Copper-Catalyzed multicomponent coupling of organoindium reagents with nitrogen-Containing aromatic heterocycles

Article abstract of DOI:10.1002/ejoc.201000231

A mild, copper-catalyzed coupling of organoindium reagents with nitrogen-containing aromatic heterocycles and chloroformates is described. This reaction proceeds with a range of organoindium reagents, yielding predominately or exclusively the 1,4-addition products with pyridine. In addition, a range of other nitrogen-containing heterocycles can be employed in this reaction (e.g. benzoxazole, benzothiazole, phthalazine). As an illustration of the utility of this reaction, this heterocycle functionalization is coupled with a subsequent oxidation to achieve the one-pot synthesis of functionalized pyridine and benzothiazole derivatives.

Full text of DOI:10.1002/ejoc.201000231

FULL PAPER
DOI: 10.1002/ejoc.201000231
Copper-Catalyzed Multicomponent Coupling of Organoindium Reagents with
Nitrogen-Containing Aromatic Heterocycles
Ramsay E. Beveridge,[a,b] Daniel A. Black,[a] and Bruce A. Arndtsen*[a]
Keywords: Nitrogen heterocycles / Organoindium reagents / Copper / Multicomponent reactions / Pyridinium salts
A mild, copper-catalyzed coupling of organoindium reagents
with nitrogen-containing aromatic heterocycles and chloro-
formates is described. This reaction proceeds with a range of
organoindium reagents, yielding predominately or exclu-
sively the 1,4-addition products with pyridine. In addition, a
range of other nitrogen-containing heterocycles can be em-
ployed in this reaction (e.g. benzoxazole, benzothiazole,
phthalazine). As an illustration of the utility of this reaction,
this heterocycle functionalization is coupled with a subse-
quent oxidation to achieve the one-pot synthesis of function-
alized pyridine and benzothiazole derivatives.
Recently, organoindium reagents have been found to be
useful organometallic coupling partners in a wide range of
metal-catalyzed carbon–carbon bond-forming reactions.[14]
These substrates can be prepared with a range of organic
fragments, demonstrate high functional-group compatibil-
ity, transfer all of their organic groups upon reaction (pro-
viding high atom economy), and generate low-toxicity InCl3
as a by-product. Although organoindium reagents are typi-
cally not reactive toward pyridines and related hetero-
cycles,[15] we have recently reported that copper complexes
can catalyze the multicomponent coupling of imines, acyl
chlorides and organoindium reagents to generate α-substi-
tuted amides.[16] Considering the resonance structure simi-
larity of imines to pyridines, we have undertaken a study of
the potential use of organoindium reagents in the reductive
functionalization of pyridines, by the postulated mechanism
shown in Scheme 1. As described below, this can provide a
mild route to reductively functionalized pyridines and a
range of other nitrogen-containing heterocycles.
Introduction
The addition of organometallic nucleophiles to pyridi-
nium salts provides a useful route to functionalized pyridine
derivatives.[1,2] A variety of nucleophiles have been used in
this chemistry, including Grignard reagents,[3] organozinc
compounds,[4] organostannanes,[5] and others.[6,7] The prod-
ucts of these reactions, 1,2- or 1,4-dihydropyridine deriva-
tives, are of interest as biologically active molecules (e.g.
NADH mimics),[8] and useful synthetic intermediates in the
synthesis of pyridines[2] and natural products.[9–11] Whereas
this synthetic approach is effective, the reactivity of many
of the nucleophiles employed in this chemistry can result in
significant functional-group incompatibility, as well as limit
the availability of many substituted variants of these sub-
strates. In addition, extension of this reaction to other
C=N-containing azaaromatic compounds (e.g. benzo-
xazole, benzothiazole, phthalazine) through N-activation
and functionalization with organometallic reagents has not
seen widespread use, due in part to the sensitivity of many
of these heterocycles to ring opening and/or deproton-
ation.[12,13] The use of more mild organometallic reagents,
such as organostannanes, has been reported to demonstrate
better functional-group tolerance and compatibility in these
reactions, but these are often restricted to the transfer of
allyl, benzyl or alkynyl units.[5,13] For these reasons, it could
be advantageous to develop a milder and more general
method to access these and related functionalized hetero-
cycles.
Scheme 1. Proposed mechanism of the copper-catalyzed coupling
of pyridine, chloroformate and organoindium reagents.
[a] Department of Chemistry, McGill University
801 Sherbrooke St. W., Montreal, QC H3A2K6, Canada
Fax: +1-514-398-3797
E-mail: bruce.arndtsen@mcgill.ca
Results and Discussion
Our initial efforts focused on the reaction of triphenylin-
dium with pyridines in the presence of ethyl chloroformate.
[b] Pfizer Global Research and Development,
Groton, CT 06320, USA
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000231.
3650
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3650–3656

Coupling of Organoindium Reagents with Nitrogen-Containing Aromatic Heterocycles
As shown in Table 1, triphenylindium is essentially unreac- Table 2. Copper-catalyzed coupling of pyridines and organoindium
reagents.[a]
tive towards in situ generated pyridinium salts in the ab-
sence of a catalyst, yielding only traces of 1a (Entry 1). In
a similar fashion to that observed with imines, the addition
of copper salt catalysts significantly improves the efficiency
of this reaction (Entries 2–5). In all cases, the reaction is
highly 1,4-regioselective, with Ͻ5% of any other isomer ob-
served. In the case of CuCl, the addition is both regioselec-
tive and high-yielding, providing 1 in 85% yield (Entry 5).
Table 1. Catalyst for coupling of Ph3In with pyridine and ethyl
chloroformate.[a]
Entry
Catalyst
Yield of 1a
1
2
3
4
5
–
8%
10% CuI
46%
48%
57%
85%
10% CuBr
10% Cu(OTf)2
10% CuCl
[a] Pyridine (40 mg, 0.50 mmol), chloroformate (61 mg, 0.60 mmol)
in CH3CN (2 mL) added to CuCl (5 mg, 0.05 mmol) in CH3CN
(1 mL), followed by InPh3 (0.18 mmol) in THF (3 mL), 45 °C, 16 h.
In addition to simple pyridine, this copper-catalyzed cou-
pling is compatible with a variety of functionalized pyridine
derivatives (Table 2). This includes 2- or 3-alkyl-, cyano-,
as well as more reactive halogen- and carbonyl-substituted
pyridines. The latter can be sensitive to the use of more
potent nucleophiles in additions.[9a] In this case, selective
carbon–carbon bond formation is observed on the pyridine
ring, likely arising from the lower nucleophilicity of the or-
ganoindium reagent. A range of organic groups can be
transferred from the indium reagent, including aryl, het-
eroaryl, and alkyl units. In the case of the para-fluoroaryl-
substituted product (Entry 3), the heterocycle spontane-
ously aromatizes upon isolation (vide infra).
These reactions yield 1,4-addition products, either exclu-
sively with pyridine, or as the major product with sterically
more encumbered 2- and 3-substituted pyridines. The ex-
ception to this is the sterically blocked 3-bromo-5-carbonyl-
substituted derivative (Entry 6). This preferred 1,4-addition
is similar to that noted in related copper-catalyzed additions
[a] Conditions of Table 1. [b] Combined yield of isomers [ratio of
4-substituted isomer to 2- or 6-substituted]. [c] 72 h. [d] 45 °C, 24 h.
[e] 55 °C, 48 h.
The results with isoquinoline suggested to us the poten-
to in situ generated pyridinium salts,[1,3] but contrasts with tial application of this approach to a broader scope of het-
our results using terminal alkynes, which are postulated to erocycles than pyridine derivatives. In principle, this copper-
generate analogous organocuprate derivatives as intermedi- catalyzed carbon–carbon bond formation can be employed
ates.[2b,17] Whereas the reason for this latter difference is at with any heterocycle that can be activated with chloro-
present unclear, it may result from interaction of the indium formates according to the mechanism in Scheme 1. The lat-
reagent with the organocuprate (or N-acylpyridinium inter- ter is illustrated in Table 3, where this same copper-cata-
mediate) after transmetallation. In contrast to these results lyzed organoindium coupling can be used to derivatize a
with pyridine, isoquinoline derivatives have only a single number of heterocycles, including phthalazine, benzoxazole,
site of activation upon chloroformate addition, and yield benzothiazole. Each of these reactions leads to the forma-
exclusively 1,2-addition products in good yield (Entries 7, tion of the 2-substituted heterocycle. In general, ethyl chlo-
8).[18]
roformate leads to the highest product yields in these sys-
Eur. J. Org. Chem. 2010, 3650–3656
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R. E. Beveridge, D. A. Black, B. A. Arndtsen
FULL PAPER
tems. In addition to aromatic groups, alkyl or vinyl units shown in Table 4, treatment of benzothiazole derivatives
can also be transferred from the organoindium reagent in with o-chloranil can allow the straightforward formation of
these reactions. It is notable that stronger nucleophilic rea- a range of 2-substituted benzothiazoles in good to excellent
gents often react with these substrates to lead to ring- yield. Overall, this provides a straightforward approach to
opened products rather than derivatization.[12,13] As with derivatize heterocycles directly from the parent structure
pyridines, these reactions are compatible with various sub- with good functional-group compatibility.
stituents on the heterocycle, including bromo and carbonyl
Table 4. Synthesis of 2-substituted benzothiazoles.
units. Whereas general with benzo-fused heterocycles, it was
found that this reaction is not compatible with simple ox-
azoles or thiazoles.[19]
Table 3. Coupling of organoindium reagents with nitrogen hetero-
cycles.[a]
[a] Heterocycle in MeCN, 1 equiv. of o-chloranil (3,4,5,6-tetra-
chloro-1,2-benzoquinone), 85 °C, 18 h. [b] . Isolated yield. [c] 45 °C,
4 h.
Conclusions
This study has shown that the copper-catalyzed coupling
of organoindium reagents with nitrogen-containing hetero-
cycles, in the presence of a chloroformate activator, can pro-
vide an approach to generate partially reduced heterocycle
derivatives. This provides a mild method to directly func-
tionalize heterocycles without strong nucleophiles or the
initial pre-derivatization of the heterocycle (e.g. halogena-
tion). The reaction displays good functional-group compat-
ibility, transfers a variety of organic groups from indium,
and generates low-toxicity InCl3 as the only by-product. In-
vestigations towards the use of this coupling to derivatize
other reagents are underway.
Experimental Section
General Methods: Unless otherwise noted, all manipulations were
performed under an inert gas in a Vacuum Atmospheres 553-2 dry
box or by using standard Schlenk or vacuum-line techniques. All
reagents were purchased from Aldrich® and used as received. Ace-
tonitrile was distilled from CaH2 under nitrogen. Deuterated aceto-
nitrile was dried like its protonated analogue, but was transferred
under vacuum from the drying agent, and stored over molecular
sieves (4 Å). Deuterated chloroform was dried with molecular si-
eves (3 Å). All organoindium reagents were prepared from com-
mercially available Grignard reagents and InCl3 by standard litera-
ture procedures[20] and used fresh. All compounds were charac-
terized by 1H and 13C NMR and HRMS and by comparison to
literature data.[21] Regioselectivity assignments for dihydropyridine
[a] Conditions of Table 1. [b] Isolated.
As an illustration of further potential utility in this reac-
tion, it was noted that dihydropyridine derivatives can be
oxidized to substituted pyridines.[2] As such, we envisioned
that incorporating oxidative conditions with this copper-
catalyzed organoindium coupling could provide a one-pot
route to generate substituted aromatic heterocycles. As compounds (Table 2) were determined by 1H NMR, 1D NOESY
3652 Eur. J. Org. Chem. 2010, 3650–3656
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Coupling of Organoindium Reagents with Nitrogen-Containing Aromatic Heterocycles
and 2D 1H-13C HMQC and HMBC experiments. 1H and 13C 4-(4-Fluorophenyl)-3-methylpyridine: Table 2, Entry 3. Isolated
NMR spectra were recorded with Varian Mercury 200 MHz,
300 MHz, 400 MHz, Unity 500 MHz, and JEOL 270 MHz spec-
trometers. 1D NOESY spectra were recorded with a Varian Mer-
yield: 45 mg, 48%. 1H NMR (500 MHz, CDCl3): δ = 8.49–8.45 (m,
2 H), 7.30–7.11 (m, 5 H), 2.25 (s, 3 H, CH3) ppm. 13C NMR
(125 MHz, CDCl3): δ = 163.8, 161.8, 151.5, 148.5, 147.5, 135.2,
130.5, 124.3, 115.8–115.6 (d, JC,F = 20 Hz), 17.4 ppm. HRMS:
calcd. for C12H10FN [M + H] 188.0896, found 188.0869.
1
cury 400 MHz spectrometer, 2D H-13C HMQC and HMBC were
recorded with a Varian Mercury 400 MHz or Unity 500 MHz spec-
trometer. Mass spectra were obtained from the McGill University
and Pfizer Global Research and Development mass spectral facili-
ties.
Phenyl 3-Formyl-4-phenylpyridine-1(4H)-carboxylate: Table 2, En-
1
try 4. Isolated yield: 58 mg, 38%. H NMR (300 MHz, CDCl3): δ
= 9.41 [s, 1 H, C(O)H], 7.91 [s, 1 H, NCH=C(CHO)], 7.48–7.20
(m, 10 H), 7.10 (d, J = 12 Hz, 1 H, NCH=CH), 5.40–5.35 [m, 1
H, (Ph)CH-CH], 4.58 (t, J = 3 Hz, 1 H, CHPh) ppm. 13C NMR
(67.9 MHz, CDCl3): δ = 189.8, 150.5, 149.4, 143.5, 139.4, 129.7,
128.6, 128.1, 127.0, 126.6, 123.8, 121.2, 121.0, 113.8, 37.0 ppm.
HRMS: calcd. for C19H15NO3 [M + Na] 328.0952, found 328.0942.
Preparation of Triorganoindium Reagents: The appropriate organo-
magnesium reagent (0.50 mmol) was added to a Schlenk flask un-
der N2 containing InCl3 (0.18 mmol, 39 mg) in THF at –78 °C over
a period of 30 min (total volume: 3 mL of THF). The solution was
then warmed to room temperature and stirred for an additional
30–60 min until the solution became homogeneous. The solution
was then transferred by syringe to the reaction mixture.
Phenyl 3-Formyl-6-phenylpyridine-1(6H)-carboxylate: Table 2, En-
1
try 4. Isolated yield: 26 mg, 17%. H NMR (200 MHz, CDCl3): δ
= 9.39 [s, 1 H, C(O)H], 7.82 [s, 1 H, NCH=CH(CHO)], 7.43–7.20
(m, 8 H), 7.12–6.89 (m, 2 H), 6.58 [d, J = 12 Hz, 1 H, (CHO)CCH],
6.00 (d, J = 8 Hz, 1 H, CHPh), 5.82–5.75 [m, 1 H, (Ph)-
CHCH=CH] ppm. 13C NMR (67.9 MHz, CDCl3): δ = 187.1,
150.5, 142.0, 129.7, 129.5, 128.9, 128.6, 128.1, 127.0, 126.4, 123.8,
121.1, 119.5, 115.7, 59.6 ppm. HRMS: calcd. for C19H15NO3 [M +
Na] 328.0952, found 328.0942.
Representative Procedure for Heterocycle Functionalization: Pyr-
idine (0.5 mmol, 40 mg), ethyl chloroformate (0.6 mmol, 62 mg)
and CuCl (0.05 mmol, 5 mg) were combined in CH3CN (3 mL) in
a screw cap vial in a glove box. To this solution was added a Ph3In
solution (0.18 mmol Ph3In) in THF (3 mL). The mixture was
stirred at 45 °C for 16 h. The solvent was removed in vacuo, then
the product dissolved in Et2O (30 mL), washed with satd. aq.
NaHCO3 (15 mL), which was then washed with Et2O (15 mL). The
organic layers were combined, dried (MgSO4), filtered, and the
product was purified by flash column chromatography on silica
gel by using 10% EtOAc/hexanes as eluent. Isolated Yield: 97 mg,
85%.
Phenyl
3-Acetyl-4-(thiophen-2-yl)pyridine-1(4H)-carboxylate:
1
Table 2, Entry 5. Isolated yield: 39 mg, 25%. H NMR (400 MHz,
CDCl3): δ = 2.30 (s, 3 H, CH3) 3.93 [s, 1 H, (COMe)CCHCS] 4.92
[dd, J = 24.00, 4.00 Hz, 1 H, (CS)CHCH] 5.29–5.50 (m, 1 H, NCH)
6.78–6.83 (m, 1 H) 6.84–6.93 (m, 2 H) 7.06–7.33 (m, 4 H) 7.38–7.46
(m, 1 H) 8.04 [s, 1 H, NCH=C(COMe)] ppm. 13C NMR (101 MHz,
CDCl3): δ = 25.54, 32.21, 54.66, 112.28, 112.98, 115.54, 120.67,
121.49, 124.61, 125.04, 127.06, 129.93, 132.92, 148.52, 150.51,
156.06, 196.37 ppm. HRMS: calcd. for C18H15NO3S [M + Na]
348.0659, found 348.0664.
Representative Procedure for the Synthesis of 2-Substituted Benzo-
thiazoles: Purified 5-bromo-2-(4-fluorophenyl)benzo[d]thiazole
(61 mg, 0.2 mmol) was dissolved in MeCN (5 mL), o-chloranil
(3,4,5,6-tetrachloro-1,2-benzoquinone, 49 mg, 0.2 mmol) added,
and the mixture was placed in a 85 °C heating bath for 18 h. The
solvent was removed in vacuo, and the crude residue purified by
flash column chromatography on silica gel by using EtOAc/hexanes
as eluent. Isolated yield: 39 mg, 63%.
Phenyl
5-Acetyl-2-(thiophen-2-yl)pyridine-1(2H)-carboxylate:
1
Table 2, Entry 5. Isolated yield: 30 mg, 19%. H NMR (400 MHz,
CDCl3): δ = 2.33 (s, 3 H, CH3) 5.86 [dd, J = 9.76, 5.66 Hz, 1 H,
(CS)CHCH] 6.26 [br. s, 1 H, NCHC(CS)] 6.82 (dd, J = 9.76,
1.17 Hz, 1 H) 6.96 (dd, J = 4.98, 3.61 Hz, 1 H) 7.07–7.17 (m, 3 H)
Ethyl 4-Phenylpyridine-1(4H)-carboxylate (1a): Table 2, Entry 1.
Isolated yield: 97 mg, 85%. 1H NMR (200 MHz, CDCl3): δ = 7.39–
7.22 (m, 5 H, Ph), 7.03–6.80 (m, 2 H), 5.07–4.85 (m, 2 H), 4.29 (q,
J = 7 Hz, 2 H, CH2CH3), 4.18 (br. s, 1 H, CHPh), 1.32 (t, J =
7 Hz, 3 H, CH2CH3) ppm. 13C NMR (67.9 MHz, CDCl3): δ =
151.5, 145.9, 128.7, 127.8, 127.2, 126.7, 109.5, 62.6, 39.2, 14.4 ppm.
HRMS: calcd. for for C14H15NO2 [M + Na] 252.1003, found
252.0998.
7.25–7.31 (m,
2 H) 7.37–7.44 (m, 2 H) 7.86 [s, 1 H,
NCH=C(COMe)] ppm. 13C NMR (100 MHz, CDCl3): δ = 23.98,
50.16, 114.29, 118.33, 120.11, 120.37, 125.45, 125.63, 125.77,
125.90, 126.28, 128.64, 132.72, 141.20, 149.41, 193.03 ppm.
HRMS: calcd. for C18H15NO3S [M + Na] 348.0659, found
348.0665.
Phenyl
3-Acetyl-2-(thiophen-2-yl)pyridine-1(2H)-carboxylate:
1
Phenyl 2-Cyano-4-phenylpyridine-1(4H)-carboxylate: Table 2, En-
Table 2, Entry 5. Isolated yield: 28 mg, 18%. H NMR (500 MHz,
CDCl3): δ = 2.39 (s, 3 H, CH3) 5.63–5.76 (m, 1 H, N-CH) 6.88–
6.96 [m, 1 H, CH=C(COMe)] 6.98 [s, 1 H, NCH(CS)] 7.08 (d, J =
12.20 Hz, 1 H) 7.13–7.24 (m, 4 H) 7.24–7.31 (m, 2 H) 7.41 (d, J =
6.83 Hz, 2 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 25.37, 49.53,
105.70, 121.74, 125.59, 126.46, 126.82, 129.76, 130.71, 131.19,
131.80, 132.73, 142.61, 150.76, 152.40, 195.20 ppm. HRMS: calcd.
for C18H15NO3S [M + Na] 348.0659, found 348.0687.
1
try 2. Isolated yield: 80 mg, 53%. H NMR (200 MHz, CDCl3): δ
= 7.48–7.24 (m, 10 H), 7.11 (d, J = 8 Hz, 1 H, NCH=CH), 6.07–
6.03 [m, 1 H, (CN)C=CH], 5.20–5.13 [m, 1 H, (Ph)CHCH], 4.34
(t, J = 5 Hz, 1 H, CHPh) ppm. 13C NMR (75.5 MHz, CDCl3): δ
= 150.6, 148.9, 142.6, 129.7, 129.4, 129.3, 127.9, 127.8, 126.5, 123.6,
121.4, 114.0, 111.5, 110.1, 40.4 ppm. HRMS: calcd. for
C19H14N2O2 [M + Na] 325.0955, found 325.0947.
Phenyl 6-Cyano-2-phenylpyridine-1(2H)-carboxylate: Table 2, En-
try 2. Isolated yield: 27 mg, 18%. H NMR (300 MHz, CDCl3): δ
Phenyl
5-Bromo-3-formyl-2-phenylpyridine-1(2H)-carboxylate:
1
1
Table 2, Entry 6. Isolated yield: 59 mg, 31%. H NMR (300 MHz,
= 7.42–7.25 (m, 10 H), 6.43 [d, J = 6 Hz, 1 H, (CN)C=CH], 6.32– CDCl3): δ = 9.40 [s, 1 H, C(O)H], 7.91 (s, 1 H, NCH=CBr), 7.50–
6.28 (m, 2 H), 6.14 [d, J = 6 Hz, 1 H, (Ph)CHCH] ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 151.8, 150.9, 137.7, 130.8, 129.6, 129.0,
127.3, 127.1, 126.3, 125.8, 121.5, 121.3, 115.0, 110.6, 55.6 ppm.
HRMS: calcd. for C19H14N2O2 [M + Na] 325.0955, found
325.0947.
7.21 (m, 10 H), 7.09–6.98 (m, 1 H), 4.69 [s, 1 H, (Br)CCHC(COH)]
ppm. 13C NMR (67.9 MHz, CDCl3): δ = 188.6, 150.4, 140.9, 137.4,
129.8, 128.6, 128.5, 127.7, 126.8, 123.5, 122.1, 121.0, 119.3, 11.7,
45.6 ppm. HRMS: calcd. for C19H14BrNO3 [M + Na] 406.0057,
found 406.0048.
Eur. J. Org. Chem. 2010, 3650–3656
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R. E. Beveridge, D. A. Black, B. A. Arndtsen
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Ethyl
1-Cyclohexyl-5-formylisoquinoline-2(1H)-carboxylate:
H, OCH2CH3), 0.79 (t, J = 7 Hz, 3 H, CHCH2CH3) ppm. 13C
1
Table 2, Entry 7. Isolated yield: 99 mg, 63%. H NMR (500 MHz, NMR (67.9 MHz, CDCl3): δ = 154.3, 142.9, 133.7, 131.3, 128.1,
CDCl3): δ = 0.89–1.16 (m, 5 H) 1.34 (d, J = 7.50 Hz), 1.42–1.52 126.4, 125.7, 124.0, 62.8, 54.9, 27.9, 14.7, 9.6 ppm. HRMS: calcd.
[m, 1 H, CH(CHN)] 1.57–1.79 (m, 5 H) 4.27 (q, J = 7.07 Hz, 2 H, for C13H16N2O2 [M + H] 233.1311, found 233.1281.
CH2CH3) 4.92–5.16 (m, 1 H, NCH) 7.02–7.15 (m, 2 H) 7.18–7.28
(m, 1 H) 7.29–7.36 (m, 1 H) 7.66–7.74 [m, 1 H, CHC(COH)] 10.22
[s, 1 H, C(O)H] ppm. 13C NMR (126 MHz, CDCl3): δ = 14.74,
26.16, 29.42, 41.44, 60.31, 61.19, 62.80, 105.37, 126.17, 128.85,
129.24, 129.62, 131.84, 132.64, 132.99, 153.43, 193.08 ppm.
HRMS: calcd. for C19H23NO3 [M + H] 314.1756, found 314.1750.
1-Chloroethyl
2-Isopropyl-1,3-benzothiazole-3(2H)-carboxylate:
1
Table 3, Entry 6. Isolated yield: 56 mg, 39%. H NMR (200 MHz,
CDCl3): δ = 7.84–7.45 (m, 1 H), 7.17–6.97 (m, 3 H), 6.68 [q, J =
9 Hz, 1 H, C(Cl)HCH3], 5.67 [d, J = 4 Hz, 1 H, CHCH(Me)2],
2.27–2.12 [m, 1 H, (Me)2CHCH], 1.92–1.84 [m, 3 H, (Cl)CHCH3],
0.98–0.86 [m, 6 H, CH(CH3)2] ppm. 13C NMR (125 MHz, CDCl3):
δ = 150.3, 138.4, 129.9, 125.2, 122.2, 118.0, 83.2, 72.9, 35.2, 25.6,
18.4, 16.2 ppm. HRMS: calcd. for C13H16ClNO2S [M + H]
286.0689, found 286.0660.
Ethyl 1-(4-Fluorophenyl)-5-formylisoquinoline-2(1H)-carboxylate:
Table 2, Entry 8. Isolated yield: 136 mg, 84%. 1H NMR (500 MHz,
CDCl3): δ = 1.33 (t, J = 7.07 Hz, 3 H, CH2CH3), 4.18–4.38 (m, 2
H, CH2CH3), 6.55 (br. s, 1 H, NCHAr), 6.94 (t, J = 8.66 Hz, 2 H),
7.01–7.14 (m, 2 H), 7.21–7.38 (m, 4 H), 7.72 [d, J = 6.83 Hz, 1 H,
CHC(COH)], 10.24 [s, 1 H, C(O)H] ppm. 13C NMR (126 MHz,
CDCl3): δ = 14.69, 57.34, 63.15, 104.06, 115.52, 115.69, 127.30,
128.46, 129.26, 129.59, 131.39, 132.93, 137.43, 153.24, 161.62,
163.58, 192.87 ppm. HRMS: calcd. for C19H16FNO3 [M + H]
326.1178, found 326.1186.
Ethyl 5-Bromo-2-(naphthalen-1-yl)benzo[d]thiazole-3(2H)-carboxyl-
ate: Table 3, Entry 7. Isolated yield: 174 mg, 84%. 1H NMR
(400 MHz, CDCl3): δ = 1.15–1.28 (m, 3 H, CH2CH3) 4.11–4.29 (m,
2 H, CH2CH3) 6.88 (s, 1 H, CHAr) 7.20–7.28 (m, 2 H) 7.37 (dd, J
= 8.59, 1.95 Hz, 1 H) 7.43–7.49 (m, 2 H) 7.66 (s, 1 H) 7.73–7.82
(m, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 14.51, 62.89,
67.54, 116.89, 118.41, 123.26, 124.18, 125.00, 126.70, 126.75,
127.91, 128.41, 128.60, 129.38, 131.08, 133.08, 133.53, 137.10,
138.90, 152.79 ppm. HRMS: calcd. for C20H16BrNO2S [M + H]
414.0150, found 414.0157.
Ethyl 2-Phenyl-1,3-benzothiazole-3(2H)-carboxylate: Table 3, En-
try 1. Isolated yield: 130 mg, 91%. 1H NMR (300 MHz, CDCl3): δ
= 7.83 (d, J = 15 Hz, 1 H), 7.35–7.22 (m, 5 H), 7.18–7.10 (m, 2 H),
7.01 (t, J = 9 Hz, 1 H), 6.97 (s, 1 H, CHPh), 4.23 (q, J = 7 Hz, 2
H, CH2CH3), 1.23 (t, J = 7 Hz, 3 H, CH2CH3) ppm. 13C NMR
(68.0 MHz, CDCl3): δ = 153.0, 142.6, 138.4, 128.8, 128.5, 127.4,
125.6, 125.4, 124.5, 122.4, 117.4, 66.9, 62.6, 14.4 ppm. HRMS:
calcd. for C16H15NO2S [M + Na] 308.0723, found 308.0714.
1-Chloroethyl 1-Phenylphthalazine-2(1H)-carboxylate: Table 3, En-
1
try 8. Isolated yield: 60 mg, 38%. H NMR (200 MHz, CDCl3): δ
= 7.79–7.86 (m, 1 H), 7.44 (t, J = 7 Hz, 1 H), 7.40–7.31 (m, 2 H),
7.28–7.20 (m, 6 H), 6.67 [q, J = 4 Hz, 1 H, C(Cl)HCH3], 6.60 (s, 1
H, CHPh), 1.92–1.85 [m, 3 H, (Cl)CHCH3] ppm. 13C NMR
(67.9 MHz, CDCl3): δ = 152.0, 143.6, 143.4, 142.8, 133.1, 132.1,
128.7, 128.6, 128.0, 127.0, 126.6, 126.3, 83.6, 57.1, 25.4 ppm.
HRMS: calcd. for C17H15ClN2O2 [M + Na] 337.0722, found
337.0712.
2,2,2-Trichloroethyl
2-Vinyl-1,3-benzoxazole-3(2H)-carboxylate:
1
Table 3, Entry 2. Isolated yield: 98 mg, 61%. H NMR (200 MHz,
CDCl3): δ = 7.63–7.47 (m, 1 H), 7.02–6.81 (m, 3 H), 6.53 (d, J =
8 Hz, 1 H, CHCH=CH2), 6.11–5.92 (m, 1 H, CH=CH2), 5.62 (d,
J = 14 Hz, 1 H), 5.43 [d, J = 8 Hz, 1 H, (H)CH=CH], 4.88–4.82
(br. s, 2 H, Cl3CCH2) ppm. 13C NMR (67.9 MHz, CDCl3): δ =
150.3, 149.8, 132.0, 128.2, 124.5, 121.6, 120.1, 114.8, 109.2, 94.9,
93.3, 75.4 ppm. HRMS: calcd. for C12H10Cl3NO3 [M + H]
321.9825, found 321.9799.
Ethyl 6-Acetyl-2-(thiophen-2-yl)benzo[d]thiazole-3(2H)-carboxylate:
Table 3, Entry 9. Isolated yield: 120 mg, 72%. 1H NMR (400 MHz,
CDCl3): δ = 1.33 (t, J = 7.03 Hz, 3 H, CH2CH3) 2.54 [s, 3 H, C(O)-
CH3] 4.31 (q, J = 7.29 Hz, 2 H, CH2CH3) 6.85–6.90 (m, 1 H) 7.00
(s, 1 H, CHAr) 7.07 (d, J = 3.51 Hz, 1 H) 7.18 (d, J = 5.08 Hz, 1
H) 7.68–7.76 (m, 1 H) 7.80 (d, J = 1.95 Hz, 2 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 13.33, 25.45, 61.96, 115.73, 121.22, 124.40,
124.89, 125.60, 125.98, 126.19, 128.13, 132.60, 139.60, 143.82,
151.08, 195.21 ppm. HRMS: calcd. for C16H15NO3S2 [M + H]
334.0578, found 334.0566.
Ethyl 5-Bromo-2-(4-fluorophenyl)benzo[d]thiazole-3(2H)-carboxyl-
ate: Table 3, Entry 3. Isolated yield: 117 mg, 61%. 1H NMR
(400 MHz, CDCl3): δ = 1.18–1.27 (m, 3 H, CH2CH3), 4.17–4.26
(m, 2 H, CH2CH3), 6.68 (s, 1 H, CHAr), 6.92–7.01 (m, 2 H), 7.18–
7.29 (m, 4 H), 7.66 (br. s, 1 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 14.51, 62.96, 66.65, 115.81, 116.02, 116.94, 118.43, 124.98,
127.38, 127.46, 128.64, 137.86, 152.63, 161.68, 164.15 ppm.
HRMS: calcd. for C16H13BrFNO2S [M + H] 381.9898, found
381.9907.
Phenyl 1-Vinyl-1H-phthalazine-2-carboxylate: Table 3, Entry 10.
Isolated yield: 118 mg, 85%. 1H NMR (400 MHz, CDCl3): δ = 5.01
[d, 1 H, (H)CH=CH] 5.12–5.19 [m, 1 H, (H)CH=CH] 5.90 (ddd, J
= 16.98, 10.25, 5.37 Hz, 1 H, CH=CH2) 6.07 (d, J = 5.27 Hz, 1 H,
CHCH=CH2) 7.17–7.26 (m, 4 H) 7.29–7.34 (m, 1 H) 7.34–7.43 (m,
3 H) 7.44–7.52 (m, 1 H) 7.74 (s, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 56.10, 117.00, 121.99, 123.81, 126.02, 126.38, 126.86,
128.86, 129.57, 132.17, 132.19, 134.80, 143.53, 151.41, 152.99 ppm.
HRMS: calcd. for C17H14N2O2 [M + H] 279.1128, found 279.1137.
Isobutyl 2-(2-Methoxyphenyl)benzo[d]oxazole-3(2H)-carboxylate:
Table 3, Entry 4. Isolated yield: 83 mg, 51%. H NMR (400 MHz,
1
CD3OD): δ = 0.58–0.87 [m, 6 H, (CH3)2CH(CH2)] 0.89–1.07 [m, 2
H, CH2CH(Me)2] 3.80 (s, 3 H, OCH3) 3.87 (br. s, 1 H, CHAr)
6.68–6.73 (m, 1 H) 6.85–6.93 (m, 3 H) 7.02 (d, J = 8.20 Hz, 1 H)
7.15–7.21 (m, 1 H) 7.24–7.29 (m, 1 H) 7.30–7.37 (m, 1 H) 7.54 (br.
s, 1 H) ppm. 13C NMR (101 MHz, CD3OD): δ = 17.87, 27.86,
54.95, 71.97, 90.11, 106.53, 108.34, 111.27, 113.40, 120.42, 120.86,
123.57, 124.37, 124.99, 126.64, 130.96, 150.48, 157.75 ppm.
HRMS: calcd. for C19H21NO4 [M + H] 328.1543, found 328.1545.
Phenyl 6-Acetyl-2-(2-phenylethynyl)benzo[d]thiazole-3(2H)-carbox-
ylate: Table 3, Entry 11. Isolated yield: 128 mg, 64%. 1H NMR
(500 MHz, CDCl3): δ = 2.59 [s, 3 H, C(O)CH3] 6.82 [s, 1 H,
CHC(CPh)] 7.24–7.37 (m, 6 H) 7.41–7.49 (m, 4 H) 7.75–7.82 (m,
1 H) 7.87 (s, 1 H) 7.99 (br. s, 1 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 26.74, 55.74, 85.71, 86.68, 115.59, 117.09, 121.69,
121.81, 122.65, 126.66, 127.61, 128.60, 129.42, 129.89, 132.15,
132.30, 134.20, 140.62, 150.58, 196.40 ppm. HRMS: calcd. for
C24H17NO3S [M + H] 400.0999, found 400.1001.
Ethyl 1-Ethylphthalazine-2(1H)-carboxylate: Table 3, Entry 5. Iso-
lated yield: 75 mg, 65%. 1H NMR (200 MHz, CDCl3): δ = 7.67–
7.61 (br. s, 1 H, CH=N), 7.44–7.21 (m, 3 H), 7.10 (d, J = 14 Hz, 1
H), 5.37 (t, J = 6 Hz, 1 H, CHEt), 4.35 (q, J = 7 Hz, 2 H, 2-Phenylbenzo[d]thiazole: Table 4, Entry 1. Isolated yield: 37 mg,
1
OCH2CH3), 1.75–1.60 (m, 2 H, CHCH2CH3), 1.36 (t, J = 6 Hz, 3 87%. H NMR (300 MHz, CDCl3): δ = 8.13–8.07 (m, 3 H), 7.91
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Eur. J. Org. Chem. 2010, 3650–3656

Coupling of Organoindium Reagents with Nitrogen-Containing Aromatic Heterocycles
B. C. Das, Eur. J. Org. Chem. 2000, 1391; d) D. Barbier, C.
(d, J = 9 Hz, 1 H), 7.54–7.45 (m, 4 H), 7.38 (t, J = 6 Hz, 1 H) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 168.3, 154.4, 135.3, 133.9,
131.2, 129.2, 127.8, 126.5, 125.4, 123.5, 121.8 ppm. HRMS: calcd.
for C13H9NS [M + H] 212.0529, found 212.0528.
Marazano, C. Riche, B. C. Das, P. Poitier, J. Org. Chem. 1998,
63, 1767; e) A. Ohno, S. Oda, N. Yamazaki, Tetrahedron Lett.
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5-Bromo-2-(4-fluorophenyl)benzo[d]thiazole: Table 4, Entry 2. Iso-
[4]
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a) R. Yamaguchi, M. Moriyasu, M. Yoshioka, M. Kawanisi,
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M. Kawanisi, Tetrahedron Lett. 1986, 27, 211; c) R. Yamagu-
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a) For an organotitanium example, see: L.-L. Gundersen, F.
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a) A. I. Meyers, T. Oppenlaender, J. Am. Chem. Soc. 1986, 108,
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Bates, S. E. Kanicha, Tetrahedron 2002, 58, 5957; c) M. Buffat,
Tetrahedron 2004, 60, 1701.
For reviews of the synthetic utility of asymmetric additions to
3-TIPS-4-methoxypyridines towards natural product synthesis,
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5, 870; b) D. L. Comins, J. Heterocycl. Chem. 1999, 36, 1491.
For examples of natural product or bio-active compound syn-
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a) A. Lemire, A. B. Charette, Org. Lett. 2005, 7, 2747; b) T.
Focken, A. B. Charette, Org. Lett. 2006, 8, 2985; c) J. T. Kue-
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Bennasar, E. Zulaica, Y. Alsonso, J. Bosch, Tetrahedron: Asym-
metry 2003, 14, 469.
a) F. Babudri, S. Florio, G. Inguscio, Synthesis 1985, 522; b) F.
Babudri, G. Bartolli, S. Florio, G. Ingrosso, Tetrahedron Lett.
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For Organotin functionalization of these substrates, see: a) T.
Itoh, H. Hasegawa, K. Nagata, A. Ohsawa, J. Org. Chem. 1994,
59, 1319; b) T. Itoh, H. Hiroshi, O. Kazuhiro, O. Mamiko, A.
Ohsawa, Tetrahedron Lett. 1992, 33, 5399; c) J.-Y. Zhou, Z.-G.
Chen, S.-H. Wu, Synlett 1995, 1117; d) T. Itoh, H. Hasegawa,
K. Nagata, M. Okada, A. Ohsama, Tetrahedron 1994, 50,
13089–13100.
For selected examples, see: a) I. Perez, J. P. Sestelo, L. A. Sa-
randeses, J. Am. Chem. Soc. 2001, 123, 4155 and references
cited therein; b) D. Rodriguez, J. P. Sestelo, L. A. Sarandeses,
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Sestelo, L. A. Sarandeses, Org. Lett. 2006, 8, 1403; d) C.-J. Li,
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1
lated yield: 39 mg, 63%. H NMR (400 MHz, CDCl3): δ = 7.18 (t,
J = 8.59 Hz, 2 H) 7.58 (dd, J = 8.59, 1.95 Hz, 1 H) 7.89 (d, J =
8.98 Hz, 1 H) 7.99–8.10 (m, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 116.39, 116.61, 119.01, 124.37, 124.46, 129.75, 130.16,
136.86, 153.15, 163.58, 166.09 ppm. HRMS: calcd. for
C13H7BrFNS [M + H] 307.9535, found 307.9539.
1-[2-(Thiophen-2-yl)benzo[d]thiazol-6-yl]ethanone: Table 4, Entry 3.
1
Isolated yield: 34 mg, 65%. H NMR (400 MHz, CDCl3): δ = 2.67
[s, 3 H, C(O)CH3] 7.15 (dd, J = 5.08, 3.90 Hz, 1 H) 7.55 (dd, J =
4.98, 1.07 Hz, 1 H) 7.70 (dd, J = 3.71, 1.17 Hz, 1 H) 8.04 (dd, J =
2.54, 1.17 Hz, 2 H) 8.47 (dd, J = 1.56, 0.78 Hz, 1 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 27.03, 122.56, 122.88, 126.98,
128.53, 129.82, 130.64, 134.15, 135.23, 137.08, 156.88, 165.20,
197.12 ppm. HRMS: calcd. for C13H9NOS2 [M + H] 260.0200,
found 260.0198.
[6]
[7]
[8]
5-Bromo-2-(naphthalen-1-yl)benzo[d]thiazole: Table 4, Entry 4. Iso-
lated yield: 37 mg, 54%. 1H NMR (500 MHz, CDCl3): δ = 7.57–
7.61 (m, 2 H) 7.63 (dd, J = 8.78, 1.46 Hz, 1 H) 7.88–7.93 (m, 1 H)
7.96–8.02 (m, 3 H) 8.09 (d, J = 1.95 Hz, 1 H) 8.21 (dd, J = 8.66,
1.59 Hz, 1 H) 8.57 [s, 1 H, (Br)CCH] ppm. 13C NMR (126 MHz,
CDCl3): δ = 119.05, 124.44, 124.52, 124.54, 127.26, 127.92, 128.00,
128.15, 129.10, 129.19, 130.17, 130.80, 133.40, 134.98, 137.00,
153.35, 168.87 ppm. HRMS: calcd. for C17H10BrNS [M + H]
339.9787, found 339.9790.
[9]
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra.
[10]
[11]
Acknowledgments
The authors would like to thank the National Sciences and Engi-
neering Research Council of Canada and the Canadian Founda-
tion for Innovation for financial support. R. E. B. and D. A. B.
would like to thank McGill University for providing graduate stud-
ent fellowships, and R. E. B. thanks Pfizer Global Research for the
use of their facilities and resources towards the completion of this
manuscript.
[12]
[13]
[1] For reviews on the chemistry of dihydropyridines including
their synthesis by nucleophilic additions to pyridinium salts,
see: a) R. Lavilla, J. Chem. Soc. Perkin Trans. 1 2002, 1141–
1156; b) A. I. Meyers, D. Stout, Chem. Rev. 1982, 82, 223–243;
c) U. Eisner, J. Kuthan, Chem. Rev. 1972, 72, 1–42.
[2] a) For a review on the regioselective synthesis of pyridines by
nucleophilic additions to pyridinium salts, see: D. L. Comins,
S. O’Connor, Adv. Heterocycl. Chem. 1988, 44, 199; for some
recent examples, see: b) R. E. Beveridge, B. A. Arndtsen, Syn-
thesis 2010, 1000–1008; c) N. A. O. Williams, C. Masdeu, J. L.
Diaz, R. Lavilla, Org. Lett. 2006, 8, 5789; d) M.-L. Bennasar,
E. Zulaica, T. Roca, Y. Alonso, M. Monerris, Tetrahedron Lett.
2003, 44, 4711; e) P. A. Krapcho, D. J. Waterhouse, A. Ham-
mach, R. D. Domenico, E. Menta, A. Oliva, S. Spinelli, Synth.
Commun. 1997, 27, 781; f) A. Lemire, M. Grenon, M. Pourash-
raf, A. B. Charett, Org. Lett. 2004, 6, 3517; g) C. Chen, B.
Wang, B. Munoz, Synlett 2003, 2404.
[14]
[3] For selected examples, see: a) D. L. Comins, A. H. Abdullah,
J. Org. Chem. 1982, 47, 4315; b) R. Yamaguchi, Y. Matsuki,
E.-I. Hata, M. Kawanisi, Bull. Chem. Soc. Jpn. 1987, 60, 215;
c) B. Guilloteau-Bertin, D. Compere, L. Gil, C. Marazano,
Eur. J. Org. Chem. 2010, 3650–3656
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3655

R. E. Beveridge, D. A. Black, B. A. Arndtsen
FULL PAPER
[15] The indium-mediated regioselective allylation of N-acylpyridi-
nium salts has been reported previously: T.-P. Loh, P.-L. Lye,
R.-B. Wang, K.-Y. Sim, Tetrahedron Lett. 2000, 41, 7779.
[16] D. A. Black, B. A. Arndtsen, Org. Lett. 2006, 8, 1991.
[17] a) D. A. Black, R. E. Beveridge, B. A. Arndtsen, J. Org. Chem.
2008, 73, 1906; b) D. A. Black, B. A. Arndtsen, Org. Lett. 2004,
6, 1107.
[18] Quinoline can also participate in this reaction, but leads to a
mixture of 1,2- and 1,4-addition products.
[19] Results not shown. Oxazole and thiazole in this copper-cata-
lyzed organoindium addition reaction did not generate product
as observed by LC-MS or NMR analysis of the crude reaction
mixtures.
[20] I. Pérez, J. P. Sestelo, L. A. Sarandeses, J. Am. Chem. Soc. 2001,
123, 4155 and references cited therein.
[21] References for known compounds are as follows: a) compound
1 (Table 2, Entry 1): (i) D. L. Comins, M. O. Killpatrick, Het-
erocycles 1990, 31, 2025; (ii) K. Akiba, Y. Iseki, M. Wada, Bull.
Chem. Soc. Jpn. 1984, 57, 1994; b) phenyl 3-formyl-4-phenyl-
pyridine-1(4H)-carboxylate (Table 2, Entry 4): D. L. Comins,
J. J. Herrick, Heterocycles 1987, 26, 2159; c) 2-phenylbenzo[d]-
thiazole (Table 4, Entry 1): Q. Ding, X.-G. Huang, J. Wu, J.
Comb. Chem. 2009, 11, 1047.
Received: February 19, 2010
Published Online: May 14, 2010
3656
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Eur. J. Org. Chem. 2010, 3650–3656