Acylation of α-(N-carbamoyl)alkylcuprates and alkyl- or aryl(halo)cuprates

Article abstract of DOI:10.1016/S0040-4020(02)01526-0

α-(N-Carbamoyl)alkylcuprates [R₂CuLi·LiX or RCuXLi (X=CN, Cl)] when prepared from THF soluble CuX·2LiCl (X=Cl, CN) undergo a reliable and generally high yield reaction with aroyl, alkanoyl, and alkenoyl chlorides to provide a rapid and efficient synthesis of α-carbamoyl ketones. Cuprates prepared from acyclic, cyclic, and a functionalized carbamate can be utilized. Although yields are a function of cuprate reagent and substrate structure, nearly quantitative yields can be obtained with reagents generated from 2RLi+CuCN·2LiCl. The use of reagents generated from CuCl·2LiCl are more efficient in the α-(N-carbamoyl)alkyl ligand, although yields are slightly lower. Acylation of alkyl(chloro)cuprates generated from one equivalent of CuCl·2LiCl and organolithium or Grignard reagents provides an efficient and high yield procedure for ketone synthesis.

Full text of DOI:10.1016/S0040-4020(02)01526-0

Tetrahedron 59 (2003) 1083–1094
Acylation of a-(N-carbamoyl)alkylcuprates
and alkyl- or aryl(halo)cuprates
*
R. Karl Dieter, Ram R. Sharma, Huayun Yu and Vinayak K. Gore
Hunter Laboratory, Department of Chemistry, Clemson University, Clemson, SC 29634-0973, USA
Received 31 July 2002; revised 25 November 2002; accepted 26 November 2002
Abstract—a-(N-Carbamoyl)alkylcuprates [R2CuLi·LiX or RCuXLi (X¼CN, Cl)] when prepared from THF soluble CuX·2LiCl (X¼Cl, CN)
undergo a reliable and generally high yield reaction with aroyl, alkanoyl, and alkenoyl chlorides to provide a rapid and efficient synthesis of
a-carbamoyl ketones. Cuprates prepared from acyclic, cyclic, and a functionalized carbamate can be utilized. Although yields are a function
of cuprate reagent and substrate structure, nearly quantitative yields can be obtained with reagents generated from 2RLiþCuCN·2LiCl. The
use of reagents generated from CuCl·2LiCl are more efficient in the a-(N-carbamoyl)alkyl ligand, although yields are slightly lower.
Acylation of alkyl(chloro)cuprates generated from one equivalent of CuCl·2LiCl and organolithium or Grignard reagents provides an
efficient and high yield procedure for ketone synthesis. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
derivatives (Weinreb amides,10b,c,15 thiol esters,10a,16
esters,17 imidazolides18 and esters derived from 2-chloro-
4,6-dimethoxy[1,3,5]triazine19) with organometallic
reagents provide particularly convenient procedures (Eq.
(1)). The former route offers opportunities for catalytic
asymmetric aziridination14c while the latter routes can
exploit the chiral pool. 2-Acylpyrrolidines and piperidines
have been prepared by bis-alkylation of N-Boc a-amino
ketones with dihalides (Eq. (2)).11 They have also been
prepared by the reaction of a-aminoalkyllithium reagents
with aldehydes followed by oxidation with the Dess–Martin
reagent.20 The present method reverses the nucleophile/
electrophile components used in the coupling process
reacting carbon nucleophiles containing an a-carbamoyl
group with acid chlorides.
The chemistry and reactivity of organometallic reagents has
often been probed by reaction with acid chlorides and the
long history of the reaction mirrors the development of
organometallic chemistry.1 Gilman first reported the acyla-
tion of an organocopper reagent2 in 1936 and this was
followed by Whitesides utilization of lithium dialkylcup-
rates3 in 1967. Shortly thereafter, Posner and Riviere
developed the reaction for the preparation of ketones.4
Despite its apparent simplicity, successful high yield
acylation of organocuprates often required the use of 2–
3 equiv. of the copper reagents, although improvements
were achieved by use of mixed phenylthio heteroatom
cuprates containing a non-transferable ligand.5 Several
groups have recently reported that organocopper species
prepared from Grignard or organolithium reagents and
1 equiv. of CuX·2LiX undergo efficient acylation with acid
chlorides in good to excellent yields.6–8 In this full account,
we report on the acylation of a-(N-carbamoyl)alkylcuprates
which provides a rapid synthetic entry to protected a-amino
ketones.8
a-Amino ketones9 and their nitrogen protected derivatives
are important intermediates for the synthesis of nitrogen
heterocycles,10 physiologically active ethanolamine deriva-
tives11,12 and peptidyl compounds.13 Although numerous
synthetic routes to these compounds exist, the aziridination
of enol ethers14 and the reaction of a-amino acids and their
ð1Þ
ð2Þ
Keywords: acylation; deprotonation; aryl cuprates; a-(N-
carbamoyl)alkylcuprates.
*
Corresponding author. Tel.: 8646565025; fax: 864656613;
e-mail: dieterr@Clemson.edu
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01526-0

1084
R. K. Dieter et al. / Tetrahedron 59 (2003) 1083–1094
2. Results and discussion
increase in the series CuCl.CuBr.CuI and has been
attributed to a rate acceleration in the reductive elimination
with increasing electronegativity of the ligands on the
transition metal.24 Recent mechanistic investigations
suggest that reductive elimination is the rate determining
step in conjugate addition reactions.25 Nevertheless, this
difference between CuCl and CuCN was not observed in the
reactions of simple alkyl or aryl cuprates with acid chlorides
(vide infra, Table 3).
The a-(N-carbamoyl)alkylcuprates were prepared by
sequential deprotonation21 of carbamates 1a–c followed
by addition of a THF solution of CuX·2LiCl (X¼CN, Cl).
Solid CuCN was employed in the initial efforts to effect
acylation of a-(N-carbamoyl)alkylcuprates and variable and
capricious yields of a-carbamoyl ketones were obtained.22
The dialkylcuprate or alkylcyanocuprate (i.e. RCuCNLi)
derived from 1a gave poor to modest yields upon reaction
with benzoyl (25 and 40%, respectively) or propionyl
chloride (R2CuLi, 46%) while the dialkylcuprate derived
from 1b fared better (57–77%) with propionyl chloride. A
subsequent investigation of a-(N-carbamoyl)alkylcuprate
preparation and reactivity found that good yields of
vinylation products could be obtained if a careful and
rigid warming and cooling protocol was followed to insure
complete formation of the cuprate reagent.23 Utilization of
THF soluble CuX·2LiCl permits rapid cuprate formation at
2788C thereby avoiding the necessity of using higher
reaction temperatures with the thermally unstable a-lithio
carbamates.23 This study also showed that commercial
samples of s-BuLi containing particulates (presumably LiH)
are not lethal to the reaction, although yields are diminished.
Treatment of the cuprate solutions in THF with the acid
chlorides [neat addition, 278 to 258C, 4 h] followed by
quenching with saturated ammonium chloride afforded the
corresponding a-carbamoyl ketones (Scheme 1).
Cuprates derived from 1a and 1b give comparable yields of
a-carbamoyl ketones with simple alkanoyl chlorides
(entries 1–3 vs 17–20, 5, 6 vs 21, 7, 8 vs 22, 23, and 9,
10 vs 24–26), although those derived from 1a give low to
modest yields with acid chlorides containing electron
withdrawing substitutents at the a-position and/or easily
enolizable substrates (entries 11, 12 vs 28 and 13 and 16).
Functionalized ketones 5 and 13 were obtained in modest
yields as previously reported, although the structures were
incorrectly drawn in the preliminary communication.8 The
notoriously difficult a-chloro acetyl chloride26 derived
ketone (10) is obtain in modest yield with the 1a derived
cuprate reagent (entry 16). The cuprates derived from 1b
give good yields with a variety of functionalized alkanoyl
acid chlorides (entries 17–29), although a low yield was
obtained with the easily enolizable ethyl 3-chloro-3-
oxopropionate (entry 30). These results are consistent with
the generally lower reactivity of primary alkylcuprate
reagents compared to secondary alkylcuprate reagents. A
cuprate reagent derived from 1c gave a modest yield of a-
carbamoyl ketone when reacted with pivaloyl chloride
(entry 31) and may reflect either the difficulty of
deprotonating N-Boc piperidine21 or the increased steric
factors in piperdinylcuprate reagents. Acylation of the
cuprate derived from 1b with methyl 4-chloro-4-oxobuty-
rate gave 15 in good yields (entry 27) which could provide a
potential route to indolizidinones. Conditions for the
cyclization of 15 or the N-Boc deprotected pyrrolidinium
salts to the indolizidine carbon skeleton, however, were not
found. The salts were readily obtained by treatment of 15
with PhOH/TMSCl (25%), CF3COOH (80%) or CF3SO2H
(85%) in CH2Cl2. The reaction with ethyl oxalyl chloride
provides a simple synthesis of b-N-carbamoyl-a-keto esters
(i.e. 17) employed in the preparation of a-diketones of
interest as enzyme inhibitors.27 The current methodology
could potentially lead to the a-diketones directly via
acylation of a-(N-carbamoyl)alkylcuprates with a-keto
acid chlorides.
Reaction of a-(N-carbamoyl)alkylcuprates with alkanoyl
acid chlorides afforded a-carbamoyl ketones in variable
yields depending upon the cuprate reagent and substrate
structure (Table 1). The highest yields were obtained with
lithium dialkylcuprates (e.g. R2CuLi) and diminished with
utilization of alkylcyanocuprate reagents (i.e. RCuCNLi,
Table 1, entries 1 vs 2, 12 vs 11, 17 and 18 vs 19). The
reagent prepared from CuCl (1.0 equiv.) generally gave
higher yields than the cyanocuprate reagent (3 vs 2, 20 vs
19), although the dialkylcuprates gave slightly higher
yields, in one instance, when prepared from CuCN rather
than CuCl (entries 24 vs 25). Although copper reagents
prepared from CuCl (1.0 equiv.) gave good yields of a-
carbamoyl ketones (i.e. 62–96%), higher yields were again
obtained with dialkylcuprates derived from CuCl (entries 25
vs. 26). These results suggest that the use of one equivalent
of CuCl gives rise to a chlorocuprate reagent (i.e. RCuClLi)
that is more reactive than the cyanocuprate reagent
RCuCNLi.23 This is consistent with the observation that
the coupling of allylic substrates with organocuprates
The reaction of organocuprate reagents with alkenoyl
chlorides is potentially fraught with chemoselectivity
problems since the product a,b-enones can
undergo conjugate addition reactions with the cuprate
reagent.4b,26,28 The reaction of a-(N-carbamoyl)alkylcup-
rates derived from 1a, b with alkenoyl chlorides gave
modest to good yields of a0-carbamoyl-a,b-enones (Table
2). Slightly lower yields of a-carbamoyl ketones were
obtained from the primary alkylcuprate derived from 1a
than from the secondary alkylcuprate derived from 1b
(entries 1, 2 vs 6, and 3 vs 8). Again, the dialkylcuprate
reagents gave higher yields than monoalkylcuprate reagents
(entries 5 vs 6 and 7 vs 8). b,b-Di-unsubstituted alkenoyl
chlorides or thiol esters gave very low yields of
Scheme 1. Acylation of a-(N-carbamoyl)alkycuprates

R. K. Dieter et al. / Tetrahedron 59 (2003) 1083–1094
Table 1. Acylation of a-(N-carbomoyl)alkyl copper and cuprate reagents
1085
Entry
Boca amine
acid chloride RCOCl
Et
CuX·2LiCl X (equiv.)b
Product
%c yield
1
2
3
1a
1a
1a
CN (0.5)
CN (1.0)
Cl (1.0)
98d
55
85d
4
1a
Med
CN (1.0)
81e
5
6
1a
1a
tBu
tBu
Cl (1.0)
Cl (1.0)
96f
95
7
8
1a
1a
Cl(CH2)3–
Cl(CH2)3-
Cl (1.0)
Cl (1.0)
68f
63
9
10
1a
1a
Ph
CN (0.5)
Cl (1.0)
100
73d
11
12
1a
1a
CN (1.0)
CN (0.5)
25
44
13
1a
EtO2CCH2–
CN (1.0)
31
14
15
1a
1a
MeO2C(CH2)2–
CN (1.0)
CN (0.5)
42
42
16
1a
ClCH2
Et
Cl (1.0)
41
17
18
19
20
1b
1b
1b
1b
CN (0.5)
CN (0.5)
CN (1.0)
Cl (1.0)
100
91f
55
70d
21
1b
tBu
Cl (1.0)
88
22
23
1b
1b
Cl(CH2)3
Cl(CH2)3
Cl (1.0)
Cl (1.0)
62
52f
24
25
26
1b
1b
1b
Ph
CN (0.5)
Cl (0.5)
Cl (1.0)
100
89–93
62d–65
27
1b
MeO2C(CH2)2
Cl (1.0)
74
28
29
1b
1b
CN (1.0)
Cl (1.0)
77
76
MeO2C
(continued on next page)

1086
R. K. Dieter et al. / Tetrahedron 59 (2003) 1083–1094
Table 1 (continued)
Entry
Boca amine
acid chloride RCOCl
CH2CO2Et
CuX·2LiCl X (equiv.)b
CN (1.0)
Product
%c yield
18
30
1b
31
1c
tBu
CN (1.0)
45
a
The carbamate was deprotonated [sec-BuLi, THF, (2)-sparteine unless noted, 2788C, 1–2 h] and added to the Cu(I) salt at 2508C unless noted.
Equivalents of Cu(I) relative to RLi.
Yields are based upon purified isolated products unless otherwise noted.
Cuprate was formed at 2788C followed by addition of acid chloride after 15–20 min. at 2788C.
Acyl bromide was employed.
b
c
d
e
f
TMEDA was used to facilitate deprotonation.
a0-carbamoyl-a,b-enones. Reaction of the alkylcyanocup-
allylic cuprate reagents29and the difficulty of deprotonating
N-Boc encarbamates.30 Although Martin30 found that
employing the N-2,4,6-triisopropylbenzenesulfonyl (Trs)
protecting group for 2,3-dihydropyrrole permitted facile
deprotonation and cuprate formation, we were unable to
effect acylation of the cuprate reagent. A cuprate reagent
derived from a N-Boc protected 4,4-dimethyloxazolidine
was successfully acylated with benzoyl chloride in 70%
yield (Eq. (3)). The acylation of a-(N-carbamoyl)alkyl-
cuprates derived from scalemic oxazolidines would provide
a rapid access to 2-acyloxazolidines31a which have been
employed in an asymmetric synthesis of scalemic a-
hydroxy aldehydes.31
rate (i.e. RCuCNLi) derived from 1b with methacryloyl
chloride gave low yields of the ketone (14%) while reaction
of the R2CuLi reagent with the corresponding phenylthiol
ester gave only the homocoupling product of the 2-
pyrrolidinyl ligand (28%). The procedure could also not
be usefully extended to a,b-alkynoyl chlorides as the a0-
carbamoyl-a,b-ynones were obtained in low yields. TLC
analysis indicated the formation of many products and the
failure of these reactions appears to reflect the greater
reactivity of the product alkynones under the reaction
conditions.
Extension of the method to more complex carbamates and
acid chlorides was briefly examined. a-(N-carbamoyl)alk-
ylcuprates were not acylated by chloroformates (e.g. ethyl
or phenyl) or anhydrides (e.g. succinic or maleic). Cuprates
derived from N-Boc 1,2,3,6-tetrahydropyridine or 1,2,3,4-
tetrahydropyridine were not successfully acylated with
propionyl chloride reflecting the problematic nature of
ð3Þ
Table 2. Acylation of a-(N-carbamoyl)alkylcuprate reagents with a,b-alkenoyl chlorides
Entry
Boc aminea
Acid chloride RCOCl
CuX·2LiCl X (equiv.)b
Product
%c Yield
1
2
1a
1a
MeCHvCH
MeCHvCH
Cl (1.0)
Cl (1.0)
55
50d
3
1a
Me2CvCH
Cl (1.0)
46–53
4
5
6
1b
1b
1b
MeCHvCH
MeCHvCH
MeCHvCH
CN (0.5)
Cl (0.5)
Cl (1.0)
70–84
84–91
60
7
8
9
1b
1b
1b
Me2CvCH
Me2CvCH
Me2CvCH
CN (0.5)
Cl (1.0)
Cl (1.0)
99
50–57
75e
a
The carbamate was deprotonated [sec-BuLi, THF, (2)-sparteine unless noted, 2788C, 1–2 h] and added to the Cu(I) salt at 2508C unless noted.
Equivalents of Cu(I) relative to RLi.
Yields are based upon purified isolated products unless otherwise noted.
Cuprate was formed at 2788C followed by addition of acid chloride after 15–20 min at 2788C.
TMEDA was used to facilitate deprotonation.
b
c
d
e

R. K. Dieter et al. / Tetrahedron 59 (2003) 1083–1094
1087
The reaction of a-(N-carbamoyl)alkylcuprates with bis-acid
chlorides was briefly examined since the resultant N-
heterocycles linked by various spacers could provide
monomer precursors for novel polymers. The reaction of
the cuprate derived from 1b with terephthaloyl chloride
afforded the diketone in modest yields (i.e. 45%) that
decreased with increasing reaction times (i.e. 30–34%) (Eq.
(4)). Slightly higher yields could be achieved using 1 equiv.
of CuBr·LiBr6,7 or CuCl·2LiCl. A significant amount (20–
30%) of starting carbamate 1b was generally recovered. The
corresponding bis phenylthiol ester of terephthalic acid gave
comparable yields of 26a with various cuprates [RCuCNLi
(60%), R2CuLi·LiCN (66%), RCuBrLi (53%)] derived from
CuCN·2LiCl or CuBr·2LiCl. Utilization of oxyal chloride or
succinoyl chloride afford complex mixtures containing
numerous by-products as indicated by many spots upon
TLC analysis. A maximum yield of 26b (21%) was obtained
with succinoyl chloride and the dialkylcuprate (i.e. R2CuLi)
derived from 1b along with significant amounts (15%) of the
1b homodimer. The yields of 26b were lower when the bis
phenylthiol ester of succinic acid was employed.
reactions.32 Although the product N-Boc protected a-amino
ketones can undergo racemization, the failure of the
acylation reactions to give any enantiomeric excess is not
understood.
The necessity of generally employing 2–3 equiv. of lithium
dialkylcuprates for good yields in acylation reactions5,33 and
the reduced reactivity of phenylthio mixed cuprates33
prompted a brief examination of alkyl(chloro)cuprates
derived from CuCl·2LiCl and organolithium or Grignard
reagents (Eq. (5)). Excellent yields of ketones were obtained
with either the lithium or magnesium aryl or alkyl(chloro)-
cuprates. The lowest yield was obtained with the tert-
butylcuprate and compares very favorably with the lithium
tert-butyl(phenylthio)cuprate offered as the most effective
reagent for acylation of tert-butylcuprates.5 This procedure
is highly efficient since the alkyl ligand is completely
utilized and only one equivalent of cuprate reagent is
required. In contrast to simple alkyl or aryl ligands,
magnesium a-(N-carbamoyl)alkylcuprates were less effec-
tive than their lithium counterparts. Treatment of a-lithio
carbamates derived from 1a, b with MgBr2 (generated in
situ from Mg and 1,2-dibromoethane) followed by
1.0 equiv. of CuCl·2LiCl afforded the magnesium cuprates
that gave modest yields of a-carbamoyl ketones upon
acylation with propionyl chloride (i.e. 39% from 1a and
60% from 1b). This reflects both the lower reactivity of
magnesium cuprates and of a-(N-carbamoyl)alkylcuprates.
The latter appear to be slightly lower in reactivity than the
corresponding simple alkylcuprate reagents.
ð4Þ
R
CuX·2LiY
product
% yield
–C6H4–
CuCN·2LiCl
CuBr·2LiBr
CuCl·2LiCl
CuCN·2LiCl
CuBr·2LiBr
CuBr·2LiCl
26a
45
60
57
7
ð5Þ
–(CH2)2–
26b
15
8
R
product
RLi
RMgX
During the early development of a-(N-carbamoyl)alkylcup-
rate chemistry, a difference in chemical yields was some-
times observed that was attributed to a differential influence
of the diamines employed to facilitate deprotonation of the
starting carbamates.23 A brief examination of the question
was undertaken. Under the reaction conditions where
CuX·2LiCl was used for cuprate formation, no significant
difference in chemical yields could be discerned when either
freshly distilled or older TMEDA or (2)-sparteine was
employed (Table 1, entries 5 vs 6, 7 vs 8, 18 vs 17 and 23
vs 22).
n–Bu
t–Bu
s–Bu
Ph
27a
27b
27c
27d
90
72
82
90
96
–
89
87
Cuprate reagents can be prepared from a variety of Cu(I)
salts and CuCN and CuBr·SMe2 have been promoted as the
most effective cuprate precursors.34 Chemical yields and
selectivity are often times a function of the Cu(I) salt
employed in cuprate formation.34 As we had previously
observed23 in the conjugate addition and vinylation
reactions of a-(N-carbamoyl)alkylcuprates little significant
difference is observed for various Cu(I) salts when they are
used in the THF soluble CuX·2LiCl form (Table 3). Both the
less reactive MeCuXLi or more reactive PhCuXLi gave
comparable yields of ketones with acid chlorides (entries 1–
6). The only exception appeared to involve alkenoyl
chlorides where the cyanocuprate reagent gave higher
yields (entries 8 vs 9).
Enantioselective acylation was briefly examined since
pyrrolidinylcuprates (e.g. R2CuLi·LiCN) are configuration-
ally stable under certain reaction conditions.32 Earlier
efforts to effect asymmetric acylation with acid chlorides
were repeatedly unsuccessful and a series of substrates were
examined in an effort to achieve some selectivity. The
reactions of a thiol ester, acyl cyanide, and acyl iodide [e.g.
PhCOX (X¼CN, SPh, I)] with the scalemic lithium di-2-
pyrrolidinylcuprate reagent gave good chemical yields (72–
100%) but no enantioselectivity. Thus, the acylation and
conjugate addition reactions of a-(N-carbamoyl)alkylcup-
rates give low to no eantionselectivity in marked contrast to
the high asymmetric induction observed in the vinylation
3. Summary
a-(N-Carbamoyl)alkylcuprates prepared at 2788C with

1088
R. K. Dieter et al. / Tetrahedron 59 (2003) 1083–1094
Table 3. Acylation of alkyl and arylcuprates with CuX·2LiCl (1.0 equiv.)
(254 nm), saturated ethanol solution of phosphomolybdic
acid or p-anisaldehyde, or iodine. Preparative thin-layer
chromatography was performed on 20 cm£20 cm Merck
silica gel plates visualized by UV light (254 nm). Column
chromatography (gravity or flash) was performed by using
silica gel (60–200 meshes or 200–400 meshes) and the
eluent as indicated in the text. Elemental analyses were done
by Atlantic Microlab, Inc. Norcross, Georgia, USA via
supplying samples which were purified by preparative TLC
or by MPLC.
Entry
R
R1
X
Product
% Yield
1
2
3
4
Ph(CH2)2–
Me
Cl
Br
I
35
30
30
40
CN
5
6
MeOCOCO–
Ph
Ph
Cl
CN
72
79
The benzyl carbamate derived from the methyl ester of
proline displays a barrier to rotation [dG ‡¼17.1–
17.4 kcal/mol] that is relatively insensitive to solvent.35
A
dG ‡¼17.4 kcal/mol corresponds to a coalescence tempera-
ture of 87.38C while a value of dG ‡¼16.7 corresponds to
61.48C for coalescence.36 Compounds containing the N-Boc
carbamate functionality generally display absorptions in the
1H and 13C NMR spectra attributable to rotomers arising
from restricted rotation about the C–N bond. Additional
absorptions due to rotamers are indicated within
parentheses.
7
MeO2C(CH2)2–
Cl
61
8
9
MeCHvCH-
Ph
Ph
Cl
CN
25
40
10
Et
Cl
78
4.2. Materials
Reaction flasks used in organocopper and cuprate exper-
iments were cleaned with 48% hydrobromic acid, rinsed
with copious amount of water, washed with acetone and
then dried in an oven (1808C) overnight. All copper
reactions were conducted under a positive, dry nitrogen
atmosphere in anhydrous solvents in flasks fitted with
rubber septa secured with parafilm. Flask to flask transfers
of air sensitive intermediates or starting materials were
made using double-tipped needles (cannula) under a
positive argon pressure maintained by double layered
balloons filled with argon. All reagents were obtained
from commercial sources and used without further purifi-
cation unless mentioned elsewhere. Tetrahydrofuran (THF)
and diethyl ether (Et2O) were distilled from sodium and
benzophenone (dark blue-purple color) under a nitrogen
atmosphere. Products 14,11 27a,37 27b,38 27c,39 27d,40 3141
and the methyl ester corresponding to 1842 are reported in
the literature while compounds 28–30 are commercially
available.
THF soluble CuX·2LiCl (X¼CN, Cl) are readily acylated in
high yields with a variety of alkanoyl, aroyl, and alkenoyl
chlorides to afford N-Boc protected a-amino ketones. a-
Heteroatom or a-carboalkoxy substituents in the acid
chloride result in diminished yields of protected a-amino
ketones. The procedure fails for alkynoyl chlorides and
generally low yields are obtained with b,b-di-unsubstituted
alkenoyl chlorides and bis acid chlorides. The free primary
or secondary amino ketones are generally unstable and the
method provides a short and reliable route to a-amino
ketones in protected form. Reaction of lithium or mag-
nesium alkyl(chloro)cuprates (i.e. RCuClLi) prepared from
THF soluble CuCl·2LiCl provides excellent yields of
ketones employing one equivalent of the reagent. This
protocol is efficient in alkyl ligand and provides a practical
and useful alternative to lithium dialkylcuprates prepared
from other Cu(I) salts. The latter reagents generally require
2–3 equiv. of reagent for good to excellent chemical yields.
4.3. General procedure A (2RLi1CuCN)
A solution of N-Boc-carbamate (1.0 mmol) in 3.0 mL of
diethyl ether was cooled to 2788C and treated with (2)-
sparteine (0.25 mL, 1.1 mmol) and sec-BuLi (0.91 mL,
1.1 mmol). The mixture was stirred for 1 h between 2788C
and 2608C then transferred to a suspension of CuCN
(0.045 g, 0.50 mmol) in 3.0 mL THF at 2608C via cannula.
The reaction mixture was slowly warmed to 2508C over
30 min and then treated with the acid chloride (0.50 mmol)
in THF (2.0 mL) via cannula. The mixture was stirred at
2508C for 10–15 min and then quickly warmed to 08C,
stirred for an additional 10 min and then quenched with H2O
(2.0 mL) and filtered through celite. The mixture was
extracted with diethyl ether (3£15 mL) and the combined
extracts were washed with saturated aqueous NH4Cl
(5.0 mL), dried over MgSO4 and then concentrated in
vacuo.
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were recorded using a
Brucker AC 300 (300 MHz) or JEOL 500 MHz spec-
trometer in deuterated chloroform. Gas chromatography-
mass spectroscopy (GC–MS) was performed using
Hewlett–Packard 5890A gas chromatograph coupled to a
Hewlett–Packard 5970B mass selective detector at 70 eV.
Infrared spectra were recorded on either a Magna 550 FT-IR
or a Nicolet 5DX spectrometer by using thin film of neat
liquid sample. Analytical thin-layer chromatography (TLC)
was performed on Merck silica gel plates with F-254
indicator. Visualization was accomplished by UV light

R. K. Dieter et al. / Tetrahedron 59 (2003) 1083–1094
1089
4.4. General procedure B (RLi1CuCN·2LiCl)
3H), 3.86 (3.95) (s, 2H); 13C NMR for rotamers (minor) d
7.22 (7.42), (28.1) 28.2, (32.5) 32.5, 35.6, 57.5 (58.2), 79.9,
(155.3) 156.0, 207.0; mass spectrum, m/z (relative intensity)
EI 201 (0.3, Mþ), 144 (16, Mþ2C4H9), 116 (0.1), 89 (0.7),
88 (9), 57 (100, C4H9). Anal. calcd for C10H19NO3: C,
59.70; H, 9.45; N, 6.96. Found: C, 59.45; H, 9.42; N, 6.93.
A solution of N-Boc-carbamate (0.50 mmol) in 3 mL of
THF was cooled to 2788C and treated with sparteine
(0.12 mL, 0.55 mmol) and sec-BuLi (0.46 mL, 0.55 mmol).
The mixture was stirred for 1 h at 2788C. To the solution
was added a premixed homogenous solution of CuCN
(0.044 g, 0.50 mmol) and LiCl (0.042 g, 1.0 mmol) in
4.0 mL THF via cannula. The reaction mixture was stirred
at 2788C for 30–40 min and then treated with the acid
chloride (0.50 mmol) in THF (2.0 mL) via cannula. The
mixture was stirred at 2788C for 35 min, quickly warmed to
room temperature, stirred for 30 min, quenched with H2O
(2.0 mL) and then filtered through celite. The mixture was
extracted with diethyl ether (3£15 mL) and the combined
extracts were washed with saturated aqueous NH4Cl
(5.0 mL), dried over MgSO4 and concentrated in vacuo.
4.6.2. 1,1-Dimethylethyl methyl(2-oxopropyl)carbamate
(3). General procedure B and acetyl bromide were
employed (1a, 0.15 g, 1.0 mmol). Purification of the crude
material by flash column chromatography (20% diethyl
ether/pet. ether, v/v) gave 3 (0.14 g, 81 %): IR (neat) 3592
(br, m), 2973 (s), 2936 (s), 2332 (w), 1737 (s), 1711 (s),
1480 (s), 1455 (s), 1396 (s), 1251 (s), 1183 (s), 894 (s), 775
(s), 579 (m), 536 (s) cm21; 1H NMR for rotamers (minor) d
1.37 (1.42) (s, 9H), 2.08 (s, 3H), 2.84 (2.88) (s, 3H), 3.87
(3.96) (s, 2H); 13C NMR for rotamers (minor) d 26.6 (26.8),
28.2 (28.3), 35.6, 58.4 (59.1), 80.1, 155.3, (156.0), 204.5;
mass spectrum m/z (relative intensity) EI 144 (29), 131 (5),
114 (13), 88 (11), 70 (12), 57 (100). Anal. calcd for
C9H17NO3: C, 57.8; H, 9.10; Found: C, 56.6; H, 9.10.
4.5. General procedure C (RLi1CuCl·2LiCl)
A solution of N-Boc-carbamate (0.54 mmol) in 3.0 mL of
THF was cooled to 2788C and treated with (2)-sparteine
(0.138 mL, 0.597 mmol) and sec-BuLi (0.52 mL,
0.60 mmol). The mixture was stirred for 1 h at 2788C. To
the solution was added a premixed homogenous solution of
CuCl (0.052 g, 0.58 mmol) and LiCl (0.048 g, 1.2 mol) in
4 mL THF via cannula. The reaction mixture was stirred at
2788C over 10 min and then treated with the acid chloride
(0.08 mL, 0.60 mmol) in THF (2.0 mL) via cannula. The
mixture was then quickly warmed to room temperature and
stirred for an additional 10–15 min, quenched with H2O
(2.0 mL) and then filtered through celite. The mixture was
extracted with diethyl ether (3£15 mL) and the combined
extracts were washed with saturated aqueous NH4Cl
(5.0 mL), dried over MgSO4 and concentrated in vacuo.
4.6.3. 1,1-Dimethylethyl methyl(3,3-dimethyl-2-oxo-
butyl)carbamate (4). General procedure C was employed
(1a, 0.15 g, 1.0 mmol). Purification of the crude material by
medium pressure liquid chromatography (20% ether/pet.
ether) gave 0.221 g (96%) [with (2)-sparteine, obtained
95% yield] of 4 as a colorless oil: IR 1702 (s), 1455 (w),
1412 (s), 1378 (w), 1259 (s), 1166 (s), 1055 (w), 885 (s), 791
1
(m) cm21; H NMR for rotamers (minor) d 1.12 (s, 9H),
1.34 (1.41) (s, 9H), 2.78 (2.81) (s, 3H), 4.07 (4.15) (s, 2H);
13C NMR for rotamers (minor) d 26.2 (26.3), 28.2 (28.3),
35.4 (35.6), 42.8 (42.9), 53.1 (53.7), 79.6, 155.5 (156.1),
(209.9) 210.4; mass spectrum, m/z (relative intensity) EI 172
(6, Mþ2C4H9), 144 (27, Mþ2C5H9O), 130 (0.3,
Mþ2C6H11ON), 116 (2, Mþ2C6H11ON), 100 (11), 88
(10), 70 (0.4), 57 (100, C4H9). Anal. calcd for C12H23NO3:
C, 62.88; H, 10.04; N, 6.11. Found: C, 62.92; H, 10.03; N,
6.01.
4.6. General procedure D (2RLi1CuCN·2LiCl)
A solution of N-Boc-carbamate (1.0 mmol) in 3.0 mL of
THF was cooled to 2788C and treated with sparteine
(0.25 mL, 1.1 mmol) and sec-BuLi (0.91 mL, 1.1 mmol).
The mixture was stirred for 1 h at 2788C. To the solution
was added a premixed homogeneous solution of CuCN
(0.045 g, 0.50 mmol) and LiCl (0.042 g, 1.0 mmol) in
4.0 mL of THF via cannula. The reaction mixture was
slowly warmed to 2558C over 60 min and then treated with
the acid chloride (0.10 mL, 1.1 mmol) in THF (2.0 mL) via
cannula. The mixture was stirred at 2508C for 10 min and
then quickly warmed to room temperature and stirred for an
additional 30 min, quenched with H2O (2.0 mL) and filtered
through celite. The mixture was extracted with diethyl ether
(3£15 mL) and the combined extracts were washed with
saturated aqueous NH4Cl (5.0 mL), dried over MgSO4 and
concentrated in vacuo.
4.6.4. 1,1-Dimethylethyl methyl(5-chloro-2-oxopentyl)-
carbamate (5). General procedure B was employed (1a,
0.059 g, 0.41 mmol). Purification of the crude product by
medium pressure (20% ether/pet. ether) liquid chroma-
tography gave 0.06 g (63%) [with TMEDA, 68% yield] of 5
as a colorless oil: IR 1702 (s), 1659 (w), 1557 (w), 1489 (w),
1463 (w), 1395 (m), 1251 (m), 1174 (s), 893 (m), 783
1
(m) cm21; H NMR for rotamers (minor) d 1.35 (1.41) (s,
9H), 2.01 (p, J¼6.6 Hz, 2H), 2.51 (t, J¼7.2 Hz, 2H), 2.84
(2.86) (s, 3H), 3.50–3.63 (m, 2H), 3.88 (3.96) (s, 2H); 13C
NMR for rotamers (minor) d 25.9, 28.1 (28.2), 28.3, 35.8
(36.1), 44.1 (44.2), 57.9 (58.6), 80.0, 155.2 (156.0), 205.6;
mass spectrum, m/z (relative intensity) EI 249 (0.3, Mþ),
176 (6, Mþ2C4H9O), 150 (0.6), 144 (23), 105 (0.3), 88
(11), 57 (92, C4H9), 44 (100). Anal. calcd for C11H20ClNO3:
C, 52.90; H, 8.01; N, 5.61; Cl, 14.22. Found: C, 53.04, H,
7.92; N, 5.51; Cl, 14.38.
4.6.1. 1,1-Dimethylethyl methyl(2-oxobutyl)carbamate
(2). General procedure D was employed (1a, 0.115 g,
0.796 mmol). Purification of the crude product by medium
pressure liquid chromatography (20% ether/pet. ether) gave
0.079 g (98%) of 2 as a colorless liquid: IR 1702 (s), 1472
(m), 1395 (s), 1251 (m), 1166 (s), 893 (m) cm21; 1H NMR
for rotamers (minor) d 0.95–1.10 (m, 3H), 1.35 (1.40) (s,
9H), 2.34 (two overlapping q, J¼6.9 Hz, 2H), 2.82 (2.85) (s,
4.6.5. 1,1-Dimethylethyl methyl(2-phenyl-2-oxoethyl)-
carbamate (6). General procedure D was employed (1a,
0.10 g, 0.71 mmol). Purification of the crude material by
medium pressure liquid chromatography (20% ether/pet.
ether) gave 0.089 g (100%) of 6 as a colorless liquid: IR

1090
R. K. Dieter et al. / Tetrahedron 59 (2003) 1083–1094
1710 (s), 1608 (w), 1497 (s), 1463 (s), 1412 (s), 1242 (s),
1
column chromatography (20% diethyl ether/pet. ether, v/v)
gave 10 (0.092 g, 41 %): IR (neat) 2974 (m), 2247 (w), 1739
(s), 1694 (s), 1482 (s), 1455 (s), 1396 (s), 1251 (s), 1166 (s),
918 (s), 732 (s) cm21; 1H NMR for rotamers (minor) d 1.38
(1.43) (s, 9H), 2.88 (2.90), (s, 3H), 3.92–4.22 (m, 4H); 13C
NMR for rotamers (minor) d 28.2 (28.3), 35.8, 45.8 (46.2),
56.0 (56.4), 80.4, 155.1 (156.0), 198.6 (198.8); mass
spectrum m/z (relative intensity) EI 221 (0.5, Mþ), 150
(5), 144 (30), 88 (10), 57 (100). Anal. calcd for
C9H16ClNO3: C, 48.8; H, 7.20; N, 6.30. Found: C, 49.75;
H, 7.54; N, 6.67.
1166 (s), 1005 (m), 893 (m), 766 (m) cm21; H NMR for
rotamers (minor) d (1.26) 1.38 (s, 9H), 2.83 (2.86) (s, 3H),
4.48 (4.58) (s, 2H), 7.24–7.55 (m, 3H), 7.81 (7.93) (d,
J¼7.8 Hz, 2H); 13C NMR for rotamers (minor) d 28.1
(28.3), 35.5, 55.0 (55.6), 79.9, 127.6 (127.8), 128.2, 128.6
(128.7), 129.9, 133.2 (133.4), 135.1, 155.6 (156.2), 194.7
(195.0); mass spectrum, m/z (relative intensity) EI 249 (0.4,
Mþ), 193 (12, Mþ2C4H8), 150 (1), 144 (46), 105 (83), 77
(32) 57 (100, C4H9). Anal. calcd for C14H19NO3: C, 67.47;
H, 7.63. Found: C, 67.68; H, 7.66.
4.6.6. (S)-1,1-Dimethylethyl methyl(3-acetoxy-2-oxo-
butyl)carbamate (7). General procedure B was employed
(1a, 0.15 g, 1.0 mmol). Purification of the crude material by
flash column chromatography (20% diethyl ether/pet. ether,
v/v) gave 7 (0.065 g, 25 %): IR (neat) 2978 (m), 2945 (m),
2353 (w), 1741 (s) 1693 (s), 1458 (m), 1243 (s), 1153 (s),
4.6.10. N-(tert-Butoxycarbonyl)-2-(1-oxopropyl)pyrroli-
dine (11). General procedure B was employed [1b (0.085 g,
0.50 mmol), THF (3.0 mL), (2)-sparteine (0.12 mL,
0.55 mmol), s-BuLi (0.46 mL, 0.55 mmol), CuCN
(0.044 g, 0.50 mmol) and LiCl (0.042 g, 1.0 mmol) in
4.0 mL THF]. Purification of the crude material by medium
pressure liquid chromatography (20% ether/pet. ether) gave
0.061 g (55%) of 11 as a colorless liquid: IR 1702 (s), 1472
(w), 1412 (s), 1259 (m), 1174 (m), 1123 (m), 885 (m), 783
1
885 (m), 776 (m) cm21; H NMR for rotamers (minor) d
1.24–1.51 (m, 12H), 2.07 (2.08) (s, 3H), 2.83 (2.84) (s, 3H),
3.99–4.16 (m, 2H), 5.07 (q, J¼6.4 Hz, 1H); 13C NMR for
rotamers (minor) d 16.0 (16.1), 20.5, 28.1 (28.2), 35.6, 54.8
(55.4), 72.9 (73.2), 80.1, 155.3 (155.9), 170.2, 203.1
(203.8); mass spectrum m/z (relative intensity) EI 223 (2),
203 (6.5), 144 (25.5), 126 (17), 115 (13), 88 (14), 57 (100).
Anal. calcd for C12H21NO5: C, 55.59; H, 8.11; N, 5.40.
Found: C, 55.55; H, 8.19; N, 5.30.
1
(m) cm21; H NMR for rotamers (minor) d 1.02–1.16 (m,
3H), 1.40 (1.46) (s, 9H), 1.74–1.96 (m, 3H), 2.08–2.29 (m,
1H), 2.35–2.61 (m, 2H), 3.40–3.61 (m, 2H), 4.25 (4.35)
(dd, J¼4.5, 8.4 Hz, 1H); 13C NMR for rotamers (minor) d
7.27 (7.37), 23.5 (24.2), 28.1 (28.2), (28.8) 30.1, 31.4 (32.2),
46.5 (46.7), 64.3 (64.8), 79.5 (79.8), 153.7 (154.4), 210.5;
mass spectrum, m/z (relative intensity) EI 227 (0.8, Mþ),
170 (22, Mþ2C3H5O), 154 (8), 128 (13), 114 (92), 82 (2),
70 (100, C4H8N), 57 (80, C4H9). Anal. calcd for
C12H21NO3: C, 63.43; H, 9.25; N, 6.16. Found: C, 63.22;
H, 9.19; N, 6.09.
4.6.7. Ethyl 4-[[(1,1-dimethylethoxy)carbonyl]methyl-
amino]-3-oxobutyrate (8). General procedure B was
employed (1a, 0.15 g, 1.0 mmol). Purification of the crude
material by flash column chromatography (20% diethyl
ether/pet. ether, v/v) gave 8 (0.081 g, 31 %): IR (neat) 2979
(m), 2249 (w), 1750 (s), 1725 (s), 1693 (s), 1396 (s), 1157
(s), 740 (s), cm21; 1H NMR for rotamers (minor) d 1.23 (t,
J¼7.1 Hz, 3H), 1.36 (1.41) (s, 9H), 2.84 (2.86) (s, 3H), 3.38
(3.39) (s, 2H), 3.96–4.22 (m, 4H); 13C NMR for rotamers
(minor) d 14.0, 28.1 (28.2), 35.6, 46.1 (46.3), 58.1 (58.7),
61.4, 80.2 (80.4), 153.2 (156.0), 166.6 (166.8), 198.9
(199.1); mass spectrum m/z (relative intensity) EI 259
(0.1, Mþ), 203 (18), 186 (11), 158 (11), 144 (29) 114 (10),
88 (22), 57 (100). Anal. calcd for C12H21N05: C, 55.60; H,
8.10; N, 5.4. Found: C, 55.47; H, 8.30; N, 5.38.
4.6.11. N-(tert-Butoxycarbonyl)-2-(2,2-dimethyl-1-oxo-
propyl)pyrrolidine (12). General procedure
C was
employed [1b (0.13 g, 0.76 mmol), 3.0 mL THF, sparteine
(0.18 mL, 0.83 mmol), sec-BuLi (0.70 mL, 0.83 mmol),
CuCl (0.078 g, 0.79 mmol) and LiCl (0.067 g, 1.6 mmol) in
4.0 mL THF]. Purification of the crude material by medium
pressure liquid chromatography (20% ether/pet. ether) gave
0.17 g (88%) of 12 as a colorless oil: IR 1702 (s), 1566 (w),
1472 (w), 1421 (s), 1174 (m), 1131 (w) cm21; 1H NMR for
rotamers (minor) d 1.16 (1.17) (s, 9H), 1.35 (1.37) (s, 9H),
1.55–2.00 (m, 3H), 2.00–2.30 (m, 1H), 3.30–3.78 (m, 2H),
4.65–4.78 (m, 1H); 13C NMR for rotamers (minor) d 22.9
(24.0), 26.8 (27.3), 28.4 (28.5), 29.9 (30.6), 42.9 (43.3), 46.7
(46.9), 59.4 (60.1), 79.1 (79.8), 153.6 (153.9), 213.4
(214.7); mass spectrum, m/z (relative intensity) EI 170
(24, Mþ2C5H9O), 156 (0.1), 138 (5), 126 (3), 114 (96), 85
(1), 70 (100), 57 (90, C4H9). Anal. calcd for C14H25NO3: C,
65.88; H, 9.80; N, 5.49. Found: C, 65.66; H, 9.70; N, 5.49.
4.6.8. Methyl 5-[[(1,1-dimethylethoxy)carbonyl]methyl-
amino]-4-oxopentanoate (9). General procedure B was
employed (1a, 0.15 g, 1.0 mmol). Purification of the crude
material by flash column chromatography (20% diethyl
ether/pet. ether, v/v) gave 9 (0.109 g, 42 %): IR (neat) 2979
(m), 2255 (m), 1733 (vs), 1694 (vs), 1455 (s), 1175 (vs), 912
(vs), 733 (vs), 655 (m) cm21; 1H NMR for rotamers (minor)
d 1.36 (1.41) (s, 9H), 2.51–2.83 (m, 4H), 2.84 (2.87) (s, 3H),
3.62 (s, 3H), 3.92 (4.00) (s, 2H); 13C NMR for rotamers
(minor) d 27.4, 28.1 (28.4), 33.8 (33.9), 35.7, 51.7, 57.9
(58.6), 80.1, 155.3 (156.0), 172.8 (173.0), 205.1; mass
spectrum m/z (relative intensity) EI 203 (16), 186 (11,
Mþ2C3H502) 172 (20, Mþ2C4H702), 88 (17) 57 (100).
Anal. calcd for C12H21NO3: C, 55.60; H, 8.11; N, 5.40.
Found: C, 55.40, H 8.14; N, 5.38.
4.6.12. N-(tert-Butoxycarbonyl)-2-(4-chloro-1-oxobutyl)-
pyrrolidine (13). General procedure C was employed (1b,
0.09 g, 0.53 mmol). Purification of the crude material by
medium pressure liquid chromatography (20% ether/pet.
ether) gave 0.085 g (62%) [with TMEDA, 52% yield] of 13
as a colorless oil: IR 1702 (s), 1659 (w), 1574 (w), 1421 (s),
1370 (w), 1259 (w), 1174 (m) cm21; 1H NMR for rotamers
(minor) d 1.36 (1.41) (s, 9H), 1.72–1.93 (m, 4H), 1.94–2.27
(m, 4H), 2.50–2.77 (m, 2H), 3.50–3.63 (m, 2H), 4.20 (4.30)
(dd, J¼4.5, 9.3 Hz, 1H); 13C NMR for rotamers (minor) d
23.6 (24.4), 25.9, (28.2) 28.3, (28.4) 29.9, 34.8 (35.6), 44.2
4.6.9. 1,1-Dimethylethyl methyl(3-chloro-2-oxopropyl)-
carbamate (10). General procedure C was employed (1a,
0.15 g, 1.0 mmol). Purification of the crude material by flash

R. K. Dieter et al. / Tetrahedron 59 (2003) 1083–1094
1091
(44.4), 46.7 (46.8), (64.7) 65.3, (79.8) 80.1, 153.8 (154.4),
(209.1) 209.2; mass spectrum, m/z (relative intensity) EI 202
(4), 170 (14, Mþ2C4H6ClO), 158 (3), 140 (0.6), 114 (68),
105 (6, C4H6ClO), 70 (100, C4H8N), 57 (93, C4H9).
diastereomers d 1.27–1.51 (m, 12H), 1.66–2.22 (m, 7H),
3.22–3.55 (m, 2H), 4.41–4.58 (m, 1H), 5.08–5.36 (m, 1H);
13C NMR for two diastereomers plus rotamers (minor) d
15.9 (16.3, 16.6), 20.5 (20.7), 22.9 (23.2, 23.9, 24.1), 28.3
(28.5), 29.5, 46.5 (46.7), 61.6 (61.8, 62.0, 62.1), 72.3 (72.5,
73.0), 79.5 (79.8, 80.0, 80.2), 153.5 (153.7, 154.2, 154.5),
169.7 (170.1, 170.2), 204.9 (205.8, 206.4, 207.6); mass
spectrum m/z (relative intensity) EI 212 (3), 197 (5), 170
(53), 114 (100), 70 (98), 57 (69); Anal. calcd for
C14H23NO5: C, 58.9; H, 8.1; N, 4.9 Found: C, 58.77; H,
8.13; N, 4.89.
4.6.13. N-(tert-Butoxycarbonyl)-2-(1-phenyl-1-oxo-
methyl)pyrrolidine (14). General procedure
D was
employed (1b, 0.12 g, 0.67 mmol). Purification of the crude
material by medium pressure liquid chromatography (20%
ether/petether)gave0.091 g(100%)of14asacolorlessoil:IR
1702 (s), 1651 (sh), 1455 (w), 1404 (s), 1242 (m), 1174 (m),
1
1123 (m), 1012 (m), 885 (m), 791 (m), 714 (m) cm21; H
NMR for rotamers (minor) d 1.18 (1.38) (s, 9H), 1.80–1.96
(m, 3H), 2.11–2.38 (m, 1H) 3.38–3.69 (m, 2H), 5.12 (5.26)
(dd, J¼3.6, 9.0 Hz, 1H), 7.30–7.58 (m, 3H), 7.74–7.88 (m,
2H); 13C NMR for rotamers (minor) d 23.4 (24.0), 28.0 (28.3),
(29.6)30.7, 46.4(46.6), (60.9)61.6, (79.4)79.6, 127.9(128.3),
(128.4) 128.5, 133.1, (134.9) 135.0, 153.7 (154.3), (198.2)
198.7; mass spectrum, m/z (relative intensity) EI 275 (0.1,
Mþ), 202 (4, Mþ2C4H9O), 170 (29), 158 (9), 114 (88), 105
(47), 70 (100, C4H8N), 57 (90, C4H9).
4.6.17. Methyl 1-[(1,1-dimethylethoxy)carbonyl]-a-oxo-
2-pyrrolidineacetate (17). General procedure C was
employed (1b, 0.17 g, 1.0 mmol). Purification of the crude
material by medium pressure liquid chromatography (20%
ether/pet. ether) gave 0.190 g (76%) of 17 as a colorless oil:
IR 1736 (s), 1696 (s), 1591 (m), 1400 (s), 1256 (m), 1164
1
(s), 1065 (m) cm21; H NMR for rotamers (minor) d 1.30
(1.35) (s, 9H), 1.74–2.08 (m, 3H), 2.05–2.40 (m, 1H), 3.45
(t, J¼7.5 Hz, 2H), 3.70 (3.81) (s, 3H), 4.71 (4.81) (dd,
J¼5.7, 8.7 Hz, 1H); 13C NMR for rotamers (minor) d 23.5
(24.3), 27.8 (28.1), (28.8) 29.9, 46.4 (46.5), 52.7, (62.0)
62.3, (80.0) 80.4, 153.0 (154.2), (160.7) 161.0, (192.3)
193.0; mass spectrum m/z (relative intensity) EI 202 (0.6),
170 (14, Mþ2C3H3O3), 156 (1), 128 (14), 114 (54), 97 (1),
70 (96), 57 (100, C4H9). Anal. calcd for C12H19NO5: C,
56.03; H, 7.39. Found: C, 55.86; H, 7.45.
4.6.14. Methyl 1-[(1,1-dimethylethoxy)carbonyl]-g-oxo-
2-pyrrolidinebutanoate (15). General procedure C was
employed (1b, 0.17 g, 1.0 mmol). Purification of the crude
material by medium pressure liquid chromatography (20%
ether/pet. ether) gave 0.21 g (74%) of 15 as a colorless
liquid: IR 1736 (s), 1696 (s), 1650 (w), 1394 (s), 1210 (w),
1170 (m), 1124 (w) cm21; 1H NMR for rotamers (minor) d
1.30 (1.35) (s, 9H), 1.70–1.93 (m, 3H), 1.93–2.18 (m, 1H),
2.37–2.60 (m, 2H), 2.60–2.79 (m, 2H), 3.35–3.50 (m, 2H),
3.55 (3.57) (s, 3H), 4.17 (4.25) (dd, J¼5.1, 8.4 Hz, 1H); 13C
NMR for rotamers (minor) d 23.4 (24.2), 27.0, 28.0 (28.1),
(28.6) 29.6, 33.0 (33.5), 46.5 (46.7), (51.4) 51.6, (64.5) 65.0,
(79.5) 80.0, 153.6 (154.4), 172.8 (173.1), (208.3) 208.4;
mass spectrum m/z (relative intensity) EI 212 (9,
Mþ2C4H9O), 198 (15), 170 (24), 154 (4), 136 (3), 114
(78), 88 (4), 70 (100), 57 (70, C4H9). Anal. calcd for
C14H23NO5: C, 58.94; H, 8.07. Found: C, 59.01; H, 8.07.
4.6.18. Ethyl 1-[(1,1-dimethylethoxy)carbonyl]-b-oxo-2-
pyrrolidinepropanoate (18). General procedure B was
employed (1a, 0.15 g, 1.0 mmol). Purification of the crude
material by flash column chromatography (20% diethyl
ether/pet. ether, v/v) gave 18 (0.052 g, 18 %): IR (neat) 2987
(s), 2254 (m), 1755 (s), 1726 (s), 1702 (s), 1404 (s), 1175 (s),
919 (s), 740 (s), 655 (s) cm21 1H NMR for rotamers
;
(minor) d 1.23 (t, J¼7.1 Hz, 3H), 1.38 (1.41) (s, 9H), 1.74–
2.24 (m, 4H), 3.32–3.59 (m, 4H), 4.07–4.46 (m, 3H); 13C
NMR for rotamers (minor) d 14.0, 23.7 (24.4), 28.2 (28.3),
29.7, 45.2, 46.7 (46.9), 61.2 (61.3), 65.0 (65.5), 80.1 (80.6),
153.7 (154.8), 166.9 (167.2), 202.6 (203.0); mass spectrum
m/z (relative intensity) EI 285 (0.1, Mþ2C3H5O2) 170 (25,
Mþ-C5H7O3), 114 (92), 70 (100), 57 (74). Anal. calcd for
C14H23NO5: C, 58.90; H, 8.10; N, 4.90. Found: C, 58.77; H,
8.16; N, 4.70.
4.6.15. 2-(1-Oxo-3-carbomethoxyprop-1-yl)pyrrolidine,
hydrochloride salt. Treatment of 15 (0.14 g, 0.50 mmol)
with phenol (1.42 g, 15.0 mmol) and TMSCl (0.64 mL,
5.0 mmol) in CH2Cl2 at room temperture for 30 min
followed by solvent removal in vacuo afforded a residue
that was dissolved in THF, cooled in liquid N2 and slowly
warmed to 258C. Excess phenol was removed under
Kugelrohr distillation and a colorless solid was obtained
4.6.19. N-(tert-Butoxycarbonyl)-2-(2,2-dimethyl-1-oxo-
propyl)piperidine (19). General procedure
B
was
1
(0.026 g, 25%): H NMR d 1.82–2.35 (m, 3H), 2.38–2.68
employed (1c, 0.19 g, 1.0 mmol). Purification of the crude
material by flash column chromatography (20% diethyl
ether/pet ether, v/v) gave 19 (0.12 g, 45%): IR (neat) 2978
(s), 2366 (w), 2255 (w), 1711 (vs), 1472 (s) 1370 (s), 1249
(s), 1159 (s), 570 (m) cm21; 1H NMR d 1.17 (s, 9H), 1.40 (s,
9H), 1.46–1.96 (m, 5H), 3.19–3.38 (m, 2H), 3.88 (br, 1H),
5.11 (br, 1H); 13C NMR for rotamers (minor) d 19.3, 24.9,
26.0, 27.1, 28.4, 40.6 (42.2), 43.5, 54.1 (55.6), 79.7, 155.4,
215.9 (216.1); mass spectrum m/z (relative intensity) EI 196
(3), 184 (14, Mþ2C5H90), 140 (6), 128 (100), 84 (67,
Mþ2C10H9O3), 57 (61). Anal. calcd for C15H27NO3: C,
66.91; H, 10.04, N, 5.20. Found: C, 66.82 H, 10.20 N, 5.31.
(m, 2H), 2.73–3.12 (m, 3H), 3.37–3.60 (m, 2H), 3.67 (s,
3H), 4.72–4.92 (m, 1H), 8.52 (br s, 1H), 10.25 (br s, 1H).
13C NMR d 23.7, 27.2, 28.1, 34.0, 45.9, 51.9, 65.2, 172.7,
203.3. Utilization of trifluoroacetic acid or trifluoromethane
sulfonic acid in CH2Cl2 afforded the corresponding amine
salts in 80 and 85% yields, respectively.
4.6.16. N-(tert-Butoxycarbonyl)-2-(2-acetoxy-1-oxopro-
pyl)pyrrolidine (16). General procedure B was employed
(1b, 0.17 g, 1.0 mmol). Purification of the crude material by
flash column chromatography (20% diethyl ether/pet. ether,
v/v) gave 16 (0.219 g, 77%): IR (neat) 3626 (br,w), 2980 (s),
2250 (w), 1739 (s), 1702 (s), 1404 (s), 1243 (s), 1175 (s),
1106 (s), 1047 (s), 765 (m), 693 (m) cm21; 1H NMR for two
4.6.20. 1,1-Dimethylethyl methyl[(E)-2-oxo-3-pentenyl]-
carbamate (20). General procedure C was employed (1a,

1092
R. K. Dieter et al. / Tetrahedron 59 (2003) 1083–1094
0.07 g, 0.48 mmol). Purification of the crude material by
medium pressure liquid chromatography (20% ether/pet.
ether) gave 0.056 g (55%) [with TMEDA, 57%] of 20 as a
colorless oil: IR 1702 (s), 1651 (w), 1455 (w), 1392 (s),
1302 (m), 1251 (m), 1157 (s), 978 (m), 885 (m), 783
Mþ2C5H7O), 136 (3), 114 (95), 83 (47), 70 (100,
Mþ2C4H8N), 57 (64, C4H9). Anal. calcd for C14H23NO3:
C, 66.40; H, 9.10; N, 5.53. Found: C, 66.12; H, 9.09; N, 5.39.
4.6.24. N-(tert-Butoxycarbonyl)-4,4-dimethyl-2-benzoyl-
1,3-oxazolidine (25). The general procedure A was
employed. A solution of N-Boc-4,4-dimethyl-1,3-oxazoli-
dine (0.20 g, 1.0 mmol) in 2.0 mL of dry THF was cooled to
2788C and treated with (2)-sparteine (0.23 mL, 1.0 mmol)
and sec-BuLi (0.90 mL, 1.1 mmol). The mixture was stirred
for 3 h at 2788C. Then a premixed homogenous solution of
CuCN (0.089 g, 1.0 mmol) and LiCl (0.085 g, 2.0 mmol) in
2.0 mL dry THF was added to the above solution via
cannula. The reaction mixture was stirred for 1 h at 2788C
followed by the addition of benzoyl chloride (0.13 mL,
1.1 mmol) via syringe. The mixture was slowly warmed up
to room temperature over 4 h. The reaction was quenched
with saturated NaHCO3 (aq) and filtered through celite. The
mixture was extracted with ether (3£10 mL) and the
combined extracts were washed with saturated NH4Cl
(aq), dried over MgSO4, then concentrated in vacuum. The
crude material was purified by flash column chroma-
tography (ether/pet. ether, 1/4, v/v) to give 0.21 g (70%)
of a white solid: m.p. 103–58C; IR (CCl4) 2977 (m), 1715
1
(m) cm21; H NMR for rotamers (minor) d 1.36 (1.42), (s,
9H), 1.87 (t, J¼5.4 Hz, 3H), 2.84 (2.87) (s, 3H), 4.02 (4.13)
(s, 2H), 6.12 (two overlapping d, J¼15.9 Hz, 1H), 6.91 (dq,
J¼6.9, 15.6 Hz, 1H); 13C NMR for rotamers (minor) d 18.4,
28.2 (28.4), 35.5, 56.0 (57.0), 79.9, 128.3 (128.8), 143.6,
155.2 (155.8), (195.1) 195.2; mass spectrum, m/z (relative
intensity) EI 157 (9, Mþ2C4H8), 144 (20), 129 (4), 113 (1),
88 (9), 81 (3), 57 (100, C4H9), 44 (95).
4.6.21. 1,1-Dimethylethyl methyl(4-methyl-2-oxo-3-pen-
tenyl)carbamate (21). General procedure C was employed
(1a, 0.059 g, 0.41 mmol). Purification of the crude material
by medium pressure liquid chromatography (20% ether/pet.
ether) gave 0.048 g (53%) of 21 as a colorless oil: IR 1702
(s), 1642 (w), 1463 (m), 1404 (m), 1251 (m), 1166 (s), 1046
(w), 961 (w), 902 (w), 774 (w) cm21; 1H NMR for rotamers
(minor) d 1.33 (1.40) (s, 9H), 1.84 (s, 3H), 2.10 (s, 3H), 2.81
(2.84) (s, 3H), 3.83 (3.95) (s, 2H), 5.97 (s, 1H); 13C NMR for
rotamers (minor) d 20.2, 27.4, 28.1 (28.2), 35.4, 58.6 (59.3),
(79.4) 79.7, 119.9 (120.2), 155.6 (156.0), 157.5, 195.7
(195.9); mass spectrum, m/z (relative intensity) EI 227 (0.3,
Mþ), 199 (1), 171 (7, Mþ2C4H8), 144 (22), 127 (2), 110
(5), 83 (96), 57 (100, C4H9). Anal. calcd for C12H21NO3: C,
63.43; H, 9.25. Found: C, 63.54; H, 9.30.
(s) 1381 (s) 1177 (m), 1062 (m) cm21 1H NMR for
;
rotamers (minor) d 1.11–1.69 (m, 15H), 3.65–3.91 (m, 2H),
6.17 (6.33) (s, 1H), 7.35–7.70 (m, 3H), 7.94–8.19 (m, 2H);
13C NMR for rotamers (minor) d 22.9 (23.6), 24.2 (25.2),
28.1 (28.3), 58.6 (59.0), 79.6 (80.2), 80.0 (80.1), 86.6 (87.5),
128.5 (128.6), 128.7, 133.4, 134.4, 150.8 (152.3), 192.5
(193.1); A DEPT experiment revealed methyl absoptions at
d 22.9, 24.2, 28.1, quaternary or carbonyl carbons at 58.6,
80.0, 134.4, 150.8, 192.5, CH carbons at 86.6, 128.5, 128.7,
133.4 and a CH2 carbon at 79.6.
4.6.22. N-(tert-Butoxycarbonyl)-2-[(E)-1-oxo-2-butenyl]-
pyrrolidine (22). General procedure D was employed (1b,
0.07 g, 0.41 mmol). Purification of the crude material by
medium pressure liquid chromatography (20% ether/pet.
ether) gave 0.045 g (84%) of 22 as a colorless oil: IR 1702
(s), 1651 (w), 1556 (w), 1463 (w), 1404 (s), 1183 (m), 1131
(m), 987 (w), 893 (w), 783 (w) cm21; 1H NMR for rotamers
(minor) d 1.26 (1.31) (s, 9H), 1.69–1.90 (m, 6H), 2.00–2.18
(m, 1H), 3.37–3.52 (m, 2H), 4.26 (4.50) (dd, J¼5.1, 8.7 Hz,
1H), 6.14 (br d, J¼15.6 Hz, 1H), 6.91 (dq, J¼6.9, 15.6 Hz,
1H); 13C NMR for rotamers (minor) d 18.2, 23.5 (24.0), 28.0
(28.2), (29.0) 30.1, 46.5 (46.7), (63.0) 64.0, (79.4) 79.7,
126.9 (128.0), 143.6 (143.7), 153.8 (154.3), (198.1) 198.5;
mass spectrum, m/z (relative intensity) EI 239 (0.1, Mþ),
211 (0.2, Mþ2C2H4), 170 (20, Mþ2C4H5O), 166 (4), 122
(8), 114 (77), 94 (2), 70 (100, –C4H8N), 57 (93, C4H9).
Anal. calcd for C13H21NO3: C, 65.27; H, 8.78. Found: C,
64.84; H, 8.73.
1
A homogeneous sample of 25 as indicated by H and 13C
NMR and TLC analysis failed to give a satisfactory m/z
value for C17H23NO4 (305.1627) or combustion analysis
data. Reaction of N-Boc-4,4-dimethyl-2-lithio-1,3-oxazoli-
dine with benzaldehyde followed by oxidation of the
resultant alcohol with CrO3 in pyridine gave a sample
1
identical with 25 by IR, H and 13C NMR analysis and by
TLC Rf values.
4.6.25. 1,4-Bis[1-oxo-(N-tert-butoxycarbonyl-20-pyrroli-
dino)]benzene (26a). General procedure B was employed.
A solution of N-Boc-pyrrolidine (0.17 g, 1.0 mmol) in
2.0 mL of dry ether was cooled to2-788C and treated with
(2)-sparteine (0.23 mL, 1.0 mmol) and sec-BuLi (0.90 mL,
1.1 mmol). The mixture was stirred for 1 h at 2788C. Then
a premixed homogenous solution of CuCN (0.089 g,
1.0 mmol) and LiCl (0.085 g, 2.0 mmol) in 2.0 mL of dry
THF was added to the above solution via cannula. The
reaction mixture was stirred for 1 h at 2788C followed by
the addition of terephthaloyl chloride (0.10 g, 0.50 mmol) in
ether (1.0 mL) via syringe. The mixture was slowly warmed
up to room temperature over 4 h. The reaction was
quenched with saturated NaHCO3 (aq) and filtered through
celite. The mixture was extracted with ether (3£10 mL) and
the combined extracts were washed with saturated NH4Cl
(aq), dried over MgSO4, then concentrated in vacuum. The
crude material was purified by flash column chroma-
tography (ether/pet. ether, 1/1, v/v) to give 0.106 g (45%)
4.6.23. N-(tert-Butoxycarbonyl)-2-(3-methyl-1-oxo-2-
butenyl)pyrrolidine (23). General procedure D was
employed (1b, 0.10 g, 0.58 mmol). Purification of the
crude product by medium pressure liquid chromatography
(20% ether/pet. ether) gave 0.076 g (99%) of 23 as a
colorless oil: IR 1702 (s), 1642 (w), 1463 (w), 1412 (s),
1174 (m), 1123 (m) cm21; 1H NMR for rotamers (minor) d
1.30 (1.39) (s, 9H), 1.69–1.93 (m, 4H), 1.84 (1.86) (s, 3H),
2.12 (s, 3H), 3.30–3.58 (m, 2H), 4.10 (4.28) (dd, J¼5.4,
8.7 Hz, 1H), 6.03 (6.06) (s, 1H); 13C NMR for rotamers
(minor) d 20.8 (20.9), 23.7 (24.1), 27.8, 28.1 (28.3), (29.0)
30.2, 46.7 (46.8), (65.3) 66.0, (79.4) 76.7, 119.4 (120.4),
154.0 (154.4), 157.4 (157.7), (199.1) 199.8; mass spectrum,
m/z (relative intensity) EI 253 (0.4, Mþ), 180 (0.4), 170 (29,

R. K. Dieter et al. / Tetrahedron 59 (2003) 1083–1094
1093
3. Whitesides, G. M.; Casey, C. P.; San Filippo, Jr. J.; Panek, E. J.
Trans. N.Y. Acad. Sci. 1967, 29, 572.
4. (a) Posner, G. H.; Whitten, C. E. Tetrahedron Lett. 1970, 4647.
of a colorless oil: IR (neat) 3432 (br, s), 3056 (s), 2978 (s),
2304 (w), 1693 (vs), 1405 (s), 1265 (vs), 1160 (s), 1116 (s),
;
915 (m), 741 (vs) cm21 1H NMR for diastereomers or
`
(b) Jallabert, C.; Luong-Thi, N. T.; Riviere, H. Bull. Soc.
Chim. Fr. 1970, 797.
rotamers (minor) d 1.22 (1.24) (s, 9H), 1.44 (s, 9H), 1.77–
2.05 (m, 6H), 2.19–2.42 (m, 2H), 3.38–3.77 (m, 4H), 5.11–
5.34 (m, 2H), 7.96–8.11 (m, 4H); 13C NMR for diaster-
eomers or rotamers (minor) d 23.5 (24.2), 28.1 (28.4), 29.6
(30.7), 46.6 (46.8), 61.3 (61.5), 79.9, 128.4 (128.7), 138.5
(138.6), 153.6 (154.4), 198.0 (198.3). High-resolution mass
spectrum m/z 472.2580 (Mþ) (calcd for C26H36N2O6
472.2573).
5. Posner, G. H.; Whitten, C. E.; McFarland, P. E. J. Am. Chem.
Soc. 1972, 94, 5106.
6. (a) Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A.
Tetrahedron Lett. 1995, 36, 7305. (b) Babudri, F.; Fiandanese,
V.; Marchese, G.; Punzi, A. Tetrahedron 1996, 52, 13513.
7. Faust, R.; Weber, C.; Fiandanese, V.; Marchese, G.; Punzi, A.
Tetrahedron 1997, 53, 14655.
8. (a) Dieter, R. K.; Sharma, R. R.; Ryan, W. Tetrahedron
Lett. 1997, 38, 783. (b) Structures 11 and 5 were drawn
incorrectly in this paper as the smaller homologues i.e.
missing one –(CH2)– unit and are correctly represented
by structures 5 and 13, respectively, in this full report.
9. For a review on a-amino ketone synthesis see: Fisher, L. E.;
Muchowski, J. M. Org. Prep. Proced. Int. 1990, 22, 399.
10. (a) Orlemans, E. O. M.; Verboom, W.; Lammerink, B. H. M.;
Reinhoudt, D. N. Recl. Trav. Chim. Pays-Bas 1989, 108, 64.
(b) Overhand, M.; Hecht, S. M. J. Org. Chem. 1994, 59, 4721.
(c) Falorni, M.; Giacomelli, G.; Spanedda, A. M. Tetrahedron:
Asymmetry 1998, 9, 3039. (d) Trost, B. M.; Scanlan, T. S.
J. Am. Chem. Soc. 1989, 111, 4988.
4.6.26. 1,4-Bis(N-tert-butoxycarbonyl-2-pyrrolidinyl)-
1,4-butanedione (26b). General procedure
B
was
employed. The crude material was purified by flash column
chromatography (ether/pet. ether, 1/1, v/v) to give 0.0148 g
(7%) of a colorless oil: IR (neat) 3502 (w), 3056 (m), 2978
(s), 2925 (m), 2882 (m), 2305 (w), 2254 (w), 1684 (s), 1396
(s), 1265 (s), 1160 (s), 1119 (s), 908 (m), 732 (s) cm21; 1H
NMR for rotamers or diastereomers (minor) d 1.39 (1.44) (s,
18H), 1.72–2.30 (m, 8H), 2.55–2.95 (m, 4H), 3.31–3.61
(m, 4H), 4.15–4.41 (m, 2H); 13C NMR for rotamers or
diastereomers (minor) d 23.7 (24.4), 28.3 (28.4), 28.9, 29.9,
31.7 (31.8), 32.1 (32.5), 46.8 (47.0), (64.6, 64.7, 64.8, 64.9)
65.3, 79.7 (79.8), 153.9 (154.7), 208.7 (208.8, 209.2).
11. Guzman, A.; Quintero, C.; Muchowski, J. M. Can. J. Chem.
1991, 69, 2059.
4.6.27. 1-Phenyl-3-heptanone (27a). A premixed solution
of CuCl (0.049 g, 0.50 mmol) and LiCl (0.042 g, 1.0 mmol)
in 4.0 mL of THF was cooled to 2788C and treated with n-
BuMgCl (0.28 mL, 0.48 mmol). The mixture was slowly
warmed to 2608C and then treated with 3-phenyl propionyl
chloride (0.08 mL, 0.53 mmol). The mixture was stirred for
5–10 min, quickly warmed to room temperature, quenched
with NaHCO3, extracted with ether (3£15 mL), dried over
MgSO4 and concentrated in vacuo. Purification of the crude
material by medium pressure liquid chromatography (5%
ether/pet. ether) gave 0.088 g (96%) of pure 27a as a
colorless liquid: IR 1727 (s), 1506 (m), 1472 (m), 1387 (m),
12. Bonte, J. P.; Piancastelli, M. C.; Lesieur, I.; Lamar, J. C.;
Beaughard, M.; Dureng, G. Eur. J. Med. Chem. 1990, 25,
361.
13. (a) Digenis, G. A.; Agha, B. J.; Tsuji, K.; Kato, M.; Shinogi,
M. J. Med. Chem. 1986, 29, 1468. (b) Fittkau, S.; Jahreis, G.;
Peters, K. J. Prakt. Chem. 1986, 328, 529.
14. (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem.
Soc. 1994, 116, 2742. (b) Lociuro, S.; Pellacani, L.; Tardella,
P. A. Tetrahedron Lett. 1983, 24, 593. (c) Adam, W.;
Roschmann, K. J.; Saha-Moller, C. R. Eur. J. Org. Chem.
2000, 3, 557.
1
1183 (m), 1089 (m), 766 (m), 714 (m) cm21; H NMR d
15. (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22,
3815. (b) Hamby, J. M.; Hodges, J. C. Heterocycles 1993, 35,
843. (c) De Luca, L.; Giacomelli, G.; Taddei, M. J. Org. Chem.
2001, 66, 2534.
0.88 (t, J¼7.5 Hz, 3H), 1.21–1.40 (m, 2H), 1.50–1.62 (m,
2H), 2.37 (t, J¼7.5 Hz, 2H), 2.71 (t, J¼7.2 Hz, 2H), 2.90 (t,
J¼7.2 Hz, 2H), 7.11–7.35 (m, 5H); 13C NMR d 13.8, 22.2,
25.8, 29.7, 42.6, 44.1, 125.9, 128.2, 128.4, 141.1, 210.2;
mass spectrum, m/z (relative intensity) EI 190 (23, Mþ), 172
(1), 148 (25), 33 (29), 105 (79, Mþ2C5H9O), 91 (100), 85
(38), 57 (60, C4H9).
16. Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 3189.
´
17. Barluenga, J.; Baragan˜a, B.; Concellon, J. M. J. Org. Chem.
1995, 60, 6696.
18. Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti, G.;
Ricci, A.; Varchi, G. Synlett 1998, 1013.
19. De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3,
1519.
Acknowledgements
20. Tomoyasu, T.; Tomooka, K.; Nakai, T. Synlett 1998, 1147.
21. Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109. and
references cited therein.
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 acknowledged
(CHE-9700278).
22. Dieter, R. K.; Dieter, J. W.; Bhinderawala, N. S.; Nice, L. E.,
unpublished results.
23. Dieter, R. K.; Topping, C. M.; Nice, L. E. J. Org. Chem. 2001,
66, 2302.
¨
24. Backvall, J.-E.; Persson, E. S. M.; Bombrun, A. J. Org. Chem.
1994, 59, 4126. and Ref. 13 cited therein.
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