Asymmetric lithiation trapping of N -boc heterocycles at temperatures above -78°C

Article abstract of DOI:10.1021/ol402395j

The asymmetric lithiation trapping of N-Boc heterocycles using s-BuLi/chiral diamines at temperatures up to -20°C is reported. Depending on the N-Boc heterocycle, lithiation is accomplished using s-BuLi and (-)-sparteine or the (+)-sparteine surrogate in the temperature range -50 to -20°C for short reaction times (2-20 min). Subsequent electrophilic trapping or transmetalation-Negishi coupling delivered functionalized N-Boc heterocycles in 47-95% yield and 77:23-93:7 er. With N-Boc pyrrolidine, trapped products can be generated in ～90:10 er even at -20°C.

Full text of DOI:10.1021/ol402395j

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Asymmetric Lithiation Trapping of N‑Boc
Heterocycles at Temperatures aboveꢀ78 °C
Giacomo Gelardi,† Graeme Barker,† Peter O’Brien,*,† and David C. Blakemore‡
Department of Chemistry, University of York, Heslington, York YO10 5DD, U. K., and
Neusentis Chemistry, Pfizer Worldwide Research and Development, The Portway
Building, Granta Park, Cambridge CB21 6GS, U. K.
peter.obrien@york.ac.uk
Received August 21, 2013
ABSTRACT
The asymmetric lithiation trapping of N-Boc heterocycles using s-BuLi/chiral diamines at temperatures up to ꢀ20 °C is reported. Depending on the
N-Boc heterocycle, lithiation is accomplished using s-BuLi and (ꢀ)-sparteine or the (þ)-sparteine surrogate in the temperature range ꢀ50 to
ꢀ20 °C for short reaction times (2ꢀ20 min). Subsequent electrophilic trapping or transmetalationꢀNegishi coupling delivered functionalized
N-Boc heterocycles in 47ꢀ95% yield and 77:23ꢀ93:7 er. With N-Boc pyrrolidine, trapped products can be generated in ∼90:10 er even at ꢀ20 °C.
In 1991, Kerrick and Beak reported the first example
of the asymmetric R-lithiation and electrophilic trapping
of a N-Boc heterocycle.1 Full details were subsequently
disclosed in 1994.2 The methodology was successful for
N-Boc pyrrolidine 1 and utilized a chiral base comprising
s-BuLi and (ꢀ)-sparteine. A typical example (1 f (S)-2 f
(R)-3 of 95:5 er) is shown in Scheme 1. These types of
asymmetric lithiation-trapping reactions are normally
conducted at ꢀ78 °C for several hours and proceed via
a configurationally stable lithiated N-Boc heterocycle
(e.g., (S)-2). Beak’s approach has been extended to a wide
range of N-Boc heterocycles including piperidine3,4 and
a piperazine.5 Furthermore, the asymmetric lithiation of
N-Boc pyrrolidine 1 has been carried out on the kg-scale by
researchers atMerck.6 Theuse of a reaction temperature of
ꢀ78 °C for several hours presents a considerable energy
cost for multikilogram-scale reactions.7 A temperature
of ꢀ20 °C is preferred for process-scale chemistry, as a
specialist low-temperature setup is not required. Thus, we
asked ourselves the question: is it possible to carry out
Beak’s R-lithiation-trapping of N-Boc heterocycles with
high enantioselectivity at temperatures above ꢀ78 °C?
Scheme 1. Beak’s Asymmetric Lithiation Trapping of N-Boc
Pyrrolidine 1 Using s-BuLi/(ꢀ)-Sparteine at ꢀ78 °C
† University of York.
‡ Neusentis Chemistry, Pfizer.
(1) Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1991, 113, 9708.
(2) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994,
116, 3231.
(3) Bailey, W. F.; Beak, P.; Kerrick, S. T.; Ma, S.; Wiberg, K. B.
J. Am. Chem. Soc. 2002, 124, 1889.
(4) (a) Stead, D.; Carbone, G.; O’Brien, P.; Campos, K. R.;
Coldham, I.; Sanderson, A. J. Am. Chem. Soc. 2010, 132, 7260. (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.
(5) McDermott, B. P.; Campbell, A. D.; Ertan, A. Synlett 2008, 875.
(6) Klapars, A.; Campos, K. R.; Waldman, J. H.; Zewge, D.;
Dormer, P. G.; Chen, C.-y. J. Org. Chem. 2008, 73, 4986.
In considering this question, we noted two observations
from our previous work. In 2010, we disclosed a “high”
temperature (ꢀ30 °C) racemic lithiation trapping of N-Boc
heterocycles which utilized s-BuLi/THF as the reactive
base, a protocol which we refer to as “diamine-free”.8
(7) Bennie, L. S.; Kerr, W. J.; Middleditch, M. J.; Watson, A. J. B.
Chem. Commun. 2011, 47, 2264.
r
10.1021/ol402395j
XXXX American Chemical Society

At ꢀ30 °C, successful reactions required lithiation times
with s-BuLi/THF of only 5 or 10 min. Subsequently, in
2011, we used in situ IR spectroscopic monitoring of the
lithiation step to show that the lithiation of N-Boc pyrro-
lidine 1 with s-BuLi/(ꢀ)-sparteine in Et2O at ꢀ78 °C was
complete within 1 h.9 Hence, with a view to developing a
more energy efficient and sustainable asymmetric version
of Beak’s R-lithiation-trapping of N-Boc heterocycles, we
decided to explore “high” temperatures (between 0 and
ꢀ40 °C) and short reaction times (<1 h). Our aim was to
identify the highest temperature for an asymmetric lithia-
tion reaction of g80:20 er. This study focused on pyrroli-
dine, piperidine, and a piperazine due to their prevalence in
blockbuster pharmaceuticals.
The four most important issues to consider as the
reaction temperature for R-lithiation trapping of N-Boc
heterocycles is raised above ꢀ78 °C are as follows: (i) the
time taken for complete lithiation which should be reduced
at higher temperatures; (ii) the chemical stability of the
lithiated N-Boc heterocycle which may be compromised at
higher temperatures; (iii) the enantioselectivity (i.e., the
kinetic selectivity due to the interaction of the s-BuLi/
chiral diamine with the N-Boc heterocycle) which will be
a function of temperature; and (iv) the configurational
stability of the intermediate lithiated N-Boc heterocycle
(e.g., (S)-2) which will almost certainly be reduced at
higher temperatures.10 Each of these factors could be
different for different N-Boc heterocycles,4 and we have
previously noted important differences between (ꢀ)-spar-
teine and the (þ)-sparteine surrogate.4a,11,12 Issues (i) and
(ii) will affect the yield of the reaction whereas issues (iii)
and (iv) will impact the enantioselectivity.
To start with, we explored the “high” temperature lithia-
tion of N-Boc pyrrolidine 1 using 1.3 equiv of s-BuLi/
(ꢀ)-sparteine in Et2O and trapping with benzaldehyde.
This gave two known13 diastereomeric products, (1R,2R)-
4 and (1S,2R)-5, which were separated and their ers
determined using chiral stationary phase (CSP)-HPLC
(Table 1). As previously reported, adducts (1R,2R)-4 and
(1S,2R)-5 are each generated with 97:3 er at ꢀ78 °C, in
86% total yield (entry 1).12 The yield and enantioselectivity
at ꢀ40 °C were evaluated first using reaction times of 1 s,
2 min, 20 min, and 1 h. From these reactions, (1R,2R)-4
and (1S,2R)-5 were formed in 90:10ꢀ93:7 er and, apart
from the 1 s reaction, in good total yield (79ꢀ87%)
(entries 2ꢀ5). Clearly, a synthetically useful level of en-
antioselectivity (g90:10 er) can be obtained at this elevated
temperature of ꢀ40 °C. The 1 s reaction time was designed
to provide information on the kinetic selectivity at a
specifictemperature (issue(iii)): withsucha shortlithiation
time, the impact of any configurational instability of the
lithiated N-Boc pyrrolidine (S)-2 on the er of the trapped
products should be minimized. In contrast, the 1 h lithia-
tion time should allow reduction in er due to any config-
urational instability to be detected (issue (iv)). At ꢀ40 °C,
the ers of (1R,2R)-4 and (1S,2R)-5 for a 1 s reaction
time (entry 2) were essentially the same as those from the
1 h lithiation (entry 5) suggesting that the (ꢀ)-sparteine-
complexed lithiated N-Boc pyrrolidine (S)-2 is configur-
ationally stable at ꢀ40 °C for 1 h. It is also notable that,
at ꢀ40 °C, a high total yield (84%) can be obtained for
lithiation trapping using s-BuLi/(ꢀ)-sparteine after just
2 min (entry 3). This represents a significant improvement
on the 1 h required to attain complete lithiation of N-Boc
pyrrolidine 1 at ꢀ78 °C.9
Table 1. Asymmetric Lithiation Trapping of N-Boc Pyrrolidine
1 Using s-BuLi/(ꢀ)-Sparteine at Temperatures above ꢀ78 °C
yield (%), er
yield (%), er
total
entry temp/°C
time
3 h
of (1R,2R)-4a of (1S,2R)-5a yield (%)b
1c
2
3
4
5
6
7
8
ꢀ78
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ20
ꢀ20
ꢀ10
0
63, 97:3
6, 92:8
23, 97:3
4, 91:9
26, 91:9
29, 92:8
27, 90:10
7, 89:11
34, 89:11
28, 87:13
30, 84:16
33, 85:15
31, 85:15
29, 80:20
27, 75:25
25, 62:38
86
10d
84
87
79
19e
92
77
72
86
82
72
67
60
1 s
2 min
20 min
1 h
58, 93:7
58, 92:8
52, 92:8
12, 89:11
58, 90:10
49, 88:12
42, 87:13
53, 86:14
51, 87:13
43, 80:20
40, 75:25
35, 65:35
1 s
2 min
20 min
1 h
1 min
2 min
30 s
9
10
11
12
13
14
10 s
1 min
0
a Yield after purification by chromatography; Enantiomer ratio (er)
determined by CSP-HPLC (see Supporting Information (SI)). b Total
yield of (1R,2R)-4 and (1S,2R)-5 after purification by chromatography.
c See ref 12. d 73% recovered starting material. e 51% recovered starting
material.
With interesting enantioselectivity at ꢀ40 °C, our atten-
tion switched to even higher temperatures. The results at
ꢀ30 °C (1 s, 2 min, 20 min, and 1 h lithiation times) (entries
6ꢀ9) were similar to those at ꢀ40 °C. Reaction times of
e20 min at ꢀ30 °C generated (1R,2R)-4 and (1S,2R)-5
in 87:13ꢀ90:10 er (entries 6ꢀ8). The slightly reduced
enantioselectivity for a 1 h lithiation at ꢀ30 °C ((1S,2R)-
5 of 84:16 er, entry 9) suggests that configurational in-
stability becomes an issue at ꢀ30 °C over extended times
(g1 h). At higher temperatures (ꢀ20, ꢀ10, or 0 °C), the
enantioselectivity was more significantly eroded despite the
use of short lithiation times (10 s to 2 min, entries 10ꢀ14).
(8) Barker, G.; O’Brien, P.; Campos, K. R. Org. Lett. 2010, 12, 4176.
(9) Barker, G.; McGrath, J. L.; Klapars, A.; Stead, D.; Zhou, G.;
Campos, K. R.; O’Brien, P. J. Org. Chem. 2011, 76, 5936.
(10) Basu, A.; Thayumanavan, S. Angew. Chem., Int. Ed. 2002, 41,
716.
(11) McGrath, M. J.; Bilke, J. L.; O’Brien, P. Chem. Commun. 2006,
2607.
(12) Carbone, G.; O’Brien, P.; Hilmersson, G. J. Am. Chem. Soc.
2010, 132, 15445.
(13) Bilke, J. L.; Moore, S. P.; O’Brien, P.; Gilday, J. Org. Lett. 2009,
11, 1935.
B
Org. Lett., Vol. XX, No. XX, XXXX

The lower enantioselectivity at these higher temperatures is
presumably due to a combination of reduced kinetic selec-
tivity and a greater degree of configurational instability.
Despite this, lithiation of N-Boc pyrrolidine 1 using s-
BuLi/(ꢀ)-sparteine at 0 °C for just 10 s and subsequent
trapping gave a total 67% yield of adducts (1R,2R)-4 and
(1S,2R)-5, each in 75:25 er (entry 13).
Next, the use of diamine (S,S)-6, which we have pre-
viously shown to be a useful (þ)-sparteine surrogate,14 was
explored. With (S,S)-6, trapping with benzophenone was
carried out to give (S)-3 and reactions at ꢀ78, ꢀ40, and
ꢀ30 °C were evaluated (Table 2). At ꢀ78 °C, an 82% yield
of (S)-3 of 95:5 er was obtained (entry 1). However, 1 s
reactions at ꢀ40 and ꢀ30 °C led to a reduced enantios-
electivity of 86:14 er and 80:20 er respectively (entries 2
and 4). This reduction in kinetic selectivity was far more
pronounced than that seen with (ꢀ)-sparteine (Table 1).
Synthetic reactions at ꢀ40 and ꢀ30 °C for 2 min gave (S)-3
in 49% yield (86:14 er) and 45% yield (81:19 er) respec-
tively (entries 3 and 5). Thus, no further work was carried
out with diamine (S,S)-6.
N-Boc pyrrolidine (R)-2 isconfigurationally stable over 1 h
at ꢀ40 or ꢀ30 °C (entries 3 and 5). In contrast, at ꢀ20 °C
for 1 h, adducts (1S,2S)-4 and (1R,2S)-5 are formed with
<90:10 er due to partial configurational instability.16
Leaving the lithiated N-Boc pyrrolidine (S)-2 or (R)-2 at
ꢀ40 °C or higher temperatures for 1 h leads to a reduction
in overall yield which is likely due to chemical instability of
the organolithium (Table 1, compare entries 3/5 and 7/9;
Table 2, compare entries 2/3, 4/5 and 6/7) (issue (ii)).
Table 3. Asymmetric Lithiation Trapping of N-Boc Pyrrolidine
1 Using s-BuLi/(þ)-Sparteine Surrogate at Temperatures above
ꢀ78 °C
temp/
°C
yield (%), er
yield (%), er
total
Table 2. Asymmetric Lithiation Trapping of N-Boc Pyrrolidine
1 Using s-BuLi/Diamine (S,S)-6 at Temperatures above ꢀ78 °C
entry
time
of (1S,2S)-4a
of (1R,2S)-5a
yield (%)b
1c
2
3
4
5
6
7
ꢀ78
ꢀ40
ꢀ40
ꢀ30
ꢀ30
ꢀ20
ꢀ20
3 h
2 min
1 h
2 min
1 h
2 min
1 h
58, 95:5
23, 94:6
30, 92:8
20, 91:9
27, 90:10
23, 90:10
23, 91:9
20, 85:15
81
95
66
92
64
73
60
65, 90:10
46, 90:10
67, 90:10
41, 89:11
50, 89:11
40, 83:17
yield of
er of
yield of
a Yield after purification by chromatography; Enantiomer ratio (er)
determined by CSP-HPLC (see SI). b Total yield of (1S,2S)-4 and
(1R,2S)-5 after purification by chromatography. c See ref 12.
entry
temp/° C
time
(S)-3 (%)a
(S)-3b
recov. 1 (%)c
1
2
3
4
5
ꢀ78
ꢀ40
ꢀ40
ꢀ30
ꢀ30
1 h
82
15
49
14
45
95:5
ꢀ
1 s
86:14
86:14
80:20
81:19
50
ꢀ
2 min
1 s
Based on the results in Tables 1 and 3, the best compro-
mise of highest temperature, highest total yield, and
∼90:10 er for N-Boc pyrrolidine 1 was obtained using
s-BuLi and (ꢀ)-sparteine or the (þ)-sparteine surrogate at
ꢀ30 °C for a 2 min lithiation time. Using these optimized
conditions with the (þ)-sparteine surrogate, CꢀC bond
forming electrophiles were explored (Scheme 2). Direct
trapping with benzophenone, dimethyl sulfate, and phe-
nylisocyanate gave (S)-3 (86:14 er), (R)-7 (92:8 er), and
(S)-8 (89:11 er) respectively. Similarly, allylation (using a
Li/Cu transmetalation protocol17) or Negishi coupling
55
15
2 min
a Yield after purification by chromatography. b Enantiomer ratio (er)
determined by CSP-HPLC (see SI). c Yield of recovered starting material
1 after purification by chromatography.
Much better results were obtained with the more “spar-
teine-like” (þ)-sparteine surrogate.15 Here, trapping with
benzaldehyde was deployed, and the results with the (þ)-
sparteine surrogate (Table 3) were generally comparable to
those obtained with (ꢀ)-sparteine (Table 1), but with the
opposite sense of induction. At ꢀ78 °C, adducts (1S,2S)-4
and (1R,2S)-5 are generated with 95:5 er and 94:6 er
respectively (81% total yield, entry 1).12 Reaction times
of 2 min at ꢀ40, ꢀ30, and ꢀ20 °C each gave (1S,2S)-4 and
(1R,2S)-5 in ∼90:10 er, in good overall yields (73ꢀ95%)
(entries 2, 4, and 6). The (þ)-sparteine complexed lithiated
with bromobenzene (via Li/Zn/Pd transmetalation6,8,9,18
)
generated (S)-9 (84:16 er) and (S)-10 (92:8 er) respectively.
Extension of this “high” temperature asymmetric lithia-
tion-trapping protocol to N-Boc piperidine and a N-Boc
piperazine was then investigated. It is well-known that N-
Boc piperidine 11 is harder to lithiate than N-Boc pyrro-
lidine 1.3,4 At ꢀ78 °C, the reactive s-BuLi/(þ)-sparteine
(16) (a) Gawley, R. E.; Zhang, Q. J. Am. Chem. Soc. 1993, 115, 7515.
(b) Coldham, I.; Dufour, S.; Haxell, T. F. N.; Patel, J. J.; Sanchez-
Jiminez, G. J. Am. Chem. Soc. 2006, 128, 10943.
(17) Dieter, R. K.; Oba, G.; Chandupatla, K. R.; Topping, C. M.; Lu,
K.; Watson, R. T. J. Org. Chem. 2004, 69, 3076.
(14) Stead, D.; O’Brien, P.; Sanderson, A. Org. Lett. 2008, 10, 1409.
(15) (a) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P.
J. Am. Chem. Soc. 2002, 124, 11870. (b) O’Brien, P.; Wiberg, K. B.;
Bailey, W. F.; Hermet, J.-P. R.; McGrath, M. J. J. Am. Chem. Soc. 2004,
126, 15480. (c) Dearden, M. J.; McGrath, M. J.; O’Brien, P. J. Org.
Chem. 2004, 69, 5789. (d) Dixon, A. J.; McGrath, M. J.; O’Brien, P. Org.
Synth. 2006, 83, 141. (e) O’Brien, P. Chem. Commun. 2008, 655.
(18) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.;
Chen, C.-y. J. Am. Chem. Soc. 2006, 128, 3538.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 5. Asymmetric Lithiation Trapping of N-Boc Piperazine
13 Using s-BuLi/(þ)-Sparteine Surrogate at Temperatures
above ꢀ78 °C
Scheme 2. Scope of the Asymmetric Lithiation Trapping of
N-Boc Pyrrolidine 1 Using s-BuLi/(þ)-Sparteine Surrogate at
ꢀ30 °C
yield of
(S)-14 (%)a
er of
(S)-14b
entry
temp/°C
time
1
2
3
ꢀ78
ꢀ50
ꢀ30
1 h
3 min
2 min
91
71
88
89:11
82:18
78:22
a Yield after purification by chromatography. b Enantiomer ratio (er)
determined by CSP-HPLC (see SI).
asymmetric lithiation trapping of a N-Boc piperazine.5
With the s-BuLi/(þ)-sparteine surrogate at ꢀ78 °C (1 h
lithiation time), ester (S)-14 of 89:11 er was formed in 91%
yield (entry 1). Higher temperatures (ꢀ50 and ꢀ30 °C) led
to reduced enantioselectivity but good yields (even though
lithiation times of only 3 and 2 min were used) (entries 2
and 3). The best enantioselectivity was achieved at ꢀ50 °C
for 3 min: ester (S)-14 of 82:18 er was generated in 71%
yield (entry 2).
Table 4. Asymmetric Lithiation Trapping of N-Boc Piperidine
11 Using s-BuLi/(þ)-Sparteine Surrogate at Temperatures
above ꢀ78 °C
In conclusion, we have shown that asymmetric lithiation
trapping of N-Boc heterocycles can be carried out using s-
BuLi/chiral diamines at temperatures well above ꢀ78 °C.
By using short lithiation times (2ꢀ30 min) and tempera-
tures in the range ꢀ50 to ꢀ20 °C, trapped products can be
obtained in respectable yields (47ꢀ95%) (issues (i) and (ii))
and with 77:23ꢀ93:7 er. At temperatures e ꢀ30 °C and
reaction times of 2ꢀ30 min, the reduction in er compared
to the ꢀ78 °C reaction results appears to be due to a
decrease in kinetic selectivity (issue (iii)) rather than due to
configurational instability of the lithiated N-Boc hetero-
cycle(issue(iv)). Thisworkdemonstratesthattemperatures
above ꢀ78 °C should be considered for any asymmetric
lithiation reaction using s-BuLi and chiral diamines. In-
deed, with N-Boc pyrrolidine 1, use of a temperature of
ꢀ30 °C delivers products in ∼90:10 er which represents a
considerable energy-saving for any proposed large-scale
asymmetric lithiation trapping of this substrate.
temp/
°C
yield of
er of
yield of
entry
time
6 h
3 h
1 h
30 min
20 min
5 min
(S)-12 (%)a
(S)-12b
recov. 11 (%)c
1d
2d
3d
4
5
6
ꢀ78
ꢀ78
ꢀ78
ꢀ50
ꢀ40
ꢀ30
78
83
24
46
64
47
88:12
87:13
86:14
79:21
80:20
77:23
ꢀ
ꢀ
ꢀ
21
15
26
a Yield after purification by chromatography. b Enantiomer ratio (er)
determined by CSP-HPLC (see SI). c Yield of recovered starting material
11 after purification by chromatography. d See ref 4.
complex is required to obtain satisfactory yields although
a 3 h lithiation time is necessary (Table 4, entries 1ꢀ3).4a
We therefore explored higher temperatures (ꢀ50 °C, ꢀ40
and ꢀ30 °C) and 5ꢀ30 min lithiation times (entries 4ꢀ6),
trapping with methyl chloroformate to give (S)-12.
At each temperature, lithiation using the s-BuLi/(þ)-
sparteine surrogate was not complete as judged by the
isolation of some recovered starting material (15ꢀ26%).
At ꢀ50 °C for 30 min and ꢀ40 °C for 20 min, satisfactory
yields (46% and 64% respectively) of ester (S)-12 of
∼80:20 er were obtained (entries 4 and 5).
Acknowledgment. We thank Pfizer, Merck, EPSRC,
and the University of York for funding. We are grateful
to James Firth (University of York) for assistance with the
piperazine. This paper is dedicated to the memory of
Robert (Bob) E. Gawley.
Supporting Information Available. Full experimental
procedures, characterization data, and copies of 1H and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
A similar set of results was obtained with N-Boc
piperazine 13 using the s-BuLi/(þ)-sparteine surrogate
(Table 5). There is only one previous report on the
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX