Hydrolytic stabilization of protected p-hydroxybenzyl halides designed as latent quinone methide precursors

Article abstract of DOI:10.1021/jo991085t

The hydrolysis rates of a series of protected p-hydroxybenzyl halides designed to generate a p-quinone methide through 1,6-elimination following photolytic deprotection have been investigated in order to optimize hydrolytic stability. A number of p-hydroxybenzyl halides containing an ether or carbonate-linked photolabile hydroxy protecting group and a fluoride, chloride, or bromide benzylic leaving group have been synthesized. The hydrolysis rates of these derivatives in different water acetonitrile mixtures and temperatures have been determined. The hydrolysis half-life of the benzyl bromide with the p-hydroxy protected as the carbonate-linked α- methylnitroveratryl (18c) is more than 750 times that of the ether-linked analogue (16c). These studies afford a Hammett σp⁺ of +0.28 for the carbonate-linked derivatives compared to a σ⁺ of -0.39 for the ether-linked derivatives. The theoretical hydrolysis half-life of the most stable benzyl fluoride in 100% water was sufficiently long so as to preclude extrapolation, while the chloride was approximately 50 h, and even the bromide was estimated to be nearly 5 h.

Full text of DOI:10.1021/jo991085t

7988
J . Org. Chem. 1999, 64, 7988-7995
Hyd r olytic Sta biliza tion of P r otected p-Hyd r oxyben zyl Ha lid es
Design ed a s La ten t Qu in on e Meth id e P r ecu r sor s
Robert G. Dyer and Kenneth D. Turnbull*
Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701
Received J uly 6, 1999
The hydrolysis rates of a series of protected p-hydroxybenzyl halides designed to generate a
p-quinone methide through 1,6-elimination following photolytic deprotection have been investigated
in order to optimize hydrolytic stability. A number of p-hydroxybenzyl halides containing an ether-
or carbonate-linked photolabile hydroxy protecting group and a fluoride, chloride, or bromide benzylic
leaving group have been synthesized. The hydrolysis rates of these derivatives in different water/
acetonitrile mixtures and temperatures have been determined. The hydrolysis half-life of the benzyl
bromide with the p-hydroxy protected as the carbonate-linked R-methylnitroveratryl (18c) is more
+
than 750 times that of the ether-linked analogue (16c). These studies afford a Hammett σp of
+
+0.28 for the carbonate-linked derivatives compared to a σp of -0.39 for the ether-linked
derivatives. The theoretical hydrolysis half-life of the most stable benzyl fluoride in 100% water
was sufficiently long so as to preclude extrapolation, while the chloride was approximately 50 h,
and even the bromide was estimated to be nearly 5 h.
Sch em e 1
In tr od u ction
The prolific role of reactive quinone methide interme-
diates in bioorganic and medicinal chemistry1 warrants
further optimization of their stability,2 reactivity,3 and
chemoselectivity4 for expanding applications.5 A preva-
lent challenge in the application of quinone methides to
bioalkylation processes is controlling the competitive
hydrolysis of the reactive precursors.6,7 In developing a
research program applying quinone methides to drug
delivery and biomolecular labeling,8 we are studying
various ways to control quinone methide formation for
reactions in biological environments.9 An initial objective
(1) (a) Thompson, D. C.; Thompson, J . A.; Sugumaran, M.; Moldeus,
P. Chem.-Biol. Interact. 1992, 86, 129. (b) Peter, M. G. Angew. Chem.,
Int. Ed. Engl. 1989, 28, 555. (c) Grauenanger, P. In Houben-Weyl
Methoden der Organischen Chemie; Mueller, E., Bayer, O., Eds.; G.
Thieme Verlag: Stuttgardt, 1979; Vol. VII/3b, pp 395-521. (d) Moore,
H. W.; Czerniak, R. Med. Res. Rev. 1981, 1, 249. (e) Moore, H. W.
Science 1977, 197, 527.
(2) (a) Angle, S. T.; Rainier, J . D.; Woytowicz, C. J . Org. Chem. 1997,
62, 5884. (b) Boger, D. L.; Nishi, T.; Teegarden, B. R. J . Org. Chem.
1994, 59, 4943.
(3) (a) Cabaret, D.; Adediran, S. A.; Garcia Gonzalez, M. J .; Pratt,
R. F.; Wakselman, M. J . Org. Chem. 1999, 64, 713. (b) Zjawiony, J .
K.; Bartyzel, P.; Hamann, M. T. J . Nat. Prod. 1998, 61, 1502. (c) Bolton,
J . L.; Turnipseed, S. B.; Thompson, J . A. Chem.-Biol. Interact. 1997,
107, 185. (d) Skibo, E. B.; Gordon, S.; Bess, L.; Boruah, R.; Heileman,
M. J . J . Med. Chem. 1997, 40, 1327. (e) Hong, S.-B.; Mullins, L. S.;
Shim, H.; Raushel, F. M. Biochemistry 1997, 36, 9022. (f) Zeng, Q.;
Rokita, S. E. J . Org. Chem. 1996, 61, 9080. (g) Thompson, D. C.; Perera,
K. Biochem. Biophys. Res. Commun. 1995, 209, 6. (h) Li, T.; Zeng, Q.;
Rokita, S. E. Bioconjugate Chem. 1994, 5, 497. (i) Richard, J . P. J .
Am. Chem. Soc. 1991, 113, 4588.
(4) (a) Ouyang, A.; Skibo, E. B. J . Org. Chem. 1998, 63, 1893. (b)
Rokita, S. E.; Yang, J .; Pande, P.; Greenberg, W. A. J . Org. Chem.
1997, 62, 3010. (c) Mayalarp, S. P.; Hargreaves, R. H. J .; Butler, J .;
O’Hare, C. C.; Hartley, J . A. J . Med. Chem. 1996, 39, 531.
(5) (a) Oded, R.; Vigalok, A.; Milstein, D. J . Am. Chem. Soc. 1998,
120, 7119. (b) Amouri, H.; Besace, Y.; Le Bras, J . J . Am. Chem. Soc.
1998, 120, 6171.
in our investigations has been to develop a hydrolytically
stable p-quinone methide precursor without altering the
rate at which it will form the reactive quinone methide.
These studies focus on optimizing the hydrolytic stability
of protected p-hydroxy benzyl halides designed as photo-
labile quinone methide precursors.
The most common method used to form p-quinone
methides for bioalkylations is through 1,6-elimination of
a p-hydroxybenzylic leaving group (2 to 3, Scheme 1).6
For controlled formation of quinone methide 3, we sought
a protecting group that could be efficiently removed
under relevant biological conditions. The reaction se-
quence would be initiated by removing the protecting
group (PG) from the protected p-hydroxybenzyl halide 1
to form phenol 2 (Scheme 1). Subsequent 1,6-elimination
of the leaving group (X) would produce quinone methide
3. The ability to control quinone methide formation will
enhance selectivity in alkylation of a target bionucleo-
phile (Nu-H) leading to the desired alkylated product 4.
(6) Wakselman, M. Nouv. J . Chim. 1983, 7, 439.
(7) (a) Meyers, J . K.; Cohen, J . D.; Widlanski, T. S. J . Am. Chem.
Soc. 1995, 117, 11049. (b) Bechet, J .-J .; Dupaix, A.; Yon, J .; Waksel-
man, M.; Robert, J .-C.; Vilkas, M. Eur. J . Biochem. 1973, 35, 527. (c)
Wang, Q.; Dechert, U.; J irik, F.; Withers, S. G. Biochem. Biophys. Res.
Commun. 1994, 200, 577.
(9) McCracken, P. G.; Bolton, J . L.; Thatcher, G. R. J . J . Org. Chem.
1997, 62, 1820.
(8) Zhou, Q.; Turnbull, K. D. J . Org. Chem. 1999, 64, 2847.
10.1021/jo991085t CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/30/1999

Hydrolytic Stabilization of Protected p-HydroxybenzylHalides
J . Org. Chem., Vol. 64, No. 21, 1999 7989
However, the competitive pathway available to protected
p-hydroxybenzyl halide 1 in aqueous systems is hydroly-
sis to form benzyl alcohol 5. This commonly limits the
efficiency of quinone methide precursors in biomolecular
alkylation applications.6,7 The rate of this competing
hydrolysis pathway can be moderated by appropriate
modification of the quinone methide precursor.7
with the monofluorinated derivative. However, they
observed a reduced rate of quinone methide formation
as well.7c
Having sought a mild method suitable for the genera-
tion of a quinone methide under biological conditions, we
have pursued photolytic initiation13 at >350 nm wave-
lengths.14 The 2-nitrobenzyl and R-methylnitroveratryl
protecting groups were chosen for phenolic protection of
latent quinone methide precursors due to their rapid
photolysis reaction rates.15 Of these, the R-methylnitro-
veratryl protecting group is known to produce less
reactive photolysis byproducts.16 These photolabile pro-
tecting groups have seen widespread use in various
bioorganic applications.14,17
We report the results of our investigations, which
demonstrate the hydrolytic instability of protected p-
hydroxybenzyl halides having an ether-linked protecting
group (PG, Scheme 1) in conjunction with a bromide or
chloride as the benzylic leaving group (X, Scheme 1).
When the benzylic leaving group is a fluoride, the
protected p-hydroxybenzyl halide is significantly more
stable toward hydrolysis. The protected p-hydroxybenzyl
halide having an electron-withdrawing carbonate-linked
protecting group shows substantial hydrolytic stability.
Importantly, the p-hydroxybenzyl halide protection modi-
fication reported here improves hydrolytic stability with-
out modifying the rate at which the quinone methide will
form or its ensuing electrophilic reactivity. This allows
independent study of the reactivity of the quinone me-
thide8 for further developments in optimizing its use in
bioalkylation processes.18
Analysis of Hammett σ values reasonably predicts the
effect of functional groups on hydrolytic stability in
compounds containing benzylic leaving groups.10 As the
benzyl ring becomes more electron withdrawing, the rate
of hydrolysis decreases. An analysis based on the ap-
plication of Hammett σ constants leads to the conclusion
that improved hydrolytic stability can be achieved when
ring substituents have more positive σ values. However,
improvement in hydrolytic stability of the protected
p-hydroxybenzyl halide through increasing the electron
deficiency of the phenyl ring with electron-withdrawing
substituents also significantly decreases the rate of
quinone methide formation. We have sought to balance
these two factors in developing a versatile latent p-
quinone methide precursor for bioalkylation.
Widlanski and co-workers have shown that the addi-
tion of a 3-nitro group (R ) NO2, R′ ) H, Scheme 1) to a
prostatic acid phosphatase mechanism-based inactivator
related to 1 [where PG was a phosphate group (σp
)
0.00)11 and X was fluoride, chloride, or bromide] improved
the hydrolytic stability of the protected p-hydroxybenzyl
halide.7a The stabilizing effect of a 3-nitro group (σm
)
+0.71)11 increased the hydrolysis half-life of the deriva-
tive having a fluoride leaving group (X ) F, Scheme 1)
from ∼6 h to more than 1 month. This also allowed access
to the benzylic bromide or chloride. As recognized by
Widlanski and co-workers, the 3-nitro group would be
expected to slow the rate of quinone methide formation.7a
A direct application using a slight modification of the
same mechanism-based inactivator to target a phospho-
triesterase (where PG was a diethyl phosphate group and
X was fluoride, chloride, or bromide) was accomplished
by Raushel and co-workers.3e They also reported the
inability of the fluoride and chloride derivatives to
inactivate the phosphotriesterase.
Resu lts a n d Discu ssion
Syn th esis of P r otected p-Hyd r oxyben zyl Ha lid es.
Our investigations required the synthesis of a series of
protected p-hydroxybenzyl halides with ether- and car-
bonate-linked photolabile protecting groups in conjunc-
tion with bromide, chloride, or fluoride leaving groups.
This was accomplished as outlined in Table 1 (without
optimization of yields). Commercially available 4-hy-
droxy-3,5-dimethylbenzaldehyde (6) was protected as the
ether (7, 8) or the carbonate (9, 10) by using the
corresponding benzyl bromide or chloroformate, respec-
Wakselman and co-workers used a coumarin derivative
in their mechanism-based inactivator of R-chymotryp-
sin.7b,12 In this protected p-hydroxybenzyl halide, the
hydroxy functionality was protected as the lactone (an
(13) Wan and co-workers readily photogenerate quinone methides
using laser flash photolysis at 266 nm (Wan, P.; Barker, B.; Diao, L.;
Fischer, M.; Shi, Y.; Yang, C. Can. J . Chem. 1996, 74, 465.); however,
this wavelength is not suitable for use in biological systems (see ref
14).
(14) (a) Corrie, J . E. T.; Trentham, D. R. In Bioorganic Photochem-
istry Volume 2: Biological Applications of Photochemical Switches;
Morrison, H., Ed.; Wiley: New York, 1993, Chapter 5. (b) McCray, J .
A.; Trentham, D. R. Annu. Rev. Biophys. Biophys. Chem. 1989, 18,
239.
(15) (a) Peng, L.; Goeldner, M. J . Org. Chem. 1996, 61, 185. (b)
Venkatesan, H.; Greenberg, M. M. J . Org. Chem. 1996, 61, 525. (c)
Holmes, C. P. J . Org. Chem. 1997, 62, 2370.
(16) Kaplan, J . H.; Forbush, B.; Hoffman, J . F. Biochemistry 1978,
17, 1929.
(17) (a) Kahl, J . D.; McMinn, D. L.; Greenberg, M. M. J . Org. Chem.
1998, 63, 4870. (b) Blawas, A. S.; Oliver, T. F.; Pirrung, M. C.; Reichert,
W. M. Langmuir 1998, 14, 4243. (c) McGall, G. H.; Barone, A. D.;
Diggelmann, M.; Fodor, S. P. A.; Gentalen E.; Ngo, N. J . Am. Chem.
Soc. 1997, 119, 5081. (d) Pirrung, M. C. Chem. Rev. 1997, 97, 473. (e)
Peng, L.; Wirz, J .; Goeldner, M. Angew. Chem., Int. Ed. Engl. 1997,
36, 398. (f) Park, C.-H.; Givens, R. S. J . Am. Chem. Soc. 1997, 119,
2453. (g) Amit, B.; Hazum, E.; Fridkin, M.; Patchornik, A. Int. J .
Peptide Protein Res. 1977, 9, 91.
ester group has σp ) +0.31 and σp ) -0.19).11 This
+
coumarin derivative showed sufficient hydrolytic stability
to inactivate R-chymotrypsin, although the authors noted
hydrolysis of the bromide derivative.7b
An alternative approach for reducing benzyl halide
hydrolysis has been to incorporate a stabilizing substitu-
ent at the benzylic position. Withers and co-workers
found the addition of a second fluoride at the benzylic
position effective in reducing the hydrolytic susceptibility
of a mechanism-based phosphatase inactivator related
to 1 (R, R′ ) H, Scheme 1), where PG was a phosphate
and X was a fluoride.7c In studies with human prostatic
acid phosphatase, the authors noted reduced hydrolysis
from their benzylic difluorinated derivative compared
(10) Takeuchi, K.; Takasuka, M.; Ohga, Y.; Okazaki, T. J . Org.
Chem. 1999, 64, 2375.
(11) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(12) Wakselman has recently reported the use of a related compound
as a â-Lactamase inhibitor (see ref 3a).
(18) A complete account of the use of the quinone methide generated
in these investigations in various alkylation processes will be reported
in due course.

7990 J . Org. Chem., Vol. 64, No. 21, 1999
Ta ble 1. Syn th esis of P r otected p-Hyd r oxyben zyl Ha lid es
Dyer and Turnbull
protection
methodb
benzyl
halide
halogenation
entry
aldehyde
P Ga
yield (%)
94
alcoholc
yield (%)
99
X
methodd
yield (%)
1
2
3
4
5
6
7
8
9
7
NBE
A
B
C
D
11
15a
15b
15c
16a
16b
16c
17a
17b
17c
18a
18b
18c
F
E
F
G
E
F
G
E
F
G
E
F
79
68
46
59
86
38
48
90
28
63
87
57
Cl
Br
F
Cl
Br
F
Cl
Br
F
Cl
Br
8
9
MVE
NBC
MVC
91
80
49
12
13
14
100
96
10
11
12
10
99
G
a
NBE ) 2-Nitrobenzyl ether; MVE ) R-methylnitroveratryl ether; NBC ) 2-nitrobenzyl carbonate; MVC ) R-methylnitroveratryl
b
carbonate. Method A: 6, 2-nitrobenzylbromide, K2CO3, DMF, rt, 3.5 h. Method B: 6, R-methylnitroveratrylbromide, K2CO3, DMF, rt,
4.5 h. Method C: 6, 2-nitrobenzylchloroformate, K2CO3, DMF, rt, 17 h. Method D: 6, R-methylnitroveratryl alcohol, triphosgene, pyridine,
CH2Cl2, -42 °C-rt, 16 h. c Sodium borohydride, ethanol, rt, 0.5 h. Method E: DAST, CH2Cl2, 0 °C or room temperature, 1 h. Method F:
d
triphosgene, pyridine, CH2Cl2, rt, 0.25-1 h. Method G: phosphorus tribromide, CH2Cl2, 0 °C or room temperature, 1-4.5 h.
tively (yields are shown in Table 1).19 2-Nitrobenzyl
bromide is commercially available, while the R-methyl-
nitroveratryl bromide is available in one step from the
alcohol.20 The necessary R-methylnitroveratryl alcohol
was readily prepared by a two-step protocol.21 The
chloroformates required for carbonate formation are
either derived from the corresponding alcohols17c or
produced in situ during the protection step.22 After
appropriate protection of 6, aldehydes 7-10 were then
reduced to alcohols 11-14 with sodium borohydride.23
The resulting alcohols were then transformed into the
desired halides (15-18, Table 1). The fluorides 15a -18a
were prepared by treatment with DAST,24 the chlorides
15b-18b were readily prepared using triphosgene,25 and
the bromides 15c-18c were generated using phosphorus
tribromide.20
Hyd r olysis of P r otected p-Hyd r oxyben zyl Ha -
lid es. The hydrolysis rates of the protected p-hydroxy-
benzyl halides (15-18) were determined by HPLC analy-
sis in various water/acetonitrile mixtures at different
temperatures. Reactions were conducted (in triplicate)
by programmed addition of a 1 mM solution (50 µL) of
the protected p-hydroxybenzyl halide in acetonitrile to
950 µL of the aqueous reaction medium (50 µM final
concentration) using a temperature-controlled ((0.02 °C)
automatic sample injector. All reactions were protected
from light exposure. Aliquots were autoinjected at defined
intervals onto a C-18 reversed-phase HPLC column. The
first-order decay was followed by determining the change
in the ratio of the areas of the hydrolysis product peak
to the starting material peak at the λmax using a photo-
diode array detector. All reactions were correlated with
1H NMR experiments and independent HPLC analysis
of authentic hydrolysis products. All experiments moni-
tored by HPLC only showed peaks corresponding to
starting benzyl halide and the corresponding benzyl
alcohol hydrolysis product.
The hydrolysis rates of the protected p-hydroxybenzyl
halides and the specific conditions under which they were
determined are shown in Table 2. Two general trends
are apparent: (i) the hydrolysis rates increase in the
expected order fluoride < chloride < bromide and (ii) the
ether-linked protected derivatives (15-16) hydrolyze
significantly faster than the corresponding carbonate-
linked derivatives (17-18). A change in the protecting
group linker from ether to carbonate results in a marked
decrease in the hydrolysis rate regardless of the specific
protecting group or leaving group used. This is the
anticipated result of the electron withdrawing capacity
of the carbonate functional group compared to the
electron-donating capacity of the ether functional group.
In the ether-linked protected compounds, a change in
the protecting group from the 2-nitrobenzyl to the R-
methylnitroveratryl group generally resulted in an ap-
proximate 2-fold increase in the hydrolysis rate of the
protected p-hydroxybenzyl halide (see Table 2, Entries
1-6, 15a -c vs 16a -c). This may be explained by the
electron donating ability of the R-methyl and the phenyl
ring methoxy substituents (present only in the R-meth-
ylnitroveratryl protecting group) in competition with the
electron withdrawing ability of the nitro substituent.
Note that, in all of the hydrolysis reactions studied, the
protecting group remained intact.
(19) Venuti, M. C.; Loe, B. E.; J ones, G. H.; Young, J . M. J . Med.
Chem. 1988, 31, 2132.
(20) McMurry, J . E.; Erion, M. D. J . Am. Chem. Soc. 1985, 107, 2712.
(21) (a) Nitration of commercially available 3,4-dimethoxyacetophe-
none following the procedure in ref 15c was accomplished in 63% yield.
(b) Reduction of the nitro ketone following the procedure in ref 23 was
accomplished in 77% yield after recrystallization from water/ethanol.
(22) Burk, R. M.; Roof, M. B. Tetrahedron Lett. 1993, 34, 395.
(23) Dai-Ho, G.; Moriano, P. S. J . Org. Chem. 1988, 53, 5113.
(24) Middleton, W. J . J . Org. Chem. 1975, 40, 574.
The carbonate protected precursors showed only minor
correlation between hydrolysis rate and the 2-nitrobenzyl
or R-methylnitroveratryl protecting group (see Table 2,
(25) Goren, Z.; Heeg, M. J .; Mobashery, S. J . Org. Chem. 1991, 56,
7186.

Hydrolytic Stabilization of Protected p-HydroxybenzylHalides
J . Org. Chem., Vol. 64, No. 21, 1999 7991
Ta ble 2. Hyd r olysis Ra tes (108k, s-1) of P r otected p-Hyd r oxyben zyl Ha lid es in Differ en t Wa ter /Aceton itr ile Mixtu r es
a n d Tem p er a tu r es
a
b
Measurements were made at 30 °C in a 50 µM solution. Measurements were made in a 50 µM solution of 40% water in acetonitrile
(v/v). c No evidence of hydrolysis was detected after 4-6 days. Less than 3% hydrolysis was detected after 4 days.
d
Ta ble 3. Selected Ha lf-Lives (h ) of P r otected
entries 7-12, 17a -c vs 18a -c). On average, the rates
p-Hyd r oxyben zyl Ha lid es a t 30 °C
of hydrolysis at 30 °C were approximately 6% faster for
the 2-nitrobenzyl carbonate derivatives relative to their
R-methylnitroveratryl carbonate analogues.
water in acetonitrile (%, v/v)
compound
60
100a
The hydrolysis rate of the protected p-hydroxybenzyl
halide with different leaving groups followed the expected
order bromide > chloride > fluoride regardless of protect-
ing group and linking group combination (Table 2). The
hydrolysis rate decreased by approximately 1 order of
magnitude in going from bromide to chloride and by an
additional 2 orders of magnitude in going from chloride
to fluoride.
The hydrolysis rates obtained in 40% water/acetonitrile
at 30, 37, and 55 °C (Table 2) allowed determination of
the hydrolysis activation parameters. On the basis of an
Arrhenius analysis of the data, the range of activation
energies (18.9-21.8 kcal/mol) are in agreement with
published values for hydrolysis of benzyl halides26 as are
the activation enthalpies (18.3-21.2 kcal/mol, 37 °C) and
entropies (-9.5 to -19.5 cal/(deg mol), 37 °C).26,27 One
apparent trend was the increase in the Gibb’s free energy
of activation by approximately 3 kcal/mol in going from
the ether-linked derivatives (Table 2, entries 1-6, 15-
16) to the carbonate-linked derivatives (Table 2, entries
7-12, 17-18). This corresponds to the degree of the
15a
15b
15c
16a
16b
16c
17a
17b
17c
18a
18b
18c
445
0.78
0.089
223
0.47
0.066
b
471
21.1
b
8.9c
0.04
0.007
4.8c
0.031
0.006
d
29.4c
3.9
d
520
23.0
50.2c
4.6
a
b
Extrapolated from experimentally determined data. No evi-
dence of hydrolysis was detected after 4-6 days. c Extrapolated
d
from only two data points. Not determined due to significant
stability.
increased stability afforded by the electron-withdrawing
carbonate linkage.
The hydrolysis half-lives of the protected p-hydroxy-
benzyl halides as determined at 30 °C in 60% water/
acetonitrile (the highest water content experimentally
determined) are shown in Table 3. A Grunwald-Winstein
analysis allowed extrapolation of the hydrolysis rate to
100% water (vide infra). These theoretical half-lives at
100% water are also shown in Table 3. Note that
compounds 17a and 18a showed no evidence of hydrolysis
after 4-6 days28 so their hydrolysis values were not
(26) Koshy, K. M.; Robertson, R. E.; Strachan, W. M. J . Can. J .
Chem. 1973, 51, 2958.
(27) Hyne, J . B.; Wills, R.; Wonkka, R. E. J . Am. Chem. Soc. 1962,
84, 2914.

7992 J . Org. Chem., Vol. 64, No. 21, 1999
Dyer and Turnbull
determined. Note also that the hydrolysis half-lives of
compounds 15a , 16a , 17b, and 18b in 100% water were
extrapolated from only two data points each due to their
significant stability under the conditions studied. Two
general trends are apparent from the half-lives. The
hydrolysis rates were clearly relative to (i) the specific
halide used at the benzylic position and (ii) the type of
linker attaching the photolabile protecting group.
Consistent with the experimentally derived hydrolysis
rate data, the extrapolated half-lives at 100% water show
an approximate gain of 1 order of magnitude in going
from bromide to chloride and an additional 2 orders of
magnitude in going from chloride to fluoride (Table 3).
Additionally, the extrapolated values for the hydrolysis
half-lives of the carbonate protected chlorides are ap-
proximately 2-3 days and those of the carbonate-
protected fluorides were not determined due to their
tremendous stability under the conditions studied. These
results indicate that the carbonate protected chlorides
and fluorides should easily be satisfactory candidates for
use in biologically relevant systems. Even the less stable
carbonate-protected benzyl bromide derivatives 17c and
18c with estimated half-lives of nearly 5 h should be
sufficiently stable for many applications.
F igu r e 1. Correlation of the log of the rate constants for
hydrolysis relative to the Y values of the solvent (r > 0.99 in
all cases). Y values correspond to the respective acetonitrile/
water mixtures.35 The log k value at Y ) 3.49 (100% H2O) is
based on extrapolation of the experimentally determined
hydrolysis rates.
Ha m m ett An a lysis of P r otectin g Gr ou p Lin k er .
+
The calculated Hammett σp value for the carbonate
a positive charge. This indicates a shift toward less
positive charge buildup in the transition state.36
group from our studies is +0.2829 based on a F value of
-4.54.30 While F values are reaction and solvent depend-
ent, the F value we selected gave reasonable calculated
values for our σp+ constants and is in the range generally
given for the solvolysis of benzyl chlorides.10,30,31 Using
the same F value, we calculated a σp+ value of -0.39 for
Con clu sion s
We have directly compared a series of protected p-
hydroxybenzyl halide latent quinone methide precursors
whose hydroxy functionality was protected with either a
carbonate-linked or an ether-linked photolabile protecting
group. The protected p-hydroxybenzyl halides having a
carbonate-linked protecting group clearly demonstrated
enhanced hydrolytic stability over the corresponding
ether-linked derivatives. Of the compounds investigated,
we found the R-methylnitroveratryl carbonate protected
p-hydroxybenzyl halide having a fluoride leaving group
to be indeterminately stable toward hydrolysis under the
conditions studied. The most stable protected p-hydroxy-
benzyl chloride has an estimated half-life in 100% water
of over 50 h. Even the most hydrolysis prone carbonate-
linked derivative, the benzyl bromide, is anticipated to
have a half-life of nearly 5 h in 100% water. This
systematic analysis will allow the rational design of
quinone methide precursors anticipated to be useful in
a variety of bioalkylation processes.18
the benzyl ether group.32 This results in ∆σp ) 0.67,
+
which is an approximate 3 orders of magnitude increase
in stabilization in going from the ether-linked to the
carbonate-linked photolabile protected p-hydroxybenzyl
halides.33
Gr u n w a ld -Win stein P lot of Selected P r otected
p-Hyd r oxyben zyl Ha lid es. The Grunwald-Winstein
plot of those protected p-hydroxybenzyl halide with
sufficient hydrolysis rates to give four data points for
extrapolation to 100% water is shown in Figure 1. The
data show a good linear correlation (r > 0.99) between
the log of the hydrolysis rate and the solvent polarity.
The slopes of the lines demonstrate a moderate to high
dependence of the hydrolysis rate on solvent polarity as
expected for a benzyl halide solvolysis reaction.34 The
average slope (0.78) of the ether-linked derivatives
(15b-c and 16b-c, Figure 1) is approximately 0.29 units
higher than the average slope (0.49) of the carbonate-
linked derivatives (17c, 18c, Figure 1). The smaller slope
for the carbonate protected precursor is characteristic of
the decreased ability of the carbonate group to stabilize
Exp er im en ta l Section
Gen er a l Meth od s. All nonaqueous reactions, except for
sodium borohydride reductions, were conducted under an inert
nitrogen atmosphere. Unless specified otherwise, solvents and
reagents are commercially available chemicals and were used
as received. Tetrahydrofuran (THF), diethyl ether, and meth-
ylene chloride were purified using the Solv-Tek ST-002 solvent
purification system.37 Dimethylformamide (DMF) was stirred
with barium oxide for 14 h and distilled under reduced
pressure from magnesium sulfate. HPLC acetonitrile was used
as received. HPLC water was purified using a Millipore Milli-Q
(28) Note also that, even at 55 °C, compounds 17a and 18a showed
no evidence of hydrolysis after 4-6 days (Table 2).
(29) The value was calculated from the 100% water extrapolated
rate using the formula σ ) log(k/k0)/ -4.54 and was adjusted for the
presence of the two m-methyl groups by subtracting -0.13 (see ref 31).
The value k0 ) 2.44 × 10-5 (30 °C, 100% H2O) is taken from:
Robertson, R. E.; Scott, J . M. W. J . Chem. Soc. 1961, 1596.
(30) Brown, H. C.; Okamoto, Y. J . Am. Chem. Soc. 1958, 80, 4979.
(31) Fuchs, R.; Carlton, D. M. J . Am. Chem. Soc. 1963, 85, 104.
(32) This may be compared to a σp value of -0.42 for a benzyloxy
substituent. J affe, H. H. Chem. Rev. 1953, 53, 191.
(35) Bentley, T. W.; Dau-Schmidt, J .-P.; Llewellyn, G.; Mayr, H. J .
Org. Chem. 1992, 57, 2387.
(36) (a) Bolton, J . L.; Valerio, L. G., J r.; Thompson, J . A. Chem. Res.
Toxicol. 1992, 5, 816. (b) Bolton, J . L.; Comeau, E.; Vukomanovic, V.
Chem.-Biol. Interact. 1995, 95, 279.
(33) Rearrangement of the formula σ ) log(k/k0)/ -4.54 leads to k/k0
) 10-4.54σ ) 10(-4.54)(0.67) ) 10-3
.
(34) (a) Winstein, S.; Grunwald, E.; J ones, H. W. J . Am. Chem. Soc.
1951, 73, 2700. (b) Winstein, S.; Grunwald, E. J . Am. Chem. Soc. 1948,
70, 846.
(37) Solv-Tek Inc., Berryville, VA.

Hydrolytic Stabilization of Protected p-HydroxybenzylHalides
J . Org. Chem., Vol. 64, No. 21, 1999 7993
RG ultrapure water purification system.38 External bath
temperatures were used to record all reaction temperatures.
Aqueous workup (solvent (number of extractions × volume
used for each extraction), drying agent) refers to the extraction
of the aqueous phase with the indicated volume of organic
solvent for the indicated number of times followed by drying
of the combined organic phases with the indicated drying
reagent and filtration to remove the drying agent. Concentra-
tion in vacuo refers to removal of solvent via distillation using
Buchi rotary evaporator at water aspirator pressure and/or
residual solvent removal at high vacuum. Melting points are
uncorrected. Unless otherwise noted, all 1H and 13C NMR
spectra were recorded in CDCl3 at 270 and 67.9 MHz,
respectively. Chemical shifts are reported as δ values in ppm
relative to TMS.
Mea su r em en t of Hyd r olysis Ra tes. Each of the sub-
strates was monitored by HPLC for hydrolytic stability in 20-
60% (v/v) water/acetonitrile mixtures at 30 °C and in a 40%
(v/v) water/acetonitrile mixture at 37 or 55 °C. Reactions were
conducted in triplicate by programmed addition of 50 µL of a
1 mM acetonitrile solution of the substrate at the specified
temperature to 950 µL of the acetonitrile/water reaction
mixture at the same temperature to form a solution whose
final concentration was 50 µM. All solutions were maintained
at the specified temperature ((0.02 °C) through circulation
of water from a constant temperature water bath. An auto-
injector was used to inject 25 µL aliquots of the reaction
mixture at predetermined intervals onto a Varian Res-Elut
column (5 µm, C18, 90A, 4.6 mm × 150 mm) eluting with 75%
acetonitrile/water (v/v). The resulting chromatograms taken
at the λmax using a photodiode array detector were analyzed
to determine the percent of the starting material remaining.
No peaks other than starting benzyl halide and the hydrolysis
product were present in the chromatograms. The hydrolysis
products were identified through comparison of retention times
and UV spectra of authentic compounds. For each experiment,
the respective value of k for hydrolysis was estimated by linear
regression from the slope of the plot of the natural logarithm
of the percent starting material remaining versus time. The
reported value of k for hydrolysis is the average of three
determinations (average deviation (2%).
4,5-Dim eth oxy-2-n itr oa cetop h en on e. A solution of 3,4-
dimethoxyacetophenone (10.0 g, 55.5 mmol) in acetic anhy-
dride (30 mL) at room temperature was added slowly over 30
min to a stirring mixture of concentrated nitric acid (200 mL)
and acetic anhydride (10 mL) at 0 °C (ice/water). This mixture
was allowed to warm slowly to room temperature with stirring
for 4 h. The reaction mixture was poured into water (1.5 L),
diluted to 2.0 L total volume, and cooled to 4 °C. The
precipitate was collected, washed with water, and dried (high
vacuum) to afford the known compound39 as a yellow solid (7.83
g, 63% yield): mp 129-133 °C (lit.39 mp 130-132 °C); 1H NMR
δ 7.60 (s, 1H), 6.74 (s, 1H), 3.97 (s, 6H), 2.49 (s, 3H).
4,5-Dim eth oxy-R-m eth yl-2-n itr oben zyl Alcoh ol. Sodium
borohydride (0.34 g, 8.8 mmol) was added to a stirring
suspension of 2-nitro-4,5-dimethoxyacetophenone (2.0 g, 8.8
mmol) in ethanol (100 mL, 0.1 M) at room temperature. After
19 h, the reaction mixture was poured into 5% acetic acid (100
mL). The mixture was diluted with water to 500 mL total
volume, and yellow crystals formed after a few minutes of
stirring. The crystals were collected by vacuum filtration and
oven dried at 80 °C for 3 h to afford the known compound40 as
bright yellow crystals (1.6 g, 77% yield): mp 125-126 °C; IR
(KBr) 3291, 3209, 1508, 1270, 1096; 1H NMR (CDCl3/CD3OD)
δ 7.40 (s, 1H), 7.20 (s, 1H), 5.36 (q, J ) 6.2 Hz, 1H), 3.84 (s,
3H), 3.78 (s, 3H), 1.34 (d, J ) 6.2 Hz, 3H); 13C NMR (CDCl3/
CD3OD) δ 154.6, 148.2, 139.9, 138.7, 109.1, 108.1, 65.5, 56.6,
56.5, 24.7.
4,5-Dim eth oxy-r-m eth yl-2-n itr oben zyl Br om id e. Phos-
phorus tribromide (46 µL, 0.48 mmol) was added to a solution
of R-methyl-2-nitro-4,5-dimethoxybenzyl alcohol (0.30 g, 1.3
mmol) in CH2Cl2 (15 mL, 0.1 M) at 0 °C and stirred for 2.5 h.
The reaction mixture was diluted with Et2O (50 mL), washed
with 5% NaHCO3 (2 × 25 mL) and brine (25 mL), dried
(MgSO4), and concentrated in vacuo to yield a yellow oil. The
oil was purified by flash chromatography on silica gel (20 g,
2:1 hexanes/CH2Cl2) to afford the known compound40 as a
yellow oil (0.33 g, 85% yield): 1H NMR δ 7.33 (s, 1H), 7.16 (s,
1H), 5.89 (q, J ) 6.7 Hz, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 1.94
(d, J ) 6.7 Hz, 3H); 13C NMR δ 153.3, 148.4, 139.6, 132.4,
111.0, 107.4, 56.5, 56.4, 43.4, 27.5; MS (EI) m/z 291 (4.0, M+,
81Br), 289 (3.7, M+, 79Br), 210 (100).
2-Nitr oben zylch lor ofor m a te. A phosgene solution (20%
w/v in toluene, 8.00 mL, 16.3 mmol) was added to a solution
of 2-nitrobenzyl alcohol in THF at room temperature and
stirred for 21 h. Excess phosgene was removed by water
aspirator through an aqueous NaOH solution. The remaining
toluene was removed by concentration in vacuo to afford the
known compound15b,41 as a brown oil (1.40 g, 99% yield): 1H
NMR δ 8.17 (d, J ) 8.2 Hz, 1H), 7.75-7.53 (m, 3H), 5.73 (s,
2H); 13C NMR δ 150.5, 147.2, 134.3, 129.8, 129.7, 129.1, 125.5,
69.6.
4-(2′-Nitr oben zyloxy)-3,5-d im eth ylben za ld eh yd e (7).
DMF (20 mL) at room temperature was added to a stirring
mixture of 4-hydroxy-3,5-dimethylbenzaldehyde (0.50 g, 3.3
mmol), potassium carbonate (0.92 g, 6.6 mmol), and 2-nitro-
benzyl bromide (0.72 g, 3.3 mmol), and stirring was continued
for 3.5 h at room temperature. The reaction was diluted with
5% NaHCO3 (200 mL), and aqueous workup (CH2Cl2 (3 × 50
mL), MgSO4) followed by concentration in vacuo afforded 7
(0.89 g, 94% yield) as a cream-colored solid: mp 116-118 °C;
IR (KBr) 1693, 1598, 1518, 1479 cm-1; 1H NMR δ 9.85 (s, 1H),
8.14 (d, J ) 7.5 Hz, 1H), 8.11 (app d, J ) 6.5 Hz, 1H), 7.74
(app t, J ) 7.7 Hz, 1H), 7.55 (s, 2H), 7.49 (t, J ) 7.5 Hz, 1H),
5.24 (s, 2H), 2.29 (s, 6H); 13C NMR δ 191.6, 160.7, 146.5, 134.3,
134.0, 132.8, 132.2, 130.9, 128.5, 128.3, 125.0, 70.2, 16.5.
4-(4′,5′-Dim eth oxy-r′-m eth yl-2′-n itr oben zyloxy)-3,5-d i-
m eth ylben za ld eh yd e (8). A solution of R-methyl-2-nitro-4,5-
dimethoxybenzyl bromide (0.47 g, 1.2 mmol) in DMF (2 mL)
at room temperature was added to a stirring suspension of
4-hydroxy-3,5-dimethylbenzaldehyde (0.18 g, 1.2 mmol) and
potassium carbonate (0.33 g, 2.4 mmol) in DMF (10 mL) at
room temperature, and stirring was continued for 4.5 h. The
reaction mixture was then poured into 5% NaHCO3 (200 mL).
Aqueous workup (CH2Cl2 (3 × 50 mL), MgSO4) followed by
concentration in vacuo yielded a brown oil that was purified
by flash chromatography on silica gel (15 g, 5:1 hexanes/ethyl
acetate) to afford 8 (0.39 g, 91% yield) as a yellow oil: IR (film)
1
1692, 1517, 1274, 1019 cm-1; H NMR δ 9.81 (s, 1H), 7.57 (s,
1H), 7.49 (s, 3H), 5.83 (q, J ) 6.2 Hz, 1H), 4.01 (s, 3H), 3.92
(s, 3H), 2.22 (s, 6H), 1.56 (d, J ) 6.2 Hz, 3H); 13C NMR δ 191.5,
160.5, 153.8, 148.1, 139.0, 134.5, 131.7, 132.1, 131.1, 109.0,
107.5, 76.6, 56.5, 56.4, 23.5, 17.6.
4-(2-Nitr oben zyloxyca r bon yloxy)-3,5-d im eth ylben za l-
d eh yd e (9). 2-Nitrobenzylchloroformate (0.52 mL, 3.3 mmol)
was added to a stirring mixture of 4-hydroxy-3,5-dimethyl-
benzaldehyde (0.50 g, 3.3 mmol) and potassium carbonate (0.92
mg, 6.7 mmol) in DMF (20 mL) at room temperature. After
being stirred for 17 h, the reaction mixture was quenched by
pouring into 5% NaHCO3 (200 mL). Aqueous workup (Et2O (3
× 35 mL), MgSO4) and concentration in vacuo afforded an off-
yellow solid that was purified by flash chromatography on
silica gel (50 g, 4:1 CH2Cl2/hexanes) to afford 9 (0.88 mg, 80%
yield) as a light yellow solid: mp 105-107 °C; IR (KBr) 1750,
1
1695, 1596, 1526, 1468 cm-1; H NMR δ 8.08 (d, J ) 7.9 Hz,
1H), 7.66 (d, J ) 3.9 Hz, 2H), 7.53 (s, 2H), 7.50-7.45 (m, 1H),
5.66 (s, 2H), 2.22 (s, 6H); 13C NMR δ 191.4, 152.7, 151.9, 147.4,
134.4, 134.1, 131.6, 131.0, 130.4, 129.5, 129.0, 125.4, 67.3, 16.1.
4-(4′,5′-Dim eth oxy-r′-m eth yl-2′-n itr oben zyloxyca r bon -
yloxy)-3,5-d im eth ylben za ld eh yd e (10). Triphosgene (0.22
(38) Millipore Corp., Molsheim, France.
(39) Wilcox, M.; Viola, R. W.; J ohnson, K. W.; Billington, A. P.;
Carpenter, B. K.; McCray, J . A.; Guzikowski, A. P.; Hess, G. P. J . Org.
Chem. 1990, 55, 1585.
(40) Aoshima, H.; Tanaka, D.; Kamimura, A. Biosci. Biotech. Bio-
chem. 1992, 56, 1086.
(41) Amit, B.; Zehavi, U.; Patchornik, A. J . Org. Chem. 1974, 39,
192.

7994 J . Org. Chem., Vol. 64, No. 21, 1999
Dyer and Turnbull
g, 0.70 mmol) in CH2Cl2 (10 mL) at room temperature was
added to a solution of R-methyl-2-nitro-4,5-dimethoxybenzyl
alcohol (0.50 g, 2.2 mmol) and pyridine (0.53 mL, 6.6 mmol)
in CH2Cl2 (20 mL) at -42 °C (CH3CN/CO2). After 2 h,
4-hydroxy-3,5-dimethylbenzaldehyde (0.33 g, 2.2 mmol) and
pyridine (0.53 mL, 6.6 mmol) in CH2Cl2 (10 mL) at room
temperature were added, and the mixture was allowed to
slowly warm to room temperature overnight. The reaction
mixture was quenched with saturated ammonium chloride (80
mL), and aqueous workup (CH2Cl2 (2 × 40 mL), MgSO4)
followed by concentration in vacuo afforded a brown solid that
was recrystallized (EtOH) to afford 10 (0.43 g, 49% yield) as a
cream-colored solid: mp 128-129 °C; IR (KBr) 1749, 1700,
21.9, 16.0; MS (EI) m/z 405 (0.3, M+), 210 (0.81), 152 (12.6),
151 (3.9). Anal. Calcd for C20H23NO8: C, 59.25; H, 5.72; N,
3.46. Found: C, 58.81; H, 5.67; N, 3.44.
4-(2′-Nitr oben zyloxy)-3,5-dim eth ylben zyl Flu or ide (15a).
DAST (70 µL, 0.53 mmol) was added to a stirring solution of
11 (0.10 g, 0.35 mmol) in CH2Cl2 (15 mL) at 0 °C (ice/water).
After 1 h, the reaction mixture was poured into saturated
NaHCO3 (10 mL). Aqueous workup (CH2Cl2 (2 × 5 mL),
MgSO4) followed by concentration in vacuo yielded a yellow
oil. This was purified by flash chromatography on silica gel (5
g, 1:1 CH2Cl2/hexanes) to afford 15a (79 mg, 79% yield) as a
white solid: mp 96-99 °C; IR (KBr) 1610, 1523, 1480 cm-1
;
1H NMR δ 8.21-8.16 (m, 2H), 7.76 (app t, J ) 7.4 Hz, 1H),
7.51 (app t, J ) 8.2 Hz, 1H), 7.09 (s, 2H), 5.29 (d, J C-F ) 48.3
Hz, 2H), 5.23 (s, 2H), 2.28 (s, 6H); 13C NMR δ 155.9, 146.6,
134.7, 134.2, 132.2 (d, J C-F ) 17.1 Hz), 131.4, 128.4, 128.2,
124.9, 128.8 (d, J C-F ) 5.2 Hz), 84.5 (d, J C-F ) 165.1 Hz), 70.1,
16.4; MS (EI) m/z 289 (8.5, M+), 153 (25.6), 136 (45.6). Anal.
Calcd for C16H16FNO3: C, 66.43; H, 5.57; F, 6.57; N, 4.84.
Found: C, 66.57; H, 5.43; F, 6.37; N, 4.81.
1
1583, 1521, 1457 cm-1; H NMR δ 9.88 (s, 1H), 7.59 (s, 1H),
7.55 (s, 2H), 7.11 (s, 1H), 6.47 (q, J ) 6.4 Hz, 1H), 3.98 (s,
3H), 3.93 (s, 3H), 2.18 (s, 6H), 1.76 (d, J ) 6.4 Hz, 3H); 13C
NMR δ 191.4, 153.8, 152.7, 151.2, 148.4, 140.1, 134.3, 132.0,
131.5, 130.4, 107.8, 107.5, 73.6, 56.6, 56.5, 22.0, 16.2.
4-(2′-Nitr oben zyloxy)-3,5-d im eth ylben zyl Alcoh ol (11).
EtOH (17 mL) was added to a mixture of sodium borohydride
(66 mg, 1.7 mmol) and 7 (0.50 g, 1.7 mmol) at room temper-
ature and allowed to sit for 2 h. The reaction mixture was
poured into 5% NaHCO3 (150 mL). Aqueous workup (CH2Cl2
(3 × 50 mL), MgSO4) followed by concentration in vacuo
afforded 11 (0.50 mg, 99% yield) as an off-white solid: mp 94-
4-(2′-Nitr oben zyloxy)-3,5-dim eth ylben zyl Ch lor ide (15b).
Pyridine (79 µL, 0.97 mmol) was added to a stirring mixture
of 11 (0.11 g, 0.39 mmol) and triphosgene (46 mg, 0.16 mmol)
in CH2Cl2 (5 mL) at room temperature. After 15 min, the
reaction mixture was concentrated in vacuo. Flash chroma-
tography on silica gel (20 g, 5:1 hexanes/ethyl acetate) afforded
15b (81 mg, 68% yield) as a white solid: mp 102-106 °C; IR
(KBr) 1521 cm-1; 1H NMR δ 8.18 (d, J ) 7.4 Hz, 1H), 8.17 (d,
J ) 8.2 Hz, 1H), 7.76 (app t, J ) 7.4 Hz, 1H), 7.51 (app t, J )
8.2 Hz, 1H), 7.09 (s, 2H), 5.23 (s, 2H), 4.52 (s, 2H), 2.27 (s,
6H); 13C NMR δ 155.6, 146.6, 134.7, 134.2, 133.5, 131.5, 129.5,
128.4, 128.2, 124.9, 70.1, 46.2, 16.4; MS (EI) m/z 307 (0.9, M+,
37Cl), 305 (2.8, M+, 35Cl), 171 (1.7), 169 (7.4), 136 (100). Anal.
Calcd for C16H16ClNO3: C, 62.85; H, 5.27; N, 4.58. Found: C,
63.24; H, 5.41; N, 4.40.
4-(2′-Nitr oben zyloxy)-3,5-dim eth ylben zyl Br om ide (15c).
Phosphorus tribromide (33 µL, 0.35 mmol) was added to a
stirring solution of 11 (0.10 g, 0.35 mmol) in CH2Cl2 (10 mL)
at 0 °C (ice/water). After being stirred for 4.5 h, the reaction
mixture was poured into an equal volume mixture of saturated
NaCl and saturated NaHCO3 (10 mL). Aqueous workup
(CH2Cl2 (2 × 5 mL), MgSO4) followed by concentration in vacuo
yielded a white solid. This was purified by flash column
chromatography on silica gel (5 g, 1:1 CH2Cl2/hexanes) to afford
15c (56 mg, 46% yield) as an off-white solid: mp 120-121 °C;
IR (KBr) 1525, 1480 cm-1; 1H NMR δ 8.17 (app d, J ) 8.1 Hz),
7.75 (app t, J ) 7.8 Hz), 7.50 (app t, J ) 7.8 Hz), 7.08 (s, 2H),
5.21 (s, 2H), 4.43 (s, 2H), 2.25 (s, 6H); 13C NMR δ 155.6, 146.6,
134.7, 134.2, 133.8, 131.6, 129.8, 128.3, 128.2, 124.9, 70.1, 33.6,
16.4; MS (EI) m/z 351 (1.9, M+, 81Br), 349 (1.9, M+, 79Br), 215
(1.0), 213 (1.0), 136 (100). Anal. Calcd for C16H16BrNO3: C,
54.87; H, 4.60; Br, 22.82; N, 4.00. Found: C, 55.13; H, 4.59;
Br, 22.76; N, 3.85.
1
95 °C; IR (KBr) 3287, 1609, 1521, 1482 cm-1; H NMR δ 8.18
(d, J ) 8.0 Hz, 1H), 8.15 (d, J ) 8.0 Hz, 1H), 7.75 (t, J ) 8.0
Hz, 1H), 7.49 (t, J ) 8.0 Hz, 1H), 7.04 (s, 2H), 5.21 (s, 2H),
4.57 (s, 2H), 2.26 (s, 6H); 13C NMR δ 154.9, 146.6, 136.9, 134.8,
134.2, 131.1, 128.4, 128.2, 127.9, 124.9, 70.1, 64.9, 16.4; MS
(EI) m/z 287 (5.6, M+), 152 (7.1), 136 (100). Anal. Calcd for
C
16H17NO4: C, 66.89; H, 5.96; N, 4.88. Found: C, 67.02; H,
5.62; N, 4.81.
4-(4′,5′-Dim eth oxy-r′-m eth yl-2′-n itr oben zyloxy)-3,5-d i-
m eth ylben zyl Alcoh ol (12). Sodium borohydride (35 mg, 0.90
mmol) was added to a stirring solution of 8 (0.33 g, 0.90 mmol)
in EtOH (7 mL) at room temperature and allowed to stir for 3
h. The reaction mixture was poured into 5% NaHCO3 (150 mL).
Aqueous workup (CH2Cl2 (3 × 50 mL), MgSO4) followed by
concentration in vacuo afforded 12 (0.33 g, 100% yield) as a
1
yellow oil: IR (film) 3529, 3404, 1518, 1021 cm-1; H NMR δ
7.59 (s, 1H), 7.55 (s, 1H), 7.00 (s, 2H), 5.73 (q, J ) 6.2 Hz,
1H), 4.56 (s, 2H), 4.04 (s, 3H), 3.95 (s, 3H), 2.18 (s, 6H), 1.56
(d, J ) 6.2 Hz, 3H); 13C NMR δ 154.6, 153.8, 147.9, 139.0,
136.1, 135.4, 131.0, 128.1, 109.2, 107.5, 76.2, 65.1, 56.5, 56.4,
23.4, 17.6; MS (EI) m/z 361 (0.2, M+), 210 (4.9), 149 (78.7).
4-(2′-Nit r ob en zyloxyca r b on yloxy)-3,5-d im et h ylb en -
zyl Alcoh ol (13). EtOH (15 mL) was added at room temper-
ature to a mixture of 9 (0.50 g, 1.5 mmol) and sodium
borohydride (57 mg, 1.5 mmol) and allowed to stir for 1 h. The
reaction mixture was poured into 5% NaHCO3 (200 mL).
Aqueous workup (CH2Cl2 (3 × 50 mL), MgSO4) followed by
concentration in vacuo afforded a yellow oil that, after addition
and removal of hexane, afforded 13 (0.48 g, 96% yield) as an
off-white solid: mp 80-82 °C; IR (KBr) 3297, 1754, 1611, 1574,
4-(4′,5′-Dim eth oxy-r′-m eth yl-2′-n itr oben zyloxy)-3,5-d i-
m eth ylben zyl F lu or id e (16a ). DAST (55 µL, 0.42 mmol) was
added to a stirring solution of 12 (0.10 g, 0.28 mmol) in CH2Cl2
(10 mL) at room temperature. After 1 h, the reaction mixture
was poured into saturated NaHCO3 (5 mL). Aqueous workup
(CH2Cl2 (2 × 5 mL), MgSO4) followed by concentration in vacuo
yielded a yellow oil. This was purified by flash chromatography
on silica gel (5 g, 1:1 CH2Cl2/hexanes) to afford 16a (59 mg,
1
1530, 1487 cm-1; H NMR δ 8.15 (d, J ) 7.9 Hz, 1H), 7.72-
7.69 (m, 2H), 7.55-7.49 (m, 1H), 7.04 (s, 2H), 5.69 (s, 2H), 4.56
(s, 2H), 2.19 (s, 6H); 13C NMR δ 152.7, 147.7, 147.3, 138.9,
134.1, 131.6, 130.3, 129.3, 128.8, 127.5, 125.4, 66.9, 64.7, 16.1;
MS (EI) m/z 331 (1.0, M+), 151 (4.6), 136 (7.8). Anal. Calcd for
C
17H17NO6: C, 61.63; H, 5.17; N, 4.23. Found: C, 61.84; H,
4.98; N, 4.09.
59% yield) as a yellow oil: IR (film) 1517, 1273, 1019 cm-1
;
4-(4′,5′-Dim eth oxy-r′-m eth yl-2′-n itr oben zyloxyca r bon -
yloxy)-3,5-d im eth ylben zyl Alcoh ol (14). EtOH (12 mL) was
added at room temperature to a stirring mixture of sodium
borohydride (47 mg, 1.2 mmol) and 10 (0.50 g, 1.2 mmol) and
allowed to stir for 1.5 h. The reaction mixture was poured into
5% NaHCO3 (100 mL). Aqueous workup (CH2Cl2 (3 × 50 mL),
MgSO4) followed by concentration in vacuo afforded 14 (0.50
mg, 99% yield) as a cream-colored solid: mp 151-152 °C; IR
(KBr) 3371, 3308, 1748, 1582, 1520, 1459 cm-1; 1H NMR δ 7.52
(s, 1H), 7.06 (s, 1H), 6.92 (s, 2H), 6.39 (q, J ) 6.4 Hz, 1H),
4.45 (s, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 2.03 (s, 6H), 1.68 (d, J
) 6.4 Hz, 3H); 13C NMR δ 153.7, 151.7, 148.1, 147.4, 139.8,
138.7, 132.3, 129.9, 127.2, 107.6, 107.4, 73.0, 64.4, 56.4, 56.3,
1H NMR 7.60 (s, 1H), 7.03 (s, 2H), δ 7.55 (s, 1H), 5.76 (q, J )
6.2 Hz, 1H), 5.24 (d, J C-F ) 48.2 Hz, 2H), 4.04 (s, 3H), 3.95 (s,
3H), 2.20 (s, 6H), 1.57 (d, J ) 6.2 Hz, 3H); 13C NMR δ 155.6
(d, J C-F ) 3.6 Hz), 153.8, 147.9, 139.0, 135.3, 131.4 (d, J C-F
)
17.1 Hz), 131.2, 129.0 (d, J C-F ) 5.2 Hz), 109.2, 107.5, 84.5 (d,
J C-F ) 164.9 Hz), 76.3, 56.5, 56.4, 22.7, 17.6; MS (EI) m/z 363
(0.6, M+), 210 (53.3), 153 (6.0). Anal. Calcd for C19H22FNO5:
C, 62.80; H, 6.10; N, 3.85. Found: C, 63.25; H, 6.09; N, 3.90.
4-(4′,5′-Dim eth oxy-R′-m eth yl-2′-n itr oben zyloxy)-3,5-d i-
m eth ylben zyl Ch lor id e (16b). Pyridine (15 µL, 0.19 mmol)
was added to a stirring mixture of 12 (27 mg, 0.070 mmol)
and triphosgene (27 mg, 0.090 mmol) in CH2Cl2 (3 mL) at room
temperature. After 1 h, the reaction mixture was filtered

Hydrolytic Stabilization of Protected p-HydroxybenzylHalides
J . Org. Chem., Vol. 64, No. 21, 1999 7995
through a layer of silica gel (5 g, 3 cm), washed with CH2Cl2
(25 mL), and concentrated in vacuo to afford pure 16b (24 mg,
86% yield) as a yellow oil: IR (film) 1580, 1273, 874 cm-1; 1H
NMR δ 7.60 (s, 1H), 7.54 (s, 1H), 7.03 (s, 2H), 5.74 (q, J ) 6.2
Hz, 1H), 4.49 (s, 2H), 4.03 (s, 3H), 3.95 (s, 3H), 2.18 (s, 6H),
1.57 (d, J ) 6.2 Hz, 3H); 13C NMR δ 155.3, 153.8, 147.9, 139.0,
135.3, 132.7, 131.3, 129.6, 109.1, 107.5, 76.2, 56.5, 56.4, 46.2,
23.5, 17.6; MS (EI) m/z 210 (5.5), 171 (0.2), 169 (0.6). Anal.
Calcd for C19H22ClNO5: C, 60.08; H, 5.84; Cl, 9.33; N, 3.69.
Found: C, 60.14; H, 5.85; Cl, 9.39; N, 3.66.
bright yellow oil that was purified by flash column chroma-
tography on silica gel (5 g, 2:1 hexanes/CH2Cl2) to afford 17c
(49 mg, 28% yield) as an off-white solid: mp 72-74 °C; IR
(KBr) 1756, 1540, 1426 cm-1; 1H NMR δ 8.17 (d, J ) 8.2 Hz),
7.72-7.65 (m, 2H), 7.58-7.47 (m, 1H), 7.09 (s, 2H), 5.70 (s,
2H), 4.41 (s, 2H), 2.19 (s, 6H); 13C NMR δ 152.5, 148.2, 135.8,
134.1, 131.5, 130.8, 129.6, 129.3, 128.8, 125.4, 67.0, 32.9, 16.1;
MS (EI) m/z 395 (6.9, M+, 81Br), 393 (5.7, M+, 79Br), 215 (4.9),
213 (5.6), 135 (100). Anal. Calcd for C17H16BrNO5: C, 51.79;
H, 4.09; N, 3.55. Found: C, 52.19; H, 4.30; N, 3.57.
4-(4′,5′-Dim eth oxy-R′-m eth yl-2′-n itr oben zyloxy)-3,5-d i-
m eth ylben zyl Br om id e (16c). Phosphorus tribromide (25 µL,
0.28 mmol) was added to a stirring solution of 12 (0.10 g, 0.28
mmol) in CH2Cl2 (10 mL) at room temperature. After being
stirred for 2 h, the reaction mixture was poured into saturated
NaHCO3 (5 mL). Aqueous workup (CH2Cl2 (2 × 5 mL), MgSO4)
followed by concentration in vacuo yielded a yellow oil that
was purified by flash column chromatography on silica gel (5
g, 1:1 CH2Cl2/hexanes) to afford 16c (45 mg, 38% yield) as a
yellow oil: IR (film) 1518, 1020 cm-1; 1H NMR δ 7.60 (s, 1H),
7.53 (s, 1H), 7.03 (s, 2H), 5.74 (q, J ) 6.2 Hz, 1H), 4.41 (s,
2H), 4.03 (s, 3H), 3.95 (s, 3H), 2.17 (s, 6H), 1.56 (d, J ) 6.2
Hz, 3H);13C NMR δ 155.3, 153.8, 148.0, 139.0, 135.2, 133.0,
131.3, 130.0, 109.2, 107.6, 76.6, 56.5, 56.4, 33.6, 23.5, 17.5; MS
(EI) m/z 425 (0.5, M+, 91Br), 423 (0.5, M+, 79Br), 215 (0.5), 213
(0.6), 210 (100). Anal. Calcd for C19H22BrNO5: C, 53.79; H,
5.23; N, 3.30. Found: C, 53.78; H, 5.20; N, 3.35.
4-(4′,5′-Dim eth oxy-r′-m eth yl-2′-n itr oben zyloxyca r bon -
yloxy)-3,5-d im eth ylben zyl F lu or id e (18a ). DAST (50 µL,
0.37 mmol) at room temperature was added to a stirring
solution of 14 (0.10 g, 0.25 mmol) in CH2Cl2 (10 mL) at 0 °C
(ice/watwer). After 0.75 h, the reaction mixture was poured
into saturated NaHCO3 (5 mL). Aqueous workup (CH2Cl2 (2
× 5 mL), MgSO4) followed by concentration in vacuo yielded
a yellow oil that was purified by flash chromatography on silica
gel (5 g, 1:1 CH2Cl2/hexanes) to afford 18a (63 mg, 63% yield)
as a white solid: mp 132-134 °C; 1H NMR δ 7.59 (s, 1H), 7.10
(s, 1H), 7.03 (s, 2H), 6.46 (q, J ) 6.4 Hz, 1H), 5.24 (d, J C-F
)
47.7 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 2.12 (s, 6H), 1.75 (d, J
) 6.4 Hz, 3H); 13C NMR δ 153.8, 151.7, 148.5 (d, J C-F ) 3.1
Hz), 148.3, 140.0, 134.2 (d, J C-F ) 17.7 Hz), 132.4, 130.4, 128.1
(d, J C-F ) 5.7 Hz), 107.8, 107.5, 84.1 (d, J C-F ) 166.1 Hz), 73.2,
56.5, 56.4, 22.1, 16.1; MS (EI) m/z 407 (4.5, M+), 210 (100),
153 (7.0). Anal. Calcd for C20H22FNO7: C, 58.96; H, 5.44; F,
4.66; N, 3.44. Found: C, 58.86; H, 5.39; F, 4.85; N, 3.28.
4-(2′-Nit r ob en zyloxyca r b on yloxy)-3,5-d im et h ylb en -
zyl F lu or id e (17a ). DAST (90 µL, 0.68 mmol) was added at
room temperature to stirring solution of 13 (0.15 g, 0.45 mmol)
in Et2O (15 mL) at 0 °C (ice/water). After 0.5 h, the reaction
mixture was poured into saturated NaHCO3 (10 mL). Aqueous
workup (Et2O (2 × 5 mL), MgSO4) followed by concentration
in vacuo yielded an oil that was purified by flash chromatog-
raphy on silica gel (5 g, 2:1 hexanes/CH2Cl2) to afford 17a (72
mg, 48% yield), which, after addition of acetonitrile, became a
yellow-white solid: mp 86-89 °C; IR (KBr) 1754, 1611, 1579,
4-(4′,5′-Dim eth oxy-r′-m eth yl-2′-n itr oben zyloxyca r bon -
yloxy)-3,5-d im eth ylben zyl Ch lor id e (18b). Pyridine (50 µL,
0.62 mmol) was added to a stirring mixture of 14 (0.10 g, 0.25
mmol) and triphosgene (95 mg, 0.32 mmol) in CH2Cl2 (5 mL)
at room temperature. After 15 min, the reaction mixture was
concentrated in vacuo. Flash chromatography (8 g, 1:1 CH2Cl2/
hexanes) afforded 18b (91 mg, 87% yield) as an off-white
solid: mp 124-126 °C; IR (KBr) 1749, 1582, 1525, 1455 cm-1
;
1H NMR δ 7.59 (s, 1H), 7.11 (s, 1H), 7.05 (s, 2H), 6.46 (q, J )
6.4 Hz, 1H), 4.47 (s, 2H), 3.97 (s, 3H), 3.94 (s, 3H), 2.11 (s,
6H), 1.75 (d, J ) 6.4 Hz, 3H);13C NMR δ 153.9, 151.7, 148.4,
148.2, 140.1, 135.4, 132.3, 130.5, 129.1, 107.9, 107.6, 73.2, 56.5,
56.4, 45.6, 22.1, 16.1; MS (EI) m/z 425 (0.05, M+, 37Cl), 423
(0.14, M+, 35Cl), 210 (11.14), 171 (0.13), 169 (0.53). Anal. Calcd
for C20H22ClNO7: C, 56.68; H, 5.23; Cl, 8.36; N, 3.30. Found:
C, 56.95; H, 5.26; Cl, 8.23; N, 3.13.
1
1526, 1564 cm-1; H NMR δ 8.17 (d, J ) 7.9 Hz, 1H), 7.72-
7.70 (m, 2H), 7.57-7.50 (m, 1H), 7.08 (s, 2H), 5.70 (s, 2H), 5.29
(d, J C-F ) 47.8, 2H), 2.22 (s, 6H); 13C NMR δ 152.5, 148.5 (d,
J C-F ) 3.6 Hz), 147.4, 134.3 (d, J C-F ) 17.7 Hz), 134.1, 131.5,
130.6 (d, J C-F ) 1.0 Hz), 129.3, 128.8, 128.1 (d, J C-F ) 5.7 Hz),
125.4, 84.1 (d, J C-F ) 166.6 Hz), 67.0, 16.1; MS (EI) m/z 333
(0.2, M+), 153 (17.2), 136 (100). Anal. Calcd for C17H16FNO5:
C, 61.26; H, 4.84; F, 5.70; N, 4.20. Found: C, 61.14; H, 4.72;
F, 5.67; N, 4.08.
4-(4′,5′-Dim eth oxy-r′-m eth yl-2′-n itr oben zyloxyca r bon -
yloxy)-3,5-d im eth ylben zyl Br om id e (18c). Phosphorus tri-
bromide (8.0 µL, 0.090 mmol) at room temperature was added
to a stirring solution of 14 (0.10 g, 0.30 mmol) in CH2Cl2 (2.5
mL) at 0 °C (ice/water). After being allowed to warm to room
temperature and stir for 1 h, the reaction mixture was washed
through a layer of silica gel (5 g, CH2Cl2). Concentration in
vacuo afforded 18c (66 mg, 57% yield) as a yellow solid: mp
4-(2′-Nit r ob en zyloxyca r b on yloxy)-3,5-d im et h ylb en -
zyl Ch lor id e (17b). Pyridine (34 µL, 0.42 mmol) was added
to a stirring solution of 13 (56 mg, 0.17 mmol) and triphosgene
(60 mg, 0.20 mmol) in CH2Cl2 (4 mL) at room temperature.
After 45 min, the reaction mixture was filtered through a layer
of silica gel (5 g, 3 cm), washed with CH2Cl2 (20 mL), and
concentrated in vacuo to afford pure 17b (53 mg, 90% yield)
as a clear oil that became an off-white solid on addition of
1
133-134 °C; IR (KBr) 1752, 1582, 1522, 1453 cm-1; H NMR
δ 7.59 (s, 1H), 7.10 (s, 1H), 7.04 (s, 2H), 6.45 (q, J ) 6.4 Hz,
1H), 4.37 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 2.09 (s, 6H), 1.74
(d, J ) 6.4 Hz, 3H); 13C NMR δ 153.8, 151.7, 148.3, 148.2,
140.1, 135.7, 132.3, 130.6, 129.5, 107.8, 107.6, 73.2, 56.6, 56.5,
32.9, 22.1, 16.1; MS (EI) m/z 469 (0.06, M+, 81Br), 467 (0.04,
M+, 79Br) 215 (0.15), 213 (0.11), 210 (2.49). Anal. Calcd for
1
hexane: mp 66-68 °C; IR (neat) 1757, 1538, 1264 cm-1; H
NMR δ 8.16 (d, J ) 7.9 Hz, 1H), 7.72-7.69 (m, 2H), 7.56-
7.50 (m, 1H), 7.09 (s, 2H), 5.70 (s, 2H), 4.50 (s, 2H), 2.20 (s,
6H); 13C NMR δ 152.7, 147.7, 147.3, 138.9, 134.1, 131.6, 130.3,
129.3, 128.8, 127.5, 125.4, 66.9, 64.7, 16.1; MS (EI) m/z 351
(0.08, M+, 37Cl), 349 (0.22, M+, 35Cl), 171 (2.64), 169 (9.70),
136 (100). Anal. Calcd for C17H16ClNO5: C, 58.38; H, 4.61; Cl,
10.14; N, 4.00. Found: C, 58.57; H, 4.59; Cl, 9.97; N, 3.79.
4-(2′-Nit r ob en zyloxyca r b on yloxy)-3,5-d im et h ylb en -
zyl Br om id e (17c). Phosphorus tribromide (43 µL, 0.45 mmol)
at room temperature was added to a stirring solution of 13
(0.15 g, 0.45 mmol) in Et2O (15 mL) at 0 °C (ice/water). After
being stirred for 1 h, the reaction mixture was poured into
saturated NaHCO3 (10 mL). Aqueous workup (Et2O (2 × 5
mL), MgSO4) followed by concentration in vacuo yielded a
C
20H22BrNO7: C, 51.30; H, 4.74; N, 2.99. Found: C, 51.95; H,
4.80; N, 2.69.
Ack n ow led gm en t. This work was supported by the
National Science Foundation (EHR-9108762 and CHE-
9734187) and the Arkansas Science and Technology
Authority (98-B-03).
J O991085T