Hypervalent iodine(III)-mediated C(sp3)H bond arylation, alkylation, and amidation of isothiochroman

Article abstract of DOI:10.1016/j.tetlet.2014.11.134

We have developed a one-step method for introducing aryl, alkyl, and amide groups at the C(1)-position of isothiochromans via an oxidation reaction using hypervalent iodine(III), [bis(trifluoroacetoxy)iodo]benzene (PIFA), followed by an nucleophilic addition reaction using Grignard reagents and an amide.

Full text of DOI:10.1016/j.tetlet.2014.11.134

Tetrahedron Letters 56 (2015) 437–440
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Hypervalent iodine(III)-mediated C(sp3)AH bond arylation,
alkylation, and amidation of isothiochroman
⇑
Wataru Muramatsu , Kimihiro Nakano
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a one-step method for introducing aryl, alkyl, and amide groups at the C(1)-position
of isothiochromans via an oxidation reaction using hypervalent iodine(III), [bis(trifluoroacetoxy)
iodo]benzene (PIFA), followed by an nucleophilic addition reaction using Grignard reagents and an
amide.
Received 13 October 2014
Revised 25 November 2014
Accepted 28 November 2014
Available online 5 December 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Isothiochroman
CAH activation
Hypervalent iodine
Arylation
Alkylation
Amidation
Methods for the selective functionalization of heterocyclic com-
pounds such as tetrahydroisoquinoline (THIQ) and isochroman
have attracted significant attention owing to the various biological
activities of heterocyclic compounds.1 Specifically, a variety of
methods used for the activation of inactive CAH bonds, including
cross-dehydrogenative-coupling (CDC) reactions,2 have been
investigated during the last few decades. Recently, we reported
the organic oxidant-mediated or catalyzed C(sp3)AH bond
arylation, alkylation, and amidation of THIQs and isochromans
under mild conditions.3 Although isothiochroman structurally
resembles THIQ and isochroman is expected to serve as a viable
candidate for drug development, the direct C(sp3)AH bond
functionalization of isothiochroman has never been reported. In
general, functionalized isothiochromans are synthesized via two
methods. One method is based on [2+2+2] or [4+2] cycloadditions.4
For example, Miranda and co-workers reported in 2007 that the
photo-induced reaction of thiobenzophenone with arylalkenes in
the presence of thiopyrylium salt (50 mol %) afforded isothiochroman
derivatives in 32–98% yields (Scheme 1-1).4c The thia-Pictet–Spengler
reaction is also used to synthesize functionalized isothiochromans.
Specifically, Lherbet and co-workers reported in 2008 that a
catalytic amount of Bi(OTf)3 accelerated the thia-Pictet–Spengler
reaction between phenylethanethiol and arylaldehydes to give
the products in 25–94% yields (Scheme 1-2).5 As a novel route
Scheme 1. Strategies for the synthesis of 1-arylisothiochromans.
⇑
Corresponding author. Tel.: +81 95 819 2431.
E-mail address: muramatu@nagasaki-u.ac.jp (W. Muramatsu).
http://dx.doi.org/10.1016/j.tetlet.2014.11.134
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

438
W. Muramatsu, K. Nakano / Tetrahedron Letters 56 (2015) 437–440
Table 1
attempted in place of PIFA (1.1 equiv); unfortunately, the yield of 2
was not improved (entries 9–12).8
PIFA-mediated C(sp3)AH bond arylation of isothiochroman
Using chloranil and o-chloranil instead of PIFA gave 2 in <1%
and 41% yields, respectively (entries 13 and 14). Under the reaction
conditions shown in entries 5–14, unsatisfactory results were
obtained. This was because the oxidation of 1 was insufficient
under these conditions, and unreacted 1 was recovered.
Next, several organometallic nucleophiles were tested in place
of PhMgBr/Et2O. The use of PhMgCl/Et2O, PhMgI/Et2O, and PhLi/
Bu2O led to a decreased yield of 2 (entries 15, 16, and 22, 33%,
74%, and 17% yields, respectively). Interestingly, the Et2O solution
of PhMgBr was more reactive than the THF solution of PhMgBr in
the C(sp3)AH bond arylation (entry 1 vs 17). When PhZnBr/Et2O
and PhZnI/Et2O were used, contrary to our expectations, neither
nucleophile coupled successfully with 1 (entries 18 and 19). On
the other hand, the best yield of 2 was afforded with Ph2Zn (entry
20, 92% isolated yield). However, most of diaryl- and dialkylzinc
reagents are not commercially available, and the synthesis and iso-
lation of such reagents in high purities are generally difficult.
Moreover, when Ph2Zn was generated in situ from PhMgBr/Et2O
and Zn(OMe)2,9 a lower yield was obtained (entry 21, 67% yield)
than when the commercially available reagent was utilized (entry
20). Therefore, we chose ArMgBr/Et2O as the nucleophilic reaction
partner for the C(sp3)AH bond functionalization. PhCl, rather than
toluene, resulted in a suitable yield (entry 23, 77% yield). On the
other hand, when the reaction was carried out in solvents other
than PhCl, only modest yields of 2 were obtained (entries 24–30,
4–59% yields).
Entry
Variation from the ‘standard’ conditions
Yielda of 2 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
None
DDQ
80 (76)b
42
71
0
68
66
3
11
5
0
Addition of DDQ (20 mol %)
No PIFA
PIDAc
PFPIFAd
C3F7(Ph)IOTf
Ts(Ph)IOH
PIFA (20 mol %), OxoneÒ (1.1 equiv)
PIFA (20 mol %), mCPBA (1.1 equiv)
PIFA (20 mol %), H2O2–urea (1.1 equiv)
PIFA (20 mol %), K2S2O8 (1.1 equiv)
Chloranil
5
11
<1
41
33
74
61
0
o-Chloranil
PhMgCl/Et2Oe
PhMgI/Et2O
PhMgBr/THF
PhZnBr/Et2O
PhZnI/Et2O
0
Ph2Zn
93 (92)b
67
17
77
43f
31
47f
26
59
25
4
PhMgBr/Et2O (4.0 equiv), Zn(OMe)2 (2.0 equiv)
PhLi/Bu2O
PhCl
Using the optimized reaction conditions, the C(sp3)AH bond
arylation of isothiochroman with a range of aryl-Grignard reagents
furnished the corresponding 1-arylisothiochromans in good yields
(Table 2). A variety of aryl-Grignard reagents bearing electron-
donating and withdrawing groups in the ortho-, meta-, and
para-positions were compatible under the reaction conditions
(products 3–7 and 9–10, 76–91% yields). Bulky Grignard reagents
such as 1-Naph- and 2-Naph-MgBr also coupled with 1 to give
the corresponding 1-arylisothiochromans 11 and 12 in 86% and 98%
yields, respectively. Unfortunately, 2-methoxyphenyl-MgBr/Et2O
exhibited low reactivity under the reaction conditions, and 8 was
only isolated in 37% yield. Next, we applied the reaction conditions
to the C(sp3)AH bond arylation of isothiochroman derivatives.
The C(sp3)AH bond arylation of a 7-membered isothiochroman
derivative10 with PhMgBr gave the coupling product 13a and side
product 13b in 44% and 23% yields, respectively.11 The C(sp3)AH
bond arylation furnished the corresponding coupled products
14–1712 in unsatisfactory yields (30–40% yields) despite the fact
that a 6-membered isothiochroman derivative13 and acyclic ben-
zylsulfide were consumed completely under the optimized reac-
tion conditions.
Finally, we demonstrated the coupling reaction of isothiochro-
man 1 with alkyl-Grignard reagent, amide, malonate, and amine
under the optimized reaction conditions. When a variety of Grignard
reagents including alkyl-, alkenyl-, and alkynyl-MgBr were used as
the nucleophilic reaction partners, moderate to excellent yields of
the corresponding coupled products 18–20 and 22–24 were
obtained.14 With t-BuMgCl, the t-Bu-group was not introduced at
the C(1)-position of 1 at all. This was because t-BuMgCl might not
have been able to approach the C(1)-position of 1 owing to steric
hindrance. The coupling reaction between 1 and succinimide pro-
ceeded and coupling product 25 was isolated in 20% yield.14 Unfor-
tunately, the coupling reaction with amines such as aniline and
dimethylamine did not proceed to afford the corresponding prod-
ucts. Further, the reaction with diethyl malonate gave not the
desired coupling compound15 but undesired byproducts.16
The proposed reaction mechanism is shown in Scheme 2. The
nucleophilic substitution reaction of isothiochroman with PIFA,
DCE
CPME
TBME
THF
Et2O
MeCN
DMF
The yield was determined by 1H NMR analysis using a calibrated 1,4-bis(tri-
fluoromethyl)benzene as the internal standard.
a
b
Isolated yield.
PIDA = [bis(acetoxy)iodo]benzene.
PFPIFA = [bis(trifluoroacetoxy)iodo]pentafluorobenzene.
PhMgCl/Et2O was provided from the solvent exchange of PhMgCl/THF.
c
d
e
f
The nucleophilic addition reaction using PhMgBr/Et2O was carried out at
ꢀ30 °C.
toward functionalized isothiochromans, herein we report the first
direct C(sp3)AH bond arylation, alkylation, and amidation of isothi-
ochroman under facile conditions (Scheme 1-3).
First, we investigated three previously reported oxidation sys-
tems3 in the C(sp3)AH bond arylation of isothiochroman 16 in tolu-
ene; the results are shown in entries 1–3 of Table 1. When we
attempted the oxidation of 1 using [bis(trifluoroacetoxy)iodo]ben-
zene (PIFA, 1.1 equiv) followed by a nucleophilic addition using
PhMgBr/Et2O (2.0 equiv), the Ph-group was introduced in the
C(1)-position of 1 to give 2 in the best yield without formation of
sulfoxides or sulfones (entry 1, 76% isolated yield). Notably, PIFA
is a useful hypervalent iodine(III) reagent, and is often used as an
alternative to toxic metallic and organic oxidants.7 The use of 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) rather than PIFA
gave 2 in a lower yield (entry 2, 42% yield). In addition, the yield
of 2 slightly decreased when a combination of a catalytic amount
of DDQ and PIFA as a co-oxidant was tested (entry 3, 71% yield).
On the basis of these results, we evaluated the reaction conditions.
In the absence of PIFA, essentially no reaction was observed (entry
4). When several hypervalent iodine(III) reagents were used instead
of PIFA, the coupling product 2 was isolated in 3–68% yields (entries
5–8). Several catalytic systems with peroxides as co-oxidants were

W. Muramatsu, K. Nakano / Tetrahedron Letters 56 (2015) 437–440
439
Table 2
PIFA-mediated C(sp3)AH bond arylation, alkylation, and amidation of isothiochroman
and its derivativesa
Scheme 2. Proposed mechanism for the C(sp3)AH bond functionalizations of
isothiochroman.
In conclusion, the PIFA-mediated C(sp3)AH bond arylation of
isothiochroman and its derivatives was achieved. The coupling
reaction can proceed with a wide range of aryl-Grignard reagents
under facile conditions. In addition, the reaction conditions can
be applied in the C(sp3)AH bond alkylation and amidation of
isothiochroman. The reaction mechanism and
a method for
catalytic and stereoselective C(sp3)AH bond functionalizations,
including the arylation, alkylation, and amidation of isothiochroman
and its derivatives, are currently under investigation.
Acknowledgments
This research was funded by Special Coordination Funds for
Promoting Science and Technology from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
11.134.
References and notes
1. (a) Taylor, E. C.; Weissberger, A.; Eds. The Chemistry of Heterocyclic
Compounds; John Wiley & Sons: New York, 1981, 1990, 1995, Vol. 38, Parts
1–3.; (b) Dalterio, S.; Bartke, A.; Burstein, S. Science 1977, 196, 1472; (c)
Charifson, P. S. Drugs Fut. 1989, 14, 1179; (d) Hoffman, B.; Cho, S. J.; Zheng, W.;
Wyrick, S.; Nichols, D. E.; Mailman, R. B.; Tropsha, A. J. Med. Chem. 1999, 42,
3217; (e) Ohtaka, A.; Ukai, M.; Hatanaka, T.; Kobayashi, S.; Ikeda, K.; Sato, S.;
Miyata, K.; Sasamata, M. Eur. J. Pharmacol. 2004, 492, 243; (f) Cardozo, L.; Lisec,
M.; Millard, R.; Trip, O. V.; Kuzmin, I.; Drogendijk, T. E.; Huang, M.; Ridder, A. M.
Urology 1919, 2004, 172.
2. (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335; (b) Liu, L.; Floreancig, P. E. Org. Lett.
2010, 12, 4686; (c) Tsang, A. S.-K.; Jensen, P.; Hook, J. M.; Hashmi, A. S. K.; Todd,
M. H. Pure Appl. Chem. 2011, 83, 655.
3. (a) Muramatsu, W.; Nakano, K.; Li, C.-J. Org. Lett. 2013, 15, 3650; (b)
Muramatsu, W.; Nakano, K.; Li, C.-J. Org. Biomol. Chem. 2014, 12, 2189; (c)
Muramatsu, W.; Nakano, K. Org. Lett. 2014, 16, 2042.
4. (a) Kamphuis, J.; Grootenhuis, P. D. J.; Bos, H. J. T. Tetrahedron Lett. 1983, 24,
1101; (b) Okuma, K.; Shiki, K.; Sonoda, S.; Koga, Y.; Shioji, K.; Kitamura, T.;
Fujiwara, Y.; Yokomori, Y. Bull. Chem. Soc. Jpn. 2000, 73, 155; (c) Argüello, J. E.;
Pérez-Ruiz, R.; Miranda, M. A. Org. Lett. 2007, 9, 3587; (d) Argüello, J. E.; Pérez-
Ruiz, R.; Miranda, M. A. Org. Lett. 1884, 2010, 12.
a
Standard reaction conditions: PIFA (1.1 equiv) in toluene at room temperature for
1.5 h, then RMgBr/Et2O at ꢀ40 °C for 3 h.
b The nucleophilic addition with 1-Naph-MgBr/Et2O was carried out at 0 °C.
c In toluene (0.20 M).
d The yields were determined by 1H NMR analysis using
(trifluoromethyl)benzene as the internal standard.
e The reaction was carried out in PhCl.
a calibrated 1,4-bis
f Et2Zn/toluene was used instead of the EtMgBr/Et2O.
g t-BuMgCl/Et2O was used.
5. Lherbet, C.; Soupaya, D.; Baudoin-Dehoux, C.; André, C.; Blonski, C.; Hoffmann,
P. Tetrahedron Lett. 2008, 49, 5449.
6. Isothiochroman
1
was provided from phenylethyl mercaptan and
h THF solution of Grignard reagents was used in place of Et2O solution.
i The reaction using succinimide was carried out at room temperature.
paraformaldehyde in trifluoroacetic acid. See: Isobe, K.; Takeda, N.; Mohri, K.;
Tsuda, Y. Chem. Pharm. Bull. 1989, 37, 3390.
7. For examples, see: (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299;
(b) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052; (c)
Zhdankin, V. V. J. Org. Chem. 2011, 76, 1185; (d) Duschek, A.; Kirsch, S. F. Angew.
Chem., Int. Ed. 2011, 50, 1524; (e) Merritt, E. A.; Olofsson, B. Synthesis 2011,
517; (f) Kita, Y.; Dohi, T.; Morimoto, K. J. Synth. Org. Chem. Jpn. 2011, 69, 1241;
(g) González, D. F.; Benfatti, F.; Waser, J. ChemCatChem 2012, 4, 955; (h)
Yusubov, M. S.; Zhdankin, V. V. Curr. Org. Synth. 2012, 9, 247.
followed by the deprotonation of the sulfonium cation intermediate
with the trifluoroacetate ion (CF3COOꢀ) gives the thionium cation
intermediate. Then, the nucleophilic addition reaction of aryl- or
alkyl-Grignard reagents to the intermediate gives the desired
coupling products.

440
W. Muramatsu, K. Nakano / Tetrahedron Letters 56 (2015) 437–440
8. (a) Hossain, M. D.; Kitamura, T. Bull. Chem. Soc. Jpn. 2006, 79, 142; (b) Page, T.
12. Isolation of 16 and 17 was difficult because plural side products were produced
under the reaction conditions. Fortunately, we could isolate a small amount of
16 and 17 with high purity to analyze both conformations.
K.; Wirth, T. Synthesis 2006, 3153; (c) Zagulyaeva, A. A.; Yusubov, M. S.;
Zhdankin, V. V. J. Org. Chem. 2010, 75, 2119.
9. Choi, J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 9102.
13. The 6-membered isothiochroman derivative was provided from 1,8-
bis(hydroxymethyl)naphthalene in two steps. See: (a) Ref. 10.; (b) Sundaresan,
A. K.; Ramamurthy, A. J. Org. Chem. 2007, 9, 3575.
14. The coupling products 24 and 25 slowly decomposed on SiO2.
15. Pellicciari, R.; Curini, M.; Ceccherelli, P. J. Chem. Soc., Perkin Trans. 1 1977, 10,
1155.
10. The 7-membered isothiochroman derivative was provided from 2,20-
bis(bromomethyl)biphenyl and sodium sulfide. See: Foubelo, F.; Moreno, B.;
Soler, T.; Yus, M. Tetrahedron 2005, 61, 9082.
11. The yields were calculated by 1H NMR analysis after a mixture of 13a and 13b
was isolated because we could not separate 13a and 13b completely by SiO2
column chromatography. Fortunately, we could isolate a small amount of 13a
with high purity to analyze the conformation.
16. Lewis acid such as InCl3 was not added in the coupling reaction with diethyl
malonate. See Zhang, Y.; Li, C.-J. Angew. Chem., Int. Ed. 2006, 118, 1983.