Direct etherification of alkyl halides by sodium hydride in the presence of N,N-dimethylformamide

Article abstract of DOI:10.1055/s-2007-991068

A novel synthetic method for the preparation of various alkyl ethers is described. The reaction between alkyl halides and sodium hydride in the presence of N,N-dimethylformamide afforded the corresponding symmetrical and unsymmetrical ethers in high yields. A reaction mechanism for etherification is also proposed.

Full text of DOI:10.1055/s-2007-991068

LETTER
2695
Direct Etherification of Alkyl Halides by Sodium Hydride in the Presence of
N,N-Dimethylformamide
D
irect Etherificat
h
ion of Alkyl
e
Halides ng Hua Jin,1 Ho Young Lee, Sang Hwi Lee, In Su Kim,1 Young Hoon Jung*
College of Pharmacy, Sungkyunkwan University, Suwon 440-746, South Korea
Fax +82(31)2907773; E-mail: yhjung@skku.ac.kr
Received 31 July 2007
Table 1 Etherification of Phenylethyl Alcohol (1) under Various
Abstract: A novel synthetic method for the preparation of various
alkyl ethers is described. The reaction between alkyl halides and so-
dium hydride in the presence of N,N-dimethylformamide afforded
the corresponding symmetrical and unsymmetrical ethers in high
yields. A reaction mechanism for etherification is also proposed.
Reaction Conditionsa
O
OH
BnBr, NaH
DMF
2
Key words: etherification, dimethylformamide, sodium hydride,
symmetrical and unsymmetrical ethers, alkyl halides
1
+
O
3a
The carbon–oxygen bond-forming reaction is one of the
most fundamental transformations utilized for the prepa-
ration of a large number of natural products, chemicals,
and drugs.2 In particular, the development of methods
capable of synthesizing symmetrical and unsymmetrical
ethers has been the subject of intensive research in the
research and industrial fields because they are present in
numerous biologically active compounds.3 Consequently,
a wide variety of synthetic methods have been developed
for the preparation of ethers from alcohols, but these
methods are not without limitations.4 The Williamson5
and Ullmann6 methods are probably the most widely used,
but requires the conversion of alcohols into halides or
sulfonates, which produces excessive amounts of waste
byproducts. To overcome this limitation, alternative
routes have been devised, e.g., with use of phase-transfer
catalyst,7 acid catalyst,8 metal catalyst,9 UV irradiation,10
and dimethyl sulfoxide.11
Entry NaH (equiv) BnBr (equiv) Time (h) Yield (%)b
2
3a
25
58
99
1
2
3
1.5
1.5
3
1.5
1.5
1.5
6
24
24
100
100
100
a All reactions were carried out at r.t.
b Isolated yield of pure materials.
As shown in entry 1, Williamson ether 2 was obtained as
a major product in only 6 hours. However, reaction of 1 in
the presence of an excessive amount of NaH and BnBr in
DMF for 24 hours provided the Williamson product 2 and
the symmetrical ether 3a in quantitative yields (as shown
in entry 3). Consequently, the yield of 3a could have been
affected by the excesses of NaH and BnBr and the pro-
longed reaction time.
N,N-Dimethylformamide (DMF) is usually used as an
aprotic polar solvent in chemical transformations, and as
a formylating reagent, e.g., in Bouveault aldehyde
synthesis12 and Vilsmeier–Haack reaction.13 Recently,
Serrano et al. demonstrated a new means of preparing
alcohols from mesylates using DMF at high temperature
(140 °C).14 However, no report has previously described
the use of DMF as an oxygen donor for the transformation
to ethers.
We considered that the oxygen atom in the dialkyl ether
3a is probably derived from DMF, and hence, we envi-
sioned that DMF could be used as an oxygen source for
the etherification of various alkyl halides to produce the
corresponding ethers.
Initially, we investigated the reaction between benzyl
bromide and NaH in DMF with a view towards opti-
mizing reaction conditions (results are summarized in Ta-
ble 2).
In our previous work on the deprotection of benzyl ethers
by chlorosulfonyl isocyanate (CSI) and sodium hydrox-
ide,15 we found that the reaction of phenylethyl alcohol (1)
with benzyl bromide and sodium hydride in the presence
of DMF affords the desired ether 2 and the unexpected
dibenzyl ether 3a in good yields (Table 1).
Treatment of 3 in DMF at 140 °C, without NaH, afforded
benzyl alcohol 3b as a major product in 50% yield (entry
1). However, the use of NaH in DMF encouraged the
formation of 3a rather than 3b (as shown in entries 2–5).
The best result was realized when 3 was exposed to 3
equivalents of NaH in DMF at room temperature, which
provided dibenzyl ether (3a) in 99% yield within 24 hours
(entry 4).
SYNLETT 2007, No. 17, pp 2695–2698
1
6
.1
0
.
2
0
0
7
Advanced online publication: 25.09.2007
DOI: 10.1055/s-2007-991068; Art ID: U07007ST
© Georg Thieme Verlag Stuttgart · New York

2696
C. H. Jin et al.
LETTER
Table 2 Etherification of Benzyl Bromide (3) under Various
Reaction Conditions
Table 3 Etherification of BnX According to the Nature of the
Leaving Group (X)a
NaH
DMF
X
Br
O
OH
NaH
DMF
O
+
3a
3
3a
3b
NaH (equiv) Temp (°C) Time (h) Yield (%)a
Entry
X
Yield (%)b
Entry
3a
20
89
82
99
89
3b
1
2
3
Cl
48
67
34
1
2
3
4
5
–
140
r.t.
90
24
24
3
50
–
OMs
OTs
1.5
1.5
3
a All reactions were carried out with NaH (3 equiv) at r.t. for 24 h.
b Isolated yields of pure materials.
–
r.t.
90
24
3
–
3
–
Consistent with these observations, we then considered
that this reaction could be applied generally to the prepa-
ration of ethers from the corresponding alkyl bromides.
Thus, we examined the homo-etherification and cross-
etherification of various alkyl bromides (3–7) using NaH
in the presence of DMF as an oxygen donor. Our results
are summarized in Table 4.16
a Isolated yields of pure materials.
Next, we investigated the relation between this type of
etherification and the nature of the leaving group, as
shown in Table 3.
As shown in entry 1, the reaction between benzyl bromide
(3) and NaH in DMF afforded the symmetrical ether 3a in
99% yield. Also, treatment of the allylic bromides 4 or 5
resulted in high conversions into the corresponding ethers
In the case of benzyl chloride (entry 1), benzyl
methanesulfonate (entry 2) and benzyl p-toluenesulfonate
(entry 3), the desired dibenzyl ether (3a) was obtained in
yields of 48%, 67% and 34%, respectively.
Table 4 Direct Etherification of Alkyl Bromides by Sodium Hydride in the Presence of DMFa
Entry
Substrate
Product
Yield (%)b
Ratioc
Br
O
1
99
3
3a
Br
O
2
85
88
4
5
4a
5a
O
Br
Br
3
4
3
3
3
O
OH
65
3.3:1
+
6a
6b
6
Br
OH
78
2:1:5
5
O
+
+
7a
7c
7b
7
76
1.8:1:1.7
O
O
6
7
3 + 4
3 + 5
+
+
+
3a
4a
8a
85
2.1:1:3.6
3a
5a
+
9a
a All the reactions were carried out with NaH (3 equiv) at r.t. for 24 h.
b Isolated yields of pure materials.
c Isomer ratios as determined by 1H NMR.
Synlett 2007, No. 17, 2695–2698 © Thieme Stuttgart · New York

LETTER
Direct Etherification of Alkyl Halides
2697
General Procedure for the Etherification of Alkyl Halides
4a (85%) and 5a (88%), respectively (entries 2 and 3).
Furthermore, the etherification of the primary alkyl halide
6 provided a separable mixture of the ether 6a and the al-
cohol 6b in a combined yield of 65% (entry 4). However,
reactions of the secondary benzylic bromides 7 furnished
the desired ether 7a, the alcohol 7b and the eliminated
compound 7c, as shown in entry 5.
To a stirred solution of alkyl halide (1 mmol) in anhyd DMF (5 mL)
was added NaH (3 mmol, 60% in mineral oil) at room temperature
under N2. The reaction mixture was stirred for 24 h at room temper-
ature and quenched with H2O (2 mL). The aqueous layer was ex-
tracted with EtOAc (20 mL) and the organic layer was washed with
H2O and brine, dried over MgSO4 and concentrated in vacuo. The
residue was purified by column chromatography (hexane–EtOAc)
to afford the corresponding ether.
These results indicate that substrates control reaction out-
comes. As was expected, the secondary halide 7 was
inevitably eliminated under strong base conditions (NaH)
to produce alkene 7c.
Acknowledgment
This work was supported by the Brain Korea 21 Program. We are
grateful to Cooperative Center for Research Facilities (CCRF) in
Sungkyunkwan University for their assistance in acquiring analyti-
cal data.
In addition, we also investigated cross-etherification, as
shown in entries 6 and 7. The reaction between 3 and 4
afforded the symmetrical ethers (3a and 4a) and unsym-
metrical ether 8a in high combined yield (76%), and the
etherification of 3 and 5 gave the corresponding ethers
(3a, 5a, and 9a) in a combined yield of 85%.
References and Notes
(1) These authors contributed equally to this work.
(2) (a) Mitsunobu, O. In Comprehensive Organic Synthesis,
Vol. 6; Trost, B. M.; Fleming, I., Eds.; Pergamon: London,
1991, 1. (b) Baggett, N. In Comprehensive Organic
Chemistry, Vol. 1; Stoddart, J. F., Ed.; Pergamon: London,
1979, 799.
A proposed reaction pathway for this formation of ethers
is provided in Scheme 1, and is initiated by an attack of the
alkyl halides by the oxygen of DMF to form the ammoni-
um salt 10,14,17 which is followed by nucleophilic attack
by the hydride anion (NaH) to yield the intermediate 11.
Resonance of the nitrogen lone pair of 11 affords the
alkoxide anion 13, which then undergoes an SN2 reaction
to generate the corresponding ether 14. Through the use of
DMF-18O,17 we demonstrated that the oxygen originates
in the DMF solvent during the formation of ethers.18
(3) Buckingham, J. Dictionary of Natural Products; University
Press: Cambridge MA, 1994.
(4) For selected reviews for the preparation of ethers, see:
(a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; Wiley-VCH: New York, 1999.
(b) Larock, R. C. Comprehensive Organic Transformation,
2nd ed.; Wiley-VCH: New York, 1999.
(5) (a) Dermer, O. C. Chem. Rev. 1934, 14, 385.
R
(b) Williamson, A. W. J. Chem. Soc. 1852, 229.
N
O
N
O
(6) For selected reviews for Ullmann ether formation, see:
(a) Nelson, T. D.; Crouch, R. D. Org. React. 2004, 63, 265.
(b) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. Rev. 2002, 102, 1359. (c) Sawyer, J. S.
Tetrahedron 2000, 56, 5045. (d) Theil, F. Angew Chem. Int.
Ed. 1999, 38, 2345.
(7) (a) Tan, S. N.; Dryfe, R. A.; Girault, H. H. Helv. Chim. Acta
1994, 77, 231. (b) Alvarez-Builla, J.; Vaquero, J. J.; Garcia-
Navio, J. L.; Cabello, J. F.; Sunkel, C.; Fau de Casa-Juana,
M.; Dorrego, F.; Santos, L. Tetrahedron 1990, 46, 967.
(c) Thoman, C. J.; Habeeb, T. D.; Huhn, M.; Korpusik, M.;
Slish, D. F. J. Org. Chem. 1989, 54, 4476.
+
R
Br
H
H
H
10
NaH
R
NaBr
RBr
N
O
H
O
R
R
O
R
13
H
14
N
H
11
(8) (a) Zolfigol, M. A.; Mohammadpoor-Baltork, I.; Habibi, D.;
Mirjalili, B. F.; Bamoniri, A. Tetrahedron Lett. 2003, 44,
8165. (b) Wang, S.; Guin, J. A. Chem. Commun. 2000, 2499.
(9) For Pd-mediated Ullmann modification, see: (a)Torraca, K.
E.; Huang, X.; Parrish, C. A.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 123, 10770. (b) Shelby, Q.; Kataoka, N.; Mann,
G.; Hartwig, J. J. Am. Chem. Soc. 2000, 122, 10718. For
Pd-mediated etherification, see: (c) Miller, K. J.; Abu-
Omar, M. M. Eur. J. Org. Chem. 2003, 1294. (d) Kim, H.;
Lee, C. Org. Lett. 2002, 4, 4369. (e) Fujii, Y.; Furugaki, H.;
Tamura, E.; Yano, S.; Kita, K. Bull. Chem. Soc. Jpn. 2005,
78, 456. (f) Bethmont, V.; Fache, F.; Lemaire, M.
Tetrahedron Lett. 1995, 36, 4235. For Pt-mediated
etherification, see: (g) Verzele, M.; Acke, M.; Anteunis, M.
J. Chem. Soc. 1963, 5598. For Rh-mediated etherification,
see: (h) Busch-Petersen, J.; Corey, E. J. Org. Lett. 2000, 2,
1641. For Zn-mediated etherification, see: (i) Paul, S.;
Gupta, M. Tetrahedron Lett. 2004, 45, 8825.
H
12
Scheme 1 Proposed mechanism for the etherification of alkyl halide
in the presence of NaH and DMF
In conclusion, it was found that the direct etherification of
various halides proceeds smoothly in the presence of
sodium hydride and N,N-dimethylformamide to produce
symmetrical and unsymmetrical ethers in high yields. Fur-
ther exploration of the scope of this reaction is in progress.
(10) Balsells, R. E.; Frasca, A. R. Tetrahedron 1982, 38, 2525.
Synlett 2007, No. 17, 2695–2698 © Thieme Stuttgart · New York

2698
C. H. Jin et al.
LETTER
(11) (a) Emert, J.; Goldenberg, M.; Chiu, G. L.; Valeri, A. J. Org.
Chem. 1977, 42, 2012. (b) Traynelis, V. J.; Hergenrother,
W. L.; Hanson, H. T.; Valicenti, J. A. J. Org. Chem. 1964,
29, 123.
(12) (a) Denton, S. M.; Wood, A. Synlett 1999, 55.
(b) Khanapure, S. P.; Manna, S.; Rokach, J.; Murphy, R. C.;
Wheelan, P.; Powell, W. S. J. Org. Chem. 1995, 60, 1806.
(c) Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49,
1078. (d) Bouveault, L. Bull. Soc. Chim. Fr. 1904, 31, 1306.
(13) (a) Meth-Cohn, O. In Comprehensive Organic Synthesis,
Vol. 2; Trost, B. M.; Fleming, I., Eds.; Pergamon: London,
1991, 777–794. (b) Vilsmeier, A.; Haack, A. Ber. Dtsch.
Chem. Ges. 1927, 60, 119.
Compound 6b: 1H NMR (300 MHz, CDCl3): d = 1.34 (br, 1
H), 1.63–1.79 (m, 4 H), 2.70 (t, J = 7.5 Hz, 2 H), 3.71 (t,
J = 6.3 Hz, 2 H), 7.22–7.36 (m, 5 H). 13C NMR (125 MHz,
CDCl3): d = 27.77, 32.58, 35.87, 63.07, 125.99, 128.54,
128.64, 142.55. 1H NMR and 13C NMR spectra were
identical to an authentic sample.
Compound 7a: 1H NMR (300 MHz, CDCl3): d = 1.45 (d,
J = 6.6 Hz, 6 H), 1.53 (d, J = 6.6 Hz, 6 H), 4.32 (q, J = 6.6
Hz, 2 H), 4.60 (d, J = 6.6 Hz, 2 H), 7.21–7.42 (m, 20 H). 13
NMR (125 MHz, CDCl3): d = 23.23, 24.93, 74.67, 74.89,
126.47, 126.56, 127.37, 127.61, 128.47, 128.69, 144.42,
C
144.50. Products 7a were 1:1 mixture of dl enantiomers and
meso compounds, as illustrated in the literature.19b
(14) Serrano, P.; Llebaria, A.; Delgado, A. J. Org. Chem. 2005,
70, 7829.
Compound 7b: 1H NMR (300 MHz, CDCl3): d = 1.54 (d,
J = 6.6 Hz, 3 H), 2.09 (br, 1 H), 4.93 (q, J = 6.6 Hz, 1 H),
7.31–7.41 (m, 5 H). 13C NMR (125 MHz, CDCl3): d = 25.38,
(15) Kim, J. D.; Han, G.; Zee, O. P.; Jung, Y. H. Tetrahedron
Lett. 2003, 44, 733.
70.65, 125.62, 127.71, 128.74, 146.06. 1H NMR and 13
NMR spectra were identical to an authentic sample.
C
(16) Compound 3a: 1H NMR (300 MHz, CDCl3): d = 4.67 (s, 4
H), 7.40–7.51 (m, 10 H). 13C NMR (125 MHz, CDCl3):
Compound 7c: 1H NMR (500 MHz, CDCl3): d = 5.30 (d,
J = 11.0 Hz, 1 H), 5.81 (d, J = 17.5 Hz, 1 H), 6.78 (dd,
J = 17.5, 11.0 Hz, 1 H), 7.31–7.49 (m, 5 H). 13C NMR (125
MHz, CDCl3): d = 114.04, 126.48, 128.06, 128.78, 137.17,
137.87. 1H NMR and 13C NMR spectra were identical to an
authentic sample.
d = 72.45, 127.95, 128.09, 128.73, 138.66. 1H NMR and 13
C
NMR spectra were identical to an authentic sample.
Compound 3b: 1H NMR (300 MHz, CDCl3): d = 1.71 (br, 1
H), 4.74 (s, 2 H), 7.30–7.43 (m, 5 H). 1H NMR spectrum was
identical to that of an authentic sample.
Compound 4a: 1H NMR (300 MHz, CDCl3): d = 4.27 (dd,
J = 6.0, 1.2 Hz, 4 H), 6.39 (dt, J = 15.6, 6.0 Hz, 2 H), 6.70
(d, J = 15.6 Hz, 2 H), 7.30–7.49 (m, 10 H). 13C NMR (125
MHz, CDCl3): d = 70.99, 126.30, 126.75, 127.93, 128.80,
132.83, 136.99. 1H NMR and 13C NMR spectra were
consistent with literature values.19a
(17) Dalton, D. R.; Smith, R. C.; Jones, D. G. Tetrahedron 2003,
44, 733.
(18) DMF–18O was prepared from chloromethylenedimethyl-
ammonium chloride and H2O-18O (ca. 10 atom%) according
to the literature.17 Mass spectrometric comparison of the
parent ion peak ratios (74 and 76) to that of DMF-16O
indicated that an enrichment of approx. 7.4% of 18O was
present. The mass spectra of dibenzyl ether prepared
from DMF-16O and DMF-18O was compared at m/e 221:223
[M + Na] and indicated that an enrichment of approx. 6.4%
of 18O was present.
Compound 5a: 1H NMR (300 MHz, CDCl3): d = 1.03 (t,
J = 7.5 Hz, 6 H), 2.04–2.14 (m, 4 H), 3.93 (dd, J = 6.3, 1.2
Hz, 4 H), 5.56–5.64 (m, 2 H), 5.72–5.81 (m, 2 H). 13C NMR
(125 MHz, CDCl3): d = 13.53, 25.51, 71.00, 125.57, 136.48.
Compound 6a: 1H NMR (300 MHz, CDCl3): d = 1.66–1.79
(m, 8 H), 2.69 (t, J = 7.5 Hz, 4 H), 3.47 (t, J = 6.3 Hz, 4 H),
7.22–7.36 (m, 10 H). 13C NMR (125 MHz, CDCl3):
d = 28.33, 29.67, 35.99, 70.98, 125.91, 128.51, 128.67,
142.76.
(19) (a) Heaney, F.; Fenlon, J.; O’Mahony, C.; McArdle, P.;
Cunningham, D. Org. Biomol. Chem. 2003, 1, 4302.
(b) Miller, K. J.; Abu-Omar, M. M. Eur. J. Org. Chem. 2003,
1294.
Synlett 2007, No. 17, 2695–2698 © Thieme Stuttgart · New York

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