Iodine-mediated α-acetoxylation of 2,3-disubstituted indoles

Article abstract of DOI:10.1021/ol302983t

A new method for direct α-functionalization of 2,3-disubstituted indoles has been developed. The present reaction provides α-acetoxy indole derivatives regioselectively under mild conditions using commercially available and nontoxic iodine reagents. This reaction is a useful synthetic tool because obtained α-acetoxy products can be transformed into various functionalized indoles by substitution reactions with nucleophiles.

Full text of DOI:10.1021/ol302983t

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Iodine-Mediated r‑Acetoxylation of
2,3-Disubstituted Indoles
Hisaaki Zaimoku, Takashi Hatta, Tsuyoshi Taniguchi,* and Hiroyuki Ishibashi
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health
Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
tsuyoshi@p.kanazawa-u.ac.jp
Received October 30, 2012
ABSTRACT
A new method for direct R-functionalization of 2,3-disubstituted indoles has been developed. The present reaction provides R-acetoxy indole
derivatives regioselectively under mild conditions using commercially available and nontoxic iodine reagents. This reaction is a useful synthetic
tool because obtained R-acetoxy products can be transformed into various functionalized indoles by substitution reactions with nucleophiles.
Indoles are compounds that have very versatile proper-
ties in chemistry and biology. Indole components are found
in many natural products and pharmaceutical agents.1
Therefore, many chemical methods for synthesis and func-
tionalization of indole compounds have been developed.2
Among these methodologies, direct functionalization of
side chains of 2,3-disubstituted indole compounds via an
oxidation process serves for preparation of a variety of
indole derivatives.3 Chloroindolenines generated by the
reaction of indoles with tert-butyl hypochlorite are typical
intermediates for R-functionalization of 2,3-disubstututed
indoles.3a Various oxidants such as bromine,3b iodine pent-
oxide (I2O5),3c selenium dioxide (SeO2),3d oxygen (O2)/
silver acetate (AgOAc),3e lead(IV) acetate (Pb(OAc)4),3f
azide reagents,3g and Vilsmeier reagents3h can be used for
activation of 2,3-disubstituted indoles. Another method is
regioselective R-alkylation of 2,3-disubstituted indoles using
strong bases.3i However, these methods often involve un-
avoidable problems such as a relatively narrow scope of
substrates, harsh reaction conditions, and the use of
hazardous reagents. Recently, useful CꢀH functiona-
lization reactions that can provide a shortcut to complex
molecules from easily available materials have attracted
much interest,4 and development of practical methods for
CꢀH functionalization of side chains of indoles is also
among these important subjects.5
(1) Reviews: (a) Ban, Y.; Murakami, Y.; Iwasawa, Y.; Tsuchiya, M.;
Takano, N. Med. Res. Rev. 1988, 8, 231–308. (b) Seigler, D. S. Plant
Secondary Metabolism; Springer: New York, 2001; Chapters 34 and 35, pp
628ꢀ667. (c) Hibino, S.; Choshi, T. Nat. Prod. Rep. 2002, 19, 148–180.
(d) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010,
110, 4489–4497.
(2) Recent reviews: (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105,
2873–2920. (b) Taber, D. F.; Tirunahari, P. K. Tetrahedron 2011, 67,
7195–7210.
(3) Representive examples: (a) Owellen, R. J.; Hartke, C. A. J. Org.
Chem. 1976, 41, 102–104. (b) Vice, S. F.; Copeland, C. R.; Forsey, S. P.;
Dmitrienko, G. I. Tetrahedron Lett. 1985, 26, 5253–5256. (c) Yoshida,
K.; Goto, J.; Ban, Y. Chem. Pharm. Bull. 1987, 35, 4700–4704. (d) Jones,
A. W.; Wahyuningsih, T. D.; Pchalek, K.; Kumar, N.; Black, D. StC.
Tetrahedron 2005, 61, 10490–10500. (e) Itahara, T.; Ouya, H.; Kozono,
K. Bull. Chem. Soc. Jpn. 1982, 55, 3861–3864. (f) Kametani, T.;
Takahashi, K.; Kigawa, Y.; Ihara, M.; Fukumoto, K. J. Chem. Soc.,
Perkin Trans. 1 1977, 28–31. (g) Ikeda, M.; Tabusa, F.; Nishimura, Y.;
Kwon, S.; Tamura, Y. Tetrahedron Lett. 1976, 27, 2347. (h) Downie,
I. M.; Earle, M. J.; Heaney, H.; Shuhaibar, K. F. Tetrahedron 1993, 49,
4015–4034. (i) Naruse, Y.; Ito, Y.; Inagaki, S. J. Org. Chem. 1999, 64,
639–640.
In the course of our progressive synthetic study of an
ꢀ
indole alkaloid, we applied the Suarez method using iodine
(I2) and iodoxybenzene diacetate (PhI(OAc)2), which is
typically used to generate alkoxy radicals,6 to a 2,3-disub-
stituted indole compound at room temperature. After
identification of products of this reaction by NMR and
(4) Recent reviews: (a) Duncton, M. A. Med. Chem. Commun. 2011,
€
2, 1135–1161. (b) Bruckl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S.
€ €
Acc. Chem. Res. 2012, 45, 826–839. (c) Tomin, A.; Bag, S.; Torok, B.
Catalytic C-H Bond Activation Reactions. In Green Techniques for
Organic Synthesis and Medicinal Chemistry; Zhang, W., Cue, B., Eds.;
John Wiley & Sons, Inc.: Hoboken, NJ, 2012; pp 69ꢀ98.
(5) A recent report of direct R-functionalization of indoles: Higuchi,
K.; Tayu, M.; Kawasaki, T. Chem. Commun 2011, 47, 6728–6730.
r
10.1021/ol302983t
XXXX American Chemical Society

mass spectrometric analysis, we noticed that an acetoxy
group was introduced into a C2R position of this indole
compound. This fact surprised us because this indole deri-
vative was apparently in an unactivated form by an electron-
withdrawing tert-butoxycarbonyl (Boc) group on a nitrogen
atom. Since iodine compounds are attractive as economical
and environmentally friendly reagents,7,8 this observation
led to the discovery of a practical R-functionalization of 2,3-
disubstituted indole compounds.
reaction and, hence, iodine should work as a reproducible
iodide source (Iꢀ).10,11 Actually, when iodine was reduced
to a catalytic amount (0.1 equiv), the yield of product 2
was improved (entry 4). Next, we found that replacement
of dichloromethane by acetic acid gave 2 in a better yield
(73%) (entry 5). Tetrabutylammonium iodide (TBAI)
was likely to work as a more effective iodide source than
iodine because it gave 2 in a similar yield (78%) in a
shorter reaction time (1 h) (entry 6).12 The use of acetic
acid as a cosolvent of dichloromethane (v/v, 1:1) resulted
in completion of the reaction in only 30 min (entry 7).
Two solvents seem to cooperate to elevate reactivity in
this reaction. Therefore, we performed the reaction at a
low temperature (0 °C) and succeeded in obtaining 2 in
excellent yield after 2 h (entry 8). However, a lower tem-
perature (ꢀ20 °C) made the reaction sluggish (entry 9).
Since the optimum reaction conditions were determined
(Table 1, entry 8), we next applied the reaction conditions
to R-acetoxylation of various indole derivatives (Figure 1).
Reactions of 6-chloro or methoxytetrahydrocarbazole
derivatives smoothly proceeded to give the corresponding
2R-acetoxylated products 3 and 4 in good yields. Inciden-
tally, the reaction of the 6-chlorotetrahydrocarbazole de-
rivative in AcOH at room temperature (the conditions in
Table 1, entry 6) gave 3 in only 49% yield after 24 h. This
result also supports the positive effect elicited by using two
solvents in the present reaction. A tetrahydrocarbazole
derivative protected by a p-toluenesulfonyl (Ts) group
instead of the Boc group was also transformed into 2R-
acetoxylated product 5 in good yield, whereas the yield of
2R-acetoxylated 6 bearing a benzyl (Bn) group was mod-
erate. This reaction and electron-rich indoles seem to be
incompatible.13 However, since nitrogen atoms of indole
derivatives are often protected by electron-withdrawing
groups such as Ts or Boc groups at the early stage in syn-
thetic studies of complex molecules, this reaction might be
synthetically convenient in such cases. Cyclic systems having
different ring sizes also gave the corresponding 2R-acetoxy-
lated products 7 and 9, but the corresponding alcohol 8 was
isolated along with 7 in the case of a five-membered ring
derivative. A 3-phenyltetrahydrocarbazole derivative un-
derwent stereoselective acetoxylation to give trans-isomer
10 in a diastereoselective manner. Interestingly, when
1-methyl tetrahydrocarbazole derivative was subjected
to the acetoxylation conditions, the regioselectivity of this
reaction was switched to the less hindered 3R position of the
indole to give 11 with high diaseteroselectivity. Apparently,
the regioselectivity seems to be controlled kinetically rather
Table 1. Optimization of Reaction Conditions
temp time yielda
entry [ I ] (equiv)
solvent
CH2Cl2
(°C)
(h)
(%)
1
2
3b
4
5
6
7
8
9
I2 (0.75)
ꢀ (0)
rt
rt
2
38
0
CH2Cl2
CH2Cl2
CH2Cl2
AcOH
24
I2 (0.75)
I2 (0.1)
I2 (0.1)
rt
24
3
0
rt
50
73
78
74
83
50
rt
3
TBAI (0.2) AcOH
rt
1
TBAI (0.2) CH2Cl2ꢀAcOH (1:1)
TBAI (0.2) CH2Cl2ꢀAcOH (1:1)
TBAI (0.2) CH2Cl2ꢀAcOH (1:1)
rt
0.5
0
2
ꢀ20
18
a Isolated yield. b Without PhI(OAc)2.
Initially, we set out to optimize reaction conditions by
using protected 1,2,3,4-tetrahydrocarbazole 1 as a model
substrate (Table 1). When compound 1 was treated with
iodine (0.75 equiv) and PhI(OAc)2 (1.5 equiv) in CH2Cl2 at
room temperature, the reaction was completed after 2 h
but gave 2R-acetoxylated product 2 in only 38% yield
(entry 1).9 Interestingly, no 3R-acetoxylated product was
detected from this reaction mixture.9 The absence of iodine
or PhI(OAc)2 did not provide acetoxylated product 2 at all
(entries 2 and 3). The former reaction (entry 2) gave a
complex mixture and a small amount of unreacted 1 (10%),
whereas the latter one (entry 3) just gave unreacted 1 and
deprotected tetrahydrocarbazole in 50% and 19% yields,
respectively. These results indicate that acetyl hypoiodite
(AcOI) generated from two reagents seems to mediate this
ꢀ
ꢀ
(6) (a) Concepcion, J. I.; Francisco, C. G.; Hernandez, R.; Salazar,
ꢀ
ꢀ
J. A.; Suarez, E. Tetrahedron Lett. 1984, 25, 1953–1956. Reviews: (b)
´
Suarez, E.; Rodrıguez, M. S. β-Fragmentation of Alkoxy Radicals:
ꢀ
Synthetic Applications. In Radicals in Organic Synthesis Vol. 2; Renaud,
P., Sibi, M. P., Eds.; WILEY-VCH: Weinheim, 2001; pp 440ꢀ454. (c)
Togo, H.; Katohgi, M. Synlett 2001, 565–581.
(7) Recent reviews: (a) Wirth, T. Angew. Chem., Int. Ed. 2005, 44,
3656–3665. (b) Silva, L. F., Jr.; Olofsson, B. Nat. Prod. Rep. 2011, 28,
1722–1754. (c) Yusubov, M. S.; Zadankin, V. V. Curr. Org. Synth. 2012,
9, 247–272.
(10) Courtneidge, J. L.; Lusztyk, J.; Page, D. Tetrahedron Lett. 1994,
35, 1003–1006.
(11) Recent examples of oxidative functionalization of double bonds
using AcOI: (a) Gottam, H.; Vinod, T. K. J. Org. Chem. 2011, 76, 974–
977. (b) Zhong, W.; Yang, J.; Meng, X.; Li, Z. J. Org. Chem. 2011, 76,
9997–10004. (c) Kim, H. J.; Cho, S. H.; Chang, S. Org. Lett. 2012, 14,
1424–1427.
(8) Examples of benzylic C-H oxidation using a hypervalent iodine:
(a) Dohi, T.; Takenaga, N.; Goto, A.; Fujioka, H.; Kita, Y. J. Org.
Chem. 2008, 73, 7365–7368. (b) Yusubov, M. S.; Zagulyaeva, A. A.;
Zhdankin, V. V. ChemꢀEur. J. 2009, 15, 11091–11094.
(9) In 1,2,3,4-tetrahydrocarbazoles, “2R” and “3R” correspond to C1
and C4 positions, respectively.
(12) Recent examples of R-functionalization of carbonyl compounds
using PhI(OAc)2/TBAI: (a) Fan, R.; Sun, Y.; Ye, Y. Org. Lett. 2009, 11,
5174–5177. (b) Lu, S.-C.; Zheng, P.-R.; Liu, G. J. Org. Chem. 2012, 77,
7711–7717.
(13) Tetrahydrocarbazolewithout a protecting group did not provide
the corresponding R-acetoxylated product.
B
Org. Lett., Vol. XX, No. XX, XXXX

reactions with allyltrimethylsilane or a trimethylsilyl enol
ether14 provided the corresponding allylated compound 22
and carbonyl derivative 23 via formation of new CꢀC bonds.
In addition, the coupling reaction with indole smoothly
proceeded to give bisindole derivative 24 in excellent yield.
Flexible functionalization of tetrahydrocarbazole deri-
vative 1 using the characteristic regioselectivity of this
acetoxylation reaction is illustrated in Scheme 1. Methyla-
tion to obtain 21 could be conducted without purification
by silica gel chromatography after acetoxylation of 1. As
Figure 1. R-Acetoxylation of various indole derivatives.
Figure 2. Reactions of 2 with nucleophiles.
aSame conditions as Table 1, entry 8. bRatios were determined by 1H
NMR analysis. cYields and ratios were determined by 1H NMR analysis
using an internal standard (mesitylene). d0.4 equiv of TBAI and 2.0 equiv
of PhI(OAc)2 were used at room temperature.
a1.5 equiv of TMSOTf was used.
than thermodynamically. A 2,3-dimethylindole derivative
gave only 2R-acetoxylated product 12 similarly, whereas
a 2-ethyl-3-methylindole derivative underwent selective
acetoxylation onto the less hindered 3R methyl group to
give 14 along with a small amount of 2R product 13.
Unexpectedly, the reaction of a 2-propyl-3-ethylindole
derivative gave a mixture of two regioisomers 15 and 16,
and 3R isomer 16 was major. When 10-substituted-8,9-
dihydropyrido[1,2-a]indol-6(7H)-one derivatives were used
as substrates, acetoxylation exclusively took place at cyclic
sites to give 17 and 18 in good yields.
The R-acetoxy indole products prepared by the present
reaction turned out to be synthetically useful intermediates
because we could gain a variety of derivatives by reactions
of 2 with nucleophiles with the aid of trimethylsilyl tri-
fluoromethansulfonate (TMSOTf) at ꢀ50 °C (Figure 2).
The use of trimethylsilyl azide (TMSN3) and trimethyl
cyanide (TMSCN) as nucleophiles provided azide 19 and
nitrile 20 from 2 in 92 and 93% yields, respectively. The
reaction of 2 with dimethyl zinc afforded methylated pro-
duct 21 in 93% yield. As a representative example, it has
been illustrated that a sequence of R-acetoxylation followed
by alkylation using organozinc reagents serves as a method
for alkylation of the R-position of indoles. Similarly,
above (Figure 1), acetoxylation of 21 exclusively occurred
at the 3R-position to give 11, and subsequent allylation
gave trans-dialkylated product 25 as a single diastereomer.
Atthispoint, we noticedthatproduct 11acetoxylatedfrom
21 was partially decomposed in the course of purification
by silica gel chromatography, and back-to-back allylation
of the crude product without purification was effective for
obtaining a good yield (82%) of 25 like the first alkylation
of 1. Eventually, we succeeded in obtaining the difunctio-
nalized tetrahydrocarbazole derivative in four steps invol-
ving two purification operations.
Scheme 1. Regioselective Functionalization of 1
(14) Fu, T.-h.; Bonaparte, A.; Martin, S. F. Tetrahedron Lett. 2009,
50, 3253–3257.
Org. Lett., Vol. XX, No. XX, XXXX
C

We examined the reaction of deuterated substrate 26 to
obtain information about a reaction pathway (Scheme 2).
The obtained product was a mixture of deuterated com-
pound 27 and normal compound 2, and the ratio was
Scheme 3. Proposed Mechanism
1
estimated to be 85:15 by H NMR analysis. This clear
isotope effect suggests that the rate of deprotonation at the
R-position of indoles is sensitive to slight differences in
molecules.
Scheme 2. Kinetic Isotope Effects
A plausible mechanism for this acetoxylation reaction is
shown in Scheme 3. As mentioned above, AcOI was surely
generated by the reaction between PhI(OAc)2 and iodide
ion.10 This could work as a strong electrophile against tetra-
hydrocarbazole derivatives and give iodonium ion inter-
mediate 28.15 Electron-pushing from a nitrogen atom would
rapidly transform 28 into iminium intermediate 29 via ring-
opening. In the case of nonsubstituted tetrahydrocarbazole
(R = H), elimination of the hydrogen atom at the 2R-
position provides dearomatized indole form 30. Both of
SN1 and SN20 mechanisms are possible in the step that
introduces an acetoxy group into 30 to give 2.16 In either
mechanism, the diastereoselective production of 10 and
11 might be attributed to the axial attack of the reac-
tive species (e.g. AcOI or AcOꢀ) from the opposite side of
a substituted group. The eliminated iodide ion from 30
would be reoxidized into AcOI by PhI(OAc)2.
The kinetic isotope effect indicated that the rate of
elimination step from 29 (R = H) to 30 was significantly
variable depending on structures of substrates (Scheme 2).
Therefore, a switching point of the regioselectivity in 2R-
substituted indole substrates should be there. If iminium
intermediate 29 (R = Me) is formed from 2R-substituted
indole derivatives 21, it is presumed that the following
elimination of a 2R-hydrogen atom is kinetically unfavor-
able due to a 1,3-allylic strain in the transition state
(For convenience, 32 is shown as an eliminated form).
Probably, formation of 29 would be fast but would be
reversible, and elimination at the 3R-position of 28 (R = Me)
affords another dearomatized indole intermediate 31
followed by the attack by acetate ion and/or acetic acid
to provide 3R-acetoxylated product 11. The regioselectivity
in the reaction affording 15 and 16 can be similarly ex-
plained by the 1,3-allylic strain of eliminated intermediates.
When elimination occurrs at the 2R-position of the 3-ethyl-
2-propylindole derivative, the resultant intermediate can
potentially cause 1,3-allylic strain against both of a C3 ethyl
group and the Boc group and would kill the predominance
of this route.
In conclusion, we have developed a new method for
CꢀH acetoxylation at the R-position of 2,3-disubstituted
indole derivatives. This reaction proceeds under mild con-
ditions without metallic reagents and follows the charac-
teristic regioselective manner. In addition, it allowed for
access to broad indole derivatives through substitution
reactions of the R-acetoxylated product with various nuc-
leophiles. We anticipate that the present reaction will serve
for the synthesis of complex indole natural products and
the search for potential lead compounds of medicines.
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology of
Japan.
(15) Acetoxy radical (AcO•), that may be formed from AcOI, is
unlikely to participate in this reaction because the high regioselectivity in
this reaction cannot be explained by the radical mechanism reasonably.
Especially, the radical mechanismwould not give compounds 11, 14, and
18 as major products because C-H abstraction by radical species should
occur at positions where resultant radicals are stabilized, such as more
substituted (secondary or tertiary) or benzylic positions.
(16) When the reaction of 1 was performed in the presence of TsNH2,
an 2R-amination product was detected along with 2. This supports the
SN1 mechanism, though the competitive SN20 mechanism cannot be
ruled out yet.
Supporting Information Available. Expermental detail
and spectroscopic data for new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX