Controlling the Selectivity Patterns of Au-Catalyzed Cyclization-Migration Reactions

Article abstract of DOI:10.1021/acs.orglett.8b03888

As little as 2 mol % of (XPhos)AuNTf₂ catalyzes the transformation of a broad range of o-acetylene-substituted styrenes into 1,2-dihydronaphthalenes. Our data suggests that this transformation occurs via a gold-stabilized cyclopropyl carbinyl cation, which triggers either a [1,2] carboxylate shift or a less favorable [1,2] aryl shift. The relative rates of these migrations can be controlled by the identity of the ligand or by stabilizing the mesomeric cation.

Full text of DOI:10.1021/acs.orglett.8b03888

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Controlling the Selectivity Patterns of Au-Catalyzed Cyclization−
Migration Reactions
Mo Chen,† Naijing Su,‡ Tianning Deng,‡ Donald J. Wink,‡ Yingwei Zhao,‡,§ and Tom G. Driver*,‡
†College of Chemistry, Nankai University, 94 Weijin Road, Tianjin 30007, People’s Republic of China
‡Department of Chemistry, University at Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, United States
§College of Chemical Engineering, Huaqiao University, 668 Jimei Boulevard, Xiamen, Fujian 361021, People’s Republic of China
S
* Supporting Information
ABSTRACT: As little as 2 mol % of (XPhos)AuNTf2 catalyzes the
transformation of a broad range of o-acetylene-substituted styrenes into
1,2-dihydronaphthalenes. Our data suggests that this transformation
occurs via a gold-stabilized cyclopropyl carbinyl cation, which triggers
either a [1,2] carboxylate shift or a less favorable [1,2] aryl shift. The
relative rates of these migrations can be controlled by the identity of
the ligand or by stabilizing the mesomeric cation.
ccessing electrophilic gold reactive intermediates from
Ainternal acetylenes has spurred significant reaction
discovery.1 The reactivity embedded in these carbenoid or
cationic intermediates has been exploited in reactions that are
often mechanistically distinct from traditional transition-metal-
catalyzed reactions even though they proceed via similar
intermediates.2 Although gold-catalyzed tandem reactions are
common,3 sequences involving a [1,2] alkyl- or aryl group shift
are scarce and limited to alleviating ring strain or establishing
aromaticity.4 Our laboratory has investigated the reactivity
patterns of aryl-substituted metal carbenes and nitrenes
(Scheme 1). Our investigations established that rhodium N-
aryl nitrenes such as 2 reacted with the proximal olefin to
initiate an electrocyclization [1,2] carboxylate migration to
construct 3H-indoles.5 In contrast, electron-rich aryl,alkyl-
disubstituted metal carbenes 6 generated from N-tosylhydra-
zones reacted with either the carbon oxygen double bond to
create α-methoxy 2H-naphthalenone 7 or the allylic C−H
bond to furnish 8 using either CuI or Rh2(esp)2 as the
catalyst.6 Because the identity of the metal controlled the site
selectivity of reaction, we were curious if a gold catalytic
intermediate generated from an internal acetylene would react
with a proximal electron-deficient olefin in a cyclization−
migration reaction or if this reactivity pattern was limited to
rhodium nitrenoids.7 Despite their potential to form
quaternary carbon stereocenters, the only tetrasubstituted
olefins reported to capture the gold acetylene intermediate
have either been cyclopropylidenes or enoxysilanes,4e,f,8 and
[1,2] carboxylate migrations in these tandem reactions are
unprecedented.9 Herein, we demonstrate that carboxylate
migrations are not limited to metal nitrenes but are a reactivity
pattern of electron-rich metal divalent catalytic intermediates
that can be accessed using cationic gold complexes.
Scheme 1. Deconvoluting the Reactivity Patterns of Metal
Divalent Intermediates
Our investigation into examining the reactivity of o-
acetylene-substituted trisubstituted styrenes toward gold
complexes was initiated using 13a (Table 1). This substrate
was chosen to determine the optimal conditions because it was
readily available from 2-bromoiodobenzene through a three-
step Sonogashira Suzuki−Miyaura sequence. After a survey of
transition-metal complexes that had been reported to catalyze
related cycloisomerization reactions,10 we discovered that 5
mol % of (Ph3P)AuNTf2 produced a new product whose
structure was confirmed to be 14a by X-ray crystallography
(entry 1). Salt metathesis was required: in the absence of
AgNTf2 no reaction was obtained. Changing the ligand on gold
Received: December 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03888
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of Cycloisomerization Reaction
Table 2. Exploration of the Scope and Limitations
a
entry
catalyst (mol %)
AgX (mol %)
solvent
yield (%)
1
2
3
4
5
6
7
8
(Ph3P)AuCl (5)
AgNTf2 (6)
AgNTf2 (6)
AgNTf2 (12)
AgNTf2 (6)
AgNTf2 (6)
AgNTf2 (2.4)
AgNTf2 (1.5)
AgOTf (6)
AgPF6 (6)
PhMe
PhMe
PhMe
PhMe
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
20
dec
<5
22
99
95
88
12
20
70
96
nr
(iPrNHC)AuCl (5)
[(dppf)(AuCl)2] (5)
(XPhos)AuCl (5)
(XPhos)AuCl (5)
(XPhos)AuCl (2)
(XPhos)AuCl (1)
(XPhos)AuCl (5)
(XPhos)AuCl (5)
(XPhos)AuCl (5)
(XPhos)AuNTf2 (5)
9
10
11
12
AgSbF6 (6)
AgNTf2
AgNTf2
b
13
nr
a
Determined using 1H NMR spectroscopy with CH2Br2 as an internal
b
standard. 2 μL of H2O added.
also affected the yield with the best outcome obtained using
XPhos (entries 2−4). The reaction conditions were further
explored using this gold complex (entries 6−10). The yield
was increased when the solvent was changed. While no
reaction or low yields were obtained in THF, MeOH, or
MeCN, switching to DCE improved the yield to 99% (entry
5). While lowering the catalyst loading to 2 mol % had a
negligible effect, the reaction yield was attenuated when only 1
mol % of catalyst was used (entries 6 and 7). Changing the
identity of the counterion to triflate, hexafluorophosphate, or
hexafluoroantimonate also produced lower yields (entries 8−
10). Control experiments were performed to determine that
the reaction was catalyzed by gold and not by either silver or
proton (entries 11−13).
Using the optimal conditions, the scope and limitations of
the tandem reaction were investigated using substrates that
varied the electronic nature of the acetylenic substituents
(Table 2). First, we found that the reaction could be scaled to
1 mmol without negatively affecting the yield of the tandem
reaction (entry 1). Next, the reaction was found to be immune
to changing the electronic nature of the R1 and R2 substituent
with only an attenuation of yield observed with a CF3 group
(entries 2−7). Changing the identity of the terminal R3 group
had a larger effect on the reaction outcome (entries 8−12).
While electron-rich and electron-poor aryl groups were
tolerated, no reaction was observed with an R3-cyclopentyl
group. To our surprise, 13l bearing a cyclopropyl R3 group was
smoothly converted to 1,2-dihydronaphthalene 14l. The lack
of ring-opening byproducts suggests that no radical inter-
mediates are formed during the transformation. While no
reaction was observed when the acetylenic substituent was an
alkyl group (13m), only decomposition was observed when
the substrate contained an isopropenyl R3 substituent (13n).
Next, the scope and limitations of this reaction were
examined by varying the identity of the alkenyl portion of
substrate 15 (Table 3). First, the identity of the ester
substituent could be changed to ethyl without negatively
impacting the reaction outcome (entry 1). Next, we found that
the size of cycloalkenyl could be changed without affecting the
a
b
Isolated yield of 14 after silica gel chromatography. 1 mmol scale.
c
d
5 mol % of (XPhos)AuCl and 6 mol % of AgNTf2 used. 100% of
13k recovered.
reaction outcome (entries 2−4). A cyclic o-alkenyl substituent
was not required: irrespective of the geometry, Z-15e or E-15f
was smoothly transformed to product (entries 5 and 6).
Exposure of 15g to reaction conditions revealed that in the
absence of the β-carboxylate only cyclization occurred to afford
naphthalene 16g (entry 7).
Our investigations into substrate control of the stereo-
selectivity of the reaction provided insight into the possible
mechanisms for product formation (Scheme 2). To test if
diastereoselectivity could be obtained, 4-tert-butyl-substituted
17a was submitted to the reaction conditions. To our surprise,
two isomers 18a and 19a were obtained in 72:28 ratio. While
18a was obtained as a single diastereomer, 19a was formed in a
3:1 ratio. The formation of both isomers provides insight into
the mechanism of the isomerization−migration reaction:
coordination of the cationic gold complex to the acetylene
triggers a cyclization to form cyclopropylcarbinyl cation 21.
Dihydronaphthalene cation 24 is formed either from a [1,2]
carboxylate shift or a [1,2] aryl shift.11−13 These [1,2] shifts
can be visualized as occurring via mesomers 22 or 23 of the
cyclopropyl carbinyl cation. Elimination of the gold cation then
produces the product. The product ratio observed from the
reaction of 17a suggests that the [1,2] carboxylate migration
reaction is preferred.
Next, we were curious if the relative rates of migration could
be modified to favor carboxylate migration by stabilizing
mesomer 22.14 To test this hypothesis, substrates 17b−e were
synthesized (Table 4). We anticipated that as the R substituent
became more electron-rich that the [1,2] carboxylate migration
B
DOI: 10.1021/acs.orglett.8b03888
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Investigation of the Effect of Changing the Ortho-
Substituent
Table 4. Electronic Control of the Relative Rates of
Cyclization
a
b
entry
no.
R1
R2
yield (%)
18/19
c
1
2
3
4
5
b
c
a
d
e
MeO
Me
H
H
F3C
H
H
H
MeO
H
74
82
76
74
56
88:12
73:27
72:28
59:41
54:46
a
b
5 mol % of (XPhos)AuCl and 6 mol % of AgNTf2 were used. As
determined using 1H NMR spectroscopy using CH2Br2 as an internal
standard. Use of 5 mol % of (JackiePhos)AuCl resulted in an 89:11
c
mixture of 18b and 19b.
charge formed in the cyclization): positioning the methoxy
group in the 4-position resulted in an 88:12 mixture of 18b
and 19b, while placing it in the 5-position, where it cannot
stabilize 21, produced a 59:41 mixture of isomers. To
determine if this electronic effect could be maximized by
changing the phosphine ligand, the reactivity of 17b was
explored using JackiePhos as the ligand to produce an 89:11
mixture of 18b and 19b.
In conclusion, we discovered that (XPhos)AuNTf2 catalyzes
the transformation of o-(alkynyl)styrenes into 1,2-dihydro-
naphthalenes. This transformation occurs through a gold-
stabilized cyclopropyl carbinyl cation that triggers either a
[1,2] carboxylate shift or a less favorable [1,2] aryl shift. The
relative rates of migration can be controlled by the phosphine
ligand or by stabilizing the mesomeric cation to illustrate the
effect that substitution has on the mechanism. Our future
experiments are aimed at further understanding and control-
ling the relative rates of cyclization to develop an
enantioselective variant of this transformation.
a
Isolated yield of 16 after silica gel chromatography.
Scheme 2. Competing Mechanisms for 1,2-
Dihydronaphthalene Formation
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03888.
Experimental procedures and analytical data (PDF)
Accession Codes
CCDC 1874905 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tgd@uic.edu.
ORCID
would become more favorable. In line with our assertion, we
found that the amount of 18 increased as the R substituent
became more electron-donating. Comparing the reaction
outcome between 17b and 17d underscores the importance
of stabilizing the positive charge in 21 (or the partial positive
Donald J. Wink: 0000-0002-2475-2392
Tom G. Driver: 0000-0001-7001-342X
C
DOI: 10.1021/acs.orglett.8b03888
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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(10) See the Supporting Information for more details.
Notes
The authors declare no competing financial interest.
(11) For monomeric cationic phosphine Au(I) internal acetylene
crystal structures, see: (a) Review: Brooner, R. E. M.; Widenhoefer,
R. A. Angew. Chem., Int. Ed. 2013, 52, 11714. (b) Shapiro, N. D.;
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(c) Hooper, T. N.; Green, M.; Russell, C. A. Chem. Commun. 2010,
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ACKNOWLEDGMENTS
■
We are grateful to the National Science Foundation CHE-
1564959, University of Illinois at Chicago, Office of the Vice-
Chancellor for Research, Huaqiao University Xiamen, the
Fujian Hundred Talents Plan, Nankai University, and the
Chinese Academy of Science for their generous financial
support. We thank Mr. Furong Sun (UIUC) for HRMS data.
́
(a) Mauleon, P.; Krinsky, J. L.; Toste, F. D. J. Am. Chem. Soc. 2009,
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DOI: 10.1021/acs.orglett.8b03888
Org. Lett. XXXX, XXX, XXX−XXX