Asymmetric deprotonation of N -boc piperidine: React IR monitoring and mechanistic aspects

Article abstract of DOI:10.1021/ja102043e

The high yielding asymmetric deprotonation trapping of N-Boc piperidine is successfully realized using s-BuLi and a (+)-sparteine surrogate. Monitoring of the lithiation by in situ React IR allowed the direct observation of a prelithiation complex.

Full text of DOI:10.1021/ja102043e

Published on Web 05/12/2010
Asymmetric Deprotonation of N-Boc Piperidine: React IR Monitoring and
Mechanistic Aspects
Darren Stead,† Giorgio Carbone,† Peter O’Brien,*,† Kevin R. Campos,‡ Iain Coldham,§ and
Adam Sanderson|
Department of Chemistry, UniVersity of York, Heslington, York YO10 5DD, U.K., Department of Process Research,
Merck Research Laboratories, Rahway, New Jersey 07065, Department of Chemistry, UniVersity of Sheffield, Brook
Hill, Sheffield, S3 7HF, U.K., and Eli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Sunninghill
Road, Windlesham, Surrey, GU20 6PH, U.K.
Received March 10, 2010; E-mail: paob1@york.ac.uk
Piperidines are widespread subunits in biologically active natural
products and pharmaceuticals. Indeed, 26 of the “Top 200 Brand-
Name Drugs by Retail Dollars in 2008”1 contain piperidine
fragments. To provide ready access to molecules for exploring new
aspects of 3-D pharmaceutical space, we have investigated the
asymmetric synthesis of 2-substituted piperidines. One of the
simplest routes to such piperidines is the asymmetric deprotonation-
trapping of N-Boc-activated piperidine 1 (f 2) (Scheme 1) mediated
by s-BuLi and chiral diamines (e.g., (-)-sparteine).2,3 Although
successful with N-Boc pyrrolidine,2 extension to the 6-ring
heterocycle is unsatisfactory.3,4 For example, lithiation of N-Boc
piperidine 1 using s-BuLi/(-)-sparteine (Et2O, -78 °C, 16 h) and
trapping with Me3SiCl gave the Me3Si-adduct (S)-3 (87:13 er) in
only 8.5% yield, despite the extended lithiation time. The best result
to date was reported by us in 2007: lithiation of 1 with s-BuLi/
(R,R)-4 (Et2O, -78 °C, 6 h) and reaction with Me3SiCl gave adduct
(S)-3 in 13% yield and 90:10 er.5 The main limitation with the
asymmetric lithiation of N-Boc piperidine 1 is the low yield.
Figure 1. In situ React IR monitoring of the lithiation of N-Boc piperidine
1 using s-BuLi/diamine in TBME at -78 °C.
Scheme 2
after 6 h, this peak was a minor component (see Figure 1a). Based
on a comparison with the lithiation of 1 using s-BuLi/TMEDA (see
Supporting Information (SI)), we assigned νCdO ) 1675 cm-1 to
prelithiation complex 6 and νCdO ) 1644 cm-1 to lithiated N-Boc
piperidine 7 (Scheme 2). At the end of the lithiation (6 h), the
mixture consisted of ∼45:45:10 of nonlithiated 1, prelithiation
complex 6, and lithiated complex 7. This is in line with Beak’s
8.5% yield of the Me3Si adduct under similar conditions.3 Notably,
this is the first direct observation of a prelithiation complex in the
lithation of N-Boc heterocycles and is consistent with a kinetic study
with N-Boc pyrrolidine.9 In contrast, reaction of 1 with 1.05 equiv
of s-BuLi/(+)-sparteine surrogate 5 led to rapid lithiation to give
lithiated complex 7 (Via prelithiation complex 6) as the major
component (Figure 1b). The higher reactivity of s-BuLi/5 set the
stage for high yielding asymmetric lithiation of N-Boc piperidine
1 (Table 1).
Lithiation of N-Boc piperidine 1 using 1.3 equiv of s-BuLi/5
(Et2O, -78 °C, 6 h) and trapping with Me3SiCl gave adduct (R)-3
(86:14 er) in 73% yield (Table 1, entry 1). Similarly, a high yield
and ∼88:12 er were obtained with a range of electrophiles in Et2O
and TBME: Bu3SnCl (f (R)-8, entry 2), CO2 (f (S)-9, entries
3/4), and MeO2CCl (f (S)-10, entries 5/6). With each of these
electrophiles, there is an ∼10-fold yield increase using s-BuLi/5
compared to that obtained with s-BuLi/(-)-sparteine. An asym-
metric deprotonation mechanistic pathway was confirmed for this
process: tin-lithium exchange with stannane rac-8 (n-BuLi, Et2O,
-78 °C, 2 h) followed by addition of diamine 5 (-78 °C, 2 h) and
trapping with MeO2CCl gave racemic adduct 10 (15% yield). This
clearly demonstrated that enantiocontrol was not a result of a
postlithiation asymmetric substitution.10 Further investigation re-
vealed that the lithiation time could be reduced to 3 h without a
Scheme 1
In previous work, we have shown that the chiral base complex
formed from s-BuLi and (+)-sparteine surrogate 56 is more reactive
than the corresponding (-)-sparteine complex.7 Thus, use of
diamine 5 in place of (-)-sparteine was explored in the lithation-
trapping of N-Boc piperidine 1 (f 2) and a high-yielding protocol
has been optimized. Herein, we report our results.
First, the known3 low-yielding lithiation of N-Boc piperidine 1
with s-BuLi/(-)-sparteine was investigated using React IR (Figure
1a).8 Thus, 1.05 equiv of (-)-sparteine and 1 were combined in
TBME at -70 °C and a peak at 1695 cm-1 was observed (assigned
to νCdO in 1). Upon addition of 1.05 equiv of s-BuLi, an ∼50:50
mixture of peaks at 1695 and 1675 cm-1 was visible. As time
progressed an additional peak at 1644 cm-1 appeared although, even
† University of York.
‡ Merck Research Laboratories.
§ University of Sheffield.
| Eli Lilly and Co. Ltd.
9
7260 J. AM. CHEM. SOC. 2010, 132, 7260–7261
10.1021/ja102043e  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Asymmetric Lithiation of N-Boc Piperidine 1 Using
s-BuLi/5
Scheme 3
entrya solvent
E+
product
E
yield (%)b
erc
1
2
3
4
5
6
7
8
9
Et2O
Et2O
Et2O
Me3SiCl
Bu3SnCld
CO2
(R)-3 SiMe3
(R)-8 SnBu3
73
82
92
85
78
68
86:14
88:12
88:12
88:12
88:12
88:12
(S)-9
(S)-9
CO2H
CO2H
TBME CO2
Et2O
TBME MeO2CCl (S)-10 CO2Me
Et2O
Et2O
Et2O
MeO2CCl (S)-10 CO2Me
MeO2CCl (S)-10 CO2Me
MeO2CCl (S)-10 CO2Me
83 (3 he) 87:13
a ligand-free route to adducts (R)-11 and (R)-12 was explored.
Tin-lithium exchange of stannane (R)-8 (88:12 er) using n-BuLi
in THF at -78 °C gave a THF-complexed lithiated intermediate
which was trapped separately with PhMe2SiCl (f (R)-11, 87:13
er) and Me2SO4 (f (R)-12, 87:13 er) in high er (Scheme 4).
24 (1 hf) 86:14
PhMe2SiCl (R)-11 SiMe2Ph
85
45
45
45
75
73:27
64:36
60:40
57:43
75:25
82:18
10 Et2O
11 Et2O
12 Et2O
13 Et2O
14 Et2O
MeId
(R)-12 Me
(R)-12 Me
(R)-13 allyl
(R)-13 allyl
Me2SO4
allyl-Br
allyl-Brg
Negishih
(S)-14 3,4-(MeO)2C6H3 33
Scheme 4
a Reaction conditions: (i) 1.3 equiv of s-BuLi/5, Et2O or TBME, -78
°C, 6 h; (ii) E+, -78 °C f rt, 16 h. b Yield after chromatography.
c Enantiomer ratio (er) determined by CSP GC or HPLC (see SI for
details). d Electrophile precooled to -78 °C. e Lithiation for
3 h.
f Lithiation for 1 h. g Reaction conditions: (i) 1.3 equiv of s-BuLi/5,
Et2O, -78 °C, 6 h; (ii) CuCN ·2LiCl, THF, -78 °C, 40 min; (iii)
allyl-Br, -78 °C f rt, 16 h. h Reaction conditions (Negishi): (i) 1.3
equiv of s-BuLi/5, Et2O, -78 °C, 6 h; (ii) ZnCl2, -78 °C, 30 min; (iii)
-78 °C f rt, 35 min; (iv) 3,4-(MeO)2C6H3Br, t-Bu3PHBF4, Pd(OAc)2,
rt, 16 h.
In conclusion, use of s-BuLi/(+)-sparteine surrogate 5 allows
the first examples of high yielding asymmetric deprotonation-
trapping of N-Boc piperidine 1. Direct lithiation-trapping to
enantioenriched 2-substituted piperidines is now possible.16
reduction in yield (entry 7). However, only a 24% yield of (S)-10
(86:14 er) was isolated after a 1 h lithiation time (entry 8). An
asymmetric Negishi coupling11 was also carried out to give a 33%
yield of arylated piperidine (S)-14 (82:18 er) (entry 14).
Acknowledgment. We thank the EPSRC, BBSRC, Eli Lilly,
and Merck for support and George Zhou for React IR assistance.
Supporting Information Available: Full experimental procedures
and characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
Although the reactions using Me3SiCl, Bu3SnCl, CO2, and
MeO2CCl all proceeded satisfactorily (entries 1-6), those with
PhMe2SiCl, MeI, Me2SO4, and allyl bromide gave lower enantio-
selectivity (57:43-73:27 er) (entries 9-12). The low er with allyl
bromide (entry 12) is probably due to the intervention of a single
electron transfer pathway;12 higher enantioselectivity (75:25 er) was
observed using Dieter-style13 transmetalation to copper (entry 13).
To explain the low ers with PhMe2SiCl, MeI, and Me2SO4, we
speculated that trapping of the lithiated complex 7 (Scheme 2) might
not occur at -78 °C due to the steric bulk of the diamine ligand.
Instead, as the solution warmed up from -78 °C to rt, trapping of 7
could occur at higher temperatures. In this scenario, lithiated complex
7 might be configurationally unstable14 at the higher temperatures
which could then account for the lower ers ultimately obtained.
To investigate the configurational stability of lithiated complex
7, N-Boc piperidine 1 was lithiated using 1.3 equiv of s-BuLi/5, in
Et2O at -78 °C for 3 h, and then incubated at -40 or -20 °C for
2 h before trapping with MeO2CCl at -78 °C. After 2 h at -40
°C, (S)-10 of 79:21 er was obtained, indicating some configurational
instability. In contrast, 7 was configurationally unstable at -20 °C:
(S)-10 of 51:49 er was formed after incubating at -20 °C for 2 h
(Scheme 3). Presumably, trapping of lithiated complex 7 by
PhMe2SiCl, MeI, and Me2SO4 occurs at temperatures at which 7
is configurationally unstable thus accounting for the low ers of (R)-
11 and (R)-12.15 The low rate of trapping of 7 by PhMe2SiCl at
-40 °C was shown by attempted reaction of 7 with PhMe2SiCl
over 2 h at -40 °C (f (R)-11, 5% yield, 80:20 er) and subsequent
addition of the more reactive electrophile, MeO2CCl (f (S)-10,
67% yield, 85:15 er) (Scheme 3).
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(15) A similar rationale has been noted for a related 6-ring N-Boc heterocycle
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Finally, since we believed that the slow rate of trapping of
lithiated complex 7 at -78 °C by PhMe2SiCl, MeI, and Me2SO4
was due to the sterically hindered (+)-sparteine surrogate 5 ligand,
JA102043E
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