An experimental and computational study of stereoselectivity and reactivity in Lewis acid promoted lithiation-substitution of tertiary amines

Article abstract of DOI:10.1021/ja0675144

Reaction of BF₃ coordinated N-ethylpyrrolidine with benzophenone, using a preformed complex of s-BuLi and (-)-sparteine for lithiation at -78 °C, affords enantio-enriched R-product (er 85:15). With a warm-cool cycle (-78° → 0°, 2 h, → -78°) pri

Full text of DOI:10.1021/ja0675144

Published on Web 03/27/2007
An Experimental and Computational Study of Stereoselectivity and Reactivity
in Lewis Acid Promoted Lithiation-Substitution of Tertiary Amines
Satinder V. Kessar,*, Paramjit Singh,* Kamal Nain Singh, P. Venugopalan, Amarjit Kaur,
†
,†
†
†
†
,
‡
†
Prasad V. Bharatam,* and Arvind K. Sharma
Department of Chemistry, Panjab UniVersity, Chandigarh, India-160014, and Department of Medicinal Chemistry,
NIPER, Mohali, India-160062
Received October 20, 2006; E-mail: svkessar@pu.ac.in
The Lewis acid promoted lithiation-electrophile reaction se-
quence (1-2-3-4) has emerged as a powerful methodology for
forming new bonds at weakly acidic R-C-H centers of tertiary
amines and phosphines (Scheme-1).1 Regarding its stereochemical
Scheme 1
-9
3
course, Vedjes has inferred that BH complexed aziridines get
lithiated syn to the boranato group under conditions of kinetic
control, and subsequent reaction with electrophile is retentive.2
However, in the case of BH complexed cyclic amines having
3
rapidly inverting delocalised R-carbanionic centers, almost exclusive
formation of anti substitution products has been observed under
certain conditions,3 while BH
,4
complexed phospholanes afford
3
9
nearly equal proportions of syn and anti substitution products. Such
substantial formation of anti substitution product is intriguing
because the equilibrium position may be expected to lie strongly
in favor of the syn lithiated intermediate having a matched
alignment of dipoles (syn-3). However, this crucial issue does not
seem to have been examined closely, and no stereochemical
investigations on equilibration or relevant computational studies
seem to be available.
Scheme 2
We have found that in the lithiation-benzophenone reaction of
BF complexes of N-ethyl pyrrolidine and indolizidine, enantiomeric
3
ratios (er) and diasteriomeric ratios (dr) of products change
markedly if the lithiated intermediates are subjected to a warm-
cool cycle (-78° f 0°, 2 h, f -78°) prior to the addition of the
electrophile (Schemes 2 and 3). These results are interpreted in
terms of a kinetic syn lithiation followed by net inversion on
equilibration at the higher temperature. B3LYP level DFT computa-
tions indicate that while in the gas phase the syn arrangement is
considerably more stable as expected, the relative stability can shift
toward the anti if the solvent dielectric constant or baring of the
carbanion are taken into consideration. These computations also
reveal strong Li-F bonding in 3a which may be responsible for
Scheme 3
specific rotation was observed and a warm-cool cycle going up
to 0 °C gave 8 as the major enantiomer (er 86:14).
Change of product configuration owing to a switch between
retentive and invertive substitution with change of electrophile,
solvent, countercation, etc. is known. Since, in the present study
all these parameters remain unchanged, with or without the warm-
cool cycle, such reversal is unlikely. Therefore the results may be
interpreted in terms of an initial enantioselective syn lithiation, with
concurrent dissymmetrisation of the quarternary nitrogen and
subsequent net carbanionic inversion on equilibration (Scheme 2).
10
superior promotion of lithiation by BF
3
.
Deprotonation of 6 in THF at -78 °C with a preformed complex
3,4
-
+
of (-)-sparteine and Schlosser base (s-BuLi + t-BuO K ) followed
by addition of benzophenone afforded a racemic alcohol in 59%
yield. However, when this reaction was carried out in a toluene/
DEE (1:1) mixture, using s-BuLi as the base, the product 7 was
formed (28%) with good enantioselectivity (er 85:15)1 and its R
configuration was deduced by correlation of the minor enantiomer
3
0
12
However, it was considered desirable to monitor the stereochemical
course of the reaction by incorporating in the substrate another
stereocenter, like the bridgehead C-H in indolizidine (Scheme 3).
(8) with L-proline (Scheme 2). For equilibration of the lithiated
intermediate, the temperature was raised to a specified level for 2
h and after cooling back to -78 °C, benzophenone was added.
Change in enantioselectivity was monitored through specific rotation
of the product which decreased in magnitude and then reversed its
sign with increasing temperature of the warm-cool cycle (-78
The BF
3
complex 9a derived from indolizidine was assigned a
trans fused structure assuming complexation with the favored
2,13
invertomer of the parent amine.
BF complex afforded the corresponding BH
was purified by silica gel chromatography to get 9b as an oil. Its
Further LAH reduction of the
7,14
3
3
complex, which
RT
RT
RT
°
C, [R]
D
-26; -50 °C, [R]
D
-23; -28 °C, [R]
D
+7; 0 °C,
RT
11
[R]
D
+23). In DEE as solvent similar inversion in product
1
H NMR exhibited the two equatorial proton low-field signal (δ
3.3-3.4) characteristic of a trans fused structure.1
3,20c
Treatment
†
‡
Panjab University.
NIPER.
of a solution of 9a in DEE with a preformed complex of s-BuLi
4506
9
J. AM. CHEM. SOC. 2007, 129, 4506-4507
10.1021/ja0675144 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 1. ∆E (in Kcal/mol) for syn-anti Conformations
and 2.01 Å) while in 3a only one but closer Li‚‚‚F contact (1.82
Å) is present.20 AIM analysis shows low electron sharing only in
21
entry
molecule
solvent dielectric constant (
ꢀ
)
∆
Ea
3
a (FLi‚‚‚F: 0.0342) which is interestingly similar to that in the C-Li
1
2
3
4
5
6
7
8
9
3a
3a‚Me
3a
3a
3a
3a
3a‚2Me
3a
3a
3a
BF
BH
0 (gas phase)
0 (gas phase)
4.335 (DEE)
7.58 (THF)
16.39 (methyl phosphate)
0 (gas phase)
0 (gas phase)
4.335 (DEE)
7.58 (THF)
16.39 (methyl phosphate)
0 (gas phase)
21.43
13.50
3.60
-0.43
-10.07
19.44
10.39
0.64
2
O
bond of 3a (F: 0.0366), and there is a five-membered-ring critical
point. Strong fluorine bonding with lithium may have a role in more
effective activation of amines by BF as compared to other boron
3
Lewis acids, although, it has been a matter of some controversy.
Delineating the effectiveness difference further, we have found that
not only BH but also more strongly electron withdrawing BH CN
3 2
fails to promote lithiation of 6, 9, and even that of an N-alkyl
azitidine.
1
2
O
-7.93
b
10
11
12
NHCH -
NHCH
-2.94
-2.26
3
2
12b,22
-
3
2
0 (gas phase)
Acknowledgment. The authors thank DST, INSA, and CSIR
a
ZPE corrected. b Syn optimizes to anti.
New Delhi, India, for funding.
Supporting Information Available: Representative procedures and
characterization of new compounds and computational details. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(
1) Kessar, S. V.; Singh, P. Chem. ReV. 1997, 97, 721 and references cited
therein.
(
2) (a) Vedjes, E.; Kendall, J. T. J. Am. Chem. Soc. 1997, 119, 6941. (b)
Vedjes, E.; Prasad, B. A. S.; Kendall, J. T.; Russel, J. S. Tetrahedron
2003, 59, 9849.
Figure 1.
(
3) Ariffin, A.; Blake, A. J.; Ebden, M. R.; Li, W. S.; Simpkins, N. S; Fox,
D. N. A. J. Chem. Soc., Perkin Trans. 1 1999, 2439.
4) Ferry, V.; Twipet, L.; Gall, T. H.; Mioskowski, C. Angew. Chem., Int.
Ed. Engl. 1996, 35, 104.
and TMEDA for 2 h at -78 °C and quenching with Ph
2
CO afforded
(
alcohol 10 (46%) almost exclusively (10/11 dr 97:3, no six-
membered ring substitution detected). Its structure was confirmed
by single-crystal X-ray analysis that showed the bridgehead H and
the substituent to be on the opposite faces of the molecule as
expected from syn lithiation/substitution of 9a.15 Interjection of a
warm-cool cycle (-78° f 0°, 2 h, f -78°) before addition of
(5) For seminal work on Lewis acid promoted deprotonative chemistry in
gas phase see: Ren, J.; Workman, D. B.; Squires, R. R. J. Am. Chem.
Soc. 1998, 120, 10511-10522.
(6) Kuck, D. Angew. Chem., Int. Ed. Engl. 2000, 39, 125.
(
7) Concellon, J. M.; Suarez, J. R.; Granda, S. G.; Diaz, M. R. Angew. Chem.,
Int. Ed. Engl. 2004, 43, 4333.
(8) Takrouri, K.; Katzhendler, J.; Srebnik, M. Organometallics 2004, 23, 2817.
(
9) Sun, X.; Kei, M.; Lam, W. W.; Shiraishi, N.; Kobayashi, J.; Shiro, M.;
Utsumi, H.; Kobayashi, S. Chem.sEur. J. 2005, 11, 361 and references
cited therein.
2
Ph CO led to the formation of an isomeric alcohol 11 along with
10 (11/10 dr 59:41). The alcohol 11 is inferred to arise from the
(
10) (a) CSP HPLC was carried out on a Chiralcell OD column. (b) Yields
are based on isolated products not taking into account the balance starting
material and no basic side products were detected.
anti lithiated intermediate formed on equilibration. Use of PhNCO
as electrophile gave essentially similar results. When lithiation of
(
11) Interconversion of enantiomeric R-lithiated N-ethyl pyrrolidines, accessed
through a multistep sequence, shows similar temperature dependence. (a)
Coldham, I.; Dufour, S.; Haxel, T. F. N.; Patel, J. J.; Jimenez, G. S. J.
Am. Chem. Soc. 2006, 128, 10943. (b) Ashweek, N. J.; Brandt, P.;
Coldham, I.; Dufour, S.; Gawley, R. E.; Haeffner, F.; Klein, R.; Sanchez-
9a in DEE/toluene (1:1) was carried out with a preformed complex
of (-) sparteine and sec-BuLi, the obtained alcohol 10 (28%)
10
exhibited an er of 90:10, and no diastereomeric product could be
detected.1 In a similar reaction using DEE as the solvent, 10 was
obtained (26%) with an er of 97:3. Thus the reaction is highly regio-
and diastereoselective and affects a kinetic resolution of racemic
6a
3
Jimenez, G. J. Am. Chem. Soc. 2005, 127, 449. (c) BH complexed
R-lithiated phospholanes undergo rapid syn-anti conversion even at -100°
C (see ref. 9).
(
3
12) (a) Since BF complexed products could not be isolated, initial syn
16b
lithiation and subsequent integrity of the quaternary center on nitrogen is
9a.
based on literature inferences (refs 2 and 3) with BH
3
complexes. (b)
B3LYP/6-31+G* level computations on model lithiated inter-
Attempted lithiation of corresponding BH
(see Supporting Information).
3 2
and BH CN complexes failed
1
4
mediates (3a, 3b, R -R dH), idealized to minimize substituent
effects, reveal the syn arrangement to be more stable by 21.4 kcal/
mol. There is a significant decrease in syn-anti energy gap with
(
13) Ringdaht, B.; Pinder, A. R.; Pereira, W. E.; Oppenheimer, N. J.;
Cymerman, C. J. J. Chem. Soc., Perkin Trans. 1 1984, 1-4.
3
(14) BF complexes of amines are less amenable to isolation and direct
characterization as compared to BH
3
complexes.
2
the binding of two Me O molecules to vacant Li coordination sites.
(
15) (a) CCDC No. 619876. (b) See Supporting Information also.
However, inclusion of a solvent dielectric constant in simple solvent
continuum calculations dramatically increases the relative stability
of the anti arrangement, and in a solvent of high dielectric constant
(16) (a) However, with a warm-cool cycle, formation of diastereomeric
products and the lowering of 10 er (56:44) is observed. (b) The yield
based on kinetic resolution of racemic 9a is 56%. No alternate procedure
for R-substitution of amino ring juncture, a feature present in a variety of
alkaloids, is available.
like methyl phosphate it becomes considerably more stable (Table
(
17) It also emphasizes the need of more refined solvent treatment, desirably
taking into account local and bulk effects, in computations of lithiation-
substitution chemistry especially when the observed selectivity is opposite
to gas phase predictions or is seemingly counterintuitive. (a) Topics in
Organnometallic Chemistry; Springer-Verlag: 2003; Vol. 5, pp 1-310.
(b) Kessar, S. V.; Singh, P.; Singh, K. N.; Venugopalan, P.; Mahinderu,
M.; Kaur, A.; Kapoor, R. Tetrahedron Lett. 2005, 46, 6753.
3
1
). Besides this dielectric effect solvation, changes in aggregation
4
9
or additives can cause ion pair separation. Thus the lithiated
intermediate may behave more like a bare carbanion in which the
negative charge is directed away from the boranato group (entry
5
11, 12; Table 1). Although no quantitative correlation of experi-
(
18) Sapre, A.-M.; Schlyer, P. v. R. Lithium Chemistry: A Theoretical and
Experimental OVerView; John Wiley: New York, 1995.
mental results with idealized computations is warranted at this stage
and inversion of relative syn/anti stability with dielectric constant
is surprising, this trend and the carbanion baring effect are relevant
for understanding the formation of the anti substitution products.1
An additional feature of interest in these computations is the Li
interaction with boranato F and H in syn-3a and -3b (Figure 1).
(
19) (a) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem.,
Int. Ed. Engl. 2004, 43, 2206. (b) van Eikema Hommes, N. J. R.; Schleyer,
P. v. R. Tetrahedron 1994, 50, 5903.
(
20) For interest in such interactions see: (a) Bremer, M.; N o¨ th, H.; Warchhold,
M. Eur. J. Inorg. Chem. 2003, 1, 111. (b) Suresh, C. H.; Gadre, S. R.;
Gejji, S. P. Theor. Chem. Acc. 2003, 98, 151. (c) Rodriguez, M. G.;
Castolo, A. A.; Merino, G.; Vela, A.; Noth, H.; Bakhmutov, V. I.;
Contreras, R. J. Am. Chem. Soc. 2001, 123, 9144.
7,18
Such interactions in a transition state or a precomplex could be
responsible for kinetically controlled syn lithiation (CIPE).2a,19
(21) Bader, R. F. W. Chem. ReV. 1991, 91 (5), 893.
(22) This supports the role of Li-F interaction in BF effectiveness.
3
Interestingly in 3b two boron hydrogens approach Li (Li‚‚‚H, 1.92
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J. AM. CHEM. SOC.
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