Stereoselective and regioselective reaction of cyclic ortho esters with phenols

Article abstract of DOI:10.1021/jo005736t

Cyclic ortho esters undergo stereoselective and regioselective reaction with phenols when treated with BF₃·OEt₂ at low temperatures. Attack of the phenol on the ortho ester occurs at an open carbon para to electron-donating groups on the phenol ("C-addition") or at the phenolic hydroxyl group ("O-addition") depending on the nature of the cation formed from reaction of the ortho ester and BF₃·OEt₂. Products resulting from O-addition undergo reversion to a mixture of starting phenol, C-addition product, and O-addition product if treated with BF₃·OEt₂ at room temperature, but C-addition products are stable under the same conditions. X-ray structural analysis of the C-addition compound indicates that its stereochemistry is opposite to that observed in reaction of similar ortho esters with chloride from TMSCl. However, the stereochemistry of the reaction can be rationalized by the ability of the ortho ester to isomerize via an intermediate benzylic cation and examination of the preferred trajectory of attack of the nucleophile on the intermediate oxonium ion.

Full text of DOI:10.1021/jo005736t

3
084
J . Org. Chem. 2001, 66, 3084-3089
Ster eoselective a n d Regioselective Rea ction of Cyclic Or th o Ester s
w ith P h en ols
J oseph J . Bozell,* Darrin Miller,1a Bonnie R. Hames, and Cheryl Loveless1b
National Renewable Energy Laboratory, 1617 Cole Boulevard, Golden, Colorado 80401
Received November 16, 2000
Cyclic ortho esters undergo stereoselective and regioselective reaction with phenols when treated
with BF
3
2
‚OEt at low temperatures. Attack of the phenol on the ortho ester occurs at an open
carbon para to electron-donating groups on the phenol (“C-addition”) or at the phenolic hydroxyl
group (“O-addition”) depending on the nature of the cation formed from reaction of the ortho ester
and BF
3
‚OEt
2
. Products resulting from O-addition undergo reversion to a mixture of starting phenol,
‚OEt at room temperature, but
C-addition product, and O-addition product if treated with BF
3
2
C-addition products are stable under the same conditions. X-ray structural analysis of the C-addition
compound indicates that its stereochemistry is opposite to that observed in reaction of similar ortho
esters with chloride from TMSCl. However, the stereochemistry of the reaction can be rationalized
by the ability of the ortho ester to isomerize via an intermediate benzylic cation and examination
of the preferred trajectory of attack of the nucleophile on the intermediate oxonium ion.
In tr od u ction
Cyclic ortho esters such as 1 are valuable intermedi-
Sch em e 1
2
ates for a variety of synthetic transformations. Upon
treatment with a Lewis acid they are converted into
highly stabilized ambident oxonium ions 2 (Scheme 1).3
The oxonium ions undergo reaction with nucleophiles at
either C-2 or C-4/5 depending on the nature of the
Sch em e 2
4
5
nucleophile. Hard nucleophiles, such as silyl enol ethers,
6
7
cuprates and titanium enolates, add at C-2 in a kineti-
cally controlled process, whereas soft nucleophiles, such
as alcohols and phenols or Co(CO)
8
-
9
4
anion, add at C-4/5
in a thermodynamic process. Silylated nucleotides react
at either site depending on reaction conditions.10
(1) (a) NREL Undergraduate Research Internship Program partici-
pant. (b) 2000 Energy Research Undergraduate Laboratory Fellowship
participant.
(2) Pindur, U. In The Chemistry of Acid Derivatives; Patai, S., Ed.;
Wiley: New York, 1992; Vol. 2, p 967.
(
(
3) Perst, H. Oxonium Ions; Academic Press: New York, 1971.
4) Pindur, U.; Muller, J .; Flo, C.; Witzel, H. Chem. Soc. Rev. 1987,
1
6, 75.
(5) Hayashi, Y.; Wariishi, K.; Mukaiyama, T. Chem. Lett. 1987, 1243.
6) Ghribi, A.; Alexakis, A.; Normant, J . F. Tetrahedron Lett. 1984,
(
2
4
357. (b) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J .
As part of our program to develop renewable biomass
as a raw material for chemical production, we required
a stereospecific synthesis of compounds 5 for the prepa-
Am. Chem. Soc. 1995, 117, 3448.
8) (a) Defaye, J .; Gadelle, A.; Pedersen, C. Carbohydr. Res. 1990,
05, 191. (b) Fujioka, H.; Kitagawa, H.; Kondo, M.; Matsunaga, N.;
11
(
2
Kitagaki, S.; Kita, Y. Heterocycles 1993, 35, 665. Hartmann, C.; Heine,
H.-G. Synthesis 1982, 952.
ration of materials that model lignin, a highly underused
source of renewable carbon (Scheme 2).
12
(
9) Chatani, N.; Kajikawa, Y.; Nishimura, H.; Murai, S. Organome-
tallics 1991, 10, 21.
10) (a) Liang, C.; Lee, D. W.; Newton, G.; Chu, C. K. J . Org. Chem.
995, 60, 1546. (b) Branalt, J .; Kvarnstrom, L.; Classon, B.; Samuels-
son, B. J . Org. Chem. 1996, 61, 3599.
11) (a) Bozell, J . J ., Ed. Chemicals and Materials from Renewable
Conventional synthesis of compounds such as 5 com-
(
13
monly gives mixtures of diastereomers. Stereoselective
1
syntheses of these compounds have been reported, but
only for dimeric and a few trimeric examples.1 Synthesis
of higher oligomers, more representative of the actual
4
(
Resources; ACS Symposium Series; American Chemical Society: Wash-
ington, DC, 2001, in press. (b) Bozell, J . J .; Moens, L.; Elliott, D. C.;
Wang, Y.; Neuenscwander, G. G.; Fitzpatrick, S. W.; Bilski, R. J .;
J arnefeld, J . L. Resour. Conserv. Recycl. 2000, 28, 227. (c) Bozell, J .
J .; Hoberg, J . O.; Dimmel, D. R. Tetrahedron Lett. 1998, 39, 2261. (d)
Bozell, J . J .; Hoberg, J . O.; Claffey, D.; Hames, B. R.; Dimmel, D. R.
In Green Chemistry: Frontiers in Benign Chemical Synthesis and
Processing; Anastas, P. T., Williamson, T., Eds.; Oxford University
Press: New York, 1998; Chapter 2. (e) Bozell, J . J .; Hames, B. R.;
Dimmel, D. R. J . Org. Chem. 1995, 60, 2398. (f) Hoberg, J . O.; Bozell,
J . J . Tetrahedron Lett. 1995, 36, 6831. (g) Dimmel, D. R.; Pan, X.;
Bozell, J . J .; J . Wood Chem. Technol. 1996, 16, 205.
(12) Lignin, the structural material in woody plants, makes up as
much as 30% of the carbon bound in organic matter. Fengel, D.;
Wegener, G. Wood: Chemistry, Ultrastructure and Reactions; Walter
DeGruyter: New York, 1984; Chapter 6.
(13) (a) Adler, E.; Lingren, B. O.; Saeden, U. Svensk Paperstidin.
1952, 55, 245. (b) Miksche, G. E.; Gratzl, J .; Fried-Matzka, M. Acta
Chem. Scand. 1966, 20, 1038. (c) Brunow, G.; Sipila, J .; Lundquist,
K.; Von Unge, S. Cell. Chem. Technol. 1988, 22, 191. (d) Landucci, L.;
Geddes, S. A.; Kirk, T. K. Holzforschung 1981, 35, 66.
1
0.1021/jo005736t CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/06/2001

Reaction of Cyclic Ortho Esters with Phenols
J . Org. Chem., Vol. 66, No. 9, 2001 3085
Sch em e 3
Sch em e 4
lignin structure, results in complex mixtures of isomers
as the number of chiral centers in the molecule in-
creases.15 We felt that setting the stereochemistry of the
R and â carbons early in the synthesis via ortho ester 3
could avoid these problems and lead to a stereoselective
preparation of models 5a or 5b upon reaction of 3 with a
Lewis acid and a phenol. Formation of oxonium ion 4
would be expected to exert a significant influence on the
direction of attack of the incoming phenol. We wish to
report a new stereoselective and regioselective arylation
of cyclic ortho esters that should be useful for the
preparation of a variety of novel compounds.
elaborated 10a and 10c.19 Deacylation to give product
1
0c appears to be Lewis acid induced because replace-
ment of BF ‚OEt with stronger Lewis acids (SnCl , TiCl )
3
2
4
4
leads to higher relative amounts of 10c, although overall
reaction yields are much lower. Product 10c also appears
at longer reaction times in the presence of BF
3
2
‚OEt .
Compound 10a was analyzed by X-ray diffraction to
indicate that reaction of 8 and 9 occurred to give the
relative stereochemistry shown in Scheme 4. The H-C
-H dihedral angle for 10a is estimated from the X-ray
data to be 169°, meaning that the observed H /H
coupling constant of 5-7.5 Hz is somewhat smaller than
expected from the Karplus equation. However, the pres-
R
-
Resu lts a n d Discu ssion
C
â
Or th o Ester Syn th esis. The starting ortho esters
were prepared as shown in Scheme 3. Starting cinnama-
tes 6 were commercially available or prepared in >90%
R
â
ence of electron-withdrawing substituents at C
â
could
yield by Knoevenagel reaction of monoethylmalonate
affect the observed J -value.2
0,21
Several other combina-
with substituted benzaldehydes.16 High yield cis-dihy-
tions of ortho ester and substituted phenols were inves-
tigated under these conditions. The results are summa-
rized in Table 1.
droxylation of trans-cinnamate esters 6 gave racemic
diols 7.17 The conversion of 7 to cyclic 1,3-dioxolane ortho
esters was achieved in yields generally >90% by treat-
ment of the diols with trimethyl orthoacetate and cata-
lytic p-TsOH. The ortho esters are obtained as a mixture
of epimers at C-2 of the dioxolane ring (normally in about
a 45/55 ratio by NMR integration) but with retention of
the relative stereochemistry at the R and â carbons set
by the cis-dihydroxylation of 6.
The chemoselectivity of the reaction displays a depen-
dence on the nature of the aryl group on the ortho ester.
The added phenol reacts with the ortho ester through a
carbon atom (“C-addition”) para to an electron-donating
group on the phenol when the arene on the starting ortho
ester is substituted with electron-donating groups (10-
1
3). If an open site exists para to both a hydroxy and
Ar yla tion of Or th o Ester s. Scheme 4 shows a typical
methoxy group, attack occurs para to the OMe (15).
C-addition correlates well with the expected amount of
cationic character present at the benzylic position of
intermediate 4 (Scheme 2). Electron-releasing groups on
arylation sequence. Ortho ester 8 (Ar
phenyl) was treated with methyl guaiacol (9) and BF
in CH Cl solvent between -78 and -20 °C. Reaction
occurred at the carbon para to the CH O group of 9 to
1
) p-methoxy-
3
‚OEt
2
2
2
3
1
the Ar substituent stabilize the partial positive charge
give R-aryl-â-acetoxy adduct 10a and the deacetylated
at the benzylic position, making it more susceptible to
reaction with the soft aromatic ring rather than the
harder oxygen of the phenol. Lower electron density on
the aryl group of the ortho ester leads to reaction
primarily through the oxygen of the added phenol (“O-
addition”, 14-18). Introduction of a nitro substituent on
the aryl group of the ortho ester decreased the reactivity
significantly to give a very slow reaction and low product
yield (18). No deacylation was observed in reactions with
derivative 10c in 81% overall yield. The reaction occurred
regioselectively at the less electron rich R-carbon of 8.18
No evidence for reaction of 9 at either the â-carbon or
C-2 of 8 was seen.
Previous reports on Lewis acid promoted arylation of
ortho esters are scarce, but indicate that simple noncyclic
ortho esters serve as acylation reagents for arenes,
forming benzaldehydes rather than the more structurally
ortho esters bearing less electron rich Ar
HPLC analysis of the reaction between ortho ester 8
Ar ) phenyl) and phenol 9, which forms both C- and
1
substituents.
(
14) (a) Ibrahim, W.; Lundquist, K. Acta Chem. Scand. 1994, 48,
1
1
49. (b) Nakatsubo, F.; Sato, K.; Higuchi, T. Holzforschung 1975, 29,
65. (c) Ralph, J .; Young, R. A. Holzforschung 1981, 35, 39.
(
1
(15) (a) Kilpelainen, I.; Tervila-Wilo, A.; Perakyla, H.; Matikainen,
O-addition products (Table 1), indicates that at -78 °C
J .; Brunow, G. Holzforschung 1994, 28, 381. (b) Ralph, J .; Ede, R. M.;
Wilkins, A. L. Holzforschung 1986, 40, 23. (c) Hyatt, J . Holzforschung
small amounts of both appear almost immediately upon
1
3
1
987, 41, 363.
16) Gagnaire, D.; Lacoste, C.; Robert, D. Bull. Soc. Chim. Fr. 1970,
, 1067.
addition of BF
3
2
‚OEt . The amounts do not change sig-
(
(17) (a) Carless, H. A. J .; Malik, S. S. J . Chem Soc., Chem. Commun.
(19) (a) Ghosh, S.; Ghatak, U. R. Proc. Indian Acad. Sci. 1988, 100,
235. (b) Gross, H.; Rieche, A.; Matthey, G. Chem. Ber. 1963, 96, 308.
(20) (a) Karplus, M. J . Chem. Phys. 1959, 30, 11. (b) Karplus, M. J .
Am. Chem. Soc. 1963, 85, 2870.
995, 2447. (b) Vedejs, E.; Dent, W. H.; Gapinsik, D. M.; McClure, C.
K. J . Am. Chem. Soc. 1987, 109, 5437.
18) (a) Goosen, A.; McCleland, C. W. J . Chem. Soc., Perkin Trans.
(
1
3
1981, 977. (b) Lakshman, M. K.; Zajc, B. Tetrahedron Lett. 1996,
7, 2529.
(21) Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C.
Tetrahedron 1980, 36, 2783.

3
086 J . Org. Chem., Vol. 66, No. 9, 2001
Bozell et al.
Ta ble 1. Ar yla tion of Or th o Ester s
nificantly at this temperature over 2 h. On warming to
20 °C, the reaction proceeds more rapidly, and the
amounts of both C- and O-addition increase.
Using HPLC, we investigated the stability of the
individual C- and O-addition products described in Table
product is stable at reaction temperatures normally
employed (-20 °C). Moreover, reaction under normal
conditions always uses a slight excess of 9, which could
further inhibit reversion. In some reactions NMR reveals
small amounts (e.g., 13a , ca. 1-5%) of other diastereo-
mers that appear to be additional C-addition products.
It is possible that these materials are formed via rever-
sion during reaction workup at room temperature.
Ster eoch em istr y of th e Rea ction . Treatment of
ortho esters with TMSCl has been used to study the
stereochemistry of the nucleophilic attack.22 As expected,
nucleophilic attack of chloride occurs stereoselectively
from the backside of the oxonium ion (i.e., 2, Scheme 1).
However, this earlier work predicts a product stereo-
chemistry opposite to that revealed by our X-ray analysis.
While we have not carried out detailed mechanistic
studies, a rationalization for the source of the stereose-
lectivity consistent with the results observed is shown
in Figure 1.
-
1
under a variety of reaction conditions. Isolated O-
addition product 14b exhibits interesting reactivity as a
function of temperature. Upon treatment with BF ‚OEt
3
2
at -78 °C, 14b remains unchanged for 3 h. Warming to
the normal reaction temperature (-20 °C) also failed to
cause any reaction, even after 72 h. However, warming
to ambient temperature induced a reversion of 14b to a
mixture of phenol 9, 14a (C-addition), and residual 14b.
Interestingly, this reversion appears to be inhibited by
excess 9. Performing the same reaction in the presence
of 9 gave significantly smaller amounts of products other
than 14b after 20 h at room temperature. In contrast,
1
4a was stable to the reaction conditions. No conversion
to other products was observed at any of the tempera-
tures studied. These results indicate that a C-addition
product can arise from the initially formed O-addition
product at sufficiently high temperatures. However, the
C-addition products described in Table 1 are probably not
formed by O-addition reversion, since the O-addition
(22) (a) Newman, M. S.; Olson, D. R. J . Org. Chem. 1973, 38, 4203.
b) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515. (c)
(
Watson, K. G.; Fung, Y. M.; Gredley, M.; Bird, G. J .; J ackson, W. R.;
Gountzos, H.; Matthews, B. R. J . Chem. Soc., Chem. Commun. 1990,
1018.

Reaction of Cyclic Ortho Esters with Phenols
J . Org. Chem., Vol. 66, No. 9, 2001 3087
F igu r e 1. Reaction paths for intermediate carbocations.
The primary reactive intermediate in Lewis acid
Con clu sion s
promoted reaction of ortho ester 8 (Ar ) p-methoxy-
1
These results indicate that aryl substituted ortho
esters will undergo reaction with added phenols to give
good yields of compounds 4. Attack of the phenol (C- vs
O-) can be controlled by the electron density of the aryl
substituent on the ortho ester. Moreover, the observed
stereochemistry of the reaction can be rationalized by a
simple Felkin-Ahn analysis. More recently, we have
found that this process can be carried out asymmetrically
to give optically active products in both good yield and
enantiomeric excess. The process also works in an in-
tramolecular fashion, affording an efficient synthesis of
benzopyrans. Detailed results of these new transforma-
tions will be reported in future publications.
phenyl) with nucleophiles is oxonium ion 19 bearing Ar
1
and COOEt groups in a trans orientation.23 The preferred
trajectory for attack of the added nucleophile on 19 is
hindered by the presence of the COOEt group and, in
any case, would result in a product stereochemistry
opposite to that observed by X-ray.24
The presence of an aromatic ring at the R-carbon of
9 suggests that it may exist in equilibrium with the
1
stabilized benzylic carbonium ion 20. Such equilbria are
known in other systems, for example, carbohydrates.25
Rotation around the C
R â
-C bond affords intermediate 21
and access to oxonium ion 22. These intermediates offer
a less hindered trajectory for the nucleophile to give the
product stereochemistry seen in the X-ray analysis. This
hypothesis is analogous to the Felkin-Ahn explanation
Exp er im en ta l Section
for the stereochemistry of nucleophilic attack on carbonyl
Gen er a l. H and 13C NMR spectra were measured in CDCl
1
groups adjacent to chiral centers.26 In our case, the ability
3
solution using a Varian Unity 300 instrument at 300 and 75
MHz, respectively. Chemical shifts are reported relative to
of an acetate group to interact with the adjacent cationic
center allows it to adopt the role of the “large” group in
this analysis. Moreover, the much larger size of the
phenolic nucleophile in comparison to the chloride nu-
cleophile used in earlier studies renders it more sensitive
to steric effects.
1
13
tetramethylsilane ( H) or solvent resonance ( C) and are
reported in δ. Infrared spectra were measured on KBr pellets
for solids (0.5 wt %, 1.5 mg sample per 300 mg KBr) or neat
for oils using a Nicolet 5SXC instrument equipped with a
-1
deuterated triglycine sulfate detector and are reported in cm
.
HPLC was performed on a Waters 2690 instrument with a
model 996 photodiode array detector. Analysis was carried out
on a 0.5 × 150 mm Novapak C18 reverse-phase column.
Typical elution conditions used a sample injection volume of
This hypothesis also suggests that cis-ortho ester 23
should give rise to the same stereochemistry, since 23
could undergo reaction with BF
3
2
‚OEt to form intermedi-
ate 22 directly. We prepared 2327 and treated it under
standard conditions with phenol 9. The only product
observed was 10a (48%), identical to that obtained from
the corresponding trans-ortho ester 8. Reaction of 23 with
phenol gave 11a identical to that starting from the
corresponding trans-cinnamate, albeit in only 8% yield.
3
2
µL, a flow rate of 0.5 mL/min, and a H O/MeCN solvent
gradient progressing from 50/50 to 5/95 over 15 min, followed
by an additional 30-60 min of run time. Routine column
chromatography was performed using Aldrich 200-400 mesh
silica gel. Thin-layer chromatography (TLC) was carried out
on Baker-Flex 1BF 2.5 × 7.5 cm silica gel plates with a variety
of solvent systems. “Degassed” refers to the procedure of
alternately evacuating a flask on the vacuum line followed by
refilling with argon. Degassing was repeated three times.
X-ray analyses were carried out by Dr. J oyce Waters of Massey
University, Auckland, NZ. High-resolution mass spectra were
obtained from the University of Colorado-Boulder. Elemental
analyses were performed by Huffman Laboratories, Golden,
CO. Melting points are uncorrected.
(
23) Pindur, U.; Flo, C. Synth. Commun. 1989, 19, 2307.
(24) Burgi, H. H.; Dunitz, J . D.; Lehn, J . M.; Wipff, G. Tetrahedron
1
974, 30, 1563.
25) Pangiot, M. J .; Curley, R. W., J r. J . Carbohydr. Chem. 1994,
3, 293. See also: Robins, M. J .; Mengel, R.; J ones, R. A. J . Am. Chem.
(
1
Soc. 1973, 95, 4074.
(
26) Ahn, N. T.; Eisenstein, O. Nouv. J . Chem. 1977, 1, 61.
(27) Ando, K, J . Org. Chem. 1997, 62, 1934. NMR indicated retention
Ma ter ia ls. THF and Et
2
O were distilled from Na/benzophe-
of the cis orientation of the aryl and carbethoxy groups upon formation
of ortho ester 23.
none prior to use. Hexane for chromatography was distilled

3
088 J . Org. Chem., Vol. 66, No. 9, 2001
Bozell et al.
before use. Other solvents were reagent grade and used
without further purification unless otherwise noted. Noncom-
mercial cinnamates and all diols were prepared according to
NMR (11c): 1.16 (t, J ) 7.2 Hz, 3H), 3.74 (br s, 1H), 3.76 (s,
3H), 4.12 (q, J ) 7.2 Hz, 2H), 4.34 (d, J ) 4.1 Hz, 1H), 4.82
(br t, J ) 4.1 Hz, 1H), 5.48 (br s, 1H), 6.59 (s, 1H), 6.75-6.81
literature methods.16,17 BF
‚OEt
was distilled under an inert
(m, 2H), 7.15-7.20 (m, 3H). C NMR 14.0, 52.7, 55.1, 61.8,
13
3
2
atmosphere and stored under argon. All other materials were
commercially available and used as received.
73.7, 113.7, 115.2, 129.4, 130.2, 131.1, 133.6, 154.7, 158.1,
173.9; IR: 3450, 2968, 2861, 1734, 1609, 1050, 1116. MS m/z
calcd 316.1311, found 316.1296.
E t h yl-2-a cet oxy-3,3-d i-(4-m et h oxyp h en yl)p r op ion a t e
(12a ). Ortho ester 8a (701 mg, 2.37 mmol) was treated with
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Or t h o
Ester s. A mixture of the diol (1 mmol) and trimethylortho-
acetate (1.5 mmol) was dissolved in THF (10 mL). The solution
was degassed and taken to -20 °C. It was treated with a
solution (2 mg/mL) of p-TsOH in THF to give a catalyst level
of 0.2-0.5 mol %. The reaction was stirred at -20 °C until
complete as indicated by TLC (usually 30-60 min). The
anisole (256 mg, 2.37 mmol, 257 µL, F ) 0.995) and BF
3
‚OEt
2
(874 µL, 7.1 mmol) according to the general procedure. Normal
workup and purification on silica gel (5:1 hexane/EtOAc) gave
429 mg (49%) of 12a as a white solid, mp 83.5-84.5 °C. Also
isolated was 141 mg (16%) of the corresponding deacylated
reaction was quenched by the addition of saturated NaHCO
50-75 µL). The solvent was removed on the rotary evaporator.
The residue was purified by rapid filtration through a 2.5 × 5
cm bed of silica gel using 1:1 hexane/Et O as the eluent.
3
1
(
product 12c as a clear oil. H NMR (12a ): 1.00 (t, J ) 7.1 Hz,
3H), 2.04 (s, 3H), 3.75 (s, 3H), 3.77 (s, 3H), 3.98 (br q, J ) 7.1
Hz, 2H), 4.49 (d, J ) 7.1 Hz, 1H), 5.64 (d, J ) 7.1 Hz, 1H),
6.82 (m, 4H), 7.19 (m, 4H). 13C NMR: 13.8, 20.6, 50.8, 55.1,
61.2, 74.9, 113.8, 129.4, 129.7, 131.7, 132.0, 158.4, 169.2, 170.3.
IR: 2975, 2834, 1758, 1610, 1521, 1461, 1380, 1250, 1031, 828.
2
Solvent removal gave the ortho ester as a clear oil. The ortho
esters were normally used immediately after preparation. The
1
H NMR spectrum for ortho ester 8b is typical for the
diastereomeric mixture obtained: 1.3 (overlapping t, 3H), 1.70
26 7
Anal. Calcd for C22H O : C, 67.73; H, 6.50; O, 25.78. Found:
1
(s, 3H), 1.75 (s, 3H), 3.40 (s, 3H), 3.43 (s, 3H), 4.25 (overlapping
C, 67.66; H, 6.72; O, 25.62. H NMR (12c): 1.30 (t, J ) 7.0
Hz, 3H), 2.98 (br s, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 4.25 (q, J )
7.0 Hz, 2H), 4.50 (d, J ) 3.9 Hz, 1H), 4.95 (br d, J ) 3.9 Hz,
1H), 6.90-6.97 (m, 4H), 7.27-7.32 (m, 4H), 7.40-7.45 (m, 4H).
m, 2H), 4.40 and 5.35 (dd, 2H), 4.44 and 5.10 (dd, 2H), 7.28-
7
.47 (m, 5H).
Gen er a l P r oced u r e for Or th o Ester Ar yla tion . The
1
3
ortho ester and phenol (1:1 molar ratio) were dissolved in
freshly distilled THF (10-15 mL/mmol). The solution was
cooled to -78 °C and stirred for 5 min. It was treated with
C NMR: 14.0, 52.6, 55.1, 61.6, 73.6, 113.6, 129.4, 130.2,
133.7, 158.4, 158.8, 173.7. IR: 3489, 2965, 2839, 1745, 1619,
1516, 1464, 1250, 1031, 734. MS m/z calcd 330.1467, found
330.1458.
Eth yl-2-a cetoxy-3-(3,4-m eth ylen ed ioxyp h en yl)-3-(3-h y-
dr oxy-4-m eth oxy-6-m eth ylph en yl)pr opion ate (13a). Ortho
ester 8c (607 mg, 1.96 mmol) was treated with methyl guaiacol
BF
reaction was warmed to -20 °C and stirred for 72 h. It was
quenched by the addition of saturated NaHCO (1 mL). The
3
‚OEt
2
(3 mmol) and stirred for 60 min at -78 °C. The
3
solvent was removed on the rotary evaporator, and the residue
was purified by column chromatography on silica gel using a
variety of solvent systems. When necessary, samples for
analysis were further purified by recrystallization at -20 °C
(9) (405 mg, 2.94 mmol, 303 µL, F ) 1.092) and BF
3
‚OEt
2
according to the general procedure. Normal workup and
purification on silica gel (4:1 hexane/EtOAc) gave 433 mg (53%)
1
from mixtures of Et
2
O/hexane.
of 13a as a white solid, mp 48.5-49.5 °C. H NMR: 1.10 (t, J
C-Ad d it ion P r od u ct s. E t h yl-2-a cet oxy-3-(4-m et h oxy-
phenyl)-3-(3-hydroxy-4-methoxy-6-methylphenyl)propionate
) 7.5 Hz, 3H), 2.15 (s, 3H), 2.25 (s, 3H), 3.94 (s, 3H), 4.08 (m,
2H), 4.68 (d, J ) 7.7 Hz, 1H), 5.58 (br s, 1H), 5.63 (d, J ) 7.8
1
3
(
10a ). Ortho ester 8a (710 mg, 2.4 mmol) was treated with
methyl guaiacol (9) (331 mg, 2.4 mmol, 303 µL, F ) 1.092) and
BF ‚OEt (886 µL, 7.2 mmol) according to the general proce-
Hz, 1H), 5.99 (dd, J ) 7.6, 1.9 Hz, 2H), 6.59-6.82 (m, 5H). C
NMR: 13.7, 19.4, 20.6, 47.5, 55.8, 61.1, 75.2, 100.9, 108.0,
109.3, 113.2, 113.4, 122.2, 128.3, 130.3, 132.5, 143.4, 145.0,
146.4, 147.6, 169.4, 170.3. IR: 3460, 2934, 1743, 1591, 1515,
3
2
dure. Normal workup and purification on silica gel (5:1 hexane/
EtOAc to 2:1 EtOAc/hexane) gave 570 mg (60%) of 10a as a
white solid, mp 147.5-148.5 °C. Also isolated was 200 mg
1438, 1376, 1234. Anal. Calcd for C22
24 8
H O : C, 63.45; H, 5.81;
O, 30.74. Found: C, 63.57; H, 5.66; O, 30.77.
(
1
3
21%) of the corresponding deacylated product 10c, mp 113.5-
E t h yl-2-a cet oxy-3-p h en yl-3-(3-h yd r oxy-4-m et h oxy-6-
m eth ylp h en yl)p r op ion a te (14a ). Ortho ester 8b (601 mg,
2.26 mmol) was treated with methyl guaiacol (9) (312 mg, 2.26
1
14.5 °C. H NMR (10a ): 0.93 (t, J ) 7.0 Hz, 3H), 2.02 (s,
H), 2.12 (s, 3H), 3.72 (s, 3H), 3.81 (s, 3H), 3.92 (m, 2H), 4.58
(
(
2
1
2
d, J ) 8.2 Hz, 1H), 5.49 (s, 1H), 5.53 (d, J ) 8.2 Hz, 1H), 6.59
mmol, 286 µL, F ) 1.092) and BF
according to the general procedure. Normal workup and
purification on silica gel (3:2 Et O/hexane) gave 152 mg (18%)
3
‚OEt
2
(833 µL, 6.77 mmol)
s, 1H), 6.75 (m, 2H), 7.06-7.12 (m, 3H). 1 C NMR: 13.6, 19.3,
3
0.6, 47.1, 55.1, 55.8, 61.1, 75.2, 113.2, 113.4, 113.7, 128.2,
29.8, 130.5, 130.7, 143.4, 144.8, 158.4, 169.5, 170.4; IR: 3441,
979, 2848, 1738, 1614, 1517, 1469, 1250, 1055, 832. Anal.
2
1
of 14a as a white solid, mp 103-104 °C. H NMR: 0.98 (t, J
) 7.0 Hz, 3H), 2.01 (s, 3H), 2.28 (s, 3H), 3.80 (s, 3H), 3.99 (m,
2H), 4.72 (d, J ) 7.6 Hz, 1H), 5.36 (s, 1H), 5.60 (d, J ) 7.6 Hz,
Calcd for C22
6
3
26 7
H O : C, 65.66; H, 6.51; O, 27.83. Found: C,
1
13
5.79; H, 6.55; O, 27.66. H NMR (10c): 1.04 (t, J ) 7.2 Hz,
1H), 6.58 (s, 1H), 6.82 (s, 1H), 7.13-7.29 (m, 5H). C NMR:
H), 2.16 (s, 3H), 3.74 (s, 3H), 3.80 (s, 3H), 4.02 (m, 2H), 4.44
13.7, 19.5, 20.6, 47.5, 55.8, 61.2, 74.3, 112.8, 115.0, 126.7, 127.3,
128.3, 128.6, 130.5, 139.6, 143.4, 145.1, 169.4, 170.2. IR: 3531,
3447, 2978, 1751, 1519, 1378, 1264, 1205, 1037. Anal. Calcd
(
d, J ) 6.2 Hz, 1H), 4.76 (br m, 1H), 5.48 (br s, 1H), 6.59 (s,
1
1
1
2
H), 6.75-6.81 (m, 2H), 7.15-7.20 (m, 3H). 13C NMR: 13.8,
9.3, 49.1, 55.2, 55.8, 61.4, 74.1, 113.1, 113.7, 114.4, 128.1,
29.6, 130.7, 132.5, 143.4, 144.9, 158.2, 173.7; IR: 3518, 3473,
953, 2842, 1729, 1617, 1513, 1461, 1250, 1093, 781. Anal.
for C21
24 6
H O : C, 67.73; H, 6.50; O, 25.78. Found: C, 67.68; H,
6.44; O, 25.88.
Eth yl-2-acetoxy-3-ph en yl-3-(3-h ydr oxy-4-m eth oxyph en -
yl)p r op ion a te (15a ). Ortho ester 8b (601 mg, 2.26 mmol) was
treated with guaiacol (336 mg, 2.7 mmol, 297 µL, F ) 1.129)
Calcd for C20
6.67; H, 6.71; O, 26.62.
Eth yl-2-acetoxy-3-(4-m eth oxyph en yl)-3-(4-h ydr oxyph en -
yl)p r op ion a te (11a ). Ortho ester 8a (585 mg, 1.97 mmol) was
treated with phenol (187 mg, 1.97 mmol) and BF ‚OEt
according to the general procedure. Normal workup and
purification on silica gel (3:2 hexane/Et O) gave 254 mg (36%)
of 11a as a white solid, mp 109.5-110.5 °C. Also isolated was
4 mg (12%) of the corresponding deacylated product 11c as
24 6
H O : C, 66.65; H, 6.71; O, 26.64. Found: C,
6
and BF
3
‚OEt (833 µL, 6.77 mmol) according to the general
2
procedure. Normal workup and purification on silica gel (3:2
Et O/hexane) gave 156 mg (19%) of 15a as a clear oil. H
2
1
3
2
NMR: 0.98 (t, 3H), 2.2 (s, 3H), 3.78 (s, 3H), 3.92-4.0 (m, 2H),
2
4.47-4.51 (d, J ) 8.3 Hz, 1H), 5.59 (s, 1H), 5.64-5.68 (d, J )
1
3
10.4 Hz, 1H), 6.68-6.8 (m, 3H), 7.19-7.34 (m, 5H). C NMR:
13.7, 20.5, 52.1, 55.8, 61.2, 74.7, 111.1, 114.2, 121.4, 126.9,
128.4, 128.5, 131.3, 139.6, 144.7, 146.3, 169.2, 170.3. IR: 3451,
2977, 2839, 1742, 1598, 1511, 1442, 1374. Anal. Calcd for
8
1
a clear oil. H NMR (11a ): 0.99 (t, J ) 7.0 Hz, 3H), 2.02 (s,
3
H), 3.75 (s, 3H), 3.98 (m, 2H), 4.45 (d, J ) 6.5 Hz, 1H), 5.62
1
3
(m, 1H), 6.60-6.80 (m, 4H), 7.05-7.24 (m, 4H). C NMR: 13.8,
C
20
H
22
O
6
: C, 67.03; H, 6.19; O, 26.79. Found: C, 67.12; H, 6.32;
2
1
1
0.6, 50.8, 55.2, 61.4, 74.9, 113.8, 115.3, 129.4, 129.6, 129.9,
31.4, 132.0, 154.8, 158.5, 169.5, 170.6; IR: 3405, 2927, 2833,
O, 26.56.
O-Ad d it ion P r od u ct s. E t h yl-2-a cet oxy-3-p h en yl-3-(2-
m eth oxy-4-m eth ylp h en oxy)p r op ion a te (14b). Ortho ester
1
761, 1250, 1030. MS m/z calcd 358.1416, found 358.1403. H

Reaction of Cyclic Ortho Esters with Phenols
J . Org. Chem., Vol. 66, No. 9, 2001 3089
8
(
b (597 mg, 2.24 mmol) was treated with methyl guaiacol (9)
309 mg, 2.24 mmol, 283 µL, F ) 1.092) and BF ‚OEt (829
µL, 6.73 mmol) according to the general procedure. Normal
workup and purification on silica gel (5:1 hexane/Et O) gave
08 mg (50%, based on recovered starting material) of 14b as
dd, J ) 5.3, 1.8 Hz, 1H), 6.92-7.06 (m, 3H), 7.28-7.58 (m,
7H). 13C NMR: 14.0, 20.4, 61.6, 74.9, 78.7, 115.2, 115.9, 121.5,
127.1, 128.4, 129.3, 136.2, 157.1, 167.7, 169.8. IR: 3641, 3471,
3051, 2983, 1756, 1593, 1491, 1458, 1376, 1219, 1047, 750, 711.
Anal. Calcd for C19H O : C, 69.50; H, 6.14; O, 24.36. Found:
20 5
C, 69.34; H, 6.34; O, 24.32.
3
2
2
3
1
a clear oil. H NMR: 1.3 (t, J ) 7.0 Hz, 2H), 2.18 (s, 3H), 2.35
s, 3H), 3.89 (s, 3H), 4.30 (q, J ) 7.0 Hz, 2H), 5.62 (d, J ) 5.4
Hz, 1H), 5.68 (d, J ) 5.4 Hz, 1H), 6.6 (d, 1H), 6.8 (s, 2H), 7.4
(
Eth yl-2-a cetoxy-3-p h en yl-3-(4-m eth oxyp h en oxy)p r op i-
on a te (17b). Ortho ester 8b (323 mg, 1.21 mmol) was treated
with 4-methoxyphenol (150 mg, 1.21 mmol)) and BF ‚OEt (447
1
3
(m, 3H), 7.6 (m, 2H). C NMR: 13.8, 20.2, 20.7, 55.5, 61.2,
3
2
7
1
1
3
4.2, 80.5, 113.4, 118.3, 120.7, 127.4, 127.9, 128.2, 132.6, 136.4,
44.0, 150.3, 167.6, 169.6. IR: 2983, 2867, 1749, 1593, 1519,
464, 1376, 1218, 1031, 703. MS m/z calcd 372.1573, found
72.1557.
µL, 3.63 mmol) according to the general procedure. Normal
workup and purification on silica gel (5:1 hexane/EtOAc) gave
1
208 mg (48%) of 17b as a clear oil. H NMR: 1.22 (t, J ) 7.1
Hz, 3H), 2.18 (s, 3H), 3.68 (s, 3H), 4.19 (m, 2H), 5.40 (s, 2H),
Eth yl-2-a cetoxy-3-p h en yl-3-(2-m eth oxyp h en oxy)p r op i-
6.75 (m, 4H), 7.26-7.42 (m, 5H). 13C NMR: 14.1, 20.5, 55.5,
on a te (15b). Ortho ester 8b (601 mg, 2.26 mmol) was treated
with guaiacol (336 mg, 2.7 mmol, 297 µL, F ) 1.129) and BF
OEt
Normal workup and purification on silica gel (4:1 hexane/
EtOAc) gave 259 mg (32%) of 15b as a clear oil. H NMR: 1.22
61.6, 74.8, 79.9, 114.5, 117.5, 127.3, 128.4, 128.5, 136.5, 151.3,
154.5, 167.8, 169.9. IR: 3049, 2958, 2832, 1756, 1504, 1455,
1372, 1218, 1039, 828, 703. MS m/z calcd 358.1416, found
358.1414.
3
‚
2
(833 µL, 6.77 mmol) according to the general procedure.
1
(
t, J ) 7.2 Hz, 3H), 2.18 (s, 3H), 3.81 (s, 3H), 4.19 (m, 2H),
Ack n ow led gm en t. We wish to thank J im Seidel of
the U. S. Environmental Protection Agency for carrying
out the HMBC and HMQC measurements and Dr. Mark
Davis for important assistance in assignment of the
NMR spectra. This work was funded by the Department
of Energy and the NREL Director’s Development Fund.
5
2
1
1
.51 (s, 2H), 6.75 (m, 2H), 6.88 (m, 2H), 7.3 (m, 3H), 7.44 (m,
1
3
H). C NMR: 13.9, 20.5, 55.8, 61.5, 74.4, 80.4, 112.6, 118.2,
20.7, 123.0, 127.5, 128.2, 128.4, 136.4, 146.5, 150.7, 167.9,
69.8. IR: 2979, 1753, 1590, 1501, 1457, 1376, 1218, 1031, 750.
Anal. Calcd for C20
C, 66.85; H, 6.13; O, 27.02.
Eth yl-2-a cetoxy-3-p h en yl-3-p h en oxyp r op ion a te (16b).
Ortho ester 8b (522 mg, 1.96 mmol) was treated with phenol
22 6
H O : C, 67.03; H, 6.19; O, 26.79. Found:
Su p p or tin g In for m a tion Ava ila ble: ORTEP diagram
(184 mg, 1.96 mmol) and BF
3
‚OEt
2
(724 µL, 5.88 mmol)
and parameter for compound 10a and 1H NMR spectra of
according to the general procedure. Normal workup and
purification on silica gel (4:1 hexane/EtOAc) gave 283 mg (46%)
compounds 11a , 11c, 12c, 14b, and 17b. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
of 16b as a clear oil. H NMR: 1.38 (t, J ) 7.5 Hz, 3H), 2.20
(s, 3H), 4.37 (m, 2H), 5.59 (dd, J ) 5.3, 1.8 Hz, 1H), 5.69 (br
J O005736T