Regioselective, directed meta acylation of aromatic compounds

Article abstract of DOI:10.1021/ja981508t

A new method for the directed meta acylation of aromatic compounds is described. This method involves an ortho lithiation procedure combined with zirconocene-benzyne chemistry. 3-Acyl-1-substituted benzene derivatives were obtained by acidic hydrolysis of the azazirconacycle intermediate which results from the coupling of a nitrile with a zirconocene-benzyne complex. Similarly, 3-acyl-2-iodo-1-substituted benzene derivatives were obtained by the iodination of the same intermediate followed by acidic hydrolysis. These procedures, which utilize simple, readily available starting materials, give good yields of regiochemically pure products.

Full text of DOI:10.1021/ja981508t

VOLUME 120, NUMBER 36
SEPTEMBER 16, 1998
©
Copyright 1998 by the
American Chemical Society
Regioselective, Directed Meta Acylation of Aromatic Compounds
†
Shuji Akai, Andrew J. Peat, and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
ReceiVed May 1, 1998
Abstract: A new method for the directed meta acylation of aromatic compounds is described. This method
involves an ortho lithiation procedure combined with zirconocene-benzyne chemistry. 3-Acyl-1-substituted
benzene derivatives were obtained by acidic hydrolysis of the azazirconacycle intermediate which results from
the coupling of a nitrile with a zirconocene-benzyne complex. Similarly, 3-acyl-2-iodo-1-substituted benzene
derivatives were obtained by the iodination of the same intermediate followed by acidic hydrolysis. These
procedures, which utilize simple, readily available starting materials, give good yields of regiochemically pure
products.
4
-7
8
Introduction
substitution and related rearrangement reactions, and radical
9
10,11
cation and transition metal-mediated processes.
Typical electrophilic reactions include the Friedel-Crafts
reaction and the Fries rearrangement. These reactions are best
for electron-rich aromatic compounds and display ortho and para
selectivity, but frequently, they are not highly regioselective.
Directed ortho lithiation has emerged as a powerful technique
There has been much effort in recent years toward the
development of methods to introduce carbon substituents onto
aromatic rings. The majority of these involve electrophilic
1
2
1
2
aromatic substitution and related rearrangement reactions,
directed ortho lithiation procedures,3 nucleophilic aromatic
(
6) For a review of nucleophilic addition to arynes, see: Kessar, S. V.
†
Overseas research scholar from Osaka University, Japan.
ComprehensiVe Organic Chemistry, Pergamon: Oxford, U.K., 1991; Vol.
4, p 483.
(1) For reviews, see: (a) Taylor, R. Electrophilic Aromatic Substitution;
Wiley: New York, 1990. (b) Heaney, H. ComprehensiVe Organic Chem-
istry; Pergamon: Oxford, U.K., 1991; Vol. 2, p 733. (c) Wynberg, H.
ComprehensiVe Organic Chemistry; Pergamon: Oxford, U.K., 1991; Vol.
(7) For reviews of vicarious nucleophilic substitution reactions, see: (a)
Makosza, M. Synthesis 1991, 103. (b) Makosza, M.; Winiarski, J. Acc.
Chem. Res. 1987, 20, 282.
(8) March, J. AdVanced Organic Chemistry, 4th ed.; Wiley: New York,
1992; Chapter 18.
(9) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.; Mitoh, S.;
Sakurai, H.; Oka, S. J. Am. Chem. Soc., 1994, 116, 3684.
(10) For reviews of transition-metal-catalyzed cross-coupling reactions,
see: (a) Kumada, M. Pure Appl. Chem. 1980, 52, 669. (b) Negishi, E. Acc.
Chem. Res. 1982, 15, 340. (c) Stille, J. K. Angew. Chem., Int. Ed. Engl.
1986, 25, 508. (d) Suzuki, A. Pure Appl. Chem. 1991, 63, 419. (e) Malleron,
J.-L.; Fiaud, J.-C.; Legros, J.-Y. Handbook of Palladium-Catalyzed Organic
Reactions. Synthetic Aspects and Catalytic Cycles; Academic Press: San
Diego, CA, 1997. (f) Beletskaya, I. P. Pure Appl. Chem. 1997, 69, 471. (g)
Metal-catalyzed Cross-coupling Reactions; Diederich, F.; Stang, P. J., Eds.;
Wiley: New York, 1998.
2
, p 769. (d) Meth-Cohn, O.; Stanforth. S. P. ComprehensiVe Organic
Chemistry; Pergamon: Oxford, U.K., 1991; Vol. 2, p 777. (e) Ishibashi,
H.; Ikeda, M. ReV. Heteroatom Chem. 1996, 14, 59.
(
(
2) For a review, see: Martin, R. Org. Prep. Proc. Int. 1992, 24, 369.
3) For reviews, see: (a) Snieckus, V. Chem. ReV. 1990, 90, 879. (b)
Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306. See also: (c) Evans,
P. A.; Nelson, J. D.; Stanley, A. L. J. Org. Chem. 1995, 60, 2298.
(4) For reviews of nucleophilic addition to electron-deficient arenes,
see: (a) Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837. (b) Paradisi,
C. ComprehensiVe Organic Chemistry; Pergamon: Oxford, U.K., 1991;
Vol. 4, p 423. (c) March, J. AdVanced Organic Chemistry, 4th ed.; Wiley:
New York, 1992; Chapter 13.
(
5) For reviews of reactions of transition metal-arene complexes, see:
(
a) Semmelhack, M. F. Pure Appl. Chem. 1981, 53, 2379. (b) Semmelhack,
(11) For a recent review of transition-metal-catalyzed addition of aromatic
C-H bonds to multiple bonds, see: Murai, S.; Chatani, N.; Kakiuchi, F.
Pure Appl. Chem. 1997, 69, 589.
M. F. ComprehensiVe Organic Chemistry; Pergamon: Oxford, U.K., 1991;
Vol. 4, p 517.
S0002-7863(98)01508-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/26/1998

9120 J. Am. Chem. Soc., Vol. 120, No. 36, 1998
Akai et al.
Scheme 1
aromatic precursors 1 (Scheme 1). Herein we describe a
general, one-pot, and regioselective procedure for the directed
acylation of aromatic compounds at the meta position of a
preexisting functional group. As shown in Scheme 1, azazir-
conacycle intermediate IV is hydrolyzed with acid to form 2,
or quenched with I2 followed by acid hydrolysis to afford
m-acyl-o-iodoarenes 3. Depending on the choice of reagents,
this protocol effects the net increase of ring substituents by one
or two.
Results and Discussion
To examine the feasibility of the above-described approach,
we first investigated the reaction of the o-lithiophenyl ether,
generated by the reaction of methoxymethyl (MOM) phenyl
ether 1a with t-BuLi, with Cp2Zr(Me)Cl. Intermediates of type
II could be transformed to product as previously described. In
a typical procedure (method A), treatment of 1a in Et2O with
for the construction of 1,2-disubstituted aromatic compounds
due to a wide variety of functional groups which can serve as
directing groups. Although nucleophilic aromatic substitution
1
.1 equiv of t-BuLi at 0 °C and then at room temperature (RT)
3
afforded I (DG ) OMOM). The reaction mixture was cooled
to -78 °C and a suspension of Cp2Zr(Me)Cl (1.1 equiv) in Et2O
was added. The mixture was slowly warmed to RT, and
benzonitrile was added. Heating the reaction mixture at 80 °C
in a resealable Schlenk flask for 15 h, followed by cooling to
RT and treatment of the reaction mixture with aqueous HCl,
produced the desired 3-benzoylphenyl MOM ether 2a in 63%
yield (Table 1, entry 1). Similar reactions could be carried out
with 7-chloroheptanonitrile and 2-cyanothiophene to provide the
corresponding 3-acylphenol ethers 2b and 2c in 82% and 81%
yields, respectively (entries 2 and 3).
reactions are usually limited to substrates having strong electron-
4
withdrawing groups, reactions of transition metal-arene com-
5
plexes such as (arene)Cr(CO)3 and those of benzyne interme-
6
diates allow for the use of the substrates having electron-
donating groups.
Unlike the other processes mentioned above which proceed
with ipso,4 ortho, or para selectivity,
,10
1-3,7-9,11
carbon-carbon
bond forming reactions of arene-metal complexes or benzynes
have been reported to take place preferentially at the position
meta to a substituent.5 However, satisfactory regioselectivites
and yields are obtained only with certain substrates and
nucleophiles. In addition, these methods require formation and
,6
In a similar manner, the o-lithiobenzamide, prepared in situ
by the reaction of the benzamide 1b with t-BuLi, was treated
with Cp2Zr(Me)Cl, and the resulting arylzirconocene was heated
in the presence of benzonitrile. This reaction required harsher
conditions for the formation of the zirconocene-benzyne
complex: the intermediate arylzirconocene was heated with the
nitrile at 120 °C for 39 h. Workup as above afforded a 72%
yield of the desired meta-acylated product 2g after hydrolysis
5
decomplexation of the metal-arene complex or the preparation
6
of multifunctional precursors for benzyne formation.
Recently, our group has reported a new method for the
functionalization of aromatic compounds employing intermedi-
ate zirconocene-benzyne complexes.12 Insertion of an unsatur-
ated compound, such as a nitrile, olefin, alkyne, or isonitrile
into the carbon-zirconium bond of the benzyne complex
produces a zirconacycle, which can be cleaved with various
electrophilic reagents to afford a variety of functionalized
aromatic compounds. The reaction of the zirconocene complex
with a nitrile is particularly interesting because the product of
this reaction (a 3-acyl-1-substituted aromatic compound) is that
which would result from an anti-Friedel-Crafts acylation of
the arene.
Although the arylzirconocene intermediate II (Scheme 1) has
usually been prepared from an aryl halide by a halogen-lithium
exchange reaction followed by reaction with Cp2Zr(Me)Cl, we
envisioned that an approach which combined our zirconocene-
benzyne chemistry with ortho lithiation should produce II
1
3
of the azazirconacycle intermediate (entry 7).
With these initial results in hand we next investigated the
use of commercially available Cp2ZrCl2 in lieu of Cp2Zr(Me)-
Cl. The latter reagent is prepared from Cp2ZrCl2 by a two-
step route, one of which involves the use of AlMe314 and must
be handled under anhydrous conditions. We have previously
shown that Cp2Zr(i-Bu)Cl can serve as a surrogate for Cp2Zr-
1
2a
(
Me)Cl in many procedures. Two methods which we con-
sidered to generate Cp2Zr(i-Bu)Cl from Cp2ZrCl2 involved the
1
2a
reaction of Cp2ZrCl2 with either t-BuLi (method B)
or
1
5
t-BuMgCl (method C). A preliminary examination of the use
of Cp2Zr(i-Bu)Cl prepared by these two methods for the reaction
of lithiated 1a and benzonitrile was carried out, and the results
are summarized in Table 1. To our delight the use of method
B gave better yields than did the use of method A (entry 1). A
similar reaction using Cp2ZrCl2/t-BuMgCl was slow and gave
a poor yield (approximately 15%) of 2a. Addition of 2.4 equiv
(Scheme 2) and, therefore, would be a more efficient method
for the synthesis of meta-acylated arenes 2. This protocol would
benefit from the use of more readily available, less-substituted
1
6
(12) (a) Barr, K. J.; Watson, B. T.; Buchwald, S. L. Tetrahedron Lett.
of 1,4-dioxane (method C) to the reaction mixture prior to
1
1
1
1
1
1
991, 32, 5465. (b) Buchwald, S. L.; King, S. M. J. Am. Chem. Soc. 1991,
13, 258. (c) Tidwell, J. H.; Peat, A. J.; Buchwald, S. L. J. Org. Chem.
994, 59, 7164. (d) Tidwell, J. H.; Buchwald, S. L. J. Am. Chem. Soc.
994, 116, 11799. (e) de Rege, F. M. G.; Buchwald, S. L. Tetrahedron
995, 51, 4291. (f) Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
18, 1028. For reviews of zirconocene-benzyne chemistry, see: (g)
(13) In this case, the solvent used for the ortho lithiation and subsequent
reaction with the zirconocene reagent (a mixture of Et2O and THF) was
replaced with toluene before heating.
(14) Wailes, P. C.; Weigold, H.; Bell, A. P. J. Organomet. Chem. 1971,
33, 181.
(15) (a) Negishi, E.; Miller, J. A.; Yoshida, T. Tetrahdron Lett. 1984,
25, 3407. (b) Swanson, D. R.; Nguyen, T.; Noda, Y.; Negishi, E. J. Org.
Chem. 1991, 56, 2590.
(16) Addition of 1,4-dioxane to a Grignard reagent is known to form
MgX2‚(1,4-dioxane)2, although we have not determined the effect of dioxane
in this case. See: Coates, G. E.; Heslop, J. A. J. Chem. Soc. (A) 1968, 514.
Buchwald, S. L.; Nielsen, R. B. Chem. ReV. 1988, 88, 1047. (h) Buchwald,
S. L.; Fisher, R. A. Chem. Scr. 1989, 29, 417. (i) Bennett, M. A.;
Schwemlein, H. P. Angew. Chem., Int. Ed. Engl. 1989, 28, 1296. (j) Broene,
R. D.; Buchwald, S. L. Science 1993, 261, 1696. (k) Buchwald, S. L.;
Broene, R. D. ComprehensiVe Organometallic Chemistry II; Elsevier: New
York, 1995; Vol. 12, p 771.

Directed Meta Acylation of Aromatic Compounds
J. Am. Chem. Soc., Vol. 120, No. 36, 1998 9121
Scheme 2. Methods for Preparation of Arylzirconocene Intermediates II
Table 1. Preparation of 3-Acyl-1-Substituted Benzenes 2a
a
b
Heated at 80-85 °C except for entries 7 and 8 (120 °C). Average of two runs, unless otherwise noted. The yield is based on 1 as the limiting
c
d
substrate. Single run. GC ratio, 52:48 for 1b:2g.
heating eliminated these problems, and 2a was obtained in good
yield (entry 1).
of side products.17 Fortunately, by employing method C, 2b and
2e could be isolated in good yield (entries 2 and 5, respectively).
The yields reported are for the one-pot conversion of 1 to the
final product 2. It is noteworthy that these procedures require
no isolation and little manipulation of any intermediates and
that only a single regioisomer is formed in all cases, corre-
sponding to an anti-Friedel-Crafts acylation. Of particular
importance is that this method tolerates a reasonable range of
functional groups including olefins, heteroaryl, and cyclopropyl
groups.
The scope of methods B and C were investigated by
examining reactions of a variety of aromatic compounds and
nitriles, and the results are summarized in Table 1. In general,
method B furnished good yields of the desired meta-acylated
products 2. For reactions with 7-chloroheptanonitrile or 1-cy-
clohexenecarbonitrile, the use of method B led to the formation
(17) Formation of cyclohexyl 3-(methoxymethoxy)phenyl ketone 4 was
observed for the reaction of entry 2 with the GC ratio 79:21 for 2a and 4.
Addition of 0.3 equiv of Me3SiCl before reaction with the nitrile for the
same method gave inferior results (2a:4 ) 15:85).
As we have previously reported,12a,b the reaction of azazir-
conacycle intermediates IV with 2.5 equiv of I2, followed by

9122 J. Am. Chem. Soc., Vol. 120, No. 36, 1998
Akai et al.
Table 2. Preparation of 3-Acyl-2-iodo-1-Substituted Benzenes 3a
a
Run by method B. b Average of two runs.
hydrolysis affords m-acyl-o-iodoarenes 3 in good yield (Table
Scientific Inc., Mead, CO. Other compounds either were available from
commercial sources or were prepared according to published procedures
and were used after either distillation or recrystallization. Flash column
chromatography was performed using ICN Flash Silica Gel (230-400
mesh). Gas chromatography analyses were performed on a Hewlett-
Packard model HP6980 with FID detector using a 25-m capillary
column HP-1. Melting points are uncorrected. Yields refer to isolated
2
). These iodinated products are potential precursors to a
10
number of polyfunctionalized aromatic compounds. As in the
previous cases, these compounds were produced as single
regioisomers.
In summary, we have developed an efficient method for the
preparation of 3-acyl-1-substituted benzene derivatives. This
method involves the combination of directed ortho lithiation
technology with our previously developed zirconocene-benzyne
chemistry. The following points are noteworthy: (1) The
overall transformation is the synthetic equivalent of a directed
meta metalation of an aromatic ring, a process not readily
achieved using previously reported methods. Furthermore, both
electron-rich and electron-deficient aromatic compounds are
compatible with this method. (2) The required compounds for
this procedure are an arene bearing a directing group, a nitrile,
Cp2ZrCl2, and t-BuLi and/or t-BuMgCl, all of which are
commercially or readily available. (3) A number of functional
groups are tolerated, providing access to aryl ketones with
diverse substituents. However, this technique still suffers from
an inability to tolerate several important functional groups such
as carbonyls and nitriles. (4) The process gives good to
excellent yields of the products. Thus, we believe this new
approach complements the powerful techniques already available
for the introduction of carbon substituents onto aromatic rings.
1
material of g95% purity as determined by H NMR, capillary GC,
and combustion analyses (performed by E & R Microanalytical
Laboratory, Inc.). Yields indicated in this section refer to a single
experiment, while those reported in the tables are an average of two
runs, so the numbers may differ slightly.
General Procedure for the Preparation of 2a-f,i,j from 1a or
1c. Method A. To an oven-dried 100-mL round-bottomed resealable
Schlenk flask fitted with a rubber septum were added 1a (0.40 mL,
3
0
1
2
.0 mmol) and Et O (15 mL), and the resulting solution was cooled to
°C. To this solution was added t-BuLi (1.7 M solution in pentane,
.95 mL, 3.3 mmol) dropwise over a period of 3 min. The resulting
yellow suspension was stirred at 0 °C for 30 min and then at RT for
2
.5 h. Cp
2
Zr(Me)Cl (0.92 g, 3.4 mmol) was placed in an oven-dried
5
0-mL Schlenk tube in the drybox, and the Schlenk tube was sealed
with a glass stopper. The Schlenk tube was taken out of the drybox
and connected to the Schlenk line, and the glass stopper was replaced
with a rubber septum. Et O (10 mL) was added, and the resulting
2
suspension was transferred via cannula over a period of 5 min to the
flask containing the ortho-lithiated compound which had been cooled
to -78 °C. The Schlenk tube was rinsed with Et O (5 mL), and the
2
washings were added to the reaction flask. The reaction mixture was
stirred at -78 °C for 20 min, gradually warmed to RT over a period
of 40 min, and stirred at RT for 1 h. The nitrile (4.1-4.5 mmol, 1.35-
1.5 equiv) was added, the septum was replaced with a Teflon screw
valve, and the flask was sealed and heated at 80 °C for 15 h. After
being cooled to RT, the reaction mixture was concentrated in vacuo
and THF (15 mL) was added. The resulting solution was cooled to 0
°C, 1 N HCl (12 mL) was added, and the resulting mixture was stirred
at RT for 5 h. At this time it was poured into a separatory funnel
containing Et O (20 mL) and saturated aqueous NaHCO (30 mL). The
Experimental Section
General Considerations. All reactions involving organometallic
reagents were conducted under an atmosphere of purified argon using
standard Schlenk techniques. Transfer and storage of air- or moisture-
sensitive zirconocene reagents were performed in a Vacuum Atmo-
1
8
spheres Co. drybox under an atmosphere of nitrogen. Resealable
Schlenk tubes and round-bottomed resealable Schlenk flasks used in
the procedures were single-neck flasks fitted with Teflon O-ring screw
valves. Caution: reactions performed in sealed tubes should be carried
out with suitable precautions such as the use of safety shields.
Tetrahydrofuran (THF), diethyl ether, and toluene were dried and
deoxygenated by continuous refluxing over sodium/benzophenone ketyl
under nitrogen or argon followed by distillation. Anhydrous chemicals,
dichloromethane, benzonitrile, 1,4-dioxane, and tetrahydropyran were
purchased from Aldrich Chemical Co. and were used without further
purification. All other nitriles were available from commercial sources
and were passed through a short plug of alumina under an atmosphere
2
3
aqueous layer was separated and extracted with Et O (20 mL). The
2
combined organic layers were washed with brine (30 mL), dried over
MgSO
evaporator. The product was purified by flash column chromatography.
ZrCl (1.05 g, 3.6 mmol) was placed
4
and filtered, and the solvents were removed using a rotary
Method B. In a drybox,18 Cp
2
2
in an oven-dried 100-mL Schlenk tube and the tube was sealed with a
glass stopper. The Schlenk tube was taken out of the drybox, connected
to the Schlenk line, and placed under vacuum (0.1 Torr) at RT for 20
min. The Schlenk tube was flushed with argon, the glass stopper was
replaced with a rubber septum, THF (18 mL) was added, and the
resulting clear solution was cooled to -78 °C. To this solution was
added t-BuLi (1.7 M solution in pentane, 2.12 mL, 3.6 mmol) dropwise
over a period of 3 min. The resulting dark red mixture was stirred at
-78 °C for 15 min, the cooling bath was removed, and the reaction
of argon immediately prior to use. Cp
2 2
ZrCl was a gift from Boulder
(18) Cp2ZrCl2 was kept in the drybox for convenience, as it is very
slightly hygroscopic. The use of a drybox is not necessary, but we
recommend that Cp2ZrCl2 be stored in the absence of moisture (e.g., in a
desiccator), particularly during humid periods of the year.1
2a.

Directed Meta Acylation of Aromatic Compounds
J. Am. Chem. Soc., Vol. 120, No. 36, 1998 9123
mixture was warmed to RT and then stirred at RT for 1 h to give a
5.22 (2 H, s), 3.54 (2 H, t, J ) 7 Hz), 3.49 (3 H, s), 2.96 (2 H, t, J )
7 Hz), 1.84-1.70 (4 H, m), 1.55-1.35 (4 H, m). 13C NMR (75 MHz,
solution of Cp Zr(i-Bu)Cl. This solution was cooled to -78 °C and
2
was added via cannula to a suspension of the ortho-lithiated 1a (3.0
CDCl
3
): δ 199.7, 157.4, 138.5, 129.6, 121.6, 121.0, 115.5, 94.5, 56.3,
mmol), prepared as shown in method A, which had been cooled to
45.2, 38.7, 32.6, 28.7, 26.9, 24.3. IR (film): 1687, 1586, 1486, 1444,
-
1
+
-
78 °C. The reaction mixture was stirred at -78 °C for 20 min,
gradually warmed to RT over a period of 40 min, and stirred at RT for
h. The nitrile (3.9-4.5 mmol, 1.3-1.5 equiv) was added, the septum
1254, 1154, 1081, 1007, 988 cm . MS (EI): m/z (%) 284/286 (M ,
6/2), 180 (100), 165 (55). Anal. Calcd for C15 : C, 63.26; H,
H21ClO
3
1
7.43. Found: C, 63.08; H, 7.32. Using method A, 7-chloroheptano-
nitrile (0.60 g, 4.1 mmol, 1.35 equiv) and 1a (0.40 mL, 3.0 mmol)
were converted to 0.75 g (86%) of 2b. Using method B, 7-chloro-
heptanonitrile (0.60 g, 4.1 mmol, 1.35 equiv) and 1a (0.40 mL, 3.0
mmol) were converted to 0.57 g (65%) of 2b.
was replaced with a Teflon screw valve, and the flask was sealed and
heated at 85 °C for 16-18 h. Upon cooling to RT, the reaction mixture
was concentrated in vacuo to half its original volume, diluted with THF
(10 mL), cooled to 0 °C, and treated with 1 N HCl (12 mL) [0.2 N
HCl (30 mL) for entry 10]. The remainder of the procedure is the
same as described in method A.
3-(Methoxymethoxy)phenyl 2-Thienyl Ketone (2c). Using method
B, 2-cyanothiophene (0.43 mL, 4.6 mmol, 1.5 equiv) and 1a (0.40 mL,
3.0 mmol) were converted to the title compound. Purification by flash
Note: the ortho lithiation of 1c (0.33 mL, 3.0 mmol) was run as
shown in method A except for the following modification: a mixture
chromatography (hexane:EtOAc ) 10:1 f 3:1) yielded 0.58 g (78%)
1
9
1
of Et
was used as solvent, and t-BuLi (1.7 M solution in pentane, 1.95 mL,
.3 mmol) was added at -30 °C. The resulting yellow suspension
2
O (5 mL) and anhydrous tetrahydropyran (0.88 mL, 9 mmol)
of a pale brown oil (2c). H NMR (300 MHz, CDCl
3
): δ 7.72 (1 H,
dd, J ) 5, 1 Hz), 7.67 (1 H, dd, J ) 4, 1 Hz), 7.53-7.48 (2 H, m),
7.41 (1 H, t, J ) 7.5 Hz), 7.28-7.24 (1 H, m), 7.16 (1 H, dd, J ) 5,
3
13
was stirred at -30 °C for 10 min and then at RT for 2 h (during
warming the suspension changed to a solution). The remainder of the
procedure is the same as described above.
3
4 Hz), 5.23 (2 H, s), 3.50 (3 H, s). C NMR (75 MHz, CDCl ): δ
187.6, 157.1, 143.5, 139.4, 134.9, 134.3, 129.5, 128.0, 122.7, 120.3,
116.8, 94.5, 56.3. IR (film) 1637, 1583, 1413, 1289, 1154, 1081, 1011
1
8
-1
+
Method C. In a drybox, Cp
2
ZrCl
2
(0.96 g, 3.3 mmol) was placed
cm . MS (EI): m/z (%) 248 (M , 65), 111 (100). Anal. Calcd for
13 12 3
C H O S: C, 62.88; H, 4.87. Found: C, 63.13; H, 4.67. Using
in an oven-dried 100-mL Schlenk tube and the tube was sealed with a
glass stopper. The Schlenk tube was taken out of the drybox, connected
to the Schlenk line, and placed under vacuum (0.1 Torr) at RT for 20
min. The Schlenk tube was flushed with argon, and the glass stopper
was replaced with a rubber septum. Toluene (20 mL) was added, and
to the resulting suspension was added t-BuMgCl (2.0 M solution in
method A, 2-cyanothiophene (0.43 mL, 4.6 mmol, 1.5 equiv) and 1a
(0.40 mL, 3.0 mmol) were converted to 0.61 g (81%) of 2c.
3-(Methoxymethoxy)phenyl 3-Pyridyl Ketone (2d). Using method
B, 3-cyanopyridine (0.44 g, 4.2 mmol, 1.4 equiv) and 1a (0.40 mL,
3.0 mmol) were converted to the title compound. Purification by flash
3
Et
2
O, 1.65 mL, 3.3 mmol) dropwise over a period of 5 min to give a
chromatography (hexane:EtOAc:Et N ) 100:100:1) yielded 0.62 g
1
mixture of an orange solution and a white precipitate. The reaction
(85%) of a pale brown oil (2d). H NMR (300 MHz, CDCl ): δ 9.01
3
1
5b
flask was covered with aluminum foil, and the mixture was stirred
at RT for 10 min and then at 50 °C for 1 h. The reaction mixture was
cooled to RT, and the aluminum foil was removed. Anhydrous 1,4-
dioxane (0.62 mL, 7.3 mmol) was added, and the mixture was stirred
at RT for 20 min. The reaction mixture was cooled to -78 °C and
was transferred via cannula to a suspension of the ortho-lithiated 1a
(1 H, d, J ) 1.5 Hz), 8.82 (1 H, dd, J ) 5, 1.5 Hz), 8.13 (1 H, dt, J
) 8, 2 Hz), 7.51-7.41 (4 H, m), 7.31 (1 H, dt, J ) 7, 2.5 Hz), 5.24 (2
13
H, s), 3.49 (3 H, s). C NMR (75 MHz, CDCl ): δ 194.4, 157.4,
3
152.9, 150.9, 138.0, 137.2, 133.1, 129.7, 123.7, 123.4, 121.2, 117.2,
-
1
94.4, 56.2. IR (film): 1664, 1583, 1285, 1154, 1081, 1015 cm . MS
+
(EI): m/z (%) 243 (M , 100), 106 (23). Anal. Calcd for C H NO :
1
4
13
3
(
3.0 mmol), prepared as shown in method A, which had been cooled
to -78 °C. The resultant reaction mixture was stirred at -78 °C for
0 min, gradually warmed to RT over a period of 40 min, and stirred
C, 69.12; H, 5.39. Found: C, 69.33; H, 5.43.
1-Cyclohexenyl 3-(Methoxymethoxy)phenyl Ketone (2e). Using
method C, 1-cyclohexenecarbonitrile (0.43 g, 4.0 mmol, 1.3 equiv) and
1a (0.40 mL, 3.0 mmol) were converted to the title compound.
Purification by flash chromatography (hexane:EtOAc ) 10:1) yielded
2
at RT for 40 min. The nitrile (3.6-4.5 mmol, 1.2-1.5 equiv) was
added, and the flask was sealed and heated at 85 °C for 19 h. The
reaction mixture was cooled to RT, concentrated in vacuo, and diluted
with THF (20 mL). The mixture was cooled to 0 °C and 1 N HCl (12
mL) [0.2 N HCl (20 mL) for entry 5] was added. The remainder of
the procedure is the same as described in method A.
1
0.48 g (65%) of a pale yellow oil (2e). H NMR (300 MHz, CDCl3):
δ 7.35-7.23 (3 H, m), 7.19-7.15 (1 H, m), 6.63-6.59 (1 H, m), 5.02
(2 H, s), 3.48 (3 H, s), 2.44-2.37 (2 H, m), 2.30-2.22 (2 H, m), 1.77-
1.63 (4H, m). 13C NMR (75 MHz, CDCl ): δ 197.9, 157.1, 144.5,
3
3
-(Methoxymethoxy)benzophenone (2a). Using method B, ben-
140.3, 138.7, 129.2, 122.8, 119.2, 116.9, 94.6, 56.2, 26.3, 24.1, 22.1,
zonitrile (0.40 mL, 3.9 mmol, 1.3 equiv) and 1a (0.40 mL, 3.0 mmol)
were converted to the title compound. Purification by flash chroma-
21.8. IR (film): 1644, 1583, 1482, 1436, 1278, 1258, 1154, 1081, 1015,
980 cm . MS (EI): m/z (%) 246 (M , 42), 214 (49), 201 (100), 185
-
1
+
tography (hexane:EtOAc ) 10:1) yielded 0.58 g (80%) of a pale orange
(53). Anal. Calcd for C H O : C, 73.15; H, 7.37. Found: C, 73.37;
15
18
3
1
oil (2a). H NMR (300 MHz, CDCl
3
): δ 7.81 (2 H, br d, J ) 7 Hz),
H, 7.63. Using method B, 1-cyclohexenecarbonitrile (0.43 g, 4.0 mmol,
1.3 equiv) and 1a (0.40 mL, 3.0 mmol) were converted to 0.36 g (48%)
of 2e.
7
7
.58 (1 H, br t, J ) 7.5 Hz), 7.50-7.44 (3 H, m), 7.42-7.35 (2 H, m),
13
.30-7.23 (1 H, m), 5.22 (2 H, s), 3.48 (3 H, s). C NMR (75 MHz,
): δ 196.1, 157.1, 138.9, 137.5, 132.4, 130.0, 129.3, 128.3, 123.8,
20.4, 117.4, 94.5, 56.2. IR (film): 1660, 1598, 1583, 1482, 1447,
CDCl
3
1
-[3-(Methoxymethoxy)phenyl]-5-hexen-1-one (2f). Using method
B, 5-cyano-1-pentene (0.40 g, 4.2 mmol, 1.4 equiv) and 1a (0.40 mL,
.0 mmol) were converted to the title compound. Purification by flash
chromatography (hexane:EtOAc ) 10:1) yielded 0.57 g (81%) of a
pale yellow oil (2f). 1H NMR (300 MHz, CDCl
): δ 7.62-7.57 (2 H,
1
1
-
1
316, 1282, 1227, 1200, 1154, 1081, 1015, 957, 726 cm . MS (EI):
3
+
m/z (%) 242 (M , 100), 212 (15), 135 (18), 105 (86). Anal. Calcd
14 3
for C15H O : C, 74.36; H, 5.82. Found: C, 74.58; H, 5.96. Using
3
method A, benzonitrile (0.46 mL, 4.5 mmol, 1.5 equiv) and 1a (0.40
mL, 3.0 mmol) were converted to 0.46 g (63%) of 2a. Using method
C, benzonitrile (0.46 mL, 4.5 mmol, 1.5 equiv) and 1a (0.40 mL, 3.0
mmol) were converted to 0.53 g (73%) of 2a.
m), 7.37 (1 H, t, J ) 8 Hz), 7.25-7.21 (1 H, m), 5.82 (1 H, ddt, J )
1
2
7, 10.5, 6.5 Hz), 5.22 (2 H, s), 5.22-4.98 (2 H, m), 3.49 (3 H, s),
.96 (2 H, t, J ) 7.5 Hz), 2.16 (2 H, q, J ) 7.5 Hz), 1.84 (2 H, quintet,
13
J ) 7.5 Hz). C NMR (75 MHz, CDCl
3
): δ 200.0, 157.6, 138.6, 138.2,
7-Chloro-1-[(3-methoxymethoxy)phenyl]heptan-1-one (2b). Us-
129.8, 121.8, 121.0, 115.6, 115.4, 94.5, 56.3, 38.0, 33.3, 23.4. IR (film):
ing method C, 7-chloroheptanonitrile (0.56 g, 3.6 mmol, 1.2 equiv)
and 1a (0.40 mL, 3.0 mmol) were converted to the title compound.
1687, 1640, 1586, 1486, 1444, 1409, 1251, 1154, 1081, 1004, 923 cm-1
.
+
MS (EI): m/z (%) 234 (M , 19), 180 (100), 165 (41). Anal. Calcd for
C H O : C, 71.77; H, 7.74. Found: C, 71.52; H, 7.63.
Purification by flash chromatography (hexane:EtOAc ) 15:1) yielded
14
18
3
1
0
.70 g (82%) of a colorless oil (2b). H NMR (300 MHz, CDCl
3
): δ
1
-[3-(Methoxyphenyl)]butan-1-one (2i). Using method B, buty-
7
.62-7.57 (2 H, m), 7.38 (1 H, t, J ) 7.5 Hz), 7.25-7.21 (1 H, m),
ronitrile (0.39 mL, 4.5 mmol, 1.5 equiv) and 1c (0.33 mL, 3.0 mmol)
were converted to the title compound. Purification by flash chroma-
(
19) Use of tetrahydropyran was reported to be effective for the ortho
tography (hexane:Et
2
O ) 15:1) yielded 0.43 g (81%) of a colorless oil
(2i). H NMR (300 MHz, CDCl ): δ 7.56-7.49 (2 H, m), 7.37 (1 H,
t, J ) 8 Hz), 7.10 (1 H, ddd, J ) 8, 2.5, 1 Hz), 3.86 (1 H, s), 2.94 (2
lithiation of phenol. See: (a) Posner, G. H.; Canella, K. A. J. Am. Chem.
Soc. 1985, 107, 2571. (b) Talley, J. J.; Evans, I. A. J. Org. Chem. 1984,
9, 5267.
1
3
4

9124 J. Am. Chem. Soc., Vol. 120, No. 36, 1998
Akai et al.
H, t, J ) 7.5 Hz), 1.77 (2 H, sextet, J ) 7.5 Hz), 1.00 (3 H, t, J ) 7.5
7.17 (5 H, m), 3.85-3.45 (2 H, m), 2.98 (2 H, t, J ) 7.5 Hz), 2.72 (2
H, t, J ) 7.5 Hz), 2.09 (2 H, quintet, J ) 7.5 Hz), 1.65-1.05 (12 H,
13
Hz). C NMR (75 MHz, CDCl
3
): δ 200.3, 159.9, 138.6, 129.6, 120.8,
1
1
19.4, 112.4, 55.5, 40.7, 18.0 14.0. IR (film): 1686, 1681, 1598, 1584,
m). 13C NMR (125 MHz, CDCl
3
): δ 199.6, 170.1, 141.7, 139.4, 137.3,
130.1, 129.0, 128.6, 128.5, 128.3, 126.1, 125.4, 51.2, 46.1, 37.9, 35.2,
-
1
+
256, 1046 cm . MS (EI): m/z (%) 178 (M , 19), 135 (100), 107
: C, 74.13; H, 7.92. Found: C, 74.16;
-
1
(27). Anal. Calcd for C11
H O
14 2
25.7, 20.8. IR (CHCl
3
) 1687, 1625, 1455, 1370, 1343 cm . MS (EI):
+
H, 7.69.
m/z (%) 351 (M , 12), 308 (15), 251 (100). Anal. Calcd for C23
H
29
-
Cyclopropyl 3-Methoxyphenyl Ketone (2j). Using method B,
cyclopropyl cyanide (0.33 mL, 4.5 mmol, 1.5 equiv) and 1c (0.33 mL,
2
NO : C, 78.59; H, 8.32. Found: C, 78.72; H, 8.48. Recrystallization
of the above product from EtOAc-hexane gave an off-white powder.
Mp: 91-92 °C.
Preparation of 2k from 1d by Method B. To an oven-dried 100-
mL round-bottomed resealable Schlenk flask fitted with a rubber septum
2
were added 1d (0.51 mL, 3.0 mmol) and Et O (15 mL), and the resulting
solution was cooled to -78 °C. To this solution was added n-BuLi
(1.6 M solution in hexane, 1.95 mL, 3.15 mmol) dropwise over a period
of 3 min. The resulting pale yellow clear solution was gradually
warmed to 0 °C over a period of 40 min with stirring and stirred at 0
°C for 3 h to give the ortho-lithiated 1d. The remainder of the
procedure is the same as described for method B for 1a [benzonitrile
(0.40 mL, 3.9 mmol, 1.3 equiv) was used], except the acid hydrolysis
of the crude reaction mixture was conducted as follows. After being
heated at 85 °C for 16 h, the reaction mixture was cooled to RT and
concentrated in vacuo to one-half its original volume. THF (20 mL)
was added, the resulting suspension was cooled to 0 °C, and 0.1 N
HCl (40 mL) was added. The reaction mixture was stirred at RT for
3
.0 mmol) were converted to the title compound. Purification by flash
chromatography (hexane:Et O ) 15:1 f 5:1) yielded 0.38 g (72%) of
a pale yellow oil (2j). H NMR (300 MHz, CDCl ): δ 7.63 (1 H, d, J
8 Hz), 7.51 (1 H, br s), 7.38 (1 H, t, J ) 8 Hz), 7.11 (1 H, dd, J )
, 2.5 Hz), 3.85 (3 H, s), 2.70-2.62 (1 H, m), 1.27-1.21 (2 H, m),
2
1
3
)
8
1
1
1
4
6
1
3
.07-1.01 (2 H, m). C NMR (75 MHz, CDCl
3
): δ 200.5, 159.9,
39.5, 129.6, 120.8, 119.3, 112.4, 55.5, 17.4, 11.9. IR (film): 1671,
597, 1582, 1261, 1035, 1008, 898 cm . MS (EI): m/z (%) 176 (M ,
1), 135 (100), 107 (26). Anal. Calcd for C11
.86. Found: C, 75.08; H, 7.07.
-
1
+
12 2
H O : C, 74.98; H,
General Procedure for the Preparation of 2g,h from 1b. Method
A. A 100-mL round-bottomed resealable Schlenk flask was charged
with 1b (615 mg, 3.0 mmol), sealed with a Teflon screw valve, and
evacuated (0.1 Torr) for 5 h at RT. The flask was flushed with argon,
2
the Teflon screw valve was replaced with a rubber septum, Et O (18
mL) and THF (2 mL) were added, and the resulting solution was cooled
to -78 °C. To this solution t-BuLi (1.7 M solution in pentane, 1.85
mL, 3.15 mmol) was added dropwise over a period of 3 min. The
resulting bright yellow suspension was stirred at -78 °C for 1.5 h. To
2.5 h and neutralized with saturated aqueous NaHCO
aqueous layer was separated and extracted with Et O (20 mL). The
combined organic layers were washed with brine (30 mL), dried over
MgSO , and filtered, and the solvents were removed using a rotary
3
(15 mL). The
2
2
this suspension was added a solution of Cp Zr(Me)Cl (0.90 g, 3.3 mmol)
4
in Et O (10 mL) and THF (2 mL) as described in method A for 1a.
2
evaporator. The residue was dissolved in THF (40 mL), and the
The reaction mixture was stirred at -78 °C for 20 min, gradually
warmed to RT over a period of 40 min, and stirred at RT for 1 h.
Toluene (20 mL) was added, and the mixture was concentrated in vacuo
to one-third of the original volume. Toluene (20 mL) and the nitrile
resulting solution was cooled to 0 °C. HCl (0.01 N, 40 mL) was added,
and the mixture was stirred at RT for 3 d. Saturated aqueous NaHCO
3
(20 mL) was added. Extractive workup, as shown immediately above,
followed by purification by flash chromatography (hexane:EtOAc )
1
(
3.6 mmol, 1.2 equiv) were added, the septum was replaced with a
Teflon screw valve, and the flask was sealed and heated at 120 °C for
9 h. After being cooled to RT, the reaction mixture was concentrated
5:1 f 2:1) yielded 0.47 g (56%) of a reddish orange gum (2k).
H
NMR (300 MHz, CDCl ): δ 8.32 (1 H, br t, J ) 2 Hz), 8.18 (1 H, dt,
3
3
J ) 8, 1.5 Hz), 7.90 (1 H, dt, J ) 8, 1.5 Hz), 7.83-7.79 (2 H, m),
7.63-7.47 (4 H, m), 4.13 (2 H, s), 1.39 (6 H, s). 13C NMR (125 MHz,
in vacuo and the resulting residue was suspended in THF (20 mL).
The suspension was cooled to 0 °C, and 1 N HCl (12 mL) was added,
followed by stirring at RT for 5 h. The reaction mixture was worked
up as described for the reaction of 1a (EtOAc was used as an extracting
solvent). The product was purified by flash column chromatography.
Method B. To a suspension of the ortho-lithiated 1b (3.0 mmol),
3
CDCl ): δ 196.2, 161.4, 138.1, 137.4, 132.9, 132.6, 132.1, 130.2, 129.7,
128.6, 79.4, 68.0, 28.6. IR (CHCl
986, 974 cm . MS (EI): m/z (%) 279 (M , 3), 264 (100), 208 (30),
3
): 1650, 1598, 1448, 1325, 1067,
-
1
+
105 (55). Anal. Calcd for C18
C, 77.55; H, 6.09.
2
H17NO : C, 77.40; H, 6.13. Found:
prepared as above, was added the solution of Cp
2
Zr(i-Bu)Cl (3.6 mmol)
General Procedure for the Preparation of 3 in Table 2 by Method
B. 1a or 1b (3.0 mmol) was ortho-lithiated and converted to the
corresponding zirconocene intermediate II as described in method B
for the preparation of 2. The nitrile (4.2-4.5 mmol, 1.4-1.5 equiv)
was added, and the reaction mixture was heated at 85 °C for 16 h.
After being cooled to RT, the reaction mixture was concentrated in
in THF as described in method B for 1a. The reaction mixture was
stirred at -78 °C for 20 min, gradually warmed to RT over a period
of 40 min, and stirred at RT for 1 h. Toluene (15 mL) was added, and
the mixture was concentrated in vacuo to one-third of the original
volume. Toluene (20 mL) and the nitrile (4.5 mmol, 1.5 equiv) were
added, and the flask was sealed and heated at 120 °C for 18 h. The
reminder of the procedure is the same as described for method A.
N,N-Diisopropyl-3-benzoylbenzamide (2g). Using method B,
benzonitrile (0.46 mL, 4.5 mmol, 1.5 equiv) and 1b (615 mg, 3.0 mmol)
were converted to the title compound. Purification by flash chroma-
vacuo, and anhydrous CH
A solution of I (1.90 g, 7.5 mmol) in THF (2 mL) and anhydrous
CH Cl (20 mL) was prepared in a 50-mL Schlenk tube. This was
added via cannula to the suspension, prepared above, which had been
cooled to 0 °C. Anhydrous CH Cl (5 mL) was added to rinse the
2 2
Cl (10 mL) was added to give a suspension.
2
2
2
2
2
tography (hexane:EtOAc ) 5:1 f 3:1) yielded 0.78 g (84%) of a yellow
Schlenk tube, and the washings were added to the reaction flask. The
reaction mixture was stirred at RT for 7 h, then poured into a 200-mL
round-bottomed flask. THF (30 mL) was used to rinse the reaction
residue into the round-bottomed flask. The reaction mixture was cooled
to 0 °C, 1 N HCl (12 mL) was added, and the reaction mixture was
stirred at RT for 14-40 h. Saturated aqueous Na SO (50 mL) was
2 3
added, and the mixture was stirred vigorously at RT for 30 min and
then was filtered through a pad of Celite. The filtrate was poured into
1
powder (2g). H NMR (300 MHz, CDCl
3
): δ 7.81 (3 H, d, J ) 8 Hz),
7
3
1
1
.73 (1 H, s), 7.61 (1 H, t, J ) 7.5 Hz), 7.56-7.47 (4 H, m), 3.95-
.42 (2 H, m), 1.72-1.00 (12 H, m). 1 C NMR (125 MHz, CDCl
96.3, 170.0, 139.2, 138.0, 137.3, 132.9, 130.4, 130.2, 129.7, 128.8,
28.6, 127.2, 51.3, 46.2, 20.9. IR (CHCl ): 1660, 1625, 1451, 1347
3
): δ
3
3
-
1
+
cm . MS (EI): m/z (%) 309 (M , 10), 266 (15), 209 (100). Anal.
Calcd for C20 : C, 77.64; H, 7.49. Found: C, 77.86; H, 7.33.
Recrystallization of the above product from Et O-hexane gave an off-
H23NO
2
2
3
a separatory funnel containing saturated aqueous NaHCO (50 mL),
and the aqueous layer was separated off and extracted with EtOAc.
The combined organic layers were washed successively with saturated
white powder. Mp: 83-85 °C. Using method A, benzonitrile (0.37
mL, 3.6 mmol, 1.2 equiv) and 1b (615 mg, 3.0 mmol) were converted
to 0.67 g (72%) of 2g.
2 3 4
aqueous Na SO (50 mL) and brine (50 mL), dried over MgSO , and
N,N-Diisopropyl-3-(4-phenylbutyryl)benzamide (2h). Using method
B, 4-phenylbutyronitrile (0.67 mL, 4.5 mmol, 1.5 equiv) and 1b (615
mg, 3.0 mmol) were converted to the title compound. Purification by
filtered. The solvents were removed using a rotary evaporator, and
the product was purified by flash column chromatography.
1-[2-Iodo-3-(methoxymethoxy)phenyl]-5-hexen-1-one (3a). Using
the general procedure, 5-cyano-1-pentene (0.40 g, 4.2 mmol, 1.4 equiv)
and 1a (0.40 mL, 3.0 mmol) were converted to the title compound. In
this example, the hydrolysis with HCl was carried out for 20 h.
flash chromatography (hexane:EtOAc ) 5:1 f 3:1) yielded 0.85 g
1
(
81%) of a brown powder (2h). H NMR (300 MHz, CDCl
3
): δ 7.92
(1 H, dt, J ) 7, 2 Hz), 7.87 (1 H, br s), 7.52-7.44 (2 H, m), 7.32-

Directed Meta Acylation of Aromatic Compounds
J. Am. Chem. Soc., Vol. 120, No. 36, 1998 9125
Purification by flash chromatography (hexane:EtOAc ) 10:1) yielded
1-(2-Iodo-3-methoxyphenyl)butan-1-one (3d). Using the general
procedure, butyronitrile (0.39 mL, 4.5 mmol, 1.5 equiv) and 1c (0.33
mL, 3.0 mmol) were converted to the title compound. In this example,
the hydrolysis with HCl was carried out for 40 h. Purification by flash
1
0
.50 g (46%) of a pale brown oil (3a). H NMR (300 MHz, CDCl
3
):
δ 7.31 (1 H, dd, J ) 8.5, 7.5 Hz), 7.10 (1 H, dd, J ) 8.5, 1.5 Hz), 6.88
(
1 H, dd, J ) 7.5, 1.5 Hz), 5.81 (1 H, ddt, J ) 17, 10.5, 6.5 Hz), 5.27
(
2
2 H, s), 5.08-4.97 (2 H, m), 3.52 (3 H, s), 2.88 (2 H, t, J ) 7 Hz),
chromatography (hexane:EtOAc ) 13:1 f 8:1) yielded 0.69 g (76%)
13
.17 (2 H, br q, J ) 7 Hz), 1.85 (2 H, quintet, J ) 7 Hz). C NMR
): δ 206.0, 156.4, 148.5, 138.1, 129.7, 120.4, 115.7,
15.6, 95.2, 84.4, 56.7, 42.0, 33.2, 23.1. IR (film): 1702, 1640, 1564,
1
of a reddish orange oil (3d). H NMR (300 MHz, CDCl
3
): δ 7.34 (1
(75 MHz, CDCl
3
H, t, J ) 8 Hz), 6.85 (1 H, d, J ) 8 Hz), 6.83 (1 H, d, J ) 8 Hz), 3.90
1
1
3
(
3 H, s), 2.85 (2 H, t, J ) 7.5 Hz), 1.75 (2 H, sextet, J ) 7.5 Hz), 1.01
-
1
458, 1421, 1257, 1203, 1154, 977, 921, 783 cm . MS (EI): m/z (%)
13
(3 H, t, J ) 7.5 Hz). C NMR (75 MHz, CDCl
3
): δ 206.4, 158.3,
+
60 (M , 15), 306 (100), 291 (38), 274 (14), 261 (18), 247 (53). Anal.
1
1
48.5, 129.8, 119.2, 111.8, 83.1, 56.8, 44.7, 17.6, 13.9. IR (film): 1702,
3
Calcd for C14H17IO : C, 46.68; H, 4.76. Found: C, 47.02; H, 4.60.
-
1
562, 1462, 1421, 1295, 1269, 1020, 1005, 780 cm . MS (EI): m/z
2-Iodo-3-(methoxymethoxy)phenyl 2-Thienyl Ketone (3b). Using
+
(%) 304 (M , 22), 261 (100), 218 (11), 203 (21). Anal. Calcd for
the general procedure, 2-cyanothiophene (0.43 mL, 4.5 mmol, 1.5 equiv)
and 1a (0.40 mL, 3.0 mmol) were converted to the title compound. In
this example, the hydrolysis with HCl was carried out for 17 h.
Purification by flash chromatography (hexane:EtOAc ) 5:1 f 3:1)
C
11
2
H13IO : C, 43.44; H, 4.31. Found: C, 43.55; H, 4.14.
1-(2-Iodo-3-methoxyphenyl)-4-phenylbutan-1-one (3e). Using the
general procedure, 4-phenylbutyronitrile (0.67 mL, 4.5 mmol, 1.5 equiv)
and 1c (0.33 mL, 3.0 mmol) were converted to the title compound. In
this example, the hydrolysis with HCl was carried out for 14 h.
Purification by flash chromatography (hexane:EtOAc ) 15:1 f 5:1)
1
yielded 0.86 g (76%) of a brown solid (3b). H NMR (300 MHz,
CDCl
3
): δ 7.51 (1 H, br d, J ) 5.5 Hz), 7.34 (1 H, br t, J ) 8 Hz),
7
.11 (1 H, br d, J ) 8 Hz), 7.02-6.94 (3 H, m), 5.29 (2 H, s), 3.54 (3
13
H, s). C NMR (75 MHz, CDCl
3
): δ 173.1, 156.5, 147.3, 143.2, 132.4,
1
yielded 0.69 g (61%) of an orange oil (3e). H NMR (300 MHz,
1
1
30.8, 129.7, 127.9, 121.6, 114.8, 95.2, 87.8, 56.7. IR (film): 3274,
3
CDCl ): δ 7.35-7.19 (6 H, m), 6.84 (1 H, dd, J ) 8, 1.5 Hz), 6.79 (1
-
1
594, 1562, 1460, 1360, 1143, 1086, 1049, 1004, 912, 874 cm . MS
H, dd, J ) 7.5, 1.5 Hz), 3.90 (3 H, s), 2.88 (2 H, t, J ) 7 Hz), 2.72 (2
+
(
EI): m/z (%) 373 (M - 1, 100), 342 (7), 214 (84), 186 (66), 110
13
H, t, J ) 7 Hz), 2.07 (2 H, quintet, J ) 7 Hz). C NMR (75 MHz,
CDCl ): δ 206.0, 158.4, 148.4, 141.7, 129.8, 128.6, 128.5, 126.1, 119.3,
11.9, 83.2, 56.8, 42.0, 35.2, 25.6. IR (film): 1702, 1602, 1583, 1562,
(
66). Anal. Calcd for C13
1.97; H, 3.16. Recrystallization of the above solid from EtOAc-
hexane gave a brown powder. Mp: 91-92 °C.
-Iodo-3-(methoxymethoxy)phenyl 3-Pyridyl Ketone (3c). Using
3
H11IO S: C, 41.73; H, 2.96. Found: C,
3
4
1
1
-1
462, 1417, 1296, 1266, 1018, 1001, 780, 748, 715 cm . MS (EI):
2
+
m/z (%) 380 (M , 0.6), 276 (100), 261 (41), 253 (27). Anal. Calcd
the general procedure, 3-cyanopyridine (0.44 g, 4.2 mmol, 1.4 equiv)
and 1a (0.40 mL, 3.0 mmol) were converted to the title compound. In
this example, the hydrolysis with HCl was carried out for 16 h.
2
for C17H17IO : C, 53.70; H, 4.51. Found: C, 53.71; H, 4.67.
Purification by flash chromatography (hexane:EtOAc:Et
3
N ) 300:200:
Acknowledgment. We thank the National Institutes of
Health for support of this work. We thank Pfizer, Novartis, and
Merck for additional funds. S.A. thanks the Ministry of
Education, Science, Sports, and Culture, Japan, for a scholarship.
We are grateful to Dr. Bryant Yang for help with the manuscript.
Boulder Scientific is thanked for a generous gift of zirconocene
dichloride.
1
1
) yielded 0.82 g (74%) of an orange oil (3c). H NMR (300 MHz,
CDCl ): δ 8.94 (1 H, dd, J ) 2.5, 1 Hz), 8.81 (1 H, dd, J ) 4.5, 1 Hz),
3
8
.17 (1 H, dt, J ) 8, 2 Hz), 7.47-7.39 (2 H, m), 7.21 (1 H, dd, J )
, 1 Hz), 6.95 (1 H, dd, J ) 7.5, 1.5 Hz), 5.31 (2 H, s), 3.54 (3 H, s).
8
13
C NMR (75 MHz, CDCl
3
): δ 226.4, 195.9, 156.5, 153.9, 151.9, 145.6,
): 1677,
137.3, 131.1, 129.9, 123.8, 121.7, 116.0, 95.2, 56.7. IR (CHCl
1
3
-
1
584, 1565, 1458, 1297, 1152, 1087, 1047, 1029, 1011, 954 cm . MS
+
(EI): m/z (%) 369 (M , 100), 370 (14). Anal. Calcd for C14
H12INO
3
:
C, 45.55 H, 3.28. Found: C, 45.75; H, 3.38.
JA981508T