Gold(I)-catalyzed intermolecular hydroarylation of allenes with nucleophilic arenes: scope and limitations

Article abstract of DOI:10.1016/j.tet.2008.10.110

The addition of nucleophilic methoxyarenes to allenes proceeds at room temperature in dichloromethane with a catalytic amount of phosphite-gold(I) precatalyst and silver additive. The addition is regioselective for the allene terminus, and generates E-all

Full text of DOI:10.1016/j.tet.2008.10.110

Tetrahedron 65 (2009) 1785–1789
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Gold(I)-catalyzed intermolecular hydroarylation of allenes with nucleophilic
arenes: scope and limitations
*
´
Michael A. Tarselli, Ann Liu, Michel R. Gagne
Caudill Laboratories, University of North Carolina, Chapel Hill, NC 27599, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 July 2008
Received in revised form 15 October 2008
Accepted 15 October 2008
Available online 24 December 2008
The addition of nucleophilic methoxyarenes to allenes proceeds at room temperature in dichloro-
methane with a catalytic amount of phosphite-gold(I) precatalyst and silver additive. The addition is
regioselective for the allene terminus, and generates E-allylation products without the need for pre-
functionalization of the synthons as organometallics or allyl bromides. Coordinating heteroaromatics and
sterically hindered allenes do not participate in the reaction.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Crude proton NMR and GC–MS analysis indicated that only one
of the two allenes participated in the reaction, indicating that
A major goal of the last decade in organic chemistry has been
the development of C–C bond-forming reactions that take place at
room temperature without the prefunctionalization of either cou-
pling partner.1 These reactions ideally proceed with catalytic
quantities of readily available metals at room temperature. This
research details the development of an allene addition to electron-
rich arenes catalyzed by gold(I), resulting in products normally
accessed by deprotonation/allylation with an allylic halide.
Additions of pronucleophiles to allenes by gold catalysts have
received much recent attention. Intramolecular cyclization of co-
valently linked allene nucleophiles by cationic gold(I) or gold(III)
have been widely reported2,3 (Scheme 1), but the corresponding in-
termolecular variants are rare. Widenhoefer recently reported an
intermolecular hydroalkoxylation of allenes,4 and Yamamoto an
intermolecular hydroamination.5 Intermolecular hydroarylations of
alkynes were achieved by Reetz6 and He7 with gold(III) catalysts
and Hashmi8 with gold(I) (Scheme 2), but, with the exception of
recent results by Widenhoefer with methylated indoles,9 there
have not been any reports on gold-catalyzed intermolecular hydro-
arylation of allenes.
substrates possessing a single allene would participate. The com-
mercially available 3-methyl-1,2-butadiene (dimethylallene, 2) was
chosen as a commercially available screening substrate, and the
results of reaction optimization are shown in Table 1.
Entries 1–5 indicate a preference for dichloromethane as solvent
in this reaction, with more coordinating or nonpolar solvents
markedly slowing reactivity. Interestingly, gold(I) precatalysts that
are found to be optimal in other gold-catalyzed reactions (entries
6
13 and 714) were less active in this reaction. The trend toward more
electrophilic phosphite ligands is evidenced when comparing
entries 10, 11, and 13. The optimal system of (4-ClPhO)3P(AuCl)15
and AgBF4 reached full conversion after 1 h, when employing allene
as the limiting reagent in the presence of 2 mol equiv of arene.
Control experiments between 1 and ethyl-2,3-butadienoate or
dimethylallene ruled out silver and acid-mediated catalysis in this
reaction.16 Another control indicated that gold(III)deither alone or
with 3.0 equiv of silver cocatalystddoes not catalyze this reaction.
2. Substrate scope
Our group recently reported an intramolecular hydroarylation
The results indicate that small and relatively unsubstituted
allenes work best in this chemistry. Functional groups such as es-
ters, ethers, and enoates were well-tolerated, but more Lewis-basic
heteroaromatic substrates did not function well (vide infra).
To probe how the electronics of the aryl system affected the
ability to add an equivalent of allene, a variety of electron-rich
methoxy-substitued arenes were tested. Shown in Table 2 are re-
actions utilizing allene 2, which generates products of traditional
prenylation. Arenes possessing constructively oriented ortho- and
para-directing groups gave higher yields. A preference for allylation
at unhindered positions on the arene, presumably due to steric
of allenes utilizing
a
triphenylphosphite-derived gold(I)
catalyst.10,11 One byproduct from a substrate intermediate was
bis(allenyl)malonate,12 which we discovered could react with
electron-rich 1,3,5-trimethoxybenzene 1 under the aforemen-
tioned conditions (Scheme 3) to form a hydroarylative product in
trace amounts (<10%).
* Corresponding author. CB #3290 Caudill Labs, Department of Chemistry, UNC,
Chapel Hill, NC 27599, USA.
´
E-mail address: mgagne@unc.edu (M.R. Gagne).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.110

1786
M.A. Tarselli et al. / Tetrahedron 65 (2009) 1785–1789
Scheme 1.
Scheme 2.
Scheme 3.
effects, is evidenced by the 6:1 ratio of products in 4 as well as the
increased yield from 6 to 10.
3. Limitations
The allene scope was next examined using 1 or 4 as the aryl
nucleophile. Table 3 presents allenes that are found to participate in
this chemistry. Allylic products were formed with E-stereochem-
istry, indicated by the 1H coupling constants of the isolated
products.
While highly nucleophilic methoxyarenes readily participate in
this chemistry, it was envisioned that the method would become
more practical if it was tolerant of heterocyclic rings, such as in-
doles, furans, and pyrroles. Unfortunately, these reactions could not
be advanced with the arenes shown in Figure 1 using heat or acid

M.A. Tarselli et al. / Tetrahedron 65 (2009) 1785–1789
1787
Table 1
Table 3
Optimization of arene–allene hydroarylation reaction
Reaction of 1 and 4 with substituted allenes
Allene Time
Product
Yield
51%
14
14
h
h
58%
(10:1 with
2-isomer)
Entry Solventa Gold source
Silver source Time Conversionb
1c
2
THF
(PhO)3P(AuCl)
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
0.5
0.5
0.5
0.5
0.5
48
20
10
h
h
h
h
h
2%
16%
8%
Toluene (PhO)3P(AuCl)
3
4
5
6
Et2O
(PhO)3P(AuCl)
(PhO)3P(AuCl)
(PhO)3P(AuCl)
CH2Cl2
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
54%
<1%
52%
55%
86%
79%
92%
88%
80%
>95%
12
16
h
90%
(t-Bu2-o-biphenyl)P(AuCl)e AgOTf
h
7
(IMes)AuClf
(PhO)3P(AuCl)
(PhO)3P(AuCl)
(PhO)3P(AuCl)
(2,4-diMe-PhO)3P(AuCl)
(2-Ph-PhO)3P(AuCl)
(4-Cl-PhO)3P(AuCl)
AgOTf
AgSbF6
AgNTf2
AgBF4
AgBF4
AgBF4
AgBF4
h
h
h
h
h
h
8d
9
g
10
10
1
1
1
10
11
12
13
h
22%
h
a
Solvents dried by passage through alumina column with Ar (tol, Et2O, CH2Cl2), or
distilled from Na0 (THF) or CaH2 (MeCN).
b
Integrated against remaining SM by GC.
Entries 1–7 run with 1:1 arene to allene molar ratio.
Entries 8–13 run with 2:1 arene to allene ratio.
Ref. 4.
Ref. 13.
Ref. 15.
c
d
e
f
g
Table 2
Prenylation with dimethylallene
Arene
Time
Product
Yielda,b
67%
4
4
h
h
Figure 1. Arenes tested, which are unreactive under the specified conditions.
71% (6:1c)
cocatalysts. Increasing the concentration of the reactants or even
running the reaction in neat arene as solvent (methylpyrrole) did
not result in useful conversion (<10%).
Unlike previously reported methods by Hashmi, furans did not
participate in either addition or phenol-rearrangement chemistry,
instead decomposing to >8 products. One hypothesis for the failure
of these reactions is that the cationic gold(I) catalyst is simply
deactivated by the excess coordinating arene in the reaction.17
18
h
53%
Allenes with more sterically demanding
a substituents were
also unreactive in this chemistry. Scheme 4 lists allenes, which do
not react under the examined conditions. Widenhoefer4 has pro-
posed a mechanism, which could rationalize such an observation.
16
12
h
h
65%
75%
Scheme 4. Allenes unreactive in the present system.
This mechanism might also explain the low reactivity of substrate
17 relative to the parent allene 2; a s-allyl gold species would be
a
General procedure: 2.0 equiv arene and 1.0 equiv allene were added to
mol % of preactivated gold catalyst in a 2-mL screwtop vial using anhydrous
better stabilized by an internal 3ꢀ carbocation (2) or a nearby
heteroatomic group (12, 15). Oshima and co-workers have noted
a similar effect on allene substitution in the Mn-catalyzed allene
allylation.18
5
CH2Cl2 at room temperature for the time indicated.
b
Isolated yield after silica gel chromatography in ethyl acetate/hexanes.
Inseparable mixture.
c

1788
M.A. Tarselli et al. / Tetrahedron 65 (2009) 1785–1789
4. Conclusion
60.9, 56.3, 56.1, 25.7, 22.6, 17.7. HRMS (ESIþ): expected 289.1416,
observed 289.1422 (MþNaþ).
A method for the addition of methoxybenzenes to allenes by
phosphite-gold(I) catalysts was reported. The reactions were stable
to air and trace moisture, and were conducted on the benchtop in
air. Electron-rich methoxybenzenes and unhindered mono-
substituted allenes were found to be the best participants in these
reactions.
5.6. 2-Methyl-4-(1,2,3-trimethoxyphenyl)-but-2-ene (9)
Clear oil. 1H NMR (400 MHz):
d 6.80 (d, 1H), 6.59 (d, 1H), 5.24 (t,
1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 3.25 (d, 2H), 1.72 (s, 6H).
13C NMR (100 MHz): 152.0, 151.8, 142.5, 131.9, 127.9, 123.5, 123.3,
107.5, 60.7, 56.0, 28.2, 25.7, 17.1.
5. Experimental section
5.1. General
5.7. 2-Methyl-4-(5-methyl-1,2,3-trimethoxyphenyl)-but-2-
ene (11)
All gold precatalysts were synthesized according to the pub-
lished methods.4,13,14 Silver bistriflimide (AgNTf2) was formed
according to the procedure of Gagosz.19 All other silver salts were
purchased from Strem Chemicals and stored in a nitrogen-atmo-
sphere glovebox, then transferred to an oven-dried vial stored in
a desiccator when used. All solvents were purified by alumina-
packed columns under Ar or distillation from Na0 or CaH2. Arenes
were purchased from Aldrich and used as received. Dimethylallene
and ethyl-2,3-butadienoate were purchased from Aldrich; alle-
nylmalonate was synthesized according to the literature
procedure.20
1H NMR (400 MHz): 1.66 (s, 3H), 1.75 (s, 3H), 2.22 (s, 3H), 3.26
(d, 2H), 3.79–3.83 (m, 9H), 5.02 (t, 1H), 6.48 (s, 1H). 13C NMR
(100 MHz): 151.8, 151.1, 140.5, 131.8, 131.0, 126.3, 123.2, 109.6, 60.9,
60.8, 55.9, 25.6, 19.6, 17.8.
5.8. Dimethyl-2-(E-4-(1,3,5-trimethoxyphenyl)-but-2-
enyl)malonate (13)
Clear oil. 1H NMR (300 MHz):
d 6.09 (s, 2H), 5.58 (dt, 1H,
J¼15.3 Hz), 5.29 (dt, 1H, J¼15.0 Hz), 3.78 (s, 3H), 3.75 (s, 6H), 3.65
(s, 6H), 3.35 (t, 1H, J¼7.5 Hz), 3.20 (d, 2H, J¼6 Hz), 2.51 (t, 2H,
J¼14.7 Hz). 13C NMR (100 MHz): 169.4, 159.5, 158.7, 132.3, 124.5,
109.4, 90.8, 55.7, 55.3, 52.2, 52.1, 31.9, 25.6. HRMS (ESIþ): expected
375.1482, observed 375.1482 (MþNaþ).
5.2. General procedure for intermolecular hydroarylation
To a 5-mL vial charged with a stirbar were added (4-ClPhO)3
-
PAuCl (9.6 mg, 15
mmol) and AgBF4 (3.0 mg, 15 mmol), and
5.9. Dimethyl-2-(E-4-(1,3-dimethoxyphenyl)-but-2-enyl)-
malonate (14a) and dimethyl-2-(E-4-(2,5-dimethoxyphenyl)-
but-2-enyl)malonate (14b)
dichloromethane (1.0 mL) by syringe, resulting in a light gray
suspension. After stirring for 2 min, 1,3,5-trimethoxybenzene
(100 mg, 0.6 mmol) was added, resulting in a color change to
light orange. After stirring for additional 2 min, dimethylallene
(20.0 mg, 0.3 mmol) was added dropwise by microsyringe. Stir-
ring was continued until GC/TLC (product Rf 0.5 in 1:7 ethyl acetate/
hexanes) analysis indicated complete consumption of the allene.
The reaction mixture was concentrated, loaded directly onto a silica
flash column, and eluted with 1:10 to 1:8 ethyl acetate/hexanes to
6:1 mixture, inseparable by column chromatography. Compound
14a. 1H NMR (300 MHz):
d 2.57 (t, 2H), 3.19 (d, 2H), 3.40 (t, 1H),
3.67 (s, 6H), 3.76 (s, 6H), 5.40 (dt, 1H, J¼15.2 Hz), 5.63 (dt, 1H,
J¼15.2 Hz), 6.38 (m, 2H), 6.94 (d, 1H). 13C NMR (100 MHz) (mix-
ture): 169.4, 160.9, 159.4, 158.1, 132.4, 129.9, 129.8, 125.9, 124.9,
121.3,106.2,104.0,102.9,100.5, 98.5, 55.7, 55.3, 55.3, 55.2, 52.2, 51.9,
32.2, 31.9, 15.2. HRMS (ESI): expected 345.1314, observed 345.1329
(MþNaþ).
yield 3 (67% yield) as a clear oil. 1H NMR (300 MHz):
d 6.13 (s, 2H),
5.16 (t, 1H), 3.79 (s, 9H), 3.26 (d, 2H), 1.75 (s, 3H), 1.65 (s, 3H). 13C
NMR (100 MHz): 159.9, 158.7, 130.6, 123.5, 111.0, 90.9, 55.7, 55.3,
25.8, 21.8, 17.6.
5.10. Ethyl-E-4-(1,3,5-trimethoxyphenyl)-but-2-enoate (16)
5.3. Tri(4-chlorophenyl)phosphite gold(I) chloride
Clear oil. 1H NMR (300 MHz):
d
7.01 (dt, 1H, J1¼15.6 Hz,
White crystalline solid. 1H NMR (CDCl3, 300 MHz):
d 7.37 (d, 2H,
J2¼6 Hz), 6.10 (s, 2H), 5.66 (dt,1H, J¼15.3 Hz), 4.11 (m, 2H), 3.79 (s,
3H), 3.76 (s, 6H), 3.42 (dd, 2H), 1.23 (t, 3H). 13C NMR (100 MHz):
167.2, 160.1, 158.8, 148.1, 129.3, 120.6, 116.7, 106.6, 104.2, 90.6, 59.9,
55.3, 25.5, 14.3. HRMS (ESIþ): expected 281.1389, observed
281.1387 (MþHþ).
J¼9 Hz), 7.12 (dd, 2H, J1¼9 Hz, J2¼1.8 Hz). 13C NMR (100 MHz):
d
147.6, 132.5, 130.6, 122.3 (d). 31P (121 MHz):
d 112.0.
5.4. 2-Methyl-4-(2,4-dimethoxyphenyl)-but-2-ene (5a) and 2-
methyl-4-(2,6-dimethoxyphenyl)-but-2-ene (5b)
5.11. 1-(1,3,5-Trimethoxyphenyl)-2E-triskadecene (18)
6:1 Mixture, inseparable by column chromatography. Compound
5a. 1H NMR (400 MHz): 1.68 (s, 3H), 1.71 (s, 3H), 3.22 (d, 2H), 3.77
(s, 3H), 3.79 (s, 3H), 5.26 (t,1H), 6.42 (m, 2H), 7.01 (d,1H). Compound
5b. 1H NMR (400 MHz): 1.65 (s, 3H), 1.74 (s, 3H), 3.32 (d, 2H), 3.79
(s, 3H), 3.80 (s, 3H), 5.19 (t, 1H), 6.53 (d, 2H), 7.09 (t, 1H). 13C NMR
(100 MHz) (mixture): 159.1, 158.1, 129.4, 123.3, 123.0, 122.6, 103.9,
98.6, 55.8, 55.3, 27.8, 25.8, 17.7.
Clear oil. 1H NMR (400 MHz):
d 0.85 (t, 4H), 1.22 (m, 22H), 1.90
(m, 2H), 3.22 (d, 2H), 3.79 (m, 12H), 5.40 (m, 2H), 6.12 (s, 2H). 13C
NMR (100 MHz): 159.3, 158.8, 130.0, 128.3, 90.9, 55.8, 55.3, 32.5,
31.9, 29.6, 29.5, 29.3, 29.2, 25.7, 22.7, 14.1. HRMS (ESIþ): expected
371.2562, observed 371.2583 (MþNaþ).
Acknowledgements
5.5. 2-Methyl-4-(1,2,3,5-tetramethoxyphenyl)-but-2-ene (7)
The authors gratefully acknowledge the National Institutes of
Health Institute of General Medicine (GM-60578) for support
of this research. We also thank John Gipson for the preparation of
phenylallene and benzylallene (Scheme 4).
1H NMR (400 MHz):
d 6.24 (s, 1H), 5.11 (t, 1H), 3.82 (s, 3H), 3.81
(s, 3H), 3.77 (s, 3H), 3.23 (d, 2H), 1.72 (s, 3H), 1.62 (s, 3H). 13C NMR
(100 MHz): 153.6, 152.4, 151.6, 130.7, 123.6, 116.5, 100.0, 93.1, 60.9,

M.A. Tarselli et al. / Tetrahedron 65 (2009) 1785–1789
1789
12. Ogasawara, M.; Ikeda, H.; Nagano, T.; Hayashi, T. Org. Lett. 2001, 3, 2615–
References and notes
2617.
13. Ref. 3, also Ref. 15.
1. Anastas, P.; Warner, J. Green Chemistry: Theory and Practice; Oxford University
Press: New York, NY, 1998.
´
S.; Herrero-Go´mez, E.; Pe´rez-Gala´n, P.; Nieto-Oberhuber, C.; Echavarren,
14. Lopez,
A. M. Angew. Chem., Int. Ed. 2006, 45, 6029–6032.
15. Phosphites were synthesized by treatment of PCl3 with triethylamine (3.
2. For recent (2007–2008) reviews concerning this topic, see: (a) Skouta, R.; Li,
C.-J. Tetrahedron 2008, 64, 4917–4938; (b) Widenhoefer, R. A. Chem.dEur. J.
2008, 14, 5382–5391; (c) Gorin, D. J.; Toste, F. D. Nature 2008, 446, 395–403; (d)
Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180–3211; (e) Fu¨rstner, A.; Davies, P. W.
Angew. Chem., Int. Ed. 2007, 46, 2–42.
3. Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2007, 9, 4821–4824.
4. Zhang, Z.; Widenhoefer, R. A. Org. Lett. 2008, 10, 2079–2081.
5. (a) Nishina, N.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006, 45, 3314–3317; (b)
Nishina, N.; Yamamoto, Y. Synlett 2007, 1767–1770.
0
equiv) and a functionalized phenol (3.0 equiv) in THF overnight, followed
by filtration over Celite. The corresponding 4-F and 4-Br analogs of the pre-
catalyst were synthesized in this manner and found to be less active than the 4-
Cl complex.
16. Catalysis with 2 mol % TfOH/CH2Cl2 or 5 mol % AgBF4 in CH2Cl2 did not lead
to any of the observed products. Addition of 5 mol % (4-ClTPOP)AuCl to silver
control after 24 h allows reaction to proceed normally, indicating an authentic
gold-catalyzed reaction.
17. Herrero-Go´ mez, E.; Nieto-Oberhuber, C.; Lo´ pez, S.; Benet-Buchholz, J.; Echa-
varren, A. M. Angew. Chem., Int. Ed. 2006, 45, 5455–5459.
18. Nishikawa, T.; Shinokubo, H.; Oshima, K. Org. Lett. 2003, 5, 4623–4626.
19. Me´zailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133–4136.
20. Zhang, Z.; Liu, C.; Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer, R. A. J. Am. Chem.
Soc. 2006, 128, 9066–9073.
6. Reetz, M. T.; Sommer, K. Eur. J. Org. Chem. 2003, 3485–3496.
7. Shi, Z.; He, C. J. Org. Chem. 2004, 69, 3669–3671.
8. Hashmi, A. S. K.; Blanco, M. C. Eur. J. Org. Chem. 2006, 4340–4342.
9. Toups, K. L.; Liu, G. T.; Widenhoefer, R. A. Unpublished results.
10. Tarselli, M. A.; Gagne´, M. R. J. Org. Chem. 2008, 73, 2439–2441.
11. For a recent phosphite–gold(I)-catalyzed hydroamination, see: Giner, X.; Najera,
C. Org. Lett. 2008, 10, 2919–2922.