Tandem gold/silver-catalyzed cycloaddition/hydroarylation of 7-aryl-1,6-enynes to form 6,6-diarylbicyclo[3.2.0]heptanes

Article abstract of DOI:10.1002/chem.201500371

Mixtures of [{PCy₂(o-biphenyl)}AuCl] and AgSbF₆ catalyze the tandem cycloaddition/hydroarylation of 7-aryl-1,6-enynes with electron-rich arenes to form 6,6-diarylbicyclo[3.2.0]heptanes in good yield under mild conditions. Experimental observations point to a mechanism involving gold-catalyzed cycloaddition followed by silver-catalyzed hydroarylation of a bicyclo[3.2.0]hept-1(7)-ene intermediate.

Full text of DOI:10.1002/chem.201500371

DOI: 10.1002/chem.201500371
Communication
&
Tandem Reactions
Tandem Gold/Silver-Catalyzed Cycloaddition/Hydroarylation of
7-Aryl-1,6-enynes to Form 6,6-Diarylbicyclo[3.2.0]heptanes
Bradley D. Robertson, Rachel E. M. Brooner, and Ross A. Widenhoefer*[a]
mediates in noble metal-catalyzed enyne cycloaddition,[3,4]
Abstract: Mixtures of [{PCy2(o-biphenyl)}AuCl] and AgSbF6
most notably in the cycloisomerization of 7-aryl-1,6-enynes to
catalyze the tandem cycloaddition/hydroarylation of 7-
bicyclo[3.2.0]hept-6-enes (Scheme 1).[4] However, in contrast to
aryl-1,6-enynes with electron-rich arenes to form 6,6-diary-
cyclopropyl carbenoid intermediates, nucleophilic trapping of
lbicyclo[3.2.0]heptanes in good yield under mild condi-
these intermediates to form bicyclo[3.2.0]heptanes remains un-
tions. Experimental observations point to a mechanism in-
documented.[5,6]
volving gold-catalyzed cycloaddition followed by silver-
We recently validated intermediates III through the spectro-
catalyzed hydroarylation of a bicyclo[3.2.0]hept-1(7)-ene
scopic characterization of complex 1, generated in the gold-
intermediate.
catalyzed cycloisomerization of enyne 2 to form bicyclo[3.2.0]-
hept-6-ene 3 (Scheme 2).[7] Identification of 1 as a local mini-
Electrophilic noble metal complexes catalyze the cycloaddition
of 1,6-enynes to form a range of products including vinylcyclo-
pentenes, alkylidenecyclohexenes, and/or bicyclo[4.1.0]hep-
tenes,[1] presumably via highly delocalized metal cyclopropyl
carbenoid intermediates (I and II; Scheme 1).[1,2] Alternatively,
Scheme 2. Spectroscopic detection of 1 in the gold-catalyzed conversion of
2 to 3.
mum on the reaction coordinate suggested that these inter-
mediates might be susceptible to nucleophilic trapping.
Guided by this hypothesis, we have developed and herein
report the gold/silver-catalyzed tandem cycloaddition/hydroar-
ylation of 7-aryl-1,6-enynes to form 6,6-diarylbicyclo[3.2.0]hep-
tanes.[8] However, in contrast to our expectations, gold was not
involved in the hydroarylation event and, rather, our experi-
mental observations point to a mechanism involving gold-cata-
lyzed cycloaddition followed by silver-catalyzed hydroarylation
of a bicyclo[3.2.0]hept-1(7)-ene intermediate.
We targeted electron-rich arenes as trapping agents for the
Scheme 1. Potential pathways and intermediates for enyne cycloaddition
gold bicycloheptyl cations generated via enyne cycloaddition
catalyzed by electrophilic noble metal complexes.
owing to the precedence for the hydroarylative trapping of cy-
clopropyl carbenoid intermediates.[1] In apparent support of
these cyclopropyl carbenoid intermediates can be trapped
with nucleophiles prior to demetallation to further expand the
palette of molecular structures accessible via enyne cycloaddi-
tion (Scheme 1).[2] In addition to intermediates I and II, metal-
stabilized bicycloheptyl cations (III) have been invoked as inter-
our hypotheses, treatment of a 1:2 mixture of enyne 2 and
1,3,5-trimethoxybenzene (TMB) with a catalytic 1:1.1 mixture of
[{PCy2(o-biphenyl)}AuCl] (4a; 5 mol%) and AgSbF6 at 258C for
3 h formed bicyclo[3.2.0]heptane 5a in 82% yield with ꢀ25:1
endo/exo selectivity (Table 1, entry 1). However, subsequent ex-
perimentation revealed the critical role of silver in the hydroar-
ylation event, which argued against the hydroarylation of
a gold-stabilized bicycloheptyl cation. In particular, reaction of
2 with TMB catalyzed by the silver-free gold complex [{PCy2(o-
[a] B. D. Robertson, R. E. M. Brooner, Prof. R. A. Widenhoefer
French Family Science Center, Duke University
Durham, NC 27708–0346 (USA)
E-mail: rwidenho@chem.duke.edu
À
biphenyl)}Au(NCMe)]+ SbF6 (4b; 5 mol%) at 258C for 6 h
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500371.
formed bicyclo[3.2.0]hept-6-ene 3 in 47% yield without forma-
Chem. Eur. J. 2015, 21, 5714 – 5717
5714
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
or gold/silver-catalyzed hydroarylation of 3 with TMB con-
firmed that hydroarylation of 3 was too slow to account for
the formation of 5a in the reaction of 2 with TMB and also es-
tablished AgSbF6 as a stand-alone catalyst for bicycloheptene
hydroarylation [Eq. (1)].
Table 1. Effect of gold, silver, and Brønsted acid on the cycloaddition/hy-
droarylation of 2 with 1,3,5-trimethoxybenzene (TMB).
Rather, hydroarylation of the bicyclo[3.2.0]hept-1(7)-ene in-
termediate 8 was implicated through the gold/silver-catalyzed
reaction of 2 with 2,4,6-trideutero-1,3,5-trimethoxybenzene
([D3]TMB; 97% deuterium incorporation), which formed [D3]5a
with approximately 75% deuterium incorporation at the C1
bridgehead position without detectable deuteration at C7
(Schemes 3 and 4).
Entry Au source Ag [mol%] HOTf [mol%] Time [h][a] 3 [%] 5 [%]
1[b]
2[c]
3[b]
4[c]
5[d]
6[c]
7[c]
4a
4b
4a
4b
none
4b
5.5
0
20
20
20
0
0
0
0
0
0
5
5
3
6
1.5
1.5
24
6
ꢁ2
47
ꢁ2
ꢁ2
ꢁ2
10
82
ꢁ2
90
87
ꢁ2
73
none
0
24
ꢁ2
ꢁ2
Owing to the potential generation of Brønsted acid from
gold/silver mixtures[10] and the recent demonstration of gold/
Brønsted acid tandem catalysis,[11,12] we evaluated the potential
role of Brønsted acid in gold/silver-catalyzed enyne cycloaddi-
tion/hydroarylation. Indeed, treatment of 2 and TMB with a 1:1
mixture of 4b and HOTf for 6 h at 258C formed 5a in 73%
[a] Reaction progress monitored by TLC (unless otherwise stated).
[b] Yield of isolated product. [c] Yield determined by 1H NMR analysis.
[d] Reaction progress monitored by GC.
1
tion of detectable quantities of 5a (Table 1, entry 2). Further in-
creasing the silver loading to 20 mol% in combination with
either 4a or 4b (5 mol%) further decreased the reaction time
to approximately 1.5 h and increased the yield of 5a (Table 1,
entries 3 and 4). Conversely, AgSbF6 alone led to no detectable
cycloaddition (Table 1, entry 5).
yield and 3 in 10% yield (by H NMR analysis; Table 1, entry 6).
Periodic analysis of a similar reaction mixture revealed that the
relative concentration of 3 increased to approximately 20%
after 56% conversion and then decreased to approximately
10% at 95% conversion, suggesting competitive hydroaryla-
tion of both 8 and 3.[9]
In the presence of a catalytic 1:4 mixture of 4a (5 mol%)
and AgSbF6 (20 mol%), 1,6-enynes possessing a 7-(2-naphthyl)
(6a) or 7-(3,5-dimethylphenyl) (6b) group, 4,4-gem-acetoxy-
methyl (6c) or acetonide (6d) groups, a 3-methyl (6e) or 3-
phenyl (6 f) group, or 3,3-gem-dimethyl (6g) groups under-
went efficient gold/silver-catalyzed cycloaddition/hydroaryla-
tion with TMB to form the corresponding bicycloheptanes 7a–
g in 64–86% yield with ꢀ25:1 endo/exo selectivity (Table 2, en-
tries 1–7). In addition to TMB, a number of mono-, di-, and tri-
substituted arenes underwent gold/silver-catalyzed cycloaddi-
tion/hydroarylation with 2 to form 6,6-diarylbicycloheptanes
5b–g in >80% yield as mixtures of endo/exo diastereomers
ranging from 1:7 in the case of 2,6-di-tert-butylphenol to
ꢀ25:1 in the case of 3,5-dimethoxytoluene (Table 2, entries 9–
13).
Scheme 3. Gold/silver-catalyzed hydroarylation of 2,4,6-trideutero-1,3,5-tri-
methoxybenzene ([D3]TMB).
A number of additional experiments employing 2 and 1,3,5-
trimethoxybenzene (TMB) were performed to further clarify the
role of silver and the nature of the intermediates involved in
the hydroarylation event of catalytic cycloaddition/hydroaryla-
tion. For example, periodic analysis of the gold/silver-catalyzed
cycloaddition/hydroarylation of 2 with TMB revealed that 3 ac-
cumulated slowly throughout the reaction, reaching a maxi-
mum relative concentration of approximately 6% at 90% con-
version,[9] which is inconsistent with the intermediacy of 3 in
the conversion of 2 to 5a. Independent analysis of the silver-
Scheme 4. Proposed mechanism for the conversion of 2 and TMB to 5a via
gold/silver tandem catalysis.
Chem. Eur. J. 2015, 21, 5714 – 5717
www.chemeurj.org
5715
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Furthermore, the greater efficacy
of AgSbF6 as a hydroarylation
Table 2. Cycloaddition/hydroarylation of 7-aryl-1,6-enynes catalyzed by a mixture of 4a (5 mol%) and AgSbF6
(20 mol%) in CH2Cl2 at 258C for 1.5 h [Z=C(CO2Me)2].
catalyst,
even
with
only
Entry
Enyne
Arene
Product (yield [%])[a]
endo/exo[b]
0.1 mol% excess relative to 4a
(Table 1, entry 2), as compared
to HOTf (5 mol%) appears incon-
gruent with hidden Brønsted
acid catalysis in the former
case.[13] We therefore propose
a mechanism for the cycloaddi-
1
2
6a (Ar=2-naphthyl)
6b (Ar=3,5-C6H5Me2)
7a (84%)
7b (84%)
ꢀ25:1
ꢀ25:1
tion/hydroarylation of
TMB involving gold-catalyzed cy-
cloaddition of followed by
2 with
2
3
4
6c [X=C(CH2OAc)2]
7c (80%)
7d (64%)
ꢀ25:1
ꢀ25:1
silver-catalyzed hydroarylation of
8, presumably via a silver-stabi-
lized
bicycloheptyl
cation
(Scheme 4). In this context, it is
worth noting that although
there is a growing body of work
that documents the ability of
silver salts to affect the out-
comes of gold(I)-catalyzed trans-
formations,[14,15] in only one case
have gold and silver been
shown to function orthogonally
in two discrete steps of
a tandem catalytic process in
which the silver salt functions as
a simple Lewis acid for carbonyl
activation.[16,17]
5
6
7
6e (R1 =Me, R2 =H)
6 f (R1 =Ph, R2 =H)
6g (R1 =R2 =Me)
7e (79%; 2:1)[c]
7 f (86%; 3:1)[c]
7g (77%)
ꢀ25:1
ꢀ25:1
ꢀ25:1
2
2
8
9
R=Me
R=H
5b (85%)
5c (83%)
1:1.8
1:2.5
In summary, we have devel-
oped an effective tandem gold/
silver-catalyzed protocol for the
cycloaddition/hydroarylation of
7-aryl-1,6-enynes to form 6,6-dia-
rylbicyclo[3.2.0]heptanes.[8] Our
experimental observations re-
garding the gold/silver-catalyzed
cycloaddition/hydroarylation of
2 with TMB point to a mecha-
nism involving sequential gold-
catalyzed conversion of 2 to 8
followed by silver-catalyzed hy-
droarylation of 8. These transfor-
mations represent the first ex-
10
11
R=Me
R = H
5d (85%)
5e (72%)
1:1.3
1:3.6
12
1:7
2
2
5 f (86%)
13
25:1
5g (88%)
1
[a] Yield of product isolated in >95% purity. [b] endo/exo ratio determined by H NMR analysis of the crude re-
action mixture. [c] Mixture of C2 diastereomers.
Although the experiments described in the preceding para-
graph established the viability of Brønsted acid-catalyzed path-
ways for bicycloheptene hydroarylation, the relevance of these
pathways to the gold/silver-catalyzed cycloaddition/hydroaryla-
tion of 2 is not clear. We previously established the participa-
tion of Brønsted acid in the gold-catalyzed cycloisomerization
of 2 to 3, specifically the isomerization of 8 to 3.[12] However,
silver was not the apparent source of Brønsted acid in these
transformations and rather, silver inhibited the conversion of
1 to 3. Similarly, attempts to generate Brønsted acid in the
gold/silver-catalyzed reaction of 2 with TMB through addition
of catalytic amounts of water led to inhibition of the reaction.
amples involving efficient trapping of the bicyclo[3.2.0]hept-
1(7)-ene intermediate generated via enyne cycloaddition to
generate functionalized bicyclo[3.2.0]heptanes.
Acknowledgements
We acknowledge the NSF (CHE-1213957) for support of this re-
search.
Keywords: aromatic substitution · cycloaddition · enynes ·
gold · silver
Chem. Eur. J. 2015, 21, 5714 – 5717
www.chemeurj.org
5716
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[1] For recent reviews on gold(I)-catalyzed enyne cycloaddition see: a) C.
Obradors, A. M. Echavarren, Acc. Chem. Res. 2014, 47, 902–912; b) A.
Fürstner, Acc. Chem. Res. 2014, 47, 925–938; c) P. Y. Toullec, V. Michelet,
Top. Curr. Chem. 2011, 302, 31–80; d) A. M. Echavarren, E. JimØnez-
NfflÇez, Top. Catal. 2010, 53, 924–930; e) A. Fürstner, Chem. Soc. Rev.
2009, 38, 3208–3221; f) E. JimØnez-NfflÇez, A. M. Echavarren, Chem. Rev.
2008, 108, 3326–3350; g) V. Michelet, P. Y. Toullec, J. P. GenÞt, Angew.
Chem. Int. Ed. 2008, 47, 4268–4315; Angew. Chem. 2008, 120, 4338–
4386.
[10] a) J. R. Cabrero-Antonino, A. Leyva-PØrez, A. Corma, Chem. Eur. J. 2013,
19, 8627–8633; b) R. E. M. Brooner, R. A. Widenhoefer, Chem. Eur. J.
2011, 17, 6170–6178; c) O. Kanno, W. Kuriyama, Z. J. Wang, F. D. Toste,
Angew. Chem. Int. Ed. 2011, 50, 9919–9922; Angew. Chem. 2011, 123,
10093–10096; d) T. T. Dang, F. Boeck, L. Hintermann, J. Org. Chem. 2011,
76, 9353–9361; e) J. G. Taylor, L. A. Adrio, K. K. Hii, Dalton Trans. 2010,
39, 1171–1175; f) C. H. Cheon, O. Kanno, F. D. Toste, J. Am. Chem. Soc.
2011, 133, 12875–12879.
[11] a) X. Wu, M.-L. Li, P.-s. Wang, J. Org. Chem. 2014, 79, 419–425; b) D.
Qian, J. Zhang, Chem. Eur. J. 2013, 19, 6984–6988; c) Z.-Y. Han, H. Xiao,
X.-H. Chen, L.-Z. Gong, J. Am. Chem. Soc. 2009, 131, 9182–9183; d) Y.
Horino, Y. Takahashi, Y. Nakashima, H. Abe, RSC Adv. 2014, 4, 6215–
6218; e) H. Wu, Y.-P. He, L.-Z. Gong, Adv. Synth. Catal. 2012, 354, 975–
980.
[2] A. Fürstner, H. Szillat, B. Gabor, R. Mynott, J. Am. Chem. Soc. 1998, 120,
8305–8314.
[3] a) F. Marion, J. Coulomb, C. Courillon, L. Fensterbank, M. Malacria, Org.
Lett. 2004, 6, 1509–1511; b) S. Couty, C. Meyer, J. Cossy, Angew. Chem.
Int. Ed. 2006, 45, 6726–6730; Angew. Chem. 2006, 118, 6878–6882;
c) S. I. Lee, S. M. Kim, M. R. Choi, S. Y. Kim, Y. K. Chung, W.-S. Han, S. O.
Kang, J. Org. Chem. 2006, 71, 9366–9372.
[12] R. E. M. Brooner, B. D. Robertson, R. A. Widenhoefer, Organometallics
2014, 33, 6466–6473.
[13] This outcome would require generation of stronger acid from gold/
silver mixtures as compared to gold/HOTf mixtures, but acid strength
in both cases should be levelled by the presence of Brønsted bases.
[14] a) M. A. Tarselli, A. R. Chianese, S. J. Lee, M. R. GagnØ, Angew. Chem. Int.
Ed. 2007, 46, 6670–6673; Angew. Chem. 2007, 119, 6790–6793; b) H. Li,
R. A. Widenhoefer, Org. Lett. 2009, 11, 2671–2674; c) D. W. Wang, R. Cai,
S. Sharma, J. Jirak, S. K. Thummanapelli, N. G. Akhmedov, H. Zhang, X. B.
Liu, J. L. Petersen, X. D. Shi, J. Am. Chem. Soc. 2012, 134, 9012–9019;
d) Y. J. Su, Y. W. Zhang, N. G. Akhmedov, J. L. Petersen, X. D. Shi, Org.
Lett. 2014, 16, 2478–2481; e) A. Homs, I. Escofet, A. M. Echavarren, Org.
Lett. 2013, 15, 5782–5785; f) F. Schrçder, C. Tugny, E. Salanouve, H. Cla-
vier, L. Giordano, D. Moraleda, Y. Gimbert, V. Mouri›s-Mansuy, J. P. God-
dard, L. Fensterbank, Organometallics 2014, 33, 4051–4056.
[4] a) A. Escribano-Cuesta, P. PØrez-Galµn, E. Herrero-Gómez, M. Sekine,
A. A. C. Braga, F. Maseras, A. M. Echavarren, Org. Biomol. Chem. 2012, 10,
6105–6111; b) K. Ota, S. I. Lee, J. M. Tang, M. Takachi, H. Nakai, T. Mori-
moto, H. Sakurai, K. Kataoka, N. Chatani, J. Am. Chem. Soc. 2009, 131,
15203–15211; c) C. Nieto-Oberhuber, P. PØrez-Galµn, E. Herrero-Gómez,
T. Lauterbach, C. Rodríguez, S. López, C. Bour, A. Rosellón, D. J. Cµrde-
nas, A. M. Echavarren, J. Am. Chem. Soc. 2008, 130, 269–279; d) T. Mat-
suda, S. Kadowaki, T. Goya, M. Murakami, Synlett 2006, 575–578; e) C.
Nieto-Oberhuber, S. López, A. M. Echavarren, J. Am. Chem. Soc. 2005,
127, 6178–6179; f) A. Fürstner, P. W. Davies, T. Gress, J. Am. Chem. Soc.
2005, 127, 8244–8245; g) Y. T. Lee, Y. K. Kang, Y. K. Chung, J. Org. Chem.
2009, 74, 7922–7934.
[5] Two related processes involving trapping of gold-stabilized g-cyclobuty-
lallyl cations have been demonstrated in the cycloaddition of alkylidene
cyclopropanes: a) S. G. Sethofer, S. T. Staben, O. Y. Hung, F. D. Toste, Org.
Lett. 2008, 10, 4315–4318; b) H. C. Zheng, R. J. Felix, M. R. GagnØ, Org.
Lett. 2014, 16, 2272–2275.
[15] a) D. Weber, M. R. GagnØ, Org. Lett. 2009, 11, 4962–4965; b) Y. Y. Zhu,
C. S. Day, L. Zhang, K. J. Hauser, A. C. Jones, Chem. Eur. J. 2013, 19,
12264–12271; c) S. G. Weber, F. Rominger, B. F. Straub, Eur. J. Inorg.
Chem. 2012, 2863–2867.
[16] Y. P. Xiao, X. Y. Liu, C. M. Che, Beilstein J. Org. Chem. 2011, 7, 1100–1107.
[17] For additional examples of tandem gold/Lewis acid-catalyzed transfor-
mations, see: a) X. Wang, S. Dong, Z. Yao, L. Feng, P. Daka, H. Wang, Z.
Xu, Org. Lett. 2014, 16, 22–25; b) Y. Xi, D. Wang, X. Ye, N. G. Akhmedov,
J. L. Petersen, X. Shi, Org. Lett. 2014, 16, 306–309; c) X. Wang, Z. Yao, S.
Dong, F. Wei, H. Wang, Z. Xu, Org. Lett. 2013, 15, 2234–2237.
[6] Oxidative trapping of bicyclo[3.2.0]hept-1(7)-enes with cyclobutyl ring
opening has been reported: a) J. Blum, H. Beer-Kraft, Y. Badrieh, J. Org.
Chem. 1995, 60, 5567–5569; b) D. V. Patil, H.-S. Park, J. Koo, J. W. Han, S.
Shin, Chem. Commun. 2014, 50, 12722–12725.
[7] R. E. M. Brooner, T. J. Brown, R. A. Widenhoefer, Angew. Chem. Int. Ed.
2013, 52, 6259–6261; Angew. Chem. 2013, 125, 6379–6381.
[8] For
a review of biologically active bicyclo[3.2.0]heptanes see: M.
Miesch, Curr. Org. Synth. 2006, 3, 327–340.
Received: January 28, 2015
[9] See the Supporting Information.
Published online on March 4, 2015
Chem. Eur. J. 2015, 21, 5714 – 5717
www.chemeurj.org
5717
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim