Gold(l)-catalyzed intermodular oxyarylation of alkynes: Unexpected regiochemistry in the alkylation of arenes

Article abstract of DOI:10.1021/ol9020578

The reaction between acetylenes and sulfoxides, studied as a test case for gold-catalyzed intermolecular addition, provides the oxyarylation compounds 3 In good yields. Unpredictably, In all cases a single regioisomer arising from the electrophilic aromat

Full text of DOI:10.1021/ol9020578

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4906-4909
Gold(I)-Catalyzed Intermolecular
Oxyarylation of Alkynes: Unexpected
Regiochemistry in the Alkylation of Arenes
Ana B. Cuenca,† Sergi Montserrat,‡ Kabir M. Hossain,† Gisela Mancha,†
Agust´ı Lledo´s,‡ Mercedes Medio-Simo´n,† Gregori Ujaque,*,‡ and
Gregorio Asensio*,†
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia,
46100 Burjassot, Valencia, Spain, and Departament de Qu´ımica, UniVersitat
Auto`noma de Barcelona, 08193 Bellaterra, Barcelona, Catalonia, Spain
gregorio.asensio@uV.es; gregori@klingon.uab.es
Received September 4, 2009
ABSTRACT
The reaction between acetylenes and sulfoxides, studied as a test case for gold-catalyzed intermolecular addition, provides the oxyarylation
compounds 3 in good yields. Unpredictably, in all cases a single regioisomer arising from the electrophilic aromatic alkylation at the position
adjacent to the sulfur atom is obtained instead of the expected Friedel-Crafts regioisomer. A new concerted mechanism based on DFT
calculations is proposed to account for the products in this intermolecular gold(I)-catalyzed reaction.
Despite the fact that the gold-catalyzed intramolecular
addition of nucleophiles to alkynes has become a mature
field,1 a number of mechanistic questions remain unresolved2
since the mechanistic information inherent to the intermo-
lecular reactions is scarce. Toste’s3a and Zhang’s groups3b
reported the intramolecular gold-catalyzed addition of sul-
foxides to alkynes which occurs through an R-carbonyl gold
carbenoid intermediate.3,4 We have developed the intermo-
lecular addition of an array of sulfoxides 2a-e to alkynes
1a-e to test the regiochemistry of the reaction between the
putative R-oxo gold-carbenoid and the nucleophile, an
important but unapproachable aspect in the intramolecular
reaction. A novel mechanistic proposal based on DFT
calculations is presented to rationalize the results of this
study.
The intermolecular reaction between acetylenes 1 and
sulfoxides 2 catalyzed by 5% Ph3PAuCl and 7.5% AgSbF6
afforded compounds 3 in good to moderated yields (Table
1). No reaction took place with the internal alkynes PhCCMe
and i-PrCCMe. Concerning the sulfoxide, the reaction went
in a very good yield with the unsubstituted phenyl benzyl
sulfoxide 2b and in a moderate yield with the more electron-
deficient sulfoxide 2c.
† Universidad de Valencia.
‡ Universitat Auto`noma de Barcelona.
10.1021/ol9020578 CCC: $40.75
Published on Web 09/28/2009
 2009 American Chemical Society

would yield the R-arylketone via a Friedel-Crafts5 type
reaction. According to this proposal, we should expect the
formation of a mixture of regioisomers. However,6 in all
cases of our reaction, only the regioisomer 3 corresponding
to the alkylation at the position adjacent to the sulfur was
obtained.7 To verify the consistency of this behavior,
asymmetric aryl-heteroaryl and diaryl sulfoxides 2d and 2e
were tested as nucleophiles. In principle, in the case of
sulfoxide 2d (eq 1) the electrophilic aromatic substitution
(EAS) should occur at the more activated C-5 position of
thiophene.8 However, unpredictably, alkylation took place
exclusively at the C-3 position (product 3ad, 71%).
The same trend was observed in the reaction of sulfoxide
2e. In this case, a 2:1 mixture of the isomers 3ce and 3′ce
was obtained in a 77% overall yield (eq 2). Once again, the
alkylation took place exclusively at the positions adjacent
to the thioaryl moiety, regardless of the presence of the
directing -OMe group. The violation of the orientation rules
of the EAS is a highly remarkable observation,9 and it led
us to consider that in this case additional factors are
overriding the expected reactivity pattern.10 To clarify these
factors and to help explain the regiochemistry observed in
products 3, we carried out a detailed mechanistic study of
the transformation.
Table 1. Gold(I)-Catalyzed Intermolecular Nucleophilic
Addition of Sulfoxides 2 to Alkynes 1
1
2
R1
R2
R3
CH3
CH2C6H5
CH3
CH3
CH3
3
yield (%)
1a
1a
1a
1b
1c
1d
1e
C6H5
C6H5
C6H5
p-ClC6H4
n-C4H9
(CH3)3C
CH3CH2O
2a
2b
2c
2a
2a
2a
2a
OCH3
H
Br
OCH3
OCH3
OCH3
OCH3
3aa
3ab
3ac
3ba
3ca
3da
3ea
87
83
49
71
84
20
50
CH3
CH3
According to the R-carbonyl gold carbenoid mechanism
proposed for the intramolecular version of the reaction,3a
formation of derivatives 3 would take place as shown in
Scheme 1. Thus, the initial nucleophilic addition of sulfoxide
Scheme 1. Observed Single Isomer Formation from Alkenyl
Gold Intermediate II According to the Mechanism Proposed for
the Intramolecular Version of the Reaction
Theoretical calculations11 on a model reaction between
propyne (1f) and sulfoxide 2a catalyzed by [PH3Au+] were
performed. The optimized geometries of the species involved
in the catalytic cycle and the energy profile are shown in
Figures 1 and 2 (for computational details, see Supporting
(2) (a) Fu¨rstner, A.; Morency, L. Angew. Chem., Int. Ed. 2008, 47, 5030.
(b) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2008, 47, 6754. (c) Seidel,
G.; Mynott, R.; Fu¨rstner, A. Angew. Chem., Int. Ed. 2009, 48, 2510, and
refs cited therein.
to the gold-activated alkyne would provide the vinyl gold
intermediate II that would rearrange to give intermediates 4
and 5. To complete the sequence, reaction between 4 and 5
(3) (a) Shapiro, N. D.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 4160.
(b) Li, G.; Zhang, L. Angew. Chem., Int. Ed. 2007, 46, 5156. For further
intramolecular gold-catalyzed oxidation of alkynes: (c) Yeom, H.-S.; Lee,
J.-E.; Shin, S. Angew. Chem., Int. Ed. 2008, 47, 7040. (d) Cui, L.; Zhang,
G.; Peng, Y.; Zhang, L. Org. Lett. 2009, 11, 1225. (e) Cui, L.; Peng, Y.;
Zhang, L. J. Am. Chem. Soc. 2009, 131, 8394.
(1) For selected rewiews on gold catalysis, see: (a) Dyker, G. Angew.
Chem., Int. Ed. 2000, 39, 4237. (b) Hashmi, A. S. K. Gold Bull. 2003, 36,
3. (c) Hashmi, A. S. K. Gold Bull. 2004, 37, 51. (d) Krause, N.; Hoffmann-
Ro¨der, A. Org. Biomol. Chem. 2005, 3, 387. (e) Hashmi, A. S. K. Angew.
Chem., Int. Ed. 2005, 44, 6990. (f) Hashmi, A. S. K.; Hutchings, G. Angew.
Chem., Int. Ed. 2006, 45, 7896. (g) Zhang, L.; Kozmin, S. A. AdV. Synth.
Catal. 2006, 348, 2271. (h) Fu¨rstner, A.; Davies, P. W. Angew. Chem., Int.
Ed. 2007, 46, 3410. (i) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395. (j)
Jime´nez-Nu´n˜ez, E.; Echavarren, A. M. Chem. Commun. 2007, 333. (k)
Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180. (l) Marion, N.; Nolan, S. P.
Angew. Chem., Int. Ed. 2007, 46, 2750. (m) Crone, B.; Kirsch, S. F.
Chem.sEur. J. 2008, 14, 3514. (n) Widenhoefer, R. A. Chem.sEur. J.
2008, 14, 5382. (o) Li, Z.; Brouwer, C.; He, C. Chem. ReV. 2008, 108,
3239. (p) Arcadi, A. Chem. ReV. 2008, 108, 3266. (q) Jime´nez-Nu´n˜ez, E.;
Echavarren, A. M. Chem. ReV. 2008, 108, 3326. (r) Gorin, D. J.; Sherry,
B. D.; Toste, F. D. Chem. ReV. 2008, 108, 3351. (s) Hashmi, A. S. K.;
Rudolph, M. Chem. Soc. ReV. 2008, 37, 1766.
(4) For analogous R-oxo gold carbenoids prepared from R-diazoesters,
see: (a) D´ıaz-Requejo, M. M.; Pe´rez, P. J. Chem. ReV. 2008, 108, 3379.
(5) (a) Olah, G. Friedel-Crafts and Related Reactions; Wiley and sons:
New York, 1964; Vols. 1 and 2. (b) In the intramolecular reaction, the
EAS pathway is supported by inverse secondary KIE consistent with
literature examples for Friedel-Crafts alkylations.
(6) (a) Miles, J. A.; Beeny, M. T.; Ratts, K. W. J. Org. Chem. 1975,
40, 343. (b) Raw, B. C.; Ghosh, K.; Jana, V. J. Org. Chem. 1996, 61, 9546.
For σp values of an ethoxy group (0.25) and thioethoxy (0.04), see: Charton,
M. Prog. Phys. Org. Chem. 1981, 13, 119.
(7) The substitution pattern observed seems to be fully independent of
the nature of the substituent at the para position in the aromatic ring on
putative intermediate 5 (see products 3aa, 3ab, and 3ac).
(8) Clementi, S.; Marino, G. J. Chem. Soc., Perkin Trans. 2 1972, 2,
71.
Org. Lett., Vol. 11, No. 21, 2009
4907

Figure 3. Proposed catalytic cycle based on DFT calculations for
the modeled reaction.
potential energy surface showed an alternative pathway
where the alkenyl gold intermediate evolves in two steps to
the final product 3fa. The reaction starts with the interaction
of the metal catalyst [PH3Au+], the sulfoxide 2a, and the
alkyne 1f giving complexes B (B-anti and B-syn)12 selected
as our energy reference.
Figure 1. Optimized geometries of the species involved in the
catalytic cycle for the anti addition.
Information). The reaction seems to proceed through an
alkenyl gold intermediate C (Figure 3).
Subsequently, two alternative anti or syn reaction pathways
were identified for the gold-promoted nucleophilic addition
of 2a to 1f. The energy barriers associated with this step,
giving rise to the isomeric alkenyl gold intermediates (E)-C
and (Z)-C, are 4.3 and 10.8 kcal/mol for ts1-anti and ts1-
syn, respectively, favoring the anti pathway by 6.5 kcal/mol.
Then, C evolves to a new intermediate D via [3,3′]-
sigmatropic rearrangement involving a six-membered cyclic
transition state, ts2, where the S-O R-bond is being broken
concomitantly with the formation of a new C3-C3′
R-bond.13 Similar relative energy barriers of 3.8 and 4.6 kcal/
mol were found in this step starting from (E)-C or (Z)-C,
respectively. The set of calculated C-Au bond lengths in
the intermediate C and ts2 are, respectively, 2.048 and 2.017
Å for the (E)- versus 2.041 and 2.020 Å for the (Z)-
(12) The 31P-NMR spectrum (CD2Cl2, 120 MHz, rt) of a 1:1.5:1:1
mixture of Ph3PAuCl, AgSbF6, 1a, and 2a reveals an equilibrium containing
an small amount of free “((Ph3)nPAu+)” (sharp singlet at δ 44.5 ppm) (see:
Harrison, T. J.; Kozak, J. A.; Corbella-Pan, M.; Dake, G. R. J. Org. Chem.
2006, 71, 4525. ) and gold complexes B containing 1a and 2a (broad singlet
Figure 2. Energy reaction profile for a model reaction between
propyne (1f and sulfoxide 2a catalyzed by [PH3Au+].
1
at δ 35.9 ppm). In the H NMR spectrum, signals of free 1a or 2a are not
observed. The δ 2.6 ppm 1H NMR signal (CD2Cl2, 300 MHz, rt) of the
S-Me group of 2a is shifted to δ 3.0 ppm in a 1:1.5:1 mixture of Ph3PAuCl,
AgSbF6, and 2a. The S-Me δ value remains unaltered when 1 equiv of 1a
is added to the former mixture proving that 2a remains complexed in the
presence of 1a.
Remarkably, our efforts to identify the formation of R-oxo
gold carbenoid 4 plus sulfide 5 (see Scheme 1) were
unsuccessful; all attempts evolved to the intermediate C or
gave rise to unreasonable structures. The analysis of the
(13) In a trapping experiment, all the attempts failed giving no
incorporation of the external nucleophile.
(9) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593.
(10) Since sometimes the metal can be replaced by a proton: ( Hashmi,
A. S. K. Catal. Today 2007, 122, 211)we heated a mixture of 1a with
sulfoxide 2a and 5% of tungstic acid, obtaining a 32% yield of 3aa.
(11) Calculations were performed with Gaussian03 using B3LYP
functional. Energy values were obtained by single-point calculations using
the 6-311++G(d,p) basis set for C, O, H, and S atoms and the SDD
pseudopotential for Au. Solvent effects were included by means of a
continuum method.
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Org. Lett., Vol. 11, No. 21, 2009

stereoisomer falling in any case within the range of a Au-C
single bond.2a Next, a 1,2-H shift amounts to the protode-
metalation of gold and rearomatization of the π-system
giving a new intermediate E in which any stereochemical
information is lost. This latter step, irrelevant for the selection
of the reaction path, occurs with energy barriers of 24.6 (ts3-
anti) and 25.5 (ts3-syn) kcal/mol. Metal releasing of 3fa from
intermediate E closes the calculated catalytic cycle. The
overall catalytic cycle is depicted in Figure 3.
present work also highlights that the intermolecular oxyary-
lation of alkynes reveals mechanistic details associated to
the regioselectivity which remained unnoticed in the study
of the intramolecular version.
Acknowledgment. This work was supported by the
Spanish MEC [CTQ2008-06866-CO2-01; CTQ 2007-65720
and Consolider-Ingenio2010 (CSD2007-00006)], Generalitat
de Catalunya (2009SGR68). S.M., G.M., and K.H. thank the
Spanish MEC and G.M. Generalitat Valenciana for fellow-
ships. We acknowledge the SCSIE (Universidad de Valencia)
for access to the instrumental facilities.
In conclusion, we report herein an intermolecular gold-
catalyzed addition of sulfoxides to alkynes which constitutes
an easy approach to functionalize selectively the ortho
position of an aryl sulfide giving a range of aryl ketones in
very good yields. Theoretical calculations performed to
explain the experimental findings have shown that this
transformation represents a novel case of gold-catalyzed
reaction proceeding through a concerted mechanism. The
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and computational
details. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL9020578
Org. Lett., Vol. 11, No. 21, 2009
4909