvent in vacuo afforded product. Purification was
accomplished using flash column chromatography eluting with
5% EtOAc-95% petroleum ether (v/v) to give 16 (0.221 g,
72%): IR (neat) 2923 (s), 2852 (m), 1700 (s), 1481 (w), 1448
(m), 1383 (s), 1361 (m), 1235 (m), 1181 (m), 1137 (m), 880 (w),
5-Butyl-5-[(E)-1-propenyl)-3-methyl-2-oxazolidinone
(22). A solution of 1 M TMSCl (6.23 mL, 49.1 mmol) in CH2-
Cl2 and 4 M phenol (13.9 g, 148 mmol) in CH2Cl2 was stirred
under a nitrogen atmosphere at room temperature for 20 min.
This solution was added by syringe to N-Boc allene 3Ac (0.84
g, 3.32 mmol) in CH2Cl2 at room temperature and stirred for
12 h. The reaction mixture was washed three times with 10
mL of 10% NaOH, and then the organic layer was dried over
MgSO4. The solvent was evaporated in vacuo and afforded 22.
Purification was accomplished using column chromatography
eluting with 10% EtOAc-90% petroleum ether (v/v) mixture
of solvent to give 22 (0.496 g, 76%): 1H NMR (CDCl3, 300 MHz)
δ 0.79 (t, J ) 6.9 Hz, 3H), 1.08-1.40 (m, 4H), 1.51-1.76 (m,
2H), 1.62 (d, J ) 6.5 Hz, 3H), 2.76 (2.78) (s, 3H), 3.31 [center
of AB quartet, JAB ) 8.4, ∆υ ) 42 Hz, δA ) 3.24, δB ) 3.38,
2H], 5.36 (d, J ) 13 Hz, 1H), 5.66 (dq, J ) 13.0 Hz, J ) 6.6
Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.7 (14.3), 17.4, 22.5,
25.1, 30.7 (30.6), 39.2 (40.2), 56.8 (58.0), 80.0 (80.9), 125.5
(126.9), 131.4 (131.9), 157.7 (157.5).
3-Isobutyl-1,5-dihydro-1-methyl-4-phenyl-(2H)-pyrrol-
2-one (30). Amino allene 4Ah (0.065 g, 0.32 mmol) was
dissolved in 1,4-dioxane (10 mL) in an autoclave (100 mL),
followed by Et3N (0.07 mL, 0.48 mmol) and Ru3(CO)12 (0.002
g). The autoclave was sealed, evacuated under vacuum, and
flushed with CO three times (directly from CO tank regulator,
50 PSI maximum). The autoclave was heated with a heating
tape to 100 °C overnight. The reaction mixture was cooled to
room temperature and transferred to a flask. The solvent was
removed under vacuum to afford the crude product, which was
1
766 (w) cm-1; H NMR (CDCl3, 300 MHz) δ 0.88 (t, J ) 6.3
Hz, 3H), 1.44 (s, 9H), 1.25-1.75 (m, 13H), 1.84 (t, J ) 7.2 Hz,
1H), 2.06 (2.07) (s, 2H), 2.79 (s, 3H), 3.71 (br s, 2H); 13C NMR
2118 J. Org. Chem., Vol. 70, No. 6, 2005

Route to R-Amino Allenes and ∆3-Pyrrolines
purified by flash chromatography (silica gel, ether/petroleum
ether, 1/1, v/v) to afford pyrrole 29 0.025 g (40%) and lactam
30 0.019 g (25%). Lactam 30: 1H NMR (CDCl3, 300 MHz) δ
0.79 (d, J ) 6.9 Hz, 6H), 1.92-2.04 (m, 1H), 2.35 (d, J ) 7.3
Hz, 2H), 3.04 (s, 3H), 4.08 (s, 2H), 7.27-7.38 (m, 5H); 13C NMR
(CDCl3, 75 MHz) δ 22.7, 22.8, 27.5, 29.3, 33.5, 54.7, 127.3,
127.4, 128.7, 133.8, 134.2, 146.8, 172.4; mass spectrum m/z
(relative intensity) EI 230 (12, M+ + 1), 229 (73, M+), 228 (54),
214 (27), 187 (100), 186 (71), 172 (47), 158 (13), 144 (12), 128
(24), 115 (18), 91 (8), 77 (10).
MHz NMR instrument is gratefully acknowledged (CHE-
9700278). We thank Dr. Rajesh Goswami for preparing
a sample of 5Ac.
Supporting Information Available: General experimen-
tal information, materials, and data reduction for 3A(b-j, l,
m), 3B(a, b, d-l, n, o), 3C(a-c, e, f), 3D(a, c, f), 4A(c-e,
g-j, l, m), 4B(a, c, g-j, l), 4C(c, f), 4D(a, c, f), 5A(c-e, g, i,
j, l, m), 5B(a, c, f-j, l), 5C(c, f), 5D(a, c, f), 17-19, 21, 23-
26, and 13C NMR spectra for 3A(d, g-j, l, m), 3B(b, g-l, n,
o), 3C(a, c, f), 3D(a, c, f), 4A(c, e, g-j, l, m), 4B(a, g-i, l),
4C(c, f), 4D(a, c, f), 5A(c-e, g), 5B(a, f-j), 5C(c, f), 5D(a, c,
f), 16, 17, 19, 20, 22, 23. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was generously sup-
ported by the National Science Foundation (CHE-
9408912 and CHE-0132539) and the National Institutes
of Health (GM-60300-01). Support of the NSF Chemical
Instrumentation Program for purchase of a JEOL 500
JO0481405
J. Org. Chem, Vol. 70, No. 6, 2005 2119