Cu- and Mo-catalysed expedient synthesis of alkynyl-substituted derivatives of 1,2-dihydropyridines, -quinolines and -isoquinolines

Article abstract of DOI:10.1002/ejoc.200900397

An efficient synthesis of 1,2-dihydroisoquinolines and -quinolines by employing dimethyl acetylenedicarboxylate activated isoquinolines and quinolines in conjuction with the CuC1₂/Et₃N catalytic system is described herein. Furthermor

Full text of DOI:10.1002/ejoc.200900397

FULL PAPER
DOI: 10.1002/ejoc.200900397
Cu- and Mo-Catalysed Expedient Synthesis of Alkynyl-Substituted Derivatives
of 1,2-Dihydropyridines, -quinolines and -isoquinolines
Gullapalli Kumaraswamy,*[a] Dasa Rambabu,[a] Neerasa Jayaprakash,[a]
Gadde Venkata Rao,[a] and Balasubramanian Sridhar[b]
Keywords: Nitrogen heterocycles / Alkynes / Copper / Molybdenum
An efficient synthesis of 1,2-dihydroisoquinolines and -quin-
process has allowed the rapid synthesis of alkynyl derivatives
olines by employing dimethyl acetylenedicarboxylate acti- of dihydroisoquinoline and -quinoline with functional group
vated isoquinolines and quinolines in conjuction with the
CuCl2/Et3N catalytic system is described herein. Further-
more, the MoO3-catalysed alkynylation of pyridines and sub-
stituted pyridines has also been achieved. Moreover, this
variations of the alkynyl group by using a low catalyst load-
ing (i.e., 1 mol-%).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Moreover, the high cost and air sensitivity of the gold(III)
chloride catalyst system limits any further potential applica-
tion of carbon–carbon bond-forming reactions. Conse-
quently, an easy and rather general process for the synthesis
of 1,2-dihydropyridines, -quinolines and -isoquinolines
using various alkynyl moieties is highly desirable.
As part of our programme for the rapid synthesis of bio-
active molecules, we focused our attention on copper-cata-
lysed multicomponent reactions.[9] Herein we report our re-
sults of the synthesis of substituted 1,2-dihydropyridines,
-quinolines and -isoquinolines using various terminal alk-
ynyl moieties.
Introduction
Aza-aromatic nuclei such as pyridine, quinoline and iso-
quinoline are frequently found as components of a wide
range of natural products, chiral ligands and synthetic
building blocks.[1] In general, the 1,2- or 3,4-dihydro and
1,2,3,4-tetrahydro reduced species of these privileged struc-
tural units act as pharmacophores. Among them, promi-
nent examples include indenoisoquinoline[2] (topoisomer-
ase I inhibitor), narciclasine[3] (anti-tumour agent) and pa-
paverin[4] (smooth-muscle relaxant). Frequently aza-aro-
matic nuclei are alkynylated through activation by N-acyl-
ation using alkyl chloroformates or acyl chloride.[5] Another
approach is the generation of a 1,4-dipolar intermediate
with electron-deficient acetylene compounds (the Huisgen
protocol) and subsequent addition of either the alkynyl
moiety without any catalyst[6] or coupling with the corre-
Results and Discussion
Initially we considered performing the one-pot reaction
sponding alkynyl moiety, which is activated mostly by cop- by employing isoquinoline (1a) (1 equiv.) and the terminal
per salts.[7]
alkyne methyl propiolate (2a; 2.1 equiv.) in the presence of
Recently, gold(III) chloride was found to catalyse the fac- 5 mol-% of CuI in dichloromethane (Scheme 1). After stir-
ile synthesis of 1,2-dihydroquinolines and -isoquinolines by ring for 1 h at ambient temperature, we isolated the desired
employing dimethyl acetylenedicarboxylate activated quin- product 3a in 70% yield. The same reaction in the absence
olines and isoquinolines followed by in situ coupling with of the catalyst did not yield the required compound. In cop-
various substituted ethynylbenzenes.[8] Despite their inter- per-promoted reactions, the efficacy of the reaction depends
est, all these protocols suffer from a lack of generality. For on the copper source. Therefore, we screened 5 mol-% of
example, many of these catalytic systems allowed the use of copper sources such as CuOTf (5%), CuCl (20%), CuCN
only aromatic alkynes for carbon–carbon bond formation. (0%), [Cu(tmeda)Cl]2 (0%), CuCl2 (75%), Cu(acac)2 (15%)
and Cu(Piv)2 (0%). Only one of the copper catalysts, CuCl2,
gave the expected product, and this showed slightly better
activity and yield than CuI. Note that the reaction proceeds
with as little as 1 mol-% of CuCl2 and furnished the prod-
uct 3a in 90% yield. Significantly, the same reaction with
5 mol-% AuCl3 did not give the target compound 3a.[8]
Chlorinated solvents such as CH2Cl2, ClCH2CH2Cl and
CHCl3 were the solvents of choice; reactions performed in
[a] Organic Division III, Indian Institute of Chemical Technology,
Hyderabad 500607, India
Fax: +91-40-27193275
E-mail: gkswamy_iict@yahoo.co.in
[b] Laboratory of X-ray Crystallography, Indian Institute of Chem-
ical Technology,
Hyderabad 500607, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900397.
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Alkynyl-Substituted Pyridines, Quinolines and Isoquinolines
CH3CN, DMSO, DMF and THF did not yield a trace of
1
the required product. In addition to the H and 13C NMR
and MS analytical data, the product 3a was unambiguously
confirmed by single-crystal X-ray analysis (Figure 1).
Figure 1. X-ray crystal structure of 3a.[10]
Scheme 1.
of 1 mol-% of CuCl2 in DCM on stirring for 2 h at ambient
Under these optimized reaction conditions, 4- and 5-bro- temperature led to the recovery of the starting material.
moisoquinolines (1b and 1c) were treated with 2a, and the With a catalytic amount of Et3N (10 mol-%), the same reac-
corresponding products 3b and 3c were isolated in 72 and tion under otherwise identical conditions led to the ex-
80% yields, respectively, whereas the reaction carried out pected product 5a in 78% isolated yield (Scheme 2). Inor-
using 1b (1 equiv.), dimethyl acetylenedicarboxylate ganic bases K2CO3, Cs2CO3 and CsOH were not effective
(DMAD, 4; 1.2 equiv.) and 2e (1.2 equiv.) in the presence for this transformation.
Table 1. CuCl2/Et3N-catalysed alkynylation of isoquinoline (1a) and DMAD (4) with various terminal alkynes.[a]
[a] All reactions were carried out with a terminal alkyne (1.2 mmol), isoquinoline (1a; 1 mmol), 4 (1.2 mmol), CuCl2 (1 mol-%) and Et3N
(10 mol-%) in CH2Cl2 (5 mL) at ambient temperature with stirring for 2 h. [b] All products were fully characterized. [c] Unoptimized
isolated yields.
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G. Kumaraswamy et al.
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with activated isoquinoline, and the anticipated monocou-
pling product 5h was isolated in 80% yield (Entry 7,
Table 1). Even when using 2.2 equiv. of 1a and 4, only the
product 5h was isolated, and no trace of compound 5j was
observed. In another experiment, the reaction of 5h with 1a
and 4 in the presence of 1 mol-% CuCl2 and 10 mol-% Et3N
with stirring at room temperature resulted in compound 5j
in 78% yield (Scheme 3).
Scheme 2.
The optimized reaction conditions were then applied to
isoquinoline (1a) activated by 4 with varying terminal al-
kynes, and our results are shown in Table 1. Various ter-
minal acetylenes, irrespective of their steric and electronic
nature, underwent coupling with isoquinolines activated by
dimethyl acetylenedicarboxylate. This was in contrast to
previous reports that only the reactions of substituted phen-
ylacetylenes with modular variations of isoquinoline were
successful.[8] For example, under typical conditions, 1-
heptyne (2d) and 2-methoxy-1-naphthylethyne (2h) reacted
with equal efficacy with activated isoquinoline and fur-
nished the products 5e and 5i (Entries 4 and 8, Table 1) in
fairly good yields.
Scheme 3.
Under a similar protocol, the reaction of quinoline (6a),
Methyl propiolate (2a) and propargyl bromide (2c) were activated by dimethyl acetylenedicarboxylate (4), with 2e re-
also coupled with activated isoquinoline, producing the cor- sulted in the desired substituted alkyne product 7a, but in
responding 1,2-dihydroisoquinolines 5b and 5d (Entries 1 poor yield (10%) after prolonged stirring at room tempera-
and 3, Table 1) in slightly lower yields. Interestingly, 1,3- ture. This problem was circumvented by employing a cata-
diethynylbenzene (2g; 1.1 equiv.) also underwent coupling lytic amount of Hünig’s base in place of Et3N. The reaction
Table 2. CuCl2/EtN(iPr)2-catalysed alkynylation of DMAD (4) activated quinolines 6a–c.[a]
[a] All reactions were carried out with a terminal alkyne (1.2 mmol), quinoline (1 mmol), 4 (1.2 mmol), CuCl2 (1 mol-%) and EtiPr2N
(10 mol-%) in CH2Cl2 (5 mL) at ambient temperature with stirring for 4 h. [b] All products were fully characterized. [c] Unoptimized
isolated yields.
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Alkynyl-Substituted Pyridines, Quinolines and Isoquinolines
carried out using 10 mol-% of Hünig’s base, 6a (1 equiv.),
dimethyl acetylenedicarboxylate (4; 1.2 equiv.) and 2e
(1.2 equiv.) in the presence of 1 mol-% of CuCl2 in DCM
with stirring for 4 h at ambient temperature led to the de-
sired substituted alkyne product 7a in 80% yield. Gratify-
ingly, under the standard protocol, dimethyl acetylenedicar-
boxylate (4) activated various substituted quinolines 6a–c,
which were coupled with substituted phenylacetylenes. The
resulting corresponding adducts 7b–h were obtained in
fairly good yields (Table 2). Under typical conditions, our
efforts to couple aliphatic alkynes such as 1-octyne (2d) and
methyl propiolate (2a) with dimethyl acetylenedicarboxylate
activated 6a were not successful.
Conclusions
We have developed an efficient strategy for the synthesis
of alkynyl derivatives of 1,2-dihydroisoquinolines, -quino-
lines and -pyridines. This methodology is significant in that
the reactions are catalysed by low-cost raw materials such
as CuCl2 and MoO3.[16] Moreover, the process allows the
rapid synthesis of alkynyl derivatives of dihydroisoquinoline
and -quinoline with functional-group variations on the alk-
ynyl by using a low level of catalyst loading (i.e., 1 mol-
%). Further work is in progress for the synthesis of various
heteroatom-containing alkynyl 1,2-dihydro nitrogen hetero-
cyclic derivatives.
In an attempt to extend this protocol to the synthesis of
substituted 1,2-dihydropyridine adducts, we performed the
one-pot reaction with pyridine (8a; 1 equiv.) and the ter-
minal alkyne ethyl propiolate (9; 2.1 equiv.) in the presence
of 1 mol-% of CuCl2 in DCM. Stirring at ambient tempera-
ture for 1 h showed the complete disappearance of the start-
ing material. Workup followed by column chromatography
resulted in a trace amount of the desired substituted alkyne
product 10a. After considerable experimentation,[11] in the
Experimental Section
General: Melting points are uncorrected. 1H NMR spectra were
recorded at 200, 300 or 400 MHz and 13C NMR spectra at 50, 75
or 100 MHz in CDCl3. FTIR spectra were measured for samples
prepared as KBr pellets or as films between KBr plates. MS data
were compiled by using electrospray ionization (ESI). Column
chromatography was carried out with silica gel (grade 60–120 and
presence of 10 mol-% of MoO3, pyridine (8a; 1 equiv.) and 100–200 mesh). CH2Cl2 was distilled from P2O5. All other chemi-
cals used were commercially available. All reactions were conducted
under nitrogen (IOLAR Grade I). Organic extracts were dried with
anhydrous Na2SO4.
the terminal alkyne ethyl propiolate (9; 3 equiv.) in DCM
with stirring for 1 h at ambient temperature yielded the de-
sired product 10a in 70% isolated yield (Scheme 4).
Typical Procedure for the Synthesis of Alkynyl-Substituted Deriva-
tives of Quinolines and Isoquinolines: Dimethyl acetylenedicarboxyl-
ate (4; 1.2 mmol) was added to a stirred solution of CuCl2
(0.01 mmol),
quinoline/isoquinoline
(1 mmol),
acetylene
(1.2 mmol) and triethylamine (0.1 mmol) in dichloromethane
(5 mL). The resulting reaction mixture was stirred at room temp.
for 1 h. The reaction mixture was passed through a Celite pad and
washed with dichloromethane (2ϫ3 mL). The combined filtrate
solutions were concentrated under reduced pressure. The crude res-
idue when subjected to silica gel column chromatography (100–
200 mesh) using hexane/ethyl acetate (9:1) as eluent afforded the
pure product.
Methyl (E)-3-[1-(3-Methoxy-3-oxoprop-1-ynyl)isoquinolin-2(1H)-yl-
]acrylate (3a): Isoquinoline (1 mmol), methyl propiolate (2.1 mmol)
and CuCl2 (0.01 mmol) were subjected to the typical procedure de-
scribed above. Yield: 268 mg (90%), pale-yellow solid, m.p. 140–
3
142 °C. 1H NMR (300 MHz, CDCl3): δ = 7.45 (d, JH,H
=
Scheme 4.
13.59 Hz, 1 H), 7.28–7.18 (m, 3 H), 7.04 (d, 3JH,H = 6.79 Hz, 1 H),
6.35 (d, JH,H = 7.55 Hz, 1 H, 3-H), 5.8 (d, JH,H = 7.55 Hz,1 H,
3
3
In the light of a recent study of the regioselective ad-
dition of metallo-alkynyl reagents to pyridinium salts,[12] we
explored the addition of alkynyl reagents to substituted pyr-
idines. Accordingly, 3-picoline (8b) and 9 were subjected to
the standard protocol. Analysis of the reaction mixture by
TLC indicated a multitude of products.[13] The reaction of
3-ethyl-4-methylpyridine (8c) with 9 proceeded to yield the
expected 2- and 6-substituted adducts of 10c in a 3:1 ratio
(82%). Similarly, the reaction of 8d with 9 resulted in 10d
in a moderate yield (65%) in a 5:1 isomeric ratio,[14] which
indicates the synthetic viability of the reaction. 4-Ethylpyr-
idine (8e) also reacted with the same efficiency, furnishing
the product 10e in 80% yield. However, 4-phenylpyridine
(8f) and 3-methylnicotine (8g) under these conditions gave
no traces of the coupled products (Scheme 4).[15]
3
4-H),5.72 (s, 1 H, 1-H), 5.19 (d, JH,H = 13.59 Hz, 1 H), 3.71 (s, 3
H, CO2Me), 3.70 (s, 3 H, CO2Me) ppm. 13C NMR (75 MHz,
CDCl3): δ = 168.2, 146.1, 129.2, 128.6, 127.5, 126.4,125.3, 106.5,
92.8, 82.5, 52.7, 51.4, 48.95 ppm. IR (KBr): ν = 3393, 2951, 2228,
˜
1707, 1616, 1166, 772 cm–1. MS (ESI): m/z = 298 [M + 1]+. HRMS:
calcd. for C17H15NO4Na 320.0898; found 320.088.
Methyl (E)-3-[4-Bromo-1-(3-methoxy-3-oxoprop-1-ynyl)isoquinolin-
2(1H)-yl]acrylate (3b): Yield: 270 mg (72%), pale-red solid,
m.p.121–123 °C. 1H NMR (200 MHz, CDCl3): δ = 7.50–7.16 (m,
3
5 H), 6.74 (s, 1 H, 3-H), 5.70 (s, 1 H, 1-H), 5.27 (d, JH,H
=
13.22 Hz, 1 H), 3.71 (s, 6 H, CO2Me) ppm. 13C NMR (75 MHz,
CDCl3): δ = 167.9, 144.9, 129.7, 129.1, 128.9, 127.6, 126.3, 125.5,
125.5, 93.9, 52.9, 51.4, 49.4 ppm. IR (KBr): ν = 3415, 2920, 2225,
˜
1712, 1617, 1250, 1167, 1050, 763, 530 cm–1. MS (ESI): m/z = 376
[M + 1]+.
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Methyl (E)-3-[5-Bromo-1-(3-methoxy-3-oxoprop-1-ynyl)isoquinolin-
2(1H)-yl]acrylate (3c): Yield: 300 mg (80%), pale-red solid,
m.p.122–124 °C. 1H NMR (200 MHz, CDCl3): δ = 7.50–7.41 (m,
Dimethyl 2-[(1-Phenylethynyl)isoquinolin-2(1H)-yl]maleate (5f):
Yield: 299 mg (80%), pale-yellow solid, m.p. 142–144 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.34–7.32 (m, 2 H), 7.24–7.21 (m, 6 H),
3
3
2 H), 7.11–7.04 (m, 2 H), 6.44 (d, JH,H = 8.08 Hz, 1 H, 3-H), 6.16
7.07–7.05 (m, 1 H), 6.28 (d, JH,H = 7.55 Hz, 1 H, 3-H), 5.91 (d,
3
3
(d, JH,H = 7.34 Hz, 1 H, 4-H), 5.71 (s, 1 H, 1-H), 5.27 (d, JH,H
=
3JH,H = 7.55 Hz, 1 H, 4-H), 5.74 (s, 1 H), 5.42 (s, 1 H, 1-H), 3.95
(s, 3 H, CO2Me), 3.70 (s, 3 H, CO2Me) ppm. 13C NMR (75 MHz,
CDCl3): δ = 166.6, 164.5, 148.6, 131.3, 128.4, 128.1, 127.9, 127.6,
127.1, 125.75, 124.7, 124.4, 108.5, 91.9, 85.5, 84.1, 52.8, 50.9,
13.95 Hz, 1 H), 3.71 (s, 6 H, CO2Me) ppm. 13C NMR (75 MHz,
CDCl3): δ = 168.0, 153.1, 145.6, 133.4, 130.4, 129.6, 128.3, 127.0,
125.8, 120.7, 105.1, 93.9, 81.9, 52.9, 51.3, 48.9 ppm. IR (KBr): ν =
˜
3416, 2925, 2852, 1713, 1615, 1552, 1309, 1052, 801, 763 cm–1. MS
(ESI): m/z = 376 [M + 1]+. HRMS: calcd. for C17H14NO4NaBr
398.0003; found 398.0009.
49.9 ppm. IR (KBr): ν = 3446, 2947, 1731, 1706, 1599, 1384, 1166,
˜
771, 544 cm–1. MS (ESI): m/z = 374 [M + 1]+. HRMS: calcd. for
C23H20NO4 374.1392; found 374. 1396.
Dimethyl 2-[4-Bromo-1-(phenylethynyl)isoquinolin-2(1H)-yl]maleate Dimethyl 2-{1-[3-(Benzyloxy)prop-1-ynyl]isoquinolin-2(1H)-yl}maleate
(5a): Yield: 352 mg (78%), red solid, m.p.122–124 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.51 (d, JH,H = 7.5 Hz, 1 H), 7.37–7.28
(m, 3 H), 7.24–7.18 (m, 5 H), 6.63 (s, 1 H, 3-H), 5.73 (s, 1 H), 5.43
(5g): Yield: 326 mg (78%), pale-yellow solid, m.p. 110–112 °C. 1H
NMR (200 MHz, CDCl3): δ = 7.27–7.13 (m, 8 H), 7.07–7.04 (m, 1
H), 6.25 (d, JH,H = 7.55 Hz, 1 H, 3-H), 5.88 (d, JH,H = 7.55 Hz, 1
3
3
3
(s, 1 H, 1-H), 3.97 (s, 3 H, CO2Me), 3.70 (s, 3 H, CO2Me) ppm.
H, 4-H), 5.57 (s, 1 H), 5.36 (s, 1 H, 1-H), 4.45 (s, 2 H, CH2Ph), 4.04
13C NMR (75 MHz, CDCl3): δ = 164.7, 148.1, 131.8, 129.0, 128.9, (s, 2 H), 3.94 (s, 3 H, CO2Me), 3.68 (s, 3 H, CO2Me) ppm. 13C NMR
128.9, 128.5, 128.2, 125.9, 125.7, 125.3, 121.6, 104.1,93.5, 86.5,
(75 MHz, CDCl3): δ = 166.9, 164.8, 148.9, 137.0, 128.8, 128.7, 128.22
84.0, 53.5, 51.5, 51.7 ppm. IR (KBr): ν = 3422, 2951, 1741, 1704,
127.7, 126.1, 125.1, 124.8, 108.7, 92.4, 82.2, 71.3, 57.0, 53.2, 51.3,
˜
1593, 1383, 1179, 1154, 751 cm–1. MS (ESI): m/z = 452 [M + 1]+.
49.8 ppm. IR (KBr): ν = 3441, 2942, 1730, 1595, 1571, 1386, 1209,
˜
1165, 773, 407 cm–1. MS (ESI): m/z = 418 [M + 1]+. HRMS: calcd.
Dimethyl 2-[1-(3-Methoxy-3-oxoprop-1-ynyl)isoquinolin-2(1H)-yl]-
maleate (5b): Yield: 270 mg (76%), white solid, m.p. 138–142 °C.
for C25H24NO5 418.1654; found 418.1652.
1H NMR (300 MHz, CDCl3): δ = 7.29–7.071 (m, 4 H), 6.27 (d,
Dimethyl
2-{1-[(3-Ethynylphenyl)ethynyl]isoquinolin-2(1H)-yl}-
3
3JH,H = 8.30 Hz, 1 H, 3-H), 5.93 (d, JH,H = 7.55 Hz, 1 H, 4-H), maleate (5h): Yield: 318 mg (80%), pale-yellow solid, m.p. 165–
5.64 (s, 1 H), 5.28 (s, 1 H, 1-H), 3.95 (s, 3 H, CO2Me), 3.72 (s, 3 167 °C. 1H NMR (75 MHz, CDCl3): δ = 7.47 (s, 1 H), 7.37–7.31
H, CO2Me), 3.70 (s, 3 H, CO2Me) ppm. 13C NMR (75 MHz,
(m, 2 H), 7.25–7.17 (m, 4 H), 7.08–7.06 (m, 1 H), 6.28 (d, JH,H
=
3
3
CDCl3): δ = 166.7, 129.3, 127.9, 126.3, 125.4, 124.8, 109.2, 93.2,
7.74 Hz, 1 H, 3-H), 5.91 (d, JH,H = 7.74 Hz, 1 H, 4-H), 5.72 (s, 1
H), 5.39 (s, 1 H, 1-H), 3.95 (s, 3 H, CO2Me), 3.71 (s, 3 H, CO2Me),
2.97 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.1, 164.9,
149.1, 135.3, 132.1, 128.8, 128.2, 127.6, 126.1, 125.1, 122.2, 108.9,
81.8, 53.3, 52.8, 51.4, 49.5 ppm. IR (KBr): ν = 3408, 2924, 2852,
˜
2233, 1714, 1600, 1167, 1105, 769 cm–1. MS (ESI): m/z = 356 [M +
1]+. HRMS: calcd. for C19H17NO6NaBr 378.0953; found 378.0960.
92.4, 85.2, 84.9, 82.4, 53.3, 51.4, 50.3 ppm. IR (KBr): ν = 3289,
˜
Dimethyl 2-{1-[(Trimethylsilyl)ethynyl]isoquinolin-2(1H)-yl}maleate
(5c): Yield: 296 mg (80%), white solid, m.p. 116–118 °C. H NMR
2923, 2853, 1742, 1704, 1592, 1568, 1439, 1205, 1164, 1040, 900,
767 cm–1. MS (ESI): m/z = 420 [M + Na]+. HRMS: calcd. for
C25H19NO4Na 420.1211; found 420.1214.
1
(200 MHz, CDCl3): δ = 7.2–7.10 (m, 3 H), 7.05–7.01 (m, 1 H), 6.22
3
3
(d, JH,H = 7.56 Hz, 1 H, 3-H), 5.86 (d, JH,H = 7.56 Hz, 1 H, 4-
H), 5.5 (s, 1 H), 5.33 (s, 1 H, 1-H), 3.93 (s, 3 H, CO2Me), 3.69 (s, Dimethyl
2-{1-[(2-Methoxynaphthalen-1-yl)ethynyl]isoquinolin-
3 H, CO2Me), 0.11 (s, 9 H, SiMe3) ppm. 13C NMR (75 MHz,
2(1H)-yl}maleate (5i): Yield: 363 mg (80%), red solid, m.p. 128–
3
CDCl3): δ = 167.1, 165.0, 148.9, 128.8, 127.5, 126.2, 124.9, 108.8,
130 °C. 1H NMR (200 MHz, [D6]DMSO): δ = 7.86 (d, JH,H
=
3
100.0, 92.3, 91.6, 53.2, 51.8, 50.5, 0.2 ppm. IR (KBr): ν = 3441,
8.43 Hz, 1 H), 7.77 (d, JH,H = 9.20 Hz, 1 H), 7.72–7.63 (m, 1 H),
˜
3
3023, 2956, 1733, 1698, 1589, 1564, 1387, 1205, 1169, 995, 845,
751 cm–1. MS (ESI): m/z = 370 [M + 1]+. HRMS: calcd. for
C20H24NO4Si 370.1474; found 370.1477.
7.41–7.11 (m, 7 H), 6.34 (d, JH,H = 7.66 Hz, 1 H, 3-H), 6.02 (d,
3JH,H = 4.60 Hz, 1 H, 4-H), 5.97 (s, 1 H), 5.62 (s, 1 H, 1-H), 3.94
(s, 6 H, CO2Me, OMe), 3.70 (s, 3 H, CO2Me) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 167.2, 165.1, 159.4, 149.1, 130.5, 128.8,
128.5, 128.2, 127.6, 126.2, 126.1, 124.9, 124.0, 112.8, 108.8, 94.2,
Dimethyl 2-[1-(3-Bromoprop-1-ynyl)isoquinolin-2(1H)-yl]maleate (5d):
1
Yield: 296 mg (76%), pale-yellow solid, m.p. 117–119 °C. H NMR
92.6, 56.7, 53.7, 51.5 ppm. IR (KBr): ν = 3422, 2945, 2254, 1734,
˜
(200 MHz, CDCl3): δ = 7.24–7.03 (m, 4 H), 6.24 (d, 3JH,H = 8.08 Hz,
1 H, 3-H), 5.68 (d, 3JH,H = 8.08 Hz, 1 H, 4-H), 5.58 (s, 1 H), 5.30 (s,
1 H, 1-H), 3.94 (s, 3 H, CO2Me), 3.82 (s, 2 H, CH2Br), 3.70 (s, 3 H,
CO2Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.9, 148.8, 128.8,
127.7, 126.1, 125.2, 124.8, 108.9, 92.6, 82.0, 53.3, 51.3, 49.9,
1711, 1599, 1382, 1271, 1167, 1027, 1002, 823, 769 cm–1. MS (ESI):
m/z = 454 [M + 1]+. HRMS: calcd. for C28H23NO5Na 476.1473;
found 476.1484.
Tetramethyl
(E)-2,2Ј-[1,1Ј-(1,3-Phenylenediethynyl)diisoquinolin-
13.7 ppm. IR (KBr): ν = 2925, 2854, 1792, 1741, 1637, 1440, 1363,
2(1H)-yl]dimaleate (5j): Yield: 522 mg (78%), white solid, m.p. 140–
˜
1
1262, 1215, 1051, 1007, 758 cm–1. MS (ESI): m/z = 391 [M + 1]+.
142 °C. H NMR (75 MHz, CDCl3): δ = 7.5–7.05 (m, 12 H), 6.27
3
3
(t, JH,H = 7.17 Hz, 2 H), 5.91 (t, JH,H = 6.79 Hz, 2 H), 5.71 (d,
3JH,H = 9.06 Hz, 2 H), 5.38 (d, JH,H = 8.30 Hz, 2 H, 1 H), 3.95 (s,
3 H, CO2Me), 3.94 (s, 3 H, CO2Me), 3.71 (s, 3 H, CO2Me), 3.69
Dimethyl 2-[1-(Hept-1-ynyl)isoquinolin-2(1H)-yl]maleate (5e): Yield:
1
301 mg (82%), white solid, m.p. 119–121 °C. H NMR (200 MHz,
3
CDCl3): δ = 7.24–7.00 (m, 4 H), 6.22 (d, JH,H = 8.08 Hz, 1 H, 3-
(s, 3 H, COOMe) ppm. IR (KBr): ν = 3020, 2952, 2853, 1741, 1705,
˜
3
H), 5.84 (d, JH,H = 8.08 Hz, 1 H, 4-H), 5.48 (s, 1 H), 5.34 (s, 1 H,
1568, 1439, 1252, 1209, 1166, 755 cm–1. MS (ESI): m/z = 691 [M
1-H), 3.93 (s, 3 H, CO2Me), 3.69 (s, 3 H, CO2Me), 2.15–2.07 (m,
2 H), 1.44 (t, JH,H = 6.61 Hz, 2 H), 1.31–1.25 (m, 4 H), 0.86 (t,
JH,H = 7.34 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
167.2, 149.1, 129.1, 128.7, 128.3, 127.4, 126.0, 125.4, 108.6, 92.1,
+ Na]+.
Dimethyl 2-[2-(Phenylethynyl)quinolin-1(2H)-yl]maleate (7a): Yield:
299 mg (80%), dark-yellow semi-solid. 1H NMR (200 MHz,
3
53.2, 51.3, 50.1, 30.9, 27.9, 22.0, 18.6, 13.8 ppm. IR (KBr): ν =
CDCl3): δ = 7.4–7.21 (m, 6 H), 7.14–6.99 (m, 3 H), 6.51 (d, JH,H
˜
3
3
3446, 2939, 1731, 1707, 1595, 1570, 1384, 1250, 1161, 771,
704 cm–1. MS (ESI): m/z = 368 [M + 1]+. HRMS: calcd. for
C22H25NO4Na 390.1681; found 390.1672.
= 9.46 Hz, 1 H, 4-H), 6.01 (dd, JH,H = 9.46, JH,H = 5.82 Hz, 1
3
H, 3-H), 5.78 (s, 1 H), 5.20 (d, JH,H = 5.82 Hz, 1 H, 2-H), 3.73 (s,
3 H, CO2Me), 3.70 (s, 3 H, CO2Me) ppm. 13C NMR (75 MHz,
4162
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4158–4164

Alkynyl-Substituted Pyridines, Quinolines and Isoquinolines
CDCl3): δ = 166.7, 150.4, 136.0, 131.7, 128.3, 127.0, 125.6, 125.2,
100.4, 52.9, 51.4, 51.2 ppm. IR (KBr): ν = 3445, 3287, 2995, 1737,
˜
124.1, 120.1, 100.4, 52.4, 51.9, 29.8 ppm. IR (KBr): ν = 3446, 2944,
1698, 1591, 1564, 1221, 1157, 784 cm–1. MS (ESI): m/z = 420 [M +
˜
1737, 1698, 1566, 1493, 1222, 1154, 1034, 979, 758 cm–1. MS (ESI):
m/z = 374 [M + 1]+. HRMS: calcd. for C23H19NO4Na 396.1211;
found 396.1204.
Na]+. HRMS: calcd. for C25H19NO4Na 420.1211; found 420.1192.
Dimethyl 2-{2-[(3-Ethynylphenyl)ethynyl]-6-methylquinolin-1(2H)-
yl}maleate (7g): Yield: 333 mg (81%), white solid, m.p. 138–140 °C.
Dimethyl 2-[6-Methyl-2-(phenylethynyl)quinolin-1(2H)-yl]maleate 1H NMR (300 MHz, CDCl3): δ = 7.45 (s, 1 H), 7.37–7.19 (m, 3
1
3
3
(7b): Yield: 302 mg (78%), pale-yellow solid, m.p. 134–136 °C. H
H), 6.92 (d, JH,H = 6.04 Hz, 3 H), 6.52 (d, JH,H = 9.63 Hz, 1 H,
3
3
NMR (200 MHz, CDCl3): δ = 7.33–7.30 (m, 2 H), 7.24–7.21 (m, 3
4-H), 5.98 (dd, JH,H = 9.44, JH,H = 5.85 Hz, 1 H, 3-H), 5.68 (s,
3
3
3
H), 6.92 (d, JH,H = 6.04 Hz, 3 H), 6.51 (d, JH,H = 9.06 Hz, 1 H,
1 H), 5.17 (d, JH,H = 5.85 Hz, 1 H, 2 H), 3.75 (s, 3 H, CO2Me),
3
3
4-H), 5.99 (dd, JH,H = 9.06, JH,H = 6.04 Hz, 1 H, 3-H), 5.71 (s,
3.70 (s, 3 H, CO2Me), 2.97 (s, 1 H), 2.30 (s, 3 H, CH3) ppm. 13C
3
1 H), 5.18 (d, JH,H = 6.04 Hz, 1 H, 2-H), 3.75 (s, 3 H, CO2Me), NMR (75 MHz, CDCl3): δ = 166.7, 165.1, 150.5, 135.2, 134.1,
3.70 (s, 3 H, CO2Me), 2.30 (s, 3 H, Me) ppm. 13C NMR (75 MHz, 133.4, 132.1, 128.9, 128.2, 127.8, 125.9, 123.7, 122.3, 120.1, 99.3,
CDCl3): δ = 166.8, 165.1, 150.5, 134.1, 133.5, 131.7, 128.7, 127.9,
84.6, 82.4, 77.8, 52.9, 51.3, 51.1, 20.7 ppm. IR (KBr): ν = 3287,
˜
125.3, 123.9, 120.1, 99.2, 85.7, 83.8, 52.8, 51.2, 20.7 ppm. IR (KBr):
2949, 1738, 1699, 1568, 1497, 1385, 1222, 1153, 1030, 818,
792 cm–1. MS (ESI): m/z = 434 [M + Na]+. HRMS: calcd. for
C26H21NO4Na 434.1368; found 434.1368.
ν = 3438, 2924, 2853, 2151, 1741, 1698, 1567, 1495, 1223, 1156,
˜
1034, 816, 752 cm–1. MS (ESI): m/z = 410 [M + Na]+. HRMS:
calcd. for C24H21NO4Na 410.1368; found 410.1368.
Dimethyl 2-{2-[(3-Ethynylphenyl)ethynyl]-6-methylquinolin-1(2H)-
yl}maleate (7h): Yield: 359 mg (84%), pale-yellow semi-solid. 1H
NMR (300 MHz, CDCl3): δ = 7.45 (s, 1 H), 7.3–7.17 (m, 3 H),
Dimethyl 2-[6-Methoxy-2-(phenylethynyl)quinolin-1(2H)-yl]maleate
(7c): Yield: 303 mg (75%), pale-yellow semi-solid. 1H NMR
3
3
(75 MHz, CDCl3): δ = 7.32–7.30 (m, 2 H), 7.25–7.21 (m, 3 H), 6.99 6.99 (d, JH,H = 8.30 Hz, 1 H), 6.71–6.65 (m, 2 H), 6.53 (d, JH,H
3
3
3
3
(d, JH,H = 8.67 Hz, 1 H), 6.69–6.65 (m, 2 H), 6.52 (d, JH,H
=
= 9.82 Hz, 1 H, 4-H), 6.02 (dd, JH,H = 9.06, JH,H = 6.04 Hz, 1
3
3
3
9.46 Hz, 1 H, 4-H), 6.04 (dd, JH,H = 9.46, JH,H = 6.30 Hz, 1 H,
H, 3-H), 5.61 (s, 1 H), 5.17 (d, JH,H = 6.04 Hz, 1 H, 2-H), 3.78 (s,
3
3-H), 5.64 (s, 1 H), 5.18 (d, JH,H = 6.30 Hz, 1 H, 2-H), 3.77 (s, 3
3 H, CO2Me), 3.76 (s, 3 H, OMe), 3.70 (s, 3 H, CO2Me), 2.97 (s,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.1, 150.7, 35.2,
32.1, 132.0, 128.2, 125.4, 124.6, 122.3, 121.6, 113.3, 11.2, 105.0,
H, CO2Me), 3.76 (s, 3 H, OMe), 3.69 (s, 3 H, CO2Me) ppm. 13C
NMR (75 MHz, CDCl3): δ = 165.1, 150.8, 131.7, 128.5, 128.1,
125.2, 124.9, 121.6, 113.3, 112.5, 98.1, 85.7, 83.6, 52.9, 51.3,
98.2, 84.4, 82.4, 55.4, 52.9, 51.3, 50.9, 29.6 ppm. IR (KBr): ν =
˜
51.1 ppm. IR (KBr): ν = 3444, 2924, 2853, 1741, 1705, 1587, 1495,
3449, 3290, 2924, 1734, 1705, 1591, 1569, 1384, 1206, 1165, 1111,
768 cm–1. MS (ESI): m/z = 450 [M + Na]+. HRMS: calcd. for
C26H21NO5Na 450.1317; found 450.1310.
˜
1220, 1158, 1034, 756 cm–1. MS (ESI): m/z = 426 [M + Na]+.
HRMS: calcd. for C24H21NO5Na 426.1317; found 426.1314.
Dimethyl
2-{2-[(4-Methoxyphenyl)ethynyl]quinolin-1(2H)-yl}- Typical Procedure for the Synthesis of Substituted 1,2-Dihydropyr-
maleate (7d): Yield: 303 mg (75%), pale-yellow solid, m.p. 175–
idines: Pyridine (1 mmol) was added to a stirred solution of MoO3
177 °C. 1H NMR (75 MHz, CDCl3): δ = 7.25–7.22 (m, 3 H), 7.16– (0.1 mmol) and ethyl propiolate (3 mmol) in dichloromethane
3
7.09 (m, 1 H), 7.04–7.00 (m, 2 H), 6.72 (d, JH,H = 9.06 Hz, 2 H),
(5 mL). The resulting reaction mixture was stirred at room temp.
for 1 h. Then the reaction contents were passed through a Celite
pad and washed with dichloromethane (2ϫ3 mL). The combined
3
3
3
6.55 (d, JH,H = 9.06 Hz, 1 H, 4-H), 6.01 (dd, JH,H = 9.06, JH,H
3
= 6.04 Hz, 1 H, 3-H), 5.78 (s, 1 H), 5.18 (d, JH,H = 6.04 Hz, 1 H,
2-H), 3.76 (s, 3 H, CO2Me), 3.74 (s, 3 H, OMe-Ph), 3.71 (s, 3 H, contents were concentrated under reduced pressure. The crude resi-
CO2Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.7, 165.1, due was subjected to silica gel column chromatography (100–
159.8, 150.4, 136.1, 133.2, 128.2, 127.1, 125.6, 124.9, 124.2, 120.1,
200 mesh) by using ethyl acetate/hexane (1:9) as eluent to give the
product.
113.7, 100.3, 85.9, 82.4, 52.2, 52.9, 51.4 ppm. IR (KBr): ν = 3445,
˜
2924, 2851, 1748, 1711, 1605, 1368, 1291, 1242, 1168, 1032, 837,
753 cm–1. MS (ESI): m/z = 426 [M + Na]+. HRMS: calcd. for
C24H21NO5Na 426.1317; found 426.1314.
Dimethyl 2-{2-[(4-Methoxyphenyl)ethynyl]-6-methylquinolin-1(2H)- 3JH,H = 7.36 Hz, 1 H, 6-H), 6.01 (m, 1 H, 5-H), 5.46 (m, 1 H, 4-
Methyl (E)-3-[2-(3-Methoxy-3-oxoprop-1-ynyl)pyridin-1(2H)-yl]ac-
rylate (10a): Yield: 193 mg (70%), pale-yellow liquid. 1H NMR
(75 MHz, CDCl3): δ = 7.48 (d, JH,H = 13.59 Hz, 1 H), 6.25 (d,
3
3
yl}maleate (7e): Yield: 304 mg (73%), pale-yellow solid, m.p. 135– H), 5.29 (d, JH,H = 5.47 Hz, 1 H, 2-H), 5.19 (m, 1 H, 3-H), 5.06
1
3
138 °C. H NMR (400 MHz, CDCl3): δ = 7.25–7.23 (m, 2 H), 6.92 (d, JH,H = 13.59 Hz, 1 H), 4.23–4.13 (m, 4 H, CO2Et), 1.33–1.25
3
3
(d, JH,H = 6.59 Hz, 3 H), 6.73 (d, JH,H = 8.79 Hz, 2 H), 6.92 (d,
(m, 6 H, CO2Et) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.8,
152.9, 146.5, 130.4, 123.7, 114.6, 102.9, 93.1, 81.3, 62.9, 59.0, 46.3,
29.1, 14.6, 13.0 ppm. IR (KBr): ν = 2982, 2929, 1728, 1615, 1371,
˜
3JH,H = 6.59 Hz, 3 H), 6.50 (d, JH,H = 9.52 Hz, 1 H, 4-H), 5.90
3
3
3
(dd, JH,H = 9.52, J = 5.86 Hz, 1 H, 3-H), 5.72 (s, 1 H), 5.17 (d,
3JH,H = 5.86 Hz, 1 H, 2-H), 3.76 (s, 3 H, CO2Me), 3.75 (s, 3 H, 1243, 1177, 1030, 753 cm–1. MS (ESI): m/z = 276 [M + 1]+. HRMS:
OMe-Ph), 3.70 (s, 3 H, CO2Me), 2.29 (s, 3 H, Me) ppm. 13C NMR calcd. for C15H18NO4 276.1235; found 276.1244.
(75 MHz, CDCl3): δ = 166.8, 159.7, 150.64, 133.2, 128.8, 127.8,
125, 124.2, 120, 133.7, 99.1, 55.2, 52.8, 51.3, 29.6, 20.7 ppm. IR
Methyl (E)-3-[3-Ethyl-2-(3-methoxy-3-oxoprop-1-ynyl)-4-methylpyr-
idin-1(2H)-yl]acrylate (10c): Yield: 260 mg (82%), liquid. 1H NMR
(KBr): ν = 3389, 2948, 2218, 1740, 1702, 1569, 1504, 1439, 1287,
˜
3
(300 MHz, CDCl3): δ = 7.36 (d, JH,H = 13.59 Hz, 1 H), 6.12 (d,
1252, 1157, 1034, 823 cm–1. MS (ESI): m/z = 418 [M + H]+.
3
3JH,H = 7.36 Hz, 1 H, 6-H), 5.10 (d, JH,H = 7.36 Hz, 1 H, 5-H),
3
Dimethyl 2-{2-[(3-Ethynylphenyl)ethynyl]quinolin-1(2H)-yl}maleate 5.05 (d, JH,H = 13.59 Hz, 1 H), 4.98 (s, 1 H, 2-H), 4.22–4.10 (m,
(7f): Yield: 322 mg (81%), pale-yellow solid, m.p. 134-136 °C. 1H
4 H, CO2Et), 2.33–2.26 (m, 1 H, CH2), 2.20–2.15 (m, 1 H, CH2),
NMR (300 MHz, CDCl3): δ = 7.45 (s, 1 H), 7.37–7.00 (m, 7 H), 1.77 (s, 3 H, CH3), 1.33–1.26 (m, 6 H, CO2Et), 1.12–1.07 (m, 3 H,
3
3
3
6.56 (d, JH,H = 9.06 Hz, 1 H, 4-H), 5.99 (dd, JH,H = 9.06, JH,H
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.6, 146.1, 126.3,
125, 122.2, 110.9, 108.6, 92.1, 91.3, 82.2, 61.7, 59.9, 59.3, 59.2, 23.2,
3
= 6.04 Hz, 1 H, 3-H), 5.75 (s, 1 H), 5.19 (d, JH,H = 6.04 Hz, 1 H,
2-H), 3.75 (s, 3 H, CO2Me), 3.17 (s, 3 H, CO2Me), 2.97 (s, 1 H) 22.1, 20.5, 17.9, 16.3, 13, 11.9 ppm. IR (KBr): ν = 2977, 2935,
˜
ppm. 13C NMR (75 MHz, CDCl3): δ = 166.6, 164.9, 135.9, 135.2,
132.1, 131.9, 128.4, 128.2, 127.2, 125.3, 124.3, 123.6, 122.2, 120.1,
1725, 1614, 1371, 1244, 1175, 1033, 755 cm–1. MS (ESI): m/z = 318
[M + 1]+. HRMS: calcd. for C18H24NO4 318.1705; found 318.1706.
Eur. J. Org. Chem. 2009, 4158–4164
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4163

G. Kumaraswamy et al.
FULL PAPER
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Commercon, J.-F. Normant, Synlett 1991, 111–113; g) T.
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Yamada, C. Morita, J. Am. Chem. Soc. 2002, 124, 8184–8185.
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3305; b) R. M. Acheson, J. Woollard, J. Chem. Soc. Perkin
Trans. 1 1975, 438–446.
[7] a) A. Alizadeh, N. Zohreh, Helv. Chim. Acta 2008, 91, 844–
848; b) R. Ghahremanzadeh, S. Ahadi, M. Sayyafi, A. Bazgir,
Tetrahedron Lett. 2008, 49, 4479–4482; c) V. Nair, S. Devipriya,
S. Eringathodi, Tetrahedron Lett. 2007, 48, 3667–3670; d) I.
Yavari, M. Ghazanfarpour-Darjani, M. Sabbaghan, Z. Hos-
saini, Tetrahedron Lett. 2007, 48, 3749–3751.
Methyl (E)-3-[2-(3-Methoxy-3-oxoprop-1-ynyl)-3,4-dimethylpyridin-
1(2H)-yl]acrylate (10d): Yield: 197 mg (65%), liquid. 1H NMR
3
(400 MHz, CDCl3): δ = 7.29 (d, JH,H = 13.18 Hz, 1 H), 6.05 (d,
3
3JH,H = 7.32 Hz, 1 H, 6-H), 4.99 (d, JH,H = 7.32 Hz, 1 H, 5-H),
3
4.95 (d, JH,H = 13.18 Hz, 1 H), 4.83 (s, 1 H, 2-H), 4.13–4.00 (m,
4 H, CO2Et), 1.76 (s, 3 H, Me), 1.67 (s, 3 H, Me), 1.24–1.17 (m, 6
H, CO2Et) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.6, 152.6,
145.8, 126.1, 124.9, 116.3, 108, 92, 81.5, 61.7, 59.3, 50.9, 29.2, 16.7,
16.1, 14, 13.8 ppm. IR (KBr): ν = 2925, 2855, 2225, 1711, 1626,
˜
1594, 1246, 1173, 1120, 1041, 754 cm–1. MS (ESI): m/z = 304 [M
+ 1]+. HRMS: calcd. for C17H22NO4 304.1548; found 304.1564.
Ethyl (E)-3-[2-(3-Ethoxy-3-oxoprop-1-ynyl)-4-ethylpyridin-1(2H)-
yl]acrylate (10e): Yield: 243 mg (80%), liquid. 1H NMR (400 MHz,
[8]
J. S. Yadav, B. V. Subba Reddy, N. N. Yadav, M. N. Gupta, B.
Sridhar, J. Org. Chem. 2008, 73, 6857–6859.
3
3
CDCl3): δ = 7.39 (d, JH,H = 13.40 Hz, 1 H), 6.12 (d, JH,H
=
[9]
a) G. Kumaraswamy, K. Ankamma, A. Pitchaiah, J. Org.
Chem. 2007, 72, 9822–9825; b) G. Kumaraswamy, A. Pitchaiah,
G. Ramakrishna, D. S. Ramakrishna, K. Sadaiah, Tetrahedron
Lett. 2006, 47, 2013–2015; c) G. Kumaraswamy, G. Venk-
ata Rao, G. Ramakrishna, Synlett 2006, 1122–1124.
3
7.88 Hz, 1 H, 6-H), 5.23 (d, JH,H = 5.52 Hz, 1 H, 5-H), 5.16 (d,
3JH,H = 5.52 Hz, 1 H, 2-H), 5.09 (dd, 3JH,H = 7.88, 3JH,H = 6.30 Hz,
3
1 H, 3-H), 5.06 (d, JH,H = 14.19 Hz, 1 H), 4.23–4.14 (m, 4 H,
CO2Et), 2.09 (q, JH,H = 7.09 Hz, 2 H, CH2), 1.32–1.27 (m, 6 H,
CO2Et), 1.05 (t, JH,H = 7.09 Hz, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 167.9, 146.2, 137.6, 129.5, 108.1, 105.3, 92.9,
[10]
Colorless block crystals, 0.19ϫ0.15ϫ0.08 mm, were grown
from hexane/EtOAc and belonged to the monoclinic space
group P21/n with cell parameters a = 9.5483(14), b = 5.0583(8),
82.3, 62.1, 59.75, 46.6, 27.4, 14.1, 12.0 ppm. IR (KBr): ν = 3402,
˜
c = 31.868(5) Å, β = 90.420(6)°, V = 1539.1(4) Å3, ρcalcd.
=
2978, 2935, 1711, 1625, 1445, 1371, 1246, 1154, 1041, 965,
754 cm–1. MS (ESI): m/z = 326 [M + Na]+. HRMS: calcd. for
C17H21NO4Na 326.1368; found 326.1365.
1.283 g/cm3, µ(Mo-Kα) = 0.092 mm–1. Data were collected with
a Bruker SMART APEX CCD diffractometer, Mo-Kα (λ =
0.71073 Å). 13870 reflections were measured of which 2698
were independent. The structure was solved by direct methods
(SHELXS97); full-matrix least-squares refinement based on
|F2| was performed (SHELXL97) (G. M. Sheldrick, SHELXS
97 and SHELXL 97, Programs for crystal structure solution
and refinement, University of Göttingen, Germany, 1997). All
hydrogen atoms were geometrically fixed and allowed to ride
on the parent atoms. The refinement converged to an R1 value
of 4.54% and an wR2 value of 11.74%; max./min. residual elec-
tron density 0.176/–0.17 eÅ–3. CCDC-725118 contains the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For this transformation, 10 mol-% of neutral and basic Al2O3
were also individually evaluated as catalysts. However, their
catalytic activity was found to be inferior to that of MoO3.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all compounds and postulated
catalytic cycle.
Acknowledgments
We are grateful to the Director of the Indian Institute of Chemical
Technology (IICT), for his constant encouragement. The Depart-
ment of Science and Technology (DST), India is also gratefully
acknowledged for the financial assistance (Grant No. SR/SI/OC-
12/2007). D. R., N. J. and G. V. R. are thankful to the Council of
Scientific and Industrial Research (CSIR), India for awarding fel-
lowships.
[11]
[12] S. Yamada, A. Toshimitsu, Y. Takahashi, Tetrahedron Lett.
2009, 50, 2329–2333.
[1] a) A. R. Katritzky, S. Rachwal, Tetrahedron 1996, 52, 15031–
15070; b) M. C. Bagley, C. Glover, E. A. Merritt, Synlett 2007,
[13] Our efforts to isolate the major spot by silica gel column
chromatography were not successful.
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basis of integration of the corresponding the 2-proton signal
versus the 6-proton signal of the minor regioisomer (not
shown). The regioisomeric ratio for compound 10d was simi-
larly estimated.
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observed by TLC, but decomposition occurred in the course
of isolation by silica column chromatography. With 8g as the
substrate, the starting material was completely recovered.
[16] The reaction mechanism remains to be explored, but the pos-
tulated catalytic cycle is shown in the Supporting Information.
The observed product can be rationalized on the basis of the
transition state between the 1,4-dipolar intermediate with elec-
tron-deficient acetylene compounds (the Huisgen protocol) and
the subsequent coupling product with the corresponding alk-
ynyl moiety which in turn was activated by either copper salts
or molybdenum oxide.
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Received: April 10, 2009
Published Online: July 13, 2009
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