Gold-catalyzed intramolecular oxidative cross-coupling of nonactivated arenes

Article abstract of DOI:10.1002/chem.201000322

(Chemical Equatation Reprentation An (Au)some coupling! Gold-catalyzed cascade C-O cyclizations of benzyl-substituted allenoate esters followed by intramolecular oxidative C-C cross-coupling involving aryl C-H functionalization were performed with Selectf

Full text of DOI:10.1002/chem.201000322

COMMUNICATION
DOI: 10.1002/chem.201000322
Gold-Catalyzed Intramolecular Oxidative Cross-Coupling of Nonactivated
Arenes
Matthew N. Hopkinson,[a] Arnaud Tessier,[a] Andrew Salisbury,[a] Guy T. Giuffredi,[a]
Lorraine E. Combettes,[a] Antony D. Gee,[b] and Vꢀronique Gouverneur*[a]
Homogeneous catalysis by gold has received considerable
interest in recent years.[1] The isolation of a gold(I) fluoride
complex stabilized by an N-heterocyclic carbene (NHC)
ligand led to the first AuI-catalyzed hydrofluorination of al-
kynes, a transformation carried out in the presence of
Et3N·3HF, a mildly acidic fluoride source.[2] In 2008, our
group explored the chemistry of AuI complexes with electro-
philic fluorinating reagents. Trifluorodihydropyranones were
obtained upon AuI-catalyzed cyclization–fluorodeauration of
Scheme 1. Reactivity of vinylgold(I) species with “F+”.
b-hydroxy-a,a-difluoroynones, a reaction performed with
Selectfluor.[3] In more recent studies by Zhang and co-work-
ers, Selectfluor was found to be a suitable oxidant for the
gold-catalyzed oxidative dimerization of propargylic ace-
tates and for oxidative cross-coupling reactions with preacti-
vated arylboronic acids.[4] The development of gold-cata-
lyzed oxidative cross-coupling reactions that do not require
preactivated arenes is more challenging and, to date, is re-
36% yield was unambiguously identified by X-ray analysis
as the tricyclic 8,8a-dihydro-2H-indeno[2,1-b]furan-2-one
AHCTUNGTRENNUNG
(2a). The separable dimeric butenolides (Æ)-(2S,2’S)-3a and
(2R,2’S)-3a were also formed and isolated in 20 and 15%
yield, respectively. X-Ray diffraction analysis of analytically
pure samples confirmed that the dimeric butenolides were,
indeed, diastereomers. The butenolide 4a resulting from
cyclization–protodeauration was not detected in the crude
reaction mixture. In a control experiment performed with
AuCl (5 mol%) in acetonitrile, but omitting Selectfluor,
compound 4a was formed as the only product after 6 days
(Scheme 2).[6,7] The formation of 2a from 1a, a new addition
to the list of gold-catalyzed oxidative cross-coupling reac-
tions reported to date,[4,5,8] is a challenging operation. Under
the same reaction conditions, but with PtCl2, CuOAc,
H2SO4, or AgOTf as the catalyst, 2a and 3a were not ob-
stricted to homocoupling reactions with PhIACTHNUTRGNEUNG
(OAc)2.[5] We re-
cently sought to investigate whether the gold-catalyzed oxi-
dative cross-coupling of nonactivated arenes might be ac-
À
complished with electrophilic N F reagents, such as Select-
fluor. We herein report the successful gold-catalyzed oxida-
À
tive intramolecular C H arylation using allenoate esters as
model substrates (Scheme 1).
The benzyl-substituted tert-butyl allenoate ester 1a was
treated with Selectfluor (2.5 equiv) and AuCl (5 mol%) in
acetonitrile. Three products were formed, none of which
were fluorinated (Scheme 2). The major product obtained in
served and with PdACHTNUGTRNEUNG(OAc)2 (5 mol%) the dimers 3a were
formed as the only products with no trace of 2a.[9,10]
Following extensive optimization studies, Ph3PAuNTf2
[a] M. N. Hopkinson, Dr. A. Tessier, A. Salisbury, G. T. Giuffredi,
L. E. Combettes, Prof. V. Gouverneur
[11]
(10 mol%) was identified as the catalyst of choice when
used in acetonitrile and H2O (10 equiv), a suitable solvent
system for Selectfluor (2.5 equiv) (Table 1, entry 5).[10]
Under these conditions, compound 2a was isolated in 62%
yield. Although Selectfluor was the best oxidant to access
dihydroindenofuranones from allenoates, N-fluorobenzene-
sulfonimide (NFSI) was also suitable, but less efficient
(Table 1, entry 6). With the latter fluorinating reagent, the
Chemistry Research Laboratory (CRL), University of Oxford
12 Mansfield Road, Oxford, OX1 3TA (UK)
Fax : (+44)1865-275-644
E-mail: veronique.gouverneur@chem.ox.ac.uk
[b] Prof. A. D. Gee
GSK Clinical Imaging Centre, Imperial College London
Hammersmith Hospital, Du Cane Road, London, W12 0NN (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000322.
Chem. Eur. J. 2010, 16, 4739 – 4743
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4739

tuted allenoate 1b was responsive to cyclization delivering
compound 2b in 70% yield (Table 2, entry 2). The reaction
proceeded rapidly (1.5 h) with allenoate 1c, which has elec-
tron-donating groups on the phenyl ring and led to 2c in
84% yield (Table 2, entry 3). The trifluoromethyl-substitut-
ed allenoate 1d cyclized successfully, but this substrate re-
quired a longer reaction time (16 h) and 2d was isolated in
much lower chemical yield (Table 2, entry 4). Under our op-
timized reaction conditions, substrate 1e with the benzyl
group geminal to the tert-butyl ester gave access to an alter-
native structural motif, the tricyclic 3,8-dihydro-1H-indeno-
AHCTUNGTREG[NNUN 2,1-c]furan-1-one (5e) (Table 2, entry 5). With allenoate 1 f
presenting two benzyl groups that could compete for the
Scheme 2. Gold(I)-catalyzed cyclization of 1a with and without Select-
fluor.
À
C C coupling event, the dihydroindenofuranones 2 f and 5 f
were obtained in 70% overall yield (Table 2, entry 6). The
successful cyclization of 1a–1h
prompted us to investigate the
efficiency of the transfer of ste-
reochemical information. Pleas-
Table 1. Optimization studies for oxidative cyclization of 1a.
Entry
Catalyst
Conditions[a]
Product ratio[b]
ingly, for (2S,5S)-1i, which was
prepared enantiopure (enantio-
meric excess (ee) >97%) and
as a single diastereomer, com-
plete axis-to-center chirality
2a/3a[c]/4a/1a (Yield [%])[d]
[e]
1
2
3
4
5
6
7
8
AuCl3
Selectfluor, MeCN, 5 d
Selectfluor, MeCN, 5 d
Selectfluor, MeCN, 24 h
Selectfluor, MeCN, H2O, 24 h
Selectfluor, MeCN, H2O, 4 h
NFSI, MeCN, H2O, 72 h
NFSI, CH2Cl2, 16 h
A, MeCN, H2O, 5 d
tBuOOH, MeCN, H2O, 6 d
Ph2SO, MeCN, H2O, 6 d
26:74:0:0 (2a=20) (3a=41)
no reaction
[e]
SIPrAuNTf2
AuCl
57:43:0:0 (2a=56)
67:33:0:0 (2a=58)
80:20:0:0 (2a=62)
38:62:0:0 (2a=20) (3a=45)
0:0:100:0 (4a=57)
no reaction
AuCl
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
À
transfer for the C O bond
forming event followed by ary-
lation delivered the single dia-
stereomer (8R,8aS)-2i in 80%
yield and >97% ee (Table 2,
entry 9).
9
0:0:50:50
0:0:69:31
10
11
12
13
PhI
N
0:100:0:0[f] (3a=23)
12:88:0:0 (2a=10) (3a=46)
100:0:0:0 (2a=95)
Oxone, MeCN, H2O, 6 d
Selectfluor, MeCN (0.01m), H2O, 4.5 h
Mechanistically, we envisage
initial AuI coordination to the
allene and addition of the pend-
ent tert-butyl ester to afford in-
termediate A, two elementary
steps for which experimental
evidence has been provided by
Hammond and co-workers.[6b,c]
[a] All reactions at RT; catalyst (10 mol%) unless otherwise stated; [1a]=0.15m unless otherwise stated, H2O
(10 equiv), oxidant (2.5 equiv); A=1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate. [b] Determined by
1H NMR spectroscopy of the crude reaction mixture. [c] (Æ)-(2S,2’S)-3a and (2R,2’S)-3a. [d] Yield of the iso-
lated product where appropriate. [e] 5 mol%. [f] Significant decomposition of 1a was observed.
reaction performed in dichloromethane afforded 57% of
the butenolide 4a as the only product (Table 1, entry 7).[7] 1-
Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate led to re-
covery of the starting material (Table 1, entry 8). Alternative
In one case, oxidative fluorination to the AuIII species B fol-
lowed by Friedel–Crafts-type arylation with fluoride dis-
placement would lead to the auracycle C, an intermediate
susceptible to AuIII/AuI reductive elimination (Path I). A
conjugated addition–reductive elimination mechanism from
B leading to 2a is also plausible (Path II). Alternatively, the
oxidative fluorination may lead to the b-fluorinated g-bute-
nolide D either directly by fluorodeauration of A or by re-
ductive elimination of B. This fluorinated intermediate
could subsequently undergo intramolecular arylation upon
addition–elimination (Path III). g-Butenolide 4a was un-
reactive under the standard oxidative cyclization conditions,
ruling out a mechanism involving the protodeaurated prod-
uct (Scheme 3).
oxidants, such as tBuOOH, Ph2SO, and PhIACTHNURGTNE(GNU OAc)2, did not
lead to 2a, but typically led to 4a or 3a (Table 1, entries 9–
11). With Oxone, compound 2a was isolated in 10% yield
(Table 1, entry 12).[10] Pleasingly, by using Ph3PAuNTf2 with
Selectfluor, the formation of the dimeric butenolides 3a was
completely suppressed upon lowering the reaction concen-
tration from 0.15 to 0.01m. Under these optimized condi-
tions, compound 2a was formed within 4.5 h and isolated in
95% yield (Table 1, entry 13).[12] The structural core of 2a is
surprisingly uncommon,[13] but presents similarities with ca-
dinane sesquiterpenes isolated from Heritiera littoralis.[14]
Experiments to probe the scope of the allenoate sub-
strates are summarized in Table 2. Access to all of the sub-
strates 1a–1i was achieved by the Wittig olefination of ke-
tenes by following literature procedures.[6a,10] The trisubsti-
To support a mechanistic scenario involving the vinyl gold
complex A, this intermediate (A; L=PPh3) was prepared
independently[6b,c] and treated with Selectfluor in CD3CN/
D2O. Pleasingly, the conversion of this complex into 2a and
3a was complete within 2 h with no detectable formation of
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Chem. Eur. J. 2010, 16, 4739 – 4743

Gold-Catalyzed Intramolecular Oxidative Cross-Coupling
COMMUNICATION
Table 2. Gold(I)-catalyzed oxidative cyclization of allenoates 1a–1i.
Entry[a] Allenoate
Product(s)
Yield[b]
[%]
1
95
70
2
3
4
84
37
Scheme 3. Plausible mechanism.
5
57
27
protodeaurated butenolide 4a. The preference for electron-
rich over electron-poor aryl-substituted allenoates supports
a mechanism based on a Friedel–Crafts arylation and argues
against a pathway involving an SNAr-type step by a nucleo-
philic organogold species.[15] The suitability of AuCl3 as a
catalyst for the reaction (Table 1, entry 1) is consistent with
the proposed mechanism. Initial activation of the allenoate
by AuIII could lead directly to an intermediate of type B,
which, upon conversion to the product, generates the pro-
posed catalytic species, AuI. The formation of the dimeric
butenolides 3a can be accounted for, by evoking transmeta-
lation from A to B followed by reductive elimination of the
6
43
46
resulting diorganogoldACHTNUTGRNEUNG
(III) species.[16] This was the major
pathway observed when 1a was treated with a stoichiomet-
ric amount of AuCl3 without Selectfluor.[10,17] In the course
of our studies, in no case could a fluorinated product be iso-
lated from the reaction mixtures.[18] To discriminate between
paths I/II and III, the b-fluorinated g-butenolide 6g was pre-
pared independently[19] and treated in acetonitrile with
Ph3PAuNTf2 (10 mol%) in the presence or in the absence of
Selectfluor. These experiments led to recovery of the start-
ing material with no detectable trace of the tricyclic product
5g,[20] which suggests that Path III is not operating
(Scheme 4).[21]
7
8
9
81
80
[a] Reaction conditions: Selectfluor (2.5 equiv), Ph3PAuNTf2 (10 mol%),
MeCN (0.01m), H2O (10 equiv), RT, 1.5–24 h. [b] Yield of the isolated
product.
Scheme 4. Reactivity of fluorinated butenolide 6g.
Chem. Eur. J. 2010, 16, 4739 – 4743
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4741

V. Gouverneur et al.
[3] M. Schuler, F. Silva, C. Bobbio, A. Tessier, V. Gouverneur, Angew.
Chem. 2008, 120, 8045–8048; Angew. Chem. Int. Ed. 2008, 47, 7927–
7930.
[4] a) Y. Peng, L. Cui, G. Zhang, L. Zhang, J. Am. Chem. Soc. 2009,
131, 5062–5063; b) G. Zhang, Y. Peng, L. Cui, L. Zhang, Angew.
Chem. 2009, 121, 3158–3161; Angew. Chem. Int. Ed. 2009, 48, 3112–
3115; c) L. Cui, G. Zhang, L. Zhang, Bioorg. Med. Chem. Lett. 2009,
19, 3884–3887.
[5] a) A. Kar, N. Mangu, H. M. Kaiser, M. Beller, M. K. Tse, Chem.
Commun. 2008, 386–388; b) A. Kar, N. Mangu, H. M. Kaiser, M. K.
Tse, J. Organomet. Chem. 2009, 694, 524–537.
[6] a) J.-E. Kang, E.-S. Lee, S.-I. Park, S. Shin, Tetrahedron Lett. 2005,
46, 7431–7433; b) L.-P. Liu, B. Xu, M. S. Mashuta, G. B. Hammond,
J. Am. Chem. Soc. 2008, 130, 17642–17643; c) L.-P. Liu, G. B. Ham-
mond, Chem. Asian J. 2009, 4, 1230–1236.
In conclusion, we have developed a novel cascade cycliza-
tion cross-coupling process leading to tricyclic dihydroinde-
nofuranone-type products. This is the first example of a
À
gold-catalyzed intramolecular C C cross-coupling reaction
involving aryl CÀH functionalization with Selectfluor as the
oxidant. Axis-to-center chirality transfer has been demon-
strated with no erosion of enantiomeric excess. Mechanistic
investigations suggest that a pathway involving fluorodeau-
ration is not operating. This reaction is a new addition to
the shortlist of oxidative cross-coupling processes performed
under gold catalysis known to date. Efforts aimed at ex-
panding the scope of this chemistry and its mechanistic as-
pects are ongoing and will be reported in due course.
[7] The solvent has a significant effect on the efficiency of protodeaura-
tion. The gold-catalyzed cyclization of 1a to 4a was much slower in
MeCN than CH2Cl2 (Scheme 2). The oxidative coupling with NFSI
was only successful in MeCN. Compound 4a was the only product
observed in CH2Cl2. For details, see the Supporting Information.
[8] For a recent review on oxidative coupling reactions with gold, see:
a) H. A. Wegner, Chimia 2009, 63, 44–48; for selected examples of
gold-catalyzed cross-coupling reactions with substrates as oxidants,
see: b) C. Gonzµlez-Arellano, A. Corma, M. Iglesias, F Sµnchez, J.
Catal. 2006, 238, 497–501; c) C. Gonzµlez-Arellano, A. Abad, A.
Corma, H. García, M. Iglesias, F. Sµnchez, Angew. Chem. 2007, 119,
1558–1560; Angew. Chem. Int. Ed. 2007, 46, 1536–1538; d) P. Li, L.
Wang, M. Wang, F. You, Eur. J. Org. Chem. 2008, 5946–5951; for a
report on the gold-catalyzed oxidative homodimerization of coumar-
ins with an external oxidant, see: e) H. A. Wegner, S. Ahles, M.
Neuburger, Chem. Eur. J. 2008, 14, 11310–11313.
Experimental Section
General procedure for oxidative cyclization of tert-butyl allenoates:
PPh3AuNTf2 (10 mol%) and Selectfluor (2.5 equiv) were added to a solu-
tion of the allenoate (1 equiv) in acetonitrile (0.01m) and water
(10 equiv). The reaction was stirred at room temperature until TLC anal-
ysis showed complete consumption of the allenoate (1.5–24 h). The reac-
tion mixture was then diluted with dichloromethane and filtered through
Celite. After drying over anhydrous sodium sulfate and filtration, the sol-
vent was removed in vacuo. The resulting crude mixture was purified by
flash column chromatography on a short pad of silica gel.
X-ray crystallographic analysis: CCDC-765540, 765541, 765542, 765543,
765544 and 765545 contain the supplementary crystallographic data for
2a, 2d, (8R,8aS)-2i, (Æ)-(2S,2’S)-3a, (2R,2’S)-3a, and 5 f, respectively.
These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[9] For a report on the oxidative homodimerization of allenic acids by
PdII, see: S. Ma, Z. Yu, Org. Lett. 2003, 5, 1507–1510.
[10] For details, see the Supporting Information.
[11] N. Mꢂzailles, L Ricard, F. Gagosz, Org. Lett. 2005, 7, 4133–4136.
[12] The cyclization of 1a with Ph3PAuNTf2 but without Selectfluor af-
forded 4a as the only product; for details, see the Supporting Infor-
mation.
[13] a) Y. Ishii, C. Gao, W. X. Xu, M. Iwasaki, M. Hidai, J. Org. Chem.
1993, 58, 6818–6825; b) E. Krawczyk, M. Koprowski, J. Luczak, Tet-
rahedron: Asymmetry 2007, 18, 1780–1787; c) E. Marchal, J.-F.
Cupif, P. Uriac, P. van de Weghe, Tetrahedron Lett. 2008, 49, 3713–
3715.
Acknowledgements
This work was supported by the EPSRC, GSK, and the EU (MEIF-CT-
2006-040558). We thank Dr. B. Odell for NMR spectroscopy studies and
Dr. A. L. Thompson and the Oxford Chemical Crystallography Service
for crystallographic services.
[14] S. P. Chavan, M. Thakkar, U. R. Kalkote, Tetrahedron Lett. 2007, 48,
643–646.
[15] For selected recent reports of vinylgold(I) complexes acting as nu-
cleophiles, see: a) P. Dubꢂ, F. D. Toste, J. Am. Chem. Soc. 2006, 128,
12062–12063; b) Y. Shi, S. D. Ramgren; S. A. Blum, Organometal-
lics, 2009, 28, 1275–1277; S. A. Blum, Organometallics, 2009, 28,
1275–1277; c) A. S. K. Hashmi, C. Lothschꢁtz, R. Dçpp, M. Ru-
dolph, T. D. Ramamurthi, F. Rominger, Angew. Chem. 2009, 121,
8392–8395; Angew. Chem. Int. Ed. 2009, 48, 8243–8246; d) Y. Shi,
K E. Roth, S. D. Ramgren, S. A. Blum, J. Am. Chem. Soc. 2009, 131,
18022–18023.
Keywords: allenes · arylation · cross-coupling · cyclization ·
gold
[1] For selected reviews on gold catalysis, see: a) A. S. K. Hashmi, G. J.
Hutchings, Angew. Chem. 2006, 118, 8064–8105; Angew. Chem. Int.
Ed. 2006, 45, 7896–7936; b) A. S. K. Hashmi, Chem. Rev. 2007, 107,
3180–3211; c) A. Fꢁrstner, P. W. Davies, Angew. Chem. 2007, 119,
3478–3519; Angew. Chem. Int. Ed. 2007, 46, 3410–3449; d) R.
Skouta, C.-J. Li, Tetrahedron 2008, 64, 4917–4938; e) J. Muzart, Tet-
rahedron 2008, 64, 5815–5849; f) Z. Li, C. Brouwer, C. He, Chem.
Rev. 2008, 108, 3239–3265; g) A. Arcadi, Chem. Rev. 2008, 108,
3266–3325; h) E. Jimꢂnez-NfflÇez, A. M. Echavarren, Chem. Rev.
2008, 108, 3326–3350; i) D. J. Gorin, B. D. Sherry, F. D. Toste, Chem.
Rev. 2008, 108, 3351–3378; j) R. A. Widenhoefer, Chem. Eur. J.
2008, 14, 5382–5391; k) N. Nishina, Y. Yamamoto, Tetrahedron
2009, 65, 1799–1808.
[16] Alternatively the diorganogold
oxyauration of a second molecule of the allenoate by B or by trans-
metalation between two gold(III) intermediates B.
ACHTUNGTRENN(UNG III) species could be formed through
AHCTUNGTRENNUNG
[17] For examples of oxidative coupling with stoichiometric or substoi-
chiometric AuIII without external oxidants, see: a) F. Zamora, P.
Amo-Ochoa, B. Fischer, A. Schimanski, B. Lippert, Angew. Chem.
1999, 111, 2415–2417; Angew. Chem. Int. Ed. 1999, 38, 2274–2275;
b) Y. Fuchita, Y. Utsunomiya, M. Yasutake, J. Chem. Soc. Dalton
Trans. 2001, 2330–2334; c) A. K. Sahoo, Y. Nakamura, N. Aratani,
K. S. Kim, S. B. Noh, H. Shinokubo, D. Kim, A. Osuka, Org. Lett.
2006, 8, 4141–4144; d) A. S. K. Hashmi, M. C. Blanco, D. Fischer,
J. W. Bats, Eur. J. Org. Chem. 2006, 1387–1389; e) H. Harkat, A. Y.
Dembelꢂ, J.-M. Weibel, A. Blanc, P. Pale, Tetrahedron 2009, 65,
1871–1879.
[2] a) D. S. Laitar, P. Mꢁller, T. G. Gray, J. P. Sadighi, Organometallics
2005, 24, 4503–4505; b) J. A. Akana, K. X. Bhattacharyya, P.
Mꢁller, J. P. Sadighi, J. Am. Chem. Soc. 2007, 129, 7736–7737;
c) B. C. Gorske, C. T. Mbofana, S. J. Miller, Org. Lett. 2009, 11,
4318–4321.
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Gold-Catalyzed Intramolecular Oxidative Cross-Coupling
COMMUNICATION
[18] In addition, no b-fluorinated g-butenolide was observed upon oxida-
tive cyclization of the alkyl-substituted tert-butyl 2-methylocta-2,3-
dienoate with Selectfluor. This reaction led to a complex mixture of
products.
[20] Subjecting a mixture of 1g and 6g to the standard oxidative cycliza-
tion conditions led smoothly to 5g after 24 h with no consumption
of 6g.
[21] The authors thank the referees for insightful suggestions.
[19] Efforts to prepare D were unsuccessful, see: C. Zhou, Z. Ma, Z. Gu,
C. Fu, S. Ma, J. Org. Chem. 2008, 73, 772–774.
Received: August 19, 2009
Revised: February 9, 2010
Published online: March 25, 2010
Chem. Eur. J. 2010, 16, 4739 – 4743
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4743