Simple and direct sp3 C-H bond arylation of tetrahydroisoquinolines and isochromans via 2,3-dichloro-5,6-dicyano-1,4- benzoquinone oxidation under mild conditions

Article abstract of DOI:10.1021/ol401534g

The 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-mediated sp³ C-H bond arylation of tetrahydroisoquinolines and isochromans is described. The corresponding products were facilely synthesized via a simple nucleophilic addition reaction betwee

Full text of DOI:10.1021/ol401534g

ORGANIC
LETTERS
Simple and Direct sp3 CÀH Bond
Arylation of Tetrahydroisoquinolines
and Isochromans via 2,3-Dichloro-5,6-
dicyano-1,4-benzoquinone Oxidation
under Mild Conditions
XXXX
Vol. XX, No. XX
000–000
Wataru Muramatsu,*,† Kimihiro Nakano,† and Chao-Jun Li*,‡
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi,
Nagasaki, Nagasaki 852-8521, Japan, and Department of Chemistry, McGill University,
801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada
muramatu@nagasaki-u.ac.jp; cj.li@mcgill.ca
Received May 31, 2013
ABSTRACT
The 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-mediated sp3 CÀH bond arylation of tetrahydroisoquinolines and isochromans is described.
The corresponding products were facilely synthesized via a simple nucleophilic addition reaction between readily available aryl Grignard reagents
and iminium (or oxonium) cations generated in situ by DDQ oxidation of tetrahydroisoquinolines (or isochromans) under mild conditions.
Owing to their wide variety of biological activities, se-
lective functionalization of tetrahydroisoquinoline (THIQ)
and isochroman has attracted considerable attention
from the synthetic community.1 For instance, Solifenacin
(VesiCare), a urinary antispasmodic of the antimuscarinic
class, is commonly used in the treatment of an overactive
bladder with or without urge incontinence.2 As another
example, Penidicitrinin B is a compound that has been
isolated from Penicillium citrinum strains and is well-known
for its potent antioxidant activity.3
Increasing environmental awareness has given rise
to a great deal of interest in the direct arylation of se-
lected CÀH bonds.4 Recent efforts have focused on cross-
dehydrogenative-coupling (CDC) reactions for forming
new CÀC bonds,5 and an excellent method for sp3 CÀH
bond arylation of THIQs with indoles has been reported in
a number of articles.6 In 2008, we reported Cu-catalyzed
sp3 CÀH bond arylation of THIQs with a variety of
arylboronic acids.7 This catalytic method has numerous
† Nagasaki University.
‡ McGill University.
(1) For examples, see: (a) Taylor, E. C., Weissberger, A., Eds. The
Chemistry of Heterocyclic Compounds; John Wiley & Sons: New York,
1981, 1990, 1995, Vol. 38, Parts 1À3. (b) Charifson, P. S. Drugs Future
1989, 14, 1179–1185. (c) Hoffman, B.; Cho, S. J.; Zheng, W.; Wyrick, S.;
Nichols, D. E.; Mailman, R. B.; Tropsha, A. J. Med. Chem. 1999, 42,
3217–3226.
(4) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107,
174–238.
(5) (a) Li, C,-J. Acc. Chem. Res. 2009, 42, 335–344. (b) Liu, L.;
Floreancig, P. E. Org. Lett. 2010, 12, 4686–4689. (c) Tsang, A. S.-K.;
Jensen, P.; Hook, J. M.; Hashmi, A. S, K; Todd, M. H. Pure Appl. Chem.
2011, 83, 655–665.
(6) (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968–6969. (b)
Boess, E.; Schmitz, C.; Klussmann, M. J. Am. Chem. Soc. 2012, 134,
5317–5325. (c) Dhineshlumar, J.; Lamani, M.; Alahiri, K.; Prabhu,
K. R. Org. Lett. 2013, 15, 1092–1095. (d) Zhong, J.-J.; Meng, Q.-Y.;
Wang, G.-X.; Liu, Q.; Chen, B.; Feng, K.; Tung, C.-H.; Wu, L.-Z.
Chem.;Eur. J. 2013, 19, 6443–6450.
(2) (a) Ohtaka, A.; Ukai, M.; Hatanaka, T.; Kpbayashi, S.; Ikeda, K.;
Sato, S.; Miyata, K.; Sasamata, M. Eur. J. Pharmacol. 2004, 492, 243–
250. (b) Cardozo, L.; Lisec, M.; Millard, R.; Trip, O. V.; Kuzmin, I.;
Drogendijk, T. E.; Huang, M.; Ridder, A. M. J. Urology 2004, 172,
1919–1924. (c) Smulders, R. A.; Krauwinkel, W. J.; Swart, P. J.; Huang,
M. J. Clin. Pharmacol. 2004, 44, 1023–1033.
(3) (a) Clark, B. R.; Capon, R. J.; Lacey, E.; Tennant, S.; Gill, J. H.
Org. Biomol. Chem. 2006, 4, 1520–1528. (b) Lu, Z.-Y.; Lin, Z.-J.; Wang,
W.-L.; Du, L.; Zhu, T.-J.; Fang, Y.-C.; Gu, Q.-Q.; Zhu, W.-M. J. Nat.
Prod. 2008, 71, 543–546. (c) Liu, H.-C.; Du, L.; Zhu, T.-J.; Li, D.-H.;
Geng, M. Y.; Gu, Q.-Q. Helv. Chim. Acta 2010, 93, 2224–2230.
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(7) Basle, O.; Li, C.-J. Org. Lett. 2008, 10, 3661–3663.
r
10.1021/ol401534g
XXXX American Chemical Society

advantages, including the use of a minimally toxic and
relatively cheap Cu salt as the catalyst. However, the reaction
required a high temperature and long reaction time to
proceed to completion. These factors are generally disad-
vantageous for achieving asymmetric CÀH bond func-
tionalization at the benzyl position, owing to the high
After a series of optimization studies, we found that the
sp3 CÀH bond arylation at C(1) in N-p-methoxyphenyl
(PMP)-protected THIQ7 proceeded efficiently in the pre-
sence of 1.1 equiv of DDQ and 2.0 equiv of PhMgBr (THF
solution) in chlorobenzene at 0 °C under an Ar atmosphere
(entry 1 of Table 1; 95% yield). The N-PMP can be easily
removed to give the R-arylated NÀH-free THIQ.10 In the
absence of DDQ, essentially no reaction was observed
(entry 2). The use of a catalytic amount of DDQ with
MnO2 as a co-oxidant gave 1 in an unsatisfactory yield of
8% (entry 3).11 When the previously reported CuBr/tert-
butyl hydroperoxide (TBHP) system7 was tested in chloro-
benzene at 0 °C, the reaction did not proceed (entry 4).
The use of CPh3BF412 or chloranil instead of DDQ gave 1
in moderate yields of 43% and 56%, respectively (entries 5
and 6). When o-chloranil was employed as the oxidant in
place of DDQ under the optimum conditions, a high yield
of 90% was achieved (entry 7). However, other common
oxidants, including oxygen, cerium ammonium nitrate
(CAN), N-hydroxyphthalimide(NHPI), andm-chloroper-
oxybenzoic acid (mCPBA), did not oxidize THIQ effec-
tively (entries 8À11). Furthermore, we examined the scope
of DDQ-mediated sp3 CÀH bond arylation with respect
to the effects of both organometallic nucleophiles and
solvents. When an Et2O solution of PhMgBr was used
instead of a THF solution, the yield was reduced to 44%
(entry 12). The solvent effect of PhMgBr (entry 1 vs 12) is
still unclear. However, it seems that the coordination of
their solvents with THIQ affects the reactivity. PhMgCl
(THF solution) could be employed in place of PhMgBr
(THF solution) as a nucleophile (entry 13; 81% yield);
however, PhZnI and PhZnBr showed very little reactivity
under the same conditions (entry 14). The sp3 CÀH bond
arylation with DDQ and PhMgBr proceeded smoothly
in less polar solvents such as benzene and toluene, as well
as chlorobenzene (entries 15À19). When hydroquinone
monomethyl ether (HQME) was added as a radical sca-
venger to help clarify the reaction mechanism, the yield
of 1 was decreased to 51% with 52% conversion of THIQ
(entry 20).
€
probability of racemization. Subsequently, Schnurch et al.
reported the Ru-catalyzed sp3 CÀH bond arylation of
THIQs with various aryl halides. However, this method also
required a high temperature (140 °C) and long reaction time
(24h).8 Yet, suitable methods for sp3 CÀH bond arylation of
isochroman have been rarely reported,9 even though the
pharmacological and physiological effects of the compounds
are likely to be as beneficial as those of THIQ. To resolve
these issues, we have investigated the direct sp3 CÀH bond
arylation of THIQ and isochroman under mild conditions.
Herein, we report a heavy-metal-free sp3 CÀH bond aryla-
tion with readily available aryl Grignard reagents via 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) oxidation.
Table 1. DDQ-Mediated CÀH Bond Arylation of THIQa
variation from the
yield of
1 (%)b
entry
“standard” conditions
1
none
>99 (95)c
2
no DDQ
0
3
DDQ (10 mol %), Mn2O (1.1 equiv)
CuBr (10 mol %), TBHP (1.1 equiv)
CPh3BF4, instead of DDQ
chloranil, instead of DDQ
o-chloranil, instead of DDQ
O2 (1 atm), instead of DDQ
CAN, instead of DDQ
8
4
0
5
43
56
90
10
11
0
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
NHPI, instead of DDQ
mCPBA, instead of DDQ
PhMgBr,d instead of PhMgBr
PhMgCl,e instead of PhMgBr
PhZnI or PhZnBr,e instead of PhMgBr
PhH, instead of PhCl
0
We next examined the scope of the oxidative arylation
reaction of THIQ with a variety of substituted ArMgBr
(Scheme 1). N-Ph- and N-Bn-protected THIQs were found
to be effective and regioselective for this transforma-
tion. Unfortunately, N-Ac-, N-Cbz, and N-Boc-protected
THIQs did not couple under the optimum conditions.
Regardless of the position of the substituents, both
electron-donating and -withdrawing substituted ArMgBr
(THF solution) successfully coupled to THIQ, giving
excellent yields. Interestingly, the sp3 CÀH bond arylation
of THIQ with the very sterically hindered 2-naphthyl-
MgBr afforded 7 in good yield.
44
81
0
75
71
42
69
19
51
PhMe, instead of PhCl
CHCl3, instead of PhCl
THF, instead of PhCl
DMF, instead of PhCl
addition of HQME (1.1 equiv)
a All data are the average of two experiments. b The yield was
determined by 1H NMR analysis versus a calibrated 1,4-bis(trifluoromethyl)-
benzene as an internal standard. c Isolated yield. d Et2O solution was used.
e THF solution was used.
(10) Taniyama, D.; Hasegawa, M.; Tomioka, K. Tetrahedron:
Asymmetry 1999, 10, 221–223.
(11) Yi, H.; Liu, Q.; Liu, J.; Zeng, Z.; Yang, Y.; Lei, A. ChemSusChem
€
(8) Dastbaravardeh, N.; Schnurch, M.; Mihovilovic, M. D. Eur. J.
Org. Chem. 2013, 2878–2890.
(9) (a) Ghobrial, M.; Harhammer, K.; Mihovilovic, M. D.;
2012, 5, 2143–2146.
€
Schnurch, M. Chem. Commun. 2010, 46, 8836–8838. (b) Ghobrial, M.;
(12) (a) de Costa, B. R.; Radesca, L. Synthesis 1992, 887–890. (b)
€
Ludwig, M.; Hoesl, C. E.; Hofner, G.; Wanner, K. T. Eur. J. Med. Chem.
€
Schnurch, M.; Mihovilovic, M. D. J. Org. Chem. 2011, 76, 8781–8793.
(c) Park, S. J.; Price, J. R.; Todd, M. H. J. Org. Chem. 2012, 77, 949–955.
2006, 41, 1003–1010.
B
Org. Lett., Vol. XX, No. XX, XXXX

derivatives and acyclic benzylamines (Scheme 2). The aryla-
tion of a THIQ derivative with ArMgBr (in THF solution)
bearing electron-donating or -withdrawing groups afforded
the corresponding products 14À17 in 78À87% yields.
On the other hand, attempts to use N-PMP-protected
isoindoline13 as a starting material did not give the corre-
sponding coupling product. The reaction with N-(PMP)2-
protected acyclic benzylamine14 gave 18 in moderate yield.
On the other hand, the use of NH-PMP-protected acyclic
benzylamine as starting materials did not afford desired
coupling product 19, but the corresponding imine in quan-
titative yield. Fortunately, this problem could be resolved by
using PhLi instead of PhMgBr (19, 91% yield).
Scheme 1. Scope of THIQ and Its Derivatives in the CÀH Bond
Arylationa
The protocol was also shown to be applicable to the
direct sp3 CÀH bond arylation of isochroman,9 phthalan,15
and acyclic benzyl ethers (Scheme 3). When PhMgBr (THF
solution) was used, the coupling with isochroman pro-
ceeded to give the product 20 in 46% yield. Interestingly,
the use of PhMgBr (Et2O solution) successfully afforded 20
in a much higher yield (85% yield). Based on these results,
we subsequently examined the coupling reaction of isochro-
man using an Et2O solution of ArMgBr. Both electron-
donating and -withdrawing substituted ArMgBr (Et2O
solution) coupled with isochroman to give 21À24 in excel-
lent yields. When phthalan was used as the starting material
under the same conditions, only disubstituted compound 25
was produced in 35% yield with good selectivity (trans/
cis = >10:1)16 with no formation of the desired monosub-
stituted coupling product. When the nucleophilic addition
using PhMgBr (Et2O solution; 3.0 equiv) in the presence
of DDQ (2.1 equiv) was carried out at 80 °C, the yield
of 25 was improved (83% yield). We additionally tried to
form a quaternary carbon center using this method with
1-methyl-isochroman; however, this was unsuccessful.
Finally, we attempted the sp3 CÀH bond arylation of
acyclic benzyl ethers and a sulfide under mild conditions.
Their coupling products were normally synthesized by
benzylation of alcohols (or thiols) in the presence of a
strong base suchasNaH,17 or by dehydration of alcohols.18
To the best our knowledge, therefore, a simple and widely
applicablemethodforsuchareactionhasnotbeenreported
thus far. When the readily available benzyl alkyl (Me and
Bu) ethers were treated with ArMgBr (Et2O solution)
bearing electron-donating or -withdrawing groups under
the same conditions, 26À31 were successfully produced in
82À97% yield. Contrary to our expectations, the coupling
of benzyl phenyl ether results in the recovery of the starting
materials with no formation of side products. The CÀH
a All data are the average of two experiments. b The oxidation using
c
DDQ was carried out at 80 °C instead of rt. The nucleophilic addi-
d
tion using ArMgBr was carried out at 20 °C instead of 0 °C. DDQ
(1.0 equiv) was used.
Scheme 2. Scope of THIQ Derivatives and Acyclic Benzylamines
in the CÀH Bond Arylationa
(13) Mourad, A.-F. E.; Nour-el-din, A. M.; Hassan, A. A. Bull. Soc.
Chim. Belg. 1986, 95, 1045–1051.
(14) Ohta, K.; Chiba, Y.; Ogawa, T.; Endo, Y. Bioorg. Med. Chem.
Lett. 2008, 18, 5050–5053.
(15) Guo, X.; Pan, S.; Liu, J.; Li, Z. J. Org. Chem. 2009, 74, 8848–
8851.
(16) Smith, J. G.; McCall, R. B. J. Org. Chem. 1980, 45, 3982–3986.
(17) For examples, see: (a) Strazzolini, P.; Runcio, A. Eur. J. Org.
Chem. 2003, 526–536. (b) Onishi, Y.; Nishimoto, Y.; Yasuda, M.; Baba,
A. Chem. Lett. 2011, 40, 1223–1225.
a All data are the average of two experiments. b The oxidation using
DDQ was carried out at 80 °C instead of rt. c PhLi in Bu2O was used as a
nucleophile.
(18) For examples, see: (a) Welch, C. M.; Smith, H. A. J. Am. Chem.
Soc. 1950, 72, 4748–4750. (b) Salehi, P.; Iranpoor, N.; Behbahani, F. K.
Tetrahedron 1998, 54, 943–948.
The optimized system was then taken forward to evaluate
the sp3 CÀH bond arylation of a wide range of THIQ
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Scope of Isochroman and Its Derivatives in CÀH
Scheme 4. Plausible Mechanism for DDQ-Mediated CÀH
Bond Arylationa
Bond Arylation
based on kinetic isotope effects by Floreancig indicated that
the most plausible among their mechanisms is the pathway
where a radical cation Bgeneratedbyasingleelectrontransfer
from isochroman to DDQ is accessed through H-atom
abstraction to form oxonium cation C.21
In conclusion, a simple and direct process for sp3
CÀH bond arylation with DDQ in high yield under mild
conditions was developed. The method was found to be
applicable to a wide range of THIQs, isochromans, and
their derivatives, providing the ability to synthesize many
potentially biologically active compounds. The optimized
protocol has numerous advantages: it is heavy-metal-
free and has high regioselectivity, a short reaction time,
and mild reaction temperature. The scope, applications,
mechanism, and asymmetric synthesis of this reaction are
currently under investigation.
b
a All data are the average of two experiments. PhMgBr in THF
solution was used instead of its Et2O solution. c The reaction was carried
out in PhCl (0.20 M). DDQ (2.1 equiv) was used, and then the
nucleophilic addition using PhMgBr in Et2O solution (3.0 equiv) was
carried out at 80 °C instead of 0 °C. e DDQ (1.3 equiv) was used.
d
bond arylation of benzyl methyl sulfide afforded 32 in 52%
yield and recovered 20% of starting material.
Acknowledgment. This research was funded by Special
Coordination Funds for Promoting Science and Technol-
ogy from the Ministry of Education, Culture, Sports,
Science and Technology, Japan. We thank Dr. Hiromasa
Mitsudera from McGill University for helpful discussions.
The mechanism for the DDQ-mediated sp3 CÀH bond
arylation can be explained in Scheme 4. In the case of
using THIQ, a radical cation A is generated by a single
electron transfer from THIQ to DDQ.5c The DDQ radical
oxygen then abstracts a H-atom from A to generate an
iminium cation C. Finally, the nucleophilic addition of an
aryl Grignard reagent generates the desired coupling product.
In the case of using isochroman, on the other hand, three
possible mechanisms for the generation of the oxonium cation
have been suggested.19,20 Most recently, the mechanistic study
Supporting Information Available. Experimental pro-
cedures, 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.
(21) Jung, H. H.; Floreancig, P. E. Tetrahedron 2009, 65, 10830–
10836.
(19) Trost, B. M. J. Am. Chem. Soc. 1967, 89, 1847–1851.
(20) (a) Zhang, X.-M.; Bordwell, F. G. J. Am. Chem. Soc. 1994, 116,
904–908. (b) Baciocchi, E.; Del Giacco, T.; Elisei, F.; Lanzalunga, O.
J. Am. Chem. Soc. 1998, 120, 11180–11181.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX