Direct sp3 C-H bond arylation, alkylation, and amidation of tetrahydroisoquinolines mediated by hypervalent iodine(iii) under mild conditions

Article abstract of DOI:10.1039/c3ob42354a

We have developed a method for the sp³ C-H bond functionalization of tetrahydroisoquinolines (THIQs) mediated by [bis(trifluoroacetoxy)iodo]benzene (PIFA). The treatment of the THIQs with various nucleophiles in the presence of PIFA in a green solvent alternative gave the coupled products, with a C-C, C-N, or quaternary carbon center in high yields. This journal is

Full text of DOI:10.1039/c3ob42354a

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Direct sp3 C–H bond arylation, alkylation, and
amidation of tetrahydroisoquinolines mediated by
hypervalent iodine(III) under mild conditions†
Cite this: Org. Biomol. Chem., 2014,
12, 2189
Received 25th November 2013,
Accepted 23rd January 2014
Wataru Muramatsu,*a Kimihiro Nakanoa and Chao-Jun Li*b
DOI: 10.1039/c3ob42354a
www.rsc.org/obc
We have developed a method for the sp3 C–H bond functionali- organic oxidants.7 During our recent investigations, we found
zation of tetrahydroisoquinolines (THIQs) mediated by [bis(tri- that [bis(trifluoroacetoxy)iodo]benzene (PIFA) was a suitable
fluoroacetoxy)iodo]benzene (PIFA). The treatment of the THIQs with oxidant, to replace DDQ, for the sp3 C–H bond arylation, alkyl-
various nucleophiles in the presence of PIFA in a green solvent ation, and amidation of THIQs. Herein, we report the direct
alternative gave the coupled products, with a C–C, C–N, or sp3 C–H bond functionalization (arylation, alkylation, and ami-
quaternary carbon center in high yields.
dation) of THIQs, to form novel C–C bonds, C–N bonds, and
quaternary carbon centers, mediated by hypervalent iodine(III),
under mild conditions.
Direct sp3 C–H bond activation such as a cross-dehydrogena-
tive-coupling (CDC) reaction1 is a widely used and powerful
method for functionalizing natural products and developing
new drug candidates in current organic synthesis. In particu-
lar, the selective sp3 C–H bond arylation of tetrahydroisoquino-
lines (THIQs) is one of the major current challenges due to
their biological activities.2 Over the recent decades, efficient
one-step methods for C–C, C–N, C–O etc. bond formation have
been reported. However, most of these methods are for the
indolation of THIQs,3 and methods for the arylations are
limited to a few articles.4 Furthermore, most of these methods
use heavy metals, such as Fe, Cu, or Ir, and required high
temperatures and long reaction times to proceed to com-
pletion. We previously reported a 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ)-mediated sp3 C–H bond arylation of
THIQs with aryl-MgBr in chlorobenzene (PhCl) under mild
conditions.5 This reaction has numerous advantages, includ-
ing the absence of heavy metals, short reaction times
(3 hours), and mild reaction temperatures (0 to 20 °C).
However, the toxicity of DDQ6 and the potential for HCN liber-
ation cannot be ignored. Furthermore, PhCl also has toxicity
issues regarding human health and the environment. Hyper-
valent iodine(III) has been widely recognized as a useful alterna-
tive oxidant in place of toxic heavy-metal oxidants and toxic
2-MeTHF was initially chosen as the solvent, due to its wide
usage in industry as a green solvent.8 As a result of the careful
scrutiny of a number of reaction parameters and conditions,
the treatment of N-p-methoxyphenyl (N-PMP)-THIQ4d with
2.0 equiv. of PhMgBr–THF in the presence of 1.0 equiv. of
PIFA in 2-MeTHF gave the corresponding coupled product 1
with the optimum yield (entry 1 of Table 1; 99% yield). The
N-PMP could be easily removed by using ammonium cerium(IV)
nitrate (CAN).9 Under the optimum conditions without
PIFA, only the starting material, N-PMP-THIQ, was recovered
in a quantitative yield (entry 2). From the economic and
environmental viewpoints, the recycling and catalytic utili-
zation of PIFA has made significant advances in various fields
of chemistry. Additionally, the formation of PIFA from phenyl
iodide (PhI) using peroxides is well known.10 We attempted to
carry out the reaction using catalytic PIFA in the presence of
an external oxidant. Unfortunately, these attempts only
resulted in a very low yield of the coupled product 1 (entries
3–6). The use of alternative hypervalent iodine(III) reagents also
resulted in low to moderate yields of 1 (entries 7–9). High
yields were obtained when PhMgCl, PhMgI, and Ph2Zn were
used instead of PhMgBr (entries 10–11 and 15). Furthermore,
an Et2O solution of PhMgBr could be employed in place of a
THF solution, without a loss in the yield (entry 12).11 On the
other hand, PhZnBr and PhZnI gave only trace amounts of 1
under the same conditions (entries 13–14), whilst PhLi
resulted in no product formation at all (entry 16). The sp3 C–H
bond arylation proceeded well in a variety of solvents (entries
17–23), with the exception of DMF, which gave only 3% of 1
(entry 24). From a the toxicity, safety and environmental
aGraduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi,
Nagasaki, Nagasaki 852-8521, Japan. E-mail: muramatu@nagasaki-u.ac.jp
bDepartment of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal,
QC H3A 0B8, Canada. E-mail: cj.li@mcgill.ca
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data for all compounds, and copies of spectra. See
DOI: 10.1039/c3ob42354a
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Table 1 PIFA-mediated sp3 C–H bond arylation of N-PMP-THIQ
Entry
Variation from the “standard” conditions
Yield of 1a (%)
1
2
None
No PIFA
>99 (99)b
0
20
5
13
31
12
61
3c
4c
5c
6d
7
PIFA (20 mol%), Oxone (1.0 equiv.)
PIFA (20 mol%), mCPBA (1.0 equiv.)
PIFA (20 mol%), H2O2·urea (1.0 equiv.)
PIFA (20 mol%), K2S2O8 (1.0 equiv.)
PIDA,e instead of PIFA
8
PFPIFA, f instead of PIFA
9
C3F7(Ph)IOTf
11
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
PhMgCl–THF, instead of PhMgBr–THF
PhMgI–THF, instead of PhMgBr–THF
PhMgBr–Et2O, instead of PhMgBr–THF
PhZnBr–THF, instead of PhMgBr–THF
PhZnI–THF, instead of PhMgBr–THF
Ph2Zn, instead of PhMgBr–THF
PhLi–Bu2O, instead of PhMgBr–THF
PhCl, instead of 2-MeTHF
PhMe, instead of 2-MeTHF
DCE, instead of 2-MeTHF
THF, instead of 2-MeTHF
TBME, instead of 2-MeTHF
CPME, instead of 2-MeTHF
MeCN, instead of 2-MeTHF
DMF, instead of 2-MeTHF
>99
>99
>99
5
5
88
0
>99
83
>99
83
90
91
>99
3
a The yield was determined by 1H-NMR analysis versus a calibrated 1,4-
bis(trifluoromethyl)benzene as an internal standard. b Isolated yield.
c The oxidation using PIFA (20 mol%) was carried out at rt for 2 h.
d The oxidation using PIFA (20 mol%) was carried out at rt for 24 h.
e PIDA = [bis(acetoxy)iodo]benzene. f PFPIFA = [bis(trifluoroacetoxy)-
iodo]pentafluorobenzene.
aspects, this method is especially valuable as the reactions pro-
ceeded well in common green solvent alternatives, such as
2-MeTHF8 and CPME,12 without the need for heavy metals.
On the basis of these findings, we next examined the direct
sp3 C–H bond arylation and alkylation of THIQ derivatives
with various aryl- and alkyl-Grignard reagents, as representa-
tive C–C coupling partners (Scheme 1). An array of THIQs,
bearing different aryl and benzyl groups, were found to
undergo the desired transformation to give the corresponding
coupled products 2–4 in good yields. Unfortunately, the coup-
ling reaction between PhMgBr and THIQs bearing several pro-
tection groups, such as Ac-, Cbz-, and the Boc-group was not
Scheme 1 PIFA-mediated sp3 C–H bond arylation and alkylation of
THIQ derivatives. a In DCE instead of 2-MeTHF. b The oxidation using
PIFA was carried out at 80 °C. c The oxidation using PIFA was carried out
for 30 min. d The nucleophilic addition using R4MgBr was carried out at
20 °C. e R4MgBr–Et2O was used. f R4MgBr (3.0 equiv.) was used.
accomplished, which is because these THIQ derivatives are not N-PMP-THIQ bearing methoxy substituents and the acyclic
oxidized by PIFA. Aryl-MgBr bearing ortho-, meta-, and para- benzylamine were found to react successfully with PhMgBr
substituents coupled successfully with N-PMP-THIQ, to give and afforded the corresponding coupled products 12 and 13,
the corresponding coupled products 5–7 in excellent yields. respectively, in high yields. The optimized system was then
When the sterically hindered 2-naphthyl-MgBr was used, applied to the sp3 C–H bond alkylation of N-PMP-THIQ deriva-
the coupling reaction fortunately proceeded in a good yield. tives and acyclic benzylamine, with a wide range of alkyl
N-PMP-THIQ coupled smoothly with both electron-rich and Grignard reagents. The alkylation of the amines using
electron-deficient aryl-MgBr species, giving the corresponding MeMgBr, EtMgBr, i-PrMgBr, and vinyl-MgBr afforded the
coupled products 9–11 in moderate to excellent yields. Finally, corresponding coupled products 14–16, 18, and 20–21 in
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75–99% yields. Attempts to use allyl-MgBr and phenylethynyl-
MgBr as the nucleophile gave the corresponding coupled pro-
ducts 17 and 19, respectively, in significantly lower yields.
Furthermore, the use of
a more bulky nucleophile,
t-BuMgBr, resulted in a very low yield (9%) of the desired
product. During these investigations, we successfully achieved
the construction of an all-carbon quaternary center at the C-1
position of N-PMP-THIQ. When MeMgBr, EtMgBr, and
i-PrMgBr were coupled with 1, the corresponding coupled pro-
ducts 22–24 were afforded in excellent yields. Disappointingly,
the use of p-TolMgBr as the nucleophile afforded the desired
coupled product 25 in a low yield using 2-MeTHF. Fortunately,
the yield of 25 could be increased by using DCE as the solvent
(51% yield). These results are the first examples of forming a
quaternary carbon center at the C-1 position of THIQ deriva-
tives using a direct sp3 C–H bond arylation and alkylation.
The synthesis of THIQ derivatives with a N–C–N moiety is
quite difficult, due to the stability of the aminal unit. Only one
method for the intermolecular sp3 C–H bond amidation has
been reported by Prabhu et al.4h Their approach is quite inter-
esting and enabled the formation of C–C, C–N, C–O, C–P
bonds formations at the C-1 position of THIQ, using catalytic
iodine under aerobic conditions. However, the aminal pro-
ducts were not isolated in a high purity. Therefore, we
attempted the direct sp3 C–H bond amidation of THIQ deriva-
tives using our method, to synthesize the corresponding
aminals in high purity (Scheme 2).
N-Ph-THIQ was reacted with 1.05 equiv. of phthalimide in
the presence of 1.0 equiv. of PIFA at room temperature. After
completion, the reaction mixture was purified by flash chrom-
atography using alumina and the corresponding coupled
product 26 was isolated in an 87% yield with high purity. The
method was also applied to the direct sp3 C–H bond amidation
of N-(p-Cl–Ph)-THIQ with phthalimide, affording product 27 in
a high yield. Unfortunately, we could not purify the coupling
products 28 (of N-PMP-THIQ with phthalimide) and 29 (of
N-(p-Cl–Ph)-THIQ with p-toluenesulfonamide), due to their
instability on the neutral silica gel and alumina.
Scheme 3 Proposed mechanism of PIFA-mediated sp3 C–H bond
functionalization.
The proposed mechanism for the PIFA-mediated sp3 C–H
bond arylation, alkylation, and amidation is illustrated in
Scheme 3. An ammonium cation is generated by a nucleophilic
substitution reaction of THIQ to PIFA. The α-proton of the
ammonium cation is deprotonated, forming an iminium
cation, by the trifluoroacetate ion (CF3COO−). Finally, the
iminium cation couples to Grignard reagent or amide, giving
the desired C–C or C–N coupled product.
In conclusion, we have developed a PIFA-mediated, one-
step method for sp3 C–H bond arylation, alkylation, and ami-
dation at the C-1 position of a wide range of THIQ derivatives
mediated by PIFA under mild conditions. This current method
has advantages over the previous methods as it avoids the use
of heavy metals and toxic organic oxidants, and proceeds suc-
cessfully in green solvent alternatives, under mild conditions.
Further studies into the scope, mechanism, and applications
of this novel reaction, as well as the development of a catalytic
and asymmetric process, are currently under investigation.
Acknowledgements
This research was funded by the Special Coordination Funds
for Promoting Science and Technology from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
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