Iron-Mediated Synthetic Routes to Unsymmetrically Substituted, Sterically Congested Benzophenones

Article abstract of DOI:10.1021/jo000421z

A new synthetic route to unsymmetrically substituted benzophenones, relying upon iron-mediated reactions in all of the key steps, is described. The key buiding block, η⁶-2-chloro-carbomethoxybenzene-η ⁵-cyclopentadienyl iron hexafluorophosphate (4), is reacted with a variety of substituted phenols, providing diaryl ether complexes (6). After hydrolysis of the ester functionalities, these complexes are subjected to Friedel-Crafts conditions. The efficiency of this intramolecular acylation reaction is very much dependent upon the substituents on the phenols. If these are appropriately chosen, xanthone complexes are isolated in fair to good yields. Regioselective ring-opening, using oxygen-nucleophiles, delivers substituted benzophenone complexes. After regioselective nucleophilic addition of cyanide ion, performed in the presence of DDQ, highly substituted benzophenones are isolated. To demonstrate the applicability of the new route, a formal synthesis of the benzophenone moiety of the protein kinase C inhibitor Balanol (3) is described.

Full text of DOI:10.1021/jo000421z

5264
J . Org. Chem. 2000, 65, 5264-5274
Ir on -Med ia ted Syn th etic Rou tes to Un sym m etr ica lly Su bstitu ted ,
Ster ica lly Con gested Ben zop h en on es
J . Peter Storm† and Carl-Magnus Andersson*,‡
Organic Chemistry 1, Department of Chemistry, Lund University, P.O. Box 124, S-221 00 Lund, Sweden,
and Synthetic Chemistry, ACADIA Pharmaceuticals A/ S, Fabriksparken 58, DK-2600 Glostrup, Denmark
cma@acadia-pharm.com
Received March 21, 2000
A new synthetic route to unsymmetrically substituted benzophenones, relying upon iron-mediated
reactions in all of the key steps, is described. The key buiding block, η6-2-chloro-carbomethoxy-
benzene-η5-cyclopentadienyl iron hexafluorophosphate (4), is reacted with a variety of substituted
phenols, providing diaryl ether complexes (6). After hydrolysis of the ester functionalities, these
complexes are subjected to Friedel-Crafts conditions. The efficiency of this intramolecular acylation
reaction is very much dependent upon the substituents on the phenols. If these are appropriately
chosen, xanthone complexes are isolated in fair to good yields. Regioselective ring-opening, using
oxygen-nucleophiles, delivers substituted benzophenone complexes. After regioselective nucleophilic
addition of cyanide ion, performed in the presence of DDQ, highly substituted benzophenones are
isolated. To demonstrate the applicability of the new route, a formal synthesis of the benzophenone
moiety of the protein kinase C inhibitor Balanol (3) is described.
In tr od u ction
interested in applying organoiron methodology for the
synthesis of unsymmetrically substituted benzophenones
not readily accessible via conventional routes.7 In par-
ticular, we decided to investigate the synthetic potential
of such an approach for the flexible synthesis of ben-
zophenones related to 2, a structural element found in
the exceptionally potent protein kinase C inhibitor Bal-
anol (3)8 as well as in its regioisomer, the antifungal
Upon coordination of an aromatic ring to a transition
metal, many useful properties are conferred onto the
ligand. Consequently, arene-metal complexes, particu-
larly in the Cr, Mn, Fe, and Ru series, have received
considerable attention as intermediates in alternative
routes to functionalized aromatic molecules.1 The most
familiar within this type of π-coordinated molecules are
the arene-chromium tricarbonyl complexes, which have
become commonplace in modern organic synthesis.2 The
related cyclopentadienyl arene-iron complexes were
discovered by Coffield et al. in 19573 and investigated in
some detail by Nesmeyanov in the 1960s,4,5 but their
application in organic synthesis has remained largely
unexplored.6 This is surprising, because these cationic
arene-iron complexes offer many attractive properties,
the most prominent, perhaps, being an expressed um-
polung of the arene ligand to become highly susceptible
to nucleophilic attack. Furthermore, the low cost and
toxicity of iron render its organometallic derivatives
attractive for stoichiometric applications. We became
ophiocordine.9 This target presents a synthetically chal-
lenging, highly substituted, and severely crowded ben-
† Lund University.
‡ ACADIA Pharmaceuticals A/S.
(1) For a review: Semmelhack, M. F. in Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.; Perga-
mon Press: Oxford, 1991; Vol. 4, Chapter 2.4.
(2) For reviews: (a) Morris, M. J . in Comprehensive Organometallic
Chemistry II; Labinger, J . A., Winter, M. J ., Abel, E. W., Stone, F. G.
A., Wilkinson, G., Eds.; Pergamon Press: Oxford, 1995; Vol. 5, Chapter
8. (b) Rose-Munch, F.; Rose, E. Curr. Org. Chem. 1999, 3, 445.
(3) Coffield, T. H.; Sandel, V.; Closson, R. D. J . Am. Chem. Soc. 1957,
79, 5826.
(4) (a) Nesmeyanov, A. N.; Vol’kenau, N. A.; Bolesova, I. N. Dokl.
Akad. Nauk. SSSR 1963, 149, 615. (b) Nesmeyanov, A. N.; Vol’kenau,
N. A.; Bolesova, I. N. Tetrahedron Lett. 1963, 1725. (c) Nesmeyanov,
A. N.; Vol’kenau, N. A.; Sirotkina, E. I.; Deryabin, V. V. Dokl. Akad.
Nauk. SSSR 1967, 177, 1110. (d) Nesmeyanov, A. N.; Vol’kenau, N.
A.; Isaeva, L. S.; Bolesova, I. N. Dokl. Akad. Nauk. SSSR, Ser. Khim.
1968, 183, 354.
(6) Vancomycin model studies: (a) Pearson, A. J .; Park, J . G.; Zhu,
P. Y. J . Org. Chem. 1992, 57, 3583. Polymers: (b) Pearson, A. J .; Sun,
L. J . Polym. Sci., Part A: Polym. Chem. 1997, 35, 447. Dendrimers:
(c) Sartor, V.; Djakovitch, L.; Fillaut, J .-L.; Moulines, F.; Marvaud, V.;
Guittard, J .; Blais, J .-C.; Astruc, D. J . Am. Chem. Soc. 1999, 121, 2929.
(d) Vale´rio, C.; Alonso, E.; Ruiz, J .; Blais, J .-C.; Astruc, D. Angew.
Chem., Int. Ed., 1999, 38, 1747. Cinnolines: (e) Sutherland, R. G.; Abd-
El-Aziz, A. S.; Pio´rko, A.; Gill, U. S.; Lee, C. C. J . Heterocycl. Chem.
1988, 25, 1107. Dibenzo[b, e][1, 4]dioxines: (f) Cambie, R. C.; J anssen,
S. J .; Rutledge, P. S.; Woodgate, P. D. J . Organomet. Chem. 1991, 420,
387.
(7) Pd-catalyzed carbonylative cross-coupling reactions: (a) Echa-
varren, A. M.; Stille, J . K. J . Am. Chem. Soc. 1988, 110, 1557. (b)
Ishiyama, T.; Kizaki, H.; Miyaura, N.; Suzuki, A. Tetrahedron Lett.
1993, 34, 7595. Friedel-Crafts reactions: (c) Taber, D. F.; Sethuraman,
M. R. J . Org. Chem. 2000, 65, 254. The Fries rearrangement: (d)
Martin, R. Org. Prep. Proced. Int. 1992, 24, 369.
(5) For reviews: (a) Astruc, D. Tetrahedron 1983, 39, 4027. (b)
Astruc, D. Top. Curr. Chem. 1992, 160, 47.
10.1021/jo000421z CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/01/2000

Iron-Mediated Routes to Functionalized Benzophenones
J . Org. Chem., Vol. 65, No. 17, 2000 5265
F igu r e 1. Retrosynthetic analysis of the benzophenone moiety (2) of Balanol (3).
Sch em e 1
zophenone, which has been prepared previously only via
fairly long sequences.8c-i We hypothesized that approach-
ing the preparation of derivatives of 2 via ring-opening
of a xanthone derivative might avoid some of the com-
plications associated with steric hindrance in the forma-
tion of the carbonyl-arene bond using advanced inter-
mediates. The key to our approach was the pioneering
work by Sutherland et al. on the nucleophilic ring-
opening of xanthone iron cyclopentadienyl hexafluoro-
phosphate (1, Scheme 1).10 Moreover, Sutherland et al.
also discovered that certain electron-withdrawing sub-
stituents allowed regioselective addition of cyanide ion
to arene-iron complexes, furnishing isolable, neutral
cyclohexadienyl complexes which could be oxidatively
Sch em e 2
(8) Isolation: (a) Kulanthaivel, P.; Hallock, Y. F.; Boros, C.; Hamil-
ton, S. M.; J anzen, W. P.; Ballas, L. M.; Loomis, C. R.; J iang, J . B.;
Katz, B.; Steiner, J . R.; Clardy, J . J . Am. Chem. Soc. 1993, 115, 6452.
(b) Ohshima, S.; Yanagisawa, M.; Katoh, A.; Fujii, T.; Sano, T.;
Matsukuma, S.; Furumai, T.; Fujiu, M.; Watanabe, K.; Yokose, K.;
Arisawa, M.; Okuda, T. J . Antibiot. 1994, 47, 639. Total syntheses:
(c) Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.; Naito, T.
J . Org. Chem. 1998, 63, 4397, and references cited therein. (d) Barbier,
P.; Stadlweiser, J . Chimia, 1996, 50, 530. For other approaches to the
benzophenone and analogues with modified benzophenone append-
ages: (e) Hollinshead, S. P.; Nichols, J . B.; Wilson, J . W. J . Org. Chem.
1994, 59, 6703. (f) Nicolaou, K. C.; Koide, K.; Bunnage, M. E. Chem.s
Eur. J . 1995, 1, 454. (g) Heerding, J . M.; Lampe, J . W.; Darges, J . W.;
Stamper, M. L. Bioorg. Med. Chem. Lett. 1995, 5, 1839. (h) Adams, C.
P.; Fairway, S. M.; Hardy, C. J .; Hibbs, D. E.; Hursthouse, M. B.;
Morley, A. D.; Sharp, B. W.; Vicker, N.; Warner, I. J . Chem. Soc., Perkin
Trans. 1 1995, 2355. (i) Denieul, M.-P.; Skrydstrup, T. Tetrahedron
Lett. 1999, 40, 4901.
(9) Isolation: (a) Kneifel, H.; Ko¨nig, W. A.; Loeffler, W.; Mu¨ller, R.
Arch. Microbiol. 1977, 113, 121. (b) Ko¨nig, W. A.; Sinnwell, V.; Witt,
S.; Kneifel, H. Chem. Ber. 1980, 113, 2221. Structure: (c) Mu¨ller, A.;
Taykar, D. K.; Witt, S.; Ko¨nig, W. A. Liebigs Ann. Chem. 1993, 651.
This structural proposal has, however, been questioned. It might be
the case that Ophiocordin and Balanol are in fact identical. See Boros,
C.; Hamilton, S. M.; Katz, B.; Kulanthaivel, P. J . Antibiot. 1994, 47,
1010.
demetalated (Scheme 2).11 Sutherland’s results inspired
an obvious arene-iron mediated retrosynthetic analysis
of benzophenones such as 2 (Figure 1). This strategy was
intriguing to us, because it involved prototypical iron-
mediated transformations at all of the key steps, and it
also appeared to allow for significant flexibility; e.g., in
the synthetic direction, complex 4 could be reacted with
a variety of nucleophiles, such as phenols, thiophenols,
or anilines. Furthermore, xanthone complex 8 (Figure 1)
could potentially undergo regiocontrolled ring-opening
(11) (a) Sutherland, R. G.; Chowdhury, R. L.; Pio´rko, A.; Lee, C. C.
J . Organomet. Chem. 1987, 319, 379. (b) Sutherland, R. G.; Chowdhury,
R. L.; Pio´rko, A.; Lee, C. C. J . Org. Chem. 1987, 52, 4618. (c) Guennec,
N.; Moinet, C. J . Organomet. Chem. 1995, 503, 171.
(10) (a) Lee, C. C.; Pio´rko, A.; Steele, B. R.; Gill, U. S.; Sutherland,
R. G. J . Organomet. Chem. 1983, 256, 303. (b) Lee, C. C.; Gill, U. S.;
Sutherland, R. G. J . Organomet. Chem. 1984, 267, 157.

5266 J . Org. Chem., Vol. 65, No. 17, 2000
Storm and Andersson
Ta ble 1. Nu cleop h ilic Ar om a tic Su bstitu tion s
Sch em e 3
P er for m ed on 4
Nu
R1
R2
product
yieldd (%)
5a a
5bb
5cc
5d b
5ec
5fb
H
OH
H
6a
6b
6d
6e
6f
6g
6h
6j
75
83
57
94
94
93
72e
79
CO2Me
1,3-dithian-2-yl
1,3-dithian-2-yl
I
OMe
Me
i-Pr
OBz
OMe
OH
OMe
OH
with various heteroatom or carbon nucleophiles, provid-
ing access to analogues carrying different substituents
in the 2,2′,6,6′ positions. Following communications
describing our initial progress toward preparation and
ring-opening of the parent ring system as well as the
application to the synthesis of the balanol appendage 2,12
the present paper describes full details of our studies
regarding iron-mediated approaches to functionalized
benzophenones.
5gc
5h c
OBz
a
b
NaOPh in acetone, -72 °C. NaH, THF, rt. c K2CO3, DMF,
d
rt. After purification by recrystallization and/or Al2O3 chroma-
tography. e Purity ≈ 53%; contaminated by C-C coupling products.
MeOH-H2O), providing the benzoic acid complexes 7a -j
in high yield (Table 2). As anticipated, the hydrolysis of
6b could be performed regioselectively in favor of the
ester on the transition-metal-coordinated aryl group. In
our preliminary study, the diaryl ether complex 7a was
treated with hot poly(phosphoric) acid in order to bring
about intramolecular Friedel-Crafts acylation, and the
xanthone complex 1 was isolated, albeit in modest yield
(Table 3).12a Unfortunately, when 7b was subjected to the
same conditions it underwent demetalation. Similarly,
treatment with other acids, e.g. concentrated sulfuric or
methanesulfonic acid, gave no reaction at room temper-
ature, whereas elevated temperatures decomposed the
substrate. However, after methylation of the phenol,
hydrolysis of the methyl ester, and conversion of the
resulting 7c into the acid chloride, a Lewis acid induced
(AlCl3) intramolecular Friedel-Crafts reaction was pos-
sible. A mixture of two xanthone complexes, 8a and a
minor chlorinated isomeric xanthone complex, which
could not be unambiguously identified, was isolated in
48% yield (Table 3). Although discouraging, this result
suggested potential access to balanol analogues, and also
served to establish that Friedel-Crafts ring closures were
attainable also with deactivated substrates in this class
of arene-iron complexes. Recognizing the requirement
for a large, nondeactivating carboxyl equivalent (R2) in
5 (R1 ) OH), we decided to explore the dithiane group,
which appeared to fulfill these criteria. The requisite
diaryl ether complex 6d was obtained in fair yield (Table
1), and exhaustive ester hydrolysis returned 7d in
excellent yield (Table 2). Unfortunately, subjecting this
compound to acidic cyclization conditions (MeSO3H, neat
or in CH2Cl2) resulted in either release of the aldehyde
or decomposition (Table 3). Instead, the methoxy deriva-
tive 7e was prepared via the ester 6e (Tables 1 and 2).
Exposure of the acid chloride derived from 7e to Lewis
acidic conditions (BF3‚Et2) did not promote the ring
closure, but instead the substrate was again decomposed
(Table 3). Aromatic iodides or bromides are known to be
excellent partners in palladium-catalyzed carbonylation
reactions.14a Therefore, an iodine atom appeared suitable
as a large carboxyl precursor in our system. The iodo-
Resu lts a n d Discu ssion
Syn th esis of (Xa n th on e)F eCp Com p lexes. The
synthesis of the key building block 4 was accomplished
by oxidizing the previously known η6-2-chlorotoluene-η5-
cyclopentadienyl iron hexafluorophosphate13 with aque-
ous potassium permanganate (Scheme 3). The benzoic
acid complex 10 could be converted into the methyl ester
4, in high overall yield, via reflux in thionyl chloride
followed by reaction with excess methanol (Scheme 3).
During our preliminary study concerning the preparation
and ring-opening of the parent ring-system, we found it
possible to substitute the chloride of 4 with phenoxide
while avoiding transesterification. Also, the resulting
diaryl ether complex, after saponification, took part in
an intramolecular Friedel-Crafts reaction yielding the
xanthone complex 1. To approach the desired substitution
pattern of the balanol appendage 2, the hydroxyarene 5
(Figure 1) should carry a hydroxyl group (R1) and a
carboxylic acid equivalent (R2). Two questions needed to
be addressed: would the required 3,5-dihydroxy arene
react cleanly as an oxygen nucleophile, and, could the
regioselectivity of the intramolecular Friedel-Crafts
reaction be controlled. In hydroxy arenes 5 where R1 was
a hydroxy group (Figure 1), the answer to the first
question turned out to be dependent on the nature of the
R2 group. Thus, 3,5-dihydroxy arenes 5 wherein R2 was
hydrogen or an electron-withdrawing group (5a , b, e)
reacted exclusively as oxygen nucleophiles, yielding dia-
ryl ethers smoothly and in high yield (Table 1). On the
other hand, electron-donating R2 groups in 5 (R2 ) Me,
i-Pr, or 1,3-dithian-2-yl) gave intractable mixtures of
diaryl ether complexes and various carbon-carbon coupled
products. However, after monoprotection of the problem-
atic dihydroxy arenes, the diaryl ether complexes 6a -j
could be synthesized in useful yields (Tables 1). The
methyl esters were uneventfully hydrolyzed (LiOH-
(12) (a) Nilsson, J . P.; Andersson, C.-M. Tetrahedron Lett. 1997, 38,
4635. (b) Storm, J . P.; Andersson, C.-M. Org. Lett. 1999, 1, 1451.
(13) Khand, I. U.; Pauson, P. L.; Watts, W. E. J . Chem. Soc. C 1968,
2261. The gegenion for all cationic arene iron complexes described in
this paper was hexafluorophosphate.

Iron-Mediated Routes to Functionalized Benzophenones
J . Org. Chem., Vol. 65, No. 17, 2000 5267
Ta ble 2. Syn th esis of Ben zoic Acid Com p lexes 7a -j
compound
R1
R2
product
R1
R2
yielda(%)
6a
6b
6c
6d
6e
6f
6g
6h
6i
H
H
OH
7a
7b
7c
7d
7e
7f
7g
7h
7i
H
H
OH
OMe
OH
OMe
OH
OMe
OH
OMe
OH
95
95
90
95
95
92
96
85b
91
95
CO2Me
CO2Me
1,3-dithian-2-yl
1,3-dithian-2-yl
CO2Me
CO2Me
1,3-dithian-2-yl
1,3-dithian-2-yl
OMe
OBz
OMe
OH
OMe
OH
I
I
OMe
Me
Me
i-Pr
OMe
Me
Me
i-Pr
OMe
OBz
6j
7j
a
b
After purification by recrystallization. Purity ≈ 60%; contaminated by C-C coupling products. c Based on a purity of 53% of the
starting material.
Ta ble 3. In tr a m olecu la r F r ied el-Cr a fts Acyla tion Rea ction s
compound
R1
R2
conditions
PPA, 80 °C
PPA, 50 °C
H2SO4, rt
H2SO4, 100 °C
MeSO3H, 50 °C
MeSO3H, 100 °C
1/SOCl2, reflux
2/AlCl3, rt
products, ratio
yield(%)
7a
7b
H
H
OH
1
41a
-
CO2Me
degradation
no reaction
degradation
no reaction
degradation
unknown/8a ,
1:6b
7c
7d
CO2Me
OMe
OH
48a
-
1,3-dithian-2-yl
MeSO3H, rt
degradation
deprot. start mat.
degradation
8b/8c, 2.7:1c
8b/8c, 1:4c
8b/8c, 1.6:1c
8d
MeSO3H/CH2Cl2, 1/9, rt
1/(COCl)2, reflux, 2/ BF3‚OEt2
MeSO3H, rt
MeSO3H, 50 °C
MeSO3H + ZnCl2, rt
MeSO3H, rt
MeSO3H, 50 °C
1/ SOCl2, reflux
2/ AlCl3, rt
7e
7f
1,3-dithian-2-yl
I
OMe
OH
-
15c
50c
35c
95a
55
7g
7h
7i
OMe
Me
Me
OMe
OH
OMe
8e/8f, 1.2:1c
8g/8h , ≈1:1c
8i/8j, 30:1c
<10
7j
i-Pr
OH
MeSO3H, rt
72a
a
b
After purification by recrystallization and/or Al2O3 chromatography. Estimated from 1H NMR integration. The identity of the minor
product could not be established. Estimated from 1H NMR integration.
c
substituted complex 6f was prepared (Table 1), and after
saponification, the acid 7f (Table 2) was stirred in
concentrated methanesulfonic acid at room temperature.
After 96 h, only 15% of xanthone complex could be
isolated, together with unreacted starting material. The
crude product consisted of two regioisomeric xanthones,
8b and 8c, in a ratio of 2.7:1 (Table 3). By increasing the
(14) (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J . Org. Chem. 1974,
39, 3318. (b) Ritter, K. Synthesis, 1993, 735.

5268 J . Org. Chem., Vol. 65, No. 17, 2000
Storm and Andersson
Sch em e 4
suitability of an alkyl group for promoting reactivity, but
not selectivity, in the cyclization, we hypothesized that
an isopropyl substituent should ideally support our
desired reaction sequence. The monoprotected isopropy-
lresorcinol 5h was synthesized from 3,5-dihydroxycar-
bomethoxybenzene and reacted with 4, to give the diaryl
ether complex 6j in good yield (Table 1). After hydrolysis
of both ester functionalities (Table 2), complex 7j was
dissolved in concentrated methanesulfonic acid. After
stirring at rt for 48 h, the xanthone complexes 8i and 8j
were isolated in 72% yield. Gratifyingly, excellent regio-
control was observed (30:1, Table 3).
Nu cleop h ilic R in g-Op en in g of (Xa n t h on e)F eCp
Com p lexes. As mentioned above, η6-xanthone-η5-cyclo-
pentadienyl iron hexafluorophosphate (1) has been re-
ported to undergo regioselective nucleophilic ring-opening
upon reaction with amines (Scheme 1).10 Preliminary
communications have described our successful treatment
of 1 with excess sodium hydroxide in aqueous methanol,
delivering the isolable, zwitterionic complex 11 as a red
solid (Table 4). This η5-oxocyclohexadienyl complex was
alkylated only sluggishly upon treatment with an excess
of iodomethane in the presence of potassium tert-butox-
ide, but complete conversion into the dimethoxy deriva-
tive 9a was acheived after 2 days at room temperature
(Table 4). When the isopropyl-substituted xanthone
complex 8i was subjected to an excess of sodium hydrox-
ide in aqueous methanol, a η5-oxocyclohexadienyl com-
plex (corresponding to 11) was isolated in quantitative
yield. Unfortunately, even after prolonged reaction times,
the hydroxyl group on the coordinated arene was only
partially alkylated with an excess of iodomethane in the
presence of potassium tert-butoxide, and the yield of
trimethoxy derivative 9d was unsatisfactory (25%). The
choice of potassium tert-butoxide as the base was made
to ensure rapid and complete methylation of the hydroxyl
group on the noncoordinated benzene ring, because
methylation of the pseudo-carbonyl oxygen on the iron-
coordinated arene was observed to promote cyclization,
returning the xanthone complex 8 (Scheme 5). In early
temperature to 50 °C, 50% conversion was observed after
72 h, but regioselectivity was reversed at this tempera-
ture, providing 8b and 8c in a ratio of 1:4 (Table 3). In
an attempt to improve regioselectivity, the reaction was
repeated in the presence of ZnCl2. Although this additive
did serve to improve selectivity (8b/8c, 1.6:1), the yield
was an unsatisfactory 35% accompanied by significant
decomposition (Table 3). Further attempts at resolving
the problematic ring closure involved reacting 4 with
commercially available 3,5-dimethoxyphenol (5f, Table
1), and hydrolyzing the resulting diaryl ether complex
6g into the benzoic acid complex 7g (Table 2), which was
obtained in excellent overall yield. This symmetrical
substrate, highly activated toward Friedel-Crafts acy-
lation, appeared an ideal entry into analogues of 2
provided that the two methoxy groups could be distin-
guished at a later stage.15 Indeed, upon stirring 7g in
concentrated methanesulfonic acid for 65 h, the xanthone
complex 8d was isolated in 95% yield (Table 3). Unfor-
tunately, subsequent attempts to selectively transform
the appropriate methoxy group into a carboxylic acid
moiety were uniformly unsuccessful.
Naito’s approach to balanol (3) employed methyl-
substituted benzophenone 22 (Scheme 4) as an inter-
mediate.8c The methyl to carboxyl transformation was
realized via radical bromination, hydrolysis, and stepwise
oxidation (Scheme 4). Inspired by this precedence we
decided to prepare the analogous 7h , which was not as
straightforward as anticipated. As mentioned above, the
presence of electron-donating R2 groups in 5 (R1 ) OH)
resulted in intractable mixtures of diaryl ether complexes
and various carbon-carbon coupled products upon at-
tempted arylation with arene-iron complex 4. Because
these byproducts could not be separated from the diaryl
ether complex 6h (Table 1), the crude mixture was
hydrolyzed to 7h (Table 2), and this mixture was dis-
solved in concentrated methanesulfonic acid. After stir-
ring at rt for 5 days, a 1:1 mixture of regioisomeric
xanthones 8e and 8f was isolated in fair yield (55% based
on 53% purity of 7h , Table 3). Treating the acid chloride
derived from complex 7i (obtained from 6h via methy-
lation, saponification, and reflux in thionyl chloride) with
Lewis acids (AlCl3 or ZnCl2) gave significantly lower
yields and approximately the same regioisomeric ratio
(8g and 8h , Table 3). Having ultimately established the
Sch em e 5
unpublished portions of this study, we noted that basic
conditions promoted the former event, while acidic condi-
tions (TMS-diazomethane/HPF6),16 allowed selective
alkylation of the coordinated phenol. Ultimately, we
managed to resolve the problematic methylation of 8i by
driving the reaction to completion with potassium hy-
droxide and excess iodomethane in DMSO.17 This one-
pot, tandem ring-opening/methylation reaction smoothly
returned the alkylated derivatives 9b-d (Table 4).
Unfortunately, all attempts to distinguish between the
methoxy groups in 9c or 8d met with failure. By treating
8d with a large excess of boron tribromide in dichlo-
romethane,18 only the xanthone complex monodepro-
tected in the 8 position, 8k , was isolated, albeit in
(15) If the appropriate methoxy group could be deprotected selec-
tively, triflation would give a substrate activated towards palladium-
catalyzed carbonylation (ref 14b). Furthermore, the wide range of other
palladium-catalyzed reactions would be available for analogue syn-
thesis. For a review, see: Tsuji, J . Palladium Reagents and Catalysts:
Innovations in Organic Synthesis; Wiley: Chichester, 1995.
(16) Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1990, 31, 5507.
(17) J ohnstone, R. A. W.; Rose, M. E. Tetrahedron, 1979, 35, 2169.
(18) Vickery, E. H.; Pahler, L. F.; Eisenbraun, E. J . J . Org. Chem.
1979, 44, 4444.

Iron-Mediated Routes to Functionalized Benzophenones
J . Org. Chem., Vol. 65, No. 17, 2000 5269
Ta ble 4. Nu cleop h ilic Rin g-Op en in g of th e Xa n th on e Com p lexes
compound
R1
R2
conditions
product
yielda(%)
1
H
H
1/ NaOH, MeOH/H2O
2/ KOt-Bu, MeI
KOH, MeI, DMSO
KOH, MeI, DMSO
KOH, MeI, DMSO
9a
81 (over two steps)
8a
8d
8i
OMe
OMe
i-Pr
CO2Me
OMe
OH
9bb
9c
9d
59b
85
59
(R2 ) OMe)
Sch em e 6
arene-iron substrates 9a -d displayed reversible addi-
tion of cyanide ion, a feature which prevented isolation
of the adducts. However, the cyanide addition/decom-
plexation sequence could be accomplished in a one-pot
procedure, employing a mixture of tetrabutylammonium
cyanide and DDQ in dichloromethane. In this manner,
the xanthone complexes 9a -d were functionalized and
demetalated, providing the heavily substituted ben-
zophenones 12-15 (Scheme 7). Separate experiments
showed 9a -d stable to DDQ at rt for 24 h. Unfortunately,
all attempts to regioselectively, or alternatively fully,
deprotect 14 were unsuccessful.
Com p letion of th e Syn th esis of 18. As expected,
conditions allowing single-step conversion of the isopropyl
group into a carboxylic acid (HNO3)23 turned out to be
too harsh when applied to 15, necessitating the develop-
ment of a stepwise procedure. Benzophenone 15 was
reacted with N-bromosuccinimide in the presence of
AIBN,24 furnishing two benzophenones. The crude mix-
ture, consisting of the R-brominated isopropylbenzophe-
none and the corresponding isopropenyl-substituted com-
pound, was homogenized to the latter via base-induced
elimination of HBr, employing sodium acetate in DMF.25
Due to the tendency of this material to polymerize when
contacted with silica gel, no purification was performed.
The crude mixture was immediately oxidized, via a
Lemieux-J ohnson procedure,26 providing methyl ketone
16 in good yield (70% over three steps) after silica-gel
flash chromatography (Scheme 8). A classical haloform
reaction27 transformed the ketone into the desired benzoic
acid 17 derivative in fair yield (56%). Attempts to hydro-
lyze the nitrile functionality using standard conditions
(sulfuric acid at various temperatures28 or highly alkaline
conditions29) did not give the expected product; only com-
plex mixtures and degradation products were isolated.
However, after warming the nitrile in a mixture of con-
centrated hydrochloric acid and methanol, and subse-
quent careful base treatment, the diacid 18 could be iso-
lated in acceptable yield (Scheme 8). Compound 18 was
an intermediate in Vicker’s total synthesis of balanol.8h
Sch em e 7
excellent yield (90%) (Scheme 6). Various other reagents
(TMSI,19 NaSi-Pr in DMF,20 and NaHMDS in DMEU21)
likewise failed to provide the desired dihydroxy xanthone
or the compound monoprotected in the 8 position. In some
cases, acetoxy groups have been shown to be orthogonal
to methoxy groups upon treatment with boron tribromide
at low temperatures.22 Interestingly, nucleophilic ring-
opening and triacetylation to the benzophenone 9e were
smoothly achieved in good yield by treating 8k with
sodium acetate in acetic anhydride (Scheme 7). However,
in our hands, selective cleavage of the methyl ether of
9e could not be realized, even at -78 °C.
Cyan ide Addition /Oxidative Decom plexation . Cer-
tain electron-withdrawing substituents have been found
to facilitate regioselective addition of cyanide ion to
arene-iron complexes, furnishing isolable, neutral pen-
tahapto complexes which could be oxidatively demeta-
lated in a subsequent step (Scheme 2).11 In our case, the
(23) Tuley, F. W.; Marvel, C. S. Org. Synth., Collect. Vol. 3 1955,
822.
(24) Manecke, G.; Creutzburg, K.; Klawitter, J . Chem. Ber. 1966,
99, 2440.
(25) Ukawa, K.; Ishiguro, T.; Kuriki, H.; Nohara, A. Chem. Pharm.
Bull. 1985, 33, 4432.
(26) Ireland, R. E.; Maienfisch, P. J . Org. Chem. 1988, 53, 640.
(27) Oida, S.; Ohashi, Y.; Ohki, E. Chem. Pharm. Bull. 1973, 21,
(19) J ung, M. E.; Lyster, M. A. J . Org. Chem. 1977, 42, 3761.
(20) Feutrill, G. I.; Mirrington, R. N. Tetrahedron Lett. 1970, 1327.
(21) Hwu, J . R.; Wong, F.-F.; Huang, J .-J .; Tsay, S.-C. J . Org. Chem.
1997, 62, 4097.
528.
(28) Clarke, H. T.; Taylor, E. R. Org. Synth., Collect. Vol. 2 1943,
588.
(22) Demuynck, M.; De Clercq, P.; Vandewalle, M. J . Org. Chem.
1979, 44, 4863.
(29) Staab, H. A.; Hauck, R.; Popp, B. Eur. J . Org. Chem. 1998, 1,
631.

5270 J . Org. Chem., Vol. 65, No. 17, 2000
Storm and Andersson
cooled on an ice bath. Addition of HPF6 (60% in water) (20
mL, 136 mmol) afforded a yellow precipitate. The yellow
crystals were filtered off and the yellow filtrate was extracted
with nitromethane until colorless. After drying (Na2SO4),
evaporation of the solvent returned additional solid, which was
combined with the precipitate above and dissolved in the
minimum volume of acetone. The addition of a large excess of
dichloromethane (approximately 5 vol) resulted in a white
precipitate, consisting of unwanted salts. After filtration and
evaporation the procedure was repeated until the residue was
completely soluble in dichloromethane. Evaporation afforded
crude material which was recrystallized from acetone-diethyl
ether. Filtration gave the title compound as a yellow powder
(17.98 g, 83%). Mp ≈ 200 °C dec. IR (KBr): 3100, 1730, 1510,
850 cm-1. HRMS-FAB+ (m/z): M+ calcd for C12H10ClFeO2,
Sch em e 8
1
276.9719; found, 276.9724. H NMR (CD3COCD3): δ 5.40 (s,
5H), 6.65 (t, J ) 6.1 Hz, 1H), 6.76 (t, J ) 6.2 Hz, 1H), 6.98 (d,
J
) 6.2 Hz, 1H), 7.01 (d, J ) 6.1 Hz, 1H). 13C NMR
Con clu sion s
(CD3COCD3): δ 81.6 (Cp), 88.3, 89.5, 90.4, 90.6, 94.0, 106.0,
165.4.
We have developed arene-iron mediated paths to
unsymmetrically substituted benzophenones, an impor-
tant class of compounds not readily accessible by con-
ventional routes. By performing a formal synthesis of the
benzophenone appendage of the PKC-inhibitor Balanol,
we have shown that combining iron-assisted reactions
can be useful in the preparation of complex molecules.
We have performed the first Friedel-Crafts reactions
with iron-bound benzoic acids. We have also extended
Sutherland’s pioneering studies on regioselective ring-
opening of the parent xanthone complex with amines and
stabilized carbon nucleophiles to include regioselective
ring-opening of substituted xanthone complexes, using
hydroxide or acetate as nucleophiles. Although the
generality of the overall methodology is limited by the
restrictions put on substituents in the Friedel-Crafts
reaction, a wide range of unsymmetrically substituted
benzophenones should be available via the paths de-
scribed in this paper.
η6-2-Ch lor oca r b om et h oxyb en zen e-η5-cyclop en t a d ie-
n yl Ir on Hexa flu or op h osp h a te (4). To a 1-L round-bot-
tomed flask, equipped with a reflux condenser and a gas trap,
the complex 10 (14.57 g, 34.5 mmol) and 400 mL of SOCl2 were
added. The mixture was refluxed for 3 h, and the excess thionyl
chloride was removed by evaporation. By coevaporating the
mixture with CH2Cl2, the last remnants of thionyl chloride
were removed. The resulting yellow crystalline oil was im-
mediately dissolved in 400 mL of methanol, and stirred at rt
under Ar for 2 h. During this time, the product started to
precipitate. The methanol was removed under reduced pres-
sure, and the residue was recrystallized from acetone-diethyl
ether. Filtration gave the title product as yellow crystals, 13.70
g (91%). Mp ≈ 125 °C dec. IR (KBr): 3110, 2960, 1740, 1270,
850 cm-1. HRMS-FAB+ (m/z): M+ calcd for C13H12ClFeO2,
1
290.9875; found, 290.9875. H NMR (CD3COCD3): δ 4.09 (s,
3H), 5.43 (s, 5H), 6.70 (t, J ) 6.1 Hz, 1H), 6.81 (t, J ) 6.1 Hz,
1H), 7.02 (d, J ) 6.2 Hz, 2H). 13C NMR (CD3COCD3): δ 54.8,
81.8 (Cp), 88.5, 89.6, 90.62, 90.65, 94.9, 106.5, 165.1.
η6-2-P h en oxyca r bom eth oxyben zen e-η5-cyclop en ta d i-
en yl Ir on Hexa flu or op h osp h a te (6a ). Sodium phenoxide30
(0.273 g, 2.34 mmol) was dissolved in 40 mL of dry acetone at
rt. After the solution was cooled to -70 °C, 4 (1.00 g, 2.29
mmol) was added in one portion. The resulting yellow solution
was stirred at -70 °C for 5 h, after which it was concentrated
to approximately 10 mL, and the product was precipitated by
the addition of approximately 50 mL of diethyl ether. Filtration
afforded a brownish-yellow solid material which was recrystal-
lized from acetone-diethyl ether. Filtration gave the title
compound as a yellow powder, 0.812 g (71%). Mp ≈ 135 °C
dec. IR (KBr): 3105, 3095, 1735, 1630, 1590, 1280, 1250, 825
cm-1. HRMS-FAB+ (m/z): M+ calcd for C19H17FeO3, 349.0527;
found, 349.0536. 1H NMR (CD3COCD3): δ 4.03 (s, 3H), 5.35
(s, 5H), 6.32 (d, J ) 6.7 Hz, 1H), 6.48 (t, J ) 6.0 Hz, 1H), 6.57
(t, J ) 6.0 Hz, 1H), 6.91 (d, J ) 6.1 Hz, 1H), 7.35 (d, J ) 7.8
Hz, 2H), 7.40 (t, J ) 7.6 Hz, 1H), 7.57 (t, J ) 8.0 Hz, 2H). 13C
NMR (CD3COCD3): δ 54.4, 78.0, 80.0 (Cp), 85.2, 86.0, 88.7,
89.0, 121.4, 127.5, 131.8, 132.9, 154.8, 165.5.
Gen er a l P r oced u r es for Nu cleop h ilic Ar om a tic Su b-
stitu tion s P er for m ed On 4 (Ta ble 1). P r oced u r e A.
Sodium hydride (60% dispersion in mineral oil) (1.1 mmol) was
placed in a two-necked flask under Ar and washed with 3 ×
10 mL of dry pentane. Dry THF (10 mL) was added, followed
by the phenol (1.1 mmol). After the mixture was stirred at rt
for 30 min, 10 mL of THF and 4 (1 mmol) were added
sequentially, and the mixture was stirred at rt until no more
starting material was present (TLC, SiO2, MeOH/NH4Cl (2 M)/
MeNO2, 7/2/1). The solution was then diluted with 40 mL of
dichloromethane, transferred into a separatory funnel, and
washed with 3 × 20 mL of water containing approximately 1
g of NH4PF6 per portion. Drying over Na2SO4, filtration, and
evaporation afforded crude material which was purified by
Exp er im en ta l Section
Gen er a l. All reactions involving iron complexes were
performed in the dark, in aluminum-foil-wrapped flasks.
Solvents and reagents were used as received from commercial
sources, unless otherwise indicated. NMR spectra were re-
corded at 400.132 MHz (1H) or 100.6 MHz (13C). The chemical
shifts are given relative to residual protio resonances of the
deuterated solvent used. FABMS spectra were recorded using
p-nitrobenzyl alcohol as a matrix in positive mode and EI
spectra were recorded at 70 eV. TLC analyses employed Merck
aluminum-backed sheets precoated with silica gel 60 F254.
Visualization was accomplished using UV-light. Flash chro-
matography separations were performed by using Matrex silica
gel. Alumina purifications were performed using Merck alu-
minum oxide 90, neutral. Recrystallizations of iron complexes
were performed by dissolving the complex in the minimum
volume of acetone and adding approximately 10 vol of diethyl
ether. The precipitated crystals were collected by suction
filtration. Melting points were uncorrected. Elemental analyses
were obtained from H. Kolbe Mikroanalytisches Laboratorium,
Mu¨lheim a. d. Ruhr, Germany.
CAUTION! Alk yla m m on iu m cya n id e com p ou n d s a r e
h igh ly toxic a n d a r e r ea d ily a bsor bed th r ou gh th e sk in .
η6-2-Ch lor oca r boxyben zen e-η5-cyclop en ta d ien yl Ir on
Hexa flu or op h osp h a te (10). To a 500-mL round-bottomed
flask, equipped with a reflux condensor were added η6-2-
chlorotoluene-η5-cyclopentadienyl iron hexafluorophosphate13
(20.02 g, 51 mmol), KMnO4 (29.84 g, 189 mmol), MgSO4 (13.49
g, 112 mmol), and 250 mL of water. The reaction mixture was
refluxed for 9 h after which the hot mixture was filtered
through a Bu¨chner funnel. To destroy the excess KMnO4,
Na2S2O5 was added, and the resulting yellow solution was
(30) Kornblum, N.; Lurie, A. P. J . Am. Chem. Soc. 1959, 81, 2710.

Iron-Mediated Routes to Functionalized Benzophenones
J . Org. Chem., Vol. 65, No. 17, 2000 5271
recrystallization from acetone-diethyl ether. The resulting
yellow crystals were filtered, dried under vacuum, and ana-
lyzed. In the case of diphenols as nucleophiles, the method was
slightly altered. To avoid triaryldiether formation, the stoi-
chiometry was adjusted to 4:2:1 (diphenol/NaH/iron-complex),31
and the reaction mixture was made acidic by the addition of
10% HCl (aq) when quenched.
P r oced u r e B. The nucleophile (1.1 mmol), K2CO3 (5 mmol),
and 4 (1 mmol) were dissolved in 20 mL of dry DMF. The
mixture was stirred at rt until no more starting material was
present (TLC, SiO2, MeOH/NH4Cl (2 M)/MeNO2, 7/2/1). a few
drops of the reaction mixture were withdrawn and dissolved
in 0.5 mL of dichloromethane and extracted with 0.5 mL of
water containing one spatula of NH4PF6). The solution was
then diluted with 50 mL of dichloromethane and transferred
into a separatory funnel, where it was washed with 5 × 50
mL of water containing approximately 1 g of NH4PF6 per
portion. Drying over Na2SO4, filtration, and evaporation
afforded crude material which was recrystallized from acetone-
diethyl ether. The resulting yellow crystals were filtered, dried
under vacuum, and analyzed.
consisting of the title compound (42%). 1H NMR (CD3-
COCD3): δ 5.24 (s, 5H), 6.73 (t, J ) 6.2 Hz, 1H), 6.92 (dt, J )
6.4, 1.2 Hz, 1H), 7.25 (dd, J ) 6.2, 1.2 Hz, 2H), 7.62-7.69 (m,
2H), 8.02 (dt, J ) 7.2, 1.8 Hz, 1H), 8.31 (dd, J ) 8.0, 1.6 Hz,
1H).
η6-8-Ca r bom eth oxy-6-m eth oxyxa n th on e-η5-cyclop en -
ta d ien yl Ir on Hexa flu or op h osp h a te (8a ). In a 100-mL
round-bottomed flask, equipped with a gas trap, the complex
7d (1.00 g, 1.76 mmol) was dissolved in 40 mL of thionyl
chloride and refluxed for 5 h. The excess reagent was removed
under reduced pressure. By coevaporating the mixture with
CH2Cl2, the last remnants of thionyl chloride were removed.
The resulting yellow crystalline oil was immediately dissolved
in 100 mL CH2Cl2, and AlCl3 (4.72 g, 35.4 mmol) was added.
After the mixture was stirred at rt under Ar for 24 h, the
reaction was quenched by the careful addition of 30 mL of ice-
water. After the addition of 3 g of NH4PF6, the yellow aqueous
phase was extracted with 4 × 30 mL of CH2Cl2. The organic
phases were combined and washed with 50 mL of water. After
this was dried over MgSO4, filtered, and evaporated, a dark
yellow residue was left. This material was purified by chro-
matography on neutral Al2O3 (the column was rinsed with
diethyl ether, after which the product was eluted with acetone),
providing yellow-brown crystals (0.461 g, 48%) consisting of
the title compound and a chlorinated byproduct in the ratio
of 6:1. IR (NaCl plates, CH2Cl2): 3105, 2953, 1734, 1674, 1575,
1303, 1226, 1130, 850 cm-1. HRMS-FAB+ (m/z): M+ calcd for
η6-2-(3-Meth oxy-5-ca r bom eth oxyp h en oxy)-ca r bom eth -
oxyben zen e-η5-cyclop en ta d ien yl Ir on Hexa flu or op h os-
p h a te (6c). The phenol 6b (0.989 g, 1.735 mmol) was dissolved
in 15 mL of dry DMF. Then MeI (1.2 mL, 19.3 mmol) and K2-
CO3 (2.502 g, 18.1 mmol) were added. The yellow solution,
containing solid K2CO3, was stirred at rt under Ar for 18 h.
The excess K2CO3 was filtered off, 50 mL of CH2Cl2 was added,
and the yellow solution was washed with 5 × 40 mL of water
containing approximately 1 g of NH4PF6 per portion. Drying
over Na2SO4, filtration, and evaporation afforded crude mate-
rial which was purified by recrystallization from acetone-
diethyl ether. Filtration gave the title compound as a yellow
powder, 0.770 g (76%). Mp ≈ 185 °C dec. Anal. Calcd for
C
21H17FeO5, 405.0425; found, 405.0432.1H NMR (CD3COC-
D3): δ 3.97 (s, 3H), 4.09 (s, 3H), 5.22 (s, 5H), 6.70 (t, J ) 6.2
Hz, 1H), 6.88 (t, J ) 6.7 Hz, 1H), 7.16 (d, J ) 2.3 Hz, 1H),
7.20 (d, J ) 6.5 Hz, 2H), 7.25 (d, J ) 2.3 Hz, 1H). 13C NMR
(CD3COCD3): δ 53.4, 57.5, 79.0, 79.7 (Cp), 80.5, 83.0, 88.4,
90.5, 103.7, 111.2, 114.5, 130.7, 137.1, 159.6, 167.0, 168.6,
177.5.
η6-6,8-Dim eth oxyxa n th on e-η5-cyclop en ta d ien yl Ir on
Hexa flu or op h osp h a te (8d ). The complex 7g (0.167 g, 0.308
mmol) was dissolved in 5 mL of methanesulfonic acid and
stirred at rt for 65 h. The red-brown reaction mixture was then
cooled to 0 °C, diluted with 15 mL of water, and transferred
into a separatory funnel. After the addition of approximately
2 g of NH4PF6, the aqueous phase was extracted with 2 × 50
mL CH2Cl2. After this was dried over Na2SO4, filtered, and
evaporated, a brown-yellow residue was left. This material was
recrystallized from acetone-diethyl ether, providing the title
compound as yellow-brown crystals (0.152 g, 95%). Mp ≈ 200
°C dec. Anal. Calcd for C20H17F6FeO4P: C, 46.00; H, 3.28.
Found: C, 45.88; H, 3.34. IR (KBr): 3096, 3041, 2995, 1671,
C
22H21F6FeO6P: C, 45.39; H, 3.64. Found: C, 45.48; H, 3.73.
IR (KBr): 3096, 2950, 1739, 1707, 1594, 1305, 1255, 829 cm-1
.
HRMS-FAB+ (m/z): M+ calcd for C22H21FeO6, 437.0687;
found, 437.0688. 1H NMR (CD3COCD3): δ 3.89 (s, 3H), 3.92
(s, 3H), 4.03 (s, 3H), 5.39 (s, 5H), 6.53 (m, 2H), 6.62 (t, J ) 5.8
Hz, 1H), 6.95 (dd, J ) 6.2, 1.3 Hz, 1H), 7.17 (t, J ) 2.3 Hz,
1H), 7.40 (dd, J ) 2.1, 1.2 Hz, 1H), 7.48 (dd, J ) 2.3, 1.2 Hz,
1H). 13C NMR (CD3COCD3): δ 52.4, 53.9, 56.0, 79.1, 79.7 (Cp),
85.0, 85.9, 88.3, 88.7, 110.9, 112.7, 112.8, 131.2, 133.8, 155.9,
162.0, 164.8, 165.6.
Gen er a l P r oced u r e for Ester Hyd r olysis (Ta ble 2). The
ester (1.0 mmol) was placed in a 100-mL flask and 30 mL of
methanol was added (the ester complexes were generally of
very low solubility in methanol). LiOH (1.2 mmol) dissolved
in 10 mL of water was added and the resulting solution was
stirred at rt until no more starting material was present (TLC,
SiO2, MeOH/NH4Cl (2 M)/MeNO2, 7/2/1). The reaction was
quenched by acidification with 10% HCl (aq); the mixture was
diluted with 100 mL of dichloromethane and transferred into
a separatory funnel, where it was washed with 3 × 20 mL of
water containing approximately 1 g of NH4PF6 per portion.
Drying over Na2SO4, filtration, and evaporation afforded crude
material which was purified by recrystallization from acetone-
diethyl ether. The resulting yellow crystals were filtered, dried
under vacuum, and analyzed.
η6-Xa n th on e- η5-cyclop en ta d ien yl Ir on Hexa flu or o-
p h osp h a te (1).10 The benzoic acid complex 7a (0.098 g, 0.204
mmol) was dissolved in 20 g of polyphosphoric acid and heated,
while being mechanically stirred, at 80 °C for 3 h. The black
reaction mixture was then cooled to rt, diluted with 20 mL of
water, and transferred into a separatory funnel, where it was
extracted with 2 × 30 mL of CH2Cl2 and 2 × 30 mL of CH3-
NO2. After the addition of approximately 1 g of NH4PF6, the
aqueous phase was extracted with CH2Cl2 until colorless. The
organic phases were combined, and after drying over Na2SO4,
filtration, and evaporation of the solvent, a yellow-brownish
semisolid remained. This material was recrystallized from
acetone-diethyl ether, to give 0.037 g of yellow-brown crystals,
1616, 1570, 1282, 1214, 1163, 829 cm-1 1H NMR (CD3-
.
COCD3): δ 4.02 (br s, 6H), 5.18 (s, 5H), 6.61 (t, J ) 6.1 Hz,
1H), 6.65-6.69 (m, 1H), 6.77 (t, J ) 5.9 Hz, 1H), 7.06 (d, J )
6.6 Hz, 1H), 7.17 (d, J ) 6.6 Hz, 1H). 13C NMR (CD3COCD3):
δ 56.9, 57.1, 78.2, 79.3 (Cp), 81.6, 83.2, 87.7, 89.8, 95.4, 97.1,
105.7, 130.2, 160.6, 163.6, 167.8, 175.3.
η6-8-Hyd r oxy-6-isop r op ylxa n t h on e-η5-cyclop en t a d ie-
n yl Ir on Hexa flu or op h osp h a te (8i). The benzoic acid
complex 7j (0.157 g, 0.292 mmol) was dissolved in 5 mL of
methanesulfonic acid and stirred at rt for 4 days. The dark
brown reaction mixture was then cooled to 0 °C, diluted with
20 mL of water, and transferred into a separatory funnel. After
the addition of 2 g of NH4PF6, the aqueous phase was extracted
with 4 × 30 mL of CH2Cl2. After this was dried over Na2SO4,
filtered, and evaporated, a dark greenish residue was left. This
material was dissolved in the minimum volume of CH2Cl2 and
approximately 10 vol of diethyl ether was added. This led to
the precipitation of yellow-brown crystals (0.109 g, 72%),
consisting of the title compound and its regioisomer in the ratio
of 30:1. Anal. Calcd for C21H19F6FeO3P: C, 48.49; H, 3.68.
Found: C, 48.35; H, 3.74. IR (NaCl plates, CH2Cl2): 3500-
2500, 3068, 2977, 1717, 1287, 1227, 761 cm-1. HRMS-FAB+
(m/z): M+ calcd for C21H19FeO3, 375.0684; found, 375.0692. 1H
NMR (CD3COCD3): δ 1.32 (d, J ) 6.9 Hz, 6H), 3.08 (sep, J )
6.9 Hz, 1H), 5.30 (s, 5H), 6.73 (t, J ) 5.8 Hz, 1H), 6.90 (d, J )
1.1 Hz, 1H), 6.92 (t, J ) 5.9 Hz, 1H), 7.01 (d, J ) 1.1 Hz, 1H),
7.20 (d, J ) 6.4 Hz, 1H), 7.29 (d, J ) 6.0 Hz, 1H), 11.60 (s,
1H). 13C NMR (CD3COCD3): δ 23.44, 23.49, 35.9, 78.6, 79.4,
(31) Pearson, A. J .; Gelormini, A. M. J . Org. Chem. 1994, 59, 4561.

5272 J . Org. Chem., Vol. 65, No. 17, 2000
Storm and Andersson
79.9 (Cp), 82.7, 88.2, 90.7, 106.7, 107.2, 111.7, 131.0, 157.1,
162.8, 163.4, 185.0.
Cl2-CH3NO2, 1:1, gave a yellow organic phase which was
washed with 3 × 40 mL of water. After this was dried over
MgSO4, filtered, and evaporated a yellow-brownish semisolid
was left. This was purified by recrystallization from acetone-
diethyl ether, followed by chromatography on neutral Al2O3,
(the column was rinsed with diethyl ether, after which the
product was eluted with acetone), providing yellow crystals
(0.063 g, 59%) consisting of the title compound and an
unknown iron complex in a ratio of 6:1. IR (NaCl plates, CH2-
η6-8-H yd r oxy-6-m et h oxyxa n t h on e-η5-cyclop en t a d ie-
n yl Ir on Hexa flu or op h osp h a te (8k ). The xanthone complex
8d (0.094 g, 0.180 mmol) was dissolved, with difficulty, in 15
mL of CH2Cl2. To the yellow solution was added BBr3 (0.100
mL, 1.046 mmol) via syringe, and the resulting orange solution
was stirred at rt for 3.5 h. To the orange reaction mixture was
added 10 mL of water, and the solution was transferred into
a separatory funnel. After the addition of approximately 2 g
of NH4PF6, the phases were separated. The aqueous phase was
extracted with 5 × 10 mL of CH2Cl2. After this was dried over
Na2SO4, filtered, and evaporated, yellow crystals remained.
This material was recrystallized from acetone-diethyl ether,
providing the title compound as yellow crystals (0.082 g, 90%).
IR (NaCl plates, CH2Cl2): 3105, 2959, 1657, 1602, 1332, 1182,
1159, 857 cm-1. HRMS-FAB+ (m/z): M+ calcd for C19H15FeO4,
Cl2): 3057, 2951, 1713, 1678, 1580, 1265, 1217, 845 cm-1
.
HRMS-FAB+ (m/z): M+ calcd for C23H23FeO6, 451.0844;
found, 451.0851. 1H NMR (CD3COCD3): δ 3.81 (s, 3H), 3.83
(s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 5.25 (s, 5H), 6.44 (t, J ) 6.2
Hz, 1H), 6.55 (d, J ) 6.6 Hz, 1H), 6.59 (d, J ) 6.3 Hz, 1H),
6.76 (dd, J ) 6.2, 1.3 Hz, 1H), 6.92 (d, J ) 2.2 Hz, 1H), 7.07
(d, J ) 2.2 Hz, 1H). 13C NMR (CD3COCD3): δ 53.2, 56.4, 56.9,
58.1, 72.2, 78.3, 79.1 (Cp), 79.7, 85.3, 88.4, 89.2, 103.1, 107.4,
132.4, 134.2, 159.6, 163.4, 167.5, 193.4.
1
363.0320; found, 363.0326. H NMR (CD3COCD3): δ 4.03 (s,
3H), 5.30 (s, 5H), 6.54 (d, J ) 2.2 Hz, 1H), 6.66 (d, J ) 2.2 Hz,
1H), 6.72 (t, J ) 6.1 Hz, 1H), 6.90 (t, J ) 6.1 Hz, 1H), 7.19 (d,
J ) 6.5 Hz, 1H), 7.26 (d, J ) 5.9 Hz, 1H), 11.94 (s, 1H). 13C
NMR (CD3COCD3): δ 57.2, 78.0, 79.6, 80.0 (Cp), 82.7, 88.2,
90.6, 96.1, 99.1, 103.1, 130.7, 158.6, 164.6, 169.5, 183.4.
(2,3,4,5,6)-η5-[2-(2-Hyd r oxyben zoyl)-oxocycloh exa d ie-
n yl]-η5-cyclop en ta d ien yl Ir on (11). The xanthone complex
1 (1.00 g, 2.17 mmol) was partially dissolved in 75 mL of
methanol. Sodium hydroxide (0.864 g, 21.6 mmol) dissolved
in 30 mL of water was added, which led to complete dissolution
and a color change from yellow to red. The reaction mixture
was stirred at rt for 4 h, after which it was acidified (pH ≈ 6)
by the dropwise addition of 10% HCl (aq). Extraction with 5
× 30 mL of CH2Cl2, drying over Na2SO4, filtration, and
evaporation of the solvent provided a red-brown solid residue.
After purification by filtration through a short plug of silica
(MeOH-CH2Cl2), a red-brown fluffy solid (0.723 g, 100%) was
isolated. Mp ≈ 100 °C dec. IR (KBr): 3500-2500, 3100, 3040,
1620, 1600, 1530 cm-1. HRMS-FAB+ (m/z): [M+H]+ calcd for
C18H15FeO3, 335.0371; found, 335.0335. 1H NMR (CD3COCD3-
CDCl3): δ 4.78 (s, 5H), 5.12 (d, J ) 6.0 Hz, 1H), 5.63 (t, J )
5.5 Hz, 1H), 5.73-5.80 (m, 2H), 6.74 (t, J ) 7.5 Hz, 1H), 6.88
(d, J ) 8.3 Hz, 1H), 7.37-7.46 (m, 2H), 12.13 (br s, 1H). 13C
NMR (CD3COCD3-CDCl3): δ 72.8, 74.0, 75.4 (Cp), 86.4, 87.5,
90.6, 118.0, 119.2, 120.6, 134.1, 136.8, 151.2, 162.5, 202.9.
η6-2-(2-Meth oxyben zoyl)-m eth oxyben zen e-η5-cyclopen -
ta d ien yl Ir on Hexa flu or op h osp h a te (9a ). The neutral red
oxocyclohexadienyl complex 11 (0.604 g, 1.808 mmol) was
dissolved in 75 mL of acetone-dichloromethane, 2:1. To this,
KOt-Bu (1.028 g, 9.17 mmol) and MeI (3.0 mL, 48.2 mmol)
were added, and the solution was stirred at rt under Ar for 48
h. The resulting yellow solution, containing solid white mate-
rial, was evaporated, and the residual orange oil was dissolved
in 15 mL of acetone. A solution of 5 g of NH4PF6 in 15 mL of
water was added. Evaporation of the acetone precipitated
yellow crystals from the remaining aqueous solution. After
filtration, drying, and recrystallization from acetone-diethyl
ether, 0.747 g of yellow crystals consisting of the title product
was isolated (81%). Mp ≈ 200 °C dec. IR (KBr): 3100, 2960,
1655, 1570, 1300, 825 cm-1. HRMS-FAB+ (m/z): M+ calcd for
η6-2-(2,4,6-tr im eth oxyben zoyl)-m eth oxyben zen e-η5-cy-
clop en ta d ien yl Ir on Hexa flu or op h osp h a te (9c). To 30 mL
of dry DMSO, powdered KOH (0.341 g, 6.08 mmol) was added
followed by 8d (0.300 g, 0.574 mmol) and MeI (0.75 mL, 12.0
mmol). The yellow solution, which quickly turned brown-red,
was stirred for 1 h at rt under Ar, after which a new portion
of KOH-MeI was added. This was repeated twice, after which
the mixture was allowed to stir at rt for 3 h. To the brown-red
solution was then added 50 mL of water containing ap-
proximately 2 g of NH4PF6, and the mixture was acidified with
10% HCl (aq), which turned it yellow. Extraction with 3 × 50
mL of CH2Cl2 and 1 × 25 mL of CH3NO2 gave a yellow organic
phase which was washed with 4 × 50 mL of water. To the
organic phase was added 20 mL of water containing 5 g of
NH4PF6. The organic solvent was evaporated off, and the
remaining aqueous solution was extracted with 3 × 40 mL of
CH2Cl2. After this was dried over Na2SO4, filtered, and
evaporated, a yellow-brown oil was left. This was dissolved in
the minimum volume of acetone, and the addition of ap-
proximately 5 volof diethyl ether led to the precipitation of
the title compound as yellow crystals, 0.279 g (85%). IR (NaCl
plates, CH2Cl2): 3114, 2950, 1666, 1598, 1470, 1282, 1223,
1170, 857 cm-1. HRMS-FAB+ (m/z): M+ calcd for C22H23FeO5,
1
423.0895; found, 423.0887. H NMR (CD3COCD3): δ 3.73 (s,
6H), 3.90 (s, 3H), 3.98 (s, 3H), 5.18 (s, 5H), 6.32 (s, 1H), 6.34
(t, J ) 6.0 Hz, 1H), 6.51-6.57 (m, 3H). 13C NMR (CD3-
COCD3): δ 56.2, 56.5, 58.1, 72.1, 78.8 (Cp), 84.6, 88.0, 88.6,
92.0, 93.5, 112.3, 134.1, 161.1, 165.5, 190.3.
η6-2-(4-Isop r op yl-2,6-d im eth oxyben zoyl)-m eth oxyben -
zen e-η5-cyclopen tadien yl Ir on Hexaflu or oph osph ate (9d).
To 30 mL of dry DMSO, the xanthone complex 8i (0.339 g,
0.651 mmol) was added followed by powdered KOH (0.30 g,
5.29 mmol) and MeI (0.82 mL, 13.2 mmol). The yellow solution,
which quickly darkened, was stirred for 1 h at rt under Ar,
after which a new portion of KOH-MeI was added. This was
repeated three times, giving a total reaction time of 5 h. To
the brownish-yellow solution was then added 50 mL of water
containing approximately 2 g of NH4PF6, and the mixture was
acidified with 10% HCl (aq). Extraction with 3 × 50 mL of
CH2Cl2 and 2 × 25 mL of CH3NO2 gave a yellow organic phase
which was washed with 4 × 100 mL of water. After this was
dried over Na2SO4, filtered, and evaporated a yellow-brownish
semisolid was left. This was dissolved in the minimum vol of
acetone, and the addition of approximately 5 vol of diethyl
ether led to the precipitation of the title compound as yellow
crystals, 0.222 g (59%). HRMS-FAB+ (m/z): M+ calcd for
C
20H19FeO3, 363.0683; found, 363.0682. 1H NMR (CD3-
COCD3): δ 3.52 (s, 3H), 3.99 (s, 3H), 5.26 (s, 5H), 6.35 (dt, J
) 6.5, 1.5 Hz, 1H), 6.48-6.56 (m, 3H), 7.09-7.17 (m, 2H), 7.67
(dt, J ) 7.0, 1.7 Hz, 1H), 7.92 (dd, J ) 7.7, 1.7 Hz, 1H). 13C
NMR (CD3COCD3): δ 56.0, 58.0, 71.2, 78.7 (Cp), 83.5, 87.5,
87.7, 99.4, 113.5, 121.9, 126.8, 131.3, 132.4, 137.1, 160.7, 191.1.
η6-2-(2-Ca r bom eth oxy-4,6-d im eth oxyben zoyl)-m eth ox-
yb en zen e-η5-cyclop en t a d ien yl Ir on H exa flu or op h os-
p h a te (9b). To 15 mL of dry DMSO, powdered KOH (0.115 g,
2.06 mmol) was added followed by 8a (0.099 g, 0.180 mmol)
and MeI (0.5 mL, 8.0 mmol). The yellow solution, which quickly
darkened, was stirred at rt in a sealed vessel for 2 h, after
which a new portion of KOH-MeI was added. After stirring
for 14 h, 30 mL of water containing 1 g of NH4PF6 was added
to the brown-yellow solution. The mixture was acidified with
10% HCl (aq) and transferred into a separatory funnel.
Extraction with 2 × 25 mL of CH2Cl2 and 1 × 20 mL of CH2-
C
24H27FeO4, 435.1259; found, 435.1248. 1H NMR (CD3-
COCD3): δ 1.28 (d, J ) 6.9 Hz, 6H), 2.97 (sep, J ) 6.9 Hz,
1H), 3.78 (s, 3H), 3.95 (s, 3H), 5.19 (s, 5H), 6.37 (dt, J ) 6.0,
1.3 Hz, 1H), 6.53-6.59 (m, 2H), 6.63 (dd, J ) 6.3, 1.2 Hz, 1H),
6.69 (s, 2H). 13C NMR (CD3COCD3): δ 24.0, 35.9, 56.5, 58.1,
66.8, 72.5, 78.9 (Cp), 85.0, 88.3, 88.7, 90.7, 103.5, 134.7, 155.9,
159.1, 192.3.
η6-2-(2,6-Diacetoxy-4-m eth oxyben zoyl)-acetoxyben zen e-
η5-cyclop en ta d ien yl Ir on Hexa flu or op h osp h a te (9e). To
10 mL of acetic anhydride, sodium acetate (0.262 g, 3.20 mmol)
was added followed by 8k (0.080 g, 0.158 mmol). The yellow

Iron-Mediated Routes to Functionalized Benzophenones
J . Org. Chem., Vol. 65, No. 17, 2000 5273
solution was stirred at rt for 21 h. After the solution was
diluted with 60 mL of CH2Cl2 and washed with 3 × 30 mL of
1M NaHCO3 (aq), the organic phase was added to 10 mL of
water containing 3 g of NH4PF6. The organic solvent was
evaporated, and the yellow aqueous phase was extracted with
30 mL of CH2Cl2. After this was dried over Na2SO4, filtered,
and evaporated, a yellow-brown oil remained. This was dis-
solved in the minimum volume of acetone, and the addition of
approximately 5 vol of diethyl ether led to the precipitation of
the title compound as light yellow crystals, 0.074 g (71%). Mp
≈ 120 °C dec. IR (NaCl plates, CH2Cl2): 3105, 2986, 1766,
1666, 1611, 1570, 1374, 1264, 1195, 1131, 839 cm-1. HRMS-
FAB+ (m/z): M+ calcd for C25H23FeO8, 507.0742; found,
507.0743.1H NMR (CD3COCD3): δ 2.00 (s, 6H), 2.06 (s, 3H),
3.93 (s, 3H), 5.31 (s, 5H), 6.63 (t, J ) 6.0 Hz, 1H), 6.71 (dd, J
) 6.2, 1.2 Hz, 1H), 6.78 (dt, J ) 6.1, 1.2 Hz, 1H), 6.87 (s, 2H),
6.88 (d, J ) 6.0 Hz, 1H). 13C NMR (CD3COCD3): δ 20.8, 21.0,
57.0, 80.9 (Cp), 84.1, 87.3, 89.0, 89.7, 96.6, 108.0, 118.2, 122.4,
152.2, 165.0, 168.5, 169.4, 188.7.
filtrate gave a dark semisolid from which the title compound
could be isolated by flash chromatography, (heptane-ethyl
acetate, 1:4, Rf ) 0.33), as off-white crystals (0.056 g, 36%).
IR (NaCl plates, CH2Cl2): 3105, 3014, 2986, 2237, 1666, 1611,
1278, 1259, 1227 cm-1. HRMS-EI (m/z): M+ calcd for C18H17
-
NO5, 327.1107; found, 327.1102.1H NMR (CDCl3): δ 3.68 (s,
6H), 3.72 (s, 3H), 3.84 (s, 3H), 6.08 (s, 2H), 7.10 (d, J ) 8.3
Hz, 1H), 7.25 (d, J ) 7.6 Hz, 1H), 7.38 (t, J ) 8.0 Hz, 1H). 13C
NMR (CDCl3): δ 55.6, 56.2, 56.7, 91.0, 111.6, 112.7, 116.0,
117.3, 125.3, 130.7, 136.6, 157.4, 161.1, 164.2, 190.5.
3-Meth oxy-2-(2,6-d im eth oxy-4-isop r op ylben zoyl) Ben -
zon itr ile (15). The complex 9d (0.076 g, 0.131 mmol) was
dissolved in 5 mL of CH2Cl2. To the yellow solution was added
n-Bu4NCN (0.107 g, 0.400 mmol) dissolved in 2 mL of CH2-
Cl2. CAUTION! Alk yla m m on iu m cya n id e com p ou n d s a r e
h igh ly toxic a n d a r e r ea d ily a bsor bed th r ou gh th e sk in .
The solution immediately turned bright red, and it was stirred
at rt under Ar for 6 h, after which DDQ (0.076 g, 0.335 mmol)
was added. The resulting dark purple solution was stirred at
rt for 2.5 h and then filtered through a short plug of Celite
diatomaceous earth. Evaporation of the filtrate gave a dark
semisolid from which the title compound could be isolated by
flash chromatography (heptane-ethyl acetate, 1:1, Rf ) 0.18),
as white crystals (0.032 g, 72%). Mp 147-148 °C. Anal. Calcd
for C20H21NO4: C, 70.78; H, 6.24; N 4.13. Found: C, 70.84; H,
6.18; N, 4.09. IR (KBr): 3105, 3032, 2986, 2858, 2830, 2237,
1675, 1602, 1579, 1296, 1250, 1232 cm-1. HRMS-EI (m/z): M+
calcd for C20H21NO4, 339.1471; found, 339.1470. 1H NMR
(CDCl3): δ 1.25 (d, J ) 6.9 Hz, 6H), 2.88 (sep, J ) 6.9 Hz,
1H), 3.67 (s, 3H), 3.70 (s, 6H), 6.41 (s, 2H), 7.09 (dd, J ) 8.4,
1.0 Hz, 1H), 7.29 (dd, J ) 7.7, 1.0 Hz, 1H), 7.40 (dd, J ) 8.4,
7.7 Hz, 1H). 13C NMR (CDCl3): δ 23.9, 35.2, 56.2, 56.6, 102.7,
112.0, 116.2, 117.3, 117.4, 125.6, 131.1, 135.8, 154.7, 157.7,
159.1, 191.9.
3-Meth oxy-2-(2-m eth oxyben zoyl) Ben zon itr ile (12). The
complex 9a (0.100 g, 0.197 mmol) was dissolved in 5 mL of
CH2Cl2. To the yellow solution was added n-Bu4NCN (0.160
g, 0.594 mmol) dissolved in 1 mL of CH2Cl2. CAUTION!
Alk yla m m on iu m cya n id e com p ou n d s a r e h igh ly toxic
a n d a r e r ea d ily a bsor bed th r ou gh th e sk in . The solution
immediately turned bright red, and it was stirred at rt under
Ar for 5 h, after which DDQ (0.096 g, 0.425 mmol) was added.
The resulting dark purple solution was stirred for 2 h and then
filtered through a short plug of Celite diatomaceous earth.
Evaporation of the filtrate gave a dark semisolid from which
the title compound could be isolated by flash chromatography
(heptane-ethyl acetate, 1:1, Rf ) 0.24), as white crystals (0.022
g, 41%). Mp 105-106 °C. IR (KBr): 3060, 3000, 2940, 2220,
1700, 1600, 1550, 1300 cm-1. HRMS-EI (m/z): M+ calcd for
C
16H13NO3, 267.0895; found, 267.0898. 1H NMR (CDCl3): δ
3-Meth oxy-2-(4-a cetyl-2,6-d im eth oxyben zoyl) Ben zon i-
tr ile (16). The benzophenone 15 (0.030 g, 0.089 mmol) was
dissolved in 4 mL of CCl4. N-bromosuccinimide (0.020 g, 0.113
mmol) and AIBN (0.0040 g, 0.0024 mmol) were added, and
the mixture was refluxed under Ar for 2 h. After cooling the
mixture to rt, succinimide was filtered off. Evaporation of the
solvent provided a brown-white residue, which (by analysis of
the crude mixture by 1H NMR) showed no traces of the starting
material; instead, signals from monobrominated, dibromi-
nated, and eliminated products (2:1:1) were observed. There-
fore, the crude mixture was taken further without purification.
The mixture was dissolved in 4 mL of DMF, and after addition
of NaOAc (0.013 g, 0.161 mmol) it was heated at 60 °C for 1 h
under Ar. After being cooled to rt, the yellow solution was
transferred to a separatory funnel and 20 mL of CHCl3 was
added. After being washed with 5 × 20 mL of water, the
organic phase was dried over Na2SO4. After filtration and
evaporation, the crude mixture was analyzed by 1H NMR, and
was found to contain the expected isopropenyl-substituted
benzophenone. Purification by flash chromatography (silica,
toluene-ethyl acetate, 4:1) was found to degrade the product,
and without further purification, the crude mixture was
dissolved in 6 mL of THF-H2O, 1:1. Osmium tetraoxide (0.010
g, 0.039 mmol) and NaIO4 (0.057 g, 0.266 mmol) were added,
and the yellow solution was stirred at rt under Ar for 12 h.
THF was then evaporated off and the remaining aqueous
solution was extracted with 4 × 5 mL of EtOAc. Drying over
Na2SO4, filtration, evaporation, and purification by flash
chromatography (silica, heptane-ethyl acetate, 1:4, Rf ) 0.27)
provided the title compound as a slightly yellowish solid, 0.021
3.61 (s, 3H), 3.72 (s, 3H), 6.92 (dd, J ) 8.4, 0.7 Hz, 1H), 7.06
(dt, J ) 7.7, 0.9 Hz, 1H), 7.15 (dd, J ) 8.5, 0.8 Hz, 1H), 7.30
(dd, J ) 7.7, 0.9 Hz, 1H), 7.45 (t, J ) 8.1 Hz, 1H), 7.53 (dt, J
) 7.3, 1.8 Hz, 1H), 7.83 (dd, J ) 7.8, 1.8 Hz, 1H). 13C NMR
(CDCl3): δ 55.9, 56.3, 111.0, 112.1, 115.6, 117.2, 121.0, 125.0,
127.1, 130.7, 131.8, 135.3, 136.2, 157.0, 159.8, 192.1.
2-(2-Cya n o-6-m et h oxyb en zoyl)-3,5-d im et h oxy-ca r b o-
m eth oxyben zen e (13). The complex 9b (0.055 g, 0.092 mmol)
was dissolved in 10 mL of CH2Cl2. To the yellow solution was
added n-Bu4NCN (0.076 g, 0.285 mmol). CAUTION! Alk yl-
a m m on iu m cya n id e com p ou n d s a r e h igh ly toxic a n d a r e
r ea d ily a bsor bed th r ou gh th e sk in . The solution im-
mediately turned red, and it was stirred at rt under Ar for 2
h, after which DDQ (0.053 g, 0.233 mmol) was added. The
resulting dark purple solution was stirred at rt for 4 h and
then filtered through a short plug of Celite diatomaceous earth.
Evaporation of the filtrate gave a dark semisolid from which
the title compound could be isolated by flash chromatography
(heptane-ethyl acetate, 1:6, Rf ) 0.34), as a slightly red solid,
contaminated by an unknown byproduct (0.012 g, 37%). IR
(NaCl plates, CH2Cl2): 3057, 2945, 2230, 1728, 1668, 1585,
1469, 1265, 1138, 1065 cm-1. HRMS-EI (m/z): M+ calcd for
C
19H17NO6, 355.1056; found, 355.1058. 1H NMR (CDCl3): δ
3.60 (s, 3H), 3.67 (s, 3H), 3.76 (s, 1H), 3.88 (s, 1H), 6.59 (d, J
) 2.3 Hz, 1H), 6.98 (d, J ) 2.3 Hz, 1H), 7.12 (dd, J ) 8.4, 0.9
Hz, 1H), 7.39 (dd, J ) 7.6, 1.0 Hz, 1H), 7.49 (dd, J ) 8.4, 7.6
Hz, 1H). 13C NMR (CDCl3): δ 52.8, 55.9, 56.5, 56.6, 102.4,
105.7, 116.8, 126.9, 132.3, 158.7, 158.9, 161.8, 167.4, 191.0 (5C,
the substituted arene carbons, and the nitrile could not be
distinguished from the impurities.)
g (70% over three steps). HRMS-EI (m/z): M+ calcd for C19H17
-
1
3-Met h oxy-2-(2,4,6-t r im et h oxyb en zoyl) Ben zon it r ile
(14). The complex 9c (0.267 g, 0.470 mmol) was dissolved in
15 mL of CH2Cl2. To the yellow solution was added n-Bu4NCN
(0.356 g, 1.324 mmol). CAUTION! Alk yla m m on iu m cya -
n id e com p ou n d s a r e h igh ly toxic a n d a r e r ea d ily a b-
sor bed th r ou gh th e sk in . The solution immediately turned
bright red, and it was stirred at rt under Ar for 5 h, after which
DDQ (0.257 g, 1.133 mmol) was added. The resulting dark
purple solution was stirred for 13 h and then filtered through
a short plug of Celite diatomateous earth. Evaporation of the
NO5, 339.1107; found, 339.1109. H NMR (CDCl3): δ 2.63 (s,
1H), 3.64 (s, 3H), 3.80 (s, 6H), 7.11 (dd, J ) 8.5, 0.9 Hz, 1H),
7.14 (s, 2H), 7.35 (dd, J ) 7.7, 1.0 Hz, 1H), 7.48 (dd, J ) 8.5,
7.7 Hz, 1H). 13C NMR (CDCl3): δ 27.0, 56.5 (3 -OCH3), 104.4,
112.8, 116.3, 117.4, 123.9, 126.3, 132.2, 133.4, 139.9, 158.3,
158.4, 191.5, 197.5.
4-(2-Cya n o-6-m et h oxyb en zoyl)-3,5-d im et h oxyb en zo-
ic Acid (17). Sodium hydroxide (0.021 g, 0.512 mmol) was
dissolved in 0.5 mL of water. The solution was cooled to -5
°C and Br2 was added. The yellow solution was diluted with

5274 J . Org. Chem., Vol. 65, No. 17, 2000
Storm and Andersson
0.5 mL of dioxane. After the solution was stirred at -5 °C for
10 min, a pre-cooled solution of 16 (5 mg, 0.0147 mmol)
dissolved in 2 mL of dioxane was added. The temperature was
allowed to rise to 5 °C, and the solution was stirred at this
temperature for 3 h. A portion of Na2SO3 (0.0652 g, 0.517
mmol) dissolved in 1.0 mL of water was added, and stirring
was continued at rt for 1 h. After acidification with 10% HCl
(aq), the reaction mixture was transferred into a separatory
funnel and extracted with 5 × 5 mL of EtOAc. After the
mixture was dried over Na2SO4, filtered, and evaporated, 2.8
mg of slightly red material was isolated (56%). HRMS-EI (m/
z): [M+H]+ calcd for C18H16NO6, 342.0978; found, 342.0984.
1H NMR (CDCl3): δ 3.65 (s, 3H), 3.80 (s, 6H), 7.32 (s, 2H),
7.39 (dd, J ) 8.6, 0.9 Hz, 1H), 7.47 (dd, J ) 7.7, 0.9 Hz, 1H),
7.65 (dd, J ) 8.5, 7.7 Hz, 1H). 13C NMR (CDCl3): δ 56.7, 56.8,
106.4, 113.4, 117.9, 118.1, 124.9, 127.0, 133.6 (3 C), 133.7,
134.2, 158.8, 167.0, 191.9.
rt for 30 min. After the solution was acidified with 10% HCl
(aq) and evaporated, the residue was dissolved in the minimum
volume of acetone, and LiCl was filtered off. Evaporation
yielded 0.62 mg (50%) of material with spectroscopic charac-
teristics in agreement with the literature.11h MS-electrospray
(m/z): M+ calcd for C18H17O7, 360.1; found, 360.1. 1H NMR
(CD3SOCD3): δ 3.56 (s, 6H), 3.64 (s, 6H), 7.17 (s, 2H), 7.18 (d,
J ) 8.0 Hz, 1H), 7.26 (d, J ) 8.0 Hz, 1H), 7.41 (t, J ) 8.0 Hz,
1H).
Ack n ow led gm en t. This work was supported by the
Swedish Natural Science Research Council and Craaford-
ska Stiftelsen. We thank Mrs. Marjana Andersson,
AstraZeneca R&D Lund, for providing HPLC-MS analy-
ses.
4-(2-Ca r b oxy-6-m et h oxyb en zoyl)-3,5-d im et h oxyb en -
zoic Acid (18).8h The nitrile 17 (1.2 mg, 3.52 µmol) was
dissolved in 0.4 mL of HCl(c)-MeOH, 1:1, and heated to 80
°C, in a sealed vessel, for 11 h. The resulting yellow solution
was evaporated to dryness and redissolved in 1 mL of
methanol. Lithium hydroxide (6.4 mg, 0.267 mmol) dissolved
in 0.5 mL of water was added and the solution was stirred at
Su p p or tin g In for m a tion Ava ila ble: Detailed description
for the preparation of 6b, 6d -j, 7a -j, 19, 20, 21, 5c, 5d , and
5h , including spectroscopic data. Representative 1H and 13C
spectra of 4, 6j, 7j, 8i, 9d , and 15. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O000421Z