One-pot etherification of ketones and aldehydes with organic halides using sodium hydride as a reductant

Article abstract of DOI:10.1080/00397910802579178

One-pot etherification reaction of aromatic and some aliphatic carbonyl compounds with organic halides in the presence of sodium hydride as a reducing reagent proceeded smoothly in dioxane, a polar solvent with higher boiling point, to provide desired ethers in moderate to high yields. Copyright Taylor & Francis Group, LLC.

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One-Pot Etherification of
Ketones and Aldehydes with
Organic Halides Using Sodium
Hydride as a Reductant
Qingwei Meng a , Bin Gong a , Chuang Hui a
Zhanxian Gao a
&
a State Key Laboratory of Fine Chemicals, Dalian
University of Technology, Dalian, China
Version of record first published: 15 Apr 2009.
To cite this article: Qingwei Meng , Bin Gong , Chuang Hui & Zhanxian Gao (2009):
One-Pot Etherification of Ketones and Aldehydes with Organic Halides Using Sodium
Hydride as a Reductant, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:10, 1708-1717
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Synthetic Communications1, 39: 1708–1717, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802579178
One-Pot Etherification of Ketones and Aldehydes
with Organic Halides Using Sodium Hydride
as a Reductant
Qingwei Meng, Bin Gong, Chuang Hui, and Zhanxian Gao
State Key Laboratory of Fine Chemicals, Dalian University of Technology,
Dalian, China
Abstract: One-pot etherification reaction of aromatic and some aliphatic
carbonyl compounds with organic halides in the presence of sodium hydride as
a reducing reagent proceeded smoothly in dioxane, a polar solvent with higher
boiling point, to provide desired ethers in moderate to high yields.
Keywords: Aldehyde, etherification, ketone, one pot, sodium hydride
Ether functionalities, especially unsymmetrical ones, have had many
useful applications in various chemical intermediates in the pharmaceuti-
cal, agricultural, and fragrance industries, for example. One of the com-
mon preparation methods of these ethers is the so-called Williamson
reaction, which features the reaction between alkoxides (sodium, lithium,
potassium, etc.) and alkyl halides. The normal sequence is to prepare the
alkoxide from the corresponding alcohol and subsequently react it with
alkyl halide via nucleophilic substitution.[1] The unsymmetrical ethers
also can be prepared via reductive etherification of carbonyl compounds
with a reducing reagent, such as decaborane[2] and triethylsilane.[3] The
employment of triethylsilane needs the combination of a Lewis acid, such
as trityl perchlorate,[3a] trimethylsilyl iodide,[3b,c] trimethylsilyl triflate,[3d]
Received July 5, 2008.
Address correspondence to Bin Gong, State Key Laboratory of Fine Chemi-
cals, Dalian University of Technology, Zhongshan Road 158, No. 90 mailbox,
Dalian 116011, China. E-mail: bodygb@163.com
1708

One-Pot Etherification
1709
bismuth bromide,[3e] copper triflate,[3f] and tris(pentafluorophenyl)-
borane.[3g] Recently, Iwanami and coworkers reported that the reductive
etherification of aldehydes and ketones proceeds with triethylsilane and
alkoxytrimethylsilane in the presence of iron(III) chloride as a catalyst.[4]
During the course of our research on the preparation of unsymmetri-
cal ethers, we found that NaH, which is usually used as a base in organic
synthesis, can be utilized as a reductive hydride source for the reduction
of ketones and aldehydes to offer sodium alkoxides, which could react
smoothly with alkyl halide in a one-pot fashion to directly provide
unsymmetrical ethers. This procedure will greatly simplify the existing
protocol for reductive etherification, and we feel it could find general
use among chemists. Herein we report our findings.
Initially, we studied the reductive etherification using various types
of metal hydride in different solvents. The results are summarized in
Table 1. Reaction between benzophenone (1a) and benzyl chloride was
chosen as a model for screening purposes. As expected, the use of LiAlH4
reduced benzophenone nicely but failed in the alkylation and provided
the corresponding alcohol 3 in quantitative yield (entry 1). During the
study, we observed complete decomposition of benzyl chloride by
LiAlH4. NaBH4 only provided the desired ether (2a) in minimum yield
Table 1. Screening of reductant and solventa
Entry
Reductant
Solvent
Yield of 2a (%)b
Yield of 3 (%)b
1
2
3
LiAlH4
NaBH4
CaH2
NaH
THF
THF
THF
THF
0
4
0
94
86
0
4
Tracec
Tracec
5
6
7
8
9
10
NaBH4
CaH2
NaH
CaH2
NaH
NaH
DME
DME
DME
Dioxane
Dioxane
Toluene
4
0
87
0
92
56
87
0
0
0
0
14
aReaction conditions: benzophenone (1.0 mmol), benzyl chloride (1.3 mmol),
reductant (1.3 mmol), and solvent (3 mL); reflux; 6 h.
bIsolated yields.
cDetected by GC.

1710
Q. Meng et al.
(4%, entries
2
and 5) using either tetrahydrafuran (THF) or
[5]
1,2-dimethoxyethane (DME) as the solvent. The use of CaH2 resulted
in no reaction (entries 3, 6, and 8). When NaH was first studied and
THF was used as a reaction solvent, only trace amounts of 2a and 3 were
observed (entry 4). However, when DME and dioxane, polar solvents
with higher boiling points than THF, were used as reaction solvents to
substitute THF, the desired ether 2a was formed in high yield (87%
and 92% respectively, entries 7 and 9). When using toluene, moderate
yield (56%) of 2a was obtained along with 3 in 14% yield (entry 10).
Then we examined the general scope of the reductive etherification
with various carbonyl substrates and organic halides. We are pleased
to find that the protocol is successful in many ketones and aldehydes
as long as they lack enolizable a-protons. Our results are summarized
in Table 2. Reductive etherification of dibenzylideneacetone (1b) with
benzyl chloride provided the desired ether product 2b in 42% yield (entry
2). Carbonyl compounds that have enolizable a-protons such as cyclo-
hexanone (1c) and acetophenone (1d) did not work in this reductive
etherification reaction (entries 3 and 4). In these cases, sodium hydride
will simply act as a strong base and abstracts the acidic proton in the car-
bonyl substrates. The acid–base reaction proceeded much faster than the
desired reduction of carbonyl group; thus, the reductive ether formation
did not happen. The evidence becomes more clear in the studies of cam-
phor (1e), which also has enolizable a-protons. The three major products
(2e, 4e, and 5e) isolated and identified from the reaction all related to the
enolated intermediate, and none of the reductive product was observed
(entry 5). From this study, we clearly see that this protocol should only
be used in carbonyl substrates lacking enolizable a-protons. In the exam-
ple of 2-admantanone (1f), which contains unenolizable a-proton because
of the rigidity of its framework, the reductive etherification worked well
to provide desired ether product in moderate to high yields (entries 6–13).
This observation and hypothesis was further supported by the reaction
shown in Scheme 1. When 1f reacted with NaH and was subsequently
quenched with water, the reduction product (alcohol) was obtained in
92% yield. The etherification did not occur between 2-admantanone
and 1-bromo-2-methylpropane (entry 14), because 1-bromo-2-methylpro-
pane decomposes rapidly in the hot solution of strong base. We also
found this protocol worked well on aldehyde substrates (entries 15–20).
Scheme 1. The evidence for supporting the hypothetic mechanism.

One-Pot Etherification
1711
Table 2. Etherification of ketones and aldehydes (1) with organic halides using
sodium hydride as a reductanta
Entry
1
Substrate
Organic halide
BnCl
Product
Yield (%)b
92
2
BnCl
42
3
4
BnCl
BnCl
Complex mixture
Complex mixture
—
—
5c
BnCl
90
6
7
BnCl
90
87
(1f)
(1f)
8
87
(Continued )

1712
Q. Meng et al.
Table 2. Continued
Entry
9
Substrate
Organic halide
Product
Yield (%)b
51
(1f)
10d
(1f)
70
11
12
(1f)
(1f)
MeꢀI
EtꢀBr
87
65
13
14
(1f)
(1f)
n-BuꢀBr
42
0
15
16
PhCHO (1g)
BnCl
BnCl
77
86
17
18
BnCl
BnCl
26
72
(Continued )

One-Pot Etherification
1713
Table 2. Continued
Entry
19
Substrate
Organic halide
Product
Yield (%)b
63
20
75
aAll reactions were carried out under nitrogen at reflux for 6 h using ketone or
aldehyde (1.0 mmol), organic halide (1.3 mmol), sodium hydride (1.3 mmol), and
dioxane (3 mL), unless otherwise noted. The reaction progress was monitored by
TLC.
bIsoleted yields.
c1.5 mmol of benzyl chloride and sodium hydride, respectively, were used. The
ratio of 2e:4e:5e is 19:8:3.
dAfter the mixture of 1f and NaH was treated at reflux for 6 h, which was
cooled to 50ꢁC, methyl iodide was added to the mixture. The reaction mixture
obtained was stirred at 50ꢁC for an additional 2 h.
Overall, we reported in this article a useful protocol for reductive
etherification in one-pot fashion. The protocol uses inexpensive and readily
available sodium hydride as reductant. From our extended study, we found
this protocol should be useful in many different types of carbonyl com-
pounds and alkyl halides. It should find general use in organic synthesis.
EXPERIMENTAL
All solvents were used with further purification. All products were puri-
fied by flash-column chromatography using silica gel 60 (200–300 mesh).
1H NMR spectra were obtained from either a Varian Inova 400 or
Bruker Avance 400 spectrometer with tetramethylsilane (TMS) as an
internal standard. The symbols s, d, t, q, and m stand for singlet, doublet,
triplet, quartet, and multiplet respectively. 13C NMR spectra were
recorded at 100 MHz on the Bruker Avance 400 spectrometer. High-
resolution mass spectra (HRMS) were recorded on a Q-TOF mass
spectrometer (Micromass, England) equipped with Z-spray ionization
source. Elemental analysis were performed on the Vario EL III spectro-
meter (Elementar, Germery).

1714
Q. Meng et al.
General Procedure for the One-Pot Reductive Etherification
The reaction mixture of carbonyl compound (2.0 mmol), sodium hydride
(2.5 mmol, 0.1 g), and organic halide (2.5 mmol) in 2.5 mL of 1,4-dioxane
was stirred under a nitrogen atmosphere at reflux for 6 h. Then the mix-
ture was filter to remove the inorganic salt, and the filtrate was evapo-
rated under reduced pressure to remove the solvent. The residual oil
was purified by flash chromatography through a silica-gel columm (ethyl
ether=petroleum ether) to afford pure products.
Data
Compound 2f
1
Colorless oil; H NMR (400 MHz, CDCl3) d 1.49–2.14 (m, 14H), 3.54
(s, 1H), 4.51 (s, 2H), 7.22–7.36 (m, 5H); 13C NMR (100 MHz, CD3OCD3)
27.5, 27.5, 31.5, 31.8, 36.3, 37.4, 69.0, 81.0, 126.9, 127.1, 128.1,
139.9. Anal. calcd. for C17H22O: C, 84.25; H, 9.15. Found: C, 83.85;
H, 9.15.
Compound 2g
Colorless oil; 1H NMR (400 MHz, CDCl3) d 1.49–2.12 (m, 14H), 3.53 (s,
1H), 4.50 (s, 2H), 7.21–7.27 (m, 3H), 7.37 (s, 1H); 13C NMR (100 MHz,
CDCl3) 27.6, 31.8, 31.9, 36.6, 37.7, 68.6, 81.7, 125.4, 127.4, 129.6, 134.3,
141.9. Anal. calcd. for C17H21OCl: C, 73.76; H, 7.65. Found: C, 73.76; H,
7.90.
Compound 2h
Light yellow oil; 1H NMR (400 MHz, CDCl3) d 1.25–2.14 (m, 14H), 3.53
(s, 1H), 3.79 (s, 6H), 4.49 (s, 2H), 6.36 (t, J ¼ 2.4 Hz, 1H), 6.54 (s, 1H),
6.55 (s, 1H); 13C NMR (100 MHz, CDCl3) 27.5, 31.7, 31.8, 36.6, 37.6,
59.3, 69.2, 81.2, 99.2, 105.1, 142.1, 160.8. Anal. calcd. for C19H26O3: C,
75.46; H, 8.67. Found: C, 75.43; H, 8.62.
Compound 2i
Colorless oil; 1H NMR (400 MHz, CDCl3) d 1.48–2.09 (m, 14H), 3.98 (s,
1H), 4.64 (s, 2H), 7.26–7.63 (m, 3H), 8.54 (d, J ¼ 4.4 Hz, 1H). Anal. calcd.

One-Pot Etherification
1715
for C16H21NO: C, 78.97; H, 8.70; N, 5.76. Found: C, 78.85; H, 8.81;
N, 5.81.
Compound 2j
1
Colorless oil; H NMR (400 MHz, CDCl3) d 1.42–2.04 (m, 14H), 3.43
(s, 1H), 3.95 (d, 2H), 5.19 (dd, J ¼ 1.6, 8.8 Hz, 1H), 5.27 (dd, J ¼ 1.6,
12.0 Hz, 1H), 5.86–5.96 (m, 1H); 13C NMR (100 MHz, CDCl3) 27.6,
31.7, 31.9, 36.7, 37.7, 68.5, 81.2, 116.0, 136.0. HRMS (EI) calcd. for
C13H20O Mþ: 192.1514. Found: 192.1515.
Compound 2k
1
Colorless oil; H NMR (400 MHz, CDCl3) d 1.38–1.96 (m, 14H), 3.26
(s, 1H), 3.27 (s, 3H); 13C NMR (100 MHz, CDCl3) 27.4, 27.4, 31.3,
31.4, 36.4, 37.6, 55.2, 83.2. HRMS (EI) calcd. for C11H18O Mþ:
166.1358. Found: 166.1357.
Compound 2l
1
Colorless oil; H NMR (400 MHz, CDCl3) d 1.21 (t, J ¼ 7.2 Hz, 3H),
1.48–2.03 (m, 14H), 3.43 (s, 1H), 3.49 (q, J ¼ 7.2 Hz, 2H);13C NMR
(100 MHz, CDCl3) 15.6, 27.5, 27.6, 31.3, 31.4, 36.5, 37.6, 64.2, 81.4.
HRMS (EI) calcd. for C12H20O: 180.1514. Found: 180.1523.
Compound 2m
1
Light yellow oil; H NMR (400 MHz, CDCl3) d 0.85 (t, J ¼ 7.2 Hz, 3H),
d 1.29–1.98 (m, 18H), 3.32–3.35 (m, 3H); 13C NMR (100 MHz, CDCl3)
13.9, 19.6, 27.5, 31.6, 31.8, 32.4, 36.6, 37.6, 67.0, 81.4. HRMS (EI) calcd.
for C14H24O Mþ: 208.1827. Found: 208.1826.
Compound 4e
1
Colorless oil; H NMR (400 MHz, CDCl3) d 0.66 (s, 3H), 0.81 (s, 3H),
1.60–0.87 (m, 6H), 1.75 (m, 1H), 1.98 (d, J ¼ 3.2 Hz, 1H), 3.25 (d,
J ¼ 14.8 Hz, 1H), 3.61 (d, J ¼ 14.8 Hz, 1H), 4.89 (d, J ¼ 11.6 Hz, 1H)
4.97 (d, J ¼ 11.6 Hz, 1H), 7.38–7.12 (m, 10H); MS (API-ES Positive),
m=z (Mþ): 332.3. Anal. calcd. for C24H28O: C, 86.70; H, 8.49. Found:
C, 86.67; H, 8.46.

1716
Q. Meng et al.
Compound 2r
1
Colorless oil; H NMR (400 MHz, CDCl3) d 3.70 (s, 6H), 4.51 (s, 2H),
4.53 (s, 2H), 6.72 (s, 2H), 6.97 (s, 1H), 7.28–7.31 (m, 5H). HRMS (EI)
calcd. for C16H18O3: 258.1256. Found: 258.1252.
Compound 2s
1
Colorless oil; H NMR (400 MHz, CDCl3) d 3.81 (s, 3H), 3.82 (s, 3H),
4.52 (s, 2H), 4.54 (s, 2H), 6.47 (m, 2H), 7.25–7.26 (m, 4H), 7.34 (s, 1H).
HRMS (EI) calcd. for C16H17O3Cl: 292.0866. Found: 292.0867.
Compound 2t
Colorless oil; 1H NMR (400 MHz, CDCl3) d 4.05 (d, J ¼ 1.6 Hz, 2H), 4.17
(d, J ¼ 4.4 Hz, 2H), 5.22 (dd, J ¼ 1.6, 8.8 Hz, 1H), 5.32 (dd, J ¼ 1.6,
15.6 Hz, 1H), 5.91–5.97 (m, 1H), 6.27–6.34 (m, 1H), 6.64 (d, J ¼ 16 Hz,
1H), 7.24–7.40 (m, 5H); HRMS (EI) calcd. for C12H14O: 174.1055.
Found: 174.1052.
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One-Pot Etherification
1717
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