BF3-mediated additions of organolithiums to ketimines: X-ray crystal structures of BF3-ketimine complexes

Article abstract of DOI:10.1021/jo0480895

(Chemical Equation Presented) Additions of lithium acetylides and n-BuLi to N-alkyl ketimines mediated by BF₃-Et₂O in THF afford hindered tert-alkylamines in moderate to good yields. Stereochemical results and crystal structures of t

Full text of DOI:10.1021/jo0480895

Although BF3-mediated organolithium additions to
aldimines are well documented,3 analogous additions to
ketimines appear to have been reported only for special-
ized cases.4 We provide herein representative examples
of BF3-mediated 1,2-additions to simple N-alkylketimines;
these reactions occur in respectable yields and display
odd stereochemistries. Several X-ray crystal structures
of BF3-ketimine complexes suggest that A1,3-strain may
be an important stereochemical determinant.7,8
BF3-Mediated Additions of Organolithiums
to Ketimines: X-ray Crystal Structures of
BF3-Ketimine Complexes
Yun Ma, Emil Lobkovsky, and David B. Collum*
Department of Chemistry and Chemical Biology,
Baker Laboratory, Cornell University,
Ithaca, New York 14853-1301
We previously reported that the crystalline, air-stable
BF3-n-Bu3N complex mediates additions to aldimines.
Attempts to extend this protocol to the addition of lithium
phenylacetylide (PhCCLi) to ketimines, however, afford
only (PhCC)3B(n-Bu3N).2,6c Returning to the more tradi-
tional procedure,3 treating ketimine 1 with 1.0 equiv of
BF3-THF complex (generated in situ from BF3-Et2O)
affords a mixture of free and BF3-complexed imine (2)
as evidenced by IR absorbances of the CdN moieties at
1659 and 1630 cm-1, respectively.9 Monitoring the reac-
tion of complex 2 with 3.0 equiv of lithium phenylacetyl-
ide with in situ IR spectroscopy reveals the instantaneous
loss of complex 2 and no measurable disappearance of
the free imine. The yield of the 1,2-addition correlates
with the extent of observable BF3-imine complexation.
The optimum yields required 2.0 equiv of BF3-THF and
3.0 equiv of PhCCLi at 4.0 M THF concentration in
toluene. The low THF concentration renders complex-
ation of the imine to BF3 more competitive. This protocol
was used for all subsequent 1,2-additions without further
optimization.
dbc6@cornell.edu
Received October 28, 2004
Additions of lithium acetylides and n-BuLi to N-alkyl
ketimines mediated by BF3-Et2O in THF afford hindered
tert-alkylamines in moderate to good yields. Stereochemical
results and crystal structures of three BF3-imine complexes
suggest that allylic strain strongly influences conformation
and may be an important determinant of reactivity and
selectivity.
BF3 has been used to facilitate reactions of organo-
lithium reagents with a wide range of electrophiles.1-5
The accelerating effects of BF3 can be spectacular,
allowing reactions that are sluggish at room temperature
to proceed instantaneously at -78 °C. Spectroscopic and
rate studies for the addition of lithium acetylides to
aldimines mediated by BF3-R3N complexes showed that
BF3 and lithium acetylides do not condense before 1,2-
addition.2,6
(1) For an extensive bibliography of BF3-mediated organolithium
reactions see ref 2.
(2) Aubrecht, K. B.; Winemiller, M. D.; Collum, D. B. J. Am. Chem.
Soc. 2000, 122, 11084.
(3) BF3-mediated additions to aldimines: Wada, M.; Sakurai, Y.;
Akiba, K. Tetrahedron Lett. 1984, 25, 1083. Uno, H.; Shiraishi, Y.;
Shimokawa, K.; Suzuki, H. Chem. Lett. 1988, 729. Uno, H.; Okada,
S.; Suzuki, H. Tetrahedron 1991, 47, 6231. Uno, H.; Okada, S.; Ono,
T.; Shiraishi, Y.; Suzuki, H. J. Org. Chem. 1992, 57, 1504. Kawate,
T.; Yamada, H.; Yamaguchi, K.; Nishida, A.; Nakagawa, M. Chem.
Pharm. Bull. 1996, 44, 1776. Campbell, J. B.; Dedinas, R. F.; Trum-
bower-Walsh, S. A. J. Org. Chem. 1996, 61, 6205. Meltz, C. N.;
Volkmann, R. A. Tetrahedron Lett. 1983, 24, 4503. Alvaro, G.; Savoia,
D. Synlett 2002, 651. Shimizu, M.; Niwa, Y.; Kawamoto, M. Tennen
Yuki Kagobutsu Toronkai Koen Yoshishu 1999, 41, 301 (CAN 132:
308565 AN 1999:776438). Kawate, T.; Yamada, H.; Yamaguchi, K.;
Nishida, A.; Nakagawa, M. Chem. Pharm. Bull. 1996, 44, 1776. Pyne,
S. G.; Dikic, B.; Skelton, B. W.; White, A. H. Aust. J. Chem. 1992, 45,
807.
(4) BF3-mediated additions of perfluoroalkyllithiums to aldimines
and a single ketimine were reported: Uno, H.; Okada, S.; Shiraishi,
Y.; Shimokawa, K.; Suzuki, H. Chem. Lett. 1988, 7, 1165.
(5) Reviews describing the organolithium chemistry of imines:
Denmark, S. E.; Nicaise, O. J.-C. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, Y., Eds; Springer-
Verlag: Heidelberg, Germany, 1999; Chapter 26.2. Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069. Enders, D.; Reinhold, U.
Tetrahedron: Asymmetry 1997, 8, 1895. Volkmann, R. A. In Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds; Pergamon:
Oxford, UK, 1991; Chapter 1.12. Bloch, R. Chem. Rev. 1998, 98, 1407.
The yields and affiliated stereoselectivities for 1,2-
additions of n-BuLi, EtCCLi, and PhCCLi are sum-
marized in Table 1 (eq 1). The ketimines were prepared
and characterized with standard procedures as described
in the Supporting Information. The mixtures resulting
from syn-anti isomerism have been studied and dis-
cussed previously.10 Stereochemistries were assigned by
(6) Previous mechanistic studies of BF3-mediated reactions of or-
ganolithiums: (a) Eis, M. J.; Wrobel, J. E.; Ganem, B. J. Am. Chem.
Soc. 1984, 106, 3693. (b) Brown, H. C.; Racherla, U. S.; Singh, S. M.
Tetrahedron Lett. 1984, 25, 2411. (c) Davies, J. E.; Raithby, P. R.;
Snaith, R.; Wheatley, A. E. H. J. Chem. Soc., Chem. Commun. 1997,
1797. (d) Barr, D.; Hutton, K. B.; Morris, J. H.; Mulvey, R. E.; Reed,
D.; Snaith, R. J. Chem. Soc., Chem. Commun. 1986, 127.
(7) Blackwell, J. M.; Piers, W. E.; Parvez, M.; McDonald, R.
Organometallics 2002, 21, 1400.
(8) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(9) IR spectroscopic studies of imine-BF3 complexes: Samuel, B.;
Snaith, R.; Summerford, C.; Wade, K. J. Chem. Soc. A 1970, 2019.
(10) Extensive leading references to the syn-anti isomerism in
imines: Liao, S.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 15114.
10.1021/jo0480895 CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/19/2005
J. Org. Chem. 2005, 70, 2335-2337
2335

TABLE 1. 1,2-Additions of Organolithiums to Ketimines
FIGURE 1. ORTEP of BF3-imine complex 24 revealing syn-
oriented BF3.
FIGURE 2. ORTEP of BF3-imine complex 25 revealing syn-
oriented BF3 and axially disposed methyl.
BF3-THF and lithium acetylides affords essentially no
adduct, instead causing the CdN absorbance to increase
due to what may be acetylide adducts of general structure
22. Analogous reaction with n-BuLi affords n-butyl
a Stereochemistry was assigned based on analogy with the
EtCCLi adduct.
adduct 16 in 29% purified yield as a single (uncharac-
terized) stereoisomer. In one instance, BF3-adduct 23
survived a basic workup and flash chromatography;11
a
standard aqueous HCl workup afforded 5.
1
1
using a combination of H,13C-HMQC, H,13C-HMBC,
1H,1H-COSY, 1H,1H-NOESY, and 1H and 13C NMR
spectroscopies or from X-ray crystallography on the
amine hydrochloride salts. The butyne and n-butyl ad-
ducts were related by hydrogenation of the alkynyl
moiety. The PhCCLi adducts were assigned by analogy
to the EtCCLi adducts, an imperfect but reasonable
method. In the most sterically congested cases, substitu-
tion at the boron of the imine-BF3 complex may be a
significant side reaction. For example, reaction of a
menthone-derived imine (see entry 9) sequentially with
Structures of BF3-Imine Complexes. Crystal struc-
tures of BF3-imine complexes 24-26 (Figures 1-3)
provided some insights into the origins of the stereose-
lectivity. In all cases, the BF3 group orients toward the
more substituted side of the imine (as drawn), presum-
ably because it is less sterically demanding than the
N-alkyl groups. This orientation contrasts with several
B(C6F5)3/imine complexes reported by Piers and co-
(11) The 1H NMR spectrum of adduct 23 displayed an AB quartet
for benzylic protons.
2336 J. Org. Chem., Vol. 70, No. 6, 2005

tional control imparted by the allylic (A1,3) strain8,13 is
important, although the details are far from obvious. The
preference for adducts 7 and 13 is interesting given that
n-BuLi addition in the absence of BF3 affords comple-
mentary isomers (6 and 12, respectively), albeit slowly
and in <10% yield. The origin of the inordinately high
preference for equatorial attack to produce 17 is unclear.
Experimental Section
BF3-Mediated Addition: A General Protocol. The in situ
IR probe was inserted through a nylon adapter fitted with an
O-ring seal into an oven-dried, cylindrical flask fitted with
magnetic stir bar and T-joint. The T-joint was capped by a
septum for injection and N2 line. After evacuation under full
vacuum and flushing with N2, the flask was charged sequentially
with 15 mL of 4.0 M THF in toluene and BF3-Et2O (0.19 mL,
0.10 mmol) and then cooled to -78 °C. After recording a
background spectrum, a ketimine (0.05 mmol) was added neat.
The lithium acetylide in THF or n-BuLi in pentane was added,
and the reaction was monitored by recording IR spectra every
30 s for 3 min. The reaction was quenched with 20% aqueous
NaOH (5 mL) and extracted with ether. The extracts were dried
over Na2SO4, concentrated, and purified by silica gel column
chromatography.
Preparation of Crystalline BF3-Imine Complexes: Gen-
eral Protocol. To a solution of imine (10.0 mmol) in pentane
(20 mL) was added BF3-Et2O (12.0 mmol) at 0 °C. Stirring at
0 °C for 15 min typically affords an off-white to brown precipi-
tate. Filtration under nitrogen and recrystallization from CH2-
Cl2/pentane affords the imine-BF3 complex as a white or off-
white crystalline solid displaying stability to limited exposure
to the atmosphere.
FIGURE 3. ORTEP of BF3-imine complex 26 revealing syn-
oriented BF3 and diaxially disposed alkyl substituents.
workers in which the hindered BAr3 orients to the less
hindered side.7 Marked A-strain is evidenced by the
axially oriented methyl in 25 and the diaxially oriented
alkyl groups in 26. NMR spectroscopy suggests that 24
and 25 are representative of the bulk material. In fact,
addition of a crystalline sample of 25 to solutions of
n-BuLi or EtCCLi provides yields and selectivities similar
to those obtained with the in situ protocol. In contrast,
the isolated solid from which a crystal of 26 was obtained
affords very complex NMR spectra consistent with a
mixture of geometric isomers and diastereomers arising
from epimerization. BF3-imine complexes 24-26 dis-
played a reluctance to hydrolyze on brief exposure to
laboratory atmosphere that was surprising given the
sensitivity of the uncomplexed imines. This stability and
ease of handling may prove synthetically useful.
Acknowledgment. We thank the National Science
Foundation for direct support of this work as well as
Dupont Pharmaceuticals, Merck Research Laboratories,
Pfizer, Aventis, R. W. Johnson, Schering-Plough, and
Boehringer-Ingelheim for indirect support.
Supporting Information Available: Preparations of the
imines, spectroscopic characterization of the 1,2-adducts, and
crystallographic characterization of three BF3-imine com-
plexes. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO0480895
Stereochemistry. Although high reaction rates thwart-
ed mechanistic studies, a few comments about the
stereochemistry are warranted. It is curious that n-BuLi
and EtCCLi add from opposite faces. This stereochem-
istry is reminiscent of that obtained in 1,2-additions to
cyclohexanones in which opposing steric and electronic
effects conspire to cause similar reversals.12 Possibly the
major n-BuLi adducts (7 and 13) represent the sterically
more accessible approach. It seems likely that conforma-
(12) Leading references to nucleophilic additions to cyclohex-
anones: Lindsay, H. A.; Salisbury, C. L.; Cordes, W.; McIntosh, M. C.
Org. Lett. 2001, 3, 4007. Yamataka, H. J. Phys. Org. Chem. 1995, 8,
445. Cieplak, A. S. Chem. Rev. 1999, 99, 1265.
(13) For stereoselective reductions of imines and iminium salts in
which allylic strain appears to be consequential, see: Hutchins, R. O.;
Su, W. Y.; Sivakumar, R.; Cistone, F.; Stercho, Y. P. J. Org. Chem.
1983, 48, 3412. See also: Meza-Leon, R. L.; Crich, D.; Bernes, S.;
Quintero, L. J. Org. Chem. 2004, 69, 3976.
(14) n-Butyllithium can be recrystallized: Hoffmann, D.; Collum,
D. B. J. Am. Chem. Soc. 1998, 120, 5810. Kottke, T.; Stalke, D. Angew.
Chem., Int. Ed. Engl. 1993, 32, 580.
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