Synthesis and reactivity of dipole-stabilized but unchelated α-aminoorganolithiums

Article abstract of DOI:10.1021/jo000786j

Two N-methyl-5-lithio-2-pyrrolidinones have been prepared by tin-lithium exchange. These two α-aminoorganolithium compounds that are stabilized by an amide dipole, but not by chelation to the amide carbonyl. Both constitute test cases for comparing the st

Full text of DOI:10.1021/jo000786j

6
196
J . Org. Chem. 2000, 65, 6196-6201
Syn th esis a n d Rea ctivity of Dip ole-Sta bilized bu t Un ch ela ted
r-Am in oor ga n olith iu m s
Donna M. Iula and Robert E. Gawley*
Department of Chemistry, University of Miami, P.O. Box 249118, Coral Gables, Florida 33124
rgawley@miami.edu
Received May 22, 2000
Two N-methyl-5-lithio-2-pyrrolidinones have been prepared by tin-lithium exchange. These two
R-aminoorganolithium compounds that are stabilized by an amide dipole, but not by chelation to
the amide carbonyl. Both constitute test cases for comparing the stability and reactivity of “dipole-
stabilized” and “unstabilized” R-aminoorganolithiums. We find that active methylene protons
interfere with the reaction, so geminal disubstitution R to the amide carbonyl was necessary to
supress side reactions. These species do not react as efficiently as unstabilized R-aminoorgano-
lithiums, or even as well as chelated dipole-stabilized R-aminoorganolithiums, toward typical
electrophiles. The tin-lithium exchange to form these species was also not as facile as with other
R-aminoorganostannanes.
In tr od u ction
The study of R-aminoorganolithium compounds over
the past 35 years has not only left us richer in our
repertoire of synthetic methods (for reviews, see refs
none occurs stereospecifically with retention,17,18 whereas
enantiopure 2 (or its pyrrolidine analog) adds to ben-
16
zophenone in a stereorandom fashion; this difference
may reflect a difference in oxidation potential of the or-
ganolithium, with more easily reduced electrophiles re-
1
-13) but also hungry to develop a unifying theory to
12,19
acting by single electron transfer (SET).
A third class
rationalize the behavior of these species. R-Aminoorgano-
3
of sp R-aminoorganolithium compounds (3) is one which
is dipole-stabilized but lacks the possibility of internal
chelation such as that seen with compounds such as 1.
lithium compounds in which the metal-bearing carbon
3
is sp can be classified as either dipole-stabilized (such
as carbamate 1) or unstabilized (such as amine 2).
Although one might take issue with the nomenclature,14
there are clear and distinct differences in the chemical
properties of these two types of functionalized organo-
lithiums (drawn for convenience in this paper as cova-
lent). For example, both types react with carbonyl
electrophiles in good to excellent yield. On the other hand,
organolithium 2 shows greater resistance to racemization
than 1.15 In addition, the dipole-stabilized systems such
as 1 do not react well with alkyl halides while their
unstabilized counterparts (e.g., 2) do so with high yields
and invertive stereoselectivities, a property that makes
them unique among nonmesomerically stabilized orga-
nolithiums.16 Last, addition of scalemic 1 to benzophe-
One obvious structural difference between 1 and 2 is
that, in 1, the lithium is probably coordinated to the
carbonyl oxygen but not the nitrogen, whereas in 2, the
20a
lithium bridges the carbon-nitrogen bond.
These
structural features are observed in crystal structures of
20b,21
similar compounds
and may contribute to the ob-
served differences in chemical behavior. Recent evidence
(
(
(
(
1) Beak, P.; Reitz, D. B. Chem. Rev. 1978, 78, 275.
2) Beak, P.; Zajdel, W. J .; Reitz, D. B. Chem. Rev. 1984, 84, 471.
3) Meyers, A. I. Aldrichimica Acta 1985, 18, 59.
shows that amide nitrogens may participate as acceptors
in hydrogen bonds.2
2,23
Would the amide nitrogen of a
4) Highsmith, T. K.; Meyers, A. I. In Advances in Heterocyclic
species such as 3 coordinate the lithium and render its
reactivity similar to 2, or would the reactivity of 3 be
more similar to that of 1? To our knowledge, dipole-
stabilized but unchelated organolithiums such as 3 are
unprecedented, although the constitutional isomer of 3,
Natural Product Synthesis; Pearson, W. H., Ed.; J AI: Greenwich, CT,
991; Vol. 1, p 95.
5) Gawley, R. E.; Rein, K. In Comprehensive Organic Synthesis.
1
(
Selectivity, Strategy, and Efficiency in Modern Organic Chemistry;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, p 65.
(
6) Gawley, R. E.; Rein, K. S. In Comprehensive Organic Synthesis;
Schreiber, S., Ed.; Pergamon: Oxford, 1991; Vol. 1, p 459.
(
7) Meyers, A. I. Tetrahedron 1992, 48, 2589.
8) Beak, P.; Basu, A.; Gallagher, D. J .; Park, Y. S.; Thayumanavan,
(17) Nikolic, N. A.; Beak, P. In Organic Syntheses; Freeman, J . P.,
Ed.; Wiley: New York, 1998; Collect. Vol. IX, p 391.
(
S. Acc. Chem. Res. 1996, 29, 552.
(18) Kopach, M. E.; Meyers, A. I. J . Org. Chem. 1996, 61, 6764.
(19) Gawley, R. E.; Low, E.; Zhang, Q.; Harris, R. J . Am. Chem. Soc.
2000, 122, 3344.
(20) (a) Lithium bridging has recently been observed spectroscopic-
ally: Low, E.; Gawley, R. E. J . Am. Chem. Soc. 2000, accepted. (b)
Boche, G.; Marsch, M.; Harbach, J .; Harms, K.; Ledig, B.; Schubert,
F.; Lohrenz, J . C. W.; Ahlbrecht, H. Chem. Ber. 1993, 126, 1887.
(21) Becke, F.; Heinemann, F. W.; R u¨ ffer, T.; Wiegeleben, P.; Boese,
R.; Bl a¨ ser, D.; Steinborn, D. J . Organomet. Chem. 1997, 548, 205.
(22) Cox, C.; Lectka, T. Org. Lett. 1999, 1, 749.
(
(
(
(
9) Yus, M. Chem. Soc. Rev. 1996, 155.
10) Gawley, R. E. Curr. Org. Chem. 1997, 1, 71.
11) Kessar, S. V.; Singh, P. Chem. Rev. 1997, 97, 721.
12) Gawley, R. E. In Advances in Asymmetric Synthesis; Hassner,
A., Ed.; J AI: Greenwich, CT, 1998; Vol. 3, p 77.
(
13) Katritzky, A. R.; Qi, M. Tetrahedron 1998, 54, 2647.
(14) Seebach, D.; Hansen, J .; Seiler, P.; Gromek, J . M. J . Organomet.
Chem. 1985, 285, 1.
(
(
15) Gawley, R. E.; Zhang, Q. Tetrahedron 1994, 50, 6077.
16) Gawley, R. E.; Zhang, Q. J . Org. Chem. 1995, 60, 5763.
(23) Cox, C.; Lectka, T. J . Am. Chem. Soc. 1998, 120, 10660.
1
0.1021/jo000786j CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/25/2000

Dipole-Stabilized but Unchelated R-Aminoorganolithiums
J . Org. Chem., Vol. 65, No. 19, 2000 6197
Sch em e 1a
lation had indeed occurred, although it had not gone to
completion, and three benzophenone adducts were found,
as shown in eq 1. As we had anticipated, deprotonation
of the lactam’s acidic proton is a competing side-reaction
as we observed two C-3 benzophenone adducts (13 and
1
4) in addition to the desired C-5 adduct 12. Clearly if
we were to study the reactivity of such a system, it would
have to be done in the absence of any acidic protons so
that we could concentrate on adducts resulting exclu-
sively from metalation at the 5-position of the pyrrolidi-
none.
azaallyl anion 4, was reported by Pearson and Stevens
shortly after we began our work.24 Herein, we wish to
report the results of our investigation into this new type
of R-aminoorganolithium. Because deprotonation is not
a viable route to such a compound, tin-lithium exchange
was planned. The questions we sought to answer were
as follows:
(
1) Could such a species be synthesized via tin-lithium
exchange? Transmetalation is sometimes problematic in
R-aminoorganostannanes.2
5-29
(2) How would the organolithium react with a variety
of electrophiles: would it behave more like chelated
dipole stabilized R-aminoorganolithiums (e.g., 1) or un-
stabilized R-aminoorganolithiums (e.g., 2)?
Resu lts
Therefore, n-BuLi-mediated tin-lithium exchange of
gem-dimethyl lactam 10 in the presence of TMEDA was
carried out at -78 °C as shown in eq 2. The reaction was
monitored by TLC for the disappearance of starting
material and quenched with benzophenone after 1.3 h
at -78 °C giving 14% of the desired product along with
The stannylated lactams used in this study were
synthesized as shown in Scheme 1. Starting from suc-
cinimide, ethoxy lactam 6 was prepared by careful NaBH
4
reduction according to Speckamp’s procedure.30 Treat-
ment of 6 with benzotriazole in acetic acid leads to
benzotriazole adduct 7, which is then treated with 2 equiv
of tri-n-butyltinlithium according to Pearson’s proce-
dure.24 Quenching of the stannylation reaction with
methyl iodide affords 1-methyl-5-tri-n-butylstannyl-2-
pyrrolidinone 8 in good yield. Monomethyl and dimethyl
analogues 9 and 10 were prepared by successive LDA
deprotonation followed by methyl iodide quenching.
To minimize possible competition of the lactam’s acidic
R-protons for the n-BuLi, we began our studies using
lactam 9. Thus, a solution of stannane 9 with 1.3 equiv
of TMEDA was treated with 1.3 equiv of n-BuLi at -78
3
4% of unreacted starting material. This yield was
improved to 30% by raising the transmetalation temper-
ature to -25 °C for 1.3 h to ensure complete transmeta-
lation. The best results, however, were obtained when
the transmetalation mixture was maintained at -78 °C
for 30 min and then placed in a bath at -50 °C for an
additional 30 min. Under these conditions, we could
isolate a 90% yield of tetrabutyltin, the byproduct of
transmetalation. The isolated yield of benzophenone
adduct 16 under these conditions was 44%.
°
C. The reaction was monitored by TLC for the disap-
pearance of starting material and quenched with ben-
zophenone after 30 min at -78 °C. TLC revealed the
presence of tetrabutyltin (the byproduct of transmetala-
tion), some unreacted starting material, benzophenone,
and three new products. After isolation, analysis of the
products by NMR and FAB-MS revealed that transmeta-
(
(
24) Pearson, W. H.; Stevens, E. P. J . Org. Chem. 1998, 63, 9812.
25) Tsunoda, T.; Fujiwara, K.; Yamamoto, Y.; It oˆ , S. Tetrahedron
Lett. 1991, 32, 1975.
(
(
26) Chong, J . M.; Park, S. B. J . Org. Chem. 1992, 57, 2220.
27) Burchat, A. F.; Chong, J . M.; Park, S. B. Tetrahedron Lett. 1993,
3
4, 51.
28) Gawley, R. E.; Evanseck, J . D.; Pearson, W. H.; Stevens, E. P.
(
To further explore the scope of 10’s reactivity, other
electrophiles were employed (eq 3). Trimethylsilyl chlo-
ride also couples effectively with the organolithium as
trimethylsilyl adduct 17 was isolated in 46% yield. Under
the same reaction conditions however, benzyl bromide
In ECHET96. Electronic Conference on Heterocyclic Chemistry; Rzepa,
H., Snyder, J ., Eds.; Royal Society of Chemistry: London, 1997; (CD-
ROM).
(
(
29) Chambournier, G.; Gawley, R. E. Org. Lett. 2000, 2, 1561.
30) Hubert, J . C.; Wijnberg, J . B. P. A.; Speckamp, W. N. Tetra-
hedron 1975, 31, 1437.

6
198 J . Org. Chem., Vol. 65, No. 19, 2000
Iula and Gawley
and cyclohexanone gave yields of only 19 and 21%
respectively.
different properties, exploring other types of dipole-
stabilized species, such as typified by 20 and its lithium
counterpart, is worthwhile. Because of kinetic barriers
and competing sites for deprotonation, tin-lithium ex-
change was chosen to access these species.
The first report of tin-lithium exchange in R-aminoor-
ganostannanes, to make dimethylaminomethyllithium,
appeared 30 years ago.3
9,40
More recently, several ex-
amples have been reported where transmetalation
fails,2
5-29
although minor structure modifications often
facilitate the tin-lithium exchange. For example, Chong
found that whereas secondary stannane 24 would not
transmetalate to 25, the derivative 26, in which a
chelating methoxy ligand is present, transmetalates
smoothly to 27.2
6,27
In 1991, Tsunoda reported the failure
of 28 to transmetalate to 29, whereas Pearson showed
that either diastereomer of 30 transmetalated to 31
smoothly.41 In these examples, transmetalation appears
to depend on the presence of an oxygen capable of
chelation.
Discu ssion
Several theoretical studies have been conducted over
the years in an effort to understand the behavior of
R-aminocarbanions and R-aminoorganolithiums. In 1981,
single-point calculations using the 4-31+G basis set on
STO-3G-optimized geometries showed that formylating
-
the nitrogen of H
2
NCH
2
provided 28 kcal/mol stabiliza-
tion.31 In this and a subsequent study, it was found that
the anionic lone pair of a dipole stabilized anion prefer-
ably occupies the nodal plane of the amide π system, a
feature that is now well documented in reactions of
32
3
1,33-35
dipole-stabilized R-aminoorganolithiums,
and con-
firmed in the solid state.1
4,20
In 1989, our group showed
that, of the four possible orientations of the anionic lone
pair, illustrated as 20-23, the most stable was 21, the
least stable 23.36 Interestingly, it is the latter anion that
most closely resembles 1, absent the lithium ion. In the
presence of a lithium ion, 23 is stabilized significantly,
and becomes the most stable (6-31G* basis set).36 The
free anion that most closely resembles 3 is 20, 10 kcal/
mol more stable than 23. Since unstabilized R-aminoor-
In THF, the mechanism of tin-lithium exchange
involves oxidative addition of BuLi to a tetraalkyltin,
producing a tin ate-complex, which then reductively
eliminates an alkyllithium to regenerate a tetraalkyltin
-
37
42
ganolithiums such as 2, modeled by CH
2
NH
2
and its
and an alkyllithium. It is thought that the reaction is
2
0,38
lithium counterpart LiCH
2
NH
2
,
have proven to be an
thermodynamically controlled, with the most stable alkyl-
1
0
43
extraordinarily versatile species, and since dipole sta-
bilization of R-aminoorganolithiums afford species, mod-
eled by 23 and its lithium counterpart, with significantly
lithium being formed. There are two possible explana-
tions for the failure of tin-lithium exchange: one is the
failure to produce the ate-complex, possibly due to steric
(
31) Rondan, N. G.; Houk, K. N.; Beak, P.; Zajdel, W. J .; Chan-
drasekhar, J .; Schleyer, P. v. R. J . Org. Chem. 1981, 46, 4108.
32) Bach, R. D.; Braden, M. L.; Wolber, G. J . J . Org. Chem. 1983,
8, 1509.
33) Seebach, D.; Wykpiel, W.; Lubosch, W.; Kalinowski, H. O. Helv.
Chim. Acta 1978, 61, 3100.
(38) Schleyer, P. v. R.; Clark, T.; Kos, A. J .; Spitznagel, G. W.; Rohde,
C.; Arad, D.; Houk, K. N.; Rondan, N. G. J . Am. Chem. Soc. 1984, 106,
6467.
(39) Peterson, D. J . J . Am. Chem. Soc. 1971, 93, 4027.
(40) Peterson, D. J . J . Organomet. Chem. 1970, 21, P63.
(41) Pearson, W. H.; Lindbeck, A. C. J . Am. Chem. Soc. 1991, 113,
8546.
(42) Reich, H. J .; Borst, J . P.; Coplein, M. B.; Phillips, N. H. J . Am.
Chem. Soc. 1992, 114, 6577.
(43) Sawyer, J . S.; Kucerovy, A.; Macdonald, T. L.; McGarvey, G. J .
J . Am. Chem. Soc. 1988, 110, 842.
(
4
(
(
(
(
(
34) Beak, P.; Lee, W. K. J . Org. Chem. 1990, 55, 2578.
35) Shawe, T. T.; Meyers, A. I. J . Org. Chem. 1991, 56, 2751.
36) Bartolotti, L. J .; Gawley, R. E. J . Org. Chem. 1989, 54, 2980.
37) Clark, T.; K o¨ rner, H.; Schleyer, P. v. R. Tetrahedron Lett. 1980,
2
1, 743.

Dipole-Stabilized but Unchelated R-Aminoorganolithiums
J . Org. Chem., Vol. 65, No. 19, 2000 6199
hindrance by the butyl groups, the other is that reductive
elimination produces a different alkyllithium than the
one you want. Pearson showed that failure of the trans-
metalation of compounds similar to 24 was not due to
steric hindrance around tin, as shown by the example
below, wherein transmetalation of 32 is achieved under
forcing conditions, but not in the desired way.28 Instead
of producing an R-aminoorganolithium by reductive
elimination, methyllithium is eliminated. Successive
cycles produce 33 and 34 in a 1:2 ratio.
lithium transmetalations depend on subtle structural
differences. Here, we have a subtle structural difference
that does not produce a failure, but does attenuate the
proclivity of a reaction. Stannanes 24, 26, 28, and 30 are
all acyclic, so the relevant comparison is to cyclic R-ami-
nostannanes 35 and 37, which require the synclinal lone
pair for successful transmetalation. While speculative,
the successful transmetalation of 9 and 10 may mean
that, in reacting with the stannane, the butyllithium is
able to substitute the π-system of an amide (or the lone
pair of an amide nitrogen) for the synclinal lone pair of
a basic nitrogen in the transmetalation.
After cooling the THF solution of 15 back down to -78
C, it was quenched with a variety of electrophiles. With
°
benzophenone and trimethylsilyl chloride, moderate yields
of coupling products 16 and 17 were obtained. An
interesting point is the mechanism of coupling with
benzophenone. Dipole-stabilized organolithium 1 adds to
benzophenone by a polar mechanism with retention of
configuration, affording enantiopure adduct (g99.5% ee)
in 73-74% yield.17 In contrast, enantiopure lithiopiperi-
dine 2, or its pyrrolidine analogue, add to benzophenone
in 50% and 70% yields, respectively, but the products are
racemic.16 Mechanistic studies suggest that the reason
for the stereorandom additions of 2 is the intervention
of a SET process.19 A question that could be posed is
whether 15 adds by SET. Since all compounds in this
study are racemic, we cannot use the steric course as an
indicator. A qualitative observation we have made over
the years is that stereorandom additions of R-aminoor-
ganolithiums to benzophenone are accompanied by an
In our laboratories, we have found that rigid stannyl-
piperidines transmetalate readily when the tin is in an
equatorial configuration (35 f 36), but fail to transmeta-
late at all when the tin is axial (37 f 38).29 In this case,
the availability of the lone pair of a basic nitrogen, in a
synclinal relationship to the tin, is a requirement.
intense blue color that has been identified as the benzo-
phenone ketyl.1
6,44
In the present instance, we saw a
green color, which could have arisen from some ketyl
blue) and the organolithium (pale yellow). Although
(
inconclusive, this could mean that some SET had oc-
curred.
The other two electrophiles tested, benzyl bromide and
cyclohexanone gave only about 20% yield of coupling
product, for reasons that are not clear. We did not find
any of stannane 10 in the product mixture, indicating
that there are pathways other than those producing
substitution products in operation. These could include
removal of a proton from the electrophile or the solvent,
fragmentation of the heterocycle, or in the case of benzyl
bromide, SET pathways. However, adducts 18 and 19
were the only identifiable products we could find. Note
that if protonation of 15 occurred, the lactam produced
would probably be very volatile and difficult to isolate
after rotary evaporation or even atmospheric distillation.
Attempts to find other products by GC-MS were unsuc-
cessful due to the large amounts of tetrabutyltin in the
product mixture.
Based on these precedents, we were interested in
evaluating the facility by which compounds of general
structure 3 could be made by tin-lithium exchange, since
a chelating atom is absent, and the nitrogen lone pair is
tied up by delocalization into the amide carbonyl. In the
first experiments with 9, our fears of complications from
proton transfers from the active methylene protons were
confirmed. The desired adduct 12 was only isolated in
1
4% yield, along with aldol adduct 13 in 6% yield.
Destannylated aldol adduct 14 was obtained in 21% yield,
indicating that a complex sequence of deprotonations and
destannylations must have occurred. The isolation of 12%
yield of recovered 9 gave us our first indication that this
type of stannane might be less susceptible to tin-lithium
exchange than the stannane precursors to either 1 or 2.
To avoid the complications of proton transfer, we
continued our investigation with trimethylpyrrolidinone
Con clu sion
We have found that R-aminoorganostannanes such as
9 and 10 undergo transmetalation with n-BuLi to yield
the corresponding dipole-stabilized organolithium which
then reacts with electrophiles in 20-50% yields. The
organolithium coupled best with benzophenone and TM-
SCl but less well with benzyl bromide and cyclohexanone.
On the basis of these studies, it appears that dipole-
1
0. The yield of tetrabutyltin, the byproduct of tin-
lithium exchange, was judged to be the most reliable
indicator of the efficiency of the transmetalation, and
treatment of 10 for 30 min at -78 °C and 30 min at -50
°C, gave a 90% yield of tetrabutyltin. This rather lengthy
treatment is considerably more vigorous than that re-
quired to produce organolithiums such as 2, which are
formed by tin-lithium exchange after only 5-10 min at
(44) Rein, K. S.; Chen, Z.-H.; Perumal, P. T.; Echegoyen, L.; Gawley,
-78 °C. As outlined above, successes and failures of tin-
R. E. Tetrahedron Lett. 1991, 32, 1941.

6
200 J . Org. Chem., Vol. 65, No. 19, 2000
Iula and Gawley
stabilized, but unchelated, R-aminoorganolithiums do not
behave as well toward electrophiles as their nonstabilized
counterparts.
period. After stirring for an additional 30 min, the reaction
mixture was cooled to -78 °C. A solution of lactam 9 (2.1 g,
5
5
.2 mmol) in THF (15 mL) was then added dropwise over a
-minute period. This caused the reaction to turn a dark yellow
color. Iodomethane (0.65 mL, 10.4 mmol) was added via
syringe and the mixture allowed to stir for 1 h. The reaction
was then diluted with diethyl ether (150 mL), washed with
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR and 13C NMR spectra were
recorded on either a 300 or a 400 MHz spectrometer. Elemen-
tal analyses were performed at Atlantic Microlab, Inc. (Nor-
cross, GA). FAB mass spectra were recorded on a single-stage
quadropole mass spectrometer. HRMS were recorded at the
University of California (Riverside) Mass Spectroscopy Facil-
ity. IR spectra were recorded on a FT-IR instrument. Column
chromatography was performed on silica gel 60 (230-400
mesh) while TLC was carried out using on aluminum backed
plates coated with 0.25 mm silica gel 60 (F-254). Solvents were
freshly distilled prior to use: THF and diethyl ether from
aqueous NH
dried over MgSO
ent: 100% Hex to 5:1 to 1:1 Hex/EA) afforded 10 (1.60 g, 74%)
as a yellow oil: 1H NMR (CDCl
, 300 MHz) δ 0.88-0.97 (15H,
4
Cl (2 × 20 mL), treated with brine (20 mL), and
4
. Column chromatography (silica gel, gradi-
3
m), 1.09 (3H, s), 1.16 (3H, s), 1.29-1.38 (6H, m), 1.46-1.54
13
(
(
4
4
6H, m), 1.88-2.10 (3H, m), 3.45 (1H, t, J ) 7.5 Hz); C NMR
CDCl , 75 MHz) δ 9.3, 14.0, 23.9, 25.6, 27.8, 27.8, 29.5, 31.4,
3
-1
+
0.2, 40.9, 46.4, 180.1; IR (neat) 1688 cm ; MS (FAB) MH
18. Anal. Calcd for C19 39NOSn: C, 54.83; H, 9.44. Found:
)
H
C, 54.86; H, 9.42.
Gen er a l P r oced u r e for Tr a n sm eta la tion a n d Electr o-
p h ile Qu en ch . To a stirring solution of lactam (490 mg, 1.18
mmol) and TMEDA (0.267 mL, 1.77 mmol) in THF was added
n-BuLi (1.6 mL, c ) 1.1 M, 1.77 mmol) at -78 °C or -82 °C
sodium-benzophenone ketyl, while CH
diisopropylamine were distilled from CaH
2
Cl
2
, DMF, TMEDA, and
. All reagents were
2
obtained commercially and used as received. The n-BuLi and
s-BuLi were titrated using 1,3-diphenylacetone p-tosylhydra-
zone as acid and indicator.
2
under Ar or N . After 30 min at this temperature the reaction
vessel was placed in a bath maintained at - 50 °C where it
remained for an additional 30 min. The reaction was then
cooled back to -78 °C and after a short while (10-30 min) is
quenched with the given electrophile (2.36 mmol) and allowed
to warm to room-temperature overnight. The reaction mixture
was then diluted with diethyl ether (100 mL), washed with
1
-Meth yl-5-(tr i-n -bu tylsta n n yl)-2-p yr r olid in on e (8). To
a 0 °C-cooled solution of diisopropylamine (4.6 mL, 32.64
mmol) in THF (100 mL) was added n-BuLi (25.90 mL, c ) 1.26
M, 32.6 mmol) dropwise via syringe over a 20 min period under
2
N . After the solution was stirred for 30 min, tributyltin
hydride (9.17 mL, 34.1 mmol) was added dropwise via syringe
over a 20-min period. The reaction mixture turned a turbid
yellow color. After 40 min, the benzotriazole-lactam 7 (3.00 g,
4.8 mmol) was added as a solid portionwise. The reaction
turned orange as the lactam was being added. After 2 h at 0
C, iodomethane (4.62 mL, 74.2 mmol) was added and the
reaction mixture was allowed to warm to room temperature
overnight. Note: the addition of the iodomethane caused the
reaction mixture to turn opaque and pink colored, which
eventually turned yellow with white precipitate. The mixture
was diluted with diethyl ether (200 mL), and water (50 mL)
was added. The organic phase was then washed with 10%
water (2 × 15 mL) then brine (15 mL) and dried over MgSO
4
.
Careful column chromatography (solvent gradient: 100% Hex
to 10:1 to 5:1 to 3:1 to 1:1 Hex/EA) afforded the desired
coupling products.
1
1
,3-Dim eth yl-5-(d ip h en ylh yd r oxym eth yl)-2-p yr r olid i-
°
n on e (12). According to the general procedure for transmeta-
lation and electrophilic quench, 12 was isolated as a yellow
solid: 1H NMR (CDCl
3
, 300 MHz) [diastereomeric mixture] δ
[
2
1.07 and 1.14] (3H, d, 7 Hz), [1.47-1.55 and 1.77-1.81 and
.14-2.27] (3H, m), [4.59 (d, J ) 8.5 Hz) and 4.74 (t, J ) 7,6
Hz)] (1H), 7.25-7.68 (10H, m); HRMS calcd for C19H22NO
2
+
(
MH ) 296.1651, found 296.1657.
NaOH (2 × 25 mL), satd NH
4
Cl (25 mL), and brine (25 mL)
and then dried over MgSO . Column chromatography (silica
1
,3-Dim e t h yl-3-(d ip h e n ylh yd r oxym e t h yl)-5-(t r i-n -
4
bu tylsta n n yl)-2-p yr r olid in on e (13). According to the gen-
gel, gradient: 100% Hex to 5:1 Hex/EA to 1:1 Hex/EA) afforded
the desired product as a yellow oil (4.71 g, 82%): H NMR
, 300 MHz) δ 0.89-0.98 (15H, m), 1.29-1.37 (6H, m),
.48-1.52 (6H, m), 2.08 (1H, m), 2.29-2.38 (3H, s), 3.53-3.58
eral procedure for transmetalation and electrophilic quench,
1
1
1
3 was isolated as a light yellow oil: H NMR (CDCl
3
, 300
(
1
(
3
3
CDCl
3
MHz) δ 0.90 (15H, t, J ) 7.1 Hz), 1.25-1.32 (6H, st, J ) 7.1
Hz), 1.40-1.48 (9H, m), 2.05-2.13 (1H, dd, J ) 13.5, 7.3 Hz),
1
3
1H, m); C NMR (CDCl
3
, 75 MHz) δ 9.5, 14.0, 24.2, 27.8, 29.5,
2
.30-2.36 (1H, dd, J ) 9.6, 7.3 Hz), 2.68 (3H, s), 3.00-3.06
-
1
+
0.8, 32.2, 51.0, 174.9; IR (neat) 1656 cm ; MS (FAB) MH
90.
,3-Dim eth yl-5-(tr i-n -bu tylstan n yl)-2-pyr r olidin on e (9).
)
(
1H, dd, J ) 13.5, 9.6 Hz), 6.77 (bs, 1H), 7.20-7.78 (10H, m);
13
C NMR (CDCl
3
, 75 MHz) δ 9.6, 14.0, 23.6, 27.7, 29.3, 31.0,
1
36.0, 47.2, 50.6, 82.0, 127.3, 127.3, 127.8, 127.9, 128.1, 128.2,
144.2, 146.4, 179.3; IR (neat) 3342 and 1655 cm ; MS (FAB)
MH ) 569.
-
1
To a 0 °C-cooled solution of diisopropylamine (2.21 mL, 15.8
mmol) in THF (30 mL) was added n-BuLi (14.36 mL, c ) 1.1
M, 15.8 mmol) dropwise via syringe over a 10-minute period.
After stirring for an additional 20 min, the reaction mixture
was cooled to -78 °C. A solution of lactam 8 (4.71, 12 mmol)
in THF (30 mL) was then added dropwise over a 20-minute
period. This caused the reaction to turn a dark olive-green
color. Iodomethane (1.5 mL, 24 mmol) was added via syringe
and the mixture allowed to stir for 1.5-2 h. The reaction was
then diluted with diethyl ether (100 mL), washed with sat.
+
1,3-Dim eth yl-3-(d ip h en ylh yd r oxym eth yl)-2-p yr r olid i-
n on e (14). According to the general procedure for transmeta-
lation and electrophilic quench, 14 was isolated as a colorless
oil: 1H NMR (CDCl , 300 MHz) δ 1.36 (3H, s), 1.91-1.98 (1H,
3
m), 2.67-2.78 (2H, m), 2.82 (3H, m), 3.22-3.29 (1H, m), 6.83
(1H, bs), 7.20-7.53 (10H, m); 13C NMR (CDCl , 75 MHz) δ 22.0,
3
30.3, 30.6, 46.7, 50.4, 82.0, 127.3, 127.3, 128.0, 128.1, 128.3,
-1
144.3, 146.3, 180.5; IR (neat) 3314 and 1659 cm ; HRMS calcd
+
NH
MgSO
4
Cl (2 × 30 mL), treated with brine (15 mL), and dried over
for C H NO (MH ) 296.1651, found 296.1642.
1
9
22
2
4
. The crude product was then purified by column
1,3,3-Tr im eth yl-5-(d ip h en ylh yd r oxym eth yl)-2-p yr r oli-
d in on e (16). According to the general procedure for trans-
metalation and electrophilic quench, 16 was isolated as a white
chromatography (silica gel, gradient: 5:1 to 3:1 to 2:1 to 1:1
Hex/EA) to afford 9 (3.75 g, 78%) as a light yellow oil: 1H NMR
1
(
CDCl
3
, 300 MHz) δ 0.87-0.94 (15H, m), 1.19 (3H, d, J ) 6.8
solid: mp ) 210-211 °C; H NMR (CDCl , 300 MHz) δ 1.13
3
Hz), 1.27-1.36 (6H, m), 1.43-1.53 (6H, m), 1.95-2.00 (1H,
(6H, s), 1.24-1.29 (1H, m), 2.38 (3H, s), 2.71 (1H, bs), 4.75
(1H, t, J ) 7.6 Hz), 7.20-7.70 (10H, m); 13C NMR (CDCl , 75
m), 2.23-2.31 (2H, m), 2.80 (3H, s), 3.44-3.48 (1H, dd, J )
3
1
3
9
2
(
.4, 3 Hz); C NMR (CDCl
9.5, 30.7, 33.2, 37.6, 48.9, 176.4; IR (neat) 1685 cm ; MS
3
, 75 MHz) δ 9.7, 14.0, 16.3, 27.8,
MHz) δ 25.8, 27.0, 32.1, 37.4, 39.9, 64.1, [125.6 and 125.7],
-
1
[127.3 and 127.6], [128.8 and 129.0], 144.9 and 146.4], 183.0;
+
-1
FAB) MH ) 404. Anal. Calcd for C18
.27. Found: C, 53.81; H, 9.23.
H
37NOSn: C, 53.57; H,
IR (neat) 3300 and 1685 cm ; HRMS calcd for C H24NO2
(MH ) 310.1807, found 310.1810. Anal. Calcd for C H23NO2:
20
2
0
+
9
1
,3,3-Tr im et h yl-5-(t r i-n -b u t ylst a n n yl)-2-p yr r olid in o-
C, 77.64; H, 7.49. Found: C, 77.90; H, 7.72
n e (10). To a 0 °C-cooled solution of diisopropylamine (0.95
mL, 6.76 mmol) in THF (20 mL) was added n-BuLi (5.0 mL,
c)1.35M, 6.76 mmol) dropwise via syringe over a 5-minute
1-Meth yl-3,3-d im eth yl-5-tr im eth ylsilyl-2-p yr r olid in o-
n e (17). According to the general procedure for transmetala-
tion and electrophilic quench, 17 was isolated as a colorless

Dipole-Stabilized but Unchelated R-Aminoorganolithiums
oil: 1H NMR (CDCl
, 300 MHz) δ 0.10 (9H, s), 1.07 (3H, s),
J . Org. Chem., Vol. 65, No. 19, 2000 6201
3
26.0, 27.7, 28.9, 29.5, 32.3, 35.0, 37.3, 40.1, 66.3, 74.3, 181.8;
-
1
+
1
7
.17 (3H, s), 1.61 (1H, dd, J ) 12 Hz), 1.85 (1H, dd, J ) 12.5,
Hz), 2.85 (3H, s), 2.93 (1H, dd, J ) 11.4, 7 Hz); 13C NMR
, 75 MHz) δ -2.9, 23.7, 25.8, 30.8, 37.6, 40.4, 47.0, 181.2;
IR (neat) 3421 and 1668 cm ; MS (FAB) MH ) 226 m/z. Anal.
Calcd for C13
10.31.
2
H22NO : C, 69.29; H, 10.29. Found: C, 69.00; H,-
(
CDCl
IR (neat) 1685 cm ; HRMS calcd for C10
99.1392, found 199.1400.
-Met h yl-3,3-d im et h yl-5-ben zyl-2-p yr r olid in on e (18).
According to the general procedure for transmetalation and
3
-
1
+
H
21NOSi (M )
1
Ack n ow led gm en t. We are grateful to the National
Institutes of Health for generous financial support (GM-
6271). Early exploratory work on this project was
performed by Professor Leonard Kellar, Florida Inter-
national University, with support from the Petroleum
Research Fund. We also thank NIH and NSF for shared
instrumentation grants for the purchase of the NMR
and MS instruments used in this work.
1
5
1
electrophilic quench, 18 was isolated as a colorless oil:
NMR (CDCl , 300 MHz) δ 1.06 (3H, s), 1.14 (3H, s), 1.55 (1H,
dd, J ) 27, 7 Hz), 1.81 (1H, dd, J ) 24, 7 Hz), 2.52 (1H, dd, J
9, 5.5 Hz), 2.89 (3H, s), 3.24 (1H, dd, J ) 8.7, 4.5 Hz), 3.65
H
3
)
1
3
(
1H, m); C NMR (CDCl
3
, 75 MHz) δ 25.7, 26.3, 28.8, 40.5,
4
0.7, 41.0, 58.2, 127.1, 129.1, 129.6, 137.5, 180.5; IR (neat) 1684
-
1
+
cm ; HRMS calcd for C14
18.1542.
-Meth yl-3,3-d im eth yl-5-(1′-h yd r oxycycloh exyl)-2-p yr -
H20NO (MH ) 218.1545, found
2
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
1
13
and C NMR for compounds 8-10, 13, 14, and 16-19. This
material is available free of charge via the Internet at http://
pubs.acs.org.
r olid in on e (19). According to the general procedure for
transmetalation and electrophilic quench, 19 was isolated as
1
a white solid: mp ) 120-122 °C; H NMR (CDCl
3
, 300 MHz)
δ 1.10 (3H, s), 1.20 (3H, s), 1.33-1.92 (13H, m), 3.00 (3H, s),
3
.39 (1H, t, J ) 8 Hz); 13C NMR (CDCl
3
, 75 MHz) δ 21.2, 21.4,
J O000786J