Radical α-C-H hydroxyalkylation of ethers and acetal

Article abstract of DOI:10.1021/jo048248k

(Chemical Equation Presented) Ethers and an acetal were found to undergo direct intermolecular addition to aldehydes under the Et₃B/air conditions. This study presents a very unique and simple means for the radical α-C-H hydroxyalkylation of oxygen-containing compounds.

Full text of DOI:10.1021/jo048248k

Radical r-C-H Hydroxyalkylation of
We have previously reported a novel means for the
Ethers and Acetal
radical C-H transformation of THF with aldehydes using
1
2,13
Et
3
B/air
3
and Et B/tert-butyl hydroperoxide (TB-
HP)1
4,15
(Scheme 1). The ease of operation and relatively
Takehiko Yoshimitsu,* Yoshimasa Arano, and
Hiroto Nagaoka*
mild conditions are the merits of the former, whereas a
short reaction time makes the latter highly efficient. We
have also demonstrated that the direct transformation
of ethereal R-C-H bonds into C-C bonds leads to greater
flexibility in the synthetic design of oxygenated molecular
frameworks (Scheme 2). For instance, the C-H function-
alization of THF enabled the unprecedented chemical
transformation of the common cyclic ether into a γ-(hy-
droxyalkyl)-γ-butyrolactone that serves as a bioactive
Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose,
Tokyo 204-8588, Japan
takey@my-pharm.ac.jp
Received October 5, 2004
(
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Εthers and an acetal were found to undergo direct intermo-
lecular addition to aldehydes under the Et3B/air conditions.
This study presents a very unique and simple means for the
radical R-C-H hydroxyalkylation of oxygen-containing com-
pounds.
1
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(
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Radicals; Kochi, J. K.,Ed.; Wiley-Interscience: New York, 1973; Vol.
Carbon-carbon (C-C) bond formation via the C-H
functionalization of organic molecules is a current topic
of interest in synthetic organic chemistry.1 Ethers and
the derivatives thereof are among the most attractive
substrates in C-H chemistry because of their ubiquity
in molecular architecture. Radical C-H functionalization
is particularly useful for this purpose due to the suscep-
tibility to hydrogen abstraction of C-H bonds R to
ethereal oxygen, which makes possible the selective
chemical transformation.4 Several notable means for
direct C-C bond formation via the radical-mediated
R-hydrogen abstraction of ethers involve the use of triflon
-3
-6
2
, p 63. (l) Giese, B. Radicals in Organic Synthesis: Formation of
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Soc. 1997, 119, 4123-4129 and references therein.
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Yamamoto, Y.; Tomioka, K. Org. Lett. 2003, 5, 1797-1799. (c)
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795-797. (d) Yamada, K.; Yamamoto, Y.; Maekawa, M.; Tomioka, K.
J. Org. Chem. 2004, 69, 1531-1534. (e) Yamamoto, Y.; Maekawa, M.;
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Jpn. 2004, 62, 1158-1165.
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3617-3620.
(10) Kim, S.; Kim, N.; Chung, W.-J.; Cho, C. H. Synlett 2001, 937-
940.
(11) (a) Fernandez, M.; Alonso, R. Org. Lett. 2003, 5, 2461-2464.
(b) Torrente, S.; Alonso, R. Org. Lett. 2001, 3, 1985-1987.
(12) Yoshimitsu, T.; Tsunoda, M.; Nagaoka, H. Chem. Commun.
1999, 1745-1746.
(13) Recent reviews of triethylborane chemistry include: (a) Ollivier,
C.; Renaud, P. Chem Rev. 2001, 101, 3415-3434. (b) Yorimitsu, H.;
Oshima, K. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.: Wiley-VCH: Weinheim, Germany, 2001; Vol. 1, pp 11-27. (c)
O’Mahony, G. Synlett 2004, 572-573.
(14) Yoshimitsu, T.; Arano, Y.; Nagaoka, H. J. Org. Chem. 2003,
68, 625-627.
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68, 7548-7550.
7
8
derivatives, dimethylzinc/air, phthalimide-N-oxyl (PINO)
9
10
radical, 2-chloroethylsulfonyl oxime ethers, and N-acyl
1
1
aldohydrazones.
(
1) Radical C-H functionalization: (a) Crabtree, R. H. Pure Appl.
Chem. 1995, 67, 39-45. (b) Hill, C. L. Synlett 1995, 127-132. (c) Fokin,
A. A.; Schreiner, P. R. Chem. Rev. 2002, 102, 1551-1593.
(
2) For reviews of metal-promoted C-H transformation of organic
molecules, see: (a) Arndtsen, B. A.; Bergman, R. G.; Mobley, T. A.;
Peterson, T. H. Acc. Chem. Res. 1995, 28, 154-162. (b) Shilov, A. E.;
Shulpin, G. B. Chem. Rev. 1997, 97, 2879-2932. (c) Naota, T.; Takaya,
H.; Murahashi, S.-i. Chem. Rev. 1998, 98, 2599-2660. (d) Dyker, G.
Angew. Chem., Int. Ed. 1999, 38, 1698-1712. (e) Guari, Y.; Sabo-
Etienne, S.; Chaudret, B. Eur. J. Inorg. Chem. 1999, 1047-1055. (f)
Kakiuchi, F.; Murai, S. In Activation of Unreactive Bonds and Organic
Synthesis; Murai, S., Ed.; Springer: Berlin, Germany, 1999; pp 47-
7
2
6
1
1
5
9. (g) Murahashi, S.-i.; Takaya, H. Acc. Chem. Res. 2000, 33, 225-
33. (h) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34,
33-639. (i) Murahashi, S.-i.; Takaya, H. Pure Appl. Chem. 2002, 74,
9-24. (j) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102,
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(
m) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861-
903.
2
(3) C-H functionalization with superacids: (a) Olah, G. A.; Moln a´ r,
A. Hydrocarbon Chemistry; Wiley: New York, 1995. (b) Sommer, J.;
Bukala, J. Acc. Chem. Res. 1993, 26, 370-376.
10.1021/jo048248k CCC: $30.25 © 2005 American Chemical Society
2342
J. Org. Chem. 2005, 70, 2342-2345
Published on Web 02/08/2005

3 3
SCHEME 1. r-C-H Hydroxyalkylation of THF with Aldehydes under Et B/Air or Et B/TBHP Conditions
SCHEME 2. r- and r′-C-H Functionalization of
THF
SCHEME 4. Radical Hydroxyalkylation of Ethyl
Vinyl Ether (24)
SCHEME 3. Radical Transformation of the C-H
Bond Adjacent to Ethereal Oxygen
TABLE 1. r-C-H Hydroxyalkylation of THF (1) with
Aldehydes under Et3B/Air Conditionsa
entry
aldehyde
time (h)
yield (%)b
3:4c
1
2
3
4
5
6
4-MeOC6H4CHO a
PhCHO b
13
11
8
83
76
80
82
89:11
86:14
88:12
71:29
64:36
88:12
Piperonal c
2-BrC6H4CHO d
C12H25CHO e
4-MeOC6H4CHO a
5
d
11
33
61
e
78
with continuous bubbling of air through a syringe needle
a
-1
-1
The reaction was carried out with a slight modification of the
original protocol (ref 12); 120 equiv of THF, 6 equiv of Et3B with
with a balloon (flow rate: ca. 30 mL‚h ‚mmol aldehyde ).
It should be emphasized that the flow rate of air strongly
influenced the reaction rate: the reaction was consider-
ably accelerated by the increased admission of air to the
-
1
-1
continuous admission of air (ca. 30 mL‚h ‚mmol aldehyde ).
b
c
1
Isolated yields based on aldehydes. Ratio determined by
H
d
NMR measurement of the threo/erythro mixture. Two-step yields
e
-1
-1
of diastereomeric acetates derived from 3e/4e. Air was introduced
reaction mixture; e.g., ca. 30 mL‚h ‚mmol for 13 h vs
-
1
-1
-1
-1
at a rate of 20 mL‚h ‚mmol aldehyde
.
ca. 20 mL‚h ‚mmol for 33 h was required for the
completion of the R-hydroxyalkylation of THF with
-methoxybenzaldehyde (Table 1, entries 1 and 6).
4
compound as well as a useful building block in organic
synthesis.
In the present study, various ethers and an acetal are
shown to undergo the R-C-H hydroxyalkylation under
3
the Et B/air conditions, thereby demonstrating the wide
applicability of this novel chemistry that provides a
unique methodology for the radical C-H functionaliza-
tion of oxygen-containing molecules (Scheme 3).
We initially set about the optimization of the originally
reported Et
tion of THF. It was found that under the Et
conditions, higher yields of the R-C-H hydroxyalkylation
products were obtained by increasing the amounts of the
1
6
Under the optimized conditions, the C-H hydroxy-
alkylation of several ethers and an acetal with 4-meth-
oxybenzaldehyde was carried out. Table 2 shows that in
addition to THF (1), such ethers and an acetal as diethyl
ether (6), oxetane (8), 2-methyltetrahydrofuran (11), and
1
,3-dioxolane (10) undergo R-C-H hydroxyalkylation to
provide adducts in good yields. Dibutyl ether (7) (64%
yield; dr 71:29), oxepane (9) (63% yield; dr 88:12), butyl
ethyl ether (12) (50% yield; 20:21 ) 58:42; dr 71:29 for
B/air12 conditions for the C-H transforma-
3
2
0, dr 72:28 for 21), and ethylene glycol dimethyl ether
3
B/TBHP
(
13) (55% yield; 22:23 ) 62:38; dr 51:49 for 22) were also
found to afford R-hydroxyalkylated ethers under the same
conditions in moderate yields.17 It is interesting to note
that the threo selectivity was generally observed in this
hydroxyalkylation reaction (entries 1-4 and 7). Unsym-
metrical cyclic ether 11 underwent the hydroxyalkylation
in moderate regioselectivity (C5:C2 ) 54:46). As there
are two hydrogens at C5 and one hydrogen at C2, the
relative reactivity for abstraction per hydrogen was
ether substrate and Et
Et B/air system (Table 1). Thus, aromatic and aliphatic
aldehydes were completely consumed within the time
shown in Table 1 by using excess THF and Et B. A
representative procedure is as follows: to a solution of
aldehyde in THF was added Et B at room temperature
3
B. This is also the case for the
3
3
3
under argon atmosphere. After removal of the argon
balloon, the mixture was stirred at the same temperature
(
17) In the case of THP, however, the yield of the adduct was found
to be low (ca. 20% yield; dr 80:20). This result seems to be related to
the previous observation of the low susceptibility to hydrogen abstrac-
(
16) Yoshimitsu, T.; Makino, T.; Nagaoka, H. J. Org. Chem. 2004,
4
e,f
6
9, 1993-1998.
tion of THP.
J. Org. Chem, Vol. 70, No. 6, 2005 2343

TABLE 2. r-C-H Hydroxyalkylation of Ethers and
Acetal with 4-Methoxybenzaldehyde under Et3B/Air
Conditions
ity to hydrogen abstraction (20:21 ) 58:42) slightly
favoring 1-butoxyethyl radical formation. The relative
reactivity of the methylene and the methyl hydrogen of
1
3 on a per-hydrogen basis was calculated to be 62/4:
8/6 ) ca. 2.5:1. Although the degree of preference in the
3
reaction of ethers 11 and 13 was low, the relative rates
of abstraction of different hydrogens with an ethyl radical
seemed to reflect thermodynamic factors that preferen-
tially produced more stable carbon-centered radicals. In
some cases, ethyl adducts and/or 4-methoxybenzyl alcohol
was produced, but the amounts of the byproducts were
generally negligible (2-7%). The hydroxyalkylation of
ether 13, which showed moderate reactivity toward
hydrogen abstraction, however, was found to provide
somewhat increased amounts of ethyl adduct (8%) and a
reduced product (13%).
When ethyl vinyl ether (24) was subjected to the Et
air-mediated R-C-H hydroxyalkylation, alcohols 21a and
1b favoring the threo isomer (21a:21b ) 72:28) were
obtained in 66% yield along with telomeric adduct 25
10%) (Scheme 4). This indicates that the addition of ethyl
3
B/
2
(
radical to the vinyl group, which is a more exothermic
process than the abstraction of hydrogen R to oxygen, is
predominant due to the small dissociation energy of the
π bond.19 Although the polarity of a nucleophilic ethyl
radical seems to be mismatched with that of electron-
rich olefin 24, ethyl radical addition takes place efficiently
in a relatively short reaction time (ca. 5 h) as the
enthalpic factors may be important in determining the
reaction rate of weak nucleophilic radicals.2
0,21
Thus, an
3
ethyl radical generated from Et B/air rapidly underwent
addition to 24 to give stable but highly nucleophilic
alkoxyalkyl radical 26, which was captured by 4-meth-
oxybenzaldehyde in the presence of an oxophilic and
3
Lewis acidic Et B to afford hydroxyalkylation products
2
1a and 21b (Scheme 5).22 Alcohol 25 was also produced
via the assembly of 4-methoxybenzaldehyde with alkoxy-
alkyl radical 27 generated from the addition of radical
2
6 to vinyl ether 24.
In conclusion, we have demonstrated that the R-C-H
hydroxyalkylation of oxygen-containing molecules such
as ethers and an acetal can be carried out by the use of
a
Aldehyde concentration in ethers or an acetal; all reactions
except entry 4 were carried out with 6 equiv of Et3B (relative to
b
-1
aldehyde). Air was introduced at a rate of ca. 30 mL‚h ‚mmol
aldehyde 1. c Isolated yields based on aldehyde. d Ratios deter-
-
3
Et B/air as the radical reagents. The ease of operation
1
e
mined by H NMR measurement of the threo/erythro mixture. 1-
makes the present method a superior means for the
synthesis of R-substituted ethers and related compounds.
As the intermolecular coupling of ether radicals with
aldehydes is rarely recognized as a strategic means for
C-C bond formation in organic synthesis, the radical
(
(
4-Methoxyphenyl)propan-1-ol (3%) and 4-methoxybenzyl alcohol
6%) were also produced. f Unreacted aldehyde (7%) and 1-(4-
g
methoxyphenyl)propan-1-ol (7%) were obtained. Ratio deter-
h
mined based on separated diastereomers. 10 equiv of Et3B was
i
used. Combined yield of regioisomeric C2/C4 hydroxyalkylation
j
products (C2:C4 ) 68:11). Combined yield of regioisomeric C5/
C2 hydroxyalkylation products (C5:C2 ) 54:46). The stereochem-
k
(19) Comprehensive reviews of the addition of carbon-centered
istry of the adducts has yet to be determined. Combined yield of
radicals to alkenes: (a) Fischer, H.; Radom, L. Angew. Chem., Int. Ed.
regioisomeric products (20:21 ) 58:42). Unreacted aldehyde (30%),
2
2
001, 40, 1340-1371. (b) Giese, B. Angew. Chem., Int. Ed. Engl. 1983,
1
-(4-methoxyphenyl)propan-1-ol (2%), and 4-methoxybenzyl alco-
2, 753-764. (c) Reference 4h. (d) Curran, D. P. In Comprehensive
l
hol (2%) were obtained. Combined yield of regioisomeric products
Organic Synthesis; Trost, B. M., Fleming, I., Semmelhack, M. F.,
Eds.: Pergamon: Oxford, UK, 1991; Vol. 4.
(20) Zytowski, T.; Fischer, H. J. Am. Chem. Soc. 1996, 118, 437-
439.
(
)
22:23 ) 62:38). Unreacted aldehyde (17%), 1-(4-methoxyphenyl-
propan-1-ol (8%), and 4-methoxybenzyl alcohol (13%) were ob-
tained.
(
21) The formation of ethyl radical adducts in this particular case
3
also indicates that under the Et B/air conditions, an ethyl radical
roughly estimated to be C2:C5 ) 46/1:54/2 ) ca. 1.7:1.18
In the case of butyl ethyl ether (12), both R positions
adjacent to ethereal oxygen exhibited similar susceptibil-
serves as the principal radical source whereas an ethoxyl radical, which
is postulated to exist in the reaction mixture, does not. Ethoxyl radical
3
generation in the Et B/air system: Sato, T.; Hibino, K.; Otsu, T. Nippon
Kagakukai Shi 1975, 1080-1084. Also, see: Chung, T. C.; Janvikul,
W.; Lu, H. L. J. Am. Chem. Soc. 1996, 118, 705-706.
(
18) The ratio was calculated without taking into consideration the
(22) Possible precoordination of triethylborane with carbonyl com-
pounds, see: Beraud, V.; Gnanou, Y.; Walton, J. C.; Maillard, B.
Tetrahedron Lett. 2000, 41, 1195-1198.
geometrical effects of the two diastereomeric hydrogens at C5 on the
rate of hydrogen abstraction.
2344 J. Org. Chem., Vol. 70, No. 6, 2005

SCHEME 5. Plausible Mechanism of Hydroxyalkylation of Ethyl Vinyl Ether (24)
C-H transformation of ethers presented in this study
will provide a basis for new C-H transformation chem-
istry.
1-ol (Ac
of the acetates by flash chromatography (Et
the reductive removal of the acetyl group with LAH (quant.).
2
O, Et
3
N, DMAP, CH
2
Cl
2
, rt; 83% yield), the separation
2
O/toluene 1:18), and
-
1 1
threo-Alcohol 14a: IR (neat) ν 3458, 2931 cm ; H NMR (400
MHz, CDCl ) δ 7.32-7.25 (m, 2H), 6.92-6.86 (m, 2H), 4.33 (d,
1H, J ) 8.2 Hz), 3.80 (s, 3H), 3.71 (dq, 1H, J ) 9.3, 7.0 Hz),
.50-3.40 (m, 2H), 1.26 (t, 3H, J ) 7.0 Hz), 0.97 (d, 3H, J ) 6.1
3
Experimental Section
3
General. For details, see the Supporting Information.
Typical Procedure for R-C-H Hydroxyalkylation of
Ethers and an Acetal with 4-meThoxybenzaldehyde under
1
3
Hz); C NMR (100 MHz, CDCl
3
) δ 159.2, 132.6, 128.3, 113.6,
+
8
0.1, 77.8, 64.4, 55.2, 15.6, 15.5; MS m/z 210 (M ), 137 (100%);
+
HRMS (EI) calcd for C12
18 3
H O (M ) 210.1256, found 210.1255.
Et
pan-1-ol (14): To a solution of 4-methoxybenzaldehyde (408 mg,
.0 mmol) in Et O (6) (60 mL, 570 mmol) was added Et B (2.6
3
B/air Conditions. 2-Ethoxy-1-(4-methoxyphenyl)pro-
-1 1
erythro-Alcohol 14b: IR (neat) ν 3446, 2979 cm ; H NMR (400
MHz, CDCl
3
) δ 7.30-7.24 (m, 2H), 6.91-6.85 (m, 2H), 4.80 (d,
3
2
3
1
1
H, J ) 3.8 Hz), 3.8 (s, 3H), 3.64-3.48 (m, 3H), 2.70-1.90 (br s,
mL, 18 mmol) at room temperature under argon atmosphere.
After removal of the argon balloon, the mixture was stirred at
the same temperature with continuous bubbling of air through
1
3
H), 1.2 (t, 3H, J ) 7.0 Hz), 0.98 (d, 3H, J ) 6.3 Hz); C NMR
) δ 158.6, 132.8, 127.4, 113.4, 79.0, 74.6, 64.3,
(
100 MHz, CDCl
3
+
5
5.2, 15.6, 13.5; MS m/z 210 (M ), 137 (100%); HRMS (EI) calcd
-
1
a syringe needle with a balloon (flow rate: ca. 30 mL‚h ‚mmol
+
for C12
18 3
H O 210.1256 (M ), found 210.1250. The NMR spectra
-
1
aldehyde ) for 22 h. [Caution: Triethylborane, a liquid,
pyrophoric toward oxygen, should be handled with care to avoid
direct exposure to air.] The reaction mixture was treated with
of the ethyl adduct and the reduction product were identical with
those of commercially available 1-(4-methoxyphenyl)propan-1-
ol and 4-methoxybenzyl alcohol.
2
8% NH
solution and CH
of an unidentified polar byproduct that may have originated in
4
OH and extracted with CH
2 2 4
Cl . [A 28% NH OH
2
Cl used in combination allow for the removal
2
Acknowledgment. This research was supported by
a Grant-in-Aid for Young Scientists (B) [No. 14771255]
funded by the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
3
Et B. The removal of the polar byproduct in the crude mixture,
which is detectable on an iodine-silica gel TLC plate, may
otherwise be difficult. The crude mixture must be washed with
2
8% NH
4
OH solution for adequate purification.] The organic
Supporting Information Available: Experimental pro-
cedures for the R-C-H hydroxyalkylation of ethers 7, 8, 9, 11,
extract was dried over MgSO
4
. Following solvent evaporation
in vacuo, the residue was purified by silica gel column chroma-
tography (AcOEt/Hex 1:4) to give an inseparable mixture of
alcohol 14 (456 mg, 72%; dr 74:26) and 1-(4-methoxyphenyl)-
propan-1-ol (13 mg, 3%) as a colorless oil, and 4-methoxybenzyl
alcohol (25 mg, 6%) as a colorless oil. Alcohols threo-14a and
erythro-14b were obtained by the following sequence: namely,
acetylation of a mixture of 14 and 1-(4-methoxyphenyl)propan-
1
2, 13, and 24 and acetal 10 and determination of the
stereochemistry of the hydroxyalkylation products, character-
1
13
ization data, and H/ C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO048248K
J. Org. Chem, Vol. 70, No. 6, 2005 2345