Gold catalysis: Experimental mechanistic insights into the anellation of phenols with 1,3-dienes Dedicated to Prof. Hubert Schmidbaur on the occasion of his 80th birthday.

Article abstract of DOI:10.1016/j.jorganchem.2015.05.034

An intermediate of the anellation reaction of phenols and 1,3-dienes could be detected, isolated and characterized as the hydroarylation product. The other conceivable intermediate, the hydroaryloxylation product, was prepared via Pd-catalysis and converted under the conditions of the gold catalysis, too. Under exactly the same conditions a very fast Claisen rearrangement took place delivering the formal hydroarylation product as well. After this fast intermolecular formation of the intermediate (formed either directly via the hydroarylation pathway or via a hydroaryloxylation/Claisen rearrangement sequence) the subsequent intramolecular reaction leading to the product turned out to be significantly slower. The major product is the cis-diastereomer (cis-3/trans-3 = 12:1).

Full text of DOI:10.1016/j.jorganchem.2015.05.034

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Journal of Organometallic Chemistry 795 (2015) 58e62
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Gold catalysis: Experimental mechanistic insights into the anellation
of phenols with 1,3-dienes
, b, *
Sarah Bay a, Alexandra Englert a, Kumara Swamy Nalivela a, A. Stephen K. Hashmi a
,
,
*
Mie Højer Larsen a
a
€
Organisch-Chemisches Institut, Universitat Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
b Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
An intermediate of the anellation reaction of phenols and 1,3-dienes could be detected, isolated and
characterized as the hydroarylation product. The other conceivable intermediate, the hydroaryloxylation
product, was prepared via Pd-catalysis and converted under the conditions of the gold catalysis, too.
Under exactly the same conditions a very fast Claisen rearrangement took place delivering the formal
hydroarylation product as well. After this fast intermolecular formation of the intermediate (formed
either directly via the hydroarylation pathway or via a hydroaryloxylation/Claisen rearrangement
sequence) the subsequent intramolecular reaction leading to the product turned out to be significantly
slower. The major product is the cis-diastereomer (cis-3/trans-3 ¼ 12:1).
Received 31 January 2015
Received in revised form
15 May 2015
Accepted 16 May 2015
Available online 29 May 2015
Dedicated to Prof. Hubert Schmidbaur on
the occasion of his 80th birthday.
© 2015 Elsevier B.V. All rights reserved.
Keywords:
1,3-Dienes
Gold
Heterocycles
Phenols
Reaction mechanisms
1. Introduction
developed by C.-J. Li et al. (Scheme 1) [4a].
With regard to the mechanism, this raises an interesting ques-
Since 2000 the exponential growth of homogeneous gold
catalysis [1] is based on the development of many new synthetic
methods. In the recent past this innovative methodology increas-
ingly has been applied in total synthesis [2]. On the other hand, the
experimental insight into the detailed mechanism of many of these
reactions is still limited [3].
While alkynes, allenes and alkenes have been studied in some
detail, 1,3-dienes have been used in homogeneous gold catalysis in
only a few examples [4]. Thus experimental studies of the reaction
mechanisms of this class of unsaturated substrates are scarce, an
important theoretical study has just been highlighted [5]. Most of
the gold-catalyzed conversions of 1,3-dienes either involve CeX
bond formation or a CeC bond formation. The only gold-catalyzed
reactions of 1,3-dienes involving both a CeX and a CeC bond for-
mation is the anellation of phenols 1 with cyclic, cisoid dienes 2
tion. The formation of the product 3 obviously involves two gold-
catalyzed steps, one hydroaryloxylation [6] and one hydro-
arylation [7] of the double bonds of the diene. But it is unknown
whether the first step is an intermolecular hydroarylation and the
second step an intramolecular hydroaryloxylation or, as the authors
state, “alternatively, the same process can occur in the reverse or-
der: intermolecular allylation on oxygen followed by intra-
molecular hydroarylation” [4a].
For the future exploitation of 1,3-dienes as interesting building
blocks for gold catalysis, we now investigated their intrinsic reac-
tivity with the ambident nucleophile phenol in detail. Here we
report our results on the chemoselectivity of the 1,3-diene 2 in the
anellation reaction.
2. Results and discussion
In addition to the published AuCl3/3AgOTf catalyst system, we
first tested the IPrAuCl/AgOTf catalyst, too. No NHC ligand had been
included in the catalyst screening of the initial investigation [4a],
but the best results were still obtained with the published 2.5 mol%
€
* Corresponding authors. Organisch-Chemisches Institut, Universitat Heidelberg,
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany.
E-mail addresses: hashmi@hashmi.de (A.S.K. Hashmi), mhv@kiku.dk
(M.H. Larsen).
http://dx.doi.org/10.1016/j.jorganchem.2015.05.034
0022-328X/© 2015 Elsevier B.V. All rights reserved.

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59
Scheme 3. Synthesis of the possible intermediate B by an “orthogonal” palladium(0)-
catalyzed route.
Scheme 1. Li's anellation method.
Table 2
Retention times of A, B and 3.
Compound
tR [min]a
Molecular Mass by GCeMS [g/mol]
A
B
3
11.83
11.02
11.13
174.1
174.1
174.1
a
GCeMS: agilent, MSD: 5975C, GC: 7890A; column: HP5, carrier gas: helium;
60 ꢀC, 15 min, 20 ꢀC/min, 250 ꢀC.
Scheme 2. Different pathways may deliver the product 3.
Table 1
GCeMS monitoring of the gold-catalyzed conversion of 1 and 2.
Entry
Temperature
Time
GCeMS
1
2
3
0
0
ꢀC
ꢀC
30 min
60 min
30 min
No conversion
No conversion
30 ꢀC
3 (tR ¼ 11.13 min)
X (tR ¼ 11.83 min)
Scheme 4. Possible reaction pathways.
AuCl3/7.5 mol% AgOTf and like with phosphane gold(I) complexes,
with the NHC ligand no conversion was observed. Control experi-
ments with triflic acid, which potentially could be formed under
the reaction conditions [8], gave only polymeric material.
Then we turned to the details of the reaction. Depending on the
reaction pathway, two different intermediates are conceivable
(Scheme 2). Either the initial step is the hydroarylation, then 3
would be formed via intermediate A. Or the initial step is the
hydroaryloxylation, then B would be the intermediate. If the
barriers of activation for the rate-limiting step of both pathways
would be similar, both pathways would contribute to the product
formation. In addition a Claisen type rearrangement between A
and B must be considered. A fast Au(III)-catalyzed Claisen rear-
rangement has already been observed with a closely related sys-
tem [9,10].
Different efforts to identify any intermediates by GCeMS are
shown in Table 1 (due to a strong signal overlap, in situ 1H NMR
spectroscopy could not be used). At 0 ꢀC no conversion is observed
(entries 1 and 2). At 30 ꢀC after 30 min both the product 3
(tR ¼ 11.13 min, m/z ¼ 174.1 [M]þ$), as well as a second compound X
with the identical molecular mass (tR ¼ 11.83 min, m/z ¼ 174.1
[M]þ$) could be detected. Monitoring the reaction at 30 ꢀC shows
that initially the portion of that second compound is higher, with
increasing conversion that species is consumed and the portion of 3
increases. This indicated that the new compound is one of the two
conceivable intermediates.
clearly shows only one olefin in the product. IR shows the
phenolic hydroxyl group.
When A was subjected to the catalyst, product 3 was formed
selectively, and the dominating diastereomer was cis-3 (cis-3/trans-
3 ¼ 12:1 for both the conversion of the mixture of 1 and 2 and for
the conversion of A).
At this point it was clear that A was involved in the formation
of 3. The observation of A only meant that k1A > k2A, which
causes the build-up of a stationary concentration of A during the
conversion. Not detecting B might mean that k1B << k2B. This
would prevent a detectable stationary concentration of B. If in
addition k1B > k1A, most of 3 could still be formed via B.
Furthermore, an equilibrium between A and B could deliver the
same intermediate A via an addition/rearrangement pathway.
Thus, in order to investigate the possible participation of B in
detail, we prepared B by a palladium-catalyzed route according to
Kawatsura and Hartwig [11]. A palladium(0)-catalyzed hydro-
aryloxylation of 2 delivers B (Scheme 3). This once more demon-
strates the difference in reactivity of the d10 systems palladium(0)
and gold(I) [12].
An initial measurement of the individual retention times of A, B
and 3 (Table 2) shows that no signal overlap is responsible for the
failure to detect B in the crude reaction mixture.
Then we subjected B to the catalyst AuCl3/3AgOTf (same catalyst
loading as shown in Scheme 1) monitoring the reaction by gas
chromatography. Within less than a minute B was completely
consumed and only intermediate A was detected. At this early stage
of the reaction no product was found. This indeed demonstrates
that the Claisen rearrangement from B to A is a very fast process
even at room temperature. As expected after longer reaction times
intermediate A was then converted to the final product.
By separating X from the crude reaction mixture after short
reaction times and stopping the catalysis reaction by the addi-
tion of 2.5 mol% triethylamine, indeed 15% of X could be ob-
tained and
a full characterization was possible. It clearly
indicated that X is the intermediate A. Only four arene protons
are detectable in the 1H NMR, only four CH in the 13C NMR; NMR

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60
S. Bay et al. / Journal of Organometallic Chemistry 795 (2015) 58e62
ΔΔGgas = -2.2 kcal/mol
ΔΔGDCM = 0.1 kcal/mol
k1A
k2A
OH
A
+
O
kAB
OH
O
k2B
3
k1B
1
2
cis-3
B
ΔΔGgas = -10.4 kcal/mol
ΔΔGDCM = -6.7 kcal/mol
ΔΔGgas = 0 kcal/mol
ΔΔGDCM = 0 kcal/mol
ΔΔGgas = 6.4 kcal/mol
ΔΔGDCM = 9.7 kcal/mol
trans-3
ΔΔGgas = -7.4 kcal/mol
ΔΔGDCM = -3.8 kcal/mol
Scheme 5. Computed relative energies of the different species involved.
In this context, it is also important to look at the relative energy
HSQC spectra.
of the species involved. This was addressed by a computational
study. Scheme 4 shows these relative energies for both the gas
phase and in DCM (B3LYP/cc-pVDZ level, solvation as single point
1. Gold-catalyzed synthesis of 3-(2-hydroxyphenyl)cyclohexene
(A)
calculation using the SMD model with dichloromethane as the
solvent at the reaction temperature, 40 ꢀC). Looking at the two
diastereomers of the product, it becomes evident that cis-3 is the
thermodynamic product of the reaction. The intermediate B clearly
is higher in energy than the starting materials, while A is almost at
the energy of the starting materials.
In a dry Schlek flask under an atmosphere of dinitrogen
300 mg (3.20 mmol) phenol 1 and 250 mg (3.20 mmol) 1,3-
cyclohexadiene 2 were added to a stirred mixture of 24.0 mg
(80.0 mmol) AuCl3 and 60.0 mg (200 mmol) AgOTf in 1.5 mL dry
DCM. The mixture is warmed to 30 ꢀC. After 30e45 min the
catalysis is stopped by the addition of triethylamine. The crude
mixture is filtered over celite and purified by column chro-
matography (SiO2, petroleum ether/ethyl acetate 200:1). The
product A could be obtained as a colorless liquid (86.0 mg,
15%).
3. Conclusions
Overall, with that experimental data still two pathways have to
be considered (Scheme 5). Pathway 1 consists of an intermolec-
ular hydroarylation/intramolecular hydroaryloxylation sequence,
while pathway 2 comprises a three step sequence namely inter-
Rf (petroleum ether/ethyl acetate 200:1) ¼ 0.5; 1H NMR
(CDCl3, 300 MHz):
d
¼ 1.36e2.24 (m, 6H), 3.60 (m, 1H), 5.32 (s,
1H), 5.97 (m, 2H), 6.73e7.16 (m, 4H); 13C NMR (CD2Cl2, 75 MHz):
¼ 22.32 (CH2), 25.94 (CH2), 30.96 (CH2), 38.36 (CH), 116.8 (CH),
molecular
hydroaryloxylation/Claisen
rearrangement/intra-
molecular hydroaryloxylation. It is noteworthy that the first
intermolecular step is faster than the final intramolecular step
towards the product. This can either be explained by the higher
reactivity of the diene system compared to the alkene interme-
diate or the hydroarylation is always a faster process than a
hydroaryloxylation process which could be the case if the reaction
would proceed via pathway 1.
d
121.4 (CH), 128.3 (Cquart), 130.3 (CH), 130.6 (CH), 131.4 (CH), 132.3
(CH), 154.9 (s); GCeMS: tR ¼ 11.83 min, m/z ¼ 174.1 [M]*, 159.0,
145.0, 131.0, 115.0, 97.0, 84.0, 70.1, 51.0; MS (EIþ, 70 eV): m/z
(%) ¼ 174 (100.0) [Mþ], 159 (26), 145 (49), 131 (35), 120 (42), 107
(22), 91 (12); HRMS (EIþ, 70 eV): [C12H14O]: calcd. 174.1045,
found 174.1034; IR (film, cmꢁ1): ~n ¼ 3464, 3020, 2927, 2857, 2109,
1647, 1488, 1453, 1265, 1218, 1095, 1046, 881, 817, 754, 740, 706,
664, 413. The data correspond to the data in Ref. [13].
4. Experimental section
The assignment of the 13C NMR signals is based on DEPT135 and

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61
2. Synthesis of cyclohex-2-enylphenylether (B)
Appendix A. Supplementary data
In a dry Schlenk flask under an atmosphere of dinitrogen
Pd(PPh3)4 (62.0 mg, 53.6 mmol) in 3 mL of dry toluene are stirred
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.jorganchem.2015.05.034.
under an atmosphere of dinitrogen 500 mg (5.31 mmol) anhy-
drous phenol and 1.70 g (21.2 mmol) 1,3-cyclohexadiene are
added. The mixture is stirred for 2 d at room temperature. Then
GCeMS does not show any more 1,3-cyclohexadiene. The solvent
is removed in vacuo and the residue is purified by column
chromatography (SiO2, petroleum ether/ethyl acetate 300:1)
yielding a colorless oil (301 mg, 33%). 1H NMR (CDCl3, 300 MHz):
References
[1] (a) G. Dyker, Angew. Chem. 112 (2000) 4407e4409. Angew. Chem. Int. Ed. 39
(2000) 4237e4239;
(b) A.S.K. Hashmi, Gold Bull. 36 (2003) 3e9;
(c) A.S.K. Hashmi, Gold. Bull. 37 (2004) 51e65;
d
¼ 1.51e2.68 (m, 1H), 1.70e2.17 (m, 5H), 4.66e4.81 (m, 1H),
€
(d) A. Hoffmann-Roder, N. Krause, Org. Biomol. Chem. 3 (2005) 387e391;
5.78e5.85 (m, 1H), 5.87e5.96 (m, 1H), 6.78 6.94 (m, 3H),
7.17e7.25 (m, 2H). The 1H NMR spectrum is in accordance with
previous reports for this compound [11].
(e) A.S.K. Hashmi, G. Hutchings, Angew. Chem. 118 (2006) 8064e8105.
Angew. Chem. Int. Ed. 45 (2006) 7896e7936;
(f) A.S.K. Hashmi, Chem. Rev. 107 (2007) 3180e3211;
(g) A. Fürstner, P.W. Davies, Angew. Chem. 119 (2007) 3478e3519. Angew.
Chem. Int. Ed. 46 (2007) 3410e3449;
3. Synthesis of 1,2,3,4,4a,9b-hexahydro-dibenzofuran (C)
(h) D.J. Gorin, B.D. Sherry, F.D. Toste, Chem. Rev. 108 (2008) 3351e3378;
(i) E. Jimenez-Núnez, A.M. Echavarren, Chem. Rev. 108 (2008) 3326e3350;
ꢀ
(j) Z.G. Li, C. Brouwer, C. He, Chem. Rev. 108 (2008) 3239e3265;
(k) A. Arcadi, Chem. Rev. 108 (2008) 3266e3325;
(l) H.C. Shen, Tetrahedron 64 (2008) 3885e3909;
(m) H.C. Shen, Tetrahedron 64 (2008) 7847e7870;
(n) J. Muzart, Tetrahedron 64 (2008) 5815e5849;
(o) A.S.K. Hashmi, M. Bührle, Aldrichim. Acta 43 (2010) 27e33;
(p) A.S.K. Hashmi, M. Rudolph, Chem. Commun. 47 (2011) 6536e6544.
[2] (a) A.S.K. Hashmi, M. Rudolph, Chem. Soc. Rev. 37 (2008) 1766e1775;
(b) M. Rudolph, A.S.K. Hashmi, Chem. Soc. Rev. 41 (2012) 2448e2462.
[3] A.S.K. Hashmi, Angew. Chem. 122 (2010) 5360e5369. Angew. Chem. Int. Ed.
49 (2010) 5232e5241.
[4] For both C-X and CeC bond formation to the 1,3-diene, see (a) R.-V. Nguyen,
X. Yao, C.-J. Li, Org. Lett. 8 (2006) 2397e2399 for only C-X bond formation to
the 1,3-diene, see;
(b) C. Brouwer, C. He, Angew. Chem. 118 (2006) 1776e1779. Angew. Chem.
Int. Ed. 45 (2006) 1744e1747;
(c) X. Li, S. Ye, C. He, Z.-X. Yu, Eur. J. Org. Chem. (2008) 4296e4303;
(d) O. Kanno, W. Kuriyama, Z.J. Wang, F.D. Toste, Angew. Chem. 123 (2011)
10093e10096. Angew. Chem. Int. Ed. 50 (2011) 9919e9922;
(e) X. Giner, C. Najera, G. Kovacs, A. Lledos, G. Ujaque, Adv. Synth. Catal. 353
(2011) 3451e3466 for only C-C bond formation to the 1,3-diene, see;
(f) R.-V. Nguyen, X. Yao, D.S. Bohle, C.-J. Li, Org. Lett. 7 (2005) 673e675;
(g) A. Fürstner, C.C. Stimson, Angew. Chem. 119 (2007) 9001e9005. Angew.
Chem. Int. Ed. 46 (2007) 8845e8849;
A solution of AuCl3 (3.45 mg, 0.011 mmol) and AgOTf (8.82 mg,
0.034 mmol) was stirred in dry CH2Cl2 (1.0 mL) at room temperature
for 2 h under N2 atmosphere. Cyclohexene A (40 mg, 0.23 mmol) was
added in dry CH2Cl2 (1.0 mL) and the resulting solution was stirred
for 16 h at 40 ꢀC under an atmosphere of dinitrogen. The crude re-
action mixture was filtered through celite and purified by column
chromatography on silica gel (ethyl acetate: petroleum ¼ 0.1: 100) to
afford the product C (0.03 g, 75%) as a colorless oil.
ꢀ
ꢀ
ꢀ
(h) D. Benitez, E. Tkatchouk, A.Z. Gonzalez, W.A. Goddard III, F.D. Toste, Org.
Lett. 11 (2009) 4798e4801;
ꢀ
ꢀ
(i) I. Alonso, B. Trillo, F. Lopez, S. Montserrat, G. Ujaque, L. Castedo, A. Lledos,
~
J.L. Mascarenas, J. Am. Chem. Soc. 131 (2009) 13020e13030;
(j) B. Trillo, F. Lopez, S. Montserrat, G. Ujaque, L. Castedo, A. Lledos,
J.L. Mascarenas, Chem. Eur. J. 15 (2009) 3336e3339;
(k) A.Z. Gonzalez, F.D. Toste, Org. Lett. 12 (2010) 200e203;
The ratio of the two diastereoisomers of C is 12: 1 ¼ syn: anti.
ꢀ
ꢀ
(assignment of the major diastereomer by NOESY):
~
syn-Isomer: 1H NMR (CDCl3, 600 MHz):
d
¼ 1.53e2.02 (m, 8H),
ꢀ
3.21 (q, J ¼ 7.2 Hz,1H), 4.70 (q, J ¼ 5.2 Hz,1H), 6.83e7.16 (m, 4H); 13
C
(l) H. Teller, S. Flügge, R. Goddard, A. Fürstner, Angew. Chem. 122 (2010)
1993e1997. Angew. Chem. Int. Ed. 49 (2010) 1949e1953;
(m) H. Kusama, Y. Karibe, Y. Onizawa, N. Iwasawa, Angew. Chem. 122 (2010)
4365e4368. Angew. Chem. Int. Ed. 49 (2010) 4269e4272;
NMR (CDCl3, 150 MHz):
d
¼ 20.5 (s), 22.0 (s), 27.5 (s), 28.2 (s), 40.6
(s), 82.5 (s), 110.0 (s), 120.4 (s),123.5 (s), 127.7 (s), 133.4 (s), 159.4 (s);
1H NMR (CD2Cl2, 300 MHz):
d
¼ 1.21e2.29 (m, 6H), 4.79 (m, 1H),
ꢀ
~
(n) H. Faustino, F. Lopez, L. Castedo, J.L. Mascarenas, Chem. Sci. 2 (2011)
633e637;
5.85 (m, 1H), 5.96 (ddt, J ¼ 3.0 Hz, 4.5 Hz, 9.0 Hz, 1H), 6.91 (m, 3H),
(o) R.A. Sanguramath, S.K. Patra, M. Green, C.A. Russell, Chem. Commun. 48
(2012) 1060e1062.
7.26 (m, 2H).
[5] For a highlight on the interaction of Au(I) and dienes see (a) R.A. Sanguramath,
T.N. Hooper, C.P. Butts, M. Green, J.E. McGrady, C.A. Russell, Angew. Chem. 123
(2012) 7734e7737. Angew. Chem. Int. Ed. 50 (2011) 7592e7595; see;
(b) I. Krossing, Angew. Chem. 123 (2011) 11781e11783; Angew. Chem. Int.
Ed. 50 (2011) 11576e11578.
[6] C.-G. Yang, C. He, J. Am. Chem. Soc. 127 (2005) 6966e6967.
[7] (a) A.S.K. Hashmi, L. Schwarz, J.-H. Choi, T.M. Frost, Angew. Chem. 112 (2000)
2382e2385. Angew. Chem. Int. Ed. Engl. 39 (2000) 2285e2288;
Acknowledgments
We thank Umicore AG & Co. KG for the generous donation of
noble metal salts. KSN is grateful to the Alexander von Humboldt
foundation for a postdoctoral fellowship.