Isomerization reactions of allylic alcohols into ketones with the Grubbs reagent

Article abstract of DOI:10.3390/90700541

Allylic alcohols were isomerized into ketones by the action of the Grubbs reagent. Some model alcohols were prepared and tested under similar conditions to reveal that less substituted alkenes rearrange more easily. More hindered alcohols are stable under

Full text of DOI:10.3390/90700541

Molecules 2004, 9, 541-549
molecules
ISSN 1420-3049
http://www.mdpi.org
Isomerization Reactions of Allylic Alcohols into Ketones with
the Grubbs Reagent
Katsuyuki Nakashima, Sanae Okamoto, Masakazu Sono and Motoo Tori*
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima,
770-8514, Japan. Tel. (+81) 88-622-9611, Fax (+81) 88-655-3051.
* Author to whom correspondence should be addressed; e-mail: tori@ph.bunri-u.ac.jp; homepage:
http://p.bunri-u.ac.jp/~tori/english/e-tori.html
Received: 26 December 2003; in revised form: 24 March 2004 / Accepted: 3 April 2004 / Published:
30 June 2004
Abstract: Allylic alcohols were isomerized into ketones by the action of the Grubbs
reagent. Some model alcohols were prepared and tested under similar conditions to
reveal that less substituted alkenes rearrange more easily. More hindered alcohols are
stable under these conditions, however, the simple allylic alcohols tend to isomerize
producing ethyl ketone and the corresponding degraded methyl ketone.
Keywords: Grubbs reagent, allylic alcohol, isomerization, ketone.
Introduction
We have previously found and reported that the allylic alcohol 1 rearranged into the ketones 2 and
3 under ring closing olefin metathesis reaction (RCM) conditions using the Grubbs reagent [Ru]
(Scheme 1) [1]. The expected 10-membered carbocycle was not formed, but rather the allylic alcohol 1
isomerized to give ketone 2 as well as the one-carbon degraded ketone 3 in a ratio of 2:1 in 68% yield.
The formation of the one-carbon degraded methyl ketone had been recorded by Hoye and Zhau in
1999 [2] and the mechanism shown to be as depicted in Scheme 2. The Grubbs reagent attacks
compound A to produce another carbene complex B, which rearranges into enol C. Then,

Molecules 2004, 9
542
tautomerization to D and reductive elimination affords the degraded ketone E. However, our
observation of the formation of the isomerized ketone 2 was the first example, although some
isomerization reactions using Ru complexes had been reported [3-5]. We became interested in the
scope of these reactions and herein we report the results of the reaction of some different allylic
alcohols with the Grubbs reagent.
Scheme 1
O
2
OMOM
[Ru]
OH
+
(20 mol%)
CH2Cl2 ( 0.05 M )
rt , 1 day
O
1
OMOM
68 %
3
OMOM
2 : 3 = 2 : 1 ( GC-MS )
Scheme 2
OH
OH
O
OH
[Ru]
OPMB
Me
OPMB
Me
Me
Me
Me
E
A
OH
O
OH
LnRu
LnHRu
LnHRu
Me
Me
D
Me
B
C
Results and Discussion
Mono-protected butanediol 4 [6] was oxidized into aldehyde 5 [6], which was alkylated as shown
in Scheme 3 to afford three kinds of alcohols 6, 7 and 8. Compound 6 was treated with the Grubbs
reagent in dichloromethane (Scheme 4). As seen in entry 1, most of the starting material remained
unchanged, but a small amount of ketone 10 [7] was formed. However, when 10 mol % of the catalyst
was used (entry 2), the starting material was consumed completely and ketones 9 and 10 [7] were

Molecules 2004, 9
543
formed in a ratio of 3:1. Use of more of the catalyst (20 mol %, entry 3) resulted in a slight change in
the ratio of 9 and 10 [7]. Raising the temperature did not affect the reaction favourably, and instead the
starting material remained unchanged (entries 4 and 5). Structures 9 and 10 [7] were easily determined
from the spectroscopic data (See Experimental).
Scheme 3
MgBr
TBDMSO
OH
THF
6
( 2 steps )
(COCl)2
DMSO
70 %
OH
MgBr
TBDMSO
CHO
TBDMSO
Et3N
CH2Cl2
TBDMSO
THF
5
OH
OH
4
7
( 2 steps )
35 %
MgBr
TBDMSO
THF
38 %
8
( 2 steps )
Scheme 4
[ Ru ]
TBDMSO
TBDMSO
TBDMSO
+
O
O
OH
10
9
6
48 %
18 %
results
6 : 9 : 10
entry
conc. (mM) temp. (°C) time (days)
mol % solvent
1
2
3
4
5
10
20
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10
10
10
10
rt
rt
1
1
1
1
26 : 0 : 1
0 : 3 : 1
0 : 2 : 1
30 : 0 : 1
rt
40
5
10
CH2Cl2
10
40
1
9 : 0 : 1

Molecules 2004, 9
544
Next, compound 7 was treated with the Grubbs reagent (initially 20 mol %) in dichloromethane at
room temperature (rt) overnight (Scheme 5). Then, 10 mol % of the catalyst was added and the mixture
stirred overnight. The starting material was recovered after 2 days (entry 1). If the concentration of the
reaction mixture was raised to 0.1 M (20 mol % of the catalyst), less than 10 % of the isomerized
ketone 9 was produced (entry 2). In the case of alcohol 8 (Scheme 6), the positional isomer of 7 with
regards to the methyl group, ketones 10 and 11 were formed in a ratio of 1:1 after 4 days but only in
minute amounts. These results indicate that the substituents on the double bond affect the ease of the
isomerization reaction. Thus, the methyl group substituted at the α-position of the hydroxyl group, as
in compound 7, interferes with the isomerization reaction, compared to the case of compound 6. On the
other hand, compound 8 seems more reactive under the conditions used in this study.
Scheme 5
[ Ru ]
TBDMSO
TBDMSO
7
+
O
OH
9
7
entry
mol %
20 + 10
20
solvent conc. (mM) temp. (°C) time (days) results
CH2Cl2
CH2Cl2
1
2
10
rt
rt
1 + 1
1
No Reaction
7 : 9 = 28 : 3
100
Scheme 6
[Ru]
(20 mol%)
8
TBDMSO
+
+
TBDMSO
TBDMSO
(0.01 M)
CH2Cl2
rt , 4 days
O
O
OH
11
= 1 : 1 (GC-MS)
10
8
10 : 11
Finally we have prepared compound 15, with two methyl groups on the double bond in the
β-position with regards to the hydroxyl group (Scheme 7). In this case the starting material was
recovered after 4 days of reaction with the Grubbs reagent (20 or 30 mol %) (entries 1-3). After three
weeks, oxidation product 16 and dehydration product 17 were produced, in yields of 1 and 47 %,
respectively. From the above results, this is reasonable, because compound 15 is much more sterically
hindered than compounds 7 and 8.

Molecules 2004, 9
545
Scheme 7
MsCl , Et3N
CH2Cl2
OMs
LiBr
THF
66 %
OH
Br
TBDMSO
TBDMSO
TBDMSO
12
13
4
( 2 steps )
O
TBDMSO
TBDMSO
16
OH
Mg / THF
[ Ru ]
+
TBDMSO
CH2Cl2
CHO
15
62 %
14
17
entry
mo l%
conc. (mM)
temp. (°C) time (days)
recovery (%)
yield ( % )
-
-
-
1
2
3
4
20
20
10
100
10
rt
40
40
rt
4
2
59
100
78
8
20 + 10
2 + 2
21
5 + 5 + 5 + 5
10
16 ( 1 ) 17 ( 47 )
Conclusions
The Grubbs catalyst attacks the terminal alkenes as shown in Scheme 2 to form a carbene complex.
Then, rearrangement and reductive elimination produce the degraded ketone. Simple isomerization
may occur by coordination of the alkene to the ruthenium complex formed in situ and results in
isomerization, although the details are not clear at this stage. The ethyl ketone 9 appears after the
methyl ketone 10 is formed. Therefore, it is reasonable to conclude that some ruthenium species
formed in the reaction may be responsible for the formation of the ethyl ketone. Consequently, when
planning a RCM reaction, it would appear that the allylic alcohol is not a promising substrate, but
rather the use of TES- or TMS-protected compounds is strongly recommended, because some of the
side reactions described here may cause problems.
Acknowledgements
We thank Ms. Yasuko Okamoto (our university) for measurement of the MS spectra.

Molecules 2004, 9
Experimental
General
546
The IR spectra were measured with a JASCO FT/IR-500 spectrophotometer. The 1H- and 13C-NMR
spectra were recorded on a Varian Unity 200 or a Varian Mercury 300 spectrometer.
Deuteriochloroform was used for NMR and chemical shifts are expressed in ppm and the coupling
constants in Hz. The mass spectra including high-resolution mass spectra were taken with a JEOL
AX-500 spectrometer. GC-MS was carried out on a HP MS-5973 with GC HP-6890 system. Silica gel
BW-300 (200-400 mesh, Fuji silycia) was used for column chromatography, and silica gel 60F254 plate
(0.25 mm, Merck) were used for TLC. All reactions were carried out under an argon atmosphere. THF
was distilled from LiAlH4 and then from Na-benzophenone prior to use. The Grubbs reagent was
purchased from Strem and used as received. The reagent was weighed in the dry box and was used
without purification. Anhydrous dichloromethane and benzene used for the reaction were purchased
from Kanto Chemical, Japan and were used without further purification.
General procedures for reactions using the Grubbs reagent.
The Grubbs reagent (20 mol%) was weighed in the dry box under an Ar atmosphere and the rubber
septum was equipped with or without a reflux condenser. A solution of substrate in CH2Cl2 was
introduced into a flask of the Grubbs reagent in one portion. The mixture was kept at the temperature
indicated in the table or text for the time indicated. When the reaction was complete, the rubber septum
was taken off to expose the reactions mixtures to air under stirring for one hour. The mixture was then
directly subjected to column chromatography eluting with an adequate solvent system to afford a crude
product. Further purification using column chromatography was carried out to give each pure
compound. GC-MS analysis was performed to determine the ratio of the products in each case.
Preparation of 6-t-butyldimethylsilyloxy-1-hexen-3-ol (6).
To a stirred solution of aldehyde 5 (306 mg, 1.5 mmol) in dry THF (15 mL), vinylmagnesium
bromide (0.95M, 3.2 mL, 3.0 mmol) was added at –78˚C and the mixture was kept at the same
temperature for 1.5 h. Water and sat. ammonium chloride soln. were added and the mixture was
extracted with ether. The organic layer was washed with brine, dried (Na2SO4), and was evaporated to
afford a residue, which was purified by silica gel column chromatography (5% hexane-EtOAc) to give
alcohol 6 (245.5 mg, 70%); FTIR: 3350, 840, 780 cm-1; 1H-NMR (300 MHz) δ 0.05 (6H, s), 0.88 (9H,
s), 1.61 (4H, m), 3.64 (2H, t, J=5.7 Hz), 4.11 (2H, m), 5.07 (1H, dt, J =10.5, 1.8 Hz), 5.22 (1H, dt, J
13
=16.2, 1.5 Hz), 5.85 (1H, ddd, J =16.2, 10.5, 5.7 Hz); C NMR (75 MHz, CDCl3) δ –5.4 (CH3×2),
18.3 (C), 25.9 (CH3×3), 28.7 (CH2), 34.4 (CH2), 63.4 (CH2), 72.6 (CH), 114.3 (CH2), 141.1 (CH); MS

Molecules 2004, 9
547
(CI) m/z 231 [M+H]+, 219, 201, 161, 127, 105, 81 (base), 75; HRMS (CI) Found m/z 231.1777
[M+H]+ C12H27O2Si requires 231.1780.
Preparation of 6-t-butyldimethylsilyloxy-2-methyl-1-hexen-3-ol (7).
The corresponding Grignard reagent was prepared from 2-bromopropene (1.1 mL, 12.4 mmol) and
Mg (0.3 g, 12.4 mmol) in dry THF (10 mL) and then a solution of aldehyde 5 (500 mg, 2.5 mmol) in
dry THF (10 mL) was added slowly. The mixture was stirred overnight, and then water and sat.
ammonium chloride soln. were added. The mixture was extracted with ether and the organic layer was
washed with brine, dried (Na2SO4), and was evaporated to afford a residue. The residue was purified
by silica gel column chromatography (10% hexane-EtOAc) to give alcohol 7 (210.8 mg, 35%); FTIR:
1
3400, 830, 780 cm-1; H-NMR (300 MHz) δ 0.04 (6H, s), 0.88 (9H, s), 1.60 (4H, m), 1.58 (3H, br s),
2.71 (1H, br s, OH), 3.64 (2H, t, J=6.0 Hz), 4.04 (1H, t, J=5.4 Hz), 4.81 (1H, br s), 4.94 (1H, br s);
13C-NMR (75 MHz) δ –5.0 (CH3×2), 18.2 (CH3), 18.7 (C), 26.3 (CH3×3), 29.2 (CH2), 32.6 (CH2), 63.7
(CH2), 75.7 (CH), 111.1 (CH2), 147.9 (C); MS (CI) m/z 245 [M+H]+, 227, 202, 187, 155, 145, 95
(base), 75, 67; HRMS (CI) Found m/z 245.1960 [M+H]+ C13H29O2Si requires 245.1937.
Preparation of (E)-7-t-butyldimethylsilyloxy-2-hepten-4-ol (8).
The Grignard reagent was prepared from trans-1-bromopropene (0.13 mL, 1.49 mmol) and Mg
(36.1 mg, 1.5 mmol) in dry THF (10 mL) and a solution of aldehyde 5 (100 mg, 0.5 mmol) in dry THF
(5 mL) was added slowly. The mixture was stirred at room temperature for 30 min. Water and sat.
ammonium chloride soln. were added and the mixture was extracted with ether. The organic layer was
washed with brine, dried (Na2SO4), and was evaporated to afford a residue, which was purified by
silica gel column chromatography (2-100 % hexane-EtOAc) to give alcohol 8 (46.2 mg, 38%); FTIR:
1
3380 cm-1; H-NMR (200 MHz) δ 0.06 (6H, s), 0.89 (9H, s), 1.59-1.83 (8H, m), 3.61-3.67 (3H, m),
13
5.36-5.74 (2H, m); C-NMR (50MHz) δ –5.5 (CH3×2), 17.6 (CH3), 18.3 (C), 25.9 (CH3×3), 28.9
(CH2), 34.5 (CH2), 63.4 (CH2), 72.7 (CH), 126.4 (CH), 134.3 (CH); MS (CI) m/z 245 [M+H]+, 243,
227, 211, 187, 169, 145, 111, 95 (base), 75, 67, 57, 41; HRMS (CI) Found m/z 245.1926 [M+H]+
C13H29O2Si requires 245.1937.
1
6-t-butyldimethylsilyloxy-3-hexanone (9); FTIR 1720 cm-1; H-NMR (300 MHz) δ 0.01 (6H, s), 0.86
(9H, s), 1.03 (3H, t, J=7.4 Hz), 1.76 (2H, quint, J =6.0 Hz), 2.41 (2H, q, J =6.0 Hz), 2.46 (2H, t, J =7.4
Hz), 3.59 (2H, t, J =6.0 Hz); 13C- NMR (75 MHz) δ –5.4 (CH3×2), 7.8 (CH3), 18.3 (C), 25.9 (CH3×3),
26.9 (CH2), 35.9 (CH2), 38.6 (CH2), 62.2 (CH2), 211.5 (C); MS (CI) m/z 231 [M+H]+, 215, 173, 139,
99 (base), 75; HRMS (CI) Found m/z 231.1791 [M+H] + C12H27O2Si requires 231.1790.
1
5-t-butyldimethylsilyloxy-2-pentanone (10); FTIR 1720 cm-1; H-NMR (300 MHz) δ -0.02 (6H, s),
0.83 (9H, s), 1.73 (2H, quint, J =6.0 Hz), 2.09 (3H, s), 2.45 (2H, t, J =6.0 Hz), 3.56 (2H, t, J =6.0 Hz);

Molecules 2004, 9
548
13C-NMR (75 MHz) δ –5.4 (CH3×2), 18.2 (C), 25.9 (CH3×3), 26.8 (CH2), 29.9 (CH2), 40.0 (CH3), 62.0
(CH2), 208.8 (C); MS (CI) m/z 217 [M+H]+, 201, 159, 125, 85 (base); HRMS (CI) Found m/z 217.1625
[M+H] + C11H25O2Si requires 217.1624.
7-t-butyldimethylsilyloxy-2-hepten-4-one (11); FTIR 1680, 1640 cm-1; 1H-NMR (300 MHz) δ 0.03 (6H,
s), 0.88 (9H, s), 1.81 (2H, quint, J =6.0 Hz), 1.89 (3H, dd, J =6.9, 1.7 Hz), 2.61 (2H, t, J =6.0 Hz), 3.62
(2H, t, J=6.0 Hz）, 6.12 (1H, dq, J=15.9, 1.7 Hz), 6.85 (1H, dq, J=15.9, 6.9 Hz); 13C-NMR (75 MHz) δ
–5.3 (CH3×2), 18.2 (CH3), 18.3 (C), 25.9 (CH3×3), 27.3 (CH2), 36.2 (CH2), 62.2 (CH2), 132.0 (CH),
142.4 (CH), 200.4 (C); MS (CI) m/z 243 [M+H]+, 228, 201, 185, 151, 111 (base), 89, 75; HRMS (CI)
Found m/z 243.1782 [M+H] + C13H27O2Si requires 243.1780.
Preparation of 4-bromo-1-t-butyldimethylsilyloxybutane (13)[8].
To a stirred solution of alcohol 4 (2.0 g, 9.8 mmol) in dichloromethane (40 mL) was added
triethylamine (1.5 mL, 10.8 mmol) and methanesulfonyl chloride (0.83 mL, 10.7 mmol) at 0˚C. The
mixture was stirred for 1 h and sat. NaHSO4 soln. was added. The mixture was extracted with ether.
The organic layer was washed with brine, dried (Na2SO4), and was evaporated to afford mesylate 12
(2.4 g, 88%). To a stirred solution of mesylate 12 (2.4 g, 8.6 mmol) in dry THF (60 mL) was added
lithium bromide (1.13 g, 13.0 mmol) and the mixture was refluxed overnight. Sat. NaHSO4 was added
and the mixture was extracted with pentane. The organic layer was washed with brine, dried (Na2SO4),
and was evaporated to afford a residue, which was purified by silica gel column chromatography
1
(5-100 % hexane-EtOAc) to give bromide 13 (1.7 g, 66%); H-NMR (300 MHz) δ 0.04 (6H, s), 0.89
(9H, s), 1.65 (2H, quint, J=6.3 Hz), 1.94 (2H, quint, J=6.6 Hz), 3.44 (2H, t, J=6.6 Hz), 3.64 (2H, t,
J=6.3 Hz); 13C-NMR (75 MHz) δ –5.3 (CH3×2), 18.3 (C), 26.0 (CH3×3), 29.5 (CH2), 31.3 (CH2), 34.0
(CH2), 62.2 (CH2); MS (CI) m/z 267 [M+H]+, 209, 187 (base), 169, 135, 89; HRMS (CI) Found m/z
267.0792 [M+H]+ C10H24OBrSi requires 267.0780.
Preparation of 8-t-butyldimethylsilyloxy-2-methyl-2-octen-4-ol (15).
A solution of aldehyde 14 (200 mg, 2.38 mmol) in dry THF (5 mL) was added slowly to the
Grignard reagent prepared from 13 (1.27 g, 4.76 mmol) and Mg (120 mg, 4.76 mmol) in dry THF (5
mL). The mixture was stirred overnight at room temperature. Water and sat. ammonium chloride soln.
were added and the mixture was extracted with ether. The organic layer was washed with brine, dried
(Na2SO4), and was evaporated to afford a residue, which was purified by silica gel column
chromatography (5-100 % hexane-EtOAc) to give alcohol 15 (399 mg, 62%); FTIR: 3350, 840, 780
cm-1; 1H-NMR (300 MHz) δ 0.02 (6H, s), 0.86 (9H, s), 1.40 (6H, m), 1.65 (3H, d, J=1.5 Hz), 1.69 (3H,
d, J=1.2 Hz), 3.58 (2H, t, J=6.6 Hz), 4.31 (1H, dt, J=8.7, 6.6 Hz), ), 5.12 (1H, br d, J=8.7 Hz);
13C-NMR (75 MHz) δ –5.3 (CH3×2), 18.2 (CH3), 18.3 (C), 21.7 (CH2), 25.8 (CH3), 25.9 (CH3×3), 32.7
(CH2), 37.4 (CH2), 63.1 (CH2), 68.6 (CH), 128.2 (CH), 134.8 (C); MS (CI) m/z 272 [M-H+H]+, 255,

Molecules 2004, 9
549
215, 197, 139, 123 (base), 85, 81; HRMS (CI) Found m/z 272.2167 [M-H+H]+ C15H32O2Si requires
272.2172.
1
8-t-butyldimethylsilyloxy-2-methyl-2-octen-4-ol (16); FTIR: 1690 cm-1; H-NMR (200 MHz) δ 0.04
(6H, s), 0.89 (9H, s), 1.57 (5H, s), 1.70 (2H, dd, J=6.4, 1.2 Hz), 1.88 (2H, d, J=1.2 Hz), 2.14 (2H, d,
J=1.2 Hz), 2.42 (1H, t, J=6.8 Hz), 3.61 (2H, t, J=6.4 Hz), 6.07 (1H, t, J=1.4 Hz); 13C-NMR (50MHz) δ
–5.3 (CH3×2), 10.0, 18.4 (C), 20.7, 26.0 (CH3×3), 27.6, 32.4, 44.0, 63.0, 123.8; MS (CI) m/z 271
[M+H]+, 255, 239, 213, 197, 171, 155, 139 (base), 123, 101, 95, 83, 75, 67, 59, 41; HRMS (CI) Found
m/z 271.2105 [M+H]+ C15H31O2Si requires 271.2093.
1
8-t-butyldimethylsilyloxy-2-methyl-1,3-octadiene (17); H-NMR (200 MHz) δ 0.05 (6H, s), 0.90 (9H,
s), 1.14-1.83 (9H, m), 2.13 (2H, q, J=6.8 Hz), 4.86 (2H, s), 5.58-5.72 (1H, m), 6.14 (1H, d, J=15.6
Hz); 13C-NMR (50 MHz) δ –5.3 (CH3×2), 18.4 (C), 18.7 (CH2), 21.7 (CH3), 25.6 (CH2), 26.0 (CH3×
3), 32.4 (CH2), 63.1 (CH2), 114.2 (CH2), 130.8 (CH), 133.0 (CH), 142.2 (C); MS (CI) m/z 255 [M+H]+,
239, 211, 197, 155, 139, 123(base), 95, 83, 75, 67, 41; HRMS (CI) Found m/z 255.2136 [M+H]+
C15H31OSi requires 255.2144.
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Sample availability: Samples are not available.
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