Synthetic Study of Selective Benzylic Oxidation

Article abstract of DOI:10.1021/jo962172d

Oxidation of bisbenzyl ethers was studied using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). Compared to other benzylic oxidations such as Kornblum type reaction of benzyl bromides or MnO₂ oxidation of benzyl alcohols, DDQ oxidation offered advantages of being mild and highly selective to provide monoaldehyde products. We have explored factors which influence the course of the reaction and exemplified the synthetic value of the approach by preparing a number of aromatic intermediates (7-8, 15-25).

Full text of DOI:10.1021/jo962172d

6598
J . Org. Chem. 1997, 62, 6598-6602
Syn th etic Stu d y of Selective Ben zylic Oxid a tion
Wuyi Wang,* Tiechao Li, and Giorgio Attardo
BioChem Therapeutic Inc., 275 Armand-Frappier Boulevard, Laval, Que´bec, Canada H7V 4A7
Received November 20, 1996X
Oxidation of bisbenzyl ethers was studied using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ).
Compared to other benzylic oxidations such as Kornblum type reaction of benzyl bromides or MnO2
oxidation of benzyl alcohols, DDQ oxidation offered advantages of being mild and highly selective
to provide monoaldehyde products. We have explored factors which influence the course of the
reaction and exemplified the synthetic value of the approach by preparing a number of aromatic
intermediates (7-8, 15-25).
In tr od u ction
aldehydes. The reaction involves hydride transfer from
an electron-rich system to form an electron-deficient
charge-transfer complex.5 As it is quite evident that such
a process may have great value in selective benzylic
oxidation, we were not aware of any study dealing with
this subject. It is therefore the purpose of this report to
discuss some of our findings with regard to the mecha-
nistic features of selective oxidation of bisbenzyl ethers
using DDQ.6 The evaluation of oxidation conditions and
preparation of some useful aromatic precursors will also
be described.
In organic synthesis, differentiation of identical func-
tional groups is of great desire but often challenging to
achieve. We have recently carried out Kornblum type
reactions1a-c on dibromoxylene (1), to achieve R-bromo-
methylbenzaldehyde2 in a selective manner. The reaction
instead gave an array of oxidized products in which the
desired aldehyde was obtained in only a minor quantity.
A search in the literature for related benzyl bromide
oxidative conversion to the aldehydes3 revealed that such
poor selectivity was not uncommon.4
Resu lts a n d Discu ssion
The benzyl ethers (2-5, 10-14) for this study have
been prepared in a straightforward manner from the
corresponding benzyl bromides via alkoxide replacement.
Oxidation of bisbenzyl ethers 2 and 3 were first examined
using conditions similar to those described in the litera-
ture.5 We found that these ethers could be indeed
oxidized selectively to give clean formation of R-alkoxy-
tolualdehydes 7 (77.5%) and 8 (90%). The selectivity was
not compromised when excessive DDQ (2 equiv) was used
on 8, as ether 3 was the only product obtained. These
results seemed to confirm our hypothesis that the in-
trinsic inertness of the aldehyde product was the key for
selective oxidation.
We next examined oxidation of diethers 11-13 repre-
senting o-, m-, and p-bisbenzyl ethers in order to look at
how aromatic substitution could affect reactivity and
selectivity. All oxidations took place cleanly and yielded
only monoaldehydes 16-18 (Table 1). We found however
that the rate of oxidation followed the order of para >
meta . ortho which was different from para > ortho >
meta as normally seen with electrophilic arene substitu-
tions. As shown in Figure 1, conversions of p- and
m-diethers (13 and 12) to the corresponding aldehydes
were rapid, whereas oxidation of o-diether (11) was
sluggish. As to be further demonstrated in the following
section, these results largely reflected the effect of steric
hindrance.
The low selectivity was presumably caused by the lack
of differentiation between the first and subsequent SN2
bromide substitution step by DMSO (or trialkylamine
N-oxide), a key step in these oxidation processes. On the
other hand, oxidations operating on electron-rich benzylic
systems (such as benzyl ethers 2 and 3) would appear
much more promising in achieving selectivity since
aldehyde product would discourage further such oxida-
tion due to its electron-deficient nature (Scheme 1).
Benzyl ethers have been oxidized by hydride-transfer
agents such as trityl tetrafluoroborate and 2,3-dichloro-
5,6-dicyanobenzoquinone (DDQ) to the corresponding
* Corresponding Author: Tel. (514) 978-7805. Fax (514) 978-7777.
E-mail: Wangwu@biochem-pharma.com.
X Abstract published in Advance ACS Abstracts, September 1, 1997.
(1) (a) Nace, H. R.; Monagle, J . J . J . Org. Chem. 1959, 24, 1792-
1793. (b) Kornblum, N.; J ones, W. J .; Anderson, G. J . J . Am. Chem.
Soc. 1959, 81, 4113-4114. (c) Godfrey, A. G.; Ganem, B. Tetrahedron
Lett. 1990, 23, 4825-4826. (d) Mukaiyama, S.; Inanaga, J .; Yamaguchi,
M. Bull. Chem. Soc. J pn. 1981, 54, 2221-2222. (e) Franzen, V.; Otto,
S. Chem. Ber. 1961, 94, 1360.
Introduction of an electron-donating group greatly
enhanced the rate of product formation without compro-
(2) For preparations of R-halomethyl benzaldehydes, see: (a) Abou-
Teim, O.; J ansen, B. R.; McOmie, J . F. W.; Perry, D. H. J . Chem. Soc.
Perkin Trans. 1 1980, 1841-1846. (b) Kobayashi, K.; Itoh, M.; Sasaki,
A.; Suginome, H. Tetrahedron 1991, 47, 5437-5452.
(3) (a) Angyal, S. J . Org. React. 1954, 8, 197-217; (b) Hass, H. B.;
Bender, M. L. J . Am Chem. Soc. 1949, 71, 1767-1769. (c) Cardillo,
G.; Orena, M.; Sandri, S. J . Chem. Soc. Chem. Commun. 1976, 190.
(d) McKillop, A.; Ford, M. E. Synth. Commun. 1974, 4, 45-50.
(4) Under various conditions R,R'-dibromo xylenes or trisbenzyl
bromides are oxidized to the corresponding benzene di- or
tricarbaldehydes: (a) Feely, W.; Lehn, W. L.; Boekellheide, V. J . Org.
Chem. 1957, 22, 1135. (b) Klandermann, B. H. J . Org. Chem. 1966,
31, 2618. (c) Reid, W.; Komgstein, F.-J . Chem. Ber. 1956, 92, 2532.
(5) (a) Piva, O.; Amougay, A.; Pete, J .-P. Tetrahedron Lett. 1991,
32 , 3993-3996. (b) Lee-Ruff, E.; Ablenas, F. J . Can. J . Chem. 1989,
67, 699-702. (c) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.;
Yonemitsu, O. Tetrahedron 1986, 42, 3061. (d) Nakajima, R. Abe,
Yonemitsu, O. Chem. Pharm. Bull. 1988, 36 (10), 4244-4247. (e) Xu,
Y.-C.; Lebeau, E.; Attardo, G.; Myers, P. L.; Gillard, J . J . Org. Chem.
1994, 59, 4868-4874.
(6) Triphenylcarbenium tetrafluoroborate, a hydride transfer agent,
was briefly examined and found to be less satisfactory.
S0022-3263(96)02172-X CCC: $14.00 © 1997 American Chemical Society

Selective Benzylic Oxidation
J . Org. Chem., Vol. 62, No. 19, 1997 6599
Sch em e 1. Mon o-Oxid a tion of Bisben zyl Eth er s
10 reacted faster than methyl ether 11. These results
suggested that the reaction was also influenced by the
electronic nature (but not the size) of the alkyl group of
the ethers. To establish this point systematically, benzyl
ethers (4-6) carrying groups of different size (therefore
different electronic density) were oxidized. The oxidation
experiments confirmed that the rate of the reaction was
greatly accelerated by electron-donating groups (t-Bu >
i-Pr > Me). It was remarkable that the reaction of tert-
butyl ether 6 was almost instantaneous. The rapid
collapse of the charge-transfer complex was evident as
the isobutene signals (1.73 ppm and 4.66 ppm) as well
as the aldehyde signals for 9 were detected shortly by
1H NMR (carried out in anhydrous CD2Cl2 at room
temperature).
F igu r e 1.
mising the selectivity. As shown in Table 1, compound
14, being an o-diether (as compared with 11), underwent
rapid oxidation to give monoaldehyde 19 in quantitative
yield. The benzyl ether para to the activating methoxy
group was specifically oxidized and the assignment of the
product was established on the basis of the deshielding
effect of the proton signal (at C-5) adjacent to the
aldehyde group.7 Reaction with 14a also proceeded
smoothly to give para-oxidized product 19a as the only
product.8 Oxidations of 14b and 14c were studied to
compare the competition between meta and ortho oxida-
tions. In the case of 14b, o-ether was electronically
favored, but it was as well more hindered by the two
flanking groups. As a result, both 19b and 19c were
obtained in essentially equal amounts. On the other
hand, 14c gave predominantly 19d from ortho oxidation.
These results indicated that the electronic nature played
a major role in determining the regioselectivity of the
reaction. But the reaction course could be altered, as we
saw with 14b and 14c, by the steric hindrance of the
system.
Finally, oxidation of 20 represented an interesting case
where Boc-protected benzyl amine was competing with
benzyl ether. As a result, benzyl carbamate was prefer-
entially oxidized to give aldehyde 8 as the only product.
In an attempt to optimize the oxidation protocol for
synthetic applications, we examined two sets of condi-
tions (damp conditions, A, and anhydrous conditions, B,
see the Experimental Section for details). Under condi-
tion A, water was present during the entire course of the
reaction such that aldehyde would form as soon as the
hydride transfer was complete. Whereas under condition
B, the aldehyde would form after quenching with water.
We found that both conditions were effective for selective
oxidation of activated ethers. However, condition A gave
generally higher yields and was also effective for relative
inert ethers such as 2 and 11, where condition B worked
poorly; A became the standard condition for our selective
oxidation study (Table 1).
Having explored the scope of the oxidation process and
established effective reaction conditions, we carried out
conversions based on initial oxidation products to various
useful intermediates including R-halotolualdehydes men-
tioned earlier in this report. These aldehydes were used
recently to generate 1-hydroxy quinodimethane9 thereby
serving as useful synthons for podophyllotoxin type of
molecules.10 Thus starting from aldehyde 8, aldehyde 21
(similarly, iodo analog 21a ) was obtained in one step
We have made further observations as we explored
other factors affecting the oxidation process. Comparing
o-ethers 2 and 3, the latter carrying the bulkier isopropyl
group reacted faster than 2. Similarly, isopropyl ether
(7) The assignment was further supported by the 1H-13C correlation
that the aldehyde carbon correlated with the C-5 proton but not with
the C-2 proton.
(8) Compounds 14, 14a , and 14c were highly reactive. Prolonged
exposure to DDQ resulted in formation of a considerable amount of
dialdehydes.
(9) Attardo, G.; Wang, W.; Kraus, J .-L.; and Belleau, B. Tetrahedron
Lett. 1994, 27, 4743-4746.
(10) Choy, W. Tetrahedron 1990, 46, 2281-2286.

6600 J . Org. Chem., Vol. 62, No. 19, 1997
Wang et al.
Ta ble 1
using a trimethylsilyl halide-mediated halogenation reac-
tion11 (Scheme 2).
Sch em e 2
The sequence of 1 f 3 f 8 represented a novel
approach for differentiating identical functional groups,
thereby providing useful means to obtain multifunctional
aromatic intermediates. As an example, 23 (difficult to
obtain otherwise) was cleanly derived from 8 and then
oxidized to 21 in high yield. In addition, 23 was also used
to prepare R-azidotolualdehyde 25 in 95% yield (Scheme
3).
zopyran molecules such as isochromans starting with
bromide 23.12 We are currently investigating synthesis
of other useful aromatic templates.
The selective oxidation approach has also been used
for synthesis of other systems. We have prepared ben-
(11) For halogenation of ethers, see: J ung, M. E.; Lyster, M. A. J .
Org. Chem. 1977, 42, 3761-3765.
(12) Unpublished results.

Selective Benzylic Oxidation
Sch em e 3
J . Org. Chem., Vol. 62, No. 19, 1997 6601
drofuran were used as received without further purification.
In the cases where anhydrous conditions were required,
anhydrous solvents purchased from Aldrich Chemical Com-
pany were used under the protection of nitrogen. The products
were purified by flash chromatography (silica gel 60, 0.040-
0.065 mm/230-400 mesh).
Gen er a l P r oced u r e for P r ep a r a tion of isop r op yl Ben -
zyl Eth er s.15 A solution of 2-propanol (2.62 mL, 34.2 mmole)
in 30 mL of THF was slowly added to a prestirred mixture of
sodium hydride (60%, 1.60 g, 39.0 mmol) and dibromide 1 (5.00
g, 15.0 mmol) in 30 mL of THF. The mixture was stirred at
rt for 4 h then quenched with water. The ethyl acetate extract
(500 mL) was washed with water (150 mL) and brine (150 mL)
and dried over magnesium sulfate. The desired ether 3 was
obtained as a white solid (3.46g, 79%) after chromatography
(eluent, hexane:ether ) 10:3): mp 44-45 °C; 1H NMR (δ) 1.20
(12 H, d, J ) 7.5 Hz), 3.69 (2H, sept., J ) 7.5 Hz), 3.77 (6H, s)
4.63 (4H, s), 6.77 (2H, s); 13C NMR (δ) 22.21, 55.60, 60.67,
71.16, 112.12, 128.07, 152.68; MS 282 (M+, 12), 222 (80), 180
(100), 149 (20); HRMS calcd 282.1831, found 282.1833.
Eth er 5: oil, 80%; 1H NMR (δ) 1.26 (6H, d, J ) 7.7 Hz),
3.79 (6H, s), 3.82 (1H, m), 4.56 (2H, s), 6.76 (1H, d, J ) 2.2
(a) NaBH4/MeOH, 0 °C to rt to give alcohol 22, 93%; then, CBr4/
Ph3P or Ph3P‚Br2, 90%; (b) NaN3/DMSO; (c) DDQ, condition A.
As discussed, the classical Kornblum reaction, as a
method for aldehyde synthesis, largely failed to afford
single oxidation amid multiple benzyl bromides. A recent
study on MnO2 oxidation of bisbenzyl alcohols13 also
suggests that it is challenging to achieve selective ben-
zylic oxidation. As demonstrated, the free radical pro-
cess, while achieving marginal single oxidation of m- and
o-bisbenzyl alcohols, failed to selectively oxidize the
p-counterpart. In the light of these results, the level of
selectivity in DDQ-effected oxidation is truly remarkable.
Despite wide use of DDQ as a mild oxidizing agent, it
has not been studied in the systems where reaction
selectivity is an issue. Our results have demonstrated
that the benzylic oxidation could be modulated by factors
of both electronic and steric origins, allowing excellent
selectivity and chemical yields, and DDQ is perhaps the
most suitable reagent6 for these transformations.
To conclude, we have studied selective oxidation using
DDQ and shown that chemically equivalent benzyl ethers
can be effectively differentiated. We have explored
factors affecting the course of the reaction and found that
both electronic and steric factors are important for the
outcome of the reactions. Our finding that oxidation is
encouraged by an electron-releasing ether alkyl group is
of synthetic value for effective oxidation of relative inert
o,o′-bisbenzyl ether. The fact that the reaction rate is
reduced by aromatic but not side chain steric hindrance
is also revealing. It suggests that an initial aromatic
stacking is perhaps required, which seems to depend on
the steric environment of the ring as well as the electronic
density of the entire system.14 The knowledge we ac-
quired during this investigation on the reactivity of
benzyl carbamate versus benzyl ether could be used for
selective chemical manipulations. Finally, the prepara-
tion of intermediates 7, 8, and 15-25 has demonstrated
that DDQ-based selective benzylic oxidation is a viable
approach that should find wide synthetic applications.
Hz), 6.77 (1H, s), 7.07 (1H, d, J ) 2.2 Hz);
13C NMR (δ) 21.28,
54.69, 54.96, 63.71, 70.34, 110.22, 111.49, 128.00, 150.06,
152.79; MS 210 (M+, 90), 167 (17), 151 (100), 137 (90), 121
(80); HRMS calcd 210.1256, found 210.1265.
Eth er 10: oil, 75%; 1H NMR (δ) 1.25 (12H, d, J ) 6.3 Hz),
3.72 (2H, m), 4.61 (4H, s), 7.28 (2H, dd, J ) 3.5 Hz, 5.5 Hz),
7.42 (2H, dd, J ) 3.5 Hz, 5.5 Hz); 13C NMR (δ) 21.2, 66.8, 70.1,
126.6, 127.7, 136.0; MS (CI) 223 (M + H+, 100), 163 (60), 120
(17); HRMS (CI) calcd 223.1698, found 223.1702.
Gen er a l P r oced u r e for th e P r ep a r a tion of Meth yl
Ben zyl Eth er s. A solution of bis- or monobenzyl bromide was
treated with excessive commercially available sodium meth-
oxide (1-2 equiv of the bromide) and stirred at room temper-
ature for a few hours until the reaction was complete. The
crude product was purified by flash chromatography using
ether/hexane as a eluent system.
1
Eth er 2: oil, 100%; H NMR (δ) 3.43 (6H, s), 3.82 (6H, s),
4.61 (4H, s), 6.85 (2H, s); 13C NMR (δ) 55.5, 57.4, 64.0, 110.9,
126.4, 151.6; MS 226 (M+, 28), 194 (95), 179 (100); HRMS calcd
226.1205, found 226.1202.
1
Eth er 4: oil, 84%; H NMR (δ) 3.34 (3H, s), 3.78 (3H, s),
3.79 (3H, s), 4.49 (2H, s), 6.80 (2H, s), 6.98 (1H, s); 13C NMR
(δ) 54.76, 55.02, 57.44, 68.47, 110.39, 112.20, 113.66, 126.75,
150.32, 152.69; MS 182 (M+, 100), 151 (73), 121 (34); HRMS
calcd 182.0943, found 182.0948.
P r ep a r a t ion of E t h er 6 (Sim ila r t o Livin gh ou se’s
Con d ition s16). To a solution of benzyl alcohol (1g, 6.06 mmol)
in 5 mL of dichloromethane cooled to -78 °C was condensed
5 mL of isobutene. To this well-stirred bilayer mixture was
added catalytic amount of triflic acid (70 µL, 0.79 mmole). The
dark-green mixture was stirred at -5 °C for 2 h to become a
solution with lightened color. Triethylamine (253 µL, 1.81
mmole) was added and the resulting product mixture was
washed with sodium bicarbonate solution. The organic layer
was dried and then evaporated. The desired product was
obtained from chromatographic purification (hexane:ether) (oil,
44%): 1H NMR (δ) 1.33 (9H, s), 3.80 (6H, s), 4.52 (2H, s), 6.77
(2H, m), 7.13 (1H, d, J ) 2.2 Hz); 13C NMR (δ) 27.00, 54.97,
55.05, 57.98, 72.61, 110.04, 111.02, 113.04, 129.00, 150.01,
152.09; MS 224 (M+, 90), 151 (100), 121 (30); HRMS calcd
224.1412, found 224.1408.
P r ep a r a tion of Eth er 14. To a solution of 3,4-dimethyl-
anisole (4.30 g, 31.6 mmole) in anhydrous carbon tetrachloride
(100 mL) was added N-bromosuccinimide (11.4 g, 63.8 mmole)
and a catalytic amount of AIBN (0.100 g). The mixture was
refluxed for 4 h. It was cooled to 50 °C and filtered. The
filtrate was evaporated and the product was purified by
Exp er im en ta l Section
Chemicals described in the study, such as 2,3-dichloro-5,6-
dicyanobenzoquinone, chlorotrimethylsilane, triphenyl phos-
phine dibromide, sodium methoxide, isobutene, were all
purchased from Aldrich Chemical Co. Reagent grade solvents
such as dichoromethane, chloroform, methanol, and tetrahy-
(15) For general benzyl ether synthesis, see: (a) Ortiz, B; Walls,
F.; Yuste, F.; Barrios, H.; Sanchez-Obregon, R.; Pinelo, L. Synth.
Commun., 1993, 23 (6), 749-756. (b) Blagg, J .; Davies, G. S.; Holman,
N. J .; Laughton, C. A.; Mobbs, B. J . Chem. Soc. Perkin Trans. 1 1986,
1581-1589. (c) Mann, S. J . Chem. Soc. 1954, 2819-2825.
(13) Constantinides, I.; Macomber, R. S. J . Org. Chem. 1992, 57,
6063-6067.
(14) The 5-bromo analog of ether 3 underwent only slow oxidation
(5% of product) using method A.
(16) Holcombe, J . L.; Livinghouse, T. J . Org. Chem. 1986, 111-113.

6602 J . Org. Chem., Vol. 62, No. 19, 1997
Wang et al.
chromatography using hexane to give the desired product as
a liquid (8.83 g, 94%): 1H NMR (δ) 3.83 (3H, s), 4.64 (2H, s),
4.67 (2H, s), 6.84 (1H, dd, J ) 8.5 and 2.7 Hz,), 6.92 (1H, d, J
) 2.7 Hz), 7.30 (1H, d, J ) 8.5 Hz); 13C NMR (δ) 29.1, 29.7,
54.5, 113.7, 115.6, 127.6, 131.6, 137.1, 159.2; 4 g of the above-
obtained product (13.6 mmole) was converted to the ether
product 14 according to the general procedure for preparation
of methyl benzyl ethers as mentioned above (2.27 g, 85%, as
an oil): 1H NMR (δ) 3.36 (3H, s), 3.42 (3H, s,), 3.82 (3H, s),
4.44 (2H, s), 4.53 (2H, s), 6.80 (1H, dd, J ) 8.3 and 2.7 Hz),
6.92 (1H, d, J ) 2.7 Hz), 7.26 (1H, d, J ) 8.3 Hz); 13C NMR (δ)
54.3, 56.9, 57.4, 70.9, 71.0, 11.65, 113.0, 127.1, 129.7, 137.5,
158.5; MS 196 (M+, 2), 164 (95), 149 (100); HRMS calcd
196.1099, found 196.1106.
70.63, 110.29, 110.73, 126.06, 130.36, 150.87, 151.06.
A
solution of this compound (22, 0.99 g, 4.14 mmole) in 80 mL
of THF was treated with triphenylphosphine (2.28g, 8.69
mmol) and carbon tetrabromide (2.88g, 8.69 mmole) and
stirred for 30 min at rt then filtered. The filtrate was
evaporated and the crude product was chromatographed to
give 1.17 g (94%) of desired bromide 23: mp 34-35 °C; 1H
NMR (δ) 1.23 (6H, d, J ) 6.3 Hz), 3.72 (1H, sept., J ) 6.3 Hz),
3.77 (3H, s), 3.84 (3H, s), 4.67 (2H, s), 4.77 (2H, s), 6.78 (1H,
d, J ) 8 Hz), 6.82 (1H, d, J ) 8 Hz); 13C NMR (δ) 21.18, 24.56,
55.40, 55.61, 59.31, 70.60, 110.84, 111.72, 126.31, 126.90,
151.08, 151.10; MS 304 (M+ + 2, 35), 302 (M+, 35), 181 (100);
HRMS calcd 302.0517, found 302.0526.
P r ep a r a tion of r-Azid otolu a ld eh yd e 25. Compound 23
(200 mg, 0.66 mmol) was stirred at rt in DMF (10 mL) with
sodium azide (64 mg, 0.99 mmole) for 2 h. The reaction
mixture was poured into water and extracted with ethyl
acetate to give azido product 24 (183 mg, 100%): 1H NMR (δ)
1.24 (6H, d, J ) 4.5 Hz), 3.73 (1H, m), 3.80 (3H, s), 3.86 (3H,
s), 4.70 (2H, s), 4.80 (2H, s), 6.80 (1H, d, J ) 6.8 Hz), 6.86
(1H, d, J ) 6.8 Hz); 13C NMR (δ) 21.20, 44.40, 55.06, 59.48,
70.42, 110.18, 111.30, 124.21, 126.49, 151.16, 151.62; MS 265
(M+, 30), 179 (30), 164 (100); HRMS calcd 265.1426, found
265.1431; IR, NaCl film, cm-1, 2975.4, 2091.9, 1488.1, 1259.3,
1097.2, 1052.7, 804.8, 719.9. A sample of this product (31 mg,
0.118 mmol) in 5 mL of dichloromethane and 0.5 mL of water
was treated with DDQ (80.6 mg, 0.355 mmol) and the reaction
mixture was vigorously stirred at room temperature for 36 h.
The mixture was washed with sodium bicarbonate (saturated)
and brine and dried over magnesium sulfate. Desired product
25 (28 mg) was obtained (95%): mp; 112-113 °C; 1H NMR (δ)
4.89 (3H, s), 4.90 (3H, s), 5.08 (2H, s), 6.98 (1H, d, J ) 6.1
Hz), 7.12 (1H, d, J ) 6.1 Hz), 10.63 (1H, s); 13C NMR (δ) 22.83,
55.38, 55.72, 75.76, 76.08, 76.40, 111.29, 116.90, 121.61,
127.21, 150.78, 156.24, 191.09; IR, NaCl film, cm-1, 2971.1,
2104.5, 1729.5, 1680.0, 1489.0, 1435.9, 1276.7, 1092.6, 1073.6,
817.3, 718.2; MS 221 (M, 7), 193 (8), 178 (100), 164 (95), 148
(52), 135 (53); HRMS calcd 221.0800, found 221.0804.
P r ep a r a tion of 20. A methanolic solution of 24 (100 mg,
0.38 mmole, 15 mL) containing di-tert-butyl dicarbonate (123
mg, 0.566 mmole) was catalytically hydrogenated (Pd/C/10%,
H2, 1 atm, 40 mg, 0.038 mmole) for 2 h at rt. The catalyst
was filtered and the filtrate was evaporated to give a product
which was further purified to give the desired product (112
mg, oil, 87%): 1H NMR (δ) 1.24, (6H, d, J ) 7.5 Hz), 1.44 (9H,
s), 3.77 (1H, m), 3.79 (6H, s), 4.45 (2H, d, J ) 5Hz), 4.66 (2H,
s), 5.45 (1H, s), 6.80 (2H, m); 13C NMR (δ) 21.20, 27.53, 35.19,
55.30, 55.60, 59.85, 70.51, 77.68, 110.17, 110.49, 126.12,
127.89, 151.28, 154.73; MS 339 (M+, 8), 209 (100), 167 (50);
HRMS calcd 339.2046, found 339.2051.
Gen er a l P r oced u r es for Selective Oxid a tion . Meth od
A.5c To diether in 10:1 dichloromethane:water (0.02-0.07 M)
was added DDQ and the reaction mixture was vigorously
stirred at room temperature. The mixture was then washed
with sodium bicarbonate (saturated) and brine and dried over
magnesium sulfate. After solvent was evaporated, the crude
product was further purified by chromatography.
1
Ald eh yd e 16: oil, 53%, H NMR (δ) 3.47 (3H, s), 4.85 (2H,
s), 7.45 (1H, m), 7.59 (1H, m), 7.84 (1H, d, J ) 7.6 Hz), 10.20
(1H, s); 13C NMR (δ) 57.67, 70.91, 126.81, 127.14, 131.50,
132.45, 132.89, 139.87, 191.81; MS 150 (M, 40), 135 (100), 118
(56), 105 (8), 90 (5); HRMS calcd, 150.0681, found 150.0684.
Meth od B. To a solution of benzyl ether (0.02-0.07 M in
dichloromethane) was added DDQ (1.5 equiv). The reaction
mixture was stirred at room temperature (or reflux for inert
ethers) overnight or longer. Then the mixture was washed
with sodium bicarbonate solution (saturated) and brine. After
evaporation of the solvent and rapid chromatographic purifica-
tion (eluent, ethyl acetate:hexane), the desired aldehyde was
obtained.
Ald eh yd e 7: oil, four days, excess DDQ, ∼50% (Method A,
three days, 77.5%); 1H NMR (δ) 3.40 (3H, s), 3.81 (3H, s), 3.83
(3H, s), 4.77 (2H, s), 6.93 (1H, d, J ) 9.2 Hz), 7.07 (1H, d, J )
9.2 Hz), 10.54 (1H, s); 13C NMR (δ) 55.4, 55.8, 57.6, 62.6, 111.5,
116.4, 124.3, 126.6, 151.6, 151.3, 155.2, 191.5; HRMS calcd
210.0896, found 210.0890.
Con ver sion of 8 to r-Ha lotolu a ld eh yd es 21 a n d 21a .
A solution of compound 8 in dichloromethane (0.05 M) was
treated with 3 equiv of trimethylsilyl bromide (or TMSI). The
reaction mixture was stirred overnight at rt and then washed
with sodium bicarbonate (saturated). Solvent was evaporated
1
to give desired product 21 (65%): mp 72-73 °C; H NMR (δ)
3.86 (3H, s), 3.87 (3H, s), 5.05 (2H, s), 6.94 (1H, d, J ) 10.6
Hz), 7.08 (1H, d, J ) 10.6 Hz), 10.60 (1H, s); 13C NMR (δ) 42.92,
55.36, 55.56, 111.69, 116.64, 123.12, 123.93, 151.28, 155.59,
191.19; MS 260 (M+ + 2, 31), 258 (M+, 32), 179 (100), 164 (20),
149 (18); HRMS calcd, 257.9891, found 257.9886.
Iod id e 21a (60%): mp 110-112 °C 1H NMR (δ) 3.85 (3H,
s), 3.90 (3H, s), 5.01 (2H, s), 6.90 (1H, d, J ) 10 Hz), 7.03 (1H,
d, J ) 10 Hz), 10.62 (1H, s); 13C NMR (δ) -3.94, 55.33, 55.47,
110.90, 116.65, 120.71, 129.43, 150.42, 156.40, 191.27; MS (M+,
7), 179 (100), 149 (10), 121 (15), 91 (23); HRMS calcd 305.9753,
found 305.9756.
Con ver sion of 8 to 23. Aldehyde 8 (1.04 g, 4.37 mmole)
in THF:MeOH (36 mL:8 mL, 0.09M) was reduced by sodium
borohydride (165.32 mg, 4.37 mmole) for 15 min as it warmed
from 0 °C to rt, to give, after acidic workup, the corresponding
alcohol 22 (1.04g, 99%): 1H NMR (δ) 1.20 (6H, d, J ) 6.1 Hz),
3.50 (1H, br s), 3.74 (1H, sept. J ) 6.1 Hz), 3.76 (3H, s), 3.78
(3H, s), 4.68 (2H, s) 4.72 (2H, s), 6.78 (1H, d, J ) 11 Hz), 6.81
(1H, d, J ) 11 Hz); 13C NMR (δ) 21.14, 55.35, 55.47, 59.94,
Ack n ow led gm en t . We thank Drs. L. Chan, J .-F.
Lavalle´e and J . W. Gillard for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Spectral data for
compounds 8, 11-13, 14a -c, 15, 17-19, and 19a -e, including
1
copies of H NMR, 13C NMR, low-resolution mass, and high-
resolution mass spectra (126 pages). This material is con-
tained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O962172D