Direct and Efficient C(sp3)-H Bond Alkylation of Tetrahydroisoquinolines and Isochroman with Alkylzinc Reagents

Article abstract of DOI:10.1002/adsc.201900023

An efficient C(sp³)?H bond alkylation of tetrahydroisoquinolines and isochroman with alkylzinc reagents was demonstrated. This transformation could be readily performed under mild conditions in the absence of a heavy metal catalyst, affording a

Full text of DOI:10.1002/adsc.201900023

Title: Direct and Efficient C(sp3)-H Bond Alkylation of
Tetrahydroisoquinolines and Isochroman with Alkylzinc Reagents
Authors: Zhihua Peng, Yilei Wang, Zhi Yu, Hao Wu, Shanshan Fu,
Linhua Song, and Cuiyu Jiang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900023
Link to VoR: http://dx.doi.org/10.1002/adsc.201900023

10.1002/adsc.201900023
Advanced Synthesis & Catalysis
VERY IMPORTANT PUBLICATION
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Direct and Efficient C(sp3)-H Bond Alkylation of
Tetrahydroisoquinolines and Isochroman with Alkylzinc
Reagents
Zhihua Peng*, Yilei Wang, Zhi Yu, Hao Wu, Shanshan Fu, Linhua Song, Cuiyu Jiang
Department of Chemistry, College of Science, China University of Petroleum (East China), Qingdao, Shandong, 266580,
P. R. China. E-mail: zpech@upc.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An efficient C(sp3)–H bond alkylation of Keywords:
C–H
functionalization;
alkylation;
tetrahydroisoquinolines and isochroman with alkylzinc tetrahydroisoquinoline; zinc reagents; catalyst-free
reagents was demonstrated. This transformation could be
readily performed under mild conditions in the absence of a
heavy metal catalyst, affording a wide range of potentially
biologically active compounds. In addition, this approach
exhibited excellent compatibility with various sensitive
functional groups such as a cyano group, an ester group as
well as a boronic acid pinacol ester group.
Introduction
During the past two decades, C−H functionalization
has been extensively developed and widely used in
organic and medicinal chemistry.[1] However, in
contrast with better developed C−H arylation
reactions, the alkylation of C(sp3)−H bonds
Figure 1. Selected biologically active 1-alkylated
tetraisoquinolines and isochromanes.
constitutes a fundamental challenge in organic
synthesis.[2] Especially, efforts to couple C(sp3)–H
bonds with organometallic reagents have generally
been far less successful.[3]
Driven by the pre-mentioned prevalence, enormous
endeavors were devoted to the synthesis of these
Heterocycles are ubiquitous structural motifs in
many facets of chemical science and can be readily
bioactive compounds. The recent use of high
found in natural products, materials, crop protection
efficiency, and step economy C–H activation methods
and pharmaceutical industries. Amongst various
represents an ideal strategy in the synthesis of
heterocycles, tetrahydroisoquinolines (THIQs) and
heterocycles. Since cross-dehydrogenative coupling
isochromans have recently received much attention
(CDC) reactions[8] emerged as a concisely synthetic
because they exhibit a wide variety of biological
method to construct C(sp3)−C(sp3) bonds, a range of
activities.[4] For instance, 1-biphenyl-4-ylmethyl-
methods for the synthesis of 1-alkylated THIQs and
1,2,3,4-tetrahydroisoquinoline-6,7-diol hydrochloride
isochromans through CDC reactions have been
(compound A, Figure 1) has cytotoxic activity in
studied.[9] However, these CDC reactions normally
required a heavy metal catalyst and harsh reaction
conditions, which largely limited the utility in organic
synthesis. An attractive alternative approach for the
construction of 1-alkylated THIQs and isochromans
involves the coupling of C(sp3)–H bonds with
organometallic reagents under oxidative conditions.
human gliomas and other diverse human cancers.[5]
Higenamine (compound B, Figure 1), having a
history of use in traditional medicine, is a β2
adrenoreceptor agonist.[6] In addition, compound C
(Sonepiprazole, Figure 1) was found to be a potent D4
antagonist.[7]
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900023
Advanced Synthesis & Catalysis
Recently, alkyl magnesium reagents[10] and alkyl
boron reagents[11] were successfully applied to the
transition-metal-free alkylation of THIQs and
benzopyrans respectively. Although the transition-
metal-catalyst free C(sp3)–H bond arylation of
tetrahydroisoquinoline (THIQ) derivatives and
isochromans with arylzinc reagents have been
achieved,[12] the alkylation of THIQ derivatives with
organozinc reagents still required the addition of
CuCl2.[13] In other words, the transition-metal-catalyst
free C-H alkylation of tetraisoquinolines and
isochromans with alkylzinc reagents which exhibit
better compatibility with sensitive functional groups
remains undeveloped. In view of the synthetic utility
and certain limitations of existing methods in
particular regarding substrate scope, herein, we
describe a convenient, transition-metal-catalyst free,
and broadly applicable oxidative cross-coupling
reaction of tetraisoquinolines and isochromans with
alkylzinc reagents to access diverse 1-alkylated
tetraisoquinoline and isochroman derivatives in an
effective manner.
Entry Oxidant
Solvent
Oxidation
temperature
25 oC
Yield of
3ab)
trace
0
1
2
3
4
DDQ
PIDA
DEAD
DEAD,
PIFAc)
PIFA
2-MeTHF
2-MeTHF
THF
25 oC
25 oC
0
THF
25 oC
0
5
6
2-MeTHF
DCE
25 oC
80 oC
80 oC
80 oC
80 oC
trace
63%
51%
62%
0
PIFA
7d)
8e)
9
PIFA
DCE
PIFA
DCE
DCE
a)General conditions: after the mixture of 1a (0.5 mmol)
and oxidant (1.1 equiv) was stirred for 2 h in solvent (2.5
o
o
mL) at 25 C to 80 C, benzylzinc reagent (1.5 mmol) was
added, and the reaction mixture was stirred for 12 h at 25
b)
c)
oC. Isolated yield. The oxidation of 1a (0.5 mmol) with
DEAD (20 mol%) and PIFA (1.1 equiv) was conducted at
25 oC within 5 h. d)1.5 Equivalents of BnZnBr·MgCl2·LiCl
was used. e)4 Equivalents of BnZnBr·MgCl2·LiCl was used.
Results and Discussion
We began to explore the alkylation of THIQs and
isochromans with alkylzinc reagents coordinated with
MgCl2 and LiCl, which displayed better reactivity
14]
because of the presence of MgCl2 and LiCl.[12,
Next, we proceeded to examine the reaction
compatibility of alkylzinc reagents with 2-benzyl-
1,2,3,4-tetrahydroisoquinoline
When the oxidation of 1a by using 2,3-dicyano-5,6-
dichlorobenzoquinone
(diacetoxyiodo)benzene
azodicarboxylate
(DDQ),
diethyl
or
under
oxidative
(PIDA),
(DEAD),
conditions (Table 2). Under similar conditions, the
oxidative cross-coupling of alkylzinc reagents
bearing a methoxy group with N-benzyl-THIQ gave
the corresponding product 3b in 81% yield.
Benzylzinc reagents substituted with electron-
withdrawing groups could also react with N-benzyl-
THIQ, giving the desired products 3c-f in 41-72%
yields. In addition, propargylzinc reagent gave the
desired product 3g. The reaction could also be readily
expanded to other alkylzinc reagents demonstrating
the generality of this process. The oxidation of 2-
benzyl-1,2,3,4-tetrahydroisoquinoline (0.5 mmol)
[bis(trifluoroacetoxy)iodo]benzene (PIFA) as an
oxidant was conducted in 2-MeTHF or THF at room
temperature, only trace of coupling product 3a were
obtained or no desired product was observed (Table
1, entries 1-5). Delightedly, the oxidation of 2-
benzyl-1,2,3,4-tetrahydroisoquinoline to an iminium
cation could be achieved by using PIFA as an organic
o
oxidant in 1,2-dichloroethane (DCE) at 80 C within
2 h. The subsequent treatment of the intermediate ion
with BnZnBr·MgCl2·LiCl, which was prepared by
the insertion of magnesium turnings into benzyl
bromide in the presence of ZnCl2 and LiCl,[14]
afforded the desired product 3a in the yield of 63%
(Table 1, entry 6). Use of 1.5 equivalents of
BnZnBr·MgCl2·LiCl decreased slightly the yield of
3a to 51% (Table 1, entry 7), and the increase in the
amounts of BnZnBr·MgCl2·LiCl to 4 equivalents
didn’t improve the yield (Table 1, entry 8). In the
absence of the oxidant, no desired product was
observed (Table 1, entry 9).
o
with PIFA (1.1 equiv) in DCE (2.5 mL) at 80 C
within 2 h, and subsequent treatment with n-butylzinc
reagent prepared by the insertion of magnesium into
1-bromobutane in the presence of ZnCl2 and LiCl
afforded the coupling product 3h in the yield of 59%.
Notably, secondary alkylation of C(sp3)–H bond with
cyclohexylzinc reagent could also be accomplished,
although steric hindrance at the α position (see 3i)
may result in a slight decrease of the reaction yield
under the similar conditions.
Table 2. Reaction scope with different alkylzinc reagents.a,
Table 1. Optimization of reaction conditionsa)
b)
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900023
Advanced Synthesis & Catalysis
a)The reaction was performed by the oxidation of 1a (0.5
o
mmol) and PIFA (1.1 equiv) in DCE (2.5 mL) at 80 C for
2 h and subsequent treatment with organozinc reagent (1.5
mmol) at 25 oC for 12 h. b)Isolated yield.
a)The reaction was performed by the oxidation of 1a (0.5
mmol) and PIFA (1.1 equiv) in DCE (2.5 mL) at 80 C for
o
As shown in Table 4, the effect of N-substituents in
THIQs on the conversion of the reaction was studied.
Besides benzyl protecting groups, the coupling of
THIQs with nitrogen bearing a phenyl group or
benzyl substituents with strong electron-donating
groups like a methoxy group also carried out well
under mild conditions, furnishing the expected
products 3n-p in good yields. Interestingly, a useful
yield (see 3q) was obtained for N-methyl-THIQ
whose reaction with arylzinc reagents was not
observed. Unfortunately, under the optimum
conditions, 2-phenylisoindoline and N-Boc-protected
THIQ as substrates did not react with alkylzinc
reagents.
2 h and subsequent treatment with organozinc reagent (1.5
mmol) at 25 oC for 12 h. b)Isolated yield.
Remarkably, the oxidative alkylation of THIQs
with
alkylzinc
reagents
showed
excellent
compatibility with various sensitive functional
groups. As shown in Table 3, under similar
conditions, benzylzinc reagents bearing an ester
group smoothly underwent C(sp3)–H bond alkylation
with N-benzyl-THIQ. The oxidation of N-benzyl-
THIQ using PIFA was carried out in DCE within 2 h
at 80 °C, and subsequent reactions with (4-
(isopropoxycarbonyl)benzyl)zinc reagent and ((2'-
(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)methyl)zinc
reagent at room temperature afforded the
corresponding products 3j-k in 72-79% yields
Table 4. C(sp3)–H Bond alkylation of THIQ derivatives. a,
b)
respectively.
Interestingly,
alkylzinc
reagent
containing a cyano group reacted well with N-benzyl-
THIQ, affording the expected product 3l in 77%
yield. Under identical conditions, the reaction of
alkylzinc reagent bearing a boronic acid pinacol ester
group
with
N-benzyl-THIQ
provided
the
corresponding coupled product 3m in the yield of
78%.
Table 3. Reaction scope with alkylzinc reagents bearing
sensitive functional groups.a, b)
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900023
Advanced Synthesis & Catalysis
a)The reaction was performed by the oxidation of 1 (0.5
mmol) and PIFA (1.1 equiv) in DCE (2.5 mL) or 2-MeTHF
(2.5 mL) at 25-80 oC for 2 h and subsequent treatment with
abstraction to form a cation.[15] The subsequent
addition of reactive alkylzinc reagents to ions affords
the desired coupling products.
o
organozinc reagent (1.5 mmol) at 25 C for 12 h. b)Isolated
yield.
Normally, the reaction of the corresponding less
reactive C(sp3)–H bonds next to an oxygen atom with
less reactive organozinc reagents is nontrivial.
Surprisingly, the substrate scope of the transition-
metal-catalyst free C-H alkylation could be expanded
to isochroman (Table 5). The oxidation of isochroman
(1 mmol) with 2,3-dicyano-5,6-dichlorobenzoquinone
o
(DDQ, 1.1 equiv) in DCE (5 mL) at 80 C within 2
h,[12b] and subsequent treatment with 2-
bromobenzylzinc reagent prepared by the insertion of
magnesium into 1-bromo-2-(bromomethyl)benzene in
the presence of ZnCl2 and LiCl afforded the coupling
product 5a in the yield of 68%. The example 5a was
noteworthy, since the presence of bromide reserved a
platform for the further products manupulation. In a
similar manner, isochroman reacted successfully with
various benzylzinc reagents bearing electron-
withdrawing groups or electron-donating groups,
furnishing the corresponding products 5b-d in 50-
79% yields. In addition, the coupling of isochroman
with unbranched n-butylzinc reagent and secondary
alkylzinc reagent provided the expected products 5e
and 5f respectively.
Scheme 1. Proposed mechanism for the C-H bond
alkylation of THIQs and isochroman with alkylzinc
reagents.
Finally, the gram-scale C-H bond alkylation of
THIQs and isochroman with alkylzinc reagents was
explored using substrate 1a and 3-methoxybenzylzinc
reagent. To our gratification, 1.5 g of 2-benzyl-
1,2,3,4-tetrahydroisoquinoline successfully afforded a
satisfactory 75% isolated yield of desired product 3b
(Scheme 2). This result renders this protocol
potentially useful in industry.
Table 5. C(sp3)–H Bond alkylation of isochroman. a, b)
Scheme 2. Gram-scale C-H bond alkylation of THIQ with
alkylzinc reagent.
Conclusion
In summary, we have developed a novel C(sp3)–H
bond alkylation of THIQs and isochroman with
alkylzinc reagents in the absence of a transition-metal
catalyst.
The
convenient,
practical
and
environmentally benign process could tolerate a wide
range of functionalities, and showed facile
accessibility to potentially biologically active
compounds. Further studies on the scope, and
applications of this reaction are now under
investigation.
a)The reaction was performed by the oxidation of 4 (1
mmol) and DDQ (1.1 equiv) in DCE (5 mL) at 80 C for 2
o
h and subsequent treatment with organozinc reagent (1.5
mmol) at 25 oC for 12 h. b)Isolated yield.
A plausible reaction mechanism for the C(sp3)-H
alkylation of THIQs and isochroman with alkylzinc
reagents is shown in Scheme 1. A radical cation
generated by a single electron transfer from THIQs or
isochroman to oxidant is accessed through H-atom
Experimental Section
General procedure for the reaction of
tetrahydroisoquinolines with alkylzinc reagents: A
dry 25-mL sealed tube was evacuated and purged
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900023
Advanced Synthesis & Catalysis
[2] For selected reviews and references, see: a) B.-J. Li, Z.-
J. Shi, Chem. Soc. Rev. 2012, 41, 5588–5598. b) L.
Ackermann, Chem. Commun. 2010, 46, 4866–4877. c)
X. Chen, K. M. Engle, D.-H. Wang, J.-Q. Yu, Angew.
Chem. Int. Ed. 2009, 48, 5094–5115. d) D. A. Colby, A.
S. Tsai, R. G. Bergman, J. A. Ellman, Acc. Chem. Res.
2012, 45, 814–825. e) D.-H. Wang, M. Wasa, R. Giri,
J.-Q. Yu, J. Am. Chem. Soc. 2008, 130, 7190–7191. f)
A. J. Young, M. S. White, J. Am. Chem. Soc. 2008, 130,
14090–14091. g) D. Shabashov, O. Daugulis, J. Am.
Chem. Soc. 2010, 132, 3965–3972. h) S.-Y. Zhang, G.
He, W. A. Nack, Y.-S. Zhao, L. Qiong, G. Chen, J. Am.
Chem. Soc. 2013, 135, 2124–2127. i) S.-Y. Zhang, Q.
Li, G. He, W. A. Nack, G. Chen, J. Am. Chem. Soc.
2013, 135, 12135–12141. j) B. Wang, X. Wu, R. Jiao,
S.-Y. Zhang, W. A. Nack, G. He, G. Chen, Org. Chem.
Front. 2015, 2, 1318–1321.
with nitrogen gas three times. To the mixture of
[bis(trifluoroacetoxy)iodo]benzene (PIFA) (1.1 equiv)
and 1,2-dichloroethane (0.2 M) was added
tetrahydroisoquinolines (1 equiv) under nitrogen
atmosphere. The reaction mixture was stirred for 2 h
o
at 80 C. The mixture was allowed to cool to room
temperature, and the corresponding alkylzinc reagent
(3 equiv) was added dropwise at room temperature.
After stirring for 12 h, water (20 mL) were then
added to the reaction mixture. The aqueous layer was
extracted with ethyl acetate (3 × 20 mL). The
combined organic phases were washed with brine and
dried over magnesium sulfate. The solvent was
removed by rotary evaporation and purification by
flash column chromatography on silica gel using
petroleum ether/ethyl acetate as an eluent gave the
expected products.
General procedure for the reaction of isochroman
with alkylzinc reagents: A dry 25-mL sealed tube
was evacuated and purged with nitrogen gas three
times. To the mixture of DDQ (1.1 equiv) and 1,2-
dichloroethane (0.2 M) was added isochroman (1
equiv) under nitrogen atmosphere. The reaction
mixture was stirred for 2 h at 80 oC. The mixture was
allowed to cool to room temperature, and the
corresponding alkylzinc reagent (3 equiv) was added
dropwise at room temperature. After stirring for 12 h,
water (20 mL) were then added to the reaction
mixture. The aqueous layer was extracted with ethyl
acetate (3 × 20 mL). The combined organic phases
were washed with brine and dried over magnesium
sulfate. The solvent was removed by rotary
evaporation and purification by flash column
chromatography on silica gel using petroleum
ether/ethyl acetate as an eluent gave the expected
products.
[3] For selected reviews, see: a) M. Wasa, K. M. Engle, J.-
Q. Yu, Isr. J. Chem. 2010, 50, 605–616. b) C.-L. Sun,
B.-J. Li, Z.-J. Shi, Chem. Commun.2010, 46, 677–685.
[4] a) S. Yamaori, M. Kushihara, I. Yamamoto, K.
Watanabe, Biochem. Pharmacol. 2010, 79, 1691–1698.
b) U. Albrecht, M. Lalk, P. Langer, Bioorg. Med. Chem.
2005, 13, 1531–1536. c) D. Ameen, T. J. Snape, Med.
Chem. Commun. 2013, 46, 893–907. d) Z.-Y. Lu, Z.-J.
Lin, W.-L. Wang, L. Du, T.-J. Zhu, Y.-C. Fang, Q.-Q.
Gu, W.-M. Zhu, J. Nat. Prod. 2008, 71, 543–546. e) M.
J. de Groot, A. A. Alex, B. C. Jones, J. Med. Chem.
2002, 45, 1983–1993. f) B. R. Clark, R. J. Capon, E.
Lacey, S. Tennant, J. H. Gill, Org. Biomol. Chem. 2006,
4, 1520−1528. g) H.-C. Liu, L. Du, T.-J. Zhu, D.-H. Li,
M. Y. Geng, Q.-Q. Gu, Helv. Chim. Acta 2010, 93,
2224−2230. h) R. Silvestri, M. Artico, G. De Martino,
R. Ragno, S. Massa, R. Loddo, C. Murgioni, A. G. Loi,
P. La Colla, A. Pani, J. Med. Chem. 2002, 45,
1567−1576. i) P. S. Charifson, Drugs Future 1989, 14,
1179–1185. j) B. Hoffman, S. J. Cho, W. Zheng, S.
Wyrick, D. E. Nichols, R. B. Mailman, A. Tropsha, J.
Med. Chem. 1999, 42, 3217–3226. k) M. Chrzanowska,
A. Grajewska, M. D. Rozwadowska, Chem. Rev. 2016,
116, 12369–12465. l) J. D. Scott, R. M. Williams,
Chem. Rev. 2002, 102, 1669–1730.
Acknowledgements
We thank the Shandong Provincial Natural Science Foundation
(ZR2012BQ006), and the National Natural Science Foundation
of China (21202205) the Fundamental Research Funds for the
Central Universities (17CX02069) for financial support.
[5] M. L. Mohler, G.-S. Kang, S.-S. Hong, R. Patil, O. V.
Kirichenko, W. Li, I. M. Rakov, E. E. Geisert, D. D.
Miller, J. Med. Chem. 2006, 49, 5845–5848.
[6] Y. Kashiwada, A. Aoshima, Y. Ikeshiro, Y.-P. Chen, H.
Furukawa, M. Itoigawa, T. Fujioka, K. Mihashi, L. M.
Cosentino, S. L. Morris-Natschke, K.-H. Lee, Bioorg.
Med. Chem. 2005, 13, 443–448.
References
[1] For selected reviews and references, see: a) T. W.
Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147–
1169. b) J. Wencel-Delord, T. Dröge, F. Liu, F. Glorius,
Chem. Soc. Rev. 2011, 40, 4740–4761. c) D. A. Colby,
A. S. Tsai, R. G. Bergman, J. A. Ellman, Acc. Chem.
Res. 2012, 45, 814–825. d) S. De Sarkar, W. Liu, S. I.
Kozhushkov, L. Ackermann, Adv. Synth. Catal. 2014,
356, 1461–1479. e) O. Daugulis, J. Roane, L. D. Tran,
Acc. Chem. Res. 2015, 48, 1053–1064. f) Z. Peng, Z.
Yu, T. Li, N. Li, Y. Wang, L. Song, C. Jiang,
Organometallics 2017, 36, 2826–2831.
[7] R. E. TenBrink, C. L. Bergh, J. N. Duncan, D. W.
Harris, R. M. Huff, R. A. Lahti, C. F. Lawson, B. S.
Lutzke, I. J. Martin, S. A. Rees, S. K. Schlachter, J. C.
Sih, M.W. Smith, J. Med. Chem. 1996, 39, 2435–2437.
[8] For selected reviews, see: a) C. S. Yeung, V. M. Dong,
Chem. Rev. 2011, 111, 1215–1292. b) S. A. Girard, T.
Knauber, C.-J. Li, Angew. Chem. Int. Ed. 2014, 53, 74–
100. c) C.-J. Li, Acc. Chem. Res. 2009, 42, 335–344. d)
J. L. Roizen, M. E. Harvey, J. Du Bois, Acc. Chem. Res.
2012, 45, 911–922. e) B. V. Varun, J. Dhineshkumar,
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900023
Advanced Synthesis & Catalysis
K. R. Bettadapur, Y. Siddaraju, K. Alagiri, K. R.
Prabhu, Tetrahedron Lett. 2017, 58, 803–824.
2650. f) W. Muramatsu, K. Nakano, Tetrahedron Lett.
2015, 56, 437–440. g) G. Oss, S. D. de Vos, K. N. H.
Luc, J. B. Harper, T. V. Nguyen, J. Org. Chem. 2018,
83, 1000–1010.
[9] For selected references, see: a) Y. Zhang, C.-J. Li, J.
Am. Chem. Soc. 2006, 128, 4242–4243. b) Y. Zhang,
C.-J. Li, Angew. Chem. Int. Ed. 2006, 45, 1949–1952.
c) M. Ghobrial, K. Harhammer, M. D. Mihovilovic, M.
Schnꢀrch, Chem. Commun. 2010, 46, 8836−8838. d) X.
Liu, B. Sun, Z. Xie, X. Qin, L. Liu, H. Lou, J. Org.
Chem. 2013, 78, 3104–3112. e) X. Pan, Q. Hu, W.
Chen, X. Liu, B. Sun, Z. Huang, Z. Zeng, L. Wang, D.
Zhao, M. Ji, L. Liu, H. Lou, Tetrahedron 2014, 70,
3447–3451. f) J. Feng, M.-F. Lv, G.-P. Lu, C. Cai, Org.
Chem. Front. 2015, 2, 60–64. g) Z. Li, C.-J. Li, J. Am.
Chem. Soc. 2005, 127, 3672–3673.
[11] W. Chen, Z. Xie, H. Zheng, H. Lou, L. Liu, Org. Lett.
2014, 16, 5988–5991.
[12] a) Z. Peng, Z. Yu, D.-H. Chen, S. Liang, L. Zhang, D.
Zhao, L. Song, C. Jiang, Synlett 2017, 28: 1835-1839.
b) Z. Peng, Y. Wang, Z. Yu, D. Zhao, L. Song, C. Jiang,
J. Org. Chem. 2018, 83, 7900–7906.
[13] T. Wang, M. Schrempp, A. Berndhäuser, O.
Schiemann, D. Menche, Org. Lett. 2015, 17, 3982–
3985.
[10] a) W. Muramatsu, K. Nakano, C.-J. Li, Org. Biomol.
Chem. 2014, 12, 2189–2192. b) W. Muramatsu, K.
Nakano, C.-J. Li, Org. Lett. 2013, 15, 3650–3653. c) W.
Muramatsu, K. Nakano, Org. Lett. 2014, 16, 2042–
2045. d) W. Muramatsu, K. Nakano, Org. Lett. 2015,
17, 1549–1552. e) K. N. Singh, S. V. Kessar, P. Singh,
P. Singh, M. Kaur, A. Batra, Synthesis 2014, 46, 2644–
[14] A. Metzger, S. Bernhardt, G. Manolikakes, P.
Knochel, Angew. Chem. Int. Ed. 2010, 49, 4665–4668.
[15] a) A. S.-K. Tsang, P. Jensen, J. M. Hook, A. S. K.
Hashmi, M. H. Todd, Pure Appl. Chem. 2011, 83, 655–665.
b) H. H. Jung, P. E. Floreancig, Tetrahedron 2009, 65,
10830–10836.
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900023
Advanced Synthesis & Catalysis
FULL PAPER
Direct and Efficient C(sp3)-H Bond Alkylation of
Tetrahydroisoquinolines and Isochroman with
Alkylzinc Reagents
Adv. Synth. Catal. Year, Volume, Page – Page
Zhihua Peng*, Yilei Wang, Zhi Yu, Hao Wu,
Shanshan Fu, Linhua Song, Cuiyu Jiang
7
This article is protected by copyright. All rights reserved.