Gold(I)-catalyzed benz[ c ]azepin-4-ol synthesis by intermolecular [5 + 2] cycloaddition

Article abstract of DOI:10.1021/jo401075n

A gold(I)-catalyzed intermolecular formal [2 + 5] cycloaddition for the preparation of benzofused N-heterocyclic azepine products is presented. A number of benz[c]azepin-4-ol products were readily prepared in one step from easily accessible phenylpropargyl acetals and benzaldimine substrates in the presence of a gold(I) catalyst. A direct one-pot procedure from the propargyl and the respective aldehyde and amine substrates was successful as well. The reaction to access the benzofused azepines could be rationalized by a cascade reaction, including a nucleophilic benzaldimine N-attack at a highly reactive phenylpropargyl-gold(I) carbenoid complex, generated from propargyl acetal. A subsequent deauration step promotes ring closure by 1,7-electrocyclization through an intramolecular Pictet-Spengler-type reaction with the aldiminium moiety.

Full text of DOI:10.1021/jo401075n

Subscriber access provided by UNIV OF NEBRASKA - LINCOLN
Article
Gold(I) Catalyzed Benzo[c]azepin-4-ol Synthesis
by Intermolecular [5 + 2] Cycloaddition
Naseem Iqbal, and Anne Fiksdahl
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401075n • Publication Date (Web): 01 Jul 2013
Downloaded from http://pubs.acs.org on July 13, 2013
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 free 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 accessible to all
readers and 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.
The Journal of Organic Chemistry 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 33
The Journal of Organic Chemistry
1
1
2
3
Gold(I) Catalyzed Benzo[c]azepin-4-ol Synthesis by Intermolecular [5 + 2] Cycloaddition
4
5
Naseem Iqbal and Anne Fiksdahl*
6
7
8
Department of Chemistry, Norwegian University of Science and Technology, NOꢀ7491 Trondheim, Norway
eꢀmail: anne.fiksdahl@chem.ntnu.no
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
Abstract
A gold(I) catalyzed intermolecular formal [2+5] cycloaddition for the preparation of benzofused
Nꢀheterocyclic azepine products is presented. A number of benzo[c]azepinꢀ4ꢀol products were
readily prepared in one step from easily accessible phenylpropargyl acetals and benzaldimine
substrates in the presence of a gold(I) catalyst. A direct oneꢀpot procedure from the propargyl and
the respective aldehyde and amine substrates was successful, as well. The reaction to access the
benzofused azepines could be rationalized by a cascade reaction, including a nucleophilic
benzaldimine Nꢀattack at a highly reactive phenylpropargylꢀgold(I) carbenoid complex, generated
from propargyl acetal. A subsequent deauration step promotes ring closure by 1,7ꢀ
electrocyclization through an intramolecular PictetꢀSpengler type reaction with the aldiminium
moiety.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 33
2
1
2
3
Introduction
4
5
6
7
8
9
The sevenꢀmembered ringꢀfused benzazepine heterocycles contain a framework that is often
observed among bioactive natural products and pharmaceuticals.1 Due to their chemotherapeutic
properties, exhibiting biological activity toward various targets, such as enzymes, ion channels,
and different receptors, these benzannulated compounds represent a particularly interesting class of
azaꢀheterocycles.2 Compounds containing the benzo[a, b or c]azepine skeleton, mainly at the
tetrahydro level, display important physiological properties and are known to exhibit strong
neuroleptic and neurotropic activities.3 Other representatives have been found to display antiꢀHIV
activity4, to promote healing of skin wounds5 and to treat cardiovascular diseases, especially
glaucoma and hypertension.6 Benzazepine derivatives are also used as antiarrythmic,7 CNS
agents,8 as inhibitors of PNMT,9 recommended for the treatment of stomach disorders10 and could
be used in the treatment of Alzheimer disease.11 Several substances that include the specific
benzo[c]azepine moiety possess useful biological properties.12 The commercially available
benzazepine Capsazepine A13 (Figure 1) is a competitive agonist for the vanilloid receptor (VR1),
used in treatment of neuropathic pain, while compound B is a Gramꢀpositive antibacterial agent14
and compound C is a potent histamine H3 receptor antagonist.15
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
Since several powerful drugs have been obtained from benzazepine compounds, considerable
efforts have been made to establish new methods for the synthesis of these heterocycles.2b,c,16,17
Different strategies, including the Heck16a coupling, intramolecular ClaisenꢀSchmidt cyclization,16c
Dieckmann cyclization,16d SnCl2 mediated reduction and cyclization16e and Michael type
addition16g have been applied for benzazepine synthesis, while ring closing metathesis
(RCM)16a,b,f,i, and a multistep tandem reaction16h have been used for the preparation of unsaturated
benzo[c]azepines. Most of these methods are complex and require several steps. Benzo[c]azepinꢀ4ꢀ
ones with the general structure D have been identified as selective muscarine antagonists. They
ACS Paragon Plus Environment

Page 3 of 33
The Journal of Organic Chemistry
3
1
2
3
were synthesized by reductive amination17c or by Mitsunobu conditions17d for heterocyclic
4
5
cyclization by the formation of the C1ꢀN bond. Benzo[c]azepinꢀ4ꢀones derivatives have been
6
7
8
17e
prepared by ester condensation18 and ring closure with formaldehyde.
Alternatively,
9
intramolecular acylation has afforded functionalized benzo[c]azepinꢀ4ꢀones by cyclization through
C4ꢀC5 bond formation.19 Benzo[c]azepinꢀ3ꢀones, potentially good candidates for new drug
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
therapies to treat skin wounds, were prepared via an intramolecular Friedel−Crafts reaction.
1
Compounds based on the general 4ꢀoxo structure E (2,3ꢀdihydroꢀ1Hꢀbenzo[c]azepinꢀ4(5H)ꢀone) or
the corresponding enol form E’ have been studied, due to their structure similarities with bioactive
natural alkaloids and, thus, potential biological activity. The 4ꢀoxo group would also offer
opportunities for further functionalization of the benzazepine skeleton.
HO
O
O
N
HO
H
N
O
N
HN
S
Ac
N
N
CHO
O
C
B
A
Cl
OH
R
O
OH
R
X
H
N
N
Ar
N
R
N
E
D
E'
Fig 1: Benzo[c]azepine-containing compounds
Propargyl esters are known to undergo a number of gold catalyzed [2+3], [2+4] and [3+4]
cycloaddition reactions.20 We have recently performed a comparative study on reactivity and
chemoselective gold(I) catalyzed alkenes cycloadditions of propargyl esters and acetals,
respectively.21 Such propargyl derivatives are known to give gold carbenoid intermediates (I, II,
Scheme 1) which can be trapped with different reagents, typically alkenes. By changing from
propargylic esters to acetals, the reaction pathway switches from a) cyclopropanation to b) [2+3]
cycloaddition. The propargyl acetals gave immediate conversion and were significantly more
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 33
4
1
2
3
reactive than the corresponding esters. Hence, the highly reactive propargyl acetals would be
4
5
6
7
8
9
promising substrates for potential cycloaddition reactions with other alternatives to alkenes, e.g.
heteroatom compounds with a C=X double bond. Thus, we wanted to investigate the potential of c)
imines to undergo cycloaddition reactions via the highly reactive propargyl acetal gold(I)
carbenoid complexes II (Scheme 1). Gold catalysis has been applied for azepine synthesis by
intramolecular hydroamination16i and [3+4] cycloadditions.20e,f However, to the best of knowledge,
neither cycloaddition, nor gold(I) catalysis have been applied in benzazepine synthesis. We herein
report the results from our study of gold(I) catalyzed cyclization reactions of propargyl acetals
with imines.
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. Gold(I) promoted reactions of propargyl substrates.
Results and Discussion
Aiming at trapping the highly reactive propargyl acetal gold(I) carbenoid complex II (Scheme 1)
with imines, cyclization reactions with Nꢀarylbenzaldimines, readily available from aniline and
benzaldehyde derivatives, were studied, focusing on phenylpropargyl acetals. Rapid and full
conversion of the substrates into benzo[c]azepinꢀ4ꢀol products, analogous to the enolic structure E’
above (Fig. 1) was observed. The reaction of phenylpropargyl acetal 1a with Nꢀbenzylideneaniline
ACS Paragon Plus Environment

Page 5 of 33
The Journal of Organic Chemistry
5
1
2
3
2a in DCM at room temperature in the presence of commercially available Au[P(tꢀBu)2(oꢀ
4
5
6
7
8
9
biphenyl)CH3CN]SbF6 gave full conversion into benzazepine product 3a within one hour (entry 1,
Table 1). The outcome of the reaction indicated that a new formal [2+5] cycloaddition of propargyl
acetal with aldimine through a gold carbenoid intermediate II took place.
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
Optimization. In order to optimize reaction conditions, an introductory study on the
cycloaddition of propargyl acetal 1a and diarylimine 2a was performed by using different
gold(I/III) catalysts and solvents (Table 1). The in situ generation of the active gold(I) catalyst by
ꢀ
ꢀ
chloride counterion exchange with NTf2 or SbF6 afforded more active catalytic systems, since full
conversion was obtained in 15 minutes, both in DCM and DCE (entries 3, 4, 11). Triphenyl
phosphine liganded gold catalysts (Au(PPh3)Cl + AgSbF6, entry 8) gave low conversion (24%) as
compared to the biphenylphosphine complex above. No reaction took place without chloride
counterion exchange (entries 2, 7). The cycloaddition reaction was not catalyzed by silver salts
(entries 5, 6) and gold (III) catalysts were also found inactive for the reaction (entries 9, 10).
Reduced efficiency of the biphenylphosphine gold(I) catalyst (30ꢀ64% conversion) was observed
in other solvents, such as THF, acetonitrile, nitromethane or toluene (entries 12ꢀ15). Since DCE
would allow higher reaction temperatures, if required, this solvent was used in the further studies
on [2+5] cycloaddition of propargyl acetals and imines in the presence of the Au[P(tꢀBu)2(oꢀ
biphenyl)]Cl + AgSbF6 catalytic system (entry 11).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 33
6
1
2
3
4
5
6
7
Table 1 Reaction optimization of [5+2] cycloaddition reaction of propargyl acetal with imine.
OMe
OMe
8
9
O
OMe
O2N
Gold catalyst
Solvent, rt
N
N
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
OMe
1a
NO2
2a
3a
Conversiona
entry
Gold catalyst
Time / solvent
Au[P(tꢀBu)2(oꢀbiphenyl)]CH3CN]SbF6
Au[P(tꢀBu)2(oꢀbiphenyl)]Cl
Au[P(tꢀBu)2(oꢀbiphenyl)]Cl + AgSbF6
Au[P(tꢀBu)2(oꢀbiphenyl)]Cl + AgNTf2
AgSbF6
1h / DCM
24h / DCM
99%
ncb
1
2
15min / DCM
15min / DCM
24h / DCM
99%
99%
ncb
ncb
ncb
3
4
5
AgNTf2
24h / DCM
6
Au(PPh3)Cl
24h / DCM
7
Au(PPh3)Cl+ AgSbF6
24h / DCM
24%
ncb
ncb
8
AuCl3(III)
24h / DCM
9
PicAuCl2(III)
24h / DCM
10
11
12
13
14
15
15min / DCE
15min / THF
15min / CH3CN
15min / CH3NO2
15min / Toluene
Au[P(t-Bu)2(o-biphenyl)]Cl + AgSbF6
Au[P(tꢀBu)2(oꢀbiphenyl)]Cl + AgSbF6
Au[P(tꢀBu)2(oꢀbiphenyl)]Cl + AgSbF6
Au[P(tꢀBu)2(oꢀbiphenyl)]Cl + AgSbF6
Au[P(tꢀBu)2(oꢀbiphenyl)]Cl + AgSbF6
99%
54%
64%
45%
30%
a conversion by GC, b no conversion
Scope and limitations. By varying the electronic and steric properties of a series of
substituted Nꢀarylꢀbenzaldimine 2a-f, the scope and limitations of the new [2+5] cycloaddition
reaction was studied (Table 2). A number of O-alkylated benzo[c]azepinꢀ4ꢀol structures 3a-j were
readily formed by cyclization of propargyl methyl acetal 1a (entries 1ꢀ5) and ethyl acetal 1b
(entries 7ꢀ10) with Nꢀbenzylideneaniline derivatives 2a-e in high yields (62ꢀ80%). The double
activation of imine 2a by an electronꢀdonating p-methoxy aniline substituent and an additional p-
nitro EWG substitution at the benzylidene moiety would afford a pushꢀpull activating effect, as
shown by the fast reaction of imine 2a with acetals 1a and 1b (15ꢀ30 min, rt, entries 1 and 6). The
imines 2b-e, being only partly activated, reacted significantly slower as the pushꢀpull effect was
ACS Paragon Plus Environment

Page 7 of 33
The Journal of Organic Chemistry
7
1
2
3
reduced. Hence, the reaction rates decreased and higher temperature was required to obtain
4
5
6
7
8
9
comparable yields (1ꢀ24h, reflux, entries 2ꢀ5 and 7ꢀ10) as the electronꢀwithdrawing effect of the
benzylidene p-substituent was reduced by replacement of more ERG substituents, such as H, Cl,
OMe, tꢀBu. Correspondingly, substitution of the aniline part also affected the reactivity, as the
nonꢀmethoxy Nꢀbenzylideneaniline 2f was significantly less reactive, affording 52% yield of
benzazepine 3k (entry 11), relative to the corresponding methoxy substrate 2a (entry 1, 80%).
Moreover, it was observed that p-substitution of the phenylpropargyl acetal may influence the
activity of the propargyl substrates (see Selectivity and reactivity and Scheme 2 below). The effects
were shown by the higher yields obtained of the benzo[c]azepine products 3l-n, as the
electrophilicity of the propargyl substrate was increased (1c/OMe, 63%; 1d/Cl, 78%; 1e/NO2,
84%; entries 12ꢀ14). The ability of the benzaldimines to undergo hydrolysis was shown by the
formation of the corresponding benzaldehyde byꢀproducts (NMR).
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 significance of the Cꢀ or Nꢀarylaldimine groups was studied. It was shown that the N-aryl
moiety was not an essential requirement for cyclization, as the aliphatic Nꢀbenzylidenethanamine
(2g) did undergo gold catalyzed [5+2] cycloaddition with propargyl acetal (1a). The reaction
afforded 2ꢀethylbenzo[c]azepine 3o (entry 15), albeit slower than the aniline analogues 2f (entry
11) and in moderate yield (45%, reflux, 16h, DCE). The Cꢀarylaldimine moiety was, however,
crucial for the cyclization to take place, as Cꢀalkylaldimines 2h and 2h’ (entry 16) failed to afford
benzazepine products. The cyclization of the bulky o-(di)nitrobenzaldimine analogues 2i,j with
propargyl acetal 1a was unsuccessful, as well (entry 17).
To further investigate the potential and reactivity of propargyl acetals with aldimines in the
presence of gold(I), we wanted to study whether alternative reactions would take place by
replacing phenylpropargyl substrates with alkylpropargyl acetals. In fact, a new nonꢀcyclic
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 33
8
1
2
3
coupling product 4 (49%, entry 18) was formed when ethylpropargyl acetal (1f) was subjected to
4
5
6
7
8
9
gold catalysis with aldimine 2a. The reaction pathway for the formation of NꢀbenzylꢀNꢀ(pentaꢀ1,3ꢀ
dienyl)aniline 4 may be explained by a related mechanism as suggested for the benzazepines 3 (see
Selectivity and reactivity and Scheme 2 below).
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
In order to study whether the significantly less reactive propargyl esters would undergo gold(I)
catalyzed [2+5] cycloaddition in a similar way, reactions of propargyl ester 1g with imines 2a,b
were performed. The reactions afforded considerably lower yields of the corresponding
benzazepine esters 5a,b (34ꢀ47%, entry 19) and full conversion could not be obtained, even within
several days of reflux.
ACS Paragon Plus Environment

Page 9 of 33
The Journal of Organic Chemistry
9
1
2
3
Table 2 Gold(I) catalyzed propargyl [2+5] cycloaddition with aldimines.
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
Imine; R3
Product, yield
3a, 80%a
3b, 74%b
3c, 68%
entry
Acetals:
Condition
1
2
3
4
5
NO2
H
DCE, rt,15min
DCE, reflux, 1h
DCE, reflux, 3h
DCE, reflux, 5h
DCE, reflux, 6h
2a
2b
2c
2d
2e
Cl
OMe
tert-Bu
3d, 61%
3e, 75%
6
7
NO2
H
DCE, reflux, 30min
DCE, reflux, 1h
DCE, reflux, 5h
DCE, reflux, 24h
3f, 69%
3g, 71%
3h, 62%
3i, 64%
3j, 70%
2a
2b
2c
2d
2e
8
Cl
9
OMe
tertꢀBu
10
DCE, reflux, 16h
11
R = H
1a
DCE, rt, 30 min
12
13
14
R = OMe
NO2
NO2
NO2
DCM, rt, 30min
DCM, rt, 15min
DCM, rt, 15min
3l, 63%
3m, 78%
3n, 84%c
1c
1d
1e
2a
2a
2a
R = Cl
R = NO2
1a
1a
1a
DCE, reflux, 16h
DCE, reflux, 72h
DCE, reflux, 72h
15
16
ncd
ncd
17
18e
2a
DCE, rt, 15, min
Ester:
19
DCE, reflux 24h
DCE, reflux 72h
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 33
10
1
a
2
3
4
5
a oneꢀpot procedure from 4ꢀnitrobenzaldehyde, 4ꢀmethoxyaniline and propargyl acetal 1a afforded 52% yield of product
3a; b a oneꢀpot procedure from benzaldehyde, 4ꢀmethoxyaniline and propargyl acetal 1a afforded 48% yield of product 3b; c a oneꢀ
d
pot procedure from 4ꢀnitrobenzaldehyde, 4ꢀmethoxyaniline and propargyl acetal 1e afforded 60% yield of product 3n; no
conversion; e the reaction afforded the nonꢀcyclic product 4.
6
7
8
Having studied the potential and limitations of the intermolecular [2+5] cycloaddition reaction of
9
propargyl acetals and benzaldimines, the potential for a oneꢀpot procedure, including both the
preceding benzaldimine condensation step and the subsequent [2+5] cycloaddition reaction, was
examined. In fact, a multiꢀstep cascade reaction of 4ꢀnitrobenzaldehyde, 4ꢀmethoxyaniline and
propargyl acetal 1a provided the benzazepine product 3a (46%) in the presence of the gold
catalyst. The reaction was slow and 24h reflux was required. However, a oneꢀpot sequential
synthesis allowed milder reaction conditions and was slightly more efficient, as overnight stirring
of the benzaldehyde and aniline precursors prior to the addition of propargyl acetal 1a and the gold
catalyst afforded the desired product 3a in 4h reflux (52% yield, entry 1, Table 2). Thus, this direct
procedure represents a convenient alternative preparation method, as the respective twoꢀstep
protocol afforded 68% overꢀall yield of 3a (85% imine condensation product 2a; 80% benzazepine
product 3a). Similarly, the oneꢀpot sequential protocol afforded products 3b and 3n in 48% and
60% yields (entries 2, 14) from the respective benzaldehyde, aniline and propargyl substrates.
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
Selectivity and reactivity. Our previous studies on gold(I) catalyzed alkenes cycloadditions of
propargyl esters21a and acetals21b have shown that the reaction pathway, going via gold carbenoid
intermediates (I, II, Scheme 2a,b), formed by gold catalyzed 1,2ꢀacyloxy and ꢀalkoxy migration,
switches from cyclopropanation to [2+3] cycloaddition by changing from propargylic esters to
acetals. The reactions might proceed through the intermediate adducts (I’, II’), formed by initial
nucleophilic attack of e.g. vinyl acetate and vinylamide at the allylic C3ꢀposition of gold
complexes I, II, to afford vinylpropane III and cyclopentenyl products IV, respectively. The
outcome of the chemoselective reactions of propargyl esters and acetals may be rationalized by the
deactivating and the corresponding activating effects of the C2ꢀacyloxy and ꢀalkoxy groups of
ACS Paragon Plus Environment

Page 11 of 33
The Journal of Organic Chemistry
11
1
2
3
adducts I’/II’. Thus, the “C3ꢀC1” reaction sequence, favoured for acetal substrates, may be
4
5
6
7
8
9
caused by the specific vinylalkoxy activation of the C1 position of adduct II’. The regioselectivity
of such [2+3] cycloadditions may be controlled by the electronic nature of the propargyl substrate,
as the opposite “C1ꢀC3” reaction order has been reported for nonꢀterminal propargyl acetals,
connected to C3ꢀEWG, with aldehydes.22 Our investigations indicated that a direct [2+3]
cycloaddition pathway, involving intermediate II’ is more likely than a subsequent ringꢀexpansion
of cyclopropane III, being discussed by others.20a,b,23
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 Proposed mechanisms of gold(I) catalysed propargyl cycloadditions
The new formal [2+5] cycloaddition (Scheme 2c) of phenylpropargyl acetals with benzaldimines
may go through the highly reactive propargyl carbenoid gold(I) complex II, as well. A subsequent
Nꢀnucleophilic imine attack would give the activated vinyl ether adduct II”. The deauration step
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 33
12
1
2
3
promotes a kind of 1,7ꢀelectrocyclization of the conjugated dieneꢀazomethine ylideꢀgold(I)
4
5
6
7
8
9
complex II” by a PictetꢀSpengler process, including ring closure of the ortho phenyl position and
the electrophilic benzaldiminium carbon to give azepine products. A final [1,5]ꢀsigmatropic
hydrogen shift takes place to give the benzo[c]azepine structure 3 by reꢀaromatization.
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 expected effects on reactivity by modifying of the electronic properties of the aldimine
reactants were discussed above for benzylideneanilines 2aꢀf (Table 2, entries 1ꢀ11). The limitation
of the cycloaddition reaction with bulky substrates is demonstrated by the unsuccessful cyclization
of the sterically hindered but electronically activated o-(di)nitroꢀbenzaldimine analogue 2i,j (entry
17). pꢀERGꢀphenylpropargyl substrates (e.g. p-OMe) would hamper the reaction by giving a less
electrophilic24 propargyl substrate 1 and gold complex II, but might also activate for the final
aromatic 1,7ꢀcyclization step. Actually, the reactivity dropped as the electron releasing character of
the p-substituent increased (entries 14/13/12, 84ꢀ63%), showing that the electronic nature of the
propargyl acetal mostly affects the reactivity of the propargylꢀgold complex intermediate II and
plays a less important role for the final cyclization.
Even if slow, the fact that a similar reaction took place with propargyl ester 1c (Table 2, entry 19),
demonstrated that the [2+5] cyclization pathway is not controlled by the different nature of the
gold(I) carbenoid complexes I and II. Thus, the fact that the cyclization pathway switches into the
formal [2+5] cycloaddition reaction with imines, indicates that the essential feature of complex II”
to selectively afford the new reaction seems to be the presence of the activated electrophilic
iminium group (Scheme 2c). Hence, the deauration step of the 1,3ꢀdipole gold complex II”
activates the vinylꢀaromatic system to favour a PictetꢀSpengler type reaction with the
benzaldiminium moiety and gives a 1,7ꢀmode of cyclization by aminoalkylation. The Pictetꢀ
Spengler reaction of electronꢀrich aromatic rings with imines represents a useful and important
ACS Paragon Plus Environment

Page 13 of 33
The Journal of Organic Chemistry
13
1
2
3
cyclization method in heterocyclic chemistry. The general challenge of the reaction appears,
4
5
6
7
8
9
however, to be the low reactivity of the imine substrate and such reactions are mostly promoted by
strong acids to generate the activated aldiminium group. In the present reaction, the important
iminium activation is performed by mild gold(I) catalysis through the goldꢀpropargylꢀiminium
adduct II’. The proposed reaction pathway is in line with a suggested mechanism25 for
benzazepine synthesis, based on a nonꢀcatalyzed related 1,7ꢀmode of ring closure from 3ꢀ
phenylpropenylbenzamide and PCl5 via imidoyl chloride and dieneꢀnitrile ylide. The mechanism is
also in accordance with previously reported gold(III) catalyzed [3+4] cycloadditions of propargyl
esters with a,bꢀunsaturated imine substrates20e or vinyl imine intermediates, generated from alkyl
azides.20f Being applied in azepine synthesis, the final ring closure of the generated iminium gold
complex included an intramolecular conjugated addition to the a,bꢀunsaturated iminium
electrophile. Propargyl esters and azomethine imines are reported to undergo [3+3] cycloaddition
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
to give biazabicycles based on a similar reaction pathway 20g
Other gold catalyzed [2+3], [2+4] and
.
[3+4] cycloaddition reactions with vinyl ethers, nitrosobenzene, cyclopentadiene as well as enones
with propargyl esters have lately been studied by others and are reported to be based on related
reaction principles of propargyl substrates.20aꢀe Gold catalyzed PictetꢀSpengler cyclizations have
also been used for the preparation of benzofused pyridoꢀNꢀheterocycles26. Gold(I)27and gold(III)28
catalyzed alkyne reactions have been combined with conventional Mannichꢀtype reactions to give
cascade or sequential oneꢀpot cyclizations for the preparation of heterocycles.27,28 Two different
catalytic systems may be applied,27aꢀc as the Mannichꢀtype enantioselective organocatalyzed
reactions of benzaldimines and enols have been combined with gold(I) catalyzed alkyne
hydroamination to give Nꢀheterocycles. Gold catalyzed carbonꢀheteroatom formation has been
reviewed,29a including hydroamination of alkynes with imines and enamines.29
b
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 33
14
1
2
3
The benzylic activation seems to be crucial, as all benzaldimine substrates (2a-g) readily
4
5
6
7
8
9
afforded cycloaddition, while the corresponding Cꢀalkylimine substrates 2h and 2h’ (entry 16,
Table 2) failed to undergo [2+5] cycloaddition, in accordance with nonꢀsuccessful acid catalyzed
PictetꢀSpengler benzazepine cyclization of aliphatic aldimines.30 The application of N-Et
benzaldimine 2g (entry 15) in the new benzazepine synthesis; demonstrates the versatility of the
new cyclization reaction.
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
Aliphatic propargyl acetals gave a different outcome by the gold(I) catalysed reaction with
benzaldimine 2a. A new openꢀchained coupling product 4 was isolated (49%, entry 18) when
ethylꢀpropargyl substrate 1f was subjected to analogous reaction conditions as above. The
formation of the nonꢀcyclic compound may be rationalized by a related reaction mechanism as for
benzazepines and is proposed to go through an analogous intermediate adduct II”’ (Scheme 2d) to
adduct II”, discussed above (Scheme 2c). The subsequent deauration step of intermediate II”’
would take place in a somewhat different manner in the absence of an aromatic group and
promotes a hydride shift to give the Nꢀbenzyl moiety of the Nꢀ(pentaꢀ1,3ꢀdienyl)aniline product 4.
NOESY NMR data indicated 1E,3E-stereochemistry.
In order to study whether the benzo[c]azepine products would be formed by some kind of ringꢀ
expansion of a cyclopropyl III or cyclopentenyl IV intermediate, attempt to identify possible
intermediates during the reaction were made. However, GC and NMR monitoring of the reaction
of acetal 1a with imine 2a, indicated no other intermediates, as only product 3a could be observed.
Thus, a direct [2+5] cycloaddition pathway, involving intermediate II” seems likely, in accordance
with our previous investigations on [2+3] cycloaddition reaction21. Investigations on similar
systems have also focussed on whether direct cycloaddition pathways or ringꢀexpansion
ACS Paragon Plus Environment

Page 15 of 33
The Journal of Organic Chemistry
15
1
2
3
4
5
mechanisms take place. The evidences are often consistent with a direct cycloaddition
mechanism rather than a stepwise cyclopropanation/ringꢀexpansion pathway.20a,b
6
7
8
9
A deuterated benzo[c]azepine d5-3a (76%) was prepared from deuterated phenylpropargyl acetal
d5-1a and Nꢀbenzylideneaniline 2a (Scheme 3). The deuterium labeling experiments showed
specific and complete incorporation of one deuterium in the 3ꢀposition (ꢀCHDꢀ). This is in
accordance with a 1,7ꢀelectrocyclization through a PictetꢀSpengler type reaction and a final reꢀ
aromatization by an o-phenyl proton shift, as shown in the proposed reaction mechanism (Scheme
2c).
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 3. Deuterium labeling [2+5] cycloaddition experiment
In conclusion, as part of our investigations on the chemistry and the potential of the highly
reactive propargyl acetals, we have developed a synthetic approach to access benzo[c]azepine
derivatives by a gold(I) catalysed formal [2+5] cycloaddition reaction. The benzo[c]azepine
products 3a-o, were readily prepared in 45ꢀ84% yield in one step from easily accessible
phenylpropargyl acetals 1a-e and benzaldimine substrates 2a-g in the presence of a gold(I)
catalyst. A oneꢀpot synthesis from propargyl acetal and the benzaldehyde and aniline precursors
could be applied, as well. To the best of our knowledge, our reported [2+5] cycloaddition
represents a new concept for the preparation of Nꢀheterocycles by an entirely gold(I) catalysed
reaction.
The favoured [2+5] cycloaddition pathway of phenylpropargyl acetals and benzaldimines could be
rationalized by a cascade reaction. An initial intermolecular nucleophilic aldimine Nꢀattack at
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 33
16
1
2
3
propargylꢀgold(I) carbenoid complex (II) would afford an activated iminiumꢀpropargylꢀgold
4
5
6
7
8
9
adduct II”. The following deauration of complex II” provides an electronꢀrich vinylꢀaromatic
group and activates for a 1,7ꢀelectrocyclization. The ring closure thus takes place by an
intramolecular PictetꢀSpengler type reaction with the activated electrophilic benzaldiminium
moiety of gold(I) adduct II”. The strong activating effect provided through deauration is also
shown by the coupling reaction of a corresponding alkyl substrate, ethylpropargyl acetal 1f,
affording the openꢀchained NꢀbenzylꢀN-((1E,3E)ꢀpentaꢀ1,3ꢀdienyl)aniline product 4 by a related
mechanism through a hydride shift.
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
General methods. All reactions were performed under argon atmosphere. Commercial grade
reagents were used as received. Dry solvents were collected from a solvent purification system
(SPSꢀ800, filter column MBꢀKOLꢀAꢀC). All reactions were monitored by GC and thinꢀlayer
chromatography (TLC) using silica gel 60 F254 (0.25ꢀmm thickness). Flash chromatography was
carried out using silica gel 60 (0.040ꢀ0.063 mm). High Throughput Flash Purification (HPFP) was
1
performed on preꢀpacked cartridges. H and 13C NMR spectra were recorded using a 400 MHz
spectrometer. Chemical shifts are reported in ppm (δ) downfield from tetramethylsilane (TMS) as
internal standard. Coupling constants (J) are reported in Hertz (Hz). The attributions of the
chemical shifts were determined by means of COSY, HMQC, HMBC and NOESY NMR
experiments. Melting points (mp) were determined using a Stuart apparatus and are uncorrected.
Accurate mass determination (HRMS) was performed using EI or ESI. Direct injection was
performed for the EI analyses at a magneticꢀelectric sector (double focusing) instrument. For ESI
analyses, samples were injected into a TOF MS instrument using HPLC. IR spectra were obtained
ACS Paragon Plus Environment

Page 17 of 33
The Journal of Organic Chemistry
17
1
2
3
using a Smart Endurance reflexion cell. Imines31 and propargyl acetals (1a-f)22 were prepared
4
5
according to a literature procedures.
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
Typical Procedure for the Gold-Catalyzed Cyclization reaction.
The gold catalyst (Au[P(tꢀBu)2(oꢀbiphenyl)]Cl and AgSbF6) was dissolved in approximately one
third of the total amount of solvent ([c = 100 mM] of propargyl acetal) and filtered through a small
pad of Celite to remove AgCl. A solution of the propargyl acetal and the imine derivative was
subsequently added. The reaction mixture was stirred/refluxed and the reaction was monitored by
TLC and GC. After full conversion the reaction mixture was either used for product isolation by
flash chromatography or filtered through a small pad of Celite for subsequent 1H NMR analysis of
the crude reaction mixture after evaporation of the solvent.
One-pot procedures i) - ii):
i) In a one-pot synthesis, the gold catalyst (Au[P(tꢀBu)2(oꢀbiphenyl)Cl and AgSbF6) was dissolved
in DCM and then a solution of 4ꢀnitrobenzaldehyde, 4ꢀmethoxyaniline and propargyl acetal 1a in
DCM was added. The mixture was refluxed for 24h. ii) In a one-pot sequential synthesis, a
solution of 4ꢀnitrobenzaldehyde and 4ꢀmethoxyaniline in DCM was stirred overnight (r.t) before a
solution of propargyl acetal 1a and gold catalyst (Au[P(tꢀBu)2(oꢀbiphenyl)Cl and AgSbF6) in DCM
was added The reaction mixture was refluxed for 4h.
In both cases, the reaction was monitored by TLC and GC. The reaction mixture was filtered
through a small pad of Celite and the crude product was purified by flash chromatography to
afford product 3a in i) 46% and ii) 52% yield, respectively.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 33
18
1
2
3
4-Methoxy-2-(4-methoxyphenyl)-1-(4-nitrophenyl)-2,3-dihydro-1H-benzo[c]azepine
3a.
4
5
6
7
8
9
According to the typical procedure from 1a (60 mg, 0.29 mmol), imine 2a (111.3 mg, 0.43 mmol,
1.5 equiv), the gold chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and AgSbF6 (4.8 mg, 14.0 ꢁmol, 0.05
equiv) in DCE for 15 min. Flash chromatography (nꢀpentane/EtOAc 20:1) yielded 3a (94 mg, 80
%) as a viscous yellow oil; Rf = 0.48 (nꢀpentane/EtOAc 10:1); 1H NMR (400 MHz, CDCl3) δ ppm
8.09 (d, J = 4.8 Hz, 2 Harom), 7.28 (d, J = 8.8 Hz, 2 Harom), 7.11ꢀ7.24 (m, 4 Harom), 6.85 (dt, J =
9.2 Hz, J = 3.6 Hz, 2 Harom), 6.75 (dt, J = 9.2 Hz, J = 3.6 Hz, 2 Harom), 5.91 (s, 1 H, CH=C), 5.50
(s, 1 H, CHN), 3.80 (d, J = 16.4 Hz, 1 H, CH2), 3.71(d, J = 16.4 Hz, 1 H, CH2), 3.70 (s, 3 H,
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
(OCH3), 3.51 (s, 3 H, (ArOCH3); C NMR (100 MHz, CDCl3) δ ppm 158.3 (1 C, C=COCH3),
152.9 (1 C, Carom), 150.0 (1 C, Carom), 146.8 (1 C, Carom), 143.5 (1 C, Carom), 136.4 (1 C, Carom),
135.0 (1 C, Carom), 130.7 (1 C, CHarom), 130.6 (1 C, CHarom), 128.8 (2 C, CHarom), 128.0 (1 C,
CHarom), 125.4 (1 C, CHarom), 123.3 (2 C, CHarom), 116.6 (2 C, CHarom), 114.4 (2 C, CHarom), 102.0
(1 C, C=CH), 68.9 (1 C, CHN), 55.4 (1 C, ArOCH3), 54.8 (1 C, OCH3), 49.1 (1 C, CH2); IR (neat,
cmꢀ1) 2989, 1286, 1062. HRMS (EI) calcd for C24H22O4N2, 402.1574, obsd 402.1575.
4-Methoxy-2-(4-methoxyphenyl)-1-phenyl-2,3-dihydro-1H-benzo[c]azepine 3b. According to
the typical procedure from 1a (60 mg, 0.29 mmol), imine 2b (92.8 mg, 0.43 mmol, 1.5 equiv), the
gold chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and AgSbF6 (4.8 mg, 14.0 ꢁmol, 0.05 equiv) in DCE
for 1h reflux. Flash chromatography (nꢀpentane/DCM 3:1) yielded 3b (77.7 mg, 74%) as a yellow
oil; Rf = 0.58 (nꢀpentane/DCM 1:1); 1H NMR (400 MHz, CDCl3) δ ppm 7.21ꢀ7.28 (m, 3 Harom),
7.02ꢀ7.18 (m, 6 Harom), 6.88 (d, J = 8.8 Hz, 2 Harom), 6.72 (d, J = 9.2 Hz, 2 Harom), 6.01 (s, 1 H,
CH=C), 5.54 (s, 1 H, CHN), 3.90 (d, J = 17.6 Hz, 1 H, CH2), 3.77(d, J = 18.0 Hz, 1 H, CH2), 3.67
(s, 3 H, OCH3), 3.55 (s, 3 H, ArOCH3); 13C NMR (100 MHz, CDCl3) δ ppm 159.0 (1 C,
C=COCH3), 152.3 (1 C, Carom), 143.3 (1 C, Carom), 141.6 (1 C, Carom), 137.5 (1 C, Carom), 134.4(1
C, Carom), 130.8 (1 C, CHarom), 130.5 (1 C, CHarom), 128.7 (2 C, CHarom), 128.3 (2 C, CHarom), 127.2
(1 C, CHarom), 127.1 (1 C, CHarom), 124.8 (1 C, CHarom), 116.4 (2 C, CHarom), 114.3 (2 C, CHarom),
ACS Paragon Plus Environment

Page 19 of 33
The Journal of Organic Chemistry
19
1
2
3
102.4 (1 C, C=CH), 68.0 (1 C, CHN), 55.4 (1 C, ArOCH3), 54.6 (1 C, OCH3), 48.4 (1 C, CH2);
4
5
IR (neat, cmꢀ1) 2899, 1316, 1112. HRMS (EI) calcd for C24H23NO2 357.1723, obsd 357.1720.
6
7
8
9
1-(4-Chlorophenyl)-4-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-benzo[c]azepine
3c.
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
According to the typical procedure from 1a (60 mg, 0.29 mmol), imine 2c (107.8 mg, 0.43 mmol,
1.5 equiv), the gold chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and AgSbF6 (4.8 mg, 14.0 ꢁmol, 0.05
equiv) in DCE for 3h reflux. Flash chromatography (nꢀpentane/DCM 3:1) yielded 3c (78.2 mg,
1
68%) as a yellow oil; Rf = 0.61 (nꢀpentane/DCM 1:1); H NMR (400 MHz, CDCl3) δ ppm 7.22
(d, J = 8.8 Hz, 2 Harom), 7.04ꢀ7.15 (m, 4 Harom), 7.02 (d, J = 8.0 Hz, 2 Harom), 6.85 (dt, J = 9.2
Hz, J = 3.6 Hz, 2 Harom), 6.72 (dt, J = 9.2 Hz, J = 3.6 Hz, 2 Harom), 5.91 (s, 1 H, CH=C), 5.52 (s,
1 H, CHN), 3.88 (d, J = 17.6Hz, 1 H, CH2), 3.73(d, J = 17.6 Hz, 1 H, CH2), 3.66 (s, 3 H, OCH3),
13
3.54 (s, 3 H, ArOCH3); C NMR (100 MHz, CDCl3) δ ppm 158.8 (1 C, C=COCH3), 152.5 (1 C,
Carom), 143.2 (1 C, Carom), 140.2 (1 C, Carom), 137.1 (1 C, Carom), 134.4 (1 C, Carom), 132.8 (1 C,
Carom), 130.8 (1 C, CHarom), 130.5 (1 C, CHarom), 129.9 (2 C, CHarom), 128.4 (2 C, CHarom), 127.5 (1
C, CHarom), 125.0 (1 C, CHarom), 116.3 (2 C, CHarom), 114.4 (2 C, CHarom), 102.3 (1 C, C=CH), 67.8
(1 C, CHN), 55.4 (1 C, ArOCH3), 54.6 (1 C, OCH3), 48.6 (1 C, CH2); IR (neat, cmꢀ1) 2969, 1277,
1088. HRMS (EI) calcd for C24H22O2NCl 391.1334, obsd 391.1335.
4-Methoxy-1,2-bis(4-methoxyphenyl)-2,3-dihydro-1H-benzo[c]azepine 3d. According to the
typical procedure from 1a (60 mg, 0.29 mmol), imine 2d (106.0 mg, 0.43 mmol, 1.5 equiv), the
gold chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and AgSbF6 (4.8 mg, 14.0 ꢁmol, 0.05 equiv) in DCE
for 5h reflux. Flash chromatography (nꢀpentane/DCM 3:1) yielded 3d (69.4 mg, 61%) as a yellow
oil; Rf = 0.51 (nꢀpentane/DCM 1:1); 1H NMR (400 MHz, CDCl3) δ ppm 7.03ꢀ7.17 (m, 4 Harom),
6.99 (dt, J = 8.8 Hz, J = 3.6 Hz, 2 Harom), 6.88 (dt, J = 9.2 Hz, J = 4.0 Hz, 2 Harom), 6.80 (dt, J
= 8.8 Hz, J = 2.4 Hz, 2 Harom), 6.72 (dt, J = 9.2 Hz, J = 3.6 Hz, 2 Harom), 5.97 (s, 1 H, CH=C),
5.55 (s, 1 H, CHN), 3.90 (d, J = 18.0Hz, 1 H, CH2), 3.83 (d, J = 19.2 Hz, 1 H, CH2), 3.75 (s, 3 H,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 33
20
1
2
3
13
ArOCH3), 3.67 (s, 3 H, OCH3), 3.58 (s, 3 H, ArOCH3); C NMR (100 MHz, CDCl3) δ ppm
4
5
6
7
159.2 (1 C, C=COCH3), 158.6 (1 C, Carom), 152.2 (1 C, Carom), 143.2 (1 C, Carom), 137.8 (1 C,
arom), 134.2 (1 C, Carom), 133.6 (1 C, Carom), 130.9 (1 C, CHarom), 130.4 (1 C, CHarom), 129.9 (2 C,
C
8
9
CHarom), 127.1 (1 C, CHarom), 124.8 (1 C, CHarom), 116.1 (2 C, CHarom), 114.4 (2 C, CHarom), 113.7
(2 C, CHarom), 102.5 (1 C, C=CH), 67.3 (1 C, CHN), 55.4 (1 C, ArOCH3), 55.1 (1 C, ArOCH3),
54.6 (1 C, OCH3), 48.3 (1 C, CH2); IR (neat, cmꢀ1) 2913, 1316, 1032. HRMS (EI) calcd for
C25H25O3N 387.1829, obsd 387.1832.
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-(4-(tert-Butyl)phenyl)-4-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-benzo[c]azepine 3e.
According to the typical procedure from 1a (60 mg, 0.29 mmol), imine 2e (117.0 mg, 0.43 mmol,
1.5 equiv), the gold chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and AgSbF6 (4.8 mg, 14.0 ꢁmol, 0.05
equiv) in DCE for 6h reflux. Flash chromatography (nꢀpentane/DCM 3:1) yielded 3e (91.1 mg,
75%) as a white solid; Rf = 0.65 (nꢀpentane/DCM 1:1), m.p 56ꢀ60oC; 1H NMR (400 MHz, CDCl3)
δ ppm 7.29 (d, J = 8.4 Hz, 2 Harom), 7.03ꢀ7.18 (m, 4 Harom), 7.00 (d, J = 8.4 Hz, 2 Harom), 6.88
(d, J = 8.4 Hz, 2 Harom), 6.73 (d, J = 9.2 Hz, 2 Harom), 6.00 (s, 1 H, CH=C), 5.55 (s, 1 H, CHN),
3.91 (d, J = 18.0 Hz, 1 H, CH2), 3.80 (d, J = 18.0 Hz, 1 H, CH2), 3.69 (s, 3 H, OCH3), 3.59 (s, 3
H, ArOCH3), 1.29 (s, 9 H, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ ppm) 159.1 (1 C,
C=COCH3), 152.2 (1 C, Carom), 150.0 (1 C, Carom), 143.2 (1 C, Carom), 138.6 (1 C, Carom), 137.7 (1
C, Carom), 134.2 (1 C, Carom), 130.9 (1 C, CHarom), 130.6 (1 C, CHarom), 128.5 (2 C, CHarom), 127.1
(1 C, CHarom), 125.3 (2 C, CHarom), 124.8 (1 C, CHarom), 116.1 (2 C, CHarom), 114.4 (2 C, CHarom),
102.5 (1 C, C=CH), 67.5 (1 C, CHN), 55.5 (1 C, ArOCH3), 54.6 (1 C, OCH3), 48.3 (1 C, CH2)
34.4 (1 C, C(CH3)3), 31.3 (3 C, C(CH3)3); IR (neat, cmꢀ1) 2972, 1196, 1042. HRMS (EI) calcd for
C28H31O2N 413.2349, obsd 413.2347.
4-Ethoxy-2-(4-methoxyphenyl)-1-(4-nitrophenyl)-2,3-dihydro-1H-benzo[c]azepine
3f.
According to the typical procedure from 1b (60.0 mg, 0.29 mmol), imine 2a (112.6 mg, 0.43
ACS Paragon Plus Environment

Page 21 of 33
The Journal of Organic Chemistry
21
1
2
3
mmol, 1.5 equiv), the gold chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and AgSbF6 (4.8 mg, 14.0
4
5
ꢁmol, 0.05 equiv) in DCE for 30min reflux. Flash chromatography (nꢀpentane/DCM 2:1) yielded
6
7
8
1
3f (84 mg, 69%) as a yellow viscous oil; Rf = 0.48 (nꢀpentane/DCM 1:1); H NMR (400 MHz,
9
CDCl3) δ ppm 8.10 (d, J = 8.8 Hz, 2 Harom), 7.30 (d, J = 8.8 Hz, 2 Harom), 7.09ꢀ7.27 (m, 4
Harom), 6.84 (dt, J = 9.2 Hz, J = 3.6 Hz, 2 Harom), 6.76 (dt, J = 9.2 Hz, J = 3.2 Hz, 2 Harom), 5.89
(s, 1 H, CH=C), 5.47 (s, 1 H, CHN), 3.83 (d, J = 16.4 Hz, 1 H, CH2), 3.78 (d, J = 16.4 Hz, 1 H,
CH2), 3.72 (s, 3 H, ArOCH3), 3.54 (dq, J = 7.2 Hz, J = 6.8 Hz, 2 H, OCH2CH3), 1.27 (t, J = 6.8
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
Hz, 3 H, OCH2CH3); C NMR (100 MHz, CDCl3) δ ppm 157.6 (1 C, C=COC2H5), 152.9 (1 C,
Carom), 150.3 (1 C, Carom), 146.9 (1 C, Carom), 143.6 (1 C, Carom), 136.5 (1 C, Carom), 135.3 (1 C,
Carom), 130.7 (1 C, CHarom), 130.5 (1 C, CHarom), 128.8 (2 C, CHarom), 128.0 (1 C, CHarom), 125.3 (1
C, CHarom), 123.3 (2 C, CHarom), 116.6 (2 C, CHarom), 114.5 (2 C, CHarom), 102.4 (1 C, C=CH), 69.1
(1 C, CHN), 63.0 (1 C, OCH2CH3), 55.5 (1 C, ArOCH3), 49.3 (1 C, CH2) 14.4 (1 C, OCH2CH3);
IR (neat, cmꢀ1) 2992, 1199, 1152. HRMS (EI) calcd for C25H24N2O4 416.1731, obsd 416.1736.
4-Ethoxy-2-(4-methoxyphenyl)-1-phenyl-2,3-dihydro-1H-benzo[c]azepine 3g. According to the
typical procedure from 1b (60 mg, 0.29 mmol), imine 2b (92.5 mg, 0.43 mmol, 1.5 equiv), the
gold chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and AgSbF6 (4.8 mg, 14.0 ꢁmol, 0.05 equiv) in DCE
for 1h reflux. Flash chromatography (nꢀpentane/DCM 2:1) yielded 3g (77mg, 71%) as a yellow
viscous oil; Rf = 0.45 (nꢀpentane/DCM 1:1); 1H NMR (400 MHz, CDCl3) δ ppm 7.04ꢀ7.29 (m, 9
Harom), 6.88 (dt, J = 9.2 Hz, J = 3.6 Hz, 2 Harom), 6.74 (dt, J = 9.2 Hz, J = 3.6 Hz, 2 Harom), 6.00
(s, 1 H, CH=C), 5.53 (s, 1 H, CHN), 3.89 (d, J = 17.6 Hz, 1 H, CH2), 3.89 (d, J = 18.0 Hz, 1 H,
CH2), 3.72 (dq, J = 6.8 Hz, J = 6.2 Hz, 2 H, OCH2CH3), 3.70 (s, 3 H, ArOCH3), 1.27 (t, J = 7.2
13
Hz, 3 H, OCH2CH3); C NMR (100 MHz, CDCl3) δ ppm 158.4 (1 C, C=COC2H5), 152.3 (1 C,
Carom), 143.4 (1 C, Carom), 141.8 (1 C, Carom), 137.5 (1 C, Carom), 134.7 (1 C, Carom), 130.7 (1 C,
CHarom), 130.6 (1 C, CHarom), 128.7 (2 C, CHarom), 128.3 (2 C, CHarom), 127.2 (1 C, CHarom), 127.0
(1 C, CHarom), 124.7 (1 C, CHarom), 116.1 (2 C, CHarom), 114.4 (2 C, CHarom), 102.9 (1 C, C=CH),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 33
22
1
2
3
68.1 (1 C, CHN), 62.8 (1 C, OCH2CH3), 55.5 (1 C, ArOCH3), 48.7 (1 C, CH2) 14.5 (1 C,
4
5
OCH2CH3); IR (neat, cmꢀ1) 2984, 1311, 992. HRMS (EI) calcd for C25H25O2N 371.1886, obsd
6
7
8
371.1880.
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
1-(4-Chlorophenyl)-4-ethoxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-benzo[c]azepine
3h.
According to the typical procedure from 1b (60 mg, 0.29 mmol), imine 2c (107.0 mg, 0.43 mmol,
1.5 equiv), the gold chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and AgSbF6 (4.8 mg, 14.0 ꢁmol, 0.05
equiv) in DCE for 5h reflux. Flash chromatography (nꢀpentane/DCM 2:1) yielded 3h (73 mg,
62%) as a yellow viscous oil; Rf = 0.49 (nꢀpentane/DCM 1:1); 1H NMR (400 MHz, CDCl3) δ ppm
7.24 (d, J = 8.8 Hz, 2 Harom), 7.05ꢀ7.18 (m, 4 Harom), 7.03 (d, J = 8.4 Hz, 2 Harom), 6.86 (dt, J =
9.2 Hz, J = 4.0 Hz, 2 Harom), 6.73 (dt, J = 8.8 Hz, J = 4.0 Hz, 2 Harom), 5.91 (s, 1 H, CH=C), 5.52
(s, 1 H, CHN), 3.89 (d, J = 17.2 Hz, 1 H, CH2), 3.73 (d, J = 16.4 Hz, 1 H, CH2), 3.70 (s, 3 H,
13
ArOCH3), 3.62ꢀ3.83 (m, 2 H, OCH2CH3), 1.28 (t, J = 7.2 Hz, 3 H, OCH2CH3); C NMR (100
MHz, CDCl3) δ ppm 158.2 (1 C, C=COC2H5), 152.5 (1 C, Carom), 143.4 (1 C, Carom), 140.4 (1 C,
Carom), 137.1 (1 C, Carom), 134.8 (1 C, Carom), 132.8 (1 C, Carom), 130.7 (1 C, CHarom), 130.5 (1 C,
CHarom), 129.9 (2 C, CHarom), 128.4 (2 C, CHarom), 127.5 (1 C, CHarom), 124.9 (1 C, CHarom), 116.3
(2 C, CHarom), 114.4 (2 C, CHarom), 102.7 (1 C, C=CH), 67.9 (1 C, CHN), 62.8 (1 C, OCH2CH3),
55.5 (1 C, ArOCH3), 48.8 (1 C, CH2) 14.4 (1 C, OCH2CH3); IR (neat, cmꢀ1) 2949, 1276, 1082.
HRMS (EI) calcd for C25H24O2NCl 405.1496, obsd 405.1489.
4-Ethoxy-1,2-bis(4-methoxyphenyl)-2,3-dihydro-1H-benzo[c]azepine 3i. According to the
typical procedure from 1b (60 mg, 0.29 mmol), imine 2d (106.0 mg, 0.43 mmol, 1.5 equiv), the
gold chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and AgSbF6 (4.8 mg, 14.0 ꢁmol, 0.05 equiv) in DCE
for 5h reflux. Flash chromatography (nꢀpentane/EtOAc 30:1) yielded 3i (75mg, 64%) as a yellow
1
oil; Rf = 0.43 (nꢀpentane/EtOAc 10:1); H NMR (400 MHz, CDCl3) δ ppm 7.03ꢀ7.17 (m, 4
Harom), 7.00 (d, J = 8.4 Hz, 2 Harom), 6.88 (d, J = 9.2 Hz, 2 Harom), 6.81 (d, J = 8.8 Hz, 2 Harom),
ACS Paragon Plus Environment

Page 23 of 33
The Journal of Organic Chemistry
23
1
2
3
6.73 (d, J = 9.2 Hz, 2 Harom), 5.96 (s, 1 H, CH=C), 5.54 (s, 1 H, CHN), 3.90 (d, J = 18.0 Hz, 1
4
5
6
7
8
9
H, CH2), 3.71ꢀ3.88 (m, 2 H, OCH2CH3), 3.75 (d, J = 18.0 Hz, 1 H, CH2), 3.77 (s, 3 H, ArOCH3),
3.69 (s, 3 H, ArOCH3), 1.29 (t, J = 6.8 Hz, 3 H, OCH2CH3); 13C NMR (100 MHz, CDCl3) δ ppm
158.6 (1 C, C=COC2H5), 158.5 (1 C, Carom), 152.2 (1 C, Carom), 143.2 (1 C, Carom), 137.8 (1 C,
Carom), 134.5 (1 C, Carom), 133.7 (1 C, Carom), 130.8 (1 C, CHarom), 130.4 (1 C, CHarom), 129.9 (2 C,
CHarom), 127.1 (1 C, CHarom), 124.7 (1 C, CHarom), 116.1 (2 C, CHarom), 114.3 (2 C, CHarom), 113.7
(2 C, CHarom), 103.0 (1 C, C=CH), 67.3 (1 C, CHN), 62.7 (1 C, OCH2CH3), 55.5 (1 C, ArOCH3),
55.2 (1 C, ArOCH3), 48.3 (1 C, CH2) 14.5 (1 C, OCH2CH3); IR (neat, cmꢀ1) 2989, 1271, 1112.
HRMS (EI) calcd for C26H27O3N 401.1985, obsd 401.1984.
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-(4-(tert-Butyl)phenyl)-4-ethoxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-benzo[c]azepine 3j.
According to the typical procedure from 1b (60 mg, 0.29 mmol), imine 2e (117.0 mg, 0.43 mmol,
1.5 equiv), the gold chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and AgSbF6 (4.8 mg, 14.0 ꢁmol, 0.05
equiv) in DCE for overnight reflux. Flash chromatography (nꢀpentane/DCM 2:1) yielded 3j
(76mg, 70%) as a yellow oil; Rf = 0.53 (nꢀpentane/DCM 1:1); 1H NMR (400 MHz, CDCl3) δ ppm
7.29 (d, J = 8.4 Hz, 2 Harom),7.02ꢀ7.18 (m, 4 Harom), 7.00 (d, J = 8.4 Hz, 2 Harom), 6.89 (dt, J =
9.2 Hz, J = 4.0 Hz, 2 Harom), 6.73 (dt, J = 9.2 Hz, J = 3.6 Hz, 2 Harom), 6.00 (s, 1 H, CH=C), 5.54
(s, 1 H, CHN), 3.90 (d, J = 18.0 Hz, 1 H, CH2), 3.80 (d, J = 17.6 Hz, 1 H, CH2), 3.77 (dm, 2 H,
OCH2CH3), 3.70 (s, 3 H, ArOCH3), 1.29 (t, J = 5.2 Hz, 3 H, OCH2CH3), 1.29 (s, 9 H, C(CH3)3);
13C NMR (100 MHz, CDCl3) δ ppm 158.4 (1 C, C=COC2H5), 152.1 (1 C, Carom), 149.9 (1 C,
Carom), 143.3 (1 C, Carom), 138.7 (1 C, Carom), 137.7 (1 C, Carom), 134.5 (1 C, Carom), 130.8 (1 C,
CHarom), 130.6 (1 C, CHarom), 128.4 (2 C, CHarom), 127.1 (1 C, CHarom), 125.2 (2 C, CHarom), 124.6
(1 C, CHarom), 116.0 (2 C, CHarom), 114.4 (2 C, CHarom), 103.1 (1 C, C=CH), 67.5 (1 C, CHN), 62.7
(1 C, OCH2CH3), 55.5 (1 C, ArOCH3), 48.5 (1 C, CH2), 34.4, (1C, C(CH3)3), 31.3, (3C, C(CH3)3),
14.5 (1 C, OCH2CH3); IR (neat, cmꢀ1) 2939, 1266, 1092. HRMS (EI) calcd for C29H33O2N
427.2511, obsd 427.2512.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 33
24
1
2
3
4-Methoxy-1-(4-nitrophenyl)-2-phenyl-2,3-dihydro-1H-benzo[c]azepine 3k. According to
4
5
6
7
8
9
the general procedure from 1a (127.0 mg, 0.62 mmol), imine 2f (211.0 mg, 0.93 mmol, 1.5 equiv),
the gold chloride (13.0 mg, 24.5 ꢁmol 0.05 equiv) and AgSbF6 (8,4 mg, 24,5 ꢁmol 0.05 equiv) in
DCE for 30 min. Flash chromatography (n-pentane:DCM, 1:1) yielded 3k (144 mg, 84 %) as a
yellow oil; Rf = 0.49 (n-pentane:DCM, 1:1); 1H NMR (300 MHz, CDCl3) δ ppm 8.10 (m, 2 Harom),
7.12ꢀ7.30 (m, 7 Harom), 6.87 (d, J = 8.1 Hz, 2 Harom), 6.79 (d, J = 7.2 Hz, 2 Harom), 6.01 (s, 1 H,
CH=C), 5.47 (s, 1 H, CHN), 3.92 (d, J = 16.2 Hz, 1 H, CH2), 3.79 (d, J = 15.9 Hz, 1 H, CH2),
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
3.50 (s, 3 H, (OCH3); C NMR (100 MHz, CDCl3 δ ppm 158.1 (1 C, C=COCH3), 150.2 (1 C,
Carom), 149.1 (1 C, Carom), 147.0 (1 C, Carom), 136.1 (1 C, Carom), 135.2 (1 C, Carom), 130.9 (1 C,
CHarom), 130.7 (1 C, CHarom), 129.3 (2 C, CHarom), 128.8 (2 C, CHarom), 128.2 (1 C, CHarom), 125.6
(1 C, CHarom), 123.4 (2 C, CHarom), 118.9 (1 C, CHarom), 114.6 (2 C, CHarom), 102.1 (1 C, C=CH),
68.2 (1 C, CHN), 55.0 (1 C, OCH3), 48.3 (1 C, CH2); IR (neat, cmꢀ1) 2931, 1251, 1089. HRMS
(EI) calcd for C23H20O3N2 372.1466, obsd 372.1466.
4,8-Dimethoxy-2-(4-methoxyphenyl)-1-(4-nitrophenyl)-2,3-dihydro-1H-benzo[c]azepine
3l.
According to the general procedure from 1c (68.7 mg, 0.29 mmol), imine 2a (112.6 mg, 0.43
mmol, 1.5 equiv), the gold chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and AgSbF6 (4.8 mg, 14.0
ꢁmol, 0.05 equiv) in DCE for 30 min. Flash chromatography (DCM) yielded 3l (79 mg, 63 %) as a
1
yellow oil; Rf = 0.45 (DCM); H NMR (400 MHz, CDCl3) δ ppm 8.11 (d, J = 8.8 Hz, 2 Harom),
7.31 (d, J = 8.8 Hz, 2 Harom), 7.09 (d, J = 8.4 Hz, 1 Harom), 6.73ꢀ6.87 (m, 6 Harom), 5.85 (s, 1 H,
CH=C), 5.44 (s, 1 H, CHN), 3.83 (d, J = 15.2 Hz, 1 H, CH2), 3.78 (s, 3 H, (OCH3), 3.73 (s, 3 H,
(ArOCH3), 3.68 (d, J = 16.4 Hz, 1 H, CH2), 3.49 (s, 3 H, (ArOCH3); 13C NMR (100 MHz, CDCl3)
δ ppm 157.3 (1 C, C=COCH3), 156.6 (1 C, Carom), 152.9 (1 C, Carom), 149.8 (1 C, Carom), 146.9 (1
C, Carom), 143.5 (1 C, Carom), 137.9 (1 C, Carom), 131.9 (1 C, Carom), 130.4 (1 C, CHarom), 129.0 (2 C,
CHarom), 124.2 (1 C, CHarom), 123.4 (2 C, CHarom), 122.6 (1 C, CHarom), 116.7 (2 C, CHarom), 114.5
(2 C, CHarom), 101.5 (1 C, C=CH), 69.0 (1 C, CHN), 55.5 (1 C, ArOCH3), 55.2 (1 C, ArOCH3),
ACS Paragon Plus Environment

Page 25 of 33
The Journal of Organic Chemistry
25
1
2
3
4
5
54.7 (1 C, OCH3), 49.1 (1 C, CH2); IR (neat, cmꢀ1) 2957, 1276, 1091. HRMS (EI) calcd for
C25H24O5N2 432.1680, obsd 432.1677.
6
7
8
9
8-Chloro-4-methoxy-2-(4-methoxyphenyl)-1-(4-nitrophenyl)-2,3-dihydro-1H-benzo[c]azepine
3m. According to the general procedure from 1d (70.0 mg, 0.29 mmol), imine 2a (112.6 mg, 0.43
mmol, 1.5 equiv), the gold chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and AgSbF6 (4.8 mg, 14.0
ꢁmol, 0.05 equiv) in DCE for 15 min. Flash chromatography (DCM) yielded 3m (100 mg, 78 %)
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
as a yellow oil; Rf = 0.38 (DCM); H NMR (400 MHz, CDCl3) δ ppm 8.12 (d, J = 8.8 Hz, 2
Harom), 7.29 (d, J = 8.4 Hz, 2 Harom), 7.08ꢀ7ꢀ19 (m, 3 Harom), 6.85 (d, J = 9.2 Hz, 2 Harom), 6.77
(d, J = 8.8 Hz, 2 Harom), 5.87 (s, 1 H, CH=C), 5.47 (s, 1 H, CHN), 3.85 (d, J = 16.8 Hz, 1 H, CH2),
13
3.72 (s, 3 H, (OCH3), 3.67 (d, J = 16.8 Hz, 1 H, CH2), 3.52 (s, 3 H, (ArOCH3); C NMR (100
MHz, CDCl3) δ ppm 159.0 (1 C, C=COCH3), 153.2 (1 C, Carom), 148.9 (1 C, Carom), 147.1(1 C,
Carom), 143.1 (1 C, Carom), 138.1 (1 C, Carom), 133.5 (1 C, Carom), 131.9 ( 1 C, Carom), 130.7 (1 C,
CHarom), 130.1 (1 C, CHarom), 129.0 (2 C, CHarom), 128.1 (1 C, CHarom), 123.5 (2 C, CHarom), 116.9
(2 C, CHarom), 114.5 (2 C, CHarom), 101.2 (1 C, C=CH), 68.4 (1 C, CHN), 55.4 (1 C, ArOCH3),
54.9 (1 C, OCH3), 49.2 (1 C, CH2); IR (neat, cmꢀ1) 2969, 1286, 1110. HRMS (EI) calcd for
C24H21ClN2O4 436.1184, obsd 436.1184.
4-Methoxy-2-(4-methoxyphenyl)-8-nitro-1-(4-nitrophenyl)-2,3-dihydro-1H-benzo[c]azepine
3n. According to the general procedure from 1e (36.6 mg, 0.14 mmol), imine 2a (56.3 mg, 0.21
mmol, 1.5 equiv), the gold chloride (3.9 mg, 7.0 ꢁmol, 0.05 equiv) and AgSbF6 (2.4 mg, 7.0 ꢁmol,
0.05 equiv) in DCE for 15 min. Flash chromatography (DCM) yielded 3n (55 mg, 84 %) as a
1
yellow oil; Rf = 0.46 (DCM); H NMR (400 MHz, CDCl3) δ ppm 8.17 (d, J = 8.8 Hz, 2 Harom),
8.05ꢀ8.08 (m, 2 Harom), 7.27ꢀ7.30 (m, 3 Harom), 6.87 (dt, J = 9.2 Hz, J = 3.6 Hz, 2 Harom), 6.77
(dt, J = 9.2 Hz, J = 3.6 Hz, 2 Harom), 6.10 (s, 1 H, CH=C), 5.65 (s, 1 H, CHN), 3.96 (d, J = 17.6
Hz, 1 H, CH2), 3.72 (s, 3 H, (OCH3), 3.73 (d, J = 18.0 Hz, 1 H, CH2), 3.63 (s, 3 H, (ArOCH3); 13C
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 33
26
1
2
3
NMR (100 MHz, CDCl3) δ ppm 163.4 (1 C, C=COCH3), 153.5 (1 C, Carom), 147.4 (1 C, Carom),
4
5
6
7
8
9
147.4 (1 C, Carom), 144.5 (1 C, Carom), 142.3 (1 C, Carom), 141.9 (1 C, Carom), 137.3 (1 C, Carom),
131.4 ( 1 C, CHarom), 129.2 (2 C, CHarom), 125.5 (1 C, CHarom), 123.8 (2 C, CHarom), 123.2 (1 C,
CHarom), 117.2 (2 C, CHarom), 114.6 (2 C, CHarom), 101.4 (1 C, C=CH), 68.2 (1 C, CHN), 55.4 (1 C,
ArOCH3), 55.2 (1 C, OCH3), 49.5 (1 C, CH2); IR (neat, cmꢀ1) 2971, 1281, 1087. HRMS (EI) calcd
for C24H21O6N3 447.1425, obsd 447.1422.
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
2-Ethyl-4-methoxy-1-phenyl-2,3-dihydro-1H-benzo[c]azepine 3o. According to the typical
procedure from 1a (60 mg, 0.29 mmol), imine 2g (58.3 mg, 0.43 mmol, 1.5 equiv), the gold
chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and AgSbF6 (4.8 mg, 14.0 ꢁmol, 0.05 equiv) in DCE for
overnight reflux. Flash chromatography (DCM) yielded 3o (37mg, 45%) as a yellow oil; Rf = 0.39
(DCM); 1H NMR (400 MHz, CDCl3) δ ppm 7.21ꢀ7.28 (m, 5 Harom), 7.13 (d, J = 7.6 Hz, 2 Harom),
7.02ꢀ7.06 (m, 1 Harom), 6.99 (d, J = 7.6 Hz, 1 Harom), 5.69 (s, 1 H, CH=C), 5.09 (s, 1 H, CHN),
3.60 (s, 3 H, OCH3), 3.37 (d, J = 17.6 Hz, 1 H, CH2), 3.63 (dq, J = 7.2 Hz, J = 1.6 Hz, 2 H,
NCH2CH3), 3.25 (d, J = 17.6 Hz, 1 H, CH2), 1.14 (t, J = 7.2 Hz, 3 H, OCH2CH3); 13C NMR (100
MHz, CDCl3) δ ppm 159.1 (1 C, C=COC2H5), 142.1 (1 C, Carom), 137.4 (1 C, Carom), 135.4 (1 C,
Carom), 130.6 (1 C, CHarom), 129.7 (1 C, CHarom), 128.8 (2 C, CHarom), 128.1 (2 C, CHarom), 127.0 (1
C, CHarom), 126.8 (1 C, CHarom), 124.8 (1 C, CHarom), 101.9 (1 C, C=CH), 69.6 (1 C, CHN), 54.4 (1
C, OCH3), 51.2 (1 C, NCH2CH3), 46.6 (1 C, CH2), 13.4 (1 C, NCH2CH3); IR (neat, cmꢀ1) 2987,
1266, 1082. HRMS (EI) calcd for C19H21ON 279.1618, obsd 279.1613.
4-Methoxy-N-((1E,3E)-2-methoxypenta-1,3-dienyl)-N-(4-nitrobenzyl)aniline 4. According to
the general procedure from 1f (45.8 mg, 0.29 mmol), imine 2a (112.6 mg, 0.44 mmol, 1.5
equiv),gold chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and AgSbF6 (4.8 mg, 14.0 ꢁmol, 0.05 equiv)
in DCM for 15min. Flash chromatography (20:1, nꢀpentane:EtOAc) yielded 4 (50 mg, 49 %) as a
yellow oil; Rf = 0.56 (10:1,nꢀpentane:EtOAc); 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (d, J = 8.4
ACS Paragon Plus Environment

Page 27 of 33
The Journal of Organic Chemistry
27
1
2
3
Hz, 2 Harom), 7.41 (d, J = 8.8 Hz, 2 Harom), 6.77 (dt, J = 9.2 Hz, J = 3.2 Hz, 2 Harom), 6.69 (dt,
4
5
J = 9.2 Hz, J = 3.6 Hz, 2 Harom), 6.16 (s, 1 H, CH3CH=CH), 6.09ꢀ6.20 (m, 2 H, CH3CH=CH ),
6
7
8
5.54 (s, 1 H, CH=COCH3), 4.71 (s, 2 H, CH2N), 3.74 (s, 3 H, (OCH3), 3.68 (s, 3 H, (ArOCH3),
9
13
1.74 (d, J = 6.0 Hz, 3 H, (CH3); C NMR (100 MHz, CDCl3) δ ppm 154.1 (1 C, C=COCH3),
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
152.5 (1 C, Carom), 147.0 (1 C, Carom), 142.6 (1 C, Carom), 128.1 (1 C, CH3CH=CH), 127.6 (2 C,
CHarom), 123.7 (2 C, CHarom), 122.0 ( 1 C, CH3CH=CH), 115.1 (2 C, CHarom), 114.6 (2 C, CHarom),
110.2 (1C, C=COCH3), 57.2 (1 C, CH2N), 55.7 (1 C, ArOCH3), 55.6 (1 C, OCH3), 18.3 (1 C,
CH3); IR (neat, cmꢀ1) 3013, 1253, 1089. HRMS (EI) calcd for C20H22O4N2 354.1574, obsd
354.1573.
2-(4-Methoxyphenyl)-1-(4-nitrophenyl)-2,3-dihydro-1H-benzo[c]azepin-4-yl pivalate 5a.
According to the general procedure from 1g (63.5 mg, 0.29 mmol), imine 2a (112 mg, 0.44 mmol,
1.5 equiv), gold chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and AgSbF6 (4.8 mg, 14.0 ꢁmol, 0.05
equiv) in DCE for 24h. Flash chromatography (DCM:nꢀpentane (4:1)) yielded 5a (65 mg, 47 %) as
a yellow oil; Rf = 0.43 (DCM); 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (d, J = 8.8 Hz, 2 Harom),
7.32 (d, J = 8.4 Hz, 2 Harom), 7.13ꢀ7ꢀ25 (m, 4 Harom), 7.04 (dt, J = 8.8 Hz, J = 4.0 Hz,2 Harom),
6.76 (dt, J = 9.2 Hz, J = 3.6 Hz, 2 Harom), 6.22 (d, J = 2.0 Hz,1 H, CH=C), 6.08 (s, 1 H, CHN),
3.97 (d, J = 19.2 Hz, 1 H, CH2), 3.75 (d, J = 19.8 Hz, 1 H, CH2), 3.69 (s, 3 H, (ArOCH3), 1.23 (s,
9 H, ((CH3)3); 13C NMR (100 MHz, CDCl3) δ ppm 177.1 (1 C, C=O), 153.4 (1 C, C=COCH3),
150.8 (1 C, Carom), 147.6 (1 C, Carom), 147.2 (1 C, Carom), 142.8 (1 C, Carom), 138.3 (1 C, Carom),
132.2 (1 C, Carom), 132.0 ( 1 C, CHarom), 130.4 (1 C, CHarom), 129.7 (1 C, CHarom), 128.0 (2 C,
CHarom), 127.3 (1 C, CHarom), 123.7 (2 C, CHarom), 121.0 (1 C, C=CH), 118.2 (2 C, CHarom), 114.4
(2 C, CHarom), 68.7 (1 C, CHN), 55.4 (1 C, ArOCH3), 48.5 (1 C, CH2), 38.8 (1 C, C(CH3)3), 27.0 (1
C, C(CH3)3); IR (neat, cmꢀ1) 2991, 1271, 1081. HRMS (EI) calcd for C28H28O5N2 472.1993, obsd
472.1994.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 33
28
1
2
3
2-(4-Methoxyphenyl)-1-phenyl-2,3-dihydro-1H-benzo[c]azepin-4-yl pivalate 5b. According
4
5
6
7
8
9
to the general procedure from 1f (63.5 mg, 0.29 mmol), imine 2a (92.5 mg, 0.44 mmol, 1.5 equiv),
gold chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and AgSbF6 (4.8 mg, 14.0 ꢁmol, 0.05 equiv) in DCE
for 72h. Flash chromatography (DCM) yielded 5b (42 mg, 34 %) as a yellow oil; Rf = 0.39
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
(DCM); H NMR (400 MHz, CDCl3) δ ppm 7.27ꢀ7.34 (m, 3 Harom), 7.12ꢀ7.19 (m, 6 Harom), 7.04
(dt, J = 8.8 Hz, J = 4.0 Hz, 2 Harom), 6.75 (dt, J = 9.2 Hz, J = 3.6 Hz, 2 Harom), 6.19 (d, J = 1.6
Hz,1 H, CH=C), 6.10 (s, 1 H, CHN), 3.93 (d, J = 18.8 Hz, 1 H, CH2), 3.84 (d, J = 20.0 Hz, 1 H,
CH2), 3.69 (s, 3 H, (ArOCH3), 1.24 (s, 9 H, ((CH3)3); 13C NMR (100 MHz, CDCl3) δ ppm 177.1 (1
C, C=O),152.7 (1 C, C=COCH3), 151.1 (1 C, Carom), 143.0 (1 C, Carom), 140.4 (1 C, Carom), 139.8
(1 C, Carom), 132.1 (1 C, Carom), 132.0 ( 1 C, CHarom), 130.5 (1 C, CHarom), 128.9 (2 C, CHarom),
128.5 (2 C, CHarom), 127.5 (1 C, CHarom), 127.3 (1 C, CHarom), 126.9 (1 C, CHarom), 120.9 (1 C,
C=CH), 117.5 (2 C, CHarom), 114.3 (2 C, CHarom), 68.5 (1 C, CHN), 55.4 (1 C, ArOCH3), 47.8 (1
C, CH2), 38.5 (1 C, C(CH3)3), 27.0 (1 C, C(CH3)3); IR (neat, cmꢀ1) 2993, 1271, 1109. HRMS (EI)
calcd for C28H29O3N 427.2142, obsd 427.2146.
(1-(2,3,4,5,6-d5-Phenyl)prop-2-yn-1-ol-d5 7. According to the reported procedure22 from
2,3,4,5,6ꢀd5ꢀbenzaldehyde 6 (666 mg, 6 mmol) in 10ml THF, ethynylmagnesium bromide (18 ml,
9 mmol, 0.5 M in THF). Flash chromatography (nꢀpentane/EtOAc 5:1) yielded 7 (641 mg, 78%) as
a colorless oil; Rf = 0.41 (nꢀpentane/EtOAc 5:1); 1H NMR (400 MHz, CDCl3) δ ppm 5.47 (d, J =
13
3.6 Hz,1 H, CH(OH)C≡C), 2.67 (d, J = 2.4 Hz,1 H, C≡CH), 2.65 (bs, 1 H, OH); C NMR (100
MHz, CDCl3) δ ppm 139.8 (1 C, Carom), 127.8ꢀ128.4 (m, 3 C, CDarom), 126.2 (t, JC-D = 24.2, 2 C,
CDarom), 83.4 (1 C, C≡CH), 74.8 (1 C, C≡CH), 64.4 (1 C, CH(OH)C≡C); IR (neat, cmꢀ1) 3410,
2969, 1296, 1092. HRMS (EI) calcd for C9H3D5O 137.0884, obsd 137.0885.
2,3,4,5,6-d5-(1-((2-Methoxypropan-2-yl)oxy)prop-2-yn-1-yl)benzene d5-1a. According to the
reported procedure22 from 7 (500 mg, 3.6 mmol), 2ꢀmethoxypropene (4 ml, solvent) and PPTS (a
ACS Paragon Plus Environment

Page 29 of 33
The Journal of Organic Chemistry
29
1
2
3
few crystals). Flash chromatography (nꢀpentane/EtOAc 50:1) yielded d5-1a (650 mg, 85%) as a
4
5
6
7
8
9
colorless viscous oil; Rf = 0.48 (nꢀpentane/EtOAc 10:1); 1H NMR (400 MHz, CDCl3) δ ppm 5.42
(d, J = 2.4 Hz,1 H, CHC≡C), 3.18 (s, 3 H, OCH3), 2.53 (d, J = 2.0 Hz, 1 H, C≡CH), 1.54 (s, 3 H,
CH3), 1.32 (s, 3 H, CH3); 13C NMR (100 MHz, CDCl3) δ ppm 140.0 (1 C, Carom), 127.2ꢀ128.2 (m,
3 C, CDarom), 126.4 (t, JC-D = 24.2, 2 C, CDarom), 101.8 (1 C, C(CH3)2), 84.4 (1 C, C≡CH), 73.6 (1
C, C≡CH), 62.5 (1 C, OCH3), 49.4 (1 C, CHC≡C), 25.3 (1 C, C(CH3)2), 24.9 (1 C, C(CH3)2); IR
(neat, cmꢀ1) 2969, 1284, 1093. HRMS (EI) calcd for C12H7D5O [MꢀMeOH]+ 177.1197, obsd
177.1195.
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
3,6,7,8,9-d5-4-Methoxy-2-(4-methoxyphenyl)-1-(4-nitrophenyl)-2,3-dihydro-1H-
benzo[c]azepine d5-3a. According to the general procedure from d5-1a (61.4 mg, 0.29 mmol),
imine 2a (112.6 mg, 0.43 mmol, 1.5 equiv), the gold chloride (7.8 mg, 14.0 ꢁmol, 0.05 equiv) and
AgSbF6 (4.8 mg, 14.0 ꢁmol, 0.05 equiv) in DCE for 15 min. Flash chromatography (nꢀ
pentane/EtOAc 20:1) yielded d5-3a (90 mg, 76 %) as a viscous yellow oil; Rf = 0.55 (nꢀ
pentane/EtOAc 10:1); 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (d, J = 8.8 Hz, 2 Harom), 7.29 (d,
J = 8.4 Hz, 2 Harom), 6.85 (d, J = 9.2 Hz, 2 Harom), 6.76 (d, J = 9.2 Hz, 2 Harom), 5.91 (s, 1 H,
CH=C), 5.50 (s, 1 H, CHN), 3.71 (s, 3 H, OCH3), 3.69 (s, 1 H, CHD), 3.52 (s, 3 H, ArOCH3); 13C
NMR (100 MHz, CDCl3) δ ppm 158.3 (1 C, C=COCH3), 152.9 (1 C, Carom), 150.0 (1 C, Carom),
146.9 (1 C, Carom), 143.5 (1 C, Carom), 136.3 (1 C, Carom), 134.9 (1 C, Carom), 130.4 (1 C, CDarom),
130.3 (t, JC-D = 23.1, 1 C, CDarom), 128.9 (2 C, CHarom), 127.5 (t, JC-D = 24.3, 1 C, CDarom), 124.9 (t,
JC-D = 22.9, 1 C, CDarom), 123.4 (2 C, CHarom), 116.6 (2 C, CHarom), 114.5 (2 C, CHarom), 102.0 (1
C, C=CH), 68.8 (1 C, CHN), 55.5 (1 C, ArOCH3), 54.8 (1 C, OCH3), 48.9 (t, JC-D = 21.0, 1 C,
CHD); IR (neat, cmꢀ1) 2981, 1298, 1087. HRMS (EI) calcd for C24H17D5O4N2 407.1888, obsd
407.1885.
ACS Paragon Plus Environment