Ruthenium(II)-Catalyzed Hydration of Terminal Alkynes in PEG-400

Article abstract of DOI:10.1055/s-0035-1561864

The ruthenium(II)-catalyzed hydration of terminal alkynes in PEG-400 to yield methyl ketones through Markovnikov addition of water across alkyne is reported.

Full text of DOI:10.1055/s-0035-1561864

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
P. S. Mainkar et al.
Letter
Synlett
Ruthenium(II)-Catalyzed Hydration of Terminal Alkynes in PEG-
400
Prathama S. Mainkar*a
Venkataraju Chippalaa,b
[(RuCl2{p-cymene})2]
O
Rambabu Chegondia
catalyst
recycled
over 5 runs
(5 mol%)
R
R
Srivari Chandrasekhar*a,b
PEG-400, H2O
r.t., 12–24 h
14 examples
50–92% yield
a Division of Natural Products Chemistry, CSIR –
Indian Institute of Chemical Technology,
Hyderabad, 500007, India
b Academy of Scientific and Innovative Research
(AcSIR), CSIR – Indian Institute of Chemical
Technology (CSIR-IICT), Hyderabad, 500007,
India
srivaric@iict.res.in
Received: 28.03.2016
Accepted after revision: 23.04.2016
Published online: 18.05.2016
metal
H2O
O
[Ru], ligand
CHO
R
DOI: 10.1055/s-0035-1561864; Art ID: st-2016-d0217-l
hydration via
Markonikov
addtion
hydration via
anti-Markonikov
addtion
R
Abstract The ruthenium(II)-catalyzed hydration of terminal alkynes in
PEG-400 to yield methyl ketones through Markovnikov addition of wa-
ter across alkyne is reported.
ref. 2–9
R
R
ref. 11
(or)
OAc
Key words PEG-400, ruthenium, methyl ketones, terminal alkynes
Synthesis of methyl ketones from terminal alkynes is a
well studied reaction.1 As summarized in Scheme 1, the ad-
dition of water to alkynes has been reported using metal
catalysts such as gold,2 silver,3 indium,4 platinum,5 rhodi-
um,6 cobalt,7 mercury,8 and iridium.9 Addition of ligands
such as porphyrins7 or trisubstituted phosphines9 to the
catalytic system helps to improve the yield of the methyl
ketone. The presence of a directing group such as a proxi-
mal hydroxyl or acetoxy substituent leads to conversion
into the ketone in higher yields.10 Addition of water in the
presence of alcohol as solvent helps in selective formation
of the ketone over aldehyde through the formation of a ke-
tal, in accordance with Markovnikov’s rule. Special cata-
lysts, such as Ru,11 have been developed for the formation of
aldehydes, which are the disfavored anti-Markovnikov
product. Ru(II) catalysts, in the presence of alcohols, have
been used to synthesize keto esters and this approach
avoids the additional step of ester formation.
These reports describe formation of carbonyl com-
pounds from terminal alkynes but, in many cases, require
strong acids as additives, which limits their application to a
wider variety of substrates. The cost of the metal catalysts
may also be a consideration. Other catalysts use ligands
such as triphenylphosphine, trialkoxy phosphite, porphyrin
or NHC. We wished to carry out the reaction in PEG-400,
which has the advantages that the reagent can be recycled,
OAc
tether-mediated
hydration
O
This work
R
R
[Au], H2O
[Ru], H2O
O
ref. 10
1. mild reaction conditions
2. functional group tolerance
3. catalyst recyclability
Scheme 1 Hydration of terminal alkynes
ligands are not required to carry out the reaction, and the
use of other solvents can be avoided.
We have used PEG extensively as an environmentally
benign solvent for reactions involving metal catalysts such
as Heck12 and Sharpless dihydroxylation reactions.13 The to-
tal synthesis of centrilobine14 has been achieved in PEG-
400 and methodologies have been developed for the syn-
thesis of pyrrole15 and 3-indole derivatives.16 In a continua-
tion of our work towards reactions in PEG-400, we decided
to explore the hydration of terminal alkynes using di-
chloro(p-cymene)ruthenium(II) dimer.
As a first step, to explore the reaction of terminal alkyne
with dichloro(p-cymene)ruthenium(II) dimer in PEG-400,
3-butynol benzyl ether (1a) was used as substrate (Scheme
2). The reaction led to the formation of 4-O-benzyl-2-buta-
none (2a) in 63% yield. Analytical data confirmed the for-
mation of 2a (Table 1).17 With this unusual result, given that
Ru (II) was expected to yield the aldehyde, we explored
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
P. S. Mainkar et al.
Letter
Synlett
more scaffolds to determine whether there would be con-
sistent ketone formation. Thus, diketone 1b, O-benzoyl-3-
butynol (1c), N-propynyl phthalimide (1d), aryl alcohol 1e,
and cyclohexanedione 1f were reacted using dichloro(p-cy-
mene)ruthenium(II) dimer in PEG-400 and the resulting
methyl ketones 2b–f were obtained in yields of 58 to 89%.
To expand the substrate scope, alkynoic acids 1g, 1h, and 1i
were reacted to isolate the keto acids 2g–i directly in 86–
92% yields, unlike previous reports where acids were con-
verted into esters. Substrates 1j, 1k, and 1l also gave the
corresponding methyl ketones 2j–l in good yields. Choles-
terol alkyne ester 1m was converted into 2m in 58% yield
and sugar ether 1n gave 2n in 50% yield. Thus, we have de-
veloped mild conditions for the synthesis of methyl ketones
for a variety of substrates without affecting other function-
alities present in the molecule, by using Ru(II) catalyst. The
only substrates that failed to generate the methyl ketones
were arylalkynes.
Table 1 Ru(II)-Catalyzed Hydration of Terminal Alkynesa,b
[(RuCl2{p-cymene})2]
O
(5 mol%)
R
R
PEG-400, H2O, r.t.
1
2
Entry
1
Alkyne
Time (h) Product
Yield (%)
63
O
1a
24
12
24
24
2a
2b
2c
2d
OBn
OBn
O
O
O
O
O
2
3
4
1b
1c
1d
78
58
88
O
OBz
OBz
O
O
N
N
O
O
O
OMe OH
O
OMe OH
5
6
1e
1f
24
12
2e
2f
73
89
OMe
O
OMe
O
O
O
O
O
OH
OH
OH
7
8
1g
1h
12
12
2g
2h
92
86
O
O
O
O
OH
2
2
O
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
P. S. Mainkar et al.
Letter
Synlett
Table 1 (continued)
Entry
Alkyne
Time (h) Product
Yield (%)
88
O
O
OH
O
OH
9
1i
12
2i
3
3
O
O
O
10
1j
12
2j
78
O
O
O
O
O
11
12
1k
1l
12
12
2k
2l
81
80
O
O
O
O
O
O
O
Me
Me
Me
Me
O
13
14
1m
1n
48
48
2m
2n
58
50
Me
H
Me
H
Me
Me
Me
Me
H
H
H
H
O
O
O
O
O
O
O
O
BnO
BnO
BnO
BnO
O
OBn
OBn
a Reactions were carried out with 1 (1 mmol) in 4:1 mixture of PEG 400/H2O (0.5 M).
b Isolated yield after column chromatography.
[(RuCl2{p-cymene})2]
O
Table 2 Recyclability of Ruthenium(II) Catalyst in PEG-400
(5 mol%)
BnO
BnO
PEG-400, H2O
r.t., 24 h, 63%
O
[(RuCl2{p-cymene})2]
O
2a
1a
Scheme 2 Initial attempts
(5 mol%)
HO
HO
PEG-400, H2O
r.t., 12 h
O
2g
1g
After studying various scaffolds for substrate specificity,
we investigated the activity of the catalyst for recyclability
(Table 2). Thus, 4-pentynoic acid was used as a substrate
and the catalyst was recycled, the second run gave good
yield (83%) and the third gave a reasonable yield (70%);
however, the yields continued to drop subsequently, possi-
bly due to loss of the catalyst during workup. The product
obtained in the repeated runs was identical in all respects
with the first run product. Thus, modification of the Ru cat-
alyst to make it less soluble in organic solvents, so that re-
cyclability is efficient, is of possible interest.
Run
Yield (%)a
1st
92
2nd
83
3rd
70
4th
65
5th
52
aIsolated yield after column chromatography.
In conclusion, a novel, mild and high yielding methodol-
ogy for conversion of alkyne acids into keto acids has been
developed. The methodology can be extended to ethers, es-
ters, and carbonyl containing compounds and to scaffolds
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
P. S. Mainkar et al.
Letter
Synlett
such as steroidal and carbohydrate derivatives. This meth-
odology avoids the use of strong acids or ligands.
Chem. Int. Ed. 2001, 40, 3884. (d) Halpern, J.; James, B. R.; Kemp,
L. W. J. Am. Chem. Soc. 1966, 88, 5142. (e) Halpern, J.; James, B.
R.; Kemp, A. L. W. J. Am. Chem. Soc. 1961, 83, 4097.
(12) Chandrasekhar, S.; Narsihmulu, Ch.; Sultana, S. S.; Reddy, N. R.
Org. Lett. 2002, 4, 4399.
(13) Chandrasekhar, S.; Kiranmai, N. Tetrahedron Lett. 2010, 51,
4058.
(14) Reddy, A. S.; Chegondi, R.; Chandrasekhar, S. Proc. Indian Natl.
Sci. Acad. 2015, 81, 1171.
(15) Chandrasekhar, S.; Patro, V.; Chavan, L. N.; Chegondi, R.; Gree, R.
Tetrahedron Lett. 2014, 55, 5932.
Acknowledgment
V.R.C. thanks the Council of Scientific and Industrial Research (CSIR),
New Delhi, for a Research Fellowship and R.C. thanks CSIR-Senior Re-
search Associateship (Scientists’ Pool Scheme) for financial assistance.
S.C. and P.S.M. thank CSIR, New Delhi for financial support as part of a
five-year program project under ORIGIN (CSC-108).
(16) Chandrasekhar, S.; Patro, V.; Reddy, G. P. K.; Gree, R. Tetrahedron
Lett. 2012, 53, 6223.
Supporting Information
(17) General Procedure for Hydration of Terminal Alkynes in
PEG-400: To a solution of alkyne (1.0 mmol) in PEG-400/H2O
(4:1) was added [Ru(p-cymene)Cl2]2 (0.01 mmol), and the
mixture stirred at room temperature. Upon completion of the
reaction (monitoring by TLC), the reaction mixture was diluted
with Et2O (10 mL), stirred for 10 min, and allowed to stand in an
ice-salt bath to solidify the PEG-400. The organic layer was
decanted, dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The residue obtained was puri-
fied by silica gel flash column chromatography (ethyl acetate–
petroleum ether) to give the pure product.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561864.
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References and Notes
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4-(Benzyloxy)butan-2-one (2a): Prepared according to the
general procedure and purified by flash chromatography
(EtOAc–hexanes, 10%). Yield: 63%; green liquid. 1H NMR (400
MHz, CDCl3): δ = 7.56–7.02 (m, 5 H), 4.51 (s, 2 H), 3.73 (t, J = 6.3
Hz, 2 H), 2.71 (t, J = 6.3 Hz, 2 H), 2.17 (s, 3 H). 13C NMR (126
MHz, CDCl3): δ = 207.2, 138.1, 128.4, 127.7, 73.3, 65.3, 43.8,
30.5. IR (neat): 2925, 2855, 1721, 1458, 1275, 1110, 707 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C11H15O2: 179.1066; found:
179.1065.
4-Oxopentanoic Acid (2g): Prepared according to the general
procedure and purified by flash chromatography (EtOAc–hex-
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δ = 9.25 (s, 1 H), 2.75 (t, J = 6.4 Hz, 2 H), 2.61 (t, J = 6.4 Hz, 2 H),
2.19 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 207.1, 178.5, 37.7,
29.8, 27.8. IR (neat): 2923, 2854, 1708, 1404, 1367, 1165,
555 cm–1. HRMS (ESI): m/z [M + H]+ calcd for C5H9O3: 117.0546;
found: 117.0557.
4-Methyl-4-(3-oxobutoxy)cyclohexa-2,5-dienone (2j): Pre-
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oil. 1H NMR (300 MHz, CDCl3): δ = 6.72 (d, J = 10.2 Hz, 2 H), 6.23
(d, J = 10.2 Hz, 2 H), 3.50 (t, J = 6.0 Hz, 2 H), 2.57 (t, J = 6.0 Hz,
2 H), 2.11 (s, 3 H), 1.33 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ =
205.4, 184.1, 150.8, 129.2, 71.5, 59.5, 42.8, 29.6, 25.4. IR (neat):
2927, 1712, 1669, 1389, 1176, 1087, 863, 701 cm–1. HRMS (ESI):
m/z [M + H]+ calcd for C11H15O3: 195.1015; found: 195.1019.
2-Methyl-2-(2-oxopropyl)cyclopentane-1,3-dione (2k): Pre-
pared according to the general procedure and purified by flash
chromatography (EtOAc–hexanes, 50%). Yield: 81%; colorless
oil. 1H NMR (400 MHz, CDCl3): δ = 3.10 (s, 2 H), 2.92–2.71 (m,
4 H), 2.00 (s, 3 H), 0.98 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ =
216.4, 206.3, 52.4, 51.7, 34.7, 28.2, 19.3. IR (neat): 2926, 2856,
1718, 1455, 1390, 1183, 1074, 802, 548 cm–1. HRMS (ESI): m/z
[M + H]+ calcd for C9H13O3: 169.0859; found: 169.0855.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D