Selective Vinylogous Reactivity of Carbene Intermediate in Gold-Catalyzed Alkyne Carbocyclization: Synthesis of Indenols

Article abstract of DOI:10.1021/acscatal.8b04144

A gold-catalyzed carbocyclization of alkynes with a pendant diazo group that is completed by reaction with a protic nucleophile for the synthesis of indenol derivatives with a tertiary center is described. Mechanistic studies and DFT calculations indicate

Full text of DOI:10.1021/acscatal.8b04144

Subscriber access provided by Iowa State University | Library
Article
Selective Vinylogous Reactivity of Carbene Intermediate in
Gold-Catalyzed Alkyne Carbocyclization: Synthesis of Indenols
Cheng Zhang, Hongli Li, Chao Pei, Lihua Qiu, Wenhao Hu, Xiaoguang Bao, and Xinfang Xu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04144 • Publication Date (Web): 01 Feb 2019
Downloaded from http://pubs.acs.org on February 3, 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 9
ACS Catalysis
1
2
3
4
5
6
7
8
9
Selective Vinylogous Reactivity of Carbene Intermediate in Gold-
Catalyzed Alkyne Carbocyclization: Synthesis of Indenols
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
Cheng Zhang,†, ‡,§ Hongli Li,‡,§ Chao Pei,‡ Lihua Qiu,‡ Wenhao Hu,*,† Xiaoguang Bao,*,‡ and Xinfang
Xu*,†,‡
†School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
‡Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Sci-
ence, Soochow University, Suzhou 215123, China
ABSTRACT: A gold-catalyzed carbocyclization of alkynes with a pendant diazo group that is completed by reaction with a protic
nucleophile for the synthesis of indenol derivatives with a tertiary center is described. Mechanistic studies and DFT calculations
indicate that the transformation is initiated by a gold-promoted 5-endo-dig carbocyclization to form the key intermediate vinyl gold-
carbene, which is intercepted by an unprecedented vinylogous addition and followed by external protic nucleophile assisted
protodeauration. Furthermore, in this catalytic alkyne transformation, various nucleophiles, including water, commercially available
1o, 2o and 3o alcohols, menthol, D-galactose, cholesterol, steroid, etc., all perform well under these mild conditions to produce the
corresponding indenol derivatives in high yields with structural diversity.
KEYWORDS: gold-catalysis, 5-endo-dig carbocyclization, diazo compound, gold carbene, indenol
INTRODUCTION
Indenols are important structural motifs found in a number of
natural compounds1 and biologically active molecules.2-4 For
example, these compounds show antiproliferative activity2a
and antimycobacterial activity;2b some are used as antitumor
antibiotics,2c molecular probes,3 and for the treatment of chron-
ic obstructive pulmonary disease (COPD) 4a,4b and CNS disor-
ders.4c Consequently, the development of effective methods
for the construction of indenol skeletons with structural diver-
sity is an attractive subject in organic synthesis.5-8 Of these
approaches, transition-metal-catalyzed carbocyclization of
alkynes with carbonyl group has been established as a power-
ful synthetic method for the direct construction of indenols
with a tertiary carbon center.6 For example, advances in this
direction via C-H bond activation are reported by Cheng,7a
Glorius,7b and Zhao,7c independently. However, the methods
for the straightforward synthesis of the ether and ester variants,
which are difficult to prepare from corresponding tertiary
indenols, are quite limited.8 Thus, the development of efficient,
diversity-oriented approaches is a useful endeavor and remains
a challenge.
Recently, gold-catalyzed alkyne transformations have expe-
rienced explosive development for the effective construction
of C-C and C-X bonds. Intermediates possessing
carbene/carbenoid character have been postulated and verified
experimentally,9,10 including both the α-carbonyl11 and α-
imino12 gold carbene species (Scheme 1a). In comparison with
Rh13 and Cu14 catalyzed metal carbene transformations, most
of the gold-catalyzed reactions of diazo compounds proceed
through carbene reactivity,15 including cyclopropanation and
cyclopropenation,16 X-H insertion,17 and others.18 However,
Scheme 1. Carbenoid vs Vinylogous Reactivity in Gold-
Catalysis
the formation of a distinct Au=C bond has been demonstrated
to have dramatic differences in both reactivity and selectivi-
ty.19 For example, X. Shi and J. Zhang have observed an ex-
clusive electrophilic aromatic substitution of arenes with α-
1
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 9
1
2
3
diazoesters, independently.20 Moreover, the ylide or
Table 1. Condition Optimizationa
zwitterionic intermediates, which were generated from gold
carbenoid species with corresponding nucleophiles, have been
successfully intercepted in various tandem processes (Scheme
1b),21 such as dihydrofuran21a and indene21b synthesis. On the
other hand, Toste has disclosed a gold-catalyzed oxidative
rearrangement of alkyne-tethered diazoketone, and a vinyl
gold-carbenoid intermediate was proposed in this report which
was formed via a gold-catalyzed 5-exo-dig carbocyclization
(Scheme 1c).22 Inspired by these milestone works on the gold-
catalyzed carbenoid reactions and as the continuation of our
interest in the carbene/alkyne metathesis (CAM) transfor-
mations,23 we are intrigued by the possibility that using the
nucleophilic carbon of a diazo compound addition with a gold-
activated alkyne to form the vinyl gold carbene species III
(Scheme 1d), instead of an N-oxide or azide to generate the α-
carbonyl and α-imino carbenoid intermediates, respectively
(Scheme 1a). New transformations via interception of this
intermediate III, especially the vinylogous reactivity that has-
n't been reported in gold-carbenoid transformations,24 could be
envisioned.25 However, preferential activation of the carbon-
carbon triple bond with the gold catalyst could be highly chal-
lenging because the competitive direct carbenoid formation
with the coexisting diazo group shows priority according to
previous reports (Scheme 1a, and 1b).15-21 Herein, we present
our recent results in this direction, the gold-catalyzed 5-endo-
dig carbocyclization of o-alkynylphenyl diazoacetates 1 occurs
in the presence of a protic nucleophile, which is found to be
the key factor to selectively facilitate the catalytic transfor-
mation. This unprecedented reaction not only provides a direct
and efficient access for the synthesis of indenol derivatives in
high to excellent yields with structural diversity, but also pre-
sents the first example of selective vinylogous reactivity in
comparison with the disclosed gold carbenoid reactions. Func-
tional groups, especially alkenyl and azide, which are de-
scribed as reactive toward the metal carbenoid or in gold-
promoted alkyne transformations,12 remain untouched in this
work, and the synthetic utility of these products with a remain-
ing azide group for the construction of tetracyclic frameworks
is also demonstrated.
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
yields (%)b
2a/A/B/C
H2O
(n equiv.)
entry
cat (x mol %)
1d
2e
3
JohnPhosAu(CH3CN)SbF6 3 (5.0)
-
-
-/-/-/-
45 f/-/-/-
3 (5.0)
3 (5.0)
5
10
5
5
5
5
5
5
5
5
92 f/-/-/-
4
3 (5.0)
85f/< 5/-/-
87 f/-/-/-
5g
3 (5.0)
6
3 (2.0)
60 f/-/-/-
7
JohnPhosAuCl (5.0) + AgNTf2 (5.0)
JohnPhosAuCl (5.0)
AuCl3 (5.0)
89 f/-/-/-
8
16/< 10/30f/18c
< 10/75 f/11/-
-/32f/35f/-
-/75 f/11/0
-/-/30 f/60c
9
10
11
12
AgSbF6 (5.0)
Rh2(OAc)4 (2.0)
.
Cu(hfacac)2 H2O (5.0)
aReaction conditions: to a solution of the catalyst in dry DCE (2.0 mL), was
added the solution of 1a (0.2 mmol) in DCE (2.0 mL) at the indicated
temperature under argon atmosphere and the reaction was stirred for 3 h
under these conditions. bYields were determined by proton NMR of the
crude reaction mixture based on the yields of isolated products. cIsolated as
a mixture of C and C’. dMost of 1a was recovered. eCommercially availa-
f
ble DCE was used as solvent and partial of 1a was reserved. Isolated
yields. gThe reaction was carried at 60 oC. DCE = dichloroethane.
loading resulted in moderate yields (entry 6). Varying the
-
-
counterion of gold catalyst from NTf2 to SbF6 shown little
effect (entry 7). Notably, this reaction was performed without
slow addition of the diazo compound via syringe pump, and
the observed chemoselectivity is unique for gold catalysis
because no indenol product 2a was generated in the presence
of silver, dirhodium, or copper catalysts (entries 10-12). By-
products A, B, C, and C' were generated in these cases via the
corresponding metal carbene reaction pathway.27
RESULTS AND DISCUSSION
Following our initial hypothesis (Scheme 1d), a variety of gold
complexes were initially evaluated for the carbocyclization
reaction of 1a, which could be easily prepared from o-
bromophenyl acetates through Sonogashira coupling and diazo
transfer reactions in high yields.26 It is surprising that, in an-
hydrous
dichloroethane
(DCE)
at
80
oC,
JohnPhosAu(CH3CN)SbF6 (3) did not catalyze any transfor-
mation of 1a, and a majority of the material was recovered
after 3 hours under these conditions (Table 1, entry 1). How-
ever, when the commercially available DCE was directly used
as the solvent, the indenol product 2a was isolated in 45%
yield (entry 2). Water was found to have a considerable impact
on the catalytic activity in this gold-catalyzed reaction, which
not only acted as a reagent but was also essential to promoting
the catalytic transformation. The reaction gave comparable
results in the presence of 5-10 equivalents of water (entries 3
SCOPE
Under the optimal reaction conditions, a wide variety of 2-
substituted indenols have been generated with this method
(Scheme 2). The impact of substituents on the alkyne motifs of
1a was initially investigated (R1), Electron-neutral, electron-
withdrawing, electron-donating, and bulky groups were all
tolerated in this transformation, and provided the correspond-
ing products in high to excellent yields (2a-2i, 75-93%).
Moreover, comparable results were obtained when the reaction
was carried out on a 2.0 mmol scale (2f, results in parenthesis).
The naphthyl- and alkyl-substituted substrates also underwent
o
and 4) at 60-80 C (entries 3 and 5), and the best results were
o
obtained in the presence of 5 equivalents of water at 80 C in
DCE (entry 3, 92% isolated yield). Decreasing the catalyst
2
ACS Paragon Plus Environment

Page 3 of 9
ACS Catalysis
1
2
3
4
5
N2
N2
3
3
(5.0 mol %)
(5.0 mol %)
RO
CO2R2
R1
HO
CO2Me
Ph
CO2R2
R1
ROH 4
DCE, 80 oC, 3 h
(5.0 equiv.)
H2O (5.0 equiv.)
DCE, 80 oC, 3 h
CO2Me
6
1a
5
Ph
Ph
2
1
7
8
9
Me
Me
RO
CO2Me
Ph
2a
, Ar = C6H5, 92%
2f
, Ar = 4-BrC6H4, 84%
HO
CO Me
2b
Me
, Ar = 4-FC6H4, 90%
, Ar = 3-FC6H4, 75%
2
(on 2.0 mmol scale, 85%)
O
2c
2d
CO2Me
2g
2h
, Ar = 4-CF3C6H4, 91%
, Ar = 4-MeOC6H4, 91%
Ar
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
5a
, R = Me, 90%
CO2Me
Ph
, Ar = 2-FC6H4, 93%
, Ar = 4-ClC6H4, 87%
Ph
5b
5c
5d
i
, R = -Pr, 93%
2e
, R = Bu, 78%
t-
a
5e
5f
, R = Bn, 95%
, 95%
, 70%
ArOCO
R
HO
CO2Me
N3
CO2Me
Ph
ArO
OH
Ph
CO2Me
Ph
OH
O
CO2Me
Ph
CO2Me
CO2Me
Me
Me
a
5ia
, Ar = 4-MeOC6H4, 48%(20%)
2k
, R =H, 90%
a
5h
, 82%
a
2l
, R =Cl, 91%
5ib
, Ar = 2,4-(MeO)2C6H3, 75%
5g
, 90%
2m
, R =Br, 89%
Ar = 4-BrC6H4
Me
Me
a
5ic
, Ar = 4-MeC6H4, 42%(22%)
Me
2n
2o
, R =CF3, 95%
, R =CH3, 92%
2i
, 90%
2j
, 85%
Me
Me
Me
Me
Me
Me
Me
O
Me
O
O
HO
O
HO
HO
O
O
CO2Me
CO2Bn
Ph
O
O
O
O
CO2Me
Ph
CO2Me
Ph
CO2Me
Ph
HO
n-C6H13
Ph
*
*
Ph
*
2r, 96%
2p
2q
, 90%
, 90%
5j
(R)- , 89%
5k
, 59%
5l
, 65%
Scheme 2. Scope of Diazo Compounds 1. The reactions were
H
carried out on a 0.2 mmol scale in DCE at 80 oC for 3 h.
H
O
H
Me
O
the reaction smoothly, leading to indenols 2j and 2p in 85%
and 90% yields, respectively. Notably, the azide group, which
was reported to form the α-imino gold carbene with alkyne in
the presence of gold catalyst,12 remained untouched under
these conditions, and corresponding products were isolated
in > 89% yields (2k-2o). These results not only showed the
preferential reactivity of diazo group over the azide, but also
offered the potential synthetic utility of these products with a
remaining azide group. Subsequently, the ester part of the
diazoacetates was investigated. It is worth mentioning that
diazoacetates bearing the groups, including benzyl and alkenyl
groups which were described as reactive toward the metal
carbene for C-H insertion and cyclopropanation reactions,
respectively, were also well-tolerated in this reaction and af-
forded indenol products in > 90% yields (2q and 2r). The
structures of products 2f and 2n were unambiguously con-
firmed by signal-crystal X-ray analysis.28
CO2Me
Ph
Me
O
CO2Me
Ph
5m
dr
5n
, 92%,
dr
1:1
, 95%,
1:1
Scheme 3. Scope of Protic Nucleophiles 4. The reactions
were carried out on a 0.2 mmol scale in DCE at 80 oC for 3 h. a
The reactions were carried out at room temperature for 5 h,
and the data in parentheses are yields of corresponding
carbene O-H insertion products, see SI for details.
5ia-5ic in fairly good yields contaminated with the direct O-H
insertion product in the cases with 5ia and 5ic. Lower reaction
temperature was necessary to ensure the high yield in the cases
with phenol and benzoic acids to avoid the direct O-H inser-
tion. Furthermore, chiral protic nucleophiles, including L-
menthol, (+)-2,3-pinanediol, and even sugar derivative
diacetone-D-galactose, all proceeded smoothly and selectively
to afford the ether products 5j, 5k, and 5l, each as a signal
enantiomer in 89%, 59%, and 65% yields, respectively. The
competition experiment has been carried out in the presence of
equal amount of isopropanol and tert-butanol, and only selec-
tive addition product with secondary alochol was formed (see
Figure S4 in the SI for details). And the chiral alcohol itself
contributed to the high stereoselectivity in this transformation.
The stereochemistry of the newly formed chiral center in 5j
was unambiguously determined to be R by single-crystal X-
ray analysis,28 and the structure 5l of 5l and was tentatively
assigned by the comparison of optical rotations.26 It is worth
mentioning that this is the first example that provided the di-
rect access for the synthesis of optical pure indenol ethers with
Encouraged by the above promising results of this gold-
catalyzed reaction in the presence of water, we envisioned that
the catalytic system may also facilitate the carbocyclization of
alkyne with other challenging substrates (Scheme 3). To our
delight, the reaction showed broad substrate generality, includ-
ing alkyl alcohol, cinnamyl alcohol, geraniol, and
phenylpropargyl alcohol all promoted the reaction smoothly
and provided the corresponding ether products 5a-5g with a
tertiary carbon center in > 70% yields. It is worth mentioning
that with the tert-butyl alcohol, the reaction provided the cor-
responding product 5c with an ethereal bond flanked by two
quaternary centers in 78% yields. Phenol was well-tolerated
under these reaction conditions, giving the cyclization product
5h in 82% yield at room temperature. Notably, benzoic acid
derivatives, which are more acidic than water or alcohol, were
also compatible, giving the corresponding cyclization products
a
tertiary center.8 In addition, two biomolecules,
dehydroepiandrosterone and cholesterol, were also tested in
3
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 9
1
2
3
4
5
6
7
8
9
this reaction, and the indene moiety was successfully linked to
deuterated product 2a-d was isolated in 92% yields in the
presence of D2O after column chromatography (Scheme 5g).
In addition, the carbenoid oxidation product D was isolated in
40% yield in the presence of diphenylsulfoxide instead of wa-
ter (Scheme 5h),22 which indicated the possibility of the for-
mation of corresponding vinyl gold carbenoid species III in
this transformation (Scheme 4, Path B). And the remaining
question is the preferential addition between the vinylogous
position (Scheme 4, red arrows) to give the product 2 and the
carbenoid O-H insertion to produce the regioisomer 2' which
is not detected in this transformation (dashed arrows).
these compounds and the products were obtained in > 92%
yields with 1:1 dr (5m and 5n). These results showed signifi-
cant potential of this underexplored pattern of reactivity for
the selective modification of bioactive molecules which pos-
sess a hydroxyl group, especially for the late-stage modifica-
tion of natural products or pharmaceuticals.
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
MECHANISTIC DISCUSSION
According to the previously reported gold-catalyzed trans-
formations, two potential catalytic pathways may be involved
in this reaction, including direct gold-carbene formation of the
diazo group,15-21 and classic alkyne activation with the π-acidic
carbophilic gold catalyst (Scheme 4, Path A and B).9-12 To
To further understand the reaction mechanism, comparison
experiments of 1a with phenylpropargyl alcohol 4g catalyzed
by gold and silver separately or in combination are carried out
(Scheme 6). Under the standard conditions, which means with
Scheme 4. Proposed Mechanism
gain insight into the initial step, control reactions of 1a and
1aa were conducted individually in the presence of gold cata-
lyst 3 Although 2a was isolated in 89% yield when the reac-
tion was conducted at 60 oC in the presence of water (Scheme
o
5a), the majority of 1a was recovered after 15 hours at 60 C
in dry CDCl3 (Scheme 5b and Figure S1). On the other hand,
complete decomposition of 1aa occurred within 3 hours in
DCE, leading to the formation of dimerized products as a Z/E
mixture (Scheme 5c and Figure S2). Interestingly, the addi-
tional diazo group on the substrate 1s survives under these
reaction conditions, and affords the cyclized product 2s in
60% yields with 10% of material recovered (Scheme 5d, de-
composition of 2s occurs slowly under these reaction condi-
tions to give the corresponding carbonyl product 2ss, see SI
for details).26 These results suggest that the activation of the
alkyne has priority in this case compared with the gold-
catalyzed diazo group decomposition, and similar preferential
reactivity was observed by Doyle and co-authors in gold-
catalysis.29 On the other hand, in the presence of Rh2(OAc)4
instead of gold catalyst 3, the cyclopropanation product 6 is
formed from 1r in 90% yield via a corresponding metal
carbene intermediate, which is distinctly different from the
product formed in the gold catalysis (Scheme 5e vs 2r in
Scheme 2). Furthermore, the O-H insertion product A is pro-
duced as the only product from 1a in the presence of degassed
water catalyzed by Rh2(OAc)4, and the cyclization products C
and C' could be obtained from A when catalyzed by 3
(Scheme 5f).27 All these results lead to the conclusion that
direct formation of the gold carbenoid intermediate I (Scheme
4, Path A) was not the initial step in this reaction. The
Scheme 5. Control Experiments
4
ACS Paragon Plus Environment

Page 5 of 9
ACS Catalysis
1
2
3
or 5. Moreover, the 31P NMR analysis results by combination
of gold catalyst 3 (0.02 mmol) and 1a (0.02 mmol) in the ab-
sence of protic nucleophile suggested the formation of a rela-
tive stable complex(s) under these conditions (see Figure S3 in
SI), and the reaction could not complete a catalytic cycle in the
absence of the protic nucleophile under current conditions. It
should be noted that other possible reaction pathway(s), such
as combination of path A and B, couldn't be totally ruled out
so far.
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
UTILITY
To demonstrate the synthetic utility of the current method,
further transformations of carbocyclization products 2 were
conducted. For example, 2a was readily converted into the
indanone product under basic aqueous conditions followed by
treatment with HCl.26 Notably, with the azide product 2k-2o,
the C-N bond formation occurred in the presence of a rhodi-
um(II) carboxylates catalyst, and the tetracyclic fused indole
products 12 precipitated out as solid and obtained after filtra-
tion in 78-93% isolated yields without further purification
(Scheme 7).31 Other derivations, including reduction and
Scheme 6. Comparison Experiments of Au- and/or Ag-
Catalysis
the gold catalyst 3 alone, the reaction forms the indenol deri-
vate 5g as the only product in 90% yield (Scheme 6a). How-
ever, by combining of gold with silver, which is supposed to
form 3 in situ, only resulted in the formation of product 5g in
30% yield, and contaminated with compounds B and 7 in 20%
and 30% yields, respectively (Scheme 6b). And these two by-
products are generated through the metal carbene intermedi-
ate.21 Additionally, when the reaction is catalyzed by AgSbF6
alone, three identifiable products B, 7, and 8 are isolated in
combined high yields, instead of 5g (Scheme 6c). These re-
sults clearly illustrate that the current reaction goes through a
reaction pathway that is different from the reported transfor-
mations, which does not involve the direct formation of metal
carbene intermediate at the diazo group (Scheme 4, Path A).
Scheme 7. Derivatization of Indenol Products 2
Density functional theory (DFT) calculations were carried
out to gain a mechanistic insight on the formation of indenol
derivatives.26 The formation of Au(I)-carbenoid intermediate
(I) could be achieved by the gold catalyzed activation of the
diazo moiety of 1a and synchronously release N2 (Figure S5,
Path A).19,30 The predicted energy barrier for Path A is 29.6
kcal/mol relative to separated 1a and the catalyst. Alternative-
ly, Path B leading to the cyclized Au(I)-carbenoid intermedi-
ate (III) via the alkyne activation with the π-acidic carbophilic
gold catalyst was explored. The calculated ∆G≠ for the cy-
clization step is 27.1 kcal/mol, which is 2.5 kcal/mol lower in
energy than that of the direct activation of diazo moiety to
form the gold carbenoid I (Figure S5 Path B). Therefore, the
computational results suggest that it is more feasible for 1a to
undergo the Au(I) promoted 5-endo-dig carbocyclization fol-
lowed by N2 dissociation to afford the gold carbenoid interme-
diate III. After the generation of III, the predicted energy bar-
rier for the vinylogous position addition step is 19.5 kcal/mol
relative to separated III and methanol (Figure S6). The proton
transfer step could be facilitated by another molecule of meth-
anol to complete the proton migration with a lower energy
barrier (see Figure S6 vs S7).26
Sonogashira coupling reaction with bromo-substituted product
2f were also conducted, and the corresponding products were
obtained in 69% and 89% yields, respectively.26
CONCLUSIONS
In summary, we have disclosed an unprecedented gold-
catalyzed carbocyclization reaction of alkyne-tethered diazo
compounds with protic nucleophiles, which provides a direct
access for the synthesis of indenol derivatives under mild reac-
tion conditions with broad substrate scope in high to excellent
yields. Various protic nucleophiles, including water, commer-
cially available alcohols, menthol, steroid, etc., are all well
tolerated under these conditions to produce the corresponding
indenol derivatives with structural diversity. Mechanistic stud-
ies and DFT calculations suggest that the vinyl gold carbenoid
is the key intermediate in this transformation, and the follow-
ing selective interception of this intermediate with protic nu-
cleophile presents the first example of vinylogous reactivity in
comparison with the disclosed gold carbenoid reactions. This
underexplored pattern of reactivity shows significant untapped
potential in selective modification of privileged bioactive mol-
ecules with a hydroxyl group, and its innovative applications
beyond organic synthesis could be expected.
Based on the above experimental studies and DFT calcula-
tions, a possible reaction mechanism was proposed (Scheme 4,
Path B). Initially, the gold-promoted 5-endo-dig
carbocyclization of 1 leads to the key intermediate vinyl gold
carbenoid III via II, followed by preferential vinylogous posi-
tion addition and external protic nucleophile assisted
protodeauration through IV to deliver the indenol derivatives 2
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org.
5
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 9
1
2
3
4
5
6
7
8
9
1
Experimental procedure, the H and 13C NMR spectra of all the
products (PDF), crystallographic data for 2f, 2n and 5j (CIF), and
computational details.
Kappen, L.; Goldberg, I. H. Convenient Synthesis of NCS-
Chromophore Metabolite Isosteres:ꢀ Binding Agents for Bulged DNA
Microenvironments. Org. Lett. 2005, 7, 71-74. (d) Ma, D.; Lin, Y.;
Xiao, Z.; Kappen, L.; Goldberg, I. H.; Kallmerten, A. E.; Jones, G. B.
Designed DNA Probes from the Neocarzinostatin Family: Impact of
Glycosyl Linkage Stereochemistry on Bulge Base Binding. Bioorg.
Med. Chem. 2009, 17, 2428-2432.
(4) (a) Prat, M.; Fernández, D.; Buil, M. A.; Crespo, M. I.; Casals,
G.; Ferrer, M.; Tort, L.; Castro, J.; Monleón, J. M.; Gavaldà, A.;
Miralpeix, M.; Ramos, I.; Doménech, T.; Vilella, D.; Antón, F.; Huer-
ta, J. M.; Espinosa, S.; López, M.; Sentellas, S.; González, M.; Albertí,
J.; Segarra, V.; Cárdenas, A.; Beleta, J.; Ryder, H. Discovery of Nov-
el Quaternary Ammonium Derivatives of (3R)-Quinuclidinol Esters as
Potent and Long-Acting Muscarinic Antagonists with Potential for
Minimal Systemic Exposure after Inhaled Administration: Identifica-
AUTHOR INFORMATION
Corresponding Author
* E-mail: huwh9@mail.sysu.edu.cn
xgbao@suda.edu.cn
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
xinfangxu@suda.edu.cn
Author Contributions
§C.Z. and L.H. contributed equally to this work.
Notes
tion
of
(3R)-3-{[Hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-
The authors declare no competing financial interest.
phenoxypropyl)-1-azoniabicyclo[2.2.2]octane Bromide (Aclidinium
Bromide). J. Med. Chem. 2009, 52, 5076-5092. (b) Prata, M.; Buila,
M. A.; Fernándezb, M. D.; Torta, L.; Monleóna, J. M.; Casalsa, G.;
Ferrera, M.; Castroa, J.; Gavaldàa, A.; Miralpeixa, M.; Ramosa, I.
Discovery of Novel Quaternary Ammonium Derivatives of (3R)-
Quinuclidinyl Amides as Potent and Long Acting Muscarinic Antago-
nists. Bioorg. Med. Chem. Lett. 2015, 25, 1736-1741. (c) Kerscher-
Hack, S.; Renukappa-Gutke, T.; Höfner, G.; Wanner, K. T. Synthesis
and Biological Evaluation of a Series of N-Alkylated Imidazole
Alkanoic Acids as mGAT3 Selective GABA Uptake Inhibitors. Eur. J.
Med. Chem. 2016, 124, 852-880.
(5) (a) Bajracharya, G. B.; Pahadi, N. K.; Gridnev, I. D.; Yamamo-
to, Y. PtBr2-Catalyzed Transformation of Allyl(o-ethynylaryl)carbinol
Derivatives into Functionalized Indenes. Formal sp3 C-H Bond Acti-
vation. J. Org. Chem. 2006, 71, 6204-6210. (b) Teng, T.-M.; Das, A.;
Huple, D. B.; Liu, R.-S. Gold-Catalyzed Stereoselective Synthesis of
9-Oxabicyclo[3.3.1]nona-4,7-dienes from Diverse 1-Oxo-4-oxy-5-
ACKNOWLEDGMENT
Support for this research from the National Natural Science Foun-
dation of China and NSFC of Jiangsu (NSFC21602148,
NSFC21642004); and the Program for Guangdong Introducing
Innovative and Entrepreneurial Teams (No. 2016ZT06Y337) are
greatly acknowledged. We also thank the reviewers for their in-
sightful comments on the reaction mechanism.
REFERENCES
(1) (a) Namdaung, U.; Aroonreek, N.; Suksamrarn, S.;
Danwisetkanjana, K.; Saenboonrueng, J.; Arjchomphu, W.;
Suksamrarn, A. Bioactive Constituents of the Root Bark
of Artocarpus Rigidus Subsp. Rigidus. Chem. Pharm. Bull. 2006, 54,
1433-1436. (b) Abdelfattah, M. S.; Rohr, J. Premithramycinone G, an
Early Shunt Product of the Mithramycin Biosynthetic Pathway Ac-
cumulated upon Inactivation of Oxygenase MtmOII. Angew. Chem.,
Int. Ed. 2006, 45, 5685-5689. (c) Oh, D.-C.; Williams, P. G.; Kauff-
man, C. A.; Jensen, P. R.; Fenical, W. Cyanosporasides A and B,
Chloro- and Cyano-cyclopenta[a]indene Glycosides from the Marine
Actinomycete “Salinispora Pacifica”. Org. Lett. 2006, 8, 1021-1024.
(d) Lee, I.-K.; Kim, Y.-S.; Jang, Y.-W.; Jung, J.-Y.; Yun, B.-S. New
Antioxidant Polyphenols from the Medicinal Mushroom Inonotus
Obliquus. Bioorg. Med. Chem. Lett. 2007, 17, 6678-6681. (e) Eea, G.
C. L.; Teoa, S. H.; Rahmania, M.; Limb, C. K.; Limc, Y. M.; Go, R.
Artomandin, a New Xanthone from Artocarpus Kemando (Moraceae).
Nat. Prod. Res. 2011, 25, 995. (f) Lane, A. L.; Nam, S.-J.; Fukuda, T.;
Yamanaka, K.; Kauffman, C. A.; Jensen, P. R.; Fenical, W.; Moore, B.
S. Structures and Comparative Characterization of Biosynthetic Gene
Clusters for Cyanosporasides, Enediyne-Derived Natural Products
from Marine Actinomycetes. J. Am. Chem. Soc. 2013, 135, 4171-4174.
(2) (a) Alonso, C.; Fuertes, M.; Gonzalez, M.; Rubiales, G.;
Tesauro, C.; Knudsen, B. R.; Palacios, F. Synthesis and Biological
Evaluation of Indeno[1,5]naphthyridines as Topoisomerase I (TopI)
Inhibitors with Antiproliferative Activity. Eur. J. Med. Chem. 2016,
115, 179-190. (b) Upadhayaya, R. S.; Shinde, P. D.; Kadam, S. A.;
Bawane, A. N.; Sayyed, A. Y.; Kardile, R. A.; Gitay, P. N.; Lahore, S.
V.; Dixit, S. S.; Földesi, A.; Chattopadhyaya, J. Synthesis and
Antimycobacterial Activity of Prodrugs of Indeno[2,1-c]quinoline
Derivatives. Eur. J. Med. Chem. 2011, 46, 1306-1324. (c) Jiang, Z.-H.;
Hwang, G.-S.; Xi, Z.; Goldberg, I. H. Formation and Structure of a
Novel Enediyne-RNA Base Covalent Adduct. J. Am. Chem. Soc. 2002,
124, 3216-3217.
ynes: A Viable Formal [4
+ 2] Cycloaddition on an s-trans-
Heterodiene Framework. J. Am. Chem. Soc. 2010, 132, 12565-12567.
(c) Chen, Y.; Chen, M.; Liu, Y. Gold-Catalyzed Cascade Cyclizations
of 1,6-Diynyl Carbonates to Benzo[b]fluorenes Involving Arylation
of Oxocarbenium Ion Intermediates and Decarboxylative Etherifica-
tion. Angew. Chem., Int. Ed. 2012, 51, 6493-6497. (d) Morán-
Poladura, P.; Rubio, E.; González, J. M. Intramolecular C-H Activa-
tion through Gold(I)-Catalyzed Reaction of Iodoalkynes. Angew.
Chem., Int. Ed. 2015, 54, 3052-3055. (e) Rao, W.; Koh, M. J.;
Kothandaraman, P.; Chan, P. W. H. Gold-Catalyzed
Cycloisomerization of 1,7-Diyne Benzoates to Indeno[1,2-c]azepines
and Azabicyclo[4.2.0]octa-1(8),5-dines. J. Am. Chem. Soc. 2012, 134,
10811-10814.
(6) Pioneering report: (a) Quan, L. G.; Gevorgyan, V.; Yamamoto,
Y. Intramolecular Nucleophilic Addition of Vinylpalladiums to Aryl
Ketones. J. Am. Chem. Soc. 1999, 121, 3545-3546. Selected recent
advances: (b) Shimamoto, Y.; Sunaba, H.; Ishida, N.; Murakami, M.
Regioselective Construction of Indene Skeletons by Palladium-
Catalyzed Annulation of Alkynylborates with o-Iodophenyl Ketones.
Eur. J. Org. Chem. 2013, 1421-1424. (c) González, J.; Santamaría, J.;
Ballesteros, A. Gold(I)-Catalyzed Addition of Silylacetylenes to
Acylsilanes: Synthesis of Indanones by C-H Functionalization
through a Gold(I) Carbenoid. Angew. Chem., Int. Ed. 2015, 54,
13678-13681.
(7) (a) Muralirajan, K.; Parthasarathy, K.; Cheng, C.-H.
Regioselective Synthesis of Indenols by Rhodium-Catalyzed C-H
Activation and Carbocyclization of Aryl Ketones and Alkynes. Angew.
Chem., Int. Ed. 2011, 50, 4169-4172. (b) Patureau, F. W.; Besset, T.;
Kuhl, N.; Glorius, F. Diverse Strategies toward Indenol and Fulvene
Derivatives: Rh-Catalyzed C-H Activation of Aryl Ketones Followed
by Coupling with Internal Alkynes. J. Am. Chem. Soc. 2011, 133,
2154-2156. (c) Zhang, J.; Ugrinov, A.; Zhao, P. Ruthenium(II)/N-
Heterocyclic Carbene Catalyzed [3+2] Carbocyclization with Aro-
matic N-H Ketimines and Internal Alkynes. Angew. Chem., Int. Ed.
2013, 52, 6681-6684.
(3) (a) Xi, Z.; Hwang, G.-S.; Goldberg, I. H.; Harris, J. L.; Pen-
nington, W. T.; Fouad, F. S.; Qabaja, G.; Wright, J. M.; Jones, G. B.
Targeting DNA Bulged Microenvironments with Synthetic Agents:
Lessons from a Natural Product. Chem. Biol. 2002, 9, 925-931. (b)
Xiao, Z.; Kappen, L. S.; Goldberg, I. H. Development of New Simple
Molecular Probes of DNA Bulged Structures. Bioorg. Med. Chem.
Lett. 2006, 16, 2895-2899. (c) Lin, Y.; Jones, G. B.; Hwang, G.-S.;
6
ACS Paragon Plus Environment

Page 7 of 9
ACS Catalysis
1
2
3
4
5
6
7
8
9
(8) (a) Tsukamoto, H.; Ueno, T.; Kondo, Y. Palladium(0)-
Formal Synthesis of 7-Methoxymitosene. Angew. Chem., Int. Ed.
2012, 51, 8624-8627. (b) Wetzel, A.; Gagosz, F. Gold-Catalyzed
Transformation of 2-Alkynyl Arylazides: Efficient Access to the
Valuable Pseudoindoxyl and Indolyl Frameworks. Angew. Chem., Int.
Ed. 2011, 50, 7354-7358. (c) Lu, B.; Luo, Y.; Liu, L.; Ye, L.; Wang,
Y.; Zhang, L. Umpolung Reactivity of Indole through Gold Catalysis.
Angew. Chem., Int. Ed. 2011, 50, 8358-8362. (d) Li, N.; Wang, T.-Y.;
Gong, L.-Z.; Zhang, L. Gold-Catalyzed Multiple Cascade Reaction of
2-Alkynylphenylazides with Propargyl Alcohols. Chem. Eur. J. 2015,
21, 3585-3588. (e) Li, N.; Lian, X.-L.; Li, Y.-H.; Wang, T.-Y.; Han,
Z.-Y.; Zhang, L. Gong, L.-Z. Gold-Catalyzed Direct Assembly of
Aryl-Annulated Carbazoles from 2-Alkynyl Arylazides and Alkynes.
Org. Lett. 2016, 18, 4178-4181.
(13) For reviews: (a) Davies, H. M. L.; Mortona, D. Guiding Prin-
ciples for Site Selective and Stereoselective Intermolecular C-H Func-
tionalization by Donor/Acceptor Rhodium Carbenes. Chem. Soc. Rev.
2011, 40, 1857-1869. (b) Padwa, A. The Interaction of Rhodium
Carbenoids with Carbonyl Compounds as a Method for the Synthesis
of Tetrahydrofurans. J. Organomet. Chem. 2005, 690, 5533-5540. (c)
Ford, A.; Miel, H.; Ring, A.; Slattery, C. N.; Maguire, A. R.;
McKervey, M. A. Modern Organic Synthesis with α-Diazocarbonyl
Compounds. Chem. Rev. 2015, 115, 9981-10080. (d) Deng, Y.; Qiu,
H.; Srinivas, H. D.; Doyle, M. P. Chiral Dirhodium(II) Catalysts for
Selective Metal Carbene Reactions. Curr. Org. Chem. 2016, 20, 61-
81.
(14) For reviews: (a) Zhu, S.-F.; Zhou, Q.-L. Transition-Metal-
Catalyzed Enantioselective Heteroatom-Hydrogen Bond Insertion
Reactions. Acc. Chem. Res. 2012, 45, 1365-1377. (b) Zhao, X.; Zhang,
Y.; Wang, J. Recent Developments in Copper-Catalyzed Reactions
of Diazo Compounds. Chem. Commun. 2012, 48, 10162-10173. (c)
Díaz-Requejo, M. M.; Pérez, P. J. Copper, Silver and Gold-based
Catalysts for Carbene Addition or Insertion Reactions. J. Organomet.
Chem. 2005, 690, 5441-5450.
(15) For reviews: (a) Qian, D.; Zhang, J. Gold-Catalyzed
Cyclopropanation Reactions Using a Carbenoid Precursor Toolbox.
Chem. Soc. Rev. 2015, 44, 677-698. (b) Liu, L.; Zhang, J. Gold-
Catalyzed Transformations of α-Diazocarbonyl Compounds: Selectiv-
ity and Diversity. Chem. Soc. Rev. 2016, 45, 506-516. (c) Fructos, M.
R.; Díaz-Requejo, M. M.; Pérez, P. J. Gold and Diazo Reagents: a
Fruitful Tool for Developing Molecular Complexity. Chem. Commun.
2016, 52, 7326-7335.
Catalyzed Regioselective and Multicomponent Synthesis of 1,2,3-
Trisubstituted 1H-Indenes. Org. Lett. 2007, 9, 3033-3036. (b) Clarke,
C.; Incerti-Pradillos, C. A.; Lam, H. W. Enantioselective Nickel-
Catalyzed anti-Carbometallative Cyclizations of Alkynyl Electro-
philes Enabled by Reversible Alkenylnickel E/Z Isomerization. J. Am.
Chem. Soc. 2016, 138, 8068-8071. (c) Myers, A. G.; Proteau, P. J.;
Handel, T. M. Stereochemical Assignment of Neocarzinostatin
Chromophore. Structures of Neocarzinostatin Chromophore-methyl
Thioglycolate Adducts. J. Am. Chem. Soc. 1988, 110, 7212-7214. (d)
Marion, N.; Díez-González, S.; Frémont, P.; Noble, A. R.; Nolan, S. P.
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
AuI-Catalyzed
Tandem
[3,3]
Rearrangement-Intramolecular
Hydroarylation: Mild and Efficient Formation of Substituted Indenes.
Angew. Chem., Int. Ed. 2006, 45, 3647-3650. (e) Thummanapelli, S.
K.; Hosseyni, S.; Su, Y.; Akhmedova, N. G.; Shi, X. Ligand-
Controlled Gold-Catalyzed Cycloisomerization of 1,n-Enyne Esters
Toward Synthesis of Dihydronaphthalene. Chem. Commun. 2016, 52,
7687-7690.
(9) Pioneering works: (a) Teles, J. H.; Brode, S.; Chabanas, M.
Cationic Gold(I) Complexes: Highly Efficient Catalysts for the Addi-
tion of Alcohols to Alkynes. Angew. Chem., Int. Ed. 1998, 37, 1415-
1418. (b) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. Highly Selective
Gold-Catalyzed Arene Synthesis. J. Am. Chem. Soc. 2000, 122,
11553-11554. (c) Nieto-Oberhuber, C.; Munoz, M. P.; Bunuel, E.;
Nevado, C.; Cardenas, D. J.; Echavarren, A. M. Cationic Gold(I)
Complexes: Highly Alkynophilic Catalysts for the exo- and endo-
Cyclization of Enynes. Angew. Chem., Int. Ed. 2004, 43, 2402-2406.
(d) Gorin, D. J.; Davis, N. R.; Toste, F. D. Gold(I)-Catalyzed
Intramolecular Acetylenic Schmidt Reaction. J. Am. Chem. Soc. 2005,
127, 11260-11261.
(10) For reviews: (a) Gorin, D. J.; Toste, F. D. Relativistic Effects
in Homogeneous Gold Catalysis. Nature 2007, 446, 395-403. (b)
Hashmi, A. S. K. Gold-Catalyzed Organic Reactions. Chem. Rev.
2007, 107, 3180-3211. (b) Li, Z.; Brouwer, C.; He, C. Gold-Catalyzed
Organic Transformations. Chem. Rev. 2008, 108, 3239-3265. (c)
Zhang, L. A Non-Diazo Approach to α-Oxo Gold Carbenes via Gold-
Catalyzed Alkyne Oxidation. Acc. Chem. Res. 2014, 47, 877-888. (d)
Dorel, R.; Echavarren, A. M. Gold(I)-Catalyzed Activation of Al-
kynes for the Construction of Molecular Complexity. Chem. Rev.
2015, 115, 9028-9072. (e) Zheng, Z.; Wang, Z.; Wang, Y.; Zhang, L.
Au-Catalysed Oxidative Cyclisation. Chem. Soc. Rev. 2016, 45, 4448-
4458.
(11) Selected recent advances: (a) Gronnier, C.; Kramer, S.;
Odabachian, Y.; Gagosz, F. Cu(I)-Catalyzed Oxidative Cyclization of
Alkynyl Oxiranes and Oxetanes. J. Am. Chem. Soc. 2012, 134, 828-
831. (b) Henrion, G.; Chavas, T. E. J.; Goff, X. L.; Gagosz, F.
Biarylphosphonite Gold(I) Complexes as Superior Catalysts for Oxi-
dative Cyclization of Propynyl Arenes into Indan-2-ones. Angew.
Chem., Int. Ed. 2013, 52, 6277-6282. (c) Wang, Y.; Ji, K.; Lan, S.;
Zhang, L. Rapid Access to Chroman-3-ones through Gold-Catalyzed
Oxidation of Propargyl Aryl Ethers. Angew. Chem., Int. Ed. 2012, 51,
1915-1918. (d) Ji, K.; Zhao, Y.; Zhang, L. Optimizing P,N-Bidentate
Ligands for Oxidative Gold Catalysis: Efficient Intermolecular Trap-
ping of α-Oxo Gold Carbenes by Carboxylic Acids. Angew. Chem.,
Int. Ed. 2013, 52, 6508-6512. (e) Luo, Y.; Ji, K.; Li, Y.; Zhang, L.
Tempering the Reactivities of Postulated α-Oxo Gold Carbenes Using
Bidentate Ligands: Implication of Tricoordinated Gold Intermediates
and the Development of an Expedient Bimolecular Assembly of 2,4-
Disubstituted Oxazoles. J. Am. Chem. Soc. 2012, 134, 17412-17415.
(f) Ji, K.; Zheng, Z.; Wang, Z.; Zhang, L. Enantioselective Oxidative
Gold Catalysis Enabled by a Designed Chiral P,N-Bidentate Ligand.
Angew. Chem., Int. Ed. 2015, 54, 1245-1249. (g) Wang, Y.; Zheng, Z.;
Zhang, L. Intramolecular Insertions into Unactivated C(sp3)-H Bonds
by Oxidatively Generated β-Diketone-α-Gold Carbenes: Synthesis of
Cyclopentanones. J. Am. Chem. Soc. 2015, 137, 5316-5319.
(16) (a) Cao, Z.-Y.; Wang, X.; Tan, C.; Zhao, X.-L.; Zhou, J.; Ding,
K. Highly Stereoselective Olefin Cyclopropanation of Diazooxindoles
Catalyzed by a C2-Symmetric Spiroketal Bisphosphine/Au(I) Com-
plex. J. Am. Chem. Soc. 2013, 135, 8197-8200. (b) Zhou, Y.; Trewyn,
B. G.; Angelici, R. J.; Woo, L. K. Catalytic Reactions of Carbene
Precursors on Bulk Gold Metal. J. Am. Chem. Soc. 2009, 131, 11734-
11743. (c) Briones, J. F.; Davies, H. M. L. Gold(I)-Catalyzed Asym-
metric Cyclopropenation of Internal Alkynes. J. Am. Chem. Soc. 2012,
134, 11916-11919.
(17) Fructos, M. R.; Belderrain, T. R.; Frémont, P.; Scott, N. M.;
Nolan, S. P.; Díaz-Requejo, M. M.; Pérez, P. J. A Gold Catalyst for
Carbene-Transfer Reactions from Ethyl Diazoacetate. Angew. Chem.,
Int. Ed. 2005, 44, 5284-5288.
(18) (a) Xu, G.; Zhu, C.; Gu, W.; Li, J.; Sun, J. Gold(I)-Catalyzed
Diazo Cross-Coupling:
A
Selective and Ligand-Controlled
Denitrogenation/Cyclization Cascade. Angew. Chem., Int. Ed. 2015,
54, 883-887. (b) Pagar, V. V.; Liu, R.-S. Gold-Catalyzed
Cycloaddition Reactions of Ethyl Diazoacetate, Nitrosoarenes, and
Vinyldiazo Carbonyl Compounds: Synthesis of Isoxazolidine and
Benzo[b]azepine Derivatives. Angew. Chem., Int. Ed. 2015, 54, 4923-
4926. (c) Lonzi, G.; López, L. A. Regioselective Synthesis of Func-
tionalized Pyrroles viaGold(I)-Catalyzed [3+2]ꢀCycloaddition of Sta-
bilized Vinyl Diazo Derivatives and Nitriles. Adv. Synth. Catal. 2013,
355, 1948-1954. (d) Yu, Z.; Qiu, H.; Liu, L.; Zhang, J. Gold-
(12) Selected recent advances: (a) Yan, Z.-Y.; Xiao, Y.; Zhang, L.
Gold-Catalyzed One-Step Construction of 2,3-Dihydro-1H-
Pyrrolizines with an Electron-Withdrawing group in the 5-position: A
Catalyzed
Construction
of
Two
Adjacent
Quaternary
Stereocenters via Sequential C-H Functionalization and Aldol Annu-
lation. Chem. Commun. 2016, 52, 2257-2260. (e) Pagar, V. V.; Jadhav,
7
ACS Paragon Plus Environment

ACS Catalysis
Page 8 of 9
1
2
3
4
5
6
7
8
9
A. M.; Liu, R.-S. Gold-Catalyzed Formal [3+3] and [4+2]
Synthetic Studies and Mechanistic Insight in Nickel-Catalyzed
[4+2+1] Cycloadditions. J. Am. Chem. Soc. 2006, 128, 2609-2614.
Our works: (h) Zheng, Y.; Mao, J.; Weng, Y.; Zhang, X.; Xu, X.
Cyclopentadiene Construction via Rh-Catalyzed Carbene/Alkyne
Metathesis Terminated with Intramolecular Formal [3+2]
Cycloaddition. Org. Lett. 2015, 17, 5638-5641. (i) Yao, R.; Rong, G.;
Yan, B.; Qiu, L.; Xu, X. Dual-Functionalization of Alkynes via Cop-
per-Catalyzed Carbene/Alkyne Metathesis: A Direct Access to the 4-
Carboxyl Quinolines. ACS Catal. 2016, 6, 1024-1027. (j) Wang, X.;
Zhou, Y.; Qiu, L.; Yao, R.; Zheng, Y.; Zhang, C.; Bao, X.; Xu, X.
Enantioselective Carbene Cascade: An Effective Approach to
Cyclopentadienes and Applications in Diels-Alder Reactions. Adv.
Synth. Catal. 2016, 358, 1571-1576. (k) Dong, K.; Pei, C.; Zeng, Q.;
Wei, H.; Doyle, M. P.; Xu, X. Selective C(sp3)-H Bond Insertion in
Carbene/Alkyne Metathesis Reactions. Enantioselective Construction
of Dihydroindoles. ACS Catal. 2018, 8, 9543-9549.
(24) Xu, X.; Zavalij, P. Y.; Doyle, M. P. Synthesis of
Tetrahydropyridazines by a Metal-Carbene-Directed Enantioselective
Vinylogous N-H Insertion/Lewis Acid-Catalyzed Diastereoselective
Mannich Addition. Angew. Chem., Int. Ed. 2012, 51, 9829-9833.
(25) For reviews: For reviews: (a) Xu, X.; Doyle, M. P. The [3+3]-
Cycloaddition Alternative for Heterocycle Syntheses: Catalytically
Generated Metalloenolcarbenes as Dipolar Adducts. Acc. Chem. Res.
2014, 47, 1396-1405. (b) Guo, X.; Hu, W. Novel Multicomponent
Reactions via Trapping of Protic Onium Ylides with Electrophiles.
Acc. Chem. Res. 2013, 46, 2427-2440. (c) Davies, H. M. L.; Lian, Y.
The Combined C-H Functionalization/Cope Rearrangement: Discov-
ery and Applications in Organic Synthesis. Acc. Chem. Res. 2012, 45,
923-935.
Cycloaddition Reactions of Nitrosobenzenes with Alkenylgold
Carbenoids. J. Am. Chem. Soc. 2011, 133, 20728-20731. (f) Pawar, S.
K.; Wang, C.-D.; Bhunia, S.; Jadhav, A. M.; Liu, R.-S. Gold-
Catalyzed Formal Cycloaddition of 2-Ethynylbenzyl Ethers with
Organic Oxides and α-Diazoesters. Angew. Chem., Int. Ed. 2013, 52,
7559-7563. (g) Briones, J. F.; Davies, H. M. L. Enantioselective
Gold(I)-Catalyzed Vinylogous [3+2] Cycloaddition between
Vinyldiazoacetates and Enol Ethers. J. Am. Chem. Soc. 2013, 135,
13314-13317. (h) Rao, S.; Prabhu, K. R. Gold-Catalyzed [2,3]-
Sigmatropic Rearrangement: Reaction of Aryl Allyl Alcohols with
Diazo Compounds. Org. Lett. 2017, 19, 846-849.
(19) (a) Benitez, D.; Shapiro, N. D.; Tkatchouk, E.; Wang, Y.;
Goddard, W. A.; Toste, F. D. A Bonding Model for Gold(I) Carbene
Complexes. Nat. Chem. 2009, 1, 482-486. (b) Seidel, G.; Fürstner, A.
Structure of a Reactive Gold Carbenoid. Angew. Chem., Int. Ed. 2014,
53, 4807-4811. (c) Wang, Y.; Muratore, M. E.; Echavarren, A. M.
Gold Carbene or Carbenoid: Is There a Difference?. Chem. Eur. J.
2015, 21, 7332-7339.
(20) (a) Xi, Y.; Su, Y.; Yu, Z.; Dong, B.; McClain, E. J.; Lan, Y.;
Shi, X. Chemoselective Carbophilic Addition of α-Diazoesters
through Ligand-Controlled Gold Catalysis. Angew. Chem., Int. Ed.
2014, 53, 9817-9821. (b) Yu, Z.; Ma, B.; Chen, M.; Wu, H.-H.; Liu,
L.; Zhang, J. Highly Site-Selective Direct C-H Bond Functionaliza-
tion of Phenols with α-Aryl-α-diazoacetates and Diazooxindoles via
Gold Catalysis. J. Am. Chem. Soc. 2014, 136, 6904-6907. (c) Ma, B.;
Chu, Z.; Huang, B.; Liu, Z.; Liu, L.; Zhang, J. Highly para-Selective
C-H Alkylation of Benzene Derivatives with 2,2,2-Trifluoroethyl α-
Aryl-α-Diazoesters. Angew. Chem., Int. Ed. 2017, 56, 2749-2753.
(21) (a) Wang, J.; Yao, X.; Wang, T.; Han, J.; Zhang, J.; Zhang, X.;
Wang, P.; Zhang, Z. Synthesis of 2,5-Dihydrofurans via a Gold(I)-
Catalyzed Formal [4+1] Cycloaddition of α-Diazoesters and
Propargyl Alcohols. Org. Lett. 2015, 17, 5124-5127. (b) Ma, B.; Wu,
Z.; Huang, B.; Liu, L. Zhang, J. Gold-Catalysed Facile Access to
Indene Scaffolds via Sequential C-H Functionalization and 5-endo-
dig Carbocyclization. Chem. Commun. 2016, 52, 9351-9354. (c) Shi,
T.; Guo, X.; Teng, S.; Hu, W. Pd(II)-Catalyzed Formal [4+1]
Cycloaddition Reactions of Diazoacetates and Aryl Propargyl Alco-
hols to form 2,5-Dihydrofurans. Chem. Commun. 2015, 51, 15204-
15207. (d) Li, Z.; Boyarskikh, V.; Hansen, J. H.; Autschbach, J.;
Musaev, D. G.; Davies, H. M. L. Scope and Mechanistic Analysis of
the Enantioselective Synthesis of Allenes by Rhodium-Catalyzed
Tandem Ylide Formation/[2,3]-Sigmatropic Rearrangement between
Donor/Acceptor Carbenoids and Propargylic Alcohols. J. Am. Chem.
Soc. 2012, 134, 15497-15504.
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
(26) See Supporting Information for details.
(27) Zhou, L.; Liu, Y.; Zhang, Y.; Wang, J. Sequential Au(I)-
Catalyzed Reaction of Water with o-Acetylenyl-Substituted
Phenyldiazoacetates. Beilstein J. Org. Chem. 2011, 7, 631-637.
(28) CCDC 1551665, CCDC 1556423, and CCDC 1556770 con-
tain the supplementary crystallographic data for 2f, 2n, and 5j, respec-
tively. These data can be obtained free of charge from the Cambridge
crystallographic data centre via www.ccdc.cam.ac.uk/data_request/cif.
(29) Qiu, H.; Srinivas, H. D.; Zavalij, P. Y.; Doyle, M. P. Unprece-
dented Intramolecular [4+2]-Cycloaddition between a 1,3-Diene and a
Diazo Ester. J. Am. Chem. Soc. 2016, 138, 1808-1811.
(30) For selected examples of computational studies on the for-
mation of gold carbenoid intermediates via diazo compounds, see (a)
Liu, Y.; Yu, Z.; Zhang, J. Z.; Liu, L.; Xia, F.; Zhang, J. Origins of
Unique Gold-Catalysed Chemo- and Site-Selective C-H Functionali-
zation of Phenols with Diazo Compounds. Chem. Sci. 2016, 7, 1988-
1995. (b) Duan, A.; Yu, P.; Liu, F.; Qiu, H.; Gu, Doyle, M. P.; F. L.;
Houk, K. N. Diazo Esters as Dienophiles in Intramolecular (4+2)
Cycloadditions: Computational Explorations of Mechanism. J. Am.
Chem. Soc. 2017, 139, 2766-2770. (c) Seidel, G.; Gabor, B.; Goddard,
R.; Heggen, B.; Thiel, W.; Fürstner, A. Gold Carbenoids: Lessons
Learnt from a Transmetalation Approach. Angew. Chem., Int. Ed.
2014, 53, 879-882.
(22) Witham, C. A.; Mauleón, P.; Shapiro, N. D.; Sherry, B. D.;
Toste, F. D. Gold(I)-Catalyzed Oxidative Rearrangements. J. Am.
Chem. Soc. 2007, 129, 5838-5839.
(23) Selected recent advances: (a) Jansone-Popova, S.; May, J. A.
Synthesis of Bridged Polycyclic Ring Systems via Carbene Cascades
Terminating in C-H Bond Insertion. J. Am. Chem. Soc. 2012, 134,
17877-17880. (b) Cambeiro, F.; López, S.; Varela, J. A.; Saá, C. Vi-
nyl Dihydropyrans and Dihydrooxazines: Cyclizations of Catalytic
Ruthenium Carbenes Derived from Alkynals and Alkynones. Angew.
Chem., Int. Ed. 2014, 53, 5959-5963. (c) González-Rodríguez, C.;
Suárez, J. M.; Varela, J. A.; Saá, C. Nucleophilic Addition of Amines
(31) Stokes, B. J.; Jovanović, B.; Dong, H.; Richert, K. J.; Riell, R.
D.; Driver, T. G. Rh2(II)-Catalyzed Synthesis of Carbazoles from
Biaryl Azides. J. Org. Chem. 2009, 74, 3225-3228.
to
Ruthenium
Carbenes: ortho-(Alkynyloxy)benzylamine
Cyclizations towards 1,3-Benzoxazines. Angew. Chem., Int. Ed. 2015,
54, 2724-2728. (d) Chen, P.; Setthakarn, K.; May, J. A. A Binaphthyl-
Based Scaffold for a Chiral Dirhodium(II) Biscarboxylate Ligand
with α-Quaternary Carbon Centers. ACS Catal. 2017, 7, 6155-6161.
(e) Torres, Ó.; Parella, T.; Solà, M.; Roglans, A.; Pla-Quintana, A.
Enantioselective Rhodium(I) Donor Carbenoid-Mediated Cascade
Triggered by a Base-Free Decomposition of Arylsulfonyl Hydrazones.
Chem. Eur. J. 2015, 21, 16240-16245. (f) Qian, Y.; Shanahan, C. S.;
Doyle, M. P. Templated Carbene Metathesis Reactions from the
Modular Assembly of Enol-diazo Compounds and Propargyl Acetates.
Eur. J. Org. Chem. 2013, 6032-6037. (g) Ni, Y.; Montgomery, J.
8
ACS Paragon Plus Environment

Page 9 of 9
ACS Catalysis
1
2
3
4
5
TOC
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
9
ACS Paragon Plus Environment