Diamine-free lithiation-trapping of N-Boc heterocycles using s-BuLi in THF

Article abstract of DOI:10.1021/ol1017799

A diamine-free protocol for the s-BuLi-mediated lithiation-trapping of N-Boc heterocycles has been developed. In the optimized procedure, lithiation is accomplished using s-BuLi in THF at -30 °C for only 5 or 10 min. Subsequent electrophilic trapping or transmetalation-Negishi coupling delivered a range of functionalized pyrrolidines, imidazolidines, and piperazines in 43-83% yield.

Full text of DOI:10.1021/ol1017799

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4176-4179
Diamine-Free Lithiation-Trapping of
N-Boc Heterocycles using s-BuLi in THF
Graeme Barker,† Peter O’Brien,*,† and Kevin R. Campos‡
Department of Chemistry, UniVersity of York, Heslington, York YO10 5DD, U.K., and
Department of Process Research, Merck Research Laboratories,
Rahway, New Jersey 07065
paob1@york.ac.uk
Received July 30, 2010
ABSTRACT
A diamine-free protocol for the s-BuLi-mediated lithiation-trapping of N-Boc heterocycles has been developed. In the optimized procedure,
lithiation is accomplished using s-BuLi in THF at -30 °C for only 5 or 10 min. Subsequent electrophilic trapping or transmetalation-Negishi
coupling delivered a range of functionalized pyrrolidines, imidazolidines, and piperazines in 43-83% yield.
In 1989, Beak and Lee described a simple and effective
method for the R-functionalization of N-Boc heterocycles
Scheme 1
.
Lithiation-Trapping of N-Boc Heterocycles 1 Using
s-BuLi/TMEDA in Et2O
1 f 2 Via lithiation-trapping (Scheme 1).1 The lithiation
was accomplished using s-BuLi and TMEDA in Et2O at -78
°C for 3.5 h, conditions that have become widely adopted
for carrying out such R-functionalizations.1,2 Indeed, recent
examples in alkaloid natural product syntheses,3 lithiation
of N-Boc piperazines,4 and synthesis of potential pharma-
ceuticals5 have all made use of these standard lithiation
conditions.
Recently, a key observation from our own work led us to
consider whether a simpler protocol for the racemic lithiation
of N-Boc heterocycles could be developed. In particular, we
speculated that the diamine may not be required and that
the lithiation could be successfully carried out at higher and
more convenient temperatures over much shorter reaction
times. In this paper, a simple and effective diamine-free
lithiation of N-Boc heterocycles at -30 °C is presented.
Our starting point in the development of a diamine-free
lithiation protocol was an observation from an attempted
asymmetric deprotonation using s-BuLi and (-)-sparteine
in THF. Thus, lithiation of N-Boc pyrrolidine 3 using s-BuLi/
(-)-sparteine in THF at -78 °C for 3 h and subsequent
trapping with benzaldehyde delivered two separable diaster-
eomeric hydroxy pyrrolidines syn-4 (62% yield) and anti-4
(35% yield) (Scheme 2). Not unexpectedly,6 both syn-4 and
anti-4 were formed in 50:50 er, a result which is most likely
explained either by a lack of complexation of (-)-sparteine
† University of York.
‡ Merck Research Laboratories.
(1) Beak, P.; Lee, W. K. Tetrahedron Lett. 1989, 30, 1197.
(2) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109
.
(3) (a) Pizzuti, M. G.; Minnaard, A. J.; Feringa, B. L. Org. Biomol.
Chem. 2008, 6, 3464. (b) Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C.;
Ramtohul, Y. K.; Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008,
130, 13745.
(4) Berkheij, M.; van der Sluis, L.; Sewing, C.; den Boer, D. J.; Terpstra,
J. W.; Hiemstra, H.; Iwema Bakker, W. I.; van den Hoogenband, A.; van
Maarseveen, J. H. Tetrahedron Lett. 2005, 46, 2369.
(5) (a) Le Bourdonnec, B.; Goodman, A. J.; Graczyk, T. M.; Belanger,
S.; Seida, P. R.; DeHaven, R. N.; Dolle, R. E. J. Med. Chem. 2006, 49,
7290. (b) Guillame, M.; Cuypers, J.; Dingenen, J. Org. Process Res. DeV.
2007, 11, 1079.
10.1021/ol1017799  2010 American Chemical Society
Published on Web 08/18/2010

Scheme 2
.
Attempted Asymmetric Lithiation-Trapping of N-Boc
Table 1. Optimization of the Diamine-Free Lithiation of N-Boc
Pyrrolidine 3
Pyrrolidine 3 Using s-BuLi/(-)-Sparteine in THF
entry
solvent
Et2O
THF
methyl-THF
Et2O
THF
methyl-THF
Et2O
THF
methyl-THF
THF
THF
methyl-THF
THF
THF
THF
THF
THF
THF
temp (°C)
time (min)
yield (%)a
1
2
3
4
5
6
7
8
-78
-78
-78
-40
-40
-40
-30
-30
-30
-30
-30
-30
-20
-20
-20
-10
-10
0
60
60
60
60
60
60
60
60
60
10
5
5
30
5
2
5
8
89
92
26
64
94
0
to s-BuLi in THF7 or by a faster rate of lithiation of N-Boc
pyrrolidine 3 by s-BuLi/THF compared to s-BuLi/(-)-
sparteine. Either way, racemic adducts syn-4 and anti-4
(formed in a total yield of 97%) will presumably have been
generated Via s-BuLi/THF-mediated lithiation of 3, suggest-
ing that the diamine is not required. This result led us to
investigate a diamine-free racemic lithiation protocol using
s-BuLi in THF.
37
0
9
10
11
12
13
14
15
16
17
18
89
84
73
10
66
57
29
0
To start with, we used the lithiation-benzaldehyde trap-
ping of N-Boc pyrrolidine 3 (using 1.3 equiv of s-BuLi) to
optimize the solvent, temperature, and lithiation time (Table
1). The diastereomeric adducts syn-4 and anti-4 were isolated
separately, but for ease of comparison of results, the
combined % yield is presented in Table 1.8 At -78 °C in
Et2O, lithiation of 3 using s-BuLi is slow, and adducts 4
were obtained in only 8% yield after a lithiation time of 60
min (entry 1). This result is consistent with the need for a
ligand (such as TMEDA) to promote the s-BuLi-mediated
lithiation in Et2O.1,2 In contrast, use of the more coordinating
solvents THF and methyl-THF9 under identical conditions
(-78 °C, 60 min lithiation time) was far more successful:
adducts 4 were obtained in 89% and 92% yields, respectively
(entries 2 and 3). Our initial objective was to determine
whether high yielding lithiation could be maintained at higher
temperatures and shorter reaction times.
1
30
0
a Combined total yield of syn-4 and anti-4 after purification by column
chromatography.
of only 10 min (89% yield, entry 10) or 5 min (84% yield,
entry 11). These lithiation conditions (-30 °C, THF or
methyl-THF, 5 or 10 min) proved optimal. At temperatures
above -30 °C, yields of adducts 4 ranged from 0 to 66%
(entries 13-18), and lower yields were generally obtained
for longer lithiation times at a particular temperature. From
this, we conclude that, at temperatures above -30 °C, some
of the s-BuLi is consumed by reaction with THF.10 To probe
the s-BuLi-mediated decomposition of THF and Et2O, we
carried out the experiments summarized in Scheme 3. Thus,
At -40 °C with a lithiation time of 60 min, a set of results
similar to those at -78 °C were obtained (entries 4-6).
However, after lithiating for 60 min at -30 °C, adducts 4
were isolated (37% yield) only in THF (entries 7-9). As a
result, our subsequent efforts focused on THF as the solvent,
and much higher yields were obtained after lithiation times
Scheme 3
.
Investigation of the s-BuLi-Mediated Decomposition
of Et2O and THF
(6) For examples of low enantioselectivity of organolithium/(-)-
sparteine-mediated reactions in THF, see: (a) Hoppe, I.; Marsch, M.; Harms,
K.; Boche, G.; Hoppe, D. Angew. Chem., Int. Ed. Engl. 1995, 34, 2158.
(b) Wu, S.; Lee, S.; Beak, P. J. Am. Chem. Soc. 1996, 118, 715. (c) Park,
Y. S.; Boys, M. L.; Beak, P. J. Am. Chem. Soc. 1996, 118, 3757. (d) Bertini
Gross, K. M.; Jun, Y. M.; Beak, P. J. Org. Chem. 1997, 62, 7679. (e)
Pakulski, Z.; Koprowski, M.; Pietrusiewicz, K. M. Tetrahedron 2003, 59,
8219. (f) Kessar, S. V.; Singh, P.; Nain Singh, K.; Venugopalan, P.; Kaur,
A.; Bharatam, P. V.; Sharma, A. K. J. Am. Chem. Soc. 2007, 129, 4506.
(g) Huang, J.; O’Brien, P. Chem. Commun. 2005, 5696.
(7) Sott, R.; Håkansson, M.; Hilmersson, G. Organometallics 2006, 25,
6047.
(8) In all cases, the diastereoselectivity was ∼75:25 syn-4:anti-4 (as
1
determined by H NMR spectroscopy of the crude product). The isolated
combining s-BuLi in Et2O at -78 °C for 60 min and then
adding benzaldehyde led to a 62% yield of a 50:50 mixture
yield of syn-4 and anti-4 obtained after chromatography is provided in the
Supporting Information.
(9) Methyl-THF is an attractive alternative solvent to THF since it is
produced from renewable resources. Aycock, D. F. Org. Process Res. DeV.
2007, 11, 156.
(10) (a) Gilman, H.; Gaj, B. J. J. Org. Chem. 1957, 22, 1165. (b)
Stanetty, P.; Koller, H.; Mihovilovic, M. J. Org. Chem. 1992, 57, 6833.
Org. Lett., Vol. 12, No. 18, 2010
4177

of diastereomeric alcohols 5. Clearly, there was no noticeable
reaction of the s-BuLi with Et2O and direct nucleophilic
addition of s-BuLi ensued. In contrast, a similar experiment
in THF at 0 °C for 30 min gave a 50:50 diastereomeric
mixture of homologated alcohols 6 (58% yield from s-BuLi
since 2 equiv are used up in generating 6). Such homologated
adducts result from R-lithiation of THF, subsequent decom-
position of lithiated THF to give a lithium enolate and
ethene,11 carbolithiation of ethene by s-BuLi to give a
homologated organolithium reagent,12 and eventual addition
of this primary organolithium to benzaldehyde.
The lithiation-transmetalation-Negishi coupling process
was further extended to synthesize the seven arylated
pyrrolidines 15-21 (Scheme 5). For this, the racemic
Scheme 5
.
Lithiation-Transmetallation-Negishi Coupling of
N-Boc Pyrrolidine 3
Ultimately, we selected 1.3 equiv of s-BuLi in THF at -30
°C for 5 min for the lithiation of N-Boc pyrrolidine 3 and
trapped with a range of electrophiles, focusing predominantly
on C-C bond-forming reactions. The results are presented in
Scheme 4. Methylation (using Me2SO4) and allylation (using
Scheme 4
.
Lithiation-Trapping of N-Boc Pyrrolidine 3 Using
s-BuLi/THF at -30 °C for 5 min
lithiated pyrrolidine was prepared using the standard lithiation
protocol (3, 1.3 equiv of s-BuLi, THF, -30 °C, 5 min). Then,
transmetalation to an organozinc reagent was accomplished
using ZnCl2 to give a stock solution. Aliquots (equivalent
to 1.0 mmol) of the stock solution were used in seven parallel
Negishi coupling reactions.15a After workup and purification,
arylated pyrrolidines 15-21 were obtained in 57-85% yields
(Scheme 5).
Next, the scope of the racemic lithiation protocol was
explored with other N-Boc heterocycles (Scheme 6). Using
Scheme 6
.
Lithiation-Trapping of N-Boc Heterocycles Using
s-BuLi/THF at -30 °C for 5 min
allyl bromide with transmetalation to the cuprate13) proceeded
smoothly to give 7 (70% yield) and 8 (65% yield), respectively.
Reaction with MeO2CCl gave 9 in only 51% yield as the
product reacted further to give the R,R-disubstituted pyrrolidine
(18% yield).14 Reaction with carbon dioxide gave a 49% yield
of adduct 10. We successfully introduced aldehyde and ketone
functionality (f 11 and 12) Via reaction with DMF and
PhCONMe2, respectively. Silylation using Me3SiCl was simi-
larly high-yielding. Finally, arylated pyrrolidine 14 was syn-
thesized in 73% yield Via a transmetalation-Negishi coupling
protocol.15
(11) Bates, R. B.; Kroposki, L. M.; Potter, D. E. J. Org. Chem. 1972,
37, 560.
N-Boc 3-pyrroline, our best result was using lithiation-DMF
trapping: aldehyde 22 was obtained in a disappointing 20%
yield. Unfortunately, we have been unable to apply the
s-BuLi/THF-mediated lithiation-trapping to N-Boc piperi-
dine and N-Boc azepine. In both cases, trapped adducts were
not detected using a wide range of conditions (e.g., -78 °C
for 3 or 6 h; -40 °C for 1 or 3 h; -30 °C for 5 min) and
(12) Bartlett, P. D.; Friedman, S.; Stiles, M. J. Am. Chem. Soc. 1953,
75, 1771.
(13) Dieter, R. K.; Oba, G.; Chandupatla, K. R.; Topping, C. M.; Lu,
K.; Watson, R. T. J. Org. Chem. 2004, 69, 3076.
(14) The formation of the R,R-disubstituted pyrrolidine indicates that
enolization of 9 by s-BuLi is faster than reaction of s-BuLi with MeO2CCl.
Use of 2.6 equiv of s-BuLi/3.0 equiv of MeO2CCl gave a 76% yield of the
R,R-disubstituted pyrrolidine (see Supporting Information).
4178
Org. Lett., Vol. 12, No. 18, 2010

different electrophiles (DMF or MeO2CCl). In one piperidine
example, we obtained a 28% yield of ester 24 from the
corresponding acetal-protected N-Boc piperidine. The lower
reactivity of N-Boc piperidine and N-Boc azepine toward
lithiation has been noted previously.16,17
Finally, we carried out the s-BuLi/THF-mediated lithiation
of N-Boc piperazine 33. Lithiation-trapping of N-Boc
piperazines using s-BuLi/TMEDA in Et2O has been de-
scribed by van den Hoogenband and van Maarseveen et al.4
and Coldham et al.20 Using s-BuLi in THF at -30 °C for 5
min, we obtained 71-83% yields of adducts 34-37 trapping
with DMF, MeO2CCl, benzophenone, and Me3SiCl (Scheme
8). A Negishi coupling was also accomplished: arylated
piperazine 38 was formed in 55% yield.19
We had better success with N-Boc imidazolidine 26 and
N-Boc piperazine 33 both of which are more active substrates
toward R-lithiation. The lithiation-trapping of N-Boc imi-
dazolidine 26 using s-BuLi in THF at -78 °C for 1 h was
reported by Coldham and co-workers.18 However, yields
were limited to 32-50%, and the authors proposed that, in
this unsymmetrical N-Boc heterocycle, rotamer interconver-
sion Via rotation about the N-CO bond is very slow at -78
°C and only one rotamer underwent lithiation. We considered
that better yields of substituted imidazolidines might be
possible at higher temperatures where rotamer interconver-
sion could be facilitated. In the end, it was found that
lithiation using 1.3 equiv of s-BuLi in THF at -30 °C for
10 min worked well and, after trapping, delivered substituted
N-Boc imidazolidines 27-32 in 43-75% yields (Scheme
7). Notably, yields in excess of 50% were obtained using
Scheme 8
.
Lithiation-Trapping of N-Boc Piperazine 33 Using
s-BuLi/THF at -30 °C for 5 min
Scheme 7. Lithiation-Trapping of N-Boc Imidazolidine 26
Using s-BuLi/THF at -30 °C for 10 min
In summary, we report the scope and limitations of a new
diamine-free protocol for the racemic lithiation-trapping of
N-Boc heterocycles. The optimized procedure uses 1.3 equiv
of s-BuLi in THF at -30 °C for only 5 min (for N-Boc
pyrrolidine 3 and N-Boc piperazine 33) or 10 min (for N-Boc
imidazolidine 26). Examples with a wide range of electro-
philes have been included in our study. Although our method
is not suitable for less reactive substrates such as N-Boc
piperidine and N-Boc azepine, it is a convenient method for
the racemic lithiation-trapping of N-Boc pyrrolidine 3,
N-Boc imidazolidine 26, and N-Boc piperazine 33.
Acknowledgment. We thank the EPSRC for a DTA award
(to G.B.) and Merck for funding.
Supporting Information Available: Full experimental
1
procedures, characterization data, and copies of H NMR
most of the electrophiles. We also carried out the first
example of a lithiation-transmetalation-Negishi coupling
with N-Boc imidazolidine 26: arylated imidazolidine 32 was
obtained in a moderate 43% yield.19
and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL1017799
(15) (a) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.;
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Leonori, D.; Patel, J. J.; Sheikh, N. S. Chem.sEur. J. 2010, 16, 4082.
(18) (a) Ashweek, N. J.; Coldham, I.; Haxell, T. F. N.; Howard, S. Org.
Biomol. Chem. 2003, 1, 1532. (b) Coldham, I.; Copley, R. C. B.; Haxell,
T. F. N.; Howard, S. Org. Lett. 2001, 3, 3799.
Chen, C.-y. J. Am. Chem. Soc. 2006, 128, 3538. (b) Coldham, I.; Leonori,
D. Org. Lett. 2008, 10, 3923
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(16) (a) Bailey, W. F.; Beak, P.; Kerrick, S. T.; Ma, S.; Wiberg, K. B.
J. Am. Chem. Soc. 2002, 124, 1889. (b) Coldham, I.; O’Brien, P.; Patel,
J. J.; Raimbault, S.; Sanderson, A. J.; Stead, D.; Whittaker, D. T. E.
Tetrahedron: Asymmetry 2007, 18, 2113. (c) Stead, D.; Carbone, G.;
O’Brien, P.; Campos, K. R.; Coldham, I.; Sanderson, A. J. Am. Chem. Soc.
(19) With 26 and 33, the Negishi coupling step required 16 h at
reflux.
(20) Robinson, S. P.; Sheikh, N. S.; Baxter, C. A.; Coldham, I.
Tetrahedron Lett. 2010, 51, 3642.
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