Hydroxy-Group-Facilitated Vinylic Iodination of ortho-Vinylnaphthols Using Molecular Iodine

Article abstract of DOI:10.1055/s-0035-1560559

An efficient and simple one-pot method for the iodination of ortho-vinylnaphthols using molecular iodine is disclosed. The reaction is believed to proceed through formation of quinone methide intermediate. The method tolerates different functional groups

Full text of DOI:10.1055/s-0035-1560559

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
P. Kaswan et al.
Letter
Synlett
Hydroxy-Group-Facilitated Vinylic Iodination of ortho-Vinylnaph-
thols Using Molecular Iodine
R2
Pinku Kaswan
R2
Ganesh M. Shelke
V. Kameswara Rao
Anil Kumar*
I
I2 (2.5 equiv)
OH
OH
MeCN, reflux, 4 h
Department of Chemistry, Birla Institute of Technology
and Science, Pilani, 333031 Rajasthan, India
anilkumar@pilani.bits-pilani.ac.in
R1
R1
56–89% yield
14 examples
Received: 14.03.2016
Accepted after revision: 08.07.2016
Published online: 03.08.2016
molecular iodine (Scheme 1). To the best of our knowledge
this is the first report on vinylic iodination of ortho-vinyl-
naphthols.
DOI: 10.1055/s-0035-1560559; Art ID: st-2016-b0174-l
Abstract An efficient and simple one-pot method for the iodination of
ortho-vinylnaphthols using molecular iodine is disclosed. The reaction is
believed to proceed through formation of quinone methide intermedi-
ate. The method tolerates different functional groups and provides cor-
responding ortho-iodovinylnaphthols in good to excellent yields.
Previous approaches
NaI
I
BF3K
R
R
Chloramine-T
NIS
I
COOH
Al(i-Bu)2
Ar
Ar
Et3N, CH2Cl2
I
Key words vinylnaphthol, iodovinylnaphthols, molecular iodine, io-
dination
NIS
Ar
Ar
22 °C, 1 h
R
R
R
R
I
NIS/Rh(III)
The vinyl iodides are the multipurpose building blocks
to synthesize organic molecules via transition-metal-cata-
lyzed cross-coupling reaction.1 The vinyl iodide moiety is
also a key fragment for several natural products and drug
molecules.2 The classical method to synthesize vinyl iodides
is hydrazone iodination where iodine reacts with hydra-
zone in the presence of a non-nucleophilic base such as
trimethylamine. Since then, several methods were devel-
oped for the synthesis of vinyl iodides.3 In recent years syn-
thesis of vinyl iodides have been achieved through halogen
exchange by CuI in the presence of amine ligands,4 iodina-
tion of organotrifluoroborates,5 decarboxylative iodination
of carboxylic acids by N-iodosuccinimide (NIS) in the pres-
ence of trimethylamine,6 hydroalumination–iodination of
alkynes,7 hydrozirconation–iodination of alkynes, rutheni-
um-catalyzed silylative coupling followed by NIS-mediated
iododesilylation,8 and rhodium-catalyzed iodination of vi-
nylic C–H bonds.9 Commercial availability of vinyl halides is
much less than aryl halides and there has been much inter-
est in efficient methods for their preparation. The develop-
ment of facile synthetic methods for vinyl halides is still re-
quired. Herein, we report our finding on hydroxy-group fa-
cilitated vinylic iodination of ortho-vinylnaphthols using
DG
H
DG
DG = directing group
Present approach
Ar
Ar
I
OH
I2, MeCN
reflux, 4 h
OH
Scheme 1 Existing routes and our approach for vinylic iodination
In our previous study on iodine-mediated synthesis of
naphthofurans,10 formation of 1-(2-iodo-1-phenylvinyl)-
naphthalen-2-ol (2a) was observed instead of expected 1-
phenylnaphthofuran when the reaction was performed
with iodine in the absence of base. Structure of 2a was elu-
1
cidated by spectral data. In the H NMR spectrum of 2a, a
characteristic singlet appeared at δ = 7.63 ppm for vinylic
proton and at δ = 5.20 ppm for hydroxyl proton along with
other proton peaks. In the 13C NMR spectrum, the charac-
teristic peak for vinylic carbon attached to iodo appeared at
δ = 86.1 ppm along with all other carbons. Finally, a peak at
m/z = 373.0087 in the HRMS spectrum corresponding to
molecular ion C18H14IO [M + H]+ confirmed the structure of
2a.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
P. Kaswan et al.
Letter
Synlett
To improve the yield of iodinated product and under-
stand the underlying mechanism we performed several ex-
periments. Initially, when 1a was treated with 1.5 equiva-
lents of I2 without K2CO3 under reflux conditions in acetoni-
trile for 2 hours, 2a was isolated in 52% yield (Table 1, entry
1). Increasing reaction duration and concentration of iodine
increased the yield of 2a (Table 1, entries 1–4). However, in-
creasing loading of of iodine more than 2.5 equivalents did
not increase the yield of 2a (Table 1, entry 5). To improve
the yield of this reaction, we examined the solvent effect. In
THF, DMSO, and toluene, 2a was obtained in 86%, 71%, and
62% yield, respectively, whereas in acetone 2a was not
formed (Table 1, entries 6–9). It is also worth mentioning
that prolonged reaction time (12 h) failed to improve the
yield of 2a (Table 1, entry 10). Decrease in yield on increas-
ing time is due to the fact that at higher temperature prod-
uct 2a is unstable. Formation of 2a was not observed when
1a was treated HI alone. Similarly use of other iodine sourc-
es such as NIS, KI, and IBD did not result in formation of 2a.
In case of NIS instead of 2a the cyclized product 1-phenyl-
naphtho[2,1-b]furan was formed in 10% yield.
well with molecular iodine under the optimized conditions
to generate the corresponding iodovinylnaphthols. The re-
sults are summarized in Table 2. The reaction is of general
nature and tolerated different functional groups such as
methoxy, methyl, bromo, and fluoro on both the aryl and
naphthyl ring and gave good to excellent yields (56–89%) of
iodovinylnaphthols. However, reaction of 4-methoxy-2-(1-
phenylvinyl)phenol and 3-buten-1-ol with iodine under
optimized reaction conditions did not result in the forma-
tion of expected iodovinyl derivatives, which mean that the
substrate scope for this reaction is limited to ortho-vinyl-
naphthols.
Table 2 Synthesis of Iodovinylnaphtholsa,12
R2
R2
I2 (2.5 equiv)
I
OH
OH
MeCN, reflux, 4 h
R1
R1
2a–m
1a–m
Entry
R1
R2
Product 2 Yield (%)b
Table 1 Optimization of Reaction Conditionsa
1
2
H
H
2a
2b
2c
2d
2e
2f
89
77
84
65
61
63
68
69
72
76
61
66
67
56
Ph
Ph
I2 (equiv)
I
H
4-Me
4-MeO
4-F
OH
OH
solvent, reflux, time
3
H
4
H
2a
1a
5
7-MeO
7-MeO
7-MeO
6-Br
6-Br
6-Br
6-Ph
6-Ph
H
6
4-Me
4-F
Entry
Iodine source (equiv) Solvent
Time (h)
Yield (%)b
7
2g
2h
2i
1
2
I2 (1.5)
I2 (1.5)
I2 (2.0)
I2 (2.5)
I2 (4.0)
I2 (2.5)
I2 (2.5)
I2 (2.5)
I2 (2.5)
I2 (2.5)
HI (2.0)
NIS (2.0)
KI (2.0)
IBD (2.0)
MeCN
MeCN
MeCN
MeCN
MeCN
THF
2
4
52
8
H
63
9
4-Me
4-MeO
H
3
4
73
10
11
12
13
14
2j
4
4
89
2k
2l
5
4
83
4-Me
H
6
4
86
4-MeOC6H4
2m
2n
7
DMSO
toluene
acetone
MeCN
MeCN
MeCN
MeCN
MeCN
4
71c
62
3,4-(MeO)2C6H3
H
8
4
a Reaction conditions: 3 (1.0 mmol), I2 (2.5 equiv), MeCN (3 mL) reflux for 4 h.
9
4
n.r.d
74
b Isolated yield.
10
11
12
13
14
12
8
To understand the underlying mechanism some control
experiments were performed (Scheme 2). Reaction of sty-
rene and 2-methoxy-1-(1-phenylvinyl)naphthalene failed
to give the corresponding iodinated product under the opti-
mized conditions. On the other hand, reaction of 1a with
iodine in the presence of radical scavenger TEMPO (1.0
equiv) gave 2a in 79% yield. Also, reaction of 1a with iodine
(1.0 equiv) in the presence of HI (1.0 equiv) was much slow-
er, and only 50% conversion was observed after 8 hours in-
dicating that HI is not catalyzing this transformation. ortho-
Allylnaphthol (7) on reaction with iodine under these con-
ditions gave 2-(iodomethyl)-1,2-dihydronaphtho[2,1-b]fu-
ran (8) in 62% yield. Formation of 8 is reported in the litera-
n.r.
e
1
–
8
n.r.d
n.r.d
1
a Reagents and conditions: 1a (1.0 mmol), I2 (1.5–4.0 equiv), solvent (3 mL)
at reflux conditions.
b Isolated yield.
c 80 °C.
d No reaction
e Cyclized product, 1-phenylnaphtho[2,1-b]furan was formed in 10%.
Having the optimized conditions in hand, we next in-
vestigated the general application of this process. ortho-Vi-
nylnaphthols having various substituent groups reacted
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
P. Kaswan et al.
Letter
Synlett
ture to occur through 5-exo-trig type iodocyclization.11
These control experiments suggested that the reaction is
assisted by the hydroxyl group, involves formation of iodo-
nium ion and proceeds through nonradical mechanism
pathway.
ed in the same orientation and hence double bond in 2f has
Z-geometry.
Based on control experiments and literature reports13
the plausible reaction mechanism for vinylic iodination of
ortho-vinylnaphthols is proposed in Scheme 3. It is believed
that initially interaction of the vinylic bond and molecular
iodine leads to intermediate A, which further converts into
iodonium intermediate B. Elimination of HI generates or-
tho-quinone methide intermediate C. Intramolecular rear-
rangement of C gives vinyl iodide derivative 2.
I
I2 (2.5 equiv), MeCN
reflux, 12 h
3
4, 0%
I
Ph
Ph
OMe
OMe
I
2 (2.5 equiv), MeCN
reflux, 4 h
δ
I
δ
I
I
I
Ar
Ar
Ar
H
5
6, 0%
OH
OH
Ar
O
I2
I
OH
I2 (2.5 equiv), MeCN
OH
A
1
B
TEMPO (1 equiv)
reflux, 4 h
I
H
Ar
I
H
2a, 79%
1a
rearrangement
O
OH
I
– HI
O
I
2 (2.5 equiv), MeCN
reflux, 4 h
OH
C
2
Scheme 3 Plausible mechanism of vinylic iodination of ortho-vinyl-
7
8, 62%
naphthols
Scheme 2 Control experiments
Further to demonstrate the efficiency and scalability of
the developed methodology, a gram-scale reaction for the
synthesis of 2a was performed. As shown in Scheme 4, 2a
could be readily synthesized in 1.36 grams (90%) from 1.0
gram of 1a in a gram-scale synthesis.
The stereochemistry about the double bond was deter-
mined by the 2D NOSEY experiment. In the 2D NOSEY spec-
trum of 2f (Figure 1), strong correlations indicating
through-space coupling among the vinylic proton and pro-
tons at the C2 and C6 carbons of the tolyl ring established
that both groups (vinylic proton and tolyl ring) were situat-
Ph
Ph
I
OH
OH
MeCN (10 mL)
reflux, 4 h
I2
+
1a (1.0 g)
2.58 g
2a (1.36 g)
Scheme 4 Gram-scale synthesis of 2a
Finally, the synthetic utility of iodovinylnaphthol was
demonstrated via acylation followed by Suzuki coupling re-
action. When acylated iodovinylnaphthol, 1-(2-iodo-1-
phenylvinyl)naphthalen-2-yl acetate (9), was reacted with
phenylboronic acid in the presence of 5 mol% Pd(dppf)Cl2,
the desired coupled product 1-(1,2-diphenylvinyl)naphtha-
len-2-yl acetate (10) was obtained in 48% yield (Scheme 5).
Ph
Ph
I
Ph
Pd(dppf)Cl2⋅CH2Cl2 (5 mol%)
OAc
Na2CO3 (2.0 equiv), PhB(OH)2
OAc
toluene, N2, 110 °C, 16 h
10, 48%
9
Figure 1 2D NOSEY spectrum of 2f
Scheme 5 Synthetic utility of ortho-vinylnaphthol
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
P. Kaswan et al.
Letter
Synlett
In summary we have demonstrated a straightforward,
atom-economical, high-yielding procedure for the synthesis
of iodovinylnaphthols. Use of molecular iodine, metal-free
conditions, good functional-group tolerance, no pre-activa-
tion requirement of the vinylic group, and high yield are the
salient features of the present methodology. The synthetic
utility, efficiency, and scalability of the method are clear.
We hope that this methodology will find widespread use in
organic synthesis.
(11) (a) Orito, K.; Hatakeyama, T.; Takeo, M.; Suginome, H.; Tokuda,
M. Synthesis 1997, 23. (b) Basu, P. K.; Ghosh, A. Org. Chem. Int.
2012, 810476. (c) Yadav, A. K.; Singh, B. K.; Singh, N.; Tripathi, R.
P. Tetrahedron Lett. 2007, 48, 6628.
(12) Synthesis of 2a
In an oven-dried 25 mL round-bottom flask compound 1a (246
mg, 1.0 mmol), I2 (634 mg, 2.5 mmol), and MeCN (3 mL) was
added. The reaction mixture was refluxed for 4 h. After cooling
the reaction mixture, the reaction was quenched with Na2S2O3
solution and extracted with EtOAc (2 × 5 mL). The combined
organic layer was dried over anhydrous Na2SO4 and then con-
centrated on rotatory evaporator under vacuum. The crude
product was purified by column chromatography over silica gel
(100–200 mesh) using hexane–EtOAc as eluent to give 2a as an
off-white viscous liquid.
Acknowledgment
Authors sincerely acknowledge the Council of Scientific and Industrial
Research (CSIR), New Delhi. PK, GMS, and VKR are thankful to CSIR,
New Delhi for senior research fellowship. We also thank Shiv Dhiman
and Nitesh K. Nandwana for recording NMR data and their help in 2D
NOESY analysis.
Spectral Data for Selected Compounds
1-(2-Iodo-1-phenylvinyl)naphthalen-2-ol (2a)
1
Yield 89%; off-white viscous liquid. H NMR (300 MHz, CDCl3):
δ = 7.86 (d, J = 9.0 Hz, 1 H), 7.81 (dd, J = 8.19, 2.30 Hz, 1 H), 7.63
(s, 1 H), 7.49 (dd, J = 8.19, 2.30 Hz, 1 H), 7.40–7.21 (m, 8 H), 5.20
(s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 149.4, 146.9, 138.7, 131.5,
130.4, 129.1, 129.0, 128.9, 128.3, 127.1, 126.5, 124.1, 123.7,
121.1, 117.7, 86.0. IR: 756, 1188, 1250, 3055, 3496 cm–1. ESI-
HRMS: m/z calcd for C18H14IO+ [M + H]+: 373.0084; found:
373.0087.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560559.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
1-(2-Iodo-1-p-tolylvinyl)-7-methoxynaphthalen-2-ol (2f)
Yield 63%; viscous liquid; 1H NMR (400 MHz, CDCl3): δ = 7.80 (d,
J = 8.8 Hz, 1 H), 7.74 (d, J = 8.9 Hz, 1 H), 7.57 (s, 1 H), 7.25 (d, J =
8.2 Hz, 2 H), 7.14 (d, J = 8.8 Hz, 1 H), 7.11 (d, J = 8.1 Hz, 2 H), 7.03
(dd, J = 8.9, 2.5 Hz, 1 H), 6.81 (d, J = 2.4 Hz, 1 H), 5.32 (s, 1 H),
3.75 (s, 3 H), 2.33 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 158.6,
150.0, 147.0, 138.9, 136.1, 132.9, 130.0, 129.8, 129.7, 126.4,
124.5, 120.6, 115.8, 115.0, 103.2, 84.7, 55.2, 21.2. IR: 795, 825,
References and Notes
(1) (a) Bates, C. G.; Saejueng, P.; Doherty, M. Q.; Venkataraman, D.
Org. Lett. 2004, 6, 5005. (b) Kabir, M. S.; Van Linn, M. L.; Monte,
A.; Cook, J. M. Org. Lett. 2008, 10, 3363.
(2) Kabalka, G. W.; Shoup, T. M.; Daniel, G. B.; Goodman, M. M.
Nucl. Med. Biol. 2000, 27, 279.
(3) (a) Quiclet-Sire, B.; Zard, S. Z. Chem. Commun. 2006, 1831.
(b) Kropp, P. J.; Crawford, S. D. J. Org. Chem. 1994, 59, 3102.
(c) Kawaguchi, S.-i.; Gonda, Y.; Masuno, H.; Vũ, H. T.;
Yamaguchi, K.; Shinohara, H.; Sonoda, M.; Ogawa, A. Tetrahe-
dron Lett. 2014, 55, 6779.
(4) Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14844.
(5) Kabalka, G. W.; Reddy Mereddy, A. Tetrahedron Lett. 2004, 45,
1417.
(6) Das, J. P.; Roy, S. J. Org. Chem. 2002, 67, 7861.
(7) Gao, F.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 10961.
(8) Pawluć, P.; Hreczycho, G.; Szudkowska, J.; Kubicki, M.;
Marciniec, B. Org. Lett. 2009, 11, 3390.
(9) Kuhl, N.; Schröder, N.; Glorius, F. Org. Lett. 2013, 15, 3860.
(10) Rao, V. K.; Kaswan, P.; Shelke, G. M.; Ryan, A.; Jha, M.; Kumar, A.
Synthesis 2015, 47, 3990.
1242, 1621, 3063, 3441 cm–1
20H18IO2+ [M + H]+: 417.0346; found: 417.0351.
. ESI-HRMS: m/z calcd for
C
6-(3,4-Dimethoxyphenyl)-1-(2-iodo-1-phenylvinyl)naphtha-
len-2-ol (2n)
Yield 56%; pale yellow liquid. 1H NMR (300 MHz, CDCl3): δ =
7.97 (s, 1 H), 7.91 (d, J = 8.2 Hz, 1 H), 7.71–7.48 (m, 3 H), 7.40–
7.12 (m, 8 H), 6.96 (d, J = 7.3 Hz, 1 H), 5.29 (s, 1 H), 3.95 (s, 3 H),
3.92 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 149.4, 149.2, 148.5,
146.9, 138.7, 136.4, 134.0, 130.5, 130.5, 129.4, 129.0, 128.9,
126.7, 126.5, 125.7, 124.6, 121.1, 119.5, 118.1, 111.6, 110.5,
86.0, 56.0. IR: 818, 1134, 1512, 1597, 3055, 3526 cm–1. ESI-
+
HRMS: m/z calcd for C26H22IO3 [M + H]+: 509.0608; found:
509.0611.
(13) (a) Zhao, D.-Y.; Guo, X.-K.; Li, J.-H.; Tang, R.-Y. Synthesis 2012,
44, 927. (b) Pan, C.; Yu, J.; Zhou, Y.; Wang, Z.; Zhou, M.-M.
Synlett 2006, 1657.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D