Mechanistic studies of thiourea-catalyzed cross-dehydrogenative C-P and C-C coupling reactions and their further applications

Article abstract of DOI:10.1016/j.tet.2017.04.033

Thiourea-based hydrogen bond donor has been recently disclosed by our group to be an efficient organocatalyst for cross-dehydrogenative coupling (CDC) reactions. Here we present a detailed mechanistic study of this reaction using NMR spectroscopy and kine

Full text of DOI:10.1016/j.tet.2017.04.033

Accepted Manuscript
Mechanistic studies of thiourea-catalyzed cross-dehydrogenative C-P and C-C
coupling reactions and their further applications
Zhiguo Zhang, Kai Gu, Zongbi Bao, Huabin Xing, Qiwei Yang, Qilong Rena
PII:
S0040-4020(17)30405-2
10.1016/j.tet.2017.04.033
TET 28634
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 March 2017
Revised Date: 11 April 2017
Accepted Date: 13 April 2017
Please cite this article as: Zhang Z, Gu K, Bao Z, Xing H, Yang Q, Rena Q, Mechanistic studies of
thiourea-catalyzed cross-dehydrogenative C-P and C-C coupling reactions and their further applications,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.04.033.
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Thiourea-based hydrogen bond donor has been recently disclosed by our group to be an
Type the title of your article here
efficient organocatalyst for cross-dehydrogenative coupling (CDC) reactions. Here we present
a detailed mechanistic study of this reaction using NMR spectroscopy and kinetic isotope
effect experiment. The results revealed that α-amino peroxide is the true intermediate within
the catalytic cycle, formed via a thiourea-catalyzed rate-determining hydrogen atom transfer
(HAT) process. These experimental investigations not only provide somewhat insight into the
mechanism of thiourea-catalyzed CDC reactions but also promote their further applications.
Mechanistic studies of thiourea-catalyzed
cross-dehydrogenative C-P and C-C coupling
reactions and their further applications
Zhiguo Zhang,a, * Kai Gu,a Zongbi Bao,a Huabin Xing,a Qiwei Yang,a and Qilong Rena
Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and
Biological Engineering, Zhejiang University, Zheda Road 38, Hangzhou 310027, China.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Mechanistic studies of thiourea-catalyzed cross-dehydrogenative C-P and C-C
coupling reactions and their further applications
Zhiguo Zhang,a, * Kai Gu,a Zongbi Bao,a Huabin Xing,a Qiwei Yang,a and Qilong Rena
a Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Zheda
Road 38, Hangzhou 310027, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Thiourea-based hydrogen bond donor has been recently disclosed by our group to be an efficient
organocatalyst for cross-dehydrogenative coupling (CDC) reactions. Here we present a detailed
mechanistic study of this reaction using NMR spectroscopy and kinetic isotope effect
experiment. The results revealed that α-amino peroxide is the true intermediate within the
catalytic cycle, formed via a thiourea-catalyzed rate-determining hydrogen atom transfer (HAT)
process. These experimental investigations not only provide somewhat insight into the
mechanism of thiourea-catalyzed CDC reactions but also promote their further applications.
Available online
Keywords:
C-C coupling
organocatalysis
C-H activation
cross-dehydrogenative coupling
thiourea
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
The selective transformation of C(sp3)-H bonds to other
functional groups represents an active and vibrant research area
over the past decades, as C(sp3)-H bonds are ubiquitous in
organic molecules.1 Among these reactions, the cross-
dehydrogenative-coupling (CDC) reaction of two C(sp3)-H or
heteroatom-bonds2 has been recognized as an elegant and
promising strategy in modern synthetic chemistry, mainly
because it can directly form a new bond without prior activation
of substrates (Scheme 1, a and b). Pioneered by the studies of
Murahashi and Li,3 the direct activation of C(sp3)-H bonds
adjacent
to
tertiary
amines,
in
particular
N-aryl
tetrahydroisoquinolines, has seen an explosion of interest.
Currently, these reactions are often dominated by the use of
transition metals as catalysts4 or visible-light mediated
photocatalysis5. Although examples of metal free systems
(SO2Cl2 , AcOH7, 2-Chloroanthra-9,10-quinone8, I2 , Eosin Y10,
KI11, DDQ12, (Diacetoxyiodo)benzene13) have progressed
considerably, profitable practical organocatalyzed CDC reactions
have not yet been developed. We recently reported for the first
time an efficient thiourea-catalyzed cross-dehydrogenative
coupling of C(sp3)-H with diethyl phosphite using N,N’-bis(3,5-
bis(tri-fluoromethyl)-phenyl)thiourea (T1), also known as
Schreiner’s catalyst,14 as the catalyst and tert-butyl peroxide as a
terminal oxidant (Scheme 1, c).15 However, our understanding of
how these thiourea-catalyzed CDC reactions occur, and what
6
9
Scheme 1. Cross-coupling reactions
conversion are lacking. Here, we present in situ probes of T1-
catalyzed oxidative coupling of N-phenyl tetrahydroisoquinolines
with different nucleophiles such as diethyl phosphite and
nitroalkanes using NMR spectroscopy and kinetic isotope effect
experiment, with an attempt to reveal the mechanism and further
expand the generality of substrates (Scheme 1, d).
2. Results and discussion
their inherent advantages and limitations for practical C(sp3)-H
———
We have previously observed that T1 facilitates the formation
*
Fax: +86-571-87952375; Tel: +86-571-87951224; E-mail: zhiguo.zhang@zju.edu.cn.

2
Tetrahedron
ACCEPTED MANUSCRIPT
To our delight, the oxidative C-C coupling reaction
couldoccur under the catalysis of T1 (20 mol%) with CH3CN as
solvent at 50 °C, to afford 3a in 64% yield. (Table 1, entry 3).
Intrigued by these results, we performed a detailed optimization
study on the T1 promoted cross-dehydrogenative coupling (CDC)
of N-phenyl tetrahydroisoquinoline (1a) with nitromethane (2a).
First, 1a was treated with 20 mol% of T1 in a mixture of
nitromethane and TBHP at different temperatures, using CH3CN
as the solvent (entries 1−4). The reaction temperature at 50 °C
proved to be optimal.
Scheme 2. Coupling of diethyl phosphite with 1a in the presence of the
radical inhibitor BHT. a Isolated yield. Number in parentheses is the isolated
yield of the reaction without BHT.
of α-amino peroxide, a possible reactive intermediate for the
oxidative coupling of N-aryl tetrahydroisoquinolines with diethyl
phosphite,15 but it is still unclear how this intermediate formed.
Based on the literature reports, there are two possible CDC
Next, we assessed the effect of other reaction parameters
including catalyst loadings, substrate/oxidant ratios, etc. on this
CDC reaction. Starting from 20 mol% of T1, the catalyst loading
can decrease to 1.0 mol% albeit at the expense of prolonged
reaction time. 15 mol% of T1 seems optimal for completion of
the reaction within reasonable reaction time (entry 9). The yield
of product can be improved as the ratio of TBHP to substrate
increases but no continuously beneficial effect was observed
when the amount of TBHP was more than 1.5 equivalents
(entries 9–12). The addition of 4Å molecular sieve was not
beneficial for the improvement of the product yield (entry 13).
mechanisms: either
a
radical mechanism or an ionic
mechanism.3d To gain insight into the mechanism of our
T1/TBHP system for C-P coupling, we first added 3.0 eq. of 2,6-
di-tert-butyl-4-methyl phenol (BHT) as radical scavenger in the
coupling reaction between N-phenyltetrahydroisoquinolines and
diethyl phosphite, a significant drop in yield was observed
(Scheme 2). This result suggested that a radical process involves
in the present reaction. Then we tried to monitor the reaction
process in situ by means of NMR spectroscopy, unfortunately, no
peaks of the intermediate have been successfully intercepted,
presumably because diethyl phosphite reacts extremely fast with
the intermediate. To address the above questions, we selected
nitromethane as a new nucleophile to investigate substrate scope
for T1/TBHP-catalyzed CDC reactions and detailed mechanism.
Table 2. T1-catalyzed CDC of N-aryl tetrahydroisoquinolines with
nitroalkanes and dimethyl malonatea
R2
R2
T1,TBHP
NuH
+
N
N
50 o
C
R3
R1
R3
R1
Nu
1
2
3
RCH2NO2
MeOOC
Table 1. Optimization of reaction conditions
NuH =
COOMe
Product (Yield [%])b
N
N
N
Entrya
2a
TBHP
[equiv.]
2
T1
Temp
[°C]
15
Time
[h]
Yield
[%]b
55
NO2
NO2
F
NO2
Cl
[equiv.]
2
[mol%]
20
3a: 84% (76%)b
3b: 91% (73%)
3c: 89% (70%)
1
48
OMe
2
2
2
20
20
20
0
30
50
70
50
50
50
50
50
50
50
50
50
50
50
50
50
32
10
5
61
64
59
trace
45
51
61
65
48
66
67
66
67
74
84
82
N
N
N
3
2
2
NO2
Me
NO2
NO2
Br
4
2
2
3d: 89% (73%)
3
e: 74% (71%)
3f: 72% (55%)
5
2
2
48
48
36
24
12
12
12
12
12
12
12
12
12
6
2
2
1
N
N
OMe
N
7
2
2
5
NO2
NO2
NO2
NO2
OMe
8
2
2
10
15
15
15
15
15
15
15
15
15
3i: 65% (58%)
3g: 67% (42%)
3h: 86% (70%)
9
2
2
MeO
MeO
10
11
12
13c
14d
15d
16d
2
1
N
N
N
2
1.5
2.5
1.5
1.5
1.5
1.5
1.5
NO2
NO2
NO2
2
3l: 68% (54%)
dr=1.3:1
3j: 82% (65%)
3k: 77% (64%)
dr=1.7:1
2
2
N
Ph
5
MeOOC
OOOMe
10
20
3m: 61% (40%)
a
17d
Reaction conditions: amine 1a (0.2 mmol), pronucleophiles 2
(10.0 equiv.), T1 (15 mol%), TBHP (0.3 mmol, 5.5 M in decane),
12 h. Yields determined by H NMR using mesitylene as an
internal standard; isolated yields are given in parentheses. dr was
determined by 1H NMR.
a
b
Reaction conditions: amine 1a (0.2 mmol), CH3CN (200 ꢀL).
b
1
1
Yields determined by H NMR using mesitylene as an internal
standard. c with 4Å molecular sieve. d without CH3CN.

3
ACCEPTED MANUSCRIPT
Scheme 3. T1-catalyzed CDC of N-phenyl tetrahydroisoquinolines with
malononitrile.a a Reaction conditions: amine 1a (0.2 mmol), malononitrile
(10.0 equiv.), T1 (15 mol%), TBHP (0.3 mmol, 5.5 M in decane), 12 h. b
isolated yields.
Scheme 5. Coupling of nitromethane with 1a in the presence of the radical
inhibitor BHT. a Isolated yield. Number in parentheses are the isolated yields
of the reaction without BHT.
To our delight, we can intercept the characteristic peak of the
intermediate 4 during the CDC reaction of N-phenyl tetrahydro-
isoquinolines with nitroalkanes with NMR spectroscopy, which
brings us great convenience to further reveal the role of 4. Then,
we investigated oxidative coupling reactions of 1a with
nitromethane using the T1/TBHP method by means of NMR to
monitor changes of reactants, products and active intermediate
during the reaction process. (Scheme 4) The curves shown in
Scheme 4 suggest that the intermediate 4 may be the direct
precursor of 3a.
Gratifyingly, when the C-C coupling reaction was performed
without a solvent, the yield can be dramatically improved with
the increase of the amount of nitromethane (entries 14–17) and
10 equivalents of nitromethane gives the best yield of 3a (entry
16). A control experiment demonstrated that when the oxidative
C-C coupling reaction was carried out in the absence of T1, only
trace amount of product was observed (entry 5).
After the optimized reaction conditions were established, the
substrate scope of this T1-catalyzed C-C coupling reaction was
investigated by treatment with various N-aryl tetrahydro-
isoquinoline derivatives. As shown in Table 2, all the substrates
with diverse substituents on N-aryl tetrahydroisoquinolines
proceeded smoothly to give the corresponding products 3a-l in
good to excellent yields (65−91%).
In line with the role of radical inhibitor 2,6-di-tert-butyl-4-
methylphenol (BHT) in the CuBr/TBHP catalyzed CDC
reactions,17 3.0 equiv of BHT was added into the CDC reaction
of N-phenyl tetrahydroisoquinolines with nitromethane catalyzed
by our T1/TBHP catalyst system to check whether the reaction
proceeds via a radical mechanism or not. As observed in T1-
catalyzed C-P coupling, adding the radical inhibitor BHT to the
reaction dramatically decreased the reaction yield (Scheme 5,
from 68% to 11%), thus suggesting that a radical mechanism
could be involved.
In addition, when nitroethane or 1-nitropropane was used both
as solvent and reactant, the coupling products were obtained in
good yields and slight diastereoselectivities, respectively (Table 2,
3k and 3l). It should be noted that this protocol was also
compatible with dimethyl malonate, affording the product in 61%
yield (3m).
Further information on radical mechanism was illustrated
from a kinetic isotope effect (KIE) experiment (Scheme 6). When
monodeuterated substrate 1-d1 was used as the subsrate, a KIE
value kH/kD with diethyl phosphite and nitromethane of 2.6 and
3.3 was obtained through NMR spectra, respectively. Based on
the KIE results as well as previous reports,18 the reaction pathway
was in agreement with a hydrogen atom transfer (HAT) rate-
determining C-H bond cleavage.
In addition to nitroalkanes and dimethyl malonate, the
catalytic system was also applied to malononitrile. Surprisingly,
no expected β-dicyano substituted derivative was obtained, but
providing the α-amino nitriles as the sole product in good yield
(Scheme 3, 55%). Although those data are similar with the results
using Eosin Y5d as the catalyst, when CuBr3d was employed as
the catalyst, both β-dicyano coupling product and α-amino
nitriles were afforded. In this context, amino nitriles are
synthetically useful intermediates, upon which the nitrile
functionality can be elaborated into α-amino acids, α-amino
aldehydes or α-amino alcohols. The developed procedure
demonstrates the potential of this organocatalytic coupling
reaction in the synthesis of α-amino nitriles without the use of
toxic cyanides and expensive metals.16
T1(20 mol%)
TBHP(3 eq.)
CH3CN, 50 oC, 12 h
O
N
+
H
P
OEt
N
Ph
H/D
Ph
EtO
EtO
OEt
P
H
D
O
1-d1
3 eq.
T1(15 mol%)
TBHP(1.5 eq.)
50 oC, 12 h
CH3NO2
+
N
N
Ph
Ph
O2N
H/D
H
D
1-d1
10 eq.
Scheme 6. Kinetic isotope effect (KIE) experiment with monodeuterated 1-d1
Scheme 4. In situ probes of the formation of products 3a (triangles, solid line)
and intermediate 4 (squares, solid line) in the T1/TBHP system with
nitromethanea a Reaction conditions: amine 1a (0.1 mmol), nitromethane
(10.0 equiv.), T1 (15 mol%), TBHP (0.15 mmol, 5.5 M in decane), CDCl3
(0.5 ml) in NMR tube.
Scheme 7. The effect of T1 in coupling nitromethane with intermediate 4

4
Tetrahedron
ACCEPTED MANUSCRIPT
In order to clarify whether T1 is also involvement in promoting
the substitution of intermediate 4 with a nucleophile,the reaction
of nitromethane with 4 was evaluated (scheme 7). The reaction
with T1 proceeds much faster (a yield of 86% over 8 h) than the
control experiment (a yield of 67% over 24 h), suggesting that T1
has a strong ability to promote this reaction.
C-nucleophiles such as nitroalkanes, dialkyl malonates and
malononitrile. N-aryltetrahydroisoquinolines bearing either
electron-withdrawing or -donating groups were well tolerated
with this method, and the corresponding α-functionalized amines
were delivered in good yields. The present method not only
expands the application of T1 further but also paves a new
avenue for thiourea-based organocatalysts. Asymmetric CDC
reaction catalyzed by chiral thiourea derivatives are underway in
our laboratory and will be reported in due course.
The detailed mechanistic investigations reveal apparent
similarities of T1/TBHP and CuBr/TBHP systems for catalytic
CDC reactions. Based on previous studies19 and our experimental
results, a plausible mechanism for the present reaction system, is
proposed and depicted in Scheme 8. T1 first interacts with TBHP
through double hydrogen bonding, generating a hydroxyl
complex T1a and a tert-butyloxy radical (eq 1). Then, a
hydrogen atom was transferred from TBHP to T1a, forming a
radical complex T1b and one molecular of water (eq 2). The tert-
butyloxy radical in eq. 1 can abstrat a hydrogen atom from 1a,
giving rise to the radical species 5 (eq 3), which reacts with T1b
to afford the intermediate 4 (eq 4). Aided by T1, the intermediate
4 will be subsequently intercepted with a nucleophile to generate
the corresponding coupling product (eq 5). Nevertheless, the
direct coupling of benzylic radical 5 with NuH can not be ruled
out either (eq 6).
4. Experimental section
4.1. General information
All commercially available materials were used as provided
without further purification unless otherwise noted. Reactions
were monitored by TLC on silica gel plates (GF254). Column
chromatography was conducted on Silica gel 200-300 and the
solvent mixtures are understood as volume/volume. The NMR
spectra were recorded on a BRUKER-AV400 spectrometer in
CDCl3, Tetramethylsilane (TMS; δ = 0.00 ppm) served as
internal standards for 1H NMR and CDCl3 was used as the
internal standard (δ = 77.0 ppm) for 13C NMR. The HRMS were
measured with Waters GCT Premier. IR spectra were measured
using a Nicolet 6700 FT-IR spectrometer and are reported in
terms of frequency of absorption (cm-1). The 1,2,3,4-
tetrahydroisoquinoline derivatives were prepared according to
reported
procedures.20
The
catalyst
1,3-bis(3,5-
bis(trifluoromethyl)phenyl)thiourea (T1) was prepared according
to reported procedures.21
4.2. General procedure of the CDC reaction
Nitroalkanes 2 (2.0 mmol) and TBHP (0.3 mmol, 5.5 M in
decane) were successively added to a mixture of N-aryl-1,2,3,4-
tetrahydroisoquinolines
1 (0.2 mmol) and N,N-bis[3,5-bis-
(trifluoromethyl) phenyl]thiourea T1 (15 mol%, 15 mg). Then
o
the reaction mixture was stirred at 50 C for 12 hours. After the
reaction was completed monitoring by TLC analysis under UV,
the reaction mixture was directed purified by column
chromatography on silica gel with a mixture of n-hexane and
ethyl acetate as the eluent (n-hexane/ethyl acetate = 10:1) to
afford the desired coupling products 3.
4.2.1. 1-(nitromethyl)-2-phenyl-1,2,3,4-
tetrahydroisoquinoline (3a)
Purified by column chromatography on silica gel (eluting with
1
hexane/ethyl acetate=10:1, Rf=0.4); Yield: 84%; H NMR (400
MHz, CDCl3) δ 7.31 – 7.10 (m, 6H), 6.97 (d, J = 8.0 Hz, 2H),
6.88 – 6.80 (m, 1H), 5.54 (t, J = 7.2 Hz, 1H), 4.87 (dd, J = 11.8,
7.8 Hz, 1H), 4.56 (dd, J = 11.8, 6.6 Hz, 1H), 3.73 – 3.54 (m, 2H),
3.15 – 3.01 (m, 1H), 2.79 (dt, J = 16.3, 4.9 Hz, 1H).13C NMR
(101 MHz, CDCl3) δ 148.38, 135.24, 132.87, 129.48, 129.16,
128.09, 126.96, 126.67, 119.39, 115.05, 78.74, 58.16, 42.02,
26.40.IR (neat): ν = 3033, 1982, 1914, 1596, 1548, 1495, 1383,
1330, 1292, 1211, 1006, 757. HRMS (GC-TOF) m/z calcd for
C16H16N2O2 [M]+: 268.1212; found: 268.1211.
Scheme 8. Proposed reaction mechanism
4.2.2. 2-(4-fluorophenyl)-1-(nitromethyl)-1,2,3,4-
tetrahydroisoquinoline (3b)
3. Conclusion
Purified by column chromatography on silica gel (eluting with
hexane/ethyl acetate=10:1, Rf=0.4); Yield: 91%; H NMR (400
1
In summary, mechanistic investigations using a combination
of NMR, KIE, as well as other experimental techniques reveal for
the first time the apparent similarities of T1/TBHP and
CuBr/TBHP systems for catalytic CDC reactions. Furthermore,
we were also able to extend this valuable methodology to C–C
bonds formation between N-aryltetraisoquinolines with various
MHz, CDCl3) δ 7.30 – 7.08 (m, 4H), 7.01 – 6.81 (m, 4H), 5.42
(dd, J = 8.6, 5.9 Hz, 1H), 4.83 (dd, J = 12.0, 8.7 Hz, 1H), 4.57
(dd, J = 12.0, 5.9 Hz, 1H), 3.69 – 3.47 (m, 2H), 3.12 – 2.90 (m,
1H), 2.72 (dt, J = 16.5, 4.2 Hz, 1H). 13C NMR (101 MHz, CDCl3)
δ 157.09 (d, J = 239.1 Hz), 145.26 (d, J = 2.2 Hz), 135.20,

5
132.47, 129.41, 128.05, 126.90, 126.71, 117.86 (d, J = 7.6 Hz),
115.81 (d, J = 22.2 Hz), 78.79, 58.67, 42.75, 25.69. IR (neat): ν =
3045, 2965, 2922, 1610, 1556, 1509, 1369, 1265, 1219, 1111,
1032, 950, 747. HRMS (GC-TOF) m/z calcd for C16H15FN2O2
[M]+: 286.1118; found: 286.1122
Purified by column chromatography on silica gel (eluting
1
ACCEPTED MANUSCRIPT
with hexane/ethyl acetate=10:1, Rf=0.4); Yield: 67%; H NMR
(400 MHz, CDCl3) δ 7.27 – 7.15 (m, 4H), 7.14 – 7.09 (m, 1H),
6.59 (dd, J = 8.2, 2.3 Hz,1H), 6.53 (t, J = 2.3 Hz, 1H), 6.41 (dd, J
= 8.0, 2.0 Hz, 1H), 5.53 (t, J = 7.2 Hz, 1H), 4.87 (dd, J = 11.8,
7.6 Hz, 1H), 4.55 (dd, J = 11.8, 6.8 Hz, 1H), 3.81 (d, J = 11.3 Hz,
3H), 3.66 – 3.55 (m, 2H), 3.15 – 3.03 (m, 1H), 2.79 (dt, J = 16.3,
5.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 160.81, 149.69,
135.19, 132.85, 130.20, 129.10, 128.13, 126.96, 126.68, 107.49,
104.03, 101.39, 78.74, 58.21, 55.17, 42.09, 26.56. IR (neat): ν =
2950, 2834, 1609, 1548, 1496, 1378, 1280, 1219, 1166, 1040,
835, 758. HRMS (GC-TOF) m/z calcd for C17H18N2O3 [M]+:
298.1317; found: 298.1317
4.2.3. 2-(4-chlorophenyl)-1-(nitromethyl)-1,2,3,4-
tetrahydroisoquinoline (3c)
Purified by column chromatography on silica gel (eluting with
1
hexane/ethyl acetate=10:1, Rf=0.4); Yield: 89%; H NMR (400
MHz, CDCl3) δ 7.28 – 7.09 (m, 6H), 6.95 – 6.81 (m, 2H), 5.57 –
5.39 (m, 1H), 4.83 (dd, J = 12.0, 8.2 Hz, 1H), 4.56 (dd, J = 12.0,
6.3 Hz, 1H), 3.68 – 3.49 (m, 2H), 3.12 – 2.97 (m, 1H), 2.77 (dt, J
= 16.4, 4.7 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 147.06,
135.03, 132.39, 129.26, 128.22, 126.85 (d, J = 14.5 Hz), 124.32,
116.43, 78.61, 58.17, 42.11, 26.07. IR (neat): ν = 3104, 3045,
2950, 1592, 1548, 1495, 1377, 1332, 1279, 1219, 1134, 744.
HRMS (GC-TOF) m/z calcd for C16H15ClN2O2 [M]+: 302.0822;
found: 302.0821
4.2.8. 2-(4-methoxyphenyl)-1-(nitromethyl)-1,2,3,4-
tetrahydroisoquinoline (3h)
Purified by column chromatography on silica gel (eluting with
hexane/ethyl acetate=10:1, Rf=0.4); Yield: 86%; H NMR (400
1
MHz, CDCl3) δ 7.30 – 7.07 (m, 4H), 6.95 – 6.86 (m, 2H), 6.85 –
6.76 (m, 2H), 5.38 (dd, J = 8.5, 5.9 Hz, 1H), 4.82 (dd, J = 11.9,
8.7 Hz, 1H), 4.55 (dd, J = 11.9, 5.8 Hz, 1H), 3.73 (s, 3H), 3.62 –
3.48 (m, 2H), 3.00 (m, J = 16.2, 9.2, 6.8 Hz, 1H), 2.68 (dt, J =
16.5, 3.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 153.89, 142.99,
135.39, 132.77, 129.42, 127.85, 126.86, 126.56, 118.78, 114.62,
78.89, 58.86, 55.51, 43.03, 25.68. IR (neat): ν = 2949, 2840,
1661, 1610, 1548, 1508, 1471, 1378, 1242, 1131, 1034, 833.
HRMS (GC-TOF) m/z calcd for C17H18N2O3 [M]+: 298.1317;
found: 298.1320
4.2.4. 2-(4-bromophenyl)-1-(nitromethyl)-1,2,3,4-
tetrahydroisoquinoline (3d)
Purified by column chromatography on silica gel (eluting with
1
hexane/ethyl acetate=10:1, Rf=0.4); Yield: 89%; H NMR (400
MHz, CDCl3) δ 7.38 – 7.29 (m, 2H), 7.28 – 7.07 (m, 4H), 6.91 –
6.76 (m, 2H), 5.60 – 5.36 (m, 1H), 4.84 (dd, J = 12.0, 8.1 Hz,
1H), 4.56 (dd, J = 12.0, 6.4 Hz, 1H), 3.71 – 3.42 (m, 2H), 3.02
(ddd, J = 42.1, 24.4, 12.1 Hz, 1H), 2.78 (dt, J = 16.4, 4.8 Hz, 1H).
13C NMR (101 MHz, CDCl3) δ 147.45, 135.01, 132.39, 132.18,
129.25, 128.25, 126.93, 126.80, 116.72, 111.51, 78.57, 58.07,
42.03, 26.13. IR (neat): ν = 3110, 3045, 2950, 1588, 1547, 1491,
1376, 1280, 1219, 1129, 1000, 947, 743. HRMS (GC-TOF) m/z
calcd for C16H15BrN2O2 [M]+: 346.0317; found: 346.0324
4.2.9. 1-(nitromethyl)-2-(4-nitrophenyl)-1,2,3,4-
tetrahydroisoquinoline (3i)
Purified by column chromatography on silica gel (eluting with
hexane/ethyl acetate=10:1, Rf=0.4); Yield: 65%; H NMR (400
1
MHz, CDCl3) δ 8.22 – 8.12 (m, 2H), 7.35 – 7.29 (m, 1H), 7.29 –
7.23 (m, 2H), 7.17 (dd, J = 6.0, 2.6 Hz, 1H), 7.01 – 6.92 (m, 2H),
5.71 (t, J = 7.2 Hz, 1H), 4.88 (dd, J = 12.0, 7.2 Hz, 1H), 4.63 (dd,
J = 12.0, 7.2 Hz, 1H), 3.88 – 3.61 (m, 2H), 3.23 – 3.08 (m, 1H),
2.97 (dt, J = 16.2, 6.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ
152.53, 138.94, 134.41, 131.92, 129.06, 128.86, 127.23, 127.04,
126.21, 111.92, 78.09, 57.49, 42.21, 26.99. IR (neat): ν = 2947,
2840, 1662, 1591, 1551, 1506, 1406, 1318, 1221, 1113, 835, 754.
HRMS (GC-TOF) m/z calcd for C16H15N3O4 [M]+: 313.1063;
found: 313.1059
4.2.5. 1-(nitromethyl)-2-(p-tolyl)-1,2,3,4-
tetrahydroisoquinoline (3e)
Purified by column chromatography on silica gel (eluting with
1
hexane/ethyl acetate=10:1, Rf=0.4); Yield: 74%; H NMR (400
MHz, CDCl3) δ 7.26 – 7.10 (m, 4H), 7.06 (d, J = 8.2 Hz, 2H),
6.93 – 6.81 (m, 2H), 5.58 – 5.40 (m, 1H), 4.84 (dd, J = 11.8, 8.1
Hz, 1H), 4.54 (dd, J = 11.8, 6.3 Hz, 1H), 3.73 – 3.37 (m, 2H),
3.12 – 2.95 (m, 1H), 2.74 (dt, J = 16.4, 4.5 Hz, 1H), 2.26 (d, J =
6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 146.33, 135.31,
132.88, 129.93, 129.24, 129.06, 127.96, 126.93, 126.58, 115.84,
78.78, 58.35, 42.24, 26.15, 20.32. IR (neat): ν = 3105, 3045,
2949, 1612, 1590, 1552, 1518, 1281, 1220, 1147, 1068, 1004,
949, 836. HRMS (GC-TOF) m/z calcd for C17H18N2O2 [M]+:
282.1368; found: 282.1376
4.2.10. 6,7-dimethoxy-1-(nitromethyl)-2-phenyl-
1,2,3,4-tetrahydroisoquinoline (3j)
Purified by column chromatography on silica gel (eluting with
1
hexane/ethyl acetate=2:1, Rf=0.4); Yield: 82%; H NMR (400
MHz, CDCl3) δ 7.30 – 7.22 (m, 2H), 7.02 – 6.90 (m, 2H), 6.89 –
6.79 (m, 1H), 6.65 (s, 1H), 6.60 (s, 1H), 5.51 – 5.41 (m, 1H),
4.85 (dd, J = 11.8, 8.1 Hz, 1H), 4.57 (dd, J = 11.8, 6.4 Hz, 1H),
3.85 (d, J = 3.0 Hz, 5H), 3.68 (dt, J = 13.2, 5.1 Hz, 1H), 3.62 –
3.53 (m, 1H), 3.05 – 2.94 (m, 1H), 2.73 – 2.60 (m, 1H). 13C NMR
(101 MHz, CDCl3) δ 148.71, 148.56, 147.66, 129.41, 127.38,
124.50, 119.53, 115.48, 111.66, 109.54, 78.75, 57.95, 56.03,
55.86, 42.01, 25.76. IR (neat): ν = 2946, 2834, 1598, 1547, 1514,
1375, 1245, 1109, 1031, 753. HRMS (GC-TOF) m/z calcd for
C18H20N2O4 [M]+: 328.1423; found: 328.1418
4.2.6. 2-(2-methoxyphenyl)-1-(nitromethyl)-1,2,3,4-
tetrahydroisoquinoline (3f)
Purified by column chromatography on silica gel (eluting with
1
hexane/ethyl acetate=10:1, Rf=0.4); Yield: 72%; H NMR (400
MHz, CDCl3) δ 7.20 (ddd, J = 23.3, 8.3, 3.5 Hz, 4H), 7.03 (dd, J
= 11.6, 4.9 Hz, 1H), 6.86 (dt, J = 15.1, 6.8 Hz, 3H), 5.50 (dd, J =
8.2, 5.1 Hz, 1H), 4.82 (dd, J = 12.0, 8.5 Hz, 1H), 4.53 (dd, J =
12.1, 5.0 Hz, 1H), 3.82 (s, 3H), 3.60 (dd, J = 13.3, 4.8 Hz, 1H),
3.54 – 3.42 (m, 1H), 2.99 (ddd, J = 17.1, 11.4, 6.2 Hz, 1H), 2.71
(d, J = 16.3 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 153.04,
138.82, 135.32, 133.59, 129.51, 127.53, 126.79, 126.40, 124.08,
121.89, 120.98, 112.42, 79.13, 58.13, 55.75, 42.91, 26.79. IR
(neat): ν = 2953, 2843, 1609, 1590, 1550, 1498, 1378, 1283,
1220, 1027, 910, 745. HRMS (GC-TOF) m/z calcd for
C17H18N2O3 [M]+: 298.1317; found: 298.1314
4.2.11. 1-(1-nitroethyl)-2-phenyl-1,2,3,4-
tetrahydroisoquinoline (3k)
Purified by column chromatography on silica gel (eluting with
hexane/ethyl acetate=10:1, Rf=0.4); Yield: 77%; dr=1.7:1; 1H
NMR (400 MHz, CDCl3) δ 7.28 – 7.00 (m, 6H), 6.96 – 6.88 (m,
2H), 6.81 – 6.70 (m, 1H), 5.17 (t, J = 8.6 Hz, 1H), 5.03 – 4.93 (m,
0.6H, major isomer), 4.82 (m, J = 8.9, 6.8 Hz, 0.4H, minor
isomer), 3.76 (m, J = 13.5, 8.2, 5.6 Hz, 0.6H, minor isomer), 3.60
4.2.7. 2-(3-methoxyphenyl)-1-(nitromethyl)-1,2,3,4-
tetrahydroisoquinoline (3g)

6
Tetrahedron
ACCEPTED MANUSCRIPT
– 3.40 (m, 1.4H, major isomer), 2.98 (m, J = 14.4, 7.1 Hz, 1H),
2.82 (m, J = 20.8, 13.5, 6.0 Hz, 1H), 1.63 (d, J = 6.8 Hz, 1H,
minor isomer), 1.47 (d, J = 6.6 Hz, 2H, major isomer). 13C NMR
(101 MHz, CDCl3, minor isomer marked*) δ 149.10*, 148.82,
135.58, 134.74*, 133.76*, 131.97, 129.41*, 129.29 (major and
minor isomers), 129.08*, 128.69*, 128.33 (J = 14.5 Hz), 128.18,
127.22*, 126.58*, 126.11, 119.31, 118.76*, 115.38, 114.44*,
88.93*, 85.39, 62.72, 61.12*, 43.54*, 42.65, 26.72*, 26.35,
17.41*, 16.36. IR (neat): ν = 2923, 2834, 1667, 1599, 1549, 1504,
1360, 1220, 949, 760. HRMS (GC-TOF) m/z calcd for
C17H18N2O2 [M]+: 282.1368; found: 282.1369
4.39 (s, 1H), 3.57 (dd, J = 11.7, 5.7 Hz, 2H), 2.99 (t, J = 5.8 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 150.52, 134.88, 134.38,
129.18, 128.50, 126.52, 126.32, 126.00, 118.62, 115.09, 50.63 –
50.00 (m), 46.46, 29.07. HRMS (GC-TOF) m/z calcd for
C15H14DN [M]+: 210.1267; found: 210.1263
4.2.16. 1-(tert-butylperoxy)-2-phenyl-1,2,3,4-
tetrahydroisoquinoline (4)
Purified by column chromatography on silica gel (eluting with
1
hexane/ethyl acetate=20:1, Rf=0.4); Yield: 82%; H NMR (400
MHz, CDCl3) δ=7.33 – 7.25 (m, 1H), 7.22 – 7.16 (m, 3H), 7.16 –
7.08 (m, 2H), 7.05 (d, J = 7.9 Hz, 2H), 6.75 (t, J = 7.3 Hz, 1H),
6.10 (s, 1H), 3.64 (ddd, J = 11.7, 7.0, 4.9 Hz, 1H), 3.53 – 3.41 (m,
1H), 3.06 – 2.82 (m, 2H), 1.05 (s, 9H). 13C NMR (101 MHz,
CDCl3) δ=147.83, 135.59, 131.91, 128.07, 127.95, 127.53,
126.67, 124.94, 117.84, 113.80, 89.66, 79.01, 41.50, 27.08, 25.49;
4.2.12. 1-(1-nitropropyl)-2-phenyl-1,2,3,4-
tetrahydroisoquinoline (3l)
Purified by column chromatography on silica gel (eluting with
hexane/ethyl acetate=10:1, Rf=0.4); Yield: 68%; dr=1.3:1; 1H
NMR (400 MHz, CDCl3) δ 7.25 – 7.00 (m, 6H), 6.92 – 6.84 (m,
2H), 6.79 – 6.65 (m, 1H), 5.16 (d, J = 9.3 Hz, 0.4H), 5.05 (d, J =
9.6 Hz, 0.6H), 4.85 – 4.71 (m, 0.6H), 4.67 – 4.51 (m, 0.4H), 3.82
– 3.71 (m, 0.6H), 3.63 – 3.39 (m, 1.4H), 3.04 – 2.92 (m, 1H),
2.87 – 2.73 (m, 1H), 2.19 – 1.94 (m, 1.5H), 1.75 (dqd, J = 14.7,
7.4, 3.0 Hz, 0.5H), 0.85 (tt, J = 6.9, 3.5 Hz, 3H). 13C NMR (101
MHz, CDCl3, minor isomer marked*) δ 149.02, 148.94*, 135.52,
134.66*, 133.87*, 132.50, 129.39, 129.31 (major and minor
isomers), 129.15, 128.66, 128.56*,128.20*, 128.15, 127.18*,
126.60*, 125.86 (s,major and minor isomers), 119.35, 118.51*,
115.77, 114.04*, 96.13*, 93.01, 62.14, 60.66*, 43.49*, 42.24,
26.80*, 25.66, 24.97*, 24.60, 10.66 (d, J = 1.2 Hz,major and
minor isomers). IR (neat): ν = 2971, 2914, 2360, 1598, 1546,
1493, 1370, 1319, 1269, 1212, 933, 809, 749. HRMS (GC-TOF)
m/z calcd for C18H20N2O2 [M]+: 296.1525; found: 296.1526
IR
(neat):
ν
=2975,2923,2359,1599,1504,1402,1362,
1196,947,924,880,754; HRMS (GC-TOF) m/z calcd for
C19H23NO2 [M]+: 297.1729; found: 297.1734.
Acknowledgements
We are grateful for financial support from the MOST
(2016YFA0202900), the National Natural Science Foundation of
China (21376212, 21436010), the Fundamental Research Funds
for the Central Universities (2016FZA4019) and the Natural
Science
Foundation
of
Zhejiang
Province,
China
(LY13B060001).
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tetrahydronaphthalen-1-yl)malonate (3m)
Purified by column chromatography on silica gel (eluting with
hexane/ethyl acetate=20:1, Rf=0.4); Yield: 82%; H NMR (400
MHz, CDCl3) δ 7.24 – 7.07 (m, 6H), 6.99 (t, J = 8.3 Hz, 2H),
6.76 (t, J = 7.3 Hz, 1H), 5.70 (d, J = 9.4 Hz, 1H), 3.95 (d, J = 9.4
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339.1468
1
4.2.14. 2-phenyl-1,2,3,4-tetrahydronaphthalene-1-
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hexane/ethyl acetate=20:1, Rf=0.4); Yield: 82%;1H NMR (400
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234.1155
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tetrahydroisoquinoline (1-d1 )
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7.10 (m, 4H), 6.98 (d, J = 8.6 Hz, 2H), 6.83 (t, J = 7.3 Hz, 1H),
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