Generation and utility of tertiary α-aminoorganolithium reagents

Article abstract of DOI:10.1021/ol049039p

A general approach to tertiary α-aminoorganolithium reagents by reductive lithiation of α-aminonitriles has been developed. This class of organolithium nucleophiles reacts efficiently with carbonyl electrophiles or in intramolecular cyclizations with teth

Full text of DOI:10.1021/ol049039p

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2745-2748
Generation and Utility of Tertiary
r-Aminoorganolithium Reagents
Scott A. Wolckenhauer and Scott D. Rychnovsky*
Department of Chemistry, 516 Rowland Hall, UniVersity of California-IrVine,
IrVine, California 92697-2025
srychnoV@uci.edu
Received May 24, 2004
ABSTRACT
A general approach to tertiary r-aminoorganolithium reagents by reductive lithiation of r-aminonitriles has been developed. This class of
organolithium nucleophiles reacts efficiently with carbonyl electrophiles or in intramolecular cyclizations with tethered phosphate leaving
groups. Transmetalation can be used to produce r-aminoorganocuprate reagents that react with alkyl halide electrophiles and in 1,4-additions
with enones. These methods establish a new approach for the synthesis of quaternary centers adjacent to nitrogen.
Since Peterson’s work on the generation of R-aminoorgano-
lithium reagents,1 the use of these intermediates in synthesis
has been extensively explored.2 Particular focus has been
given to the development of enantioselective processes that
take advantage of the high configurational stability associated
with these species.3 Frequently utilized methods for the
preparation of primary and secondary R-aminoorganolithiums
include (1) tin-lithium exchange and (2) deprotonation aided
by the proximity of a coordinating functional group. The
utility of these methods for the preparation of tertiary
R-aminoorganolithiums has not been well demonstrated. To
the best of our knowledge, no examples of tin-lithium
exchange to generate a tertiary R-aminoorganolithium have
been reported and deprotonation does not appear to be a
general strategy.4-6
An alternate approach to tertiary R-aminoorganolithium
reagents involves reductive lithiation of an aryl sulfide using
lithium di-tert-butylbiphenylide (LiDBB).7,8 In a similar
manner, reductive decyanation of R-aminonitriles under
traditional dissolving metal conditions (lithium or sodium
in liquid ammonia) generates R-metalloamines, albeit as
fleeting intermediates due to rapid protonation of the strongly
basic tertiary organometallics.9 Although R-aminonitriles are
(4) Deprotonation/lithiation at a benzylic position: (a) Meyers, A. I.;
Du, B.; Gonzalez, M. A. J. Org. Chem. 1990, 55, 4218-4220. (b) Meyers,
A. I.; Guiles, J.; Warmus, J. S.; Gonzalez, M. A. Tetrahedron Lett. 1991,
32, 5505-5508. (c) Park, Y. S.; Boys, M. L.; Beak. P. J. Am. Chem. Soc.
1996, 118, 3757-3758. (d) Hara, O.; Ito, M.; Hamada, Y. Tetrahedron
Lett. 1998, 39, 5537-5540.
(5) Deprotonation/lithiation at a cyclopropyl position: Beak, P.; Wu, S.;
Yum, E. K.; Jun, Y. M. J. Org. Chem. 1994, 59, 276-277.
(6) Seebach has used the N-nitroso group to faciliate lithiation at a tertiary
position; however, the potential carcinogenicity of N-nitrosoamines is likely
responsible for lack of further development of this method. See: (a) Seebach,
D.; Enders, D. Angew. Chem., Int. Ed. 1972, 11, 1101-1102. (b) Seebach,
D.; Enders, D. Angew. Chem., Int. Ed. 1975, 14, 15-32.
(7) LiDBB is an arene radical anion reducing agent first described by
Freeman: Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924-
1930.
(1) (a) Peterson, D. J. J. Organomet. Chem. 1970, 21, P63-64. (b)
Peterson, D. J. J. Am. Chem. Soc. 1971, 93, 4027-4031. (c) Peterson, D.
J.; Ward, J. F. J. Organomet. Chem. 1974, 66, 209-217.
(2) Reviews: (a) Beak, P.; Zajdel, W. J.; Reitz, D. B. Chem. ReV. 1984,
84, 471-523. (b) Katritzky, A. R.; Qi, M. Tetrahedron 1998, 54, 2647-
2668. (c) Gawley, R. E.; Coldham, I. R-Amino-organolithium Compounds.
In The Chemistry of Organolithium Compounds (Patai Series); Rappoport,
Z., Marek, I., Eds.; Wiley: Chichester, 2003; pp 997-1053.
(3) (a) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan,
S. Acc. Chem. Res. 1996, 29, 552-560. (b) Gawley, R. E.; Low, E.; Zhang,
Q.; Harris, R. J. Am. Chem. Soc. 2000, 122, 3344-3350. (c) Clayden, J.
Organolithiums: SelectiVity for Synthesis; Pergamon: Elmsford, NY, 2002;
Vol. 23.
(8) (a) Tsunoda, T.; Fujiwara, K.; Yamamoto, Y.-I.; Ito, S. Tetrahedron
Lett. 1991, 32, 1975-1978. (b) Florio, S.; Capriati, V.; Galio, A.; Cohen,
T. Tetrahedron Lett. 1995, 36, 4463-4466.
(9) Husson has extensively developed this method. For a review of his
elegant work, see: Husson, H.-P.; Royer, J. Chem. Soc. ReV. 1999, 28,
383-394.
10.1021/ol049039p CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/03/2004

readily accessed and elaborated10 and would appear to be
ideal precursors for this chemistry,11 their use in generation
of tertiary R-aminoorganolithiums under aprotic conditions
is essentially unknown.12-14 At the outset of our studies, we
sought to develop a general preparative strategy toward
tertiary R-aminoorganolithiums from R-aminonitriles as a
means of accessing polysubstituted amines (Figure 1).
2 (Table 1). When aldehydes or ketones are employed, the
intermediate lithium alkoxides undergo intramolecular cy-
clization upon warming to displace tert-butoxide and form
the depicted bicyclic carbamates.18 While low to moderate
levels of diastereoselectivity were observed in most cases,
addition of pivalaldehyde afforded a single detectable dia-
stereomer (entry 5).
Direct addition of alkyl halides to the organolithium
reagent derived from R-aminonitrile 2 is not an efficient
reaction. For example, addition of methyl iodide provides
desired addition product 14 in 13% yield along with side
products 17 and 18 in yields of 20 and 18%, respectively
(Table 2). These side products may arise from an intervening
single-electron transfer (SET) pathway.19 Meyers has found
that transmetalation of an R-aminoorganolithium to the
corresponding cuprate was effective in raising the yield of
desired addition products by limiting SET.19a,b In a modifica-
tion of this procedure, we have observed significantly
increased yields by performing the reductive lithiation and
then adding a solution of P(OMe)3-solubilized 1-hexynyl-
copper20 in THF prior to addition of an alkyl halide
electrophile (Table 2).
Figure 1. Polysubstituted Amines from R-Aminonitriles.
Importantly, the compatibility of these reactive intermediates
with various common electrophiles would need to be
addressed. Herein, we present initial results of our studies.
As a precursor for the bulk of our studies, we focused on
R-aminonitrile 2, synthesized in two steps from 2-cyano-
piperidine15 (Scheme 1). This compound undergoes rapid
The R-aminoorganocuprate reagents produced in this way
also engage in 1,4-addition with enones. Methyl vinyl ketone
(12) The following reference contains a cyclization that may proceed
through a tertiary R-aminoorganolithium reagent generated by LiDBB-
mediated reductive lithiation of an R-aminonitrile: Ribeiro, C. M. R.; de
Melo, S. J.; Bonin, M.; Quirion, J.-C.; Husson, H.-P. Tetrahedron Lett.
1994, 35, 7227-7230.
Scheme 1. Synthesis of R-Aminonitrile 2
(13) Grierson has prepared secondary R-aminoorganolithium reagents
by reductive metalation of R-aminonitriles: (a) Zeller, E.; Grierson, D. S.
Heterocycles 1988, 27, 1575-1578. (b) Zeller, E.; Grierson, D. S. Synlett
1991, 878-880.
(14) An additional, but relatively unexplored, method for the generation
of tertiary R-aminoorganolithium reagents involves lithium naphthalenide-
mediated reductive lithiation of imines: Guijarro, D.; Yus, M. Tetrahedron
1993, 49, 7761-7768.
(15) In a modification of De Kimpe’s procedure, 2-cyanopiperidine was
synthesized by adding KCN to 2,3,4,5-tetrahydropyridine, prepared using
Rapoport’s method. (a) Bender, D. R.; Bjeldanes, L. F.; Knapp, D. R.;
Rapoport, H. J. Org. Chem. 1975, 40, 1264-1269. (b) De Kimpe, N.;
Stevens, C. J. Org. Chem. 1993, 58, 2904-2906.
reductive lithiation with LiDBB in THF at -78 °C to produce
solutions of the desired lithiated piperidines,16,17 which show
good stability over a useful range of temperatures as dem-
onstrated by deuterium quenching experiments (Figure 2).
(16) Representative Reductive Lithiation Procedure. A solution of
100 mg (0.446 mmol) of R-aminonitrile 2 and 1 crystal of 1,10-
phenanthroline in 5.0 mL of THF was cooled to -78 °C and treated with
a few drops of n-butyllithium/hexanes solution to a brown endpoint (this
procedure serves to quench adventitious proton sources). A solution of
LiDBB (ca. 0.5 M) was added rapidly via a gastight syringe until the dark
green color persisted, indicating a slight excess of reducing agent and
complete consumption of the starting R-aminonitrile. The solution of
R-aminoorganolithium was then treated with an appropriate electrophile.
See Supporting Information for specific experimental details.
(17) By virtue of the Boc-protecting group, these intermediates fall under
the classification of “stabilized” R-aminoorganolithiums. We are also
studying the use of the reductive lithiation procedure to generate the related
“nonstabilized” (N-alkyl) R-aminoorganolithiums.
Figure 2. Deuterium Quenching Experiments.
(18) Beak has observed this behavior in similar systems: (a) Beak, P.;
Lee, W. K. J. Org. Chem. 1990, 55, 2578-2580. (b) Beak, P.; Lee, W. K.
J. Org. Chem. 1993, 58, 1109-1117.
The reductive lithiation/electrophilic addition protocol was
next extended to carbonyl compounds. Carbon dioxide,
methyl chloroformate, and a variety of aldehydes and ke-
tones, including those with acidic R-protons, react efficiently
with the organolithium reagent derived from R-aminonitrile
(19) Oxidation products similar to 18 have previously been observed in
reactions of 2-lithiopiperidines with alkyl halides. tert-Butylformamidine-
protected systems: (a) Meyers, A. I.; Edwards, P. D.; Rieker, W. F.; Bailey,
T. R. J. Am. Chem. Soc. 1984, 106, 3270-3276. (b) Meyers, A. I.; Milot,
G. J. Am. Chem. Soc. 1993, 115, 6652-6660. Oxazoline-protected
systems: (c) Gawley, R. E.; Hart, G. C.; Bartolotti, L. J. J. Org. Chem.
1989, 54, 175-181. Me-protected systems: (d) Chambournier, G.; Gawley,
R. E. Org. Lett. 2000, 2, 1561-1564. Boc-protected systems: (e) Bertini
Gross, K. M.; Beak, P. J. Am. Chem. Soc. 2001, 123, 315-321.
(20) Corey developed the use of alkynes as nontransferable ligands for
cuprate chemistry: Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1972,
94, 7210-7211.
(10) (a) Albright, J. D. Tetrahedron 1983, 39, 3207-3233. (b) Enders,
D.; Shilvock, J. P. Chem. Soc. ReV. 2000, 29, 359-373. (c) Gro¨ger, H.
Chem. ReV. 2003, 103, 2795-2827.
(11) Yus reported the first examples of reductive decyanation/lithiation
mediated by LiDBB in non R-amino systems: Guijarro, D.; Yus, M.
Tetrahedron 1994, 50, 3447-3452.
2746
Org. Lett., Vol. 6, No. 16, 2004

Table 1. Reductive Lithiation/Electrophilic Addition of
Table 2. Addition of Alkyl Halides to R-Aminoorganolithium
Carbonyl Compounds
and Cuprate Nucleophiles
yield (%)
via
via
entry
1
E+
MeI
product
organolithium
organocuprate
E ) Me
14
E ) C7H15
15
E ) allyl
16
13
a
52
51
60
2
3
C7H15
I
allylBr
29
a 5-Chloro-1-iodopentane afforded a 13% yield.
and 2-cyclohexenone produce adducts 20 and 21 in yields
of 64 and 60%, respectively (Scheme 2).21 In neither case
were the 1,2-addition products 12 or 13 observed. These
appear to be the first reported examples of the generation
and usage of tertiary R-aminoorganocuprate reagents.22
Scheme 2. 1,4-Addition Products
We have also extended this methodology to acyclic
R-aminonitrile 23 (Scheme 3). Applying the procedures used
for 2 afforded benzaldehyde addition product 24 in 75% yield
via the corresponding R-aminoorganolithium reagent. The
transmetalation protocol was also successful for aminonitrile
23, providing products 25 and 26 in 38 and 57% yields by
addition of n-iodoheptane or 2-cyclohexenone, respectively,
to the R-aminoorganocuprate reagent.
(21) TMS-Cl was used as an additive in each case. For the beneficial
effect of TMS-Cl in cuprate 1,4-additions, see: (a) Corey, E. J.; Boaz, N.
W. Tetrahedron Lett. 1985, 26, 6015-6018. (b) Corey, E. J.; Boaz, N. W.
Tetrahedron Lett. 1985, 26, 6019-6022.
(22) For a review of other applications of R-aminoorganocuprate
chemistry, see: Dieter, R. K. Heteroatomcuprates and R-Heteroatomalkyl-
cuprates in Organic Synthesis. In Modern Organocopper Chemistry; Krause,
N., Ed.; John Wiley & Sons: New York, 2002; pp 114-122.
a In cases where diastereomers were obtained, the major diastereomer is
shown. See Supporting Information for details of stereochemistry assign-
ment. b Determined by GC analysis of crude reaction mixtures. c Single
diastereomer was obtained.
Org. Lett., Vol. 6, No. 16, 2004
2747

Scheme 3. Acyclic R-Aminonitrile 23 and Addition Products
Scheme 4. Synthesis of 2-Spiropiperidines
electrophiles or in spirocyclizations with tethered phosphate
leaving groups. Transmetalation produces R-aminoorgano-
cuprates that will react with alkyl halides and enones in 1,4-
additions. Current efforts in our laboratory are focused on
directing this chemistry toward enantio- and diastereoselec-
tive processes, with a particular interest in the synthesis of
the spirocyclic cores of 2-spiropiperidine alkaloids.
Finally, we have applied our reductive lithiation procedure
toward the synthesis of simple 2-spiropiperidine ring systems
similar to those found in naturally occurring alkaloids such
as pinnaic acid23 and histrionicotoxin.24 Alkylation of amino-
nitrile 1 with iodides 27 or 28 produces cyclization precursors
29 and 30, respectively, having pendant phosphate leaving
groups (Scheme 4). Reductive lithiation and resultant cy-
clization produces the desired spiro[4.5] and [5.5] ring
systems.12,13,25
In summary, we have developed a method for the
generation of tertiary R-aminoorganolithium reagents from
R-aminonitriles using LiDBB-mediated reductive lithiation.
These intermediates react in good yield with carbonyl
Acknowledgment. This work was supported in part by
the National Institutes of Health (GM-65338). S.A.W.
acknowledges Amgen for a predoctoral fellowship. We are
grateful to Drs. John Greaves and John Mudd for mass
spectral analyses and Dr. Joe Ziller for determining the
crystal structure of compound 21.
(23) Chou, T.; Kuramoto, M.; Otani, Y.; Skiano, M.; Yazawa, K.;
Uemura, D. Tetrahedron Lett. 1996, 37, 3871-3874.
(24) Daly, J. W.; Karle, I. L.; Myers, C. W.; Tokuyama, T.; Waters, J.
A.; Witkop, B. Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 1870-1875.
(25) For similar reductive cyclizations, see: Rychnovsky, S. D.; Takaoka,
L. R. Angew. Chem., Int. Ed. 2003, 42, 818-820.
Supporting Information Available: Preparation and
characterization of the described compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL049039P
2748
Org. Lett., Vol. 6, No. 16, 2004