Efficient Synthesis of Symmetrical 2,5-Disubstituted Benzoquinones via Palladium-Catalyzed Double Negishi Coupling

Full text of DOI:10.1021/jo9721812

3764
J . Org. Chem. 1998, 63, 3764-3768
the selectivity, and the yield in these reactions are
Efficien t Syn th esis of Sym m etr ica l
2,5-Disu bstitu ted Ben zoqu in on es via
P a lla d iu m -Ca ta lyzed Dou ble Negish i
Cou p lin g
remarkably dependent upon the quinone substituents
and electronic properties.12 In an ongoing program aimed
at the design of an asymmetric palladium-catalyzed 1,4-
oxidation of dienes, a range of new benzoquinone struc-
tures were needed.13 In particular, access to chiral C2-
symmetric quinones that could function as ligands was
desirable. In the literature, there is only one previous
procedure reported on the synthesis of symmetrical 2,5-
disubstituted 1,4-benzoquinones.14 In that procedure,
quinones were synthesized by addition of organolithium
reagents to 2,5-diethoxybenzoquinones followed by hy-
drolyses. Our strategy was to introduce chains in the 2-
and 5-positions of a quinone skeleton utilizing the two-
directional chain synthesis.4 The functional group toler-
ance of many transition-metal-catalyzed reactions would
allow the connection of the two arms to a protected
hydroquinone in a single operation. We have focused on
the Negishi coupling,15 a palladium(0)-catalyzed carbon-
carbon bond-forming reaction between an organohalide
and an organozinc reagent. The zinc reagents are
compatible with a large number of functional groups16
and tolerate esters, amines, and cyanides, thus fulfilling
our goals for synthetic flexibility. In this paper, we have
examined the scope and generality of the Negishi-type
bis cross-coupling for the preparation of symmetrical 2,5-
disubstituted benzoquinones.
Andreas Palmgren, Atli Thorarensen, and
J an-E. Ba¨ckvall*,†
Department of Organic Chemistry, University of Uppsala,
Box 531, S-751 21 Uppsala, Sweden
Received December 2, 1997
In tr od u ction
Current synthetic methodology in organic synthesis is
heavily directed toward rapid ways of preparing new
molecules with increased concern about the efficiency of
the chosen route.1,2 A wealth of reactions have been
designed to accomplish these goals, exemplified by vari-
ous cascade and tandem reactions.3 An alternative
approach to increase synthetic efficiency is the simulta-
neous two-directional synthesis of molecules pioneered
by Schreiber.4 Benzoquinones5 are a class of compounds
found in nature as subunits in many natural products.6
In addition, benzoquinones have found use in organic
synthesis, as oxidizing and dehydrogenation agents,7,8
and as reactive dienophiles in [4 + 2] cycloadditions.9
Several palladium(II)-catalyzed oxidations have been
designed that employ 1,4-benzoquinone as a stoichiomet-
ric oxidant or as a catalytic electron carrier.10-12 One role
of the benzoquinone in the latter reactions is to regener-
ate the catalytic species by reoxidation of palladium(0)
to palladium(II). Another role of the quinone is to act
as a ligand for palladium(II).
Resu lts a n d Discu ssion
The retrosynthetic analysis for the preparation of
symmetrical 2,5-disubstituted benzoquinones utilizing a
Negishi bis cross-coupling revealed that 2,5-dibromo-1,4-
dimethoxybenzene (1) was required as the central unit
in the coupling reactions (eq 1). The quinone structure
is then accessible by oxidative demethylation with ceric
ammonium nitrate (CAN).17
Previous investigations, in which a wide range of
quinones were tested, have shown that the reaction rate,
† Present adress: Department of Organic Chemistry, Arrhenius
Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
(1) Cornforth, J . W. Aldrich Chim. Acta 1994, 27, 71.
(2) Trost, B.; Bartmann, W. SelectivitysA goal for synthetic Ef-
ficiency; Verlag Chemie: Weinheim, 1984.
(3) (a) Posner, G. H. Chem. Rev. 1986, 86, 831. (b) Tietze, L. F.;
Beifuss, U. Angew. Chem., Int. Ed. Engl. (c) Hall, N. Science 1994,
266, 32. (d) Ho, T. L: Tandem Organic Reactions; Wiley: New York,
1992.
(4) (a) Schreiber, S. L. Chem. Scr. 1987, 27, 563. (b) Poss, C. S.;
Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9. (c) Poss, C. S.; Rychnovsky,
S. D.; Schreiber, S. L. J . Am. Chem. Soc. 1993, 115, 3360. (d) Schreiber,
S. L.; Goulet, M. T. J . Am. Chem. Soc. 1987, 109, 4718.
(5) (a) Patai, S. The Chemistry of the Quinonoid Compounds;
Wiley: Chichester, 1988. (b) Mu¨ller, E.; Bayer. O. Methoden der
Organischen Chemie; Thieme, Stuttgart, 1977.
The desired core unit was prepared by a modification
of a literature procedure18 by dibromination of dimethoxy-
benzene in acetic acid (eq 2). The dibromination could
be carried out on a large scale, allowing easy preparation
of multiple grams of 1.
(6) For examples, see: (a) Nagoaka, H,; Kishi, Y. Tetrahedron 1981,
37, 3873. (b) Furusaki, A.; Watanabe, T. Chem. Pharm. Bull. 1973,
21, 931. (c) Maddaford, S. P.; Andersen, N. G.; Cristofoli, W. A.; Keay,
B. A. J . Am. Chem. Soc. 1996, 118, 10766.
(7) Walker, D.; Hiebert, J . D. Chem. Rev. 1967, 67, 153.
(8) Tripathy, R.; Carroll, P. J .; Thornton, E. R. J . Am. Chem. Soc.
1990, 76, 153.
(9) (a) Marchand, A. P.; Allen, R. W. J . Org. Chem. 1974, 39, 1596.
(b) Hill, R. K.; Newton, M. G.; Pantaleo, N. S.; Collins, K. M. J . Org.
Chem. 1980, 45, 1953. (c) Kozikowski, A. P.; Hiraga, K.; Springer, J .
P.; Wang, B. C.; Xu, Z.-B. J . Am. Chem. Soc. 1984, 106, 1845. (d)
Danishiefsky, S.; Craig, T. A. Tetrahedron 1981, 37, 4081.
(10) (a) Ba¨ckvall, J . E. Palladium-Catalyzed 1,4-Oxidations of
Conjugateted Dienes. Review in Metal-catalyzed Cross-coupling Reac-
tions; Stang, P., Diederich, F., Eds.; VCH: Weinheim, 1998; pp 339-
385.
(13) Thorarensen, A.; Palmgren, A.; Itami, K.; Ba¨ckvall, J . E.
Tetrahedron Lett. 1997, 38, 8541.
(14) Moore, W. M.; Sing, Y. L.; Sidhu, R. S. J . Org. Chem. 1977, 42,
3320.
(15) (a) Negishi, E. J . Org. Chem. 1977, 42, 1821. (b) Negishi, E.;
Liu, F. in Metal-catalyzed Cross-coupling Reactions; Stang, P., Dieder-
ich, F., Eds.; VCH: Weinheim, 1998; pp 1-47.
(16) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117 and
reference cited therein.
(11) Ba¨ckvall, J . E.; Nordberg, R. E.; Wilhelm, D. J . Am. Chem. Soc.
1985, 107, 6892.
(12) Ba¨ckvall, J . E.; Bystro¨m, S. E.; Nordberg, R. E. J . Org. Chem.
1984, 49, 4619.
(17) J acob, P., III; Callery, P. S.; Shutgin, A. T.; Castagnoli, N., J r.
J . Org. Chem., 1976, 41, 3627.
S0022-3263(97)02181-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/08/1998

Notes
P r ep a r a tion of Or ga n ozin c Rea gen ts.19 Several
J . Org. Chem., Vol. 63, No. 11, 1998 3765
Ta ble 1. P d (0)-Ca ta lyzed Bis-Cou p lin gsa
methods have been used to prepare organozinc com-
pounds.16 We have focused mainly on two different
methods for the conversion of aryl and alkyl halides to
the corresponding zinc reagent. In the first procedure,
activated Rieke-zinc20 was reacted with an aryl or alkyl
halide. Reaction of the activated zinc suspension with
the appropriate aryl or alkyl halide afforded the corre-
sponding organozinc derivatives. The reaction was run
to 100% completion as judged by GC. In the case of aryl
bromides, a substantially larger amount of Rieke-zinc
was needed (3-4 equiv).
In the second method,21 an organolithium compound
was allowed to react with anhydrous zinc chloride, which
afforded the corresponding zinc reagent. The organo-
lithium compounds employed were either commercially
available or prepared from the organohalide by a metal-
halogen exchange with tert-butyllithium in THF at -78
°C. Irrespective of the method employed for the prepara-
tion, it was important that a complete conversion of the
alkyl or aryl halide had occurred as judged by GC.
P a lla d iu m -Ca ta lyzed Bis-cou p lin g of Dibr om id es
w ith Or ga n ozin c Rea gen ts. The appropriate zinc
reagent was added to a solution of 7 mol % of Pd(PPh3)4
and 1,4-dibromo-2,5-dimethoxybenzene (1) in THF. All
the coupling reactions were carried out under an atmo-
sphere of argon due to the sensitivity of the palladium-
(0) reagents, and the reaction mixture was allowed to stir
at 55 °C for 12 h. To obtain good yields of the bis-coupled
product, an excess of the zinc reagent was required (1.5
equiv). The results of the double Negishi coupling to give
symmetrical 2,5-disubstituted benzoquinones are given
in Table 1. Good to excellent yields were obtained with
several aryl- and vinylzinc reagents (Table 1, entries 1
and 3-6). The (p-cyanophenyl)zinc reagent gave a
slightly lower yield (Table 1, entry 2), which may be due
to a lower reactivity of this electron-deficient aryl. On
the other hand, the ortho-ester aryl (Table 1, entry 4)
gave an excellent yield (93%) of the bis-coupling product
2d , probably due to a favored coordination by the ortho-
ester group. Primary alkylzinc reagents also gave the
desired bis-coupling product, but only in moderate yields
(Table 1, entries 7 and 8).
The mechanism of the bis-coupling reaction involves
an oxidative addition followed by transmetalation and
reductive elimination (Scheme 1). Although we cannot
exclude that the oxidative addition, transmetalation, and
reductive elimination occur as separate sequences in the
2- and 5-position, respectively, of 1, we have outlined a
double addition for simplicity.
Interestingly, when the secondary butylzinc reagent
3i was employed in the palladium-catalyzed coupling
with 1, the product isolated was the bis-n-butyl product
2g (Scheme 2), which is identical to the product obtained
from coupling with the n-butylzinc reagent (Table 1,
entry 7). An explanation for the formation of 2g in the
cross-coupling reaction of 3i with 1 is that the sec-
butylpalladium intermediate (4) initially formed isomer-
a
b
The reactions were run at 55 °C for 12 h. General procedure
for the preparation of the zinc reagents: (A) commercially available
lithium reagent was added to 1 equiv of anhydrous ZnCl2 at -78
°C; (B) the organobromide was added to activated zinc, and the
mixture was then refluxed; (C) the organobromide was lithiated
with tert-butyllithium and then added to 1 equiv of anhydrous
ZnCl2 at rt. The coupling with 1 was performed in the presence of
0.07 equiv of Pd(PPh3)4. c Isolated yields. 4 equiv of activated zinc
d
was used for the preparation of the zinc reagent. e 3 equiv of
activated zinc was used for the preparation of the zinc reagent.
f The organozinc reagent was prepared by stirring overnight at
rt.
izes to the n-butyl derivative (5) (Scheme 2). This
isomerization involves a â-hydride elimination-readdi-
tion sequence. The facile â-elimination from alkylpalla-
dium intermediates also explains the low yield obtained
with alkylzinc derivatives. In these reactions, the â-
elimination will compete with the desired reductive
elimination.
Oxid a tive Dem eth yla tion of Cou p lin g P r od u cts.
Selected coupling products were deprotected by oxidative
demethylation employing ceric ammonium nitrite (CAN)
(Table 2). The oxidation was performed by addition of a
water solution of CAN to the dimethoxy compound in
acetonitrile at room temperature. The reaction required
only a few minutes to reach completion. The selectivity
and the mildness of the reaction was illustrated by the
fact that a variety of functional groups were tolerated.
In most cases good yields were obtained.
Bis-a r ylben zoqu in on es a s a Cor e for Ch ir a l C2-
Sym m etr ic Qu in on es. Numerous functional groups
have been demonstrated to have affinity for palladium-
(II). The exploration of two such groups, sulfoxide and
amides, has resulted in the first report of an asymmetric
palladium-catalyzed 1,4-oxidation of 1,3-dienes.13 C2-
Symmetric quinones of the general structure 6 have the
potential to act as chelating ligands to palladium(II).
(18) Kohn, M.; Guttmann, L. W. Monatsh. Chem. 1924, 45, 573.
(19) Erdik, E. Tetrahedron 1987, 43, 2203. (b) Rieke, R. D.; Manson,
M. V. Tetrahedron 1997, 53, 1925. (c) Fu¨rstner, A. Active Metals;
VCH: Weinheim, 1996.
(20) Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J . Org. Chem. 1991,
56, 1445.
(21) Negishi, E.; Takahashi, T.; King, A. O. Org. Synth. 1988, 66,
67.

3766 J . Org. Chem., Vol. 63, No. 11, 1998
Notes
Ta ble 2. Oxid a tive Dem eth yla tion of Selected Cou p lin g
P r od u cts
Sch em e 1. Mech a n ism of Bis-Cou p lin g Rea ction
(L ) P P h 3)
Sch em e 2. P r op osed Mech a n ism for th e
F or m a tion of 2g fr om 3i
a
Isolated yields.
Sch em e 3
Ligand 6 is available by the present methodology and is
obtained from 2d according to Scheme 3.
As mentioned before, this type of chiral quinones could
be useful as ligands in the asymmetric 1,4-oxidation.22
In summary, we have developed an efficient two-step
synthesis of 2,5-disubstituted 1,4-benzoquinones. This
procedure provides an entry into a range of structurally
different C2-symmetric quinones, which are potential
ligands in palladium(II)-catalyzed oxidations.
Exp er im en ta l Section
Gen er a l Meth od s. Tetrakis(triphenylphosphine)palladium23
and 2-phenyl-1,3-cyclohexadiene24 were prepared according to
literature procedures. ZnCl2 was dried under vacuum at 70 °C
for 1 h and then overnight at 100 °C.
(22) Subjecting ligand 6 to the standard conditions13 for the 1,4-
oxidation of 2-phenyl-1,3-cyclohexadiene (7) afforded 3,6-diacetoxy-1-
phenylcyclohexane (8) in moderate yield (43%) with a cis/trans ratio
of 86/14. Disappointingly, the cis and the trans product were obtained
as racemates. The interesting observation is that the cis/trans selectiv-
ity (86/14) is reversed compared to any previously employed ligands
in the reaction under chloride-free conditions (see: Grennberg, H.;
Langer, V.; Ba¨ckvall, J . E. J . Chem. Soc., Chem. Commun. 1991, 1190).
This high cis selectivity in the oxidation indicates a bis-chelation of
the ligand to palladium during the activation of the π-allyl complex.
The bis-coordination prevents coordination of acetate to palladium, and
as a result, mainly external attack by acetate occurs, affording the
cis-product.
2,5-Dibr om o-1,4-d im eth oxyben zen e (1). 1,4-Dimethoxy-
benzene (20.0 g, 0.149 mol) was dissolved in acetic acid (40 mL),
and bromine (46.3 g, 0.289 mol, 2.0 equiv) in acetic acid (15 mL)
was slowly added at room temperature. The reaction was stirred
for 2 h, and during this time the desired dibromide crystallized
out. The reaction mixture was cooled to 0 °C, which induced
(24) (a) Reich, H. J .; Wolowitz, S. J . Am. Chem. Soc. 1982, 104, 7051.
(b) Karlstro¨m, A. S. E.; Ro¨nn, M.; Thorarensen, A.; Ba¨ckvall, J . E. J .
Org. Chem. 1998, 63, 2517. (c) Ro¨nn, M. Studies on Palladium(II)-
Catalyzed Aerobic Oxidations of Olefins and Conjugated Dienes in
DMSO In Comprehensive Summaries of Uppsala Dissertationes from
the faculty of Science and Technology no. 274, Uppsala, 1997.
(23) Heck, R. F. Palladium Reagents in Organic Synthesis; Academic
Press: New York, 1990.

Notes
J . Org. Chem., Vol. 63, No. 11, 1998 3767
crystallization. The white crystals were collected by filtration
and washed with cooled (0 °C) methanol. The mother liquid was
diluted with water (0.5 L) and extracted with EtOAc (0.2 L),
washed with 2 N NaOH (0.3 L), dried (MgSO4), filtered, and
concentrated in vacuo to give a second crop. The combined crude
product was recrystallized from MeOH to afford 37.7 g (88%) of
the dibromomethoxybenzene 1 as a white crystalline solid: mp
146 °C [recrystalliized from EtOH (lit.25 mp 144-145 °C)].
formed according to procedure B. The crude product was
purified by silica gel chromatography (CH2Cl2/Et2O 98:2), af-
fording 3.51 g (93%) of 2d as white crystals: mp 172 °C
[recrystallized from HOAc (lit.27 mp 174-175 °C)].
2,5-Bis(2,5-dim eth oxyph en yl)-1,4-dim eth oxyben zen e (2e).
The reaction of 2-bromo-1,4-dimethoxybenzene was performed
according to general procedure C. The crude product was
recrystallized from EtOAc to give 0.202 g (65%) of white crystals.
2,5-Bis-tr a n s-(2-p h en yleth en yl)-1,4-d im eth oxyben zen e
(2f). The reaction of (2-bromovinyl)benzene was performed
according to procedure B, except that the organohalide was
stirred with the active zinc at room temperature overnight. The
crude product was purified by silica gel chromatography (pen-
tane/CH2Cl2 70:30) to yield 0.317 g (80%) of 2f as yellow crystals
(80%).
2,5-Dibu tyl-1,4-d im eth oxyben zen e (2g). The reaction of
4-bromobutyric acid ethyl ester was performed according to
general procedure A. The crude product was purified by silica
gel chromatography (pentane/Et2O 95:5) to give 0.047 g (30%)
of a colorless oil.
2,5-Dip h en yl-1,4-d im eth oxyben zen e (2a ). Gen er a l P r o-
ced u r e A for th e Cou p lin g Rea ction . Phenyllithium (1.39
mL, 2.51 mmol) was added to anhydrous ZnCl2 (0.347 g, 2.70
mmol) dissolved in THF (5 mL) at -78 °C under argon. The
reaction mixture was stirred for 1 h, warmed to room temper-
ature, and stirred for an additional 1 h. To a solution of 1,4-
dibromo-2,5-dimethoxybenzene (0.241 g, 0.83 mmol) and Pd-
(PPh3)4 (0.067 g, 0.058 mmol) in THF (5 mL) was added the
phenylzinc chloride reagent under an argon atmosphere. The
reaction mixture was warmed to 55 °C and stirred for 12 h. The
reaction was then diluted with saturated NH4Cl (20 mL) and
extracted with a 1:1 mixture of Et2O/CH2Cl2 (2 × 50 mL). The
combined organic layers were dried (Na2SO4) and concentrated
in vacuo. The crude product was purified by silica gel chroma-
tography (pentane/CH2Cl2 70:30) to afford 0.182 g (76%) of white
crystals: mp 149 °C [recrystallized from ethanol (lit.26 mp 154
2,5-Bis(3-ca r beth oxyp r op yl)-1,4-d im eth oxyben zen e (2h ).
The reaction was performed according to procedure B. The crude
product was purified by silica gel chromatography (CH2Cl2/Et2O
96:4) to give 0.265 g (42%) of a colorless oil.
1
°C)]; H NMR δ 7.63-7.61 (m, 4 H), 7.48-7.44 (m, 4 H), 7.39-
2,5-Dip h en yl-1,4-ben zoqu in on e (4a ). Gen er a l P r oced u r e
for Oxidative Dem eth ylation . Ceric ammonium nitrite (CAN)-
(0.594 g, 1.09 mmol) in water (1 mL) was added dropwise over
5 min to a solution of 2,5-diphenyl-1,4-dimethoxybenzene (0.173
g, 0.405 mmol) dissolved in hot acetonitrile. A disappearing
blue-black color was observed. The reaction was stirred for
another 5 min and then quenched with water, which resulted
in precipitation of the product. The precipitate was collected
and dried to give 0.084 g (80%) of yellow crystals: mp 215-216
°C [recrystallized from pentane/CH2Cl2 (lit.28 mp 217-218 °C)];
1H NMR δ 7.57-7.54 (m, 4 H) 7.48-7.46 (m, 6 H), 6.97 (s, 2 H);
13C NMR δ 186.9, 145.6, 133.1, 132.5, 130.1, 129.3, 128.5; IR
7.34 (m, 2 H), 7.01 (s, 2 H) 3.81 (s, 6 H); 13C NMR δ 150.7, 138.3,
130.4, 129.5, 128.1, 127.1, 114.8, 56.5; IR (KBr) 1484, 1211 cm-1
.
2,5-Bis(5-cyan oph en yl)-1,4-dim eth oxyben zen e (2b). Gen -
er a l P r oced u r e B for th e Cou p lin g Rea ction . Freshly cut
lithium metal (0.152 g, 22.0 mmol) and naphthalene (2.83 g, 22.0
mmol) were stirred in THF (5 mL) under an argon atmosphere.
The resulting dark green solution was stirred for 12 h. Zinc
chloride (dried under vacuum at 100 °C overnight, 1.49 g, 10.9
mmol) dissolved in THF (5 mL) was added dropwise over 15 min
to the lithium naphthalide to give a black solution of suspended
zinc metal. p-Bromobenzonitrile (0.50 g, 2.75 mmol) dissolved
in THF (5 mL) was added to the active zinc at room temperature,
and the reaction mixture was refluxed for 3 h. The solution was
then transferred via a cannula to a stirred solution of Pd(PPh3)4
(0.0716 g, 0.062 mmol) and 2,5-dibromo-1,4-dimethoxybenzene
(0.255 g, 0.88 mmol) in THF (5 mL) under argon. The dark
solution was stirred at 55 °C for 12 h. The reaction was then
diluted with saturated NH4Cl and extracted with Et2O/CH2Cl2
(1:1, 2 × 50 mL). The combined organic layers were dried (Na2-
SO4) and concentrated in vacuo. The crude product was purified
by silica gel chromatography (CH2Cl2/Et2O 98:2) to give 0.159 g
(53%) of white crystals: mp 278 °C (recrystallized from EtOAc);
1H NMR δ 7.74-7.67 (m, 8 H), 6.95 (s, 2 H), 3.81 (s, 6 H); 13C
NMR δ 150.7, 142.7, 131.9, 130.1, 129.6, 118.9, 114.4, 111.0, 56.4;
(KBr), 1641, 1604, 1440 cm-1
.
2,5-Bis(5-m eth oxyp h en yl)-1,4-ben zoqu in on e (4c). The
oxidative demethylation was performed according to the general
procedure. The crude product was purified by silica gel chro-
matography (pentane/CH2Cl2 70:30), affording 0.085 g (92%) of
4c as deep red crystals.
2,5-Bis(2-ca r bom eth oxyp h en yl)-1,4-ben zoqu in on e (4d ).
The oxidative demethylation was performed according to the
general procedure. The reaction was quenched with water,
which resulted in precipitation of the product. The precipitate
was collected and dried to give 0.076 g (81%) of yellow crystals.
2,5-Dib u t yl-1,4-b en zoq u in on e (4g). The oxidative de-
methylation was performed according to the general procedure.
The reaction was quenched with water, which resulted in
precipitation of the product. The precipitate was collected and
dried to give 0.048 g (65%) of yellow crystals.
2,5-Bis(3-ca r beth oxyp r op yl)-1,4-ben zoqu in on e (4h ). The
oxidative demethylation was performed according to the general
procedure. The reaction was quenched with water, and the
reaction mixture was extracted with CH2Cl2/Et2O (1:1, 3 × 15
mL). The combined organic layers were dried (Na2SO4), con-
centrated, and purified by silica gel chromatography (CH2Cl2/
Et2O 94:6), affording 0.089 g (95%) of 4c as a deep red oil.
1,4-Dim eth oxy-2,5-bis(2-ca r boxyp h en yl)ben zen e (5). A
solution of the bis-ester (1.90 g, 4.67 mmol), lithium iodide (6.24
g, 46.7 mmol), and sodium cyanide (0.457 g, 9.33 mmol) in DMF
(130 mL) was heated at reflux for 24 h, during which time a
large amount of precipitate formed. The mixture was cooled to
room temperature and was made acidic with HCl (red to litmus),
which dissolved all the precipitate. Note: Potentially toxic HCN
can be formed under those conditions, and this should therefore
only be performed in a well-ventilated hood. The mixture was
diluted with water (2 L), and the solid was collected by filtration
to afford 1.53 g (87%) of 5: 1H NMR (400 MHz, DMSO-d6) δ
7.74-7.35 (m, 8 H), 6.85 (s, 2 H), 3.63 (s, 6 H); 13C NMR (100
MHz, DMSO-d6) δ 168.9, 149.8, 137.5, 133.1, 131.2, 130.9, 129.5,
IR (KBr) 2224, 1606, 1490 cm-1
.
2,5-Bis(5-m et h oxyp h en yl)-1,4-d im et h oxyb en zen e (2c).
Gen er a l P r oced u r e C for th e Cou p lin g Rea ction . To a
solution of p-bromoanisole (1.00 g, 5.35 mmol) in THF (10 mL)
at -78 °C under argon was added tert-butyllithium (7.60 mL,
10.7 mmol). The reaction was stirred for 1 h at - 78 °C and
then slowly warmed to room temperature over 2 h. The lithium
reagent was added to anhydrous zinc chloride (0.802 g, 5.88
mmol) in THF (10 mL). The solution was stirred for 1 h at room
temperature. To a solution of 2,5-dibromo-1,4-dimethoxyben-
zene (0.492 g, 1.70 mmol) and Pd(PPh3)4 (0.137 g, 0.119 mmol)
in THF (10 mL) was added the zinc reagent. The reaction was
stirred for 12 h at 55 °C. The reaction was then quenched by
the addition of saturated NH4Cl (50 mL). The mixture was
extracted with CH2Cl2/EtOAc (1:1, 2 × 50 mL), and the combined
organic layers were dried (Na2SO4) and concentrated in vacuo.
The crude product was recrystallized from EtOAc/pentane to give
0.496 g (84%) of white crystals: mp 193 °C (recrystallized from
1
EtOAc and pentane); H NMR δ 7.53-7.52 (m, 4 H) 6.99-6.97
(m, 4 H) 6.95 (s, 2 H) 3.86 (s, 6 H), 3.79 (s, 6 H); 13C NMR δ
158.8, 150.6, 130.7, 130.5, 129.6, 114.6, 113.6, 56.5, 55.3; IR
(KBr) 1609 cm-1
.
2,5-Bis[2-(ca r b om e t h oxy)p h e n yl]-1,4-d im e t h oxyb e n -
zen e (2d ). The reaction of 2-(bromomethyl)benzoate was per-
(27) Erdtman, H.; Nilsson, M. Acta Chem. Scand. 1956, 10, 737.
(28) Allen, C. F. H.; Bell, A.; Clark, J . H.; J ones, J . E. J . Am. Chem.
Soc. 1944, 66, 1617.
(25) Irine, F. M.; Smith, J . C. J . Chem. Soc. 1927, 129, 76.
(26) Gripenberg, J .; Hase, T. Acta Chem. Scand. 1963, 17, 2250.

3768 J . Org. Chem., Vol. 63, No. 11, 1998
Notes
128.7, 127.0, 112.9, 55.5; IR (KBr) 3567, 1675, 1594 cm-1. Anal.
Calcd for C22H18O6: C, 69.83; H, 4.79. Found: C, 69.93; H, 4.96.
(+)-1,4-Bis[d ip h en yl-[(1-(R)-1-a za p h en yleth yl)-2-ca r box-
ylic]a m id e]-2,5-ben zoqu in on e (6). To a solution of bis-acid
5 (0.800 g, 2.11 mmol) in THF (50 mL) was added pyridine (0.34
mL, 4.22 mmol), followed by the addition of thionyl chloride (0.77
mL, 10.55 mmol). The reaction was stirred for 5 h, residual solid
was filtered off, and the solvent was removed in vacuo. (Note:
it is very important that the acid is completely dissolved before
the addition of the thionyl chloride). The residue was partially
dissolved in THF (75 mL), (R)-phenylethylamine (1.20 mL, 9.28
mmol) was added, and the resulting solution was stirred at room
temperature for 12 h. The reaction was diluted with CH2Cl2,
and the organic phase was washed with 2 N HCl, dried (MgSO4),
filtered, and concentrated in vacuo. The residue was purified
by multiple silica gel chromatography (CH2Cl2/MeOH 1:0, 19:1)
to afford 0.467 g (38%) of the amide.
residue was purified by silica gel chromatography (CH2Cl2/
MeOH 19:1) to afford 0.351 g (79%) of (+)-6 as a brown solid
1
that was heat and light sensitive: mp 141-144 °C; H NMR δ
7.60-7.28 (m, 8 H), 6.75 (s, 2 H), 6.28 (d, 2 H, J ) 7.6 Hz), 5.17
(quint, 2 H, J ) 7.1 Hz), 1.58 (d, 6 H, J ) 6.9 Hz); 13C NMR δ
185.7, 167.8, 148.6, 142.6, 136.4, 132.9, 132.3, 130.9, 130.6, 129.6,
128.7, 127.4, 126.6, 126.4, 49.4, 21.4; IR (KBr) 3304, 1625, 1635,
1592 cm-1; [R]20 +110.7° (CHCl3, c ) 0.29).
D
Ackn owledgm en t. Financial support from the Swed-
ish Natural Research Council and the Swedish Research
Council for Engineering are gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for 1, 2a -h , 4a -h , 5, 6, and 8 together with copies of 1H
and 13C spectra of 1, 2a -h , 4a ,c,d ,g,h , 5, 6, and 8 (36 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
To a solution of the amide in acetonitrile (26 mL) was added
a solution of CAN (1.14 g, 2.07 mmol) in water (26 mL). The
reaction was stirred at room temperature for 10 min, during
which time the reaction changed color from white to purple and
then to orange. The mixture was diluted with CH2Cl2, washed
with water, dried (MgSO4), filtered, and concentrated. The
J O9721812