TMSCH2Li-induced regioselective lithiation of (S)-nicotine

Article abstract of DOI:10.1039/b612786j

The first regioselective C-4 lithiation of (S)-nicotine has been realized using TMSCH₂Li as basic reagent in toluene. The reaction proceeded under mild conditions with a small excess of electrophile. The 4-chloro derivative was subsequently met

Full text of DOI:10.1039/b612786j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
TMSCH2Li-induced regioselective lithiation of (S)-nicotine
Philippe C. Gros,*a Abdelatif Doudouha and Christopher Woltermannb
Received 4th September 2006, Accepted 10th October 2006
First published as an Advance Article on the web 24th October 2006
DOI: 10.1039/b612786j
The first regioselective C-4 lithiation of (S)-nicotine has been realized using TMSCH2Li as basic
reagent in toluene. The reaction proceeded under mild conditions with a small excess of electrophile.
The 4-chloro derivative was subsequently metallated at C-5 with the same basic reagent in THF at
−78 ◦C. This methodology opens a straightforward access to functional diversity in (S)-nicotine
chemistry.
Introduction
Much interest is currently focused on the chemical modification of
naturally occurring bioactive molecules. The aim is to modulate
the properties of the natural product using only a few reaction
steps. This time- and money-saving approach becomes even more
important when optically active compounds are needed. The
preparation of a chiral molecule analogue often draws the chemist
to design sophisticated multistep synthetic sequences from achiral
precursors, implying yield-consuming asymmetric resolutions as
the final step. (S)-Nicotine 1 is a naturally abundant chiral
alkaloid, efficient for the treatment of neurodegenerative diseases.1
However, there are many drawbacks of using (S)-nicotine, such as
addiction and intrinsic toxicity leading to dramatic cardiovascular
Scheme 1 Metallations of (S)-nicotine reported in the literature. LiD-
and digestive complications.
MAE = LiO(CH2)2NMe2.
The synthesis of new (S)-nicotine analogues potentially display-
ing weaker side effects is thus of critical importance and opens an
exciting challenge for chemists. Also important is the synthesis of
nicotine vaccines for fighting against tobacco addiction.2 Besides
multistep reaction sequences reported in the literature,1c some
attractive straightforward one-step modifications via lithiation of
the pyridine ring have been reported recently by Comins and co-
workers (Scheme 1).3
Recently, we have reported the efficient metallation of pyridine
derivatives using TMSCH2Li-based lithiating agents.7 The new
non-nucleophilic TMSCH2Li–LiDMAE reagent used in stoichio-
metric amount led to an unexpected regioselectivity in the metal-
lation of 4-DMAP, which was functionalized exclusively at C-3 for
the first time.8 We felt that such a reagent could provide new levels
of selectivity with other amino-substituted pyridines such as 1.
For example, a range of moieties was introduced at the C-
6 position of 1 by lithiation with the BuLi–LiDMAE reagent3a
previously developed by Gros and Fort.4 The C-2 position was
metallated using LiTMP.3a Unfortunately, the functionalization
was made possible only by trapping the lithio intermediate with
base-compatible electrophiles, obviously limiting the functional
diversity. Kondo’s TMP-zincate5 was also tried, leading to mix-
tures of C-2- and C-4-substituted compounds in poor yield.
To date, the best reported way to functionalize cleanly the C-4
position is the nucleophilic addition of a Grignard or cuprate
reagent to activated (S)-nicotine.6 However, two additional steps
are needed, since the nucleophilic agents have first to be prepared,
and a sulfur treatment is subsequently necessary to release the
target compounds.
Results and discussion
The metallation of 1 was investigated with several TMSCH2Li–
LiDMAE combinations under various conditions (Scheme 2,
Table 1). Preliminary experiments showed that 1 was entirely
recovered when reacted at 0 ◦C. In contrast, C-4 lithiation was
obtained exclusively at 20 ◦C whatever the TMSCH2Li/LiDMAE
ratio or solvent used.
aSynthe`se Organome´tallique et Re´activite´, UMR CNRS-UHP 7565 Univer-
site´ Henri Poincare´, Faculte´ des Sciences, Boulevard des Aiguillettes, 54506,
Vandoeuvre-le`s-Nancy, France. E-mail: philippe.gros@sor.uhp-nancy.fr;
Fax: +33 3836 84785; Tel: +33 3836 84979
Scheme 2 Metallation of 1 with TMSCH2Li-containing reagents.
All reactions were very clean, providing easily separable 2a and
unreacted 1. The best yield (90% isolated) was obtained using
2 equiv. of TMSCH2Li in toluene for 5 h at room temperature
bFMC Corporation, Lithium Division, Highway 161 Box 795, Bessemer City,
NC, 28016, USA. E-mail: CHRIS_WOLTERMANN@fmc.com; Fax: +1
704 868 5496; Tel: +1 704 868 5421
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Table 1 Condition screening for lithiation of 1a
Entry
TMSCH2Li (equiv.)
LiDMAE (equiv.)
Solvent
t/h
2a (%)b
1
2
3
4
5
6
7
8
2
2
2
2
1.5
2
1.5
2
1
2
0
0
0
0
0
1
Hexane
Hexane
Hexane
Hexane
Hexane
Toluene
Toluene
Toluene
1
4
4
5
5
5
5
3
14
72
81
88
82
95 (90c)
88
91
a All reactions performed on 1.84 mmol of 1. b Yield determined by 1H NMR of the crude product; the remaining material is unreacted 1. c Isolated yield.
(entry 6). However, excellent yields could be also attained using
1.5 equiv. of the basic reagent (entry 7). The metallation time could
be shortened (to 3 h) using TMSCH2Li and LiDMAE in a 2 : 1
ratio (entry 8). Interestingly, all reactions were performed with only
a stoichiometric amount of electrophile. This illustrated the low
nucleophilicity of TMSCH2Li, since an excess of this reagent did
not consume the electrophile before its reaction with the lithiated
pyridine.
This lithiation regioselectivity was unexpected, since the metal-
lation affected the less acidic proton, as shown by the calculated
charge on protons in 1 (Fig. 1(a)).9 A tentative explanation of this
selectivity could be a cooperative chelating effect of the pyrrolidine
nitrogen, placing TMSCH2Li at the appropriate place to abstract
the H-4 proton (Fig. 1(b)).
Scheme 3 Preparation of 4-substituted nicotine derivatives. Reagents
and conditions: i) TMSCH2Li (2 equiv.), toluene, 20 ◦C,
5 h.
Fig. 1 (a) PM3 proton charge calculations in 1. (b) Proposed coordination
mode of TMSCH2Li to pyrrolidine nitrogen.
ii) ClSiMe3/C2Cl6/CBr4/I2/ClSnBu3/PhCONMe2, as appropriate (1.1
equiv.), toluene, −78 ◦C to rt. For 2h and 2i the electrophiles were
respectively PhCHO and o-MeOC6H4CHO (2 equiv.) added in THF. *
1H NMR showed a 1 : 1 diastereoisomeric ratio.
The reactivity of TMSCH2Li here contrasts with that of n-BuLi,
since BuLi–LiDMAE has been reported to induce selectively the
C-6 lithiation of 1 (Scheme 1).2
We then focused on the synthetic potential of this new method-
ology for the preparation of several C-4-substituted nicotine
derivatives. The simplest and most practical conditions (Table 1,
entry 6) were chosen to examine the reaction with several
electrophilic reagents (Scheme 3).
A range of new functionalities was introduced for the first time
at C-4 of 1. Good yields were obtained using small excesses
of electrophiles. This was found to be highly valuable for the
preparation of stannane 2f, avoiding the usual tedious separation
of tin by-products. Note that the iodo derivative 2e was obtained
as a single product in 64% yield, while the same compound could
be obtained only in 24% yield (in non-selective manner) using
Kondo’s reagent.3a Our compound 2e gave an optical rotation
comparable to the literature value under similar conditions,
indicating the absence of racemization during our metallation
process (see Experimental section). We also demonstrated the
applicability of the process for the multigram scale preparation
of the useful chloro derivative 2c.10 The reaction proceeded
as well on 28 mmol of 1, producing 5 g of 2c (88% yield).
The reaction of prochiral aldehydes was also investigated for a
1
straightforward access to chiral alcohols. The H NMR spectra
did not reveal any diastereoselection, indicating the weak influence
of the chiral pyrrolidine moiety during the aldehyde condensation
step. However, both the diastereoisomers from 2h and 2i were
found to be separable by column chromatography.
Finally, we examined the metallation of the chloro derivative 2c.
The aim was to exploit the ortho-directing power of chlorine at C-4
to introduce functionalities at C-5. Our first attempts at applying
the previous metallation conditions led to sluggish and poorly
selective reactions. The solvent was then changed and the reaction
was performed at 0 ◦C with 2 equiv. of TMSCH2Li in THF. Under
these conditions, only the C-5-substituted product 3 was obtained
(Scheme 4). The formation of 3 can be explained by pyridyne
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The orange solution was then cooled to −78 ◦C and treated with
a solution of the appropriate electrophile (2 mmol) in toluene
(2 mL), added dropwise. After the addition, stirring was main-
tained for 30 min at −78 ◦C, and then for 1 h at room temperature.
Hydrolysis was performed at −78 ◦C with H2O (10 mL). After
extraction with Et2O, drying and evaporation of the organic phase,
the crude product was purified by column chromatography using
AcOEt–hexane–Et3N (30 : 70 : 10) as eluent (this was found to be
convenient for all compounds). For the preparation of alcohols 2h
and 2i, the above procedure was employed except that 3.68 mmol
of benzaldehyde or ortho-anisaldehyde were used. For reasons of
solubility ortho-anisaldehyde was added as a solution in THF
(4 mL).
Scheme 4 Introduction of the TMSCH2 group at C-5.
formation and subsequent attack at the more electrophilic site by
the remaining equivalent of TMSCH2Li.
This reaction clearly indicated that lithium was successfully
introduced at the C-5 position but was too instable to be trapped
at 0 ◦C. Thus, the temperature was lowered to improve the
stabilization. After a short temperature screening, we found
that performing the reaction at −78 ◦C, while decreasing the
conversion, cleanly provided alcohols 4 and 5 (as 1 : 1 mixtures
of inseparable diastereoisomers) in acceptable yields (Scheme 5).
Note that the starting material was recovered in 25 and 47%
respectively. This iterative lithiation is also of particular interest,
since the C–Cl bond at C-4 is known to be easily reduced
under several conditions, giving a straightforward access to C-
5-substituted derivatives.
(S)-4-(Methylsulfanyl)nicotine (2a). Yield 90%, white solid,
◦
mp 76 C. [a]2D7 −191.5 (c 1.03, CHCl3). (Found: C, 63.51; H,
7.63; N, 13.58. C11H16N2S requires C, 63.42; H, 7.74; N, 13.45%).
dH (200 MHz, CDCl3) 1.47–2.01 (m, 3H), 2.22 (s, 3H), 2.10–2.40
(m, 2H), 2.46 (s, 3H), 3.25 (t, J = 7.2 Hz, 1H), 3.42 (t, J = 8.4 Hz,
1H), 7.01 (d, J = 5.3 Hz, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.58 (s,
1H). dC (50 MHz, CDCl3) 14.1, 22.7, 32.7, 40.6, 57.1, 65.9, 117.5,
134.9, 147.4, 147.8, 149.0. m/z (EI) 209 (3%), 208 (M+, 13%), 207
(13%), 193 (41%), 165 (24%), 159 (14%), 84 (100%).
(S)-4-(Trimethylsilyl)nicotine (2b). Yield 79%, pale yellow oil.
[a]2D7 −169.0 (c 1.04, CHCl3). (Found: C, 66.74; H, 9.53; N, 12.08.
C13H22N2Si requires C, 66.61; H, 9.46; N, 11.95%). dH (200 MHz,
CDCl3) 0.36 (s, 9H), 1.48–1.85 (m, 3H), 2.22 (s, 3H), 2.28–2.41
(m, 2H), 3.23–3.49 (m, 2H), 7.27 (d, J = 4.6 Hz, 1H), 8.43 (d,
J = 4.6 Hz, 1H), 8.86 (s, 1H). dC (50 MHz, CDCl3) 0.8, 23.1, 36.8,
40.7, 57.2, 69.2, 128.1, 144.8, 147.3, 147.9, 149.4. m/z (EI) 234
(M+, 4%), 219 (7%), 205 (3%), 84 (100%), 73 (11%).
(S)-4-Chloronicotine (2c). Yield 91%, pale yellow oil. [a]D27
−182.1 (c 1, CHCl3). (Found: C, 61.29; H, 6.74; N, 14.18.
C10H13ClN2 requires C, 61.07; H, 6.66; N, 14.24%). dH (200 MHz,
CDCl3) 1.48–1.62 (m, 1H), 1.72–1.85 (m, 2H), 2.21 (s, 3H), 2.32–
2.38 (m, 2H), 3.23 (dt, J = 9.2 and 1.8 Hz, 1H), 3.58 (t, J = 8.3 Hz,
1H), 7.21 (d, J = 5.2 Hz, 1H), 8.31 (d, J = 5.2 Hz, 1H), 8.75 (s,
1H). dC (50 MHz, CDCl3) 23.2, 33.8, 40.9, 57.2, 65.6, 124.4, 137.3,
143.7, 148.8, 150.5 m/z (EI) 197 (3%), 196 (M+, 8%), 195 (8%),
169 (5%), 167 (15%), 85 (8%), 84 (100%).
Scheme 5 Synthesis of 4,5-disubstituted nicotine derivatives.
Conclusion
In summary, the first regioselective C-4 lithiation of (S)-nicotine
has been realized. The metallation proceeded smoothly at room
temperature using TMSCH2Li as a basic reagent in toluene, lead-
ing to a range of new derivatives. The C-4-chlorinated derivative
was prepared on a multigram scale and successfully functionalized
(S)-4-Bromonicotine (2d). Yield 67%, orange gummy solid.
[a]2D7 −51.9 (c 0.92, CHCl3). (Found: C, 49.93; H, 5.54; N, 11.71.
C10H13BrN2 requires C, 49.81; H, 5.43; N, 11.62%). dH (200 MHz,
CDCl3) 1.48–1.92 (m, 3H), 2.22 (s, 3H), 2.30–2.50 (m, 2H), 3.20–
3.32 (m, 1H), 3.57 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 5.3 Hz, 1H),
8.27 (d, J = 5.3 Hz, 1H), 8.74 (s, 1H). dC (50 MHz, CDCl3) 22.9,
33.5, 40.7, 56.9, 67.7, 127.5, 134.3, 147.9, 148.4, 150.2. m/z (EI)
242 (4%), 241 (M+, 4%), 239 (4%), 199 (2%), 84 (100%).
◦
at C-5 using the same metallating agent in THF at −78 C. The
new methodology disclosed here is a significant advance in (S)-
nicotine chemistry in terms of selectivity and functional diversity.
Work is now progressing to investigate in more detail the origin of
the selectivity at C-4 as well as the scope of this reaction.
(S)-4-Iodonicotine3 (2e). Yield 64%, white solid, mp 96 ◦C (lit.3
Experimental
◦
97–98 C). [a]2D7 −130.5 (c 1.03, CHCl3) and (for comparison)
General procedure for lithiation of (S)-nicotine. Preparation of
compounds 2a–i
[a]2D5 −118 (c 4.05, CH2Cl2) (lit.3 [a]2D3 −120 (c 4.2, CH2Cl2)). dH
(200 MHz, CDCl3) 1.42–1.65 (m, 1H), 1.75–1.95 (m, 2H), 2.24 (s,
3H), 2.32–2.45 (m, 2H), 3.20–3.35 (m, 1H), 3.39 (t, J = 8.3 Hz,
1H), 7.70 (d, J = 5.3 Hz, 1H), 8.04 (d, J = 5.3 Hz, 1H), 8.61 (s,
1H). dC (50 MHz, CDCl3) 23.1, 34.1, 40.9, 57.2, 72.7, 111.5, 134.5,
142.2, 148.5, 149.9. m/z (EI) 288 (M+, 6%), 287 (6%), 259 (5%),
84 (100%), 82 (10%), 63 (10%).
A solution of 1 (299 mg, 1.84 mmol) in anhydrous toluene (4 mL)
was cooled to 0 ◦C, and TMSCH2Li (3.68 mmol, 4 mL of a
0.92 M solution in hexanes) was added dropwise. At the end of the
addition (ca. 5 min), the reaction medium was allowed to warm
to rt (typically 20 ◦C) and stirred for 5 h at this temperature.
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(S)-4-(Tributylstannyl)nicotine (2f). Yield 61%, colorless oil.
[a]2D7 −74.6 (c 1.03, CHCl3). (Found: C, 58.63; H, 8.84; N, 6.32.
C22H40N2Sn requires C, 58.46; H, 8.93; N, 6.21%). dH (200 MHz,
CDCl3) 0.9–2.0 (m, 31H), 2.19 (s, 3H), 2.30 (q, J = 8.6 Hz, 1H), 3.0
(t, J = 8.6 Hz, 1H), 3.25 (dt, J = 7.6 and 1.9 Hz, 1H), 7.31 (d, J =
4.9 Hz, 1H), 8.38 (d, J = 4.9 Hz, 1H), 8.67 (s, 1H). dC (50 MHz,
CDCl3) 10.9, 13.5, 22.5, 26.9, 29.2, 36.5, 40.8, 56.9, 72.8, 131.4,
145.2, 146.1, 148.5, 152.1
CDCl3) 1.22–2.23 (m, 8H), 3.10–3.45 (m, 2H), 3.80 (s, 3H), 5.37
(brs, 1H), 6.39 (s, 1H), 6.88 (m, 2H), 7.05 (dd, J = 7.6 and 1.2 Hz,
1H), 7.31 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 4.9 Hz, 1H), 8.36 (d,
J = 4.9 Hz, 1H), 8.63 (s, 1H). dC (50 MHz, CDCl3) 22.6, 33.7,
40.5, 55.4, 56.6, 65.9, 66.9, 110.7, 120.8, 121.6, 128.5, 129.2, 131.2,
135.7, 147.8, 149.5, 150.7, 156.5. m/z (EI) 298 (M+, 10%), 296
(25%), 281 (34%), 173 (40%), 159 (50%), 135 (23%), 84 (100%), 77
(62%), 63 (27%).
(S)-[3-(1-Methylpyrrolidin-2-yl)pyridin-4-yl](phenyl)methanone
(2g). Yield 60%, yellow oil. [a]2D7 −76.4 (c 0.84, CHCl3). (Found:
C, 76.79; H, 6.71; N, 10.63. C17H18N2O requires C, 76.66; H, 6.81;
N, 10.52%). dH (200 MHz, CDCl3) 1.62–1.9 (m, 3H), 1.99 (s, 3H),
2.05–2.31 (m, 2H), 2.75–2.85 (m, 1H), 3.45 (t, J = 8.0 Hz, 1H),
7.13 (d, J = 4.9 Hz, 1H), 7.44 (t, J = 6.8 Hz, 2H), 7.56 (t, J =
6.9 Hz, 1H), 7.70 (d, J = 6.8 Hz, 2H), 8.58 (d, J = 4.9 Hz, 1H),
8.81 (s, 1H). dC (50 MHz, CDCl3) 23.4, 35.4, 40.8, 56.0, 66.6,
112.1, 127.2, 128.4, 128.6, 128.9, 133.2, 137.3, 146.2, 148.1, 150.3,
194.4. m/z (EI) 266 (42%), 251 (58%), 210 (20%), 159 (15%), 105
(24%), 84 (100%), 82 (21%), 77 (84%), 51 (38%).
Lithiation of (S)-4-chloronicotine (2c). A solution of 2c
(299 mg, 1.84 mmol) in anhydrous THF (4 mL) was cooled to
−78 ◦C, and TMSCH2Li (3.68 mmol, 4 mL of a 0.92 M solution
in hexanes) was added dropwise. At the end of the addition (ca.
5 min.), the reaction medium was stirred for 5 h at the same
temperature. The orange solution was then treated dropwise with
a solution of the appropriate electrophile (2 mmol) in THF (2 mL).
After the addition, the stirring was maintained for 30 min at
−78 ◦C, and then for 1 h at room temperature. Hydrolysis was
performed at −78 ◦C with H2O (10 mL). After extraction with
Et2O, drying, and evaporation of the organic phase, the crude
product was purified by column chromatography using AcOEt–
hexane–Et3N (30 : 70 : 10) as eluent (this was found to be
convenient for all compounds).
[3-(1-Methylpyrrolidin-2-yl)pyridin-4-yl](phenyl)methanol (2h).
Yield 85%, obtained as a 1 : 1 mixture of diastereoisomers, which
were separated. The absolute configuration was not determined.
Diastereoisomer 2h-1. Yield 47%, viscous colorless oil. [a]D27
−38.7 (c 1.24, CHCl3). (Found: C, 76.15; H, 7.62; N, 10.53.
C17H20N2O requires C, 76.09; H, 7.51; N, 10.44%). dH (200 MHz,
CDCl3) 1.90–2.52 (m, 8H), 3.21–3.42 (m, 2H), 6.15 (s, 1H), 6.70
(d, J = 5.1 Hz, 1H), 7.25–7.45 (m, 5H), 8.33 (d, J = 5.1 Hz, 1H),
8.46 (s, 1H). dC (50 MHz, CDCl3) 24.1, 32.5, 40.5, 57.1, 66.8, 69.9,
71.3, 123.3, 127.1, 127.3, 127.8, 128.5, 135.0, 137.6, 141.1, 149.6,
151.1, 152.5. m/z (EI) 268 (M+, 9%), 210 (10%), 196 (15%), 168
(13%), 120 (19%), 84 (100%), 79 (22%), 77 (48%).
3-(1-Methylpyrrolidin-2-yl)-5-(trimethylsilanylmethyl)pyridine
(3). This compound was obtained when the metallation was
performed at 0 ◦C instead of −78 ◦C. Yield 51%, yellow oil.
(Found: C, 67.73; H, 9.66; N, 11.35. C14H24N2Si requires C, 67.68;
H, 9.74; N, 11.28%). dH (200 MHz, CDCl3) 0.04 (s, 9H), 1.73–2.32
(m, 9H), 3.03 (t, J = 8.0 Hz, 1H), 3.20–3.32 (m, 1H), 7.35 (s, 1H),
8.17 (d, J = 1.6 Hz, 1H), 8.24 (d, J = 1.9 Hz, 1H). dC (50 MHz,
CDCl3) 0.04, 22.5, 23.8, 35.3, 40.4, 57.0, 68.9, 133.9, 136.2, 137.9,
145.5, 147.9. m/z (EI) 248 (M+, 9%), 247 (6%), 219 (5%), 147 (2%),
85 (6%), 84 (100%), 73 (28%).
◦
Diastereoisomer 2h-2. Yield 37%, white solid, mp 135 C. [a]D27
−28.6 (c 0.68, CHCl3). (Found: C, 76.19; H, 7.46; N, 10.62.
C17H20N2O requires C, 76.09; H, 7.51; N, 10.44%). dH (200 MHz,
CDCl3) 1.20–1.40 (m, 1H), 1.42–1.81 (m, 2H), 2.10–2.42 (m, 4H),
3.12–3.42 (m, 2H), 5.92 (s, 1H), 7.10–7.45 (m, 6H), 8.48 (d, J =
5.0 Hz, 1H), 8.54 (s, 1H). dC (50 MHz, CDCl3) 22.4, 32.6, 40.5,
56.5, 68.7, 76.7, 123.9, 123.9, 127.3, 127.7, 128.6, 135.2, 141.1,
144.1, 148.7, 151.2, 152.4. m/z (EI) 268 (M+, 11%), 210 (11%),
196 (15%), 168 (13%), 120 (19%), 84 (100%), 79 (31%), 77 (60%).
[4-Chloro-5-(1-methylpyrrolidin-2-yl)pyridin-3-yl](2-methoxy-
phenyl)methanol (4). Yield 70% (as a 1 : 1 mixture of diastereoiso-
◦
mers), yellow solid, mp 122 C. [a]2D7 −115.8 (c 1.02, CHCl3). dH
(200 MHz, CDCl3) 1.52–2.10 (m, 4H), 2.25 (s, 3H), 2.26 (s, 3H),
2.25–2.50 (m, 4H), 3.23–3.65 (m, 6H), 3.86 (s, 6H), 6.42 (s, 2H),
6.91–7.08 (m, 4H), 7.09 (d, J = 6.9 Hz, 2H), 7.31 (t, J = 6.9 Hz,
2H), 8.59 (s, 1H), 8.62 (s, 1H), 8.74 (s, 2H). dC (50 MHz, CDCl3)
23.2, 33.7, 41.1, 55.7, 57.2, 65.8, 67.2, 110.9, 121.0, 128.1, 128.9,
130.5, 136.5, 136.8, 142.7, 148.5, 157.1. m/z (EI) 334 (4%), 332
(M+, 9%), 303 (5%), 152 (7%), 137 (24%), 135 (18%), 84 (100%),
77 (5%).
(2-Methoxyphenyl)[3-(1-methylpyrrolidin-2-yl)pyridin-4-yl]-
methanol (2i). Yield 85%, obtained as a 1 : 1 mixture of di-
astereoisomers, which were separated. The absolute configuration
was not determined.
Diastereoisomer 2i-1. Yield 44%, colorless oil. [a]2D7 −50.0 (c 2.12,
CHCl3). (Found: C, 72.53; H, 7.56; N, 9.49. C18H22N2O2 requires
C, 72.46; H, 7.43; N, 9.39%). dH (200 MHz, CDCl3) 1.90–2.52
(m, 8H), 3.28–3.42 (m, 2H), 3.64 (s, 3H), 6.37 (s, 1H), 6.63 (d, J =
5.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.34
(t, J = 8.0 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 8.29 (d, J = 5.2 Hz,
1H), 8.43 (s, 1H). dC (50 MHz, CDCl3) 24.4, 40.6, 55.2, 55.3, 65.5,
70.0, 110.0, 120.8, 121.8, 127.5, 128.5, 129.2, 134.9, 149.8, 150.8,
152.5, 156.1. m/z (EI) 298 (M+, 10%), 296 (18%), 281 (20%), 173
(23%), 159 (31%), 84 (100%), 77 (43%), 63 (21%).
[4-Chloro-5-(1-methylpyrrolidin-2-yl)pyridin-3-yl](4-methoxy-
phenyl)methanol (5). Yield 40% (as a 1 : 1 mixture of diastereoiso-
mers), pale yellow oil. [a]2D7 −86.2 (c 1.05, CHCl3). dH (200 MHz,
CDCl3) 1.20–2.0 (m, 4H), 2.15 (s, 3H), 2.17 (s, 3H), 2.23–2.32 (m,
4H), 3.15–3.55 (m, 4H), 3.74 (s, 6H), 4.4 (brs, 2H), 6.09 (s, 2H),
6.83 (d, J = 8.2 Hz, 4H), 7.27 (d, J = 8.2 Hz, 4H), 8.58 (s, 2H),
8.67 (s, 1H), 8.69 (s, 1H). dC (50 MHz, CDCl3) 23.2, 33.7, 41.1,
55.6, 57.2, 59.2, 64.8, 65.8, 71.4, 114.2, 128.9, 134.9, 137.0, 137.7,
147.7, 148.4, 148.6, 159.4. m/z (EI) 332 (M+, 4%), 331 (1%), 144
(18%), 143 (98%), 130 (29%), 105 (25%), 84 (100%), 77 (15%).
◦
Diastereoisomer 2i-2. Yield 33%, white solid, mp 135 C. [a]D27
−88.2 (c 0.78, CHCl3). (Found: C, 72.33; H, 7.46; N, 9.25.
C18H22N2O2 requires C, 72.46; H, 7.43; N, 9.39%). dH (200 MHz,
4334 | Org. Biomol. Chem., 2006, 4, 4331–4335
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3 (a) F. C. Fe´vrier, E. D. Smith and D. L. Comins, Org. Lett., 2005, 7,
5457; (b) F. F. Wagner and D. L. Comins, Eur. J. Org. Chem., 2006,
3562; (c) F. F. Wagner and D. L. Comins, Org. Lett., 2006, 8, 3549.
4 For a review on the BuLi–LiDMAE reagent, see: P. Gros and Y. Fort,
Eur. J. Org. Chem., 2002, 3375.
5 (a) Y. Kondo, M. Uchiyama and T. Sakamoto, J. Am. Chem. Soc., 1999,
121, 3539; (b) T. Imahori, M. Uchiyama, T. Sakamoto and Y. Kondo,
Chem. Commun., 2001, 2450.
6 (a) D. L. Comins, L. S. King, E. D. Smith and F. C. Fe´vrier, Org. Lett.,
2005, 7, 5059; (b) E. D. Smith, F. C. Fe´vrier and D. L. Comins, Org.
Lett., 2006, 8, 179; (c) D. L. Comins and E. D. Smith, Tetrahedron Lett.,
2006, 47, 1449.
7 (a) A. Doudouh, P. C. Gros, Y. Fort and C. Woltermann, Tetrahedron,
2006, 62, 6166; (b) For patented metallations using TMSCH2Li, see:
C. J. Woltermann and D. E. Sutton, FMC Corporation, PCT Int. Appl.,
WO 2004092125, 2004 (Chem. Abstr., 141, 366136).
8 P. C. Gros, A. Doudouh and C. Woltermann, Chem. Commun., 2006,
2673.
Acknowledgements
The authors would like to thank the FMC Corporation (Lithium
Division) for financial support and Dr J. P. Joly (Nancy) for helpful
assistance with polarimetry measurements.
References
1 (a) M. K. Holladay, M. J. Dart and J. K. Lynch, J. Med. Chem., 1997, 40,
4169; (b) E. D. Levin, J. Neurobiol., 2002, 53, 633; (c) S. R. Breining,
Curr. Top. Med. Chem., 2004, 4, 609; (d) A. A. Jensen, B. Fro¨lund,
T. Liljefors and P. J. Krogsgaard-Larsen, J. Med. Chem., 2005, 48,
4705.
2 (a) S. H. L. de Villiers, N. Lindblom, G. Kalayanov, S. Gordon, A.
Malmerfelt, A. M. Johansson and T. H. Svensson, Respiration, 2002,
69, 247; (b) N. Lindblom, S. H. L. de Villiers, G. Kalayanov, S. Gordon,
A. M. Johansson and T. H. Svensson, Respiration, 2002, 69, 254; (c) Y.
Tuncok, D. E. Keyler, S. Ennifar, A. Fattom, Y. Hieda, S. Brown and
P. R. Pentel, Exp. Clin. Psychopharmacol., 2001, 9, 228; (d) M. M.
Meijler, M. Matsushita, L. J. Altobell, III, P. Wirching and K. D. Janda,
J. Am. Chem. Soc., 2003, 125, 7164.
9 The PM3 calculation of proton charges reflects the relative proton
acidities.
10 For the synthetic usefulness of chlorine at C-4 in nicotine derivatives,
see: J. R. Lennox, S. C. Turner and H. J. Rapoport, J. Org. Chem., 2001,
66, 7078.
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