Direct C-H Bond Imidation with Benzoyl Peroxide as a Mild Oxidant and a Reagent

Article abstract of DOI:10.1021/acs.joc.9b01765

A simple and mild Cu-catalyzed oxidative three-component oxidative Ugi-type method for the synthesis of a variety of substituted imides has been developed. In this direct imidation approach, benzoyl peroxide serves as both the oxidant and the carboxylate source, allowing not only the functionalization of C(sp³)-H bonds in α-position to an amine but also benzylic substrates. This procedure presents a wide substrate-type and functional group tolerance. Moreover, the mildness of the method permitted us to extend its application to the late stage functionalization of complex natural products such as the alkaloids brucine and strychnine, leading to interesting highly functionalized imide derivatives. On the basis of experimental and computational studies, a plausible mechanism has been proposed.

Full text of DOI:10.1021/acs.joc.9b01765

Subscriber access provided by Macquarie University
Article
Direct C-H Bond Imidation with Benzoyl
Peroxide as Both Mild Oxidant and Reagent
Tobias Brandhofer, Andrea Gini, Sebastian Stockerl, Dariusz G. Piekarski, and Olga Garcia Mancheno
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01765 • Publication Date (Web): 28 Aug 2019
Downloaded from pubs.acs.org on August 29, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
Direct C-H Bond Imidation with Benzoyl Peroxide as Both Mild
Oxidant and Reagent
7
8
9
Tobias Brandhofer,a,b Andrea Gini,b Sebastian Stockerl,a Dariusz G. Piekarski,a Olga García
Mancheñoa*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Institute of Organic Chemistry, University of Münster, 48149 Münster
b
Institute for Organic Chemistry, University of Regensburg, 93053 Regensburg
Phone: +49 251 83 36514, Fax: +49 251 83 36503, e-mail: olga.garcia@uni-muenster.de
Table of Contents/Abstract Graphic
Abstract
A simple and mild Cu-catalyzed oxidative three-component oxidative Ugi-type method for the
synthesis of a variety of substituted imides has been developed. In this direct imidation approach,
benzoyl peroxide serves as both the oxidant and carboxylate source, allowing not only the
functionalization of C(sp3)-H bonds in alpha position to an amine, but also benzylic substrates. This
procedure presents a wide substrate-type and functional group tolerance. Moreover, the mildness of
the method permitted to extend its applicability to the late stage functionalization of complex natural
products such as the alkaloids Brucine and Strychnine, leading to interesting highly functionalized
imide derivatives. Based on experimental and computational studies, a plausible mechanism has been
proposed.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 35
1
2
3
4
Introduction
5
6
7
8
Imides are an important class of compounds present in natural products and with a wide application
spectrum in the polymer, agrochemical and pharmaceutical industry.1 Although they are structurally
related to anhydrides, imides are more resistant toward hydrolysis, which makes them highly
interesting for the development of new drug targets less susceptible to fast biodegradation (Figure 1).
Thus, besides the more acknowledged cyclic imides, such as Lenalidomide (I)2 or Amonafine (II)3
with anti-cancer properties, acyclic imide-containing compounds have recently awakened high
interest due their rich potential in medical applications.1,4 In particular, they present interesting
activities as antibiotic (e.g. natural product Fumaramidmycin) (III)),5 anti-cancer (e.g. PI3K inhibitor
IV)6 or pulmonary hypertension treatment (e.g. endothelin antagonist V)7 agents.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
O
H
N
H2N
N
N
O
IV
PI3K inhibitor
anti-cancer agent
NH2
Lenalidomide
I
N
N
multiple myeloma treatment
N
N
O
O
NH2
N
H2N
O
N
H
III
Fumaramidmycin
MeO
antibiotic
O
O
H2N
N
N
OH
O
O
O
O
N
N
N
O
O
nPr
II
V
endothelin antagonists
pulmonary hypertension treatment
Amonafide
Leukemia treatment
Figure 1. Selected representative bioactive imides.
Considering the high applicability of imides, several approaches for their synthesis, such as by N-
alkylation, reaction of amines with the corresponding cyclic imides, amide -oxidation, and N-
acylation or C-N oxidative coupling of amides, have been developed (Scheme 1, a).8 Another
important approach relies on the variant of the Ugi multicomponent reaction with secondary amines.9
However, new straightforward methods based on C-H bond functionalization of readily available
ACS Paragon Plus Environment

Page 3 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
substrates are still highly desirable.10 In this regard, the oxidative Ugi-type reaction between amines,
isocyanides and carboxylic acids has been recently introduced as a powerful alternative (Scheme 1,
b).11 Nevertheless, the methods are restricted to amine substrates with activated -C-H bonds, leading
to bis-amides11 or imides11l depending on the substitution at the nitrogen atom.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Synthesis of imides and the oxidative Ugi-type approach.
Continuing our research program on mild, selective oxidative C-H functionalization,12 and aiming at
overcoming some of the current restrains, we have recently developed a method, in which benzylic
substrates such as acridanes 1 could now be imidated (Scheme 2).13 Thus, we have established an
original approach for the preparation of an innovative family of acridinium photocatalysts 3 based on
a Cu-catalyzed oxidative Ugi-type strategy using benzoyl peroxide (BPO) as key step.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 35
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Oxidative Ugi-type conditions for the synthesis of acridinium photocatalysts.
Herein, we present the applicability, scope and mechanism of our novel approach using benzoyl
peroxide as both mild oxidant and carboxylate reagent in oxidative Ugi-type reactions (Scheme 1, c).
This mild and robust procedure allows not only the functionalization of classical substrates with C-H
bonds in alpha position to a N-atom, but also benzylic derivatives, as well as complex alkaloid natural
products.
Results and Discussion
To test the feasibility of the method for a broad substrate scope, we decided to start our study with
the barely explored dibenzylic substrates in oxidative Ugi-reactions (Table 1). Following the initial
optimized conditions for N-methyl acridane (1a),13 several acridanes and xanthenes were subjected
to the oxidative Ugi-reaction with cyclohexyl isocynanide (2a). Thus, the reactions were carried out
using 10 mol% of Cu(OTf)2 as catalyst and 30 mol% of the 2,2’-bipyridine (bpy) ligand, in
combination with 1.2 equivalents of BPO and 2.0 equivalents of the isocyanide reagent at room
temperature. The reaction tolerated well various N-alkylic (1a, Me and 1b, Bn) and arylic (1c, Ph)
substituted acridanes, providing to the corresponding imides 3a-c in good yields (66-70%). It is
worthy to note that in the case of the N-alkyl substituted derivatives 1a and 1b, a selective addition
to the benzylic position occurred, without any substitution at the -alkyl group of the amine. Similarly,
the reaction of xanthene (1d) with 2a delivered the desired imide 3d, however the yield was
significantly lower compared to its parent nitrogen-derivative 1a (21% vs. 66%). This could be
explained due to the fact that acridanes are electron richer heterocycles than xanthenes. Therefore,
ACS Paragon Plus Environment

Page 5 of 35
The Journal of Organic Chemistry
1
2
3
methoxy substituted derivatives were next reacted under the standard conditions, leading to the
4
5
corresponding imides 3e and 3f in good yields (58 and 67%, respectively).
6
7
8
9
Table 1. Reaction with dibenzylic substratesa),b)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a)
Substrate 1 (0.2 mmol, 1.0 eq.), isocyanide 2a (2.0 eq.), benzoyl peroxide (1.2 equiv.), Cu(OTf)2
(10 mol%) and 2,2’-bipyridyl (30 mol%) in MeCN (0.1 M) at r.t. for 18 h in a pressure schlenk tube
under N2 atmosphere. b) Isolated yields.
Encouraged by these results, we continued our investigations with N-aryl tetrahydroisoquinolines
(THIQs) as typical substrates in oxidative Csp3-H functionalization (Table 2).10 We found out that
the reaction of this type of cyclic heterocycles was highly effective, allowing reducing the amount of
the isocyanide reagent from 2.0 to 1.2. equivalents and the easy scaling up of the reaction of the
prototypical N-phenyl THIQ 4a with 2a from 0.2 and 0.4 to 1 mmol (5a, 68, 85 and 74%,
respectively). Moreover, in this case other isocyanide with alkylic (2b, tBu and 2c, nBu), arylic (2d,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 35
1
2
3
4
5
6
7
8
9
2-naphtyl), benzylic (2e) or ethylacetate rests (2f) provided the corresponding imides 5b-f in good to
excellent yields (66-92%). Finally, the effect on the reactivity of various substituents at the THIQ
core or N-aryl group were explored (5g-k). Electron rich THIQs provided the products in excellent
yields (5g), while electron deficient derivatives were not efficiently enrolled in the reaction (e.g. 4h).
Conversely, both electron donating (OMe) and withdrawing (CN, F) groups at the N-aryl moiety were
well tolerated, giving consistent high yields.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Oxidative Ugi-reaction with THIQs 4a),b)
a) THIQ 4 (0.2 – 1.0 mmol, 1.0 eq.), 2 (1.2 eq.), benzoyl peroxide (1.2 eq.), Cu(OTf)2 (10 mol%) and
2,2’-bipyridyl (30 mol%) in MeCN (0.1 M) at r.t. for 18 h in a pressure schlenk tube under N2
atmosphere. b) Isolated yield.
ACS Paragon Plus Environment

Page 7 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The methodology was next extended to N,N-dimethyl anilines. It turned out that this type of
compounds reacts sluggish under the conditions given above for THIQs. Therefore, a short re-
optimization of the reaction of N,N-dimethyl aniline (6a) with isocyanide 2a was first carried out
(Table 3). While an excess of the isocyanide was crucial (entries 1-5), an increase of the amount of
peroxide (entry 6) or the use of higher concentrations (from 0.1 to 0.2 and 0.4 M, entries 7 and 8) did
not improve the yield. As a result, the best yield (entry 4, 50%) was obtained when employing 2
equivalents of 2a, as in the initial conditions for the benzylic derivatives (see Table 1).
Table 3. Re-optimization of the reaction for N,N-dimethyl anilinea)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry 2a (eq.) BPO (eq.) [M] Yield (%)b)
1
2
3
4
5
6
7
8
1.2
1.6
1.8
2.0
2.4
2.0
2.0
2.0
1.2
1.2
1.2
1.2
1.2
1.4
1.2
1.2
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.4
36
42
45
50
47
46
35
32
a)
N,N-Dimethyl aniline (6a) (0.2 mmol, 1.0 eq.), isocyanide 2a, benzoyl peroxide, Cu(OTf)2
(10 mol%) and 2,2’-bipyridyl (30 mol%) in MeCN (0.1 M) at r.t. for 18 h in a pressure schlenk tube
under N2 atmosphere. b) Isolated yield.
The scope of the reaction with anilines 6 was then investigated (Table 4). Although in systematically
inferior conversions than the THIQs 4, N,N-dimethyl anilines 6 also did react with a variety of aryl
and alkyl-substituted isocyanides 2 to form the imides 7b-f. However, the best results were obtained
with the cyclohexyl and 2-naphthyl isocyanides (50 and 59% yield; 7a and 7b, respectively).
Consequently, they were next employed in the reaction with differently para-substituted anilines. The
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 35
1
2
3
4
5
6
7
8
9
4-methyl and methoxy derivatives 7g-k were obtained in good yields (60-67%), while the anilines
bearing halogen atoms (such as bromo or fluoro) gave the products 7l-m in moderate yields. It is also
important to note that not only benzoyl peroxide but also other substituted derivatives such as lauroyl
peroxide could be used as both oxidant and carboxylic reagent, providing the imide 7h with a C11-
alkylic chain product in 45% yield. Moreover, more demanding bio-derivatives such as the N,N-
dimethyl coumarin 6n could also be enrolled, forming the imide 7n in a 38% yield. Furthermore, the
reaction with 6a and 6b as representative substrates could be efficiently carried out up to a gram-scale
(6b, 7 mmol), leading to 7a and 7g in similar good yields.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Scope of the reaction with N,N-dimethyl anilines 6a),b)
a) N,N-Dimethyl aniline 6 (0.2 mmol, 1.0 eq.), isocyanide 2 (2.0 eq.), peroxide (1.2 equiv.), Cu(OTf)2
(10 mol%) and 2,2’-bipyridyl (30 mol%) in MeCN (0.1 M) at r.t. for 18 h in a pressure schlenk tube
under N2 atmosphere. b) Isolated yield. c) 0.5 mmol scale. d) 3 mmol scale. e) 7 mmol scale.
ACS Paragon Plus Environment

Page 9 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Finally, we challenged our method with more complex molecules such as the natural products brucine
and strychnine, possessing two reactive allylic C-H bonds in alpha position to nitrogen (blue) or
oxygen (red) (Figure 2). We were delighted to observe the imidation of these alkaloids in good to
high yields (54-76%) and in a high regioselectivity towards the allylic position in alpha to the N-atom
(8 and 8’) vs. to the O-atom14 (8#) (e.g. 8a:8a’:8a# in a 3.5:1.0:1.2 ratio, and with a 78:22 d.r. for
8a/8a‘, see Exp. Sect. and S.I.). Furthermore, the Tröger’s base selectively reacted as well, delivering
the corresponding mono-imide 9 in a moderate 30% yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. C-H bond imidation of natural products.
Moreover, we probed that the imide unit could be transformed into the corresponding amide by acyl-
group elimination upon treatment with hydrazine. This was illustrated with the model THIQ-imide
product 5a, which undergoes a mild benzoyl deprotection leading to the amide 10 in a good 87%
yield (Scheme 3).
Scheme 3. Representative N-benzoyl deprotection of the imide group to the corresponding amide.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 35
1
2
3
4
5
6
7
8
9
In order to shed some light into the mechanism of this oxidative Ugi-type reaction with benzoyl
peroxide, the role of the Cu-catalyst was studied. Thus, the reaction of 6b in the absence of the
CuOTf2/bpy catalytic system under heating conditions (80 °C) for promoting the thermal homolytic
cleavage of the BPO oxidant required for the first step led to a 54% yield of the Ugi-product 7g.15
This shows that the Cu-catalyst only plays a key role in the activation of the oxidant. Moreover, a
competition experiment with 6a and 1 equivalent of BPO in the presence of 3 equivalents of p-toluic
acid was performed (Scheme 4). Then, the products 7a and 7o were obtained in a statistical 2:3 ratio
in a 46% yield, which indicates the in situ formation of 2 equivalents of benzoate from BPO during
the course of the reaction. Based on these experimental observations and previous reports,10,12b,16 the
initial oxidation of the substrate should proceed through a CuI-catalyzed homolytic cleavage of BPO
to benzoyl radical, which upon a single electron transfer (SET) forms the radical cation I (or
corresponding benzylic radical for substrates 1) and one equivalent of benzoate. Subsequently, I
suffers a second oxidation with the generated CuII-carboxylate to provide the iminium intermediate
II that further reacts with the isocyanide and free carboxylate.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 11 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
Scheme 4. Mechanistic studies and proposed first-step Cu-catalyzed C-H oxidation mechanism.
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Assuming the in situ formation of the cationic iminium intermediates and carboxylate as described
above, a density functional theory (DFT) mechanistic study was next carried out. The reaction profile
with N,N-dimethyl aniline (6a) as model substrate was analyzed computationally starting with the
iminium intermediate II as initial point (Figure 3). The calculations were performed at DFT level of
theory using the M06-2X functional17 with the 6-31++G(d,p)18 basis set within the Gaussian 09
software.19 The relative Gibbs free energies were calculated including entropic effects at 298.15K
and a 1 M concentration with corrections for low vibration modes (<100 wavenumbers)20 using the
python code21 on the top of the gas phase optimized geometries. The solvation effects of acetonitrile
were also calculated at the BP86/TZVP22 level of theory with the COSMOtherm program,23 and the
solvation energies were added to the Gibbs free energies. The connections between minima (all
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 35
1
2
3
4
5
positive frequencies) and transition states (one negative eigenvalue of the Hessian) on the Gibbs free
energy surfaces were assured by intrinsic reaction coordinate calculations. The computational study
6
7
unveiled a mechanism that proceeds via two consecutive steps according to the equation:
8
9
푟푒푎푟푟푎푛푔푒푚푒푛푡
퐴 + 퐵 + 퐶⟶(퐴퐵퐶)⟶ 푖푛푡푒푟푚푒푑푖푎푡푒
푝푟표푑푢푐푡 ퟕ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Therefore, the Gibbs free energy profiles were constructed for the reaction between three molecules:
the iminium intermediate II (A) formed from 6a upon a first oxidation with BPO, methylisocyanide
(B) and benzoate (C). We considered both a i) concerted or a ii) stepwise reaction mechanisms
involving the calculated intermediate III formed from the three components (A+B+C), which
undergoes a further Mumm-rearrangement24 leading to the product 7a. Figure T1 shows the computed
free energy profile for the most probable concerted mechanism, which presents a barrier of 5.4 kcal
mol-1 (TS1), leading to a notably more stable intermediate III (-42.2 kcal mol-1) (see S.I. for all found
pathways). The next step involves a small barrier for the rotation along the N-C-C-N and C-C-O-C
dihedral angles in TS2 (approx. 9 kcal mol-1). Finally, the product 7a is formed in a concerted step
via a Mumm-type rearrangement through a barrier (TS3) at -15.6 kcal mol-1 lower than the reference
point (see S.I. for details).
ACS Paragon Plus Environment

Page 13 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. The free reaction pathway calculated at DFT-M06-2X/6-31G(d,p) level of theory for the
reaction 6a. The relative Gibbs free energies with corrections for low frequencies and solvation
effects of acetonitrile are in kcal mol-1.
Conclusion
In summary, we have developed a general Cu-catalyzed oxidative Ugi-type three-component reaction
for the synthesis of valuable imides using benzoyl peroxide as mild oxidant and carboxylate source.
Besides the more classical substrates employed in oxidative C(sp3)-H functionalization such as
tertiary amines like tetrahydroisoquinolines or N,N-dimethylanilines, this benign method also allows
to enrol dibenzylic substrates to generate valuable imide-substituted compounds. It was also shown
that the procedure could be extended to other acyl peroxides such as lauroyl peroxide, although the
benzoyl substitution provided the best results. Moreover, the mildness of the process permitted to
extend its applicability to the late stage functionalization of complex natural products such as the
alkaloids Brucine and Strychnine, leading to demanding highly functionalized imide derivatives.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 35
1
2
3
4
5
6
7
Based on experimental and computational studies, a plausible mechanism has been proposed, in
which three weakly interacting substrate molecules form in a concerted manner a covalently bonded
intermediate that undergoes a further Mumm-type rearrangement leading to the final imide product.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
General Experimental Methods
13
13
1H and C spectra were recorded in CDCl3 (reference signals:25 1H = 7.26 ppm, C = 77.16 ppm,
CDCl3) on a Bruker ARX-300, a Bruker ARX-400 or a Jeol JNM-ECS 400 MHz. Chemical shifts ()
are given in ppm and spin-spin coupling constants (J) are given in Hz. Analytical thin layer
chromatography was performed using silica gel 60 F254 and I2 served as staining agent. Column
chromatography was performed on silica gel 60 (0.040-0.063 mm). Exact masses (HRMS) were
recorded on an Agilent Q-TOF 6540 UHD spectrometer using electrospray ionization (ESI)
techniques or on an Finnigan MAT SSQ 710 A spectrometer using electron impact (EI) techniques.
The starting materials acridanes12b and xanthenes 1,12b,26 N-aryl THIQs 427 and N,N-dimethyl anilines
628 were prepared following known literature procedures. CH3CN was distilled over CaH2.
Commercially available benzoyl peroxide contains the 30% w/w of water. In order to remove the
water, the oxidant was dissolved in ethyl acetate and the obtained solution was washed 3 times with
brine. The obtained organic phase was dried under MgSO4, filtered, the solvent evaporated and the
obtained white solid dried under vacuum. Other solvents and commercially available reagents were
used without further purification.
General procedure for the oxidative Ugi-reaction: In an oven-dried screw cap schlenk under
nitrogen atmosphere, anhydrous Cu(OTf)2 (7.2 mg, 0.02 mmol, 10 mmol%) (note: avoid moisture,
copper(II) triflate is slightly hydroscopic. The catalyst was pre-dried at 50 °C for several hours under
high vacuum), 2,2’-bipyridyne (9.4 mg, 0.06 mmol, 30 mol%) and the substrate (0.20 mmol, 1.0
equiv.) were added following this order. The mixture was dissolved in acetonitrile (0.1 M), and the
isocyanide 2 (2.0 equiv.; or 1.2 equiv. for THIQs) and benzoyl peroxide (58.1 mg, 0.24 mmol, 1.2
ACS Paragon Plus Environment

Page 15 of 35
1
The Journal of Organic Chemistry
2
3
4
5
6
7
equiv.) were then added. The obtained mixture was stirred at room temperature for 18 h. After
evaporating the solvent, the crude product was purified by flash column chromatography using a
hexane/ethyl acetate mixture as eluent.
8
9
N-benzoyl-N-cyclohexyl-10-methyl-acridane-9-carboxamide (3a): According to the general
procedure, the title product was provided after flash column chromatography (hexane/EtOAc, 9:1) as
a white solid (51.8 mg, 0.122 mmol, 61 %). 1H NMR (400 MHz, CDCl3) δ 7.77 – 7.73 (m, 2H), 7.70
– 7.64 (m, 1H), 7.59 – 7.52 (m, 2H), 7.26 – 7.20 (m, 2H), 6.96 – 6.91 (m, 2H), 6.88 – 6.83 (m, 2H),
6.76 – 6.71 (m, 2H), 4.94 (s, 1H), 4.02 (tt, J = 12.0, 3.6 Hz, 1H), 3.40 (s, 3H), 1.80 – 1.67 (m, 2H),
1.65 – 1.56 (m, 2H), 1.52 – 1.42 (m, 1H), 1.32 – 1.25 (m, 2H), 1.16 – 0.96 (m, 3H). The spectroscopic
data are in accordance with the literature.13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-benzoyl-N-cyclohexyl-10-benzyl-xanthene-9-carboxamide (3b): According to the general
procedure, the title product was provided after flash column chromatography (hexane/EtOAc, 9:1) as
a white solid (70.1 mg, 0.140 mmol, 70 %). 1H NMR (400 MHz, CDCl3) δ 7.85 – 7.75 (m, 2H), 7.75
– 7.67 (m, 1H), 7.64 – 7.55 (m, 2H), 7.33 – 7.21 (m, 3H), 7.20 – 7.15 (m, 2H), 7.14 – 7.05 (m, 2H),
6.89 – 6.82 (m, 2H), 6.79 – 6.73 (m, 4H), 5.19 (s, 2H), 5.01 (s, 1H), 4.06 (tt, J = 12.1, 3.5 Hz, 1H),1.82
– 1.69 (m, 2H), 1.67 – 1.60 (m, 2H), 1.56 – 1.47 (m, 1H), 1.34 – 1.26 (m, 2H), 1.17 – 0.99 (m, 3H).
The spectroscopic data are in accordance with the literature.13
N-benzoyl-N-cyclohexyl-10-phenyl-acridane-9-carboxamide (3c): According to the general
procedure, the title product was provided after flash column chromatography (hexane/EtOAc, 9:1) as
slightly yellow solid (68.1 mg, 0.138 mmol, 69 %). 1H NMR (400 MHz, CDCl3): δ 7.83 – 7.77 (m,
2H), 7.75 – 7.65 (m, 1H), 7.63 – 7.54 (m, 4H), 7.53 – 7.45 (m, 1H), 7.42 – 7.35 (m, 2H), 7.03 – 6.95
(m, 2H), 6.85 – 6.76 (m, 4H), 6.34 (d, J = 8.2 Hz, 2H), 5.09 (s, 1H), 4.10 (tt, J = 11.9, 3.5 Hz, 1H),
1.84 – 1.73 (m, 2H), 1.66 – 1.59 (m, 2H), 1.55 – 1.46 (m, 1H), 1.35 – 1.27 (m, 2H), 1.18 – 0.99 (m,
3H). The spectroscopic data are in accordance with the literature.13
N-Benzoyl-N-cyclohexyl-xanthene-9-carboxamide (3d): According to the general procedure, the
title product was provided after flash column chromatography (hexane/EtOAc, 9:1) as a white solid
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 35
1
2
3
4
5
6
7
8
(17 mg, 0.04 mmol, 21 %). 1H NMR (400 MHz, CDCl3) δ 7.85 – 7.81 (m, 2H), 7.72 – 7.65 (m, 1H),
7.61 – 7.54 (m, 2H), 7.27 – 7.22 (m, 2H), 7.14 – 7.11 (m, 2H), 7.04 – 6.98 (m, 2H), 6.95 – 6.91 (m,
2H), 4.98 (s, 1H), 4.05 (tt, J = 12.0, 3.6 Hz, 1H), 1.86 – 1.71 (m, 3H), 1.66 – 1.59 (m, 2H), 1.45 –
1.37 (m, 2H), 1.13 – 0.96 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 179.0, 175.3, 152.3, 133.5,
129.6, 129.5, 129.2 128.4, 123.3, 119.6, 117.3, 116.8, 59.8, 49.1, 29.8, 26.3, 25.2. HRMS (ESI-TOF):
m/z [M+H]+ Calcd for C27H26NO3 412.1907; found 412.1912.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-Benzoyl-N-cyclohexyl-3methoxy-xanthene-9-carboxamide (3e): According to the general
procedure, the title product was provided after flash column chromatography (hexane/EtOAc, 9:1) as
a white solid (53 mg, 0.12 mmol, 58 %). 1H NMR (400 MHz, CDCl3) δ 7.87 – 7.81 (m, 2H), 7.73 –
7.66 (m, 1H), 7.62 – 7.55 (m, 2H), 7.28 – 7.22 (m, 1H), 7.11 (d, J = 8.1 Hz, 1H), 7.03 – 6.98 (m, 1H),
6.95 – 6.91 (m, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 6.60 (dd, J = 8.5, 2.6 Hz, 1H),
4.92 (s, 1H), 4.07 (tt, J = 12.1, 3.1 Hz, 1H), 3.80 (s, 3H), 1.88 – 1.74 (m, 2H), 1.70 – 1.61 (m, 2H),
1.54 – 1.41 (m, 3H), 1.18 – 0.99 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ176.3, 175.2, 160.3,
153.1, 152.1, 137.2, 133.5, 129.5, 129.4, 129.0, 128.9, 128.4, 123.2, 119.8, 119.7, 117.1, 111.7, 111.6,
110.2, 102.0, 59.6, 55.5, 48.4, 29.8, 26.2, 25.2. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C28H28NO4
442.2013; found 442.2022.
N-Benzoyl-N-cyclohexyl-3,6-dimethoxy-xanthene-9-carboxamide (3f): According to the general
procedure, the title product was provided after flash column chromatography (hexane/EtOAc, 4:1) as
a white solid (63 mg, 0.13 mmol, 67 %). 1H NMR (400 MHz, CDCl3) δ 7.88 – 7.76 (m, 2H), 7.72 –
7.65 (m, 1H), 7.63 – 7.50 (m, 2H), 6.82 (d, J = 8.5 Hz, 2H), 6.66 (d, J = 2.6 Hz, 2H), 6.60 (d, J = 2.5
Hz, 1H), 6.58 (d, J = 2.6 Hz, 1H), 4.84 (s, 1H), 4.07 (tt, J = 12.0, 3.6 Hz, 1H), 1.88 – 1.74 (m, 2H),
1.69 – 1.62 (m, 2H), 1.53 – 1.42 (m, 3H), 1.19 – 1.01 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
176.7, 175.3, 160.3, 153.0, 137.3, 133.5, 129.5, 129.5, 129.0, 111.91, 110.1, 102.0, 59.7, 55.6, 47.8,
29.9, 26.3, 25.2. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C29H30NO5 472.2118; found 472.2126.
N-Benzoyl-N-cyclohexyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
(5a):
According to the general procedure, the title product was provided after flash column chromatography
ACS Paragon Plus Environment

Page 17 of 35
1
The Journal of Organic Chemistry
2
3
4
5
6
7
8
9
(hexane/EtOAc, 8:2) as an orange solid (60 mg, 0.136 mmol, 68 %). The scale-up reactions using 0.4
mmol (84 mg) and 1 mmol (209 mg) of 4a, led to the product in 85% (149 mg, 0.34 mmol) and 74%
(325 mg, 0.74 mmol), respectively. 1H NMR (300 MHz, CDCl3) δ 7.41 (d, J = 7.2 Hz, 2H), 7.30 –
7.22 (m, 2H), 7.18 – 7.05 (m, 4H), 6.95 – 6.85 (m, 3H), 6.66 (t, J = 7.3 Hz, 1H), 6.32 (d, J = 8.0 Hz,
2H), 4.93 (s, 1H), 4.10 (tt, J = 11.7, 3.2 Hz, 1H), 3.63 – 3.46 (m, 1H), 3.22 (ddd, J = 13.9, 11.1, 4.6
Hz, 1H), 2.62 (ddd, J = 16.6, 11.1, 5.6 Hz, 1H), 2.48 (d, J = 15.1 Hz, 1H), 2.01 (qd, J = 12.1, 3.2 Hz,
1H), 1.84 – 1.57 (m, 5H), 1.49 (d, J = 11.5 Hz, 1H), 1.27 – 0.94 (m, 3H). 13C{1H} NMR (75 MHz,
CDCl3) δ 173.6, 171.5, 146.4, 135.0, 134.4, 132.4, 131.6, 130.1, 128.8, 128.7, 128.1, 127.5, 125.8,
120.7, 116.6, 61.1, 58.6, 44.6, 31.6, 29.2, 26.3, 25.4, 25.2. HRMS (ESI-TOF): m/z [M + H]+ Calcd
for C29H31N2O2 439.2380; found 439.2407.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-Benzoyl-N-(tert-butyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
(5b):
According to the general procedure, the title product was provided after flash column chromatography
(hexane/EtOAc, 9:1) as a yellow solid (120 mg, 0.29 mmol, 72 %). 1H NMR (400 MHz, CDCl3) δ
7.60 – 7.48 (m, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.26 – 7.12 (m, 4H), 7.08 (td, J = 7.4, 1.2 Hz, 1H), 6.92
– 6.79 (m, 3H), 6.66 (t, J = 7.3 Hz, 1H), 6.09 (d, J = 8.0 Hz, 2H), 4.97 (s, 1H), 3.30 – 3.20 (m, 1H),
3.17 – 3.03 (m, 1H), 2.53 (dd, J = 11.7, 5.6 Hz, 1H), 2.46 – 2.39 (m, 1H), 1.43 (s, 9H). 13C{1H} NMR
(100 MHz, CDCl3) δ 172.6, 170.5, 145.0, 136.3, 134.3, 132.5, 131.8, 130.5, 128.9, 128.8, 128.6,
128.0, 127.5, 125.8, 120.8, 116.7, 61.2, 59.2, 44.8, 28.7, 25.2. HRMS (ESI-TOF): m/z [M + H]+ calcd
for C27H29N2O2 413.2224; found 413.2229.
N-Benzoyl-N-butyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (5c): According to
the general procedure, the title product was provided after flash column chromatography
1
(hexane/EtOAc, 9:1) as an orange oil (107 mg, 0.26 mmol, 66 %). H NMR (400 MHz, CDCl3) δ
7.51 – 7.43 (m, 3H), 7.39 – 7.36 (m, 1H), 7.35 – 7.27 (m, 2H), 7.25 – 7.18 (m, 2H), 7.12 – 7.07 (m,
3H), 6.80 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 7.9 Hz, 2H), 5.67 (s, 1H), 3.74 – 3.59 (m, 3H), 3.56 – 3.42
(m, 1H), 2.85 – 2.72 (m, 2H), 1.63 – 1.42 (m, 2H), 1.24 (h, J = 7.4 Hz, 2H), 0.83 (t, J = 7.3 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 175.4, 173.6, 147.7, 135.0, 134.3, 132.5, 132.2, 129.1, 128.8,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 35
1
2
3
4
5
128.4, 127.7, 126.1, 120.1, 116.4, 61.2, 47.5, 44.7, 30.9, 26.2, 20.2, 13.7. HRMS (ESI-TOF): m/z [M
+ H]+ Calcd for C27H29N2O2 413.2224; found 413.2231.
6
7
8
9
N-Benzoyl-N-(naphthalene-2-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline-8-carboxamide (5d):
According to the general procedure, the title product was provided after flash column chromatography
(hexane/EtOAc, 9:1) as a colorless solid (179 mg, 0.37 mmol, 92 %). 1H NMR (400 MHz, CDCl3) δ
7.65 (dd, J = 8.9, 4.3 Hz, 2H), 7.56 – 7.52 (m, 1H), 7.44 – 7.39 (m, 3H), 7.36 – 7.29 (m, 2H), 7.29 –
7.22 (m, 2H), 7.22 – 7.16 (m, 2H), 7.12 (tt, J = 7.2, 4.3 Hz, 5H), 7.00 (dd, J = 8.8, 2.2 Hz, 1H), 6.77
(t, J = 7.3 Hz, 1H), 6.71 – 6.66 (m, 2H), 6.07 (s, 1H), 3.72 – 3.61 (m, 1H), 3.50 (dt, J = 12.3, 5.3 Hz,
1H), 2.82 (t, J = 6.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 176.4, 171.7, 148.1, 136.6, 135.6,
133.8, 133.4, 132.4, 132.3, 132.2, 129.9, 129.3, 129.2, 128.9, 128.7, 128.3, 128.0, 127.8, 126.6, 126.4,
126.0, 125.4, 120.1, 116.4, 61.6, 44.9, 27.0. HRMS (ESI-TOF): m/z [M + H]+ Calcd for C33H27N2O2
483.2067; found 483.2074.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-Benzoyl-N-benzyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (5e): According to
the general procedure, the title product was provided after flash column chromatography
(hexane/EtOAc, 9:1) as an orange solid (156 mg, 0.35 mmol, 88 %). 1H NMR (400 MHz, CDCl3) δ
7.34 – 7.21 (m, 5H), 7.16 – 7.08 (m, 7H), 7.06 – 7.01 (m, 2H), 6.99 (d, J = 7.4 Hz, 2H), 6.70 (t, J =
7.3 Hz, 1H), 6.53 (d, J = 8.5 Hz, 2H), 5.58 (s, 1H), 4.86 (d, J = 14.9 Hz, 1H), 4.74 (d, J = 14.9 Hz,
1H), 3.53 (dt, J = 13.0, 5.2 Hz, 1H), 3.34 (ddd, J = 13.0, 8.8, 5.5 Hz, 1H), 2.77 – 2.52 (m, 2H).
13C{1H} NMR (100 MHz, CDCl3) δ 175.7, 173.6, 147.7, 137.1, 135.3, 134.5, 132.4, 132.1, 129.1,
129.0, 128.8, 128.7, 128.5, 128.4, 128.3, 127.8, 127.6, 126.2, 120.0, 116.1, 61.5, 50.7, 44.7, 26.1.
HRMS (ESI-TOF): m/z [M + H]+ Calcd for C30H27N2O2 447.2067; found 447.2070.
Ethyl
N-benzoyl-N-(2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonyl)glycinate
(5f):
According to the general procedure, the title product was provided after flash column chromatography
(hexane/EtOAc, 9:1) as a yellow solid (169 mg, 0.38 mmol, 76 %). 1H NMR (400 MHz, CDCl3) δ
7.62 – 7.58 (m, 2H), 7.47 – 7.41 (m, 1H), 7.34 – 7.30 (m, 1H), 7.29 – 7.24 (m, 2H), 7.22 – 7.18
(m, 2H), 7.10 – 7.04 (m, 3H), 6.82 – 6.75 (m, 1H), 6.61 (d, J = 7.9 Hz, 2H), 5.65 (s, 1H), 4.43 (d, J =
ACS Paragon Plus Environment

Page 19 of 35
1
The Journal of Organic Chemistry
2
3
4
5
6
7
8
9
17.2 Hz, 1H), 4.26 (d, J = 17.2 Hz, 1H), 4.14 (qd, J = 7.1, 2.5 Hz, 2H), 3.74 – 3.65 (m, 1H), 3.61
(ddd, J = 13.1, 8.6, 6.0 Hz, 1H), 2.80 – 2.73 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 175.7, 172.8, 168.6, 147.8, 135.2, 133.9, 132.7, 131.7, 129.2, 129.1, 128.9, 128.8,
128.5, 127.8, 126.1, 120.3, 116.5, 61.6, 61.3, 48.3, 45.0, 25.9, 14.2. HRMS (ESI-TOF): m/z [M + H]+
Calcd for C27H27N2O4 443.1971; found 443.2003.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-Benzoyl-6,7-dimethoxy-N-(naphthalen-2-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-
carboxamide (5g): According to the general procedure, the title product was provided after flash
1
column chromatography (hexane/EtOAc, 9:1) as a brown solid (185 mg, 0.34 mmol, 84 %). H NMR
(400 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.43
– 7.40 (m, 2H), 7.38 (s, 1H), 7.23 – 7.15 (m, 5H), 7.12 (s, 1H), 6.97 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H),
6.72 (d, J = 8.2 Hz, 2H), 6.67 (s, 1H), 6.03 (s, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 3.72 – 3.66 (m, 1H),
3.59 – 3.52 (m, 1H), 2.80 (t, J = 5.7 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 176.4, 171.5, 148.7,
147.9, 147.6, 136.5, 133.6, 133.4, 132.3, 132.1, 130.0, 129.3, 129.2, 128.3, 127.9, 127.7, 126.6, 126.5,
125.8, 125.2, 123.8, 119.9, 116.3, 111.6, 111.3, 61.1, 55.9, 55.9, 45.2, 26.3. HRMS (ESI-TOF): m/z
[M + H]+ Calcd for C35H31N2O4 543.2284 ; found 543.2293.
N-benzoyl-2-(2-cyanophenyl)-N-cyclohexyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (5i):
According to the general procedure, the title product was provided after flash column chromatography
(hexane/EtOAc, 9:1) as a yellow solid (137 mg, 0.27 mmol, 67 %). 1H NMR (400 MHz, CDCl3) δ
7.74 (dd, J = 7.9, 4.0 Hz, 2H), 7.64 (dt, J = 8.6, 1.8 Hz, 3H), 7.51 – 7.45 (m, 2H), 7.45 – 7.38 (m,
3H), 7.38 – 7.31 (m, 1H), 7.30 – 7.26 (m, 3H), 7.26 – 7.21 (m, 3H), 7.16 (dd, J = 5.3, 3.7 Hz, 1H),
6.96 (td, J = 7.6, 1.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.06 (s, 1H), 4.03 (dd, J = 7.8, 4.2 Hz, 2H),
2.86 – 2.72 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 175.2, 173.1, 153.2, 136.4, 135.3, 134.6,
134.0, 133.7, 133.3, 132.4, 132.3, 131.1, 130.2, 129.6, 129.5, 129.2, 128.5, 128.4, 128.1, 127.9, 127.8,
127.6, 127.2, 126.8, 126.6, 126.5, 125.9, 122.5, 121.0, 118.4, 105.9, 62.6, 46.9, 26.3. HRMS (ESI-
TOF): m/z [M + H]+ Calcd for C34H26N3O2 508.2025; found 508.2037.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 35
1
2
3
N-Benzoyl-2-(4-methoxyphenyl)-N-(naphthalene-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-
4
5
6
7
8
9
carboxamide (5j): According to the general procedure, the title product was provided after flash
column chromatography (hexane/EtOAc, 9:1) as a brown solid (174 mg, 0.34 mmol, 86 %). 1H NMR
(400 MHz, CDCl3) δ 7.78 – 7.63 (m, 1H), 7.60 (dd, J = 9.0, 3.0 Hz, 2H), 7.51 – 7.47 (m, 1H), 7.44
(d, J = 5.6 Hz, 1H), 7.38 – 7.30 (m, 2H), 7.30 – 7.27 (m, 2H), 7.26 – 7.20 (m, 2H), 7.13 – 7.10 (m,
2H), 7.09 – 7.06 (m, 2H), 7.01 – 6.97 (m, 1H), 6.58 – 6.53 (m, 2H), 6.46 – 6.40 (m, 2H), 5.70 (s, 1H),
3.57 (s, 3H), 3.52 (ddd, J = 10.3, 7.4, 5.1 Hz, 1H), 3.36 – 3.26 (m, 1H), 2.75 – 2.53 (m, 2H). 13C{1H}
NMR (100 MHz, CDCl3) δ 175.8, 170.9, 154.4, 141.7, 136.3, 135.1, 133.7, 133.4, 132.6, 132.1,
131.9, 131.8, 130.1, 129.3, 129.2, 128.9, 128.8, 128.2, 127.9, 127.7, 127.2, 126.6, 126.5, 125.2, 119.4,
114.5, 61.8, 55.6, 46.0, 26.2. HRMS (ESI-TOF): m/z [M + H]+ Calcd for C34H29N2O3 513.2173;
found 513.2189.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-Benzoyl-2-(4-fluorophenyl)-N-(naphthalene-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-
carboxamide (5k): According to the general procedure, the title product was provided after flash
column chromatography (hexane/EtOAc, 9:1) as a brown solid (165 mg, 0.33 mmol, 83 %). 1H NMR
(400 MHz, CDCl3) δ 7.66 (d, J = 8.9 Hz, 2H), 7.58 – 7.52 (m, 1H), 7.51 – 7.44 (m, 2H), 7.39 (dd, J
= 6.8, 2.1 Hz, 1H), 7.36 – 7.31 (m, 2H), 7.31 – 7.25 (m, 2H), 7.24 – 7.12 (m, 4H), 7.10 (dd, J = 7.1,
1.9 Hz, 1H), 7.05 (dd, J = 8.8, 2.2 Hz, 1H), 6.77 (dd, J = 9.1, 8.3 Hz, 2H), 6.53 (dd, J = 9.1, 4.4 Hz,
2H), 5.88 (s, 1H), 4.00 – 3.55 (m, 1H), 3.52 – 3.21 (m, 1H), 2.76 (dd, J = 7.2, 4.9 Hz, 2H). 13C{1H}
NMR (100 MHz, CDCl3) δ 176.0, 171.4, 158.7, 156.3, 144.3, 136.4, 135.2, 133.7, 133.4, 132.7,
132.2, 131.7, 130.0, 129.4, 129.2, 128.9, 128.4, 128.0, 127.9, 127.8, 126.7, 126.6, 126.4, 125.7, 125.2,
19
118.4, 118.3, 115.8, 115.6, 61.8, 45.9, 26.4. F NMR (376 MHz, CDCl3) δ -123.88. HRMS (ESI-
TOF): m/z [M + H]+ Calcd for C33H26FN2O2 501.1973; found 501.1979.
N-Cyclohexyl-N-(N-methyl-N-phenylglycyl)benzamide (7a): According to the general procedure,
the title product was provided after flash column chromatography (hexane/EtOAc, 9:1) as a yellow
oil (35 mg, 0.10 mmol, 50 %). The scale-up reaction using 0.5 mmol (61 mg) of 6a led to the product
in 53% (93 mg, 0.27 mmol). 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.47 (m, 3H), 7.30 (t, J = 7.8 Hz,
ACS Paragon Plus Environment

Page 21 of 35
1
The Journal of Organic Chemistry
2
3
4
5
6
7
8
9
2H), 7.14 (td, J = 7.4, 1.9 Hz, 2H), 6.78 (t, J = 7.3 Hz, 1H), 6.43 (d, J = 7.9 Hz, 2H), 3.99 (tt, J =
11.9, 3.4 Hz, 1H), 3.86 (s, 2H), 2.60 (s, 3H), 1.91 (qd, J = 12.5, 12.1, 3.6 Hz, 2H), 1.72 (m, 4H), 1.22
– 1.16 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ 174.2, 173.2, 133.0, 130.2, 129.2, 129.1, 128.6,
122.1, 118.8, 113.5, 58.8, 58.4, 40.1, 30.1, 26.4, 25.3. HRMS (ESI-TOF): m/z [M + H]+ Calcd for
C22H27N2O2 351.2073; found 351.2076.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(N-Methyl-N-phenylglycyl)-N-(naphthalen-2-yl)benzamide (7b): According to the general
procedure, the title product was provided after flash column chromatography (hexane/EtOAc, 9:1) as
an orange oil (47 mg, 0.12 mmol, 58 %). 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J = 10.8, 7.7 Hz,
2H), 7.69 – 7.62 (m, 1H), 7.45 – 7.40 (m, 5H), 7.32 – 7.23 (m, 4H), 7.11 (t, J = 7.7 Hz, 2H), 6.84 (t,
J = 7.3 Hz, 1H), 6.69 (d, J = 8.4 Hz, 2H), 4.46 (s, 2H), 2.89 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ 176.1, 172.1, 148.7, 136.0, 133.5, 133.1, 132.6, 132.3, 130.0, 129.6, 129.4, 128.3, 128.0, 127.8,
126.7, 126.7, 125.9, 125.3, 118.3, 112.8, 58.6, 40.7. HRMS (ESI-TOF): m/z [M + H]+ Calcd for
C26H23N2O2 395.1754; found 395.1776.
N-(4-Methoxyphenyl)-N-(N-methyl-N-phenylglycyl)benzamide (7c): According to the general
procedure, the title product was provided after flash column chromatography (hexane/EtOAc, 9:1) as
a red oil (34 mg, 0.09 mmol, 44 %). 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.31 (m, 3H), 7.27 – 7.21
(m, 2H), 7.20 – 7.14 (m, 2H), 6.98 – 6.92 (m, 2H), 6.83 – 6.75 (m, 3H), 6.69 – 6.64 (m, 2H), 4.42 (s,
13
2H), 3.71 (s, 3H), 2.90 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 176.1, 172.2, 158.9, 148.8,
133.59, 132.4, 131.1, 129.9, 129.3, 128.8, 128.2, 118.0, 114.8, 112.7, 58.6, 55.5, 40.6. HRMS (ESI-
TOF): m/z [M + H]+ Calcd for C23H23N2O3 375.1709; found 375.1710.
N-Butyl-N-(N-methyl-N-phenylglycyl)benzamide (7d): According to the general procedure, the
title product was provided after flash column chromatography (hexane/EtOAc, 9:1) as a yellow oil
(26 mg, 0.08 mmol, 38 %). 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.47 (m, 3H), 7.38 (t, J = 7.7 Hz,
2H), 7.18 (dd, J = 8.6, 7.4 Hz, 2H), 6.76 (t, J = 7.3 Hz, 1H), 6.54 (d, J = 8.3 Hz, 2H), 4.18 (s, 2H),
3.65 – 3.58 (m, 2H), 2.82 (s, 3H), 1.51 (ddt, J = 12.5, 7.7, 3.9 Hz, 2H), 1.21 (tq, J = 14.8, 7.7 Hz,
2H), 0.81 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 175.0, 174.1, 148.8, 134.3, 132.7,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 35
1
2
3
4
130.3, 129.2, 128.8, 118.1, 112.9, 58.6, 46.9, 40.3, 31.1, 20.1, 13.7. HRMS (ESI-TOF): m/z [M + H]+
Calcd for C20H25N2O2 325.1916; found 325.1924.
5
6
7
8
9
N-(tert-Butyl)-N-(N-methyl-N-phenylglycyl)benzamide (7e): According to the general procedure,
the title product was provided after flash column chromatography (hexane/EtOAc, 9:1) as a yellow
oil (23 mg, 0.07 mmol, 36 %). 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, J = 8.2, 1.0 Hz, 2H), 7.50 –
7.39 (m, 1H), 7.23 (t, J = 7.9 Hz, 2H), 7.09 (td, J = 7.3, 2.0 Hz, 2H), 6.75 (t, J = 7.3 Hz, 1H), 6.32 (d,
J = 8.1 Hz, 2H), 3.83 (s, 2H), 2.52 (s, 3H), 1.45 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ 173.8,
172.5, 148.2, 135.5, 133.3, 129.3, 129.0, 128.4, 118.6, 113.1, 59.6, 58.9, 39.6, 28.5. HRMS (ESI-
TOF): m/z [M + H]+ Calcd for C20H25N2O2 325.1916; found 325.1940.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-Benzyl-N-(N-methyl-N-phenylglycyl)benzamide (7f): According to the general procedure, the
title product was provided after flash column chromatography (hexane/EtOAc, 9:1) as a yellow oil
(25 mg, 0.07 mmol, 33 %). 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.47 (m, 1H), 7.43 (dd, J = 8.2, 1.2
Hz, 2H), 7.34 (t, J = 7.7 Hz, 2H), 7.26 – 7.20 (m, 3H), 7.20 – 7.13 (m, 4H), 6.76 (t, J = 7.3 Hz, 1H),
13
6.55 – 6.50 (m, 2H), 4.87 (s, 2H), 4.19 (s, 2H), 2.80 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ
175.3, 174.1, 149.1, 137.3, 134.8, 133.0, 129.6, 129.1, 129.1, 129.0, 128.5, 128.0, 118.5, 113.3, 58.9,
50.3, 40.5. HRMS (ESI-TOF): m/z [M + H]+ Calcd for C23H23N2O2 359.1760; found 359.1774.
N-Cyclohexyl-N-(N-methyl-N-(p-tolyl)glycyl)benzamide (7g): According to the general
procedure, the title product was provided after flash column chromatography (hexane/EtOAc, 9:1) as
a yellow oil (44 mg, 0.12 mmol, 60 %). The scale-up reactions using 3 mmol (406 mg) and 7 mmol
(1.0 g) of 6g, led to the product in 58% (637 mg,1.75 mmol) and 55% (1.40 g, 3.89 mmol),
respectively. 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 8.2, 1.3 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H),
7.31 (d, J = 7.7 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.36 (d, J = 8.6 Hz, 2H), 4.02 (tt, J = 12.0, 3.6 Hz,
1H), 3.79 (s, 2H), 2.53 (s, 3H), 2.24 (s, 3H), 1.88 (qd, J = 12.5, 3.7 Hz, 2H), 1.78 – 1.67 (m, 4H),
1.24 – 1.03 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ 173.9, 172.9, 145.9, 135.1, 132.90 129.6,
129.4, 129.1, 128.6, 114.2, 59.0, 58.3, 40.5, 30.2, 26.4, 25.3, 20.5. HRMS (ESI-TOF): m/z [M + H]+
Calcd for C23H29N2O3 365.2224; found 365.2241.
ACS Paragon Plus Environment

Page 23 of 35
1
The Journal of Organic Chemistry
2
3
4
5
6
7
8
9
N-Cyclohexyl-N-(N-methyl-N-(p-tolyl)glycyl)dodecanamide (7h): According to the general
procedure, the title product was provided after flash column chromatography (hexane/EtOAc, 10:1)
as a yellow oil (40 mg, 0.09 mmol, 45 %). 1H NMR (300 MHz, CDCl3) δ 7.01 (d, J = 8.2 Hz, 2H),
6.56 (d, J = 8.7 Hz, 2H), 4.31 (s, 2H), 3.73 – 3.62 (tt, J = 12.2, 3.4 Hz, 1H), 2.98 (s, 3H), 2.49 (t, J =
7.5 Hz, 2H), 2.23 (s, 3H), 2.17 (m, 2H), 1.83 – 1.78 (m, 2H), 1.64 – 1.60 (m, 4H), 1.30 (m, 4H), 1.26
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(m 18H), 0.88 (t, J = 6.3 Hz, 3H). C{1H} NMR (75 MHz, CDCl3) δ 177.7, 171.2, 130.7, 130.3,
127.2, 122.7, 55.0, 45.6, 37.3, 33.9, 32.0, 31.1, 29.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 25.8, 25.7,
24.9, 22.8, 14.3. HRMS (ESI-TOF): m/z [M + H]+ Calcd for C28H47N2O2 443.3638; found 443.3657.
N-(N-Methyl-N-(p-tolyl)glycyl)-N-(naphthalen-2-yl)benzamide (7i): According to the general
procedure, the title product was provided after flash column chromatography (hexane/EtOAc, 9:1) as
1
a yellow oil (47 mg, 0.13 mmol, 63 %). H NMR (400 MHz, CDCl3) δ 7.76 (dd, J = 11.3, 9.1 Hz,
2H), 7.69 – 7.64 (m, 1H), 7.43 (td, J = 8.1, 2.4 Hz, 5H), 7.32 – 7.23 (m, 2H), 7.12 (t, J = 7.8 Hz, 2H),
7.08 (d, J = 8.5 Hz, 2H), 6.61 (d, J = 8.6 Hz, 2H), 4.40 (s, 2H), 2.85 (s, 3H), 2.30 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 176.6, 172.2, 146.9, 136.3, 133.8, 133.5, 132.9, 132.6, 130.4, 130.2,
129.8, 128.6, 128.3, 128.1, 127.9, 127.0, 126.1, 125.6, 113.5, 59.1, 41.1, 20.8. HRMS (ESI-TOF):
m/z [M + H]+ Calcd for C27H25N2O2 409.1916; found 409.1921.
N-Cyclohexyl-N-(N-(4-methoxyphenyl)-N-methylglycyl)benzamide (7j): According to the
general procedure, the title product was provided after flash column chromatography (hexane/EtOAc,
9:1) as a yellow oil (50 mg, 0.13 mmol, 65 %). 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.52 (m, 2H),
7.48 (t, J = 7.4 Hz, 1H), 7.31 (t, J = 7.8 Hz, 2H), 6.75 – 6.69 (m, 2H), 6.43 – 6.38 (m, 2H), 4.06 (tt, J
= 11.8, 3.4 Hz, 1H), 3.75 (s, 3H), 3.72 (s, 2H), 2.47 (s, 3H), 1.84 (dd, J = 12.3, 9.3 Hz, 2H), 1.71 (t,
J = 15.6 Hz, 4H), 1.24 – 1.03 (m, 4H). C{1H} NMR (100 MHz, CDCl3) δ 174.0, 172.5, 153.4,
13
142.5, 135.3, 132.8, 129.1, 128.5, 115.7, 114.5, 59.19, 58.1, 55.8, 40.9, 30.2, 26.4, 25.4. HRMS (ESI-
TOF): m/z [M + H]+ Calcd for C23H29N2O3 381.2178; found 381.2192.
N-(N-(4-Methoxyphenyl)-N-methylglycyl)-N-(naphthalen-2-yl) benzamide (7k): According to
the general procedure, the title product was provided after flash column chromatography
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 35
1
2
3
4
5
6
7
8
(hexane/EtOAc, 9:1) as an orange oil (55 mg, 0.13 mmol, 67 %). 1H NMR (400 MHz, CDCl3) δ 7.76
(dd, J = 10.6, 7.7 Hz, 2H), 7.68 – 7.65 (m, 1H), 7.44 (ddd, J = 9.6, 7.6, 2.3 Hz, 5H), 7.30 (t, J = 7.4
Hz, 1H), 7.22 (dd, J = 8.7, 2.0 Hz, 1H), 7.13 (t, J = 7.8 Hz, 2H), 6.91 – 6.82 (m, 2H), 6.67 – 6.64 (m,
2H), 4.36 (s, 2H), 3.80 (s, 3H), 2.82 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 174.0, 172.5, 153.4,
142.5, 135.3, 132.8, 130.6, 129.1, 128.5, 115.7, 114.5, 59.2, 58.1, 55.8, 40.9, 30.2, 26.4, 25.4. HRMS
(ESI-TOF): m/z [M + H]+ Calcd for C27H25N2O3 425.1865; found 425.1849.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(N-(4-Bromophenyl)-N-methylglycyl)-N-(naphthalen-2-yl)benzamide (7l): According to the
general procedure, the title product was provided after flash column chromatography (hexane/EtOAc,
9:1) as a yellow-brown solid (43 mg, 0.09 mmol, 4 5%). 1H NMR (400 MHz, CDCl3) δ 7.78 (dd, J =
13.0, 7.7 Hz, 2H), 7.71 – 7.65 (m, 1H), 7.48 – 7.42 (m, 5H), 7.36 – 7.33 (m, 2H), 7.31 (d, J = 7.4 Hz,
1H), 7.22 (dd, J = 8.7, 2.2 Hz, 1H), 7.16 (t, J = 7.8 Hz, 2H), 6.61 – 6.55 (m, 2H), 4.47 (s, 2H), 2.90
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 175.4, 172.1, 147.9, 135.8, 133.4, 133.1, 132.8, 132.4,
132.1, 123.0, 129.7, 129.0, 128.4, 128.0, 127.8, 127.2, 126.9, 126.8, 126.1, 125.3, 114.4, 110.3, 58.6,
40.7. HRMS (ESI-TOF): m/z [M + H]+ Calcd for C26H22BrN2O2 473.0865; found 473.0887.
N-(N-(4-Fluorophenyl)-N-methylglycyl)-N-(naphthalen-2-yl)benzamide (7m): According to the
general procedure, the title product was provided after flash column chromatography (hexane/EtOAc,
9:1) as an orange oil (33 mg, 0.08 mmol, 41 %). 1H NMR (400 MHz, CDCl3) δ 7.86 – 7.70 (m, 2H),
7.73 – 7.61 (m, 1H), 7.52 – 7.40 (m, 5H), 7.33-7.11 (m, 4H), 7.09 – 6.92 (m, 2H), 6.61 (m, 2H), 4.44
(m, 2H), 3.08 – 2.70 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 175.8, 172.0, δ 156.4 (d, J = 236.7
Hz), 145.3, 135.9, 133.5, 133.1, 132.7, 132.3, 130.0, 129.6, 129.0, 128.3, 128.0, 127.8, 126.8 (d, J =
4.0 Hz), 125.9, 125.2, 115.8 (d, J = 22.2 Hz), 114.0 (d, J = 7.4 Hz), 58.9, 41.1. 19F NMR (375 MHz,
CDCl3) δ -127.23. HRMS (ESI-TOF): m/z [M + H]+ Calcd for C26H22FN2O2 413.1665; found
413.1694.
N-Cyclohexyl-N-(N-methyl-N-(2-oxo-2H-chromen-6-yl)glycyl)benzamide (7n): According to the
general procedure, the title product was provided after flash column chromatography (hexane/EtOAc,
8:2) as a yellow oil (34 mg, 0.08 mmol, 38 %). 1H NMR (300 MHz, CDCl3) δ 7.57 – 7.49 (m, 4H),
ACS Paragon Plus Environment

Page 25 of 35
1
The Journal of Organic Chemistry
2
3
4
5
6
7
8
9
7.38 – 7.31 (m, 2H), 7.14 (d, J = 9.1 Hz, 1H), 6.64 (dd, J = 9.1, 3.0 Hz, 1H), 6.44 (d, J = 3.0 Hz, 1H),
6.40 (dd, J = 9.5, 3.0 Hz, 1H), 3.99 (tt, J = 11.9, 3.6 Hz, 1H), 3.91 (s, 2H), 2.66 (s, 3H), 1.97 – 1.83
(m, 2H), 1.82 – 1.63 (m,4H), 1.27 – 1.08 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ 173.4, 161.3,
159.1, 147.4, 145.4, 143.6, 134.8, 133.7, 129.2, 128.8, 119.2, 117.9, 117.4, 117.2, 110.5, 58.9, 58.8,
40.5, 30.2, 26.3, 25.3. HRMS (ESI-TOF): m/z [M + H]+ Calcd for C25H27N2O4 419.1971; found
419.1970.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4aR,4a1R,5aS,8aR,8a1S,15aS)-N-Benzoyl-N-cyclohexyl-10,11-dimethoxy-14-oxo-
2,4a,4a1,5,5a,
7,8,8a1,15,15a
decahydro-14H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-
de]pyrrolo[2,3-h]quinoline-16-carboxamide (8a): According to the general procedure, the title
product was provided after flash column chromatography (DCM + 1% NEt3) as a white solid (87 mg,
0.14 mmol, 76 %) as a 3.5:1.0:1.2 mixture of isomers 8a:8a’:8a# and in a diastereomeric ratio of
78:22 (8a:8a’). The scale-up reaction using 0.5 mmol (197 mg) of brucine led to the product in 78%
(243 mg, 0.39 mmol) and the same isomeric distribution. HRMS (ESI-TOF): m/z [M + H]+ Calcd for
C37H42N3O6 624.3074; found 624.3076.
The diasteroisomers (C16-epimers) 8a and 8a’ were isolated using a preparative Knauer-HPLC
(Nucleodur 100-10 C18sec, CH3CN:H2O 99:1, flow rate 2.5 mL/min):
1
8a (major isomer): H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.48 – 7.39 (m, 5H), 6.67 (s, 1H),
5.68 (t, J = 7.5 Hz, 1H), 4.58 (tt, J = 11.7, 3.8 Hz, 1H), 4.26 (dt, J = 8.5, 3.3 Hz, 1H), 4.06 (dd, J =
14.0, 7.0 Hz, 1H), 3.97 – 3.92 (m, 1H), 3.92 – 3.90 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.81 (d, J =
10.8 Hz, 1H), 3.13 – 3.10 (m, 1H), 3.09 – 3.05 (m, 1H), 2.62 – 2.59 (m, 1H), 2.59 – 2.55 (m, 1H),
2.32 – 2.26 (m, 1H), 2.10 (d, J = 13.7 Hz, 1H), 2.05 – 2.01 (m, 1H), 1.96 – 1.91 (m, 2H), 1.88 – 1.84
(m, 2H), 1.73 – 1.69 (m, 2H), 1.63 – 1.59 (m, 2H), 1.55 (dt, J = 10.8, 3.4 Hz, 1H), 1.50 (d, J = 14.8
Hz, 1H), 1.39 – 1.34 (m, 2H), 1.18 – 1.14 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 173.4, 167.7,
158.4, 149.3, 145.3, 139.3, 139.0, 138.1, 135.8, 131.4, 128.3, 121.2, 109.7, 100.3, 78.0, 68.7, 64.8,
60.9, 57.1, 56.8, 56.2, 56.0, 51.3, 47.5, 46.3, 42.3, 42.0, 33.9, 33.2, 33.1, 31.4, 30.9, 26.6, 26.4, 25.6,
25.3, 24.9.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 35
1
2
3
4
5
6
7
8
8a’ (minor diastereoisomer): 1H NMR (600 MHz, CDCl3) δ 7.72 (s, 1H), 7.65 (d, J = 7.4 Hz, 2H),
7.54 (d, J = 7.6 Hz, 3H), 6.84 (s, 1H), 6.08 – 6.06 (m, 1H), 4.67 – 4.61 (m, 1H), 4.33 (dd, J = 14.3,
7.2 Hz, 1H), 4.26 (d, J = 8.9 Hz, 1H), 4.20 (d, J = 6.2 Hz, 1H), 4.14 (d, J = 7.3 Hz, 1H), 4.00 (d, J =
9.0 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.67 (d, J = 10.4 Hz, 1H), 3.58 (d, J = 6.1 Hz, 1H), 3.25 –
3.23 (m, 1H), 3.21 (d, J = 3.6 Hz, 1H), 3.11 – 3.06 (m, 2H), 2.93 (dd, J = 15.1, 6.5 Hz, 1H), 2.87 –
2.82 (m, 2H), 2.60 (dd, J = 17.6, 3.0 Hz, 2H), 2.16 – 2.12 (m, 2H), 1.81 – 1.77 (m, 4H), 1.57 – 1.55
(m, 2H), 1.13 (d, J = 11.7 Hz, 2H). 13C{1H} NMR (150 MHz, CDCl3) δ 179.7, 177.5, 174.0, 167.1,
147.4, 146.1, 144.2, 134.8, 129.3, 128.6, 127.9, 123.9, 104.2, 100.0, 99.8, 98.9, 82.9, 67.1, 63.2, 55.6,
55.5, 55.4, 52.0, 51.7, 48.4, 47.9, 41.5, 41.2, 40.7, 38.7, 30.1, 29.7, 28.8, 25.3, 25.3, 24.8, 24.0.
The isomeric compound 8a# (benzylic and alpha to O-atom) could not be isolated and characterized
due to decomposition during the purification process.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4aR,4a1R,5aS,8aR,8a1S,15aS)-N-Benzoyl-N-cyclohexyl-14-oxo-2,4a,4a1,5,5a,7,8,8a1,15,15a-
decahydro-14H-4,6-methanoindolo[3,2,1-ij]oxepino[2,3,4-de]pyrrolo[2,3-h]quinoline-16-
carboxamide (8b): According to the general procedure, the title product was provided after flash
column chromatography (DCM + 1% NEt3) as a white solid (62 mg, 0.11 mmol, 54 %) as a 2.5:1.4:1.0
mixture of isomers 8b:8b’:8b# and in a diastereomeric ratio of 72:28 (8b:8b’). The scale-up reaction
using 0.5 mmol (167 mg) of strychnine, led to the product in 53% (149 mg, 0.27 mmol) and the same
isomeric distribution. HRMS (ESI-TOF): m/z [M + H]+ Calcd for C35H38N3O4 564.2862; found
564.2865.
The diasteroisomers (C16-epimers) 8b and 8b’ were isolated using a preparative Knauer-HPLC
(Nucleodur 100-10 C18sec, CH3CN:H2O 99:1, flow rate 2.5 mL/min):
8b (major isomer): 1H NMR (600 MHz, CDCl3) δ 7.70 (d, J = 6.9 Hz, 1H), 7.62 – 7.59 (m, 1H), 7.52
– 7.46 (m, 3H), 7.44 – 7.40 (m, 1H), 7.25 – 7.21 (m, 1H), 7.18 (dt, J = 7.4, 1.2 Hz, 1H), 7.10 (td, J =
7.5, 1.1 Hz, 1H), 5.62 (s, 1H), 4.28 (tt, J = 12.1, 3.7 Hz, 1H), 3.94 (dt, J = 8.4, 4.2 Hz, 1H), 3.85 (dd,
J = 12.9, 11.0 Hz, 1H), 3.81 (s, 1H), 3.66 (d, J = 10.1 Hz, 1H), 3.57 (dd, J = 12.8, 6.6 Hz, 1H), 3.42
– 3.35 (m, 1H), 3.20 – 3.16 (m, 1H), 3.15 – 3.11 (m, 1H), 2.98 (dd, J = 16.6, 8.5 Hz, 1H), 2.92 – 2.89
ACS Paragon Plus Environment

Page 27 of 35
1
The Journal of Organic Chemistry
2
3
4
5
6
7
8
9
(m, 1H), 2.47 (dd, J = 16.6, 4.4 Hz, 1H), 2.23 (dt, J = 13.7, 8.5 Hz, 1H), 2.18 (dt, J = 13.5, 3.6 Hz,
1H), 2.05 (dd, J = 12.9, 4.4 Hz, 1H), 1.98 – 1.95 (m, 1H), 1.86 (ddd, J = 14.0, 10.2, 3.9 Hz, 1H), 1.83
– 1.79 (m, 2H), 1.65 – 1.61 (m, 1H), 1.55 – 1.51 (m, 1H), 1.42 (d, J = 7.9 Hz, 3H), 1.26 (d, J = 8.8
Hz, 2H), 1.20 – 1.14 (m, 1H). 13C{1H} NMR (150 MHz, CDCl3) δ 174.0, 170.3, 166.8, 141.6, 137.3,
133.8, 133.4, 131.4, 130.4, 129.5, 129.2, 128.7, 128.6, 126.9, 124.7, 122.0, 116.2, 78.2, 69.1, 64.4,
59.1, 58.5, 55.3, 53.7, 46.9, 41.3, 33.4, 32.2, 31.9, 28.8, 27.1, 26.5, 26.3, 25.7, 25.4, 24.9, 22.9.
8b’ (minor diastereoisomer): 1H NMR (600 MHz, CDCl3) δ 7.87 – 7.84 (m, 2H), 7.62 – 7.56 (m, 2H),
7.55 – 7.51 (m, 2H), 7.48 – 7.45 (m, 1H), 7.25 – 7.22 (m, 1H), 7.08 (td, J = 7.5, 1.1 Hz, 1H), 7.01
(dd, J = 7.7, 1.3 Hz, 1H), 5.92 – 5.78 (m, 1H), 4.44 (d, J = 14.2 Hz, 1H), 4.20 (dt, J = 8.4, 3.3 Hz,
1H), 4.16 – 4.06 (m, 2H), 3.97 – 3.92 (m, 1H), 3.82 (d, J = 10.5 Hz, 1H), 3.70 (dd, J = 11.5, 7.0 Hz,
1H), 3.37 (d, J = 3.3 Hz, 1H), 3.07 (dd, J = 17.3, 8.4 Hz, 1H), 2.95 (dd, J = 5.2, 2.2 Hz, 1H), 2.82 (s,
1H), 2.81 – 2.74 (m, 1H), 2.64 – 2.60 (m, 1H), 2.59 – 2.54 (m, 1H), 2.29 – 2.21 (m, 1H), 2.15 (dt, J
= 15.2, 4.4 Hz, 1H), 2.08 (t, J = 9.0 Hz, 1H), 1.95 (h, J = 3.6 Hz, 2H), 1.68 – 1.64 (m, 1H), 1.61 (d, J
= 12.9 Hz, 1H), 1.50 (d, J = 15.2 Hz, 1H), 1.45 – 1.42 (m, 1H), 1.29 (td, J = 11.3, 9.7, 4.9 Hz, 2H),
1.13 (dt, J = 13.1, 3.4 Hz, 1H). 13C{1H} NMR (150 MHz, CDCl3) δ 171.9, 169.4, 166.5, 149.3, 142.0,
137.2, 136.0, 133.6, 132.4, 130.3, 129.2, 129.0, 128.6, 128.2, 124.6, 122.5, 116.4, 77.5, 65.9, 64.5,
62.7, 59.9, 57.5, 55.7, 52.9, 49.0, 47.8, 42.4, 41.6, 31.2, 29.5, 27.5, 26.4, 26.3, 25.5.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The isomeric compound 8b# (benzylic and alpha to O-atom) could not be isolated and characterized
due to decomposition during the purification process.
N-Benzoyl-N-cyclohexyl-2,8-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-6-
carboxamide (9): According to the general procedure, the title product was provided after flash
column chromatography (hexane/EtOAc, 4:1) as a white solid (29 mg, 0.06 mmol, 29 %). 1H NMR
(400 MHz, CDCl3) δ 7.84 – 7.78 (m, 2H), 7.50 – 7.41 (m, 3H), 7.05 (d, J = 8.2 Hz, 1H), 7.00 – 6.96
(m, 1H), 6.93 – 6.88 (m, 2H), 6.65 (s, 1H), 6.51 (s, 1H), 4.86 (d, J = 17.3 Hz, 1H), 4.30 – 4.16 (m,
2H), 3.94 (d, J = 17.3 Hz, 1H), 3.80 (d, J = 16.6 Hz, 1H), 3.62 (d, J = 16.5 Hz, 1H), 2.21 (s, 3H), 2.14
(s, 3H), 1.75 – 1.64 (m, 3H), 1.56 – 1.49 (m, 2H), 1.38 – 1.31 (m, 1H), 1.23 – 1.11 (m, 3H), 1.09 –
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 35
1
2
3
4
5
6
7
8
13
1.00 (m, 1H). C{1H} NMR (100 MHz, CDCl3) δ 171.2, 170.4, 146.7, 140.7, 137.2, 134.8, 134.0,
132.3, 128.9, 128.8, 128.5, 128.3, 127.8, 127.4, 126.9, 126.8, 125.5, 125.0, 74.5, 58.2, 58.0, 53.7,
31.1, 28.8, 26.4, 25.4, 21.1. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C31H34N3O2 480.2646; found
480.2651.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Deprotection of the benzoyl group:
N-Cyclohexyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (10): In an oven-dried
screw cap schlenk under nitrogen atmosphere, the imide 5a (0.1 mmol, 1.0 equiv.) was solved in 1
mL dry THF. Then hydrazine (1 M in THF) (0.15 mmol, 1.5 equiv.) was added and the solution was
stirred at room temperature for 5 h. The solvent was removed under vacuum and the crude was
purified by flash column chromatography (hexane/EtOAc, 8:2), obtaining the product (29.1 mg, 0.087
mmol, 87 %) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 6.9, 2.1 Hz, 1H), 7.27 –
7.23 (m, 2H), 7.20 – 7.15 (m, 2H), 7.10 – 7.07 (m, 1H), 6.87 – 6.84 (m, 2H), 6.71 (d, J = 8.6 Hz, 1H),
4.89 (s, 1H), 3.81 – 3.76 (m, 1H), 3.65 (dddd, J = 10.8, 8.8, 6.8, 4.4 Hz, 1H), 3.26 (td, J = 10.7, 4.1
Hz, 1H), 3.04 – 2.85 (m, 2H), 1.82 – 1.67 (m, 2H), 1.61 – 1.44 (m, 4H), 1.11 – 0.86 (m, 4H). The
spectroscopic data are in accordance with the literature.29
Associated Content
The following file is available free of charge: Supporting Information. Competitive mechanistic
experiments, quantum chemistry calculations and proposed mechanism, copies of NMRs of the
products (PDF).
Author Information
All authors have given approval to the final version of the manuscript.
Acknowledgements
INTERREG V A, ETZ 2014-2020 - Bayern-Czech Republic (project 41) and the Deutsche
Forschungsgemeinschaft (DFG), are gratefully acknowledged for generous support. We also thank
ACS Paragon Plus Environment

Page 29 of 35
1
The Journal of Organic Chemistry
2
3
the European Cooperation in Science and Technology (COST) within the COST Action “C–H
4
5
Activation in Organic Synthesis (CHAOS)” (CA15106).
6
7
8
9
References
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1) (a) Kavitha, K.; Praveena, K. S. S.; Ramarao, E. V. V. S.; Murthy, N. Y. S.; S. Pal, Chemistry of
Cyclic Imides: An Overview on the Past, Present and Future. Curr. Org. Chem. 2016, 20, 1955-2001.
(b) Luzzio, F. A. Imides: Medicinal, Agricultural, Synthetic Applications and Natural Products
Chemistry In Developments in Organic Chemistry (Series Ed.: Smith, M. B.), Elservier, Amsterdam,
2019; and references cited therein.
(2) (a) Armoiry, X.; Aulagner, G.; Facon, T. Lenalidomide in the treatment of multiple myeloma: a
review. J. Clin. Pharm. Ther. 2008, 33, 219–226. (b) Tageja, N. Lenalidomide - Current
Understanding of Mechanistic Properties. Anti-Cancer Agents Med. Chem. 2011, 11, 315–326.
(3) See e.g.: (a) Kornek, G.; Raderer, M.; Depisch, D.; Haider, K.; Fazeny, B.; Dittrich, C.;
Scheithauer, W. Amonafide as First-line Chemotherapy for Metastatic Breast Cancer. Eur. J. Cancer
1994, 30A, 398−400. (b) Malviya, V. K.; Liu, P. Y.; O’Toole, R.; Alberts, D. S.; Surwit, E.; Rosenoff,
S.; Ward, J. H.; Yu, A.; O’Sullivan, J.; Craig, J. B. Phase II Trial of Amonafide in Patients with
Advanced Metastatic or Recurrent Endometrial Adenocarcinoma A Southwest Oncology Group
Study. Am. J. Clin. Oncol. 1994, 17, 37−40. (c) Misra, S. K.; Kampert, T. L.; Pan, D. Nano-Assembly
of Pamitoyl-Bioconjugated Coenzyme-A for Combinatorial Chemo-Biologics in Transcriptional
Therapy. Bioconjugate Chem. 2018, 29, 1419−1427.
(4) See e.g.: (a) Pettit, G. R.; Kamano, Y.; Dufresne, C.; Cerny, R. L.; Herald, C. L.; Schmidt, J. M.
Isolation and Structure of the Cytostatic Linear Depsipeptide Dolastatin 15. J. Org. Chem. 1989, 54,
6005-6006. (b) Koehn, F. E.; Longley, R. E.; Reed, J. K. Microcolins A and B, New
Immunosuppressive Peptides from the Blue-Green Alga Lyngbya Majuscule. J. Nat. Prod. 1992, 55,
613-619. (c) Nagle, D. G.; Paul, V. J.; Roberts, M. A. Ypaoamide, a New Broadly Acting Feeding
Deterrent from the Marine Cyanobacterium Lyngbya Majuscule. Tetrahedron Lett. 1996, 37, 6263-
ACS Paragon Plus Environment