Green alcohol couplings without transition metal catalysts: Base-mediated β-alkylation of alcohols in aerobic conditions

Article abstract of DOI:10.1039/c0gc00079e

Benzylic secondary alcohols can be alkylated in good yields at the β-position with primary alcohols promoted by KOH and NaOH, eliminating the need for toxic and expensive transition metal catalysts.

Full text of DOI:10.1039/c0gc00079e

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www.rsc.org/greenchem | Green Chemistry
Green alcohol couplings without transition metal catalysts: base-mediated
b-alkylation of alcohols in aerobic conditions†
Laura J. Allen and Robert H. Crabtree*
Received 4th May 2010, Accepted 15th June 2010
First published as an Advance Article on the web 29th June 2010
DOI: 10.1039/c0gc00079e
Benzylic secondary alcohols can be alkylated in good yields
at the b-position with primary alcohols promoted by KOH
and NaOH, eliminating the need for toxic and expensive
transition metal catalysts.
lowering the base to sub-stoichiometric amounts,3,7,11 lowering
the reaction temperature, and using less toxic metals. The only
previous reports on homogeneous catalysts for b-alkylation of
secondary alcohols involve complexes of ruthenium and iridium,
which are considered to be metals with safety concerns.12–14
Important recent studies have shown the use of alkali metal
bases for oxidation of alcohols to the corresponding carbonyl
through an Oppenauer pathway and reduction of aldehydes
and ketones to alcohols through a Meerwein–Ponndorf–Verley
(MPV) type mechanism.15–17 We now show that alkali metal
bases can also mediate the b-alkylation of secondary alcohols
with primary alcohols in good yield.
Avoidance of mutagenic and waste-forming reagents is a funda-
mental strategy for green transformations.1 With this in mind,
modern processes are emerging to replace conventional routes to
common synthetic building blocks. For example, the traditional
route to b-alkylated alcohols from a secondary alcohol requires
a three-step procedure that involves stoichiometric oxidation,
alkylation with an alkyl halide, and finally, stoichiometric
reduction (Scheme 1).2–5
All of the previous reported systems for b-alkylation have
relied on a transition metal catalyst together with a base, such
as potassium hydroxide, for product formation. From control
reactions in our transition metal studies, we have found that
the metal catalyst is not required – simple alkali metal bases are
sufficient. In view of the much lower cost of bases, such as KOH,
over the majority of transition metal catalysts, the new procedure
has been studied in detail. Because many of the previous systems
relied on KOH, we started our optimization with this alkali
metal hydroxide (Table 1). KOH shows complete conversion
of 1-phenylethanol and benzyl alcohol to the corresponding
b-alkylated products within 4 h (78% alcohol, 21% ketone, entry
2) in aerobic and solventless conditions. Other bases examined
include NaOH, K2CO3, Cs2CO3, K3PO4, KOtBu, and Ba(OH)2.
NaOH took longer than KOH for complete consumption of
Scheme 1 Classic route to b-alkylated products.
As latent electrophiles, alcohols can replace the mutagenic
halide because carbonyl derivatives are produced upon oxida-
tion. One of the first reports of one-pot b-alkylation reactions
of secondary alcohols involved RuCl2(PPh3)3 as a catalyst;
however, the reaction was not atom-economical due to the super-
stoichiometric use of base (potassium hydroxide), H2 acceptor
(1-dodecene), and H2 donor (dioxane) required for H2 transfer
to and from the metal.6 A subsequent study revealed [Cp*IrCl2]2,
along with stoichiometric base, as an active catalyst for the
reaction.4 Efficient b-alkylation was seen in our group with
ruthenium and iridium catalysts under nitrogen (N2) atmosphere
or even in air (Scheme 2).7,8 This strategy significantly decreased
the reaction time (to as little as 30 min) over previous systems,
which required between 8–24 h.3,4,6,9,10
Table 1 Comparison of bases for b-alkylationa
Conversion
Time (h) (%)b
Alcohol :
ketone
Entry Base
Yield (%)c
1
Cs2CO3
26
4
4
55
99
99
95
85
100
90
5
6
83 : 17
78 : 21
83 : 17
93 : 7
99 : 1
37 : 63
86 : 14
1 : 1
2d
3
KOH
99
76
69
75
81
72
2.5
0
KOHe
4
5
6
7
8
9
NaOH
NaOHe
NaOHe
KOtBu
K2CO3
K3PO4
4
5
Scheme 2 One-pot b-alkylation.
25f
4
These systems are examples of green reactions because they
minimize waste formation, avoid the use of protecting groups,
and maximize atom economy, leaving only water as a by-
product.1 Nevertheless, this system could be improved further by
20
20
0
—
10
Ba(OH)2 20
KOH 20
43
18
24
15
42 : 58
100 : 0
11g
a Conditions: 2.0 mmol 1-phenylethanol and benzyl alcohol, 100 mol%
base, 0.75 mL toluene (reflux), open to air. b Conversions were deter-
mined by consumption of the 1◦ alcohol. c Yields were determined by 1H
NMR using an internal standard (1,3,5-trimethoxybenzene). d Reaction
completed in solventless conditions. e Denotes use of semiconductor-
grade metal hydroxide. f Continuation of entry 5 for an additional 20 h.
g N2 atmosphere.
Yale Chemistry Department, 225 Prospect St., New Haven, CT, 06511,
USA. E-mail: robert.crabtree@yale.edu; Fax: +1 203 432 6144; Tel: +1
203 432 3915
† Electronic supplementary information (ESI) available: Experimental
details and 1H NMR chemical shifts of all products. See DOI:
10.1039/c0gc00079e
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starting materials, but showed greater selectivity for the alcohol
product. Because reagent-grade KOH and NaOH are known
to have transition metal contaminants, semiconductor-grade
KOH and NaOH, 99.99% pure based on trace metal analysis
(Sigma-Aldrich), were also examined (entries 3, 5, 6). As seen
in Table 1, the use of semiconductor-grade NaOH and KOH
did not dramatically change the product distribution or yield
versus the reagent-grade base. The product of alcohol to ketone
does, however, change dramatically over time, most likely due
to aerobic oxidation (entry 6). When the reaction was run under
nitrogen atmosphere, we found only 18% conversion of the
starting material and only the alcohol alkylation product in 15%
yield (entry 11).
in our reaction mixtures, another pathway must be responsible
for product formation. We propose that air oxidation of the
secondary alcohol produces some ketone that is required for
an Oppenauer mechanism to operate, followed by a base-
assisted aldol reaction to give the enone, and then an MPV
reduction and isomerization to give the observed products
(Scheme 3). Both trans-chalcone and (E)-1,3-diphenylprop-2-
en-1-ol are converted to the alcohol and ketone products under
KOH conditions with either primary or secondary alcohol as
reductant, supporting the proposed pathway.
With the success of the general reaction with 1-phenylethanol
and benzyl alcohol, the substrate scope was examined. KOH
shows moderate to good yields with various derivatives of benzyl
alcohol and 1-phenylethanol; however, some substrates required
longer reaction times (Table 2). With aliphatic alcohols, KOH
mediates the reaction of primary alcohols with 1-phenylethanol
(entries 13 and 14) but not the reaction of secondary alcohols
with benzyl alcohol (entries 15 and 16).
In many cases the conversion was quantitative but the
product yields were somewhat lower. We noted that an insoluble,
unidentifiable polymer was formed for the majority of the
reactions. As shown in Tables 1 and 2, the ratio of alcohol to
ketone was generally high. Even on prolonged reaction in air,
the alcohol was never completely oxidized to the ketone (Table
1, entry 6). The role of the alkali metal was probed by addition
of a sequestering agent. When 18-crown-6, a known potassium
chelator, was added, no reaction was seen, suggesting direct
potassium involvement in the mechanism.
The mechanism for transition-metal-catalyzed b-alkylation
has previously been attributed to a “hydrogen-borrowing”
process in which both alcohols are oxidized, followed by an
aldol condensation with loss of water, and finally reduction to
give alcohol product.18 Because no transition metal is included
Scheme 3 Possible route for b-alkylation.
In conclusion, the atom-economical one-pot b-alkylation of
secondary alcohols with primary alcohols has been demon-
strated to proceed without requiring transition metal catalysts.
Inexpensive alkali metal hydroxides (NaOH or KOH, 1.0 eq.)
promote the reaction in air with various 1-phenylethanol
derivatives and primary alcohols to give the b-alkylated product
in good yields. Further mechanistic studies are underway to
Table 2 b-alkylation of secondary alcohols with primary alcohols catalyzed by alkali metal hydroxides
Entrya
R
R¢
Base
Time (h)
Conversion (%)b
Yield (%)c
Alcohol : ketone
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
KOH, neat
KOH, neat
NaOH
KOH
NaOH
KOH
NaOH
KOH
KOH
KOH
KOH
KOH
KOH
4
4
23
4
25
4
4
4
4
4
99
97
100
100
100
91
90
97
98
86
100
0
99
93
78 : 21
89 : 11
63 : 37
87 : 13
42 : 58
90 : 10
87 : 13
66 : 34
95 : 5
90 : 10
90 : 10
—
p-BrC6H4
p-BrC6H4
p-ClC6H4
p-ClC6H4
p-tBuC6H4
p-tBuC6H4
p-MeC6H4
Ph
76
79 (63)d
66
85 (62)d
92
94
68
9
p-ClC6H4
p-MeC6H4
10
11
12
13
14
15
16
Ph
71
Ph
Ph
Ph
Ph
nPr
Et
p-nBuOC6H4
PhCH2
nPentyl
nPr
4
100 (80)d
22
20
20
20
20
0
59
13
0
28
10
0
100 : 0
100 : 0
—
KOH
KOH
KOH
Ph
Ph
0
0
—
a Conditions: 2.0 mmol 1◦ and 2◦ alcohol, 100 mol% base, 0.75 mL toluene (reflux), open to air. b Conversions were determined by consumption of
the 1◦ alcohol. c Yields were determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. d Isolated yields.
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determine the role of base in the reaction. These data indicate
that base-only control reactions are needed for transition-
metal-catalyzed versions, and that some previous conclusions in
aerobic systems may need to be re-examined in light of this work.
Acknowledgements
Financial support from the ACS-GCI Pharmaceutical
roundtable (LJA) and DOE grant DE-GF02-84ER13297
(RHC) are gratefully acknowledged.
Experimental
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1364 | Green Chem., 2010, 12, 1362–1364
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The Royal Society of Chemistry 2010
©