Synthesis of triazolo isoquinolines and isochromenes from 2-alkynylbenzaldehyde via domino reactions under transition-metal-free conditions

Article abstract of DOI:10.1021/jo401929q

We describe two simple straightforward syntheses of triazolo isoquinolines (3) and isochromenes (7) from 2-alkynylbenzaldehydes (1) as a common synthon. The synthetic strategy for 3 involves formation of the (E)-1-(2-nitrovinyl)-2- (alkynyl)benzene species 2 via condensation of synthon 1 with nitromethane followed by a [3 + 2] cycloaddition/extrusion of the nitro group/regioselective 6-endo cyclization domino sequence. In yet another strategy, the synthon 1 was condensed with nitromethane followed by electrophilic iodo cyclization of the resulting 2-nitro-1-(2-(alkynyl)phenyl)ethanol (6) to furnish iodo isochromene derivatives. The salient feature of the above two strategies involves formation of the corresponding heterocycles under metal-free conditions in good yields.

Full text of DOI:10.1021/jo401929q

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Article
Synthesis of Triazolo Isoquinolines and Isochromenes
from 2-Alkynylbenzaldehyde via Domino
Reaction under Transition Metal Free Conditions
Rajesh Kumar Arigela, Srinivas Samala, Rohit Mahar, Sanjeev Kumar Shukla, and Bijoy Kundu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 30 Sep 2013
Downloaded from http://pubs.acs.org on October 1, 2013
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Synthesis of Triazolo Isoquinolines and Isochromenes from 2-
Alkynylbenzaldehyde via Domino Reaction under Transition
Metal Free Conditions
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Rajesh K. Arigela,a Srinivas Samala,a Rohit Mahar,b Sanjeev K. Shukla,b and Bijoy
Kundu*a,b,c
a Medicinal and Process Chemistry Division, b Sophisticated Analytical Instrumental Facility,
c
CSIR-Central Drug Research Institute, Lucknow-226001, India. Academy of Scientific and
Innovative Research, New Delhi, 110001, India.
*Corresponding author. Tel.: +91 522 2612411-18; fax: +91 522 2623405; e-mail:
bijoy_kundu@yahoo.com, b_kundu@cdri.res.in
Abstract
We describe two simple straightforward synthesis of triazolo isoquinolines (3) and
isochromenes (7) from 2-alkynylbenzaldehydes (1) as a common synthon. The synthetic
strategy for the 3 involves formation of (E)-1-(2-nitrovinyl)-2-(alkynyl) benzene 2 via
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condensation of synthon 1 with nitromethane followed by [3+2] cycloaddition/ extrusion of
the nitro group/ regioselective 6-endo cyclization domino sequence. In yet another strategy,
the synthon 1 was condensed with nitromethane followed by electrophilic iodo-cyclization of
the resulting 2-nitro-1-(2-(alkynyl)phenyl)ethanol (6) to furnish iodo isochromene
derivatives. The salient feature of the above two strategies involves formation of
corresponding heterocycles under metal free conditions in good yields.
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Introduction
An efficient and rapid construction of polyheterocyclic molecules from readily available
reactants in a one-pot format via domino1/cascade2 reactions remains a challenging task for
synthetic organic chemists. In particular, one-pot synthesis of nitrogen/oxygen containing
annulated polyheterocyles3 has drawn much attention due to their ubiquitous core structure,
present in a numerous biologically active natural products4 and pharmaceutically important
compounds.5 Among variety of O/N-heterocycles, triazoloisoquinolines6 and isochromenes7
are important classes of heteroaromatic compounds present in many bioactive natural
products,8 pharmaceuticals,9 and materials.10 Besides, structurally fused isoquinolines11
possess a broad spectrum of biological activities like anti fertility, anti-inflammatory activity,
CNS anti depressant6 anti tumor activity.12
In our laboratory, we have been interested in the development of new synthetic
strategies in a one pot format for the construction of nitrogen-containing fused heterocycles
from terminal/internal alkynes as one of the reactants.13 In this continuation, we next directed
our efforts on a one-pot transformation of a suitably derivatized bifunctionalized internal
alkyne such as 2-alkynylbenzaldehyde into O/N-heterocycles triazoloisoquinolines and
isochromenes (Figure 1). The 2-alkynylbenzaldehyde (1) has been extensively used as a
synthon by us13b,c and others14 for the synthesis of structurally diverse polyheterocycles in a
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one pot format. In particular, Verma et al14g demonstrated the potential of 1 by synthesizing
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several structurally diverse polyheterocycles both in non aqueous and aqueous solvents.
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Figure 1: 2-alkynylbenzaldehydes (1) as a versatile synthon in one-pot format.
The versatility of synthon 1 for the synthesis of 3, and 7 in a one-pot format can be
envisaged by their retrosynthetic analysis (Figure 2). It suggests that triazolo isoquinolines 3
can be obtained in a domino fashion from (E)-1-(2-nitrovinyl)-2-(alkynyl) benzene 2, which
in turn can be derived from 2-alkynylbenzaldehyde and nitro methane. The strategy is likely
to proceed via three new C-N bond formations resulting in the formation of two annulated
heterocyclic rings. Similarly, the isochromene derivatives 7 can be obtained via
iodocyclization of 6 which again can be obtained by treating 2-alkynylbenzaldehyde with
nitro methane. A careful survey of the literature revealed synthesis of isochromene from
synthon 1 employing Au as a catalyst,15 however, the reaction suffered from a drawback
involving poor regioselectivity as it was accompanied with the formation of an additional
byproduct 1,3-dihydroisobenzofurans (Figure 3).
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Figure 2: Retrosynthetic strategies for the synthesis of triazolo isoquinolines 3 and
isochromenes 7 from 2-alkynylbenzaldehyde 1.
Figure 3. Non regioselective synthesis of isochromene reported in the literature15 from 1
Results and Discussion
In the first instance, we investigated the reaction conditions for the condensation of 2-
alkynyl nitro olefin16 (2) (obtained from 2-alkynylbenzaldehyde) and sodium azide. We
envisaged that initially the nitro olefin may undergo aza Michael addition to form triazoles
which could be then followed by the intramolecular hydroamination involving N-H of
triazole and the internal alkyne present in its close proximity to furnish thermodynamically
stable annulated products. Accordingly, we treated 2a with sodium azide in the presence of
CuI at 100 °C in DMSO. The reaction was found to be complete within 30 min and after its
work up furnished a new regioselective product 3a in 85% isolated yield (Table 1, entry 1)
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Table 1. Optimization of the reaction conditiona for the synthesis of 3a.
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Entry
catalyst
Solvent
DMSO
temp °C
100
100
80
time (min)
yield (%)
85
1
2
3
4
5
6
7
8
9
CuI
30
30
-
-
-
-
DMSO
85
DMSO
40
78/b
62/b
72
DMSO
r.t
16(h)
40
DMF
100
90
DCE
40
N.R
N.R
53
-
-
-
H2O
100
90
45
CH3CN:H2O (9:1)
Toulene:H2O (9:1)
45
100
45
60
aReaction conditions: 2a (1.0 mmol), NaN3 (2.0 mmol) in 5 ml of DMSO. N.R = no reaction. b starting material.
with no detectable formation of regioisomers 4 and 5. The structure of resulting product was
elucidated by various NMR studies that led to its identification as triazolo isoquinoline 3a
(entry 1). Next, we performed the same reaction without any catalyst and maintained the
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thermal condition (100 °C) constant and to our delight within 30 minutes we obtained 3a
(entry 2) in 85% isolated yield. Carrying out reaction at reduced temperature at 80 °C or at
room temperature not only made the reaction sluggish but furnished products in reduced
yields with recovery of unchanged 2a (entries 3 and 4). Switching solvents from DMSO to
DMF afforded 3a in diminished yields with no reaction being observed in DCE and water
(entries 5, 6 and 7). On the other hand, carrying out reaction in a mixture of toulene:H2O and
CH3CN:H2O (9:1) in order to facilitate solubility of NaN3, produced 3a in 53% (entry 8) and
60% (entry 9) isolated yield respectively.
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Figure 4. Plausible mechanism for the formation of 3a from 2a
A plausible mechanism (Figure 4) for the formation of 3a may involve an aza Michael
addition of sodium azide with 2a to afford an azide appended intermediate I, which may then
transform into a triazole intermediate II. Next, the II undergoes aromatization via extrusion
of HNO2 to afford a N-H triazole containing intermediate III.17 Latter upon tautomerisation
may give IV followed by intramolecular hydroamination via 6-endo-dig cyclization to
furnish the final product 3a. To the best of our knowledge, reports dealing with the formation
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of intramolecular C-N bond formation on to the alkyne via in situ hydroamination under the
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transition-metal free condition are scarce.18
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Scheme 1. Synthesis of triazolo isoquinoline derivatives 3a-p.a
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aReaction condition: 2a (1.0 mmol), NaN3 (1.5 mmol) in 5 ml of DMSO.
Once we had the optimized reaction condition in hand for the synthesis of 3a, we then
embarked to examine the scope and limitation of substrates. The R1 in the aromatic ring of
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the 2-alkynyl nitro olefin synthon 2 has been substituted with 5-methoxy, 4, 5-dimethoxy and
5-fluro groups whereas R2 in the alkyne included both aliphatic, aromatic (with electron
donating groups) and trimethylsilyl moieties. It is interesting to note that in all cases products
were obtained with minimal variation in isolated yields (Scheme 1; 70-88%). However,
replacing R2 in the alkyne with either aliphatic moiety or H afforded 3m-o in slightly reduced
isolated yields (70-78%). Further, it has been observed that when R2 in the alkyne is replaced
by an electron-withdrawing group such as 4-fluoro, formation of the corresponding product
3p was obtained in 72% isolated yield. In contrast, replacing R2 with a relatively strong
electron withdrawing group such as 4-cyano, formation of the corresponding desired product
3q was not observed.
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Encouraged by the potential of 2-alkynylbenzaldehyde 1 as a synthon to furnish
annulated polyheterocycles, we next examined its versatility by converting it into yet another
nitro derivative 2-nitro-1-(2-(phenylethynyl)phenyl)ethanol 6.19 We envisioned that the
hydroxyl group and the internal alkyne moiety present in 6 can be subjected to electrophilic
O-cyclization to afford yet another biologically demanding structure isochromenes. Although
many groups have synthesized isochromes7b/analogues structures either by metal
catalysed20,15 / metal free7b,21 conditions with various substrates, we followed a alternative
approach to accomplish the isochromene via electophilic iodo-cyclization. Over the past few
years, molecular iodine has become a major tool for synthesizing various class of
heterocycles of biological significance via electrophilic cyclization,22 C-H activation,23
decarboxylation24 cycloaddition reactions25 and in multicomponent reactions.12c,26 Moreover,
iodocyclization generally leaves an iodine functionality attached to the product, that can be
further modified using palladium-catalyzed coupling reactions.
Accordingly, we commenced our reaction by treating 1.0 mmol of 6a with 3.0 mmol of
each I2 and NaHCO3 and after 12 h stirring from 0 °C to rt, we were delighted to observe a
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new product in 68% isolated yield (Table 2, entry 1). The resulting product was characterized
by various NMR techniques and found it to be regioselective iodo-derivative of isochromene
7a. Next, in an attempt to improve the yield, we screened various solvents like DCM and
THF and bases such as Na2CO3 and K2CO3. However, none of the changes could improve the
yield of the final product (entries 2-5). Next, we changed the iodine source to ICl, which
Table 2. Optimization of reaction conditions for the synthesis of isochromene derivativesa.
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yield
entry
catalyst
base
solvent
7a/8a (%)
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2
3
4
5
6
I2
I2
NaHCO3
NaHCO3
NaHCO3
K2CO3
CH3CN
DCM
68/n.d
62/n.d
58/n.d
60/n.d
62/n.d
I2
THF
I2
CH3CN
CH3CN
CH3CN
I2
Na2CO3
NaHCO3
b
ICl
-
aReaction conditions: 6 (1.0 mmol), I2 (3.0 mmol) and NaHCO3 (3.0 mmol) in acetonitrile under N2. bUn
separetable mixtures. n.d = Not detected.
resulted an unseparatable mixtures (entry 6). With the optimized conditions in hand, we then
investigated the scope of the reaction with respect to substitution on the phenyl rings and
results have been summarized in Scheme 2. As is evident, the R1 in the aromatic ring of the
synthon (6) has been substituted with 5-methoxy, and 5-fluro groups, whereas R2 in the
alkyne included both aliphatic (1-cyclohexene) and aromatic furnished corresponding
products with minimal variation in isolated yield (62-70%). It is noteworthy, that the reaction
was not went fruitful with other aliphatic alkyl moieties such as hex-1-yne, and trimethyl
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Scheme 2. Synthesis of isochromene derivatives via electrophilic iodo cyclization (7a-7j).
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9
OH
O2N
R1
R1
NO2
R2
I2
NaHCO3
O
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CH3CN
0o-rt
10-12 hr
R2
I
6a-j
7a-j
R1= H, 5-OMe, 5-Fluro
R2 = C6H5, C6H9,
C6H13, 4-Me-C6H4
NO2
NO2
NO2
O
O
O
I
I
I
7a,
(68%)
7c,
(70%)
7b,
(68%)
NO2
NO2
O
NO2
O
O
O
O
O
I
7d,
I
I
(65%)
NO2
O
7e, (68%)
7f, (68%)
NO2
NO2
F
O
O
O
I
I
I
7g,
(66%)
NO2
7i, (63%)
7h, (62%)
NO2
O
NO2
O
F
O
Si
(0%)
I
I
I
7l,
7j,
(70%)
7k,
(0%)
Reaction conditions: 6a (1.0 mmol), I2 (3.0 mmol), NaHCO3 (3.0 mmol) in 5 ml of CH3CN under N2.
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sillyl. A plausible mechanism for the formation of 6a may first involve the formation of
iodonium complex V with the internal alkyne 6a. This is then followed by the attack of
concomitant nucleophile on to the complex to afforded 7a.
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Figure 5: A Plausible mechanism for the formation of isochromene from 6a
In conclusion, we have developed an efficient methodology to construct two
biologically important scaffolds i.e. triazoloisoquinolines, and isochromene derivatives from
a single and readily available synthon 2-alkynylbenzaldehyde under transition metal free
domino process. Further studies are in progress to expand the potential application of synthon
to the synthesis of other annulated polyheterocycles and the results will be published
elsewhere.
Experimental
I General Information and methods. All reagents and solvents were purchased from
commercial sources and used without purification. NMR spectra were recorded with 300 and
1
13
400 MHz spectrometers for H NMR 75 and 100 MHz for C NMR. Chemical shifts δ are
given in ppm relative to the residual signals of tetramethylsilane in CDCl3 or deuterated
solvent CDCl3/DMSO-d6 for 1H and 13C NMR. Multiplicities are reported as follows: singlet
(s), doublet (d), doublet of doublets (dd), triplet (t), broad singlet (bs), multiplet (m). High
resolution mass spectra were taken with a mass spectrometer. Column chromatography was
performed using silica gel (100-200 mesh) as the stationary phase. All reactions were
monitored by thin layer chromatography (TLC). The purity and characterization of these
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compounds were further established using HR/ESI Mass spectroscopy and UV detection at
220/254 nm. Melting points were measured on a capillary melting point apparatus and are
uncorrected.
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II: General Procedure for Synthesis of (E)-1-(2-nitrovinyl)-2-(phenylethynyl) (2a-2o)
The titled compound 2a was prepared according to the literature procedure.16 A solution of 1a
(1g, 4.85mmol, 1equiv.) and ammonium acetate (373mg, 5.82 mmol, 1.0 equiv.) in dry
nitromethane (5.0 mL) was stirred at 110 °C for 1h. After completion of the reaction by TLC
analysis, the temperature of the reaction mixture was allowed to come at rt followed by
addition of 10 ml of water. The aqueous layer was extracted with EtOAc, (3x20 ml) and the
combined organic layers were washed with water and brine, dried over Na2SO4 and
concentrated under reduced pressure. The crude reaction mixture was purified by column
chromatography (EtOAc:hexanes = 10%) to afford the product 2a (1.027g, 85%).
In some cases we noticed formation of isomers (E/Z) (2b, 2e, 2n), we proceeded with the
mixture for final product synthesis.
Compounds 2a, 2c, 2k, 2j, 2p were matching well with the reported data13.
(E)-1-((4-tert-butylphenyl)ethynyl)-2-(2-nitrovinyl)benzene. (2b)
Yellow solid; Rf = 0.5 (10% ethyl acetate/hexanes); (258 mg, 74%) (isomers formed in 1:0.23
ratio based on NMR analysis.); mp 98-100 °C; FT-IR (KBr) 3402, 3021, 2965, 761 cm-1; 1H
NMR (300 MHz, CDCl3): δ 8.54 (d, J = 12.0 Hz, 1H), 7.82 (d, J = 16.0 Hz, 1H), 7.67-7.64
(m, 1H), 7.62-7.59 (m, 1H), 7.57-7.52 (m, 2H), 7.47-7.38 (m, 3H + 1H of isomer), 7.36-7.33
(m, 1H), 1.34 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3): δ 152.6, 138.2, 137.2, 133.3, 131.5,
131.2, 128.6, 128.0, 125.7, 125.5, 119.3, 97.4, 86.0, 34.9, 31.2 ppm; HRMS (ESI) calcd for
C20H20NO2 [M + H] 306.1494 found 306.1489.
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(E)-4-methoxy-2-(2-nitrovinyl)-1-(p-tolylethynyl)benzene. (2d)
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Yellow solid; Rf = 0.5 (10% ethyl acetate/hexanes); (228 mg, 78%); mp 75-77 °C; FT-IR
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(KBr) 3400, 3021, 2929, 2401, 1291 cm-1; H NMR (300 MHz, CDCl3): δ 8.48 (d, J = 12.0
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Hz, 1H), 7.78 (d, J = 12.0 Hz, 1H), 7.55-7.53 (m, 1H), 7.46-7.44 (m, 2H), 7.20-7.17 (m, 2H),
7.03-6.98 (m, 2H), 3.85 (s, 3H), 2.38 (s, 3H) ppm; 13C NMR (100 MHz,CDCl3): δ 159.5,
139.1, 138.4, 137.3, 134.6, 132.4, 131.4, 129.3, 119.6, 118.0, 112.6, 95.8, 85.9, 55.6, 21.6
ppm; HRMS (ESI) calcd for C18H16NO3 [M + H] 294.1130 found 294.1126.
(E)-1-((4-tert-butylphenyl)ethynyl)-4-methoxy-2-(2-nitrovinyl)benzene. (2e)
Yellow solid; Rf = 0.40 (10 % ethyl acetate/hexanes); (234 mg, 68%); (isomers formed in
1:0.3 ratio based on 1H NMR analysis.) mp 98-100 °C; FT-IR (KBr): 3970, 3778, 3401, 670
1
cm-1; H NMR (300 MHz, CDCl3): δ 8.49 (d, J = 16.0 Hz, 1H), 7.79 (d, J = 20.0 Hz, 1H),
7.56-7.49 (m, 4H for both isomers), 7.41-7.39 (m, 2H), 7.04-7.00 (m, 2H), 3.86 (s, 3H ), 3.83
(s, 1H of isomer), 1.33 (s, 9H) ppm; 13C NMR (75 MHz,CDCl3): δ 159.5, 152.2, 138.4,
137.3, 134.6, 132.5, 131.3, 125.6, 119.6, 119.2, 118.0, 112.6, 95.8, 85.9, 55.7, 55.6, 34.9,
31.2 ppm; HRMS (ESI) calcd for C21H22NO3 [M + H] 336.1600 found 336.1591.
(E)-4-methoxy-2-(2-nitrovinyl)-1-(phenylethynyl)benzene. (2f)
Yellow solid; Rf = 0.50 (10% ethyl acetate/hexanes); (126 mg, 66%); mp 88-90 °C; FT-IR
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(KBr) 3776, 3407, 3019, 1293 cm-1; H NMR (300 MHz, CDCl3): δ 8.50 (d, J = 15.0 Hz,
1H), 7.78 (d, J = 15.0 Hz, 1H), 7.57-7.55 (m, 3H), 7.39-7.33 (m, 3H), 7.05-7.00 (m, 2H),
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3.87 (s, 3H) ppm; C NMR (100 MHz, CDCl3): δ 159.7, 138.5, 137.2, 134.7, 132.6, 131.5,
128.8, 128.6, 122.7, 118.0, 117.7, 113.5, 112.6, 95.5, 86.5, 55.6 ppm; HRMS (ESI) calcd for
C17H14NO3 [M + H] 280.0974 found 280.0970.
(E)-4-methoxy-1-((4-methoxyphenyl)ethynyl)-2-(2-nitrovinyl)benzene. (2g)
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Yellow solid; Rf = 0.45 (10% ethyl acetate/hexanes); (203 mg 70%); mp 92-94 °C; FT-IR
(KBr) 3402, 3021, 2401, 670 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.49 (d, J = 16.0 Hz, 1H),
7.79 (d, J = 20.0 Hz, 1H), 7.55-7.50 (m, 3H), 7.04-6.99 (m, 2H), 6.98-6.89 (m, 2H) 3.86 (s,
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3H), 3.84 (s, 3H) ppm; C NMR (100 MHz, CDCl3): δ 160.1, 159.4, 138.4, 137.4, 134.5,
133.0, 132.3, 118.2, 118.0, 114.8, 114.3, 112.5, 95.7, 85.4, 55.6, 55.4 ppm; HRMS (ESI)
calcd for C18H16NO4 [ M +H] 310.1079 found 310.1071.
(E)-1,2-dimethoxy-4-(2-nitrovinyl)-5-(p-tolylethynyl)benzene. (2h)
Yellow solid; Rf = 0.45 (10% ethyl acetate/hexanes); (263 mg, 76%); mp 96-98 °C; FT-IR
(KBr) 3772, 3682, 3405, 2400, 1333 cm-1; H NMR (300 MHz, CDCl3): δ 8.54 (d, J = 12.0
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Hz, 1H), 7.74 (d, J = 12.0 Hz, 1H), 7.50-7.48 (m, 2H), 7.21-7.19 (m, 2H), 7.07-6.98 (m, 2H)
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3.97 (s, 3H), 3.95 (s, 3H), 2.39 (s, 3H) ppm; C NMR (100 MHz, CDCl3): δ 152.2, 149.6,
139.3, 137.4, 136.3, 131.5, 129.4, 124.4, 120.0, 119.4, 114.8, 109.2, 96.3, 85.9, 56.3, 56.1,
21.6 ppm; HRMS (ESI) calcd for C19H18NO4 [M + H] 324.1236 found 324.1228.
(E)-1,2-dimethoxy-4-(2-nitrovinyl)-5-(phenylethynyl)benzene. (2i)
Yellow solid; Rf = 0.42 (10% ethyl acetate/hexanes); (220 mg, 76%); mp 94-96 °C; FT-IR
(KBr) 3403, 3022, 2401, 1629, 759 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.54 (d, J = 15.0 Hz,
1H), 7.72 (d, J = 15.0 Hz, 1H), 7.60-7.59 (m, 2H), 7.40 (m, 3H), 7.08-7.00 (m, 2H), 3.97 (s,
3H), 3.95 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 152.2, 149.7, 137.3, 136.4, 131.6,
129.0, 128.6, 124.5, 122.4, 119.8, 114.8, 109.0, 96.0, 86.4, 56.3, 56.2 ppm; HRMS (ESI)
calcd for C18H16NO4 [M + H] 310.1079 found 310.1068.
(E)-1-((4-tert-butylphenyl)ethynyl)-4-fluoro-2-(2-nitrovinyl)benzene. (2l)
Yellow solid; Rf = 0.48 (10% ethyl acetate/hexanes); (242 mg, 78%); mp 93-95 °C; FT-IR
(KBr) 3404, 3021, 2966, 1215 cm-1; H NMR (300 MHz, CDCl3): δ 8.48 (d, J = 15.0 Hz,
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1H), 7.75 (d, J = 12.0 Hz, 1H), 7.64-7.60 (m, 1H), 7.53-7.50 (m, 2H), 7.43-7.40 (m, 2H),
7.28-7.25 (m, 1H), 7.24-7.14 (m, 1H), 1.34 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3): δ
163.7, 160.4, 152.7, 139.1, 136.2, 135.2, 135.0, 133.2 (d, J = 16.5 Hz), 131.4, 125.7 (d, J =
9.0 Hz), 121.8 (d, J = 6.0 Hz), 119.2 (d, J = 22.5 Hz), 119.0, 114.3 (d, J = 46.5 Hz), 97.1,
84.9, 35.0, 31.2 ppm; HRMS (ESI) calcd for C20H19FNO2 [M + H] 324.1400 found 324.1394.
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(E)-1-(cyclohexenylethynyl)-4-fluoro-2-(2-nitrovinyl)benzene. (2m)
Yellow solid; Rf = 0.55 (10% ethyl acetate/hexanes); (222 mg, 75%); mp 78-80 °C; FT-IR
(KBr) 3740, 2823, 1508, 1201, 638 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.42 (d, J = 15.0 Hz,
1H), 7.56 (d, J = 6.0 Hz, 1H), 7.29-7.25 (m, 1H), 7.20-7.18 (m, 1H), 7.17-7.11 (m, 1H), 6.38-
6.30 (m, 1H), 2.33-2.26 (m, 4H), 1.90-1.80 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3): δ
163.4, 160.1, 138.9, 136.7 (d, J = 132.0 Hz), 134.9 (d, J = 16.5 Hz), 132.9 (d, J = 15.0 Hz),
122.1, 120.1, 118.9 (d, J = 43.5 Hz), 114.3 (d, J = 46.5 Hz), 96.9, 83.1, 28.9, 25.9, 22.2, 21.4
ppm; HRMS (ESI) calcd for C16H15FNO2 [M + H] 272.1087 found 272.1082.
(E)-1-(hex-1-ynyl)-2-(2-nitrovinyl)benzene. (2n)
Yellow Oil; Rf = 0.58 (10% ethyl acetate/hexanes); (167 mg, 68%); (compound formed in
1:0.3 ratio); FT-IR (Neat) 3403, 3021, 2964, 2401, 760 cm-1; 1H NMR (300 MHz, CDCl3): δ
8.46 (d, J = 16.0 Hz, 1H), 7.74 (d, J = 16.0 Hz, 1H), 7.55-7.49 (m, 3H for both isomers ),
7.41-7.32 (m, 3H for both isomers), 2.54-2.50 (m, 2H), 1.68-1.50 (m, 4H), 1.00-0.96 (m, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 138.0, 137.5, 133.4, 131.4, 131.2, 128.1, 127.6, 126.3,
98.9, 30.6, 22.1, 19.4, 13.6 ppm; HRMS (ESI) calcd for C14H16NO2 [M + H] 230.1181 found
230.1171.
(E)-trimethyl((2-(2-nitrovinyl)phenyl)ethynyl)silane. (2o)
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White solid; Rf = 0.6 (10% ethyl acetate/hexanes); (157 mg, 65%); mp 68-70 °C; FT-IR
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(KBr) 3404, 3021, 2401, 1634 cm-1; H NMR (300 MHz, CDCl3): δ 8.44 (d, J = 12.0 Hz,
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1H), 7.82 (d, J = 12.0 Hz, 1H), 7.58-7.54 (m, 3H), 7.40-7.38 (m, 1H), 0.31 (s, 9H) ppm; C
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NMR (100 MHz, CDCl3): δ 138.5, 137.2, 133.8, 131.4, 129.1, 128.0, 125.0, 103.3, 102.0, -
0.17 ppm; HRMS (ESI) calcd for C13H16NO2Si [M + H] 246.0950 found 246.0947.
(E)-4-((2-(2-nitrovinyl)phenyl)ethynyl)benzonitrile. (2q)
Yellow solid; Rf = 0.50 (10% ethyl acetate/hexanes); (231 mg, 65%); mp 88-90 °C; FT-IR
(KBr) 3404, 3021, 2220, 1550 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.54 (d, J = 6.8 Hz, 1H),
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7.78 (d, J = 6.0 Hz, 1H), 7.71-7.65 (m, 6H), 7.55-7.46 (m, 2H) ppm; C NMR (100 MHz,
CDCl3): δ 138.7, 136.8, 133.7, 132.4, 132.3, 131.8, 129.9, 127.8, 124.3, 118.4, 112.6, 94.9,
90.5 ppm; HRMS (ESI) calcd for C17H11N2O2 [M + H] 275.0821 found 275.0852.
III: General Procedure for the Preparation of intermediates.15 (6a-6i)
To a stir bar-equipped flame-dried 50 mL round bottom flask containing a stirring mixture of
2-alkynylbenzaldehyde 1 (1.00 g, 4.854 mmol), nitromethane (0.592mL, 9.708 mmol, 2
equiv), and ethanol (10 mL) in an ice water bath was added a solution of KOH (0.289 g,
5.365 mmol, 1.1 equiv) in anhydrous ethanol (10 ml), dropwise. After stirring for 1 hour the
reaction mixture was quenched with AcOH (3.0 ml) and water (20 ml) and extracted with
EtOAc (3 × 20 ml). The combined organic layers were dried over Na2SO4 and concentrated
to afford an oil. The crude product was taken up in a small amount of CH2Cl2 and added to
silica gel, and the mixture was evaporated to dryness. The resulting powder was purified by
column chromatography with elluent (20 % EtOAc: hexanes ) to give the product.
1-{2-[2-(4-methylphenyl)ethynyl]phenyl}-2-nitroethan-1-ol. (6a)
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Yellow solid: Rf = 0.35 (1:5 ethyl acetate/hexanes); (530 mg, 83%); mp (125-127 oC); FT-IR
(KBr) 3778, 3399, 3015, 2402, 1215 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.54-7.53 (m, 1H),
7.52-7.44 (m, 1H), 7.42-7.40 (m, 2H) 7.35-7.33 (m, 1H), 7.32-7.31 (m, 1H), 7.19-7.17 (m,
2H), 6.02-6.00 (m, 1H), 4.83-4.80 (m, 1H), 4.55-4.50 (m, 1H), 3.04 (bs, 1H), 2.83 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 139.5, 139.3, 132.3, 131.6, 129.4, 129.0, 128.5, 128.5,
120.1, 119.3, 96.7, 85.0, 80.4, 69.7, 21.6 ppm; HRMS (ESI) calcd for C17H16NO3 [M + H]
282.1130 found 282.1125.
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1-(2-{2-[4-(tert-butyl)phenyl]ethynyl}phenyl)-2-nitroethan-1-ol. (6b)
Yellow oil; Rf = 0.35 (1:5 ethyl acetate/hexanes); (542 mg, 88%); FT-IR (Neat) 3778, 3683,
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3403, 3020, 2965, 1216 cm-1; H NMR (400 MHz, CDCl3): δ 7.65-7.63 (m, 1H), 7.55-7.53
(m, 1H), 7.50-7.48 (m, 2H) 7.41-7.33 (m, 3H), 7.25 (s, 1H), 6.02-6.00 (m, 1H), 4.83-4.80 (m,
1H), 4.55-4.52 (m, 1H), 2.98-2.97 (m, 1H), 1.32 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3):
δ 152.5, 139.6, 132.3, 131.4, 129.0, 128.5, 121.0, 119.3, 96.7, 85.0, 80.4, 69.7, 35.0, 31.2
ppm; HRMS (ESI) calcd for C20H22NO3 [M + H] 324.1600 found 324.1597.
2-nitro-1-[2-(2-phenylethynyl)phenyl]ethan-1-ol. (6c)
Yellow oil; Rf = 0.41 (1:5 ethyl acetate/hexanes); (466 mg, 72%); FT-IR (Neat) 3402, 3021,
1555, 1216 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.66-7.56 (m, 1H), 7.55-7.54 (m, 3H), 7.43-
7.39 (m, 1H), 7.39-7.31 (m, 4H), 6.03-6.00 (m, 1H), 4.88-4.83 (m, 1H), 4.55-4.49 (m, 1H),
2.87 (bs, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 139.6, 132.3, 131.6, 129.1, 129.0, 128.9,
128.6, 125.7, 122.3, 120.6, 96.4, 85.5, 80.4, 69.6 ppm; HRMS (ESI) calcd for C16H14NO3 [M
+ H] 268.0974 found 268.0971.
1-(5-methoxy-2-((4-methylphenyl)ethynyl)phenyl)-2-nitroethanol.(6d)
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Yellow solid; Rf = 0.35 (1:5 ethyl acetate/hexanes); (528 mg, 85%); m.pt 98-100 C; FT-IR
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(KBr) 3710, 3548, 3403, 3020, 2965, 1216 cm-1; H NMR (400 MHz, CDCl3): δ 7.45-7.40
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(m, 3H), 7.18-7.14 (m, 3H), 6.85-6.82 (m, 1H), 5.95-5.92 (m, 1H), 4.83-4.80 (m, 1H), 4.51-
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4.45 (m, 1H), 3.82 (s, 3H), 3.08 (bs, 1H), 2.35 (s, 3H) ppm; C NMR (100 MHz, CDCl3): δ
160.2, 141.5, 138.8, 133.7, 131.3, 129.3, 119.6, 114.4, 112.8, 111.2, 95.2, 85.2, 80.3, 69.7,
55.5, 21.6 ppm; HRMS (ESI) calcd for C18H18NO4 [M + H] 312.1236 found 312.1225
1-[5-methoxy-2-(2-phenylethynyl)phenyl]-2-nitroethan-1-ol. (6e)
Yellow oil; Rf = 0.38 (1:5 ethyl acetate/hexanes); (503 mg, 80%); FT-IR (Neat) 3402, 3021,
2965, 1500 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.56-7.55 (m, 2H), 7.54-7.40 (m, 1H) 7.39-
7.37 (m, 3H), 7.28-7.23 (m, 1H), 6.90-6.88 (m, 1H), 6.02-6.00 (m, 1H), 4.88-4.84 (m, 1H),
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4.57-4.51 (m, 1H), 3.88 (s, 3H), 3.06 (bs, 1H) ppm; C NMR (100 MHz, CDCl3): δ 160.3,
141.5, 133.8, 131.4, 128.6, 122.7, 114.4, 112.5, 111.2, 95.0, 85.6, 80.3, 69.6, 55.5 ppm;
HRMS (ESI) calcd for C17H16NO4 [M + H] 298.1079 found 298.1071.
1-(2-{2-[4-(tert-butyl)phenyl]ethynyl}-5-methoxyphenyl)-2-nitroethan-1-ol. (6f)
Colourless oil; Rf = 0.38 (1:5 ethyl acetate/hexanes); (471 mg, 78%); FT-IR (Neat) 3777,
3403, 3020, 1216 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.51-7.46 (m, 3H), 7.45-7.37 (m, 2H)
7.25-7.19 (m, 1H), 6.87-6.84 (m, 1H), 5.98-5.96 (m, 1H), 4.85-4.82 (m, 1H), 4.55-4.48 (m,
13
1H), 3.85 (s, 3H), 2.98 (bs, 1H), 1.32 (s, 9H) ppm; C NMR (100 MHz, CDCl3): δ 160.2,
152.0, 141.3, 139.7, 131.1, 125.5, 119.6, 114.3, 112.7, 111.2, 95.2, 84.9, 80.2, 69.6, 55.5,
34.8, 31.1 ppm; HRMS (ESI) calcd for C21H24NO4 [M + H] 354.1705 found 354.1697.
1-(2-{2-[4-(tert-butyl)phenyl]ethynyl}-5-fluorophenyl)-2-nitroethan-1-ol. (6g)
Yellow oil; Rf = 0.40 (1:5 ethyl acetate/hexanes); (487 mg, 80%); FT-IR (Neat) 3776, 3681,
3401, 1521, 1343 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.54-7.53 (m, 1H), 7.52-7.50 (m, 2H),
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1H), 3.01 (bs, 1H), 1.33 (s, 9H) ppm; C NMR (100 MHz, CDCl3): δ 164.2, 161.7, 152.5,
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142.4 (d, J = 12.0 Hz), 134.2 (d, J = 12.0 Hz), 125.7, 119.2, 116.8, 115.8 (d, J = 33.0 Hz)
113.5 (d, J = 36.0 Hz), 96.4, 84.1, 80.1, 69.3, 35.0, 31.2 ppm; HRMS (ESI) calcd for
C20H21FNO3 [M + H] 342.1505 found 342.1526.
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1-[2-(2-cyclohex-1-en-1-ylethynyl)-5-methoxyphenyl]-2-nitroethan-1-ol. (6h)
Colourless oil; Rf = 0.38 (1:5 ethyl acetate/hexanes); (476 mg, 76%); FT-IR (Neat) 3776,
3656, 1560, 1047 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.36-7.34 (m, 1H), 7.15-7.14 (m, 1H),
6.82-6.79 (m, 1H), 6.22-6.20 (m, 1H), 5.83-5.81 (m, 1H), 4.78-4.73 (m, 1H), 4.50-4.43 (m,
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1H), 3.82 (s, 3H), 3.00 (bs, 1H), 2.20-2.14 (m, 4H), 1.70-1.60 (m, 4H) ppm; C NMR (100
MHz, CDCl3): δ 160.0, 141.1, 135.7, 133.6, 120.4, 114.3, 113.1, 111.2, 97.0, 83.0, 80.2, 69.6,
55.5, 29.1, 25.9, 22.3, 21.5 ppm; HRMS (ESI) calcd for C17H20NO4 [M + H] 302.1392 found
302.1386
1-(2-(2-cyclohex-1-en-1-ylethynyl)phenyl)-2-nitroethanol (6i).
Colourless oil; Rf = 0.5 (1:5 ethyl acetate/hexanes); (465 mg, 72%); FT-IR (Neat) 3763, 3562,
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1260, 1043 cm-1; H NMR (3400 MHz, CDCl3): δ 7.53-7.50 (m, 1H), 7.36-7.35 (m, 1H),
7.34-7.28 (m, 1H), 7.23-7.18 (m, 1H), 6.20-6.19 (m, 1H), 5.80-5.78 (m, 1H), 4.68-4.65 (m,
1H), 4.44-4.39 (m, 1H), 2.92 (bs, 1H), 2.15-2.20 (m, 4H), 1.62-1.54 (m, 4H) ppm; 13C NMR
(100 MHz, CDCl3): δ 139.3, 136.7, 132.2, 128.6, 125.7, 121.2, 120.3, 98.5, 83.1, 69.7, 29.1,
25.9, 22.3, 21.5 ppm; HRMS (ESI) calcd for C16H17NO3: [M + H] 271.1208 found 271.1213
1-(5-fluoro-2-(4-methylphenylethynyl)phenyl)-2-nitroethanol (6j)
Yellow solid; Rf = 0.42 (1:5 ethyl acetate/hexanes); (500 mg, 80%); m.pt 108-110 oC; FT-IR
(KBr) 3770, 3652, 1521, 1343 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.45-7.43 (m, 1H), 7.42-
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7.36 (m, 2H), 7.33-7.30 (m, 2H), 7.10-7.09 (m, 1H), 7.00-6.93 (m, 1H),5.90-5.88 (m, 1H),
4.78-4.74 (m, 1H), 4.43-4.37 (m, 1H), 3.00 (bs, 1H), 2.30 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 164.1, 161.6, 142.3 (d, J = 14.0 Hz), 139.4, 134.1 (d, J = 16 Hz), 129.4, 119.
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1, 116.7 (d, J = 6.0 Hz), 115.7 (d, J = 44.0 Hz), 113.4 (d, J = 48.0 Hz), 96.4, 84.1, 80.0, 69.2,
21.6 ppm; HRMS (ESI) calcd for C17H15FNO3: 300.1036 [M + H] found 300.1045
IV: Typical Procedure for the Preparation of final products (3a-3p).
To a stir bar-equipped flame-dried 50 mL round bottom flask containing a stirring mixture of
(E)-1-(2-nitrovinyl)-2-(phenylethynyl)benzene 2a (250 mg, 1.0 mmol) in DMSO (5 ml) was
added sodium azide (97 mg, 1.5 mmol). After stirring for 0.5 hour, the temperature of the
reaction mixture was brought to rt and diluted with water (10 ml) the aqueous layer was
extracted with EtOAc (3 × 20 ml). The combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure. The crude product was purified on a 100-200 mesh
column (30:70 EtOAc:hexanes) to give the product.
5-phenyl[1,2,3]triazolo[5,1-a]isoquinoline. (3a)
White solid; Rf = 0.43 (1:5 ethyl acetate/hexanes); (216 mg, 88%); mp 166-168 °C; FT-IR
(KBr) 3776, 3681, 3408, 2400, 1215 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.44 (s, 1H), 8.10-
8.08 (m, 1H), 7.91-7.90 (m, 2H), 7.75-7.73 (m, 1H) 7.58-7.56 (m, 2H), 7.55-7.17 (m, 3H),
13
7.16 (s, 1H) ppm; C NMR (75 MHz, CDCl3): δ 136.1, 133.4, 132.2, 129.9, 129.7, 129.4,
129.2, 128.6, 127.5, 126.1, 123.9, 122.3, 115.6 ppm; HRMS (ESI) calcd for C16H12N3 [M +
H] 246.1031found 246.1027.
5-[4-(tert-butyl)phenyl][1,2,3]triazolo[5,1-a]isoquinoline. (3b)
Brown solid; Rf = 0.40 (1:5 ethyl acetate/hexanes); (214 mg, 87%); mp 170-172 °C; FT-IR
(KBr) 3779, 3403, 3016, 2926, 1216 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.53 (s, 1H), 8.20-
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8.17 (m, 1H), 7.95-7.92 (m, 2H), 7.84-7.81 (m, 1H), 7.68-7.64 (m, 2H), 7.63-7.57 (m, 2H),
7.24 (s, 1H), 1.40 (s, 9H) ppm;13C NMR (75 MHz, CDCl3): δ 153.3, 136.3, 133.5, 129.9,
129.4, 129.2, 128.4, 127.5, 126.2, 126.0, 125.7, 124.0, 122.3, 115.3, 35.0, 31.3 ppm; HRMS
(ESI) calcd for C20H20N3 [M + H] 302.1657 found 302.1649.
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5-(4-methylphenyl)[1,2,3]triazolo[5,1-a]isoquinoline. (3c)
Brown solid; Rf = 0.41 (1:5 ethyl acetate/hexanes); (209 mg, 85%); mp 168-170 °C; FT-IR
(KBr) 3787, 3681, 3401, 3019, 1481 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 8.04 -
8.03 (m, 1H), 8.02-7.69 (m, 2H), 7.69-7.67 (m, 1H), 7.53-7.48 (m, 2H), 7.23-7.16 (m, 2H),
13
7.09 (s, 1H), 2.36 (s, 3H) ppm; C NMR (75 MHz, CDCl3): δ 140.1, 136.1, 129.7, 129.3,
129.1, 128.3, 127.4, 123.8, 122.2, 115.2, 21.5 ppm; HRMS (ESI) calcd for C17H14N3 [M + H]
260.1188 found 260.1182.
9-methoxy-5-(4-methylphenyl)[1,2,3]triazolo[5,1-a]isoquinoline. (3d)
Brown solid; Rf = 0.40 (1:5 ethyl acetate/hexanes); (197 mg, 80%); mp 166-168 °C; FT-IR
(KBr) 3402, 3131, 3009, 2842, 1616 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.48 (s, 1H), 7.87-
7.85 (m, 2H), 7.74-7.71 (m, 1H), 7.51 (s, 1H), 7.36-7.34 (m, 2H), 7.25 (s, 1H), 7.17 (s, 1H),
13
4.00 (s, 3H), 2.45 (s, 3H) ppm; C NMR (75 MHz, CDCl3): δ 160.7, 139.8, 129.6, 129.3,
129.3, 129.1, 124.0, 123.7, 119.0, 115.0, 105.2, 55.8, 21.5 ppm; HRMS (ESI) calcd for
C18H16N3O [M + H] 290.1293 found 290.1291.
5-[4-(tert-butyl)phenyl]-9-methoxy[1,2,3]triazolo[5,1-a]isoquinoline. (3e)
Brown solid; Rf = 0.40 (1:5 ethyl acetate/hexanes); (202 mg, 82%); mp 172-174 °C; FT-IR
(KBr) 3787, 3681, 3404, 2972, 1215 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.50 (s, 1H), 7.91
(d, J = 9.0 Hz, 2H), 7.74 (d, J = 9.0 Hz, 1H), 7.58-7.53 (m, 3H), 7.26 (s, 1H), 7.19 (s, 1H),
13
4.00 (s, 3H), 1.39 (s, 9H) ppm; C NMR (75 MHz, CDCl3): δ 159.6, 152.8, 133.9, 133.1,
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129.5, 129.0, 126.0, 125.5, 123.8, 118.9, 115.0, 105.1, 55.7, 34.8, 31.3 ppm; HRMS (ESI)
calcd for C21H22N3O [M+ H] 332.1763 found 332.1764.
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9-methoxy-5-phenyl[1,2,3]triazolo[5,1-a]isoquinoline. (3f)
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Brown solid; Rf = 0.42 (1:5 ethyl acetate/hexanes); (197 mg, 80%); mp 176-178 °C; FT-IR
(KBr) 3778, 2402, 1308, 670 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.51 (s, 1H), 7.99-7.96 (m,
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2H), 7.77-7.45 (m, 1H), 7.53 (s, 4H), 7.26-7.21 (m, 2H), 4.00 (s, 3H) ppm; C NMR (75
MHz, CDCl3): δ 159.6, 133.7, 133.0, 132.3, 129.6, 129.3, 129.0, 128.5, 126.0, 123.7, 123.6
118.9, 115.4, 105.0, 55.7 ppm; HRMS (ESI) calcd for C17H14N3O [M + H] 276.1137 found
276.1130.
9-methoxy-5-(4-methoxyphenyl)-[1,2,3]triazolo[5,1-a]isoquinoline. (3g)
White solid; Rf = 0.32 (1:5 ethyl acetate/hexanes); (185 mg, 75%); mp 184-186 °C; FT-IR
(KBr) 3787, 3681, 3405, 2400, 1181 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.50 (s, 1H), 7.93
(d, J= 9.0 Hz, 2H), 7.74 (d, J = 6.0 Hz, 1H), 7.52 (d, J = 3.0 Hz, 1H), 7.26 (s, 1H), 7.16 (s,
1H), 7.07 (d, J = 9.0 Hz, 2H), 4.00 (s, 3H), 3.90 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ
160.7, 159.6, 130.8, 129.0, 124.8, 124.0, 123.5, 119.0, 114.7, 114.0, 105.2, 55.8, 55.5 ppm;
HRMS (ESI) calcd for C18H16N3O2 [M + H] 306.1243 found 306.1235.
8,9-dimethoxy-5-(4-methylphenyl)[1,2,3]triazolo[5,1-a]isoquinoline. (3h)
Brown solid; Rf = 0.40 (1:5 ethyl acetate/hexanes); (190 mg, 77%); mp 178-180 °C; FT-IR
(KBr) 3787, 3405, 3019, 1216 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.87 (d, J =
6.0 Hz, 2H), 7.47 (s, 1H), 7.35 (d, J = 6.0 Hz, 2H), 7.16 (d, J = 12.0 Hz, 2H), 4.08 (s, 3H),
13
4.02 (s, 3H), 2.45 (s, 3H) ppm; C NMR (75 MHz, CDCl3): δ 150.8, 150.4, 139.7, 134.5,
133.1, 129.5, 129.2, 129.1, 124.7, 124.6, 116.6, 114.6, 107.6, 104.3, 56.3, 56.1, 21.4 ppm;
HRMS (ESI) calcd for C19H18N3O2 [M+ H] 320.1399 found 320.1394.
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8,9-dimethoxy-5-phenyl[1,2,3]triazolo[5,1-a]isoquinoline. (3i)
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White solid; Rf = 0.45 (1:5 ethyl acetate/hexanes); (197 mg, 72%); mp 180-182 °C; FT-IR
(KBr) 3777, 3683, 3614, 3020, 1506, 1216 cm-1; 1H NMR (300 MHz, CDCl3):δ 8.41 (s, 1H),
8.00-7.97 (m, 2H), 7.55-7.48 (m, 4H), 7.20-7.17 (m, 2H), 4.09 (s, 3H), 4.03 (s, 3H) ppm; 13C
NMR (75 MHz, CDCl3): δ 150.6 (d, J = 26.2 Hz), 134.2, 132.4, 129.5, 128.5, 124.5, 116.6,
115.0, 107.6, 104.2, 56.3, 56.1 ppm; HRMS (ESI) calcd for C18H16N3O2 [M + H] 306.1243
found 306.1236.
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9-fluoro-5-phenyl[1,2,3]triazolo[5,1-a]isoquinoline. (3j)
Brown solid; Rf = 0.44 (1:5 ethyl acetate/hexanes); (197 mg, 80%); mp 168-170 °C; FT-IR
(KBr) 3776, 3681, 3400, 3019, 2400 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.52 (s, 1H), 7.98-
7.96 (m, 2H), 7.86-7.82 (m, 2H), 7.57-7.55 (m, 3H), 7.42-7.36 (m, 1H), 7.24 (s, 1H) ppm; 13C
NMR (75 MHz, CDCl3): δ 163.9, 160.5, 132.0, 130.1, 129.9, 129.4, 128.7, 126.4, 118.1 (d, J
= 46.5 Hz) 115.0, 109.6 (d, J = 46.5 Hz) ppm; HRMS (ESI) calcd for C16H11FN3 [M + H]
264.0937 found 264.0934.
9-fluoro-5-(4-methylphenyl)[1,2,3]triazolo[5,1-a]isoquinoline. (3k)
Brown solid; Rf= 0.40 (1:5 ethyl acetate/hexanes); (202 mg, 82%); mp 172-174 °C; FT-IR
(KBr) 3776, 3679, 3019, 757 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.45 (s, 1H), 7.88-7.80 (m,
4H), 7.37-7.35 (m, 3H), 7.20 (s, 1H), 2.46 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 163.8,
160.4, 140.3, 135.7, 130.0, 129.8, 129.4, 129.3, 129.2, 126.5, 123.7 (d, J = 19.5 Hz), 123.6,
118.0 (d, J = 46.5 Hz), 114.5, 109.5 (d, J = 46.5 Hz), 21.5 ppm; HRMS (ESI) calcd for
C17H13FN3 [M + H] 278.1094 found 278.1088.
5-[4-(tert-butyl)phenyl]-9-fluoro[1,2,3]triazolo[5,1-a]isoquinoline. (3l)
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Brown solid; Rf= 0.42 (1:5 ethyl acetate/hexanes); (192 mg, 78%); mp 176-178 °C; FT-IR
(KBr) 3855, 3787, 3681, 3658, 1417 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 7.92-
7.83 (m, 2H), 7.82-7.80 (m, 2H), 7.58 (d, J = 9.0 Hz, 2H), 7.40-7.35 (m, 1H), 7.22 (s, 1H),
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1.39 (s, 9H) ppm; C NMR (75 MHz, CDCl3): δ 163.7, 160.4, 153.3, 135.7, 135.7, 132.9,
132.8, 130.0, 129.8, 129.1, 126.6, 126.5, 125.7, 123.7 (d, J = 19.5 Hz), 118.2 (d, J = 46.5
Hz), 114.6, 109.5 (d, J = 45 0 Hz), 34.9, 31.3 ppm; HRMS (ESI) calcd for C20H19FN3 [M +
H] 320.1563 found 320.1570.
5-cyclohex-1-en-1-yl-9-fluoro[1,2,3]triazolo[5,1-a]isoquinoline. (3m)
Brown solid; Rf = 0.38 (1:5 ethyl acetate/hexanes); (192 mg, 78%); mp 158-160 °C; FT-IR
(KBr) 3775, 3681, 3401, 3019, 1215 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.43 (s, 1H), 7.87-
7.73 (m, 2H), 7.38-7.30 (m, 1H), 7.04 (s, 1H), 6.60 (s, 1H), 2.67 (s, 2H), 2.34-2.33 (m, 2H),
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1.89-1.79 (m, 4H) ppm; C NMR (75 MHz, CDCl3): δ 163.0, 160.0, 137.9 (d, J = 3.0 Hz),
132.7, 131.4, 129.6 (d, J = 18.0 Hz), 126.4, 126.1, 123.4 (d, J = 19.5 Hz), 117.7 (d, J = 45.0
Hz), 112.6, 109.2 (d, J = 46.5 Hz), 27.4, 25.8, 22.5, 21.9 ppm; HRMS (ESI) calcd for
C16H15FN3 [M + H] 268.1250 found 268.1253.
5-butyl[1,2,3]triazolo[5,1-a]isoquinoline. (3n)
Brown solid; Rf = 0.45 (1:5 ethyl acetate/hexanes); (176 mg, 72%); mp 162-164 °C; FT-IR
(KBr) 3776, 3680, 3400, 3019, 669 cm-1; H NMR (400 MHz, CDCl3): δ 8.48 (s, 1H), 8.15-
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8.13 (m, 1H), 7.77-7.45 (m, 1H), 7.62-7.60 (m, 2H), 7.00 (s, 1H), 3.34-3.30 (s, 2H), 1.97-
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1.90 (m, 2H), 1.58-1.49 (m, 2H), 1.03-1.01 (m, 3H) ppm; C NMR (100 MHz, CDCl3): δ
137.2, 132.8, 129.7, 129.0, 127.8, 126.9, 126.1, 123.8, 122.0, 113.0, 30.5, 28.9, 22.5, 13.9
ppm; HRMS (ESI) calcd for C14H16N3 [M+ H] 226.1344 found 226.1338.
5-butyl[1,2,3]triazolo[5,1-a]isoquinoline. (3o)
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Brown solid; Rf= 0.36 (1:5 ethyl acetate/hexanes); (120 mg, 70%); mp 154-156 °C; FT-IR
(KBr) 3399, 3020, 2401, 760 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.52 (d, J = 6.0 Hz, 1H),
8.43 (s, 1H), 8.16 (d, J = 6.0 Hz, 1H), 7.81 (d, J = 6.0 Hz, 1H), 7.70-7.62 (m, 2H), 7.21-7.20
(m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 132.5, 129.1, 129.1, 128.9, 127.6, 125.8,
124.0, 123.0, 122.6, 116.1 ppm; HRMS (ESI) calcd for C10H8N3 [M + H] 170.0718 found
170.0710.
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5-(4-fluorophenyl)-[1,2,3]triazolo[5,1-a]isoquinoline. (3p)
Brown solid; Rf = 0.36 (1:5 ethyl acetate/hexanes); (56 mg, 72%); mp 182-184 °C; FT-IR
(KBr) 3818, 3756, 3692, 1417 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 8.90 (s, 1H), 8.46 (d,
J = 0.8 Hz, 1H), 8.44-8.04 (m, 3H), 7.77-7.55 (m, 2H), 7.75-7.66 (m, 1H), 7.48-7.43 (m, 2H)
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ppm; C NMR (100 MHz, DMSO-d6): δ 164.0, 161.5, 133.9, 132.9, 131.7 (d, J = 4.0, Hz),
129.3 (d, J = 6.5, Hz), 128.5, 128.4, 127.8, 126.6, 124.0, 121.8, 115.8, 115.4 (d, J = 11.0, Hz)
ppm; HRMS (ESI) calcd for C16H11FN3 [M + H] 264.0937 found 264.0930.
V: Typical Procedure for the Preparation of final products (7a-7i).
To a stir bar-equipped flame-dried 50 mL round bottom flask containing a stirring mixture of
2-nitro-1-(2-(p-tolylethynyl)phenyl)ethanol 6a (300 mg, 1.0 mmol), I2 (809 mg, 3.0 mmol),
and NaHCO3 ( 265 mg, 3.0 mmol) in CH3CN (5 ml). After completion of the reaction by
TLC analysis the reaction mixture was quenched with Na2S2O3 solution and diluted with
water (10 ml) and extracted with EtOAc (3 × 20 ml). The combined organic layers were dried
over Na2SO4 and concentrated under reduced pressure. The crude product was purified on a
100-200 mesh column (1:9 EtOAc:hexanes).
4-iodo-3-(4-methylphenyl)-1-(nitromethyl)-1H-isochromene. (7a)
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3120, 2970, 2401, 1216 cm-1; H NMR (400 MHz, CDCl3): δ 7.55-7.52 (m, 1H), 7.50-7.43
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6.07 (m, 1H), 5.12-5.06 (m, 1H), 4.47-4.43 (m, 1H), 2.38 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 152.9, 140.4, 133.0, 132.7, 130.5, 130.3, 130.1, 128.8, 128.5, 125.8, 124.0, 76.8,
75.3, 72.0, 21.7 ppm; HRMS (ESI) calcd for C17H15INO3 [M + H] 408.0097 found 408.0120.
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3-[4-(tert-butyl)phenyl]-4-iodo-1-(nitromethyl)-1H-isochromene (7b)
Green oil; Rf = 0.50 (1:9 ethyl acetate/hexanes); (283 mg, 68%); FT-IR (Neat) 3775, 3404,
3019, 2967, 1215 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.56-7.55 (m, 3H), 7.54-7.33 (m, 3H),
7.31-7.28 (m, 1H), 7.07-7.05 (m, 1H), 6.11-6.08 (m, 1H),5.14-5.08 (m, 1H) 4.49-4.45 (m,
1H), 1.34 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3): δ 153.3, 152.6, 132.7, 132.6, 130.2,
130.0, 128.4, 125.8, 124.9, 123.8, 76.6, 75.2, 34.9, 31.3 ppm; HRMS (ESI) calcd for
C20H21INO3[M + H] 450.0566 found 450.0557.
4-iodo-1-(nitromethyl)-3-phenyl-1H-isochromene. (7c)
Green oil; Rf = 0.50 (1:9 ethyl acetate/hexanes); (308 mg, 70%); (compound formed in 1:018
ratio 7c:8c) FT-IR (Neat) 3404, 3022, 2402, 1604, 921 cm-1; 1H NMR (400 MHz, CDCl3): δ
7.60-7.58 (m, 2H), 7.57-7.41 (m, 1H), 7.33-7.31 (m, 1H), 7.29-7.25 (m, 3H), 7.18-7.14 (m,
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1H), 7.07-7.05 (m, 1H), 6.14-6.01 (m, 1H), 5.14-5.08 (m, 1H) 4.48-4.45 (m, 1H) ppm; C
NMR (100 MHz, CDCl3): δ 152.7, 135.8, 132.4, 130.5, 130.2, 130.1, 128.6, 128.0, 125.7,
123.9, 76.7, 75.2, 72.5 ppm; HRMS (ESI) calcd for C16H13INO3 [M +H] 393.9940 found
393.9938.
4-iodo-7-methoxy-3-(4-methylphenyl)-1-(nitromethyl)-1H-isochromene (7d)
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Green oil; Rf = 0.40 (1:9 ethyl acetate/hexanes); (265 mg, 63%); FT-IR (Neat) 3772, 3540,
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3200, 2840, 2401, 1216 cm-1; H NMR (400 MHz, CDCl3): δ 7.52-7.48 (m, 3H), 7.28-7.22
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(m, 2H), 6.97-6.94 (m, 1H), 6.66-6.65 (m, 1H), 6.07-6.03 (m, 1H), 5.14-5.08 (m, 1H), 4.50-
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4.46 (m, 1H), 3.87 (s, 3H), 2.38 (s, 3H) ppm; C NMR (100 MHz, CDCl3): δ 160.0, 150.5,
140.0, 132.9, 131.8, 130.4, 128.7, 127.0, 125.5, 114.7, 109.7, 75.2, 71.7, 55.7, 21.6 ppm;
HRMS (ESI) calcd for C18H17INO4 [M + H] 438.0202 found 438.0192.
4-iodo-7-methoxy-1-(nitromethyl)-3-phenyl-1H-isochromene (7e)
Green oil; Rf = 0.50 (1:9 ethyl acetate/hexanes); (267 mg, 68%); FT-IR (Neat) 3785, 3680,
3402, 3019, 2959, 1215 cm-1; H NMR (400 MHz, CDCl3): δ 7.60-7.58 (m, 2H), 7.57-7.50
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(m, 1H), 7.47-7.39 (m, 3H), 6.95-6.93 (m, 1H), 6.63 (s, 1H), 6.05-6.02 (m, 1H), 5.12-5.07
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(m, 1H), 4.48-4.45 (m, 1H), 3.84 (s, 3H) ppm; C NMR (75 MHz, CDCl3): δ 160.0, 150.5,
135.9, 131.8, 130.5, 129.8, 128.0, 127.0, 125.3, 114.8, 109.7, 75.2, 72.2, 55.7 ppm; HRMS
(ESI) calcd for C17H15INO4 [M + H] 424.0046 found 424.0034.
3-[4-(tert-butyl)phenyl]-4-iodo-7-methoxy-1-(nitromethyl)-1H-isochromene (7f)
Green oil; Rf = 0.50 (1:9 ethyl acetate/hexanes); (276 mg, 68%); FT-IR (Neat) 3776, 3681,
3401, 3019, 1215 cm-1; 1H NMR(400 MHz, CDCl3): δ 7.54-7.53 (m, 2H), 7.48-7.46 (m, 1H),
7.41-7.40 (m, 2H), 6.93-6.91 (m, 1H), 6.62 (s, 1H), 6.03-6.00 (m, 1H), 5.10-5.04 (m, 1H)
4.46-4.43 (m, 1H), 3.83 (s, 3H), 1.33 (s, 9H) ppm; 13C NMR (100 MHz,CDCl3): δ 160.0,
153.0, 132.7, 131.8, 130.1, 127.0, 125.4, 124.7, 114.7, 109.6, 76.5, 75.1, 71.5, 55.6, 34.8,
31.2 ppm; HRMS (ESI) calcd for C21H23INO4 [M + H] 480.0672 found 480.0691.
3-[4-(tert-butyl)phenyl]-7-fluoro-4-iodo-1-(nitromethyl)-1H-isochromene (7g)
. Green oil; Rf = 0.50 (1:9 ethyl acetate/hexanes); (271 mg, 66%); FT-IR (Neat) 3787, 3681,
3403, 3019, 1215 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.55-7.52 (m, 3H), 7.43-7.40 (m, 2H),
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7.14-7.08 (m, 1H), 6.85-6.82 (m, 1H), 6.06-6.02 (m, 1H), 5.13-5.05 (m, 1H), 4.50-4.45 (m,
1H), 1.33 (s, 9H) ppm; 13C NMR (100 MHz,CDCl3): δ 163.7, 161.2, 153.5, 152.1, 132.4,
129.8 (d, J = 154.0 Hz), 127.3 (d, J = 26.0 Hz), 125.0, 116.7 (d, J = 44.0 Hz), 111.0 (d, J =
48.0 Hz), 76.2, 74.7, 70.5, 35.0, 31.3 ppm; HRMS (ESI) calcd for C20H20FINO3 [M + H]
468.0472 found 468.0454
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3-cyclohex-1-en-1-yl-4-iodo-7-methoxy-1-(nitromethyl)-1H-isochromene (7h)
Green oil; Rf = 0.50 (1:9 ethyl acetate/hexanes); (263 mg, 62%); FT-IR (Neat) 3778, 3399,
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2967, 760 cm-1; H NMR (400 MHz, CDCl3): δ 7.38-7.36 (m, 1H), 6.90-6.86 (m, 1H), 6.57
(s, 1H), 6.04 (s, 1H), 5.91-5.88 (m, 1H), 4.96-4.90 (m, 1H), 4.36-4.31 (m, 1H), 3.83 (s, 3H),
2.26-2.06 (m, 4H), 1.7-1.60 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ 159.6, 152.9,
134.3, 134.2, 131.5, 126.9, 125.2, 114.5, 109.7, 76.3, 74.5, 70.7, 55.6, 26.3, 25.2, 22.4, 21.7
ppm; HRMS (ESI) calcd for C17H19INO4[M + H] 428.0359 found 428.0345.
3-cyclohex-1-en-1-yl-4-iodo-1-(nitromethyl)-1H-isochromene (7i)
Green oil; Rf = 0.60 (1:9 ethyl acetate/hexanes); (276 mg, 63%); FT-IR (Neat); 3390, 2956,
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760 cm-1; H NMR (400 MHz, CDCl3): δ 7.46-7.44 (m, 1H), 7.37-7.36 (m, 1H), 7.24-7.23
(m, 1H), 7.00-7.98 (m, 1H), 6.07-6.06 (m, 1H), 5.97-5.95 (m, 1H), 4.97-4.92 (m, 1H), 4.36-
4.32 (m, 1H), 2.18-2.15 (m, 4H), 1.7-1.60 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ
155.0, 134.5, 134.2, 132.3, 129.9, 129.8, 125.0, 123.9, 76.4, 74.5, 71.0, 26.3, 25.2, 22.4, 21.6
ppm; HRMS (ESI) calcd for C16H17INO3: [M + H] 398.0253 found 398.0255
7-fluoro-4-iodo-1-(nitromethyl)-3-4-methylphenyl-1H-isochromene (7j)
Green oil; Rf= 0.53 (1:9 ethyl acetate/hexanes); (297 mg, 70%); FT-IR (Neat) 3785, 3665,
3403, 1215 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.54-7.53 (m, 1H), 7.49-7.47 (m, 2H), 7.22-
7.20 (m, 2H), 7.13-7.09 (m, 1H), 6.84-6.82 (m, 1H), 6.05-6.02 (m, 1H), 5.11-5.06 (m, 1H),
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