Ruthenium-catalyzed self-coupling of primary and secondary alcohols with the liberation of dihydrogen

Article abstract of DOI:10.1021/jo4008699

The dehydrogenative self-condensation of primary and secondary alcohols has been studied in the presence of RuCl₂(IiPr)(p-cymene). The conversion of primary alcohols into esters has been further optimized by using magnesium nitride as an additive, which allows the reaction to take place at a temperature and catalyst loading lower than those described previously. Secondary alcohols were dimerized into racemic ketones by a dehydrogenative Guerbet reaction with potassium hydroxide as the additive. The transformation gave good yields of the ketone dimers with a range of alkan-2-ols, whereas more substituted secondary alcohols were unreactive. The reaction proceeds by dehydrogenation to the ketone, followed by an aldol reaction and hydrogenation of the resulting enone.

Full text of DOI:10.1021/jo4008699

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Article
Ruthenium-Catalyzed Self-Coupling of Primary and
Secondary Alcohols with the Liberation of Dihydrogen
Ilya S. Makarov, and Robert Madsen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4008699 • Publication Date (Web): 03 Jun 2013
Downloaded from http://pubs.acs.org on June 4, 2013
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Ruthenium-Catalyzed Self-Coupling of Primary and Secondary Alcohols
with the Liberation of Dihydrogen
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Ilya S. Makarov and Robert Madsen*
Department of Chemistry, Technical University of Denmark, DKꢀ2800 Lyngby, Denmark
Eꢀmail: rm@kemi.dtu.dk
_____________________________________________________________________________
Abstract
The dehydrogenative selfꢀcondensation of primary and secondary alcohols has been studied in
the presence of [RuCl2(IiPr)(pꢀcymene)]. The conversion of primary alcohols into esters has
been further optimized by using magnesium nitride as an additive which allowed the reaction to
take place at a lower temperature and catalyst loading than described previously. Secondary
alcohols were dimerized into racemic ketones by a dehydrogenative Guerbet reaction with
potassium hydroxide as the additive. The transformation gave good yields of the ketone dimers
with a range of alkanꢀ2ꢀols while more substituted secondary alcohols were unreactive. The
reaction proceeds by dehydrogenation to the ketone followed by an aldol reaction and
hydrogenation of the resulting enone.
_________________________________________________________________________________________________________________
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INTRODUCTION
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The metalꢀcatalyzed dehydrogenative coupling of alcohols with carbon and heteroatom
nucleophiles has received significant attention during the past decade.1ꢀ3 The reaction proceeds
by oxidation of the alcohol to the carbonyl compound followed by attack of the nucleophile to
afford products such as amines, ketones, esters and amides. The most attractive protocol is to
perform the transformation in the absence of hydrogen acceptors since only molecular hydrogen
and/or water is then formed as the byproduct(s).
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The selfꢀcoupling of an alcohol or the crossꢀcoupling of two different alcohols constitutes a
key transformation in this category to afford higher alcohols, ketones and esters.1ꢀ3 In fact, the
homodimerization of primary and secondary alcohols, the soꢀcalled Guerbet reaction, has been
known for more than a century.4 This transformation results in βꢀalkylated dimer alcohols where
the new CꢀC bond is generated by an aldol condensation and a molecule of water is released.5 In
the original procedure the reaction was promoted by the corresponding sodium alkoxide at
temperatures exceeding 200 °C4 during which reversible hydrogen transfer occurs to form the
carbonyl compounds.6 More recently, late transition metal complexes based on iridium and
rhodium have been shown to catalyze the Guerbet reaction at temperatures ranging from 120 to
140 °C.7ꢀ9 The reaction has been extended to the selective βꢀalkylation of secondary alcohols
with primary alcohols which has been achieved with metal catalysts based on iridium,10ꢀ13
ruthenium,13ꢀ18 palladium,19 copper20,21 and iron.22 The crossꢀcoupling is performed in the
presence of a base at temperatures between 80 and 135 °C and often produces the corresponding
ketone as a minor byproduct.10ꢀ21 The ketone can also be obtained as the major product from the
βꢀalkylation if the reaction is carried out with the heterogeneous catalysts AuꢀPd/HT,23
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Ag/Al2O324 or Pd/C25 although only 1ꢀphenylethanol and analogs have been employed as the
secondary alcohol in these cases. Besides CꢀC bond formation the coupling of primary alcohols
can also lead to esters as shown with several ruthenium,26ꢀ31 iridium32 and osmium33,34 catalysts
in the absence of hydrogen scavengers.
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Figure 1. Structure of ruthenium NHC complex 1.
We have recently exploited the ruthenium Nꢀheterocyclic carbene complex 1 (Figure 1) as a
catalyst for dehydrogenative couplings with primary alcohols. In the presence of an amine and
KOtBu the coupling affords the amide35,36 while in the absence of a base the corresponding
imine is formed.37 For the amidation the mechanism has been thoroughly investigated by a
combination of experimental and theoretical methods.38 If another nucleophile is not present
primary alcohols will undergo homodimerization into esters and molecular hydrogen upon
treatment with complex 1 (2.5 mol%), PCy3 (4.5 mol%) and KOH (10 mol%).39 Under these
conditions, pentanꢀ1ꢀol was fully converted into pentyl pentanoate upon reflux in mesitylene at
163 °C for 18 h.39 However, for benzylic alcohols the esterification was accompanied by
significant decarbonylation of the intermediate aldehyde which is presumably caused by the high
reaction temperature. Therefore, we decided to reinvestigate the ester formation with complex 1
in an attempt to achieve the reaction at a lower temperature. During these studies we discovered
a new dehydrogenative selfꢀcoupling of secondary alcohols which proceeds by alkylation in the
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βꢀposition and dehydrogenation to the ketone. Herein, we report the conditions for the improved
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ester synthesis from primary alcohols and the new synthesis of ketones from secondary alcohols.
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RESULTS AND DISCUSSION
The studies began with the same catalytic system that was used in our mechanistic
investigation of the rutheniumꢀcatalyzed amidation, i.e. complex 1 (5 mol%), PCy3•HBF4 (5
mol%) and KOtBu (15 mol%) in refluxing toluene.38 The HBF4 salt of PCy3 was selected since
PCy3 is easily oxidized by air and in our experience commercial samples of PCy3 contain
various amounts of impurities that are difficult to remove. Since a base is already required in the
esterification it will also serve the purpose of deprotonating PCy3•HBF4.40
Our earlier studies had shown that PCy3 and KOtBu only gave a moderate yield of the ester39
and this was confirmed with the PCy3•HBF4 salt (Table 1, entry 1). The previous optimization
had only focused on various hydroxide and carbonate bases giving rise to KOH as the optimum
choice.39 However, in the development of the amidation reaction we investigated several
ammonia equivalents in an attempt to prepare primary amides.35 Surprisingly, exclusive ester
formation was observed with Mg3N241 as the ammonia source (entry 2). This result prompted us
to investigate the significance of Mg3N2 in closer detail since the esterification is now achieved
in toluene in good yield and at a lower temperature of 110 °C. The phosphine and the base were
still important components since very low conversion was observed in the absence of PCy3 and
with a lower amount of KOtBu (entries 3 – 4). Changing the phosphine to PPh3 or dppe also
gave lower conversion (entries 5 – 6) which indicates that PCy3 is still the optimum phosphine.
At this moment, it was decided to change the alcohol to pentanꢀ1ꢀol to achieve a better
comparison with the earlier results.39 To establish the optimum amount of Mg3N2 the catalyst
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loading was lowered to 1.25% and the reaction stopped already after 2 h. This showed that the
highest rate was observed with 16.7% of Mg3N2 (entries 7 – 11). This is an interesting number
since 1 equiv. of Mg3N2 can theoretically react as a base with 6 equiv. of the alcohol. To
determine whether other properties are important, Mg3N2 was replaced with similar additives
(entries 12 – 18). No ester was formed with MgBr2 and only a low yield was observed with the
weaker bases MgO and Cs2CO3 (entries 12 – 14). On the contrary, high yields were achieved
with the stronger bases Ca3N2, Li3N and K3PO4 (entries 15 – 17) and it appears that the most
important property of the additive is basicity. The amount of complex 1 could be lowered to
0.5% at the expense of a longer reaction time and a slightly lower yield (entries 18 – 20). Thus,
the conversion of pentanꢀ1ꢀol into pentyl pentanoate has now been achieved at a lower
temperature and catalyst loading than in our previous study.39 The conditions were also applied
to pꢀmethoxybenzyl alcohol which gave the lowest yield of all substrates in our earlier study due
to extensive decarbonylation. With Mg3N2 as the additive the esterification of this alcohol was
significantly improved and less decarbonylation observed (entries 21 – 24).
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Table 1. Synthesis of Esters with Complex 1
________________________________________________________________________________________
Entry alcohol x (%) additive % additive conversion (%) yield (%)a
________________________________________________________________________________________
1
2
5
ꢀ
ꢀ
100
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2
3b
2
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2
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Mg3N2
Mg3N2
Mg3N2
Mg3N2
Mg3N2
Mg3N2
Mg3N2
Mg3N2
Mg3N2
Mg3N2
MgBr2
MgO
100
100
100
100
100
4.2
8.3
16.7
27
100
50
50
50
16.7
33
100
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21
89
82
ꢀ
84
14
1
4c
5d
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36
61
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0
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11
95
80
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70
93
98
33
48
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81
6e
7f
1.25
1.25
1.25
1.25
1.25
1.25
2.5
1.25
1.25
1.25
1.25
0.5
1.25
5
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8f
ꢀ
ꢀ
ꢀ
ꢀ
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ꢀ
ꢀ
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ꢀ
9f
10f
11f
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18g
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20h
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Cs2CO3
Ca3N2
Li3N
K3PO4
Mg3N2
Mg3N2
Mg3N2
Mg3N2
Mg3N2
Mg3N2
Mg3N2
33
16.7
16.7
16.7
16.7
16.7
100
100
ꢀ
2.5
5
2.5
5
65
67
80
100
_________________________________________________________________________________________
a GC yield. b Without PCy3•HBF4 and with 10% KOtBu. c With 5% KOtBu. d With PPh3 instead
of PCy3•HBF4 and 10% KOtBu. e With dppe instead of PCy3•HBF4 and 10% KOtBu. f Reaction
time 2 h. g Reaction time 72 h. h Reaction time 3 h.
At this point, it was decided not to continue the investigations with other primary alcohols
since the outcome most likely would be a rather predictable improvement of our previous
substrate study. Instead, selective crossꢀesterifications were attempted which had not been
possible so far with complex 1. First, an equimolar mixture of benzyl alcohol and 2ꢀ
phenylethanol were reacted under the optimized conditions, but this only resulted in a near equal
mixture of all four possible esters. Then, the crossꢀesterification was attempted with 2ꢀ
phenylethanol and 1ꢀphenylethanol, but this only produced traces of the desired ester while 2ꢀ
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phenylethanol was almost completely converted into the symmetrical ester and 1ꢀphenylethanol
to acetophenone. Since the latter seems to be easily dehydrogenated under the reaction
conditions, an experiment was also performed with 1ꢀphenylethanol in the absence of a primary
alcohol. Surprisingly, this now produced a 95% GC yield of racemic ketone dimer 5 (Scheme 1).
This transformation can be envisioned as a dehydrogenative Guerbet reaction with a secondary
alcohol – a reaction that to the best of our knowledge has not been described previously with a
homogeneous catalyst.
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Scheme 1. Self-Condensation of 1-Phenylethanol
Therefore, we decided to investigate this transformation in further detail and began by
optimizing the conditions (Table 2). Heptanꢀ2ꢀol was selected for these studies since 1ꢀ
phenylethanol is a relatively special substrate in this context. At first, heptanꢀ2ꢀol only produced
the corresponding ketone under the conditions in Scheme 1 and no dimerization was observed
(entry 1). Apparently, Mg3N2 will not promote the subsequent aldol reaction with this ketone
and other additives were therefore investigated. Similar results were observed with Ca3N2,
K3PO4, K2CO3, NaHCO3 and DBU where the reaction also stopped at the ketone stage (results
not shown). Most likely, the lower acidity of the α protons in heptanꢀ2ꢀone as compared to
acetophenone is responsible for hampering the aldol reaction. As a result, stronger bases were
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included in the study and fortunately Li3N, LDA, NaH, KOtBu and KOH all gave ketone dimer
7 as the major product (entries 2 – 6). The importance of basicity was clearly illustrated when
KOH, NaOH and LiOH were compared since the former gave dimer 7 as the major product
while the latter only furnished heptanꢀ2ꢀone (entries 6 – 8). With Li3N several other ligands and
solvents were also investigated, but in all cases a lower yield of the desired ketone was obtained
(entries 9 – 17). With KOH it was possible to leave out KOtBu and even lower the amount of
complex 1 without compromising the yield of 7 (entries 18 – 20). Only when lower amounts of
KOH were employed did the yield of 7 decrease slightly (entry 21). Consequently, it was
decided to use a small excess of KOH and catalytic amounts of complex 1 and PCy3•HBF4 in
refluxing toluene as the general protocol for the dehydrogenative coupling.
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Table 2. Dehydrogenation of Heptan-2-ol with Complex 1
______________________________________________________________________________________
Entry additive % additive solvent yield of 6 (%)a yield of 7 (%)a
______________________________________________________________________________________
1
2
3
4
5
Mg3N2
Li3N
LDA
16.7
33
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
38
12
6
2
0
0
86
56
92
78
95
55
0
100
100
100
100
100
33
NaH
KOtBu
KOH
NaOH
LiOH
Li3N
6
7
2
44
64
1
8
9b
10c
33
33
50
69
Li3N
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11d
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Li3N
Li3N
Li3N
Li3N
Li3N
Li3N
Li3N
KOH
KOH
KOH
KOH
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33
33
33
33
toluene
toluene
oꢀxylene
heptane
benzene
dioxane
water
toluene
toluene
toluene
toluene
10
2
0
34
23
39
7
18
36
0
94
97
92
87
0
21
10
14
2
1
2
16
33
33
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17
18f
19f,g
20
107.5
115
185
50
21f
12
_______________________________________________________________________________________
a GC yield. b Without PCy3•HBF4 and with 5% KOtBu. c With PPh3 instead of PCy3•HBF4 and
with 5% KOtBu. d With dppe instead of PCy3•HBF4 and with 5% KOtBu. e With pyridine
instead of PCy3•HBF4 and with 5% KOtBu. f Without KOtBu. g With 1.25% 1 and PCy3•HBF4.
These conditions were then applied to a variety of other secondary alcohols (Table 3). Alkanꢀ
2ꢀols ranging from hexanꢀ2ꢀol to nonanꢀ2ꢀol were converted into the corresponding ketone
dimers in high yields (entries 1 – 5). A further increase in the length of the aliphatic chain
resulted in a lower reactivity as shown with undecanꢀ2ꢀol and tetradecanꢀ2ꢀol (entries 6 – 7). The
former required a longer reaction time in order to give a good yield while the latter was only
oxidized to the ketone and no aldol reaction was observed. Methyl carbinols containing a
cyclohexyl or a phenyl group were also converted in good yield (entries 8 – 12) while the
halogenated substrates 1ꢀ(pꢀchlorophenyl)ꢀ and 1ꢀ(pꢀbromophenyl)ethanol gave mixtures of
several ketones due to partial dehalogenation (results not shown). Attempts to convert alkanꢀ3ꢀ
ols failed and the same was observed with nonanꢀ5ꢀol (entries 13 – 16). Even the more easily
oxidized propiophenone only gave a very low yield of the coupling product (entry 17).
Cycloalkanols, on the other hand, were completely transformed into the αꢀalkylated ketones.
Unfortunately, cyclopentanol and cyclohexanol both gave a mixture of the monoalkylated and
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the α,α’ꢀdialkylated ketone where the ratio was 1:7 with cyclopentanol and 1:1 with
cyclohexanol. No attempts were made to separate these product mixtures. Cycloheptanol, on the
other hand, afforded exclusively the monoalkylated product which was isolated in good yield
(entry 18). In all, the dehydrogenative dimerization of secondary alcohols with complex 1 works
well with a range of methyl carbinols while other acyclic secondary alcohols are not sufficiently
reactive to undergo the coupling. Cycloalkanols are transformed in good yield, but only
cycloheptanol gives complete regioselectivity for the monoalkylated product.
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Table 3. Dehydrogenative Self-Coupling of Secondary Alcohols
Entry
1
R
R'
H
product
yield (%)a
95
nꢀC4H9
2
secꢀC4H9
H
80
3
4
nꢀC5H11
nꢀC6H13
nꢀC7H15
nꢀC9H19
H
H
H
H
92
92
94
87
5
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nꢀC12H25
H
H
ꢀ
0
Cy
92
7
8
9
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12
13
14
15
16
17
18
19
20
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9
Ph
H
H
H
H
95
95
10
11
12
pMeOPh
pCF3Ph
BnCH2
80c
88
13
14
15
16
C2H5
CH3
CH3
CH3
ꢀ
ꢀ
ꢀ
0
0
0
0
nꢀC3H7
iꢀC3H7
nꢀC4H9
nꢀC3H7
ꢀ
17
Ph
CH3
5c
18
ꢀ(CH2)5ꢀ
70
a Isolated yield. b Reaction time 65 h. c GC yield.
The reaction with 1ꢀphenylethanol was monitored over time by GCMS where the
corresponding ketone and βꢀalkylated alcohol were observed as intermediates (Scheme 2 and
Figure 2). None of the α,βꢀunsaturated enone could be detected, but this compound is most
likely hydrogenated rapidly and serves as an in situ hydrogen scavenger at the beginning of the
reaction. To gain more information about the ruthenium species involved in the catalytic cycle
the selfꢀcondensation of 1ꢀphenylethanol was also monitored by NMR in tolueneꢀd8. After one
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hour several signals in the hydride region of the 1H NMR spectrum were detected. This includes
doublets at –22.13 (JPH = 40 Hz) and –22.24 ppm (JPH = 35 Hz) which can be assigned to
ruthenium monohydride species with PCy3 trans to the Nꢀheterocyclic carbene ligand.42 In
addition, signals at –6.47, –6.63 and –6.93 ppm were observed which can be ascribed to
ruthenium dihydride species.43,44 The dehydrogenative coupling was also performed with the
monodeuterated alcohol, i.e. 1ꢀdeuteroꢀ1ꢀphenylethanol, where rapid scrambling of deuterium
and hydrogen in the αꢀposition was observed under the reaction conditions. This shows that the
dehydrogenation of the alcohol is a reversible process and that the ruthenium species thus
formed is a dihydride. The same rapid scrambling was observed in the esterification, imination
and amidation with complex 1 and primary alcohols.37ꢀ39 The pꢀcymene ligand on complex 1
was quickly displaced during the reaction which was shown by an additional NMR experiment
with octanꢀ2ꢀol as the substrate where complete release of pꢀcymene was observed after 20 min.
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Scheme 2. Mechanism for Dehydrogenative Self-Coupling
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Figure 2. Composition of Reaction Mixture as a Function of Time.
In conclusion, we have described an improved procedure for the formation of esters from
primary alcohols and a new protocol for the selfꢀcoupling of secondary alcohols. Both
transformations are catalyzed by the ruthenium NHC complex 1 and occur with the liberation of
molecular hydrogen.
EXPERIMENTAL SECTION
General Information. All solvents were of HPLC grade and were not further purified. Column
chromatography separations were performed on silica gel (220 – 440 mesh). NMR chemical
shifts were measured relative to the signals of residual CHCl3 (δH 7.26 ppm) and CDCl3 (δC
77.16 ppm). HRMS measurements were made using ESI with TOF detection. 1ꢀDeuteroꢀ1ꢀ
phenylethanol45 and 1ꢀ(4ꢀ(trifluoromethyl)phenyl)ethanol46 were prepared according the
reported procedures.
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General Procedure for Esterification of Primary Alcohols. A Schlenk tube was charged with
[RuCl2(IiPr)(pꢀcymene)] (1)35 (23 mg, 0.05 mmol), PCy3•HBF4 (18.4 mg, 0.05 mmol), KOtBu
(16.8 mg, 0.15 mmol), Mg3N2 (16.9 mg, 0.17 mmol) and a stir bar. A cold finger was attached
and the tube was evacuated and refilled with argon three times. The primary alcohol (4 mmol)
and nonane (257 mg, 2 mmol) were dissolved in toluene to give a 1 M solution of the alcohol
(total volume 4 mL). This solution was transferred to the Schlenk tube which was then placed in
a preheated oil bath (T = 120 °C). Samples for GCMS analysis were withdrawn after the
indicated time periods.
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General Procedure for Self-Coupling of Secondary Alcohols. A Schlenk tube was charged
with 135 (46 mg, 0.1 mmol), PCy3•HBF4 (36.8 mg, 0.1 mmol), KOH (298 mg, 5.3 mmol) and a
stir bar. A cold finger was attached and the tube was evacuated and refilled with argon
three times. The secondary alcohol (5 mmol) and nonane (321 mg, 2.5 mmol) were dissolved in
toluene to give a 1 M solution of the alcohol (total volume 5 mL). This solution was transferred
to the Schlenk tube which was then placed in a preheated oil bath (T = 120 °C). After 24 h the
reaction mixture was cooled to room temperature and filtered through a pad of Celite which was
washed with pentane. The collected solution was evaporated in vacuo and the resulting liquid
purified either by vacuum distillation or column chromatography (EtOAc/pentane 50/1 → 15/1).
7-Methylundecan-5-one (Table 3, Entry 1). Distilled in vacuo to give a colorless liquid. Yield
437 mg (95%). bp 91 °C/5 mmHg (lit.47 bp 103–105 °C/9 mmHg). 1H NMR (300 MHz, CDCl3)
δ
0.85–0.92 (m, 9H), 1.18–1.36 (m, 8H), 1.88 (p, J = 7.5 Hz, 2H), 1.92–2.03 (m, 1H), 2.14–2.22
(m, 1H), 2.31–2.40 (m, 3H). 13C NMR (75 MHz, CDCl3)
δ
14.0, 14.2, 20.0, 22.5, 23.0, 26.0,
29.3, 29.4, 36.8, 43.3, 50.5, 211.6. IR (neat) 1712 cm−1. HRMS m/z calcd for C12H25O 185.1905
[M + H]+, found 185.1899.
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3,6,7-Trimethylnonan-4-one (Table 3, Entry 2). Distilled in vacuo to give a colorless liquid.
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Yield 367 mg (80%). bp 70 °C/5 mmHg. 1H NMR (300 MHz, CDCl3)
(d, J = 6.0 Hz, 3H), 1.07–1.41 (m, 3H), 1.59–1.73 (m, 1H), 2.01–2.48 (m, 3H). 13C NMR
δ 0.74–0.89 (m, 9H), 1.03
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(75 MHz, CDCl3) δ 11.0, 11.8, 11.9, 12.2, 12.2, 14.5, 14.5, 14.8, 14.9, 15.9, 15.9, 16.0, 16.0,
16.1, 16.1, 17.3, 17.3, 19.9, 25.9, 25.9, 26.0, 26.1, 26.1, 26.5, 27.4, 32.2, 32.9, 33.0, 34.6, 35.9,
38.9, 38.9, 39.5, 45.0, 45.0, 46.0, 46.9, 48.2, 48.2, 48.3, 48.4, 214.9, 214.9, 215.1, 215.1. IR
(neat) 1708 cm−1. HRMS m/z calcd for C12H25O 185.1905 [M + H]+, found 185.1900.
8-Methyltridecan-6-one (Table 3, Entry 3). Distilled in vacuo to give a colorless liquid. Yield
488 mg (92%). bp 111–112 °C/5 mmHg. 1H NMR (300 MHz, CDCl3)
δ 0.85–0.90 (m, 9H),
1.19–1.34 (m, 12H), 1.55 (p, J = 7.5 Hz, 2H), 1.92–2.04 (m, 1H), 2.14–2.22 (m, 1H), 2.33–2.40
(m, 3H). 13C NMR (75 MHz, CDCl3)
δ
14.1, 14.2, 20.0, 22.6, 22.8, 23.6, 26.8, 29.4, 31.6, 32.1,
37.1, 43.5, 50.5, 211.7. IR (neat) 1712 cm−1. HRMS m/z calcd for C14H29O 213.2218 [M + H]+,
found 213.2212.
9-Methylpentadecan-7-one (Table 3, Entry 4). Distilled in vacuo to give a colorless liquid. Yield
552 mg (92%). bp 130–131 °C/5 mmHg. 1H NMR (300 MHz, CDCl3)
δ 0.84–0.89 (m, 9H),
1.16–1.34 (m, 16H), 1.50–1.59 (m, 2H), 1.92–2.03 (m, 1H), 2.14–2.22 (m, 1H), 2.32–2.39 (m,
3H). 13C NMR (75 MHz, CDCl3)
δ
14.2, 14.2, 20.0, 22.6, 22.8, 23.9, 27.1, 29.1, 29.4, 29.6,
31.8, 32.0, 37.1, 43.6, 50.5, 211.7. IR (neat) 1713 cm−1. NMR data are in accordance with
literature values.48
10-Methylheptadecan-8-one (Table 3, Entry 5). Distilled in vacuo to give a colorless liquid.
Yield 630 mg (94%). bp 154 °C/5 mmHg. 1H NMR (300 MHz, CDCl3)
δ 0.84–0.89 (m, 9H),
1.18–1.31 (m, 20H), 1.50–1.59 (m, 2H), 1.92–2.03 (m, 1H), 2.14–2.21 (m, 1H), 2.31–2.39 (m,
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3H). 13C NMR (75 MHz, CDCl3)
δ 14.2, 14.2, 20.0, 22.8, 22.8, 24.0, 27.1, 29.2, 29.4, 29.4,
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29.5, 29.9, 31.8, 32.0, 37.1, 43.5, 50.5, 211.6. IR (neat) 1713 cm−1. HRMS m/z calcd for
C18H36O 269.2839 [M + H]+, found 269.2844.
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12-Methylheneicosan-10-one (Table 3, Entry 6). Distilled in vacuo to give a colorless liquid
which crystallized upon standing. Yield 705 mg (87%). bp 197 °C/5 mmHg. 1H NMR
(300 MHz, CDCl3)
δ 0.85–0.89 (m, 9H), 1.25 (br s, 28H), 1.50–1.59 (m, 2H), 1.94–2.03 (m,
1H), 2.14–2.22 (m, 1H), 2.33–2.40 (m, 3H). 13C NMR (75 MHz, CDCl3)
δ
14.3, 14.3, 20.1,
22.8, 22.8, 24.0, 27.1, 29.4, 29.5, 29.6, 29.7, 29.8, 29.8, 29.9, 29.9, 32.0, 32.1, 37.1, 43.6, 50.5,
211.7. IR (neat) 1714 cm−1. HRMS m/z calcd for C22H44O 325.3465 [M + H]+, found 325.3467.
1,3-Dicyclohexylbutan-1-one (Table 3, Entry 8). Distilled in vacuo to give a colorless liquid.
Yield 543 mg (92%). bp 146 °C/5 mmHg. 1H NMR (300 MHz, CDCl3)
δ 0.80 (d, J = 6.7 Hz,
3H), 0.92–1.39 (m, 11H), 1.59–1.96 (m, 11H), 2.17–2.34 (m, 2H), 2.44 (dd, J = 4.8, 16.1 Hz,
1H). 13C NMR (75 MHz, CDCl3)
δ
16.8, 25.8, 25.9, 26.0, 26.8, 26.8, 26.9, 28.5, 28.7, 29.2,
30.5, 33.9, 42.9, 45.6, 51.3, 214.7. IR (neat) 1705 cm−1. HRMS m/z calcd for C16H29O 237.2218
[M + H]+, found 237.2213.
1,3-Diphenylbutan-1-one (Table 3, Entry 9). Purified by column chromatography to give a
yellow solid. Yield 532 mg (95%). NMR data are in accordance with literature values.49
1,3-Bis(4-methoxyphenyl)butan-1-one (Table 3, Entry 10). Purified by column chromatography
to give a colorless liquid. Yield 675 mg (95%). 1H NMR (300 MHz, CDCl3)
δ 1.30 (d, J =
6.9 Hz, 3H), 3.05–3.24 (m, 2H), 3.39–3.50 (m, 1H), 3.78 (s, 3H), 3.85 (s, 3H), 6.84 (d, J =
8.7 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.91 (d, J = 8.9 Hz, 2H). 13C
NMR (75 MHz, CDCl3)
δ
22.2, 35.1, 47.1, 55.4, 55.6, 113.8, 114.0, 127.9, 130.4, 130.5, 130.7,
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138.9, 158.0, 163.5, 197.9. IR (neat) 1672 cm−1. HRMS m/z calcd for C18H21O3 285.1481 [M +
H]+, found 285.1488.
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1,3-Bis(4-(trifluoromethyl)phenyl)butan-1-one (Table 3, Entry 11). After 24 h the reaction
mixture was passed through a plug of Celite which was washed with pentane. The resulting
solution was evaporated in vacuo to give 701 mg of a red liquid. The NMR spectrum showed
approx. 85% of the desired product and GCMS also revealed the desired ketone as the major
product. However, attempts to isolate the product quantitatively by column chromatography
failed due to partial decomposition of the compound. Eluted twice through a column with silica
gel (pentane/EtOAc 50/1 → 15/1) to give a reddish liquid. Yield 198 mg (22%). 1H NMR
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(300 MHz, CDCl3)
δ 1.29 (d, J = 7.0 Hz, 3H), 3.11–3.30 (m, 2H), 3.45–3.56 (m, 1H), 7.29 (d,
J = 8.0 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H). 13C
NMR (75 MHz, CDCl3)
δ
22.0, 35.3, 46.9, 125.5–125.9 (m), 127.4, 128.3, 128.5, 129.4, 139.7,
−62.8, −62.0. IR (neat) 1692 cm−1. HRMS m/z calcd
150.3, 197.5. 19F NMR (75 MHz, CDCl3)
δ
for C18H15F6O 361.1027 [M + H]+, found 361.1028.
5-Methyl-1,7-diphenylheptan-3-one (Table 3, Entry 12). Purified by column chromatography to
give a slightly yellow liquid. Yield 308 mg (88%). 1H NMR (300 MHz, CDCl3)
δ 0.86 (d, J =
6.4 Hz, 3H), 1.32–1.58 (m, 2H), 1.90–2.03 (m, 1H), 2.13–2.21 (m, 1H), 2.30–2.37 (m, 1H),
2.41–2.64 (m, 4H), 2.78–2.83 (m, 2H), 7.07–7.22 (m, 10H). 13C NMR (75 MHz, CDCl3)
δ
19.9,
29.1, 29.9, 33.5, 38.8, 44.9, 50.6, 125.9, 126.2, 128.5, 128.6, 141.6, 142.5, 209.9. IR (neat) 1712
cm−1. HRMS m/z calcd for C20H25O 281.1905 [M + H]+, found 281.1902.
2-Cycloheptylcycloheptanone (Table 3, Entry 19). Distilled in vacuo to give a colorless liquid.
Yield 364 mg (70%). bp 136 °C/5 mmHg. 1H NMR (300 MHz, CDCl3)
δ 1.16–1.63 (m, 16H),
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1.76–1.91 (m, 5H), 2.21–2.38 (m, 2H), 2.43–2.53 (m, 1H). 13C NMR (75 MHz, CDCl3)
δ 25.5,
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26.8, 26.9, 27.6, 28.2, 28.3, 28.6, 30.3, 30.9, 32.9, 42.2, 43.4, 59.5, 217.4. IR (neat) 1696 cm−1.
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HRMS m/z calcd for C14H25O 209.1905 [M + H]+, found 209.1895.
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ACKNOWLEDGMENT
We thank the Danish Council for Independent Research – Technology and Production Sciences
for financial support.
Supporting Information. Copies of 1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
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