Selective monoarylation of benzenediols via dianion intermediates

Article abstract of DOI:10.1080/00397910701648769

Application of the SNAr reaction on benzenediols with arylfluorides revealed an enhancement in monosubstitution selectivity over bis substitution when excess base was used. This trend was studied using symmetrical and nonsymmetrical benzenediols with vari

Full text of DOI:10.1080/00397910701648769

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Selective Monoarylation of Benzenediols via
Dianion Intermediates
Chaoyu Xie a , Kevin A. Sullivan a , Michael E. Laurila a , David N. Mitchell a
& Y. John Pu a
a Lilly Research Laboratories, Chemical Product Research and Development,
Indianapolis, Indiana, USA
Published online: 25 Jan 2008.
To cite this article: Chaoyu Xie , Kevin A. Sullivan , Michael E. Laurila , David N. Mitchell & Y. John Pu
(2007) Selective Monoarylation of Benzenediols via Dianion Intermediates, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:1, 21-32, DOI:
10.1080/00397910701648769
To link to this article: http://dx.doi.org/10.1080/00397910701648769
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Synthetic Communicationsw, 38: 21–32, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701648769
Selective Monoarylation of Benzenediols via
Dianion Intermediates
Chaoyu Xie, Kevin A. Sullivan, Michael E. Laurila, David N.
Mitchell, and Y. John Pu
Lilly Research Laboratories, Chemical Product Research and
Development, Indianapolis, Indiana, USA
Abstract: Application of the SNAr reaction on benzenediols with arylfluorides
revealed an enhancement in monosubstitution selectivity over bis substitution when
excess base was used. This trend was studied using symmetrical and nonsymmetrical
benzenediols with various levels of steric hindrance. The effect of various bases was
examined. A 100% monoselectivity was achieved in the presence of 2.5 equiv. of
Cs2CO3. The methodology was employed in the synthesis of an important pharma-
ceutical product, 1, an arylether.
Keywords: SNAr, benzenediol, selective monoarylation, resorcinal
INTRODUCTION
The efficient preparation of monoarylethers of hydroquinone and resorcinols is
important in the search for bioactive small molecules and advancing these
molecules into clinical development.[1] In the course of an ongoing project,
we required an expedient and practical method that would be readily
adaptable to kilogram scales to produce monoarylated resorcinol derivatives,
such as 2. However, the monoarylation of resorcinol represents a problem
for which no generally satisfactory procedure has yet been documented.
Traditional methods of differentiating the phenol moieties on hydro-
quinone or resorcinols have numerous drawbacks.[2] One tends to achieve
Received in the USA June 1, 2007
Address correspondence to Chaoyu Xie, Lilly Research Laboratories, Chemical
Product Research and Development, Indianapolis, IN 46285, USA. E-mail: xiech@
lilly.com
21

22
C. Xie et al.
Scheme 1.
the selectivity of mono- vs. bis arylation via careful control of the stoichi-
ometry of base and arylating agents. However, arylation of the monoanion
with 1 equiv. of arylating agent generally gave poor selectivity.[1b,3] Adding
a large excess of benzenediol may minimize the bisarylation,[4] but it is not
economical and increases the burden of purification.
Further literature surveys revealed several other procedures for the prep-
aration of monoarylated bisphenols, such as the condensation of haloaniline
with phenol, followed by diazotization to afford the phenol derivative;[5]
coupling of 3-iodophenylbenzyl ether with phenol, followed by deprotection
of benzyl group;[6a] Bayer–Villager oxidation of phenoxybenzaldehyde;
and SNAr reactions via halobenzene–FeCp complexes.[6b] Herein, we report
a general and practical method for the selective arylation of hydroquinones
and resorcinols.
RESULTS AND DISCUSSION
Our initial work was inspired by Newman and Cella’s studies[7] on monoalk-
ylation of hydroquinone. By using the disodium salt of hydroquinone,
Newman and Cella achieved moderate to good yields. The scope of their
research was limited to hydroquinone alkylations, and the application was
limited. We therefore intended to explore the dianion approach to produce a
general, high-yielding, and selective synthesis of monoarylated benzenediols
via the SNAr reaction with arylfluoride.
Investigation of the monoselective arylation was first carried out using
hydroquinone (5) and 4-fluoronitrobenzene (6) (Table 1). The dianion
sodium salt of hydroquinone has relatively poor solubility in most organic
solvents,[7] but it is soluble in the water–organic mix solvents. Aqueous
5 N NaOH solution in dimethyl sulfoxide (DMSO) was then chosen to accom-
modate the solubilities of both the dianion sodium salt of hydroquinone and
organic substrates. 4-Fluoronitrobenzene was used as the electrophile in the
initial studies mainly because of its strong electrophilicity in SNAr reactions
and ease of product isolation by direct crystallization from reaction mixtures.
Comparison of entries 1a–4a or 1b–4b (Table 1) clearly show the
enhanced yields and mono/bis selectivities when excess NaOH was used.
The mono/bis ratio increased from 1:1 to 6:1 when the NaOH amount was

Monoarylation of Benzenediols
23
Table 1. Effect of base stoichiometry and addition rate
5 N NaOH
(equiv.)
Addition
ratea
Yieldb
(%)
Entry
Mono:bis
1a
1b
2a
2b
3a
3b
4a
4b
1.0
1.0
2.0
2.0
2.5
2.5
3.0
3.0
One portion
Slowly
31
36
62
77
69
86
72
87
1:1
1:1
One portion
Slowly
3:1
8:1
One portion
Slowly
5:1
17:1
6:1
One portion
Slowly
22:1
aEntries 1a–4a: Electrophile added at once to rt solution of nucleophile, then heated
to 508C.
bEntries 1b–4b: Electrophile added slowly (over 30–60 min) to 508C solution of
nucleophile.
increased from 1.0 equiv. to 3.0 equiv. (entries 1a and 4a). Slow addition
(30–60 min) of the electrophile to the preformed hydroquinone dianion
solution was crucial to minimize the bis-product formation. The mono/bis
ratio was elevated from 6:1 to 22:1 when applying the slow addition
method in the case using 3 equiv. of 5 N NaOH (entries 4a, 4b).
The relationship of the yield increase of 7 vs. NaOH equiv. is illustrated in
Fig. 1. Greater yield increase occurred when raising the NaOH amount from
1.0 to 2.0 equiv., but insignificant change was observed for the base equiv.
between 2.5 and 3.0. We then chose 2.5 equiv., which was applied in all sub-
sequent studies.
The mechanistic rational for excess base (.2 equiv.) was proposed on the
basis of several literature precedents.[7,8] The aromatic substitution reaction
rate of hydroquinone dianion with 6 (k1) is greater than the rate of
monoanion (k2) (Scheme 2), and their relative reactivity determined the
mono/bis selectivity. In detail, Breslow et al.[8] observed that the initial
reaction rate of hydroquinone dianion alkylation was faster than that of the
phenoxide anion.
To generalize the methodology with application to our ongoing project,
we expanded the reaction scope to different benzenediols. Table 2 illustrates
the results of resorcinol derivatives (4) with 4-fluoronitrobenzene (6). In
general, monoselectivity on hydroquinone (Table 1, entry 4) is better than

24
C. Xie et al.
Figure 1. Yield vs. base stoichiometry.
Scheme 2.
that on resorcinol derivatives, which could be attributed to the pKa differences
of hydroquinone and resorcinol. ACD pKa prediction: (a) hydroquinone; pKa
1 ¼ 9.68; pKa 2 ¼ 11.55; d pKa ¼ 1.87; (b) resorcinol: pKa 1 ¼ 8.91; pKa
2 ¼ 10.38; d pKa ¼ 1.47. Interestingly, when using 1.0 equiv. of NaOH, the
mono/bis ratios for all resorcinol derivatives were the same (1:2), favoring
the bis arylation, but the trend with excess of NaOH remained the same as
that of hydroquinone (mono-product yields increased 40–50% when raising
the base amount from 1.0 to 2.5 equiv.).
We have not extended our efforts to investigate a wide range of
electrophiles. Besides 4-fluoronitrobenzene (6), we have only examined
2-fluoronitrobenzene, 3-bromo-4-fluorobenzotrifluoride, 2-fluoro-5-nitroben-
zene, 4-fluorobenzotrifluororide, and 3-methyl-4-fluoronitrobenzene with
resorcinol. All of these examples provided similar results to those of 6 (see
the experimental section).
Base Screen
Aqueous NaOH solution is one of the cheapest bases available and is very easy
to handle. However, the question is whether similar monoselectivities could
be effected with other bases. With this in mind, we investigated Cs2CO3,
K2CO3, and NaH in DMSO (Table 3).
The reactions using Cs2CO3 and K2CO3 in dry DMSO with prolonged
stirring (entries 8c and 10c) caught our attention. Evidently, the initial rate

Monoarylation of Benzenediols
25
Table 2. Resorcinol derivatives as nucleophiles
5 N NaOH
(equiv.)
Yield
(mono)
Entry
Nucleophile
Mono:bis
5a
5b
6a
6b
7a
7b
Resorcinol
Resorcinol
2-Me Resorcinol
2-Me Resorcinol
Orcinol
1.0
2.5
1.0
2.5
1.0
2.5
19%
63%
19%
72%
27%
77%
1:2
5:1
1:2
7:1
1:2
5:1
Orcinol
of the bis-product formation is equal to that of the mono-product, resulting
in a moderate ratio of 1:1 (entries 8b and 10b). However, the bis-products
slowly underwent nucleophilic cleavage[9] with resorcinol dianion to
provide high yields of desired mono-products (Scheme 3). The nucleophilic
cleavage reaction only occurred in the dry solvent system. Both K2CO3
and Cs2CO3 in aqueous DMSO system exhibited no selectivities (entries 8d
and 10d).
Asymmetrical Benzenediol Nucleophiles
Hydroquinone, resorcinol, 2-substituted resorcinols, and 5-substituted
resorcinols are symmetrical benzenediols. We then explored several
unsymmetrical hydroquinone and resorcinol derivatives under the same
reaction conditions. Experiments in Table 4 demonstrated that high selectivity
of mono vs. bis was achieved as expected. The regioselectivity of both mono-
products was determined by the steric bulkiness of the substituent. For
example, changes of the alkyl group from methyl to ethyl to tert-butyl
improved the regioisomer ratios from 1:1.5 to 1:4.1. 2,5-Dihydroxyacetophe-
none was the only substrate with a substituent other than an alkyl group (entry
14). Both regio- and monoselectivities were excellent, although the yield was
moderate.

26
C. Xie et al.
Table 3. Base screen on resorcinol with 4-fluoronitrobenzenea
Entry
Base
Base equiv.
Yield (mono)
Mono:bis
5a
5b
5 N NaOH
5 N NaOH
Cs2CO3
1.0
2.5
1.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
19%
63%
1:2
5:1
8a
8b
12%
1:4
1:1
b
Cs2CO3
36% at 2 h
93%
33%
8c
8d
Cs2CO3 (24 h)
Cs2CO3 (aq.)
NaH
.100:1
1:1
6:1
9b
87%
39%
10b
10c
10d
K2CO3 (5 h)
K2CO3 (7 days)
K2CO3 (aq.)
1:1
81%
32%
12:1
1:1
aAll reactions were worked up after 24 h unless indicated.
bOnly acquired data at 5 min, 15 min, 1.5 h, and 2 h. All showed 1:1 ratio, but
different conversion. The next data point is at 19 h, resulting in a ratio of 61:1.
Scheme 3.
Table 4. Asymmetrical benzenediol nucleophiles
NaOH
(equiv.)
Mono 1/
mono 2
Mono total/
bis
Entry
Nucleophile
11a
11b
12a
12b
13
1.0
2.5
1.0
2.5
2.5
1:1.5
1:1
1:1
50:1
1:2
1:2.4
1:1.8
1:4.1
7:1
17:1
14
2.5
24:1
1:0

Monoarylation of Benzenediols
27
Scheme 4.
Synthesis of 2
Having successfully demonstrated this methodology, we decided to apply
these conditions to our target molecule 2. We chose 5 N NaOH because of
its ease of handling and safety advantages over other bases during scaling.
An efficient purification procedure via liquid–liquid extraction for removing
the small amount of bisarylated product and the excess orcinol was
developed, providing the clean product 2.
CONCLUSION
In summary, we have achieved our goal of developing a general and practical
method for high-yielding, monoselective SNAr reactions of various symmetric
and asymmetric benzenediols with aryl fluorides using excess base. The
monoselectivity was influenced by base choice where the mono/bis ratio of
1:0 was attained by using 2.5 equiv. of Cs2CO3. When asymmetric benzene-
diols were used, the ratio of mono-products was influenced by steric
hindrance. Finally, we employed the developed method to synthesize an
important active pharmaceutical ingredient, 1.
EXPERIMENTAL SECTION
General
All the reagents were purchased and used without further purification. 1H and
13C NMR spectra were recorded at 400 MHz on a Varian Inova spectrometer
with the solvents as internal standard. J values are given in hertz.
4-(4-Nitro-phenoxy)-phenol (7) and 1,4-Bis(4-nitrophenoxy)
benzene (8)
A 250-mL reaction flask equipped with mechanical stirrer, thermocouple/
probe, heating mantle, and nitrogen blanket was charged with dimethyl
sulfoxide (40.0 mL) and aqueous 5 N NaOH (17.5 mL, 87.7 mmol,
2.50 eq.). The colorless biphasic solution was stirred at ambient temperature

28
C. Xie et al.
for 5–10 min and charged with hydroquinone (4.68 g, 42.1 mmol, 1.20 eq.) as
a solid in one portion.
The mixture was heated to 508C and stirred for 10–15 min. A solution of
4-fluoronitrobenzene (5.00 g, 35.1 mmol) in dimethyl sulfoxide (10.0 mL)
was prepared and added slowly (over 30–60 min) to the reaction mixture at
508C. The reaction mixture was held at 508C for 5 h, then cooled to
ambient temperature and stirred overnight.
After cooling to 10–158C, deionized water (100 mL) was charged, and the
pH was adjusted to 6–7 with aqueous concentrated HCl, keeping the tempera-
ture colder than 308C. The resulting product slurry was stirred at ambient temp-
erature, filtered by suction, rinsed with 1:1/DMSO–H2O and then water. The
wet cake was dried in a vacuum oven at 508C to constant weight to afford 7.01 g
(86.4% yield) mono-compound 7 and 0.55 g (10.3% yield) bis-compound
8 (1,4-bis(4-nitrophenoxy)benzene). Known compound commercially
available from Scientific Exchange Product List and Aurora Screening Library.
Preparation of 9a and 10a
Dimethyl sulfoxide (40.0 mL) and aqueous 5 N NaOH (17.5 mL, 87.7 mmol,
2.50 eq.) were added to a 250-mL reaction flask equipped with mechanical
stirrer, thermocouple probe, heating mantle, and nitrogen blanket. The
colorless biphasic solution was stirred at ambient temperature for 5–10 min.
Resorcinol (4.68 g, 42.1 mmol, 1.20 eq.) was added as a solid in one portion.
The mixture was heated to 508C and stirred for 10–15 min. A solution of
4-fluoronitrobenzene (5.00 g, 35.1 mmol) in dimethyl sulfoxide (10.0 mL)
was prepared and added slowly (over 30–60 min) to the reaction mixture at
508C. The reaction mixture was held at 508C for 5–24 h (5 h here), then
cooled to ambient temperature.
After cooling to 10–158C, deionized water (50 mL) was charged, and the
pH was adjusted to 6–7 with aqueous concentrated HCl, keeping the tempera-
ture colder than 308C. EtOAc (50 mL) was added, and the reaction mixture was
stirred until a complete biphasic solution resulted. The layers were separated,
and the aqueous layer was extracted with additional EtOAc (2 ꢀ 50 mL). The
combined organic layers were dried (Na2SO4) and filtered, the spent drying
agent was rinsed with EtOAc, and the filtrate was concentrated in vacuo to
give a crude mixture of products as an oil. The oil was purified by silica-gel
chromatography (CH2Cl2 or 3:1 heptane–EtOAc) to afford 5.18 g (63.9%
yield) of mono 9a and 1.74 g (28.2% yield) of bis 10a products.[11]
Compounds 9b and 10b
Following the procedure for the preparation of 9a and 10a, the reaction was
run on a 5.00-g scale. The crude products were isolated by filtration and

Monoarylation of Benzenediols
29
purified as indicated to afford 6.65 g (77.3% yield) of mono 9b and 1.79 g
(14.0% yield) of bis 10b[10] products.
Data for mono-compound 9b: 1H NMR (400 MHz, DMSO-d6) d 9.67 (bs, 1H),
8.22 (m, 2H), 7.10 (m, 2H), 6.50 (s, 1H), 6.38 (s, 1H), 6.31 (m, 1H), 2.21
(s, 3H); 13C NMR (100 MHz, DMSO-d6) d 163.4, 159.4, 155.6, 142.6,
141.4, 126.6, 117.9, 113.7, 111.7, 105.0, 21.5. HRMS m/z calcd. for
C13H11NO4 246.0766 (M þ 1); found 246.0765. Anal. calcd. for
C13H11NO4: C, 63.67; H, 4.52; N, 5.71. Found: C, 63.54; H, 4.47, N, 5.44.
Compounds 9c and 10c
Following the procedure for preparation of 9a and 10a, the reaction was run on
a 5.00-g scale. The crude products were isolated and purified by silica-gel
chromatography (4:1 heptane–EtOAc) to afford 6.16 g (71.6% yield) of
mono 9c and 1.24 g (19.2% yield) of bis 10c products.
Data for mono-compound 9c: 1H NMR (400 MHz, DMSO-d6) d 9.75 (bs, 1H),
8.20 (m, 2H), 7.08 (t, 1H, J ¼ 7.9), 6.99 (m, 2H), 6.77 (d, 1H, J ¼ 7.9), 6.53
(d, 1H, J ¼ 7.5), 1.90 (s, 3H); 13C NMR (100 MHz, DMSO-d6) d 163.6, 157.7,
153.2, 142.3, 127.7, 126.7, 17.1, 116.6, 112.8, 112.0, 9.3. HRMS m/z calcd.
for C13H11NO4 246.0766 (M þ 1); found 246.0771.
Data for bis-compound 10c: 1H NMR (400 MHz, DMSO-d6) d 8.24 (m, 5H),
7.43 (t, 1H, J ¼ 8.2), 7.12 (m, 5H), 1.94 (s, 3H); 13C NMR (100 MHz, DMSO-
d6) d 163.0, 154.0, 142.8, 129.2, 126.7, 119.0, 117.2, 9.7. HRMS m/z calcd.
for C19H14N2O6 367.0930 (M þ 1); found 367.0934. Anal. calcd. for
C19H14N2O6: C, 62.30; H, 3.85; N, 7.65. Found: C, 62.11; H, 3.86: N, 7.53.
Reaction of Resorcinol with 2-Fluoronitrobenzene
Followed the procedure for preparation of 9a and 10a, the reaction was ran on
a 5.00-g scale. The crude products were isolated and purified by silica-gel
chromatography (CH2Cl2 gradient to 98:2 CH2Cl2–MeOH) to afford 5.03 g
(61.3% yield) of mono-product and 1.08 g (17.3% yield) of bis-product.
Data for mono-compound: 1H NMR (400 MHz, DMSO-d6) d 9.69 (bs, 1H), 8.02
(m, 1H), 7.67 (m, 1H), 7.34 (m, 1H), 7.17 (m, 2H), 6.59 (m, 1H), 6.44 (m, 1H),
6.04 (t, 1H, J ¼ 2.4); 13C NMR (100 MHz, DMSO-d6) d 159.5, 157.3, 149.5,
141.8, 135.4, 131.1, 125.9, 124.7, 121.7, 112.0, 109.2, 105.9. HRMS m/z
calcd. for C12H9NO4 232.0610 (M þ 1); found 232.0584. Anal. calcd. for
C12H9NO4: C, 62.34; H, 3.92; N, 6.06: Found: C, 62.22; H, 3.61; N, 5.86.
Data for bis-compound: 1H NMR (400 MHz, DMSO-d6) d 8.04 (d, 2H,
J ¼ 7.91), 7.70 (t, 2H, J ¼ 7.47), 7.43 (t, 1H, J ¼ 8.35), 7.37 (dd, 2H,
J ¼ 7.91, 7.47), 7.23 (d, 2H, J ¼ 7.91), 6.85 (d, 2H, J ¼ 8.35), 6.79 (s, 1H);

30
C. Xie et al.
13C NMR (100 MHz, DMSO-d6) d 157.7, 149.0, 141.8, 135.6, 132.0, 126.2,
125.3, 122.0, 114.4, 109.3. HRMS m/z calcd. for C18H12N2O6 353.0774
(M þ 1); found 353.0797. Anal. calcd. for C18H12N2O6: C, 61.37; H, 3.43;
N, 7.95. Found: C, 61.50; H, 3.26; N, 7.89.
Reaction of Resorcinol with 3-Bromo-4-fluorobenzotrifluoride
The same procedure was as before on 3.00-g scale. The crude products were
isolated and purified by silica-gel chromatography (2:1 CH2Cl2–heptane
gradient to CH2Cl2) to afford 2.12 g (52.6% yield) of mono- and 0.40 g
(12.0% yield) of bis-products.
1
Data for mono-compound: H NMR (400 MHz, DMSO-d6) d 9.76 (s, 1H),
8.10 (app. split s, 1H), 7.72 (app. d, 1H, J ¼ 8.8), 7.21 (t, 1H, J ¼ 8.35),
7.09 (d, 1H, J ¼ 8.35), 6.63 (m, 1H), 6.48 (m, 1H), 6.41 (t, 1H, J ¼ 2.20);
13C NMR (100 MHz, DMSO-d6) d 159.6, 157.14, 157.13, 156.6, 131.31,
131.20, 131.17, 127.12, 127.08, 120.0, 114.1, 112.4, 109.8, 106.4. HRMS
m/z calcd. for C13H8BrF3O2 330.9582 (M 2 1); found 330.9592.
Data for bis-compound: 1H NMR (400 MHz, DMSO-d6) d 8.11 (s, 2H), 7.74
(app. d, 2H, J ¼ 8.8), 7.48 (dd, 1H, J ¼ 7.9 Hz, 8.3), 7.20 (d, 2H, J ¼ 8.3),
6.92 (m, 3H); 13C NMR (100 MHz, DMSO-d6) d 157.0, 156.6, 132.3, 131.5
(m), 127.2 (m), 120.5, 115.4, 114.4, 110.4. HRMS m/z calcd. for
C20H10Br2F2O2 554.9030 (M þ 1); found 554.9028. Anal. calcd. for
C20H10Br2F2O2: C, 43.20; H, 1.81. Found: C, 43.40; H, 1.98.
Reaction of Resorcinol with 2-Fluoro-5-nitrobenzene
The same procedure as before was used on a 3.00-g scale. The crude products
were isolated and purified by silica-gel chromatography (CH2Cl2 gradient to
96:4 CH2Cl2–MeOH) to afford 2.92 g (62.2% yield) of mono- and 1.05 g
(28.8% yield) of bis-products.
1
Data for mono-compound: H NMR (400 MHz, DMSO-d6) d 9.76 (s, 1H),
8.20 (m, 1H), 8.04 (m, 1H), 7.22 (dd, 1H, J ¼ 8.3, 7.9), 6.87 (d, 1H,
J ¼ 8.8), 6.64 (m, 1H), 6.49 (m, 1H), 6.45 (m, 1H), 2.33 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) d 161.2, 159.6, 156.5, 142.6, 131.3, 129.7, 126.9,
123.9, 117.0, 112.5, 110.4, 107.1, 16.2. HRMS m/z calcd. for C13H11NO4
246.0766 (M þ 1), found 246.0777.
1
Data for bis-compound: H NMR (400 MHz, DMSO-d6) d 8.21 (app. split s,
2H), 8.05 (dd, 2H, J ¼ 8.8, 9.2), 7.52 (dd, 1H, J ¼ 8.3, 7.9), 6.97 (m, 4H), 6.90
(dd, 1H, J ¼ 2.6, 2.2), 3.32 (s, 6H); 13C NMR (100 MHz, DMSO-d6) d 160.7,
157.0, 143.0, 132.4, 130.1, 127.1, 123.9, 117.5, 116.2, 111.6, 16.2. HRMS m/z
calcd. for C20H16N2O6 403.0906 (M þ Na); found 403.0925.

Monoarylation of Benzenediols
31
Reaction of 4-Fluoronitrobenzene with 2,5-Dihydroxyacetophenone
To a flask, 7 mL of NaOH and 5 N (2.5 eq., 35.4 mmol) and 20 mL of DMSO
(10 vols.) were added and stirred for 10 min. 2,5-Dihydroxyacetophenone
(2.57 g, 1.2 eq., 17 mmol) was added and stirred for 30 min. 4-Fluoronitroben-
zene (2 g), LR, 14.1 mmol) was added. The reaction system was stirred at
508C for 5 h. The reaction was cooled, and water (10 vols.) was added. pH
was adjusted to 1.0 with 5 N HCl, and the reaction was extracted with
EtOAc (3 ꢀ 20 vol. portions). The combined organics were washed with
brine (10 vols.), dried over Na2SO4, filtered, and concentrated. The crude
oil was purified by silica-gel chromatography (20 ꢀ SiO2) with 25%
EtOAc/hexanes. Yield 20% and purity 99.42% by GC. Mass spec: exact
mass 273.06; 13C NMR (400 MHz, DMSO-d6) d 203, 163, 158, 146, 142,
129, 126, 123, 122, 120, 117, 28.
Synthesis of 2
In a 22-L flask fitted with a thermocouple, temperature controller, and heating
mantle, 2.4 L of DMSO and 620 mL of 5 N NaOH (3.1 mol, 3.1 eq.) were
added. The temperature rose to approximately 408C. Then 186.2 g of
orcinol (1.5 mol, 1.5 eq.) were added. The resulting solution was stirred and
heated to 808C. Then 3-bromo-4-fluoro-benzotrifluoride (242.98 g, 1 mol, 1
eq.) was added over 20 to 45 min, with the temperature at 80–868C. The
reaction was stirred for 1.5 to 2 h after addition and cooled to 20–258C, the
transferred to a separation vessel and extracted with heptane.
The resulting aqueous layer was extracted three times with 2 L each of
ethyl acetate. The combined ethyl acetate layers were combined and
washed with a solution of 200 mL of 5 N HCl (1 mol) in 1 L of H2O to
convert the product to the free phenol. The ethyl acetate solution was
washed with 1 L H2O and then dried over sodium sulfate. The filtered ethyl
acetate solution was evaporated to provide 250 g (72%) of 2 as a brown oil.
1
Purity was .99% by H NMR.
Data for 2: 1H NMR (400 MHz, DMSO-d6) d 9.62 (s, 1H), 8.08 (d, 1H, J ¼ 2),
7.71 (dd, 1H, J ¼ 8.5), 7.08 (d, 1H, J ¼ 8.5), 6.45 (s, 1H), 6.32 (s, 1H), 6.21
(dd, 1H, J ¼ 2.5, 2), 2.20 (s, 3H); 13C NMR (100 MHz, DMSO-d6) d 159.3,
157.2, 156.4, 141.3, 131.1, 127.1, 122.7, 120.0, 114.0, 113.0, 110.5, 107.5,
103.7, 21.5.
ACKNOWLEDGMENTS
The authors thank Lisa Zollars for NMR NOE work in identifying the asym-
metric monoarylated products. We also thank Richard Hoying for the scale-up

32
C. Xie et al.
of 2 and the Lilly Analytical Technologies department for structural
characterization.
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