Novel tandem reaction of benzyne with cyclic ethers and active methines: synthesis of ω-trichloroalkyl phenyl ethers

Article abstract of DOI:10.1016/j.tetlet.2008.03.058

The reaction of benzenediazonium carboxylate with chloroform in refluxing tetrahydrofuran afforded 5,5,5-trichloropentyl phenyl ether in 61% yield along with benzoic acid (7%). When dichloroacetonitrile was used as a reactant, 5,5-dichloro-5-cyanopentyl phenyl ether was obtained in 65% yield. Reactive benzyne derived from diazonium carboxylate initially reacted with THF to give a dipole intermediate, which further reacted with chloroform or dichloroacetonitrile to give ring opened products.

Full text of DOI:10.1016/j.tetlet.2008.03.058

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3063–3066
Novel tandem reaction of benzyne with cyclic ethers and
active methines: synthesis of x-trichloroalkyl phenyl ethers
a,
a
a
a
b
*
Kentaro Okuma , Yuta Fukuzaki , Akiko Nojima , Kosei Shioji , Yoshinobu Yokomori
a Department of Chemistry, Faculty of Science, Fukuoka University, Jonan-ku, Fukuoka 814-0180, Japan
b National Defense Academy, Hashirimizu, Yokosuka, 239-8686, Japan
Received 23 February 2008; accepted 11 March 2008
Available online 14 March 2008
Abstract
The reaction of benzenediazonium carboxylate with chloroform in refluxing tetrahydrofuran afforded 5,5,5-trichloropentyl phenyl
ether in 61% yield along with benzoic acid (7%). When dichloroacetonitrile was used as a reactant, 5,5-dichloro-5-cyanopentyl phenyl
ether was obtained in 65% yield. Reactive benzyne derived from diazonium carboxylate initially reacted with THF to give a dipole
intermediate, which further reacted with chloroform or dichloroacetonitrile to give ring opened products.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
to describe novel tandem reaction of benzyne with cyclic
ethers and active methines.
Arynes are widely used as reactive intermediates and
react with many dienes to afford corresponding cyclo-
adducts.1 Recent reports on the formation of arynes
illustrate the continued interest in this area.2 Recently,
many insertion reaction of benzyne with single bonds con-
taining Sn–Sn, Sn–C, N–C, C–C using o-trimethylsilyl-
phenyl triflate (1) as a benzyne precursor has been
reported.3 Due to our ongoing interest in the exploration
of reactive benzyne for the synthesis of functionalized
S-heterocycles, we have also investigated the synthesis of
benzothietes, benzothianes, and 1,3-benzodithioles by
using 1, benzenediazonium carboxylate (2), or phenyl[o-tri-
methylsilylphenyl]iodonium triflate as benzyne precur-
sors.4,5 Although the insertion reaction of benzyne with
THF and water was reported to produce d-phenoxybutyl-
N-phenylanthranilic acid (17%), and 1,4-diphenoxybutane
(4%) by Wolthuis et al.,6 another type of insertion reaction
of arynes with styrene oxide was recently reported.7 These
results prompted us to investigate further precise reaction
of benzyne with cyclic ethers. In this Letter, we would like
Birkett et al. reported the formation of x-iodoalkyl
o-iodophenyl ethers by tandem reaction of benzyne with
cyclic ethers and N-iodosuccinimide, while the yields were
only 24–35%.8 If more reactive nucleophile is formed in
the reaction, yields of tandem reaction products will be
improved. To confirm this possibility, we first tried the
reaction of benzyne with THF in refluxing chloroform.
The treatment of isolated benzenediazonium carboxylate
2, prepared from anthranilic acid and isoamyl nitrite, with
3 equiv of THF in refluxing chloroform resulted in the
formation of 5,5,5-trichloropentyl phenyl ether (3a) and
benzoic acid (4) in 21% and 11% yields, respectively. When
a mixture of 2 and chloroform (5 equiv) was refluxed in
THF, 3a was obtained in 52% yield along with 4 (8%)
(Scheme 1). To optimize this novel tandem reaction,
we varied the reaction conditions, including benzyne
precursor, temperature, and equivalent of chloroform.
The results are shown in Table 1.
When 20 equiv of chloroform was used in refluxing THF,
5,5,5-trichloropentyl phenyl ether 3a was obtained in 61%
yield along with acid 4 (8%) (entry 1), whereas the reaction
of 3 equiv of chloroform with 2 gave 3a in 42% yield (entry
2). When in situ formed benzenediazonium carboxylate was
*
Corresponding author. Tel.: +81 92 871 6631; fax: +81 92 865 6030.
E-mail address: kokuma@fukuoka-u.ac.jp (K. Okuma).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.058

3064
K. Okuma et al. / Tetrahedron Letters 49 (2008) 3063–3066
N2
O
+
CCl3
O
2
2
or
3a
+
CHCl3
+
CO2H
TMS
+ TBAF
OTf
4
1
Scheme 1.
Table 1
Reaction of benzyne with THF followed by the addition of chloroform
Entry Precursor Chloroform Temperature Time Products
(equiv)
(h)
3a
4
1
2
3
4
5
6
2
20
3
1
5
5
Reflux
Reflux
Reflux
Reflux
rt
2
3
3
3
12
12
61
42 10
18 13
8
—
—
8
2
2
2a
15
—
38
Fig. 1. Ortep drawing of 6,6,6-trichlorohexyl phenyl ether 3b. Selected
bond lengths: C(1)–O(1) 1.364(4), C(7)–(1) 1.441, C(10)–C(11) 1.515(4).
Bond angles: C(1)–O(1)–C(7) 119.0(3), C(11)–C(12)–Cl(1) 110.1(2).
1
o-Carboxybenzene-
diazonium
5
Reflux
chloride
a
Benzenediazonium carboxylate 2 was used without isolation.
(5b) gave 6b in 34% yield. Interestingly, when 2 was added
to a refluxing solution of dichloroacetone (5c) (3 equiv) in
THF, the corresponding O-attacked ether (7) was obtained
in 27% yield (Scheme 3). The results are shown in Table 2.
reacted with chloroform in refluxing THF, 3a was obtained
in only 8% yield (entry 4). By using o-trimethylsilylphenyl
triflate 1 as a benzyne precursor, unidentified complex mix-
ture was produced (entry 5). Additionally, when o-carbo-
xybenzenediazonium chloride was used as a benzyne
precursor, ether 3a was not obtained (entry 6). Thus, iso-
lation of 2 must be required for the completion of the
reaction.
The reaction of 2 with chloroform in tetrahydropyran
(THP) gave 6,6,6-trichlorohexyl phenyl ether (3b) in 40%
yield (Scheme 2). Fortunately, single crystals were
obtained, thus the structure of 3b was confirmed by
X-ray crystallographic analysis9 (Fig. 1).
To investigate the scope and limitation of this novel
tandem reaction, we then tried the reaction of benzyne with
other active methylenes and methines. Unfortunately,
active methylenes such as dichloromethane, malononitrile,
and methyl acetoacetate did not afford the corresponding
tandem reaction products. Then 2 was added to a refluxing
solution of dichloroacetonitrile 5a (5 equiv) in THF, the
corresponding ether (6a) was obtained in 65% yield along
with benzoic acid (8%). Similarly, methyl dichloroacetate
H
R
5a: R=CN
C
5b: R=COOMe
5c: R=COCH
Cl
Cl
O
3
2
O
R'
n
n
6a: n= 2, R'= C(Cl)2CN
6b: n= 2, R'= C(Cl)2COOMe
6c: n= 3, R'= C(Cl)2CN
6d: n= 3, R'= C(Cl)2COOMe
6e: n= 1, R'= C(Cl)2CN
7: n= 2, R'=
O
Cl
H3C
Cl
Scheme 3.
Table 2
Reaction of 2 with active methines in refluxing cyclic ethera
Substrate 5
Cyclic ether
Time (h)
Product
Yield (%)
5a
5a
5a
5b
5b
5c
a
THF
THP
Oxetane
THF
THP
5
3
6
5
5
5
6a
6c
6e
6b
6d
7
65
52
48
34
28
27
O
2
+
O
CCl3
THF
3b
Conditions: 1 mmol of 2, 5 mmol of 5, and 10 mmol of cyclic ether
were used.
Scheme 2.

K. Okuma et al. / Tetrahedron Letters 49 (2008) 3063–3066
3065
CH3
CH3
CH3
O
CH3
N2
-N2, -CO2
O
+
O
CO2
8
a'
a
CH3
CH3
CH3
Cl
Cl
H
O
H
O
H
CCl2(CN)
CCl2(CN)
C
+
O
CN
9a
H
b'
CH3
b
+
H
Cl
Cl
C
O
CN
9b
Scheme 4.
When 6-methylbenzenediazonium 2-carboxylate (8) was
treated with dichloroacetonitrile, 5,5-dichloro-5-cyano-
pentyl o-methylphenyl ether (9a) and 5,5,5-trichloropentyl
m-methylphenyl ether (9b) were obtained in 25% and
17% yields, respectively. Thus, the reaction might proceed
as follows. Carboxylate 5 initially extruded nitrogen and
carbon dioxide to afford benzyne, which reacted with
THF to give THF-stabilized dipole intermediates (a and
a0). These dipoles abstracted the hydrogen of dichloro-
acetonitrile to afford oxonium ions (b and b0) and dichlor-
ocyanomethyl anion. When cations b and b0 were finally
attacked by methyl anion, the corresponding ethers 9a
and 9b were formed (Scheme 4). The reason that complex
mixture was obtained by using 1 as a benzyne precursor
might be the existence of ammonium salt, which prevented
the formation of oxonium ion intermediate b.
intermediate a. Interestingly, when carboxylate 2 was
treated with chloroform in refluxing 2-methyltetrahydro-
furan (10 equiv), two isomers (10a,b) were obtained in
51% yield (10a:10b = 2:5), suggesting that trichloro-
methyl carbanion attacked to the less bulky carbon
(Scheme 5).
Thus, this method provides a new route to x-chlorinated
alkyl phenyl ethers. The extension of this novel tandem
reaction and the application of the x-chlorinated ethers
are in progress.
2. Typical experiment
2.1. Reaction of benzenediazonium carboxylate with
chloroform in THF
Since Birkett et al. denied the existence of initially
formed dipole intermediate a in the reaction of benzyne
prepared from 1-aminobenzotriazole with N-iodosuccin-
imide in THF,8 reaction of benzyne with THF (5 equiv)
was carried out in refluxing CDCl3. The corresponding
o-deuterated 5,5,5-trichloropentyl phenyl ether (95%
deuterated) was obtained in 32% yield, which clearly
showed the hydrogen abstraction of chloroform by
A mixture of benzenediazonium carboxylate 2 (1 mmol),
chloroform (20 mmol), molecular sieves 3 A (0.2 g) in THF
˚
(3 mL) was stirred for 2 h then refluxed for 1 h. The reac-
tion mixture was evaporated to give a brown oil, which
was chromatographed over silica gel by elution with
hexane:ethyl acetate (10:1) to give 5,5,5-trichloropentyl
phenyl ether 3a (0.61 mmol) and benzoic acid (0.08 mmol).
1
Compound 3a: colorless oil H NMR (CDCl3) d 1.84–2.10
(m, 4H, CH2), 2.77 (dd, 2H, J = 7.0 Hz and 7.2 Hz, CH2),
4.01 (t, 2H, J = 5.6 Hz, OCH2), 6.90 (d, 2H, J = 8.0 Hz,
o-Ph), 6.95 (t, 1H, J = 7.2 Hz, p-Ph), 7.24–7.32 (m, 2H,
m-Ph). 13C NMR (CDCl3) d 24.05 (CH2), 28.65 (CH2),
55.37 (CH2), 67.64 (OCH2), 100.28 (q-C), 114.84 (Ph),
121.10 (Ph), 129.76 (Ph), 159.02 (Ph).
O
CH3
CCl3
2 + CHCl3
O
O
CH3
10a
X-ray crystallographic data for 3b: crystal data for
C12H15Cl3O. Mp 50–51 °C. crystallized from dichloro-
methane–hexane. FW 281.59, Monoclinic, space group =
CH3
˚
CCl3
C2/m, a = 21.1430(8), b = 7.3410(3), c = 8.8680(3) A,
3
˚
a = 90.00°, b = 98.181(3)°, c = 90.00°, V = 1362.40(9) A ,
10b
Z = 4, Dx = 1.373 Mg mꢀ3, the final R and wR were
Scheme 5.
0.0867 and 0.2006, respectively, using 1316 reflections.

3066
K. Okuma et al. / Tetrahedron Letters 49 (2008) 3063–3066
M. J. Am. Chem. Soc. 2005, 127, 5340–5341 (C–C bond); Lin, W.;
Appendix A. Supplementary data
Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. 2005, 44, 4258–4261
(N–Mg bond).
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.
03.058.
4. Okuma, K.; Shirokawa, T.; Yamamoto, T.; Kitamura, T.; Fujiwara, Y.
Tetrahedron Lett. 1996, 37, 8883–8886; Okuma, K.; Shiki, K.; Shioji,
K. Chem. Lett. 1998, 79–80; Okuma, K.; Sonoda, S.; Koga, Y.; Shioji,
K. J. Chem. Soc., Perkin Trans. 1 1999, 2997–3000; Okuma, K.; Shiki,
K.; Sonoda, S.; Koga, Y.; Shioji, K.; Kitamura, T.; Fujiwara, Y.;
Yokomori, Y. Bull. Chem. Soc. Jpn. 2000, 73, 155–161; Shigetomi, T.;
Soejima, H.; Nibu, Y.; Shioji, K.; Okuma, K.; Yokomori, Y. Chem.
Eur. J. 2006, 12, 7742–7748.
5. Paquer, D.; Reffet, D.; Andrieu, C. G. Recl. Trav. Chim. Pays-Bas
1978, 97, 88; Nakayama, J.; Kimata, A.; Taniguchi, H.; Takahashi, F.
Bull. Chem. Soc. Jpn. 1996, 69, 2349–2354.
6. Wolthuis, E.; Bouma, B.; Modderman, J.; Sytsma, L. Tetrahedron Lett.
1970, 407–408; Hayashi, S.; Ishikawa, N. Bull. Chem. Soc. Jpn. 1972,
45, 642–644; Hayashi, S.; Ishikawa, N. Bull. Chem. Soc. Jpn. 1975, 48,
1467–1470.
References and notes
1. Reviews: Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Aca-
demic Press: New York, 1967; Gilchrist, T. L. In The Chemistry of
Functional Groups, Supplement C; Patai, S., Rappoport, Z., Eds.;
Wiley: Chichester, 1983, Chapter 11; Hard, H. In The Chemistry of
Triple-bonded Functional Groups, Supplement C2; Patai, S., Ed.; Wiley:
Chichester, 1994, Chapter 18.
2. Kitamura, T.; Yamane, M.; Todaka, M.; Fukatsu, N.; Meng, Z.;
Fujiwara, Y. J. Am. Chem. Soc. 1999, 121, 11674–11679; Sapountszis,
I.; Lin, W.; Fischer, M.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
4364–4366; Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett.
1983, 1211–1214.
7. Beltran-Rodil, S.; Pena, D.; Guitian, E. Synlett 2007, 1308–1310.
8. Birkett, M. A.; Knight, D. W.; Little, P. B.; Mitchell, M. B.
Tetrahedron 2000, 56, 1013–1023.
9. Crystallographic data of 3b was deposited with Cambridge Crystallo-
graphic Centre. Deposition No. CCDC 678705 for phenyl ether 3b.
Copies of the data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html.
3. For some recent representative examples, see: Yoshida, H.; Honda, Y.;
Shirakawa, E.; Hiyama, T. Chem. Commun. 2001, 1880–1881 (Sn–C
bond); Yoshida, H.; Tanino, K.; Ohshita, J.; Kunai, A. Angew. Chem.,
Int. Ed. 2004, 43, 5052–5055 (Sn–Sn bond); Tamber, U. K.; Stoltz, B.