Reactivity series for s-BuLi/diamine-mediated lithiation of N-Boc pyrrolidine: Applications in catalysis and lithiation of N-Boc piperidine

Article abstract of DOI:10.1039/b603804m

Using competition experiments between a range of ligands and (-)-sparteine, a reactivity series for N-Boc pyrrolidine lithiation using s-BuLi/diamines has been constructed; the results indicate that the s-BuLi/(+)-sparteine surrogate complex is more reactive than s-BuLi/(-)-sparteine and this has been exploited in the selection of ligand pairs for ligand exchange catalytic asymmetric lithiation of N-Boc pyrrolidine and lithiation of N-Boc piperidine. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b603804m

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Reactivity series for s-BuLi/diamine-mediated lithiation of N-Boc
pyrrolidine: applications in catalysis and lithiation of N-Boc piperidine{
Matthew J. McGrath, Julia L. Bilke and Peter O’Brien*
Received (in Cambridge, UK) 14th March 2006, Accepted 20th April 2006
First published as an Advance Article on the web 10th May 2006
DOI: 10.1039/b603804m
s-BuLi/diamine complexes for the lithiation of N-Boc pyrrolidine
1. For this, an operationally simple approach was devised in which
competition experiments between two different ligands would be
used to assay relative reactivity. We proposed to investigate the
lithiation-Me3SiCl trapping of N-Boc pyrrolidine 1 using (2)-
sparteine as a reference diamine in competition with either chiral
diamines that give the opposite sense of asymmetric induction to
(2)-sparteine or achiral diamines. In this way, the enantiomer ratio
(er) of adduct 4 would be used as a measure of the relative
reactivity of s-BuLi/diamine compared to s-BuLi/(2)-sparteine and
this would ultimately enable us to compile a reactivity series.
Mixtures of two chiral ligands have previously been used to
investigate relative reactivities by Corey18 and Kagan19 (asym-
metric dihydroxylations), by Bolm,20 Noyori21 and Soai22 (addi-
tions of Et2Zn to benzaldehyde) and by Blackmond (asymmetric
hydrogenation).23,24 However, a competition experiment approach
using different chiral ligands for asymmetric deprotonation has not
previously been described. Herein, we present a reactivity series for
N-Boc pyrrolidine lithiation using s-BuLi and a range of chiral and
achiral ligands. This series is compiled from a set of competition
experiments. Furthermore, we demonstrate how this reactivity
order can be used to identify suitable ligand pairs for our recently
disclosed ligand exchange catalytic asymmetric deprotonation25
and to develop a higher yielding enantioselective lithiation of
N-Boc piperidine.
Using competition experiments between a range of ligands and
(2)-sparteine, a reactivity series for N-Boc pyrrolidine lithiation
using s-BuLi/diamines has been constructed; the results indicate
that the s-BuLi/(+)-sparteine surrogate complex is more reactive
than s-BuLi/(2)-sparteine and this has been exploited in the
selection of ligand pairs for ligand exchange catalytic asym-
metric lithiation of N-Boc pyrrolidine and lithiation of N-Boc
piperidine.
There is considerable evidence to indicate that diamines such as
(2)-sparteine ((2)-sp) and TMEDA influence the reactivity of
organolithium reagents.1 The effects imparted on organolithiums
complexed by (2)-sparteine have led to the development of high
yielding and highly enantioselective deprotonation reactions a to
nitrogen,2 oxygen3 and phosphorus.4 A typical example is the
s-BuLi/(2)-sparteine-promoted lithiation–Me3SiCl trapping of
N-Boc pyrrolidine 15 (1 A 4) which is believed to proceed by a
three-step process.6,7 In the first step, reversible precomplexation of
the s-BuLi/(2)-sparteine complex to N-Boc pyrrolidine 1 generates
complex 2. Rate limiting lithiation then occurs to give a-amino
organolithium 3 which is usually configurationally stable and is
subsequently trapped by a reaction with Me3SiCl to give adduct 4
(Scheme 1).8,9
Although y25 different chiral diamines have been examined for
the conversion of 1 A 4, these studies have, not surprisingly,
focused on the enantioselectivity that arises.10–16 As a result,
information that allows effective comparison of reactivity of
s-BuLi/diamine complexes is sparse. Indeed, to the best of our
knowledge, only one quantitative rate comparison of RLi/diamine
complexes has been described: Collum et al. investigated
nucleophilic addition to an imine and imine a-deprotonation for
a range of n-BuLi/diamine and PhLi/diamine complexes.17 Thus,
we set out to determine an empirical order of reactivity of different
Initially, we chose to evaluate the relative reactivity of the s-BuLi
complexes of (2)-sparteine and N-Me diamine 5. The s-BuLi/
N-Me diamine 5 complex reacts with N-Boc pyrrolidine 1 to give,
after trapping with Me3SiCl, adduct (R)-4 of 95 : 5 er (84% yield)
making it an effective (+)-sparteine surrogate.12 To our surprise,
when 2.6 equiv of s-BuLi was combined with 1.3 equiv of each of
(2)-sparteine and N-Me diamine 5 for the deprotonation-trapping
of N-Boc pyrrolidine 1, adduct (R)-4 of 90 : 10 er (i.e. the same
sense as (+)-sparteine surrogate deprotonation) was formed in 62%
yield (Scheme 2). This result shows that s-BuLi/diamine 5 is more
Scheme 1
Department of Chemistry, University of York, Heslington, York, UK
YO10 5DD. E-mail: paob1@york.ac.uk; Fax: +44-1904-432516;
Tel: +44-1904-432535
{ Electronic supplementary information (ESI) available: Representative
experimental procedures for results in Tables 1/2 and Scheme 3, and
information on ligand synthesis. See DOI: 10.1039/b603804m
Scheme 2
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conclusion, together with the higher reactivity of s-BuLi/N-Me
Table 1 Lithiation-trapping of N-Boc pyrrolidine 1 to give 4 using
s-BuLi/(2)-sparteine/diamine (competition experiment) and s-BuLi/
diamine (normal experiment)
diamine 5 over s-BuLi/(2)-sparteine is not obvious from the
isolated yields of the normal experiments which are in the range
84–87% (entries 1, 2 and 4) and indicates the usefulness of the
competition approach. In a similar fashion, we used competition
experiments to establish the reactivity order of s-BuLi/diamine
complexes of (+)-sparteine surrogates 5 (N-Me), 7 (N-Et) and 9
Competition experimentaNormal experimentb
Entry Ligand
Yield (%)c Er, S : Rd Yield (%)c Er, S : Rd
1
2
3
4
5
6
7
8
9
(2)-sp
TMEDA
rac-TMCDA 57
5
6
—
63
—
87e
86
95 : 5
rac
yrac
5 : 95
rac
10 : 90
11 : 89
rac
yrac
rac
52 : 48
51 : 49
10 : 90
69 : 31
68 : 32
68 : 32
84 : 16
90 : 10
95 : 5
t
(N-CH2 Bu). The two least reactive s-BuLi/diamine complexes
89f
84e
29
(from 9 and 10) had the most sterically hindered N-alkyl groups. In
these cases, adduct (S)-4 was generated in 90 : 10 er (for 9, Entry 9)
and 95 : 5 er (for 10, entry 10) indicating that reactivity was
dominated by the s-BuLi/(2)-sparteine complex. Reassuringly,
diamines 9 and 10 also gave low yields when combined with
s-BuLi for the normal experiments (entries 9–10). On the basis of
the competition experiments shown in Table 1, a ligand order for
ten ligands in the s-BuLi/diamine-mediated lithiation of N-Boc
pyrrolidine 1 was established (Fig. 1).29
62
67
78
64
81
42
77
7
73g
27g
37
8
PMDETA
9
10
35g
5
10
a
Competition experiment: (i) 2.6 eq s-BuLi, 1.3 eq (2)-sp, 1.3 eq
b
ligand, 278 uC, 5 h; (ii) Me3SiCl. Normal experiment: (i) 1.3 eq
s-BuLi, 1.3 eq ligand, 278 uC, 5 h; (ii) Me3SiCl. Isolated yield after
chromatography. Er determined by chiral GC. Ref. 12. Beak
c
d
e
f
reported that use of (R,R)-TMCDA gave 89% GC yield of yrac-4
(ref. 10). Ref. 16.
To illustrate the usefulness of ligand reactivity orders such as
that depicted in Fig. 1, we used it to identify effective chiral
catalyst/bulk ligand combinations for ligand exchange catalytic
asymmetric deprotonation of N-Boc pyrrolidine 1.25 When s-BuLi
and sub-stoichiometric amounts of (2)-sparteine are used to
deprotonate 1, low yield and moderate enantioselectivity result.
This is presumably because the (2)-sparteine is ‘‘trapped’’ in
complex 3 (Scheme 1) and is not recycled to regenerate the reactive
s-BuLi/(2)-sparteine complex. Thus, to solve this problem, we
included an ‘‘unreactive’’ s-BuLi/bulk diamine complex in the
reaction mixture so that the bulk diamine could exchange with
the chiral catalyst (e.g. (2)-sparteine) to allow efficient catalysis.
The key design feature is that the s-BuLi/chiral diamine catalyst
complex should be considerably more reactive than the s-BuLi/
bulk diamine complex. Thus, we selected the three diamines
(PMDETA, 9 and 10) that give the least reactive s-BuLi/diamine
complexes (Fig. 1) and studied ligand exchange catalysis with
s-BuLi and 0.3 equiv of each of (2)-sparteine and the (+)-sparteine
surrogate, N-Me diamine 5 (Table 2).
g
reactive than s-BuLi/(2)-sparteine even though the two diamines
are similarly sterically hindered. Our interpretation of this
competition result assumes that we are measuring the relative rate
of deprotonation (2 A 3) from a complex 2 composed of one of
each of N-Boc pyrrolidine, s-BuLi and diamine (which is consistent
with the rate law9 and a computational investigation of the
reaction26) rather than the relative rate of irreversible complexa-
tion27 of s-BuLi/diamines. We also assume that (2)-sparteine
and diamine 5 are each fully complexed to s-BuLi. Further
support for the enhanced reactivity of s-BuLi/diamine 5 was
obtained by carrying the deprotonation of N-Boc pyrrolidine 1
using 1.3 equiv of s-BuLi, 0.4 equiv of diamine 5 and 0.7 equiv of
(2)-sparteine as this gave an 83% yield of essentially racemic
product 4 (51 : 49 er).28
To complete the full ligand reactivity order, we performed
analogous competition experiments between (2)-sparteine and a
range of diamines (TMEDA and 6–10) and one triamine
(PMDETA) (Table 1). Full details on the synthesis of the diamines
are given in the electronic supplementary information.{ The results
of the competition experiments should be compared with those
obtained with s-BuLi/(2)-sparteine alone (entry 1) and with each
of the individual s-BuLi/diamine results (normal experiment).
When TMEDA and (2)-sparteine were competed with each
other, adduct (S)-4 of 52 : 48 er was obtained (63% yield) (Entry
2), clearly showing that the s-BuLi/TMEDA complex is more
reactive than s-BuLi/(2)-sparteine (equal reactivity of the s-BuLi/
diamine complexes would have given 4 in y75 : 25 er). This
Initially, we used PMDETA as the bulk ligand and found that
s-BuLi/(2)-sparteine gave lower enantioselectivity (60 : 40 er, entry
1) than s-BuLi/diamine 5 (79 : 21 er, entry 2). From this, we
conclude that even less reactive s-BuLi/bulk diamine complexes are
needed for efficient catalytic asymmetric deprotonation and the
larger the difference in reactivity between the s-BuLi/diamine
complexes, the more efficient the catalysis. Indeed, using the least
reactive s-BuLi/diamine complexes (from 9 and 10), improved
catalytic results were observed and crucially, in all cases, s-BuLi/
N-Me diamine 5 complex gave higher yield and er than s-BuLi/
(2)-sparteine. Under optimum conditions (1.3 equiv s-BuLi,
0.3 equiv. diamine 5 and 1.0 equiv. bulk diamine 10), adduct
Fig. 1 Reactivity order for s-BuLi/diamine complexes in the lithiation-trapping of N-Boc pyrrolidine 1.
2608 | Chem. Commun., 2006, 2607–2609
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Table 2 Catalytic asymmetric deprotonation of N-Boc pyrrolidine 1
Notes and references
1 (a) D. Hoppe and T. Hense, Angew. Chem., Int. Ed. Engl., 1997, 36,
2282; (b) D. B. Collum, Acc. Chem. Res., 1992, 25, 448.
2 R. E. Gawley and I. Coldham, The Chemistry of Organolithium
Compounds. In The Chemistry of Functional Groups, ed. Z. Rappoport
and I. Marek, Wiley, Chichester, 2004, 997.
3 D. Hoppe and G. Christoph, The Chemistry of Organolithium
Compounds, in The Chemistry of Functional Groups, ed. Z. Rappoport
and I. Marek, Wiley, Chichester, 2004, 1077.
Entry
Catalyst
Bulk ligand
Yield (%)a
Er, S:Rb
4 A. R. Muci, K. R. Campos and D. A. Evans, J. Am. Chem. Soc., 1995,
117, 9075.
5 P. Beak, S. T. Kerrick, S. Wu and J. Chu, J. Am. Chem. Soc., 1994, 116,
3231.
6 M. C. Whisler, S. MacNeil, V. Snieckus and P. Beak, Angew. Chem.,
Int. Ed., 2004, 43, 2206.
7 K. M. Bertini Gross and P. Beak, J. Am. Chem. Soc., 2001, 123, 315.
8 D. J. Gallagher, S. T. Kerrick and P. Beak, J. Am. Chem. Soc., 1992,
114, 5872.
1
2
3
4
5
6
a
(2)-sp
5
(2)-sp
5
(2)-sp
PMDETA
PMDETA
9
9
10
10
64
70
69
84
69
78
60:40
21:79
83:17
11:89
88:12
6:94
5
b
Isolated yield after chromatography. Er determined by chiral GC.
9 D. J. Gallagher and P. Beak, J. Org. Chem., 1995, 60, 7092.
10 D. J. Gallagher, S. Wu, N. A. Nikolic and P. Beak, J. Org. Chem., 1995,
60, 8148.
11 X. Li, L. B. Schenkel and M. C. Kozlowski, Org. Lett., 2000, 2, 875.
12 M. J. Dearden, C. R. Firkin, J.-P. R. Hermet and P. O’Brien, J. Am.
Chem. Soc., 2002, 124, 11870.
(R)-4 of 94 : 6 er was generated in 78% yield (entry 6) which is
nearly the same as the stoichiometric result (84% yield, 95 : 5 er;12
Table 1, entry 4).
Finally, we reasoned that it should be possible to use the most
reactive s-BuLi/diamine complexes (TMCDA and N-Me diamine
5) to carry out asymmetric lithiation-trapping reactions that
proceed in low yield using s-BuLi/(2)-sparteine. Previously, Beak
reported that deprotonation of N-Boc piperidine 11 using s-BuLi/
(2)-sparteine gave only an 8% isolated yield of adduct (S)-12 of
87 : 13 er30 (use of s-BuLi/TMEDA gave rac-12 in 94% yield31).32
Under slightly modified conditions (excess of diamines), we
obtained a 28% yield of (R)-12 of 73 : 27 er with diamine 5 and
a 36% yield of (R)-12 of 55 : 45 er with (R,R)-TMCDA
(Scheme 3).33 Under these conditions with (2)-sparteine, none of
adduct 12 was formed. This shows the lower reactivity of s-BuLi/
(2)-sparteine compared to s-BuLi/N-Me diamine 5 or TMCDA
and is in line with our competition experiment-derived reactivity
order (Fig. 1).
13 B. Danieli, G. Lesma, D. Passarella, P. Piacenti, A. Sacchetti, A. Silvani
and A. Virdis, Tetrahedron Lett., 2002, 43, 7155.
14 J.-P. R. Hermet, D. W. Porter, M. J. Dearden, J. R. Harrison,
T. Koplin, P. O’Brien, J. Parmene, V. Tyurin, A. C. Whitwood,
J. Gilday and N. M. Smith, Org. Biomol. Chem., 2003, 1, 3977.
15 P.-W. Phuan, J. C. Ianni and M. C. Kozlowski, J. Am. Chem. Soc.,
2004, 126, 15473.
16 P. O’Brien, K. B. Wiberg, W. F. Bailey, J.-P. R. Hermet and
M. J. McGrath, J. Am. Chem. Soc., 2004, 126, 15480.
17 J. L. Rutherford, D. Hoffmann and D. B. Collum, J. Am. Chem. Soc.,
2002, 124, 264.
18 E. J. Corey, M. C. Noe and S. Sarshar, J. Am. Chem. Soc., 1993, 115,
3828.
19 S. Y. Zhang, C. Girard and H. B. Kagan, Tetrahedron: Asymmetry,
1995, 6, 2637.
20 C. Bolm, K. Muniz and J. P. Hildebrand, Org. Lett., 1999, 4, 491.
21 M. Kitamura, S. Suga, M. Niwa and R. Noyori, J. Am. Chem. Soc.,
1995, 117, 4832.
22 F. Lutz, I. Sato and K. Soai, Org. Lett., 2004, 6, 1613.
23 D. G. Blackmond, T. Rosner, T. Neugebauer and M. T. Reetz, Angew.
Chem., Int. Ed., 1999, 38, 2196.
24 For a review on this topic, see: K. Mun˜iz and C. Bolm, Chem.-Eur. J.,
2000, 6, 2309.
25 M. J. McGrath and P. O’Brien, J. Am. Chem. Soc., 2005, 127, 16378.
26 K. B. Wiberg and W. F. Bailey, J. Am. Chem. Soc., 2001, 123, 8231.
27 The following experiment demonstrates that complexation of the
s-BuLi/(2)-sparteine complex with N-Boc amines is reversible. N-Boc
diisopropylamine (which Beak has shown complexes to s-BuLi/(2)-
sparteine but is not lithiated – see ref. 9) was mixed with s-BuLi/(2)-
sparteine in Et2O at 278 uC for 1 h and then N-Boc pyrrolidine 1 was
added. After a further 4 h, Me3SiCl was added and it was found that
y26% (by GC) of (S)-4 of 98 : 2 er had been generated.
28 This result also suggests that ligand exchange catalysis (see ref. 25) is
occurring to some extent, with the less reactive s-BuLi/(2)-sparteine as
the regenerating system.
29 This reactivity order should be treated as a guide for use in synthesis as it
assumes that essentially all of each diamine is complexed to the s-BuLi.
30 W. F. Bailey, P. Beak, S. T. Kerrick, S. Ma and K. B. Wiberg, J. Am.
Chem. Soc., 2002, 124, 1889.
31 P. Beak and W. K. Lee, J. Org. Chem., 1993, 58, 1109.
32 A similar reactivity difference between s-BuLi/TMEDA and s-BuLi/(2)-
sparteine was noted in the lithiation of a N-Boc bispidine:J. R. Harrison
and P. O’Brien, Tetrahedron Lett., 2000, 41, 6161.
Scheme 3
In conclusion, a reactivity series for N-Boc pyrrolidine lithiation
using s-BuLi/diamines has been constructed. Of particular note,
the results indicate that the s-BuLi/N-Me diamine 5 ((+)-sparteine
surrogate) complex is more reactive than s-BuLi/(2)-sparteine.
Consequently, ligand exchange catalytic asymmetric deprotona-
tion of N-Boc pyrrolidine 1 and lithiation of N-Boc piperidine 11
are more efficient using s-BuLi/diamine 5 than with s-BuLi/(2)-
sparteine. This therefore opens up new synthetic opportunities for
s-BuLi/diamine 5-mediated asymmetric deprotonation reactions.
We thank the EPSRC for funding (of MJM), The Leverhulme
Trust for funding (of JLB) and The Royal Society of Chemistry
for the award of a J W T Jones Travelling Fellowship (to PO’B)
for a sabbatical stay at the University of Geneva. We are also
grateful to the referees for several useful comments.
33 Er determined by chiral HPLC on the p-bromobenzamide of 12 or by
chiral GC. Absolute configuration assigned by analogy with the (R)-
N-Boc stannane which was transformed into the known (R)-N-Me
stannane. For the (S)-N-Me stannane, see: R. E. Gawley, G. Barolli,
S. Madan, M. Saverin and S. O’Connor, Tetrahedron Lett., 2004, 45,
1759.
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Chem. Commun., 2006, 2607–2609 | 2609