An Unprecedented, Lewis Acid-Mediated, Metal-Free Iodoannulation Strategy to Aromatic Iodides

Article abstract of DOI:10.1002/asia.201801454

A direct transformation of ortho-alkynylated aromatic vinyl ethers to 1-iodonaphthalenes and other iodo-heterocycles under mild Lewis acidic conditions in the presence of iodide as an external nucleophile is reported. The first example of an iodoannulation strategy using a nucleophilic source of iodine, coupled with good to excellent yields, exclusive alpha regioselectivity and a broad substrate scope makes this work an attractive avenue towards the construction of aromatic iodides.

Full text of DOI:10.1002/asia.201801454

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Accepted Article
Title: An unprecedented, Lewis acid mediated, metal-free
iodoannulation strategy to aromatic iodides
Authors: Krishna Pillai Kaliappan, Trisha Banik, and Vipul V Betkekar
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An unprecedented, Lewis acid mediated, metal-free
iodoannulation strategy to aromatic iodides
Trisha Banik,[a] Vipul V. Betkekar[a] and Krishna P. Kaliappan*[a]
Abstract: A direct transformation of ortho-alkynylated aromatic
vinyl ethers to 1-iodonaphthalenes and other iodo-heterocycles
under mild Lewis acidic conditions in the presence of iodide as an
external nucleophile is reported. The first example of an
iodoannulation strategy using a nucleophilic source of iodine,
coupled with good to excellent yields, exclusive alpha
regioselectivity and a broad substrate scope makes this work an
attractive avenue towards the construction of aromatic iodides.
to produce 6, 7-dimethoxy-1-iodonaphthalene 3. Once the
structure of the newly formed product was confirmed, a survey
of existing literature re-established that iodoannulation with
good selectivity and generality is a difficult transformation to
achieve in the same pot and hence this particular area remains
quite unexplored in the synthetic arena. Certainly the
incorporation of iodine in the less electron rich nucleus of a
naphthalene system was found to be complementary to what is
observed for typical aromatic electrophilic iodination on
naphthalene derivatives.
Annulation1,2 is a process of building rings through creation of a
new bond onto a pre-existing cyclic or acyclic system, giving
rise to highly complex molecular architecture in one step. Using
annulation strategies, formations of rings of all sizes have been
developed by a number of synthetic methods over the years.
Annulation accompanied by a secondary functionalization on
the newly formed cyclic framework adds value to the overall
transformation. Introduction of an iodo group during cyclization
would lead to the formation of aromatic iodo-compounds in
one-pot and this overall process may be termed as
“iodoannulation”.
Of the few approaches known for the construction of polycyclic
aromatic iodides, each of them proceeds via an iodonium ion
carbocyclization, which makes the mechanism electrophile
induced.
Aryl and heteroaryl iodides are universal precursors and basic
building blocks used in chemistry for many important
transformations, such as metalation processes,3,4 nucleophilic
aromatic substitutions,5 and transition-metal catalyzed cross-
coupling reactions.6,7 Iodonaphthalene possesses C-MITOTIC
action and also plays an important role in chemical and
biological processes especially 1-iodonapthalene is known for
its antimicrobial properties.8 Though ring annulations strategies
have been successfully used for the formation of iodoarenes,
most of them use either harsh conditions or metal catalysts.9
Scheme 2. Earlier reports on iodoannulation
Intramolecular electrophilic cyclization of diarylated acetylenes
utilizing electrophilic iodine source such as I(py)2BF4 has been
reported by Swager11 and Barluenga.12 Later on Larock and
co-workers used ICl or I2 to simplify the iodine source.13 In 2002,
Iwasawa and co-workers reported the transformation of pre-
iodinated terminal alkynes to 1-iodonaphthalene derivatives by
using an expensive route via tungsten mediated 6π-
electrocyclization (Scheme 2).14 During the preparation of our
manuscript, Kwon and co-workers published the synthesis of
β–silylalkenyl triflates via an alkenyl carbocation intermediate,15
where the weakly nucleophilic triflate only quenches the highly
reactive vinylic carbocation intermediate. There are only a
handful of reports where such annulations are driven by
Scheme 1. Preliminary observation
Recently, during the course of an ongoing project in our
laboratory on the synthesis of atisane type alkaloids,10 an
attempted hydrolysis of the vinyl ether 1 to its corresponding
aldehyde 2 using NaI and TMSCl led to the formation of an
unexpected product in excellent yield. Upon careful analysis of
this serendipitous product, we concluded that the vinyl ether
had undergone an interesting Lewis acid mediated cyclization
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nucleophiles, but in most cases these are internal nucleophiles
already embedded in the system.16 This prompted us to
develop our serendipitous observation into a more general
methodology for the synthesis of polycyclic aromatic iodides.
To the best of our knowledge, till date there are no reports
known for iodoannulations using external nucleophilic iodine
source.
methoxyvinyl)benzene 14 as our test substrate. For the
preparation of the same, 2-bromobenzaldehyde 12 was
converted to the corresponding TMS-alkyne 13 by Sonogashira
coupling, which in turn was homologated to enol ether 10 using
(methoxymethyl)triphenylphosphonium
chloride.
Once
compound 10 was formed, the terminal TMS group was
removed with TBAF to obtain the terminal alkyne (Scheme 3).
At the outset of our studies, we treated our test substrate 14
with NaI in presence of TMSCl. Unlike the electron rich
substrates, the unsubstituted alkynyl vinyl ether provided a
moderate yield of 48% in CH3CN. Replacement of the iodide
source with KI reduced the yield to 31%. Polar aprotic solvents
like THF, DMSO, DMF or DCE did not provide any significant
product formation even after 24 h. Non-polar solvent like
toluene at room temperature yielded 44% of the iodoannulated
product. However refluxing temperatures in toluene and
acetonitrile improved the yield significantly to 83% and 87%
respectively and also reduced the reaction time considerably.
Table 2. Attempted preparation of aryne precursors
Scheme 3. Synthesis of (alkynyl)aryl vinyl ethers
Herein, we report a versatile method for the synthesis of
polycyclic aromatic iodides in high yields under mild reaction
conditions using vinylated phenyl acetylenes and NaI as a
nucleophilic source in the presence of a mild Lewis acid TMSCl.
The fact that this cyclization is driven by a nucleophile makes
this method mechanistically different from the existing ones.
Table 1. Optimization of iodoannulation
Entry
Solvent
CH3CN
Toluene
Temp.
Rt
Time
3.5 h
4 h
Isolated Yield
84%
1
2
Rt
79%
Entry
Solvent
Temp.
Time
Isolated Yield
We envisioned that an iodonaphthalene derivative with a TMS
group intact at the 2-position would be an ideal aryne
precursor17, 18 and in order to achieve this, we carried out the
reaction with the terminal TMS group intact in the vinyl ether.
Unfortunately the TMS group proved to be too labile under
these reaction conditions and we obtained the same 1-
iodonaphthalene 11, but in lesser reaction times and at room
temperature.
1
2
3
4
5
6
7
8
9
CH3CN
CH3CNa
THF
rt
36 h
48 h
24 h
24 h
24 h
24 h
36 h
2.5 h
2.5 h
48%
31%
-
rt
rt
DMSO
DMF
rt
rt
Trace
-
DCE
rt
-
So, even though we could not achieve the synthesis of our
desired aryne precursor by this route, it was a blessing in
disguise as it reduced one step in the preparation of our
iodoannulated precursors. The TMS-protected alkyne 10
provided 1-iodonaphthalene with a yield of 79% in toluene,
while acetonitrile yielded 84%, which were very much
comparable to our earlier conditions (Table 1, Entries 8 and 9).
We decided to compromise the small decrease in yield, in order
to accommodate the other advantages of a lesser reaction time
and much milder conditions.
Toluene
Toluene
CH3CN
rt
44%
83%
87%
reflux
reflux
[a] KI used instead of NaI
In order to standardize the reaction conditions in general, we
chose the unfunctionalized system, 1-ethynyl-2-(2-
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With the optimized reaction condition in hand (Entry 2, Table 2),
the scope of this interesting transformation was examined. It is
worth mentioning that electron rich aromatic nuclei afforded
very good yields, whilst substrates with electron withdrawing
groups like –NO2 failed to furnish the desired product at all.
Electron withdrawing groups attached on the terminal position
of the alkyne reacted well, while methyl substituted alkynes
returned moderate results. However, bulky alkyne substituents
like TIPS or Ph failed to provide the iodonaphthalenes,
presumably due to steric issues.
An extension of our method was envisaged by replacing the
alkyne with a nitrile group in few of our vinyl ether substrates.
This furnished 1-iodoisoquinolene19 under the standard
conditions, which happens to be a privileged scaffold in
heterocyclic chemistry (Scheme 4).
Scheme 6. Evidences for oxonium ion formation
A couple of important observations provided us a lead towards
elucidating a plausible mechanism of the annulation reaction
(Scheme 6). When we stopped the reaction after 1 h, aldehyde
34 was isolated which suggested a predictable hydrolysis of the
vinyl ether 33 under Lewis acidic conditions, via an
intermediate oxonium ion. So the first step of our cyclization
process should be the formation of the oxonium ion catalyzed
by the in situ generated TMSI, thereby generating intermediate
36. Another independent experiment with a hard nucleophile
like sodium azide resulted in the direct quenching of the
oxonium ion to provide the azido-ether 35 (Scheme 6).
Scheme 4. Substrate scope for iodoannulation
We also explored the scope of α-substituted vinyl ethers
derived from acetophenone or benzophenone derivatives to
afford the 1,4-disubstituted naphthalenes with equally efficient
results. Substituted alkynes attached to ketone derivatives
provided the 1,2,4-trisubstituted naphthalenes, although in poor
yields, probably due to the highly congested nature of the
intermediates. The test substrate was iodoannulated in gram
scale with reproducible yield, which establishes the scalability
of the method.
Scheme 7. Plausible mechanism for iodoannulation protocol
This led us to believe that a softer nucleophile like iodide would
quench the oxonium ion indirectly by a relay nucleophilic attack
on the internal carbon of the triple bond, which would in turn
complete the ring formation through a 6-exo-trig type cyclization
Scheme 5. Iodoannulation leading to isoquinoline derivatives
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to generate intermediate 37. This process is analogous to Prins
type cyclization,20 where the oxonium ion is quenched by the
triple bond and the newly formed carbocation is stabilized by β-
stabilizing effect of silicon. Finally a second equivalent of iodide
aromatizes the ring by elimination of –OMe and TMS groups to
generate the silylated iodonaphthalene 38, which undergoes
protodesilylation to provide our desired 1-iodonaphthalene 11 in
situ (Scheme 7). As we have used dry CH3CN, freshly dried NaI
and distilled TMSCl, chances of HI being formed during the
reaction is minimal. This eliminates an alternative possibility of
our reaction being driven by a strong Bronsted acid like HI.
In addition, iodinated derivatives of isoquinoline were also
synthesized which have immense value in the construction of
various biologically active moieties. The scope of this method
has been further extended by carrying out various coupling
reactions on our aromatic iodo-compounds to provide a wide
range of polyaromatic scaffolds, which are not always easily
accessible. Mechanistically, the reaction is driven by the Lewis
acid mediated formation of an oxonium ion followed by relay
quenching of the same by iodide ion, via a nucleophile
mediated 6-exo-trig cyclization. To the best of our knowledge,
this is the first example of such a nucleophile mediated
iodoannulation strategy and it holds a lot of potential towards
the construction of 1-aromatic iodides and their derivatives.
To further extend the scope of our iodoannulated products, a
few self-coupling reactions were performed with our
iodoannulated products which led to the formation of some
interesting binaphthyl compounds, which have enormous scope
in the field of asymmetric synthesis as axially chiral ligands.
Experimental Section
Please check the supporting information.
Acknowledgements
K.P.K acknowledges SERB (EMR/2017/000578) and Astra
Zeneca Research Foundation for the financial support. T.B
acknowledges IIT Bombay for fellowship. V.V.B acknowledges
CSIR, New Delhi for his fellowship. The instrumental facility of
IIT Bombay is gratefully acknowledged.
1]
(a) J. Li, Y. Le, Y. Zhang, Org. Chem. Front. 2018, 5, 864. (b) G. A.
Molander, Acc. Chem. Res. 1998, 31, 603.
[2]
(a) E. Negishi, S. J. Holmes, J. M. Tour, J. A. Miller, F. E.
Cederbaum, D. R. Swanson, T. Takahashi, J. Am. Chem. Soc. 1989,
111, 3336. (b) R. L. Danheiser, S. K. Gee, H. Sard. J. Am. Chem.
Soc. 1982, 104, 7670. (c) M. E. Jung, Tetrahedron 1976, 32, 3. (d) B.
P. Mundy, J. Chem. Edn. 1973, 50, 110.
Scheme 8. Coupling products obtained from the iodoannulated derivatives
Some well known coupling reactions like Suzuki coupling, Heck
[3]
[4]
(a) D. Tilly, F. Chevallier, F. Mongin, P. C. Gros, Chem. Rev. 2014,
114, 1207. (b) C. Najera, J. M. Sansano, M. Yus, Tetrahedron 2003,
59, 9255. (c) N. Sotomayor, E. Lete, Curr. Org. Chem. 2003, 7, 275.
(d) F. Leroux, M. Schlosser, Angew. Chem., Int. Ed. 2002, 41, 4272.
(a) P. Kurach, S. Lulinski, J. Serwatowski, Eur. J. Org. Chem. 2008,
3171. (b) M. Dąbrowski, J. Kubicka, S. Lulinski, J. Serwatowski,
Tetrahedron 2005, 61, 6590. (c) M. Schlosser, Angew. Chem., Int.
Ed. 2005, 44, 376. (d) P. Knochel, W. Dhole, N. Gommermann, F. F.
Kneisel, F. Kopp, T. Korn, I. Sapountzis, V. A. Vu, Angew. Chem.,
Int. Ed. 2003, 42, 4302. (e) H. Pellissier, M. Santelli, Tetrahedron
2003, 59, 701.
coupling
and
Sonogashira
coupling
utilizing
our
iodonaphthalene derivatives with various coupling partners
were carried out, which furnished some interesting
polyaromatic compounds with excellent yield and a broad
scope (Scheme 8).
Conclusion
[5]
[6]
[7]
(a) J. F. Hartwig, Synlett 2006, 9, 1283. (b) J. F. Bunnett, R. Zahler,
Chem. Rev. 1951, 49, 273.
In conclusion, we have reported a direct transformation of 2-
alkynylated aromatic vinyl ethers to various aromatic iodides,
which are useful substrates for various coupling reactions.
C. Bolm, J. P. Hildebrand, K. Muniz, N. Hermanns, Angew. Chem.,
Int. Ed. 2001, 40, 3284.
Arising from
a
serendipitous observation, the reaction
(a) G. Evano, N. Blanchard, M. Toumi, Chem. Rev. 2008, 108, 3054.
(b) D. Ma, Q. Cai, Acc. Chem. Res. 2008, 41, 1450.
conditions were carefully optimized to synthesize a wide
number of 1-iodonaphthalene derivatives with good to excellent
yields, employing a mild and scalable condition at room
temperature. Exclusive alpha-regioselectivity irrespective of
substituents was observed in the less electron rich nucleus of
the naphthalene derivatives, which is contrary to what occurs in
aromatic electrophilic iodination.
[8]
[9]
A. Levan, G. Ostergren, Hereditas 1943, 29, 381.
(a) M. Gulias, J. L. Mascarenas, Angew.Chem. Int. Ed. 2016, 55,
11000. (b) L. Souillart, N. Cramer, Chem. Rev. 2015, 115, 9410. (c)
M. Gulias, F. Lopez, J. L. Mascarecas, Pure Appl. Chem. 2011, 83,
495.
[10]
(a) H. Cheng, F.-H. Zeng, Y-J. Meng, L. Xu, F.-P. Wang, Angew.
Chem., Int. Ed. 2016, 55, 392. (b) G. Zhu, R. Liu, B. Liu, Synthesis
For internal use, please do not delete. Submitted_Manuscript
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10.1002/asia.201801454
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2015, 47, 2691. (c) E. M. Cherney, J. M. Lopchuk, J. C. Green, P. S.
Baran, J. Am. Chem. Soc. 2014, 136, 12592.
[11]
[12]
[13]
[14]
M. B. Goldfinger, K. B. Crawford, T. M. Swager, J. Am. Chem. Soc.
1997, 119, 4578.
J. Barluenga, M. Trincabo, E. Rubio, J. M. Gonzalez, Angew. Chem.,
Int. Ed. 2003, 42, 2406.
(a) T. Yao, M. A. Campo, R. C. Larock, Org. Lett. 2004, 6, 4. (b) X.
Zhang, S. Sarkar, R. C. Larock, J. Org. Chem. 2006, 71, 236.
(a) T. Miura, N. Iwasawa, J. Am. Chem. Soc. 2002, 124, 518. (b) V.
Mamane, P. Hannen, A. Furstner, Chem. Eur. J. 2004, 10, 4556.
C. J. Lee, M. Swain, O. Kwon, Org. Lett. 2018,
[15]
[16]
(a) S. J. Gharpure, V. Prasath, V. Kumar, Chem. Commun. 2015, 51,
13623. (b) X. Peng, L. Zhu, Y. Hou, Y. Pang, Y. Li, J. Fu, L. Yang, B.
Lin, Y. Liu, M. Cheng, Org. Lett. 2017, 19, 3402.
[17]
[18]
(a) J.-A. Garcia-Lopez, M. F. Greaney, Chem. Soc. Rev. 2016, 45,
6766. (b) P. M. Tadross, B. M. Stoltz, Chem. Rev. 2012, 112, 3550.
(a) S. N. Ross, T. R. Hoye, Nat. Chem. 2017, 9, 523. (b) Y. Dong, Y.
Li, Y.-L. Wei, J. C. Wang, J.-P. Ma, J. Ji, B.-J. Yao, Y.-B. Dong,
Chem. Commun. 2016, 52, 10505. (c) K. M. Allan, C. D. Gilmore, B.
M. Stoltz, Angew. Chem., Int. Ed. 2011, 50, 4488. (d) S. M. Bronner,
N. K. Garg, J. Org. Chem. 2009, 74, 8842. (e) Z. Liu, R. C. Larock, J.
Org. Chem. 2006, 71, 3198. (f) U. K. Tambar, B. M. Stoltz, J. Am.
Chem. Soc. 2005, 127, 5340. (g) C. Dockendorff, S. Sahli, M, Olsen,
L, Milhau, M. Lautens, J. Am. Chem. Soc. 2005, 127, 15028.
(a) Z. Hu, J. Dong, Y. Men, Y. Li, X. Xu, Chem. Commun. 2017, 53,
1739. (b) D. Yuan, Z. Duan, Y. Rao, M-W. Ding, Tetrahedron 2016,
72, 338.
[19]
[20]
(a) P. O. Miranda, M. A. Ramirez, V. S. Martin, J. I. Padron, Org.
Lett. 2006, 8, 1633. (b) L. E. Overman, E. J. Velthuisen, Org. Lett.
2004, 6, 3853. (c) R. Jasti, C. D. Anderson, S. D. Rychnovsky, J.
Am. Chem. Soc. 2005, 127, 9939. (d) P. O. Miranda, D. D. Diaz, J. I.
Padron, J, Bermejo, V. S. Martin Org. Lett. 2003, 5, 1979.
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Trisha Banik, Vipul V. Betkekar, Krishna
P. Kaliappan*
Page No. – Page No.
A
unprecedented,
Lewis
acid
mediated metal free, iodoannulation
strategy to aromatic iodides
Alpha wins the relay race: A direct transformation of ortho-alkynylated aromatic
vinyl ethers to 1-iodonaphthalenes and other iodo-heterocycles under mild Lewis
acidic conditions in presence of iodide as an external nucleophilic source has been
described. The first example of an iodoannulation strategy using a nucleophilic
source of iodine, coupled with good to excellent yields, exclusive alpha
regioselectivity, high scalability and a broad substrate scope makes this work an
attractive avenue towards the construction of aromatic iodides.
This article is protected by copyright. All rights reserved.