α-Haloacrylates as acceptors in the [3 + 2] cycloaddition reaction with NaN3: An expedient approach to N-unsubstituted 1,2,3-triazole-4-carboxylates

Article abstract of DOI:10.1039/c3ob42276c

An expedient synthesis of N-unsubstituted 1,2,3-triazole-4-carboxylates has been demonstrated through [3 + 2] cycloaddition of sodium azide with α-haloacrylates. The process is highly reliable and exhibits an unusually wide scope with respect to α-fluoro-

Full text of DOI:10.1039/c3ob42276c

Organic &
Biomolecular Chemistry
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α-Haloacrylates as acceptors in the [3 + 2]
cycloaddition reaction with NaN3: an expedient
approach to N-unsubstituted 1,2,3-triazole-
4-carboxylates†
Cite this: Org. Biomol. Chem., 2014,
12, 2280
John Kallikat Augustine,* Chandrakantha Boodappa and Srinivasa Venkatachaliah
An expedient synthesis of N-unsubstituted 1,2,3-triazole-4-carboxylates has been demonstrated through
[3 + 2] cycloaddition of sodium azide with α-haloacrylates. The process is highly reliable and exhibits an
unusually wide scope with respect to α-fluoro-, α-chloro-, α-bromo-, and α-iodoacrylates. The potential
of selected 1,2,3-triazole-4-carboxylates in the preparation of 1,5-dihydro-4H-[1,2,3]-triazolo-[4,5-c]-
quinolin-4-one has also been illustrated.
Received 14th November 2013,
Accepted 4th February 2014
DOI: 10.1039/c3ob42276c
www.rsc.org/obc
Introduction
1,2,3-Triazoles are an important class of heterocycles and
widely employed as intermediates in pharmaceuticals, agro-
chemicals and materials science.1 The Huisgen 1,3-dipolar
cycloaddition between organic azides and terminal alkynes is
a useful and extensively applicable method for the synthesis of
1,2,3-triazoles.2 Since inorganic azides are not good substrates
in these reactions, most of these developed methods lead to
N-substituted 1,2,3-triazoles.3 Consequently, N-unsubstituted
1,2,3-triazoles, which also have a wide selection of uses4 such
as MetAP2 inhibitors,4a inhibitors against tuberculosis,4b
neurokinin-1 receptor antagonists,4c HIV-protease inhibitors,4d
anticancer agents,4e antiallergic agents,4f HER2 tyrosine kinase
inhibitors4g and so forth, cannot be prepared directly by using
the click chemistry strategy, but instead demand sequences
involving deprotection steps and the utilization of more
refined azides.5 Of the only few other routes to N-unsubsti-
tuted 1,2,3-triazoles,6–10 the [3 + 2] cycloaddition between
sodium azide with electron deficient olefins followed by elimi-
nation (Scheme 1)10 has been the subject of intensive
research. Interestingly, in many of these reactions, the elimi-
nating group has been strongly deactivating in nature such as
nitro, benzenesulphonyl or cyano as shown in Scheme 1.
Scheme 1 General method for the preparation of (NH)-1,2,3-triazoles.
Scheme 2 N-Unsubstituted-1,2,3-triazole-4-carboxylates through [3 + 2]
cycloaddition pathway.
preparation of polymers, amino acids, natural products, and
heterocycles of biological importance.11 Recently we have
reported an exceptionally stereoselective synthesis of (Z)-
α-haloacrylates.12 We decided to explore the utility of α-halo-
acrylates as acceptors in the reaction with an azide to generate
1,2,3-triazole-4-carboxylates. Herein, we report our findings
regarding a convenient procedure to access N-unsubstituted-
1,2,3-triazole-4-carboxylates through [3 + 2] cycloaddition of
sodium azide with α-haloacrylates (Scheme 2). Contrary to the
reported methods wherein the leaving groups are strongly
deactivating in nature (Scheme 1),10 we observed the elimin-
ation of halogens which are weakly deactivating, and accord-
ingly this finding is significant. Further, to our knowledge,
there is no literature on the eliminating group being weakly
deactivating in such reactions. A mechanism is proposed to
α-Haloacrylic acid derivatives are useful building blocks
from a synthetic point of view and widely used in the
Syngene International Ltd., Biocon Park, Plot Nos. 2 & 3, Bommasandra IV Phase,
Jigani Link Road, Bangalore 560 099, India. E-mail: john.kallikat@syngeneintl.com,
john.kallikat@gmail.com; Fax: +91 80 2808 3150; Tel: +91 80 2808 3131
†Electronic supplementary information (ESI) available: Copies of 1H NMR
spectra, 13C NMR spectra, IR and HPLC of all compounds prepared by the
method. See DOI: 10.1039/c3ob42276c
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explain the experimental results obtained. Further, the syn-
thetic utility of the methodology in accessing N-unsubstituted-
1,2,3-triazole-4-carbonitriles as well as synthetic applications
of selected 1,2,3-triazole-4-carboxylates in the preparation of
1,5-dihydro-4H-[1,2,3]-triazolo-[4,5-c]-quinolin-4-one is illustrated.
Table 2 Screening of the influence of α-halogen substituents on the
rate of reactiona
Entrya
Substrate
X
Time (min)
Yieldb (%) 2a
Results and discussion
1
2
3
4
1b
1c
1a
1d
F
90
140
185
410
97
98
97
94
We discovered following a series of assessments in a variety of
solvents that (Z)-methyl 2-bromo-3-phenylacrylate 1a12 could
easily be transformed into methyl 5-phenyl-1H-1,2,3-triazole-4-
carboxylate 2a in 97% yield by treatment with sodium azide
(1.5 equiv.) in DMSO at 90 °C (Table 1, entry 10). The product
2a was isolated as a yellow solid following an aqueous work-up
and recrystallization from a mixture of hexane and EtOAc. As
Cl
Br
I
a Reactions were performed on 0.1 mol scale. b Isolated yields.
observed from Table 1, the solvent specificity of the reaction is 10 hours of refluxing, probably due to the poor solubility of 1a
significant indeed. Only DMSO promoted the [3 + 2] cyclo-
addition of sodium azide with 1a to a large extent (Table 1,
in water. Interestingly, a mixture of DMF and water (1 : 1) gave
a better conversion than either of the solvents when employed
entries 8–11). While very low conversion was achieved in DMF separately (Table 1, entry 13). These experiments prove that the
(Table 1, entries 3 and 4), no conversion at all was observed for
other solvents such as 1,4-dioxane, THF, EtOH and MeCN. The
above conditions (Table 1, entry 10) were most suitable for the
formation of 1,2,3-triazoles as there were no considerable
changes in the duration of reaction or yield while performing
optimal solubility of both NaN3 and substrate in the reaction
medium is vital for better outcome of reaction.
Having found that (Z)-α-bromoacrylates are good substrates
to yield N-unsubstituted-1,2,3-triazoles, we next investigated if
other (Z)-α-haloacrylates such as α-chloroacrylates, α-fluoro-
the reaction at an elevated temperature in the presence of an acrylates and α-iodoacrylates could be used as effective sub-
excess of NaN3 (Table 1, entry 11). Nevertheless, no decompo-
strates in the reaction. Accordingly the reactivity of (Z)-methyl
2-fluoro-3-phenylacrylate 1b,12 (Z)-methyl 2-chloro-3-phenyl-
sition of starting materials was observed while the reaction
was performed at 130 °C in DMSO. To explore if the solubility acrylate 1c,12 and (Z)-methyl 2-iodo-3-phenylacrylate 1d12 with
effect of NaN3 in DMSO indeed proved beneficial for superior
sodium azide was compared with that of 1a (Table 2). By care-
yield, the reaction was performed in water at reflux (Table 1,
fully monitoring the cycloaddition reactions, we observed two
entry 12). However, the reaction did not proceed even after phenomena: (a) regardless of the kind of halogen atom
(α-fluoro, α-chloro, α-bromo or α-iodo) attached to the acrylate,
the [3 + 2] cycloaddition reaction affords 1,2,3-triazole; (b) the
rate of the reaction is reliant on the atomic size of the halogen
Table 1 Optimization of the model reactiona
attached to the substrate, to be exact, the smaller the size of
halogen atom attached to the α-haloroacrylate, the higher the
rate of reaction. For instance, while it took just 90 min for
fluoro-acrylate 1b to undergo complete transformation,
140 min were required for the chloro-acrylate 1c and about
185 min were necessary for the bromo-acrylate 1a for complete
conversion to 2a (Table 2). Notably the reaction took approxi-
mately 7 h for completion when α-iodo-acrylate 1d was
employed as the substrate in the reaction (Table 2, entry 4).
Interestingly, in all the cases, 1,2,3-triazole 2a was obtained in
comparable yields and the reaction showed a general tolerance
towards the halogen functionality.
At this point, we were interested to know if (E)-α-haloacry-
lates could be employed as useful substrates in the synthesis
of N-unsubstituted-1,2,3-triazoles. Thus, (E)-methyl 2-bromo-3-
phenylacrylate 1e was prepared via the modified Still–Gennari
olefination13 and subjected to react with NaN3 under the stan-
dard reaction conditions (Scheme 3). As evidenced by us, the
isolated yields of 1,2,3-triazole 2a and the duration of reaction
were still satisfactory. To be precise, the outcome of reaction is
independent of the stereochemistry of the α-haloacrylate used.
Entry
Solvent
Time (h)
Temp. (°C)
Yieldb (%) 2a
1
2
Dioxane
Dioxanec
DMF
DMF
THF
10
6
8
10
8
8
6
9
5
3
100
100
90
130
Reflux
Reflux
Reflux
25
90
90
0
0
11
16
0
0
0
42
78
97
97
0
3
4d
5
6
7
8
9
EtOH
MeCN
DMSO
DMSO
DMSO
DMSO
H2O
10d
11e
12
13
3
10
10
130
Reflux
100
H2O–DMF
63
a Unless otherwise specified, reactions were performed in the presence
of NaN3 (1.2 equiv.). b Isolated yields. c Reaction was performed in the
presence of water (10 equiv.). d 1.5 equiv. of NaN3 were used. e 3.0
equiv. of NaN3 were used.
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Table 3 N-Unsubstituted-1,2,3-triazole-4-carboxylates: scope of the
reaction using diverse (Z)-α-haloacrylatesa
Scheme 3 Evaluation of an (E)-α-haloacrylate in the synthesis of 1,2,3-
triazole-4-carboxylates.
Entry
1
Substrate
Product
Yieldb (%)
98
The high efficiency of [3 + 2] cycloaddition of sodium azide
was maintained to the same extent with structurally diverse
(Z)-α-haloacrylates, and it can be observed that the method is
general (Table 3). Seeing that the duration of reaction was
longer for α-iodoacrylates, it was decided not to consider them
as good substrates in the reaction. Accordingly, a broad variety
of α-fluoro-, α-chloro- and α-bromoacrylates equipped with
various substituents were prepared following literature pro-
cedures12 and successfully employed in the reaction. The
reaction was unchallenging for all substrates tested and the
respective N-unsubstituted-1,2,3-triazoles were isolated in
excellent yields. All the products (Table 3, 2b–p) were easily
extracted with EtOAc following an aqueous work-up and
purified by recrystallization or by passing through a small plug
of silica. As described in Table 3, electronic disparity of the
aromatic substituents did not reduce the efficiency of reaction.
Besides aromatic α-haloacrylates (Table 3, entries 1–10),
various heteroaromatic and alicyclic α-haloacrylates turned
out to be compatible with the reaction conditions to yield
N-unsubstituted-1,2,3-triazoles in excellent yields (Table 3,
entries 11–15). The reactions were complete in less than 2 h
for all acrylates possessing α-fluoro and α-chloro substituents
(Table 3, entries 1–3, 9–12 and 15). However, somewhat longer
heating was necessary for the acrylates possessing an α-bromo
substituent and they took 3–4 h to afford the respective 1,2,3-
triazole-4-carboxylates in good yields (Table 3, entries 4–8,
13 and 14).
2
96
3
4
5
6
98
96
97
95
Besides α-haloacrylates, the methodology could easily be
extended over to other electron deficient vinyl halides such as
α-haloacrylonitriles14 to produce the 1,2,3-triazole-4-carbo-
nitriles (Table 4). The transformation seems to be general and
the reactions were complete within 2 h at 90 °C to provide the
respective N-unsubstituted-1,2,3-triazole-4-carbonitriles 2q–t in
excellent yields (Table 4, entries 1–4).
7
97
8
9
95
99
Mechanism
The reaction was initially assumed to proceed through α-azi-
doacrylates 3 generated by the nucleophilic substitution of
sodium azide to α-haloacrylates (Scheme 4). The 1,5-electro-
cyclization of vinyl azide 3 would subsequently give 1,2,3-tria-
zole-4-carboxylates 2.15
In an attempt to prove this hypothesis, we carried out the
synthesis of vinyl azide 3a following literature procedures.16
Interestingly, compound 3a did not undergo cyclization to
1,2,3-triazole 2a even after 10 h of heating in DMSO at 90 °C
(Scheme 5). Upon prolonged heating at 120 °C, decomposition
10
98
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Table 3 (Contd.)
Table 4 Synthesis of N-unsubstituted-1,2,3-triazole-4-carbonitriles
from α-chloroacrylonitrilesa
Yieldb (%)
94
Entry
1
Substrateb
Product
Yield (%)
98
Entry
11
Substrate
Product
2
96
12
13
14
98
97
92
3
4
95
98
a Conditions: α-chloroacrylonitrile (1.0 equiv.), NaN3 (1.5 equiv.),
1–2 h. b Substrates were used as a mixture of (E/Z) isomers.
15
96
a Reactions were performed on 0.1 mol scale. b Purified by
recrystallization or chromatography.
of vinyl azide was observed. These observations leave out the
possibility of any involvement of vinyl azides 3 in the for-
mation of 1,2,3-triazoles from α-haloacrylates.
Thus it is likely that the mechanism involves 1,3-dipolar
cycloaddition as proposed in Scheme 6. The [3 + 2] cyclo-
addition of sodium azide with α-haloacrylate and the sub-
sequent elimination of HX (X = halogen) yield 1,2,3-triazole
sodium derivative 5 or its tautomer. This intermediate instan-
taneously reacts with HX liberated in the process to release the
1,2,3-triazoles 2 with the exclusion of sodium halide.
Scheme 4 Originally assumed pathway.
The mechanism was further probed by reacting substrate 1f
with benzyl azide (1.1 equiv.) under the standard conditions
(Scheme 7). After 2 hours of heating at 90 °C the starting
materials were completely consumed to yield a mixture of 6a
and 6b in the ratio 6 : 4. The structures of 6a and 6b were
Scheme 5 Evidence not in support of Scheme 3.
Synthetic utilities of 1,2,3-triazole-4-carboxylates. 1,2,3-Tria-
unambiguously determined by NOESY experiments.17 Besides zole-4-carboxylates bearing an ortho-NO2 substituent on the
supporting the presence of triazole tautomers in the reaction aryl ring can be further utilized as synthons for the prepa-
as shown in Scheme 6, the outcome also points to a [3 + 2] ration of heterocycles such as 1,5-dihydro-4H-[1,2,3]triazolo-
cycloaddition pathway as opposed to stepwise Michael [4,5-c]-quinolin-4-one. To demonstrate this, compound 2k was
addition, thereby yielding a mixture of regioisomers.
subjected to reductive ring closure under hydrogenation
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in the preparation of 1,5-dihydro-4H-[1,2,3]-triazolo-[4,5-c]-qui-
nolin-4-one have been illustrated.
Experimental
General considerations
All the reactions were performed in DMSO under a nitrogen
atmosphere. α-Haloacrylates12 and α-haloacrylonitriles14
were synthesized prior to use following literature procedures.
1H NMR (400 MHz) and 13C NMR (100.6 MHz) spectra were
recorded in DMSO-d6 on a Bruker ARX-400 spectrometer. Mass
spectra were measured with a Micro mass Q-TOF spectrometer.
Melting points of the newly synthesized compounds were
recorded (uncorrected) on Buchi Melting Point B-545 appar-
atus. Infrared spectra were recorded on a Thermo Scientific
Nicolet 6700 FT-IR spectrometer. Compounds described in the
literature were characterized by comparison of their 1H, and/or
13C NMR spectra to the previously reported data.
Scheme 6 Proposed pathway for 1,2,3-triazole generation.
General procedure for the synthesis of N-unsubstituted
1,2,3-triazole-4-carboxylates
A mixture of α-haloacrylate (0.01 mol) and NaN3 (0.015 mol) in
DMSO (15 mL) was stirred at 90 °C for 2–4 h. When the reac-
tion was complete (monitored by TLC: Pet ether–EtOAc – 9 : 1),
the dark brown mixture was cooled and diluted with water.
The product was extracted with EtOAc (2 × 20 mL) and the
combined organic phase was dried over Na2SO4. The solvent
was removed under reduced pressure and the crude product
was passed through a small plug of silica to afford the desired
N-unsubstituted 1,2,3-triazole-4-carboxylate in excellent yield.
Methyl 5-phenyl-1H-1,2,3-triazole-4-carboxylate (2a). White
solid: 740 mg, 97%, Mp = 165.6 °C; IR (neat, cm−1) 3103.2,
2883.5, 1730.1, 1497.3, 1172.3, 1130.1, 808.9, 689.0; 1H NMR
(400 MHz, DMSO-d6) δ 15.99 (s, 1 H), 7.75–7.74 (m, 2 H),
7.49–7.47 (m, 3 H), 3.80 (s, 3 H); 13C NMR (100 MHz, CDCl3)
δ 161.8, 130.5, 129.8, 129.4, 128.7, 128.0, 125.4, 52.31; HRMS
(ESI+): found 226.0595; exact mass calcd for C10H9N3NaO2
[M + Na]+: 226.0592.
Scheme 7 Control experiment to determine the reaction pathway.
Scheme 8 Synthesis of 1,5-dihydro-4H-[1,2,3]-triazolo-[4,5-c]-quino-
lin-4-one.
Methyl
5-(4-bromophenyl)-1H-1,2,3-triazole-4-carboxylate
conditions to readily afford 7-(trifluoromethyl)-1,5-dihydro-4H-
[1,2,3]triazolo[4,5-c]quinolin-4-one (Scheme 8).18 Interestingly,
methods to access such important heterocycles are scarce.19
(2b). White solid: 920 mg, 98%, Mp = 105.8 °C; IR (neat,
cm−1) 3131.8, 2920.0, 1735.5, 1472.3, 1169.5, 1133.5, 1031.2,
1
1004.3, 827.4; H NMR (400 MHz, DMSO-d6) δ 16.02 (s, 1 H),
7.74 (dd, J = 6.8, 1.9 Hz, 2 H), 7.67 (dd, J = 6.8, 1.9 Hz, 2 H),
3.80 (s, 3 H); 13C NMR (100 MHz, DMSO-d6) δ 162.5, 146.0,
134.2, 128.6, 120.7, 117.4, 115.4, 112.2, 52.6; HRMS (ESI+):
Conclusion
found 304.9779; exact mass calcd for
C10H9BrN3NaO2
In conclusion, an expedient synthesis of N-unsubstituted 1,2,3- [M + Na]+: 304.9776.
triazole-4-carboxylates has been demonstrated through [3 + 2] Methyl 5-(3-methoxyphenyl)-1H-1,2,3-triazole-4-carboxylate
cycloaddition of sodium azide with α-haloacrylates. The (2c). White solid: 1.1 g, 96%, Mp = 60.3 °C; IR (neat, cm−1
)
process is highly reliable and exhibits an unusually wide scope 3105.9, 2892.9, 1727.8, 1482.9, 1267.0, 1237.8, 1129.0, 1054.4,
with respect to α-fluoro-, α-chloro-, α-bromo-, and α-iodoacry- 1025.3, 781.1; 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1 H),
lates. Further, the synthetic utility of the methodology in acces- 7.40–7.37 (m, 2 H), 7.39–7.30 (m, 1 H), 6.96 (d, J = 8.0 Hz, 1 H),
sing N-unsubstituted-1,2,3-triazole-4-carbonitriles as well as 3.88 (s, 3 H), 3.80 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 161.7,
synthetic applications of selected 1,2,3-triazole-4-carboxylates 159.3, 146.7, 133.9, 129.3, 128.9, 121.5, 115.6, 114.5, 55.3, 52.3;
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HRMS (ESI+): found 265.0701; exact mass calcd for 8.0 Hz, 2 H), 3.80 (s, 3 H); 13C NMR (100 MHz, DMSO-d6) δ
C11H11N3NaO3 [M + Na]+: 256.0698.
162.0, 145.0, 134.8, 133.9, 132.5, 130.0, 119.1, 111.6, 52.3;
Methyl 5-(benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazole-4-car- HRMS (ESI+): found 251.0546; exact mass calcd for
boxylate (2d). White solid: 860 mg, 98%, Mp = 147.5 °C; IR C11H8N4NaO2 [M + Na]+: 251.0545.
(neat, cm−1) 3118.3, 2896.5, 1732.4, 1472.7, 1347.6, 1235.6,
Methyl 5-(2-nitro-4-(trifluoromethyl)phenyl)-1H-1,2,3-tria-
1022.2, 934.8; 1H NMR (400 MHz, DMSO-d6) δ 15.8 (s, 1 H), zole-4-carboxylate (2k). Light brown solid: 1.65 g, 98%, Mp =
7.33–7.28 (m, 2 H), 7.03 (d, J = 7.60 Hz, 1 H), 6.09 (s, 2 H), 3.80 172.8 °C; IR (neat, cm−1) 2931.8, 1728.2, 1634.7, 1542.8,
(s, 3 H); 13C NMR (100 MHz, DMSO-d6) δ 161.5, 148.1, 147.1, 1323.9, 1142.3, 1021.9; 1H NMR (400 MHz, CDCl3) δ 8.45 (s,
123.2, 109.2, 108.1, 101.4, 51.8; HRMS (ESI+): found 270.0492; 1 H), 7.95 (d, J = 8.0 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 3.91 (s,
exact mass calcd for C11H9N3NaO4 [M + Na]+: 270.0491.
3 H); 13C NMR (100 MHz, CDCl3) δ 160.7, 148.7, 149.8, 135.7,
Methyl 5-(4-nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (2e). 133.7, 133.1 (q), 129.6 (q), 126.7, 123.9, 122.1 (q), 52.9; HRMS
White solid: 730 mg, 96%, Mp = 300 °C (decomposed); IR (ESI+): found 339.0317; exact mass calcd for C11H7F3N4NaO4
(neat, cm−1) 2929.9, 2361.3, 1635.8, 1160.3, 793.4; 1H NMR [M + Na]+: 339.0317.
(400 MHz, DMSO-d6) δ 8.17 (s, 4 H), 3.71 (s, 3 H); 13C NMR
Ethyl 5-(6-methoxypyridin-3-yl)-1H-1,2,3-triazole-4-carboxy-
(100 MHz, DMSO-d6) δ 128.4, 126.4, 122.6, 117.3, 79.0, 78.7, late (2l). White solid: 890 mg, 94%, Mp = 122.8 °C; IR (neat,
78.4, 50.4; HRMS (ESI+): found 271.0445; exact mass calcd for cm−1) 2800.0, 2361.5, 2008.6, 1704.7, 1446.8, 1283.1, 1144.8,
1
C10H8N4NaO4 [M + Na]+: 271.0443.
1002.4; H NMR (400 MHz, DMSO-d6) δ 15.8 (s, 1 H), 8.54 (s, 1
Methyl 5-(4-(dimethylamino)phenyl)-1H-1,2,3-triazole-4-car- H), 8.05 (d, J = 8.0 Hz, 1 H), 6.93 (d, J = 8.0 Hz 1 H), 4.30–4.25
boxylate (2f). White solid: 1.35 g, 97%, Mp = 170.3 °C; IR (q, 2 H), 3.90 (s, 3 H), 1.25 (t, 3 H); 13C NMR (100 MHz, DMSO-
(neat, cm−1) 3110.3, 2799.7, 2360.7, 2181.5, 1722.8, 1610.2, d6) δ 163.2, 160.5, 145.3, 142.3, 141.2, 133.3, 118.5, 109.7, 60.5,
1
1518.7, 1143.0, 811.8; H NMR (400 MHz, DMSO-d6) δ 7.63 (d, 53.9, 13.2; HRMS (ESI+): found 271.0809; exact mass calcd for
J = 8.4 Hz, 2 H), 7.87 (d, J = 8.9 Hz, 2 H), 3.79 (s, 3 H), 2.96 (s, C11H12N4NaO3 [M + Na]+: 271.0807.
6 H); 13C NMR (100 MHz, CD3OD) δ 162.5, 146.0, 134.2, 128.6,
Ethyl
124.7, 120.7, 117.6, 114.8, 52.6; HRMS (ESI+): found 269.1017; (2m). Brick-red solid: 1.38 g, 98%, Mp = 184.7 °C; IR (neat,
exact mass calcd for C12H14N4NaO2 [M + Na]+: 269.1014. cm−1) 3101.7, 2895.0, 1721.2, 1403.6, 1199.8, 1125.1, 1035.5;
5-(benzofuran-2-yl)-1H-1,2,3-triazole-4-carboxylate
Methyl 5-(3-fluoro-4-methoxyphenyl)-1H-1,2,3-triazole-4-car- 1H NMR (400 MHz, DMSO-d6) δ 16.3 (s, 1 H), 7.85 (s, 1 H), 7.78
boxylate (2g). White solid: 1.13 g, 95%, Mp = 153.1 °C; IR (d, J = 8.0 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.42 (d, J = 8.0 Hz,
(neat, cm−1) 3102.5, 2940.5, 2884.9, 1731.7, 1623.5, 1455.5, 1 H), 7.31 (t, J = 8.1 Hz, 1 H), 4.42–4.37 (q, 2 H), 1.34 (t, 3 H);
1121.0, 888.7; 1H NMR (400 MHz, DMSO-d6) δ 15.8 (s, 1 H), 13C NMR (100 MHz, DMSO-d6) δ 160.3. 154.1, 145.0, 127.8,
7.62 (dd, J = 12.0, 2.0 Hz, 1 H), 7.62 (d, J = 8.8 Hz, 1 H), 7.26 (t, 125.9, 123.5, 122.1, 111.2, 109.1, 61.1, 14.0; HRMS (ESI+):
J = 8.0 Hz, 1 H), 3.89 (s, 3 H), 3.82 (s, 3 H); 13C NMR (100 MHz, found 280.0698; exact mass calcd for C13H11N3NaO3 [M + Na]+:
DMSO-d6) δ 161.3, 152.0, 149.6, 148.0, 144.0, 125.8, 121.1, 280.0698.
116.4, 113.4, 56.0, 51.8; HRMS (ESI+): found 274.0606; exact
mass calcd for C11H10FN3NaO3 [M + Na]+: 274.0604.
Methyl 5-(5-bromothiophen-2-yl)-1H-1,2,3-triazole-4-carboxy-
late (2n). Light brown solid: 1.21 g, 97%, Mp = 213.6 °C; IR
Methyl 5-(3,4-dichlorophenyl)-1H-1,2,3-triazole-4-carboxylate (neat, cm−1) 3105.7, 2927.3, 1730.8, 1480.0, 1420.6, 1395.5,
(2h). White solid: 1.42 g, 97%, Mp = 193.8 °C; IR (neat, cm−1
)
1292.1, 1171.0, 1129.9; 1H NMR (400 MHz, DMSO-d6) δ 16.0 (s,
3136.1, 2961.7, 1737.5, 1464.4, 1308.7, 1288.2, 1202.2, 1176.2, 1 H), 7.78 (d, J = 4.0 Hz, 1 H), 7.31 (d, J = 4.0 Hz 1 H), 3.88 (s, 3
1040.4, 825.2, 790.5, 568.4; 1H NMR (400 MHz, DMSO-d6) δ H); 13C NMR (100 MHz, DMSO-d6) δ 161.1, 147.1, 139.2, 131.6,
16.0 (s, 1 H), 8.11 (d, J = 4.0 Hz, 1 H), 7.81–7.74 (m, 2 H), 3.82 130.7, 127.3, 124.1, 52.6; HRMS (ESI+): found 309.9262; exact
(s, 3 H); 13C NMR (100 MHz, DMSO-d6) δ 161.8, 137.5, 133.0, mass calcd for C8H6BrN3NaO2S [M + Na]+: 309.9262.
132.3, 131.4, 131.1, 130.9, 129.5, 125.9, 52.5; HRMS (ESI+):
found 293.9814; exact mass calcd for C10H7Cl2N3NaO2 Colorless gum: 900 mg, 92%; IR (neat, cm−1) 3143.3, 2952.6,
[M + Na]+: 293.9813. 2099.5, 1709.6, 1589.4, 1233.8, 1195.6, 1114.2, 1063.8; 1H NMR
Methyl 5-cyclopropyl-1H-1,2,3-triazole-4-carboxylate (2o).
Methyl
5-(naphthalen-2-yl)-1H-1,2,3-triazole-4-carboxylate (400 MHz, DMSO-d6) δ 15.1 (s, 1 H), 3.83 (s, 3 H), 3.55–3.49 (m,
(2i). White solid: 920 mg, 95%, Mp = 143.4 °C; IR (neat, cm−1
)
1 H), 1.07–1.06 (m, 2 H), 0.89–0.86 (m, 2 H); 13C NMR
1
3123.0, 2951.0, 1736.0, 1463.0, 1272.0, 1123.0, 792.6. H NMR (100 MHz, DMSO-d6) δ 162.1, 150.4, 135.2, 52.1, 9.46, 6.02;
(400 MHz, DMSO-d6) δ 15.7 (s, 1 H), 8.36 (s, 1 H), 8.01–7.96 (m, HRMS (ESI+): found 190.0595; exact mass calcd for
3 H), 7.87–7.84 (m, 1 H), 7.60–7.55 (m, 2 H), 3.82 (s, 3 H); 13C C7H9N3NaO2 [M + Na]+: 190.0592.
NMR (100 MHz, DMSO-d6) δ 161.9, 133.3, 132.8, 128.8, 128.7,
Methyl 5-cyclohexyl-1H-1,2,3-triazole-4-carboxylate (2p). Col-
128.0, 127.4, 127.0, 126.9, 126.2, 52.3; HRMS (ESI+): found orless gum: 1.36 g, 96%, IR (neat, cm−1) 3932.3, 2849.4,
276.0751; exact mass calcd for C14H11N3NaO2 [M + Na]+: 1730.6, 1479.2, 1447.6, 1331.3, 1103.5; 1H NMR (400 MHz,
276.0749.
DMSO-d6) δ 3.96 (s, 3 H), 3.38–3.32 (m, 1 H), 1.99–1.86 (m, 2
Methyl 5-(4-cyanophenyl)-1H-1,2,3-triazole-4-carboxylate (2j). H), 1.85–1.74 (m, 3 H), 1.59–1.56 (m, 4 H), 1.50–1.45 (m, 1 H);
Light brown solid: 1.18 g, 99%, Mp = 184.5 °C; IR (neat, cm−1
)
13C NMR (100 MHz, DMSO-d6) δ 162.0, 152.1, 134.2, 52.1, 34.2,
1
3119.8, 2895.3, 1727.4, 1480.2, 1197.5, 1149.8, 842.2; H NMR 31.9, 26.2, 25.7; HRMS (ESI+): found 232.1064; exact mass
(400 MHz, DMSO-d6) δ 8.01 (d, J = 8.0 Hz, 2 H), 7.92 (d, J = calcd for C10H15N3NaO2 [M + Na]+: 232.1062.
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General procedure for the synthesis of N-unsubstituted
1,2,3-triazole-4-carbonitriles
Opin. Drug Discovery, 2012, 7, 489; (b) S. G. Agalave,
S. R. Maujan and V. S. Pore, Chem.–Asian J., 2011, 6, 2696;
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Chem. Soc. Rev., 2007, 36, 1249.
A
mixture of α-haloacrylonitrile (0.01 mol) and NaN3
(0.015 mol) in DMSO (15 mL) was stirred at 90 °C for 2–3 h.
When the reaction was complete (monitored by TLC:
Pet ether–EtOAc – 9 : 1), the dark brown mixture was cooled
and diluted with water. The product was extracted with EtOAc
(2 × 20 mL) and the combined organic phase was dried over
Na2SO4. The solvent was removed under reduced pressure and
the crude product was recrystallized from a mixture of ethyl
acetate and hexane to afford the desired N-unsubstituted 1,2,3-
triazole-4-carbonitrile in good yield and purity.
3 Selected references: (a) D. Wang, M. Zhao, X. Liu, Y. Chen,
N. Li and B. Chen, Org. Biomol. Chem., 2012, 10, 229;
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10825; (e) D. Fournier, R. Hoogenboom and U. S. Schubert,
Chem. Soc. Rev., 2007, 36, 1369; (f) M. V. Gil, M. J. Arévalo
and Ó. López, Synthesis, 2007, 1589; (g) Z. Y. Yan,
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hedron: Asymmetry, 2006, 17, 3288; (h) H. J. Cristau,
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2004, 10, 5607; (i) V. D. Bock, H. Hiemstra and
J. H. van Maarseveen, Eur. J. Org. Chem., 2006, 51;
( j) V. V. Rostovtsev, L. G. Green, V. V. Fokin and
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(k) H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew.
Chem., Int. Ed., 2001, 40, 2004.
4 (a) L. S. Kallander, Q. Lu, W. Chen, T. Tomaszek, G. Yang,
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M. A. Cascieri, G. G. Chicchi, S. Sadowski, N. M. J. Rupniak
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1533.
5-Phenyl-1H-1,2,3-triazole-4-carbonitrile (2q). 1.3 g, 98%; IR
(neat, cm−1) 3103.7, 2903.7, 2808.6, 2361.0, 2238.5, 1608.6,
1
1490.3, 1269.9, 1219.1; H NMR (400 MHz, DMSO-d6) δ 16.55
(s, 1 H), 7.89–7.62 (m, 2 H), 7.62–7.53 (m, 3 H); 13C NMR
(100 MHz, DMSO-d6) δ 146.2, 130.6, 129.4, 126.6, 125.5, 116.1,
113.3; These data are consistent with that reported in the
literature.10b
5-(Benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazole-4-carbonitrile
(2r). 710 mg, 96%, Mp = 178 °C; IR (neat, cm−1) 3082.7,
1
2992.7, 2241.1, 1488.4, 1452.9, 1256.1, 1035.1, 926.5; H NMR
(400 MHz, DMSO-d6) δ 7.41–7.36 (m, 2 H), 7.15 (d, J = 8.0 Hz,
1 H), 6.13 (s, 2 H); 13C NMR (100 MHz, DMSO-d6) δ 149.5, 148.5,
146.3, 121.6, 119.9, 115.8, 114.1, 109.6, 107.0, 102.35. These
data are consistent with that reported in the literature.10b
5-(4-(Dimethylamino)phenyl)-1H-1,2,3-triazole-4-carbonitrile
(2s). Pale yellow solid: 1.16 g, 95%, Mp = 222.5 °C; IR (neat,
cm−1) 3182.3, 3082.9, 2845.0, 2231.0, 1605.4, 1517.7, 1373.2,
1
1198.6, 824.7; H NMR (400 MHz, DMSO-d6) δ 16.17 (s, 1 H),
7.70 (d, J = 9.0 Hz, 2 H), 6.87 (d, J = 9.0 Hz, 2 H), 2.98 (s, 6 H);
13C NMR (100 MHz, DMSO-d6) δ 152.04, 145.5, 128.0, 114.5,
114.3, 112.5, 111.3, 39.9; HRMS (ESI+): found 236.0914; exact
mass calcd for C11H11N5Na [M + Na]+: 236.0912.
5-(5-Methylfuran-2-yl)-1H-1,2,3-triazole-4-carbonitrile (2t).
White solid: 970 mg, 98%, Mp = 163.5 °C; IR (neat, cm−1
)
3114.1, 2944, 2617, 2239.9, 1639.5, 1575.8, 1639.5, 1575.8,
1
1281.6, 1033.2, 804.6; H NMR (400 MHz, CDCl3) δ 7.09 (d, J =
4.0 Hz, 1 H), 6.22 (d, J = 4.0 Hz, 1 H), 2.43 (s, 3 H); 13C NMR
(100 MHz, DMSO-d6) δ 155.2, 139.6, 138.7, 114.6, 113.1, 113.0,
109.2, 13.7; HRMS (ESI+): found197.0440; exact mass calcd for
C8H6N4NaO [M + Na]+: 197.0439.
5 (a) S. Kamijo, T. Jin, Z. Huo and Y. Yamamoto, J. Am. Chem.
Soc., 2003, 125, 7786; (b) T. Jin, S. Kamijo and
Y. Yamamoto, Eur. J. Org. Chem., 2004, 3789; (c) J. C. Loren,
A. Krasiński, V. V. Fokin and K. B. Sharpless, Synlett, 2005,
2847; (d) S. Kamijo, Z. Huo, T. Jin, T. C. Kanazawa and
Y. Yamamoto, J. Org. Chem., 2005, 70, 6389; (e) A. H. Yap
and S. M. Weinreb, Tetrahedron Lett., 2006, 47, 3035.
6 For (NH)-1,2,3-triazoles via rearrangement of propargyl
azides, see: (a) K. Banert, Chem. Ber., 1989, 122, 911;
(b) K. Banert, Chem. Ber., 1989, 122, 1175; (c) K. Banert,
Chem. Ber., 1989, 122, 1963; (d) K. Banert and
M. Hagedorn, Angew. Chem., 1989, 101, 1710; K. Banert and
M. Hagedorn, Angew. Chem., Int. Ed. Engl., 1989, 28,
Notes and references
1 For general reviews on the chemistry and applications of
1,2,3-triazoles: (a) W.-Q. Fan and A. R. Katritzky, in
Comprehensive Heterocyclic Chemistry II, ed. A. R. Katritzky,
C. W. Rees and E. F. V. Scriven, Elsevier Science, Oxford,
1996, vol. 4, pp. 1–126; (b) H. Dehne, in Methoden der Orga-
nischen Chemie (Houben-Weyl), ed. E. Schumann, Thieme,
Stuttgart, 1994, vol. E8d, pp. 305–405; (c) A. C. Tome, Sci.
Synth., 2004, 13, 415–601.
2 For recent reviews on click chemistry and 1,2,3-triazoles:
(a) J. Hou, X. Liu, J. Shen, G. Zhao and P. G. Wang, Expert
2286 | Org. Biomol. Chem., 2014, 12, 2280–2288
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Paper
1675(e) J. C. Loren and K. B. Sharpless, Synthesis, 2005,
1514.
1431.9, 1273.2, 1225.6; 1H NMR (400 MHz, DMSO-d6) δ
8.21 (s, 1 H), 7.93–7.89 (m, 1 H), 7.79 (d, J = 8.0 Hz, 1 H),
7.29 (t, J = 8.0 Hz, 1 H), 3.89 (s, 3 H), 3.80 (s, 3 H); 13C NMR
(100 MHz, DMSO-d6) δ 163.0, 151.8, 149.3, 139.2, 128.2,
125.6, 117.1, 113.2, 110.5, 56.1, 53.5; HRMS (ESI+): found
311.9774; exact mass calcd for C11H11BrFNaO3 [M + Na]+:
311.9773 (c) Characterization data of 1l: white solid, 1.9 g,
97%; Mp = 101.5 °C; IR (neat, cm−1) 1721.1, 1261.5, 1238.0,
1034.2, 868.6; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1 H),
7.98 (d, J = 1.8 Hz, 1 H), 7.68 (dd, J = 8.4, 1.8 Hz, 1 H), 7.51
(d, J = 8.0 Hz, 1 H) 3.92 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 163.3, 138.4, 134.2, 133.5, 132.8, 131.6, 130.4,
129.3, 114.5, 53.7; HRMS (ESI+): found 308.9087; exact
mass calcd for C10H8BrCl2O2 [M + H]+: 308.9085.
7 For (NH)-1,2,3-triazoles via Pd-catalyzed reactions, see:
(a) J. Barluenga, C. Valdés, G. Beltrén, M. Escribano and
F. Aznar, Angew. Chem., Int. Ed., 2006, 45, 6893; (b) J. Li,
D. Wang, Y. Zhang, J. L. Baohua and B. Chen, Org. Lett.,
2009, 11, 3024; (c) N. Li, D. Wang, J. Li, W. Shi, C. Li and
B. Chen, Tetrahedron Lett., 2011, 52, 980.
8 For (NH)-1,2,3-triazoles from anti-3-aryl-2,3-dibromopropa-
noic acids, see: (a) W. Zhang, C. Kuang and Q. Yang, Syn-
thesis, 2010, 283; (b) Y. Jiang, C. Kuang and Q. Yang,
Synthesis, 2010, 4256.
9 For (NH)-1,2,3-triazoles via the [3
+ 2] cycloaddition
between internal/terminal alkynes and an azide anion, see:
(a) M. Journet, D. Cai, J. J. Kowal and R. D. Larsen, Tetra- 13 K. Tago and H. Kogen, Tetrahedron, 2000, 56, 8825.
hedron Lett., 2001, 42, 9117; (b) A. R. Katritzky, Y. Zhang 14 α-Chloroacrylonitriles were synthesized as a mixture of
and S. Singh, Heterocycles, 2003, 60, 1225; (c) L.-H. Lu,
J.-H. Wu and C.-H. Yang, J. Chin. Chem. Soc., 2008, 55, 414;
(d) I. Benghiat and E. I. Becker, J. Org. Chem., 1958, 23, 885;
(e) F. P. Woerner and H. Reimlinger, Chem. Ber., 1970, 103,
1908; (f) L. W. Hartzel and F. R. Benson, J. Am. Chem. Soc.,
1954, 76, 667; (g) H. S. G. Beckmann and V. Wittmann, Org.
Lett., 2007, 9, 1; (h) K. Barral, A. D. Moorhouse and
J. E. Moses, Org. Lett., 2007, 9, 1809.
(E/Z)-isomers according to the procedure reported by:
(a) J. R. Falck, A. Bandyopadhyay, D. K. Barma, D.-S. Shin,
A. Kundu and R. V. K. Kishore, Tetrahedron Lett., 2004, 45,
3039; (b) J. R. Falck, R. Bejot, D. K. Barma,
A. Bandyopadhyay, S. Joseph and C. Mioskowski, J. Org.
Chem., 2006, 71, 8179; (c) Characterization data of 1v: Pale
yellow solid: 2.10 g, 89%; Mp = 67 °C; IR (neat, cm−1
)
2907.4, 2212.5, 1615.6, 1587.2, 1495.5, 1446.3, 1031.8; 1H
NMR (400 MHz, DMSO-d6) δ 7.86 (s, 0.47 H), 7.81 (s, 0.53
H), 7.46 (s, 0.44 H), 7.39–7.36 (m, 0.48 H), 7.34 (s, 0.52 H),
7.29–7.08 (m, 0.57 H), 7.08 (s, 0.52 H), 7.06 (s, 0.46 H), 6.13
(s, 2 H); 13C NMR (100 MHz, DMSO-d6) δ 150.48, 150.45,
148.39, 148.13, 146.34, 143.16, 127.82, 126.17, 125.82,
125.72, 117.32, 116.08, 109.58, 109.38, 109.24, 107.51,
102.58, 102.55, 97.12, 96.36; HRMS (ESI+): found 229.9987;
exact mass calcd for C10H6ClNNaO2 [M + Na]+: 229.9985
(d) Characterization data of 1w: Leaf green solid: 1.6 g,
91%; Mp = 61.5 °C; IR (neat, cm−1) 2916.9, 2202.8, 1610.5,
1578.2, 1522.1, 1370.9; 1H NMR (400 MHz, DMSO-d6) δ
7.73–7.60 (m, 3 H), 6.77–6.73 (m, 2 H), 2.99 (s, 6 H); 13C
NMR (100 MHz, DMSO-d6) δ 152.57, 152.45, 146.73, 143.19,
133.12, 130.91, 119.47, 118.56, 118.35, 117.26, 112.10,
111.84, 92.43, 91.11, 39.97; HRMS (ESI+): found 229.0510;
exact mass calcd for C11H11ClN2Na [M + Na]+: 229.0509
(e) Characterization data of 1x: Pale brown liquid: 1.80 g,
93%; IR (neat, cm−1) 2214.3, 1613.9, 1509.2, 1196.7, 1024.8;
1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 0.34 H), 7.64 (s,
0.57 H), 7.19–7.18 (d, J = 3.5 Hz, 0.37 H), 6.92 (d, J = 3.3 Hz,
0.62 H), 6.44 (d, J = 3.4 Hz, 0.36 H), 6.38 (d, J = 3.4 Hz, 0.58
H), 2.50 (s, 1.2 H), 2.35 (s, 1.8 H); 13C NMR (100 MHz,
DMSO-d6) δ 157.67, 157.29, 146.83, 145.89, 132.67, 130.90,
121.61, 120.40, 117.31, 116.03, 110.67, 110.30, 94.22, 93.30,
14.04; HRMS (ESI+): found 190.0038; exact mass calcd for
C8H6ClNNaO [M + Na]+: 190.0036.
10 For (NH)-1,2,3-triazoles via the [3
+ 2] cycloaddition
between sodium azide and electron deficient olefins, see:
(a) B. Quiclet-Sire and S. Z. Zard, Synthesis, 2005, 3319;
(b) D. Amantini, F. Fringuelli, O. Piermatti, F. Pizzo,
E. Zunino and L. Vaccaro, J. Org. Chem., 2005, 70, 6526;
(c) Z. Dong, K. A. Hellmund and S. G. Pyne, Aus. J. Chem.,
1993, 46, 1431; (d) N. A. Anisimova, V. M. Berestovitskaya,
G. A. Berkova and N. G. Makarova, Russ. J. Org. Chem.,
2007, 43, 652; (e) S. Sengupta, H. Duan, W. Lu,
J. L. Petersen and X. Shi, Org. Lett., 2008, 10, 1493;
(f) T. Wang, X.-C. Hu, X.-J. Huang, X.-S. Li and J.-W. Xie,
J. Braz. Chem. Soc., 2012, 23, 1119; (g) T. Ponpandian and
S. Muthusubramanian, Tetrahedron Lett., 2012, 53, 59.
11 For various synthetic applications of α-haloacrylates, see:
(a) L. C. Larock, Comprehensive Organic Transformations,
Wiley-VCH, New York, 2nd edn, 1999, p. 715;
(b) M. U. Kahveci and Y. Yagci, Macromolecules, 2011, 44,
5569; (c) M. Egen, R. Voss, B. Griesebock, R. Zentel,
S. Romanov and C. S. Torres, Chem. Mater., 2003, 15, 3786;
(d) M.-Y. Chang, P.-P. Sun, S.-T. Chen and N.-C. Chang,
Tetrahedron Lett., 2003, 44, 5271; (e) S. N. Filigheddu and
M. Taddei, Tetrahedron Lett., 2002, 43, 3857; (f) M. Toyota,
T. Asano and M. Ihara, Org. Lett., 2005, 7, 3929;
(g) R. Lavilla, O. Coll, J. Bosch, M. Orozco and F. J. Luque,
Eur. J. Org. Chem., 2001, 3719; (h) P. E. Mironiuk,
E. Kolaczkowska and W. Sas, Tetrahedron Lett., 2002, 43,
8351; (i) S. Hanessian, H. Y. Yun, Y. H. Hou and 15 J. S. Meek and J. S. Fowler, J. Am. Chem. Soc., 1967, 89,
M. Tintelnot-Blomley, J. Org. Chem., 2005, 70, 6746. 1967.
12 (a) J. K. Augustine, A. Bombrun, S. Venkatachaliah and 16 F. Lehmann, M. Holm and S. Laufer, Tetrahedron Lett.,
A. Jothi, Org. Biomol. Chem., 2013, 11, 8065; 2009, 50, 1708.
(b) Characterization data of 1k: white solid, 1.45 g, 95%; 17 For 1H NMR and NOESY correlation of 6a and 6b, see
Mp = 115.8 °C; IR (neat, cm−1) 1710.6, 1605.9, 1507.4,
ESI.†
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Organic & Biomolecular Chemistry
18 Characterization data of 7: Off-white solid, 910 mg, 95%; Mp
119.1, 115.2, 113.5; HRMS (ESI+): found 277.0315; exact
mass calcd for C10H5F3N4NaO [M + Na]+: 277.0313.
= 297 °C; IR (neat, cm−1) 3243.0, 2926.0, 2893.0, 1690.0,
1396.0, 1322.0, 1196.0; 1H NMR (400 MHz, DMSO-d6) δ 16.7 19 For the biological activity exploration of such compounds,
(s, 1 H), 11.9 (s, 1 H), 8.27 (d, J = 8.0 Hz, 1 H), 7.7 (s, 1 H), 7.64
(d, J = 8.0 Hz, 1 H); 13C NMR (100 MHz, DMSO-d6) δ 156.2,
141.4, 137.8, 130.1 (q), 129.8 (q), 125.6, 124.6, 122.9 (q),
see: F. Suzuki, T. Kuroda, Y. Nakasato, H. Manabe,
K. Ohmori, S. Kitamura, S. Ichikawa and T. Ohno, J. Med.
Chem., 1992, 35, 4045.
2288 | Org. Biomol. Chem., 2014, 12, 2280–2288
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