Synthesis of 2-cyclohexenone derivatives via gold(I)-catalyzed hydrative cyclization of 1,6-diynes

Article abstract of DOI:10.1021/jo800974x

(Chemical Equation Presented) The gold(I) complex (MeAuPPh₃) was found to be a highly effective catalyst for the hydrative cyclization of 1,6-diynes to form the corresponding 3-methyl hex-2-enone derivatives with good to excellent yield. The proposed mechanism is described.

Full text of DOI:10.1021/jo800974x

TABLE 1. Gold(I)-Catalyzed Hydrative Cyclization of 1a
Synthesis of 2-Cyclohexenone Derivatives via
Gold(I)-Catalyzed Hydrative Cyclization of
1,6-Diynes
Chen Zhang,*,† Dong-Mei Cui,‡ Li-Ying Yao,†
Bi-Song Wang,† Yong-Zhou Hu,† and Teruyuki Hayashi*,§
cat.
(2 mol %)
H2O
(mol %)
yield of
entry
acid (mol %)
solvent
2 (%)b
ZJU-ENS Joint Laboratory of Medicinal Chemistry, School
of Pharmaceutical Sciences, Zhejiang UniVersity,
Hangzhou 310058, People’s Republic of China, College of
Pharmaceutical Science, Zhejiang UniVersity of Technology,
Hangzhou 310014, People’s Republic of China, and National
Institute of AdVanced Industrial Science and Technology,
Tskuba, Ibaraki 305-8568, Japan
1
2
3
4
5
6
7
8
MeAuPPh3
MeAuPPh3
MeAuPPh3
MeAuPPh3
MeAuPPh3
MeAuPPh3
MeAuPPh3
MeAuPPh3
MeAuPPh3
MeAuPPh3
MeAuPPh3
MeAuPPh3
AuCIPPh3
NaAuCl4
100
50
s
CF3SO3H (50)
CF3SO3H (50)
CF3SO3H (50)
CF3SO3H (50)
CF3SO3H (20)
CF3SO3H (50)
CF3SO3H (50)
H3PW12O40 (4)
H3PMo12O40 (4) MeOH
H4SiW12O40 (4) MeOH 29
CH3SO3H (50)
H2SO4 (50)
CF3SO3H (50)
CF3SO3H (50)
CF3SO3H (50)
CF3SO3H (50)
s
MeOH 94 (84)
MeOH 42
MeOH
0
200
100
100
100
100
100
100
100
100
100
100
100
100
100
100
MeOH 25
MeOH 76
EtOH
toluene
60
0
MeOH 21
9
5
chenzhang@zju.edu.cn
10
11
12
13
14
15
16
17
18
MeOH 96 (89)
ReceiVed May 20, 2008
MeOH 44
MeOH 15
MeOH 42
MeOH 23
MeOH trace
HAuCl4
AuCl3
MeAuPPh3
s
MeOH
MeOH
0
0
CH3SO3H (50)
a Reactions were conducted with 0.5 mmol of 1, 0.5 mmol of H2O,
50 mol % of acidic additives, and 2 mol % of gold catalyst in 2.0 mL
of solvent for 1 h. b GC yield using dodecane as an internal standard.
Isolated yields are shown in parentheses.
The gold(I) complex (MeAuPPh3) was found to be a highly
effective catalyst for the hydrative cyclization of 1,6-diynes
to form the corresponding 3-methyl hex-2-enone derivatives
with good to excellent yield. The proposed mechanism is
described.
of gold(I) complex in conjunction with acidic cocatalysts
efficiently catalyzed hydrative cyclization of 1,6-diynes to form
highly substituted cyclohexenones;4 the latter are commonly
found in natural products and biologically active molecules.5
Our initial studies focused on testing the feasibilities for the
hydrative cyclization of 4-substituted 1,6-diyne, catalyzed by
gold(I) salts (Table 1). In a preliminary experiment, a mixture
of 4,4-(dimethoxycarbonyl)hepta-1,6-diyne (1, 0.5 mmol),
[(Ph3P)AuCH3] (0.01 mmol, 2 mol %), trifluoromethanesulfonic
acid (TfOH) (0.25 mmol, 50 mol %), and H2O (0.5 mmol) in
methanol (2 mL) was heated for 1 h at 70 °C, affording the
corresponding hydrative cyclization product cyclohexenone (2)
in 94% GC yield (entry 1), without possible hydration product
diketone or methanol addition.6,7 Structure of 2 was determined
on 1H, 13C NMR, GC-mass spectrum, and elemental analysis.
We observed that formation of 2 was closely related with
the amount of H2O: when the amount of H2O was reduced to
50 mol % or increased to 200 mol %, the yield of cyclohexenone
derivative 2 became considerably lower (entries 2 and 4).
Importantly, no reaction takes place in the absence of H2O (entry
3). Different solvents were screened, and methanol was found
to be the best one (entries 6 and 7). A useful yield of 2 (76%)
During the past 10 years, several research groups have
developed gold-catalyzed homogeneous catalytic reactions.1 A
variety of organic transformations have been shown to be
mediated by gold(I) or gold(III) complexes in solution.2 In
addition to its ability to activate alkynes and related substrates,
the catalysis of nucleophilic addition by gold complexes for
the formation of carbon-carbon and carbon-heteroatom bonds
has been one of the most investigated reactions in modern
organometallic catalysis.3 Herein, we first report a new process
† Zhejiang University.
‡ Zhejiang University of Technology.
§ National Institute of Advanced Industrial Science and Technology.
(1) For recent reviews, see: (a) Hashmi, A. S. K. Chem. ReV. 2007, 107,
3180. (b) Hashmi, A. S. K. Gold Bull. 2004, 37, 51. (c) Arcadi, A.; Di, Giuseppe,
S. Curr. Org. Chem. 2004, 8, 795.
(2) 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.; Kurpejovi, E.; Frost, T. M.; Miehlich, B.; Frey, W.;
Bats, J. W. Chem.sEur. 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. (i) Me´zailles, N.; Ricard, L.;
Gagosz, F. Org. Lett. 2005, 7, 4133.
(4) Zhang, C.; Yao, L. Y.; Wang, B. S. ZL 2006 1 0050316.7.
(5) For examples, see: (a) Antioxidant: Braca, A.; Tommasi, N. D.; Bari,
L.-D.; Pizza, C.; Politi, M.; Morelli, I. J. Nat. Prod. 2001, 64, 892. (b) Facilitate
neurite outgrowth: Girlanda-Junges, C.; Keyling-Bilger, F.; Schmitt, G.; Luu,
B. Tetrahedron 1998, 54, 7735.
(3) (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.
(6) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew. Chem., Int.
Ed. 2002, 41, 4563.
(7) Mizushima, E.; Cui, D.-M.; Nath, D. C. D.; Hayashi, T.; Tanaka, M.
Org. Synth. 2006, 83, 55.
10.1021/jo800974x CCC: $40.75
Published on Web 08/28/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7811–7813 7811

TABLE 2. Gold-Catalyzed Hydrative Cyclization Reaction of
1,6-Heptadiynesa
SCHEME 1. Proposed Catalytic Cycle for Hydrative
Cyclization
obtained in good yields. The hydrative cyclization reaction of
1,6-heptadiyne (7) occurred rapidly under the same conditions,
and 3-methyl cyclohex-2-enone (8) was obtained with useful
yield (71%, entry 4). Only esterified product 2 was isolated from
reaction of diacid 1,6-diyne 19 with 40% yield (entry 10). The
possible product of intramolecular addition of carboxylic acid
to alkyne was not observed.3a Reaction of 5-cyano-5-phenyl 1,6-
diyne (20) with H2O produced the corresponding cyclic product
(21) and its esterified product (18) (1:1) with 47% total yield
(entry 11).
The proposed catalytic cycle for hydrative cyclization is
shown in Scheme 1. The gold cation coordinates with diynes
to form complex I, H2O attacks the gold cation chelated C≡OC
band to form the intermediator II, and it soon isomerizes to the
gold cyclohexenone complex III by intramolecular nucleophilic
attack of the enolic ion of II to the Au+-binding triple bond.8
Then the cyclic product IV was released from active intermedi-
ate III via the metal elimination and tandem double-bond
isomerization processes.
a All reations were performed with 0.5 mmol of substrate and H2O,
50 µL of methanesulfonic acid, and 2 mol % of gold catalyst in 2.0 mL
of MeOH at 70 °C. b Isolated yield. c 18:21 ) 1:1.
was also obtained with 20 mol % of TfOH (entry 5). Other
acid catalysts, such as heteropolyacids (H3PW12O40, H3PMo12-
O40, H4SiW12O40) were utilized to afford 2 with lower yields
(entries 8-10). Methanesulfonic acid can also play the same
role as an excellent cocatalyst (entry 11). Indeed, the inorganic
acid H2SO4, which was effective for Au(I)-catalyzed hydration
of alkynes,6,7 was used in this reaction, and the cyclic compound
2 could be observed only with 44% yield (entry 12). However,
superior efficiency of (Ph3P)AuCH3 was demonstrated through
a comparison with AuClPPh3, NaAuCl4, HAuCl4, and AuCl3
under the same conditions (entries 13-16). The reaction did
not proceed in the absence of either the Au catalyst or proton
acid (entries 17 and 18).
The scope of this hydrative cyclization process was studied,
and the results are shown in Table 2. Various 4-substituted 1,6-
diynes were investigated, and the hydrative cyclization pro-
ceeded in mostly good to excellent efficiencies. The 5,5-
di(alkoxycarbonyl)-substituted cyclohex-2-enones (2, 4, and 6)
or 5-ethoxycarbonyl cyclohex-2-enone (16) were isolated with
high yields (entries 1-3 and 8). Alkyloxymethyl-substituted
cyclohex-2-enones (10 and 12) were also isolated with excellent
yields (entries 5 and 6). The cyclic products with different
substituent group pairs, such as diphenylphosphoryl and ethoxy-
carbonyl (14), or phenyl and methoxy carbonyl (18), were
We have described a useful process of ionic gold-catalyzed
hydrative cyclization of 1,6-heptadiyne to provide 3-methyl
5-substituted hex-2-enone derivatives. Efforts to explore further
applications are currently in progress in our laboratory.
Experimental Section
General Process for the Cyclization Reaction: The substrate
(0.5 mmol), gold catalyst (0.01 mmol, 2 mol %), MeOH (2.0 mL),
methanesulfonic acid (50 µL), and H2O (10 µL) were added to the
sealed tube subsequently. The mixture was stirred at 70 °C for
0.5-3.0 h. After that, saturated aqueous NaHCO3 was added to
the mixture to neutralize methanesulfonic acid. The mixture was
extracted with ethyl acetate (3 × 50 mL), and the combined organic
layers were dried over Na2SO4. Solvent was evaporated under
reduced pressure. Purification by the flash chromatography (petro-
leum/ethyl acetate) gave the expected products.
(8) For insertion of alkynes into a carbon-Au bond, see: Lian, J.-J.; Chen,
P.-C.; Lin, Y.-P.; Ting, H.-C.; Liu, R.-S. J. Am. Chem. Soc. 2006, 128, 11372.
7812 J. Org. Chem. Vol. 73, No. 19, 2008

Dimethyl 3-methyl-5-oxocyclohex-3-ene-1,1-dicarboxylate (2): A
colorless oil; bp 120 °C/5 mmHg; Rf 0.35 (petroleum/ethyl acetate
MHz, CDCl3) δ 8.06-8.02 (m, 2 H), 7.90-7.85 (m, 2 H),
7.69-7.47 (m, 6 H), 5.84 (s, 1 H), 3.93-3.79 (m, 2 H), 3.03-2.83
(m, 4 H), 1.92 (s, 3 H), 0.91-0.86 (m, 3 H); 13C NMR (100 MHz,
CDCl3) δ 194.4 (d, Jc-p ) 11.3 Hz), 170.8 (d, Jc-p ) 20.2 Hz),
1
) 5:1); H NMR (500 MHz, CDCl3) δ 5.88 (br, 1 H), 3.75 (s, 6
H), 2.90 (s, 2 H), 2.87 (s, 2 H), 2.01 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 194.5, 170.2, 158.7, 126.2, 55.5, 53.3, 41.7, 36.3, 24.3:
IR (neat, cm-1) 2957, 1735, 1675, 1436, 1380, 1300, 1249, 1075,
1054; GC-MS (M+) 226. Anal. Calcd for C13H18O5: C, 58.40; H,
6.24. Found: C, 58.43; H, 6.25.
159.2 (d, Jc-p ) 12.4 Hz), 132.2 (q, Jc-p ) 2.8 Hz), 131.9 (d, Jc-p
)
8.9 Hz), 131.6 (d, Jc-p ) 8.9 Hz), 129.0 (d, Jc-p ) 10.6 Hz), 128.3
(d, Jc-p ) 2.0 Hz), 128.2 (d, Jc-p ) 2.0 Hz), 128.0 (d, Jc-p ) 11.0
Hz), 125.6, 61.7, 60.0, 53.0 (d, Jc-p ) 57.0 Hz), 39.1, 33.9, 24.1,
20.6 (d, Jc-p ) 4.1 Hz), 13.1; 31P NMR (201.7 MHz, CDCl3) 30.02
(s); IR (CHCl3, cm-1) 2982, 1717, 1672, 1632, 1438, 1377, 1290,
1252, 1191, 1113, 1065; HRMS (ESI) calcd for C22H23O4P
382.1334, found 405.1219.
Diethyl 3-methyl-5-oxocyclohex-3-ene-1,1-dicarboxylate (4): A
colorless oil; bp 130 °C/4 mmHg; Rf 0.5 (petroleum/ethyl acetate
) 5:1); 1H NMR (500 MHz, CDCl3) δ 5.88 (q, J ) 1.2 Hz, 1 H),
4.20 (q, J ) 7.0 Hz, 4 H), 2.89 (s, 2 H), 2.86 (s, 2 H), 2.01 (d, J
) 1.2 Hz, 3 H), 1.24 (t, J ) 7.0 Hz, 6 H); 13C NMR (100 MHz,
CDCl3) δ 194.8, 169.8, 158.7, 126.2, 62.2, 55.5, 41.7, 36.2, 24.3,
13.9; IR (neat, cm-1) 2983, 1733, 1678, 1300, 1244, 1188, 1073,
1053, 855; GC-MS (M+) 254. Anal. Calcd for C13H18O5: C, 61.40;
H, 7.14. Found: C, 61.32; H, 7.30.
Methyl 3-methyl-5-oxocyclohex-3-enecarboxylate (16): A color-
1
less oil; Rf 0.65 (petroleum/ethyl acetate ) 15:1); H NMR (400
MHz, CDCl3) δ 5.91 (s, 1 H), 3.72 (s, 3 H), 3.10-3.04 (m, 1 H),
2.67-2.51 (m, 4 H), 2.00 (s, 3 H); 13C NMR (100 MHz, CDCl3)
δ 196.8, 173.5, 160.2, 126.5, 52.1, 39.6, 38.6, 33.0, 24.2; IR (CHCl3,
cm-1) 3018, 2954, 2848, 1735, 1668, 1437, 1380, 1344, 1246, 1197,
1047, 1025; HRMS (ESI) calcd for C9H12O3 168.0786, found
191.0682.
Diisopropyl 3-methyl-5-oxocyclohex-3-ene-1,1-dicarboxylate (6):
1
A colorless oil; Rf 0.4 (petroleum/ethyl acetate ) 10:1); H NMR
(400 MHz, CDCl3) δ 5.875 (m, 1 H), 5.04 (hept, J ) 6.4 Hz, 2 H),
2.85 (s, 2 H), 2.83 (s, 2 H), 2.0 (s, 3 H), 1.23 (d, J ) 6.0 Hz, 6 H),
1.21 (d, J ) 6.0 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 194.8,
169.1, 158.5, 125.9, 69.5, 55.3, 41.6, 35.9, 24.1, 21.3, 21.2; IR
(neat, cm-1) 2982, 2937, 1730, 1678, 1636, 1377, 1297, 1245, 1193,
1147. Anal. Calcd for C15H22O5: C, 63.81; H, 7.85. Found: C, 64.06;
H, 7.89.
Methyl 3-methyl-5-oxo-1-phenylcyclohex-3-enecarboxylate (18):
1
White solid; mp 83.0-84.0 °C; H NMR (400 MHz, CDCl3) δ
7.37-7.28 (m, 5 H), 5.93 (d, J ) 1.6 Hz, 1 H), 3.64 (s, 3 H),
3.29-3.21 (m, 2 H), 2.81-2.73 (m, 2 H), 2.05 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 196.6, 174.0, 160.4, 140.0, 128.9, 127.7,
126.5, 125.5, 52.8, 51.8, 45.1, 40.1, 24.6; IR (neat, cm-1) 2977,
1725, 1666, 1499, 1431, 1380, 1327, 1287, 1260, 1191, 1072. Anal.
Calcd for C15H16O3: C, 73.75; H, 6.60. Found: C, 73.58; H, 6.58.
3-Methyl-5-oxo-1-phenylcyclohex-3-enecarbonitrile (21): White
solid; mp 76.5-78.9 °C; 1H NMR (400 MHz, CDCl3) δ 7.49-7.39
(m, 5 H), 6.12 (s, 1 H), 3.01-2.90 (m, 4 H), 2.07 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ 193.6, 157.5, 137.4, 129.3,128.8.126.9,
125.5, 121.6, 46.1, 43.1, 42.1, 24.1; IR (CHCl3, cm-1) 2924, 2237,
1668, 1600, 1497, 1379, 1250, 1066. Anal. Calcd for C14H13NO:
C, 79.59; H, 6.20; N, 6.63. Found: C, 79.70; H, 6.22; N, 6.52.
3-Methyl cyclohex-2-enone (8): A colorless oil; Rf 0.75
(petroleum-ethyl acetate ) 20:1); 1H NMR (500 MHz, CDCl3) δ
5.88 (d, J ) 1.2 Hz, 1 H), 2.58-2.40 (m, 2 H), 2.36-2.28 (m 2
H), 2.09-1.98 (m, 2 H), 1.96 (d, J ) 0.65 Hz, 1 H).
5,5-Bis(methoxymethyl)-3-methylcyclohex-2-enone (10): A buff
1
oil; Rf 0.6 (petroleum/ethyl acetate ) 15:1); H NMR (400 MHz)
δ 5.86 (s, 1 H), 3.30 (s, 6 H), 3.23 (s, 4 H), 2.34 (s, 2 H), 2.32 (s,
2 H), 1.94 (s, 3 H); 13C NMR (100 MHz) δ 198.9, 159.8, 125.4,
77.2, 76.9, 76.6, 75.4, 59.2, 53.3, 41.6, 41.3, 34.8, 24.3; IR (neat,
cm-1) 2925, 1669, 1438, 1379, 1248, 1105; HRMS (ESI) calcd
for C11H18O3 198.1256, found 221.1149.
5,5-Bis(benzyloxymethyl)-3-methylcyclohex-2-enone (12): A buff
oil; Rf 0.45 (petroleum/ethyl acetate ) 10:1); 1H NMR (400 MHz,
CDCl3) δ 7.32-7.22 (m, 10 H), 5.82 (d, J ) 1.2 Hz, 1 H), 4.45
(dd, J ) 12.4, 4.8 Hz, 4 H), 3.36 (s, 4 H), 2.41 (s, 2 H), 2.36 (s,
2 H), 1.88 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 198.6, 159.7,
138.1, 128.1, 127.4, 127.2, 125.3, 73.0, 72.7, 41.7, 41.4, 34.9, 24.2;
IR (CHCl3, cm-1) 3030, 2858, 1666, 1496, 1453, 1363, 1249, 1206,
1093, 1027, 905. Anal. Calcd for C23H26O3: C, 78.83; H, 7.48.
Found: C, 78.33; H, 7.48.
Acknowledgment. This work was partially supported by the
Natural Science Foundation of China (20572094, 20672099).
Qianjiang Talent Program from the Government of Zhejiang
Province of China (2007R10022) is gratefully acknowledged.
1
Supporting Information Available: Copies of H and 13C
NMR spectra for all isolated products. This material is available
free of charge via the Internet at http://pubs.acs.org.
Ethyl 1-(diphenylphosphoryl)-3-methyl-5-oxocyclohex-3-enecar-
1
boxylate (14): White solid; mp 122.3-125.5 °C; H NMR (400
JO800974X
J. Org. Chem. Vol. 73, No. 19, 2008 7813