Organocatalytic approach for C(sp3)-H bond arylation, alkylation, and amidation of isochromans under facile conditions

Article abstract of DOI:10.1021/ol5006399

A new catalytic approach for the synthesis of isochroman derivatives via direct C(sp³)-H bond arylation is described. The oxidation reaction with [bis(trifluoroacetoxy)iodo]benzene facilitates the regeneration of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in the C(sp³)-H bond arylation of isochroman. The reaction conditions can also be used for alkyl Grignard reagents and amides to afford the corresponding isochroman derivatives.

Full text of DOI:10.1021/ol5006399

Letter
pubs.acs.org/OrgLett
Organocatalytic Approach for C(sp3)−H Bond Arylation, Alkylation,
and Amidation of Isochromans under Facile Conditions
Wataru Muramatsu* and Kimihiro Nakano
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, Nagasaki 852-8521, Japan
S
* Supporting Information
ABSTRACT: A new catalytic approach for the synthesis of
isochroman derivatives via direct C(sp3)−H bond arylation is
described. The oxidation reaction with [bis(trifluoroacetoxy)-
iodo]benzene facilitates the regeneration of 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone in the C(sp3)−H bond arylation of
isochroman. The reaction conditions can also be used for alkyl
Grignard reagents and amides to afford the corresponding
isochroman derivatives.
ith the rapid development of synthetic organic
chemistry over the past few decades, significant progress
Scheme 1. General Methods for C(sp3)−H Bond Arylation
of Isochromans
W
has been made in carrying out very difficult chemical reactions,
in particular, C−H bond activation reactions such as cross-
dehydrogenative-coupling (CDC) reactions.1 We are primarily
interested in investigating the activation of the inert C(sp3)−H
bond of benzyl ethers such as isochroman. Because isochroman
derivatives exhibit various potential bioactivities2 and may serve
as important building blocks in drug development in the future,
the C−H bond activation reaction has attracted attention as
one of the most efficient synthetic methods. Studies on the
direct C(sp3)−C(sp3) and C(sp3)−C(sp) bond formations at
the C(1) position of isochroman via C(sp3)−H bond activation
have been widely reported.3 Additionally, in recent years, Liu
and co-workers have also reported a one-pot enantioselective
C(sp3)−C(sp3) bond formation with a chiral organocatalyst.4
On the other hand, only a few methods for the catalytic and
noncatalytic C(sp3)−H bond arylation at the C(1) position of
isochroman have been reported by four research groups.5
Schnurch and co-workers first developed the catalytic system by
̈
employing 5.0 mol % of Fe(NO3)3·9H2O and 1.3 equiv of
TBHP as the oxidant in 2010 (eq 1 of Scheme 1).5a,b Todd and
co-workers utilized 10 mol % of CuCl2 and 1.1 equiv of 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as the oxidant
in 2012 (eq 2 of Scheme 1).5c MacMillan and co-workers
succeeded in the C(sp3)−H bond arylation of isochroman via
photoredox catalysis in 2014 (eq 3 of Scheme 1).5e Recently,
we reported that the desired coupled products with an aryl
group at the C(1) position of isochroman could be obtained in
77−91% yields when isochroman was oxidized with 1.1 equiv of
DDQ, followed by treatment with ArMgBr/Et2O (eq 4 of
Scheme 1).5d Our method can be considered as an inexpensive,
effective, and highly versatile reaction because it not only
affords the desired coupling products in a short period under
mild reaction conditions but also does not require expensive
heavy-metal catalysts. However, because a stoichiometric
amount of DDQ is needed, its toxicity should be considered.6
Herein we report the first organocatalytic method with high
efficiency and functional compatibility for the direct C(sp3)−H
bond arylation of isochroman (eq 5 of Scheme 1), and
application of the method to C(sp3)−H bond alkylation and
amidation.
Listed in Table 1 is some information about variations from
“standard” conditions for the catalytic C(sp3)−H bond
Received: February 28, 2014
Published: March 27, 2014
© 2014 American Chemical Society
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Letter
Table 1. DDQ-Catalyzed C(sp3)−H Bond Arylation of
synthesized from inexpensive and readily available chemicals
such as iodobenzene, trifluoroacetic acid (TFA), and Oxone.8
As expected, PIFA alone was not effective in promoting the
oxidation of isochroman (entry 2). Moreover, in the absence of
PIFA, the catalytic reaction hardly progressed because DDQ
could not be regenerated (entry 3, 18% yield). To the best of
our knowledge, as of today, seven oxidants9 including PIFA9c
have been reported in the oxidation of 2,3-dichloro-5,6-
dicyanohydroquinone (DDHQ) to DDQ. We then tested the
DDQ-catalyzed C(sp3)−H bond arylation of isochroman using
these oxidants.
Isochroman
a
entry
variation from the “standard” conditions
yield of 1 (%)
b
1
2
3
4
5
6
7
8
none
86 (84)
However, when these oxidants except for electrolysis9d were
used instead of PIFA, poor yields of the coupling products 1
were obtained (entries 4−8 of Table 1). Although isochroman
was consumed completely, the yield (86% NMR yield) given in
entry 1 was lower than the expected result. This is probably
because of the decomposition of 1 or the neutralization of
PhMgI by TFA generated by the reduction of PIFA. To
overcome this limitation, several bases were added; however,
the yields did not improve (entries 9−13). The few organic
oxidants and hypervalent iodine(III) reagents investigated did
not lead to improvement in yields (entries 14−18). When a 1.0
M Et2O solution of PhMgI was used instead of a 2.0 M
solution, the yield decreased slightly (entry 19, 76% yield).
When PhMgCl/Et2O and PhMgBr/Et2O were used instead of
PhMgI/Et2O, 1 was obtained in a desirable yield (entries 20
and 21, 77% and 81% yields, respectively). In our previous
studies, we reported that the use of a THF solution of a
Grignard reagent with a stoichiometric amount of DDQ gave a
significantly lower yield than the use of a Et2O solution of a
Grignard reagent.5d In the case of this catalysis, surprisingly, the
THF solution of Grignard reagents could be used in place of
the Et2O solution (entries 22 and 23, 85% and 81% yields,
respectively). On the other hand, when PhZnBr/Et2O, PhZnI/
Et2O, Ph2Zn, and PhLi/Bu2O were used, low yields of 1 were
obtained (entries 24−27). The effect of solvent on the catalytic
reaction was remarkable. Although the reactions in PhCl, 1,1-
DCE, DBE, and MeCN proceeded well, polar and ether
solvents did not give satisfactory results (entries 28−36).
Under the best suitable conditions, a variety of aryl-Grignard
reagents reacted with isochroman, isochroman derivatives, and
acyclic benzyl ethers (Scheme 2). A high yield was observed for
aryl-Grignard reagents with both electron-donating and -with-
drawing groups (79−90% yields of 2−5 and 7−9). Increased
steric bulk was well tolerated (80%, 72%, and 66% yields of 6,
10, and 11, respectively). 4-Me-isochroman10 coupled
smoothly in 76% yield of 12 with good selectivity (trans/cis
= >7: 3). Isochroman bearing Me- and Cl-groups at the C(5)
position were found to react successfully with PhMgI/Et2O and
afforded the corresponding coupled products 13 and 14,
respectively, in high yields.10 Isochroman bearing the MeO-
group at the C(6) position was one of the less reactive coupling
partners.5c Under our reaction conditions, gratifyingly, the
isochroman derivative10 gave the desired coupling product 15
in 25% yield. When six- and seven-membered cyclic benzyl
ethers were used,11 single addition of the Ph-group proceeded
selectively to form 16 and 17. On the other hand, the DDQ-
catalyzed C(sp3)−H bond arylation of phthalan afforded only a
double additional compound 18 in 54% yield with excellent
selectivity (trans/cis = >9: 1). Acyclic benzyl ethers were also
compatible with the coupling system, though only moderate
yields were obtained (54%, 70%, and 53% yields of 19, 20, and
21, respectively). Applications for our catalytic system were
no DDQ
<1
18
9
no PIFA
MnO2, instead of PIFA
Mn(OAc)3, instead of PIFA
HCl/EtOH, PbO2, instead of PIFA
HNO3, instead of PIFA
13
5
<1
<1
81
64
80
17
66
6
N2O4/DCE instead of PIFA
addition of NaHCO3 (2.0 equiv)
addition of Na2CO3 (2.0 equiv)
addition of K2CO3 (2.0 equiv)
addition of pyridine (2.0 equiv)
addition of 2,4,6-collidine (2.0 equiv)
chloranil, instead of DDQ
o-chloronil, instead of DDQ
PIDA, instead of PIFA
c
9
c
10
c
11
c
12
c
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
22
54
55
<1
76
77
81
85
81
5
PFPIFA, instead of PIFA
C3F7(Ph)IOTf, instead of PIFA
PhMgI/Et2O (1.0 M), instead of 2.0 M
PhMgCl/Et2O, instead of PhMgBr/Et2O
PhMgBr/Et2O, instead of PhMgI/Et2O
PhMgI/THF, instead of PhMgI/Et2O
PhMgBr/THF, instead of PhMgI/Et2O
PhZnBr/Et2O, instead of PhMgI/Et2O
PhZnI/Et2O, instead of PhMgI/Et2O
Ph2Zn, instead of PhMgI/Et2O
PhLi/Bu2O, instead of PhMgI/Et2O
PhCl, instead of DCE
4
66
21
69
38
50
57
5
PhMe, instead of DCE
d
30
1,1-DCE, instead of DCE
DBE, instead of DCE
e
31
d
32
THF, instead of DCE
d
33
Et2O, instead of DCE
<1
8
34
35
36
CPME, instead of DCE
MeCN, instead of DCE
59
DMF, instead of DCE
9
a
The yield was determined by 1H NMR analysis using a calibrated 1,4-
b
bis(trifluoromethyl)benzene as the internal standard. Isolated yield.
c
The base was added after the oxidation with cat. DDQ and PIFA was
d
carried out. The oxidation with cat. DDQ and PIFA was carried out
under reflux. The nucleophilic addition by using PhMgI/Et2O was
e
carried out at 20 °C.
arylation of isochroman. When 1.0 equiv of a hypervalent
iodine(III) reagent, [bis(trifluoroacetoxy)iodo]benzene
(PIFA), was used as the co-oxidant in combination with 20
mol % of DDQ, the desired coupling product 1 was formed in a
similar yield, as reported earlier by using a stoichiometric
amount of DDQ (entry 1 of Table 1, 84% yield vs eq 4 of
Scheme 1, 85% yield). In recent years, several hypervalent
iodine(III) reagents have been used as an alternative to toxic
metals and organic oxidants and have attracted attention as
user- and eco-friendly oxidants.7 In addition, PIFA can be easily
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Organic Letters
Letter
Scheme 2. DDQ-Catalyzed C(sp3)−H Bond Arylation,
Alkylation, and Amidation of Isochroman and Its Derivatives
next investigated. The coupling reaction of isochroman with
alkyl-, allyl-, and vinyl-Grignard reagents proceeded successfully
with 75−87% yields of 22−26 in a single step.
Unfortunately, neither 1 nor 22 led to the desired coupling
products with a quaternary carbon center, although 1 and 22
were consumed sufficiently by formation of the corresponding
oxocarbenium cations.
Further examples for C(sp3)−N bond formation of isochro-
man were also demonstrated. Sulfonamides, H2NTs and
HNMeTs, underwent the C(sp3)−H bond amidation with
isochroman in satisfactory yields (90% and 73% yields of 27
and 28, respectively). Azide was also a good coupling partner
and furnished the C(sp3)−N bonded product 29 in 75% yield.
The plausible reaction mechanism for this organocatalytic
reaction is shown in Scheme 3. First, the one-electron oxidation
Scheme 3. Plausible Mechanism for DDQ-Catalyzed sp3 C−
H Bond Functionalization
of isochroman with DDQ affords a radical cation. Second, the
abstraction of the H-radical by the DDHQ radical anion affords
the oxocarbenium cation and the DDHQ anion.12 Finally, we
presume that the nucleophilic addition of the Grignard reagent
to the oxocarbenium cation affords the desired coupling
product. The DDHQ anion is oxidized by PIFA to regenerate
DDQ, thus completing the catalytic cycle.9c
In summary, a new organocatalytic approach for C(sp3)−H
bond arylation of isochroman has been developed. The
coupling reaction can now proceed with a catalytic amount of
DDQ in high yield under simple and facile conditions.
Additionally, the catalytic method was applicable to a
C(sp3)−H bond arylation, alkylation, and amidation of a
wide range of isochroman derivatives and benzyl ethers. A
method for enantioselective C(sp3)−H bond functionalizations
of isochroman as well as cyclic and acyclic benzyl ethers is
currently under investigation.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, and copies of
spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
a
The nucleophilic addition by using RMgI/Et2O was carried out at 0
°C. b RMgBr/Et2O was used. c In DCE (0.20 M). d RMgBr/THF was
used. The ratio was determined by H NMR analysis. PIFA (2.0
equiv) and RMgBr/Et2O (4.0 equiv) were used. The oxidation with
cat. DDQ and PIFA was carried out at 40 °C. The nucleophilic
additions by using H2NTs, HNMeTs, and NaN3, respectively, were
carried out at room temperature.
e
1
f
g
AUTHOR INFORMATION
Corresponding Author
h
■
*E-mail: muramatu@nagasaki-u.ac.jp.
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Organic Letters
Letter
K.; Takeda, N.; Mohri, K.; Tsuda, Y. Chem. Pharm. Bull. 1989, 37,
3390−3392.
Notes
The authors declare no competing financial interest.
(11) These cyclic benzyl ethers are provided in the following
references. See: (a) Azzena, U.; Demartis, S.; Pilo, L.; Piras, E.
Tetrahedron 2000, 56, 8375−8382. (b) Mihara, M.; Ishino, Y.;
Minakata, S.; Komatsu, M. Synlett 2002, 1526−1528.
(12) Jung, H. H.; Floreancig, P. E. Tetrahedron 2009, 65, 10830−
10836.
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.
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