Gold(I)-catalyzed intramolecular hydroarylation of allenes

Article abstract of DOI:10.1021/jo7024948

(Chemical Equation Presented) Gold(I) complexes react with 4-allenyl arenes in an exo fashion to furnish vinyl-substituted benzocycles. Phosphite gold(I) monocations were found to be optimal, and the catalyst was tolerant of ethers, esters, and pyrroles. Reactions proceeded in unpurified solvent at room temperature.

Full text of DOI:10.1021/jo7024948

SCHEME 1. Recent Gold(I)-Catalyzed Allene Arylations4,5
Gold(I)-Catalyzed Intramolecular Hydroarylation
of Allenes
Michael A. Tarselli and Michel R. Gagne´*
Caudill Laboratories, UniVersity of North Carolina at Chapel
Hill, Chapel Hill, North Carolina 27599
mgagne@unc.edu
ReceiVed NoVember 27, 2007
attack by the alkene to generate an intermediate carbenium ion.
Elimination and protodeauration yielded the vinylcyclohexene
with variable regiocontrol.
Gold(I) complexes react with 4-allenyl arenes in an exo
fashion to furnish vinyl-substituted benzocycles. Phosphite
gold(I) monocations were found to be optimal, and the
catalyst was tolerant of ethers, esters, and pyrroles. Reactions
proceeded in unpurified solvent at room temperature.
Arenes exhibit a wide range of π-nucleophilicities as char-
acterized by the Mayr N values,9 which quantify and rank their
rates of reaction with a common electrophile. Comparing these
values to the allene activations reported in the literature revealed
a focus on alkene (N ) -1.00 to 1.20) and heteroaromatic
(furan/indole/pyrrole; N ) 3.60-7.00) nucleophiles (Scheme
2).10
The Friedel-Crafts reaction has been a part of many
successful transformations in organic chemistry.1 The reaction
has been accelerated by strong acids and by stoichiometric and
catalytic quantities of various metals. Recent developments on
the topic of catalytic cycloarylation reactions include the gold-
(I)-catalyzed arylation of allenes2,3 by indoles (Widenhoefer4)
and pyrroles (Nelson5) and the gold(III)-catalyzed hydroarylation
of alkynes reported by He6 (Scheme 1). Hashmi has also shown
that intermolecular addition of furans to allenes can be achieved.7
The mechanisms are presumed to proceed by an initiating allene
activation by the electrophilic gold(I) cation.
SCHEME 2. Representative N Values8 for π-Nucleophiles
Related to these first demonstrations is our recent gold(I)-
catalyzed cycloisomerization of 1,6-ene-allenes8 (eq 1). The
proposed mechanism paralleled the Nelson/Widenhoefer systems
with gold(I) acting as an allene activator for intramolecular
(1) (a) Olah, G. A. Friedel-Crafts and Related Reactions; Wiley-
Interscience: New York, 1963-1965. (b) Bandini, M.; Emer, E.; Tommasi,
S.; Umani-Ronchi, A. Eur. J. Org. Chem 2006, 3527-3544.
(2) For recent reviews on gold catalysis, see: (a) Hashmi, A. S. K. Chem.
ReV. 2007, 107, 3180-3211. (b) Fu¨rstner, A.; Davies, P. W. Angew. Chem.,
Int. Ed. 2007, 46, 3410-3449. (c) Hashmi, A. S. K.; Hutchings, G. J. Angew.
Chem., Int. Ed. 2006, 45, 7896-7936.
Since a number of interesting nucleophiles occupy the
spectrum between alkenes and N-heterocycles, we initiated
efforts to examine arene-allene cycloisomerizations. One ex-
pected benefit was the rearomatization-driven regioselective
elimination to products. To develop this concept, we began with
the relatively activated dimethoxy substrate 2 and the optimum
catalyst for the ene-allene cycloisomerization 3,5-xylyl-BINAP-
(AuCl)2/AgBF4. Gratifyingly, the desired vinylated product 3
was obtained, but the rate was slower than desired (>16 h for
full conversion).
(3) For recent examples of gold-catalyzed C-nucleophile additions to
allenes, see: (a) Huang, X.; Zhang, L. Org. Lett. 2007, 9, 4627-4630. (b)
Luzung, M.; Mauleon, P.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12402-
12403. (c) Kim, S. M.; Park, J. H.; Choi, S. Y.; Chung, Y. K. Angew. Chem.,
Int. Ed. 2007, 46, 6172-6175. (d) Linghu, X.; Kennedy-Smith, J. J.; Toste,
F. D. Angew. Chem., Int. Ed. 2007, 46, 7671-7673.
(4) (a) Liu, C.; Widenhoefer, R. A. Org. Lett. 2007, 9, 1935-1938. (b)
Zhang, Z.; Liu, C.; Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer, R. A.
J. Am. Chem. Soc. 2006, 128, 9066-9073.
(5) Liu, Z.; Wasmuth, A.; Nelson, S. G. J. Am. Chem. Soc. 2006, 128,
10352-10353.
(6) Shi, Z.; He, C. J. Org. Chem. 2004, 69, 3669-3671.
(7) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285-2288.
(9) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66-
77.
(10) As this manuscript was being completed, Fujii and Ohno reported
a (PR3)Au(OTf) catalyzed, endo-selective hydroarylation of allenes (Wa-
tanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2007, 9, 4821-4824).
(8) Tarselli, M. A.; Chianese, A. R.; Lee, S. J.; Gagne´, M. R. Angew.
Chem., Int. Ed. 2007, 46, 6670-6673.
10.1021/jo7024948 CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/16/2008
J. Org. Chem. 2008, 73, 2439-2441
2439

TABLE 2. Au-Catalyzed Cyclohydroarylation of Allenesa
SCHEME 3. Optimized Conditions with Activated
Substrate 2
TABLE 1. Optimization of Solvent and Silver Counterion for the
Conversion of 2 to 3 (Scheme 3)a
entry
solventb
X-
conversionc (% 3)d
1
2
3
4
5
6
7
8
9
CH2Cl2
toluene
hexane
Et2O
OTf
OTf
OTf
OTf
OTf
OTf
BF4
NTf2
PF6
SbF6
OTs
ClO4
92
52
73
20
36
55
100 (75)
79 (80)
35 (72)
89 (88)
51 (58)
92 (76)
THF
MeNO2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10
11
12
a Reaction conditions: 5 mol % of 1, 7 mol % of AgX, 0.2 M in 2 at rt.
b Commercial bottles of dichloromethane, hexane, nitromethane, and ether
were used without prior purification. c As determined by GC integration
against remaining SM. d Fraction of all products that was the desired cyclic
isomer.
To improve the reaction rate, a number of alternative catalysts
were examined. The best of these was the triphenylphosphite-
derived catalyst11 1, which was an easily prepared, colorless,
crystalline material that was bench stable for several weeks.12
The less basic phosphite ligand13 generated a catalyst that was
significantly more effective (Scheme 3).14 The reaction produces
benzocyclic products that are similar to those reported by Ma15
from Brønsted activation of allylic alcohols and by Cook16
utilizing In(III)-mediated atom-transfer cyclization.
As shown in Table 1, dichloromethane in combination with
-
the SbF6 counterion was optimum with regard to rate and yield
of 3. Under these conditions, the catalyst load could be reduced
to 3 mol % with reasonable reaction times and little change in
yield.
a General Procedure: To a vial charged with 1 and AgSbF6 was added
CH2Cl2 by syringe. After stirring 2 min, a white precipitate was observed.
Addition of substrate by pipet led to a deeply colored suspension, which
was stirred at rt for 4-24 h. b Products were directly loaded onto silica gel
and eluted with appropriate mixture of hexanes and ethyl acetate; see
Supporting Information.
Utilizing the standard protocol shown in Scheme 3, a variety
of arene nucleophiles were examined (Table 2). Generally
speaking, the scope was limited to electron-rich arenes but was
tolerant of ethers, acetals, and, not surprisingly, a pyrrole.5 The
naphthalene substrate (Mayr parameter9 N ) -3.9) was
especially well-behaved. Unfortunately, coordinating aromatics
such as triazoles, isoxazoles, and oxazoles were not effective,
likely due to nonproductive coordination to the gold(I) catalyst.
Substrates for this chemistry were obtained from the benzylation
of monoallenylmalonate4b with base in THF/DMF.17
In cases where the arene nucleophile N parameter was
sufficiently high, the catalyst loading could be lowered to further
increase reaction efficiency (Table 3, entry 7). The catalyst was
also tolerant of substitution at the allene terminus and variation
of the malonate linker (Scheme 4).
To ensure that the above transformations were indeed
proceeding by gold catalysis, a series of control experiments
were carried out. Interestingly, 3 was obtained from 2 using
(11) Schneider, D.; Schier, A.; Schmidbaur, H. J. Chem. Soc., Dalton
Trans. 2004, 1995-2005.
(12) The catalyst can be recrystallized from CH2Cl2/hexanes in a vapor
chamber and exhibits a gradual darkening over the course of 1 month.
(13) Tolman, C. A. Chem. ReV. 1977, 77, 313-348.
(14) A phosphite-Au(I) catalyst for alkyne activation has recently
appeared; see: Nieto-Oberhuber, C.; Pe´rez-Gala´n, P.; Herrero-Go´mez, E.;
Lauterbach, T.; Rodr´ıguez, C.; Lo´pez, S.; Bour, C.; Rosello´n, A.; Ca´rdenas,
D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2008, 130, 269-279.
(15) (a) Ma, S.; Zhang, J. Tetrahedron Lett. 2002, 43, 3435-3438. (b)
Ma, S.; Zhang, J. Tetrahedron 2003, 59, 6273-6283.
(16) Hayashi, R.; Cook, G. R. Org. Lett. 2007, 9, 1311-1314.
(17) Makino, T.; Itoh, K. J. Org. Chem. 2004, 69, 395-405.
2440 J. Org. Chem., Vol. 73, No. 6, 2008

TABLE 3. Control Experimentsa Using 2 to Test for Ag+ or H+
Background Catalysis
catalyst
amount
time, temp
products
1
5 mol %
5 mol %
100 mol %
1 mol %
5 mol %
1 mol %
1 mol %
5 mol %
16 h, rt
16 h, rt
14 h, 35 °C
6 h, rt
6 h, rt
6 h, rt
nr
nr
90% 3
AgSbF6
AgSbF6
TfOH
TfOH
HNTf2
HBF4•OEt2
HBF4•OEt2
<5% conv
30% conv, <1% 3c
b
nr
nr
nr
6 h, rt
6 h, rt
Attempts to minimize the allene hydration by using anhydrous
CH2Cl2 and adding 4 Å MS only led to low conversions (<30%,
72 h). We speculate that the adventitious water acts as a proton
shuttle to modulate the rearomatization and protodeauration steps
of the mechanism.19
a Reaction conditions: 0.2 M 2 in CH2Cl2, in air at rt. Conversion was
monitored by GC. b Tf ) trifluoromethanesulfonyl. c Six products were
observed by GC-MS, the predominant (∼30%) being allene hydrolysis to
the methyl ketone (m/z ) 352).
In summary, a highly electrophilic phosphite gold(I) catalyst
has been applied to the intramolecular allene hydroarylation
reaction, producing vinylbenzocycles in good to excellent yields.
The catalyst is tolerant of trace water and oxygen, it is bench-
stable, and it can be utilized in air with unpurified commercial
solvent.
stoichiometric amounts of silver but only at higher temperature
and longer reaction times (Table 3). Catalytic quantities of triflic
acid (5 mol %), HNTf2 (1 mol %), or HBF4 (1 and 5 mol %)
did not produce 3, ruling out the possibility of a Brønsted
pathway. As expected, leaving out the halide abstraction agent
did not provide an active catalyst, reinforcing the notion of a
P(OPh)3Au+ active catalyst.
Experimental Section
Representative Cycloisomerization Procedure: To a 5 mL vial
charged with a stirbar, 1 (27.2 mg, 0.05 mmol, 1.0 equiv), and
AgSbF6 (24.0 mg, 0.07 mmol, 1.4 equiv) was added dichlo-
romethane (1.0 mL) by syringe, at which point a white-gray
suspension formed. After 2 min, 2 (168 mg, 0.5 mmol, 10 equiv)
was added by pipet. The suspension turned deep green within 20
min. After 6 h, the reaction was loaded directly onto a silica flash
column and purified with 1:7 ethyl acetate/hexanes. Yield: 85%
SCHEME 4. Variation in Linker/Allene Substitution
1
of 3 as a clear oil. H NMR (400 MHz, CDCl3): δ 6.23 (s, 2H),
5.74 (m, 1H), 4.90 (d, 1H, J ) 10.4 Hz), 4.68 (d, 1H, J ) 17.2
Hz), 3.77 (s, 3H), 3.70 (s, 3H), 3.66 (s, 3H), 3.64 (s, 3H), 3.34 (d,
1H, J ) 16 Hz), 2.99 (d, 1H, J ) 16.4 Hz), 2.48 (m, 1H), 2.29 (m,
1H). 13C (100 MHz): δ 171.8, 171.7, 159.1, 158.6, 141.3, 135.8,
113.3, 104.3, 97.1, 55.3, 55.2, 52.6, 52.4, 35.4, 35.0, 34.3. HRMS-
ESI+: 357.131 calcd for C18H22O6 + Na, found 357.131.
Acknowledgment. Support from the National Institute of
General Medicine (GM-60578) is greatly appreciated.
With less activated aryl rings, such as the 4-tert-Bu substrate
20, a major byproduct was allene hydration to methyl ketone
21 (eq 2). The N value of ∼ -4.0 for a tert-butylphenyl group
likely represents the lower limit for sufficient π-nucleophilicity
to add to the Au+-activated allene. More electron-deficient
arenes (NO2Ar, BrAr, IAr, etc.) were cleanly converted to the
methyl ketone with no trace of cycloisomerized product. A
related transformation was recently reported.18
Supporting Information Available: Experimental procedures,
1H, 13C, and HRMS data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO7024948
(19) The Ohno conditions reported in ref 10 include 10% acetic acid to
modulate this step; their reported rates are higher than the present results.
In a single experiment, we have shown that 2 is converted to 3 (as a mixture
of alkene isomers) by 3 mol % of 1/5 mol % of AgSbF6 in 10:1 DCM/
AcOH in <1 h.
(18) Hydration of allenyl acetates under solvolysis conditions has been
observed: Alameda-Angulo, C.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron
Lett. 2006, 47, 913-916.
J. Org. Chem, Vol. 73, No. 6, 2008 2441