Iodide as a Nucleophilic Trigger in Aryne Three-Component Coupling for the Synthesis of 2-Iodobenzyl Alcohols

Article abstract of DOI:10.1021/acs.orglett.9b01621

The synthetic potential of KI as the iodide source in aryne three-component coupling has been demonstrated using aldehydes as the third component. This mild and transition-metal-free coupling reaction allowed the straightforward synthesis of 2-iodobenzyl alcohols in moderate to good yields with good functional group compatibility. Moreover, KBr and KCl could be used as the nucleophilic trigger in this aryne multicomponent coupling (MCC) and N-methylisatin and CO₂ could be used as the electrophilic third components.

Full text of DOI:10.1021/acs.orglett.9b01621

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iodide as a Nucleophilic Trigger in Aryne Three-Component
Coupling for the Synthesis of 2‑Iodobenzyl Alcohols
Subrata Bhattacharjee, Avishek Guin, Rahul N. Gaykar, and Akkattu T. Biju*
Department of Organic Chemistry, Indian Institute of Science, Bangalore-560012, India
S
* Supporting Information
ABSTRACT: The synthetic potential of KI as the iodide source in
aryne three-component coupling has been demonstrated using
aldehydes as the third component. This mild and transition-metal-
free coupling reaction allowed the straightforward synthesis of 2-
iodobenzyl alcohols in moderate to good yields with good functional
group compatibility. Moreover, KBr and KCl could be used as the
nucleophilic trigger in this aryne multicomponent coupling (MCC)
and N-methylisatin and CO2 could be used as the electrophilic third
components.
ulticomponent coupling (MCC) involving arynes has
been widely used for the convenient synthesis of
arenes, which can easily be functionalized to valuable
compounds. It is important to note in this context that the
use of halides as electrophilic source in aryne MCCs has been
uncovered by the groups of Yoshida,15 Wang,16 and Hu.17
Moreover, the reaction of arynes with an electrophilic iodide
source for the iodoalkynylation of arynes was demonstrated by
Hamura, Suzuki and co-workers.18 Herein, we report the use of
KI as the iodide source for the aryne MCCs using aldehydes as
the third component for the transition-metal-free and mild
synthesis of 2-iodobenzyl alcohols (eq 2).
Inspired by the potential of aryne MCCs triggered by
nucleophilic species, the present study was initiated by treating
4-nitrobenzaldehyde 1a with the Kobayashi aryne precursor
2a19 and KI. When the aryne was generated using the
combination of KF/18-crown-6 in THF at 25 °C, the 2-
iodobenzyl alcohol 3a was formed in 64% yield (Table 1, entry
1). Compared to KI, other iodide sources such as NaI and
tetrabutylammonium iodide (TBAI) furnished a reduced yield
of 3a (entries 2, 3). Moreover, the fluoride sources such as CsF
and tetrabutylammonium fluoride (TBAF) returned a
diminished yield of 3a (entries 4,5). The reaction temperature
was found to be optimal at 25 °C as the reaction provided a
lower yield of 3a when performed at 50 °C and at 0 °C (entries
6, 7). The reaction performed in DME afforded 53% of 3a
(entry 8). Interestingly, the product was formed in 67% yield
when the concentration was doubled (entry 9). Increasing the
amount of aryne precursor 2a slightly increased the yield of 3a
(entry 10). Finally, performing the reaction using 2.5 equiv of
KI resulted in the formation of 3a in 70% isolated yield (entry
11).20
M
versatile and structurally complex 1,2-disubstituted ben-
zenes.1,2 In a typical aryne MCC, the nucleophile having no
acidic hydrogen atoms adds to the highly electrophilic aryne
generating the aryl anion intermediate, which is subsequently
intercepted by the electrophilic coupling partner leading to the
formation of 1,2-disubstituted arenes (the nucleophile and
electrophile are separate entities).1b,d The commonly used
nucleophiles in aryne MCCs include isocyanides,3 amines,4
imines,5 nitrogen heterocycles (such as pyridine,6 (iso)-
quinoline,7 and aziridines),8 phosphines,9 and solvents such
as DMF,10 DMSO,11 and THF (Scheme 1, eq 1).12 The
Scheme 1. Transition-Metal-Free Aryne MCCs
electrophilic third components usually employed are alde-
hydes, activated ketones, and CO2.13 Although a series of
nucleophilic species can initiate the aryne MCCs, the use of
halides as the nucleophilic trigger has received only scant
attention,14 and employing iodide for the aryne MCCs is not
known to the best of our knowledge. Notably, the use of iodide
as the trigger could result in the synthesis of 2-iodo substituted
With the optimized reaction conditions in hand, we then
evaluated the scope and limitations of this transition-metal-free
reaction. A series of aromatic aldehydes having electron-neutral
Received: May 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01621
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope: Variation of Aldehydes
b
entry
variation of standard conditions
none
NaI instead of KI
yield of 3a (%)
1
2
3
64
<5
37
18
<5
49
58
53
67
72
TBAI instead of KI
c
4
CsF instead of KF/18-crown-6
TBAF instead of KF/18-crown-6
50 °C instead of 25 °C
0 °C instead of 25 °C
DME instead of THF
1.0 mL of THF instead of 2.0 mL
2.5 equiv of 2a in 1.0 mL of THF
2.5 equiv of KI in 1.0 mL of THF
5
6
7
8
9
d
10
11
e
f
73 (70)
a
Standard conditions: 1a (0.25 mmol), 2a (0.50 mmol), KI (2 equiv),
KF (4 equiv), 18-crown-6 (4 equiv), THF (2.0 mL), 25 °C for 24 h.
b
Yields based on the 1H NMR analysis of the crude reaction products
c
using CH2Br2 as the internal standard. Reaction was performed in
CH3CN. Reaction performed using 5.0 equiv each of KF and 18-
crown-6. Reaction performed using 2.5 equiv of 2a, 5.0 equiv each of
KF and 18-crown-6. Isolated yield of 3a.
d
e
f
a
General conditions: 1 (0.50 mmol), 2a (1.25 mmol), KI (1.25
and -withdrawing groups at the 4-position of the benzene ring
are tolerated under the iodide-triggered reaction, and the
respective 2-iodobenzyl alcohols were formed in moderate to
good yields (Scheme 2, 3b−3j).21 The formation of 3a and 3i
in 69% yield on a 3.0 mmol scale reaction demonstrates the
practical nature of the present reaction. Moreover, substitution
at the 3-position did not affect the reactivity (3k), but the
reactions using 2-substituted benzaldehydes afforded the
desired products only in moderate yields (3l−3n). In addition,
the reactions carried out using disubstituted aldehydes
provided the expected product in moderate to good yields
(3o−3r). Furthermore, this iodide triggered reaction worked
reasonably fine with pyrene carboxaldehyde, heteroaromatic
aldehydes, and aliphatic aldehydes (3s−3w).
Then, we examined the scope of this reaction with
differently substituted arynes (Table 2). The reaction carried
out using electronically different symmetrical and disubstituted
arynes generated from the corresponding precursors (2b−2e)
underwent smooth three-component coupling with KI and 4-
nitrobenzaldehyde to afford the respective 2-iodobenzyl
alcohol derivatives in moderate to good yields (3x−3aa).
Notably, the unsymmetrical naphthalyne generated from 2f
furnished a single regioisomer 3ab in 54% yield, and 3-
methoxybenzyne generated from 2g provided 3ac in 79% yield.
The structure of 3ac was confirmed by X-ray analysis (CCDC
1905768). The reaction using the unsymmetrical 4-methyl-
benzyne formed from 2h resulted in an inseparable mixture of
regioisomers 3ad and 3ad′ in 49% yield and 1:1 ratio.
mmol), KF (5.0 equiv), 18-crown-6 (5.0 equiv), THF (2.0 mL), 25
b
°C, 24 h. Yields of the isolated products are given. Reaction
c
performed on a 0.25 mmol scale. Yield of the reaction carried out in
3.0 mmol scale.
Moreover, CO2 was also used as the third component in this
iodide triggered aryne MCC furnishing 2-iodobenzoic acid in
29% yield (eq 4).13
To shed light on the mechanism of the reaction, we
performed some mechanistic experiments. Treatment of aryne
precursor 2a with KI under the optimized conditions in the
presence of D2O resulted in the formation of iodobenzene with
86% D incorporation at the 2-position (Scheme 4, eq 5). This
indicates the initial nucleophilic attack of the iodide to the
generated aryne followed by the trapping of the formed aryl
anion equivalent with D2O. Moreover, when the reaction of 1a,
2a, and KI was performed in the presence of D2O under the
optimized conditions, the product 3a was formed in 40% yield
along with the iodobenzene with 90% D incorporation at the
2-position (eq 6). Notably, when the reaction was performed
with excess D2O, the desired product 3a was formed only in
9% yield and the iodobenzene with D at the 2-position was
formed in improved yield implying that the protonation of the
aryl anion is faster than the nucleophilic attack to aldehydes.
We also performed the functionalization of the 2-iodobenzyl
alcohols utilizing Pd-catalyzed cross-coupling of the iodo
moiety. Reaction of 3a with phenylacetylene in the presence of
Pd and Cu catalysts resulted in the efficient Sonogashira
coupling leading to the formation of the functionalized
diphenylacetylene 7a in 91% yield (Scheme 5). Gold-catalyzed
cyclization of 7a afforded the 1,3-dihydroisobenzofuran 8a in
82% yield and the 3-phenyl-1H-isochromen derivative 8b in
15% yield. The structure of 8a was confirmed by X-ray analysis
(CCDC 1911771). Moreover, the Heck coupling of 3a with
This iodide triggered aryne MCC was not only limited to
aldehydes as the third components, but instead an activated
cyclic ketone such as isatin could be used as the third
component resulting in the synthesis of tertiary alcohols.22 For
instance, treatment of N-methylisatin 4a with aryne generated
from 2a under the heating conditions afforded the 2-iodo
oxindole derivative 5a in 49% yield (Scheme 3, eq 3).
B
DOI: 10.1021/acs.orglett.9b01621
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Variation of the Aryne Moiety
Scheme 5. Functionalization of 2-Iodobenzyl Alcohols
our attention on bromides and chlorides. Interestingly, by
employing KBr as the nucleophilic trigger in this aryne MCC,
the desired 2-bromobenzyl alcohol 3ae was formed in 74%
yield under the optimized reaction conditions (Scheme 6).
a
Scheme 6. Substrate Scope: Variation of Halides
a
General conditions: 1a (0.25 mmol), 2 (0.625 mmol), KI (0.625
mmol), KF (5.0 equiv), 18-crown-6 (5.0 equiv), THF (1.0 mL), 25
b
°C, 24 h. Yields of the isolated products are given. Yield of the
c
reaction carried out in 3.0 mmol scale. Determined by the 1 H NMR
analysis of crude reaction mixture.
Scheme 3. Using N-Methyl Isatin and CO2 as Electrophiles
a
General conditions: 1 (0.25 mmol), 2 (0.625 mmol), KX (0.625
mmol), KF (5.0 equiv), 18-crown-6 (5.0 equiv), THF (1.0 mL), 25
b
°C, 24 h. Yields of the isolated products are given. Yield of the
Scheme 4. Reaction Using D2O
c
reaction carried out in 3.0 mmol scale. Reaction performed on a 0.5
mmol scale.
Moreover, 2-chlorobenzyl alcohol 3af was isolated in 62% yield
when KCl was used as the halide source. This reaction was
found to be general as benzaldehyde, benzofuran 2-
carboxaldehyde, isobutyraldehyde, and the symmetrical aryne
generated from 2c furnished the respective products in
moderate to good yields (3ag−3am).
In conclusion, we have developed transition-metal-free and
mild iodide triggered aryne MCCs using aldehydes as the third
components for the synthesis of 2-iodobenzyl alcohol
derivatives. The reaction proceeds via the initial formation of
aryl anion equivalents by the nucleophilic attack of iodide to
arynes, followed by subsequent interception with aldehydes.
The other halides such as bromide and chloride could also be
used as the nucleophilic trigger in this reaction, and N-
substituted isatin and CO2 could be used as the electrophilic
styrene under Pd-catalysis afforded the stilbene derivative 9a in
84% yield. In addition, treatment of 3a with phenylboronic
acid in the presence of a Pd(0) catalyst under Suzuki
conditions furnished the biaryl derivative 10a in 79% yield.
Encouraged by the use of iodide as the nucleophilic trigger
in aryne MCCs and given the fact that other halides are not
well demonstrated in this realm of MCCs,14 we then focused
C
DOI: 10.1021/acs.orglett.9b01621
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) For selected recent reports, see: (a) Yoshioka, E.; Kohtani, S.;
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third component in this MCC. Further studies on related aryne
MCCs triggered by ionic nucleophiles are ongoing in our
laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
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Seo, J.; Ko, H. M. J. Org. Chem. 2018, 83, 8417. (c) Bhojgude, S. S.;
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01621.
Details on experimental procedures, characterization,
NMR spectra of 2-halobenzyl alcohol derivatives, and X-
ray data of 3ac and 8a (PDF)
Accession Codes
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CCDC 1905768 and 1911771 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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a related Pd-catalyzed three-component coupling triggered by
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: atbiju@iisc.ac.in.
ORCID
(7) Bhunia, A.; Porwal, D.; Gonnade, R. G.; Biju, A. T. Org. Lett.
2013, 15, 4620.
Akkattu T. Biju: 0000-0002-0645-8261
Notes
(8) (a) Roy, T.; Thangaraj, M.; Gonnade, R. G.; Biju, A. T. Chem.
Commun. 2016, 52, 9044. (b) Roy, T.; Baviskar, D. R.; Biju, A. T. J.
Org. Chem. 2015, 80, 11131. (c) Roy, T.; Bhojgude, S. S.; Kaicharla,
T.; Thangaraj, M.; Garai, B.; Biju, A. T. Org. Chem. Front. 2016, 3, 71.
(d) Stephens, D.; Zhang, Y.; Cormier, M.; Chavez, G.; Arman, H.;
Larionov, O. V. Chem. Commun. 2013, 49, 6558.
(9) (a) Bhunia, A.; Kaicharla, T.; Porwal, D.; Gonnade, R. G.; Biju,
A. T. Chem. Commun. 2014, 50, 11389. (b) Bhunia, A.; Roy, T.;
Gonnade, R. G.; Biju, A. T. Org. Lett. 2014, 16, 5132.
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Tetrahedron Lett. 2014, 55, 1402. (c) Yoshioka, E.; Tanaka, H.;
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Chem. Commun. 2016, 52, 1665. (b) Okuma, K.; Fukuzaki, Y.;
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support by Science and Engineering
Research Board-DST, Government of India (File Number:
EMR/2016/007021) is gratefully acknowledged. S.B. and A.G.
thank CSIR and R.G. thanks IISc, respectively, for a research
fellowship. We thank Mr. Tony Roy (CSIR-NCL) for helpful
discussions and Ms. Rekha Kumari (SSCU-IISc) for collecting
the X-ray data of 3ac and 8a.
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