Gold-catalyzed hydroalkoxylation of alkoxyallenes

Article abstract of DOI:10.1021/jo802513a

We report synthesis of allylic acetals via gold-catalyzed hydroalkoxylation of alkoxyallenes with alcohols containing primary and secondary alcohols in good to excellent yields under mild condition.

Full text of DOI:10.1021/jo802513a

the hydroalkoxylation of enol ether substructures.7 As part of our
ongoing studies on metal-catalyzed atom-economical reactions, we
have been interested in the use of gold for simple and highly
efficient transformations.8 As a continuation of our studies on gold-
catalyzed addition, in this paper, we wish to develop a gold(I)
complex catalyzed hydroalkoxylation of alkoxyallenes to synthesize
allylic acetals in mild condition.9
Gold-Catalyzed Hydroalkoxylation of Alkoxyallenes
Dong-Mei Cui,*,† Zhi-Ling Zheng,† and Chen Zhang*,‡
College of Pharmaceutical Science, Zhejiang UniVersity of
Technology, Hangzhou 310014, People’s Republic of China,
and School of Pharmaceutical Sciences, Zhejiang UniVersity,
Hangzhou 310058, People’s Republic of China
Our initial explorations focused on the reaction of 3,4-
dimethoxybenzyoxyallene (1a) (0.2 mmol) with phenylmethanol
(2a) (0.4 mmol) in the presence of a catalytic amount of
(Ph3P)AuNO310 (2 mol %) in dichloroethane (1.5 mL) at -15 °C
to room temperature for 4 h, which proceeded efficiently to form
allylic acetal 3a in 67% yield (Table 1, entry 1). Efficient
hydroalkoxylation was realized with significantly lower catalyst
loading (Table 1, entry 2). Investigation of starting material
stoichiometries revealed that a slight excess of allene (1.5-2 equiv)
was necessary to drive the alcohol to full conversion (Table 1,
entries 4-6).11 The yields of the acetals depended upon their
sensitivity to decomposition during workup. Adding a small amount
of triethylamine after reaction completion allowed the acetals to
be isolated in high yields (Table 1, entry 6). Different solvents
were screened, and dichloroethane was found to be the best one
(Table 1, entries 7-9). The reaction did not proceed in the absence
of the Au catalyst (Table 1, entry 10).
cuidongmei@zjut.edu.cn
ReceiVed NoVember 11, 2008
We report synthesis of allylic acetals via gold-catalyzed
hydroalkoxylation of alkoxyallenes with alcohols containing
primary and secondary alcohols in good to excellent yields
under mild condition.
To assess the scope of this process, we have examined the
hydroalkoxylation of several alkoxyallenes with alcohols under the
optimized condition indicated in entry 6 of Table 1. The results
are summarized in Table 2. In alcohols, secondary alcohols can
serve as good substrates to afford the allylic acetals (Table 2, entries
2 and 3). Benzyl alcohols with not only an electron-donating alkoxy
group but also an electron-withdrawing chloro group on the
The hydroalkoxylation of alkoxyallenes represents one of the
most effective and atom-economical methods to prepare allylic
acetals which are invaluable precursors for synthesis of natural
products and other potentially biologically relevant substances.1
In 1997, Alper et al.2 reported the first example of a palladium-
mediated hydroalkoxylation of alkoxyallenes and later further
developed by Rutjes.3 But, it is worthy to note that other transition
metals have not been used in this hydroalkoxylation, besides the
palladium complex. On the other hand, Au salts are power soft
Lewis acids and readily activate unsaturated C-C bonds toward
attacks by a variety of nucleophiles for the formation of
carbon-carbon and carbon-heteroatom bonds.4-6 A variety of
structural motifs have been efficiently accessed under exceedingly
mild reaction condition. Recently, Hashmi et al. have also reported
(4) For recent reviews, see:(a) Skouta, R.; Li, C.-J. Tetrahedron 2008, 64,
4917. (b) Shen, H. C. Tetrahedron 2008, 64, 3885. (c) Muzart, J. Tetrahedron
2008, 64, 5815. (d) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180. (e) Hashmi,
A. S. K. Gold Bull. 2004, 37, 51. (f) Arcadi, A.; Di Giuseppe, S. Curr. Org.
Chem. 2004, 8, 795.
(5) For examples see:(a) Skouta, R.; Li, C. J. Angew. Chem., Int. Ed. 2007,
46, 1117. (b) Dube, P.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 12062. (c)
Casado, R.; Contel, M.; Laguna, M.; Romero, P.; Sanz, S. J. Am. Chem. Soc.
2003, 125, 11925. (d) Gonzalez-Arellano, C.; Abad, A.; Corma, A.; Garcia, H.;
Iglesias, M.; Sanchez, F. Angew. Chem., Int. Ed. 2007, 46, 1536. (e) Zhang,
Z. B.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2007, 46, 283. (f) Hashmi,
A. S. K.; Weyrauch, J. P.; Kurpejovie`, E.; Frost, T. M.; Miehlich, B.; Frey, W.;
Bats, J. W. Chem. Eur. J. 2006, 12, 5806. (g) LaLonde, R. L.; Sherry, B. D.;
Kang, E. J.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2452. (h) Me′zailles, N.;
Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133.
(6) (a) Genin, E.; Toullec, P. Y.; Antoniotti, S.; Brancour, C.; Geneˆt, J.-P.;
Michelet, V. J. Am. Chem. Soc. 2006, 128, 3112. (b) Sun, J.; Conley, M. P.;
Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2006, 128, 9705. (c) Sherry, B. D.;
Maus, L.; Laforteza, B. N.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 8132.
(7) (a) Hashmi, A. S. K.; Enns, E.; Frost, T. M.; Scha¨er, S.; Frey, W.;
Rominger, F. Synthesis 2008, 2707. (b) Hashmi, A. S. K.; Scha¨er, S.; Wo¨fle,
M.; Diez Gil, C.; Fischer, P.; Laguna, A.; Blanco, M. C.; Concepcion Gimeno,
M. Angew. Chem. 2007, 119, 6297. (c) Hashmi, A. S. K.; Scha¨er, S.; Wo¨fle,
M.; Diez Gil, C.; Fischer, P.; Laguna, A.; Blanco, M. C.; Concepcion Gimeno,
M. Angew. Chem., Int. Ed. 2007, 46, 6184. (d) Hashmi, A. S.; Rudolph, K. M.;
Bats, J. W.; Frey, W.; Rominger, F.; Oeser, T. Chem. Eur. J. 2008, 14, 6672.
(8) Zhang, C.; Cui, D.-M.; Yao, L.-Y.; Wang, B.-S.; Hu, Y.-Z.; Hayashi, T.
J. Org. Chem. 2008, 73, 7811.
† Zhejiang University of Technology.
‡ Zhejiang University.
(1) For examples see:(a) Donnard, M.; Tschamber, T.; Desrat, S.; Hinsinger,
K.; Eustache, J. Tetrahedron Lett. 2008, 49, 1192. (b) Donohoe, T. J.; Kershaw,
N. M.; Orr, A. J.; Wheelhouse, K. M. P.; Fishlock, L. P.; Lacy, A. R.; Bingham,
M.; Procopion, P. A. Tetrahedron Lett. 2008, 49, 809. (c) Attolino, E.; Rising,
T. W. D. F.; Heidecke, C. D.; Fairbanks, A. J. Tetrahedron: Asymmetry 2007,
18, 1721. (d) Attolion, E.; Fairbanks, A. J. Tetrahedron Lett. 2007, 48, 3061.
(e) Donohoe, T. J.; Orr, A. J.; Gosby, K.; Bingham, M. Eur. J. Org. Chem.
2005, 1969. (f) Yu, X. M.; Han, H. J.; Blagg, B. S. J. J. Org. Chem. 2005, 70,
5599. (g) Gallagher, B. M., Jr.; Fang, F. G.; Johannes, C. W.; Pesant, M.;
Tremblay, M. R.; Zhao, H. J.; Akacaka, K.; Li, X. Y.; Liu, J.; Littlefield, B. A.
Bioorg. Med. Chem. Lett. 2004, 14, 575. (h) Held, C.; Fro¨hlich, R.; Metz, P.
Angew. Chem., Int. Ed. 2001, 40, 1058. (i) Nadolski, G.; Davidson, B. S.
Tetrahedron Lett. 2001, 42, 797. (j) Doodeman, G.; Rutjes, F. D. J. T.; Hiemstra,
H. Tetrahedron Lett. 2000, 41, 5979. (k) Ovaa, H.; Leeuwenburgy, M. A.;
Overkleeft, H. S.; Marel, G. A.; Boom, J. H. Tetrahedron Lett. 1998, 39, 3025.
(l) Panetta, J. A.; Rapoport, H. J. Org. Chem. 1982, 47, 946.
(9) For recent reports on Au-catalyzed intramolecular hydroalkoxylation of
alkoxyallenes see: (a) Dugovie`, B.; Reissig, H.-U. Synlett 2008, 769. (b) Brasholz,
M.; Reissig, H.-U. Synlett 2007, 1294.
(10) Mueting, A. M.; Alexander, B. D.; Boyle, P. D.; Casalnuovo, A. L.;
Ito, L. N.; Johnson, B. J.; Pignolet, L. H. Inorg. Synth. 1992, 29, 280.
(11) 3,4-Dimethoxybenzyoxy allene was found to decompose to 3,4-
dimethoxyphenole under the reaction condition.
(2) Okuro, K.; Alper, H. J. Org. Chem. 1997, 62, 1566.
(3) (a) Kinderman, S. S.; Doodeman, R.; Beijma, J. W. V.; Russcher, J. C.;
Tjen, K. C. M. F.; Kooistra, T. M.; Mohaselzadeh, H.; Maarseveen, J. H. V.;
Hiemstra, H.; Schoemaker, H. E.; Rutjies, F. P. J. T. AdV. Synth. Catal. 2002,
344, 736. (b) Rutjes, F. P. J. T.; Kooistra, T. M.; Hiemstra, H.; Schoemaker,
H. E. Synlett 1998, 192.
1426 J. Org. Chem. 2009, 74, 1426–1427
10.1021/jo802513a CCC: $40.75 2009 American Chemical Society
Published on Web 12/19/2008

TABLE 1. Au (I)-Catalyzed Hydroalkoxylation of Alkoxyallenesa
SCHEME 1. Proposed Mechanism for Hydroalkoxylation
ofAlkoxyallene
[Au]
(mol %)
ratio
1a:2a
time
(h)
temp
(°C)
yield
(%)
entry
solvent
1
2
3
4
5
6
7
8
9
2
1
2
2
2
2
2
2
2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
CH2Cl2
toluene
THF
(CH2Cl)2
1:2
1:2
1:2
1.5:1
2:1
1.5:1
1:2
1:2
1:2
1:2
4
4
3
3
3
3
4
4
4
3
-15 to rt
-15 to rt
-15 to 50
-15 to rt
-15 to rt
-15 to rt
-15 to rt
-15 to rt
-15 to rt
-15 to rt
67
63
63
80
80
90b
57
52
50
0
10
a The reactions were performed with 0.2-0.4 mmol of allene 1a,
0.2-0.4 mmol of 2a, and (Ph3P)AuNO3 in 1.5 mL of solvent; entries 1-3
and 7-10 with 0.2 mmol of 1a and 0.4 mmol of 2a; entries 4 and 6 with
0.3 mmol of 1a and 0.2 mmol of 2a; entry 5 with 0.4 mmol of 1a and 0.2
mmol of 2a. b Adding a small amount of triethylamine after reaction
completion.
Experimental Section
General Procedure. To a reactor containing allene (0.3 mmol),
PPh3AuNO3 (2.1 mg, 0.004 mmol, 2 mol %), and 1,2-dichloroethane
(1.5 mL) was added alcohol (0.2 mmol) at -15 °C. The mixture was
then sealed and stirred at rt. After 3 h, a small amount of triethylamine
was added to terminate the reaction. The solution was concentrated
and the residue was purified by flash chromatography to give the pure
product.
TABLE 2. Gold-Catalyzed Hydroalkoxylation of Allenea
4-((1-(Benzyloxy)allyloxy)methyl)-1,2-dimethoxybenzene (3a):
colorless oil; Rf 0.44 (petroleum-ethyl acetate ) 5:1); 1H NMR (500
MHz, CDCl3) δ 7.36-7.28 (m, 5H), 6.88 (d, J ) 8.0 Hz, 1H), 6.86
(s, 1H), 6.83 (d, J ) 8.0 Hz, 1H), 5.95 (ddd, J ) 17.5, 10.5, 5.0 Hz,
1H), 5.50 (d, J ) 17.5 Hz, 1H), 5.37 (d, J ) 10.5 Hz, 1H), 5.12 (d,
J ) 5.0 Hz, 1H), 4.66 (d, J ) 11.5 Hz, 1H), 4.61 (d, J ) 11.5 Hz,
1H), 4.58 (d, J ) 11.5 Hz, 1H), 4.52 (d, J ) 11.5 Hz, 1H), 3.88 (s,
3H), 3.86 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 149.0, 148.6, 138.1,
135.0, 130.6, 128.4, 127.7, 127.6, 120.4, 118.9, 111.3, 111.0, 100.3,
67.2, 67.2, 55.9, 55.8; IR (KBr, cm-1) 2930, 1026, 939, 807; HRMS
(EI) calcd for C19H22O4 314.1518, found 314.1543
1,2-Dimethoxy-4-((1-methoxyallyloxy)methyl)benzene (3b):
colorless oil; Rf 0.30 (petroleum-ethyl acetate ) 5:1); 1H NMR (500
MHz, CDCl3) δ 6.90 (d, J ) 8.0 Hz, 1H), 6.85 (s, 1H), 6.84 (d, J )
8.0 Hz, 1H), 5.87 (ddd, J ) 17.5, 10.5, 5.0 Hz, 1H), 5.45 (dt, J )
17.5, 1.5 Hz, 1H), 5.34 (dt, J ) 10.5, 1.5 Hz, 1H), 4.93 (dt, J ) 5.0,
1.5 Hz, 1H), 4.51 (d, J ) 11.5 Hz, 1H), 4.48 (d, J ) 11.5 Hz, 1H),
3.89 (s, 3H), 3.88 (s, 3H), 3.36 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 149.0, 148.6, 134.8, 130.6, 120.4, 118.9, 111.2, 110.9, 101.5, 67.2,
55.9, 55.8, 52.7; IR (KBr, cm-1) 2936, 1029, 938, 808; HRMS (EI)
calcd for C13H18O4 238.1205, found 238.1209.
4-((1-Isopropoxyallyloxy)methyl)-1,2-dimethoxybenzene (3c):
colorless oil; Rf 0.5 (petroleum-ethyl acetate ) 5:1); 1H NMR (500
MHz, CDCl3) δ 6.91-6.82 (m, 3H), 5.91 (ddd, J ) 17.0, 10.5, 5.0
Hz, 1H), 5.49 (dt, J ) 17.0, 1.5 Hz, 1H), 5.37 (dt, J ) 10.5, 1.5 Hz,
1H), 5.03 (dt, J ) 5.0, 1.5 Hz, 1H), 4.56 (d, J ) 12.0 Hz, 1H), 4.49
(d, J ) 12.0 Hz, 1H), 3.96-3.91 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H),
1.24 (d, J ) 6.0 Hz, 3H), 1.17 (d, J ) 6.0 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 149.0, 148.5, 135.9, 130.9, 120.2, 118.1, 111.1, 111.0,
99.6, 68.5, 66.5, 55.9, 55.8, 23.2, 22.4; IR (KBr, cm-1) 2970, 1029,
934, 806; HRMS (EI) calcd for C15H22O4 266.1518, found 266.1527.
entry
1
R1
R2
3
yield (%)
1
2
3
4
5
6
7
8
1a 3,4-(MeO)2C6H3 Me
1a 3,4-(MeO)2C6H3 iPr
1a 3,4-(MeO)2C6H3 C6H4(Me)CH
1a 3,4-(MeO)2C6H3 4-MeOC6H4CH2
1a 3,4-(MeO)2C6H3 3,4-(MeO)2C6H3CH2 3f
1a 3,4-(MeO)2C6H3 4-ClC6HCH2
1a 3,4-(MeO)2C6H3 (E)-C6H5CHCHCH2
1b 4-MeOC6H3
1c C6H5
3b
3c
3d
3e
90
75
75
85
95
99
99
69
90
98
79
60
99
3g
3h
3,4-(MeO)2C6H3CH2 3e
3,4-(MeO)2C6H3CH2 3a
Bn 3i
3,4-(MeO)2C6H3CH2 3g
4-MeOC6H3CH2
4-ClC6H3CH2
9
10
11
12
13
1c C6H5
1d 4-ClC6H5
1d 4-ClC6H5
1d 4-ClC6H5
3j
3k
a All reactions were performed with allene (0.3 mmol), alcohol (0.2
mmol), and (Ph3P)AuNO3 (2 mol %) in dichloroethane (1.5 mL) at - 15
°C to rt for 3 h.
benzene ring gave good yields of the corresponding allylic acetals
(Table 2, entries 4-6). Under the same reaction condition (E)-3-
phenylprop-2-en-1-ol was also converted into the expected addition
product (Table 2, entry 7). Furthermore, allenes 1c and 1d bearing
aromatic groups of various electron density also worked well and
reacted with alcohols to afford products with good yields (Table
2, entries 8-13).
The proposed mechanism of the gold-catalyzed hydroalkoxy-
lation of alkoxyallenes is shown in Scheme 1. The gold cation
coordinated with the more electron-rich oxygen-substituted double
bond of allene to form an Au-π-alkyne complex A. The alcohol
as the nucleophile attacks to the gold cation-chelated CdC bond
to form a vinylgold species B. Then, the organogold intermediate
B liberates the adducts 3 and the gold catalyst by protodemetalation.
In summary, we have developed gold-catalyzed hydroalkoxylation
of alkoxyallenes with different alcohols to provide allylic acetals.
This reaction took place under mild conditions with good yields
and may be used in the synthesis of strongly functionalized building
blocks, potentially biologically active substances, and natural
products.
Acknowledgement. This work was partially supported by the
Natural Science Foundation of China (Nos. 20672099 and
20572094).
Supporting Information Available: Experimental procedures,
compound characterization, and copies of 1H and 13C NMR spectra
for all isolated products. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO802513A
J. Org. Chem. Vol. 74, No. 3, 2009 1427