Cyclopropanation of Benzene Rings by Oxidatively Generated α-Oxo Gold Carbene: One-Pot Access to Tetrahydropyranone-Fused Cycloheptatrienes from Propargyl Benzyl Ethers

Article abstract of DOI:10.1002/adsc.201701322

Cyclopropanations of benzene rings by oxidatively generated α-oxo gold carbenes are for the first time demonstrated in a Buchner reaction, in which readily available propargyl benzyl ethers are converted in one-pot to tetrahydropyranone-fused cycloheptatrienes via sequential oxidative gold catalysis and base-promoted isomerization. Additional examples of arene cyclopropanations without fragmentation of the cyclopropane ring are also realized. (Figure presented.).

Full text of DOI:10.1002/adsc.201701322

Title: Cyclopropanation of Benzene Rings by Oxidatively Generated
α-Oxo Gold Carbene: One-Pot Access to Tetrahydropyranone-
Fused Cycloheptatrienes from Propargyl Benzyl Ethers
Authors: Kegong Ji and Liming Zhang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701322
Link to VoR: http://dx.doi.org/10.1002/adsc.201701322

Advanced Synthesis & Catalysis
10.1002/adsc.201701322
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Cyclopropanation of Benzene Rings by Oxidatively Generated
α-Oxo Gold Carbene: One-Pot Access to Tetrahydropyranone-
Fused Cycloheptatrienes from Propargyl Benzyl Ethers
Kegong Ji, a,b* and Liming Zhang b*
a
Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F
University, 3 Taicheng Road, Yangling 712100, Shaanxi, China. E-mail: jikegong@nwsuaf.edu.cn
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California (USA), E-mail:
b
zhang@chem.ucsb.edu.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Cyclopropanations of benzene rings by
oxidatively generated α-oxo gold carbenes are for the
first time demonstrated in a Buchner reaction, in which
readily available propargyl benzyl ethers are converted
in one-pot to tetrahydropyranone-fused cycloheptatrienes
via sequential oxidative gold catalysis and base-
promoted isomerization. Additional examples of arene
cyclopropanations without fragmentation of the
cyclopropane ring are also realized.
We surmised, as shown in Scheme 1B, that a
readily available benzyl propargyl ether 1 could
enable us to study cyclopropanations of arenes by α-
oxo gold carbenes of type A. Our prior studies have
revealed that the gold carbene generated from
[9]
propargylic ethers can readily undergo cyclization.
The norcaradiene intermediate 4 would then be
formed and undergo known reversible electrocyclic
ring opening to afford the tetrahydropyranone-fused
cycloheptatriene 3‘ in the form of a Buchner
Keywords: Cyclopropanation; Gold Carbene; Oxidation;
Buchner reaction; Cycloheptatriene
[10]
reaction, which could isomerize to the conjugated
enone 3, or undergo alternative ring opening under
acidic conditions to afford the Friedel-Crafts products
Gold-catalyzed intermolecular oxidation of
[
1]
alkynes
has become a valuable synthetic
[
2]
strategy since the original report in 2010, owing
to the efficient and expedient access to α-oxo
gold carbene intermediates and/or their
precursors and their exceptional reactivities and
synthetic versatilities. A diverse range of
functional structures of significant synthetic
[
2-4]
utilities have been developed.
Comparing to
the Rh/Cu carbene chemistry based on diazo
5
carbonyl compounds, this chemistry employs
benign and readily available alkynes substrates
and hence circumvents the use of hazardous and
potentially explosive α-diazo ketone precursors
(
Scheme 1A).
These α-oxo gold carbene
intermediates typically display exceptional
electrophilicities, and can be trapped by tethered
or
cyclopropanation of tethered alkenes.
However, cyclopropanation of the more
challenging benzene ring, owing to the loss of
aromaticity, has so far not been demonstrated in
the oxidative gold catalysis, despite the reports of
Rh/Cu catalysis based on hazardous diazo
carbonyl substrates.[
external
nucleophiles,
including
[
3e, 3g, 4a, 4n, 6]
[
7]
5
. Notably, the related Rh-catalyzed Buchner reaction
5b, 8]
using the related diazo ketone counterpart of 1
1
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201701322
Scheme 1. Background and Design.
between 4 and 3‘. To our delight, the desired bicyclic
heptatriene 3a was indeed formed in 7 % NMR yield
(
Scheme 1C) has only been reported once,[11] where
(entry
1).
Screening
of
various
other
[12]
the
tetrahydropyranone-fused
cycloheptatriene
pyridine/quinoline N-oxides (entries 2-6) revealed
product was formed in a low yield.
that sterically hindered oxidants derived from
Herein, we report the implementation of our
design, which results in rapid access to the bicyclic
heptatrienes.
electron-deficient
pyridine
ring,
i.e.,
2,6-
dichloropyridine N-oxide (2c, entry 3), 2,6-
dibromopyridine N-oxide (2d, entry 4) and the
[3c]
Hantzsch ester N-oxide 2g (entry 6) are among the
most effective, with the halogenated ones being the
best and equally effective and affording the desired
product 3a in around 72% NMR yield. A range of
Table 1. Initial discovery of gold-catalyzed oxidation
of benzyl aryl ether 1a and screening of reaction
conditions. [
a]
other gold catalysts derived from typical ligands such
t
as Ph
3
P, IPr, JohnPhos (entry 7) and BuXPhos (entry
8
) were ineffective, affording trace amount (<5%) of
3
a. Sterically demanding BrettPhos (entry 9) and
AdBrettPhos (entry 10) faired better, but are still
substantially inferior to even more hindered
t
Me
4
BuXPhos, attesting the importance of ligand
bulkiness in this chemistry. AntPhosAuCl/NaBARF
4
was also tested but led to no reaction (entry 11).
Deviation from the best conditions in entry 3 by
lowering the reaction temperature to 0 ˚C led to a
lower yield (entry 12), and by changing the chloride
N-
oxide
Gold catalyst
Additives
Yield[b]
Entry
(5 mol %)
(7.5mol %) 3a
5a
7% <2%
15% <2%
t
F
1
2
3
4
5
6
7
8
9
2a Me
2b Me
2c Me
2d Me
2f Me
2g Me
2c
2c
2c
2c AdBrettPhosAuCl
2c
2c Me
2c Me
4
BuXPhosAuCl NaBAr
4
t
BuXPhosAuCl NaBArF
scanvenger from NaBArF
4
4
to AgNTf resulted in
4
2
t
F
[c]
4
BuXPhosAuCl NaBAr
4
72% <2%
predominant formation of the Friedel-Crafts product
a (entry 13). In this latter case, the slightly exccess
of acidic AgNTf is likely enough to promote the
t
F
4
4
4
BuXPhosAuCl NaBAr
BuXPhosAuCl NaBArF
BuXPhosAuCl NaBArF
4
4
4
4
4
71% <2%
5 % <2%
52 % <2%
3% <2%
4% <2%
32% <2%
25% <2%
5
t
t
2
alternatively cyclopropane ring opening during the
gold catalysis (Scheme 1B, from 4 to 5).
JohnPhosAuCl
BuXPhosAuCl
BrettPhosAuCl
NaBArF
t
F
NaBAr
With the optimal conditions (Table 1, entry 3) in
hand, the reaction scope was examined. As shown in
Table 2, entries 1 and 3, benzylic ethers possessing an
electron-donating 4-Me or 4-MeO group at the
benzene ring reacted as expected, despite exhibiting
moderate yields. A poor regioselectivity along with a
low yield was detected in the case of a meta-methyl
group (entry 2). On the other hand, electron-
withdrawing arene substituents are detrimental to the
gold catalysis and, for example, little desired product
was formed with an ortho-Br and para-CN. This can
be attributed to the decreased nucleophilicity of the
benzene ring. Interestingly, aliphatic substitutions at
the substrate benzyl position including methyl (entry
NaBArF
4
F
1
1
0
1
NaBAr
NaBAr
4
4
4
F
[d]
AntPhosAuCl
nr
[
e]
t
BuXPhosAuCl NaBArF
1
2
4
65% <2%
[
f]
t
1
3
4
BuXPhosAuCl
AgNTf
2
<2% 49%
[
a]
[b]
[
1a] = 0.05M, and 1.3 equiv of the oxidant.
yield using diethyl phthalate as the internal reference.
Isolated yield is 69%. DCE = 1,2-dichloroethane.
of SM was recovered.
NMR
[
c]
[
d]
95%
[
e]
The reaction was carried out at
[
f]
0
℃ for 6 h. 49% of 4a was isolated after 2.5 h.
4
), phenethyl (entry 5) and the sterically demanding
isopropyl (entry 6) and cyclohexyl group (entry 7) are
readily accommodated and moreover, the
corresponding gold catalyses afforded the bicyclic
cycloheptatrienes (i.e., 3e-h) in good yields. An allyl
and a benzyl group are also readily tolerated at the
benzyl position (entries 8 and 9), and their π bonds do
not noticeably interfere with the desired
cyclopropanation, likely due to the formation of
larger rings and hence slower cyclization kinetics.
Moreover, double substitutions at the benzyl position
with aliphatic, aromatic and/or allyl group were
uneventful (entries 10-12). On the other hand, a
methyl substitution at the propargylic position, as in
entry 13, led to 3n in only 40% yield.
At the outset, we employed the parent propargyl
benzyl ether, i.e., 1a, for reaction discovery and
condition optimization, some results of which are
shown in Table 1. Initially, the sterically highly
hindered Me tBuXPhos was employed as the ligand
4
as it was previously proved to be highly effective in
promoting cyclization of α-oxo gold carbenes to
[9]
tethered benzene rings and C-C triple bonds. With
NaBARF (7.5 mol %) as the chloride scavenger and
2
-bromopyridine N-oxide (2a, 1.3 equiv) as the
oxidant, the reaction was carried out in 1,2-
dichloroethane (DCE) at room temperature for 2.5 h,
and the resulting mixture was then treated with
triethylamine (3 equiv) in order to isomerize 3‘ into 3
As the norcaradiene intermediate 4 (Scheme 1B)
can undergo alternative cyclopropane ring opening
under acidic conditions, we treated the resulting
(
see Scheme 1B) and hence abolish the equilibrium
2
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201701322
mixture of 1a upon the oxidative gold catalysis with
likely that the base treatment decomposed some of
the para-norcaradiene isomer.
trifluoroacetic acid (3 equiv) instead of Et
3
N. As
Table 2. Reaction scope.[a, b]
We attempted to extend the chemistry to the all-
carbon counterpart of 1a, i.e., 1o. As shown in Eqn
(
3), the desired Buchner product 3o and the Friedel-
Crafts benzocycloheptanone 5o were formed in a
combined 59% isolated yields with a moderate
regioselectivity.
[14]
Notably, the reaction required
heating (60 ˚C) and no acid or base treatment was
needed.
We are interesting in systems where the
electrocyclic ring opening of the norcaradiene 4 is
retarded. As such, the cyclopropanation of a benzene
ring by in situ-generated α-oxo gold carbenes can be
confirmed beyond doubt. We examined the propargyl
1
-naphthylmethyl ether 1p. It is known in metal
[15]
carbene chemistry
that vicinal-benzene-fused
norcaradienes (i.e., the benzene ring next to the
cyclopropane ring) do not readily undergo
electrocyclic ring-opening due to the necessity of loss
of aromaticity in the process. Indeed, our gold
catalysis cleanly affords the cyclopropane product 4p
[Eqn (4)]. With the substrate 1q easily prepared from
2-indanone, the benzene cyclopropanation product 4q
was readily formed in a decent yield [Eqn (5)], the
stability of which can be readily attributed to the
avoidance of bridgehead double bonds in the ring
open form. Interestingly, 4q possesses the core
[
a]
[16]
The reactions were run in a vial without exclusion of
air and moisture, and the substrate concentration was
structure of salvileucalin B,
thus revealing the
synthetic potential of the oxidative gold catalysis.
.05 M. [ Yields of isolated products are reported.
b]
0
These experimental results point to [17] a reaction
mechanism consistent with that shown in Scheme 1B,
where α-oxo gold carbenes readily cyclopropanate
benzene rings.
expected, the 1,5-dihydrobenzo[c]oxepin-4(3H)-one
5
[13]
a
was formed in 68% isolated yield. On the other
hand, treatment of 3a with trifluoroacetic acid for
much longer 10 h expectedly resulted in no formation
of 5a. Likewise, substrate 1c with a meta-methyl
substitution on the benzene ring also led to the
oxepinones 5c/5c’ in 73% combined yield [Eqn (2)].
However,
the
inferred
cyclopropanation
regioselectivity, i.e., para:ortho = 3.8:1, is higher
than that observed upon base treatment (1.7:1, Table
In summary, we have realized cyclopropanations
of benzene rings by oxidatively generated α-oxo gold
carbene intermediates. From readily available
propargyl benzyl ethers, this chemistry enables an
expedient synthesis of various tetrahydropyranone-
2, entry 2). Considering the difference in yields, it is
3
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201701322
fused cycloheptatrienes upon basic treatment, while
avoiding the use of hazardous diazo carbonyl
substrates. Alternative acidic workup provides rapid
access to 3, 5-dihydrobenzo[c]oxepin-4(1H)-ones.
We have also demonstrated that some norcaradiene
intermediates, e.g. 4p and 4q, can be isolated, thereby
confirming the arene cyclopropanation in these
oxidative gold catalysis.
Ed., 2013, 52, 4229-4234; g) H.-B. Ling, Z.-S. Chen, F.
Yang, B. Xu, J.-M. Gao, K. Ji, J. Org. Chem. 2017, 82,
7070−7076; h) G. Henrion, T. E. J. Chavas, X. Le
Goff and F. Gagosz, Angew. Chem., Int. Ed., 2013, 52,
6277-6282; i) J. Fu, H. Shang, Z. Wang, L. Chang, W.
Shao, Z. Yang and Y. Tang, Angew. Chem., Int. Ed.,
2013, 52, 4198-4202; j) N. Sun, M. Chen and Y. Liu, J.
Org. Chem., 2014, 79, 4055–4067; k) M. Chen, Y.
Chen, N. Sun, J. Zhao, Y. Liu and Y. Li, Angew. Chem.,
Int. Ed., 2015, 1200-1204; l) C. Shu, R. Liu, S. Liu, J.-
Q. Li, Y.-F. Yu, Q. He, X. Lu and L.-W. Ye, Chem. -
Asian J., 2015, 10, 91-95; m) S. Ferrer and A. M.
Echavarren, Angew. Chem., Int. Ed., 2016, 55, 11178-
Experimental Section
General procedure for one-pot gold-catalyzed oxidative
propargyl benzyl ethers to tetrahydropyranone-fused
cycloheptatrienes 3: 2, 6-dichloropyridine N-oxide 2c
1
1182. n) X. Yao, T. Wang, X. Zhang, P. Wang, B.
t-
Zhang, J. Wei, Z. Zhang, Adv. Synth. Catal. 2016, 358,
1534-1539.
(
42.4 mg, 0.26 mmol), and Me
4
BuXPhosAuCl (7.1 mg,
0
7
.010 mmol, 5 mol %) and NaBArF
.5 mol %) were added sequentially to a solution of the
4
(13 mg, 0.015 mmol,
propargyl benzyl ethers 1 (0.20 mmol) in DCE (4 mL.
[5] a) D. F. Taber, in Carbon-Carbon σ-Bond Formation,
ed. G. Pattenden, Pergamon Press, Oxford, England ;
New York, 1991, vol. 3, pp. 1045-1062; b) M. P.
Doyle, M. A. McKervey and T. Ye, Modern catalytic
methods for organic synthesis with diazo compounds:
from cyclopropanes to ylides, Wiley, New York, 1998;
c) H. M. L. Davies and R. E. J. Beckwith, Chem. Rev.,
2003, 103, 2861-2903.
0
.05M) at room temperature. The resulting reaction
mixture was stirred at RT, and the progress of the reaction
was monitored by TLC. The reaction typically took 1–3 h.
Upon completion, the reaction mixture was added 3 equiv.
3
Et N and stirred for 0.5 h at room temperature. The
reaction mixture was concentrated under vacuum. The
residue was purified by chromatography on silica gel
(
eluent: hexanes/ethyl acetate) to afford the desired
products 3.
[
6] a) D. Qian and J. Zhang, Chem. Commun., 2011, 47,
11152-11154; b) D. Qian, H. Hu, F. Liu, B. Tang, W.
Ye, Y. Wang and J. Zhang, Angew. Chem., Int. Ed.,
2014, 53, 13751-13755.
Acknowledgements
This work is supported financially by NIH (R01GM123342). K. Ji
thanks the National Natural Science Foundation of China (NSF-
2
1502150) Northwest A&F University Youth Training
[7] For cyclopropanation of furans, see: a)A. S. K. Hashmi,
Programme (Z109021601) for support. K. Ji also thanks
Professor Wenjun Tang for providing the ligand AntPhos.
T. M. Frost and J. W. Bats, J. Am. Chem. Soc., 2000,
1
22, 11553-11554. b) A. S. K. Hashmi, M. Rudolph,
H.-U. Siehl, M. Tanaka, J. W. Bats, W. Frey, Chem.
Eur. J. 2008, 14, 3703-3708. c) A. S. K. Hashmi,
Angew. Chem. Int. Ed. 2010, 49, 5232-5241.
References
[
[
1] L. Zhang, Acc. Chem. Res., 2014, 47, 877–888.
[8] H. Lebel, J.-F. Marcoux, C. Molinaro and A. B.
Charette, Chem. Rev., 2003, 103, 977-1050.
2] a) L. Ye, W. He and L. Zhang, J. Am. Chem. Soc.,
2
010, 132, 8550-8551; b) L. Ye, L. Cui, G. Zhang and
[9] a) K. Ji, X. Liu, B. Du, F. Yang and J. Gao, Chem.
Commun., 2015, 51, 10318-10321; b) Z. Zheng and L.
Zhang, Org. Chem. Front., 2015, 2, 1556-1560.
L. Zhang, J. Am. Chem. Soc., 2010, 132, 3258-3259.
[
3] For additional work by us, see: a) W. He, C. Li and L.
Zhang, J. Am. Chem. Soc., 2011, 133, 8482-8485; b) Y. [10] For gold-catalyzed retro-Buchner reactions, see: a) C.
Luo, K. Ji, Y. Li and L. Zhang, J. Am. Chem. Soc.,
012, 134, 17412-17415; c) Y. Wang, K. Ji, S. Lan
and L. Zhang, Angew. Chem., Int. Ed., 2012, 51, 1915-
918; d) K. Ji, Y. Zhao and L. Zhang, Angew. Chem.,
Int. Ed., 2013, 52, 6508-6512; e) K. Ji and L. Zhang,
Org. Chem. Front., 2014, 1, 34-38; f) H. Chen and L.
Zhang, Angew. Chem., Int. Ed., 2015, 54, 11775–
S. R. Solorio-Alvarado, Y. Wang and A. M.
Echavarren, J. Am. Chem. Soc., 2011, 133, 11952–
11955; b) T. Lauterbach, T. Higuchi, M. W. Hussong,
M. Rudolph, F. Rominger, K. Mashima and A. S. K.
Hashmi, 2015, 357, 775-781; c) Y. Wang, P. R.
McGonigal, B. Herlé, M. Besora and A. M. Echavarren,
J. Am. Chem. Soc., 2014, 136, 801-809; d) B. Herlé, P.
M. Holstein and A. M. Echavarren, ACS Catal., 2017, 7,
3668-3675.
2
1
1
1779; g) K. Ji, Z. Zheng, Z. Wang and L. Zhang,
Angew. Chem., Int. Ed., 2015, 54, 1245-1249.
[
4] For selected work by other research groups, see: a) D.
Vasu, H.-H. Hung, S. Bhunia, S. A. Gawade, A. Das
and R.-S. Liu, Angew. Chem., Int. Ed., 2011, 50, 6911-
[11] a) M. P. Doyle, M. N. Protopopova, C. S. Peterson, J.
P. Vitale, M. A. McKervey and C. F. García, J. Am.
Chem. Soc., 1996, 118, 7865-7866; b)Y. Liu, Y. Deng,
P. Y. Zavalij, R. Liu, M. P. Doyle, Chem. Commun.,
2015, 51, 565-568; c) X. Xu, X. Wang, P.Y. Zavalij, M.
P. Doyle, Org. Lett. 2015, 17, 790−793.
6
914; b) P. W. Davies, A. Cremonesi and N. Martin,
Chem. Commun., 2011, 47, 379-381; c) D. Qian and J.
Zhang, Chem. Commun., 2012, 48, 7082-7084; d) M.
Xu, T.-T. Ren and C.-Y. Li, Org. Lett., 2012, 14, 4902-
[
12] Y. Wang and L. Zhang, Synthesis, 2015, 47, 289-305.
4
905; e) S. Bhunia, S. Ghorpade, D. B. Huple and R.-S.
Liu, Angew. Chem., Int. Ed., 2012, 51, 2939-2942; f) S.
Ghorpade, M.-D. Su and R.-S. Liu, Angew. Chem., Int.
[13] Z. Xu, H. Chen, Z. Wang, A. Ying and L. Zhang, J.
Am. Chem. Soc., 2016, 138, 5515-5518.
4
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201701322
[
[
14] M. Kennedy, M. A. McKervey, A. R. Maguire, S. M.
Lett., 2008, 10, 4429-4432; b) S. Levin, R. R. Nani and
S. E. Reisman, J. Am. Chem. Soc., 2011, 133, 774-776.
Tuladhar and M. F. Twohig, J. Chem. Soc. Perk. T1,
1
990, 1047-1054.
[
17] a) R. Dorel, A. M. Echavarren, Chem. Rev. 2015, 115,
9028-9072. b) A. S. K. Hashmi, Angew. Chem. Int. Ed.
2010, 49, 5232-5241.
15] a) P. Manitto, D. Monti and G. Speranza, J. Org.
Chem., 1995, 60, 484-485; b) P. J. Pérez, M. M. Díaz-
Requejo and I. Rivilla, Beilstein J. Org. Chem., 2011, 7,
6
53-657.
[
16] a) Y. Aoyagi, A. Yamazaki, C. Nakatsugawa, H.
Fukaya, K. Takeya, S. Kawauchi and H. Izumi, Org.
5
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201701322
COMMUNICATION
Cyclopropanation of Benzene Rings by Oxidatively
Generated α-Oxo Gold Carbene: One-Pot Access to
Tetrahydropyranone-Fused Cycloheptatrienes from
Propargyl Benzyl Ethers
Adv. Synth. Catal. Year, Volume, Page – Page
K. Ji, and L. Zhang *
*
6
This article is protected by copyright. All rights reserved.