Iodoindenes: Synthesis and application to cross-coupling

Article abstract of DOI:10.1016/j.tetlet.2020.152427

An expeditious synthesis of 5-, 6-, and 7-iodoindenes from the corresponding aminoindan-1-ones in more than 70% yield employing readily available precursors and ubiquitous reagents is reported. The 4-iodoindene has been prepared analogously in 40% overall yield. A three-step sequence involves diazotization-iodination of aminoindan-1-one followed by the reduction and dehydration. The iodoindenes serve as effective substrates for the regioselective Stille coupling with vinyl stannanes but isomeric mixtures are produced during Sonogashira coupling with alkynes in the presence of triethylamine.

Full text of DOI:10.1016/j.tetlet.2020.152427

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iodoindenes: Synthesis and application to cross-coupling
a
a
b
a
A. Hasan Howlader a, , Keili Diaz , Alexander M. Mebel , Ralf I. Kaiser , Stanislaw F. Wnuk
⇑
a Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, United States
b Department of Chemistry, University of Hawaii at Manoa, Honolulu, HI, 96822, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An expeditious synthesis of 5-, 6-, and 7-iodoindenes from the corresponding aminoindan-1-ones in
more than 70% yield employing readily available precursors and ubiquitous reagents is reported. The
4-iodoindene has been prepared analogously in 40% overall yield. A three-step sequence involves diazo-
tization-iodination of aminoindan-1-one followed by the reduction and dehydration. The iodoindenes
serve as effective substrates for the regioselective Stille coupling with vinyl stannanes but isomeric mix-
tures are produced during Sonogashira coupling with alkynes in the presence of triethylamine.
Ó 2020 Elsevier Ltd. All rights reserved.
Received 14 July 2020
Revised 25 August 2020
Accepted 30 August 2020
Available online xxxx
Keywords:
Iodoindenes
Iodoindanones
Bromovinylindene
Alkynylindene
Diazotization-iodination
Introduction
molecules containing five-member rings [11]. Herein, we report a
straightforward synthesis of 4-, 5-, 6-, and 7-iodoindenes isomers
The haloindenes are convenient precursors in the organic and
bioorganic synthesis [1]. For example, 6-bromoindene is used to
prepare ethylene-bis(indenyl) ligand via Suzuki coupling [2]. The
4-, 5-, or 6-bromo(or chloro)indenes are utilized in the synthesis
of inhibitors of the Na+/H+ exchanger [3] and histone lysine specific
demethylases [4]. Moreover, 5- and 6-bromoindene are used to
study the mechanism of dioxygenase-catalyzed benzylic hydroxy-
lation of indene [5]. The 6-chloroindene serves as precursor for the
synthesis of 6-chloro-N-hydroxy-1H-indene-2-carboxamide, used
to study the structure–activity relationships of neurotoxin A
protease inhibitors [6], as well as fullerene-based photovoltaic
acceptor materials [7]. Haloindenes are also used to synthesize
halo-substituted isoquinoline derivatives [8].
from readily available 7-, 6-, 5-, and 4-aminoindanones, as well
as their regioselective alkenylation and further alkynylation since
the enyne derivatives of indene represent potential reaction prod-
ucts of
r indenyl radicals with vinylacetylene and hence can serve
as calibration compounds in studying the growth mechanism of
PAH.
Although there are several reports for the synthesis of 5- or 6-
chloro- and bromoindenes [5,6,8a,12], there is only one method
for the preparation of more reactive 5- or 6-iodoindene which
requires expensive intermediates [13] and several steps [8].
Furthermore, reported yields for 5- or 6-iodoindenes obtained by
the reduction of the corresponding 5- or 6-nitroindene followed
by diazotization-iodination of the resulting unstable 5- or 6-
aminoindene were only 20% and 7% (see Schemes S1 and S2 in SI
section) [8a]. The 5-nitroindene and 6-nitroindene precursors
were prepared from 1-aminoindane [14] or 5-aminoindan-1-one
[8a], respectively. Therefore, we have undertaken efforts to
develop a general method for the synthesis of iodoindenes which
employs iodoindan-1-ones [15] as convenient precursors and
avoids the use of expensive nitroindenes, unstable aminoindenes
and potentially explosive trifluoroperacetic acid.
Recently, we demonstrated that pyrolysis of different bromoin-
denes at 1500 K produces resonance-stabilized and thermodynam-
ically most stable 1-indenyl
p radical which was found not to be an
effective precursor for the further growth of polycyclic aromatic
hydrocarbons (PAH) [9] through the hydrogen abstraction-
acetylene (or vinylacetylene) addition [10]. Alternatively, we antic-
ipate that pyrolysis of 5-, or 6-iodoindene isomers might lead to
the formation of
r radicals localized in the phenyl ring of indene
because C-I bond is weaker than C-Br bond. These 5- and 6-indenyl
radicals might then act as precursors for growth of non-planar PAH
Results and discussion
Electrophilic nitration of indan-1-one
1 with KNO3/H2SO4
⇑
afforded separable mixture of 6-nitro- 2a and 4-nitroindan-1-one
2b (80%, 4:1 ratio; Scheme 1) [16]. Selective reduction 2a or 2b
Corresponding author.
E-mail address: mhowl006@fiu.edu (A.H. Howlader).
https://doi.org/10.1016/j.tetlet.2020.152427
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: A. H. Howlader, K. Diaz, A. M. Mebel et al., Iodoindenes: Synthesis and application to cross-coupling, Tetrahedron Letters, https://
doi.org/10.1016/j.tetlet.2020.152427

A.H. Howlader et al.
Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. Synthesis of 5-iodoindene 6a and 7-iodoindene 6b.
with Fe powder/NH4Cl [17] gave 6-amino- 3a and 4-aminoindan-
1-one 3b in excellent yield. Subsequent, diazotization-iodination
of 3a or 3b with t-BuONO [18] /CH2I2/I2/CuI afforded 6-iodo- 4a
and 4-iodoindanones 4b (>90%) in addition to diiodo substituted
by-products (~4%). Reduction of 4a or 4b with NaBH4 provided sec-
ondary alcohols 5a and 5b (>98%). Subsequent dehydration with
aqueous HCl in THF/H2O yielded selectively 5- and 7-iodoindenes,
6a and 6b (>80%). Isomerization to different indene isomers was
not observed during this reaction sequence. It is noteworthy that
dehydration of 5a or 5b with p-toluenesulfonic acid in refluxed
toluene, used successfully for dehydration of the corresponding
nitroindanoles [8a], failed to produce expected iodoindenes. Our
general method allows preparation of expensive 5-iodoindene
[19] and unreported 7-iodoindene in high yields utilizing readily
available and cost-effective reagents.
Subjection of the commercially available 5-aminoindan-1-one
3c to the same sequence of diazotization-iodination followed by
the reduction and dehydration yielded 6-iodoindene 6c in 71%
overall yield (Scheme 2). This represents a significant improve-
ment to the reported five-step procedure which gave 6c from 3c
in 3% overall yield [8a]. Our method avoids oxidation of 3c to 5-
nitroindan-1-one with trifluoroperacetic acid and does not
require reduction of 6-nitroindene to unstable 6-aminoindene
intermediate [8a] (Scheme S2 in SI). Analogous diazotization-
iodination of 7-aminoindan-1-one 3d gave 7-iodoindan-1-one 4d
(51%) as a major product in addition to 4-iodoindan-1-one 4b
(5.5%) and
a diiodo byproduct (20%) which was tentatively
assigned as 4,7-diiodoindan-1-one. Analogous treatment of 3d
with tert-butyl nitrite at ambient temperature for 8 h gave a
similar distribution of products. Reduction and dehydration of 4d
afforded 4-iodoindene 6d in 79% yield.
Stille coupling of 6a with trans-1,2-bis(tributylstannyl)ethylene
in the presence of catalytic Pd(PPh3)4 in toluene (100 °C/1h)
afforded regio- and stereoselectively the E-vinylstannane 7a with
no isomerization of the indene five-membered double bond
(Scheme 3). Compound 7a was directly used in the next step since
attempted purification on silica gel column resulted in pro-
tiodestannylation yielding 5-vinylindene instead. Treatment of
crude 7a with NBS in DCM (À10 °C/30 min) gave 5(E)-(2-bro-
movinyl)indene 8a (70% from 6a) as a single product. Similarly,
Stille coupling of 6c yielded selectively 6(E)-(2-bromovinyl)indene
8c also with no isomerization which would lead to 8a. Treatment
of 8a or 8c with trimethylsilylacetylene in the presence of catalytic
Pd(PPh3)2Cl2/CuI in Et3N at rt gave the TMS-protected enyne as an
inseparable mixture of 5-enyneindene, 9a and 6-enyneindene, 9c
(91%; 1:1.5). Desilylation of mixture 9a and 9c with anhydrous
K2CO3 in MeOH/DCM (1:1) afforded a mixture of 5- and 6-enynein-
denes 10a and 10c (92%; 1:1.5). The ratio of enynes in mixtures
9a/9c or 10a/10c was assigned based on the chemical shift pattern
in 1H NMR and differences in the chemical shift values (e.g., H4 in
6a (7.75 ppm) and H7 in 6c (7.81 ppm)).
Sonogashira alkynylation of 6a with trimethylsilylacetylene in
the presence of catalytic Pd(PPh3)4/CuI in Et3N produced
5-alkynylindene 11a and 6-alkynylindene 11c as 1:1.5 isomeric
mixture in 90% yield (Scheme 4). Analogous treatment of 6c gave
an identical mixture of 11a and 11c. Attempted coupling of 6a
(or 6c) with TMS-acetylene in the presence of 2.0 equiv. of Et3N
in dry THF resulted only in the isomerization of substrate 6a (or
6c) to a 1:1 mixture of 6a/6c. Desilylation of mixture of 11a/11c
(1:1.5) with anhydrous K2CO3 in MeOH/DCM yielded mixture of
12a/12c (90%; 1:1.7). Separations of either protected 11a/11c or
deprotected 12a/12c enynes on silica gel columns were not suc-
cessful because of identical mobility in several eluting systems.
Pd-catalyzed coupling of 12a/12c mixture (1:1.7) with vinylbro-
mide (CuI/Et3N/rt/5 h) gave mixture of 5-enyne- 13a and
6-enyneindene 13c (70%) in 1:1.5 ratio.
Stirring of pure 6a or 6c in the presence of Et3N in THF at rt for
1 h resulted in the formation of 1:1 isomeric mixture of 6a/6c (see
SI section for spectra) confirming that substituted indenes are
prone to base-catalyzed isomerization [20]. Moreover, when 2:1
Scheme 2. Synthesis of 6-iodoindene 6c and 4-iodoindene 6d.
2

A.H. Howlader et al.
Tetrahedron Letters xxx (xxxx) xxx
Scheme 3. Regioselective bromovinylation of iodoindenes 6a and 6c, and subsequent alkynylation.
Scheme 5. Regioselective synthesis of indene derivatives.
Scheme 4. Synthesis of isomeric enyneindenes via Sonogashira coupling.
(tributylstannyl)ethylene followed by bromodestannylation with
NBS. Sonogashira coupling of iodoindenes with terminal alkyne
in the presence of Et3N gave isomeric ethynylindenes. The 5- and
6-iodoindenes and their enyne derivatives may act as substrates
and/or calibration compounds in studying the growth mechanism
of PAH.
mixture of 6a/6c was subjected to the similar experiments a 1:1
ratio was also observed at equilibrium. These results demonstrate
that the double bond in the five-member ring of the substituted
indenes can shift in the presence of base leading to the observed
isomers under the conditions of the coupling reactions.
To avoid isomerization of indene ring during Sonogashira cou-
pling and in order to get regioselective access to indenyl alkynes,
we attempted synthesis of single 12a from 6-iodoindan-1-ol 5a.
Thus, coupling of 5a with trimethylsilylacetylene provided the
trimethylsilylalkyne 14 (90%) as the sole product from which the
trimethylsilyl group was removed with K2CO3 to give 6-ethynylin-
dan-1-ol 15. (Scheme 5). Dehydration of either 14 or 15 with aque-
ous HCl led to the formation of indene products without
isomerization of a double bond in cyclopentadiene ring of indene
but the simultaneous addition of water or HCl to the triple bond
gave acetyl 16 (80%) and 1-chlorovinyl 17 (20%) products.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
AHH is recipient of the FIU Presidential Fellowship. This work
was partially supported by the U.S. Department of Energy, Basic
Energy Sciences, DE-FG02-04ER15570 to Florida International
University.
Conclusions
In summary, we have developed an expeditious synthesis of 4-,
5-, 6-, and 7-iodoindenes isomers from the corresponding
aminoindan-1-ones utilizing readily available reagents. A three-
step sequence involves diazotization-iodination of aminoindan-1-
ones followed by the reduction and dehydration. The iodoindenes
were regio- and stereoselectively converted to the corresponding
(E)-bromovinylindenes utilizing Stille coupling with trans-1,2-bis
Appendix A. Supplementary data
Supplementary data (Experimental Section, Schemes for the
reported in literature synthesis of 5- and 6-iodoindenes and NMR
spectra for compounds) to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152427.
3

A.H. Howlader et al.
Tetrahedron Letters xxx (xxxx) xxx
(d) L. Zhao, B. Xu, U. Ablikim, W. Lu, M. Ahmed, M.M. Evseev, E.K. Bashkirov, V.
N. Azyazov, A.H. Howlader, S.F. Wnuk, A.M. Mebel, R.I. Kaiser, ChemPhysChem
20 (2019) 791–797;
(e) L. Zhao, M.B. Prendergast, R.I. Kaiser, B. Xu, U. Ablikim, M. Ahmed, B.-J. Sun,
Y.-L. Chen, A.H.H. Chang, R.K. Mohamed, F.R. Fischer, Angew. Chem. Int. Ed. 58
(2019) 17442–17450;
References
[1] (a) C. Holt, G. Alachouzos, A.J. Frontier, J. Am. Chem. Soc. 141 (2019) 5461–
5469;
(b) C.-R. Liu, F.-L. Yang, Y.-Z. Jin, X.-T. Ma, D.-J. Cheng, N. Li, S.-K. Tian, Org. Lett.
12 (2010) 3832–3835;
(c) S. Akbar, K. Srinivasan, RSC Adv. 5 (2015) 5542–5545.
[2] (a) A.P. Panarello, O. Vassylyev, J.G. Khinast, Tetrahedron Lett. 46 (2005) 1353–
1356;
(b) A.P. Panarello, O. Vassylyev, J.G. Khinast, Synlett 2005 (2005) 0797–0800.
[3] N. Rackelmann, H. Matter, H. Englert, M. Follmann, T. Maier, J. Weston, P.
Arndt, W. Heyse, K. Mertsch, K. Wirth, L. Bialy, J. Med. Chem. 59 (2016) 8812–
8829.
(f) K.O. Johansson, M.P. Head-Gordon, P.E. Schrader, K.R. Wilson, H.A.
Michelsen, Science 361 (2018) 997–1000.
[10] (a) L. Zhao, M.B. Prendergast, R.I. Kaiser, B. Xu, W. Lu, U. Ablikim, M. Ahmed, A.
D. Oleinikov, V.N. Azyazov, A.M. Mebel, A.H. Howlader, S.F. Wnuk,
ChemPhysChem 20 (2019) 1437–1447;
(b) L. Zhao, R.I. Kaiser, W. Lu, B. Xu, M. Ahmed, A.N. Morozov, A.M. Mebel, A.H.
Howlader, S.F. Wnuk, Nat. Commun. 10 (2019) 3689.
[11] Our recent experiments show that 5- and 6-iodoindenes dissociate to the 5-
and 6-indenyl radicals further reacting with vinylacetylene and producing
various CH13H10 isomers including enyne derivatives of indene: Zhao, L.;
Kaiser, R. I.; Lu, W.; Ahmed, M.; Evseev, M. M.; Bashkirov, E. K.; Oleinikov, A.
D.; Azyazov, V. N.; Mebel, A. M.; Howlader, A. H.; Wnuk, S. F. Phys. Chem.
Chem. Phys. (Submitted).
[12] M. Imai, G.R. Morais, B. Al-Hindawi, M.A.M. Al-Sulaibi, M. Meetani, T.
Thiemann, J. Chem. Res. 34 (2010) 325–329.
[13] The price for 5-nitroindene and 5-aminoindene is $ 880/1 g (ChemShuttle; CA,
USA) and $ 1028/1 g (FCH Group, Ukraine), respectively.
[14] R.D. Haworth, D. Woodock, J. Chem. Soc. (1947) 95–96.
[15] (a) For selected application of haloindanones in organic synthesis, see: L.A.M.
Cornelius, D.W. Combs Synth. Commun. 24 (1994) 2777–2788;
(b) P. Nguyen, E. Corpuz, T.M. Heidelbaugh, K. Chow, M.E. Garst, J. Org. Chem
68 (2003) 10195–10198;
[4] Y.-Y. Ji, S.-D. Lin, Y.-J. Wang, M.-B. Su, W. Zhang, H. Gunosewoyo, F. Yang, J. Li, J.
Tang, Y.-B. Zhou, L.-F. Yu, Eur. J. Med. Chem. 141 (2017) 101–112.
[5] D.R. Boyd, N.D. Sharma, N.I. Bowers, R. Boyle, J.S. Harrison, K. Lee, T.D.H. Bugg,
D.T. Gibson, Org. Biomol. Chem. 1 (2003) 1298–1307.
ˇ
[6] K. Capková, Y. Yoneda, T.J. Dickerson, K.D. Janda, Bioorg. Med. Chem. Lett. 17
(2007) 6463–6466.
[7] J.P. Barham, S. Tanaka, E. Koyama, N. Ohneda, T. Okamoto, H. Odajima, J.-I.
Sugiyama, Y. Norikane, J. Org. Chem. 83 (2018) 4348–4354.
[8] (a) R.B. Miller, J.M. Frincke, J. Org. Chem. 45 (1980) 5312–5315;
(b) J.R. Young, S.X. Huang, T.F. Walsh, M.J. Wyvratt, Y.T. Yang, J.B. Yudkovitz, J.
Cui, G.R. Mount, R.N. Ren, T.-J. Wu, X. Shen, K.A. Lyons, A.-H. Mao, J.R. Carlin, B.
V. Karanam, S.H. Vincent, K. Cheng, M.T. Goulet, Bioorg. Med. Chem. Lett. 12
(2002) 827–832;
(c) S.E. Pearson, S.M. Fillery, K. Goldberg, J.E. Demeritt, J. Eden, J. Finlayson, A.
Patel, Synthesis 50 (2018) 4963–4981.
(c) Also Ref. [3] and Ref. [17]..
[9] (a) For the mechanisms of gas phase synthesis and molecular mass growth
processes of PAH in extraterrestrial and combustion environments, see: L.
Zhao, M. Prendergast, R.I. Kaiser, B. Xu, U. Ablikim, W. Lu, M. Ahmed, A.D.
Oleinikov, V.N. Azyazov, A.H. Howlader, S.F. Wnuk, A.M. Mebel Phys. Chem.
Chem. Phys. 21 (2019) 16737–16750;
[16] (a) M.E. Caputto, L.E. Fabian, D. Benítez, A. Merlino, N. Ríos, H. Cerecetto, G.Y.
Moltrasio, A.G. Moglioni, M. González, L.M. Finkielsztein, Bioorg. Med. Chem.
19 (2011) 6818–6826;
(b) X. Guan, P. Luo, Q. He, Y. Hu, H. Ying, Molecules 22 (2016) 32.
[17] Y.-N. Duan, L.-Q. Cui, L.-H. Zuo, C. Zhang, Chem. Eur. J. 21 (2015) 13052–13057.
[18] For Application of t-BuONO in organic synthesis, see: A. Dahiya, A.K. Sahoo, T.
Alam, B.K. Patel Chem. Asian J. 14 (2019) 4454–4492.
[19] The 5-iodoindene is commercially available from Sigma-Aldrich at price of
$1726/1 g.
[20] J. Andraos, A.J. Kresge, V.V. Popik, J. Am. Chem. Soc. 116 (1994) 961–967.
(b) L. Zhao, R.I. Kaiser, B. Xu, U. Ablikim, W. Lu, M. Ahmed, M.M. Evseev, E.K.
Bashkirov, V.N. Azyazov, M.V. Zagidullin, A.N. Morozov, A.H. Howlader, S.F.
Wnuk, A.M. Mebel, D. Joshi, G. Veber, F.R. Fischer, Nat. Commun. 10 (2019)
1510;
(c) L. Zhao, R.I. Kaiser, B. Xu, U. Ablikim, M. Ahmed, M.V. Zagidullin, V.N.
Azyazov, A.H. Howlader, S.F. Wnuk, A.M. Mebel, J. Phys. Chem. Lett. 9 (2018)
2620–2626;
4