Intramolecular insertions into unactivated C(sp3)-H bonds by oxidatively generated β-diketone-α-gold carbenes: Synthesis of cyclopentanones

Article abstract of DOI:10.1021/jacs.5b02280

Generation of reactive α-oxo gold carbene intermediates via gold-catalyzed oxidation of alkynes has become an increasing versatile strategy of replacing hazardous diazo carbonyl compounds with benign and readily available alkynes in the development of efficient synthetic methods. However, one of the hallmarks of metal carbene/carbenoid chemistry, i.e., insertion into an unactivated C(sp³)-H bond, has not be realized. This study reveals for the first time that this highly valuable transformation can be readily realized intramolecularly by oxidatively generated β-diketone-α-gold carbenes using ynones as substrates. Substrate conformation control via the Thorpe-Ingold effect is the key design feature that enables generally good to excellent efficiencies, and synthetically versatile cyclopentanones including spiro-, bridged, and fused bicyclic ones can be readily accessed.

Full text of DOI:10.1021/jacs.5b02280

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Communication
Intramolecular Insertions into Unactivated C(sp3)-H Bonds by Oxidatively
Generated #-Diketone-#-Gold Carbenes: Synthesis of Cyclopentanones
Youliang Wang, Zhitong Zheng, and Liming Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 02 Apr 2015
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Intramolecular Insertions into Unactivated C(sp3)-H Bonds by
Oxidatively Generated β-Diketone-α-Gold Carbenes: Synthesis of
Cyclopentanones
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Youliang Wang, Zhitong Zheng, and Liming Zhang*
Department of Chemistry & Biochemistry, University of California, Santa Barbara, CA 93106
Supporting Information Placeholder
alkanes (used as solvent, Scheme 1C).3a To reconcile these
apparent difference in reaction outcomes, we reasoned that α-oxo
ABSTRACT: Generation of reactive α-oxo gold carbene
intermediates via gold-catalyzed oxidation of alkynes has become
gold carbenes are capable of C-H insertions but prefer electrophilic
reactions.3b In the cases of their oxidative generations, various
nucleophiles present in the reaction mixture, such as the oxidants,
their reduced counterparts and even solvents,6,9 can readily trap
these highly electrophilic species and thereby divert them from
significant and observable C-H insertions. We anticipated that by
suitable substrate design and by optimization of reaction conditions
insertions into unactivated C(sp3)-H bonds by oxidatively
generated α-oxo gold carbenes can be realized and become
synthetically useful, thereby circumventing the use of diazo
substrates in this class of highly valuable transformations. Herein
an increasing versatile strategy of replacing hazardous diazo
carbonyl compounds with benign and readily available alkynes in
the development of efficient synthetic methods. However, one of
the hallmarks of metal carbene/carbenoid chemistry, i.e., insertion
into an unactivated C(sp3)-H bond, has not be realized. This study
reveals for the first time that this highly valuable transformation
can be readily realized intramolecularly by oxidatively generated
β-diketone-α-gold carbenes using ynones as substrates. Substrate
conformation control via the Thorpe-Ingold effect is the key design
feature that enable generally good to excellent efficiencies, and
synthetically versatile cyclopentanones including spiro-, bridged,
and fused bicyclic ones can be readily accessed.
we disclose our preliminary results on this topic.
A. Oxidative generation of -oxo gold carbene
external
oxidant
Z
O
O-Z
O
Insertions into unactivated C(sp3)-H bonds by reactive metal
carbene/carbenoids are powerful synthetic strategies in the
constructions of complex functional structures. The most practiced
approach uses diazo compounds as precursors to the reactive metal
intermediates, resulting in the development of a plethora of
efficient methods and the documentation of an array of elegant
applications.1 While many preparative methods have been
developed for diazo compounds,1a they remain as highly hazardous
materials and are toxic and potentially explosive. Moreover, the
reagents used for their synthesis tend to be energetic and thereby
put further strain on operational safety.
A few years ago we2 developed an intermolecular oxidative gold
catalysis that permits facile access to α-oxo gold carbenes (i.e., A)
by using benign and readily available alkynes instead of diazo
carbonyl compounds3 (Scheme 1A). This approach opens a readily
accessible venue to probe the reactivities of these reactive
intermediates and explore their synthetic utilities. Indeed, a range
of useful synthetic methods have been developed by us4 and others5
based on this non-diazo strategy. From all the documented
reactivities, α-oxo gold carbenes appear to be more electrophilic
than their Rh carbenoid counterparts and react readily with various
nucleophiles including solvents,6 hence displaying more of the
characteristics of gold-stabilized carbocations.7 As a consequence,
insertions into C(sp3)-H bonds, hallmarks of carbene reactivities,
have so far not been observed with thus-generated α-oxo gold
carbenes, despite a formal instance in the versatile gold-catalyzed
oxidative formation of cyclopentenone reported by Liu,5j where the
formation of an α-oxo gold carbene intermediate is deemed
unlikely (Scheme 1B), and cases involving intramolecularly
generated more electron-rich counterparts.8 Notwithstanding, the
gold carbenes/carbenoid generated from ethyl diazoacetate (EDA)
have been shown to be capable of inserting into the C-H bonds of
high electrophilic
intermediate
[Au]
A
[Au]
[Au]
[Au]
[Au]
O
equivalent
hazardous and
potentially explosive
O-Z
N2
B. Work by Liu
Me
IPrAuCl/AgNTf2 (5%)
DCE, 80 C, 2.5 h
+
N+
Me O-
1a (3 equiv)
O
83%
C. Work by Nolan, Díaz-Requejo and Pérez
IPrAuCl
CO2Et
Me
Me
Me
Me
NaBArF
O
4
Me
+
Me
CO2Et
N2
Me
Me
OEt
90%
Me
Me
solvent
Me
4.9
:
1
Scheme 1. α-Oxo gold carbenes and C-H insertion reactions.
At the outset, we chose the alkynone 2a as the substrate (Table
1) for the following considerations: a) the likely generated β-
diketone-α-gold(I) carbene (i.e., B, Scheme 2) upon gold-promoted
oxidation of the alkynone moiety should be even more electrophilic
than the α-oxo gold carbene counterpart A and thereby more
reactive toward C-H insertion, b) the additional acyl group would
provide extra steric hindrance to dissuade intermolecular side
reactions, and c) the gem-dimethyl groups would provide beneficial
conformation control of the carbon backbone due to the Thorpe-
Ingold effect. Much to our delight, C-H insertions occurred even
with Ph3PAuNTf2 in the presence of 8-methylquinoline N-oxide
(1a) and three different C-H insertion products, i.e., 3a-5a, were
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Table 1. Initial reaction discovery and conditions optimizationa
morpholine ring of Mor-DalPhos showed slight increase of
1
2
3
4
5
6
7
8
selectivity of 3a over 4a (comparing entries 5 and 6), the ligands
containing a piperidine ring, i.e., L2, and methyl-substituted ones,
i.e., L3 and L4,4d led to steadily improved selectivities and yields,
the trend of which appears correlate to the increasing basicity of the
nitrogen atom and shielding by the piperidine ring (entries 7-9). A
good regioselectivity of 13.2 /1 was achieved with L4 as ligand
-
(entry 9), along with an acceptable 72% yield. Replacing NTf2
with other counter anions led to lower selectivities and/or decreased
reaction yields (entries 10-12). The oxidant was then varied. 8-
Isopropylquinoline N-oxide (1b),4f a more hindered oxidant, led to
an improved 84% yield (entry 13), while others including 2,6-
dichloropyridine N-oxide (entry 14) were not as effective. Finally,
replacing L4 with IMes led to a slightly better selectivity but a
lower yield (comparing entry 15 with entry 13). In all these cases,
acetophenone was detected as a side product.
yieldb
ent
ry
1
2
3
4
5
6
7
8
9
10
11
catalyst (5 mol %)
N-oxide
3a/4a/5ac
9
6a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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60
30% (9.5/1/1.1) 7%
61% (1.1/1/1) 20%
63% (7.9/1/0) 11%
57% (15.7/1/0) 7%
70% (6.7/1/0) 12%
59% (7.7/1/0) 7%
65% (10.0/1/0) 10%
68% (11.0/1/0) 8%
72% (13.2/1/0) 7%
67% (12.8/1/0) 12%
67% (12.2/1/0) 10%
71% (9.5/1/0) 5%
84%e (13.7/1/0) 8%
75% (13.0/1/0) 6%
74% (13.8/1/0) 10%
Ph3PAuNTf2
BrettPhosAuNTf2
IPrAuNTf2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
IMesAuCl/AgNTf2
MorDalPhosAuNTf2
L1AuCl/AgNTf2
L2AuCl/AgNTf2
L3AuCl/AgNTf2
L4AuCl/AgNTf2
L4AuCl/AgOTf
L4AuCl/AgSbF6
12d L4AuCl/NaBArF4 (10 mol %) 1a
13
14f
15
L4AuCl/AgNTf2
L4AuCl/AgNTf2
IMesAuCl/AgNTf2
1b
1c
1b
a [2a] = 0.05 M. b Estimated by 1H NMR using diethyl phthalate as
the internal reference. c As mixtures of tautomers and diastereomers.
d 12 h. Isolated yield. e 77% isolated yield. f Overnight.
Scheme 2. A proposed mechanism for the reaction of 2a.
A plausible mechanism is proposed in Scheme 2 to explain the
reaction outcomes and in particular the formation of 6a. Based on
the ease of insertion into unactivated C(sp3)-H bonds including
those of methyl, it is likely that the β-diketone-α-gold carbene B is
generated as the key reactive intermediate via oxidative gold
catalysis and, moreover, the C-H insertions are concerted. On the
other hand, a competitive hydride abstraction12 of the β-methylene
group would lead to the formation of the carbocation intermediate
C, which would then undergo C-C bond fragmentation to deliver
the acylketene D. This intermediate could then undergo hydrative
decarboxylation to yield 6a by adventitious H2O during the reaction
and/or upon workup. In addition, the formation of the other side
product, i.e., 2-methyl-2-octene, in the process is supported by GC-
MS analysis of one of the reaction mixtures. The likelihood that
both C and 4a might be formed via the same transition state but
with subsequent bifurcation13 is intriguing and will be subjected to
future DFT calculations.
formed, albeit only in a 27% combined yield as mixtures of
tautomers and insertion products, i.e., 3a-5a, were formed, albeit
only in a 30% combined yield as mixtures of tautomers and
diastereomers at the β-diketone moieties (Table 1, entry 1). In
addition, acetophenone (6a) was also formed in 7% yield. While
the formation of the major product, cyclopentanone 3a, via carbene
insertion into γ-CH2 was expected, the formations of the minor
cyclobutanones 4a and 5a via carbene insertion into β-CH2 and β-
CH3, respectively, were somewhat surprising, especially in the
latter case. These results indicate that the gold carbene generated is
indeed highly reactive and very capable of inserting into
unactivated C(sp3)-H bonds. With the bulky and electron-rich
BrettPhos as ligand, the combined yield of the C-H insertion
products was much improved, although the regioselectivity
suffered (entry 2). When the N-hetereocyclic carbene IPr was used
as ligand, the reaction yield was moderate but with serviceable
regioselectivity (entry 3). Notable in this case is that there was no
insertion into the methyl C-H bond, indicating the gold carbene
intermediate is less reactive than those generated in entries 1 and 2,
consistent with the fact that IPr is a stronger σ-donor than
phosphines. This was also the case with IMes, another frequently
used NHC, despite an even better selectivity of the cyclopentanone
3a over the cyclobutanone 4a (15.7:1) was realized (entry 4). We
have previously reported that P,N-bidentate ligands can attenuate
the reactivity of α-oxo gold carbenes via the formation of tris-
coordinated gold centers.4b-e Indeed, when Mor-DalPhos11 was
used, the insertion into methyl C-H bonds likewise did not occur,
while the reaction yield and the ratio of 3a and 4a remained
moderate (entry 5). Other P,N-bidentate ligands, i.e., L1-L4, were
also examined. In all the cases, no cyclobutanone 5a was detected
(entries 6-9). While the substitution of methyl groups on the
Mindful of the beneficial Thorpe-Ingold effect in facilitating the
C-H insertion, we first probed the reaction scope using ynones
possessing fully substituted α-carbons under the optimal conditions
outlined in Table 1, entry 13. As shown in Table 2, the phenyl group
of 2a can be replaced with an n-butyl in the case of the ynone
substrate 2b, and the gold catalysis was highly efficient and
regioselective (entry 1). Insertion by the gold carbene intermediate
into a sterically more hindered C-H bond, as in the case of 2c, was
more efficient and selective with IMesAuCl/AgNTf2 (5 mol%) as
catalyst (entry 2); moreover, in this case no product derived from
insertion into the more labile methine C-H bond was detected,
indicating a strong preference of forming five-membered rings. The
expected insertion into an ethereal and hence activated C-H bond
in the case of 2d, however, did not occur. With IPrAuNTf2 as
catalyst, the cyclic acetal 3d was isolated in 60% yield along with
12% of 3d’(entry 3). The former product must be formed via an
initial hydride abstraction12 at the γ-CH2 followed by cyclization of
the gold enolate oxygen, and the latter via the same process as 2-
methyl-2-octene in Scheme 2. It is important to point out that the
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isolated in the reaction was the side product 3i’, the formation of
Table 2. Scope with ynones featuring fully substituted α-
carbons a
1
2
3
which can be ascribed to silyloxy oxygen trapping of the carbene
center followed by silyl migration. This finding suggests the
importance of properly masking a competing nucleophilic site in
order to facilitate the desired C-H insertion process.
yieldb
entry
substrate 2
product 3
Me Me
O
4
5
6
7
8
9
94%
1
(>25/1)c
To further explore the synthetic utility of this C-H insertion
chemistry, we turned our attention to substrates offering access to
fused bicyclic cyclopentanones, as in the case of 2f (cf. Table 2,
entry 5). For the cases examined in Table 3, IPrAuNTf2 turned out
to be the optimal catalyst, and in some cases (entries 3-5) the
oxidant loadings were lowered to 1.5 equiv. In the absence of the
Thorpe-Ingold effect, the cyclohexyl-containing alkynone 2j still
underwent the desired reaction, affording mainly the trans-fused
product 3j albeit in only 40% yield (entry 1). The use of a C-C
double bond to limit conformational flexibility in the case of 2k did
improve the reaction to some extent (entry 2).5j Much to our delight,
the Thorpe-Ingold effect again significantly facilitates the reaction,
and as shown in entries 3-4 the bicyclic cyclopentanones 3l and 3m
were both formed in good yields. Different from the cases of 3f and
3j, they are mainly or exclusively cis-fused, likely the result of the
gold carbene moiety mostly or completely residing at the
cyclohexane ring axial position. The symmetric nature of the 1,3-
diketone-2-gold carbene generated in these oxidative gold catalysis
suggests that 3m should be accessible from the isomeric phenyl
alkynyl ketone 2m’. Indeed, the reaction of 2m’proceeded with an
identical yield and the same exclusive cis-selectivity (entry 5). This
oxidative gold catalysis was also conducive to the construction of
5,5-fused cyclopentanones, which are exclusive cis-fused (entries
6-8). Again, the phenyl alkynyl ketones 2o and 2p were suitable
substrates. The low yield of the latter (entry 8) again reflected the
importance of sterically shielding of the HO group as the side
product 3p’, owing to the competing oxygen attack, was formed in
an equal amount.
nBu
2b
3b
nBu
Me Me
O
78%
2d,e
(15/1)c
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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51
52
53
54
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56
57
58
59
60
Ph 2c
3c
Me Me
O
3f
4
60%
TIPSO
2d
3d
Ph
Me
Me
96%
(18.2/1)c
O
Bz
2e
2f
3e
72%
(trans/cis
: >20/1)
5
3f
85%
75%
76%
6
7
2g
2h
3g
3h
Bz
Table 3. Constructions of fused bicyclic cyclopentanonesa
O
8f
entry
substrate 2
cyclopentanone 3
yieldb
2i
OTBS3i
O
40%
(trans/cis:
>8/1)
a
Reaction conditions: 2 (0.05 M in PhF), L4AuCl/AgNTf2 (5
1c
mol%), 1b (2 equiv), rt, 2 h. Isolated yield. c Cyclopentanone
b
d
2j
3j
3/cyclobutanones 4 and 5. IMesAuCl/AgNTf2 (5 mol%) as
Ph
O
e
catalyst. 58% yield and 3/(4+5) = 2/1 with L4AuCl/AgNTf2 as
catalyst. f IPrAuNTf2 (5 mol%) as catalyst
2
48%
Ph
OTBS
O
Me
Me
2k
3k
Ph
TIPSO
Me
O
O
83%
(cis/trans:
3.5/1)
3d'
3d
3i' (20%)
absence of any product of type 3d in the prior cases as well as in
the ensuing cases suggest that insertions into non-activated C-H
bonds by β-diketone-α-gold carbenes might not involve similar
hydride abstractions and hence likely be concerted. Entries 4-6
show the reactions of ynone substrates possessing a cyclohexane
ring at the γ-, β-, α-carbon, and the formed cyclopentanone
products featured spiro-, fused, and bridged bicyclic skeletons,
respectively, in good to excellent yields. Of note is that 3f was
formed predominantly as the 5,6-trans-fused isomer, and the high
efficiency of forming 3g, despite the strained nature of the
bicycle[3.2.1]octane ring. The TIPS-protected hydroxylalkynone
2h, readily accessible from cyclohexanone in three steps by using
Katritzky’s alkynylacyl anion equivalent, i.e., deprotonated 1-
(benzotriazol-1-yl)propargyl ethyl ether,14 also underwent the
oxidative gold catalysis in good efficiency (entry 7). Overall, this
entry opens a facile four-step strategy to construct the synthetically
versatile bridged bicycle from cyclohexanone. By following the
same 4-step sequence with the exception of the gold catalyst, the
TBSO-substituted hexahydro-1,4-methanopentalen-2(1H)-one 3i
was prepared from norcamphor in a good yield (entry 8). Also
2l
3l
Ph
OTIPS
O
75%
(cis only)
4d
5d
6
2m
2m’
2n
3m
3m
3n
3o
Ph
OTIPS
75%
(cis only)
Bz
67%
(cis only)
67%
(cis only)
7
2o
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Corresponding Author
1
2
3
4
5
6
7
zhang@chem.ucsb.edu
Notes
The authors declare no competing financial interests.
8
40%
2p
3p
a
Reaction conditions: 2 (0.05 M in PhF),
b
IPrAuNTf2 (5 mol %), 1b (2 equiv), rt, 2 h.
Isolated yield. c DCE as solvent. d 1.5 equiv. of
1b.
ACKNOWLEDGMENT
The authors thank NSF (CHE-1301343) and NIH (R01
GM084254) for financial support.
8
9
REFERENCES
To gain additional insights to the reaction mechanism, we
examined the gold-catalyzed reactions of the α-diazo β-diketone 7
(Scheme 3A). While too slow with either IPrAuNTf2 or L4AuNTf2,
(1) For reviews, see: a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
catalytic methods for organic synthesis with diazo compounds: from
cyclopropanes to ylides; Wiley: New York, 1998; b) Davies, H. M. L.;
Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861; c) Taber, D. F. In
Carbon-Carbon σ-Bond Formation; Pattenden, G., Ed.; Pergamon
Press: Oxford, England ; New York, 1991; Vol. 3, p 1045.
(2) Zhang, L. Acc. Chem. Res. 2014, 47, 877.
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57
58
59
60
t
the reaction in the presence of BuBrettPhosAuNTf2 (5 mol%)
proceeded to completion in
4 days. In comparison, the
corresponding oxidative gold catalysis using the same catalyst took
only 2 h and, moreover, afforded higher yields, highlighting the
additional advantages of our oxidative gold catalysis over the diazo
approach. Importantly, the nearly identical ratios of 3a/4a/5a
corroborate the likely formation of a common reactive intermediate
(i.e., B) in both cases. The C-H insertion step was probed by
deuterium kinetic isotope effect (KIE). As shown in Scheme 3B, in
the internal competition a KIE of 2.34 was observed.15 This value
indicates that the C-H bond is significantly elongated in the
insertion transition state. In contrast, inverse KIEs were observed
with donor-substituted gold carbenes.8c
(3) For selected examples using diazo substrates, see: a) Diaz-Requejo, M.
M.; Perez, P. J. Chem. Rev. 2008, 108, 3379; b) Fructos, M. R.;
Belderrain, T. R.; de Fremont, P.; Scott, N. M.; Nolan, S. P.; Diaz-
Requejo, M. M.; Perez, P. J. Angew. Chem. Int. Ed. 2005, 44, 5284; c)
Prieto, A.; Fructos, M. R.; Mar Díaz-Requejo, M.; Pérez, P. J.; Pérez-
Galán, P.; Delpont, N.; Echavarren, A. M. Tetrahedron 2009, 65, 1790;
d) Jadhav, A. M.; Pagar, V. V.; Liu, R.-S. Angew. Chem., Int. Ed. 2012,
51, 11809; e) Briones, J. F.; Davies, H. M. L. J. Am. Chem. Soc. 2012,
134, 11916; f) Cao, Z.-Y.; Wang, X.; Tan, C.; Zhao, X.-L.; Zhou, J.;
Ding, K. J. Am. Chem. Soc. 2013, 135, 8197; g) Yu, Z.; Ma, B.; Chen,
M.; Wu, H.-H.; Liu, L.; Zhang, J. J. Am. Chem. Soc. 2014, 136, 6904;
h) Xi, Y.; Su, Y.; Yu, Z.; Dong, B.; McClain, E. J.; Lan, Y.; Shi, X.
Angew. Chem., Int. Ed. 2014, 53, 9817.
(4) For our selected work, see: a) Ye, L.; Cui, L.; Zhang, G.; Zhang, L. J.
Am. Chem. Soc. 2010, 132, 3258; b) Wu, G.; Zheng, R.; Nelson, J.;
Zhang, L. Adv. Synth. Catal. 2014, 356, 1229; c) Ji, K.; Zhang, L. Org.
Chem. Front. 2014, 1, 34; d) Ji, K.; Zhao, Y.; Zhang, L. Angew. Chem.,
Int. Ed. 2013, 52, 6508; e) Luo, Y.; Ji, K.; Li, Y.; Zhang, L. J. Am.
Chem. Soc. 2012, 134, 17412; f) Lu, B.; Li, C.; Zhang, L. J. Am. Chem.
Soc. 2010, 132, 14070.
(5) For selected work, see: a) Ghorpade, S.; Su, M.-D.; Liu, R.-S. Angew.
Chem., Int. Ed. 2013, 52, 4229; b) Vasu, D.; Hung, H.-H.; Bhunia, S.;
Gawade, S. A.; Das, A.; Liu, R.-S. Angew. Chem., Int. Ed. 2011, 50,
6911; c) Qian, D.; Zhang, J. Chem. Commun. 2012, 48, 7082; d)
Davies, P. W.; Cremonesi, A.; Martin, N. Chem. Commun. 2011, 47,
379; e) Henrion, G.; Chavas, T. E. J.; Le Goff, X.; Gagosz, F. Angew.
Chem., Int. Ed. 2013, 52, 6277; f) Xu, M.; Ren, T.-T.; Li, C.-Y. Org.
Lett. 2012, 14, 4902; g) Wang, T.; Shi, S.; Hansmann, M. M.;
Rettenmeier, E.; Rudolph, M.; Hashmi, A. S. K. Angew. Chem., Int.
Ed. 2014, 53, 3715; h) Shi, S.; Wang, T.; Yang, W.; Rudolph, M.;
Hashmi, A. S. K. Chem. Eur. J. 2013, 19, 6576; i) Sun, N.; Chen, M.;
Liu, Y. J. Org. Chem. 2014, 79, 4055; j) Bhunia, S.; Ghorpade, S.;
Huple, D. B.; Liu, R.-S. Angew. Chem., Int. Ed. 2012, 51, 2939; k)
Chen, M.; Chen, Y.; Sun, N.; Zhao, J.; Liu, Y.; Li, Y. Angew. Chem.,
Int. Ed. 2015, 1200.
(6) He, W.; Xie, L.; Xu, Y.; Xiang, J.; Zhang, L. Org. Biomol. Chem. 2012,
10, 3168.
(7) Wang, Y.; Muratore, M. E.; Echavarren, A. M. Chem. - Eur. J. 2015,
DOI: 10.1002/chem.201406318.
(8) a) Lemiere, G.; Gandon, V.; Cariou, K.; Hours, A.; Fukuyama, T.;
Dhimane, A. L.; Fensterbank, L.; Malacria, M. J. Am. Chem. Soc. 2009,
131, 2993; b) Escribano-Cuesta, A.; López-Carrillo, V.; Janssen, D.;
Echavarren, A. M. Chem. - Eur. J. 2009, 15, 5646; c) Horino, Y.;
Yamamoto, T.; Ueda, K.; Kuroda, S.; Toste, F. D. J. Am. Chem. Soc.
2009, 131, 2809.
(9) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011, 133, 8482.
(10)See supporting information for details.
(11)Hesp, K. D.; Stradiotto, M. J. Am. Chem. Soc. 2010, 132, 18026.
(12)a) Bhunia, S.; Liu, R.-S. J. Am. Chem. Soc. 2008, 130, 16488; b) Bolte,
B.; Gagosz, F. J. Am. Chem. Soc. 2011, 133, 7696.
(13)For an example of gold catalysis involving bifurcation, see: Ye, L.;
Wang, Y.; Aue, D. H.; Zhang, L. J. Am. Chem. Soc. 2012, 134, 31.
(14)Katritzky, A. R.; Lang, H. J. Org. Chem. 1995, 60, 7612.
(15)Similar KIEs are reported on metal carbene insertions into unactivated
C(sp3)-H bonds. For references, see: a) Davies, H. M. L.; Hansen, T.;
Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063; b) Mbuvi, H. M.;
Woo, L. K. Organometallics 2008, 27, 637.
A
t
 BuBrettPhosAuNTf2 (5 mol %), 1b (1.5 equiv), DCE, 2 h
Me Me
O


1.00
1.55
0.70
0.82
)
23% (
Me
)
36% (
)
16% (
)
19% (

nBu
Me
Me
C6H13
O
O
O
2a
Ph
Me
C5H11
O
Me
Ph
Me
nBu

Me Me
Bz
Bz
Bz
6a
13% (0.68)
O
5a
4a
3a



19% (1.00)
30% (1.56)
14% (0.73)
nBu
Bz
O
N2
7
tBuBrettPhosAuNTf2 (5 mol %), DCE, 4 days
B
Me Me
L4AuCl/AgNTf2
Me
Me
Me
nBu
Me
Me
O
Me
(5 mol%)
1b
(2 equiv)
H
D
O
PhF, rt, 2 h
O
nBu
nBu
Bz
nBu
D
D
H
Bz
Bz
KH/ KD = 2.34
H
Ph
2a-d
90.2%
4a-d (8%)
3a-d (43.7%)
3a (26.3%)
Scheme 3. Mechanistic studies.
In summary, we have discovered for the first time that
oxidatively generated gold carbenes in the form of β-diketone-α-
gold carbenes can easily insert intramolecular into unactivated
C(sp3)-H bonds in likely concerted manners. Substrate
conformation control via the Thorpe-Ingold effect is the key design
feature that enable the generally good to excellent efficiencies in
the examined cases. This novel reactivity offers efficient access to
synthetically versatile cyclopentanones including spiro-, bridged,
and fused bicyclic ones from readily available ynone substrates.
This study represents a remarkable advance in replacing toxic and
potentially explosive diazo ketones with benign and easily
available alkynes in achieving one of the hallmark and most
valuable transformation of metal carbenes/carbenoids, i.e.,
insertions into unactivated C(sp3)-H bonds.
ASSOCIATED CONTENT /
Supporting Information
Experimental details, compound characterization and spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
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