Iminium Ion and N-Hydroxyimide as the Surrogate Components in DEAD-Promoted Oxidative Ugi Variant

Article abstract of DOI:10.1021/acs.joc.8b01868

A practical metal-free oxidative Ugi-type three-component assembly has been achieved efficiently, employing a tertiary-amine-derived iminium ion as an imine surrogate, N-hydroxyimide as an acid surrogate, and DEAD as an oxidant. This dual-surrogate Ugi variant proceeded with a broad substrate scope and desired functional group tolerance, leading to a wide range of N-alkyl-N-acyl aminophthalimide and N-alkyl-N-acylaminosuccinimide derivatives in good isolated yields.

Full text of DOI:10.1021/acs.joc.8b01868

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Article
Iminium Ion and N-hydroxyimide as the Surrogate
Components in DEAD-Promoted Oxidative Ugi Variant
Jiankun Wang, Yilin Sun, Mu-Han Jiang, Tian-Yu Hu, Yong-
Jie Zhao, Xin Li, Guangji Wang, Kun Hao, and Le Zhen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01868 • Publication Date (Web): 15 Oct 2018
Downloaded from http://pubs.acs.org on October 17, 2018
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Iminium Ion and N-hydroxyimide as the Surrogate Components in
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DEAD-Promoted Oxidative Ugi Variant
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Jiankun Wang, Yilin Sun, Mu-Han Jiang, Tian-Yu Hu, Yong-Jie Zhao, Xin Li, Guangji
Wang,* Kun Hao* and Le Zhen*
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical
University, 24 Tongjia Xiang, Nanjing 210009, Jiangsu, China
∗ Corresponding author. E-mail: i_m_zhenle@163.com, cpu_haokun@aliyun.com,
guangjiwang@hotmail.com
N
N
Ar
Ar
R
N
N
O
O
DEAD
O
oxidative
Ugi-type reaction
O
O
+
R
NC
+
N
N
Ar
OH
imine surrogate:
iminium ion
acid surrogate:
N-hydroxyimide
30 examples
up to 91% yields
ABSTRACT
A practical metal-free oxidative Ugi-type three-component assembly has been
achieved efficiently, employing tertiary amine-derived iminium ion as an imine
surrogate, N-hydroxyimide as an acid surrogate, and DEAD as an oxidant. This
dual-surrogate Ugi variant proceeded with a broad substrate scope and desired functional
group tolerance, leading to a wide range of N-alkyl-N-acyl aminophthalimide and
N-alkyl-N-acylaminosuccinimide derivatives in good isolated yields.
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INTRODUCTION
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Ugi reaction is considered as one of the most well-known multicomponent reactions
(MCRs), because of its practical application for the construction of chemical libraries and
pharmaceutical scaffolds for drug research.1,2 As the demand for molecular diversity
grew considerably, exploration of novel multicomponent Ugi reactions has become a
pivotal solution, involved in unearthing novel surrogates for the indispensible
components in traditional Ugi processes, including imines, carboxylic acids and
isocyanides (Scheme 1a).
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Since isocyanide is the core component in Ugi reaction, surrogates for isocyanide are
less common than the ones for imine and acid. The first “isocyanide-free” Ugi reaction
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was revealed by El Kaïm in 2009. In this reaction, precursors of isocyanide such as
benzyl halide were regarded as the isocyanide surrogate, reaching the in situ isocyanide
formation with the treatment of AgCN. In 2015, Dömling introduced a second practical
“isocyanide-less” strategy, in which the isocyanide was yielded via the
4
trisphosgene-promoted dehydration of the formamide.
Both of the above
transformations were compatible with the subsequent Ugi reaction.
Extensive researches, perusing for novel Ugi component’s functional equivalents,
have been performed and various workable replacements to imine and carboxylic acid
have been summarized in an excellent book and some reviews. 2,5 Among the existing
imine surrogates, iminium ions, directly transformed from secondary or tertiary amines
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through the action of various oxidants, have seduced many organic chemists in oxidative
Ugi-type reaction over recent years. 6,7 For example, in 2007, Zhu's group pioneered the
first oxidative Ugi-type reaction, in which 1,2,3,4-tetrahydroisoquinolines (THIQs) were
converted into the corresponding cyclic imines, using IBX (2-iodoxybenzoic acid) as a
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6b
mild and efficient oxidant. Ugi-type three-component assemblies, employing copper
and peroxides as oxidants, were accomplished by Xie in 2010. 7a Alternatively, the first
photoredox-catalyzed oxidative Ugi-type reactions were reported by Rueping's group in
7c
2013. The surrogate iminium ions could also be formed through the cascade event
6g
involving sequential imine formation and decarboxylation.
Subsequently, taking
advantage of the redox-neutral iminium ions formation and amine C–H functionalization
6h
of pyrrolidines and THIQs, Seidel performed a new variant of Ugi reaction.
We
recently reported a Brønsted-acid-catalyzed three-component reaction involving the
8
oxidation of tertiary amines triggered by a 1,5-hydride shift. In addition, we also
described a metal-free oxidative Ugi-type reaction, in which the tertiary amines, oxidized
by DEAD, were converted into the corresponding iminium ions. 9,10,11
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(a) Surrogates in Ugi-type Reaction
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Imine
imine surrogates
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aldehyde amine
+
[Ox]
Iminium ions
Surrogates
Ugi-type Reaction
in this work:
N-hydroxyimides
Carboxylic Acid
Isocyanide
acid surrogates
isocyanide surrogates
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(b) N-hydroxyimides as acid surrogates
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ZnCl2
O
O
N
N
R2 NH2
R1 CHO
R3 NC
+
+
+
R1
O
O
N
R2
R3
OH
N
H
O
(c) This work: Oxidative Ugi-type Reaction with two surrogates
N
Ar
R
DEAD
N
N
O
O
+
+
R
NC
N
O
O
Ar
O
N
OH
Scheme 1. Surrogate components in Ugi-type Reaction.
Well-studied acid surrogates, such as hydrazoic acids, cyanates, thiocyanates,
thioacetic acid, phenols, thiophenol and even mineral acids and CO2, have expanded the
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diversity of the Ugi reaction outcomes.
Notably, the above reactions employing
carboxylic acids or their surrogates always underwent a N-C bond formation in the
Mumm-type rearrangement. Recently, the first two examples of N-N bond formation in
the Mumm-type rearrangement were illustrated successively by El Kaïm and Dömling.
13,14
The Dömling's work verified N-hydroxyimide as a new acid surrogate in the Ugi
reaction, and provided straightforward access to α-hydrazino amides in the presence of
Lewis acid (Scheme 1b). To expand the application of this strategy further, we initially
supposed that the DEAD-promoted oxidative Ugi-type reaction of tertiary amines could
allow the efficient unification with the iminium ion (imine surrogate), the
N-hydroxyimide (acid surrogate) and isocyanide (Scheme 1c). In addition, we also
focused on the feasibility of the Mumm-like migration of the phthalimide or succinimide
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to the isocyanide nitrogen atom.
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RESULTS AND DISCUSSION
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Table 1. Optimization of Reaction Conditions. [a]
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N
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Ts
O
N
N
O
O
N
azodicarboxylate
O
O
N
Ts
N
+
+
OH
solvent, rt, 6h
1a
2a
NHPI
3a
entry azodicarboxylate solvent
yield[b]
60
1
DEAD
DIAD
THF
2
THF
43
3
DBAD
DEAD
DEAD
DEAD
DEAD
DEAD
DEAD
THF
13
4
DCM
DCE
90
5
88
6
toluene
CH3CN
DMF
DCM
DCM
DCM
DCM
34
7
65
8
52
9[c]
87
10[d] DEAD
11[e] DEAD
12[f] DEAD
88
82
83
[a] 1a (0.3 mmol), azodicarboxylate (0.33 mmol), 2a (0.33 mmol), NHPI (0.33 mmol), solvent
(3.0 mL). azodicarboxylate and 2a were added at the same time. [b] Isolated yield. [c] DEAD
(0.66 mmol). [d] 2a (0.66 mmol). [e] NHPI (0.66 mmol). [f] 1a was treated with DEAD for 1 h,
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and subsequently 2a and NHPI were added. NHPI = N-Hydroxyphthalimide. DIAD = diisopropyl
azodicarboxylate. DBAD = di-tert-butyl azodicarboxylate.
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The optimization of reaction conditions was initially carried out, with
2-phenyl-1,2,3,4-tetrahydro-isoquinoline 1a, p-toluene sulfonyl isocyanide 2a and
N-hydroxyphthalimide (NHPI) as standard substrates. At the outset, DEAD was selected
as the oxidant in this Ugi-type reaction, which was performed in THF at room
temperature (25 oC), and the anticipated acyl hydrazide 3a was rapidly obtained within 6
hours in 60% yield (Table 1, entry 1). When the oxidant was changed to DIAD or
DBAD, the conversion of 3a sharply decreased to 43% and 13%, respectively (Table 1,
entries 2−3). Although NHPI was slightly soluble in DCM and DCE, the reaction
processed smoothly, affording the desired products in excellent yields (Table 1, entries
4−5). However, yield improvements were not attained when toluene, acetonitrile or DMF
were used as solvent (Table 1, entries 6−8). Next, the influence of the equivalents was
investigated. When the equivalent of DEAD, 2a or NHPI was doubled respectively, the
isolated yields of 3a were almost constant (Table 1, entries 9−11). The adjustment of
additive sequencedid not improve the reaction yield (Table 1, entries 12). According to
the above results, the oxidative Ugi-type reaction of 1a (1.0 equiv), 2a (1.1 equiv) and
NHPI (1.1 equiv), with DEAD (1.1 equiv) as the oxidant, was optimally carried out in
DCM (0.1 M) at room temperature.
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O
NHPI NHS
or
3a-9a, R2
3b-9b, R2
=
=
N
N
N
O
DEAD
R1
Ts
N
R1
O
+
DCM, rt, 6h
O
Ts
N
R2
1
2a
N
6
O
7
8
9
N
O
N
O
N
N
Ts
N
R2
Ts
N
R2
Ts
N
R2
O
Ts
N
R2
O
O
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3a,
3b,
4a,
4b,
5a,
5b,
6a,
6b,
90%
85%
91%
80%
82%
77%
76%
82%
O
O
O
N
O
N
O
N
Ts
N
R2
Ts
N
R2
Br
Ts
N
R2
O
7a,
7b,
8a,
8b,
9a,
9b,
87%
76%
75%
68%
67%
59%
Scheme 2. Scope of the reaction in terms of substrates 1.
With optimized conditions in hand, we next probed the scope of substrate 1 to
confirm the generality of this protocol (Scheme 2). Both NHPI and
N-hydroxysuccinimide (NHS) were employed as the acid component in these reactions,
which provided 3a-9a and 3b-9b in the presence of 1, 2a and DEAD. The nitrogen-linked
benzene rings with both electron-donating such as methyl, methoxyl (3a-7a, 3b-7b) and
electron-withdrawing bromide (8a and 8b) were well tolerated under the
DEAD-promoted system, affording the desired products in good to excellent yields.
Notably, little influence of substituent position was observed when the o-, m-, and
p-methyl or methoxyl-substituted tetrahydro-isoquinoline substrates were used. Similarly,
the substrate carrying 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety provided 9a
and 9b in 67% and 59% yields, respectively. In addition, most reactions with NHPI
provided slightly higher yields than the one with NHS.
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O
NHPI NHS
or
10a-17a, R2
R1
=
=
N
N
N
O
DEAD
R1
O
N
2
+
R2
R
DCM, rt, 6h
O
N
R
10b-17b, R2
N
1
O
7
8
9
N
N
O
N
N
R2
R2
R2
R2
N
N
O
N
N
O
O
O
O
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10a,
10b,
11a,
11b,
12a,
12b,
13a,
13b,
68%
35%
67%
53%
72%
62%
83%
76%
O
O
N
O
N
N
O
N
R2
R2
R2
R2
N
O
N
O
O
O
N
N
O
16a,
16b,
17a,
17b,
49%
53%
60%
72%
14a,
14b,
15a,
15b,
66%
57%
73%
70%
Scheme 3. Scope of the reaction in terms of isocyanides.
As shown in Scheme 3, a diverse range of isocyanides 2 were next subjected to this
transformation to survey the reaction compatibility. The isocyanides bearing alkyl groups
such as cyclohexyl and benzyl gave the corresponding products (10a, 10b, 11a, 11b) in
moderate yields. Methyl isocyanoacetate, combined with the standard substrate and the
methyl-substituted derivative, provided four desired products (12a, 12b, 13a, 13b) in
moderate to good yields. Several aryl isocyanides, including 4-anisyl and 2-naphthyl
group, could serve as tolerable substrates in the transformation for the successful
production of the corresponding products (14a-17a, 14b-17b).
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N
5
6
7
NaOH
N
Ts
O
N
N
O
O
EtOH, rt, 12h, 81%
O
N
H
O
3a
18
8
9
N
10
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N
O
Ph
O
N
N
O
O
NaOH
EtOH, rt, 12h, 77%
Ph
N
H
11a
19
N
80% NH2NH2 aq
N
O
Ph
O
N
N
O
O
MeOH, rt, 12h, 63%
Ph
N
H
11a
19
N
AlCl3
N
O
Ts
O
N
N
O
O
DCE, rt, 6h, 59%
Ts
N
H
3b
20
Scheme 4. Further experiments.
To explore the synthetic utility of this methodology, two gram scale reactions
employing NHPI and NHS were carried out respectively in the presence of 1a, 2a and
DEAD for 12 h, affording 3a in 86% yield and 3b in 82% yield (the average of three
runs). Moreover, further structural derivatization of 3a and 3b was conducted (Scheme
4). The substitution of the tosyl group of 3a by ethoxy group was achieved with the aid of
NaOH, affording alkoxymethylamide 18 in 81% yield. In this reaction, to our surprise,
the imide group was spontaneously removed by the strong basic condition. When
compound 11a was treated as the reactant, the cleavage of the imide group also occurred,
affording compound 19 in 77% yield. 15 Similarly, the amide compound 19 was obtained
in 63% yield by the direct cleavage of imide group of 11a, but not by the deprotection of
phthaloyl group via hydrazinolysis.14 The cleavage of the succinimide moiety in 3b was
achieved with the treatment of Lewis acid such as AlCl3, affording amide 20 in 59%
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yield.
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7
8
9
Ar
Ar
N
N
N
COOEt
COOEt
Ar
N
N
H
A
N
HN
COOEt
COOEt
C
N
R
H
N
EtOOC
COOEt
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H
O
N
N
N
EtOOC
O
N
+
Ar
Ar
N
COOEt
DEAD
1
O
H
N
N
N
COOEt
Ar
N
EtOOC
H
R
N
R
N
O
O
O
Mumm
Ugi-type reaction
N
N
O
O
O
rearrangement
3
B
Scheme 5. Proposed mechanism.
The plausible reaction pathway was illustrated in Scheme 5. The iminium ion A was
obtained through two tandem steps: The nucleophilic addition initially occured between 1
and DEAD, and then the corresponding two intermediates in the bracket could be in
equilibrium with each other by an intramolecular hydrogen transfer and furnish the
iminium ion A, pairing with its basic counter anion (1H-DEAD anion). Next, the actived
iminium ion A readily paticipated the Ugi-type reaction with isocyanides and NHPI
(NHPI could be deprotonated by the 1H-DEAD anion), affording the intermediate B. The
subsequent Mumm rearrangement occured at the nitrogen of the imide, but not the
tertiary amine, which completed the oxidative Ugi-type reaction effectively and gave rise
to acyl hydrazide 3. Notably, during these transformations, DEAD served as the oxidant
and 1H-DEAD anion served as the base.
CONCLUSIONS
In conclution, we have developed a novel protocol for the preparation of
N-alkyl-N-acylaminophthalimide/N-alkyl-N-acylaminosuccinimide via oxidative Ugi
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reaction upon DEAD promotion, employing tertiary amine-derived iminium ion as an
imine surrogate, N-hydroxyimide as an acid surrogate. Under the mild conditions, this
surrogate-combined Ugi reaction proceeded with a broad substrate scope and desired
functional group tolerance, giving the target compounds in good yields and extending the
skeletal diversity of the products. The N-alkyl-N-acylaminophthalimide products and the
N-alkyl hydrazine derivatives, demonstrating potential for further applications in
medicinal research, are now involved in the ongoing project in our laboratory.
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EXPERIMENTAL SECTION
General Methods
1H and 13C NMR spectra were recorded on an ACF* 300Q and 500Q Bruker
spectrometer. High resolution mass spectra were recorded in electrospray ionization mass
spectrometry measurements. Reactions were monitored by TLC on silica gel 60 F254
plates. Column chromatography was carried out on silica gel (200-300 mesh). Data for
1H NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d =
doublet, t = triplet, m = multiplet or unresolved, br s = broad singlet, coupling constant
13
(s) in Hz, integration). Data for C NMR are reported in terms of chemical shift (δ,
ppm).
General procedure for synthesis of substrate 1:
2-phenyl-1,2,3,4-tetrahydroisoquinoline (1a): A two-neck flask was charged with
copper (I) iodide (1.30 g, 6.70 mmol) and potassium phosphate (28.30 g, 133.30 mmol).
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After the two-neck flask was evacuated and back filled with argon, a solution of
1,2,3,4-tetrahydroisoquinoline (12.52 mL, 100 mmol) and iodobenzene (7.43 mL, 66.70
mmol) in isopropanol (100 mL) and ethylene glycol (7.42 mL, 133.30 mmol) was added.
The mixture was heated at 90 °C for 60~90 h and then allowed to cool to room
temperature. Diethyl ether (50 mL) and water (50 mL) were added to the reaction. The
aqueous layer was extracted with diethyl ether (3 × 30 mL). The combined organic layer
was washed with brine and dried over Na2SO4. The mixture was filtered and evaporated
under reduced pressure. The residue was purified by flash chromatography (petroleum
ether/ethyl acetate = 500:1-10:1) to give 2-phenyl- 1,2,3,4-tetrahydroisoquinoline (1a)
(4.30 g, 31% yield). The other substrates 1b-g could be prepared with the above
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mentioned method. The 1H NMR data were identical with those reported in the literature.
16-18
2-phenyl-1,2,3,4-tetrahydroisoquinoline (1a):
N
1
Off-white solid, 4.30 g, 31% yield. H NMR (300 MHz, CDCl3) δ 7.32 (dd, J = 8.5, 7.5
Hz, 2H), 7.23–7.15 (m, 4H), 7.01 (d, J = 8.0 Hz, 2H), 6.86 (t, J = 7.3 Hz, 1H), 4.44 (s,
2H), 3.59 (t, J = 5.8 Hz, 2H), 3.01 (t, J = 5.8 Hz, 2H).
2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline (1b):
N
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Light yellow solid, 261 mg, 39% yield. H NMR (300 MHz, CDCl3) δ 7.37–7.08 (m,
6
7
8
9
6H), 6.95 (d, J = 8.4 Hz, 2H), 4.39 (s, 2H), 3.54 (t, J = 5.8 Hz, 2H), 3.02 (t, J = 5.7 Hz,
2H), 2.32 (s, 3H).
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2-(m-tolyl)-1,2,3,4-tetrahydroisoquinoline (1c):
N
1
Brown oil, 187 mg, 28% yield. H NMR (300 MHz, CDCl3) δ 7.25–7.12 (m, 6H),
6.88-6.79 (m, 2H), 6.68-6.63 (m, 1H), 4.43 (s, 2H), 3.58-3.55 (m, 2H), 3.10-3.02 (m,
2H), 2.37 (s, 3H).
2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (1d):
N
O
White solid, 315 mg, 44% yield. 1H NMR (300 MHz, CDCl3) δ 7.18 – 7.10 (m, 4H), 6.97
(d, J = 8.8 Hz,, 2H), 6.85 (d, J = 8.8 Hz,, 2H), 4.28 (s, 2H), 3.77 (s, 3H), 3.45-3.40 (m,
2H), 3.01-2.96 (m, 2H).
2-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (1e):
O
N
White solid, 142 mg, 20% yield. 1H NMR (300 MHz, CDCl3) δ 7.41 – 7.24 (m, 4H), 7.24
– 7.15 (m, 2H), 7.15 – 7.03 (m, 2H), 4.48 (s, 2H), 4.07 (s, 3H), 3.59 (t, J = 5.9 Hz, 2H),
3.16 (t, J = 5.9 Hz, 2H).
2-(4-bromophenyl)-1,2,3,4-tetrahydroisoquinoline (1f):
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N
5
6
Br
7
8
9
White solid, 104 mg, 12% yield. 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J = 8.8 Hz, 2H),
7.25–7.09 (m, 4H), 6.84 (d, J = 8.9 Hz, 2H), 4.38 (s, 2H), 3.54 (t, J = 5.8 Hz, 2H), 2.99 (t,
J = 5.8 Hz, 2H).
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6,7-dimethoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline (1g):
O
N
O
1
Yellow solid, 121 mg, 15% yield.. H NMR (300 MHz, CDCl3) δ 7.30 (t, J = 7.8 Hz,
2H), 6.99 (d, J = 8.2 Hz, 2H), 6.84 (t, J = 7.2 Hz, 1H), 6.66 (d, J = 3.0 Hz, 2H), 4.35 (s,
2H), 3.88 (s, 3H), 3.88 (s, 3H), 3.56 (t, J = 5.8 Hz, 2H), 2.91 (t, J = 5.7 Hz, 2H).
General Procedure for the Synthesis of Compounds 3a-17a and 3b-17b
Compound 1 (0.3 mmol), isocyanide 2 (0.33 mmol), NHPI or NHS (0.33 mmol), and
CH2Cl2 (3.0 mL) were added to a 10 mL flask. DEAD (52 μL, 58 mg, 0.33 mmol, 1.1
equiv.) was then added, and the resulting mixture was stirred at room temperature. The
reaction was monitored by TLC until complete consumption of the starting material was
observed. The solvent was directly extracted with ethyl acetate (3 x 5 mL) and the
combined organic layer was washed with saturated NaHCO3 solution (3 x 10 mL) and
brine and dried over Na2SO4. After the organic phase removed under reduced pressure,
the resulting residue was purified by flash chromatography (petroleum ether/ethyl
acetate, 20:1–2:1) to give the desired product 3a-17a and 3b-17b, which was further
purified by trituration with diethyl ether or diethyl ether/hexane.
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N-(1,3-dioxoisoindolin-2-yl)-2-phenyl-N-(tosylmethyl)-1,2,3,4-tetrahydroisoquinoline
-1-carboxamide (3a):
8
9
10
11
12
13
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N
Ts
O
N
N
O
O
White solid, 152 mg, 90%. m.p. 185–186oC; H NMR (300 MHz, CDCl3) δ 7.93 – 7.75
(m, 4H), 7.61 – 7.49 (m, 1H), 7.36 (t, J = 7.7 Hz, 2H), 7.32 – 7.26 (m, 4H), 7.26 – 7.19
(m, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 6.95 (d, J = 7.9 Hz, 2H), 5.61
(s, 1H), 4.78 (d, J = 14.5 Hz, 1H), 4.41 (d, J = 14.5 Hz, 1H), 3.89 – 3.76 (m, 1H), 3.58 –
3.40 (m, 1H), 3.23 – 3.07 (m, 1H), 3.07 – 2.90 (m, 1H), 2.34 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 164.2, 151.5, 146.6, 137.4, 137.0, 136.5, 132.7, 132.1, 131.8, 131.6, 131.6,
131.5, 131.2, 130.5, 130.1, 129.5, 126.2, 125.1, 122.2, 70.8, 62.2, 50.4, 31.1, 24.2.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C32H27N3O5S 566.1744; Found 566.1767.
N-(2,5-dioxopyrrolidin-1-yl)-2-phenyl-N-(tosylmethyl)-1,2,3,4-tetrahydroisoquinolin
e-1-carboxamide (3b):
1
N
Ts
O
N
N
O
O
White solid, 132 mg, 85% yield. m.p. 211–212oC. 1H NMR (300 MHz, CDCl3) δ 7.53 (d,
J = 7.8 Hz, 2H), 7.42 – 7.13 (m, 9H), 7.12 – 6.97 (m, 2H), 5.53 (s, 1H), 4.76 (d, J = 14.5
Hz, 1H), 4.49 (d, J = 14.5 Hz, 1H), 3.84 – 3.69 (m, 1H), 3.54 – 3.37 (m, 1H), 3.10 – 2.86
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(m, 2H), 2.69 (s, 4H), 2.48 (s, 3H). C NMR (126 MHz, CDCl3) δ 169.1, 160.6, 148.7,
6
7
8
9
144.5, 134.8, 134.5, 130.0, 129.5, 128.8, 128.6, 127.9, 127.5, 126.7, 122.3, 119.3, 68.2,
59.2, 47.3, 28.1, 25.5, 21.6. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C28H27N3O5SNa
540.1564; Found 540.1570.
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N-(1,3-dioxoisoindolin-2-yl)-2-(p-tolyl)-N-(tosylmethyl)-1,2,3,4-tetrahydroisoquinoli
ne-1-carboxamide (4a):
N
Ts
O
N
N
O
O
1
White solid, 158 mg, 91% yield. m.p. 184–186oC. H NMR (300 MHz, CDCl3) δ 7.95 –
7.76 (m, 4H), 7.61 – 7.49 (m, 1H), 7.39 – 7.26 (m, 4H), 7.25 – 7.14 (m, 3H), 7.08 (d, J =
8.2 Hz, 2H), 6.96 (d, J = 7.9 Hz, 2H), 5.55 (s, 1H), 4.81 (d, J = 14.6 Hz, 1H), 4.40 (d, J =
14.6 Hz, 1H), 3.87 – 3.73 (m, 1H), 3.50 – 3.36 (m, 1H), 3.21 – 3.07 (m, 1H), 3.07 – 2.93
13
(m, 1H), 2.36 (d, J = 2.8 Hz, 6H). C NMR (75 MHz, CDCl3) δ 163.2, 148.1, 145.3,
136.2, 135.8, 133.7, 131.6, 131.5, 130.5, 130.3, 130.0, 129.2, 128.8, 128.2, 125.0, 121.5,
69.6, 61.3, 49.6, 30.0, 23.0, 22.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C33H30N3O5S 580.1901; Found 580.1920.
N-(2,5-dioxopyrrolidin-1-yl)-2-(p-tolyl)-N-(tosylmethyl)-1,2,3,4-tetrahydroisoquinoli
ne-1-carboxamide (4b):
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N
6
7
8
Ts
O
N
N
O
O
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White solid, 127 mg, 80% yield. m.p. 186–187oC. H NMR (300 MHz, DMSO) δ 7.52
(d, J = 7.8 Hz, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.34 – 7.07 (m, 7H), 6.99 (d, J = 8.1 Hz,
2H), 5.46 (s, 1H), 4.77 (d, J = 14.5 Hz, 1H), 4.47 (d, J = 14.5 Hz, 1H), 3.84 – 3.66 (m,
1H), 3.50 – 3.29 (m, 2H), 3.13 – 2.87 (m, 1H), 2.69 (s, 4H), 2.48 (s, 3H), 2.34 (s, 3H).
13C NMR (75 MHz, CDCl3) δ 170.5, 162.2, 147.8, 145.8, 136.2, 135.9, 133.5, 131.4,
130.8, 130.2, 130.0, 129.1, 128.8, 128.0, 121.2, 69.6, 60.9, 49.3, 29.6, 26.9, 23.0, 22.0.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C29H30N3O5S 532.1901; Found 532.1914.
N-(1,3-dioxoisoindolin-2-yl)-2-(m-tolyl)-N-(tosylmethyl)-1,2,3,4-tetrahydroisoquinoli
ne-1-carboxamide (5a):
1
N
Ts
O
N
N
O
O
1
White solid, 142 mg, 82% yield. m.p. 153–155oC. H NMR (300 MHz, CDCl3) δ 7.91 –
7.76 (m, 4H), 7.62 – 7.56 (m, 1H), 7.39 – 7.16 (m, 6H), 7.07 – 6.92 (m, 4H), 6.89 (d, J =
7.5 Hz, 1H), 5.59 (s, 1H), 4.81 (d, J = 14.7 Hz, 1H), 4.45 (d, J = 14.7 Hz, 1H), 3.89 –
3.75 (m, 1H), 3.54 – 3.40 (m, 1H), 3.21 – 3.08 (m, 1H), 3.07 – 2.92 (m, 1H), 2.41 (s, 3H),
13
2.35 (s, 3H). C NMR (75 MHz, CDCl3) δ 161.52, 148.85, 143.92, 139.41, 134.82,
134.36, 133.94, 130.19, 129.31, 129.15, 129.02, 128.81, 128.50, 127.88, 127.46, 126.83,
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123.59, 123.34, 120.03, 116.44, 68.15, 59.63, 47.93, 28.58, 21.61, 21.55. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C33H30N3O5S 580.1901; Found 580.1908.
N-(2,5-dioxopyrrolidin-1-yl)-2-(m-tolyl)-N-(tosylmethyl)-1,2,3,4-tetrahydroisoquinol
ine-1-carboxamide (5b):
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N
Ts
O
N
N
O
O
White solid, 122 mg, 77% yield. m.p. 175–176oC. 1H NMR (300 MHz, CDCl3) δ 7.51 (d,
J = 7.9 Hz, 2H), 7.42 (d, J = 7.5 Hz, 1H), 7.33 – 7.12 (m, 6H), 6.98 – 6.76 (m, 3H), 5.50
(s, 1H), 4.79 (d, J = 14.6 Hz, 1H), 4.52 (d, J = 14.6 Hz, 1H), 3.83 – 3.69 (m, 1H), 3.50 –
3.34 (m, 1H), 3.12 – 2.87 (m, 2H), 2.69 (s, 4H), 2.48 (s, 3H), 2.37 (s, 3H). 13C NMR (75
MHz, CDCl3) δ 168.99, 160.52, 148.62, 144.41, 139.36, 134.81, 134.45, 130.06, 129.44,
129.28, 128.74, 128.53, 127.79, 127.54, 126.68, 123.09, 119.68, 116.12, 68.11, 59.28,
47.51, 28.25, 25.52, 21.62, 21.57. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C29H30N3O5S 532.1901; Found 532.1918.
N-(1,3-dioxoisoindolin-2-yl)-2-(4-methoxyphenyl)-N-(tosylmethyl)-1,2,3,4-tetrahydro
isoquinoline-1-carboxamide (6a):
N
Ts
O
N
N
O
O
O
1
White solid, 135 mg, 76% yield. m.p. 112–114oC. H NMR (300 MHz, CDCl3) δ 7.93 –
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7.75 (m, 4H), 7.55 – 7.45 (m, 1H), 7.40 – 7.18 (m, 6H), 7.18 – 7.07 (m, 2H), 7.02 – 6.83
(m, 4H), 5.44 (s, 1H), 4.85 (d, J = 14.6 Hz, 1H), 4.25 (d, J = 14.6 Hz, 1H), 3.84 (s, 3H),
3.77 – 3.66 (m, 1H), 3.39 – 3.27 (m, 1H), 3.23 – 3.09 (m, 1H), 3.04 – 2.91 (m, 1H), 2.34
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(d, J = 2.0 Hz, 3H). C NMR (75 MHz, CDCl3) δ 163.3, 157.6, 145.3, 144.2, 136.0,
135.7, 135.4, 131.8, 130.5, 130.3, 130.0, 129.1, 128.6, 128.2, 125.0, 124.2, 116.2, 69.5,
62.4, 56.9, 50.6, 30.3, 22.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C33H30N3O6S
596.1850; Found 596.1867.
N-(2,5-dioxopyrrolidin-1-yl)-2-(4-methoxyphenyl)-N-(tosylmethyl)-1,2,3,4-tetrahydr
oisoquinoline-1-carboxamide (6b):
N
Ts
O
N
N
O
O
O
White solid, 135 mg, 82% yield. m.p. 134–135oC. 1H NMR (300 MHz, CDCl3) δ 7.53 (d,
J = 7.8 Hz, 2H), 7.44 – 7.12 (m, 6H), 7.07 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H),
5.36 (s, 1H), 4.79 (d, J = 14.5 Hz, 1H), 4.34 (d, J = 14.5 Hz, 1H), 3.83 (s, 3H), 3.75 –
3.61 (m, 1H), 3.38 – 3.22 (m, 1H), 3.17 – 3.01 (m, 1H), 3.01 – 2.85 (m, 1H), 2.68 (s, 4H),
13
2.49 (s, 3H). C NMR (75 MHz, CDCl3) δ 170.6, 162.3, 157.4, 145.9, 144.0, 136.0,
135.9, 131.6, 130.8, 130.8, 130.2, 130.0, 129.1, 128.6, 128.0, 124.0, 116.1, 69.5, 61.9,
56.8, 50.3, 30.1, 26.9, 23.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C29H30N3O6S
548.1850; Found 548.1865.
N-(1,3-dioxoisoindolin-2-yl)-2-(2-methoxyphenyl)-N-(tosylmethyl)-1,2,3,4-tetrahydro
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isoquinoline-1-carboxamide (7a):
6
7
8
O
N
9
Ts
O
N
N
O
O
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White solid, 155 mg, 87% yield. m.p. 180–181oC. 1H NMR (300 MHz, DMSO) δ 7.81 (s,
4H), 7.43 (d, J = 6.8, 2.2 Hz, 1H), 7.36 – 7.22 (m, 6H), 7.18 (t, J = 7.8 Hz, 1H), 7.03 (t, J
= 7.6 Hz, 1H), 6.95 (t, J = 7.2 Hz, 3H), 5.86 (s, 1H), 4.87 (d, J = 14.5 Hz, 1H), 4.08 (d, J
= 14.6 Hz, 1H), 3.95 (s, 3H), 3.89 – 3.76 (m, 1H), 3.42 – 3.28 (m, 1H), 3.25 – 3.12 (m,
1H), 3.11 – 2.98 (m, 1H), 2.33 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 163.2, 155.0, 145.2,
138.9, 136.2, 135.6, 132.1, 130.5, 130.4, 130.0, 128.9, 128.6, 127.9, 126.7, 124.9, 124.8,
122.8, 113.0, 69.4, 59.2, 57.0, 48.6, 30.6, 22.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C33H30N3O6S 596.1850; Found 596.1860.
N-(2,5-dioxopyrrolidin-1-yl)-2-(2-methoxyphenyl)-N-(tosylmethyl)-1,2,3,4-tetrahydr
oisoquinoline-1-carboxamide (7b):
O
N
Ts
O
N
N
O
O
White solid, 124 mg, 76% yield. m.p. 168–169oC. 1H NMR (300 MHz, CDCl3) δ 7.52 (d,
J = 8.2 Hz, 2H), 7.37 – 7.06 (m, 8H), 7.02 – 6.85 (m, 2H), 5.75 (s, 1H), 4.73 (d, J = 14.5
Hz, 1H), 4.13 (d, J = 14.4 Hz, 1H), 3.91 (s, 3H), 3.86 – 3.70 (m, 1H), 3.37 – 3.22 (m,
1H), 3.18 – 2.93 (m, 2H), 2.60 (s, 4H), 2.47 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 170.5,
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170.0, 162.3, 154.7, 145.8, 138.9, 136.2, 136.0, 131.9, 131.1, 130.8, 130.4, 130.1, 128.9,
128.6, 128.0, 127.8, 126.6, 124.7, 122.8, 112.9, 69.4, 58.7, 56.9, 48.3, 30.4, 26.9, 23.0.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C29H30N3O6S 548.1850; Found 548.1859.
2-(4-bromophenyl)-N-(1,3-dioxoisoindolin-2-yl)-N-(tosylmethyl)-1,2,3,4-tetrahydrois
oquinoline-1-carboxamide (8a):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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49
50
51
52
53
54
55
56
57
58
59
60
N
Ts
O
N
N
O
O
Br
1
White solid, 145 mg, 75% yield. m.p. 162–164oC. H NMR (300 MHz, CDCl3) δ 7.91 –
7.78 (m, 4H), 7.62 – 7.55 (m, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.36 – 7.16 (m, 6H), 6.99
(dd, J = 17.0, 8.1 Hz, 4H), 5.55 (s, 1H), 4.78 (d, J = 14.5 Hz, 1H), 4.38 (d, J = 14.5 Hz,
1H), 3.85 – 3.72 (m, 1H), 3.52 – 3.37 (m, 1H), 3.26 – 3.07 (m, 1H), 3.07 – 2.92 (m, 1H),
13
2.36 (s, 3H). C NMR (75 MHz, CDCl3) δ 161.5, 148.1, 144.5, 134.8, 132.7, 132.5,
130.0, 129.5, 129.2, 129.0, 128.8, 128.5, 128.4, 127.7, 127.4, 127.2, 124.0, 121.0, 68.4,
59.7, 48.1, 28.8, 21.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C32H27N3O5SBr
644.0849; Found 644.0871.
2-(4-bromophenyl)-N-(2,5-dioxopyrrolidin-1-yl)-N-(tosylmethyl)-1,2,3,4-tetrahydroi
soquinoline-1-carboxamide (8b):
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5
N
6
7
8
Ts
O
N
N
O
O
Br
9
10
11
12
13
14
15
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17
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59
60
White solid, 121 mg, 68% yield. m.p. 167–168oC. 1H NMR (300 MHz, CDCl3) δ 7.49 (d,
J = 7.9 Hz, 2H), 7.46 – 7.33 (m, 3H), 7.32 – 7.07 (m, 5H), 6.90 (d, J = 8.4 Hz, 2H), 5.46
(s, 1H), 4.77 (d, J = 14.5 Hz, 1H), 4.45 (d, J = 14.6 Hz, 1H), 3.82 – 3.62 (m, 1H), 3.48 –
3.32 (m, 1H), 3.12 – 2.86 (m, 2H), 2.69 (s, 4H), 2.48 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ 170.4, 161.5, 148.9, 146.1, 135.9, 135.7, 133.7, 131.0, 130.9, 130.2, 130.0, 129.4,
128.9, 128.3, 121.7, 69.5, 60.4, 48.8, 29.6, 26.9, 23.1. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C28H27N3O5SBr 596.0849; Found 596.0855.
N-(1,3-dioxoisoindolin-2-yl)-6,7-dimethoxy-2-phenyl-N-(tosylmethyl)-1,2,3,4-tetrahy
droisoquinoline-1-carboxamide (9a):
O
N
O
Ts
O
N
N
O
O
1
Light yellow solid, 125 mg, 67% yield. m.p. 142–144oC. H NMR (300 MHz, CDCl3) δ
7.80 (d, J = 3.2 Hz, 4H), 7.36 (t, J = 7.8 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 7.14 (d, J =
7.9 Hz, 2H), 7.11 – 7.01 (m, 2H), 6.91 (d, J = 7.8 Hz, 2H), 6.64 (s, 1H), 5.45 (s, 1H),
4.70 (d, J = 14.8 Hz, 1H), 4.52 (d, J = 14.8 Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.81 –
3.66 (m, 1H), 3.41 – 3.25 (m, 1H), 3.21 – 3.04 (m, 1H), 2.85 (d, J = 15.9 Hz, 1H), 2.33
13
(s, 3H). C NMR (75 MHz, CDCl3) δ 161.8, 149.1, 148.7, 148.3, 144.0, 134.4, 133.8,
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129.5, 129.1, 128.9, 128.3, 126.6, 123.7, 123.5, 123.0, 121.6, 120.3, 110.9, 109.4, 67.9,
59.6, 56.0, 55.8, 49.7, 28.8, 21.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C34H32N3O7S 626.1955; Found 626.1962.
10
11
12
13
14
15
16
17
18
19
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59
60
N-(2,5-dioxopyrrolidin-1-yl)-6,7-dimethoxy-2-phenyl-N-(tosylmethyl)-1,2,3,4-tetrahy
droisoquinoline-1-carboxamide (9b):
O
N
O
Ts
O
N
N
O
O
Light yellow solid, 102 mg, 59% yield. m.p. 148–150oC. 1H NMR (300 MHz, CDCl3) δ
7.54 – 7.26 (m, 5H), 7.17 (t, J = 8.7 Hz, 3H), 7.06 (t, J = 7.4 Hz, 1H), 6.96 (s, 1H), 6.62
(s, 1H), 5.39 (s, 1H), 4.67 (s, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.80 – 3.63 (m, 1H), 3.40 –
3.22 (m, 1H), 3.18 – 3.02 (m, 1H), 2.95 – 2.78 (m, 1H), 2.70 (s, 4H), 2.46 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ 170.14, 162.22, 150.31, 150.04, 149.52, 145.92, 135.69,
130.84, 130.69, 129.60, 127.83, 124.33, 122.93, 121.61, 112.21, 110.74, 69.23, 60.77,
57.20, 57.19, 51.12, 30.09, 26.90, 22.97. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C30H32N3O7S 578.1955; Found 578.1967.
N-cyclohexyl-N-(1,3-dioxoisoindolin-2-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-
carboxamide (10a):
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2
3
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5
N
6
7
8
N
N
O
O
O
9
10
11
12
13
14
15
16
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59
60
1
White solid, 98 mg, 68% yield. m.p. 136–138oC. H NMR (300 MHz, CDCl3) δ 7.97 –
7.79 (m, 2H), 7.79 – 7.71 (m, 2H), 7.50 – 7.42 (m, 1H), 7.42 – 7.18 (m, 7H), 6.99 (t, J =
7.3 Hz, 1H), 5.78 (s, 1H), 4.01 (dt, J = 12.6, 6.5 Hz, 1H), 3.69 – 3.50 (m, 2H), 3.11 (t, J =
13
5.8 Hz, 2H), 1.54 – 0.60 (m, 10H). C NMR (75 MHz, CDCl3) δ 163.3, 152.4, 149.7,
135.1, 134.1, 132.1, 129.5, 129.0, 128.9, 127.4, 126.2, 123.3, 121.4, 119.5, 57.6, 55.5,
45.6, 33.8, 33.1, 28.8, 25.5, 23.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C30H30N3O3 480.2282; Found 480.2296.
N-cyclohexyl-N-(2,5-dioxopyrrolidin-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline-1
-carboxamide (10b):
N
N
N
O
O
O
1
White solid, 46 mg, 35% yield. m.p. 131–132oC. H NMR (300 MHz, CDCl3) δ 7.52 –
7.12 (m, 8H), 6.97 (t, J = 7.2 Hz, 1H), 5.72 (s, 1H), 4.07 – 3.88 (m, 1H), 3.73 – 3.43 (m,
2H), 3.23 – 2.88 (m, 2H), 2.69 (s, 4H), 1.75 – 1.61 (m, 1H), 1.57 – 1.38 (m, 3H), 1.37 –
13
1.00 (m, 4H), 0.90 (s, 2H). C NMR (75 MHz, CDCl3) δ 170.0, 151.7, 149.6, 135.1,
132.0, 129.2, 129.0, 128.8, 127.5, 127.3, 126.2, 121.3, 119.5, 57.5, 55.7, 45.3, 34.0, 33.3,
25.5, 23.8, 23.7. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H30N3O3 432.2282;
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Found 432.2291.
6
7
N-benzyl-N-(1,3-dioxoisoindolin-2-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-car
8
9
boxamide (11a):
10
11
12
13
14
15
16
17
18
19
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59
60
N
Ph
O
N
N
O
O
White solid, 98 mg, 67% yield. m.p. 86–88oC. 1H NMR (300 MHz, CDCl3) δ 7.92 – 7.76
(m, 2H), 7.76 – 7.67 (m, 2H), 7.54 (d, J = 7.0 Hz, 1H), 7.39 – 7.26 (m, 4H), 7.26 – 7.14
(m, 3H), 7.14 – 7.04 (m, 3H), 6.98 (t, J = 7.3 Hz, 1H), 6.84 (s, 2H), 5.80 (s, 1H), 4.60 (d,
J = 16.1 Hz, 1H), 4.43 (d, J = 16.2 Hz, 1H), 4.03 – 3.87 (m, 1H), 3.74 – 3.55 (m, 1H),
13
3.22 – 2.96 (m, 2H). C NMR (75 MHz, CDCl3) δ 164.4, 157.9, 150.8, 140.6, 136.6,
135.6, 132.9, 130.8, 130.7, 130.2, 129.3, 129.0, 128.8, 128.0, 128.0, 127.6, 124.9, 122.7,
120.0, 59.5, 51.9, 47.8, 30.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C31H26N3O3
488.1969; Found 488.1983.
N-benzyl-N-(2,5-dioxopyrrolidin-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-car
boxamide (11b):
N
Ph
O
N
N
O
O
White solid, 70 mg, 53% yield. m.p. 117–118oC. H NMR (300 MHz, CDCl3) δ 7.48 (s,
1
1H), 7.39 – 7.08 (m, 10H), 7.06 – 6.87 (m, 3H), 5.74 (s, 1H), 4.60 (d, J = 16.0 Hz, 1H),
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4.44 (d, J = 16.2 Hz, 1H), 4.01 – 3.82 (m, 1H), 3.72 – 3.50 (m, 1H), 3.11 – 2.95 (m, 2H),
6
7
13
2.68 (s, 4H). C NMR (75 MHz, CDCl3) δ 171.3, 157.2, 150.6, 140.9, 136.6, 132.8,
8
9
130.7, 130.2, 129.5, 129.0, 128.9, 128.2, 127.9, 127.8, 122.6, 120.0, 59.4, 52.0, 47.6,
29.7, 27.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H26N3O3 440.1969; Found
440.1980.
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Methyl N-(1,3-dioxoisoindolin-2-yl)-N-(2-phenyl-1,2,3,4-tetrahydroisoquinoline-
1-carbonyl)glycinate (12a):
N
MeOOC
O
N
N
O
O
1
White solid, 102 mg, 72% yield. m.p. 114–116oC. H NMR (300 MHz, CDCl3) δ 7.99 –
7.80 (m, 2H), 7.80 – 7.54 (m, 3H), 7.52 – 7.14 (m, 7H), 7.02 (t, J = 7.3 Hz, 1H), 5.66 (s,
1H), 4.14 (d, J = 18.0 Hz, 1H), 4.05 – 3.82 (m, 2H), 3.65 – 3.50 (m, 1H), 3.39 (s, 3H),
13
3.22 – 3.08 (m, 1H), 3.08 – 2.93 (m, 1H). C NMR (75 MHz, CDCl3) δ 173.7, 170.0,
158.1, 149.4, 135.3, 134.6, 131.3, 129.7, 129.1, 128.1, 128.0, 127.0, 123.9, 122.1, 119.2,
59.2, 51.9, 48.9, 47.6, 28.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H24N3O5
470.1710; Found 470.1730.
Methyl N-(2,5-dioxopyrrolidin-1-yl)-N-(2-phenyl-1,2,3,4-tetrahydroisoquinoline-
1-carbonyl)glycinate (12b):
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N
6
7
8
MeOOC
O
N
N
O
O
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10
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59
60
White solid, 78 mg, 62% yield. m.p. 131–132oC. 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J
= 7.0 Hz, 1H), 7.41 – 7.22 (m, 4H), 7.22 – 7.07 (m, 3H), 6.99 (t, J = 7.4 Hz, 1H), 5.60 (s,
1H), 4.15 (d, J = 18.5 Hz, 1H), 3.94 (d, J = 18.5 Hz, 1H), 3.90 – 3.78 (m, 1H), 3.59 (s,
4H), 3.17 – 2.90 (m, 2H), 2.78 (s, 4H). 13C NMR (75 MHz, CDCl3) δ 170.4, 170.2, 156.9,
149.3, 135.4, 131.1, 129.7, 129.1, 128.1, 127.0, 121.9, 118.9, 59.1, 52.1, 48.7, 47.3, 28.5,
26.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H24N3O5 422.1710; Found
422.1719.
Methyl N-(1,3-dioxoisoindolin-2-yl)-N-(2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline-
1-carbonyl)glycinate (13a):
N
MeOOC
O
N
N
O
O
White solid, 120 mg, 83% yield. m.p. 140–141oC. 1H NMR (300 MHz, CDCl3) δ 7.93 –
7.81 (m, 2H), 7.81 – 7.63 (m, 3H), 7.50 – 6.99 (m, 7H), 5.61 (s, 1H), 4.15 (d, J = 17.9
Hz, 1H), 3.94 (d, J = 18.0 Hz, 1H), 3.93 – 3.81 (m, 1H), 3.58 – 3.42 (m, 1H), 3.42 (s,
3H), 3.27 – 3.07 (m, 1H), 3.08 – 2.92 (m, 1H), 2.35 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ 169.7, 157.9, 147.0, 135.0, 134.2, 131.5, 131.0, 129.9, 129.4, 128.8, 127.6, 126.6,
123.5, 119.5, 59.2, 51.5, 48.5, 47.8, 28.6, 20.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
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for C28H26N3O5 484.1867; Found 484.1879.
6
7
Methyl N-(2,5-dioxopyrrolidin-1-yl)-N-(2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline
8
9
-1-carbonyl)glycinate (13b):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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57
58
59
60
N
MeOOC
O
N
N
O
O
White solid, 99 mg, 76% yield. m.p. 177–179oC. 1H NMR (300 MHz, CDCl3) δ 7.64 (d, J
= 7.1 Hz, 1H), 7.38 – 7.24 (m, 2H), 7.24 – 7.13 (m, 3H), 7.08 (d, J = 8.3 Hz, 2H), 5.54 (s,
1H), 4.18 (d, J = 17.6 Hz, 1H), 3.94 (d, J = 18.6 Hz, 1H), 3.89 – 3.78 (m, 1H), 3.61 (s,
13
3H), 3.54 – 3.40 (m, 1H), 3.18 – 2.91 (m, 2H), 2.79 (s, 4H), 2.33 (s, 3H). C NMR (75
MHz, CDCl3) δ 170.1, 169.9, 156.8, 146.8, 135.0, 131.3, 130.8, 129.9, 128.7, 127.6,
126.6, 119.2, 59.2, 51.7, 48.3, 47.6, 28.3, 25.6, 20.6. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C24H26N3O5 436.1867; Found 436.1874.
N-(1,3-dioxoisoindolin-2-yl)-N-(4-methoxyphenyl)-2-phenyl-1,2,3,4-tetrahydroisoqui
noline-1-carboxamide (14a):
N
O
N
N
O
O
O
White solid, 100 mg, 66% yield. m.p. 116–117oC. H NMR (300 MHz, CDCl3) δ 7.87 –
7.78 (m, 2H), 7.76 – 7.66 (m, 2H), 7.48 (d, J = 7.2 Hz, 1H), 7.41 – 7.25 (m, 4H), 7.22 (d,
J = 7.3 Hz, 1H), 7.10 – 6.88 (m, 3H), 6.65 (d, J = 8.3 Hz, 2H), 6.27 (d, J = 8.4 Hz, 2H),
1
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