Synthesis of benzofuranyl and indolyl methyl azides by tandem silver-catalyzed cyclization and azidation

Article abstract of DOI:10.1039/c6ob00191b

Ag(i)-catalyzed synthesis of 2-azidomethyl benzofurans/indoles from linear and readily available hydroxyl/amino-phenyl propargyl alcohols is described via a highly regioselective C-O and C-N bond formation. Control experiments reveal that the reaction involves the sequential Ag(i)-catalyzed 5-exo-dig cyclization and a catalyst free γ-allylic azidation. The synthetic utility of this method has been demonstrated by using the azidomethyl unit of the above synthesized heterocycles as the base for a variety of other functionalizations, such as triazole-, tetrazole-, amide-, amine-, and pyrido-derivatives.

Full text of DOI:10.1039/c6ob00191b

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Synthesis of benzofuranyl and indolyl methyl azides by tandem
silver-catalyzed cyclization and azidation
Gadi Ranjith Kumar,a,b Yalla Kiran Kumar,a Ruchir Kantc and Maddi Sridhar Reddya,b
Received 00th January 20xx,
Accepted 00th January 20xx
Ag(I)-catalyzed synthesis of 2-azidomethyl benzofurans/indoles from linear and readily available
hydroxyl/amino-phenyl propargyl alcohols is described via a highly regioselective C-O and C-N bond
formations. Control experiments reveal that the reaction involves the sequential Ag(I)-catalyzed 5-exo-dig
cꢀclizatioꢁ aꢁd a catalꢀst free ꢂ-allylic azidation. The synthetic utility of this method has been demonstrated
by using azidomethyl unit of the above synthesized heterocycles as base for variety of other
functionalizations, like triazole-, tetrazole-, amide-, amine-, pyrido-derivatives.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Scheme 1. Synthesis of allyl alcohols and their azidation.
Introduction
For practical considerations as well as green chemistry point of
view, cascade/tandem reactions are ideal approaches in organic
synthesis to build up intricate architectures. Electrophilic cyclization
of functionalized alkynes forms an excellent platform for various
tandem
transformations,
viz.
couplings,
isomerizations,
rearrangements, etc.1 A wide range of metal catalysts are identified
as soft enough to activate the alkynes for the requisite cyclization.
The incipient carbo/hetero metallated intermediate would undergo
the said tandem reactions depending on their compatibility with
the conditions employed. Although very attractive, this strategy is
still underutilized because it needs a careful development of the
reaction conditions as the independent reactions may have
different requirements, and combining them as such is mostly not
possible. Thus a careful study is required to set the appropriate
conditions to execute such cascade transformations. As part of our
on-going program of uncovering the new activities of activated
functionalized alkynes,2 we herein disclose a one pot tandem Ag(I)-
catalyzed 5-exo-dig oꢃꢀ/aꢄiꢁo cꢀclizatioꢁ aꢁd catalꢀst free ꢂ-
azidative allylic hydroxyl displacement for azidomethyl
benzofurans/indoles (Scheme 1D). Azides are undoubtedly highly
useful groups that serve as ready precursors for various N-
containing functional groups like amines, imines, triazoles,
tetrazoles and amides within
a
single-step transformation.3
Additionally, azides have also achieved a significant position in
medicinal chemistry, bio-conjugation and material science.4
a.Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, BS-
10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India.
b.Academy of Scientific and Innovative Research, New Delhi 110001, India.
c. Molecular & Structural Biology Division, CSIR-CDRI, Lucknow 226031, India.
Electronic Supplementary Information (ESI) available: See
Depending on the site of the requirement, there are different
strategies reported to introduce azide group in to the molecule. For
DOI: 10.1039/x0xx00000x
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example, donating group assisted azidation on
C
(SP2)-H,5
Table 1. Optimization studies
decarboxylative azidation on C(SP3)-H,6 direct Mn or Fe catalysed
azidation on tertiary C(SP3)-H,7 etc. in addition to the conventional
nucleophilic substitution approaches on C(SP3)-X where X is halide.8
Preactivation of hydroxyl group to tosylates, triflates, esters and
silyl ethers also allow the azidation through substitution.9 Direct
substitution of hydroxyl group,10 especially in catalytic conditions11
would offer a straightforward, practical and site selective synthesis
of C(SP3)-azides. To date, a very few attempts are made in this
direction.11
We herein report
a catalyst free aromatization-driveꢁ ꢂ-
azidation of allylic alcohols prepared in situ from Ag(I)-catalyzed
intramolecular oxy/amino- metallation of alkynes.1k-l This azidation
at ꢂ-positioꢁ is iꢁ coꢁtrast to the silver catalꢀsed α-azidative
displacement reported by Rueping et al (Scheme 1C).11a
Results and Discussion
The optimization studies (Table 1) were initiated with the
conversion of 1a1m to 3a. When a mixture of 1a, 2 equiv of TMSN3
and 5 mol % AgOAc in MeCN was stirred at rt, an unidentified
mixture of products was obtained (entry 1). Addition of TMSN3 after
2 h of the reaction (after cyclization) led to the isolation of the
intermediate 21m (entry 2). Still, no intended product was detected.
Raise of temperature to 80 oC did not bring any change in the
course of the reaction (entry 3). No reaction took place in toluene
o
at rt and the elevation of the temperature to 80 C resulted in 40%
of 2 (entries 4-5). Remarkably, switching of solvent to DMSO cleanly
afforded the product in 80% yield at 80 oC (entry 6). Reaction at
room temperature led only a slow conversion of the substrate to
intermediate 2 (entry 7). However, no reaction was observed in the
absence of the silver catalyst (entry 8). Pleasingly, change of
catalyst to Ag2CO3 afforded the required product in increased yield
of 86% (entry 10). Other Ag(I)-catalysts were found to be either
ineffective or low productive (entries 11-15). Other metal catalysts
like Pd(II) and Cu(II) could not promote the reaction (entries 16-17).
To get insight in to the reaction mechanism, we isolated the
o
intermediate 21m and treated with TMSN3 in DMSO at 80 C in the
absence of the Ag(I)-catalyst (Scheme 2). Surprisingly, the
conversion to the product 3a was very clean (90% yield), suggesting
that the catalyst was required only for the initial cyclization, and the
dehꢀdroꢃꢀlative ꢂ-azidation was driven by aromatization. With this
exciting result in hand, we explored the scope and limitation of this
tandem cyclization/azidation reaction. A number of hydroxyphenyl
propargyl alcohols were initially applied under the optimal reaction
conditions as shown in Table 2. Similar to 1a, alkyl
substitutedsubstrates afforded the products cleanly with the yields
ranging from 62% to 90%. Interestingly, the closer the methyl
group to hydroxyl the higher was the yield, suggesting that the
efficiency of the reaction was dependent on the nucleophility of the
hydroxyl group. Halogen groups (Br and Cl) could survive the
reaction comfortably and gave the corresponding products in 45-
56% yields. Electron rich methoxy substrate 3h participated
very well in the reaction (58%) whereas its electron deficient
counterpart 3i was found to be completely reluctant to initial
cyclization and led to only the isolation of the starting
Scheme 2. Controlled experiment for the conversion of 1a to 3a
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material. In fact, earlier reports on such cyclizations1k-l also did not
include any nitro substituted substrates. Obviously, nucleophilic
nature of phenoxyl group is substantially reduced by the highly
electronegative nitro group and hence it cannot afford for
nucleophilic attack required in cyclization. The substrates with
embedded naphthalene ring moiety (1j) or with a pendant of
electron-withdrawing and electron-donating containing phenyl ring
on the aryl nucleus (1k-o) were found to proceed well, furnishing
3k-o in 52-92% yields.
yield of 49% whereas para-methoxy- and dimeVthieowxAyrticlpehOennlinyel
DOI: 10.1039/C6OB00191B
compounds showed good to excellent reactivities (3w and 3x, 65%
and 82% respectively). Setting a limitation, the reaction worked for
arylacetylene substrates only. The aliphatic alkyne based substrates
simply gave cyclized intermediates 2 which further did not react
with TMSN3 even after the prolonged reaction times. This indicates
that the extended conjugation from aryl groups facilitate the
azidatioꢁ at ꢂ-position while assisting the olefinic bond
isomerization (migration) to allylic position. We next aimed at the
Table 2. Evaluation of substrate scope in tandem cyclization/azidation.
Table 3. Substrate scope with respect to substitution on alkyne
terminus.
applicatioꢁ of this taꢁdeꢄ cꢀclizatioꢁ/ꢂ-azidation to indole
derivatives from readily available aminophenyl propargyl alcohols
(Table 4).1l Initially, 2-amino acetophenone based propargyl
alcohols were tested under the standard conditions. Pleasingly,
unsubstituted- and, methyl-, butyl- and methoxy-phenyl acetylenic
substrates 4a-d underwent the reaction cleanly to afford the
targeted adducts 5a-d in 68-78% yields. Propiophenone based
substrates reacted well under the standard conditions, but furnishd
the corresponding adducts (5e-f) in moderate yields of 45-52%.
Next, benzophenone derived materials were subjected to the title
transformation to obtain diaryl adducts 5g-j successfully in 45-75%
yields. Halogen (Br and Cl) containing substrates showed poor
reactivity and thus produced the corresponding products (5k-l) in
moderate yields (36-40%). X-ray crystallographilic analysis of 5b
unambiguously established its structure.12
Proceeding further, we tested the substrates with substitution
variation on alkyne terminal of 1 (Table 3). Substrates with methyl-,
n-butyl- and t-butyl-phenyl groups on alkyne (1p-r) participated well
in the reaction to give corresponding products (3p-r) in excellent
yields (70-75%). Halo substituents were found to slightly discourage
the reaction to produce the corresponding products 3s-u in
moderate 36-44% yields. Next, position and number of methoxy
groups on phenyl group were found to show clear influence on the
outcome of the reaction, demonstrating that the electronic nature
of the alkyne group is a crucial factor for the reaction. Thus 1v with
meta-methoxyphenyl group led to the product (3v) in moderate
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Scheme 3. Synthesis of triazoles
6 and tetrazoles 7 from
Table 4. Conversion of aminophenyl propargyl alcohols
azidomethyl indoles
4 to
azidomethyl benzoheteroles.
5
.
Scheme 4. Regioselective oxidative cleavage of 3 to 8.
Further, the synthetic utility of the above 2-azidomethyl
benzoheteroles obtained via tandem cyclization/azidation reaction
was examined. A substrate from each category was subjected to
triazolation (click reaction) with phenyl acetylene to obtain 6a-b in
92-95% yields (Scheme 3A). An oxidative cleavage for tetrazole
forꢄatioꢁ usiꢁg Jiao’s coꢁditioꢁs13 surprisingly led to selective
formation of regioisomers 7a-b12 via preferential migration of
phenyl group over benzofuranyl group (Scheme 3B). Using this
information, we immediately verified the fate of similar oxidative
cleavage14 for amide formation (Scheme 4). Pleasingly, when
treated 3q with 10 mol% FeCl2 and equiv DDQ in aqueous acetic
acid furnished a single regioisomer 8a in 68% yield along with 12%
of the ketone (2- benzoylfuran) via mere oxidation. Considering the
significance of benzofuranamides in medicinal chemistry,15 we
examined the reaction for its generality. Similar to the phenyl
migration in 3q for 8a synthesis, methoxy- and dimethoxy phenyl
groups also migrated selectively as with the synthesis of 8b-c in 50-
58% yields. The reaction was smoother also with alkyl substitution
on the benzofuran nucleus. Thus, 8d-e were obtained in 70% yields.
Afterward, continuing the various possible derivatizations of the
adducts, azide group in 3a was reduced to obtain corresponding
amine 9 in 85% yield using 2.2 equiv PPh3 in aqueous THF (Scheme
5). It was then tosylated to obtain known compound 1016 to
unambiguously establish the structure of 3a, as none of the
compound in this category was reported in the literature.
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Scheme 5. Structure establishement of 3a via conversion to known
compound 10.
was demonstrated by the conversion of azidomethyl unit to various
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other useful functionalities via reduction, oxidation and cyclization
reactions.
Experimental Section
General Information: All reagents and solvents were purchased
from commercial sources and used without purification. NMR
1
spectra were recorded with a 400 MHz spectrometer for H NMR,
100 MHz for 13C NMR spectroscopy. Chemical shifts are reported
relative to the residual signals of tetramethylsilane in CDCl3 or
deuterated solvent CDCl3 for 1H and 13C NMR spectroscopy.
Multiplicities are reported as follows: singlet (s), doublet (d),
doublet of doublets (dd), triplet (t), quartet (q), multiplet (m). HRMS
were recorded by using QTof mass spectrometer. Starting materials
was prepared by literature procedure.18 Column chromatography
was performed with silica gel (100–200 mesh) as the stationary
phase. All reactions were monitored by using TLC. The purity and
characterization of compounds were further established by using
HRMS.
Finally, we attempted an oxidative [4+2] cycloaddition with alkyne
diester 11 to obtain benzofuropyridine nucleus 12 (Scheme 6). The
thought was aroused based on the knowledge that azides get
oxidized to imines,17 which in facilitating appropriate reaction
conditions might undergo an in situ Diels-Alder reaction with
asuitable dienophile. With the higher electron density, olefin group
in benzofuran should join imine to form diene unit over the one in
phenyl group. As expected, the reaction of 3a with 11 with 5 mol%
[RuCl2(p-cymene)]2, 1 equiv Cu(OAc)2 and 2 equiv of NaOAc in DCE
at 80 oC cleanly furnished the cyclized adduct 12a in 70% yield.
Three more similar adducts were synthesized with methyl
substitution either on core nucleus or the pendant phenyl ring.
2.1. General Procedure for the Synthesis of 3 from 1 Using the
Synthesis of 3a as an Example:
Scheme 6. Oxidative [4+2] addition of 3 with alkyne diesters for
benzofurano pyridines 11.
To a stirred solution of 2-(1-hydroxy-3-phenylprop-2-yn-1-yl) phenol
1a (112 mg, 0.5 mmol) in 2 mL of DMSO was added Ag2CO3 (6.8 mg,
0.025 mmol) and heated to 80 oC for 2h, Then added TMSN3 (115
mg, 1 mmol) at the same temperature and stirred for 6h. The
reaction mixture was cooled to rt then diluted with water (10 ml)
and extracted with EtOAc (2x10 ml). The combined extracts were
washed with brine (15 mL) and dried over Na2SO4. After removal of
the solvent under reduced pressure crude material was purified by
column chromatography (silica gel, using 2-5% EtoAc in hexanes) to
get pure product 3a (106 mg, 86%) as yellow oil.
2-(azido(phenyl)methyl)benzofuran (3a): 86% yield (106 mg);
1
yellow oil; Rf = 0.80 (SiO2, 10% EtOAc/Hexanes); H NMR (400 MHz,
CDCl3ꢅ ꢆ: 7.55-7.53 (m, 1H); 7.47-7.38 (m, 6H); 7.31-7.26 (m, 1H);
7.24-7.20 (m, 1H); 6.60 (s, 1H); 5.78 (s, 1H); 13C NMR (100 MHz,
CDCl3ꢅ ꢆ: ꢇꢈꢈ.ꢉ, ꢇꢈꢈ.ꢊ, ꢇꢋꢌ.ꢉ, ꢇꢍꢎ.ꢊ, ꢇꢍꢎ.ꢊ, ꢇꢍꢏ.ꢐ, ꢇꢍꢏ.ꢏ, ꢇꢍꢉ.ꢐ,
ꢇꢍꢋ.ꢇ, ꢇꢍꢇ.ꢉ, ꢇꢇꢇ.ꢈ, ꢇꢊꢈ.ꢌ, ꢌꢍ.ꢏ; IR ν ꢑcꢄ-1) 3393, 1637, 1069, 669;
HRMS (ESI-TOF) m/z calcd for C15H12NO[M + H - N2]+ 222.0919,
found 222.0911.
2-(azido(phenyl)methyl)-7-methylbenzofuran (3b): 90% yield (118
1
mg); yellow oil; Rf = 0.80 (SiO2, 10% EtOAc/Hexanes); H NMR (400
MHz, CDCl3ꢅ ꢆ: ꢏ.ꢈꢊ-7.38 (m, 6H); 7.16 (t, J = 7.3 Hz, 1H); 7.16 (d, J =
7.3 Hz, 1H); 6.58 (s, 1H); 5.82 (s, 1H); 2.54 (s, 3H); 13C NMR (100
MHz, CDCl3ꢅ ꢆ: ꢇꢈꢉ.ꢏ, ꢇꢈꢉ.ꢈ, ꢇꢋꢌ.ꢈ, ꢇꢍꢐ.ꢎ, ꢇꢍꢐ.ꢐ, ꢇꢍꢏ.ꢏ,
ꢇꢍꢏ.ꢍ,ꢇꢍꢈ.ꢏ, ꢇꢍꢋ.ꢍ, ꢇꢍꢇ.ꢏ, ꢇꢇꢐ.ꢏ, ꢇꢊꢈ.ꢎ, ꢌꢍ.ꢌ, ꢇꢈ.ꢇ; IR ν ꢑcꢄ-1) 3400,
2101, 1644, 1069, 668; HRMS (ESI-TOF) calcd for C16H14NO[M + H -
N2]+ 236.1075, found 236.1068.
In summary, an efficient synthetic route to 2-azidomethyl
benzoheteroles based on tandem Ag(I)-catalyzed intramolecular
cꢀclizatioꢁ aꢁd aroꢄatizatioꢁ driveꢁ ꢂ-azidation from readily
available linear propargyl alcohols is reported. While it did not
require exclusion of air or moisture, the reaction was applicable
over a wide range of substrates. The synthetic utility of the reaction
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2-(azido(phenyl)methyl)-5-methylbenzofuran (3c): 62% yield (81 2-(azido(phenyl)methyl)naphtho[1,2-b]furan (3j): 52% yield
1
1
mg); yellow oil; Rf = 0.80 (SiO2, 10% EtOAc/Hexanes); H NMR (400 (78mg); yellow semi solid; Rf = 0.80 (SiO2, 10% EtOAc/Hexanes); H
MHz, CDCl3ꢅ ꢆ: ꢏ.ꢉꢈ ꢑꢄ, ꢌHꢅ; ꢏ.ꢍꢏ ꢑd, J = 0.6 Hz, 1H); 7.06-7.04 (m, NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢊꢏ ꢑd, J = 8.0 Hz, 1H); 7.93 (d, J = 8.0 Hz,
1H);6.54 (t, J = 0.8 Hz, 1H); 5.76 (s, 1H); 2.45 (s, 3H); 13C NMR (100 1H); 7.73 (d, J = 8.9 Hz, 1H); 7.62 (d, J = 8.9 Hz, 1H); 7.59-7.55 (m,
MHz, CDCl3ꢅ ꢆ: ꢇꢈꢈ.ꢊ, ꢇꢈꢋ.ꢐ, ꢇꢋꢌ.ꢉ, ꢇꢋꢍ.ꢌ, ꢇꢍꢐ.ꢎ, ꢇꢍꢐ.ꢎ, ꢇꢍꢏ.ꢎ, 1H); 7.50-7.41 (m, 6H); 7.67 (s, 1H); 5.89 (s, 1H); 13C NMR (100 MHz,
ꢇꢍꢏ.ꢏ, ꢇꢍꢌ.ꢊ, ꢇꢍꢇ.ꢇ, ꢇꢇꢇ.ꢊ, ꢇꢊꢈ.ꢉ, ꢌꢍ.ꢏ, ꢍꢇ.ꢉ; IR ν ꢑcꢄ-1) 3423, 2101, CDCl3ꢅ ꢆ: ꢇꢈꢉ.ꢍ, ꢇꢈꢋ.ꢊ, ꢇꢋꢌ.ꢈ, ꢇꢋꢇ.ꢐ, ꢇꢋꢊ.ꢉ, ꢇꢍꢎ.ꢊ, ꢇꢍꢎ.ꢊ, ꢇꢍꢐ.ꢎ,
1639, 1070, 668; HRMS (ESI-TOF) calcd for C16H14NO[M + H - N2]+ ꢇꢍꢏ.ꢏ, ꢇꢍꢌ.ꢈ, ꢇꢍꢈ.ꢐ, ꢇꢍꢉ.ꢐ, ꢇꢍꢋ.ꢉ, ꢇꢍꢋ.ꢊ, ꢇꢇꢍ.ꢉ, ꢇꢊꢉ.ꢐ, ꢌꢍ.ꢐ; IR ν
236.1075, found236.1068.
(cm-1) 3400, 2102, 1638, 1069, 669; HRMS (ESI-TOF) calcd for
C19H14NO[M + H - N2]+ 272.1075, found 272.1065.
2-(azido(phenyl)methyl)-6,7-dimethylbenzofuran (3d): 81% yield
1
(112 mg); yellow oil; Rf = 0.80 (SiO2, 10% EtOAc/Hexanes); H NMR 2-(azido(phenyl)methyl)-5-phenylbenzofuran (3k): 92% yield (149
(400 MHz, CDCl3ꢅ ꢆ: ꢏ.ꢉꢎ-7.42 (m, 5H); 7.28 (d, J = 7.8 Hz, 2H); 7.07 mg); yellow solid; mp 85-87 oC; Rf
= 0.80 (SiO2, 10%
1
(d, J = 7.8 Hz, 2H); 6.53 (s, 1H); 5.80 (s, 1H); 2.45 (s, 3H); 2.41 (s, 3H); EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢏ.ꢏꢋ ꢑt, J = 1.1 Hz,
13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢈꢈ.ꢊ, ꢇꢈꢉ.ꢍ, ꢇꢋꢌ.ꢌ, ꢇꢋꢋ.ꢍ, ꢇꢍꢐ.ꢐ, 1H); 7.62-7.59 (m, 2H); 7.52 (d, J = 1.1 Hz, 2H); 7.48-7.41 (m, 7H);
ꢇꢍꢐ.ꢐ, ꢇꢍꢏ.ꢏ, ꢇꢍꢈ.ꢍ, ꢇꢍꢈ.ꢇ, ꢇꢍꢊ.ꢊ, ꢇꢇꢏ.ꢐ, ꢇꢊꢈ.ꢎ, ꢌꢍ.ꢏ, ꢇꢎ.ꢍ, ꢇꢇ.ꢐ; IR ν 7.36 (s, 1H); 6.66 (s, 1H); 5.81 (s, 1H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ:
(cm-1) 3399, 2101, 1642, 1070, 669; HRMS (ESI-TOF) calcd for 155.6, 155.0, 141.6, 136.9, 136.3, 129.0, 128.9, 128.3, 127.7, 127.5,
C17H16NO[M + H - N2]+ 250.1232, found 250.1231.
ꢇꢍꢏ.ꢇ, ꢇꢍꢉ.ꢈ, ꢇꢇꢎ.ꢐ, ꢇꢇꢇ.ꢌ, ꢇꢊꢈ.ꢐ, ꢌꢍ.ꢏ; IR ν ꢑcꢄ-1) 3399, 2102, 1601,
1070, 669; HRMS (ESI-TOF) calcd for C21H16NO[M +H - N2]+
298.1232, found 298.1231.
2-(azido(phenyl)methyl)-5-(tert-butyl)benzofuran (3e): 85% yield
1
(129 mg); yellow oil; Rf = 0.80 (SiO2, 10% EtOAc/Hexanes); H NMR
(400 MHz, CDCl3ꢅꢆ: ꢏ.ꢈꢈ ꢑs, ꢇHꢅ; ꢏ.ꢉꢈ-7.36 (m, 7H); 6.60 (s, 1H); 5.78 2-(azido(phenyl)methyl)-5-(4-ethylphenyl)benzofuran (3l): 90%
1
(s, 1H); 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢈꢈ.ꢊ, ꢇꢈꢋ.ꢌ, yield (158 mg); yellow oil; Rf = 0.80 (SiO2, 10% EtOAc/Hexanes); H
146.3, 136.5, 128.9, 128.9, 127.7, 127.5, 122.8, 117.5, 110.8, 105.8, NMR (400 MHz, CDCl3ꢅ ꢆ: 7.73-7.72 (m, 1H); 7.55-751 (m, 4H); 7.47-
ꢌꢍ.ꢏ, ꢋꢉ.ꢐ, ꢋꢇ.ꢎ; IR ν ꢑcꢄ-1) 3400, 3019, 1638, 1069, 669; HRMS (ESI- 7.40 (m, 5H); 7.30 (d, J = 8.3 Hz, 2H); 6.66 (s, 1H); 5.81 (s, 1H); 2.72
TOF) calcd for C19H20NO[M + H - N2]+ 278.1545, found 278.1537.
(q, J = 7.5 Hz, 2H); 1.31 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
ꢆ: ꢇꢈꢈ.ꢈ, ꢇꢈꢉ.ꢎ, ꢇꢉꢋ.ꢍ, ꢇꢋꢐ.ꢎ, ꢇꢋꢌ.ꢎ, ꢇꢋꢌ.ꢋ, ꢇꢍꢎ.ꢊ, ꢇꢍꢐ.ꢉ, ꢇꢍꢐ.ꢋ,
127.ꢏ, ꢇꢍꢏ.ꢉ, ꢇꢍꢉ.ꢉ, ꢇꢇꢎ.ꢌ, ꢇꢇꢇ.ꢌ, ꢇꢊꢈ.ꢐ, ꢌꢍ.ꢏ, ꢍꢐ.ꢌ, ꢇꢈ.ꢏ; IR ν ꢑcꢄ-1)
3400, 2102, 1638, 1069, 669; HRMS (ESI-TOF) calcd for C23H20NO[M
+ H - N2]+ 326.1545, found 326.1543.
2-(azido(phenyl)methyl)-5-bromobenzofuran (3f): 56% yield (91
1
mg); yellow oil; Rf = 0.80 (SiO2, 10% EtOAc/Hexanes); H NMR (400
MHz, CDCl3ꢅ ꢆ: ꢏ.ꢌꢉ ꢑd, J = 1.9 Hz, 1H); 7.44-7.30 (m, 7H); 6.55 (s,
1H); 5.76 (s, 1H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢈꢌ.ꢉ ꢇꢈꢉ.ꢇ, ꢇꢋꢌ.ꢊ,
129.8, 129.1, 129.1, 127.7, 127.7, 124.0, 116.2, 113.0, 105.0, 62.6; 2-(azido(phenyl)methyl)-5-(4-methoxyphenyl)benzofuran
IR ν ꢑcꢄ-1) 3400, 2103, 1644, 1069, 669; HRMS (ESI-TOF) calcd for (3m):88% yield (156 mg); white solid; mp 78-80 o C; Rf = 0.80 (SiO2,
1
1
C15H11BrNO[M + H - N2]+ 300.0024, found 300.0019.
10% EtOAc/Hexanes); H NMR (400 MHz, CDCl3) H NMR (400 MHz,
CDCl3ꢅ ꢆ: 7.69 (t, J = 0.9 Hz, 1H); 7.54 (d, J = 8.8 Hz, 2H); 7.49-7.41
(m, 7H); 7.00 (d, J = 8.8 Hz, 2H); 6.65 (s, 1H); 5.80 (s, 1H); 3.86 (s,
3H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢈꢎ.ꢊ, ꢇꢈꢈ.ꢈ, ꢇꢈꢉ.ꢏ, ꢇꢋꢌ.ꢌ, ꢇꢋꢌ.ꢋ,
134.1, 129.0, 128.5, 128.3, 127.7, 124.2, 119.3, 114.3, 111.5, 105.8,
ꢌꢍ.ꢏ, ꢈꢈ.ꢉ; IR ꢑꢁeatꢅ ν ꢋꢉꢊꢊ, ꢍꢇꢊꢍ, ꢇꢌꢋꢎ, ꢇꢊꢌꢎ, ꢌꢌꢎ; HRMS ꢑESI-TOF)
calcd for C22H18NO2 [M + H - N2]+ 328.1338, found 328.1333.
2-(azido(phenyl)methyl)-5-chlorobenzofuran (3g): 45% yield (63
1
mg); yellow oil; Rf = 0.80 (SiO2, 10% EtOAc/Hexanes); H NMR (400
MHzꢅ ꢆ: ꢏ.ꢈꢊ ꢑd, J = 2.0 Hz, 1H); 7.44-7.36 (m, 6H); 7.24 (dd, J = 8.6,
2.0 Hz, 1H); 6.56 (s, 1H); 5.77 (s, 1H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ:
156.6, 153.7, 136.0, 129.1, 129.1, 129.1, 128.8, 127.7, 125.0, 120.9,
ꢇꢇꢍ.ꢈ, ꢇꢊꢈ.ꢇ, ꢌꢍ.ꢌ; IR ν ꢑcꢄ-1) 3400, 2103, 1644, 1068, 669; HRMS
(ESI-TOF) calcd for C15H11ClNO[M + H - N2]+ 256.0529, found 5-(2-(azido(phenyl)methyl)benzofuran-5-yl)benzo[d][1,3]dioxole
256.0513.
(3n): 78% yield (143 mg); yellow oil; Rf = 0.80 (SiO2, 10%
EtOAc/Hexanes); 1H NMR (400 MHz, CDCl3ꢅꢆ: ꢏ.ꢌꢋ (d, J = 1.3 Hz,
1H); 7.48-7.39 (m, 7H); 7.07-7.03 (m, 2H); 6.89-6.87 (d, J = 7.9 Hz,
1H); 6.66 (S, 1H); 6.00 (s, 2H); 5.79 (s, 1H); 13C NMR (100 MHz,
CDCl3ꢅ ꢆ: ꢇꢈꢈ.ꢌ, ꢇꢈꢉ.ꢐ, ꢇꢉꢐ.ꢍ, ꢇꢉꢌ.ꢎ, ꢇꢋꢌ.ꢏ, ꢇꢋꢌ.ꢋ, ꢇꢋꢌ.ꢊ, ꢇꢍꢎ.ꢊ,
128.3, 127.7, 124.3, 120.9, 119.5, 111.6, 108.6, 108.1, 105.7, 101.2,
ꢌꢍ.ꢏ, ꢍꢎ.ꢐ; IR ν ꢑcꢄ-1) 3399, 2102, 1638, 1069, 669; HRMS (ESI-TOF)
calcd for C22H16NO3[M + H - N2]+ 342.1130, found 342.1128
2-(azido(phenyl)methyl)-6-methoxybenzofuran (3h): 58% yield (81
1
mg); yellow oil; Rf = 0.80 (SiO2, 10% EtOAc/Hexanes); H NMR (400
MHzꢅ ꢆ: ꢏ.ꢉꢐ-7.40 (m, 6H); 7.03 (d, J = 2.0 Hz, 1H); 6.90 (dd, J = 8.5,
2.2 Hz, 1H); 6.54 (s, 1H); 5.77 (s, 1H); 3.84 (s, 3H); 13C NMR (100
MHz, CDCl3ꢅ ꢆ: ꢇꢈꢐ.ꢋ, ꢇꢈꢌ.ꢉ, ꢇꢈꢋ.ꢐ, ꢇꢋꢌ.ꢈ, ꢇꢍꢐ.ꢎ, ꢇꢍꢐ.ꢐ, ꢇꢍꢏ.ꢌ,
ꢇꢍꢇ.ꢉ, ꢇꢍꢊ.ꢎ, ꢇꢇꢍ.ꢋ, ꢇꢊꢈ.ꢌ, ꢎꢌ.ꢊ, ꢌꢍ.ꢏ, ꢈꢈ.ꢏ; IR ν ꢑcꢄ-1) 3399, 2101,
1624, 1069, 669; HRMS (ESI-TOF) calcd for C16H14NO2 [M + H - N2]+
252.1025, found 252.1017.
2-(azido(phenyl)methyl)-5-(6-methoxynaphthalen-2-yl)benzofuran
(3o): 85% yield (172 mg); white solid; mp 87-89 o C; Rf = 0.80 (SiO2,
1
10% EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢏ.ꢎꢌ ꢑd, J = 1.4
6 | J. Name., 2012, 00, 1-3
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Hz, 1H); 7.82-7.78 (m, 3H); 7.71 (dd, J = 8.5, 1.6 Hz, 1H); 7.62 (dd, J = HRMS (ESI-TOF) calcd for C15H11FNO[M + H - N2]+ 24V0ie.0w8A2rt5ic,lefoOunlninde
DOI: 10.1039/C6OB00191B
8.6, 1.8 Hz, 1H); 7.53 (d, J = 8.5 Hz, 1H); 7.48-7.40 (m, 5H); 7.20-7.17 240.0825.
(m, 2H); 6.67 (s, 1H); 5.81 (s, 1H); 3.94 (s, 3H); 13C NMR (100 MHz,
2-(azido(4-fluorophenyl)methyl)benzofuran (3u): 40% yield (53
CDCl3ꢅ ꢆ: ꢇꢈꢏ.ꢐ, ꢇꢈꢈ.ꢌ, ꢇꢈꢉ.ꢎ, ꢇꢋꢌ.ꢎ, ꢇꢋꢌ.ꢏ, ꢇꢋꢌ.ꢋ, ꢇꢋꢋ.ꢏ, ꢇꢍꢎ.ꢏ,
1
mg); yellow oil; Rf = 0.80 (SiO2, 10% EtOAc/Hexanes); H NMR (400
129.3, 129.0, 128.4, 127.7, 127.4, 126.5, 125.9, 124.6, 119.9, 119.3,
ꢇꢇꢇ.ꢏ, ꢇꢊꢈ.ꢐ, ꢇꢊꢈ.ꢏ, ꢌꢍ.ꢏ, ꢈꢈ.ꢉ; IR ν ꢑcꢄ-1) 3399, 2102, 1632, 1069,
MHz, CDCl3ꢅ ꢆ: ꢏ.ꢈꢍ ꢑdd, J = 7.5, 0.6 Hz, 1H ); 7.45-7.37 (m, 3H);
669; HRMS (ESI-TOF) calcd for C26H20NO2 [M +H - N2]+ 378.1495,
7.29-7.25 (m, 1H); 7.23-7.19 (m, 1H); 7.11-7.05 (m, 2H); 6.59 (s, 1H);
5.75 (s, 1H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢌꢋ.ꢊ ꢑd, J = 248 Hz),
found 378.1489.
155.4, 154.6, 132.2, 129.5 (d, J = 8 Hz), 127.7, 124.9, 123.2, 121.4,
2-(azido(p-tolyl)methyl)benzofuran (3p): 75% yield (98 mg); yellow 116.0, 115.8 (d, J = ꢍꢇ Hzꢅ, ꢇꢊꢈ.ꢌ, ꢌꢍ.ꢊ; IR ν ꢑcꢄ-1) 3399, 1643, 1069,
1
oil; Rf = 0.80 (SiO2, 10% EtOAc/Hexanes); H NMR (400 MHz, CDCl3) 669; HRMS (ESI-TOF) calcd for C15H11FNO[M + H - N2]+ 240.0825,
ꢆ: ꢏ.ꢈꢈ-7.53 (m, 1H); 7.46 (dd, J = 8.0, 0.6 Hz, 1H); 7.33 (d, J = 8.1 Hz, found 240.0825.
2H); 7.31-7.27 (m, 2H); 7.25-7.21 (m, 3H); 6.61 (t, J = 0.8 Hz, 1H);
5.75 (s, 1H); 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢈꢈ.ꢉ, ꢇꢈꢈ.ꢍ,
2-(azido(3-methoxyphenyl)methyl)benzofuran (3v): 49% yield (67
1
mg); yellow oil; Rf = 0.60 (SiO2, 10% EtOAc/Hexanes); H NMR (400
138.9, 133.3, 129.6, 127.8, 127.7, 124.7, 123.1, 121.3, 111.5, 105.4,
ꢌꢍ.ꢌ, ꢍꢇ.ꢋ; IR ν ꢑcꢄ-1) 3399, 2092, 1645, 1069, 747; HRMS (ESI-TOF)
MHz, CDCl3ꢅ ꢆ: ꢏ.ꢈꢋ ꢑd, J = 7.2 Hz, 1H); 7.45 (dd, J = 8.1, 0.5 Hz, 1H);
calcd for C16H14NO[M + H - N2]+ 236.1075, found 236.1068.
7.33 (t, J = 8.0 Hz, 1H); 7.30-7.26 (m, 1H); 7.23-7.20 (m, 1H); 7.01 (d,
J = 7.6 Hz, 1H); 6.99 (t, J = 2.1 Hz, 1H); 6.93-6.91 (m, 1H); 6.61 (s,
2-(azido(4-butylphenyl)methyl)benzofuran (3q): 70% yield (106 1H); 5.75 (s, 1H); 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢌꢊ.ꢇ,
1
mg); yellow oil; Rf = 0.70 (SiO2, 10% EtOAc/Hexanes); H NMR (400 155.4, 154.8, 137.8, 130.0, 127.8, 124.8, 123.1, 121.4, 120.0, 114.4,
MHz, CDCl3ꢅ ꢆ: ꢏ.ꢈꢐ-7.56 (m, 1H); 7.50 (d, J = 7.9 Hz, 1H); 7.38 (d, J = ꢇꢇꢋ.ꢉ, ꢇꢇꢇ.ꢈ, ꢇꢊꢈ.ꢌ, ꢌꢍ.ꢌ, ꢈꢈ.ꢉ; IR ν ꢑcꢄ-1) 3399, 3019, 1601, 1069,
8.1 Hz, 2H); 7.34-7.24 (m, 4H); 6.64 (s, 1H); 5.78 (s, 1H); 2.67 (t, J = 669; HRMS (ESI-TOF) calcd for C16H14NO2 [M + H - N2]+ 252.1025,
7.6 Hz, 2H); 1.69-1.62 (m, 2H); 1.46-1.37 (m, 2H); 0.98 (t, J = 7.1 Hz, found252.1017.
3H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢈꢈ.ꢋ, ꢇꢈꢈ.ꢍ, ꢇꢉꢋ.ꢐ, ꢇꢋꢋ.ꢈ, ꢇꢍꢎ.ꢊ,
2-(azido(4-methoxyphenyl)methyl)benzofuran (3w): 65% yield (90
ꢍꢍ.ꢉ, ꢇꢉ.ꢊ; IR ν ꢑcꢄ-1) 3399, 2101, 1638, 1069, 668 ; HRMS (ESI-TOF)
mg); yellow oil; Rf = 0.60 (SiO2, 10% EtOAc/Hexanes); H NMR (400
127.8, 127.6, 124.7, 123.1, 121.3, 111.5, 105.4, 62.6, 35.4, 33.5,
1
calcd for C19H20NO[M + H - N2]+ 278.1545, found 278.1537.
MHz, CDCl3ꢅ ꢆ: ꢏ.ꢈꢏ-7.52 (m, 1H); 7.45 (dd, J = 7.9, 0.6, 1H); 7.38-
7.34 (m, 2H); 7.30-7.20 (m, 2H); 6.96-6.92 (m, 2H); 6.66 (s, 1H); 5.73
2-(azido(4-(tert-butyl)phenyl)methyl)benzofuran (3r): Yield 72 % (s, 1H); 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢌꢊ.ꢇ, ꢇꢈꢈ.ꢉ,
(109 mg);yellow gum; Rf = 0.70 (SiO2, 10% EtOAc/Hexanes); 1H NMR 155.3, 129.1, 128.4, 127.8, 124.7, 123.1, 121.3, 114.4, 111.5, 105.4,
(400 MHz, CDCl3ꢅ ꢆ: ꢏ.ꢈꢌ ꢑd, J = 7.5 Hz, 1H); 7.52-7.43 (m, 3H); 7.43- ꢌꢍ.ꢋ, ꢈꢈ.ꢉ; IR ν ꢑcꢄ-1) 3400, 1639, 1329, 1068, 669; HRMS (ESI-TOF)
7.35 (m, 2H); 7.35-7.20 (m, 2H); 6.64 (s, 1H); 5.78 (s, 1H); 1.36 (s, calcd for C16H14NO2 [M + H - N2]+ 252.1025, found 252.1017.
9H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢈꢈ.ꢉ, ꢇꢈꢈ.ꢇ, ꢇꢈꢍ.ꢊ, ꢇꢋꢋ.ꢋ, ꢇꢍꢎ.ꢐ,
2-(azido(3,4-dimethoxyphenyl)methyl)benzofuran (3x): 82% yield
127.9, ꢇꢍꢈ.ꢎ, ꢇꢍꢉ.ꢏ, ꢇꢍꢋ.ꢇ, ꢇꢍꢇ.ꢋ, ꢇꢇꢇ.ꢈ, ꢇꢊꢈ.ꢈ, ꢌꢍ.ꢈ, ꢋꢉ.ꢐ, ꢋꢇ.ꢉ; IR ν
1
(127 mg); yellow oil; Rf = 0.40 (SiO2, 10% EtOAc/Hexanes); H NMR
(cm-1) 1644, 1217, 1069, 668 cm-1; HRMS (ESI-TOF) calcd for
C19H20NO[M + H - N2]+ 278.1545, found 278.1535.
(400 MHz, CDCl3ꢅ ꢆ: ꢏ.ꢈꢈ-7.53 (m, 1H); 7.46 (dd, J = 8.0, 0.5 Hz, 1H);
7.31-7.21 (m, 2H); 7.00-6.96 (m, 2H); 6.88 (d, J = 8.1 Hz, 1H); 6.62 (s,
2-(azido(3-chlorophenyl)methyl)benzofuran (3s): 44% yield (62 1H); 5.74 (s, 1H); 3.89 (s, 3H); 3.88 (s, 3H); 13C NMR (100 MHz,
1
mg); yellow oil; Rf = 0.80 (SiO2, 10% EtOAc/Hexanes); H NMR (400 CDCl3ꢅ ꢆ: ꢇꢈꢈ.ꢋ, ꢇꢈꢈ.ꢇ, ꢇꢉꢎ.ꢈ, ꢇꢉꢎ.ꢉ, ꢇꢍꢐ.ꢏ, ꢇꢍꢏ.ꢏ, ꢇꢍꢉ.ꢏ, ꢇꢍꢋ.ꢇ,
MHz, CDCl3ꢅ ꢆ: ꢏ.ꢈꢏ-7.55 (m, 1H); 7.48-7.45 (m, 2H); 7.38-7.29 (m, ꢇꢍꢇ.ꢋ, ꢇꢍꢊ.ꢋ, ꢇꢇꢇ.ꢉ, ꢇꢇꢇ.ꢇ, ꢇꢇꢊ.ꢌ, ꢇꢊꢈ.ꢋ, ꢌꢍ.ꢈ, ꢈꢌ.ꢊ, ꢈꢌ.ꢊ; IR ν ꢑcꢄ-1)
4H); 7.26-7.24 (m, 1H); 6.64 (s, 1H); 5.77 (s, 1H); 13C NMR (100 MHz, 3019, 2102, 1730, 1645, 1156, 669 cm-1; HRMS (ESI-TOF) calcd for
CDCl3ꢅ ꢆ: ꢇꢈꢈ.ꢉ, ꢇꢈꢉ.ꢇ, ꢇꢋꢐ.ꢉ, ꢇꢋꢉ.ꢎ, ꢇꢋꢊ.ꢍ, ꢇꢍꢎ.ꢇ, ꢇꢍꢏ.ꢐ, ꢇꢍꢏ.ꢌ, C17H16NO3[M + H - N2]+ 282.1130, found 282.1134.
125.8, ꢇꢍꢈ.ꢊ, ꢇꢍꢋ.ꢋ, ꢇꢍꢇ.ꢈ, ꢇꢇꢇ.ꢌ, ꢇꢊꢈ.ꢎ, ꢌꢍ.ꢊ; IR ν ꢑcꢄ-1) 3400,
2-(azido(phenyl)methyl)-3-methyl-1-tosyl-1H-indole (5a): 78%
2103, 1644, 1069, 668; HRMS (ESI-TOF) calcd for C15H11ClNO[M + H
- N2]+ 256.0529, found 256.0513.
yield (162 mg); white solid; mp 136-138 oC; Rf = 0.70 (SiO2, 10%
1
EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢍꢎ ꢑd, J = 7.9 Hz,
2-(azido(3-fluorophenyl)methyl)benzofuran (3t): 36% yield (48 1H); 7.52 (d, J = 7.2 Hz, 2H); 7.46-7.37 (m, 3H); 7.32-7.27 (m, 5H);
1
mg); yellow oil; Rf = 0.80 (SiO2, 10% EtOAc/Hexanes); H NMR (400 7.13 (d, J = 7.2 Hz, 2H); 6.99 (s, 1H); 2.32 (s, 3H); 2.05 (s, 3H); 13C
MHz, CDCl3ꢅ ꢆ: ꢏ.ꢈꢎ-7.57 (m, 1H); 7.50 (dd, J = 8.0, 0.6 Hz, 1H); 7.42- NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢉꢈ.ꢇ, ꢇꢋꢐ.ꢊ, ꢇꢋꢌ.ꢏ, ꢇꢋꢈ.ꢎ, ꢇꢋꢋ.ꢊ , ꢇꢋꢇ.ꢍ,
7.37 (m, 1H); 7.35-7.31 (m, 1H); 7.29-7.20 (m, 3H); 7.13-7.08 (m, 129.9, 128.6, 127.8, 127.0, 126.5, 125.7, 123.8, 121.4, 119.2, 115.6,
1H); 6.66 (s, 1H); 5.80 (s, 1H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢌꢍ.ꢐ ꢑd, ꢌꢊ.ꢇ, ꢍꢇ.ꢌ, ꢎ.ꢐ; IR ν ꢑcꢄ-1) 3399, 1643, 1068, 768; HRMS (ESI-TOF)
J = 247 Hz), 155.4, 154.2, 138.8 (d, J = 7 Hz), 130.5 (d, J = 8 Hz), calcd for C23H21N2O2S [M + H - N2]+ 389.1324, found 389.1320.
127.6, 125.0, 123.3, 123.2, 121.4, 115.9 (d, J = 21 Hz), 114.7 (d, J =
ꢍꢍ Hzꢅ, ꢇꢇꢇ.ꢈ, ꢇꢊꢈ.ꢐ, ꢌꢍ.ꢊ; IR ν ꢑcꢄ-1) 3399, 2013, 1644, 1069, 669;
2-(azido(p-tolyl)methyl)-3-methyl-1-tosyl-1H-indole (5b): 70% yield
(150 mg); white solid; mp 116-118 oC; Rf = 0.70 (SiO2, 10%
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DOI: 10.1039/C6OB00191B
1
EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢋꢊ ꢑd, J = 8.3 Hz, 2-(azido(phenyl)methyl)-3-phenyl-1-tosyl-1H-indole (5g): 65% yield
1H); 7.54-7.52 (m, 2H); 7.49-7.47 (m, 1H); 7.41-7.39 (m, 1H);7.34- (155 mg); white solid; mp 140-142 oC; Rf = 0.70 (SiO2, 10%
1
7.28 (m, 2H); 7.15-7.13 (m, 6H); 6.96 (s, 1H); 2.36 (s, 3H); 2.34 (s, EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢋꢊ ꢑd, J = 8.5 Hz,
3H); 2.10 (s, 3H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢉꢉ.ꢎ, ꢇꢋꢏ.ꢈ, ꢇꢋꢌ.ꢌ, 1H); 7.68 (d, J = 8.3 Hz, 2H); 7.42-7.38 (m, 1H); 7.26-7.19 (m, 7H);
135.8, 134.9, 133.0, 131.2, 129.8, 129.2, 126.9, 126.4, 125.5, 123.7, 7.12-7.08 (m, 5H); 7.05-7.03 (m, 2H); 6.82 (s, 1H); 2.36 (s, 3H); 13C
ꢇꢍꢇ.ꢇ, ꢇꢇꢎ.ꢇ, ꢇꢇꢈ.ꢈ, ꢌꢊ.ꢊ, ꢍꢇ.ꢈ, ꢍꢇ.ꢇ, ꢎ.ꢐ; IR ν ꢑcꢄ-1) 3399, 2099, NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢉꢈ.ꢇ, ꢇꢋꢐ.ꢊ, ꢇꢋꢌ.ꢉ, ꢇꢋꢌ.ꢊ, ꢇꢋꢋ.ꢈ, 132.0,
1638, 1069, 668; HRMS (ESI-TOF) calcd for C24H23N2O2S [M + H - N2]+ 130.6, 130.1, 129.9, 128.0, 127.9, 127.6, 127.5, 127.2, 126.6, 126.5,
403.1480, found 403.1468.
ꢇꢍꢈ.ꢎ, ꢇꢍꢋ.ꢎ, ꢇꢍꢊ.ꢉ, ꢇꢇꢈ.ꢍ, ꢌꢊ.ꢍ, ꢍꢇ.ꢌ; IR ν ꢑcꢄ-1) 3399, 2100, 1637,
1069, 669; HRMS (ESI-TOF) calcd for C28H23N2O2S [M + H - N2]+
451.1480, found 451.1471.
2-(azido(4-(tert-butyl)phenyl)methyl)-3-methyl-1-tosyl-1H-indole
(5c): 68% yield (160 mg); yellow gum; Rf = 0.70 (SiO2, 10%
1
EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢍꢐ ꢑd, J = 8.4 Hz, 2-(azido(p-tolyl)methyl)-3-phenyl-1-tosyl-1H-indole (5h): 52% yield
1H); 7.48-7.45 (m, 3H); 7.40-7.36 (m, 1H); 7.32-7.28 (m, 3H); 7.19 (127 mg); white solid; mp 130-132 oC; Rf = 0.50 (SiO2, 10%
1
(d, J = 7.8 Hz, 2H); 7.08 (d, J = 8.3 Hz, 2H); 6.96 (s, 1H); 2.31 (s, 3H); EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢍꢎ ꢑd, J = 8.5 Hz,
2.12 (s, 3H); 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢈꢊ.ꢎ, ꢇꢉꢉ.ꢎ, 1H); 7.65 (d, J = 7.6 Hz, 2H); 7.42-7.38 (m, 1H); 7.28-7.25 (m, 3H);
136.7, 135.9, 134.9, 133.1, 131.3, 129.8, 126.8, 126.5, 125.6, 125.5, 7.23-7.21 (m, 2H); 7.18 (d, J = 8.0 Hz, 2H); 7.13-7.02 (m, 2H); 6.96-
123.8, 121.2, 119.1, ꢇꢇꢈ.ꢌ, ꢌꢊ.ꢇ, ꢋꢉ.ꢌ, ꢋꢇ.ꢉ, ꢍꢇ.ꢌ, ꢎ.ꢐ; IR ν ꢑcꢄ-1) 6.91 (m, 4H); 6.75 (s, 1H); 2.36 (s, 3H); 2.26 (s, 3H); 13C NMR (100
3399, 2100, 1639, 1069, 669; HRMS (ESI-TOF) calcd for C27H29N2O2S MHz, CDCl3ꢅ ꢆ: ꢇꢉꢈ.ꢇ, ꢇꢋꢏ.ꢇ, ꢇꢋꢌ.ꢌ, ꢇꢋꢌ.ꢇ, ꢇꢋꢈ.ꢇ, ꢇꢋꢋ.ꢏ, ꢇꢋꢍ.ꢋ,
[M + H - N2]+ 445.1950, found 445.1948.
130.8, 130.2, 129.9, 128.8, 128.1, 127.7, 127.4, 126.7, 125.9, 124.0,
ꢇꢍꢊ.ꢈ, ꢇꢇꢈ.ꢋ, ꢌꢊ.ꢉ, ꢍꢇ.ꢏ, ꢍꢇ.ꢇ; IR ν ꢑcꢄ-1) 3399, 1642, 1068, 669;
HRMS (ESI-TOF) calcd for C29H25N2O2S [M + H - N2]+ 465.1637, found
465.1627.
2-(azido(4-methoxyphenyl)methyl)-3-methyl-1-tosyl-1H-indole
(5d): 72% yield (160 mg); yellow gum; Rf = 0.50 (SiO2, 10%
1
EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢍꢈ ꢑd, J = 8.3 Hz,
1H);7.48-7.46 (m, 3H); 7.37-7.36 (m, 1H); 7.31-7.29 (m, 1H); 7.16 (d, 2-(azido(4-(tert-butyl)phenyl)methyl)-3-phenyl-1-tosyl-1H-indole
J = 8.5 Hz, 2H); 7.09 (d, J = 8.0 Hz, 2H); 6.91 (s, 1H); 6.82-6.80 (m, (5i): 45% yield (120 mg); yellow gum; Rf = 0.50 (SiO2, 10%
1
2H); 3.79 (s, 3H); 2.31 (s, 3H); 2.11 (s, 3H); 13C NMR (100 MHz, EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢋꢊ ꢑd, J = 8.5 Hz,
CDCl3ꢅ ꢆ: ꢇꢈꢎ.ꢋ, ꢇꢉꢈ.ꢊ, ꢇꢋꢌ.ꢏ, ꢇꢋꢈ.ꢎ, ꢇꢋꢋ.ꢍ, ꢇꢋꢇ.ꢋ, ꢇꢋꢊ.ꢊ, ꢇꢍꢎ.ꢎ, 1H); 7.67 (d, J = 8.2 Hz, 2H); 7.41-7.37 (m, 1H); 7.23-7.19 (m, 8H);
128.4, 126.5, 125.6, 123.8, 121.1, 119.1,115.6, 114.0, 60.0, 55.4, 7.10-7.08 (m, 4H); 6.94 (d, J = 8.2 Hz, 2H); 6.81 (s, 1H); 2.36 (s, 3H);
ꢍꢇ.ꢌ, ꢎ.ꢎ; IR ν ꢑcꢄ-1) 3399, 2099, 1609, 1089, 667; HRMS (ESI-TOF) 1.26 (s, 9H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢈꢊ.ꢍ, ꢇꢉꢈ.ꢇ, ꢇꢋꢌ.ꢈ,
calcd for C24H23N2O3S [M + H - N2]+ 419.1429, found 419.1428.
136.1, 135.0, 134.0, 132.2, 130.9, 130.2, 129.9, 128.0, 127.6, 127.5,
126.7, 126.5, 125.9, 124.9, 124.0, 120.5, 115.3, 60.3, 34.5, 31.4,
ꢍꢇ.ꢏ; IR ν ꢑcꢄ-1) 3400, 2101, 1638, 1069, 668; HRMS (ESI-TOF) calcd
for C32H30NO2S [M - N3]+ 492.1997, found 492.1998.
2-(azido(phenyl)methyl)-3-propyl-1-tosyl-1H-indole (5e): 45% yield
(100 mg); white solid; mp 82-84 oC; Rf = 0.50 (SiO2, 10%
1
EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢋꢊ ꢑd, J = 8.4 Hz,
2H); 7.58-7.55 (m, 1H); 7.40-7.35 (m, 1H); 7.29-7.25 (m, 7H); 7.15 2-(azido(4-methoxyphenyl)methyl)-3-phenyl-1-tosyl-1H-indole
(d, J = 7.9 Hz, 2H); 7.00 (s, 1H); 2.50-2.37 (m, 2H); 2.33 (s, 3H); 1.48- (5j): 75% yield (190 mg); yellow gum; Rf = 0.50 (SiO2, 10%
1
1.39 (m, 1H); 1.19-1.10 (m, 1H); 0.77 (t, J = 7.3 Hz, 3H); 13C NMR EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢍꢎ (d, J = 8.4 Hz,
(100 MHz, CDCl3ꢅ ꢆ: ꢇꢉꢈ.ꢇ, ꢇꢋꢐ.ꢈ, ꢇꢋꢏ.ꢊ, ꢇꢋꢌ.ꢇ, ꢇꢋꢍ.ꢎ, ꢇꢋꢊ.ꢌ, ꢇꢍꢎ.ꢎ, 1H); 7.65 (d, J = 8.4 Hz, 2H); 7.42-7.37 (m, 1H); 7.29-7.27 (m, 3H);
128.5, 127.7, 126.7, 126.5, 126.2, 125.5, 123.7, 119.7, 115.7, 59.9, 7.23-7.18 (m,4H); 7.12 (d, J =3.6 Hz, 2H); 6.98 (d, J = 8.3 Hz, 2H);
ꢍꢏ.ꢊ, ꢍꢍ.ꢏ, ꢍꢇ.ꢈ, ꢇꢉ.ꢉ; IR ν ꢑcꢄ-1) 3400, 2101, 1638, 1069, 668; 6.76 (s, 1H); 6.65 (d, J = 8.8 Hz, 2H); 3.74 (s, 3H); 2.36 (s, 3H); 13C
HRMS (ESI-TOF) calcd for C25H25N2O2S [M + H - N2]+ 417.1637, found NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢈꢐ.ꢎ, ꢇꢉꢈ.ꢇ, ꢇꢋꢌ.ꢈ, ꢇꢋꢌ.ꢍ, ꢇꢋꢋ.ꢎ, ꢇꢋꢍ.ꢋ,
417.1629.
130.9, 130.2, 129.9, 128.1, 127.7, 127.3, 126.7, 125.9, 124.0, 120.5,
ꢇꢇꢈ.ꢋ, ꢇꢇꢋ.ꢈ, ꢌꢊ.ꢍ, ꢈꢈ.ꢉ, ꢍꢇ.ꢏ; IR ν ꢑcꢄ-1) 3399, 3019, 2100, 1637,
1069, 668; HRMS (ESI-TOF) calcd for C29H25N2O3S [M + H - N2]+
481.1586, found 481.1574.
2-(azido(p-tolyl)methyl)-3-isopropyl-1-tosyl-1H-indole (5f): 52%
yield (115 mg); yellow gum; Rf = 0.50 (SiO2, 10% EtOAc/Hexanes); 1H
NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢋꢐ ꢑd, J = 8.5 Hz, 1H); 7.69 (d, J = 7.7 Hz,
1H); 7.63-7.61 (m, 2H); 7.40-7.36 (m, 1H); 7.28-7.23 (m, 4H); 7.22- 2-(azido(phenyl)methyl)-5-bromo-3-methyl-1-tosyl-1H-indole (5k):
7.16 (m, 4H); 7.07 (s, 1H); 3.12-3.01 (m, 1H); 2.35 (s, 3H); 1.32 (d, J = 40% yield (98 mg); yellow gum; Rf 0.50 (SiO2, 10%
=
1
7.0 Hz, 3H); 0.88 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢇꢌ ꢑdd, J = 8.9, 0.3
145.3, 138.7, 137.7, 136.2, 132.1, 130.9, 130.0, 128.6, 128.3, 127.5, Hz, 1H); 7.58-7.57 (m, 1H); 7.50-7.46 (m, 3H); 7.31-7.27 (m, 3H);
126.6, 126.4, 125.1, 123.2, 121.7, 115.9, 59.3, 26.3, 22.2, 21.6, 20.3; 7.24-7.21 (m, 2H); 7.15-7.12 (m, 2H); 6.94 (s, 1H); 2.33 (s, 3H); 2.01
IR ν ꢑcꢄ-1) 3400, 2100, 1597, 1069, 669; HRMS (ESI-TOF) calcd for (s, 3H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢉꢈ.ꢈ, ꢇꢋꢏ.ꢏ, ꢇꢋꢈ.ꢌ, ꢇꢋꢈ.ꢉ,
C25H25N2O2S [M + H - N2]+ 417.1637, found 417.1629.
134.4, 133.0, 130.1, 128.7, 128.5, 128.0, 126.9, 126.5, 122.1, 120.5,
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
ꢇꢇꢏ.ꢉ, ꢇꢇꢏ.ꢇ, ꢌꢊ.ꢊ, ꢍꢇ.ꢏ, ꢎ.ꢐ; IR ν ꢑcꢄ-1) 3400, 2101, 1597, 1068, DDQ (227 mg, 1.0 mmol), TMSN3 (115 mg, 1.0 mmolV),ie4w AArticMle OSn(l5in0e
o
668; HRMS (ESI-TOF) calcd for C23H19BrNO2S [M - N3]+ 452.0320, mg) at room temperature under nitrogen atmosphere. The reaction
DOI: 10.1039/C6OB00191B
found 452.0316.
mixture was stirred at 80 oC until complete conversion of starting
material monitored by TLC (8h). The reaction mixture was diluted
with water (10ml) and extracted with EtOAc (2x10ml). The
combined extracts were dried over Na2SO4. After removal of the
solvent under reduced pressure the crude material was purified by
column chromatography (silica gel, using 20% EtoAc in hexanes) to
get pure product 7a (104 mg, 80 %) as white solid.
2-(azido(phenyl)methyl)-5-chloro-3-phenyl-1-tosyl-1H-indole (5l):
36% yield (92 mg); yellow gum; Rf
= 0.50 (SiO2, 10%
1
EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢍꢉ ꢑd, J = 8.9 Hz,
1H); 7.66 (d, J = 8.4 Hz, 2H); 7.37-7.34 (m, 1H); 7.28-7.22 (m, 5H);
7.16 (d, J = 2.0 Hz, 2H); 7.12-7.08 (m, 2H); 7.06-7.00 (m, 4H); 6.80 (s,
1H); 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢉꢈ.ꢈ, ꢇꢋꢏ.ꢐ, ꢇꢋꢈ.ꢐ,
135.1, 134.8, 132.1, 131.4, 130.1, 130.0, 128.3, 128.1, 128.0, 127.5, 5-(benzofuran-2-yl)-1-phenyl-1H-tetrazole (7a): 80% yield (104
ꢇꢍꢌ.ꢐ, ꢇꢍꢌ.ꢏ, ꢇꢍꢌ.ꢌ, ꢇꢍꢌ.ꢍ, ꢇꢍꢊ.ꢊ, ꢇꢇꢌ.ꢈ, ꢌꢊ.ꢍ, ꢍꢇ.ꢏ; IR ν ꢑcꢄ-1) 3399, mg); white solid; mp 150-152 oC; Rf
0.5 (SiO2, 20%
=
2100, 1638, 1072, 668; HRMS (ESI-TOF) calcd for C28H22ClN2O2S [M + EtOAc/Hexanes);1H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢏ.ꢏꢍ-7.58 (m, 4H);
H - N2]+ 485.1091, found 485.1080.
7.58-7.50 (m, 2H); 7.48-7.42 (m, 1H); 7.42-7.34 (m, 1H); 7.33-7.23
(m, 1H); 7.15 (s, 1H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢈꢈ.ꢌ, ꢇꢉꢏ.ꢊ,
140.3, 134.4, 131.1, 129.9, 127.2, 127.1, 125.9, 124.2, 122.4, 112.1,
ꢇꢇꢇ.ꢉ; IR ν ꢑcꢄ-1) 3019, 1645, 1069, 909, 669 cm-1; HRMS (ESI-TOF)
calcd for C15H11N4O [M + H]+ 263.0933, found 263.0934.
General Procedure for the Synthesis of 6a & 6b from 3s & 5a.
Using the Synthesis of 6a as an Example:
t
Azide3s (152 mg, 0.5 mmol) was dissolved in BuOH/H2O (1:2 v/v,
1.5 mL), were added CuSO4.5H2O (6.2 mg, 0.025 mmol), sodium
ascorbate (4.9 mg, 0.025 mmol), and phenylacetylene (102 mg, 1
mmol) at rt. The reaction mixture was stirred for 4 hours at the
same temperature, then CH2Cl2 (10 mL) was added to the crude
mixture and extracted with water. The water layers were extracted
2 times with CH2Cl2. The combined extracts were dried over Na2SO4,
filtered and concentrated. The crude product was purified by
column chromatography (silica gel, using 10-15% EtoAc in hexanes)
to get pure product 6a (187 mg, 92%) as a yellow gum.
5-(benzofuran-2-yl)-1-(4-methoxyphenyl)-1H-tetrazole (7b):60%
1
yield (88 mg); yellow gum; Rf = 0.5 (SiO2, 20% EtOAc/Hexanes); H
NMR (400 MHz, CDCl3ꢅ ꢆ: ꢏ.ꢌꢊ ꢑd, J = 7.5 Hz, 1H); 7.54-7.34 (m, 4H);
7.34-7.21 (m, 1H); 7.18-6.98 (m, 3H); 3.93 (s, 3H); 13C NMR (100
MHz, CDCl3ꢅ ꢆ: ꢇꢌꢇ.ꢈ, ꢇꢈꢈ.ꢌ, ꢇꢉꢏ.ꢍ, ꢇꢉꢊ.ꢍ, ꢇꢋꢌ.ꢐ, ꢇꢍꢏ.ꢉ, ꢇꢍꢏ.ꢍ,
ꢇꢍꢏ.ꢇ, ꢇꢍꢉ.ꢇ, ꢇꢍꢍ.ꢋ, ꢇꢇꢈ.ꢊ, ꢇꢇꢍ.ꢇ, ꢇꢇꢇ.ꢇ, ꢈꢈ.ꢐ; IR ν ꢑcꢄ-1) 3019,
1644, 1385, 1069, 909, 668 cm-1; HRMS (ESI-TOF) calcd for
C16H13N4O2 [M + H]+ 293.1039, found 293.1031.
General Procedure for the Synthesis of 8 from 3. Using the
Synthesis of 8a as an Example:
1-(benzofuran-2-yl(4-(tert-butyl)phenyl)methyl)-4-phenyl-1H-
1,2,3-triazole (6a): 92% yield (187 mg); yellow gum; Rf = 0.60 (SiO2,
20% EtOAc/Hexanes); 1H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢏ.ꢐꢌ-7.82 (m, To a stirred solution of 2-(azido(4-butylphenyl)methyl)benzofuran
3H); 7.56 (d, J = 7.6 Hz, 1H); 7.48 (d, J = 8.2 Hz, 1H); 7.43-7.38 (m, (152 mg, 0.5 mmol,) in 2 mL of AcOH was added FeCl2 (7 mg, 0.01
4H); 7.27-7.21 (m, 4H); 6.68 (s, 1H); 1.32 (s, 9H); 13C NMR (100 MHz, mmol), DDQ (227 mg, 1.0 mmol), TMSN3 (115 mg, 1.0 mmol), H2O
CDCl3ꢅ ꢆ: ꢇꢈꢈ.ꢈ, ꢇꢈꢍ.ꢎ, ꢇꢈꢍ.ꢉ, ꢇꢉꢐ.ꢊ, ꢇꢋꢍ.ꢎ, ꢇꢋꢊ.ꢌ, ꢇꢍꢐ.ꢎ, ꢇꢍꢐ.ꢋ, (18 mg, 1.0 mmol) at room temperature under nitrogen
127.6, 127.3, 126.2, 125.9, 125.3, 123.4, 121.6, 119.5, 111.7, 107.7, atmosphere. The reaction mixture was stirred at rt until complete
ꢌꢍ.ꢉ, ꢋꢉ.ꢐ, ꢋꢇ.ꢋ; IR ν ꢑcꢄ-1) 3400, 3019, 1643, 1068, 669; HRMS (ESI- conversion of starting material (6h). The reaction mixture was
TOF) calcd for C27H26N3O [M + H]+ 408.2076, found 408.2074.
neutralized with Na2CO3 (1 g), and evaporated under reduced
pressure. The residue was diluted with water (10ml) and extracted
with CH2Cl2 (2x15ml). The combined extracts were dried over
Na2SO4. After removal of the solvent under reduced pressure, crude
material was purified by column chromatography (silica gel, using 8-
12% EtoAc in hexanes) to get pure product 8a (100 mg, 68 %) as
yellow gum.
3-methyl-2-(phenyl(4-phenyl-1H-1,2,3-triazol-1-yl)methyl)-1-tosyl-
1H-indole (6b): 95% yield (246mg); yellow solid; mp 220-222 oC; Rf =
1
0.30 (SiO2, 10% EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: 8.29-
8.26 (m, 2H); 7.79 (d, J = 7.9 Hz, 2H); 7.63 (s, 1H); 7.47-7.40 (m, 4H);
7.35-7.30 (m, 5H); 7.19 (d, J = 8.1 Hz, 2H); 6.93-6.87 (m, 4H); 2.08 (s,
3H); 1.76 (s, 3H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢉꢏ.ꢍ, ꢇꢉꢉ.ꢎ, ꢇꢋꢐ.ꢇ,
136.8, 135.2, 131.7, 131.1, 130.4, 129.6, 128.8, 128.2, 128.1, 126.5, N-(4-butylphenyl)benzofuran-2-carboxamide (8a): 68% yield
126.1, 125.9, 125.6, 123.9, 123.9, 120.8, 119.4, 115.7, 59.7, 21.2, (100mg); yellow gum; Rf = 0.60 (SiO2, 20% EtOAc/Hexanes); 1H NMR
ꢎ.ꢎ; IR ν ꢑcꢄ-1) 3400, 1643, 1384, 1071, 668; HRMS (ESI-TOF) calcd (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢋꢍ ꢑs, ꢇHꢅ; ꢏ.ꢏꢋ ꢑd, J = 7.9 Hz, 1H); 7.67-7.56
for C31H27N4O2S [M + H]+ 519.1855, found 519.1844.
(m, 4H); 7.48 (t, J = 7.6 Hz, 1H); 7.35 (t, J = 7.6 Hz, 1H); 7.23 (d, J =
7.8 Hz, 2H); 2.63 (t, J = 7.2 Hz, 2H); 1.68-1.58 (m, 2H); 1.43-1.34 (m,
2H); 0.96 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢈꢌ.ꢌ,
154.9, 148.8, 139.8, 134.9, 129.2, 127.9, 127.3, 124.0, 122.9, 120.2,
ꢇꢇꢇ.ꢎ, ꢇꢇꢇ.ꢉ, ꢋꢈ.ꢋ, ꢋꢋ.ꢐ, ꢍꢍ.ꢉ, ꢇꢉ.ꢇ; IR ν ꢑcꢄ-1) 3408, 1652, 1390,
1067, 759; HRMS (ESI-TOF) calcd for C19H20NO2 [M + H]+ 294.1494,
found 294.1485.
General Procedure for the Synthesis of 7 from 3. Using the
Synthesis of 7a as an Example:
To a stirred solution of 2-(azido(phenyl)methyl)benzofuran (124 mg,
0.5 mmol) in 2 mL of CH3CN was added CuI (10mg, 0.05 mmol),
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J. Name., 2013, 00, 1-3 | 9
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DOI: 10.1039/C6OB00191B
N-(4-methoxyphenyl)benzofuran-2-carboxamide (8b): 58% yield column chromatography (silica gel, using 10-12% EtoAc in hexanes)
(77mg); white solid; mp 118-120 oC; Rf
0.60 (SiO2, 20% to get pure product 9 (95 mg, 85% yield) as a white solid
=
EtOAc/Hexanes); 1H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢍꢈ ꢑs, ꢇHꢅ; ꢏ.ꢏꢋ-7.67
(m, 1H); 7.65-7.59 (m, 2H); 7.59-7.52 (m, 2H); 7.48-7.41 (m, 1H);
7.36-7.28 (m, 1H); 6.95-6.89 (m, 2H); 3.82 (s, 3H); 13C NMR (100
MHz, CDCl3ꢅ ꢆ: ꢇꢈꢌ.ꢎ, ꢇꢈꢌ.ꢌ, ꢇꢈꢉ.ꢎ, ꢇꢉꢐ.ꢏ, ꢇꢋꢊ.ꢉ, ꢇꢍꢏ.ꢐ, ꢇꢍꢏ.ꢍ,
ꢇꢍꢋ.ꢎ, ꢇꢍꢍ.ꢎ, ꢇꢍꢇ.ꢎ, ꢇꢇꢉ.ꢉ, ꢇꢇꢇ.ꢐ, ꢇꢇꢇ.ꢍ, ꢈꢈ.ꢌ; IR ν ꢑcꢄ-1) 3400,
1644, 1070, 772; HRMS (ESI-TOF) calcd for C16H14NO3 [M + H]+
268.0974, found 268.0968
benzofuran-2-yl(phenyl)methanamine (9): 85% yield (95 mg);
colourless oil; Rf = 0.40 (SiO2, 30% EtOAc/Hexanes); 1H NMR (400
MHz, CDCl3ꢅ ꢆ: ꢏ.ꢈꢋ-7.49 (m, 1H); 7.48-7.35 (m, 5H); 7.34-7.29 (m,
1H); 7.26-7.17 (m, 2H); 6.52 (s, 1H); 5.30 (s, 1H); 1.96 (s, 2H); 13C
NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢌꢊ.ꢎ, ꢇꢈꢈ.ꢇ, ꢇꢉꢍ.ꢋ, ꢇꢍꢐ.ꢐ, ꢇꢍꢐ.ꢉ, ꢇꢍꢏ.ꢎ,
ꢇꢍꢏ.ꢍ, ꢇꢍꢋ.ꢎ, ꢇꢍꢍ.ꢐ, ꢇꢍꢊ.ꢎ, ꢇꢇꢇ.ꢋ, ꢇꢊꢍ.ꢐ, ꢈꢉ.ꢌ; IR ν ꢑcꢄ-1) 3670,
3398, 1638, 1068, 669; HRMS (ESI-TOF) calcd for C15H11O [M - NH2]
N-(3,4-dimethoxyphenyl)benzofuran-2-carboxamide (8c): Yield +207.0810, found 207.0811.
50% (74mg); light yellow gum; Rf = 0.40 (SiO2,20% EtOAc/Hexanes);
1H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢍꢎ ꢑs, ꢇHꢅ; ꢏ.ꢏꢊ ꢑd, J = 7.8 Hz, 1H);
7.60-7.49 (m, 3H); 7.49-7.38 (m, 1H); 7.36-7.27 (m, 1H); 7.09 (dd, J =
General Procedure for the Synthesis of 10 from 9:
To a stirred solution of benzofuran-2-yl(phenyl)methanamine (111
mg, 0.5 mmol) in 3 mL of CH2Cl2 was added TEA (151mg, 1.5 mmol).
8.6, 2.4 Hz, 1H); 6.87 (d, J = 8.6 Hz, 1H); 3.93 (s, 3H); 3.89 (s, 3H); 13
C
NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢈꢌ.ꢌ, ꢇꢈꢉ.ꢎ, ꢇꢉꢎ.ꢋ, ꢇꢉꢐ.ꢏ, ꢇꢉꢌ.ꢉ, ꢇꢋꢊ.ꢎ,
127.8, 127.3, 124.0, 112.1, 111.9, 111.5, 111.3, 105.0, 56.2, 56.1; IR
ν ꢑcꢄ-1) 3399, 1645, 1385, 104569, 669; HRMS (ESI-TOF) calcd for
C17H16NO4 [M + H]+ 298.1079, found 298.1071
o
Reaction mixture was cooled to 0 C then added TsCl (105 mg, 0.55
mmol), slowly reaction mixture was heated to room temperature
and stirred until complete conversion of starting material
monitored by TLC (12h). The reaction mixture was diluted with
water (10ml) and extracted with EtOAc (2x10ml). The combined
extracts were dried over Na2SO4. After removal of the solvent under
reduced pressure crude material was purified by column
chromatography (silica gel, using 6-8% EtoAc in hexanes) to get
pure product 10 (171 mg, 91 %) as light yellow solid.
6-methyl-N-phenylbenzofuran-2-carboxamide (8d): 70% yield
1
(88mg); yellow gum; Rf = 0.60 (SiO2, 20% EtOAc/Hexanes); H NMR
(400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢋꢇ ꢑs, ꢇHꢅ; ꢏ.ꢏꢉ-7.71 (m, 2H); 7.59 (s, 1H);
7.54-7.50 (m, 1H); 7.42-7.37 (m, 2H); 7.27-7.21 (m, 2H); 7.20-7.16
(m, 1H); 2.60 (s, 3H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢈꢌ.ꢎ, ꢇꢈꢉ.ꢍ,
148.3, 137.3, 129.3, 128.2, 127.4, 124.9, 124.1, 122.2, 120.4, 120.3,
ꢇꢇꢍ.ꢊ, ꢇꢈ.ꢋ; IR ν ꢑcꢄ-1) 3429, 1638, 1385, 1068, 769; HRMS (ESI-
TOF) calcd for C16H14NO2 [M + H]+ 252.1025, found 252.1024.
N-(benzofuran-2-yl(phenyl)methyl)-4-methylbenzenesulfonamide
(10): 91% yield (171 mg); light yellow solid; mp 150-152 oC; Rf = 0.60
(SiO2, 20% EtOAc/Hexanes); 1H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢏ.ꢈꢌ ꢑd, J =
8.3 Hz, 1H); 7.41 (m, 1H); 7.26-7.13 (m, 8H); 7.00 (d, J = 7.9 Hz, 1H);
6.40 (s, 1H); 5.74 (d, J = 8.0 Hz, 1H); 5.39 (d, J = 8.0 Hz, 1H); 2.22 (s,
3H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢈꢉ.ꢎ, ꢇꢈꢉ.ꢉ, ꢇꢉꢋ.ꢉ, ꢇꢋꢏ.ꢏ, ꢇꢋꢏ.ꢇ,
129.2, 128.8, 128.4, 127.8, 127.4, 127.2, 124.4, 123.0, 121.1, 111.2,
105.6, 55.9, 21.4; IR ν ꢑcꢄ-1) 3399, 1643, 1385, 1068, 669; HRMS
(ESI-TOF) calcd for C22H19NNaO3S [M + Na]+ 400.0983, found
400.0993.
5-(tert-butyl)-N-phenylbenzofuran-2-carboxamide (8e): 70% yield
(102mg); white solid; mp;134-136 oC; Rf
= 0.60 (SiO2, 20%
EtOAc/Hexanes);1H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢏ.ꢏꢉ-7.70 (m, 2H);
7.68 (dd, J = 1.9, 0.5 Hz, 1H); 7.56 (d, J = 0.9 Hz, 1H); 7.53 (dd, J =
8.9, 1.9 Hz, 1H); 7.49-7.46 (m, 1H); 7.41-7.37 (m, 2H); 7.19-7.14 (m,
1H); 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢈꢌ.ꢐ, ꢇꢈꢋ.ꢋ, ꢇꢉꢐ.ꢏ,
147.3, 137.4, 129.3, 127.6, 125.6, 124.8, 120.1, 118.9, 111.9, 111.2,
ꢋꢉ.ꢎ, ꢋꢇ.ꢐ; IR ν ꢑcꢄ-1) 3399, 3019, 1644, 1068, 669; HRMS (ESI-TOF)
calcd for C19H20NO2 [M + H]+ 294.1494, found 294.1485.
General Procedure for the Synthesis of 12 from 3. Using the
Synthesis of 12a as an Example:
General Procedure for the Synthesis of 9 from 3:
To a stirred solution of 2-(azido(phenyl)methyl)benzofuran (124 mg,
0.5 mmol,) in 2 mL of DCE was added [RuCl2(p-cymene)]2 (15 mg,
0.025 mmol), Cu(OAc)2 (90 mg, 0.5 mmol), NaOAc (82 mg, 1.0
mmol), alkyne (170 mg, 0.6 mmol) at room temperature under
nitrogen atmosphere. The reaction mixture was heated to 80 oC and
stirred until complete conversion of starting material (12h). The
reaction mixture was cooled to room temperature and diluted with
water (10ml) and extracted with EtOAc (2x10ml). The combined
extracts were dried over Na2SO4. After removal of the solvent under
reduced pressure crude material was purified by column
chromatography (silica gel, using 10-15% EtoAc in hexanes) to get
pure product 12a (135 mg, 70%) as yellow gum.
Azide3a (124 mg, 0.5 mmol) was dissolved in a mixture of THF (1.5
mL) and H2O (0.3 mL) and treated with PPh3 (288 mg, 1.1 mmol).
The reaction was stirred overnight at room temperature under
nitrogen atmosphere and then the reaction mixture was
concentrated by rotary evaporation. The residue was transferred
into a separatory funnel with CH2Cl2 and extracted twice with HCl
1M (4.0 mL). The acid aqueous layer was washed 4 times with
EtOAc (5.0 mL). The aqueous phase was then made basic (pH: 10-
11) with NaOH 2M and extracted with DCM (5.0 mL). The last
combined organic layers were dried over Na2SO4. After removal of
the solvent under reduced pressure crude material was purified by
10 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
diethyl 4-phenyldibenzo[b,d]furan-1,2-dicarboxylate (12a): 70%
yield (135 mg); yellow gum; Rf = 0.40 (SiO2, 20% EtOAc/Hexanes); 1H
NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢈꢋ-8.49 (m, 2H); 8.21 (d, J = 8.0 Hz, 1H);
7.75 (d, J = 8.3 Hz, 1H); 7.71-7.66 (m, 1H); 7.62-7.57 (m, 2H); 7.55-
7.50 (m, 1H); 7.49-7.44 (m, 1H); 4.60 (q, J = 7.2 Hz, 2H); 4.51 (q, J =
7.2 Hz, 2H); 1.48 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ:
166.4, 165.8, 157.5, 150.9, 143.2, 141.6, 135.0, 131.0, 130.8, 130.4,
129.4, 128.9, 124.4, 124.3, 122.5, 121.0, 112.7, 62.5, 62.3, 14.4,
ꢇꢉ.ꢍ; IR ν ꢑcꢄ-1) 3398, 3019, 1719, 1632, 1066, 769, 669; HRMS (ESI-
TOF) calcd for C23H20NO5[M + H]+ 390.1341, found 390.1331.
Notes and references
View Article Online
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Almendros and J. M. Alonso, Org. Biomol. Chem. 2011,
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9
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3395. (i) S. P. Bew, G. M. M. E. Taeb, S. Jones, D. W. Knight
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diethyl 4-(p-tolyl)dibenzo[b,d]furan-1,2-dicarboxylate (12b): 58%
yield (116mg); white solid; mp 110-112 oC; Rf = 0.40 (SiO2, 20%
1
EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢉꢇ ꢑd, J = ꢐ.ꢍ Hz,
2H); 8.21 (d, J = 8.0 Hz, 1H); 7.73 (d, J = 8.4 Hz, 1H); 7.69-7.64 (m,
1H); 7.47-7.42 (m, 1H); 7.39 (d, J = 8.2 Hz, 2H); 4.59 (q, J = 7.2 Hz,
Kothandaraman and P. W. H. Chan, J. Org. Chem. 2012, 77
,
7166. (m) H. Harkat, A. Blanc, J. -M. Weibel and P. Pale, J.
Org. Chem. 2008, 73, 1620.
2H); 4.51 (q, J = 7.2 Hz, 2H); 2.46 (s, 3H); 1.47 (t, J = 7.2 Hz, 6H); 13
C
2
3
4
a) Y. K. Kumar, G. R. Kumar and M. S. Reddy, Org. Biomol.
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Babu, V. Dwivedi, R. Kant and M. S. Reddy, Angew. Chem.
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NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢌꢌ.ꢉ, ꢇꢌꢈ.ꢎ, ꢇꢈꢏ.ꢈ, ꢇꢈꢊ.ꢏ, ꢇꢉꢋ.ꢉ, ꢇꢉꢇ.ꢌ,
140.7, 132.3, 130.9, 130.7, 129.6, 129.3, 124.4, 124.2, 122.1, 121.1,
ꢇꢇꢍ.ꢏ, ꢌꢍ.ꢉ, ꢌꢍ.ꢋ, ꢍꢇ.ꢏ, ꢇꢉ.ꢉ, ꢇꢉ.ꢍ; IR ν ꢑcꢄ-1) 3399, 1725, 1644,
1385, 1065, 769, 669; HRMS (ESI-TOF) calcd for C24H22NO5 [M + H]+
404.1498, found 404.1488.
diethyl
7-methyl-4-phenyldibenzo[b,d]furan-1,2-dicarboxylate
(12c): 62% yield (124mg); yellow gum; Rf = 0.40 (SiO2, 20%
1
EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢈꢇ ꢑꢄ, ꢍHꢅ; ꢐ.ꢊꢏ ꢑd,
J = 8.1 Hz, 1H); 7.61-7.49 (m, 4H); 7.28-7.26 (m, 1H); 4.58 (q, J = 7.2
Hz, 2H); 4.51 (q, J = 7.2 Hz, 2H); 2.58 (s, 3H); 1.49-1.44 (m, 6H); 13C
NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢌꢌ.ꢋ, ꢇꢌꢈ.ꢐ, ꢇꢈꢏ.ꢎ, ꢇꢈꢊ.ꢏ, ꢇꢉꢍ.ꢐ, ꢇꢉꢍ.ꢍ,
141.6, 134.9, 130.9, 130.1, 129.2, 128.7, 125.6, 123.8. 121.9, 118.3,
ꢇꢇꢍ.ꢌ, ꢌꢍ.ꢍ, ꢌꢍ.ꢇ, ꢍꢍ.ꢍ, ꢇꢉ.ꢍ, ꢇꢉ.ꢇ; IR ν ꢑcꢄ-1) 3399, 3020, 1648,
1068, 669; HRMS (ESI-TOF) calcd for C24H22NO5 [M + H]+ 404.1498,
found 404.1488.
(a) M. Grammel and H. C. Hang, Nat. Chem. Biol. 2013, 9,
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10882. (e) F. Chen, C. Qin, Y. Cui and N. Jiao, Angew. Chem.,
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Diethyl
8-methyl-4-phenyldibenzo[b,d]furan-1,2-dicarboxylate
(12d): 60% yield (120mg); white solid; mp 104-106 oC; Rf = 0.40
1
(SiO2, 20% EtOAc/Hexanes); H NMR (400 MHz, CDCl3ꢅ ꢆ: ꢐ.ꢈꢇ ꢑꢄ,
1992, 114, 1906. (i) E. F. V. Scriven,. Chem. Rev. 1988, 88
297. (j) R. Huisgen, Angew. Chem. Int. Ed. 1963, , 565.
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2
2H); 8.52-8.48 (m, 2H); 7.97-7.95 (m, 1H); 7.63-7.56 (m, 3H); 7.57-
7.47 (m, 2H); 4.60 (q, J = 7.2 Hz, 2H); 4.51 (q, J = 7.2 Hz, 2H); 2.53 (s,
3H); 1.51-1.45 (m, 6H); 13C NMR (100 MHz, CDCl3ꢅ ꢆ: ꢇꢌꢌ.ꢈ, ꢇꢌꢈ.ꢎ,
155.9, 151.2, 143.1, 141.3, 135.1, 134.0, 132.3, 130.7, 130.3, 129.3,
ꢇꢍꢐ.ꢐ, ꢇꢍꢉ.ꢊ, ꢇꢍꢍ.ꢌ, ꢇꢍꢊ.ꢎ, ꢇꢇꢍ.ꢍ, ꢌꢍ.ꢈ, ꢌꢍ.ꢋ, ꢍꢇ.ꢌ, ꢇꢉ.ꢉ, ꢇꢉ.ꢍ; IR ν
(cm-1) 3399, 3019, 1643, 1068, 669; HRMS (ESI-TOF) calcd for
C24H22NO5 [M + H]+ 404.1498, found 404.1488.
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Acknowledgements
5
6
GRK and YKK thank CSIR for the fellowships. We thank SAIF division
CSIR-CDRI for the analytical support and Dr. Tejender S. Thakur,
Molecular and Structural Biology Division, CSIR-CDRI for supervising
the X-ray data collection and structure determination of compounds
5b and 7a. We gratefully acknowledge the financial support by DST
(SB/FT/CS-102/2012). CDRI Communication No: (will be inserted if
accepted).
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Journal Name
View Article Online
DOI: 10.1039/C6OB00191B
7
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files of 5b and 7a
.
13 F. Chen, C. Qin, Y. Cui and N. Jiao, Angew. Chem. Int. Ed.
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Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C6OB00191B
Synthesis of benzofuranyl and indolyl methyl azides by tandem
silver-catalyzed cyclization and azidation
Gadi Ranjith Kumar, Yalla Kiran Kumar and Maddi Sridhar Reddy*
A
tandem Agꢀcatalyzed 5ꢀexoꢀdig cyclization and catalyst free γꢀazidative allylic hydroxyl displacement for
benzofuranyl/indolyl methyl azides from hydroxyl/aminoꢀphenyl propargyl alcohols is presented. The synthetic utility is
demonstrated by the conversion of azidomethyl unit to various functionalizations, like triazoleꢀ, tetrazoleꢀ, amideꢀ, amineꢀ,
pyridoꢀderivatives.