Synthesis OF 5,6-dihydrophenanthridine (DHPA) sulfonamides and subsequent acid-catalyzed rearrangement to diaryl sulfones

Article abstract of DOI:10.1080/00397911.2010.515329

As part of an ongoing investigation into the rearrangement of cyclic aryl aminesulfonanilides to diarylsulfones, a series of novel 5,6- dihydrophenanthridine (DHPA) sulfonamides were synthesized. Acid catalysts were used to rearrange them to DHPA arylsulfones. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.515329

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Synthesis of 5,6-Dihydrophenanthridine
(DHPA) Sulfonamides and Subsequent
Acid-Catalyzed Rearrangement to Diaryl
Sulfones
Lisa Marie Neuls Meseroll a , James R. McKee a & Murray Zanger a
a Department of Chemistry and Biochemistry, University of the
Sciences in Philadelphia, Philadelphia, Pennsylvania, USA
Version of record first published: 29 Jun 2011
To cite this article: Lisa Marie Neuls Meseroll, James R. McKee & Murray Zanger (2011): Synthesis
of 5,6-Dihydrophenanthridine (DHPA) Sulfonamides and Subsequent Acid-Catalyzed Rearrangement
to Diaryl Sulfones, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:17, 2557-2568
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Synthetic Communications1, 41: 2557–2568, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515329
SYNTHESIS OF 5,6-DIHYDROPHENANTHRIDINE
(DHPA) SULFONAMIDES AND SUBSEQUENT
ACID-CATALYZED REARRANGEMENT TO
DIARYL SULFONES
Lisa Marie Neuls Meseroll, James R. McKee, and
Murray Zanger
Department of Chemistry and Biochemistry, University of the Sciences
in Philadelphia, Philadelphia, Pennsylvania, USA
GRAPHICAL ABSTRACT
Abstract As part of an ongoing investigation into the rearrangement of cyclic aryl
aminesulfonanilides to diarylsulfones, a series of novel 5,6-dihydrophenanthridine (DHPA)
sulfonamides were synthesized. Acid catalysts were used to rearrange them to DHPA
arylsulfones.
Keywords 5,6-Dihydrophenanthridine; rearrangement; sulfonamides; sulfones
INTRODUCTION
In this laboratory, rearrangement of the cyclic aryl aminesulfonanilides to
diaryl sulfones with heating in the presence of concentrated sulfuric acid provided
a convenient one-step route to diaryl sulfones.[1a–c] Because diaryl sulfones possess
great potential for biological activity, already demonstrating utility in the treatment
of HIV,[1d] tuberculosis,[2] and other bacterial infections,[3] the mechanism for
rearrangement is a valuable tool that this laboratory continues to investigate. Here,
a novel series of 5,6-dihydrophenanthridine (DHPA) sulfonamides was synthesized
Received January 26, 2010.
Address correspondence to Murray Zanger, Department of Chemistry and Biochemistry,
University of the Sciences in Philadelphia, 600 S. 43rd Street, Philadelphia, PA 19104-4418, USA.
E-mail: m.zanger@usp.edu
2557

2558
L. M. N. MESEROLL, J. R. MCKEE, AND M. ZANGER
for further investigation into the acid-catalyzed rearrangement en route to a new
series of DHPA diaryl sulfones.
To gain a better understanding of the process of acid-catalyzed rearrangement,
various heterocyclic sulfonanilides are being explored in this laboratory to determine
how functionality of the benzo-fused heterocycle affects these rearrangements. The
primary goal of this project is to synthesize a series of new 5,6-DHPA sulfonanilides
and evaluate their behavior under a series of rearrangement conditions. Standard
heating by a conventional oven and heating using microwave energy were used to
compare reaction efficiency. Ultimately, a new series of 5,6-DHPA sulfonamides
was synthesized along with their corresponding sulfone isomers, which were accessed
via acid-catalyzed rearrangement.
Recently, phenanthridinone-containing compounds have demonstrated anti-
HIV activity[4] and have piqued the interest of this laboratory. Because phenanthridi-
none is a precursor in the synthesis of 5,6-DHPA, phenanthridinone sulfonanilides
were investigated as well. However, they were extremely unreactive to sulfonylation,
and only 5,6-DHPA sulfonamides and sulfones were actually synthesized.
RESULTS AND DISCUSSION
All 5,6-DHPA sulfonanilides were synthesized from 9-fluorenone (1) by
Beckmann rearrangement[5] to 5(H)-phenanthridin-6-one (3) (Scheme 1). 5(H)-
Phenanthridin-6-one was subsequently reduced via LiAlH4 to 5,6-dihydrophenanthri-
dine (4) and sulfonylated using a mixture of pyridine and the desired benzene
sulfonylchloride (para-toluenesulfonyl chloride or ortho-nitrobenzene sulfonyl
chloride). To access the para-chloro derivatives, 5(H)-phenanthridin-6-one was first
refluxed in benzene with sulfuryl chloride, and the chlorination product was isolated
before reduction by LiAlH4 and sulfonylation, similar to the nonhalogenated phenantr-
hidines. Rearrangement of sulfonanilides to their corresponding diaryl sulfone were
evaluated via the four acids [H2SO4, polyphosphoric acid (PPA), TfOH, AlCl3] and
with both conventional heating methods and microwave heating (when appropriate).
For most of the compounds, sulfuric acid proved to be the most effective cata-
lyst for rearrangements with DHPA sulfonamides. Trifluoromethane sulfonic acid
(triflic acid; TfOH) offered an advantage in the rearrangement to 2-chloro-4-
[(2-nitrophenyl)sulfonyl]-5,6-DHPA (11b). The nitro group increases the reaction
rate, which was evident immediately upon addition of acid. Most likely, the slight
deactivating effect the chloro group has on the adjacent aromatic ring, coupled with
the benzenesulfonylonium ion stabilized by an electron-withdrawing ortho nitro
group, drive the formation of the unexpected product in sulfuric acid (Scheme 2).
Again, if hydrolysis were a competing process with rearrangement to the ortho
sulfone, using an acid catalyst devoid of water in an oxygen-poor environment
should resolve this problem. The reaction was repeated in a mixture of triflic acid
and triflic anhydride under an argon atmosphere. The expected ortho sulfone was
obtained, supporting our hypothesis.
With the investigation of each new series of heterocycles, a better understand-
ing of the utility of this valuable route to compounds with the biologically desireable
diaryl sulfone moiety was obtained. Future projects will be designed to prepare

PHENANTHRIDINE SULFONAMIDES AND SULFONES
2559
Scheme 1. Total synthesis of DHPA sulfonanilides and sulfones.
several substituted sulfones where the substituents will be selected to enhance phar-
macological activity, particularly by decreasing logP to optimal values.
Using the reaction pathway outlined in Scheme 1, 2-nitro-N-[(4-methylphenyl)
sulfonyl]-5,6-DHPA was synthesized in good yield. Attempts to rearrange this
Scheme 2. Attempted sulfuric acid rearrangement of 2-chloro-4-[(2-nitrophenyl)sulfonyl]-5,6-
dihydrophenanthridine.

2560
L. M. N. MESEROLL, J. R. MCKEE, AND M. ZANGER
Scheme 3. Attempted rearrangement of 2-nitro-4-[(4-methylphenyl)sulfonyl]-5,6-dihydrophenanthridine.
sulfonamide to the diaryl sulfone isomer in triflic or sulfuric acids under a variety of
conditions were unsuccessful. At best, trace amounts of rearranged products were
recovered after tedious workup using column chromatography (Scheme 3). The
major product of this reaction, 2-nitrophenanthridine (19), was recovered in
excellent yield (79%).
After experimenting with sulfuric, triflic, and polyphosphoric acids, it was clear
sulfuric acid was optimal for inducing rearrangements of derivatives in this family of
compounds. It was gratifying to see that rearrangement had occurred successfully,
and attempts were made to determine if microwave reactions using AlCl3 could
further improve the efficiency of these reactions.
N-[(4-Methylphenyl)sulfonyl]-5,6-DHPA (10a) was heated (with AlCl3) for
time periods ranging from 20 min to 3 h in multiple attempts to obtain maximum
sulfone yield (Scheme 2). Unfortunately, under these conditions, N-[(4-methyl
phenyl)sulfonyl]-5,6-DHPA (10a) failed to rearrange to its corresponding sulfone;
instead, hydrolysis and oxidation products were isolated (Scheme 4). Microwave
reactions using AlCl3 do not appear to benefit rearrangement efforts on DHPA
sulfonamides. Table 1 lists the sulfonamides and sulfones that were prepared
and characterized.
Scheme 4. Microwave=AlCl3 reaction of N-[(4-methylphenyl)sulfonyl]-5,6-dihydrophenanthridine.

PHENANTHRIDINE SULFONAMIDES AND SULFONES
2561
Table 1. New sulfonamides and diaryl sulfones
No.
Type
Formula
R1
R2
R3
Yield (%)
Mp (ꢀC)
10a
11a
10b
11b
12
I
I
C
C
C
20H17NO2S
20H16ClNO2S
19H14N2O4S
H
Cl
H
H
H
CH3
CH3
H
69
65
40
53
62
19
12
21
16
112–113
134–135
147–148
175–176
292–294
191–193
256–257
248–249
157–158
I
NO2
NO2
H
I
C19H13ClN2O4S
Cl
NO2
H
H
I
C
C
C
20H16N2O4S
20H15NO2S
20H14ClNO2S
CH3
CH3
CH3
H
13a
14a
13b
14b
II
II
II
II
H
Cl
H
H
C19H12N2O4S
19H11ClN2O4S
NO2
NO2
C
Cl
H
EXPERIMENTAL
Synthesis of 9-Fluorenone Oxime (2)
In a 50:50 mixture of 125 mL pyridine and 125 mL methanol, 9-fluorenone (1)
(34.35 g, 0.19 mol) was refluxed with hydroxylamine hydrochloride (26.50 g,
0.38 mol) for 1.5 h. The solvent was evaporated, and the remaining pale green crys-
tals were recrystallized from ethanol to yield 33.74 g (0.17 mol) 9-fluorenone oxime.
1
Yield: 91%, mp 207–209 ꢀC. H NMR (400 MHz, DMSO-d6) d 12.58 (s, 1H), 8.35
(d, 1H), 7.81 (m, 2H), 7.72 (d, 1H), 7.48 (t, 1H), 7.33 (m, 3H).
Synthesis of 5-H-Phenanthridin-6-one (3)
9-Fluorenone oxime (38.28 g, 0.20 mol) was heated with stirring in concen-
trated PPA (120 mL). The acid became much less viscous and was easily stirred.
Once the temperature of the mixture reached 160 ꢀC, it was maintained at
160–180 ꢀC for 20 min. Over the course of heating, the oxime dissolved and the mix-
ture became dark brown-orange. Following heating, the mixture was maintained at
room temperature without stirring for 15 h. The cool mixture was then warmed
slightly so the viscous acidic mixture could be poured over 3 inches of ice in a
600-mL beaker. After stirring several minutes, the dark tarry material began to sol-
idify, and a pale tan precipitate was liberated. The precipitate was washed several
times with water and collected by vacuum filtration. The resulting pale tan crystals
were recrystallized from pyridine to give 32.90 g (0.17 mol) of cream-colored
1
5-H-phenanthridin-6-one. Yield: 86%, mp 316–317 ꢀC, (lit. 290–292 ꢀC). H NMR

2562
L. M. N. MESEROLL, J. R. MCKEE, AND M. ZANGER
(400 MHz, DMSO-d6) d 11.69 (s, 1H), 8.50 (d, 1H), 8.38 (d, 1H), 8.31 (d, 1H), 7.85 (t,
1H), 7.64 (t, 1H), 7.48 (t, 1H), 7.37 (d, 1H), 7.26 (t, 1H).
Synthesis of 5,6-Dihydrophenanthridine (4)
LiAlH4 (1.11 g, 29.3 mmol) was refluxed in 100 mL anhydrous tetrahydrofuran
(THF). 5-H-Phenanthridin-6-one (4.20 g, 22 mmol) was added carefully in portions
to the refluxing mixture. The mixture immediately turned bright green upon addition
of 5-H-phenanthridin-6-one. The mixture was refluxed an additional 4 h before the
reaction was quenched by dropwise addition of water. The disappearance of the
bright green color, replaced by a pale gray-white salt, indicated the reaction was
quenched. The solution containing 5,6-DHPA was separated from the salts by grav-
ity filtration. The THF filtrate was evaporated, and the resulting pale yellow solid
was recrystallized from ethanol and water (90:10) to give 2.33 g (12.9 mmol) of shiny
white crystalline 5,6-DHPA. Yield: 60%, mp 126–127 ꢀC. 1H NMR (400 MHz,
d-CDCl3) d 7.70 (m, 2H), 7.33 (t, 1H), 7.24 (t, 1H), 7.12 (m, 2H), 6.88 (t, 1H),
6.72 (d 1H), 4.42 (s, 2H).
Synthesis of 2-Chloro-5-H-phenanthridin-6-one (5)
5-H-Phenanthridin-6-one (6.23 g, 31.9 mmol) was added to 75 mL of benzene.
Sulfuryl chloride (8 mL) was added to the stirred solution, and the mixture was
refluxed 3 h. The mixture was poured into an evaporating dish. When all the solvent
had evaporated, the remaining solid was recrystallized from ethyl acetate, resulting
in fine, white solid 2-chloro-5-H-phenanthridin-6-one (5.36 g, 23.3 mmol). Yield:
1
73%, mp 340–341 ꢀC. H NMR (400 MHz, DMSO-d6) d 11.79 (s, 1H), 8.56 (d,
1H), 8.47 (s, 1H), 8.32 (d, 1H), 7.86 (t, 1H), 7.69 (t 1H), 7.53 (d, 1H), 7.37 (d, 1H).
Synthesis of 2-Chloro-5,6-dihydrophenanthridine (6)
LiAlH4 (0.63 g, 16.6 mmol) was refluxed in 80 mL anhydrous THF. 2-Chloro-
5-H-phenanthridin-6-one (1.91 g, 8.30 mmol) was added carefully in portions to the
refluxing mixture. The mixture immediately turned bright green upon addition of
2-chloro-5-H-phenanthridin-6-one. The mixture was refluxed an additional 4 h
before the reaction was quenched by dropwise addition of water. The disappearance
of the bright green color, replaced by a pale gray-yellow salt, indicated the reaction
was quenched. The 2-chloro-5,6-DHPA was separated from the salts by gravity
filtration. The yellow-green THF filtrate was evaporated, and the resulting yellow
solid was recrystallized from ethanol and water (90:10) giving 0.75 g (3.5 mmol) of
pale yellow, solid 2-chloro-5,6-DHPA. Yield: 42%, mp 68–69 ꢀC. 1H NMR
(400 MHz, DMSO-d6) d 7.75 (d, 1H), 7.68 (s, 1H), 7.26 (m, 2H), 7.16 (d, 1H),
7.05 (d, 1H), 6.68 (d 1H), 6.15 (s, 1H), 4.29 (s, 2H).
Synthesis of 2-Nitro-5-H-phenanthridin-6-one (7)
5-H-Phenanthridin-6-one (4.12 g, 21.1 mmol) was dissolved in 25 mL nitric acid
with stirring. Over the course of 1 h, a thick yellow precipitate began to form. After

PHENANTHRIDINE SULFONAMIDES AND SULFONES
2563
standing overnight, most of the nitric acid had evaporated, and the solid was washed
with several portions of cold water and collected by vacuum filtration. The solid was
washed with ethanol and recrystallized from glacial acetic acid to remove other iso-
mers of the nitration. NMR confirmed the remaining light tan solid as 2-nitro-5-H-
phenanthridin-6-one (3.55 g, 14.8 mmol). Yield: 70%, mp 402–404 ꢀC. 1H NMR
(400 MHz, DMSO-d6) d 11.85 (s, 1H), 9.34 (s, 1H), 8.58 (d, 1H), 8.34 (d, 1H),
8.29 (d, 1H), 7.91 (t 1H), 7.74 (d, 1H), 7.56 (t, 1H).
Synthesis of 2-Nitro-5,6-dihydrophenanthridine (8)
LiAlH4 (1.05 g, 27.7 mmol) was refluxed in 40 mL anhydrous THF.
2-Nitro-5-H-phenanthridin-6-one (3.55 g, 14.8 mmol) in 100 mL anhydrous THF
was added in portions to the refluxing mixture. The mixture immediately turned
bright orange-red upon addition. The mixture was refluxed an additional 4 h
before the reaction was quenched with dropwise addition of water. The disap-
pearance of the bright red-orange color, replaced by a pale orange salt, indicated
the reaction was quenched. The 2-nitro-5,6-DHPA was separated from the salts
by gravity filtration. The orange THF filtrate was evaporated, and the resulting
yellow solid was recrystallized from ethanol and water (90:10), giving 0.87 g
(3.85 mmol) of orange-brown solid 2-nitro-5,6-DPHA. Yield: 26%, mp
1
390–392 ꢀC. H NMR (400 MHz, DMSO-d6) d 10.99 (s, 1H), 8.35 (d, 1H), 8.23
(d, 1H), 7.78 (t, 1H), 7.57 (t, 1H), 7.52 (s 1H), 7.16 (d, 1H), 6.87 (d, 1H), 4.76
(s, 2H).
Identification of 5,6-Dihydrophenanthridine Sulfonanilides and
Diaryl Sulfones
Characterization of all novel sufonamides and sulfones discussed in this section
include 1H NMR, 13C NMR, infrared (IR), and mass spectra. All of the spectra were
consistent with the proposed structures, and no significant unassigned peaks were
observed. See Table 1.
Synthesis of N-[(4-Methyl)phenyl]sulfonyl-5,6-
dihdrophenathridine (10a)
In a 125-mL Erlenmeyer flask, 5,6-DPHA (0.98 g, 5.4 mmol) was dissolved in
7 mL of pyridine. The mixture quickly turned orange-yellow as p-toluenesulfonyl
chloride (1.22 g, 6.2 mmol) was added in portions at 0 ꢀC with stirring. The mixture
was placed in the freezer for 24 h. During this time, a solid precipitate slowly formed.
When the mixture was removed from the freezer, 75 mL of water were added directly
to the Erlenmeyer flask with stirring. The tacky pale pink mixture quickly hardened,
and stirring continued until a fine white precipitate remained. The white powder was
collected by vacuum filtration and recrystallized from ethanol to give 1.24 g
(3.7 mmol) of shiny tan crystals of N-[(4-methyl)phenyl]sulfonyl-5,6-DPHA. Yield:
69%, mp 112–113 ꢀC. 1H NMR (400 MHz, DMSO-d6) d 7.76 (m, 1H), 7.63 (d,
1H), 7.41 (m, 3H), 7.26 (m, 1H), 7.16 (m, 2H), 6.94 (t, 2H), 6.84 (m, 2H), 4.85 (s,
2H), 2.12 (s, 3H). 13C NMR (101 MHz, DMSO-d6) 143.88, 136.24, 135.19, 132.04,

2564
L. M. N. MESEROLL, J. R. MCKEE, AND M. ZANGER
130.98, 129.49 (2C), 128.42, 128.18, 127.42, 127.06, 125.00 (2C), 123.78, 49.88, 21.65.
IR (KBr pellet) (cmꢁ1) 1165.30 (SO2 sym str.). m=z ASAP (þmode) 336.1050
(C20H17NO2S).
Synthesis of N-[(2-Nitro)phenyl]sulfonyl-5,6-
dihdrophenathridine (10b)
In a 125-mL Erlenmeyer flask, 5,6-DHPA (3.38 g, 18.5 mmol) was dissolved in
15 mL of pyridine. The mixture quickly turned orange as o-nitrobenzenesulfonyl
chloride (5.0 g, 22.6 mmol) was added in portions at 0 ꢀC with stirring. The mixture
was placed in the freezer for 24 h. During this time, a solid precipitate slowly formed.
When the mixture was removed from the freezer, 100 mL of water were added
directly to the Erlenmeyer flask with stirring. The tacky red mixture quickly har-
dened, and the aqueous phase was decanted. The tacky solid was washed several
times with water to remove pyridine and dissolved in methylene chloride. Silica
gel (1 g) was added, and the methylene chloride evaporated. Column chromato-
graphy using chloroform was used to remove impurities and isolate the nitro
phenanthridine sulfonanilide. After evaporation of fractions containing the sulfona-
nilide, the remaining yellow solid was recrystallized from ethanol to yield shiny white
crystals of N-[(2-nitro)phenyl]-sulfonyl-5,6-DPHA (2.47 g, 7.34 mmol). Yield: 40%,
mp 147–148 ꢀC. 1H NMR (400 MHz, DMSO-d6) d 7.91 (d, 1H), 7.65 (m, 3H),
7.53 (d, 1H), 7.46 (m, 2H), 7.38 (m, 3H), 7.30 (d, 1H), 7.20 (m, 2H), 4.92 (s, 2H).
13C NMR (101 MHz, DMSO-d6) 147.89, 138.52, 135.67, 133.52, 132.31, 131.95,
131.11, 130.79, 130.62, 130.49, 129.36, 129.03, 128.84, 127.85, 127.26, 125.20,
124.27, 123.94, 49.58. IR (KBr pellet) (cmꢁ1) 1173.87 (SO2 sym str.). m=z ASAP
(þmode) 367.0747 (C19H14N2O4S).
Synthesis of 2-Chloro-N-[(4-methyl)phenyl]sulfonyl-5,6-
dihdrophenathridine (11a)
In a 125-mL Erlenmeyer flask, 2-chloro-5,6-DHPA (0.72 g, 3.34 mmol) was
dissolved in 10 mL of pyridine. The mixture quickly turned orange-yellow as p-
toluenesulfonyl chloride (0.70 g, 3.6 mmol) was added in portions at 0 ꢀC with
stirring. The mixture was placed in the freezer for 24 h. During this time, a solid
precipitate slowly formed. When the mixture was removed from the freezer,
75 mL of water were added directly to the Erlenmeyer flask with stirring. The tacky
pale pink mixture quickly hardened, and stirring continued until a fine white
precipitate remained. The white powder was collected by vacuum filtration
and recrystallized from ethanol to yield shiny white crystals of 2-chloro-N-
[(4-methyl)phenyl]sulfonyl-5,6-DHPA, (0.80 g, 2.16 mmol). Yield: 65%, mp
1
134–135 ꢀC. H NMR (400 MHz, DMSO-d6) 7.84 (d, 1H), 7.64 (d, 1H), 7.48 (m,
2H), 7.24 (m, 2H), 7.15 (t, 1H), 6.98 (d, 2H), 6.87 (d, 2H), 4.86 (s, 2H), 2.13 (s,
3H). 13C NMR (101 MHz, DMSO-d6) 144.12, 135.06, 135.00, 132.98, 132.13,
130.02, 129.86, 129.65, 129.49, 128.53, 127.45, 127.17, 124.72, 124.21, 49.70,
21.63. IR (KBr pellet) (cmꢁ1) 1165.49 (SO2 sym str.). m=z ASAP (þmode)
370.0663 (C20H16ClNO2S).

PHENANTHRIDINE SULFONAMIDES AND SULFONES
2565
Synthesis of 2-Chloro-N-[(2-nitro)phenyl]sulfonyl-5,6-
dihdrophenathridine (11b)
In a 125-mL Erlenmeyer flask, 2-chloro-5,6-DHPA (1.96 g, 9.09 mmol) was dis-
solved in 10 mL of pyridine. The mixture quickly turned bright red as 2-nitrobenze-
nesulfonyl chloride (2.27 g, 10.2 mmol) was added in portions at 0 ꢀC with stirring.
The mixture was placed in the freezer for 24 h. During this time, a solid precipitate
slowly formed. When the mixture was removed from the freezer, 50 mL of water
were added directly to the Erlenmeyer flask with stirring. The tacky red mixture
quickly hardened, and the aqueous phase was decanted. The tacky solid was washed
several times with water to remove pyridine and dissolved in dichloromethane. Silica
gel (1 g) was added, and dichloromethane was evaporated. Column chromatography
using chloroform was used to remove impurities and isolate the sulfonanilide. The
remaining yellow solid was recrystallized from ethanol to yield shiny white crystals
of 2-chloro-N-[(2-nitro)phenyl]sulfonyl-5,6-DHPA (1.92 g, 4.79 mmol). Yield: 53%,
1
mp 175–176 ꢀC. H NMR (400 MHz, DMSO-d6) 7.97 (d, 1H), 7.68 (d, 1H), 7.59
(m, 1H), 7.54 (t, 1H), 7.51 (m, 3H), 7.39 (t, 1H), 7.33 (m, 1H), 7.20 (m, 2H), 4.95
(s, 2H). 13C NMR (101 MHz, DMSO-d6) 147.86, 135.80, 134.27, 133.49, 132.74,
132.40, 131.99, 130.82 (2C), 130.32, 129.86, 129.50, 129.12, 129.03, 127.36, 124.97,
124.36, 124.25, 49.45. IR (cmꢁ1) 1173.71 (SO2 sym str.). m=z ASAP (þmode)
401.0357 (C19H13ClN2O4S).
Synthesis of 2-Nitro-N-[(4-methyl)phenyl]sulfonyl-5,6-
dihdrophenathridine (12)
In a 125-mL Erlenmeyer flask, 2-nitro-5,6-DHPA (0.84 g, 3.71 mmol) was dis-
solved in 10 mL of pyridine. The mixture quickly turned orange as p-toluenesulfonyl
chloride (0.92 g, 4.8 mmol) was added in portions at 0 ꢀC with stirring. The mixture
was placed in the freezer for 24 h. During this time, a solid precipitate slowly formed.
When the mixture was removed from the freezer, 75 mL of water were added directly
to the Erlenmeyer flask with stirring. The tacky pale orange mixture quickly har-
dened, and stirring continued until a fine white precipitate remained. The tan-orange
powder was collected by vacuum filtration and recrystallized from ethanol to yield
shiny tan crystals of 2-nitro-N-[(4-methyl)phenyl]sulfonyl-5,6-DHPA (0.87 g,
1
2.29 mmol). Yield: 62%, mp 292–294 ꢀC. H NMR (400 MHz, DMSO-d6) 11.64 (s,
1H), 10.20 (s, 1H), 8.30 (d, 1H), 8.15 (d, 1H), 7.96 (s, 1H), 7.87 (t, 1H), 7.66
(t, 3H), 7.32 (d, 2H), 7.23 (m, 2H), 7.19 (m, 2H), 2.30 (s, 3H). 13C NMR
(101 MHz, DMSO-d6) 161.28, 144.08, 137.33, 134.11, 133.90, 133.87, 130.52,
129.16, 127.68, 126.66, 124.30, 122.87, 118.57, 117.78, 116.02, 21.78. IR (cmꢁ1
1154.55 (SO2 sym str.).
)
Sulfuric Acid Rearrangement of N-[(4-Methyl)phenyl]sulfonyl-5,6-
dihdrophenathridine (10a) to 4-[(4-Methyl)phenyl]sulfonyl
Phenanthridine (13a)
The sulfonanilide, 5-[(4-methylphenyl)sulfonyl]-5,6-DHPA (0.95 g, 2.83 mmol)
was dissolved in 98% sulfuric acid and placed in the oven (105 ꢀC) for 30 min. The

2566
L. M. N. MESEROLL, J. R. MCKEE, AND M. ZANGER
mixture gradually darkened from colorless to red-brown. After heating, the mixture
was quenched over ice and stirred with aqueous sodium bicarbonate to remove any
acid. The solid crude material was washed several times with water and collected by
vacuum filtration. Recrystallization from ethanol yielded 0.18 g (0.54 mmol) of the
rearranged sulfone, 4-[(4-methylphenyl)sulfonyl]-5,6-DHPA. Yield: 19%, mp
191–193 ꢀC. 1H NMR (400 MHz, DMSO-d6) d 9.39 (s, 1H), 9.13 (d, 1H), 8.82
(d, 1H), 8.63 (d, 1H), 8.16 (d, 1H), 8.00 (m, 4H), 7.80 (t, 1H), 7.34 (d, 2H), 2.30
(s, 3H). 13C NMR (101 MHz, DMSO-d6) 155.08, 144.43, 140.37, 139.96, 138.89,
133.00, 131.92, 130.42, 130.40, 129.94 (3C), 129.69, 129.46 (2C), 127.50, 126.45,
125.62, 123.43, 21.84. IR (KBr pellet) (cmꢁ1) 1144.84 (SO2 sym str.). m=z
334.08787 (þmode) (C20H16NO2S).
Sulfuric Acid Rearrangement of N-[(2-Nitro)phenyl]sulfonyl-5,6-
dihdrophenathridine (10b) to 4-[(2-Nitro)phenyl]sulfonyl
Phenanthridine (13b)
The sulfonanilide, 5-[(2-nitrophenyl)sulfonyl]-5,6-DHPA (0.85 g, 2.32 mmol)
was dissolved in 98% sulfuric acid and placed in the oven (105 ꢀC) for 30 min. The
mixture gradually darkened from colorless to red-brown. After heating, the mixture
was quenched over ice and stirred with aqueous sodium bicarbonate to remove any
acid. The solid crude material was washed several times with water and collected by
vacuum filtration. Column chromatography was used to isolate the rearranged pro-
duct. Using 20 g of silica gel, the crude material was loaded onto the column and
chloroform was used to elute the sulfone while impurities remained on the column.
The single fraction collected from the column was evaporated. Recrystallization of
the remaining solid from ethanol yielded 0.10 g (0.27 mmol) of the rearranged
sulfone, 4-[(2-nitrophenyl)sulfonyl]-5,6-DHPA. Yield: 12%, mp 248–249 ꢀC.
1H NMR (400 MHz, DMSO-d6) d 9.39 (s, 1H), 9.23 (d, 1H), 8.90 (d, 1H), 8.75
(d, 1H), 8.50 (d, 1H), 8.25 (d, 1H), 8.07 (m, 3H), 7.85 (d, 3H). 13C NMR
(101 MHz, DMSO-d6) 155.32, 149.32, 140.04, 138.49, 135.93, 135.36, 134.49,
133.29, 133.20, 131.96, 130.84, 130.30, 130.17, 129.86, 127.57, 125.80, 125.58,
125.25, 123.35. IR (KBr pellet) (cmꢁ1) 1159.78 (SO2 sym str.). m=z 365.05740
(þmode) (C19H12N2O4S).
Sulfuric Acid Rearrangement of 2-Chloro-N-
[(4-methyl)phenyl]sulfonyl-5,6-dihdrophenathridine (11a) to
2-Chloro-4-[(4-methyl)phenyl]sulfonyl Phenanthridine (14a)
The sulfonanilide, 2-chloro-N-[(4-methylphenyl)sulfonyl]-5,6-DHPA (0.66 g,
1.78 mmol) was dissolved in 98% sulfuric acid and placed in the oven (105 ꢀC)
for 3 min. The mixture gradually darkened from colorless to red-brown. After heat-
ing, the mixture was quenched over ice and stirred with aqueous sodium bicarbon-
ate to remove any acid. The solid crude material was washed several times with
water and collected by vacuum filtration. Recrystallization from ethanol yielded
0.14 g (0.38 mmol) of the rearranged sulfone, 2-chloro-4-[(4-methylphenyl)sulfonyl]-
1
5,6-DHPA. Yield: 21%, mp 256–257 ꢀC. H NMR (400 MHz, DMSO-d6) 9.38 (s,
1H), 9.18 (s, 1H), 8.87 (d, 1H), 8.52 (s, 1H), 8.24 (d, 1H), 8.05 (d, 2H), 7.98 (t,

PHENANTHRIDINE SULFONAMIDES AND SULFONES
2567
1H), 7.88 (t, 1H), 7.37 (t, 2H), 2.34 (s, 3H). 13C NMR (101 MHz, DMSO-d6)
155.36, 144.80, 141.07, 139.63, 139.20, 133.18, 132.24, 131.29, 130.33, 130.17,
130.00 (2C), 129.97, 129.60 (2C), 129.56, 127.38, 126.76, 123.88, 21.80. IR (KBr
pellet) (cmꢁ1
(C20H15ClNO2S).
)
1147.95 (SO2 sym str.). m=z ASAP (þmode) 368.04886
Triflic Acid Rearrangement of 2-Chloro-N-
[(2-nitro)phenyl]sulfonyl-5,6-dihydrophenathridine (11b) to
2-Chloro-4-[(2-nitro)phenyl]sulfonyl Phenanthridine (14b)
The sulfonanilide, 2-chloro-N-[(2-nitrophenyl)sulfonyl]-5,6-DHPA (0.50 g,
mmol), was dissolved in trifluoromethane sulfonic acid (5 mL) and placed in the
oven (105 ꢀC) for 5 min. The mixture gradually darkened from colorless to
red-brown. After heating, the mixture was allowed to cool to room temperature
and quenched over ice. The solid crude material was washed several times with
water and collected by vacuum filtration. Column chromatography was used to iso-
late the rearranged product. Using 20 g of silica gel, the crude material was loaded
onto the column, and chloroform was used to elute the sulfone while impurities
remained on the column. Recrystallization from ethanol yielded 0.08 g of the rear-
ranged sulfone, 2-chloro-4-[(2-nitrophenyl)sulfonyl]phenanthridine. Yield: 16%,
1
mp 157–158 ꢀC. H NMR (400 MHz, DMSO-d6) 9.30 (d, 2H), 8.93 (d, 1H), 8.73
(d, 1H), 8.40 (s, 1H), 8.25 (d, 1H), 8.04 (m, 2H), 7.95 (m, 3H). 13C NMR
(101 MHz, DMSO-d6) 155.36, 144.80, 141.07, 139.63, 139.20, 133.18, 132.24,
131.29, 130.33, 130.12, 130.00 (2C), 129.97, 129.60 (2C), 129.56, 127.38, 126.76,
123.88, 21.80. IR (KBr) t 1150.29 (SO2 sym str.) cmꢁ1. m=z ASAP (þmode)
399.01564 (C19H12 ClN2O4S).
Attempted Rearrangement of 2-Nitro-N-
[(4-methyl)phenyl]sulfonyl-5,6-dihdrophenathridine (12) to
2-Nitro-4-[(4-methyl)phenyl]sulfonyl Phenanthridine (15)
The sulfonanilide, 2-nitro-N-[(4-methylphenyl)sulfonyl]-5,6-DHPA (0.87 g,
mmol), was dissolved in a mixture of triflic acid and triflic anhydride, loosely
corked, and then placed in the oven (105 ꢀC) for 60 min. Shorter times in the oven
resulted in recovery of mostly starting material. The mixture gradually darkened
from colorless to red-brown. After heating, the mixture was quenched over ice
and stirred with aqueous sodium bicarbonate to remove any acid. The solid crude
material was washed several times with water and collected by vacuum filtration.
Thin-layer chromatography (TLC) using ethyl acetate revealed multiple compo-
nents. Column chromatography was used to isolate any sulfone that would have
eluted quickly from the column. Recrystallization from ethanol yielded trace
amounts of the rearranged sulfone, 2-nitro-4-[(4-methylphenyl)sulfonyl]-5,6-DHPA
1
as well as oxidized 2-nitrophenanthridine. H NMR confirmed that a small amount
of sulfone had formed; however, quantities were too small for recrystallization. As
we had expected, the nitro group on the adjacent aromatic ring is not ideal for
rearrangement.

2568
L. M. N. MESEROLL, J. R. MCKEE, AND M. ZANGER
REFERENCES
1. (a) Gennaro, A.; Zanger, M. 1,2,3,4-Tetrahydroquinoline-8-sulfones. J. Org. Chem. 1971,
36, 1321; (b) Ren, H.; Zanger, M.; McKee, J. R. Synthesis of tetrahydrobenzazepinesulfo-
namides and their rearrangment to diarylsulfones. Synth. Commun. 2006, 36, 355; (c)
Raszka, B.; Zanger, M.; McKee, J. R. Rearrangement of indolinesulfonamides to sulfones
using polyphosphoric acid (PPA). Synth. Commun. 2010, 40, 1837; (d) Buckheit, Jr., R. W.;
Fliakas-Boltz, V.; Russell, J. D.; Snow, M.; Pallansch, L. A.; Yang, S. S.; Dader, J. P.;
Khan, T. N.; Zanger, M. A diarylsulphone non-nucleoside reverse transcriptase inhibitor
with a unique sensitivity profile to drug-resistant virus isolates. Antivir. Chem. Chemother.
1996, 7, 243.
2. (a) Jones, P. B.; Parrish, N. M.; Houston, T. A.; Stapon, A.; Bansal, N. P.; Dick, J. D.;
Townsend, C. A. A new class of antituberculosis agents. J. Med. Chem. 2000, 43, 3304;
(b) Vannada, J.; Bennett, E. M.; Wilson, D. J.; Boshoff, H. I.; Barry III, C. E.; Aldrich,
C. C. Design, synthesis, and biological evaluation of b-ketosulfonamide adenylation inhi-
bitors as potential antitubercular agents. Org. Lett. 2006, 8, 4707.
3. Hansch, C.; Leo, A.; Elkins, D. Exploring QSAR. Chem. Rev. 1971, 71(6), 525.
4. Patil, S.; Kamath, S.; Sanchez, T.; Neamati, N.; Schinazi, R. F.; Boulamwini, J. K.
Synthesis
and
biological
evaluation
of
novel
5(H)-phenanthridin-6-ones,
5(H)-phenanthridin-6-one diketo acid, and polycyclic aromatic diketo acid analogs as
new HIV-1 integrase inhibitors. Bioorg. Med. Chem. 2007, 15, 1212.
5. Beckmann, E. Zur Kenntniss der Isonitrosoverbindungen. Chem. Ber. 1886, 19, 988.