Synthesis of fused-ring nicotine derivatives from (S)-nicotine

Article abstract of DOI:10.1021/jo9026929

(Figure Presented) The synthesis of novel fused-ring bicyclic (4-6) and tricyclic (7-10) nicotine derivatives from natural (S)-nicotine are described. Enantiopure bicyclic dioxino, dihydrofuro, and dihydropyranol nicotine derivatives as well as tricylic benzofuro and benzopyran derivatives were synthesized from simple alkoxy or halonicotine intermediates. Attempts to synthesize furonicotines (11, 12) resulted in formation of the furonicotine dimers 42 and 49.

Full text of DOI:10.1021/jo9026929

pubs.acs.org/joc
Synthesis of Fused-Ring Nicotine Derivatives from (S)-Nicotine
Pauline W. Ondachi and Daniel L. Comins*
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204
daniel_comins@ncsu.edu
Received December 21, 2009
The synthesis of novel fused-ring bicyclic (4-6) and tricyclic (7-10) nicotine derivatives from natural
(S)-nicotine are described. Enantiopure bicyclic dioxino, dihydrofuro, and dihydropyranol nicotine
derivatives as well as tricylic benzofuro and benzopyran derivatives were synthesized from simple
alkoxy or halonicotine intermediates. Attempts to synthesize furonicotines (11, 12) resulted in
formation of the furonicotine dimers 42 and 49.
Introduction
Current synthetic efforts are directed toward the develop-
ment of analogues that are more selective to specific subtypes
of nicotinic acetylcholine receptors (nAChRs).4 Reported in
the literature is the synthesis of a plethora of nicotine analogues
of diverse variations (see examples, 3a-j, Figure 2). Of these
analogues, some have substitutions on either the pyrrolidine or
pyridine rings,5,6 modifications such as a linker between the
two heterocyclic rings,7 or pyrrolidine ring opening or replace-
ment,8 and in some cases the pyridine has been replaced with a
surrogate ring.9 Reports reveal that among the most active
nicotine analogues, those with fused rings, bridged or con-
strained conformations have surfaced as the most attractive
candidates for selective nAChRs-targeting ligands.8,10,11
Recently, (S)-nicotine (1, Figure 1), the most abundant
alkaloid isolated from dried leaves of the tobacco plants
Nicotiana tabacum and N. rustica,1,2 and nicotine derivatives
have drawn a lot of interest from both medicinal and
synthetic chemists due to their potential pharmacological
role in the treatment of Parkinson’s disease, Alzheimer’s
disease, depression, and other central nervous system related
disorders.3 Despite the beneficial pharmacological proper-
ties of nicotine, its clinical utility is limited by its cardiovas-
cular, gastrointestinal, and neuromuscular side effects and
its addictive liability. Consequently, there is a need to deve-
lop nicotine analogues that exhibit the beneficial properties
of 1 but are devoid of its undesirable effects.
(5) Lin, N.-H.; Carrera, G. M.; Anderson, D. J. J. Med. Chem. 1994, 37,
3542–3553.
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4169–4190. (b) Kim, K. H.; Lin, N.; Anderson, D. J. Bioorg. Med. Chem.
1996, 4, 2211–2217. (c) Gotti, C.; Zoli, M.; Clementi, F. Trends Pharm. Sci.
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Chem. 2004, 4, 299–334. (b) Glennon, R. A. Medicinal Chemistry of R4β2
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pp 55-123. For reviews on nicotine related synthesis, see: (c) Seeman, J. I.
Heterocycles 1984, 22, 165–193. (d) Breining, S. P. Curr. Top. Med. Chem.
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1706 J. Org. Chem. 2010, 75, 1706–1716
Published on Web 02/09/2010
DOI: 10.1021/jo9026929
r
2010 American Chemical Society

Ondachi and Comins
JOCArticle
Results and Discussion
Bicyclic dioxino (4), hydropyranol (5), and dihydrofuro
(6) nicotine derivatives, as well as tricylic benzofused-ring
derivatives (7-10), were targeted and synthesized (Figure 3).
Attempts to prepare furo-fused nicotine derivatives 11 and
12 were unsuccessful and resulted in the formation of
unexpected dimers.
FIGURE 1. Natural agonists for nAChRs, (S)-nicotine (1) and
epibatidine (2).
I. Synthesis of Dioxino Nicotine Derivative 4. Initial at-
tempts to prepare the known6b 4 via a one-pot process
through a copper(I)-catalyzed reaction of (S)-6-chloro-5-
iodonicotine (13) with ethylene glycol in the presence of a
1,10-phenanthroline as ligand resulted in only a 4% yield of
the desired product along with a mixture of the alcohols 14
and 15 (Scheme 1). A better synthesis of 4 was accomplished
in two steps from the alkoxynicotine derivative 16 as shown
in Scheme 2. The dihalo- and alkoxynicotines 13 and 16 were
synthesized in two steps from (S)-nicotine as reported in
our earlier work.15 Lithiation of 16 at the C-5 position
was accomplished via a directed ortho metalation19 using
3.0 equiv of mesityllithium as base in THF at 0 °C. The lithio
anion was quenched with iodine to provide the intermediate
15 in a 43% yield. Attempts to cyclize 15 via copper-
mediated reactions were unfruitful, but use of Buchwald’s
conditions20 for palladium-catalyzed intramolecular C-O
bond formation gave the cyclized product 4 in a 64% yield.
II. Synthesis of Dihydropyranol Nicotine Derivative 5. Our
initial strategy for the synthesis of the dihydropyranol
derivative 5 was as outlined in Scheme 3. Derivative 5 was
envisioned to come from the cyclization of 18 through an
intramolecular C-O bond formation (Scheme 3). Further-
more, it appeared that 18 could be derived from a hydro-
boration reaction21 of the allylic moiety in intermediate 19,
which would come from 13 via a Stille reaction.
A Stille cross-coupling of dihalonicotine 13 with allyltri-
butylstannne under standard conditions provided the nico-
tine intermediate 19 in 94% yield. With 19 in hand, the
hydroboration reaction was investigated. Use of less than
3.0 equiv of 9-BBN resulted mainly in recovery of starting
material (entry 1, Table 1). This was mainly attributed to a
competing complexation of the borane with the two basic
nitrogens in nicotine.22 The use of 3.0 equiv of 9-BBN
provided the desired product 18 upon oxidation with alka-
line hydrogen peroxide (entry 2); however, the excess borane
used in the reaction resulted in what was concluded to be a
complexed boron impurity in the product observed in the 1H
and 13C NMR spectra. All efforts to purify 18 by chromato-
graphy or to remove the impurity by refluxing in MeOH
were unfruitful. Attempts at using a more reactive borane,
BH3 in THF, or 1.0 equiv of 9-BBN in the presence of
This trend is partially attributed to the discovery of epibatidine
(2, Figure 1), an alkaloid containing a bridged structure that
displays strong activity despite its toxicity.12 Several bridged or
conformationally restricted nicotine analogues have exhibited
much higher affinity and better selectivity than nicotine for
nAChRs.13,14
Our group has been engaged in the enantioselective
synthesis of nicotine derivatives by starting with commer-
cially available natural nicotine.15 Although the use of
(S)-nicotine as a starting material is attractive because it
avoids a resolution step to obtain enantiopure analogues,
it was necessary to develop appropriate methodologies to
introduce functionalities around the pyridine ring. From
this effort, regioselective substitutions at all positions of
nicotine’s pyridine ring, C-6,15a,c C-5,15a,d,f C-4,15a,b and
C-2,15c,f have effectively been accomplished. In addition,
utilizing the methodologies developed, two syntheses of
SIB-1508Y15g,h (3a) in five and six steps from (S)-nicotine
and a six-step synthesis of the nicotine-related natural
product (S)-brevicolline15e have been reported. As part of
this program, we were interested in synthesizing cyclic ether
and benzofuro fused-ring derivatives of nicotine as poten-
tial nAChRs agonists. Heterocycle-containing analogues16
and in particular benzofuran derivatives17 are of consider-
able interest because they are common structural motifs in
biologically active compounds and drug candidates.18 We
report herein the enantioselective synthesis of fused bicyclic
and tricyclic nicotine derivatives from commercially avail-
able (S)-nicotine.
(12) Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J. C.;
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1978, 43, 2125–2127. (c) Glassco, W.; Suchocki, J.; George, C.; Martin, B. R.;
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E. D.; Comins, D. L. Org. Lett. 2005, 7, 5457–5460. (d) Smith, E. D.; Fevrier,
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BF3 OEt2, which can complex with the basic nitrogens as
3
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D. L. Org. Lett. 2006, 8, 3549–3552. (f ) Wagner, F. F.; Comins, D. L. Eur. J.
Org. Chem. 2006, 3562–3565. (g) Comins, D. L.; Smith, E. D. Tetrahedron
Lett. 2006, 47, 1449–1451. (h) Wagner, F. F.; Comins, D. L. J. Org. Chem.
2006, 71, 8673–8675.
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FIGURE 2. Examples of some reported synthetic analogues of (S)-nicotine.
FIGURE 3. Fused-ring nicotine analogues targeted for synthesis from natural (S)-nicotine.
SCHEME 1. Synthesis of 4 from 13 via a Copper-Mediated
Reaction
SCHEME 2. Improved Synthesis of Dioxino Nicotine
Derivative 4
With unsatisfactory results obtained, another route to the
synthesis of the intermediate 18 was developed after a series
of investigations. A Sonogashira cross-coupling of 13 with
propargyl alcohol furnished the alkynylnicotine derivative
20 in 82% yield (Scheme 4). Catalytic hydrogenation of 20 at
room temperature under balloon pressure with Pd/C in ethyl
acetate or Pt/C in methanol provided intermediate 18 in high
1708 J. Org. Chem. Vol. 75, No. 5, 2010

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SCHEME 3. Retrosynthetic Route to Nicotine Derivative 5
SCHEME 4. Synthesis of Dihydropyranol Derivative 5
TABLE 1. Synthesis of Intermediate 18 via a Hydroboration Route
SCHEME 5. Attempted Ozonolysis of 20 To Prepare 22
entry
1
conditions
results
sm
1. 9-BBN (1.2-2.0 equiv), THF, rt, 24 h f 3 d
2. NaOH/H2O2
1. 9-BBN (3.0 equiv), THF, rt, 10 h or reflux
2. NaOH/H2O2
1. BF3 OEt2 (2.2 equiv), 0 °C f rt
2. NaOH/H2O2
1. BF3 OEt2, (2.0 equiv), rt
2. 9-BBN, 0 °C (1.2 equiv), overnight
3. TMEDA (0.5 equiv)
4. NaOH/H2O2
2
3
4
18a
b
3
the Levine reagent23 (23) gave the methyl vinyl ether 24 in
63% yield as a mixture of inseparable diastereomers
(Table 2). Hydrolysis of the vinyl ether was limited to mild
acidic conditions due to the presence of the basic pyrrolidine
ring that is prone to ring opening. Unfortunately, hydrolysis
of the vinyl ether under all conditions examined failed,
presumably due to the unusual stability of the methyl vinyl
ether. Notably, further attempts to reduce the vinyl ether by
catalytic hydrogenation followed by demethylation of the
resulting alkyl methyl ether to provide 21 failed at the
demethylation step. Other unsuccessful attempts to obtain
21 included efforts to carry out hydrosilylation24 on (S)-6-
chloro-5-vinylnicotine followed by a Fleming-Tamao-
Kumada25 oxidation, a method that allows silyl groups to
be used as masked hydroxyl groups, and preparation of an
sm
sm
3
5
1. BF3 OEt2, (4.0 equiv), rt
3
2. 9-BBN, 0 °C (1.2 equiv), overnight
3. TMEDA (1.0 equiv)
4. NaOH/H2O2
aPurification of product not achieved. 1H NMR showed signals in
the alkyl region most likely due to borane-pyrrolidine complexation.
bConditions decomposed 19.
yield. Subsequently, the cyclization step to complete the
synthesis of dihydropyranol nicotine 5 was accomplished
in 76% yield by refluxing 18 in THF in the presence of NaH.
III. Synthesis of Dihydrofuro Nicotine Derivative 6. Dihydro-
furo derivative 6 was envisioned to arise from cyclization of 21
in an approach similar to that used for the synthesis of 5
(Scheme 5). However, preparation of 21 proved to be more
challenging than expected, and several routes had to be exami-
ned. Initially, the potential of preparing 21 via a one-pot
reaction through cleavage of the olefin bond in 19 via ozono-
lysis and a reductive workup with NaBH4 was explored.
Unfortunately, bubbling ozone into a solution of 19 in MeOH
at -78 °C for 5 min, followed by addition of NaBH4 at -78 °C
(warmed to rt), led only to decomposition.
(23) Levine, S. G. J. Am. Chem. Soc. 1958, 80, 6150–6151.
(24) (a) Ojima, I. The Hydrosilylation Reaction. In The Chemistry of Organic
Silicon Compounds; Patai S., Rappoport, Z., Eds.; Wiley: Chichester, U.K., 1989;
Vol. 1, Chapter 25, pp 1479-1526. (b) Evans, P. A.; Qin, J.; Robinson, J. E.;
Bazin, B. Angew Chem., Int. Ed. 2007, 46, 7417–7419.
(25) For reviews on Fleming-Tamao-Kumada oxidations, see: (a)
Angelaud, R.; Landais, Y. Tetrahedron 2000, 56, 2025–2036. (b) Jones, G.;
Landais, Y. Tetrahedron 1996, 52, 7599–7662. (c) Fleming, I.; Henning, R.;
Parker, D. C.; Plaut, H. E.; Sanderson, P. E. J. J. Chem. Soc., Perkin Trans.1
1995, 317–337. (d) Tamao, K.; Ishinda, N.; Tanaka, K.; Kumada, M.
Organometallics 1983, 2, 1694–1696. (e) Tamao, K.; Ishinda, N. Tetrahedron
Lett. 1984, 25, 4245–4248.
A second route aimed at obtaining a β-aldehyde via a one-
carbon homologation of (S)-6-chloro-5-formylnicotine15f
(22) also proved problematic. Wittig olefination of 22 with
(26) (a) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7996–800. (b) Kondo, Y.; Inamoto, K.; Uchiyama, M.; Sakamoto, T. Chem.
Commun. 2001, 2704–2705.
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Ondachi and Comins
SCHEME 6. Completion of the Synthesis of 6
JOCArticle
TABLE 2. Attempts To Prepare the Aldehyde Intermediate 25
entry
conditions
result
1
2
3
4
5
6
oxalic acid (3.0 equiv), THF/H2O (4:1), 65 °C, 20 h
oxalic acid (5.0 equiv), MeOH, reflux
formic acid, Et2O, H2O, rt, overnight
TMSCl, NaI (3.0 equiv), MeCN, rt
BBr3 (3.2 equiv), CH2Cl2, -78 °C f rt
1. PPTS (1.0 equiv), acetone, rt
24
a
24
25b
using LiTMP at -78 °C in THF. The aryllithium was
transmetalated with Cu by addition of a solution of
c
24
CuCN 2LiCl in THF, or PhSCu, at -78 °C. The reaction
2. NaBH4, MeOH, CH2Cl2
pTsOH (2.0 equiv), H2O (10 equiv), MeCN, 40 °C, 24 h 24
aPyrrolidine ring opened. bOnly one diastereomer was hydrolyzed.
Product was formed in ∼20% yield. cTrace amount of product with a lot
of decomposition.
3
7
was warmed up to 0 °C when no additive was added, or to
room temperature in the presence of P(OMe)3. The cross-
coupling halide partners, 2-iodoethyl benzoate (entries 1 and
2, Table 3) and ethyl 2-bromoacetate (entries 3 and 4), were
added at -20 °C and stirred at room temperature for several
hours to provide the derivatives 27 and 28, respectively, in
modest yields. Hydrolysis of 27 using aqueous NaOH pro-
vided 21 in 71% yield. Similarly, reduction of the ester 28
using LiBH4 in ether provided 21 in a lower yield of 37%.
Completion of the synthesis of the dihydrofuro derivative 6
was accomplished by refluxing 21 with NaH in THF to
afford the cyclized product in near quantitative yield
(Scheme 6).
TABLE 3. Synthesis of 27 and 28
IV. Synthesis of Tricyclic Benzofuronicotine Derivatives 7
and 8. The synthesis of the benzofuro derivatives was ex-
pected to proceed via a two-step procedure from the appro-
priate dihalonicotines. In the case of derivative 7, a Suzuki
cross-coupling of 13 with the commercially available
2-hydroxyphenylboronic ester 29 was anticipated to provide
an intermediate that could then be cyclized after isolation.
Unexpectedly, when 13 was heated at 80 °C for 48 h in the
presence of 1.2 equiv of 29, Pd(PPh3)4 as catalyst, K3PO4 as
base, and DMF as solvent, the cyclized product 7 was
obtained directly in 75% yield (Scheme 7). The basic reaction
conditions must have provided an alkoxide of intermediate A
that readily undergoes an intramolecular cyclization to form
the five-membered ring. Similarly, the C4-C5 benzofuran-
2-ly derivative 8 was synthesized in a 60% yield from the
cross-coupling of 29 with chloroiodonicotine 31. (S)-4-
Chloronicotine (30) was prepared from nicotine using
TMSCH2Li as base in toluene at room temperature as
reported by Gros and co-workers.28 Lithiation of 30 at
the C-5 position was also done using TMSCH2Li in THF
at -78 °C for 5 h, followed by addition of iodine, to afford 31
in 80% yield.
entry
CuX
RX
product yield (%)a
1b
2
3
4
CuCN 2LiCl/ P(OMe)3 BzOCH2CH2I
27
27
28
28
43
61
27
44
3
PhSCu
CuCN 2LiCl
PhSCu
BzOCH2CH2I
EtO2CCH2Br
EtO2CCH2Br
3
aIsolated yields after radial PLC. bP(OMe)3 (1.9 equiv) was added,
and the reaction was warmed to rt.
R-aryl ester via Buchwald’s conditions26 via palladium-
catalyzed cross-coupling of 13 with tert-butyl acetate.
After extensive experimentation, an efficient synthesis of
intermediate 21 was accomplished through hydrolysis of the
benzoate ester in nicotine derivative 27 or by reduction of the
ester in the β-ester derivative 28 (Table 3). Both 27 and 28
were obtained from a copper(I)-catalyzed cross-coupling
reaction of C-5 metalated (S)-6-chloronicotine (26) with
2-iodoethyl benzoate and R-bromoacetate, respectively.
Knochel and co-workers27 reported a protocol where aryl
Grignards undergo a transmetalation with CuCN 2LiCl,
3
with or without trimethyl phosphite as an additive, to
provide a stable arylcopper compound that undergoes a
cross-coupling reaction with functionalized alkyl iodides.
Adopting this protocol, 26 was lithiated at the C-5 position
V. Synthesis of Tricyclic Nicotine Derivatives 9 and 10. In
the same vein, the benzopyran nicotine derivative 9 was
prepared in two steps from (S)-6-chloro-5-(tributylstannane)-
nicotine (32). A Stille cross-coupling reaction of 32 with
(27) (a) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42, 4302–
4320. (b) Dohle, W.; Lindsey, D. M.; Knochel, P. Org. Lett. 2001, 3, 2871–
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2006, 4, 4331–4335.
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SCHEME 7. Synthesis of Tricyclic Benzofuro Derivatives 7
and 8
SCHEME 8. Two-Step Synthesis of Benzopyran Derivative 9
from 32
SCHEME 9. Retrosynthetic Route to Tricyclic Derivative 10
analogues 42 and 49 commenced from halonicotine inter-
mediates 39 and 46. Preparation of 39 via ortho-lithiation
of (S)-6-methoxynicotine with MesLi has previously been
reported from our laboratories.15a The intermediate 46 was
prepared in two steps from (S)-6-chloro-4-iodonicotine (43).
Heating 43 in a sealed tube in the presence of CuI/1,10-
phenathroline catalyst, MeOH, and Cs2CO3 provided 44 in
modest yield. Lithiation of 44 with n-BuLi in THF and
quenching with iodine afforded 46 in 67% yield. The demethy-
lation of intermediates 39 and 46 was troublesome, resulting in
a lot of decomposition or recovery of the starting materials.
However, use of 3.0 equiv of BBr3 in CH2Cl2 at -78 f 0 °C
provided the demethylated products 40 (21%) and 47 (19%)
albeit in low yields. A Sonogashira cross-coupling of 40 and 47
with trimethylsilylacetylene at room temperature provided the
products 41 and 48 in 65% and 41% yield, respectively. With
the o-hydroxylacetylene derivatives in hand, ring cyclization
was attempted by heating each of the acetylenes 41 and 48 at
75 °C in the presence of CuI in EtOH/Et3N (1:1) as solvent
overnight, followed by addition of K2CO3 at room tempera-
ture, a protocol that has been reported in the literature.30
Surprisingly, both reactions resulted in the formation of
the dimers 42 and 49 instead of the expected furonicotines
commercially available 2-iodobenzyl alcohol (33) provided
38% yield of the coupled product 34. Cyclization of 34 in
DMF at 100 °C in the presence of NaH provided the benzo-
pyran 9 in 53% yield (Scheme 8).
As shown in Scheme 9, the fused furo derivative 10 would be
obtained by a cross-coupling of 13 with 2-(tributylstannane)-
furan-3-carbaldehyde (36), which could be derived from com-
mercially available 3-furaldehyde (35) via an R-amino alkoxide
directed lithiation.29 Following this protocol, 36 was prepared
by treatment of 3-furaldehyde with 1.2 equiv of LTMDA
(lithium salt of N,N,N0-trimethylethylenediamine) at -78 °C,
to form the R-amino alkoxide in situ, followed by addition of
2.0 equiv of n-BuLi to effect C-2 deprotonation. Quenching of
the anion with Bu3SnCl followed by hydrolysis of the amino
alkoxide upon aqueous workup provided 36 in 73% yield
(Scheme 10). A Stille cross-coupling of 36 with 13 using
Pd(PPh3)2Cl2 as catalyst and refluxing in THF provided the
cross-coupled aldehyde 37. Reduction of the aldehyde with
NaBH4 gave the alcohol 38 (70%), which upon heating in
DMF in the presence of NaH furnished the furo derivative 10
in high yield.
VI. Attempted Synthesis of Furofused Nicotines 11 and 12.
As outlined in Schemes 11 and 12, the synthesis of nicotine
(30) (a) Houpis, I. N.; Choi, W. B.; Reider, P. J.; Molina, A.; Churchill,
H.; Lynch, J.; Volante, R. P. Tetrahedron Lett. 1994, 35, 9344–9358. (b)
Wishka, D. G.; Graber, D. R.; Seest, E. P.; Dolak, L. A.; Han, F.; Watt, W.;
Morris, J. J. Org. Chem. 1998, 63, 7851–7859.
(29) (a) Comins, D. L.; Killpack, M. O. J. Org. Chem. 1987, 52, 104–109.
(b) For a review of R-amino alkoxide directed lithiations, see: Comins, D. L.
Synlett 1992, 615–625.
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SCHEME 10. Synthesis of Furo Derivative 10
SCHEME 12. Synthesis of Heteroannulated Nicotine Dimer 49
SCHEME 11. Synthesis of Heteroannulated Nicotine Dimer 42
Conclusion
In summary, we have accomplished the synthesis of enantio-
pure dioxino (4), dihydropyranol (5), dihydrofuro (6), and
benzofuro and benzopyrano (7-10) nicotine derivatives in
good yields from readily available natural (S)-nicotine.
Appropriate methodologies to prepare the key intermediates
via directed ortho lithiations and Pd- or Cu-catalyzed reactions
were developed. Attempts to synthesize furonicotines resulted
in formation of the furonicotine dimers. This work is part of an
ongoing program to develop appropriate methodologies for
the synthesis of nicotine derivatives as potential pharmaceu-
ticals, insecticides, synthetic intermediates, and novel ligands
for catalytic asymmetric synthesis.
Experimental Section
For general information see Supporting Information.
(S )-6-(2-Hydroxy)ethoxy-5-iodonicotine (15). To a solution
of t-BuLi (422 μL, 1.7 M in pentane, 0.54 mmol, 6.0 equiv) in
freshly distilled THF (1 mL) at -78 °C was added dropwise
bromomesitylene (40 μL, 0.27 mmol, 3.0 equiv). After the
mixture stirred at -78 °C for 1 h, a solution of 16 (20 mg,
0.09 mmol, 1.0 equiv) in THF (1 mL) was added dropwise, and
then the mixture was warmed to 0 °C. After 2 h at 0 °C, the
temperature was lowered to -78 °C, and a solution of iodine
1
11 and 12. This was established from analysis of H and 13C
NMR data and confirmed by high resolution mass spectro-
metry (HRMS). We suggest that the unexpected products
resulted from hydrolysis of the TMS group under the reaction
conditions. The unprotected acetylene then undergoes cross-
coupling in the presence of copper iodide leading to the
formation of bis-acetylene nicotines which upon cyclization
form the dimer as illustrated in Scheme 13. Exploring other
routes for achieving the synthesis of the furonicotines 11 and 12
is part of the ongoing work in our laboratories.
˚
(27 mg, 0.11 mmol, 1.2 equiv) in THF (stored over 4 A sieves)
was added to the mixture. The reaction was stirred for an
additional 5 min and then quenched with a 2-mL aqueous
solution of saturated NaHCO3. The mixture was extracted
with CH2Cl2 (2 ꢀ 10 mL). The combined organic layers were
dried over anhydrous K2CO3, filtered through Celite, and
1712 J. Org. Chem. Vol. 75, No. 5, 2010

Ondachi and Comins
JOCArticle
SCHEME 13. Proposed Mechanism for Dimer Formation
1:1 mixture of ammonium hydroxide and ammonium chloride
was added. The mixture was extracted with CH2Cl2 (2 ꢀ 15 mL).
The combined organic layers were dried over anhydrous
K2CO3, filtered through Celite, and concentrated in vacuo.
The crude product was purified by radial PLC (SiO2, 1%
TEA/20% EtOAc/ hexanes) to afford 344 mg (94%) of 19 as a
1
bright yellow oil. [R]33 -123 (c 1.3, CH2Cl2); H NMR (400
D
MHz, CDCl3) δ 8.16 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.0 Hz,
1H), 5.89-5.98 (m, 1H), 5.12 (dd, J = 12, 1.6 Hz, 2H), 3.47 (d,
J = 6.8 Hz, 1H), 3.22 (dt, J = 8.8, 2 Hz, 1H), 3.05 (t, J = 8.8 Hz,
1H), 2.28 (q, J = 9.2 Hz, 1H), 2.22-2.12 (m, 1H), 2.14 (s, 3H),
1.88-1.98 (m, 1H), 1.75-1.85 (m, 1H), 1.61-1.71 (m, 1H); 13
C
NMR (100 MHz, CDCl3) δ 22.7, 35.5, 37.4, 40.6, 57.2, 68.3,
117.6, 134.3, 138.0, 138.5, 147.1, 150.1; IR (neat) 2965, 2780,
1407, 1349, 1162, 1065, 914 cm-1; HRMS calcd for C13H17ClN2
(M þ H)þ 237.1159, found 237.1153.
(S )-3-(2-Chloro-5-(1-methylpyrrolidin-2-yl)pyridine-3-yl)prop-
2-yn-1-ol (20). A solution of 13 (150 mg, 0.465 mmol, 1.0 equiv)
in triethylamine (2 mL) was added to a mixture of Pd(Ph3)2Cl2
(32.6 mg, 0.047 mmol, 0.10 equiv) and copper(I) iodide (17.7 mg,
0.093 mmol, 0.20 equiv) in a flame-dried flask. Methylene
chloride (2 mL) was added, and then the mixture was degassed
with argon for 15 min. Propargyl alcohol (110 μL, 1.860 mmol,
4.0 equiv) was added, and the mixture was stirred at rt overnight.
Water (2 mL) was added, and then the mixture was extracted
with CH2Cl2 (2 ꢀ 10 mL). The combined organic layers were
dried with anhydrous Na2SO4, filtered through Celite, and
concentrated in vacuo. Purification by radial PLC (SiO2, 5%
MeOH/CH2Cl2) afforded 95.8 mg (82%) of 20 as a white solid,
mp103-110 °C. [R]23D -98(c 1.8, CH2Cl2); 1H NMR (400 MHz,
CDCl3) δ 8.23 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 4.55
(s, 2H), 3.23 (dt, J = 8.8, 2.4 Hz, 1H), 3.09 (t, J = 8.0 Hz, 1H),
2.62-2.40 (broad OH signal), 2.32 (q, J = 9.2 Hz, 1H),
2.26-2.18 (m, 1H), 2.16 (s, 3H), 2.02-1.88 (m, 1H), 1.88-1.76
(m, 1H), 1.72-1.62 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
22.7, 35.2, 40.5, 51.4, 57.1, 68.0, 80.4, 95.4, 120, 137.7, 141.2,
148.2, 151; IR (neat) 3640, 3350, 2942, 2790, 1401, 1359, 1198,
1092 cm-1; HRMS calcd for C13H15ClN2O (M þ H)þ 251.0951,
found 251.0950.
concentrated under reduced pressure. The crude product was
purified by radial PLC (SiO2, 1% TEA/20% EtOAc/hexanes) to
afford 13.3 mg (43%) of 15 as a colorless oil. [R]33D -85 (c 1.2,
1
CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 1.6 Hz,
1H), 7.94 (d, J = 2.0 Hz, 1H), 4.48 (dt, J = 8.8, 2 Hz, 2H), 3.95
(dt, J = 8.8, 2 Hz, 2H), 3.40 (s, 1H), 3.20 (dt, J = 8.8, 2.4 Hz,
1H), 2.97 (t, J = 8.8 Hz, 1H), 2.26 (q, J = 8.8 Hz, 1H), 2.14
(s, 3H), 2.09-2.19 (m, 1H), 1.88-1.99 (m, 1H), 1.61-1.71 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 22.7, 35.2, 40.5, 57.1, 62.4,
67.7, 70.1, 80.8, 134.3, 145.5, 147.8, 161.2; IR (neat) 3434, 2963,
1642, 1447, 1306, 1248, 1048 cm-1
; HRMS calcd for
(S )-3-(2-Chloro-5-(1-methylpyrrolidin-3-yl)propan-1-ol (18).
To a solution of 20 (300 mg, 1.2 mmol, 1.0 equiv) in EtOAc
(10 mL) was added a catalytic amount of Pd/C. The mixture was
flushed with hydrogen gas and then was stirred under a balloon
pressure of hydrogen at rt for 2 h. Filtration through Celite and
concentration in vacuo afforded 300 mg (98%) of 18 that was
C12H17IN2O2 (M þ H)þ 349.0413, found 349.0406.
(S )-2,3-Dihydro[1,4]dioxino[5,6-b]nicotine (4). A solution of
15 (44 mg, 0.13 mmol, 1.0 equiv) in toluene (1 mL) was added to
a mixture of Pd(OAc)2 (4.0 mg, 0.016 mmol, 0.1 equiv), Cs2CO3
(77.2 mg, 0.24 mmol, 1.5 equiv), and racemic-2-(di-tert-
butylphosphino)-1,10-binaphthyl (75.5 mg, 0.19 mmol, 1.2
equiv) in 3 mL of toluene. The mixture was purged with argon
for 20 min and then heated to 80 °C. After 24 h, the reaction
mixture was cooled to rt, diluted with EtOAc (2 mL), filtered
through a pad of Celite, and concentrated in vacuo. Purification
by radial PLC (SiO2, 1% TEA/20% EtOAc/hexanes) afforded
18 mg (64%) of 4 as a colorless oil. [R]30D -79 (c 0.7, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 1.6 Hz, 1H), 7.21 (d,
J = 1.6 Hz, 1H), 4.4 (dt, J = 4.4, 3.2 Hz, 2H), 4.23 (dt, J = 4.0,
2.4 Hz, 2H), 3.2 (dt, J = 8.8, 2.0 Hz, 1H), 2.99 (t, J = 8.6 Hz,
1H), 2.25 (q, J = 8.8 Hz, 2.15 (s, 3H), 2.16- 2.09 (m, 1H),
1.98-1.84 (m, 1H), 1.82- 1.76 (m, 1H), 1.72-1.64 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 22.6, 35.1, 40.5, 57.1, 64.1, 65.1,
68.3, 123.7, 134.2, 139.2, 139.7, 150.6; IR (neat) 2967, 2943,
used in the next reaction without further purification. [R]25
D
1
-100 (c 1.4, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.12 (d,
J = 2.4 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 3.68-3.64 (m, 2H),
3.21 (dt, J = 7.6, 2.0 Hz, 1H), 3.04 (t, J = 8.4 Hz, 1H), 2.81 (t,
J = 8.0 Hz, 1H), 2.51 (s, OH signal), 2.27 (q, J = 8.4 Hz, 1H),
2.17-2.14 (m, 1H), 2.13 (s, 3H), 1.98-1.85 (m, 3H), 1.85-1.75
(m, 1H), 1.72-1.60 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
22.7, 29.6, 32.1, 35.3, 40.5, 57.1, 61.7, 68.2, 136.0, 138.1, 138.2,
146.9, 150.1; IR (neat) 3368, 3046, 2943, 1665, 1565, 1409, 1359,
1153 cm -1; HRMS calcd for C13H19ClN2O (M þ H)þ 255.1264,
found 255.1253.
(S )-6-(1-Methylpyrrolidin-2-yl)-3,4-dihydro-2H-pyrano[2,3-b]-
pyridine (5). Solid NaH (93 mg, 3.88 mmol, 3.0 equiv) was
weighed under a nitrogen atmosphere and placed in a flame-
dried flask followed by THF (2 mL). To this was added a solution
of 18 (330 mg, 1.29 mmol, 1.0 equiv) in THF (2 mL), and the
reaction mixture was refluxed for 24 h. The reaction was allowed
to cool to rt, 1 mL of water was added, and the mixture was
extracted with EtOAc (2 ꢀ 10 mL). The combined organic layers
were dried over MgSO4, filtered through a plug of Celite, and
concentrated in vacuo. Purification by radial PLC (SiO2, 1%
TEA/20% EtOAc/hexanes) afforded 213.5 mg (76%) of 5 as a
pale yellow oil. [R]30D -126 (c 1.8, CH2Cl2); 1H NMR (400 MHz,
1581, 1481, 1429, 1357, 1282 cm-1
; HRMS calcd for
C12H16N2O2 (M þ H)þ 221.1290, found 221.1286.
(S )-5-Ally-6-chloronicotine (19). A mixture of 13 (500 mg, 1.6
mmol, 1.0 equiv), allyltributylstannane (580 μL, 1.9 mmol, 1.2
equiv), Pd(PPh3)4 (125 mg, 0.11 mmol, 7 mol %), and CuI
(35 mg, 0.19 mmol, 12 mol %) in toluene (3 mL) was placed in a
pressure vessel and degassed for 20 min with argon. The vessel
was sealed, and the reaction mixture was stirred at 100 °C for 2 d.
The mixture was allowed to cool to rt, and a 2-mL solution of a
J. Org. Chem. Vol. 75, No. 5, 2010 1713

Ondachi and Comins
JOCArticle
CDCl3) δ 7.92 (d, J = 2.4 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 4.32
(dd, J = 5.2, 4.8 Hz, 2H), 3.22 (dt, J = 8.8, 1.6 Hz, 1H), 2.96 (t,
J = 8.0 Hz, 1H), 2.79 (t, J = 6.4 Hz, 2H), 2.26 (q, J = 8.8 Hz,
1H), 2.14 (s, 3H), 2.16-2.10 (m, 1H), 2.0-1.85 (m, 1H),
2.01-1.98 (dd, J = 4.0, 1.6 Hz, 2H), 1.84-1.78 (m, 1H),
1.76-1.66 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 21.9, 22.4,
24.9, 34.8, 40.3, 57.0, 67.2, 68.3, 117.3, 131.6, 137.4, 145.8, 160.9;
IR (neat) 2963, 2944, 1578, 1477, 1459, 1275, 1260 cm-1; HRMS
calcd for C13H19N2O (M þ H)þ 219.1491, found 219.1494.
(S )-6-Chloro-5-(2-methoxyvinyl)nicotine (24). A solution of
potassium tert-butoxide (5.56 mL, 1 M solution in THF, 5.56
mmol, 3.0 equiv) was added to a solution of the Levine reagent
(1.91 g, 5.56 mmol, 3.0 equiv) in THF (15 mL) at 0 °C under
argon. The resulting dark red suspension was stirred for 0.5 h at
0 °C. To this mixture was added a solution of 22 (417 mg,
166.3; IR(neat) 2968, 2943, 2840, 2781, 1719, 1584, 1452,
1274, 1113 cm-1; HRMS calcd for C19H21ClN2O2 (M þ H)þ
345.1360, found 345.1364.
(S)-2-(2-Chloro-5-(1-methylpyrrolidin-3-yl)ethanol (21). A solu-
tion of 27 (58 mg, 0.168 mmol, 1.0 equiv) in a 1:1 methanol/ THF
(2 mL) was treated with 0.5 mL of aqueous 20% NaOH solution.
The mixture was stirred at rt for 1 h. The solvent was removed
under reduced pressure. The residue was dissolved in CH2Cl2, and
the solution was dried over MgSO4, filtered through Celite, and
concentrated in vacuo. The crude product was purified by radial
PLC (SiO2, 1% TEA/50% EtOAc/hexanes) to afford 29 mg
(71%) of 21 as clear oil. [R]25D -126 (c 1.0, CH2Cl2); 1H NMR
(400 MHz, CDCl3) δ 8.15 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 2.4Hz,
1H), 3.90 (dt, J = 6.8, 1.6 Hz, 2H), 3.22 (dt, J = 8.4, 2.0 Hz, 1H),
3.07 (t, J = 8.8 Hz, 1H), 3.07 (t, J = 8.4 Hz, 1H), 2.98 (dt, J = 6.8,
1.6 Hz, 2H), 2.37(s, OH signal), 2.2 (q, J = 9.2 Hz, 1H), 2.24-2.16
(m, 1H), 2.14 (s, 3H), 2.01-1.88 (m, 1H), 1.87-1.76 (m, 1H),
1.74-1.64 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 22.7, 35.1,
36.5, 40.5, 57.1, 61.0, 68.1, 133.3, 137.9, 138.9, 147.2, 150.3; IR
˚
1.85 mmol, 1.0 equiv) in THF (2 mL over 4 A molecular sieves),
and the ensuing mixture was allowed to warm to rt and stirred
overnight. The mixture was poured into an aqueous saturated
solution of NH4Cl (6 mL) and then extracted with Et2O (3 ꢀ
10 mL). The combined organic layers were washed sequentially
with water (8 mL) and brine (8 mL), dried over anhydrous
Na2SO4, filtered through Celite, and concentrated in vacuo. The
crude product was purified by radial PLC (SiO2, 1% TEA/2%
EtOAc/hexanes) to afford 294 mg (63%) of 24 as a pale yellow
oil containing a mixture inseparable diastereomers in the ratio of
2:1 (cis:trans). [R]29D -95 (c 1.5, CH2Cl2); 1H NMR (400 MHz,
CDCl3) cis diastereomer: δ 8.27 (d, J = 2.8 Hz 1H), 8.10 (d, J =
2.8 Hz 1H), 6.32 (d, J = 9.2 Hz, 1H), 5.55 (d, J = 9.2 Hz, 1H),
3.81 (s, 3H), 2.17 (s, 3Hs); trans diastereomer: δ 8.07 (d, J =
2.8 Hz 1H), 7.65 (d, J = 2.8 Hz 1H), 7.07 (d, J = 17.2 Hz 1H),
6.00 (d, J = 17.2 Hz 1H), 3.74 (s, 3H), 2.16 (s, 3Hs); overlapped
signals: δ 3.22 (t, J = 11.2 Hz, 2 Hs), 3.04 (t, J = 11.2 Hz, 2 Hs),
2.34-2.24 (m, 2H), 2.23-2.12 (m, 2Hs), 2.02-1.88 (m, 2Hs),
1.87-1.62 (m, 4Hs); 13C NMR (100 MHz, CDCl3) δ 22.7, 35.3,
35.5, 40.6, 57.0, 57.1, 61.4, 67.9, 68.4, 68.6, 99.9, 110.5, 130.1,
132.2, 137.6, 138.8, 145.7, 146.2, 147.5, 151.1, 152.0; IR (neat)
(neat) 3369, 2947, 2878, 2783, 1765, 1411, 1357, 1074 cm-1
;
HRMS calcd for C12H17ClN2O (M þ H)þ 240.1100, found
240.1102.
(S )-5-(1-Methylpyrrolidin-2-yl)-2,3-dihydrofuro[2,3-b]pyridine
(6). A solution of 21 (243 mg, 1.0 mmol, 1.0 equiv) in THF (2 mL)
was added to NaH (48.5 mg, 2.0 mmol, 2.0 equiv) in THF (1 mL)
at rt, and the mixture was refluxed overnight. After cooling to rt,
water (1 mL) was added, and the mixture was extracted with
CH2Cl2 (2 ꢀ 10 mL). The combined organic layers were dried
over MgSO4 and then filtered through a plug of Celite and silica
gel. The solvent was removed in vacuo to afford 205 mg (99%) of
6 as a white solid, mp 62-64 °C. [R]31D -145 (c 1.1, CH2Cl2); 1H
NMR (400 MHz, CDCl3) δ 7.70 (d, J = 2.4 Hz, 1H), 7.42 (d, J =
2.4 Hz, 1H), 4.46 (dt, J = 5.6, 2.8 Hz, 2H), 3.09 (dt, J = 5.6,
2.8 Hz, 2H), 3.08-3.07 (m, 1H), 2.89-2.83 (m, 1H), 2.14 (q, J =
8.4 Hz, 1H), 2.01 (s, 3H), 2.05-1.95 (m, 1H), 1.86-1.76 (m, 1H),
1.70-1.62 (m, 1H), 161-1.53 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 22.3, 27.9, 34.6, 10.1, 56.8, 68.3, 69.1, 120.0, 131.0,
132.5, 145.8, 168.3; IR (neat) 2967, 2944, 2776, 1613, 1595, 1464,
1410, 1351, 1224 cm-1; HRMS calcd for C14H16N2O (M þ H)þ
205.1335, found 205.1334.
2980, 2936, 2904, 1718, 1587, 1476, 1393, 1271, 1104, 1010 cm-1
;
HRMS calcd for C13H17ClN2O (M þ H)þ 253.1106, found
253.1102.
(S )-2-(2-Chloro-5-(1-methylpyrrolidin-2-yl)pyridin-3-yl)ethyl
Benzoate (27). A solution of 2,2,6,6-tetramethylpiperidine
(630 μL, 3.69 mmol, 1.1 equiv) in dry THF (5 mL) at -78 °C
was treated with n-BuLi (1.69 mL, 2.5 M in hexanes, 3.69 mmol,
1.1 equiv), and the mixture was stirred for 1 h. A solution of 26
(659 mg, 3.35 mmol, 1.0 equiv) in THF (1 mL) was added
dropwise. After an additional 1 h at -78 °C, copper(I) thio-
phenolate (694 mg, 4.02 mmol, 1.2 equiv) was added directly
into the reaction mixture by removing the septum briefly. The
temperature of the reaction was slowly allowed to warm up to
0 °C. The reaction mixture was cooled to -20 °C, 2-iodoethyl
benzoate (2.78 g, 10.1 mmol, 3.0 equiv) was added, and stirring
was continued at rt for 6 h. The reaction was quenched with an
aqueous saturated solution of NH4Cl (3 mL) and then the
mixture was filtered through Celite. The filtrate was extracted
with EtOAc (2 ꢀ 15 mL). The combined organic extracts were
washed with aqueous 10% NH4OH, dried over anhydrous
Na2SO4, filtered through Celite, and concentrated in vacuo.
Purification of the residue by radial PLC (silica gel, 1% TEA/
2% EtOAc/ hexanes) afforded 698 mg (61%) of 27 as a clear oil.
[R]30D -86 (c 0.9, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.15
(d, J = 2.4 Hz, 1H), 7.94 (dd, J = 8.4, 1.2 Hz, 1H), 7.65 (d, J =
2.4 Hz, 1H), 7.49 (dt, J = 8.0, 1.2 Hz, 1H), 7.36 d, J = 8.0, 1.2
Hz, 2H), 4.56 (t, J = 6.4 Hz, 2H), 3.16 (dt, J = 6.4, 0.8 Hz, 2H),
3.15 (dt, J = 7.6, 2.0 Hz, 1H) 3.01 (t, J = 8.0 Hz, 1H), 2.23 (q,
J = 8.8 Hz, 1H), 2.14-2.04 (m, 1H), 2.05 (s, 3H), 1.92-1.80 (m,
1H), 1.80-1.68 (m, 1H), 1.62-1.50 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 22.7, 32.7, 35.4, 40.4, 57.0, 63.1, 67.9, 128.4,
128.5, 129.6, 130.0, 132.2, 133.1, 138.6, 138.9, 147.5, 150.0,
(S )-3-(1-Methylpyrrolidin-2-yl)benzofuro[2,3-b]pyridine (7).
A solution of 13 (158 mg, 0.49 mmol, 1.0 equiv), K3PO4 (416 mg,
1.96 mmol, 4.0 equiv), Pd(Ph3)4 (57 mg, 0.05 mmol, 10 mol %),
and 29 (140 mg, 0.637 mmol, 1.3 equiv) in DMF (3 mL) was
degassed with argon for 20 min. The mixture was heated at 80 °C
for 48 h. The DMF was removed under reduced pressure, and the
residue was dissolved in Et2O, filtered through Celite, and
concentrated in vacuo. The crude product was purified by radial
PLC (SiO2, 1% TEA/20% EtOAc/hexanes) to afford 93 mg
(75%) of 7 as a white solid, mp 94-97 °C. [R]25 -131 (c 1.2,
D
1
CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 2.4 Hz,
1H), 8.31 (d, J = 2.4 Hz, 1H), 7.92 (dt, J = 7.6, 0.8 Hz, 1H), 7.60
(dt, J = 8.4, 0.8 Hz, 1H), 7.48 (dt, J = 8.4, 0.8 Hz, 1H), 7.35 (dt,
J = 7.2, 0.8 Hz, 1H), 3.29 (dt, J = 7.6, 0.8 Hz, 1H), 3.24 (t, J =
8.0 Hz, 1H), 2.36 (q, J = 9.2 Hz, 1H), 2.30-2.22 (m, 1H), 2.19 (s,
3H), 2.19-1.96 (m, 1H), 1.91-1.76 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 22.7, 35.9, 40.6, 57.2, 69.0, 112.3, 117.3, 121.6,
122.7, 123.4, 128.4, 128.6, 134.6, 146.4, 155.1, 163.1; IR (neat)
3030, 2968, 2944, 2844, 2779, 1558, 1476, 1471 cm-1; HRMS
calcd for C16H16N2O (M þ H)þ 253.1335, found 253.1338.
(S )-4-Chloro-5-iodonicotine (31). To a solution of 30 (125 mg,
0.635 mmol, 1.0 equiv) in THF (2 mL) at -78 °C was added
TMSCH2Li (1.3 mL, 1.0 M in hexanes, 1.27 mmol, 2.0 equiv),
and the mixture was stirred for 3 h at -78 °C. Iodine (355 mg,
ꢀ
˚
1.4 mmol, 2.2 equiv) in 1 mL of THF (over 4 A sieves) was
added, stirring was continued for an additional 10 min, and then
the reaction was quenched with water (2 mL). The mixture was
extracted with CH2Cl2 (2 ꢀ 10 mL), and the combined organic
1714 J. Org. Chem. Vol. 75, No. 5, 2010

Ondachi and Comins
JOCArticle
TEA/20% EtOAc/ hexanes) to afford 56 mg (46%) of 37 as a
layers were washed with 2 mL of saturated aqueous sodium
thiosulfate. The organic portion was dried over MgSO4, filtered
through Celite, and concentrated in vacuo. The residue was
purified on radial PLC (SiO2, 1% TEA/ 20% EtOAc/hexanes
to afford 163 mg (80%) of 31 as a white solid, mp 65-68 °C.
[R]23D -172 (c 1.3, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.79
(s, 1H), 8.69 (s, 1H), 3.62 (t, J = 8.0 Hz, 1H), 3.24 (dt, J = 8.0,
2.0 Hz, 1H), 2.44-2.32 (m, 2H), 2.24 (s, 3H), 1.96-1.76 (m, 2H),
1.58-1.49 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 23.1, 33.5,
57.0, 66.8, 98.8, 139.4, 146.7, 149.1, 156.2; IR (neat) 2963, 2945,
2845, 2787, 1553, 1527, 1452, 1411, 1349, 1332, 1209þ, 1135, 1070
cm-1; HRMS calcd for C10H12ClIN2 (M þ H) 322.9806,
found 322.9806.
clear oil. [R]25 -148 (c 1.1, CH2Cl2); 1H NMR (400 MHz,
D
CDCl3) δ 9.87 (s, 1H), 8.44 (d, J = 1.6 Hz, 1H), 7.89 (d, J =
1.6 Hz, 1H), 7.58 (s, 1H), 6.92 (s, 1H), 3.26-3.18 (2H’s
overlapped), 2.33 (q, J = 9.2 Hz, 1H), 2.20 (s, 3H), 2.29-2.22
(m, 1H), 2.04-1.91 (m, 1H), 1.90-1.80 (m, 1H), 1.79-1.64
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 22.9, 35.8, 40.6, 57.1,
67.7, 109.0, 124.8, 125.3, 139.0, 140.1, 144.4, 149.0, 150.6, 157.1,
185.1; IR (neat) 3126, 3042, 2966, 2784, 2668, 1685, 1608, 1574,
1513, 1440, 1407, 1148 cm-1; HRMS calcd for C15H15ClN2O2
(M þ H)þ 291.0895, found 291.0897.
(S)-(2-(2-Chloro-5-(1-methylpyrrolidin-2-yl)-pyridin-3-yl)furan-
3-yl)methanol (38). A solution of 37 (80.0 mg, 0.280 mmol, 1.0
equiv) in 1:1 CH2Cl2/MeOH (3 mL) was treated with NaBH4
(58.0 mg, 1.56 mmol, 5.0 equiv), and the mixture was stirred at rt
for 20 min. The mixture was diluted with CH2Cl2 (10 mL), and
then water (2 mL) was added. The organic layer was extracted
CH2Cl2 (2 ꢀ 10 mL), and the combined organic layers were dried
over MgSO4, filtered through a plug a Celite, and concentrated
in vacuo. The residue was purified by radial PLC (SiO2, 1% TEA/
50% EtOAc/hexanes) to afford 56 mg (69%) of 38 as clear oil.
[R]32D -80 (c 1.4, CH2Cl2)); 1H NMR (400 MHz, CDCl3) δ 8.29
(s, 1H), 7.79 (s, 1H), 7.50 (s, 1H), 6.61 (s, 1H), 4.51 (s, 2H),
3.19-3.10 (2H’s overlapped), 3.06-2.88 (broad OH signal), 2.30
(q, J = 9.2 Hz, 1H), 2.24-2.14 (m, 1H), 2.15 (s, 3H), 1.93-1.85
(m, 1H), 1.84-1.74 (m, 1H), 1.73- 1.62 (m, 1H)); 13C NMR (100
MHz, CDCl3) δ 22.7, 35.4, 40.5, 56.8, 57.1, 68.0, 112.1, 124.4,
126.5, 138.1, 139.5, 143.4, 145.7, 148.9, 149.1; IR (neat)
3500-3200, 2944, 2785, 1586, 1557, 1505, 1402, 1349, 1153,
1116, 1084 cm-1; HRMS calcd for C15H17ClN2O2 (M þ H)þ
293.1051, found 293.1049.
(S )-4-(1-Methylpyrrolidin-2-yl)benzofuro[3,2-c]pyridine (8).
Prepared from 31 and 29 using a similar procedure as outlined
for derivative 7. [R]25 -138 (c 1.1, CH2Cl2); H NMR (400
1
D
MHz, CDCl3) δ 9.14 (s, 1H), 8.68 (s, 1H), 8.00 (d, J = 8.0 Hz,
1H), 7.62 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.34 (d, J
= 7.4 Hz, 1H), 3.69 (t, J = 8.0 Hz, 1H), 3.33 (t, J = 8.4 Hz, 1H),
2.46-2.32 (m, 2H), 2.28 (s, 3H), 2.38-2.00 (m, 2H), 1.98-1.84
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 23.1, 33.2, 41.0, 57.3,
64.4, 112.4, 121.2, 121.3, 122.0, 123.2, 123.9, 128.3, 142.2, 146.6,
156.1, 159.8; IR (neat) 3046, 2945, 2831, 2779, 1576, 1466, 1429,
1340, 1281, 1193, 1128, 1042 cm-1
; HRMS calcd for
C14H20N2O2 (M þ H)þ 252.1263, found 252.1267.
(S)-{2-[2-Chloro-5-(1-methylpyrrolidin-2-yl)pyridn-3-yl]-phenyl}-
methanol (34). A solution of 32 (57.8 mg, 0.119 mmol, 1.0 equiv) in
DMF (1 mL) was added to a mixture of Pd(PPh3)2Cl2 (8.4 mg,
0.12 mmol, 10 mol %), 33 (41.8 mg, 0.179 mmol, 1.5 equiv), and CuI
(4.5 mg, 0.021 mmol, 20 mol %) in DMF (3 mL). The mixture was
degassed for 15 min and then heated at 100 °C overnight. The
reaction mixture was allowed to cool to rt, and the DMF was
removed in vacuo. The product was purified by radial PLC (SiO2,
1% TEA/20% EtOAc/hexanes) to afford 13.8 mg (38%) of 34 as a
(S)-8-(-Methyl-pyrrolidin-2-nyl)-4H-1,5-dioxa-6-aza-cyclopenta-
[a]naphthalene (10). To a mixture of NaH (8 mg, 0.322 mg,
2.0 equiv) in DMF (1 mL) was added a solution of 38 (47.1 mg,
0.161 mmol, 1.0 equiv) in DMF (1 mL), and then the mixture was
heated overnight at 80 °C. The mixture was allowed to cool to rt and
concentrated in vacuo. The residue was dissolved in ether, filtered
through a plug of Celite and silica gel, and concentrated
in vacuo to yield 38.2 mg (93%) of 10 as a white solid that needed
no further purification. Mp 76-81 °C; [R]31D -145 (c 1.0, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 2.0 Hz, 1H), 7.67 (d,
J=2.0Hz, 1H), 7.45(d,J= 1.2 Hz, 1H), 6.29 (d, J= 1.2 Hz, 1 H),
5.58 (s, 2H), 3.23 (t, J = 8.8 Hz, 1H), 2.99 (t, J = 8.4 Hz, 1H), 2.28
(q, J = 9.2 Hz, 1H), 2.20-2.12 (m, 1H), 2.17 (s, 3H), 2.02-1.88 (m,
1H), 1.85-1.70 (m, 2H); 13C NMR (100 MHz, CDCl3) δ22.7, 35.0,
40.5, 57.2, 66.7, 68.5, 108.3, 112, 114.5, 126.5, 133.1, 141.5, 145.0,
145.7, 159.4; IR (neat) 3118, 2960, 2875, 2841, 2779, 1647, 1571,
1470, 1392, 1355, 1214, 1006 cm-1; HRMS calcd for C15H16N2O2
(M þ H)þ 257.1284, found 257.1287.
clear oil. [R]30 -108 (c 0.96, CH2Cl2); 1H NMR (400 MHz,
D
CDCl3) δ 8.33 (s, 1H), 7.65-7.33 (m, 5H), 7.18 (d, J = 8.0 Hz,
1H), 4.53 (m, 1H), 4.41 (m, 1H), 3.23-3.12 (m, 2H), 2.32 (q, J=8.8
Hz, 1H), 2.18 (s, 3H), 2.26-2.12 (m, 1H), 1.98-1.84 (m, 1H),
1.84-1.76 (m, 1H), 1.76-1.64 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 22.8, 35.6, 40.6, 57.2, 63.1, 68.1, 127.7, 127.8, 128.1, 128.3,
129.1, 129.9, 130.0, 132.3, 139.2, 139.3, 148.5; IR (neat) 3413, 2969,
2875, 2780, 1645, 1401, 1211 cm-1; HRMS calcd for C17H19ClN2O
(M þ H)þ 303.1259, found 303.1263.
(S)-2-(1-Methylpyrrolidin-2-yl)-6H-isochromeno(3,4-b)pyridine
(9). A solution of 34 (64.3 mg, 0.212 mmol, 1.0 equiv) in DMF
(3 mL) was added to NaH (10.1 mg, 0.427 mmol, 2.0 equiv) in
DMF (1 mL). The mixture was heated overnight at 105 °C, and
then the DMF was removed in vacuo. The residue was redissolved
in EtOAc, filtered through Celite, and concentrated in vacuo. The
crude product was purified by radial PLC (SiO2, 1% TEA/50%
EtOAc/hexanes) to afford 30 mg (53%) of 9 as a clear oil. [R]23
(S)-6-Chloro-4-methoxynicotine (44). A mixture of 43 (960 mg,
2.98 mmol, 1.0 equiv), CuI (56.7 mg, 0.298 mmol, 10 mol %), 1,
10-phenanthroline (108 mg, 0.595 mmol, 20 mol %), and Cs2CO3
(1.94 mg, 5.95 mmol, 2.0 equiv) in 1:1 MeOH/toluene (6 mL) was
heated at 110 °C in a 15-mL pressure vessel for 24 h. After cooling
to rt, the solvent was removed in vacuo, and EtOAc was added to
the residue. The mixture was filtered through Celite and concen-
trated in vacuo, and the residue was purified by radial PLC (SiO2,
1% TEA/2% EtOAc/hexanes) to afford 301 mg (45%) of 44 and
50 mg (7.4%) of 45 as white solids. 44: white solid, mp 86-88 °C;
[R]25D -189 (c 1.1, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.27
(s 1H), 6.72 (s, 1H), 3.82 (s, 3H), 3.36 (t, J = 8.0 Hz, 1H), 3.16 (t,
J = 8.8 Hz, 1H) 2.25 (q, J = 8.0 Hz, 1H), 2.28-2.12 (m, 1H), 2.17
(s, 3H), 1.90-1.68 (m, 2H), 1.56-1.46 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 22.7, 33.3, 40.9, 55.8, 57.0, 62.5, 105.9, 126.9,
148.3, 150.9, 165.3; IR (neat) 2968, 2943, 2875, 2840, 2779, 2669,
D
-91 (c 1.5, CH2Cl2)); 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H),
8.05 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H),
7.30 (t, J = 7.2 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 5.32 (s, 2H),
3.25 (t, J = 9.2 Hz, 1H), 3.06 (t, J = 8.8 Hz, 1H), 2.30 (q, J = 8.8
Hz, 1H), 2.24-2.14 (m, 1H), 2.18 (s, 3H), 2.04-1.92 (m, 1H),
188-1.72 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 22.6, 35.3,
40.5, 57.1, 68.6, 69.1, 117.3, 122.7, 124.8, 128.6, 128.7, 129.2,
130.9, 131.0, 133.7, 147.6, 160.8; IR (neat) 3049, 2964, 2836, 2781,
1601, 1566, 1415, 1259, 1207, 1029 cm-1; HRMS calcd for
C17H18N2O (M þ H)þ 267.1492, found 267.1496.
(S)-2-(2-Chloro-5-(1-methylpyrrolidin-2-yl)pyridine-3-yl)furan-
3-carbaldehyde (37). To a solution of 13 (135 mg, 0.417 mmol,
1.0 equiv) and 36 (241 mg, 0.625 mmol, 1.5 equiv) in THF (2 mL)
was added solid Pd(PPh3)2Cl2 (29 mg, 0.042 mmol, 0.1 equiv).
The mixture was degassed with argon for 15 min then heated to
reflux overnight. The reaction was cooled to rt and concentrated
in vacuo. The residue was purified by radial PLC (SiO2, 1%
1581, 1477, 1437, 1371, 1290 cm-1
C11H15ClN2O (M)þ 226.0873, found 226.0872.
; HRMS calcd for
J. Org. Chem. Vol. 75, No. 5, 2010 1715

Ondachi and Comins
JOCArticle
(S )-4,6-Dimethoxynicotine (45). White solid, mp 48-50 °C;
[R]25D -165 (c 1.1, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.02
(s, 1H), 6.13 (s, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.23 (t, J = 8.4 Hz,
1H), 3.16 (t, J = 8.4 Hz, 1H) 2.19 (q, J = 9.2 Hz, 1H), 2.18-2.10
(m, 1H), 2.17 (s, 3H), 1.90-1.80 (m, 1H), 1.78-1.68 (m, 1H),
1.66-1.56 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 22.7, 33.1,
40.9, 53.5, 55.4, 57.2, 63.1, 91.9, 121.3, 145.5, 165.0, 166.1; IR
(neat) 3073, 2993, 2945, 2839, 2667, 1606, 1575, 1493, 1383, 1250
cm-1; HRMS calcd for C12H18N2O (M)þ 222.1368, found
222.1366.
(S)-5-(1-Methylpyrrolidin-2-yl)-3-((trimethylsilyl)ethynyl)pyridin-
2(1H)-one (41). White solid, mp 97-102 °C; [R]25 -115 (c 1.7,
D
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 2.4 Hz, 1H),
7.36 (d, J= 2.4 Hz, 1H), 3.18 (t, J= 8.0 Hz, 1H), 2.82 (t, J=8.2Hz,
1H), 2.24 (q, J = 8.8 Hz, 1H), 2.14 (s, 3H), 2.12-2.04 (m, 1H),
1.96-184 (m, 1H), 1.93-1.74 (m, 1H), 1.72-1.62 (m, 1H) 0.24 (s,
9H); 13CNMR(100MHz,CDCl3) δ0.21, 22.6, 34.2, 40.3, 56.8, 67.6,
100.2, 100.5, 115.7, 122.1, 133.8, 145.7, 164.7; IR (neat) 3261, 3145,
2962, 2906, 2780, 2154, 1651, 1620, 1549, 1294, 1248 cm-1; HRMS
calcd for C15H22N2OSi (M)þ 274.1501, found 274.1500.
(S )-6-Chloro-5-iodo-4-methoxynicotine (46). To a solution of
44 (290 mg, 1.28 mmol, 1.0 equiv) in THF at -45 °C was added
dropwise n-BuLi (680 μL, 2.5 M in hexanes, 1.54 mmol,
1.2 equiv). After 1 h, a solution of iodine (520 mg, 2.05 mmol,
(S )-2-Chloro-5-(1-methylpyrrolidin-2-yl)-3-((trimethylsilyl)-
ethynyl)pyridin-4-ol (48). White solid, mp 135-137 °C; [R]25
D
1
-113 (c 1.3, CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.74 (s,
1H), 3.61 (t, J = 8.8 Hz, 1H), 3.42- 3.36 (m, 1H) 2.55 (q, J = 8.4
Hz, 1H), 2.42 (s, 3H), 2.32-2.24 (m, 1H), 2.06-1.88 (m, 4H),
0.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 0.17, 23.2, 33.6,
40.2, 55.5, 68.9, 96.7, 105.6, 108.9, 119.0, 146.3, 153.7, 169.1; IR
(neat) 3354, 2945, 2876, 2782, 1769, 1607, 1490, 1384, 1283, 1248
cm-1; HRMS calcd for C15H21ClN2OSi (M)þ 308.1112, found
308.1110.
General Procedure for Formation of the Dimers 42 and 49. A
solution of 41 or 48 (1.0 equiv) in 1:1 EtOH/Et3N was added to
solid CuI (5 mol %) in a flame-dried flask, and the mixture was
heated at 70 °C for 24 h. Solid K2CO3 (1.0 equiv) was added, and
then stirring was continued for an additional 24 h at rt. The
mixture was quenched with an aqueous solution of EDTA and
was extracted with EtOAc (2 ꢀ 10 mL). The combined organic
layers were dried over MgSO4, filtered through Celite, and
concentrated in vacuo. The residue was purified by radial PLC
(SiO2, 1% TEA/50% EtOAc/hexanes to afford 42 or 49,
respectively.
˚
2.0 equiv) in 1 mL THF (over 4 A sieves) was added, and stirring
was continued for an additional 40 min. The reaction was
quenched with a saturated aqueous solution of NaHCO3, and
the mixture was extracted with CH2Cl2 (2 ꢀ 10 mL). The
combined organic extracts were washed with a saturated aqu-
eous solution of sodium thiosulfate, dried over MgSO4, filtered
through Celite, and concentrated in vacuo. The residue was
purified by radial PLC (SiO2, 1% TEA/20% EtOAc/hexanes)
to afford 300 mg (67%) of 46 as a white solid, mp 56-58 °C.
[R]25 -126.5 (c 1.3, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
D
8.41 (s, 1H), 3.85 (s, 3H), 3.40 (t, J = 8.4 Hz, 1H), 3.21 (dt, J =
8.4, 2.0 Hz, 1H) 2.25 (q, J = 9.2 Hz, 1H), 2.26-2.18 (m, 1H),
2.16 (s, 3H), 1.98-1.86 (m, 1H), 1.86-1.74 (m, 1H), 1.68-1.58
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 23.1, 35.0, 40.8, 57.0,
62.0, 63.3, 93.4, 133.2, 150.4, 154.6, 167.7; IR (neat) 2966, 2941,
2871, 2838, 2783, 2667, 1556, 1533, 1452, 1358 cm-1; HRMS
calcd for C11H14ClIN2O (M)þ 351.9839, found 351.9842.
General Demethylation Procedure for Synthesis of 40 and 47.
To a solution of the methoxynicotine (1.0 equiv) in dry CH2Cl2
at -78 °C was added dropwise BBr3 (1.0 M in CH2Cl2,
3.0 equiv). The mixture was allowed to warm up to -10 °C
and then quenched with MeOH (5 mL). The pH of the solution
was lowered to 8-9 by addition a few drops of NaOH. Brine was
added, and then the mixture was extracted with 10% MeOH/
CH2Cl2 (2 ꢀ 10 mL). The combined organic layers were dried
over Na2SO4, filtered through Celite, and concentrated in vacuo.
The residue was purified by radial PLC (SiO2, 2% TEA/70%
EtOAc/hexanes) to afford the demethylated product.
5,50-Bis(1-methyl-pyrrolidin-2-yl)-[2,20-bi[furo[2,3-b]pyridinyl]
(42). White solid, mp 200-204 °C; [R]25D -204 (c 1.1, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 2.4 Hz, 1H), 8.00 (d,
J = 1.6 Hz, 1H), 3.28 (dt, J = 8.4, 1.6 Hz, 1H), 2.34 (q, J = 8.4
Hz, 1H), 2.30-2.22 (m, 1H), 2.19 (s, 3H), 2.06-1.94 (m, 1H),
1.90-1.72 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 22.8, 35.9,
40.6, 57.2, 69.1, 103.8, 120.9, 129.5, 135.8, 145.2, 147.1, 162.0; IR
(neat) 3450, 3272, 3116, 2951, 2873, 2840, 2779, 2665, 1631,
1537, 1466, 1242 cm-1; HRMS calcd for C24H26N4O2 (M)þ
402.2056, found 402.2051.
4,40-Dichloro-7,70-bis((S)-1-methylyrrodin-2-yl)-2,20-bifuro-
(S )-3-Iodo-5-(1-methylpyrrolidin-2-yl)pyridin-2(1H)-one (40).
[3,2-c]pyridine (49). White solid, mp 295-300 °C; [R]26 -130
D
1
1
White solid, mp 196-198 °C; [R]25 -117 (c 1.6, CH2Cl2); H
(c 0.22, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H),
D
NMR (400 MHz, CDCl3) δ 8.14 (d, J = 1.6 Hz, 1H), 7.40 (d,
J = 1.6 Hz, 1H), 3.15 (t, J = 8.4 Hz, 1H), 2.80 (t, J = 8.4 Hz, 1H)
2.23 (q, J = 8.8 Hz, 1H), 2.12 (s, 3H), 2.12-2.02 (m, 1H),
7.30 (s, 1H), 3.70 (t, J = 8.0 Hz, 1H), 3.33 (t, J = 7.6 Hz, 1H)
2.42-2.39 (m, 2H), 2.30 (s, 3H), 2.14-2.05 (m, 1H), 2.02-1.92
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 23.3, 33.6, 41.0, 57.3,
63.5, 103.4, 123.3, 124.5, 143.1, 144.0, 147.6, 159.3; IR (neat)
1.95-1.82 (m, 1H), 1.81-1.70 (m, 1H), 1.68-1.58 (m, 1H); 13
C
NMR (100 MHz, CDCl3) δ 22.6, 34.3, 40.3, 56.71, 67.1, 92.0,
123.8, 133.6, 150.5, 162.8; IR (neat) 3464, 3116, 2943,
2843, 2783, 1857, 1729, 1647, 1619, 1533, 1454, 1292, 1226
cm-1; HRMS calcd for C10H13IN2O (M)þ 304.0073, found
304.0073.
(S)-2-Chloro-3-iodo-5-(1-methylpyrrolidin-2-yl)pyridin-4-ol (47).
White solid, mp 196-198 °C; [R]25D -78 (c 1.0, CH2Cl2); 1H NMR
(400 MHz, CDCl3) δ 7.73 (s, 1H), 3.66 (t, J = 8.4 Hz, 1H),
3.5-3.44 (m, 1H), 2.66 (q, J = 8.4 Hz, 1H), 2.45 (s, 3H), 2.36-2.28
(m, 1H), 2.12-1.93 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 23.2
33.3, 39.9, 55.1, 69.2, 88.2, 117.6, 146.9, 155.1, 169.2; IR (neat)
3392, 3047, 29245, 2854, 1722, 1648, 1575, 1502, 1465, 1373, 1286
cm-1; HRMS calcd for C10H12ClIN2O (M)þ 337.9683, found
337.9677.
3354, 2945, 2876, 2782, 1769, 1607, 1490, 1384, 1283, 1248 cm-1
;
HRMS calcd for C24H24Cl2N4O2 (M)þ 470.1276, found
470.1269.
Acknowledgment. NMR and mass spectra were obtained
at NCSU instrumentation laboratories, which were esta-
blished by grants from North Carolina Biotechnology
Center and National Science Foundation (Grant No.
CHE-0078253). The authors acknowledge Targacept Inc.
for financial support. P.W.O also thanks Targacept Inc. for
funding of a Research Assistantship.
1
Supporting Information Available: Copies of H and 13C
NMR spectra of compounds 4-10, 15, 18-21, 24, 27, 31, 34,
37-38, 40-42, and 44-49. This material is available free of
charge via the Internet at http://pubs.acs.org.
Procedure for synthesis of 41 and 48 via a Sonogashira cross-
coupling was as outlined in the case of derivative 20.
1716 J. Org. Chem. Vol. 75, No. 5, 2010