An efficient approach to 3-bromo-6-chloro-phenanthrene-9,10-dione

Article abstract of DOI:10.1021/op8001678

A practical and efficient synthesis of 3-bromo-6-chloro-phenanthrene-9,10- dione was developed and demonstrated on a large scale. The synthetic approach involves six chemical steps and two isolations in 73% overall yield. The key transformations feature a

Full text of DOI:10.1021/op8001678

Organic Process Research & Development 2008, 12, 1269–1272
An Efficient Approach to 3-Bromo-6-chloro-phenanthrene-9,10-dione
John Limanto,* Benjamin T. Dorner, Frederick W. Hartner, and Lushi Tan
Merck & Co., Inc., Department of Process Research, Merck Research Laboratories, Rahway, New Jersey 07065, U.S.A.
Abstract:
Scheme 1. Retrosynthetic analysis of phenanthrenedione 1
A practical and efficient synthesis of 3-bromo-6-chloro-phenan-
threne-9,10-dione was developed and demonstrated on a large
scale. The synthetic approach involves six chemical steps and two
isolations in 73% overall yield. The key transformations feature
an anionic cyclization for generation of the phenanthrene ring,
followed by sequential tribromination and hydrolysis for the
incorporation of the bromo-diketone functionality.
of stilbene derivatives. While these methods certainly provide
access to phenanthrene-9,10-diones, the use of a large excess
of toxic and expensive metal oxidants is impractical and
undesirable for large-scale productions.
Introduction
Phenanthrene-9,10-diones (9,10-phenanthrenequinones) are
oxidative metabolites of polyaromatic hydrocarbons, possessing
interesting physical and chemical properties and potent biologi-
cal activities. While the highly toxic unsubstituted (parent)
We recently required an efficient route to differentially
substituted dihalophenanthrenequinone 1, which is a useful
building block for accessing other modularly derivatized
phenanthrenequinones or pharmaceutically important phenan-
1
2
compound has been detected in polluted air samples and used
as a redox-dependent receptor for the recognition of urea and
8
threneimidazoles. Our strategy involves an oxidative bromi-
3
amide groups, other functionalized derivatives have been
utilized to probe polyaromatic-induced carcinogenicity and
certain immunological-related diseases. Furthermore, some of
these quinoids have been studied as potential anticancer agents
and clinically administered as chemotherapeutic agents.
Several methods for the preparation of phenanthrene-9,10-
diones have been published and reviewed. The most common
nation of chlorophenanthrol 2, which would, in turn, be prepared
via an anionic cyclization of biaryl amide 3 (Scheme 1). This
latter intermediate could then be generated from readily acces-
sible boronic acid 4a via a Suzuki-Miyaura cross-coupling
reaction.
4
5
6
7
procedure involves oxidation of phenanthrenes, which are
generally prepared via a photochemical electrocyclic ring closure
Results and Discussion
Preparation of boronic acid 4a started with amidation of
p-chlorobenzoyl chloride with diethylamine under Schotten-
Baumann conditions to give the corresponding amide 5 in 99%
yield. Without further purification, the crude amide was then
subjected to a directed ortho metalation with LDA (1.4 equiv)
in dry DME in the presence of B(i-OPr)
*
Corresponding author. E-mail: john_limanto@merck.com.
(
1) (a) Rodriguez, C. E.; Kukuto, J. M.; Taguchi, K.; Froines, J.; Cho,
A. K. Chem.-Biol. Interact. 2005, 155, 97. (b) Shimada, H.; Oginuma,
M.; Hara, A.; Imamura, Y. Chem. Res. Toxicol. 2004, 17, 1145. (c)
Bindoli, A.; Rigobello, M. P.; Deeble, D. J. Free Radical Biol. Med.
9
1
992, 13, 391.
(
2) (a) Phillips, D. H. Mutat. Res. 1999, 443, 139. (b) Kumagai, Y.;
Arimoto, T.; Shinyashiki, M.; Shimojo, N.; Nakai, Y.; Yoshikawa,
T.; Sagai, M. Free Radical Biol. Med. 1997, 22, 479. (c) Bindoli, A.;
Rigobello, M. P.; Deeble, D. J. Free Radical Biol. Med. 1992, 13,
(1.6 equiv) at -30
3
°C to afford the corresponding boronic acid 4a in >97:1
regioselectivity. The regioselectivity on the borylation was
highly dependent on the reaction solvent, with DME being the
best (4a:4b ) >97:1) and heptane the worst (4a:4b ) 6:1)
3
91.
3) (a) Ge, Y.; Miller, L.; Quimet, T.; Smith, D. K. J. Org. Chem. 2000,
5, 8831. (b) Ge, Y.; Lilienthal, R. R.; Smith, D. K. J. Am. Chem.
(
(
6
Soc. 1996, 118, 3976.
(Scheme 2).
4) (a) Wang, Q.; Dub e´ , D.; Friesen, R. W.; LeRiche, T. G.; Bateman,
K. P.; Trimble, L.; Sanghara, J.; Pollex, R.; Ramachandran, C.; Gresser,
M. J.; Huang, Z. Biochemistry. 2004, 43, 4294. (b) Chapdelaine, M. J.;
Knappenberger, K.; Steelman, G.; Suchard, S.; Sygowski, L.; Urbanek,
R.; Veale, C. A. PCT Int. Appl. 42, 2001. (c) Urbanek, R. A.; Suchard,
S. J.; Steelman, G. B.; Knappenberger, K. S.; Sygowski, L. A.; Veale,
C. A.; Chapdelaine, M. J. J. Med. Chem. 2001, 44, 1777.
5) (a) Afrasiabi, Z.; Sinn, E.; Padhye, S.; Dutta, S.; Padhye, S.; Newton,
C.; Anson, C. E.; Powell, A. K. J. Inorg. Biochem. 2003, 95, 306. (b)
Nose, H.; Hara, O.; Yoshida, S.; Fukuyasu, S.; Nagasawa, M.; Takagi,
M. Jpn. Kokai Tokkyo Koho 1993, 4.
Subjection of the crude boronic acid 4a (1 equiv) to
2-iodotoluene (0.93 equiv) in the presence of 0.5 mol %
2 3 2 3
Pd(OAc) ,1 mol% PPh , and K CO (2.5 equiv) under biphasic
(
(8) For a general preparation of phenanthreneimidazoles from phenan-
threnediones, see: (a) Lantos, I. J. Org. Chem. 1975, 40, 1641. (b)
Sakaino, Y.; Kakisawa, H.; Kusumi, T. J. Chem. Soc., Perkin Trans.
1 1975, 2361. (c) McCoy, G.; Day, A. R. J. Am. Chem. Soc. 1943,
65, 2159. (d) Steck, E. A.; Day, A. R. J. Am. Chem. Soc. 1943, 65,
452.
(
(
6) (a) Lee, K. H. Med. Res. ReV. 1999, 19, 569. (b) Workman, P. Oncol.
Res. 1994, 6, 461.
7) 7 For a review, see: (a) Echavarren, A. M.; Porcel, S. Sci. Synth. 2006,
(9) For directed metalation-borylation of benzamide derivatives with
organolithium reagents, see for examples: (a) Sattelkau, T.; Qandil,
A. M.; Nichols, D. E. Synthesis 2001, 262. (b) Mccombie, S. W.;
Lin, S.-I.; Vice, S. F. Tetrahedron Lett. 1999, 40, 8767. (c) Sharp,
M. J.; Snieckus, V. Tetrahedron Lett. 1985, 26, 5997.
2
8, 507, and references thereinFor a report on TiCl4-mediated
intramolecular Friedel-Crafts cyclization of 1,2-dicarbonyls in
CH2Cl2, see: (b) Yoshikawa, N.; Doyle, A.; Tan, L.; Murry, J. A.;
Akao, A.; Kawasaki, M.; Sato, K. Org. Lett. 2007, 9, 4103.
1
0.1021/op8001678 CCC: $40.75

2008 American Chemical Society
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•
1269
Published on Web 09/13/2008

Scheme 2. Preparation of boronic acid 4a
Scheme 4. Oxidative bromination approach to
phenanthrenedione 1
10
Suzuki-Miyaura cross-coupling conditions afforded the cor-
responding biaryl amide 3 in 89% overall assay yield from the
11
12
starting amide 5. Subsequent anionic cyclization was per-
formed by subjecting 3 to lithium diethylamide (LEA) in DME
at -45 °C to cleanly generate chlorophenanthrol 2 in 95% assay
yield (Scheme 3). While lithium diisopropylamide (LDA) could
also be used to effect this transformation, under identical
the corresponding 6-chloro-3,10-dibromo-9-phenanthrol 7 in
2 3
75% yield, after aqueous Na SO workup and crystallization
from CHCl . Heating dibromophenanthrol 7 to 80 °C in
3
15
DMSO for 1 h promoted the oxidation event to afford the
desired phenanthrenedione 1 in 93% isolated yield (Scheme 4).
Further investigation of the bromination step revealed that
2 2
reaction conditions, a transamidation event (Et N f i-Pr N)
was observed to subsequently afford somewhat less effective
cyclization (90% vs 95% assay yield). Crystallization of the
crude product from toluene/methylcyclohexane afforded pure
2 2 2
when using 2.5-3 mol equiv of Br in either AcOH, CH Cl ,
or DME, the only entity observed by NMR spectroscopy at
2
in 85% isolated yield or in 76% overall yield from amide 5.
16
the end of reaction was the tribromoketone 6. Upon workup
with aqueous Na SO or during purification attempts by
Scheme 3. Synthesis of phenanthrol 2
2
3
crystallization from acetone, this tribromo intermediate under-
went a reduction to yield the corresponding dibromophenanthrol
7. These results led us to investigate the possibility of directly
hydrolyzing the R,R-dibromoketone functionality in 6 to the
corresponding diketone. Gratifyingly, subjection of the crude
bromination reaction mixture in DME to a 16 wt % aqueous
2 3
Na CO (3 equiv) or to a 50 wt % aqueous NaOH (2 equiv) at
5
9
5 °C for 12 h cleanly afforded the corresponding phenanthrene-
,10-dione 1. After most of the DME was distilled away, the
compound directly crystallized from the reaction mixture to
afford pure 1 in 97% isolated yield.
Conclusion
With 6-chloro-9-phenanthrol 2 in hand, subsequent bromi-
nation at the 3-position and oxidation at the 10-position of the
phenanthrene ring was investigated. While monobromination
of 9-phenanthrol at the 10-position has been established,
selective monobromination at the 3-position was less well-
known. On the other hand, dibromination at both the 3- and
In summary, an efficient and practical approach to differ-
entially substituted dihalophenanthrene-9,10-dione 1 has been
identified and demonstrated on few hundred grams scale.
Furthermore, the current process and procedures have been
sufficiently developed in order to support potential pilot-plant
activities or other multikilogram campaigns. The titled com-
pound offers modular derivatization of the halide groups to
provide rapid entries to other pharmaceutically and biologically
important phenanthrodione or phenanthroimidazole derivatives.
The key transformation involves a sequential bromination of
13
1
0-position of 9-phenanthrol using Br
2
in CS
been reported. In our hands, treatment of 2 with Br
equiv) in either AcOH or CH Cl at 30 °C for 24-36 h afforded
2
has previously
14
2
(2.5-3.0
2
2
(10) For a review on metal-catalyzed aryl-aryl bond-forming transforma-
tions, see: (a) Hassan, J.; S e´ vignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. ReV. 2002, 102, 1359. (b) For a review on Suzuki-Miyaura
cross coupling reactions in organic synthesis, see Kotha, S.; Lahiri,
K.; Kashinath, D. Tetrahedron 2002, 58, 9633. For a review on directed
ortho metalation-cross coupling sequence, see: (c) Anctil, E. J.-G.;
Snieckus, V. J. Organomet. Chem. 2002, 653, 150.
chlorophenanthrol 2 with Br
hydrolysis of the resulting tribromoketone intermediate 6 with
Na CO in DME/H O to afford the titled compound in 97%
2
in DME, followed by in situ
2
3
2
isolated yield. The current route, involving six chemical steps
(
11) Due to the fact that 2-iodotoluene is the limiting reagent (0.93 equiv),
the maximum theoretical yield for the Suzuki-Miyaura cross-coupling
reaction is 93%.
(15) For similar oxidation conditions of bromo-dihydrodibenzothiepinone,
see: Ueda, I. Bull. Chem. Soc. Jpn. 1975, 48, 2306.
(
12) (a) Fu, J.-m.; Sharp, M. J.; Snieckus, V. Tetrahedron Lett. 1988, 29,
(16) Reaction monitoring by reverse-phase HPLC (MeCN/H2O eluent)
indicated fast initial bromination in AcOH or CH2Cl2 at 20-25 °C,
consuming all starting material within 15 min, followed by subsequent
slower di- and tribromination events, which took over 24-36 h at 30
°C. A faster reaction time was obtained when performing the
tribromination in DME at 45 °C, in which a full conversion was
observed within 3-4 h.
5
459. (b) Fu, J.-m.; Snieckus, V Can. J. Chem. 2000, 78, 905.
(
13) (a) Pe n˜ a, D.; P e´ rez, D.; Guiti a´ n, E.; Castedo, L. J. Org. Chem. 2000,
5, 6944. (b) Koreeda, M.; Gopalaswamy, R.; Yang, J.; Tuinman, R. J.
6
Tetrahedron Lett. 1996, 37, 8267.
(
14) (a) Ota, E.; Shintani, H. Nippon Kagaku Kaishi 1987, 4, 762. (b)
Schmidt, J.; Spoun, O. Chem. Ber. 1910, 43, 1802.
1
270
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and two isolation steps, allows for the preparation of 1 in 73%
overall yield, starting from inexpensive p-chlorobenzoyl chloride.
suspension, which was used directly in the next step without
further purification. HPLC t : 2.29 min.
R
N,N′-Diethyl-4-chloro-2-(o-tolyl)benzamide (3). The previ-
ously quenched suspension of crude boronic acid 4a (1.16 mol,
Experimental Section
General Methods. All reagents and HPLC-grade or anhy-
drous solvents are purchased from commercial suppliers and
used directly without further purification or treatment. MP-TMT
1
(
.0 equiv) in DME/THF/H
1.18 L, total of ∼4.5 vol or 2 M of K
DME (300 mL, total of ∼6 vol). Successively, solid K
401 g, 2.9 mol, 2.5 equiv), 2-iodotoluene (240 g, 1.08 mol,
.93 equiv), PPh (3.04 g, 11.6 mmol, 0.01 equiv), and
Pd(OAc) (1.3 g, 5.80 mmol, 0.005 equiv) were added, and
2
O was diluted with degassed water
CO ) and additional
CO
2
3
2
3
(
trimercaptotriazine) resins were obtained from Biotage (previ-
ously Argonaut Laboratories) and Ecosorb C-941 from Graver
Technologies. All reactions were conducted under N atmo-
(
0
3
2
2
sphere. Concentration in Vacuo refers to removal of the solvent
using a rotary evaporator at reduced pressure (10-20 Torr).
High performance liquid chromatography (HPLC) analysis was
performed using Waters Xbridge C18 (250 mm × 4.6 mm I.D.)
column under the following mobile phase: 20% MeCN (A):
the resulting biphasic suspension was degassed several times
at RT. The reaction mixture was then heated to 70 °C and aged
for 8 h, at which point a complete consumption of 2-iodotoluene
was observed. At this point, the slurry mixture was then
concentrated to about one-third of its volume, diluted with 8
mL/g of MTBE (2.4 L), and filtered. The resulting biphasic
layer was separated, and the organic layer was washed with
3 4 2
80% 0.1% v H PO /H O (B) ramped to 90% A:10% B over
1
7 min, 1.5 mL/min flow rate, 210 nm, 40 °C column
1
13
temperature. H and C NMR spectra were all measured on
either a 400 or 500 MHz instrument. Infrared (IR) spectra were
reported in wavenumbers and measured on an FT-IR spec-
trometer. Melting points were uncorrected. Elemental analyses
were performed by an external specialist.
1
5% aqueous NaCl (250 mL), followed by brine (250 mL) and
concentrated to dryness to give 3 as yellow oil (311.5 g assay,
9% yield). The material was then used directly in the next
8
1
step without further purification. HPLC t
500 MHz, CDCl , ppm): δ 7.40-7.10 (7H, series of m),
.91-2.60 (4H, br m), 2.23 (3H, br s), 0.91 (3H, br m), 0.69
R
: 6.67 min. H NMR
(
3
3
N,N-Diethyl-p-chlorobenzamide 5. To a solution of Et
131 mL, 1.25 mol, 1.1 equiv) in MTBE (1.6 L) was added
solid Na CO (72.3 g, 0.68 mol, 0.6 equiv), followed by H
600 mL) to give a clear biphasic layer, which was then cooled
2
NH
(
13
(
1
1
3H, br t, J ) 7.0 Hz). C NMR (125 MHz, CDCl
3
, ppm): δ
69.2, 140.3 (br), 137.9 (br), 135.7, 135.3, 134.1, 132.2, 130.3,
28.8, 128.2, 127.9, 127.6, 125.5, 42.5, 38.1, 20.3, 13.8, 11.8.
-Chloro-phenanthren-9-ol (2). To a precooled solution of
the crude amide 3 (311 g, 1.03 mol, 1 equiv) in 7 mL/g DME
2.18 L) at -45 °C was added a freshly prepared 1.44 M
solution of LiNEt (0.93 L, 1.34 mol, 1.3 equiv) in THF (1.3
equiv of HNEt in 1 vol THF, 1.31 equiv of 2.5 M n-BuLi in
2
3
2
O
(
to 15 °C. Neat p-chlorobenzoyl chloride (200 g, 1.14 mol, 1.0
equiv) was then added over 30 min, while maintaining the
temperature below 25 °C. At the end of addition, the mixture
was aged for another 30 min, and the aqueous layer was
separated. The organic layer was then washed with brine and
concentrated to dryness to give colorless oil (238 g, 99.9 wt
6
(
2
2
hexanes) over 25 min. The resulting brown solution was aged
at -45 °C for 2 h, at which >99.5% conversion of starting
material was observed by HPLC. The reaction was then
quenched by a slow addition of 6 N HCl (0.69 L, 4.12 mol, 4
equiv), while maintaining the temperature between 0-5 °C (pH
of solution was 2-3). The resulting orange solution was then
concentrated to about one-third of its volume and then diluted
with MTBE (2.18 L, 7 vol wrt SM). The organic layer was
separated and was washed with 15 wt % aqueous NaCl (2 ×
%
, 98.7% assay yield), which was used directly in the next
1
step without further purification. HPLC t
500 MHz, CDCl , ppm): δ 7.35 (2H, dm, J ) 8.4 Hz), 7.30
2H, dm, J ) 8.4 Hz), 3.51 (2H, br m), 3.23 (2H, br m), 1.14
R
: 3.93 min. H NMR
(
(
3
13
(6H, br m). C NMR (125 MHz, CDCl
3
, ppm): δ 170.2, 135.7,
1
3
1
7
35.2, 128.6, 128.1, 43.4, 39.5, 14.2, 13.0. IR (NaCl thin film):
555, 3486, 3048, 2974, 2936, 2876, 1632, 1597, 1463, 1426,
382, 1364, 1316, 1288, 1220, 1194, 1096, 1016, 875, 838,
-1
58, 562, 503 cm . Anal. Calcd for C11H14ClNO: C, 62,41;
300 mL) and then brine (300 mL). The crude organic solution
H, 6.67; Cl, 16.75. Found: C, 62.81; H, 6.73; Cl, 16.76.
was then treated with 1% MP-TMT resin and 1% Ecosorb
C-941, aged at RT over 1.5 h and then filtered through a plug
of SiO gel (30 wt % wrt SM, 93 g). The filtrate was then
2
assayed to contain 225 g of the desired product (95% yield).
The organic layer was then concentrated, and the solvent was
3
switched to PhCH at 8 vol (wrt to product assay, 1.8 L), while
maintaining the temperature above 70 °C during the solvent
switch. At the end of the solvent switch, the slurry was further
concentrated to about 6 vol wrt product (1.3 L) and heated to
reflux to give a homogeneous brown solution. Crystallization
was then initated by cooling the solution to 95-98 °C, and the
slurry was further cooled to 70 °C and then treated with
methylcyclohexane (8 vol, 1.8 L) over 1 h at this temperature.
The needle-thread-like slurry was then cooled to RT over 30
min, aged at RT for 2 h and then at -10 °C for another 2 h.
The slurry was then filtered, and the wetcake was washed with
a cold 1:4 mixture of toluene/methyl cyclohexane, followed by
Aryl Boronic Acid 4a. To a solution of crude amide 5
(245.7 g, 1.16 mol, 1.0 equiv) in 6 mL/g dry DME (1.47 L)
was added neat triisopropyl borate (356 g, 1.86 mol, 1.6 equiv),
and the resulting solution was cooled to -35 °C. A freshly
prepared solution of LDA (1.62 mol, 1.4 equiv) in THF was
then added dropwise over 45 min, while maintaining the internal
temperature between -35 to -25 °C. [LDA was generated
according to a typical procedure by treatment of N,N′-diiso-
propylamine (231 mL, 1.62 mol, 1.4 equiv) in THF (237 mL)
with 2.5 M solution of n-butyllithium in hexanes (654 mL, 1.64
mol, 1.41 equiv), maintaining the temperature below 0 °C during
the addition.] At the end of addition, the reaction mixture was
aged for additional 15 min at -25 °C, at which point all starting
material has been consumed to give the corresponding boronic
acid in >97:1 regioselectivity as analyzed by both HPLC and
NMR spectroscopy. The mixture was then slowly quenched
with 150 mL of H O at -10 to 0 °C to give a yellow
2
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•
1271

drying under a constant flow of N
solid contained 200 g of the desired product (100 wt %, 85%
2
for 1 day at RT. The dry
then concentrated at 35-40 °C (35-40 Torr) to about a third
of its volume (∼1.2 L, 8 vol) and then solvent switched to give
yield from 3 or 76% from 5). Mp: 197-198 °C. HPLC t
R
: 6.38
a 9:1 mixture of H O/DME. The slurry was filtered at this
2
1
min. H NMR (500 MHz, d
6
-acetone, ppm): δ 9.35 (1H, s),
temperature, and the wetcake was successively washed with
8.78 (1H, d, J ) 2.1 Hz), 8.68 (1H, d, J ) 8.5 Hz), 8.38 (1H,
4:1 H O/DME (5 vol) and H O (10 vol) and then dried under
2
2
d, J ) 8.8 Hz), 7.74 (1H, dd, J ) 8.0, 1.2 Hz), 7.65 (1H, dd,
a constant flow of N at 30 °C. Pure 1 was obtained in 97%
2
13
J ) 8.8, 2.1 Hz), 7.55 (1H, m), 7.49 (1H, m), 7.18 (1H, s). C
NMR (125 MHz, d -acetone, ppm): δ 150.7, 134.0, 132.9,
27.6, 126.7, 126.4, 125.2, 124.8, 124.7, 124.1, 122.8, 122.2,
05.7. IR (KBr pellet): 3307,1677, 1581, 1470, 1392, 1271,
yield as a yellow solid. Mp: 282-285 °C. HPLC t
R
: 8.56 min.
-DMSO, ppm): δ 8.65 (1H, d, J ) 1.99
Hz), 8.53 (1H, d, J ) 1.99 Hz), 8.02 (1H, d, J ) 8.34 Hz),
1
6
H NMR (500 MHz, d
6
1
1
1
7
.93 (1H, d, J ) 8.34 Hz), 7.77 (1H, dd, J ) 8.34, 1.99 Hz),
-1
223, 1080, 918, 895, 821 cm . Anal. Calcd for C14
9
H ClO:
13
6
7.62 (1H, dd, J ) 8.34, 1.99 Hz). C NMR (125 MHz, d -
C, 73.53; H, 3.97; Cl, 15.50. Found: C, 73.08; H, 3.76; Cl,
5.57.
-Bromo-6-chloro-phenanthrene-9,10-dione (1). To a so-
lution of 2 (150 g, 656 mmol, 1 equiv) in dry DME (15 vol,
.25 L) at 10 °C was added Br (118 mL, 2296 mmol, 3.5 equiv)
DMSO, ppm): δ 177.6, 177.4, 140.5, 135.9, 135.9, 132.7, 130.8,
30.8, 130.7, 130.4, 129.9, 129.7, 127.7, 124.9. IR (NaCl thin
1
1
3
film): 1677, 1581, 1470, 1392, 1271, 1223, 1080, 918, 895,
-1
8
21 cm . HRMS (TOF) Calcd for [C14
H
H
6
BrClO
2
+H]: 320.9318.
: C, 52.29; H,
2
2
Found: 320.9324. Anal. Calcd for C14
6
BrClO
2
over 30 min, at which a 20 °C exotherm was observed during
the addition. The resulting suspension was then heated to 45
1.88. Found: C, 52.43; H, 1.65.
°
C and aged for 4 h to give a clear, red solution, at which a
complete conversion of the starting material to tribromoketone
intermediate 6 was obtained. A solution of Na SO (24.8 g,
31 mmol, 0.2 equiv) in 100 mL of H O was then added,
followed by a solution of Na CO (209 g, 1968 mmol, 3 equiv)
in 900 mL of H O over 30 min. The resulting suspension was
warmed to 55 °C and aged for 6 h, at which a complete
hydrolysis was obtained (additional of H O might be necessary
to redissolve precipitated Na CO ). The reaction mixture was
Acknowledgment
We are grateful to Mr. Bob Reamer and Ms. Lisa DiMichele
for their assistance with the NMR interpretations and structural
confirmations.
2
3
1
2
2
3
2
Received for review July 18, 2008.
OP8001678
2
2
3
1
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Vol. 12, No. 6, 2008 / Organic Process Research & Development