Utility of Ligand Effect in Homogenous Gold Catalysis: Enabling Regiodivergent π-Bond-Activated Cyclization

Article abstract of DOI:10.1021/jacs.6b01707

Comprehensive utilization of both electronic and steric properties of ligands in homogeneous gold catalysis is achieved in the regiodivergent intramolecular hydroarylation of alkynes. A flexible electron-deficient phosphite ligand, combined with the readily transformable directing group methoxyl amide, is attached to a cationic Au(I) center in three-coordinate mode, affording sterically hindered ortho-position cyclization. Meanwhile, para-position cyclization is exclusively achieved with the assistance of a rigid electron-abundant phosphine ligand-based Au(I) catalyst, in which ligands manifest the compensating effect for cyclization through steric hindrance and electronic properties. By combining gold with silver catalysts, tetrahydropyrroloquinolinones possessing a congested tricyclic structure are obtained via a proven Au/Ag relay catalytic process.

Full text of DOI:10.1021/jacs.6b01707

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Communication
Utility of Ligand Effect in Homogenous Gold Catalysis:
Enabling Regiodivergent #-bond-activated Cyclization
Dong Ding, Tao Mou, Minghao Feng, and Xuefeng Jiang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 08 Apr 2016
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Utility of Ligand Effect in Homogenous Gold Catalysis: Enabling
Regiodivergent πꢀbondꢀactivated Cyclization
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，†，‡
Dong Ding, Tao Mou, Minghao Feng and Xuefeng Jiang*
†Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East
China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, P. R. China.
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. China.
Supporting Information Placeholder
Scheme 1. GoldꢀCatalyzed Intramolecular Hydroarylation
of Alkynes and Cascade Cyclization.
ABSTRACT: A comprehensive utilization of both electronic
and steric properties from the ligands in homogenous gold
catalysis is achieved through being applied to regiodivergent
intramolecular hydroarylation of alkynes reactions. Flexible
electronꢀdeficient phosphite ligand, combining with readily
transformable directing group methoxyl amide, is attached to
cationic gold(I) center in threeꢀcoordinate mode affording
sterically hindered orthoꢀposition cyclization. Meanwhile,
paraꢀposition cyclization is exclusively achieved by the assistance
of a rigid electronꢀabundant phosphine ligand based gold(I)
catalyst, in which ligands manifest the compensating effect for
cyclization through steric hinderance and electronic properties.
Combining
gold
with
silver
catalysts,
tetrahydropyrroloquinolinones possessing congested tricyclic
structure are obtained, which is proved to be Au/Ag relay catalytic
process.
Homogenous gold catalysis underwent
a
flourishing
development in the past decade and emerged as an efficient and
powerful tool for constructing complex molecules, largely due to
its preponderant function as carbophilic πꢀacid activating
carbonꢀcarbon multiple bonds.1 Ligands play a crucial role in
boosting the progress of homogenous gold catalysis for steering
properties of catalysts, leading to the variation of reactions.2ꢀ3
Intramolecular hydroarylation of alkyne reactions catalyzed by
gold have been useful methods for obtaining fused heteroarenes in
virtue of its highly efficient atom economy.4 In 2005, Echavarren
group reported the first gold(I) catalyzed regioselective version of
intramolecular hydroarylation with one substrate bearing
electronꢀrich hydroxyl group.4c Then regiocontrol of
intramolecular hydroarylation on indole scaffolds was achieved
by switching gold(I) and gold(III) catalyst that also disclosed by
Echavarren et al.4d Although massive attention has been paid to
goldꢀcatalyzed alkyne hydroarylation processes from then on,4eꢀ4k
regioselectivity of substituted aromatics and utilization of
electronꢀdeficient substrates still remains stubborn challenges
(Scheme 1, A). Following the understanding of ligand effect5 in
our research and combiningwith directing concept in CꢀH
activation,6 solution for problems mentioned above is envisioned.
Electrophilic gold complexes, tuned by electronꢀdeficient ligands,
will permit another coordination with directing group which
simultaneously “pull” goldꢀcoordinated πꢀsystem to sterically
hindered ortho position on aromatic rings for further cyclization.7
Alternatively, the rigid bulky electronꢀrich ligands supplement
steric hinderance and electronic properties, which eventually
“push” πꢀsystem to para position (Scheme 1, B). Herein, we
report the gold(I)ꢀcatalyzed regiodivergent intramolecular
hydroarylation of alkynes, in which sterically hindered
orthoꢀposition cyclization is governed by the electronꢀdeficient
ligand via threeꢀcoordinate gold and bulky electronꢀrich ligand
surmounts the defect of electronic and steric requirement.
We commenced the study with the model substrate 1a equipped
with methoxyl amide which was unfolded as the best directing
group8 to test gold(I) catalysts with diverse electronic and steric
properties (Table S1).9 As assumed, electronꢀdeficient
tris(2,4ꢀdiꢀtertꢀbutylphenyl) phosphite ligand resulted in smooth
orthoꢀposition cyclization, generating dihydroquinoline 2a in 61%
isolated yield. The ligand compensating effect was demonstrated
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Table 1. Scope of Both Ortho- and Para-Position Cyclizationa, b, c, d
Page 2 of 5
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OMe
NH
O
OMe
NH R1
OMe
HN
PCy2
iPr
P
O
tBu
tBu
R1
X
O
O
iPr
R2
L1AuOTf (5 mol%)
Condition A
L2AuNTf2 (5 mol%)
Condition B
H
R2
X
R2
iPr
L2
R1
3
X
L1
H
3
1
2
7
8
FG
R
9
FG
R = H,
2-Me, 3b, 73%
3-OMe, 3c, 68%
4-Br,
4-Cl,
3a, 87%
R = H
2a, 61% o:p = 5.6:1
NTs
2-Me, 2b, 68%, o:p = 10.1:1
3-OMe, 2c, 70%, o:p = 12.2:1
4-Br,
4-Cl,
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R
3d, 65%
3e, 61%
N
2d, 66%, o:p = 4.2:1
2e, 64%, o:p = 4.5:1
3a
2a
Ts
3a-3e
2a-2e
FG
FG
FG
FG
Me
S
FG
FG
FG
FG
Me
NTs
NMs
O
O
N
Br
N
O
O
Ts
Ts
2g, 79%e
S
2f, 61%
2i, 81% (60%, 5 mmol)h
2j, 78%f
3j, 75%f
3f, 85%
FG
3h, 84%
3i, 82% (65%, 5mmol)
(o:p = 4.0:1)
(o:p > 20:1)
(o:p > 20:1)
(o:p > 20:1)
O
FG
Me
H
O
FG
Me
H
O
FG C4H9
FG
FG
H
H
H
FG
FG
O
O
O
H
O
O
O
C4H9
O
O
3k, 60%f
O
2k, 66%f
2l, 76%g
2m, 62%g
2n, 56%
(o:p > 20:1)
3l, 67%g
3m, 65%g
3n, 77%
(o:p > 20:1)
(o:p > 20:1)
(o:p > 20:1)
aFG = CONHOMe. Condition A: 1a (0.1 mmol), (2,4ꢀtBu2PhO)3PAuOTf (5 mol%) in DCE (1.0 mL) at 80 C for 8 h. Condition B: 1a
b
o
(0.1 mmol), XphosAuNf2 (5 mol%) in DCE at 80 oC for 8 h. c Isolated yields of pure product, in the right table isolated yields refer to the
1
e
yields of orthoꢀcyclized products.. d The ratio was determined by HNMR. (2,4ꢀtBu2PhO)3PAuNTf2 was used and 1 equivalent of acetic
acid was added. f3 h. g5 h. ho:p = 10.8:1
Table 2. Au/Ag relay cascade cyclization.a,b
when gold(I) complexes coordinated with rigid bulky
electronꢀrich Xphos ligand, leading to the exclusive formation of
dihydroquinoline 3a in 87% yield via paraꢀposition cyclization.
As shown on the right section of Table 1, R1 substituted with
electronꢀdonating groups, provided better yields and higher
regioselectivity than substituted with electronꢀwithdrawing groups,
probably owing to the poorer coordination of electronꢀdeficient
alkynes with gold catalyst (Table 1, 2bꢀ2e). Particularly, when the
aromatic ring contained metaꢀsubstituted bromine group,
orthoꢀposition cyclization occurred with great regioselectivity
(>20:1) (Table 1, 2g). In addition, when oxygen atom employed
as linker in substrate, the selectivity was attained with over 20:1
for orthoꢀposition cyclization, since oxygen linkage gave open
and flexible space for facile coordination of ligand. (Table 1,
2iꢀ2n). Furthermore, substrates bearing heterocycles such as
thiophene and furan also worked well for orthoꢀposition
cyclization (Table 1, 2jꢀ2k). In particular, alkyne substituted with
threeꢀmembered ring was compatible and the strained ring
remained intact (Table 1, 2m). Remarkably, natural product
estrone could be equipped with alkynes and proceeded
orthoꢀposition cyclization well with moderate yield and excellent
regioselectivity (Table 1, 2n). The corresponding paraꢀposition
cyclization is shown on the left section of Table 1. In general,
both electronꢀrich and electronꢀdeficient substituents of R1 and R2
successfully achieved this transformation, generating the desired
products with sole regioisomers (Table 1, 3bꢀ3f). Notably,
paraꢀposition cyclization was equally tolerated with heterocycles,
aliphatic groups and complex steroids as well (Table 1, 3iꢀ3n).
Gratifyingly, gramꢀscale operations were feasible in both orthoꢀ
and paraꢀcyclization, affording 2i and 3i in moderate yields.
Moreover, to demostrate the facile removal of the directing group,
dihydroquinolines 2a and 3a were readily transformed into
corresponding aldehyde and ketone with high yields.11 With
attempt to explore the catalyst efficiencies, turnover numbers
aReaction conditions: 1a (0.1 mmol), (2,4ꢀtBu2PhO)3PAuCl (5
mol%), AgOTf (10 mol%), PhCl (1.0 mL), 110 oC, 12 h. bIsolated
yields.
(TON) were studied. When 0.5 mol% phosphite gold(I) catalyst
was applied, TON is 60 for orthoꢀcyclization. While Xphos based
gold(I) catalyst for paraꢀcyclization gave a higher TON of 164.
However, regioselectivity of corresponding products were
decreased dramaically in both cyclizations when lowering the
catalyst loading.
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Table 3. Paraꢀposition cyclization of subtle steric hindered
Interestingly, tetrahydropyrrolo[2,3,4ꢀde]quinolinꢀ5(1H)ꢀone 4a
and electronꢀdeficient aromatic nucleophiles.a,b
1
2
3
4
5
6
7
8
was obtained directly by subjecting 1a to the mixture of gold and
silver (Table S1, Entry 10), which was further confirmed by Xꢀray
analysis(Table 2, 4a).10 After testing the ratio of gold(I) catalyst
with silver additive, 5 mol% of gold(I) catalyst and 10 mol% of
silver salt were identified as the best proportions. Substrate scope
of this cascade cyclization was consequently evaluated under
optimized conditions (Table 2). Both electronꢀdonating and
electronꢀwithdrawing substituents of R1 and R2 accomplished this
transformation efficiently, affording products with quaternary
substituted carbon center in good to excellent yields (Table 2,
4cꢀ4g). Comparatively, the cyclization of substrates with oxygen
atom linker, delivered the oxygenated product 4iꢀ4n in excellent
yields and over 20:1 (o:p) regioselectivity (Table 2, 4iꢀ4n).
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Control experiments were conducted subsequently (Scheme 2).
There was no formation of 4a resulting in 77% yield of 2a
recovered, when cationic gold catalyst (2,4ꢀtBu2PhO)3PAuOTf
was solely utilized. Combination of (2,4ꢀtBu2PhO)3PAuCl with
excess catalytic amount of AgOTf afforded the desired product in
80% yield. 4a could be obtained in 85% yield with complete
consumption of 2a, even when silver triflate was applied alone,
demonstrating that silver was the authentic catalyst in the second
cyclization step. These results showed the different phenomenon
in gold chemistry, which indicated the exclusive catalytic effect of
silver towards double bonds rather than simple additive for
precipitating halide anions. 12
aReaction conditions: 1a (0.1 mmol), XphosAuNTf2 (5 mol%),
c
DCE (1.0 mL), 80 oC. bIsolated yields. tBuXphosAuNTf2 was
used instead of XphosAuNTf2.
Scheme 4 Proposed Mechanism
Rigid Framework
Umbrella-Shaped
Two-coordinate gold(I) complex
Three-coordinate gold(I) complex
Cy
Cy
P
iPr
+
iPr
Ph
Au
O
OMe
tBu
O
tBu
O
Cy
Cy
P
HN
Scheme 2. Control experiments of Au/Ag relay cyclization.
Au+
P
TsN
tBu
tBu
tBu
iPr
Au+
tBu MeO
iPr
O
Ph
Ph
iPr
HN
O
D
N
Ts
1a
TsN
iPr
C
A
MeO
O
N
L2Au+ L1Au+
H
ortho-position
para-position
cyclization
cyclization
OMe
NH
O
Cy
Ph
To further demonstrate the ligand compensating effect, we
investigated the aromatic nucleophiles bearing electronꢀdeficient
and substituted functional groups with subtle steric hinderance
(Table 3). Notably, dihydroquinoline 5o could be exclusively
obtained only with methyl group substituted on metaꢀposition,
which was assisted by tBuXphosꢀbased gold(I) catalyst (Table 3,
5o). Furthermore, substrate bearing fluoro atom, which barely
possesses steric hinderance, also afforded corresponding product
solely in high yield (Table 3, 5p). Moreover, this transformation
could be compatible with hydrogenꢀbond containing hydroxyl
group generating corresponding product 5s (Table 3, 5s).10
Delightedly, electronꢀwithdrawing substituents, such as ketone
(5t), Weinreb amide (5u), aldehyde (5v), ester (5w) and sensitive
imines (5x, 5y) were all well tolerated in good to excellent yields.
Cy
AuL
P
iPr
iPr
Au
Ph
N
3a
B
Ts
OMe
NH
Ph
2a
TsN
iPr
O
+
Ag
E
Ag+
OMe
OMe
N
O
N
O
N
H
Ph
F
Ts
Ag+
relay catalysis
N
OMe
O
Ts
4a
NH
Ph
Ag
N
Ts
G
gold center. Then gold(I) catalyst demands to be trapped by lone
pair electrons on amide group, allowing for the formation of
threeꢀcoordinate gold(I) πꢀalkyne intermediate A.7 Additionally,
flexibly bulky aryl moieties on phosphite ligand offers
umbrellaꢀshaped protection, further stabilizing intermediate A.
Through FriedelꢀCrafts type addition, intermediate B is generated
and subsequently followed by protonation, affording sterically
hindered orthoꢀposition cyclization forming dihydroquinoline
product 2a. Subsequently, the carbonꢀcarbon double bond in 2a is
activated by silver catalyst, giving rise to intermediate F, which
undergoes nucleophilic addition to obtain the congested tricyclic
product 4a. Moreover, rigid and bulky electronꢀabundant Xphos
Scheme 3. KIE Experiments.
Intermolecular kinetic isotope effect (KIE) experiment was
conducted at orthoꢀposition cyclization resulted in the value of
1.6:1. This demonstrated the secondary kinetic isotope effect for
this transformation, which indicated the cleavage of
carbonꢀhydrogen bond was not rateꢀdetermining step (Scheme 3).
Based on these results, the tunable pathway mechanisms by ligand
effect are shown in Scheme 4. Both flexible electronꢀdeficient
tris(2,4ꢀdiꢀtertꢀbutylphenyl) phosphite (L1) and weakly
coordinating OTfꢀ anion would increase the electrophilicity of
ꢀ
ligand (L2) and a bit stronger coordinated NTf2 could jointly
lower the electrophilicity of gold center to increase the stability of
intermediate C and minimizes the conformation leading to
orthoꢀposition cyclization. The electronꢀrich triꢀisopropylphenyl
ring on ligand compensates for electronꢀdeficient phenyl moiety
of substrate through πꢀπ interaction, which affords the smooth
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3736. (e) Xi, Y.; Su, Y.; Yu, Z.; Dong, B.; McClain, E. J.; Lan, Y.; Shi, X.
Angew. Chem. Int. Ed. 2014, 53, 9817.
cyclization of electronꢀdeficient aromatics. Finally, paraꢀposition
selective cyclization is successfully achieved after the sequential
cyclization and protonation.
1
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(3) For selected examples of elegant ligandꢀcontrolled regiodivergent
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In conclusion, we have developed
a ligand controlled
gold(I)ꢀcatalyzed regiodivergent intramolecular hydroarylation of
alkynes reaction. Orthoꢀ and paraꢀposition cyclization are
successfully established respectively through fineꢀtuning
electronic and steric effects of the ligands derived from gold
complexes. Altering threeꢀcoordinate gold(I) complexes is the key
in the adjacent cyclization. And rigid electronꢀrich ligand allows
paraꢀposition cyclization exclusively, in which aromatic
nucleophiles bearing electronꢀdeficient functional groups and
subtle steric difference could afford the cyclization highly
selectively. Moreover, silver instead of gold catalyst was proved
to be the prior activator of double bonds in the second cyclization
of cascade cyclization. Further synthetic applications of these
tunable transformations are currently under investigation in our
group.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures, NMR spectral, XꢀRay, and analytical
data for all new compounds. The Supporting Information is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
xfjiang@chem.ecnu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors are grateful for financial support provided by NBRPC
(973 Program, 2015CB856600), NSFC (21472050, 21272075),
Fok Ying Tung Education Foundation (141011), the program for
Shanghai Rising Star (15QA1401800), Professor of Special
Appointment (Eastern Scholar) at Shanghai Institutions of Higher
Learning, and the Changjiang Scholar and Innovative Research
Team in University.
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Widenhoefer, R. A. Chem. Eur. J. 2008, 108, 3351. (h) Abu Sohel, S. M.
(7) For tricoordinated gold(I) complexes, please see: (a) Gimeno, M. C.;
Laguna, A. Chem. Rev. 1997, 97, 511. (b) Teles, J. H.; Brode, S.;
Chabanas, M. Angew. Chem. Int. Ed. 1998, 37, 1415. (c) Ito, H.; Saito,T.;
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H.; Nakazawa, H.; Mercy, M.; Maron, L.; Amgoune, A.; Bourissou, D.
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(8) For effect of other directing groups, please see SIꢀS4 for details.
(9) For details of optimization, please see SIꢀS3.
(10) CCDCꢀ1058363 (2a), CCDCꢀ1058364 (3a), CCDCꢀ1058366 (4a),
CCDCꢀ1058362 (5s), for CIF data, please see SIꢀS41.
(2) For selected ligandꢀcontrolled goldꢀcatalyzed reactions, please see: (a)
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P.; DíazꢀRequejo, M. M.; Pérez, P. J. Angew. Chem. Int. Ed. 2005, 44,
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FG
L2Au+
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FG Ph
H
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PCy2
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three-coordinate gold(I)
iPr
iPr
Au
Ag
low steric requirements
electronic contradiction
sterically hindered cyclization
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iPr
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OMe
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Au/Ag relay catalysis
quanternary substituted carbon
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