A mild anionic method for generating o-quinone methides: Facile preparations of ortho-functionalized phenols

Article abstract of DOI:10.1021/jo001752e

A low-temperature method for generating o-quinone methides is described which permits facile introduction of assorted R substituents onto the aryl ring system at low temperature. The method is useful for the efficient preparation of ortho-ring-alkylated phenols.

Full text of DOI:10.1021/jo001752e

J . Org. Chem. 2001, 66, 3435-3441
3435
A Mild An ion ic Meth od for Gen er a tin g o-Qu in on e Meth id es:
F a cile P r ep a r a tion s of Or th o-F u n ction a lized P h en ols
Ryan M. J ones, Ryan W. Van De Water, Christopher C. Lindsey, Christophe Hoarau,
Thay Ung, and Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, University of California,
Santa Barbara, California 93106-9510
pettus@chem.ucsb.edu
Received December 15, 2000
A low-temperature method for generating o-quinone methides is described which permits facile
introduction of assorted R substituents onto the aryl ring system at low temperature. The method
is useful for the efficient preparation of ortho-ring-alkylated phenols.
In tr od u ction
Ortho-functionalized phenols are ubiquitous among
natural products. Often the riposte for their synthesis
has been rearrangement,1 electrophilic substitution,2
halogenation,3 or a metal-mediated coupling process.4,5
However, these methods (Figure 1) do not address all
types of ring-alkylated phenols effectively. For instance,
consider converting hydroquinone or resorcinol into an
allylated derivative with differentiated hydroxyl residues.
Devising an efficient preparation for these types of
substances is not a straightforward affair. While some
reactions may introduce an alkyl residue onto the electron-
rich aryl ring in a regioselective manner, distinguishing
between the hydroxy residues and controlling the sub-
stitution at R and γ branched sites usually requires a
lengthy or inefficient synthetic sequence; in particular,
consider the usual methods for preparing ortho-preny-
lated phenols such as 35-36 shown in Table 3.6
In principle, an o-quinone methide, such as 1, may pose
a useful solution for constructing substituted aromatic
systems of these kinds. However, beyond the customary
[4 + 2] cycloadditions (i),7 (Figure 3) the traditional
forceful methods for generating 1 [I, II, III, IV, V, VI,
Figure 2] are incompatible with most other types of
reactions.
F igu r e 1. Traditional methods for ortho elaboration of
phenols.
We speculated that an anionic triggering mechanism
would be compatible with several other synthetically
useful reactions. For example, if 1 is generated under
anionic conditions, then it should undergo a conjugate
additionssignificantly increasing the synthetic scope of
monocyclic o-quinone methides. Furthermore, low-tem-
perature generation of 1 may overcome complications
that have hampered widespread use of previous methods,
F igu r e 2. Prior methods for generating o-quinone methides
1.
(1) For work regarding Claisen rearrangement, see: Rhoads, S. J .
Organic Reactions; J ohn Wiley & Sons, Inc.: New York, 1974; Vol.
22, p 1. For work regarding the Fries rearrangement, see: Martin R.
Org. Prep. Proc. Int. 1992, 24, 369-435.
such as an intolerance for other functional groups and
low endo/ exo selectivity in [4 + 2] reactions (Figure 3).
Two reports suggested to us that a mild anionic
triggering mechanism for generating 1 was plausible.
McLoughlin8 and Mitchell9 independently showed that
(2) Nagata, W.; Okada, K.; Aoki, T. Synthesis 1979, 365-368.
(3) Mitchell, R. H.; Lai, Y-H.; Williams, R. V. J . Org. Chem. 1979,
44, 4733-4735.
(4) Snieckus, V. Chem. Rev. 1990, 90, 879-933.
(5) Oxidative insertion with electron-rich aryl halides is difficult.
Knochel, P.; Majid, T. Tetrahedron Lett. 1990, 31, 4413-4416.
(7) A variety of targets have been constructed using monocyclic
o-quinone methides in [4 + 2] reactions including carpanone, bruceol,
cannibinol, troglitazone, pisatin, nipradilols, and tocopherol.
(8) McLoughlin, B. J . J . Chem. Soc., Chem. Commun. 1969, 540-
541.
(6) For
a fairly complete list of aryl prenylation methods, see:
Nicolaou, K. C.; Pfefferkorn, J . A.; Roecker, A. J .; Cao, G.-Q.; Barlu-
enga, S.; Mitchell, H. J . J . Am. Chem. Soc. 2000, 122, 9939-9953, S4
of supporting information.
10.1021/jo001752e CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/21/2001

3436 J . Org. Chem., Vol. 66, No. 10, 2001
J ones et al.
Ta ble 1. Rin g-Alk yla ted P h en ols fr om Ald eh yd es,
Keton es, a n d Ester s
F igu r e 3. Reactions compatible with an anionic trigger.
F igu r e 4. Mild anionic triggering mechanism.
reduction of ortho-O-acylated phenones results in a
phenol displaying an ortho saturated alkyl substituent.
Presumably, hydride addition results in alkoxide 3, which
proceeds to the phenoxide 5 via the o-ester 4. The cascade
then continues to the o-quinone methide 6, which is
subsequently reduced by a second hydride equivalent
(Figure 4).
It seemed reasonable that 3 might also be accessible
by combination of an aryl aldehyde, such as 2, and an
organometallic reagent. From a synthetic perspective,
this combination would be of greater use. Moreover, 2
seems more readily accessible than the o-quinone me-
thide precursors shown in Figure 2. However, regulation
of the cascade remained as a significant obstacle. If the
reaction was not carefully controlled, only products with
two or more of the same substituent would be formed as
in the reports of McLoughlin and Mitchell with hydride.8,9
Resu lts a n d Discu ssion
Herein, we report that the cascade is controllable and
access to an assortment of transient o-quinone methides
can be achieved in a single operation resulting in a means
to easily synthesize a range of ortho-ring-alkylated phe-
nols.10 The solution resides with the choice of the O-acyl
residue [P] and other factors governing the addition,
migration, and elimination, such as temperature, solvent,
concentration, and the oxyphillic nature of the metal
cation [M]. Three types of reactions were examined. Table
1 recounts products obtained upon addition of organo-
metallic reagents to aldehydes, ketones, and esters 9-17.
Table 2 discloses products obtained from subjecting
aldehydes 9-11 to reduction with various hydride re-
agents. Table 3 displays the outcome of the addition of
organometallic reagents to benzyl alcohols.
hydes 9-11 at 0 °C suggested these were the highest
yields that could be expected for a particular substitution
pattern in subsequent reactions. For example, the iso-
propyl derivatives 18-20 are obtained in 86%, 97%, and
57%, respectively, by simply adding 2.5 equiv of MeMgCl
to the respective aldehydes and stirring at 0 °C for 1 h.
This trend in yield held true in subsequent reactions for
the respective aldehydes (Table 1, entries 13-20). How-
ever, 20 can be prepared in 86%, averting formation of
the side product 44 (Figure 5) by inverting the mode of
addition (Table 1, entry 4). Inverse addition of aryl esters
15-17 and acetophenones 12-13 (0.1 M in Et2O) to
MeMgCl afforded the tert-butyl derivatives 21-23 in good
yield (Table 1, entries 5-9). However, small amounts of
Ta ble 1. The data (Table 1, entries 1-3) obtained by
straightforward addition of MeMgCl (2.5 equiv) to alde-
(9) Mitchell, D.; Doecke, C. W.; Hay, L. A.; Koenig, Thomas M.;
Wirth, David D. Tetrahedron Lett. 1995, 36, 5335-5338.
(10) For the initial communication of this work, see: Van De Water,
R. W.; Magdziak, D. J .; Chau, J . N.; Pettus, T. R. R. J . Am. Chem.
Soc. 2000, 122, 6502-6503.

Mild Anionic Method for o-Quinone Methides
J . Org. Chem., Vol. 66, No. 10, 2001 3437
Ta ble 2. Red u ction of 9-11 w ith Va r iou s Hyd r id e
Sou r ces
F igu r e 5. Side products formed in several of these reactions.
acetophenones 12-13, we conclude that 43 arises from
the initial alkoxide proceeding through the cascade rather
than collapsing to the corresponding acetophenone. The
small amounts of styrenyl adduct observed most likely
arise from competition between 1,5-sigmatropic shift and
intermolecular 1,4-conjugate addition of the correspond-
ing â-disubstituted o-quinone methide.
Organolithium reagents did not lead to the anticipated
adducts 18-23. All attempts at multiple additions of
organolithium reagents to aldehydes 9-11 and ester 16
failed. Quenching reactions initiated by organolithiums
at low temperatures (-40 to -78 °C) resulted in isolation
of the alcohol, the phenol that results from BOC migra-
tion, or mixtures of these products. However, since
MeMgCl adds twice at -40 °C to 9-11 while MeLi does
not, we concluded that the lithium species does not
readily proceed to the corresponding o-quinone methide.
The styrenyl adducts 24-26 further support this claim.
These styrenyl adducts are formed quite rapidly when
MeLi (1.0 equiv) is combined with the corresponding
acetophenones 12-14 (0.1 M in Et2O) at -78 °C (Table
1, entries 10-12). Although a 1,5-sigmatropic shift via a
â-disubstituted o-quinone methide intermediate can ex-
plain the formation of these products, the fact that the
identical intermediate generated by addition of MeMgCl
(Table 1, entries 5-9) undergoes 1,4-addition suggests
that â-disubstituted o-quinone methides are stable for a
short period of time in solution. We therefore conclude
that the styrenyl products 24-26 arise from intermo-
lecular deprotonation of the corresponding cyclic carbon-
ate, which arise from divergent collapse of intermediate
4, facilitated by the lithium counterion.11 This series of
reactions demonstrate the importance of the identity of
the counterion in controlling the course of the reaction.
a
Optimal procedure, yield after purification by chromatography.
Ta ble 3. Syn th esis of Rin g-Alk yla ted P h en ols fr om
Ben zyla d eh yd es
In general, substitution of aldehydes 9-11 with two
different nucleophiles to produce 27-34 (Table 1, entries
13-20) is accomplished by controlling the temperature
of the initial nucleophilic addition, adding the less
reactive nucleophile first, or initiating the cascade with
an organolithium species. However, the substituents on
the aryl aldehyde affect the conditions that can be
employed. In regard to the addition of PhMgCl to
aldehyde 9, the resulting alkoxide 3 is evident by TLC
at -78 °C, but if left untended slowly proceeds to multiple
unidentified compounds. On the other hand, the type 3
alkoxides, formed from aldehydes 10 and 11, appear
stable by TLC at -40 °C for up to 9 h. Thus, we surmise
that the o-quinone methides 7 and 8 form between -40
and 0 °C, while the o-quinone methide 6 forms at
substantially lower temperatures. The specific temper-
ature depends on the size of the â-substituent; a larger
â-substituents requires a higher temperature.
several other compounds were evident in product mix-
tures. These include type 43 (Figure 5) methyl ethers
(Table 1, entries 5-7, <5%) and styrenyl adducts corre-
sponding to 24-26 (Table 1, entries 5-9, <5%). Since
the undesired ether adduct is absent in reactions of
(11) See ref 10 for additional information.

3438 J . Org. Chem., Vol. 66, No. 10, 2001
J ones et al.
Aldehyde 10 proved most forgiving. Several conditions
led to differently branched products in similar yields. For
instance, addition of methyllithium followed by the
addition of PhMgCl, addition of PhMgCl followed by the
addition of MeLi, and addition of PhMgCl followed by
the addition of MeMgCl all afford 31 in similar yield.
Compound 28 is prepared by adding MeLi (1.05 equiv)
at -78 °C followed shortly thereafter by the addition of
excess CH2dCHMgCl at -20 °C. Addition of the vinyl
species as the second nucleophile prevents formation of
the undesired 1,6-conjugate addition product that indeed
does arise when the order of addition is reversed. Lactone
33 is produced in a manner analogous to that of com-
pound 28, with formation of the o-quinone methide
initiated by addition of PhMgBr to 10.
The window for successfully adding different nucleo-
philes to aldehyde 9 is narrower and likely reflects an
increased electrophilicity of the carbonyl residues in the
aldehyde and the carbonate. In particular, the BOC-
residue ortho to the aldehyde is more susceptible to
cleavage if the organometallic reagent used exhibits a
significant amount of either LiOH or Mg(OH)2. A second
problem for these systems is the volatility of the phenol
product. Since the o-quinone methide 6 forms at very low
temperatures, the time between addition of the first and
second reagent is kept to a minimum. Addition of freshly
prepared PhMgBr, followed in 5 min by the addition of
MeMgCl, affords 30 in 71%. In the case of 27, however,
MeLi is added to a solution of the aldehyde 9 (0.18 M in
Et2O), which is precooled to -78 °C. This addition is
immediately followed by the addition of vinylmagnesium
bromide. Warming to room temperature affords 27 in
56% along with 17% of 18.
Substitution of 11 with two different nucleophiles
proved to be challenging because of undesired formation
of dimeric products of type 44 (Figure 5). However, this
problem is surmountable by carefully regulating the
temperature. Addition of MeLi (1.1 equiv) to 11 (0.18 M
in THF at -78 °C) followed after 1 h by addition of CH2d
CHMgBr (2 equiv) affords 29 in 65% after warming to
room temperature. Similarly, addition of PhMgBr to 11
(0.1 M in toluene at -40 °C) followed in 20 min by
addition of either MeMgCl or the sodium enolate of
dimethyl malonate affords 32 and 34 in 50% and 62%,
respectively.
Ta ble 2. To construct nonbranched ortho-substituted
phenols, reliable conditions for reducing aldehydes 9-11
to the corresponding benzyl alcohols were needed that
averted potential dimer formation or over-reduction
(Table 2). In some instances, the benzylic alcohol product
decomposed on chromatography so the conditions had to
proceed cleanly. McLoughlin’s combination of NaBH4/
THF/H2O had worked well with 10, only if the reaction
was carefully monitored and stopped after 10-30 min.
However, the reduction of 9 occurred so rapidly that the
formation of C could not be prevented. Thus, we paused
to investigate other methods to reduce aldehydes 9-11,
determining the relative percentages of A, B, and C for
various reduction conditions by examining crude 1H NMR
spectra to which DMF [1 equiv] had been added as an
internal standard. In the case of 9, addition of 1 equiv of
NaBH4 (1 M THF/H2O) to 9 in THF at 0 °C for 10 min
affords 40% and 12% of A and C, respectively. Addition
of L-Selectride (1 M THF) to 9 (-78 °C, 10 min) leads to
B contaminated with a significant amount of unidentifi-
able products. Reduction of 9 with LiAl(OtBu)3H (1 M
THF, -78 °C, 1 h), however, afforded the benzyl alcohol
quite cleanly. Aldehydes 10 and 11 underwent a clean
reduction over a greater range of conditions. However,
in general, reduction applying LiAl(OtBu)3H required less
diligent attention.
Ta ble 3. Equipped with efficient conditions for reduc-
ing aldehydes 9-11 to the corresponding benzyl alcohols
(Table 2, entries 4, 7, and 5, respectively), yields for
subsequent addition of nucleophiles were measured.
Although adducts 35-42 can be obtained in one pot by
addition of L-Selectride followed by addition of the
corresponding nucleophile or by reduction of the aldehyde
and addition of excess nucleophile to the crude benzyl
alcohol, the best results are achieved by reducing the
corresponding aldehyde with the appropriate conditions
(see Table 2) and then adding excess of the nucleophile
to the desired alcohol which has been purified by chro-
matography. Rapid addition of the respective anion to
clean benzylic alcohol (0.1 M in Et2O) stirring at 0 °C
keeps formation of dimers 44 and 45 to a minimum. For
example, quick addition of BrMgCHdC(CH3)2 to the
corresponding crystalline alcohol afforded the prenyl
derivatives 35-36 in 68% and 58%, respectively, or 60%
and 52% when measured from the starting aldehydes 10
and 11 (Table 3, entries 1-2). To the best of our
knowledge, this method is among the most efficient for
preparing prenylated aromatics of this type. In interest-
ing contrast to Table 1, entries 14 and 20, addition of a
sodium hydride/methyl malonate solution in THF to the
unbranched benzylic alcohol (0.1 M in Et2O) provided the
opened noncyclized diesters 37-39 (Table 3, entries 3-5).
Nitriles 40-42 (Table 3, entries 6-8) are produced by
addition of Bu4NCN in THF to the alcohol (0.1 M in
Et2O), followed by the addition of t-BuMgCl to reinitiate
the cascade. However, in the case of entries 3 and 6 the
corresponding crude benzyl alcohol was used.
Con clu sion s
A new general procedure has been developed that
permits a wide range of ortho-ring-alkylated phenols to
be constructed including branched and unbranched ana-
logues 18-42, some of which are not easily accessible by
other methods. The reaction proceeds by way of a
manageable monocyclic o-quinone methide intermediate,
which is not isolated but reacted in subsequent 1,4-
additions.12 Further applications using this anionic trig-
gering mechanism, such as for initiating successive inter-
and intramolecular [4 + 2] reactions (Figure 3), will be
reported shortly.
Exp er im en ta l Section
Gen er a l In for m a tion . These reactions required reagents
of the highest quality. All the reagents were newly purchased
or freshly prepared as stipulated. Starting aryl aldehydes that
were not scrupulously dried often led to lower than expected
yields. Sublimation of 11 was necessary to remove H2O. Lower
than expected yields generally indicated a corrupt organome-
tallic reagent, such as one that had undergone air oxidization
or contained a large amount of Mg(OH)2 or LiOH in the
(12) o-Quinone methides are of use in the alkylation of DNA, see:
Pande, P.; Shearer, J .; Yang J .; Greenberg, W. A.; Rokita, S. E. J . Am.
Chem. Soc. 1999, 121, 6773-6779. For other o-quinone methide
chemistry, see: Taing, M.; Moore, H. J . Org. Chem. 1996, 61, 329-
340 and Turnbull, K.; Dyer, R. G. J . Org. Chem. 1999, 64, 7988-7995.

Mild Anionic Method for o-Quinone Methides
J . Org. Chem., Vol. 66, No. 10, 2001 3439
reaction mixture. All column chromatography was conducted
using silica gel with the indicated solvent systems.
(35), 213 (71), 57 (100); HRMS (CI) m/z calcd for C18H24O7
369.1549, found 369.1560.
17. Isolated yield, 93%. H NMR [CDCl3, 200 MHz] δ 7.83
1
Gen er a l P r oced u r e for P r otection w ith BOC2O (9-17).
To a solution of the phenol (2.60 g, 18.8 mmol, 0.5 M in THF)
at 0 °C was added the di-tert-butyl dicarbonate (10.29 g, 47.1
mmol) followed by sodium hydride (1.41 g, 47.1 mmol, 80%
dispersion in mineral oil). The mixture was stirred at room
temperature for 4 h, after which the reaction was diluted with
ether. The solution was then washed with water (caution: H2
gas evolved) and brine, dried (MgSO4), and concentrated.
Chromatography with silica gel (1:10 EtOAc/petroleum ether)
furnished the BOC material, as a white solid for all compounds
except acetophenone derivatives 9, 12, and 15.
(d, 1H, J ) 2.9 Hz), 7.37 (dd, 1H, J 1 ) 8.8 Hz, J 2 ) 2.9 Hz),
7.19 (d, 1H, J ) 8.8 Hz), 3.89 (s, 3H), 1.58 (s, 18H); 13C NMR
[CDCl3, 100.6 MHz] δ 164.40, 151.64, 151.55, 148.54, 148.19,
128.55, 126.85, 124.76, 124.65, 84.38, 84.16, 52.68, 27.87; IR
[CH2Cl2 solution, νmax cm-1] 1762.14, 1731.76; MS (CI) m/z 313
(53), 168 (66), 57 (100); HRMS (CI) m/z calcd for C18H24O7
369.1549, found 369.1540.
Gen er a l P r oced u r e for th e Ad d ition of MeMgCl to
Ald eh yd es 9-11, Keton es 12-14, a n d Ester s 15-17. To a
stirring solution of the ortho-Boc aldehyde, phenone, or ester
(1 equiv) in Et2O (0.2 M) at 0 °C was added the Grignard
(equivalents shown in Table 1) in a dropwise fashion. The
reaction was stirred at 0 °C until complete consumption of
starting material was observed by TLC. HCl (0.5 N) was added
while the reaction was still cold. After warming to room
temperature, the mixture was extracted with Et2O, washed
with brine, dried (Na2SO4), and concentrated in vacuo. Chro-
matography with silica gel (1:9 EtOAc/petroleum ether) yielded
the title compounds.
9. Isolated yield, 87%. Yellow oil. 1H NMR [CDCl3, 400 MHz]
δ 10.20 (s, 1H), 7.90 (dd, 1H, J 1 ) 7.7 Hz, J 2 ) 1.6 Hz), 7.67-
7.62 (m, 1H), 7.43-7.39 (m, 1H), 7.29-7.27 (m, 1H), 1.59 (s,
9H); 13C NMR [CDCl3, 100.6 MHz] δ 188.9, 152.2, 151.5, 135.5,
130.9, 128.5, 126.6, 123.3, 84.7, 27.8; IR [CH2Cl2 solution, vmax
cm-1] 2985.6, 2926.8, 2861.2, 1762.8, 1699.2, 1605.6; MS (CI)
m/z 167 (40), 123 (49), 57 (100); HRMS (CI) m/z calcd for
C
12H14O4 223.0970, found 223.0970.
10. Isolated yield, 94%, mp 58-60 °C. 1H NMR [CDCl3, 400
1
MHz] δ 10.14 (s, 1H), 7.90 (dd, 1H, J 1 ) 8.2 Hz, J 2 ) 0.4 Hz),
7.25-7.22 (m, 2H), 1.58 (s, 9H), 1.57 (s, 9H); 13C NMR [CDCl3,
100.6 MHz] δ 187.8, 156.1, 153.0, 151.0, 150.5, 131.7, 125.8,
119.3, 116.3, 85.1, 84.9, 27.8 (1 unresolved); IR [CH2Cl2
solution, vmax cm-1] 2984, 1765, 1699, 1694, 1608; MS FAB
m/z 227 (43), 183 (100), 139 (62); FAB MS m/z calcd for
18. Isolated yield, 86%. H NMR [CDCl3, 400 MHz] δ 7.22
(dd, 1H, J 1 ) 8.4 Hz), 7.08 (td, 1H, J 1 ) 7.7 Hz, J 2 ) 1.7 Hz),
6.93 (td, 1H, J 1 ) 7.5 Hz, J 2 ) 1.1 Hz), 6.76 (dd, 1H, J 1 ) 8.0
Hz, J 2 ) 1.2 Hz), 4.79 (s, 1H, OH), 3.23 (septet, 1H, J ) 6.96),
1.27 (d, 6H, J ) 6.8 Hz); 13C NMR [CDCl3, 100.6 MHz] δ 152.9,
134.6, 126.9, 126.6, 121.2, 115.4, 27.2, 22.8; IR [CH2Cl2
solution, vmax cm-1] 3586 (OH), 2965, 2933, 2869, 1671, 1606;
MS (EI) m/z 121 (100), 103 (20), 77 (18); LRMS (EI) calcd for
C9H12O 136.0888, found 135.9025.
C
17H23O7 339.1444, found 339.1458.
11. Isolated yield, 98%. H NMR [CDCl3, 400 MHz] δ 10.16
1
(s, 1H), 7.71 (d, 1H, J ) 2.9 Hz), 7.44 (dd, 1H, J 1 ) 8.9 Hz J 2
) 2.9 Hz), 7.30 (d, 1H, J ) 8.9 Hz), 1.58 (s, 9H), 1.57 (s, 9H);
13C NMR [CDCl3, 100.6 MHz] δ 187.75, 151.47, 151.3, 149.55,
149.00, 129.00, 128.29, 124.39, 122.74, 84.97, 84.54, 27.86,
27.83; IR [CH2Cl2, νmax cm-1] 2984.6, 1762.8, 1698.2; MS (CI)
m/z 283 (100), 227 (86), 57 (38); HRMS (CI) m/z calcd for
1
19. Isolated yield, 97%. H NMR [CDCl3, 400 MHz] δ 7.16
(d, 1H, J ) 8.4 Hz), 6.71 (dd, 1H, J 1 ) 8.4 Hz, J 2 ) 2.4 Hz),
6.59 (d, 1H, J ) 2.4 Hz), 5.05 (s, 1H, OH), 3.15 (septet, 1H, J
) 7.0 Hz), 1.57 (s, 9H), 1.22 (d, 6H, J ) 7.0 Hz); 13C NMR
[CDCl3, 100.6 MHz] δ 153.5, 152.4, 149.5, 132.4, 127.0, 113.5,
C
17H22O7 339.1444, found 339.1444.
108.8, 83.8, 27.9, 26.9, 22.7; IR [CH2Cl2 solution, vmax cm-1
]
12. Isolated yield, 88%. Yellow oil. 1H NMR [CDCl3, 400
3586 (OH), 2966, 2932, 2873, 1757; MS (EI) m/z 152 (37), 137
(81), 57 (100); HRMS (EI) m/z calcd for C14H20O4 252.1363,
found 252.1362.
MHz] δ 7.82 (dd, 1H, J 1 ) 7.8 Hz, J 2 ) 1.7 Hz), 7.56-7.52 (m,
1H), 7.37-7.29 (td, 1H, J 1 ) 7.6 Hz, J 2 ) 1.1 Hz), 7.20 (dd,
1H, J 1 ) 8.1 Hz, J 2 ) 1.1 Hz), 2.59 (s, 3H), 1.58 (s, 9H); 13C
NMR [CDCl3, 100.6 MHz] δ 197.8, 151.7, 149.6, 133.6, 131.2,
130.5, 126.3, 123.8, 84.3, 29.7, 27.9; IR [CH2Cl2 solution, vmax
cm-1] 2986, 2935, 1760, 1690, 1602; MS (EI) m/z 136 (21), 121
(31), 57 (100); HRMS (EI) m/z calcd for C13H16O4 237.1127,
found 237.1121.
1
20. Isolated yield, 86%. H NMR [CDCl3, 400 MHz] δ 6.96
(d,1H, J ) 2.9 Hz), 6.86 (dd, 1H, J 1 ) 8.6 Hz, J 2 ) 2.9 Hz),
6.67 (d, 1H, J ) 8.6), 4.85 (s, 1H), 3.18 (septet, 1H, 6.8 Hz),
1.56 (s, 9H), 1.23(d, 6H, J ) 7.0 Hz); 13C NMR [CDCl3, 100.6
MHz] δ 152.76, 150.66, 144.97, 135.82, 119.34, 119.25, 115.83,
83.55, 27.95, 27.33, 22.55; IR [CH2Cl2, νmaxcm-1] 3592.73 (OH),
1755.87; MS (EI) m/z 152 (82), 137 (82), 57 (100); HRMS (EI)
m/z calcd for C14H20O4 252.1362, found 252.1362.
13. Isolated yield, 95%, mp ) 72-73 °C (sharp). 1H NMR
[CDCl3, 400 MHz] δ 7.82 (d, 1H, J ) 8.6 Hz), 7.16 (dd, 1H, J 1
) 8.6 Hz, J 2 ) 2.2 Hz), 7.11 (d, 1H, J ) 2.2 Hz), 2.55 (s, 3H),
1.55 (s, 9H), 1.54 (s, 9H); 13C NMR [CDCl3, 100.6 MHz] δ 196.4,
154.5, 151.1, 150.7, 150.5, 131.4, 128.3, 118.8, 116.7, 84.5, 84.4,
29.7, 27.8, 27.7; IR [CH2Cl2 solution, vmax cm-1] 2985, 1763,
1689, 1607; MS FAB m/z 219 (85), 153 (83); FAB MS m/z (M+
+ Na) calcd for C18H24O7Na 375.1420, found 375.1409.
1
21. Isolated yield, 75%. H NMR [CDCl3, 400 MHz] δ 7.29
(dd, 1H, J 1 ) 7.7 Hz, J 2 ) 1.65 Hz), 7.11-7.07 (m, 1H), 6.91-
6.87 (m, 1H), 6.68 (dd, 1H, J 1 ) 7.9 Hz, J 2 ) 1.3 Hz), 4.82 (s,
1H, OH), 1.43 (s, 9H); 13C NMR [CDCl3, 100.6 MHz] δ 154.4,
136.3, 127.3, 127.2, 116.7, 34.7, 29.8.13
1
22. Isolated yield 90%, a white solid: mp ) 95-98 °C. H
1
14. Isolated yield, 82%. H NMR [CDCl3, 400 MHz] δ 7.62
NMR [CDCl3, 400 MHz] δ 7.23 (d, 1H, J ) 8.4 Hz), 6.67 (dd,
1H, J 1 ) 8.4 Hz, J 2 ) 2.4 Hz), 6.54 (d, 1H, J ) 2.4 Hz), 5.15
(s, 1H, OH), 1.57 (s, 9H), 1.37 (s, 9H); 13C NMR [CDCl3, 100.6
MHz] δ 154.9, 152.3, 149.8, 134.1, 127.7, 112.9, 109.8, 83.8,
34.5, 29.8, 27.9; IR [CH2Cl2 solution, vmax cm-1] 3577 (OH),
2963, 2873, 1758; MS (EI) m/z 166 (25), 151 (100), 57 (69);
HRMS (EI) m/z calcd for C15H22O4 266.1518, found 266.1527.
(d, 1H, J ) 2.9 Hz), 7.36 (dd, 1H, J 1 ) 8.8 Hz, J 2 ) 2.9 Hz),
7.21 (d, 1H, J ) 8.8 Hz), 2.57 (s, 3H), 1.57 (s, 18H); 13C NMR
[CDCl3, 100.6 MHz] δ 196.7, 151.6, 151.5, 148.6, 146.9, 131.8,
126.4, 124.8, 123.1, 84.5, 84.4, 29.7, 27.9; IR [CH2Cl2, νmaxcm-1
]
1761.17, 1691.75; MS (CI) m/z 297 (43), 241 (43) 57 (100);
HRMS (CI) m/z calcd for C18H24O8 353.1600, found 353.1590.
15. Isolated yield, 88%. Yellow oil. 1H NMR [CDCl3, 400
MHz] δ 8.01 (dd, 1H, J 1 ) 7.8 Hz, J 2 ) 1.7 Hz), 7.58-7.54 (m,
1H), 7.34-7.30 (m, 1H), 7.18 (dd, 1H, J 1 ) 8.1 Hz, J 2 ) 1.1
Hz), 3.89 (s, 3H), 1.58 (s, 9H); 13C NMR [CDCl3, 100.6 MHz] δ
165.3, 151.8, 150.8, 134.0, 132.0, 126.3, 123.8, 94.6, 83.9, 52.5,
27.9; IR [CH2Cl2 solution, vmax cm-1] 2986, 2957, 1760, 1726,
1610; MS FAB m/z 197 (100), 165 (92), 121 (40); HRMS (CI)
m/z calcd for C13H16O5 253.1076, found 253.1070.
1
23. Isolated yield, 78%. H NMR [CDCl3, 200 MHz] δ 7.03
(d, 1H, J ) 2.7 Hz), 6.88 (dd, 1H, J 1 ) 8.4 Hz, J 2 ) 2.9 Hz),
6.61 (d, 1H, J ) 8.6 Hz), 4.83 (s, 1H), 1.56 (s, 9H), 1.39 (s,
6H); 13C NMR [CDCl3, 100.6 MHz] δ 152.78, 152.07, 144.56,
137.45, 120.20, 119.44, 116.91, 83.50, 34.84, 29.54, 27.97; IR
[CH2Cl2, νmaxcm-1] 3580.68 (OH), 1757.80; MS (EI) m/z 166
(58), 151 (51), 57 (100); HRMS (EI) m/z calcd for C15H22O4
266.1518, found 266.1517.
1
16. Isolated yield, 94%. H NMR [CDCl3, 400 MHz] δ 8.03
Gen er a l P r oced u r e for th e Ad d ition of MeLi to Ke-
t on es 12-14. A solution of the acetophenone derivative
(d, 1H, J ) 8.6 Hz), 7.17 (dd, 1H, J 1 ) 8.8 Hz, J 2 ) 2.4 Hz),
7.11 (d, 1H, J ) 2.2 Hz), 3.88 (s, 3H), 1.56 (s, 18 H); 13C NMR
[CDCl3, 100.6 MHz] δ 164.7, 154.9, 151.7, 151.4, 150.7, 132.9,
120.9, 118.9, 116.8, 84.6, 84.2, 52.5, 27.9, 27.8; IR [CH2Cl2
solution, vmax cm-1] 2986, 1764, 1727, 1611; MS (CI) m/z 257
(13) The 1H and 13C NMR spectra are identical to those of the
commercially available 2-tert-butylphenol.

3440 J . Org. Chem., Vol. 66, No. 10, 2001
J ones et al.
(0.0766 mmol) was taken up in 1 mL of THF and cooled to
-78 °C. MeLi (1.1 equiv, 1.3 M in ether) was then added in a
dropwise fashion to the stirring reaction. After 25 min the
reaction was diluted with ether, washed with 0.5 N HCl,
washed with brine, dried (Na2SO4), and concentrated. Purifica-
tion by flash chromatography (1:9 EtOAc/petroleum ether)
yielded product.
31. Isolated yield, 74%. 1H NMR [CDCl3, 400 MHz] δ 7.33-
7.20 (m, 6H), 6.77 (dd, 1H, J 1 ) 8.5 Hz, J 2 ) 2.4 Hz) 6.26 (d,
1H, J ) 2.39 Hz), 4.82 (s, 1H, OH), 4.32 (quartet, 1H, J )
7.18 Hz), 1.61 (d, 3H, J ) 7.34 Hz) 1.56 (s, 9H); 13C NMR
[CDCl3, 100.6 MHz] δ 154.0, 152.2, 150.3, 145.1, 129.8, 128.9,
128.5, 127.7, 126.8, 113.6, 109.5, 83.8, 38.7, 27.9, 21.2; IR [CH2-
Cl2 solution, vmax cm-1] 3593 (OH), 2981, 2938, 2876, 1756,
1603; MS (EI) m/z 276 (65), 255 (71), 199 (100); HRMS (EI)
m/z calcd for C19H22O4 314.1518, found 314.1509.
24. Isolated yield, 57%. 1H NMR [CDCl3, 400 MHz] δ 7.17-
7.14 (m, 2H) 6.95-6.88 (m, 2H), 5.69 (s, 1H), 5.42 (t, 1H, J )
1.65 Hz), 5.16, (s, 1H), 2.13 (s, 3H).14
Gen er a l P r oced u r e for th e Ad d ition of Tw o Or ga n o-
m eta llic Rea gen ts to 11. The first organometallic reagent
(1.1 equiv) was added in a dropwise fashion to a stirring
solution of the aldehyde 11 (1 equiv) in THF (0.18 M) at -78
°C. After stirring for 30 min, the Grignard (2 equiv) was added,
the cooling bath was removed, and the reaction was stirred at
room temperature until complete. The reaction was then
quenched with 0.5 N HCl, extracted with Et2O, washed with
brine, dried (Na2SO4), and concentrated in vacuo. Chromatog-
raphy (95:5 petroleum ether/EtOAc) yielded the title com-
pounds.
25. Isolated yield, 97%. a colorless oil. 1H NMR [CDCl3, 400
MHz] δ 7.12 (d, 1H, J ) 8.4 Hz), 6.77 (d, 1H, J ) 2.4 Hz), 6.73
(d, 1H, J 1 ) 8.4 Hz, J 2 ) 2.4 Hz), 5.78 (s, 1H, OH), 5.41 (s,
1H), 5.13 (s, 1H), 2.10 (s, 3H), 1.57 (s, 9H); 13C NMR [CDCl3,
100.6 MHz] δ 152.9, 152.0, 151.1, 141.8, 128.5, 126.7, 116.2,
113.3, 109.1, 83.8, 27.9, 24.5; IR [CH2Cl2 solution, vmax cm-1
]
3509 (OH), 2979, 1758; MS (EI) m/z 150 (61), 57 (100); HRMS
(EI) m/z calcd for C14H18O4 250.1205, found 250.1210.
26. Isolated yield, 69%. 1H NMR [CDCl3, 400 MHz] δ 6.98-
6.95 (m, 2H), 6.90 (dd, 1H, J 1 ) 8.3 Hz, J 2 ) 0.8 Hz), 5.62 (s,
1H), 5.43 (t, 1H, J ) 1.5 Hz), 5.18 (s, 1H), 2.11 (s, 3H), 1.56 (s,
9H); 13C NMR [CDCl3, 100.6 MHz] δ 152.5, 149.8, 144.3, 141.6,
129.5, 121.5, 120.5, 116.6, 116.3, 83.6, 27.9, 24.3; IR [CH2Cl2
solution, vmax cm-1] 3525 (OH), 2986, 1760; MS (EI) m/z 150
(65), 57 (100); HRMS (EI) m/z calcd for C14H18O4 250.1205,
found 250.1212.
Gen er a l P r oced u r e for th e Ad d ition of Tw o Or ga n o-
m eta llic Rea gen ts to 9. The first organometallic reagent
(1.05 equiv) was added in a dropwise fashion to a stirring
solution of the aldehyde 9 (1 equiv) in Et2O (0.2 M) at -78 °C.
The Grignard (2 equiv) was added immediately after addition
of the first organometallic, the cold bath was removed, and
the reaction stirred at room temperature until complete. The
reaction was then quenched with 0.5 N HCl, extracted with
Et2O, washed with brine, dried (Na2SO4), and concentrated.
Chromatography (95:5 petroleum ether/EtOAc) yielded the
title compounds.
1
29. Isolated yield, 65%. H NMR [CDCl3, 400 MHz] δ 6.94
(s, 1H), 6.92 (s, 1H), 6.78 (dd, 1H, J 1 ) 7.7 Hz, J 2 ) 1.3 Hz),
6.09-6.01 (m, 1H) 5.23-5.17 (m, 2H), 5.12 (s, 1H, OH), 3.69-
3.66 (m, 1H), 1.56 (s, 9H), 1.38 (d, 3H, J ) 7.1 Hz); 13C NMR
[CDCl3, 100.6 MHz] δ 152.5, 151.5, 145.0, 142.0, 131.4, 120.8,
120.4, 116.8, 115.1, 83.5, 37.9, 27.9, 18.8; IR [CH2Cl2 solution,
vmax cm-1] 3582 (OH), 3489, 2976, 2932, 1755; MS (EI) m/z
164 (35), 149 (19), 57 (100); HRMS (EI) m/z calcd for C15H20O4
264.1362, found 264.1365.
32. Isolated yield, 50%. 1H NMR [CDCl3, 400 MHz] δ 7.22-
7.25 (m, 5H), 7.05 (d, 1H, J ) 2.7 Hz), 6.94 (dd, 1H, J 1 ) 8.6
Hz, J 2 ) 8.6 Hz), 6.72 (s, 1H, J ) 8.6 Hz), 4.63 (s, 1H, OH),
4.32 (q, 1H, J ) 7.32 Hz), 1.61 (d, 3H, J ) 7.3 Hz), 1.57 (s,
9H); 13C NMR [CDCl3, 100.6 MHz] δ 152.48, 151.11, 145.04,
144.88, 133.022, 129.00, 127.73, 126.86, 120.830, 120.23,
116.60, 83.52, 39.11, 27.95, 21.24. IR [CH2Cl2, νmax cm-1
]
3586.95 (OH), 1755.87; MS (EI) m/z 214 (100), 199 (67), 57
(83); HRMS (EI) m/z calcd for C19H22O4 314.1518, found
314.1509.
27. Isolated yield, 56%. 1H NMR [CDCl3, 400 MHz] δ 7.17-
7.12 (m, 2H), 6.93 (td, 1H, J 1 ) 7.5 Hz, J 2 ) 1.3 Hz), 6.82 (dd,
1H, J 1 ) 7.9 Hz, J 2 ) 1.3 Hz), 6.14-6.06 (m, 1H), 5.23-5.17
(m, 2H), 5.04 (s, 1H, OH), 3.74-3.68 (m, 1H), 1.41 (d, 3H, J )
7.1 Hz); 13C NMR [CDCl3, 100.6 MHz] δ 153.9, 142.6, 130.5,
128.2, 127.8, 121.2, 116.35, 114.56, 37.85, 18.96.15
Gen er a l P r oced u r e for th e Ad d ition of a n Or ga n om e-
ta llic to Ald eh yd e 10, F ollow ed by a n En ola te. The
Grignard (1.05 equiv) was added dropwise to aldehyde 10 (0.1
M in Et2O) at -78 °C. After stirring for 25 min, the cold bath
was removed. After an additional 10 min, a mixture of sodium
hydride (2 equiv) and methyl malonate (2 equiv) in THF (0.1
M) was added. The reaction was stirred until complete. The
reaction was then quenched with 0.5 N HCl, extracted with
Et2O, washed with brine, dried (Na2SO4), and concentrated
in vacuo. Chromatography (95:5 petroleum ether/EtOAc)
yielded the title compounds.
30. Isolated yield, 71%. 1H NMR [CDCl3, 400 MHz] δ 7.33-
7.19 (m, 6H), 7.14 (td, 1H, J 1 ) 7.7 Hz, J 2 ) 1.65 Hz), 6.96
(td, 1H, J 1 ) 7.5 Hz, J 2 ) 1.3 Hz), 6.77 (dd, 1H, J 1 ) 7.9 Hz,
J 2 ) 1.2 Hz), 4.62 (s, 1H, OH), 4.38 (q, 1H, J ) 7.3 Hz), 1.64
(d, 3H, J ) 7.3 Hz); MS (EI) m/z 85 (37), 71 (56), 57 (100);
HRMS (EI) m/z calcd for C14H14O 198.1045, found 198.1049.13
Gen er a l P r oced u r e for th e Ad d ition of Tw o Or ga n o-
m eta llic Rea gen ts to 10. The first organometallic reagent
(1.05 equiv) was added in a dropwise fashion to a stirring
solution of the aldehyde 10, (1 equiv) in THF (0.2 M) at -78
°C. After stirring for 25 min, the cold bath was removed. After
an additional 10 min, the Grignard was added and the reaction
was stirred at room temperature until complete. The reaction
was then quenched with 0.5 N HCl, extracted with Et2O,
washed with brine, dried (Na2SO4), and concentrated in vacuo.
Chromatography (95:5 petroleum ether/EtOAc) yielded the
title compounds.
1
33. Isolated yield 73%. H NMR [CDCl3, 400 MHz] δ 7.38-
7.30 (m, 3 H) 7.18-7.15 (m, 2H), 7.03 (d, 1H, J ) 2.2 Hz),
6.95-6.90 (m, 2H), 4.72 (d, 1H, 8.6 Hz), 3.98 (d, 1H, J ) 8.5
Hz), 3.66 (s, 3H), 1.57 (s, 9H); 13C NMR [CDCl3, 100.6 MHz] δ
167.3, 163.9, 151.5, 151.4, 151.3, 138.1, 129.5, 128.4, 128.2,
121.6, 118.2, 110.7, 84.4, 53.8, 53.3, 44.0, 27.8; IR [CH2Cl2
solution, vmax cm-1] 3679 (OH), 3065, 2987, 2957, 2933, 1761,
1620, 1598, 1501; MS (EI) m/z 239 (47), 57 (100); HRMS (EI)
m/z calcd for C22H22O7 398.1366, found 398.1377.
Gen er a l P r oced u r e for th e Ad d ition of a n Or ga n om e-
ta llic to Ald eh yd e 11, F ollow ed by a n En ola te. The
Grignard (1.1 equiv) was added to the aldehyde (1 equiv, 0.1
M in Et2O) at -78 °C. In a separate flask, NaH (2 equiv) was
dissolved in THF (0.1 M) and dimethyl malonate (2 equiv) was
added. This enolate solution was then added to the aldehyde/
Grignard mixture at -78 °C. The mixture was stirred at room
temperature until complete. The reaction was then quenched
with 0.5 N HCl, extracted with ether, washed with brine, dried
(Na2SO4), and concentrated. To complete closure of product
34, the crude product was redissolved in THF and stirred in
the presence of camphorsulfonic acid (5 equiv) for 8 h. Flash
chromatography (95:5 petroleum ether/EtOAc) yielded the title
compounds.
1
28. Isolated yield, 86%. H NMR [CDCl3, 400 MHz] δ 7.11
(d, 1H, J ) 8.5 Hz), 6.73 (dd, 1H, J 1 ) 8.5 Hz, J 2 ) 2.4 Hz),
6.65 (d, 1H, J ) 2.4 Hz), 6.09-6.01 (m, 1H), 5.34 (s, 1H, OH),
5.22-5.16 (m, 2H), 3.68-3.65 (m, 1H), 1.56 (s, 9H), 1.37 (d,
3H, J ) 7.2 Hz); 13C NMR [CDCl3, 100.6 MHz] δ 154.5, 152.2,
150.4, 142.3, 128.6, 128.2, 114.8, 113.7, 109.7, 83.8, 37.5, 27.9,
18.9; IR [CH2Cl2 solution, vmax cm-1] 3578 (OH), 3492, 3079,
2979, 2935, 2879, 1757, 1603, 1502; MS (EI) m/z 164 (67), 149
(100); HRMS (EI) m/z calcd for C15H20O4 264.1362, found
264.1359.
(14) For previous characterization, see: Oude-Alink, B. A. M.; Chan,
A. W. K.; Gutsche, C. D. J . Org. Chem 1973, 38, 1993-2001.
(15) Habich, A.; Barner, R.; Roberts, R. M.; Schmid, H. Helv. Chim.
Acta 1962, 45, 1943.
34. Isolated yield, 62%. 1H NMR [CDCl3, 400 MHz] δ 7.37-
7.32 (m, 3H), 7.17 (s, 4H), 6.73 (s, 1H), 4.73 (d, 1H, J ) 9.0

Mild Anionic Method for o-Quinone Methides
J . Org. Chem., Vol. 66, No. 10, 2001 3441
Hz), 3.98 (d, 1H, J ) 9.0 Hz), 3.66 (s, 3H), 1.52 (s, 9H); 13C
(s, 6H), 3.16 (d, 1H, J ) 7.1 Hz), 1.55 (s, 9H); 13C NMR [CDCl3,
100.6 MHz] δ 170.3, 152.6, 152.2, 144.7, 125.2, 123.6, 121.5,
117.9, 83.6, 53.2, 52.7, 29.4, 27.9; IR [CH2Cl2 solution, vmax
cm-1] 3584, 3387, 2986, 2957, 1753; MS (EI) m/z 254 (74), 190
(38), 57 (100); HRMS (EI) m/z calcd for C17H22O8 354.1315,
found 354.1315.
Gen er a l P r oced u r e for th e Ad d ition of a Cya n o Gr ou p
to th e Ben zylic Alcoh ols. Tetrabutylammonium cyanide (2
equiv) was dissolved in THF (0.5 M) and added to a stirring
solution of the alcohol in Et2O (0.1 M) at 0 °C. Next, t-BuMgCl
(1.1 equiv, 2 M in THF) was added, and the reaction was
stirred at room temperature until complete. The reaction was
then quenched with 0.5 N HCl, extracted with Et2O, washed
with brine, dried (Na2SO4), and concentrated in vacuo. Chro-
matography (95:5 petroleum ether/EtOAc) yielded the title
compounds.
NMR [CDCl3, 100.6 MHz] δ ; IR [CH2Cl2 solution, vmax cm-1
]
2984, 2930, 1759; MS (CI) m/z 343 (100), 299 (43), 239 (38);
HRMS (CI) m/z calcd for C22H22O7 399.1444, found 399.1429.
Gen er a l P r oced u r e for th e Ad d ition of a n Or ga n om e-
ta llic to Ben zylic Alcoh ols. The alcohol (1 equiv) was
dissolved in Et2O (0.1 M), and to this solution was added the
Grignard (3 equiv) at 0 °C. The reaction was stirred for 1 h at
0 °C, warmed to room temperature, and stirred for an
additional 10 h. The reaction was quenched with 0.5 N HCl,
extracted with ether, washed with brine, dried (Na2SO4), and
concentrated in vacuo. Chromatography (95:5 petroleum ether/
EtOAc) yielded the title compounds.
1
35. Isolated yield, 60%. H NMR [CDCl3, 400 MHz] δ 7.07
(d, 1H, J ) 8.1 Hz), 6.68 (dd, 1H, J 1 ) 8.3 Hz, J 2 ) 2.4 Hz),
6.64 (d, 1H, J ) 2.4 Hz), 5.33 (s, 1H, OH), 5.29 (m, 1H), 3.32
(d, 2H, J ) 6.9 Hz), 1.77 (s, 6H), 1.56 (s, 9H); 13C NMR [CDCl3,
100.6 MHz] δ 155.0, 152.2, 150.4, 135.3, 130.4, 124.7, 121.7,
113.5, 109.3, 83.7, 29.5, 27.9, 26.0, 18.1; IR [CH2Cl2 solution,
vmax cm-1] 3584 (OH), 3446, 2982, 2932, 1757, 1600, 1502; MS
(EI) m/z 178 (38), 123 (53), 57 (100); HRMS (EI) m/z calcd for
40. Isolated yield, 62%. 1H NMR [CDCl3, 400 MHz] δ 7.36-
7.34 (m, 1H), 7.24-7.19 (m, 1H), 6.98-6.94 (m, 1H), 6.8 (dd,
1H, J 1 ) 7.9 Hz, J 2 ) 1.0 Hz), 5.47 (s, 1H, OH), 3.74, (s, 2H);
13C NMR [CDCl3, 100.6 MHz] δ 153.3, 129.8, 129.7, 121.5,
118.2, 117.1, 115.5, 18.7; IR [CH2Cl2 solution, vmax cm-1] 3577,
3380, 2928, 2256, 1602, 1503; MS (EI) m/z 106 (49), 78 (84);
HRMS (EI) m/z calcd for C8H7NO 133.0528, found 133.0526.
C
16H22O4 278.1518, found 278.1523.
36. Isolated yield, 52%. 1H NMR [CDCl3, 400 MHz] δ 6.92-
6.89 (m, 2H), 6.78-6.76 (m, 1H), 5.32-5.30 (m, 1H), 5.08 (s,
1H, OH), 3.33 (d, 1H, J ) 7.3 Hz), 1.78-1.77 (m, 6H), 1.56 (s,
9H); 13C NMR [CDCl3, 100.6 MHz] δ 152.1, 144.7, 135.6, 128.0,
122.6, 121.3, 120.2, 116.3, 94.6, 83.5, 27.9, 26.0, 18.1; IR [CH2-
Cl2 solution, vmax cm-1] 3577, 2985, 2929, 2854, 1755, 1496,
1371, 1276, 1251, 1143; MS (EI) m/z 232 (33), 178 (50), 57
(100); HRMS (EI) m/z calcd for C16H22O4 278.1518, found
278.1528.
1
41. Isolated yield, 76%. H NMR [CDCl3, 400 MHz] δ 7.32
(d, 1H, J ) 8.3 Hz), 6.76 (dd, 1H, J 1 ) 8.3 Hz, J 2 ) 2.2 Hz),
6.62 (d, 1H, J ) 2.2 Hz), 5.95 (s, 1H, OH), 3.64 (s, 2H), 1.58 (s,
9H); 13C NMR [CDCl3, 100.6 MHz] δ 154.0, 152.3, 151.5, 130.3,
117.9, 115.1, 114.0, 109.1, 84.6, 27.9, 18.3; IR [CH2Cl2 solution,
vmax cm-1] 3577, 3372, 2986, 2935, 2861, 2256, 1759, 1726,
1613, 1515; MS FAB m/z 191 (37), 154 (100), 136 (70); HRMS
(CI) m/z calcd for C13H15NO4 250.1079, found 250.1084.
Gen er a l P r oced u r e for th e Ad d ition of a n En ola te to
th e Ben zylic Alcoh ols. The in situ generated sodium enolate
of dimethyl malonate (2 equiv, 0.1 M in THF) was added to a
stirring solution of the alcohol (1 equiv, 0.1 M in Et2O) at 0
°C. After addition of the enolate, t-BuMgCl (1.1 equiv, 2 M in
THF) was added and the cold bath was removed, allowing the
reaction to proceed at room temperature until complete. The
reaction was then quenched with 0.5 N HCl, extracted with
Et2O, washed with brine, dried over Na2SO4, and concentrated
in vacuo. Chromatography (95:5 petroleum ether/EtOAc)
yielded the title compounds.
1
42. Isolated yield, 60%. H NMR [CDCl3, 400 MHz] δ 7.14
(s, 1H), 6.95 (d, 1H, J ) 8.6 Hz), 6.66 (d, 1H, J ) 8.6 Hz), 3.66
(s, 2H), 1.57 (s, 9H), OH unresolved; 13C NMR [CDCl3, 100.6
MHz] δ 152.9, 151.3, 144.6, 122.5, 122.3, 118.2, 117.7, 116.2,
84.3, 27.9, 18.7; IR [CH2Cl2 solution, vmax cm-1] 3577, 3387-
(OH), 2978, 2927, 2256, 1757, 1713, 1510; MS (CI) m/z 194
(22), 149 (26), 57 (45); HRMS (CI) m/z calcd for C13H15NO4
249.1001, found 249.1006.
Ack n ow led gm en t. Dedicated with great respect
and admiration to Professor Maurice Maxwell J r. “Max”,
upon his retirement from teaching at Longwood College
in Virginia. Research Grants from UCSB’s committee
on Research (UC-50217), Research Corporation (R10296),
the UC Committee on Cancer Research (19990641), the
National Science Foundation (CHE-9971211), the Pe-
troleum Research Fund (PRF34986-G1), and UC-AIDS
(K00-SB-039) are greatly appreciated. R.W.V. funds
provided by the J ohn H. Tokuyama Memorial Graduate
Fellowship.
37. Isolated yield, 51%. 1H NMR [CDCl3, 400 MHz] δ 7.16-
(
7.10 (m, 2H) 6.89-6.85 (m, 2H), 6.61 (s, 1H, OH), 3.81 t, 1H,
J ) 7.14 Hz), 3.74 (s, 6H), 3.2 (d, 2H, J ) 7.14 Hz); 13C NMR
[CDCl3, 100.6 MHz] δ 170.5, 154.4, 131.3, 128.8, 124.4, 121.2,
117.4, 53.2, 53.0, 29.4; IR [CH2Cl2 solution, vmax cm-1] 3569,
3387, 2949, 1737; MS (EI) m/z 147 (100), 107 (35); HRMS (EI)
m/z calcd for C12H14O5 238.0841, found 238.0847.
38. Isolated yield, 70%. 1H NMR [CDCl3, 400 MHz] δ 7.10-
7.08 (m, 1H), 7.02 (s, 1H), 6.71-6.68 (m, 2H), 3.77-3.74 (m,
7H), 3.15 (d, 2H, J ) 7.2 Hz), 1.55 (s, 9H); 13C NMR [CDCl3,
100.6 MHz] δ 170.4, 155.3, 152.0, 151.1, 131.6, 122.1, 114.0,
110.7, 83.8, 53.2, 53.0, 28.9, 27.9; IR [CH2Cl2 solution, vmax
cm-1] 3577, 3343, 2957, 2985, 2931, 1756, 1609, 1502; MS (EI)
m/z 254 (83), 163 (68), 57 (100); HRMS (EI) m/z calcd for
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 9-42. This material is available free of charge via
the Internet at http://pubs.acs.org.
C
17H22O8 354.1315, found 354.1312.
39. Isolated yield, 68%. 1H NMR [CDCl3, 400 MHz] δ 6.94-
6.91 (m, 2H), 6.83-6.79 (m, 2H), 3.79 (t, 1H, J ) 7.3 Hz), 3.74
J O001752E