Efficient synthesis of γ-Keto esters through neighboring carbonyl group-assisted regioselective hydration of 3-Alkynoates

Article abstract of DOI:10.1021/jo802450n

The Au(III)-catalyzed hydration of 3-alkynoates led to a practical one-step synthesis of γ-keto esters in high yields, through a carbonyl group participation enabled by a favored 5-endodig cyclization. This mild-aqueous ethanol, room temperature, and atom

Full text of DOI:10.1021/jo802450n

Efficient Synthesis of γ-Keto Esters through Neighboring Carbonyl
Group-Assisted Regioselective Hydration of 3-Alkynoates
Weibo Wang, Bo Xu,† and Gerald B. Hammond*,†
Department of Chemistry, UniVersity of LouisVille, LouisVille, Kentucky 40292
gb.hammond@louisVille.edu
ReceiVed NoVember 3, 2008
The Au(III)-catalyzed hydration of 3-alkynoates led to a practical one-step synthesis of γ-keto esters in
high yields, through a carbonyl group participation enabled by a favored 5-endodig cyclization. This
mild-aqueous ethanol, room temperature, and atom-economical method has been used effectively with a
wide range of substrates. Using the same conditions, a 2-alkynoate produced the corresponding ꢀ-keto
ester in high yield.
1,4-Dicarbonyl compounds are starting materials and inter-
mediates in many important natural products and synthetic drug
syntheses.1 Unlike their 1,3 or 1,5 counterparts, the disconnec-
tion of 1,4-dicarbonyl compounds, especially of highly substi-
tuted 1,4-dicarbonyl compounds like γ-keto-R,R-substituted
esters, is not trivial. Radical or carbene2 methods or some other
relatively complex methods3 have been used to synthesize them.
A tactical approach that enables a one-step synthesis of highly
substituted γ-keto esters could be the directed hydration of
3-alkynoates, provided this transformation can be carried out
regioselectively, under mild conditions, and with good functional
group tolerance. The attractiveness of this approach lies in the
fact that the hydration of alkynes is one of the most straight-
forward methods to obtain carbonyl compounds. Unlike other
syntheses of carbonyl compounds, the hydration of alkynes is
an atom-economical addition of water without energy-intensive
redox chemistry.4a In addition, the alkyne functionality is
chemically inert toward many reaction conditions, and so it can
be considered a masked ketone. Herein we report a neighboring
carbonyl group-assisted hydration of internal alkynes in the
presence of a gold(III) catalyst that yields a highly regioselective
synthesis of γ-keto esters.
The mercury(II)-catalyzed hydration of alkynes has been
known for more than a century.4b To avoid the use of toxic
mercury(II) salts, various catalysts such as Brønsted acids5 and
metal catalysts such as Ru(II),6 Ru(III),7 Rh(III),8 Ir,9 Pt(II),10
and Au11 as well as other systems12 have been examined. There
are excellent catalysts for terminal alkynes but internal alkynes
remain a challenge, in part because of regioselectivity issues.
Gold catalysis is especially promising for the hydration of
alkynes because of the higher affinity of gold toward alkynes
compared to other common oxygen- or nitrogen-containing
† B.X. and G.B. H. share senior authorship.
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Y.; Nemoto, H.; Yamamoto, Y. J. Org. Chem. 1991, 56, 7195–7196. (d) Aoki,
S.; Nakamura, E. Tetrahedron 1991, 47, 3935–3946. (e) Aoki, S.; Nakamura,
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Chem. 2004, 2, 2517–2529. (c) Cai, Y.; Roberts, B. P. Tetrahedron Lett. 2003,
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10.1021/jo802450n CCC: $40.75 2009 American Chemical Society
Published on Web 01/26/2009

Efficient Synthesis of γ-Keto Esters
TABLE 1. Screening of Metal Catalysts for the Hydration of 1a
SCHEME 1. Directed Gold-Catalyzed Hydration of Alkynes
through Neighboring Group Assistance
functional groups. In 1991, Fukuda and co-workers reported
the use of a Au(III) salt in refluxing aqueous methanol for the
hydration of terminal alkynes to methyl ketones (Markovnikov
addition).11c But their hydration of internal alkynes was sluggish
and nonregioselective. Many other gold catalysts also have been
examined, but only terminal alkynes showed good regioselec-
tivity (Markovnikov products), and most reactions needed
elevated temperatures or strong acid cocatalysts.11
In general, the regioselective hydration of internal alkynes
may only proceed in the presence of a directing functionality
(like heteroatoms, or aromatic rings) nearby.13 We proposed
that with internal alkynes possessing a nucleophilic site, Nu,
nearby (Scheme 1), this nucleophile could attack a gold activated
triple bond to form two regioisomeric cyclic intermediates.
Although both carbons in the triple bond are prone to nucleo-
philic attack, one cyclic intermediate may be favored over the
other according to Baldwin’s rules. If Nu is a carboxylic ester,
this neighboring group assistance may then lead to a highly
regioselective synthesis of γ-keto esters through an alkyne
hydration process.
To test this hypothesis, we first examined the effect of
transition metal catalysts on the hydration of 3-alkynoate 1a
(Table 1). 3-Alkynoate 1 can be synthesized easily by using
our published procedure.14 Our selection of metal catalysts was
based on the known alkynophilicity of gold(I), gold(III),
a
Yields are based on H NMR. b CH2Cl2 saturated with water.
1
TABLE 2. Screening of Solvents and Additives
catalyst (5%)/
entry
additive
solvent
time, h yield,a
%
1
2
3
4
5
6
7
8
AuBr3
AuBr3
AuBr3
AuBr3
AuBr3
CH2Cl2 (S)b
12
12
72
12
12
12
12
12
12
24
24
12
12
12
12
12
12
70
17
trace
25
35
MeOH/H2O (10:1)
CH2Cl2/H2O (100:1)
t-BuOH/H2O (10:1)
CH3CN/H2O (10:1)
AuBr3/Bu4NBr (5%) CH2Cl2 (S)
6
AuBr3/Bu4NBr (5%) MeOH/H2O (10:1)
AuBr3/pyridine (5%) MeOH/H2O (10:1)
AuBr3/P(OEt)3 (5%) MeOH/H2O (10:1)
trace
NRd
NRd
33
complex
71
56
33
78
9
10
11
12
13
14
15
16
17
AuCl3
MeOH/H2O (10:1)
(6) (a) Tokunaga, M.; Wakatsuki, Y. Angew. Chem., Int. Ed. 1998, 37, 2867.
(b) Ackermann, L.; Kaspar, L. T. J. Org. Chem. 2007, 72, 6149–6153. (c)
Grotjahn, D. B.; Lev, D. A. Chem. Ind. 2005, 104, 227–236.
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(9) Kim, S. Y.; Chin, C. S.; Eum, M.-S. J. Mol. Catal. A 2006, 253, 245–
248.
AuCl3/AgOTf (15%) MeOH/H2O (10:1)
NaAuCl4 ·2H2O
NaAuCl4 ·2H2O
NaAuCl4 ·2H2O
NaAuCl4 ·2H2O
NaAuCl4 ·2H2O
NaAuCl4 ·2H2O
CH2Cl2 (S)
t-BuOH/H2O
EtOH/H2O (50:1)
EtOH/H2O (4:1)
EtOH/H2O (1:1)
MeOH/H2O (10:1)
33
mixturec
(10) (a) Lucey, D. W.; Atwood, J. D. Organometallics 2002, 21, 2481–2490.
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Hartman, J. W.; Hiscox, W. C.; Jennings, P. W. J. Org. Chem. 1993, 58, 7613–
7614. (d) Hiscox, W.; Jennings, P. W. Organometallics 1990, 9, 1997–1999.
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M. Org. Synth. 2006, 83, 55–60. (b) Mizushima, E.; Sato, K.; Hayashi, T.;
Tanaka, M. Angew. Chem., Int. Ed. 2002, 41, 4563–4565. (c) Fukuda, Y.;
Utimoto, K. J. Org. Chem. 1991, 56, 3729–3731. (d) Casado, R.; Contel, M. a.;
Laguna, M.; Romero, P.; Sanz, S. J. Am. Chem. Soc. 2003, 125, 11925–11935.
(12) (a) Grotjahn, D. B.; Lev, D. A. J. Am. Chem. Soc. 2004, 126, 12232–
12233. (b) Liu, W.-J.; Li, J.-H. Youji Huaxue 2006, 26, 1073–1078. (c)
Vasudevan, A.; Verzal, M. K. Synlett 2004, 631–634. (d) Meier, I. K.; Marsella,
J. A. J. Mol. Catal. 1993, 78, 31–42. (e) Finiels, A.; Geneste, P.; Lasperas, M.;
Marichez, F.; Moreau, P. Stud. Surf. Sci. Catal. 1991, 59, 565–571. (f) Finiels,
A.; Geneste, P.; Marichez, F.; Moreau, P. Catal. Lett. 1989, 2, 181–184. (g)
Olah, G. A.; Meidar, D. Synthesis 1978, 671.
(13) (a) Imi, K.; Imai, K.; Utimoto, K. Tetrahedron Lett. 1987, 28, 3127–
3130. (b) Detert, H.; Meier, H. Liebigs Ann./Recl. 1997, 1565. (c) Utimoto, K.
Pure Appl. Chem. 1983, 55, 1845. (d) Stork, G.; Borch, R. J. Am. Chem. Soc.
1964, 86, 935. (e) Francisco, L. W.; Moreno, D. A.; Atwood, J. D. Organome-
tallics 2001, 20, 4237–4245. (f) Arcadi, A.; Cerichelli, G.; Chiarini, M.; Di
Giuseppe, S.; Marinelli, F. Tetrahedron Lett. 2000, 41, 9195–9198. (g) Jennings,
P. W.; Hartman, J. W.; Hiscox, W. C. Inorg. Chim. Acta 1994, 222, 317–322.
(14) (a) Wang, W.; Xu, B.; Hammond, G. B. Org. Lett. 2008, 10, 3713–
3716. (b) Liu, L.-P.; Xu, B.; Hammond, G. B. Org. Lett. 2008, 10, 3887–3890.
a Yields are based on 1H NMR. b CH2Cl2 saturated by water.
c Mixture of 2a and corresponding methyl ester. d NR ) no reaction.
platinum(II), and silver(I).15 A strong acid alone5 had no effect
on 1a (Table 1, entry 1). Treatment of 1a with Au(I) or PtCl2
catalysts gave traces of hydration product 2a at room temper-
ature (Table 1, entries 2-5). Conversely, the addition of a strong
acid to AuCl or Au(PPh3)Cl produced the desired ketone but in
less than desirable yields, due to side reactions induced by the
prevailing acidic conditions (Table 1, entries 6 and 7). On the
other hand, the use of Au(III) catalysts such as AuBr3, AuCl3,
or NaAuCl4 ·2H2O offered hope (Table 1, entries 8-10). We
decided to investigate the effects of solvents and additives/
ligands on the hydration of 1a employing Au(III) catalysts.
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2006, 128, 9705–9710.
J. Org. Chem. Vol. 74, No. 4, 2009 1641

Wang et al.
TABLE 3. Au(III)-Catalyzed Hydration of Internal 3-Alkynoatesa
Using AuBr3 in various solvent combinations did not improve
the yield of 2a significantly (Table 2, entries 1-5). We then
tested a combination of AuBr3 with various additives or ligands,
such as nBu4NBr, P(OEt)3, or pyridine, with disappointing
results (Table 2, entries 6-9). A complex mixture was observed
when a combination of AuCl3 and AgOTf in MeOH/H2O was
used, whereas AuCl3 alone produced 2a in only 33% yield
(Table 2, entries 10 and 11).
After screening NaAuCl4 ·2H2O with different solvent com-
binations (Table 2, entries 12-17), we concluded that
NaAuCl4 ·2H2O in EtOH/H2O (4:1) offered the best conditions
for the hydration of alkyne 1a. When methanol was used as
solvent, the reaction gave a mixture of 2a and corresponding
methyl ester because of transesterification (Table 2, entry 17).
When a smaller catalyst loading (NaAuCl4 ·2H2O, 2%) was used
the reaction was slower, but hydration of compound 2a still
could be completed after 24 h. With optimal conditions in hand,
we explored the scope of this reaction (Table 3). The hydration
proceeded smoothly in high yields and regioselectivity, and was
tolerant of ether, double bond, and other ester functionalities
(Table 3, entries 4, 5, and 8, respectively). Indeed, only one
regioisomer was detected in all the crude products examined.
The steric hindrance of the quaternary R-carbon could be ruled
out as the reason for the high selectivity of the hydration because
a 3-alkynoate possessing no substituents in its R-carbon also
showed excellent regioselectivity after hydration (Table 3, entry
10). The stereoelectronic effects of a phenyl group could account
for the lower yield observed in entry 7 (Table 3). The hydration
of 2-fluoro-3-alkynoate 1k gives R,ꢀ-unsaturated ester 2k (Table
3 entry 11) through concomitant elimination of HF during the
hydration process.
The adjacent carbonyl group in alkyne 1 plays an important
role in both reaction rate and regioselectivity. For example, the
hydration of dec-2-yne 1l under similar conditions was much
slower (Scheme 2, top), and although the chemical yield was
high, the regioselectivity was poor. The hydration of the
sterically demanding 4,4-dimethylpent-2-yne 1m was even
slower; indeed, after 72 h, almost no reaction had taken place
(Scheme 2, bottom). These results were in sharp contrast with
the hydration of ꢀ-alkynyl esters, for even the hydration of
sterically encumbered ꢀ-alkynyl esters 1h and 1i proceeded
smoothly at room temperature (Table 3, entries 8 and 9).
It is noteworthy that in some cases we obtained small or trace
amounts of a cyclic byproduct (e.g., 3c in eq 1).
a Reactions were performed with 5 mol % of NaAuCl4 ·2H2O, alkyne
1 (0.5 mmol), EtOH/H2O (4:1, 1.0 mL).
SCHEME 2. Hydration of Simple Internal Alkynes
The proposed mechanism for the reaction based on similar
reaction systems3c,16 is shown in Scheme 3. First, the gold(III)
catalyst coordinates with alkyne 1, activating the triple bond;
this triggers the nucleophilic carbonyl group nearby, which then
goes after the triple bond to form a cyclized vinyl gold
intermediate of type A or B.17 According to Baldwin’s rules,18
if the carbonyl oxygen attacks the ꢀ-carbon, it is considered a
4-exo-dig process, which is disfavored. But if the carbonyl
oxygen attacks the γ-carbon, it would then be a 5-endo-dig
attack, which is favored.19,20 Hashmi and co-workers have
reported the cyclization of an ethynyl ketone to a furan through
the 5-endodig process.19 Thus, B should be the predominating
intermediate. Then, upon interacting with water, B forms the
(17) (a) Nakamura, I.; Sato, T.; Terada, M.; Yamamoto, Y. Org. Lett. 2007,
9, 4081–4083. (b) Akana, J. A.; Bhattacharyya, K. X.; Muller, P.; Sadighi, J. P.
J. Am. Chem. Soc. 2007, 129, 7736–7737.
(16) Fustero, S.; Fernandez, B.; Bello, P.; delPozo, C.; Arimitsu, S.;
Hammond, G. B. Org. Lett. 2007, 9, 4251–4253.
(18) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736.
1642 J. Org. Chem. Vol. 74, No. 4, 2009

Efficient Synthesis of γ-Keto Esters
SCHEME 3. Proposed Mechanism for the Hydration of 3-Alkynoates
ring-opened product C, which in turn would form intermediate
D by proto-deauration. Finally, isomerization of D produced
γ-keto ester 2. A competing side reaction, namely the elimina-
tion of R2OH from B, is also possible. This would account for
the trace amounts of cyclic byproduct obtained in some cases
(eq 1). Hydration of 2-alkynoate 4a by using the optimized
conditions described above furnished the ꢀ-keto ester 5a in high
yield (eq 2); this reaction is also highly regioselective. Its
selectivity may be the result of the strong electron withdrawing
effect of the conjugated ester; the ꢀ-carbon of 4a is more
electronically deficient, promoting an attack by water to this
position to give 5a.
products. With a propargyl ester this reaction yields ꢀ-keto esters
in high yield.
Experimental Section
Synthesis of 2a (General Procedure for Hydration of
Alkyne 1). NaAuCl4 ·2H2O (3 mg, 5% equiv) was added to a
stirring solution of alkyne 1a (71.4 mg, 0.3 mmol) in EtOH/H2O
(4:1, 1 mL). After stirring for 12-18 h at rt, the reaction mixture
was concentrated under reduced pressure and the crude product
was purified by flash silica gel chromatography (EtOAc/hexane 1:
20 to 1:4) to give the final product 2a as a colorless oil (60 mg,
78%). IR (neat) 2957, 2930, 2859, 1734, 1457, 1177, 1134 cm-1
;
1H NMR (500 MHz, CDCl3) δ 0.83-0.89 (m, 6H), 1.20 (s, 3H),
1.22-1.32 (m, 9H), 1.52-1.67 (m, 4H), 2.34-2.38 (m, 2H), 2.49
(d, J ) 17.5 Hz, 1H), 2.89 (d, J ) 17.5 Hz, 1H), 4.13 (q, J ) 7.0
Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 8.7, 14.2, 14.4, 21.3, 22.7,
24.0, 29.1, 31.8, 32.7, 43.6, 44.0, 50.8, 60.6, 176.8, 209.1; GC/MS
(EI) m/z 257, 211, 171, 143, 113, 85, 69, 42; HRMS (ESI) calcd
for (C15H28O3 + Na)+ 279.1936, found 279.1930.
In summary, we have developed an effective and straight-
forward hydration of 3-alkynoates in the presence of catalytic
amounts of Au(III) salt in aqueous ethanol at room temperature
to give γ-keto esters regioselectively and in high yields. This
mild and atom-economical method can be used effectively with
a wide range of substrates, yielding densely functionalized
Acknowledgment. We are grateful to the National Science
Foundation for financial support (CHE-0809683). The authors
also thank Dr. Leping Liu for supplying compounds 1h and 1i.
Supporting Information Available: Experimental proce-
dures and spectral data for 1, 2, and 5. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) Stephen, K. A.; Hashmi, L. S.; Choi, J.-H.; Frost, T. M. Angew. Chem.,
Int. Ed. 2000, 39, 2285–2288.
(20) Liu, Y.; Liu, M.; Guo, S.; Tu, H.; Zhou, Y.; Gao, H. Org. Lett. 2006,
8, 3445–3448.
JO802450N
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