Base-Mediated Cyclocondensation of Salicylaldehydes and 2-Bromoallyl Sulfones for the Synthesis of 3-Sulfonylchromene Derivatives and Their Regioselective Friedel-Crafts Heteroarylation Reactions

Article abstract of DOI:10.1021/acs.joc.5b02324

Cesium carbonate-mediated reaction of 2-hydroxybenzaldehydes and 2-bromoallyl sulfones afforded 2H- and 4H-chromenol derivatives endowed with a 3-arylsulfonyl group. 2-Bromoallyl sulfones functioned as synthetic equivalents of allenyl sulfones under these conditions. The 2H- and 4H-chromenol derivatives underwent regioselective Friedel-Crafts reactions with heteroarenes in the presence of p-toluenesulfonic acid to afford 4-heteroaryl-4H-chromene derivatives in excellent yields.

Full text of DOI:10.1021/acs.joc.5b02324

Article
pubs.acs.org/joc
Base-Mediated Cyclocondensation of Salicylaldehydes and
2‑Bromoallyl Sulfones for the Synthesis of 3‑Sulfonylchromene
Derivatives and Their Regioselective Friedel−Crafts Heteroarylation
Reactions
Anand Kumar, Srinivas Thadkapally, and Rajeev S. Menon*
Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
S
* Supporting Information
ABSTRACT: Cesium carbonate-mediated reaction of 2-
hydroxybenzaldehydes and 2-bromoallyl sulfones afforded
2H- and 4H-chromenol derivatives endowed with a 3-
arylsulfonyl group. 2-Bromoallyl sulfones functioned as
synthetic equivalents of allenyl sulfones under these
conditions. The 2H- and 4H-chromenol derivatives underwent
regioselective Friedel−Crafts reactions with heteroarenes in the presence of p-toluenesulfonic acid to afford 4-heteroaryl-4H-
chromene derivatives in excellent yields.
Scheme 1. Base-Mediated Cyclocondensations of Salicyclic
Aldehydes and Electron Deficient Allenes for the Synthesis
of Chromene Derivatives
INTRODUCTION
■
Unsaturated 1-benzopyran derivatives, commonly known as
chromenes, form the central unit of many biologically active
natural products as well as synthetic therapeutic agents.1 The
chromene nucleus is, therefore, generally regarded as a
privileged scaffold in medicinal chemistry. It exists in two
isomeric forms, 2H-chromene 1 and 4H-chromene 2, that can
be distinguished by the site of unsaturation (Figure 1).
Figure 1. Isomeric forms of chromene.
Consequently, method development for chromene synthesis
has become an important and fertile area of investigation.2,3
Although a number of methods are available for their
construction, there is considerable demand for general
approaches that deliver substituted chromenes from readily
available precursors.
afford 2H- and 4H-chromenes (Scheme 1b).6 Our interest in
the cyclocondensation reactions of unsaturated sulfones7
prompted us to explore their utility in the synthesis of
sulfone-bearing chromenes. In the process, it was revealed that
3-sulfonylchromenes can be readily synthesized from salicyclic
aldehydes and bromoallyl sulfones 6 via a base-mediated
annulation (Scheme 1c). Importantly, the direct use of sensitive
allenyl sulfones8 was avoided by devising and exploiting a base-
mediated vinylic bromide displacement on bromoallyl sulfone
6.
Salicyclic aldehydes constitute a group of useful building
blocks for the synthesis of 1-benzopyran derivatives. Recent
investigations by Shi, Brase, and others have established that
̈
the base-mediated cyclocondensation of salicylic aldehydes and
α,β-unsaturated carbonyl compounds is a versatile method for
accessing dihydrobenzopyran derivatives.4 More pertinent to
the work reported here is the use of o-hydroxybenzaldehydes
and electron deficient allenes as building blocks for chromene
derivatives. DBU-catalyzed cyclocondensation of allenyl
phophonates 3 and salicylaldehyde 4a was developed by
Kumara Swamy (Scheme 1a).5 Shi reported that allenyl esters 5
react with 4a in the presence of catalytic quantities of base to
Received: October 7, 2015
© XXXX American Chemical Society
A
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reactivity. Salicylaldehyde as well as o-hydroxybenzaldehydes
carrying electron-donating substituents generally afforded 2H-
chromene derivatives 9 preferentially (Table 1, entries 1−6).
On the other hand, o-hydroxybenzaldehydes endowed with one
or more electron-withdrawing substituents furnished isomeric
4H-chromene derivatives 10 as the sole or major product
(Table 1, entries 8 and 10−14). Halogen-bearing salicylalde-
hydes deviated from this general trend to some extent (entries
7 and 9). It may be noted that formation of 2H- and 4H-
chromenes was observed in the base-catalyzed reactions of
salicylaldehydes and allenoates by Shi; however, no clear trend
in reactivity was discernible.6a
RESULTS AND DISCUSSION
■
The results described in this article originated from our
observation that bromoallyl sulfone 6a9 readily undergoes base-
mediated vinylic substitution reactions with nucleophiles. For
example, the treatment of 6a with 4-chlorophenol 7 in the
presence of 2 equiv of cesium carbonate afforded enol ether 8
in 84% yield (eq 1). Evidently, 8 is formed via a formal vinylic
To gain insights into the mechanistic underpinnings of this
transformation, the reaction of bromoallyl sulfones with cesium
carbonate was conducted. An inseparable mixture of allenyl
sulfone 1111 and propargyl sulfone 1212 was obtained after
workup and column chromatography. Further treatment of the
mixture of 11 and 12 with salicylaldehyde 4a and base afforded
2H-chromene 9aa in 22% yield (eq 3). The use of bromoallyl
substitution that usually requires the use of transition metal
catalysts. Analogous vinylic displacement reactions of sulfona-
mide nucleophiles and subsequent gold-catalyzed cycloisome-
rization reactions were recently developed in our laboratory.10
We surmised that under the basic conditions of vinylic
substitution, the sulfonylmethylene moiety of the enol ether
product (such as 8) may be deprotonated and engaged in an
annulation reaction with a tethered electrophile. Although
deprotonation adjacent to sulfonyl group typically requires a
strong base such as butyl lithium, our recent investigations
revealed that milder bases like cesium carbonate and DBU are
effective in promoting intramolecular condensations of sulfones
and aldehydes.7 Thus, salicylaldehyde 4a was employed as the
phenol component in the vinylic substitution, and in the event,
2H-chromene derivative 9aa was obtained as the product in
69% yield (eq 2).
sulfone 6 in this transformation is, therefore, advantageous in
view of the improved pot-economy as well as overall efficiency.
Moreover, allenyl sulfones (such as 11) are base-sensitive and
tend to undergo nucleophile-triggered oligomerization reac-
tions.8 The relative scarcity of studies involving allenyl sulfones
̀
vis-a-vis analogous allenoates may be attributed to these factors.
Here, the utility of 2-bromoallyl sufones 6a and 6b as stable and
readily available surrogates of allenyl sulfones is demonstrated.
Additionally, it was observed that 4H-chromene 10eb readily
isomerized to furnish the corresponding 2H-isomer 9eb in near
quantitative yield upon exposure to catalytic PTSA in DMSO
(eq 4).
Further experiments to explore the scope and generality of
this annulation reaction revealed an interesting pattern of
a
Table 1. Scope of the Cyclocondensation of Salicylic Aldehydes and 2-Bromoallyl Sulfones
b
entry
aldehyde
bromoallyl sulfone
6a, R4 = Ph
6b, R4 = p-tolyl
6a, R4 = Ph
6b, R4 = p-tolyl
6a, R4 = Ph
6b, R4 = p-tolyl
6a, R4 = Ph
6b, R4 = p-tolyl
6a, R4 = Ph
6b, R4 = p-tolyl
6a, R4 = Ph
time (h)
product(s)
9aa
yield (%)
1
4a, R1 = R2 = R3 = H
4a, R1 = R2 = R3 = H
1
2
3
4
2
2
2
2
4
4
4
4
4
4
69
65
61
75
55
60
52
67
53
62
66
77
55
54
2
9ab
3
4b, R1 = OMe, R2 = R3 = H
4b, R1 = OMe, R2 = R3 = H
4c, R1 = H, R2 = OMe, R3 = H
4c, R1 = H, R2 = OMe, R3 = H
4d, R1 = Cl, R2 = R3 = H
4d, R1 = Cl, R2 = R3 = H
4e, R1 = Br, R2 = R3 = H
4e, R1 = Br, R2 = R3 = H
4f, R1 = Cl, R2 = H, R3 = Br
4f, R1 = Cl, R2 = H, R3 = Br
4g, R1 = NO2, R2 = H, R3 = Br
4g, R1 = NO2, R2 = H, R3 = Br
9ba
4
9bb
5
9ca
6
9cb
7
9da
8
10db
9ea and 10ea
10eb
10fa
c
9
10
11
12
13
14
d
6b, R4 = p-tolyl
6a, R4 = Ph
6b, R4 = p-tolyl
9fb and 10fb
10ga
10gb
a
b
c
Reaction conditions: 4a−g (1.0 mmol), 6a or 6b (1.5 mmol), Cs2CO3 (2.5 mmol), and CH3CN (8 mL). Isolated yield. A 10:3 inseparable
d
mixture. A 4:10 inseparable mixture.
B
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Table 2. Optimization of Conditions for the Acid-Mediated
a
Reaction of 9aa and Indole
In view of these observations (eq 3), allenyl sulfone 11 is
deemed to be a very likely intermediate in the reaction of
salicylaldehyde with bromoallyl sulfones 6. A mechanistic
rationale for the formation of chromene derivatives is presented
in Scheme 2. Conjugate addition of the phenoxide ion 13 to the
b
entry
1
catalyst (mol %)
BF3-OEt2 (50)
solvent
products
16a
yields (%)
CH2Cl2
EtOH
CH2Cl2
EtOH
CH2Cl2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
42
16a and Et-9aa
16a
51 and 23
48
Scheme 2. Plausible Mechanistic Rationalization for the
Formation of Chromene Derivatives
2
3
Bi(OTf)3 (50)
Yb(OTf)3 (50)
16a and Et-9aa
16a
57 and 13
44
16a and Et-9aa
16a and Et-9aa
16a and Et-9aa
16a and Et-9aa
16a and Et-9aa
16a
52 and 27
40 and 15
49 and 24
51 and 28
44 and 41
72
4
AlCl3 (50)
FeCl3 (50)
SnCl4 (50)
ZnCl2 (50)
p-TSA (50)
p-TSA (60)
p-TSA (70)
5
6
7
8
9
16a
84
10
16a
99
a
Reaction conditions: indole (0.15 mmol), 9aa (0.2 mmol), acid
b
mediator (50−70 mol %), solvent (2 mL), 25 °C, 2 h. Isolated yields.
found that a variety of indoles react in an analogous fashion to
afford the corresponding 4-(3-indolyl)-4H-chromenes 16−22
in excellent yields (Table 3). Other heterocyclic aromatics such
as pyrrole and furan also furnished the corresponding 4-
hetroaryl-4H-chromenes 23−26. It is important to note that 4-
heteroaryl-4H-chromenes were formed from isomeric chrome-
nol 9 or 10. This is illustrated by the formation of products 22
and 24 from 4H-chromenol 10eb as well as the formation of 25
from 10fa. This observation is consistent with the intermediacy
of the purported benzopyrilium ion. Additionally, attempted
reactions of aromatic compounds such as thiophene, toluene,
and benzene led to the formation of ethanol-derived ketal Et-
9aa. The latter was isolated in 71% yield when the reaction was
run without any heteroarene. A variety of 4-aryl-4H-chromenes
have been shown to possess excellent anticancer activities,14
and this protocol allows for the facile construction of hitherto
unknown sulfonyl derivatives of 4-heteroaryl-4H-chromenes. It
may be mentioned here that our efforts to reductively remove
or substitute the sulfonyl groups of 4-heteroaryl-4H-chromenes
were not successful.
sulfonyl allene 11 generates an α-sulfonyl carbanion 14.
Intramolecular nucleophilic addition of the α-sulfonyl carban-
ion to the aldehyde and subsequent double-bond isomerization
affords the 4H-chromene derivative 10. Isomerization of the
latter to the 2H-chromene derivative 9 may proceed via the
benzopyrilium ion 15. A similar isomerization was observed by
Shi in the base-catalyzed reaction of salicylaldehydes with
allenyl carboxylates.6a The preferential formation of the 2H-
chromene derivatives 9 from o-hydroxybenzaldehydes carrying
electron-releasing groups on the ring may be explained by the
enhanced stability of the corresponding benzopyrilium ions 15.
The apparent involvement of benzopyrilium ions 15 in the
formation of 9 prompted us to explore the possibility of its
reactions with electron rich aromatic compounds such as indole
with an eye on generating heteroaryl chromene derivatives.13
The reaction of 9aa with indole was attempted in the presence
of various acid catalysts in ethanol and dichloromethane, and
the results are summarized in Table 2. In almost all cases, facile
conversion of 9aa to 4H-chromene 16a was observed. The 4-
(3-indolyl)-4H-chromene derivative 16a was characterized by
spectroscopic analysis. The benzylic proton of 16a appeared as
a singlet at δ 5.53, and the corresponding carbon resonated at δ
The base-mediated cyclocondensation reaction initiated by
the vinylic displacement of the bromoallyl sulfone 6a can also
be adapted for the construction of other related heterocycles
(eq 5). In light of our recent findings about the addition of
1
33.5 in the H and 13C NMR spectra. All other signals were in
agreement with the assigned structure. The reactions in ethanol
consistently afforded higher yields of 16a, albeit with varying
amounts of ethyl ketal Et-9aa. The use of p-toluenesulfonic acid
as the mediator (50 mol %), however, produced only the 4H-
chromene derivative 16a in 72% yield (entry 8). The
quantitative yield of 16a was obtained when the loading of p-
TSA was increased to 70 mol % (entry 10).
It is conceivable that the corresponding benzopyrilium ion
15 underwent a regioselective Friedel−Crafts reaction with
indole at the more accessible secondary benzylic carbon. The
scope of this reaction was examined subsequently, and it was
sulfonamide nucleophiles to bromoallyl sulfones,10 we surmised
that the β-(aminosulfonyl)aldehyde 2715 could partake in a
vinylic displacement−cyclization reaction with bromoallyl
sulfone 6a to afford a six-membered nitrogen heterocycle.
The widespread occurrence of piperidines and piperidones in
C
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a
Table 3. Scope of the p-TSA-Mediated Reaction of Heteroaromatic Compounds with 9 and 10
a
Reaction conditions: heteroarene (0.30 mmol), 2H-chromene (0.40 mmol), p-TSA (0.21 mmol), EtOH (2 mL), 25 °C, 2 h. Isolated yields given.
Reaction conducted under the conditions described in footnote a but in the absence of heteroarene.
b
natural alkaloids and synthetic compounds of medicinal
Preliminary results suggest that the vinylic bromide displace-
ment method can also be applied for the construction of six-
membered nitrogen heterocycles.
importance provided an additional impetus for this preliminary
study.16 Gratifyingly, the reaction of 27 with 6a under the
conditions of vinylic displacement afforded the substituted
piperidine 28 in 76% yield. Oxidation of the latter by
pyridinium chlorochromate (PCC) furnished the 4-piperidone
derivative 29 in 86% yield. It may be noted that the oxidation
was accompanied by the migration of the exocyclic double
bond of 28 to an endocyclic position in conjugation with the
carbonyl group (eq 5).
EXPERIMENTAL SECTION
■
All reactions were performed in flame-dried round-bottom flasks, fitted
with rubber septa under a positive pressure of nitrogen. Analytical
thin-layer chromatography (TLC) was performed using aluminum-
backed UVF254 precoated silica gel flexible plates. Removal of solvent
under reduced pressure refers to distillation with a rotary evaporator
attached to a vacuum pump (∼3 mmHg). Technical grade ethyl
acetate and petroleum ether used for column chromatography were
distilled prior to use. Column chromatography was conducted using
silica gel (60−120 mesh and 100−200 mesh) packed in glass columns.
Melting points were obtained in open capillary tubes using a
micromelting point apparatus and are uncorrected. NMR spectra
were recorded on a 300, 400, or 500 MHz nuclear magnetic resonance
spectrometer. The proton resonances are annotated as chemical shifts
(δ) relative to tetramethylsilane (δ 0.0) using the residual solvent
signal as an internal standard or tetramethylsilane itself: chloroform-d
(δ 7.26, singlet), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; br, broad), coupling constant (J, in hertz), and the
number of protons for a given resonance indicated by nH. The
chemical shifts of 13C NMR are reported in parts per million relative to
the central line of the triplet at 77.0 ppm for CDCl3. IR spectra were
recorded on an FT-IR spectrometer, and wavenumbers of maximal
absorption peaks are presented in inverse centimeters. High-resolution
mass analyses (HRMS) were performed on a mass spectrometer using
ESI-TOF techniques. Acetonitrile (LR grade), dimethyl sulfoxide (LR
CONCLUSION
■
The following important developments have emerged from this
study. (i) A transition metal-free, vinylic bromide displacement
reaction of bromoallyl sulfones 6 with phenolate nucleophiles
was discovered. (ii) Under these conditions, 6 functioned as a
synthetic equivalent of allenyl sulfones and underwent a
smooth cyclocondensation with salicylic aldehydes. (iii) The
sulfonyl chromenols thus formed underwent acid-mediated
regioselective Friedel−Crafts reactions to afford 4-heteroaryl-
4H-chromenes. Additionally, in view of the biological activities
displayed by chromenes in general and 4-aryl-4H-chromenes in
particular, the synthetic methods described here have potential
for applications in medicinal chemistry programs. The success
of p-TSA-mediated addition of heteroaromatics to the
chromenols bodes well for the development of asymmetric
versions of the reaction by using chiral Brønsted acids.17
D
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grade), ethanol (95%), cesium carbonate (AR), and p-toluenesulfonic
acid were purchased from local suppliers and used as received. 2-
Hydroxybenzaldehydes 4a−g, 2,3-dibromopropene, sodium benzene-
sulfinate, sodium p-toluenesulfinate, 3-amino-1-propanol, pyridinium
chlorochromate (PCC), and the heteroarenes used for the Friedel−
Crafts reactions were used as received from suppliers. 2-
(Bromoallylsulfonyl)benzene 6a,9 allenyl sulfone 11,11 and propargyl
sulfone 1212 are known compounds and were identified by
comparison of their spectroscopic data with the reported values. N-
(3-Oxopropyl)benzenesulfonamide 27 was prepared from 3-amino-1-
propanol as reported previously.15
3H); 13C NMR (75 MHz, CDCl3) δ 152.7, 140.4, 135.2, 134.1, 133.5,
133.2, 129.5, 129.1, 128.1, 122.2, 118.3, 117.0, 97.4, 26.6; IR (KBr)
νmax 3438, 3062, 2924, 1688, 1613, 1481, 1303, 1149, 1113, 941, 862,
751, 727, 682, 641 cm−1; HRMS (ESI) calcd for C16H14O4SNa (M +
Na) 325.0510, found 325.0508.
2-Methyl-3-tosyl-2H-chromen-2-ol (9ab). Yellow solid (205 mg,
1
65%): Rf = 0.4 (30% ethyl acetate in hexanes); mp 161−163 °C; H
NMR (300 MHz, CDCl3) δ 7.84 (d, J = 8.1 Hz, 2H), 7.79 (s, 1H),
7.38−7.33 (m, 4H), 7.07−7.02 (m, 1H), 6.97 (d, J = 8.1 Hz, 1H), 3.51
(s, 1H), 2.44 (s, 3H), 1.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
152.7, 144.6, 137.4, 134.7, 134.4, 133.1, 129.8, 129.4, 128.2, 122.2,
118.4, 117.0, 97.5, 26.5, 21.6; IR (KBr) νmax 3447, 3063, 2952, 1618,
1304, 1146, 943, 754, 676 cm−1; HRMS (ESI) calcd for C17H16O4SNa
(M + Na) 339.0667, found 339.0670.
General Procedure for the Preparation of 1-(2-Bromoallyl)-
sulfonylbenzene 6a or 1-(2-Bromoallyl)sulfonyl-4-methylben-
zene 6b. Sodium benzenesulfinate or sodium p-toluenesulfinate (10
mmol) was added to DMF (10 mL) in a round-bottom flask and left
to stir for 20 min. To this suspension was added 2,3-dibromopropene
(technical grade 80%, 1.22 mL, 10 mmol), and the mixture was stirred
at room temperature under nitrogen for 12 h. After the completion of
the reaction, ice and ethyl acetate (20 mL) were added and the
mixture was stirred for 15 min. Water (20 mL) was added, and the
organic layer was separated in a separatory funnel. The aqueous layer
was extracted with ethyl acetate (2 × 15 mL); the organic layers were
combined, and the solvent was removed on a rotavapor. The residue
obtained was purified by column chromatography on silica gel using
ethyl acetate/hexane mixtures as the eluent to obtain pure samples of
6a or 6b.
6-Methoxy-2-methyl-3-(phenylsulfonyl)-2H-chromen-2-ol (9ba).
Yellow solid (202 mg, 61%): Rf = 0.5 (30% ethyl acetate in hexanes);
mp 155−157 °C; 1H NMR (500 MHz, CDCl3) δ 7.97−7.95 (m, 2H),
7.78 (s, 1H), 7.65−7.62 (m, 1H), 7.57−7.53 (m, 2H), 6.94 (dd, J =
2.8, 8.9 Hz, 1H), 6.90 (d, J = 8.9 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H),
3.80 (s, 3H), 3.47 (s, 1H), 1.59 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 154.5, 146.8, 140.4, 135.2, 134.7, 133.5, 129.1, 128.2, 119.9, 118.6,
117.9, 112.7, 97.3, 55.8, 26.3; IR (KBr) νmax 3457, 3105, 3009, 2945,
1572, 1491, 1301, 1148, 1083, 940, 725, 690 cm−1; HRMS (ESI) calcd
for C17H16O5SNa (M + Na) 355.0616, found 355.0620.
6-Methoxy-2-methyl-3-tosyl-2H-chromen-2-ol (9bb). Pale yellow
solid (260 mg, 75%): Rf = 0.3 (30% ethyl acetate in hexanes); mp
148−150 °C; 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 7.8 Hz, 2H),
7.74 (s, 1H), 7.34 (d, J = 7.8 Hz, 2H), 6.94−6.89 (m, 2H), 6.85 (s,
1H), 3.80 (s, 3H), 3.47 (s, 1H), 2.44 (s, 3H), 1.59 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 154.5, 146.8, 144.6, 137.3, 135.0, 134.7, 129.8,
128.2, 119.8, 118.7, 117.9, 112.6, 97.3, 55.8, 26.2, 21.6; IR (KBr) νmax
3407, 3083, 2951, 1569, 1488, 1305, 1267, 1149, 1095, 1027, 822, 687
cm−1; HRMS (ESI) calcd for C18H18O5SNa (M + Na) 369.0773,
found 369.0778.
7-Methoxy-2-methyl-3-(phenylsulfonyl)-2H-chromen-2-ol (9ca).
Pale yellow solid (183 mg, 55%): Rf = 0.4 (30% ethyl acetate in
hexanes); mp 124−126 °C; 1H NMR (300 MHz, CDCl3) δ 7.96 (d, J
= 7.2 Hz, 2H), 7.79 (s, 1H), 7.65−7.60 (m, 1H), 7.56−7.52 (m, 2H),
7.26 (d, J = 8.5 Hz, 1H), 6.61 (dd, J = 2.2, 8.5 Hz, 1H), 6.50 (d, J = 2.2
Hz, 1H), 3.81 (s, 3H), 3.57 (s, 1H), 1.58 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 164.0, 154.6, 140.8, 135.4, 133.4, 130.7, 130.4, 129.1, 128.0,
111.6, 109.6, 101.7, 97.8, 55.6, 26.4; IR (KBr) νmax 3447, 3064, 2930,
1616, 1297, 1147, 1093, 730, 622 cm−1; HRMS (ESI) calcd for
C17H16O5SNa (M + Na) 355.0616, found 355.0619.
7-Methoxy-2-methyl-3-tosyl-2H-chromen-2-ol (9cb). Pale yellow
solid (208 mg, 60%): Rf = 0.4 (30% ethyl acetate in hexanes); mp
136−138 °C; 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J = 7.6 Hz, 2H),
7.77 (s, 1H), 7.35−7.25 (m, 3H), 6.61 (d, J = 8.3 Hz, 1H), 6.51 (s,
1H), 3.82 (s, 3H), 3.67 (s, 1H), 2.45 (s, 3H), 1.59 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 163.8, 154.5, 144.3, 137.8, 134.9, 130.8, 130.6,
129.7, 128.1, 111.7, 109.5, 101.7, 97.8, 55.5, 26.4, 21.6; IR (KBr) νmax
3447, 3000, 2944, 1609, 1285, 1141, 1091, 673 cm−1; HRMS (ESI)
calcd for C18H18O5SNa (M + Na) 369.0773, found 369.0770.
6-Chloro-2-methyl-3-(phenylsulfonyl)-2H-chromen-2-ol (9da).
Pale yellow solid (175 mg, 52%): Rf = 0.6 (30% ethyl acetate in
hexanes); mp 145−147 °C; 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J
= 7.5 Hz, 2H), 7.73 (s, 1H), 7.67−7.64 (m, 1H), 7.58−7.55 (m, 2H),
7.33−7.29 (m, 2H), 6.91 (d, J = 8.5 Hz, 1H), 3.51 (s, 1H), 1.61 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 151.2, 140.0, 135.6, 133.9, 133.8,
132.8, 129.2, 128.6, 128.3, 127.2, 119.5, 118.5, 97.8, 26.6; IR (KBr)
νmax 3436, 3061, 3006, 2950, 1619, 1476, 1308, 1156, 1087, 950, 866,
730, 685 cm−1; HRMS (ESI) calcd for C16H13ClO4SNa (M + Na)
359.0121, found 359.0127.
(2-Bromoallylsulfonyl)benzene (6a).9 White solid (1.51 g, 58%): Rf
1
= 0.6 (30% ethyl acetate in hexanes); mp 77−79 °C; H NMR (500
MHz, CDCl3) δ 7.94 (d, J = 8.5 Hz, 2H), 7.71−7.68 (m, 1H), 7.60−
7.57 (m, 2H), 5.84 (d, J = 2.1 Hz, 1H), 5.77 (d, J = 2.1 Hz, 1H), 4.16
(s, 2H); 13C NMR (100 MHz, CDCl3) δ 137.7, 134.1, 129.1, 128.7,
126.5, 117.1, 66.2; IR (KBr) νmax 3423, 2981, 2919, 1622, 1584, 1447,
1393, 1307, 1256, 1141, 907 cm−1.
1-(2-Bromoallylsulfonyl)-4-methylbenzene (6b). White solid (1.56
1
g, 57%): Rf = 0.6 (30% ethyl acetate in hexanes); mp 89−91 °C; H
NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2
Hz, 2H), 5.83 (d, J = 2.1 Hz, 1H), 5.77 (d, J = 2.1 Hz, 1H), 4.14 (s,
2H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.2, 134.8,
129.7, 128.7, 126.3, 117.3, 66.3, 21.6; IR (KBr) νmax 2920, 1623, 1467,
1393, 1308, 1256, 1141, 1084, 908 cm−1; HRMS (ESI) calcd for
C10H11BrO2SNa (M + Na) 296.9561, found 296.9568.
General Procedure for the Cesium Carbonate-Mediated
Reaction of Phenolic Substrates (4a−g and 7) with 2-
Bomoallyl Sulfones 6a and 6b. 2-Bromoallyl sulfonylbenzene 6a
or 2-bromoallyl sulfonyl-4-methylbenzene 6b (1.5 mmol) and the
phenolic substrate (1.0 mmol) were dissolved in acetonitrile (8 mL) at
room temperature in a 25 mL round-bottom flask. Cesium carbonate
(815 mg, 2.5 mmol) was added, and the reaction mixture was stirred
under nitrogen for the required amount of time. Upon completion, the
solvent was evaporated on a rotavapor, water (20 mL) was added, and
the resulting solution was extracted with dichloromethane (3 × 20
mL). The combined organic extracts were dried over anhydrous
sodium sulfate and evaporated on a rotavapor, and the residue
obtained was subjected to column chromatography on silica gel using
an ethyl acetate/hexane mixture as the eluent.
1-Chloro-4-[3-(phenylsulfonyl)prop-1-en-2-yloxy]benzene (8).
White solid (259 mg, 84%): Rf = 0.6 (30% ethyl acetate in hexanes);
1
mp 78−80 °C; H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 7.5 Hz,
2H), 7.69−7.66 (m, 1H), 7.59−7.56 (m, 2H), 7.28−7.26 (m, 2H),
6.79 (d, J = 8.5 Hz, 2H), 4.42 (d, J = 2.1 Hz, 1H), 4.20 (d, J = 2.1 Hz,
1H), 4.04 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 152.5, 151.6,
138.8, 133.9, 130.2, 129.8, 129.08, 128.6, 122.3, 96.1, 61.3; IR (KBr)
νmax 2926, 2358, 1643, 1485, 1318, 1290, 1218, 1149, 1083, 968 cm−1;
HRMS (ESI) calcd for C15H13ClO3SNa (M + Na) 331.0172, found
331.0166.
6-Chloro-2-methyl-3-tosyl-4H-chromen-4-ol (10db). Pale yellow
solid (235 mg, 67%): Rf = 0.6 (30% ethyl acetate in hexanes); mp
181−183 °C; 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 8.3 Hz, 2H),
7.48 (d, J = 2.3 Hz, 1H), 7.37−7.28 (m, 3H), 7.02 (d, J = 8.3 Hz, 1H),
5.70 (d, J = 3.8 Hz, 1H), 3.70 (d, J = 3.8 Hz, 1H), 2.45 (s, 6H); 13C
NMR (125 MHz, CDCl3) δ 160.5, 147.9, 144.4, 138.7, 130.1, 129.9,
129.8, 129.5, 127.2, 122.6, 117.9, 116.1, 60.8, 21.6, 18.5; IR (KBr) νmax
2-Methyl-3-(phenylsulfonyl)-2H-chromen-2-ol (9aa). Yellow solid
(208 mg, 69%): Rf = 0.5 (30% ethyl acetate in hexanes); mp 143−145
°C; 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 8.1 Hz, 2H), 7.83 (s,
1H), 7.66−7.62 (m, 1H), 7.57−7.54 (m, 2H), 7.38−7.35 (m, 2H),
7.06 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 3.52 (s, 1H), 1.62 (s,
E
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The Journal of Organic Chemistry
Article
3486, 2914, 1635, 1480, 1303, 1248, 1146, 1088, 983, 819, 677, 604
cm−1; HRMS (ESI) calcd for C17H15ClO4SNa (M + Na) 373.0277,
found 373.0278.
3H); 13C NMR (75 MHz, CDCl3) δ 159.9, 153.3, 144.8, 144.6, 138.2,
130.0, 127.3, 126.4, 125.1, 122.1, 117.6, 117.2, 60.5, 21.6, 18.4; IR
(KBr) νmax 3477, 3097, 2924, 2854, 1642, 1535, 1343, 1298, 1247,
1146, 1091, 681 cm−1; HRMS (ESI) calcd for C17H15NO6SNa (M +
Na) 384.0518, found 384.0526.
6-Bromo-2-methyl-3-(phenylsulfonyl)-2H-chromen-2-ol (9ea)
and 6-Bromo-2-methyl-3-(phenylsulfonyl)-4H-chromen-4-ol
(10ea) (1:0.3 inseparable mixture). Pale yellow solid (201 mg,
CS2CO3-Mediated Conversion of 2-Bromoallyl Sulfones 6a
to Allenyl Sulfone 11 and Propargyl Sulfone 12. Cesium
carbonate (391 mg, 1.2 mmol) was added to a solution of bromoallyl
sulfone 6a (260 mg, 1.0 mmol) in acetonitrile (2 mL) at room
temperature and stirred for 2h. The solvent was removed on a
rotavapor; deionized water (10 mL) was added, and the aqueous
solution was extracted with ethyl acetate (3 × 10 mL). The combined
organic extracts was washed with brine, dried over anhydrous sodium
sulfate, and concentrated on a rotavapor. The residue on column
chromatography on silica gel using a petroleum ether/ethyl acetate
eluent afforded 130 mg of an oil that was identified as a 5:1 mixture of
allenyl sulfone 1111 and propargyl sulfone 12.12 The reaction of the
isolated mixture of 11 and 12 with salicylaldehyde was conducted
according to the general procedure to obtain 9aa in 22% isolated yield.
1
53%): Rf = 0.5 (30% ethyl acetate in hexanes); H NMR (300 MHz,
CDCl3) δ 8.00−7.94 (m, 2.6H), 7.72 (s, 1H), 7.65−7.43 (m, 6.8H),
6.96 (d, J = 8.9 Hz, 0.3H), 6.86 (d, J = 8.5 Hz, 1H), 5.71 (d, J = 2.6
Hz, 0.3H), 3.67 (d, J = 2.6 Hz, 0.3H), 3.55 (s, 1H), 2.43 (s, 1H), 1.61
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 151.8, 140.0, 135.7, 133.8,
133.7, 133.4, 132.7, 132.5, 131.6, 129.3, 129.2, 128.3, 127.9, 127.1,
120.0, 118.9, 118.2, 114.3, 97.7, 60.7, 26.6, 18.6; IR (KBr) νmax 3486,
3441, 3058, 1477, 1306, 1247, 1150, 1105, 1084, 881, 719, 648 cm−1;
HRMS (ESI) calcd for C16H13BrO4SNa (M + Na) 402.9616, found
402.9608.
6-Bromo-2-methyl-3-tosyl-4H-chromen-4-ol (10eb). Yellow solid
(244 mg, 62%): Rf = 0.6 (30% ethyl acetate in hexanes); mp 206−208
°C; 1H NMR (300 MHz, CDCl3) δ 7.86 (d, J = 8.1 Hz, 2H), 7.62 (d, J
= 2.3 Hz, 1H), 7.42 (dd, J = 2.3, 8.9 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H),
6.95 (d, J = 8.9 Hz, 1H), 5.68 (d, J = 3.2 Hz, 1H), 3.70 (d, J = 3.2 Hz,
1H), 2.44 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 160.4, 148.4, 144.5,
138.7, 132.7, 132.5, 129.9, 127.2, 123.0, 118.2, 117.5, 116.2, 60.7, 21.6,
18.5; IR (KBr) νmax 3486, 3065, 2910, 1635, 1477, 1299, 1247, 1145,
1088, 980, 817, 674 cm−1; HRMS (ESI) calcd for C17H15BrO4SNa (M
+ Na) 416.9772, found 416.9777.
1
NMR Data for the Mixture of 11 and 12. H NMR (500 MHz,
CDCl3) δ 8.00−7.98 (m, 0.4H), 7.93−7.91 (m, 2H), 7.72−7.69 (m,
0.2H), 7.66−7.62 (m, 1H), 7.61−7.59 (m, 0.4H), 7.58−7.54 (m, 2H),
6.26 (t, J = 6.4 Hz, 1H), 5.45 (d, J = 6.4 Hz, 2H), 3.97 (d, J = 2.7 Hz,
0.4H), 2.39 (t, J = 0.2H); 13C NMR (125 MHz, CDCl3) δ 209.3,
141.1, 134.3, 133.5, 129.2, 129.1, 128.8 (2), 127.5, 127.3, 100.9, 84.1,
76.2, 71.5, 48.3.
8-Bromo-6-chloro-2-methyl-3-(phenylsulfonyl)-4H-chromen-4-ol
(10fa). Pale yellow solid (273 mg, 66%): Rf = 0.7 (30% ethyl acetate in
hexanes); mp 176−178 °C; 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J
= 8.5 Hz, 2H), 7.65−7.62 (m, 1H), 7.58−7.55 (m, 3H), 7.43 (s, 1H),
5.70 (d, J = 3.8 Hz, 1H), 3.66 (s, 1H), 2.50 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 160.7, 145.2, 141.4, 133.6, 133.0, 130.3, 129.4, 128.8,
127.2, 123.6, 116.5, 111.0, 61.1, 18.5; IR (KBr) νmax 3460, 3070, 2922,
1639, 1455, 1326, 1253, 1149, 1089, 1020, 726, 628 cm−1; HRMS
(ESI) calcd for C16H12BrClO4SNa (M + Na) 436.9226, found
436.9231.
8-Bromo-6-chloro-2-methyl-3-tosyl-2H-chromen-2-ol (9fb) and
8-Bromo-6-chloro-2-methyl-3-tosyl-4H-chromen-4-ol (10fb) (0.4:1
inseparable mixture). Pale yellow solid (330 mg, 77%): Rf = 0.6 (30%
ethyl acetate in hexanes); 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J =
8.2 Hz, 2H), 7.82 (d, J = 8.4 Hz, 0.8H), 7.66 (s, 0.4H), 7.56 (d, J = 2.4
Hz, 0.4H), 7.54 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.35 (d, J
= 8.2 Hz, 2.8H), 7.28 (d, J = 2.4 Hz, 0.4H), 5.67 (d, J = 3.5 Hz, 1H),
3.72 (d, J = 3.5 Hz, 1H), 3.69 (s, 0.4H), 2.50 (s, 3H), 2.45 (s, 1.2H),
2.44 (s, 3H), 1.69 (s, 1.2H); 13C NMR (75 MHz, CDCl3) δ 160.4,
148.5, 145.2, 145.1, 145.0, 144.6, 138.4, 137.0, 136.8, 135.2, 132.9,
130.2, 129.9, 128.7, 128.4, 127.8, 127.2, 123.7, 120.4, 116.8, 111.5,
111.0, 98.9, 61.0, 26.6, 21.7, 21.6, 18.4; IR (KBr) νmax 3447, 2927,
1639, 1454, 1325, 1293, 1251, 1143, 1089, 1042, 680 cm−1; HRMS
(ESI) calcd for C17H14BrClO4SNa (M + Na) 450.9382, found
450.9386.
PTSA-Catalyzed Isomerization of 4H-Chromene 10eb to 2H-
Chromene 9eb. To a solution of 4H-chromene 10eb (39 mg, 0.1
mmol) in dimethyl sulfoxide (0.5 mL) was added PTSA (0.4 mg, 20
mol %), and the reaction mixture was allowed to sir at 25 °C
overnight. Water (5 mL) was added, and the solution was extracted
with ethyl acetate (3 × 5 mL). The organic extracts were combined
and washed with a saturated sodium bicarbonate solution (10 mL) and
brine. After evaporation of the solvent on a rotavapor, the residue was
chromatographed on a silica column using hexane/ethyl acetate
mixtures as the eluent to obtain 6-bromo-2-methyl-3-tosyl-2H-
chromen-2-ol 9eb as a white solid (39 mg, 99%): Rf = 0.5 (30%
1
ethyl acetate in hexanes); mp 160−162 °C; H NMR (400 MHz,
CDCl3) δ 7.83 (d, J = 8.2 Hz, 2H), 7.67 (s, 1H), 7.46 (d, J = 2.3 Hz,
1H), 7.43 (dd, J = 2.3, 8.6 Hz, 1H), 7.35 (d, J = 8.2 Hz, 2H), 6.86 (d, J
= 8.6 Hz, 1H), 3.53 (s, 1H), 2.45 (s, 3H), 1.60 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 151.8, 144.9, 137.2, 136.2, 135.6, 133.1, 131.6,
129.9, 128.5, 120.2, 118.9, 114.3, 97.9, 26.6, 21.6; IR (KBr) νmax 3450,
2920, 1618, 1475, 1397, 1312, 1267, 1247, 1170, 1151, 1095, 945
cm−1; HRMS (ESI) calcd for C17H15BrO4SNa (M + Na) 416.9772,
found 416.9780.
Optimized General Procedure for the PTSA-Mediated
Reaction of Chromenes (9 and 10) with Heteroarenes.
Chromene derivative 9 or 10 (0.40 mmol) and the (hetero)arene
(0.30 mmol) were dissolved in ethanol (2 mL) at room temperature.
PTSA (36 mg, 0.21 mmol) was added, and the reaction mixture was
stirred for 2 h. Water (10 mL) was added, and the solution was
extracted with ethyl acetate (3 × 10 mL). The organic extracts were
combined and washed with a saturated sodium bicarbonate solution
(10 mL) and brine. After evaporation of the solvent on a rotavapor,
the residue was chromatographed on a silica column using hexane/
ethyl acetate mixtures as the eluent to obtain analytically pure samples
of products 16−27.
2-Methyl-6-nitro-3-(phenylsulfonyl)-4H-chromen-4-ol (10ga).
Pale yellow solid (191 mg, 55%): Rf = 0.5 (30% ethyl acetate in
1
hexanes); mp 212−214 °C; H NMR (500 MHz, CDCl3) δ 8.44 (s,
1H), 8.21 (d, J = 8.9 Hz, 1H), 8.01 (d, J = 7.6 Hz, 2H), 7.65−7.58 (m,
3H), 7.20 (d, J = 8.9 Hz, 1H), 5.80 (s, 1H), 3.87 (s, 1H), 2.49 (s, 3H).
Because of the poor solubility of 10ga in CDCl3, 13C NMR was
measured in DMSO-d6. During measurement, 10ga isomerized to
generate a mixture of 2H-chromenes 9ga and 10ga: 13C NMR (125
MHz, DMSO-d6) δ 160.4, 157.6, 153.1, 144.0, 142.3, 141.5, 140.6,
136.5, 133.8, 133.6, 133.4, 129.4, 129.3, 127.8, 127.4, 126.0, 125.7,
125.1, 124.6, 118.7, 117.7, 117.5, 98.6, 79.2, 58.7, 26.8, 18.3; IR (KBr)
νmax 3509, 3086, 2925, 1642, 1526, 1342, 1294, 1242, 1139, 1086, 985,
756, 640 cm−1; HRMS (ESI) calcd for C16H13NO6SNa (M + Na)
370.0361, found 370.0365.
3-[2-Methyl-3-(phenylsulfonyl)-4H-chromen-4-yl]-1H-indole
(16a). Pale yellow solid (119 mg, 99%): Rf = 0.5 (40% ethyl acetate in
1
hexanes); mp 187−189 °C; H NMR (500 MHz, CDCl3) δ 7.90 (s,
1H), 7.26−7.23 (m, 3H), 7.19−7.09 (m, 5H), 7.06−6.95 (m, 5H),
6.90 (t, J = 7.2 Hz, 1H), 5.53 (s, 1H), 2.52 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 159.4, 148.9, 142.1, 136.3, 131.8, 129.1, 127.9, 127.6,
126.3, 125.3, 124.9, 124.2, 122.7, 121.9, 119.7, 119.0, 118.6, 116.0,
115.5, 111.1, 33.5, 19.0; IR (KBr) νmax 3389, 3060, 2886, 1638, 1487,
1452, 1318, 1286, 1237, 1141, 1089, 757, 727, 630 cm−1; HRMS (ESI)
calcd for C24H19NO3SNa (M + Na) 424.0983, found 424.0972.
3-(2-Methyl-3-tosyl-4H-chromen-4-yl)-1H-indole (16b). Colorless
solid (114 mg, 91%): Rf = 0.6 (40% ethyl acetate in hexanes); mp
2-Methyl-6-nitro-3-tosyl-4H-chromen-4-ol (10gb). Pale yellow
solid (195 mg, 54%): Rf = 0.6 (30% ethyl acetate in hexanes); mp
185−187 °C; 1H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 8.20 (d, J =
8.7 Hz, 1H), 7.88 (d, J = 7.0 Hz, 2H), 7.36 (d, J = 7.0 Hz, 2H), 7.19
(d, J = 8.7 Hz, 1H), 5.76 (s, 1H), 3.85 (s, 1H), 2.49 (s, 3H), 2.44 (s,
F
DOI: 10.1021/acs.joc.5b02324
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173−175 °C; 1H NMR (500 MHz, CDCl3) δ 7.93 (s, 1H), 7.23 (d, J =
8.1 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.14−7.09 (m, 5H), 7.06−6.99
(m, 2H), 6.96 (dt, J = 1.1, 7.5 Hz, 1H), 6.91−6.88 (m, 1H), 6.77 (d, J
= 8.1 Hz, 2H), 5.51 (s, 1H), 2.51 (s, 3H), 2.17 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 159.0, 148.9, 142.7, 139.2, 136.4, 129.1, 128.5, 127.6,
126.6, 126.4, 125.3, 124.9, 124.3, 122.7, 121.8, 119.6, 119.0, 118.6,
115.9, 111.1, 33.6, 21.3, 18.9; IR (KBr) νmax 3370, 3052, 2920, 1636,
1489, 1316, 1287, 1238, 1143, 1088, 742, 671, 608 cm−1; HRMS (ESI)
calcd for C25H21NO3SNa (M + Na) 438.1140, found 438.1123.
5-Methoxy-3-[2-methyl-3-(phenylsulfonyl)-4H-chromen-4-yl]-1H-
indole (17a). Colorless solid (122 mg, 94%): Rf = 0.5 (40% ethyl
acetate in hexanes); mp 110−112 °C; 1H NMR (500 MHz, CDCl3) δ
7.80 (s, 1H), 7.27−7.25 (m, 2H), 7.22−7.19 (m, 1H), 7.15−7.11 (m,
2H), 7.08−7.06 (m, 2H), 7.03−6.97 (m, 4H), 6.72−6.70 (m, 2H),
5.50 (s, 1H), 3.70 (s, 3H), 2.51 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 159.3, 153.9, 149.0, 142.1, 131.9, 131.4, 129.2, 127.9, 127.7, 126.3,
125.7, 125.0, 124.1, 123.4, 118.7, 115.8, 115.5, 112.1, 111.8, 100.4,
55.6, 33.5, 18.9; IR (KBr) νmax 3388, 3061, 2927, 1636, 1583, 1485,
1452, 1299, 1230, 1146, 1088, 755, 629 cm−1; HRMS (ESI) calcd for
C25H21NO4SNa (M + Na) 454.1089, found 454.1084.
2H), 5.49 (s, 1H), 3.99 (q, J = 7.3 Hz, 2H), 2.53 (s, 3H), 2.16 (s, 3H),
1.38 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 158.8, 148.8,
142.5, 139.3, 136.0, 129.0, 128.4, 127.5, 126.3, 126.0, 125.6, 124.8,
124.5, 121.2, 119.1, 118.9, 117.4, 115.9, 109.1, 40.6, 33.4, 21.2, 19.0,
15.4; IR (KBr) νmax 3431, 3048, 2972, 2927, 1636, 1590, 1463, 1321,
1292, 1234, 1146, 765, 736, 696, 661 cm−1; HRMS (ESI) calcd for
C27H25NO3SNa (M + Na) 466.1453, found 466.1449.
2-Methyl-3-[2-methyl-3-(phenylsulfonyl)-4H-chromen-4-yl]-6-
nitro-1H-indole (20). Yellow solid (123 mg, 89%): Rf = 0.2 (40% ethyl
acetate in hexanes); mp 254−256 °C; 1H NMR (500 MHz, CDCl3) δ
8.06 (s, 1H), 8.03 (s, 1H), 7.86 (dd, J = 2.1, 8.9 Hz, 1H), 7.23 (d, J =
7.4 Hz, 2H), 7.15−7.12 (m, 2H), 7.08 (d, J = 8.2 Hz, 1H), 7.06 (d, J =
8.9 Hz, 1H), 6.98−6.95 (m, 4H), 5.56 (s, 1H), 2.65 (s, 3H), 2.56 (s,
3H); 13C NMR [75 MHz, (CD3)2SO + CDCl3] δ 158.6, 147.7, 141.0,
140.0, 137.9, 135.6, 131.2, 128.2, 127.2, 127.1, 125.1, 124.9, 124.3,
122.8, 115.4, 115.2, 113.5, 109.7, 31.1, 18.1, 11.0; IR (KBr) νmax 3376,
3051, 2924, 2362, 1643, 1479, 1326, 1231, 1151, 756, 719, 626 cm−1;
HRMS (ESI) calcd for C25H20N2O5SNa (M + Na) 483.0991, found
483.0998.
3-[6-Methoxy-2-methyl-3-(phenylsulfonyl)-4H-chromen-4-yl]-1H-
indole (21). Orange solid (128 mg, 99%): Rf = 0.4 (40% ethyl acetate
in hexanes); mp 172−174 °C (CH2Cl2/hexane); 1H NMR (400 MHz,
CDCl3) δ 7.90 (s, 1H), 7.26−7.22 (m, 3H), 7.19−7.15 (m, 2H), 7.10
(d, J = 2.3 Hz, 1H), 7.05 (t, J = 7.1 Hz, 1H), 7.00−6.95 (m, 3H),
6.92−6.88 (m, 1H), 6.66 (dd, J = 2.9, 8.9 Hz, 1H), 6.61 (d, J = 2.9 Hz,
1H), 5.50 (s, 1H), 3.64 (s, 3H), 2.50 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 159.6, 156.5, 143.1, 142.2, 136.4, 131.8, 127.9, 126.2, 125.4,
124.9, 122.7, 121.9, 119.7, 118.8, 118.6, 116.9, 114.4, 113.8, 113.1,
111.1, 55.5, 34.0, 19.0; IR (KBr) νmax 3350, 3055, 2919, 2845, 1625,
1497, 1285, 1227, 1143, 1089, 744, 622 cm−1; HRMS (ESI) calcd for
C25H21NO4SNa (M + Na) 454.1089, found 454.1080.
5-Methoxy-3-(2-methyl-3-tosyl-4H-chromen-4-yl)-1H-indole
(17b). Pale yellow solid (123 mg, 92%): Rf = 0.5 (40% ethyl acetate in
1
hexanes); mp 190−192 °C; H NMR (400 MHz, CDCl3) δ 7.86 (s,
1H), 7.14−7.07 (m, 6H), 7.02−6.96 (m, 2H), 6.80 (d, J = 7.7 Hz,
2H), 6.71−6.68 (m, 2H), 5.48 (s, 1H), 3.70 (s, 3H), 2.49 (s, 3H), 2.19
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.9, 153.9, 149.1, 142.7,
139.2, 131.5, 129.2, 128.6, 127.7, 126.4, 125.8, 125.0, 124.2, 123.4,
118.8, 115.8, 112.0, 111.7, 100.6, 55.6, 33.5, 21.3, 18.9; IR (KBr) νmax
3340, 2922, 1639, 1485, 1453, 1297, 1234, 1144, 1087, 1039, 751, 667
cm−1; HRMS (ESI) calcd for C26H23NO4SNa (M + Na) 468.1245,
found 468.1240.
5-Bromo-3-[2-methyl-3-(phenylsulfonyl)-4H-chromen-4-yl]-1H-
indole (18a). Yellow solid (137 mg, 95%): Rf = 0.4 (40% ethyl acetate
in hexanes); mp 188−190 °C; 1H NMR (500 MHz, CDCl3) δ 8.04 (s,
1H), 7.33−7.31 (m, 3H), 7.21 (t, J = 7.3 Hz, 1H), 7.16−7.09 (m, 3H),
7.07−7.02 (m, 5H), 6.98 (dt, J = 1.2, 7.6 Hz, 1H), 5.46 (s, 1H), 2.56
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.5, 148.7, 141.9, 134.9,
132.1, 128.9, 128.1, 127.9, 126.9, 126.3, 125.0, 124.7, 124.0, 123.8,
121.1, 118.7, 116.2, 115.2, 112.9, 112.7, 33.4, 19.0; IR (KBr) νmax
3331, 3661, 2922, 1638, 1451, 1322, 1289, 1231, 1140, 1087, 764, 721,
628 cm−1; HRMS (ESI) calcd for C24H18BrNO3SNa (M + Na)
502.0088, found 502.0010.
3-(6-Bromo-2-methyl-3-tosyl-4H-chromen-4-yl)-1H-indole (22).
Pale yellow solid (105 mg, 71%): Rf = 0.6 (40% ethyl acetate in
1
hexanes); mp 160−162 °C; H NMR (400 MHz, CDCl3) δ 8.00 (s,
1H), 7.22−7.19 (m, 3H), 7.16 (d, J = 8.0 Hz, 1H), 7.12−7.04 (m,
4H), 6.91−6.88 (m, 2H), 6.76 (d, J = 8.1 Hz, 2H), 5.45 (s, 1H), 2.51
(s, 3H), 2.17 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.7, 148.0,
142.8, 138.9, 136.4, 131.8, 130.7, 128.6, 126.4, 126.3, 125.2, 122.9,
122.0, 119.8, 118.4, 118.3, 117.8, 117.1, 115.8, 111.2, 33.5, 21.3, 18.9;
IR (KBr) νmax 3442, 3125, 3060, 2922, 1638, 1477, 1318, 1292, 1230,
1146, 1089, 814, 741, 672 cm−1; HRMS (ESI) calcd for
C25H20BrNO3SNa (M + Na) 518.0224, found 518.0229.
5-Bromo-3-(2-methyl-3-tosyl-4H-chromen-4-yl)-1H-indole (18b).
Yellow solid (145 mg, 98%): Rf = 0.4 (40% ethyl acetate in hexanes);
mp 178−180 °C; 1H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.29 (s,
1H), 7.20 (d, J = 8.2 Hz, 2H), 7.14−7.08 (m, 3H), 7.04−6.95 (m,
4H), 6.84 (d, J = 8.2 Hz, 2H), 5.42 (s, 1H), 2.55 (s, 3H), 2.19 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 159.1, 148.6, 143.0, 138.8, 134.9,
128.85, 128.7, 127.8, 126.9, 126.35, 124.9, 124.5, 124.0, 123.8, 121.1,
118.6, 116.1, 115.5, 112.8, 112.6, 33.4, 21.3, 18.9; IR (KBr) νmax 3400,
2922, 1635, 1456, 1289, 1233, 1145, 1090, 752, 674 cm−1; HRMS
(ESI) calcd for C25H20BrNO3SNa (M + Na) 518.0224, found
518.0218.
2-[2-Methyl-3-(phenylsulfonyl)-4H-chromen-4-yl]-1H-pyrrole
(23a). Colorless solid (88 mg, 84%): Rf = 0.7 (40% ethyl acetate in
1
hexanes); mp 193−195 °C; H NMR (400 MHz, CDCl3) δ 8.92 (s,
1H), 7.55−7.50 (m, 3H), 7.43−7.39 (m, 2H), 7.26−7.22 (m, 1H),
7.18 (dd, J = 1.2, 7.6 Hz, 1H), 7.13−7.09 (m, 1H), 7.04 (d, J = 8.2 Hz,
1H), 6.67−6.65 (m, 1H), 6.03−6.01 (m, 1H), 5.47−5.45 (m, 1H),
5.26 (s, 1H), 2.29 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.6,
150.0, 142.4, 134.0, 132.8, 129.3, 129.0, 128.2, 126.6, 125.1, 122.6,
117.5, 116.1, 115.9, 108.2, 106.9, 34.9, 18.8; IR (KBr) νmax 3370, 2924,
1642, 1289, 1242, 1146, 1089, 760, 724, 629 cm−1; HRMS (ESI) calcd
for C20H17NO3SNa (M + Na) 374.0827, found 374.0834.
2-(2-Methyl-3-tosyl-4H-chromen-4-yl)-1H-pyrrole (23b). Colorless
solid (107 mg, 98%): Rf = 0.7 (40% ethyl acetate in hexanes); mp
186−188 °C; 1H NMR (500 MHz, CDCl3) δ 8.98 (s, 1H), 7.42 (d, J =
8.3 Hz, 2H), 7.26−7.17 (m, 4H), 7.12−7.09 (m, 1H), 7.03 (d, J = 8.1
Hz, 1H), 6.68−6.66 (m, 1H), 6.02 (dd, J = 2.8, 5.8 Hz, 1H), 5.44 (s,
1H), 5.23 (s, 1H), 2.38 (s, 3H), 2.28 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 160.3, 150.1, 143.8, 139.5, 134.1, 129.6, 129.3, 128.2, 126.7,
125.0, 122.7, 117.5, 116.2, 116.0, 108.1, 106.8, 34.9, 21.5, 18.7; IR
(KBr) νmax 3366, 2927, 1637, 1322, 1297, 1236, 1145, 753, 730, 667
cm−1; HRMS (ESI) calcd for C21H19NO3SNa (M + Na) 388.0983,
found 388.0984.
1-Ethyl-3-[2-methyl-3-(phenylsulfonyl)-4H-chromen-4-yl]-1H-in-
dole (19a). Pale yellow solid (127 mg, 99%): Rf = 0.7 (40% ethyl
acetate in hexanes); mp 170−172 °C; 1H NMR (500 MHz, CDCl3) δ
7.24 (d, J = 8.1 Hz, 1H), 7.21 (dd, J = 1.1, 8.4 Hz, 2H), 7.17−7.09 (m,
4H), 7.07−7.04 (m, 1H), 7.02 (dd, J = 0.9, 8.1 Hz, 1H), 6.98−6.93
(m, 4H), 6.90−6.87 (m, 1H), 5.51 (s, 1H), 3.97 (q, J = 7.3 Hz, 2H),
2.54 (s, 3H), 1.37 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
159.1, 148.8, 142.2, 136.0, 131.6, 129.1, 127.7, 127.5, 126.1, 126.0,
125.6, 124.9, 124.4, 121.3, 119.1, 118.8, 117.4, 115.9, 115.6, 109.1,
40.6, 33.4, 19.0, 15.3; IR (KBr) νmax 3448, 3123, 3054, 2962, 2927,
1637, 1321, 1297, 1235, 1149, 745, 719, 628 cm−1; HRMS (ESI) calcd
for C26H23NO3SNa (M + Na) 452.1296, found 452.1291.
2-(6-Bromo-2-methyl-3-tosyl-4H-chromen-4-yl)-1H-pyrrole (24).
1-Ethyl-3-(2-methyl-3-tosyl-4H-chromen-4-yl)-1H-indole (19b).
Colorless solid (132 mg, 99%): Rf = 0.7 (40% ethyl acetate in
hexanes); mp 144−146 °C; 1H NMR (500 MHz, CDCl3) δ 7.24 (d, J
= 7.9 Hz, 1H), 7.14−7.04 (m, 6H), 7.01 (dd, J = 1.1, 8.2 Hz, 1H),
6.97−6.93 (m, 2H), 6.89 (dt, J = 0.9, 7.9 Hz, 1H), 6.73 (d, J = 8.1 Hz,
Colorless solid (130 mg, 98%): Rf = 0.7 (40% ethyl acetate in
1
hexanes); mp 191−193 °C; H NMR (300 MHz, CDCl3) δ 8.98 (s,
1H), 7.40 (d, J = 8.1 Hz, 2H), 7.35−7.31 (m, 2H), 7.22 (d, J = 8.1 Hz,
2H), 6.92 (d, J = 8.5 Hz, 1H), 6.69 (s, 1H), 6.05−6.04 (m, 1H), 5.47
(s, 1H), 5.18 (s, 1H), 2.39 (s, 3H), 2.28 (s, 3H); 13C NMR (125 MHz,
G
DOI: 10.1021/acs.joc.5b02324
J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
CDCl3) δ 160.0, 149.2, 144.0, 139.2, 133.3, 131.8, 131.3, 129.7, 126.7,
124.8, 117.9, 117.8, 117.3, 116.3, 108.3, 107.1, 34.7, 21.5, 18.7; IR
(KBr) νmax 3376, 2925, 1635, 1478, 1317, 1291, 1235, 1145, 1123,
1086, 814, 727, 674 cm−1; HRMS (ESI) calcd for C21H18BrNO3SNa
(M + Na) 466.0088, found 466.0083.
2-[8-Bromo-6-chloro-2-methyl-3-(phenylsulfonyl)-4H-chromen-
4-yl]-1H-pyrrole (25). Pale yellow solid (138 mg, 99%): Rf = 0.7 (40%
ethyl acetate in hexanes); mp 213-215 °C (CH2Cl2/hexane); 1H NMR
(500 MHz, CDCl3) δ 8.82 (s, 1H), 7.56−7.50 (m, 3H), 7.46−7.41 (m,
3H), 7.11 (d, J = 2.0 Hz, 1H), 6.67 (s, 1H), 6.05 (d, J = 2.6 Hz, 1H),
5.55 (s, 1H), 5.22 (s, 1H), 2.36 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 160.2, 145.8, 141.8, 133.2, 132.6, 131.7, 130.1, 129.1, 128.1, 126.7,
125.5, 118.0, 116.8, 110.9, 108.6, 107.4, 35.4, 18.6; IR (KBr) νmax
3393, 3071, 2932, 1644, 1452, 1284, 1245, 1136, 1089, 726, 687 cm−1;
HRMS (ESI) calcd for C20H15BrClNO3SNa (M + Na) 485.9542,
found 485.9530.
dihydropyridin-4(1H)-one 29 as a brown solid (86 mg, 86%): Rf = 0.6
(50% ethyl acetate in hexanes); mp 196−198 °C; 1H NMR (500
MHz, CDCl3) δ 8.00 (d, J = 7.4 Hz, 2H), 7.87 (d, J = 7.4 Hz, 2H),
7.75−7.73 (m, 1H), 7.65−7.50 (m, 5H), 4.23−4.21 (m, 2H), 2.89 (s,
3H), 2.57−2.55 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 186.7,
164.5, 142.4, 139.3, 134.7, 133.1, 130.1, 128.7, 127.8, 126.9, 124.4,
47.1, 37.9, 19.0; IR (KBr) νmax 3424, 3063, 2922, 1666, 1508, 1368,
1327, 1300, 1152, 1078, 919, 735, 686, 533 cm−1; HRMS (ESI) calcd
for C18H18NO5S2 (M + H) 392.0626, found 392.0619.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02324.
■
S
1H and 13C NMR spectra for all new compounds (PDF)
4-(Furan-2-yl)-2-methyl-3-tosyl-4H-chromene (26). White solid
(49 mg, 45%): Rf = 0.7 (40% ethyl acetate in hexanes); mp 163−165
AUTHOR INFORMATION
Corresponding Author
*E-mail: rajeevmenon@iict.res.in or srajeevmenon@gmail.com.
Notes
1
■
°C; H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.1 Hz, 2H), 7.21−
7.16 (m, 4H), 7.12 (s, 1H), 7.09−7.06 (m, 1H), 7.01 (d, J = 8.0 Hz,
1H), 6.19−6.18 (m, 2H), 5.36 (s, 1H), 2.43 (s, 3H), 2.37 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 160.7, 155.3, 149.4, 143.4, 141.9, 139.4,
129.4, 128.7, 128.2, 127.0, 125.0, 121.8, 116.3, 114.2, 110.3, 106.6,
35.6, 21.5, 19.0; IR (KBr) νmax 3308, 3064, 2963, 2926, 2854, 1716,
1623, 1557, 1278, 1229, 1183, 1127, 879, 768, 727 cm−1; HRMS (ESI)
calcd for C21H18O4SNa (M + Na) 389.0823, found 389.0832.
2-Ethoxy-2-methyl-3-(phenylsulfonyl)-2H-chromene (Et-9aa).
Pale yellow solid (70 mg, 71%): Rf = 0.7 (40% ethyl acetate in
hexanes); mp 118−120 °C; 1H NMR (500 MHz, CDCl3) δ 7.96−7.93
(m, 3H), 7.62−7.59 (m, 1H), 7.54−7.51 (m, 2H), 7.36−7.33 (m, 2H),
7.03−7.00 (m, 1H), 6.92 (d, J = 8.5 Hz, 1H), 3.27−3.21 (m, 1H),
3.14−3.08 (m, 1H), 1.87 (s, 3H), 0.69 (t, J = 7.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 153.6, 141.2, 136.3, 133.2, 133.1, 132.8, 129.5,
128.9, 128.2, 121.8, 117.8, 115.9, 99.9, 58.0, 25.8, 14.6; IR (KBr) νmax
3425, 3061, 3016, 2972, 2928, 2886, 2363, 1623, 1447, 1307, 1154,
1114, 1084, 1047, 765, 725, 691, 630 cm−1; HRMS (ESI) calcd for
C18H18O4SNa (M + Na) 353.0823, found 353.0809.
Synthesis of 2-Methylene-1,3-bis(phenylsulfonyl)piperidin-
4-ol (28). Cesium carbonate (408 mg, 1.25 mmol) was added to a
solution of N-(3-oxopropyl)benzenesulfonamide15 27 (107 mg, 0.50
mmol) and 2-bromoallyl sulfonylbenzene 6a (195 mg, 0.75 mmol) in
acetonitrile (5 mL) kept at room temperature. The reaction mixture
was stirred for 3 h, and the solvent was evaporated on a rotavapor.
Water (20 mL) was added, and the resulting solution was extracted
with dichloromethane (3 × 10 mL). The combined organic extracts
were dried over anhydrous sodium sulfate and evaporated on a
rotavapor, and the residue obtained was subjected to column
chromatography on silica gel using an ethyl acetate/hexane mixture
as the eluent to afford 2-methylene-1,3-bis(phenylsulfonyl)piperidin-4-
ol 28 (149 mg, 76%) as a pale yellow viscous liquid: Rf = 0.4 (50%
ethyl acetate in hexanes); 1H NMR (500 MHz, CDCl3) δ 7.97 (d, J =
7.3 Hz, 2H), 7.74 (d, J = 7.2 Hz, 2H), 7.65 (td, J = 1.2, 7.5 Hz, 2H),
7.58−7.55 (m, 2H), 7.51 (t, J = 7.85 Hz, 2H), 5.25 (d, J = 1.2 Hz, 1H),
4.76−4.74 (m, 1H), 4.20 (d, J = 1.2 Hz, 1H), 3.69−3.64 (m, 2H),
3.57−3.52 (m, 1H), 2.66 (d, J = 3.1 Hz, 1H), 2.38−2.32 (m, 1H),
1.87−1.82 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 138.7, 136.1,
134.1, 133.1, 132.0, 129.5, 129.0, 128.8, 128.3, 113.7, 73.4, 63.6, 42.0,
29.3; IR (KBr) νmax: 3452, 2926, 2855, 1714, 1630, 1446, 1310, 1153,
1084, 762, 570 cm−1; HRMS (ESI) calcd for C18H20NO5S2 (M + H)
394.0783, found 394.0780.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Department of Science and Technology (DST), India, is
acknowledged for the award of a Ramanujan fellowship and a
Start-up Research Grant (young scientists) to R.S.M. Financial
support in part from the XIIth five year plan project “Affordable
Cancer Therapeutics (ACT)” from the Council of Scientific
and Industrial Research (CSIR), India, is also acknowledged.
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DOI: 10.1021/acs.joc.5b02324
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