Azo Group-Assisted Nucleophilic Aromatic Substitutions in Haloarene Derivatives: Preparation of Substituted 1-Iodo-2,6-bispropylthiobenzenes

Article abstract of DOI:10.1021/jo0302399

Aryldiazo substituents were usfed in nucleophilic aromatic substitution reactions of halogens. The Ph-N=N- group activates ortho fluorine atoms toward alkylthiolation under mild conditions. In contrast, the Me2N-C6H4-N=N- group has virtually no activation effect in nucleophilic aromatic substitution, and serves as a "neutral" mask for the amino group. The Ph-N=N- group was efficiently introduced by diazo coupling of aryllithium with dry PhN2(1+)BF4(1-) salt.

Full text of DOI:10.1021/jo0302399

Azo Gr ou p -Assisted Nu cleop h ilic Ar om a tic Su bstitu tion s in
Ha loa r en e Der iva tives: P r ep a r a tion of Su bstitu ted
1-Iod o-2,6-bisp r op ylth ioben zen es
J ason, T. Manka,§ Virginia C. McKenzie, and Piotr Kaszynski*
Organic Materials Research Group, Chemistry Department, Vanderbilt University,
Nashville, Tennessee 37235
piotr@ctrvax.vanderbilt.edu
Received J uly 25, 2003
Aryldiazo substituents were used in nucleophilic aromatic substitution reactions of halogens. The
Ph-NdN- group activates ortho fluorine atoms toward alkylthiolation under mild conditions. In
contrast, the Me2N-C6H4-NdN- group has virtually no activation effect in nucleophilic aromatic
substitution, and serves as a “neutral” mask for the amino group. The Ph-NdN- group was
-
efficiently introduced by diazo coupling of aryllithium with dry PhN2+BF4 salt.
Further progress in the study of stable free heterocyclic
radicals1,2 required3 4-substituted 1-iodo-2,6-bis(propyl-
thio)benzenes 1 as synthetic intermediates. Such iodides
could be obtained from the corresponding amines 2 as
was already demonstrated for 1a .4 Therefore, we focused
on the preparation of 2 by propanethiolation of appropri-
ate 1,3-dihalides bearing a nitrogen-containing substitu-
ent N in position 2.
conditions for nonactivated halides5,7 and high temper-
atures and long reaction times for deactivated substrates
such as chloroanilines.6,8
The use of a nitro group as an activating group for
chloroarenes and as a precursor to the amino functional-
ity is very attractive but it is also limited. The NO2 has
higher leaving group mobility than the Cl substituent9
and can be replaced with nucleophiles in preference to
Cl.5,10 Thus, thiolation of 2,6-dichloro-1-nitrobenzene (3,
R ) H) gave the products of halogen displacement 4, R
) H, and nitro group substitution 5, R ) H, in about a
1:1 ratio.4 However, in the case of 3,5-dichloro-4-ni-
trobenzoic acid (3, R ) COOH) the undesired 3,5-dichloro-
4-propylthiobenzoic acid (5, R ) COOH) was formed
exclusively (Scheme 1).
Searching for another functional group N that could
(i) activate halogens in the ortho positions toward nu-
cleophilic aromatic substitution (NAS), (ii) would not
compete with the halogens in NAS, and (iii) can easily
be converted to NH2, we focused on the azo group.11 It
has been reported that the Ph-NdN- group has a
-
relatively high substituent constant12 σp of +0.65 (cf.
σp-(NO2) ) +1.27), and moderately activates halogens
in the ortho and para positions toward nucleophilic
displacement.9,13,14 For instance, it accelerates the rate
of substitution of chlorine in 4-substituted 1-chloro-2-
Alkylthiolation by displacement of halogens in aryl
halides is well-studied and documented.5,6 The process
is very facile for haloarenes activated by electron accept-
ing groups such as nitro, but it requires polar aprotic
* Author for correspondence should be sent. Phone: (615) 322-3458.
Fax: (615) 334-1234.
(7) Testaferri, L.; Tingoli, M.; Tiecco, M. J . Org. Chem. 1980, 45, 5,
4376-4380.
§ Present address: Roche Palo Alto LLC, Palo Alto, CA 94304.
(1) Kaszynski, P. In Magnetic Properties of Organic Materials; Lahti,
P. M., Ed.; Marcel Dekker: New York, 1999; pp 305-324.
(2) Benin, V.; Kaszynski, P. J . Org. Chem. 2000, 65, 8086-8088.
(3) Manka, J . T.; Guo, F.; Huang, J .; Yin, H.; Farrar, J . M.;
Sienkowska, M.; Benin, V.; Kaszynski, P. J . Org. Chem. 2003, 68,
9574-9588.
(8) Acylation of the nitrogen atom shortens the reaction time and
increases the yield. This could be an alternative way to prepare 2b
from 4-amino-3,5-dichlorobenzoic acid.
(9) Miller, J . Aromatic Nucleophilic Substitution; Elsevier: New
York, 1968, and references therein.
(10) Beck, J . R.; Yahner, J . A. J . Org. Chem. 1978, 43, 2048-2052
and 2052-2055.
(11) The chemistry of the hydrazo, azo and azoxy groups, Part 1;
Patai, S., Ed.; Wiley & Sons: New York, 1975.
(12) Syz, M.; Zollinger, H. Helv. Chim. Acta 1965, 48, 383-385.
(13) Badger, G. M.; Cook, J . W.; Vidal, W. P. J . Chem. Soc. 1947,
1109.
(4) Sienkowska, M.; Benin, V.; Kaszynski, P. Tetrahedron 2000, 56,
165-173.
(5) Paradisi, C. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Perhamon Press: New York, 1991; Vol. 4, pp 441-
444 and references therein.
(6) Caruso, A. J .; Colley, A. M.; Bryant, G. L. J . Org. Chem. 1991,
56, 862-865.
(14) Courtney, J . J .; Geipel, L. E.; Shriner, R. L. Iowa Acad. Sci.
1955, 62, 264-267.
10.1021/jo0302399 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/13/2004
J . Org. Chem. 2004, 69, 1967-1971
1967

Manka et al.
SCHEME 1
SCHEME 3
SCHEME 2
Extension of this method to the preparation 2c was
unsuccessful. The thiolation of 8 with sodium 1-pro-
panethiolate in DMSO gave a mixture of compounds
among which the dithiolated product was identified by
1H NMR to be the 2,5-bis(propylthio) derivative 9 instead
of the desired 2,6-bis(propylthio) isomer 10 (Scheme 3).
The conditions to effect the thiolation of 6 and 8
suggest that the 4-Me2N-C6H4-NdN- substituent has a
“neutral” character in NAS and the halides are non-
activated. This is consistent with the formation of the
2,5-regioisomer 9 instead of the 2,6-derivative 10 in
thiolation of 8, which parallels the formation of 1,4-bis-
(alkylthio)-2,5-dichlorobenzene as the sole product of
thiolation of 1,2,4,5-tetrachlorobenzene under PTC condi-
tions.15 Also, the observation of small amounts of the
1
mono- and trithiolated derivatives, as identified by H
NMR, suggests that the thiolation of 8, and presumably
6, is qualitatively not different from the reaction of the
parent chloroarene. Thus, the weak activating effect of
the parent Ph-NdN- group appears to be compensated
by the strong positive resonance effect of the Me2N
substituent, and the role of the 4-Me2N-C6H4-NdN-
group in NAS can be described best as a neutral mask
for the amino functionality.
To increase the regioselectivity of the thiolation, we
focused on partially fluorinated arenes, since it has been
reported that thiolate anions exclusively replace fluorine
on benzene rings when both bromine and fluorine atoms
are present.16,17 It was also expected that use of Ph-Nd
N- instead of 4-Me2N-C6H4-NdN- group should have a
significant effect on activation of ortho halogens. There-
fore, the strategy of making the azo compounds was
changed and it took advantage of the regioselective ortho-
lithiation reported17,18 for 11d and diazo coupling with
aromatic carbanions.19-22
nitrobenzenes by a factor of about 500 relative to H,
which compares to about 103 for an ester and 105 for the
NO2 group.9 In addition, the azo group cannot be dis-
placed by the thiolate anion, and can easily be reduced
to the requisite amino group. Therefore, we focused on
the aryldiazo group to activate halogens as a key step in
the preparation of 2.
The phenyldiazo group could not be introduced easily
into 3,5-dichlorobenzoic acid, and therefore the 4-di-
methylaminophenyldiazo group was used instead. Thus,
azo acid 6, prepared from 4-amino-3,5-dichlorobenzoic
acid by diazo coupling, was converted to its sodium salt
and reacted with propanethiolate anion under polar
aprotic conditions to give the expected bispropylthio
derivative 7 (Scheme 2). The optimum temperature for
the reaction was between 90 and 100 °C. At lower
temperatures the reaction was slow, and above 100 °C,
the reduction of the azo functionality by the thiolate was
observed. Both of the azo compounds 6 and 7 were
difficult to purify and were used in their crude forms.
Reduction of 7 with iron or sodium dithionate gave the
amino acid 2b in about 17% overall yield based on the
starting amino acid. Diazotization of 2b followed by
reaction with iodide gave the desired 4-iodo-3,5-bis-
(propylthio)benzoic acid (1b) in 38% unoptimized yield.
(15) Brunelle, D. J . J . Org. Chem. 1984, 49, 1309-1311.
(16) Frazee, W. J .; Peach, M. E. J . Fluorine Chem. 1979, 13, 225-
233.
(17) Manka, J . T.; Kaszynski, P. J . Fluorine Chem. 2003, 124, 39-
43.
(18) Coe, P. L.; Waring, A. J .; Yarwood, T. D. J . Chem. Soc., Perkin
Trans. 1 1995, 2729-2737.
1968 J . Org. Chem., Vol. 69, No. 6, 2004

1-Iodo-2,6-bispropylthiobenzenes
SCHEME 4
The thiolation of a cis and trans mixture of isomers
12 with sodium 1-propanethiolate occurred smoothly in
warm ethanol yielding a single isomer of bispropylthio
derivative 13. This is in sharp contrast with the results
for 6 and 8. Considering that 11d , in which the azo group
is absent, is completely inert toward the thiolate in hot
ethanol during 48 h, the Ph-NdN- substituent activates
the ortho fluorine atoms for NAS. The observed signifi-
cantly higher reactivity of 12c as compared to 8 is related
to a combination of two effects:9 (a) higher mobility of F
than Cl by a factor of 102-103 and (b) higher ability of
the Ph-NdN- group to accommodate the negative charge
as compared to the 4-Me2N-C6H4-NdN- substituent.
Reduction of the crude azo 13 with iron in acetic acid
gave amine 2 in about 90% overall yield based on azo 12
(Scheme 4). The amine 2 was converted to the iodide 1
via the corresponding diazonium salt prepared in acetic
acid. Substitution of propionic acid for acetic acid im-
proved the procedure and the yield (1c) by decreasing
the viscosity of the reaction mixture at low temperatures
and more efficient stirring. Both iodides 1c and 1d are
nonpolar oils and their purification proved to be quite
difficult, especially the dichloro derivative 1c. Repeated
column chromatography allowed both iodides to be
isolated in >95% purity, which was sufficient for further
transformations.
This study demonstrates that the phenyldiazo group
is a useful alternative to a nitro group in the activation
of fluorine atoms toward nucleophilic aromatic substitu-
tion (NAS) with an alkanethiolate nucleophile. The azo
group can be conveniently introduced by diazo coupling
to an aryl anion generated by ortho lithiathion with LDA.
This sequence and another involving azo condensation26-
NAS-reduction can, in principle, be extended to other
fluoro(chloro)benzenes and haloanilines.
The starting difluoroarenes 11 were prepared by
halogenation of the appropriate 1-halo-2,4-difluoroben-
zenes (Scheme 4). Chlorination of 1-chloro-2,4-difluo-
robenzene to form 11c was accomplished with NCS by
using conditions for the bromination of deactivated
compounds with NBS.23 The quality of the NCS was
found to be crucial for efficient and complete chlorination,
and only freshly purchased reagent gave high yields of
11c. The original procedure24 for the preparation of 11d
was modified to make it more efficient for large-scale
synthesis.
The lithiation of 11 with LDA at -78 °C gave the
corresponding phenyl anion.17 Its subsequent reaction
with dry benzenediazonium salt gave the azo derivatives
12c and 12d in 65% and 74% optimized yield, respec-
tively, as a mixture of cis and trans isomers in ratios as
high as 2:3 (12d ).25 The temperature of the lithiation and
the reaction with the diazonium salt proved to be
important for yield and purity of the azo product. If the
temperature was allowed to increase from -78 °C due
to fast addition of reagents, especially the dry diazonium
salt, the formation of other compounds was observed by
TLC and the purification of the product 12 was more
difficult.
Exp er im en ta l Section
4-Iodo-3,5-bis(pr opylth io)ben zoic Acid (1b). Solid NaNO2
(120 mg, 1.8 mmol) was added to concentrated H2SO4 (1.8 mL).
The mixture was stirred and heated to 70 °C until full
dissolution of the solid. The resultant nitrosylsulfuric acid was
cooled to 0 °C, and amino acid 2b (150 mg, 0.53 mmol)
dissolved in AcOH (1.1 mL) was added dropwise at 0 °C. After
45 min of stirring, a solution of KI (340 mg, 2.2 mmol) in water
(3.8 mL) was added. The reaction was stirred at 70 °C for 0.5
h and then poured into water (50 mL). The organics were
extracted with CH2Cl2, and the crude product was purified on
a silica gel column (benzene/EtOAc, 3:1) to give acid 1b (80
mg, 38% yield) as a white solid. An analytical sample of 1b
was obtained by recrystallizing from AcOH: mp 136-137 °C;
1H NMR δ 1.11 (t, J ) 7.2 Hz, 6H), 1.80 (sextet, J ) 7.4 Hz,
4H), 2.97 (t, J ) 7.3 Hz, 4H), 7.57 (s, 2H); 13C NMR δ 13.7,
21.5, 36.2, 108.4, 122.3, 129.3, 145.4, 171.5; IR (KBr) 1689 (Cd
O), 1290 (C-O) cm-1. Anal. Calcd for C13H17IO2S2: C, 39.40;
H, 4.32. Found: C, 39.52; H, 4.37.
(25) The cis and trans isomers of 12 were separated either by column
chromatography or by slow cocrystallization from methanol, followed
by careful separation of two crystalline forms (12d ). The less polar
isomer was identified as the trans azo derivative based on chromato-
graphic (Gerson, F.; Heilbronner, E.; van Veen, A.; Wepster, B. M. Helv.
Chim. Acta 1960, 43, 1889-1898) and spectroscopic (Tait, K. M.;
Parkinson, J . A.; Bates, S. P.; Ebenezer, W. J .; J ones, A. C. J .
Photochem. Photobiol. A 2003, 154, 179-188. Crogan, C.; Fields, R.;
Pratt, A. C.; Saleem, L. M. N.; Dawson, P. E. J . Fluorine Chem. 1983,
22, 61-72) trends in azobenzenes.
(19) Nomura, Y.; Anzai, H.; Tarao, R.; Shiomi, K. Bull. Chem. Soc.
J pn. 1964, 37, 967-969. Nomura, Y.; Anzai, H. Bull. Chem. Soc. J pn.
1964, 37, 970-973.
(20) Curtin, D. Y.; Tveten, J . L. J . Org. Chem. 1961, 26, 1764-1768.
(21) Garst, M. E.; Lukton, D. Synth. Commun. 1980, 10, 155-160.
(22) Barbero, M.; Degani, I.; Dughera, S.; Fochi, R.; Perracino, P.
Synthesis 1998, 1235-1237.
(23) Duan, J .; Zhang, L. H.; Dolbier, W. R., J r. Synlett 1999, 1245-
1246.
(24) Wang, Z.-X.; Duan, W.; Wiebe, L. I.; Balzarini, J .; De Clercq,
E.; Knaus, E. E. Nucleosides Nucleotides Nucleic Acids 2001, 20, 11-
40.
(26) Lang-Fugmann, S. In Organische Stickstoff-Verbindung IV;
Klamann, D., Ed.; Georg Thieme: New York, 1992; Vol. E16d, pp 56-
59.
J . Org. Chem, Vol. 69, No. 6, 2004 1969

Manka et al.
1,5-Dibr om o-3-iod o-2,4-bis(p r op ylth io)ben zen e (1d ). A
solution of amine 2d (595 mg, 1.5 mmol) in AcOH (5 mL) was
added dropwise with stirring to nitrosylsulfuric acid (1.9 mmol
of NaNO2; see 1b) at 5 °C. After 0.5 h, a solution of KI (840
mg, 5.1 mmol) in water (10 mL) was added at once, and the
resultant mixture was stirred for 20 min at 70 °C. This mixture
was then poured into 5% Na2S2O5 solution (100 mL) and
extracted (CH2Cl2). The extracts were dried (Na2SO4) and
passed through a short silica gel column (CH2Cl2). The crude
product was dissolved in pentane and placed in a freezer
overnight to separate a white fluffy byproduct. Pentane was
removed, and the oily residue was purified on a silica gel
column (CH2Cl2/hexanes, 1:7) to give iodide 1d (380 mg, 50%
yield) as a pale yellow oil: 1H NMR δ 1.04 (t, J ) 7.4 Hz, 6H),
1.65 (sextet, J ) 7.3 Hz, 4H), 2.90 (t, J ) 7.4 Hz, 4H), 8.01 (s,
1H); 13C NMR δ 13.7, 22.7, 39.2, 127.5, 129.6, 136.8, 142.2;
EI-MS m/z 512, 510, 508 (M, 34:58:26), 218 (100). Anal. Calcd
for C12H15Br2IS2: C, 28.26; H, 2.96. Found: C, 28.40; H, 2.98.
4-Am in o-3,5-bis(p r op ylth io)ben zoic Acid (2b). A sus-
pension of 4-amino-3,5-dichlorobenzoic acid (5.00 g, 24.3 mmol)
in AcOH (60 mL) was added dropwise to nitrosylsulfuric acid
(36.2 mmol of NaNO2; see 1b) at 0-5 °C. After the mixture
was stirred for 1.5 h, ice (300 g) was added, and the reaction
mixture was added to a stirring solution of N,N-dimethyl-
aniline (4.00 g, 33.1 mmol) in AcOH (70 mL) at 0 °C. The
mixture was stirred overnight at room temperature. The
resultant dark-red mixture was neutralized to pH 6-7 with
aqueous NaOH and refrigerated for several hours. The pre-
cipitate that formed upon neutralization was filtered off and
washed with brine. On the basis of NMR, the crude product
(4.36 g) contained about 75% 4-(4-(N,N-dimethylamino)phe-
nyldiazo)-3,5-dichlorobenzoic acid (6), and it was used in the
subsequent step without further purification: 1H NMR (major
peaks) δ 3.14 (s, 6H), 6.78 (d, J ) 9.2 Hz, 2H), 7.94 (d, J ) 9.9
Hz, 2H), 8.09 (s, 2H).
NaH (60% dispersion in mineral oil, 2.80 g, 70 mmol) was
carefully added to a solution of crude azo acid 6 (7.35 g, 21.73
mmol) in dry DMSO (80 mL) at room temperature. 1-Pro-
panethiol (3.33 g, 43.5 mmol) was slowly added to the flask
via syringe and the solution was stirred at 100 °C overnight.
The mixture was slowly poured into 1 M HCl (350 mL) and
the precipitate that formed was either filtered or extracted
with CH2Cl2. On the basis of NMR, the resulting crude 4-(4-
(N,N-dimethylamino)phenyldiazo)-3,5-bis(propylthio)benzoic acid
(7) product (5.34 g) was about 75-80% pure, and it was used
in the subsequent step without further purification: 1H NMR
(major peaks) δ 1.06 (t, J ) 7.4 Hz, 6H), 1.72 (sextet, J ) 7.3
Hz, 4H), 2.93 (t, J ) 7.3 Hz, 4H), 3.12 (s, 6H), 6.77 (d, J ) 9.2
Hz, 2H), 7.96 (d, J ) 9.2 Hz, 2H), 8.08 (s, 2H).
combined extracts were passed through a silica gel plug (CH2-
Cl2). The solvent was removed and the crude product was
purified on a silica gel column (CH2Cl2/hexanes, 1:4) to give
amine 2d (3.61 g, 93% yield from 12d ) as an off-white solid:
mp 45-46 °C; 1H NMR δ 0.99 (t, J ) 7.4 Hz, 6H), 1.58 (sextet,
J ) 7.4 Hz, 4H), 2.74 (t, J ) 7.3, 4H), 5.79 (br s, 2H), 7.29 (s,
1H); 13C NMR δ 13.5, 23.1, 36.8, 117.1, 124.5, 133.3, 154.1; IR
(KBr) 3450 and 3341 (N-H) cm-1; EI-MS m/z 401, 399, 397
(M, 56:100:46). Anal. Calcd for C12H17Br2NS2: C, 36.11; H,
4.29; N, 3.51. Found: C, 36.37; H, 4.30; N, 3.53.
3,5-Dich lor o-4-p r op ylth ioben zoic Acid (5, R ) COOH).
A mixture of crude acid 3 (R ) COOH; 7.4 g, 31.4 mmol),
1-propanethiol (8.6 mL, 100 mmol), NaOH (6.4 g, 160 mmol),
o
and water (125 mL) was stirred at 90 C for 5 h. A spoonful of
charcoal was added, the reaction mixture was filtered, and the
crude product was precipitated by adding concentrated HCl.
The product was filtered and, after drying, recrystallized twice
(hexanes) to give acid 5 (R ) COOH, 5.8 g, 70% yield) as a
1
white solid: mp 124-125 °C; H NMR δ 1.01 (t, J ) 7.3 Hz,
3H), 1.58 (sextet, J ) 7.3 Hz, 2H), 2.98 (t, J ) 7.2 Hz, 2H),
8.06 (s, 2H); 13C NMR δ 13.3, 23.2, 37.5, 129.5, 130.1, 140.4,
141.3, 170.1. Anal. Calcd for C10H10Cl2S: C, 45.30; H, 3.80.
Found: C, 45.37; H, 3.84.
1,3-Dibr om o-4,6-d iflu or o-5-p h en yld ia zoben zen e (12d ).
A 2.4 M solution of n-BuLi (24 mL, 57.6 mmol) was slowly
added to diisopropylamine (6.3 g, 62.3 mmol) in dry THF (30
mL) under N2 at -5 °C. After 0.5 h, the solution of LDA was
transferred via cannula to a jacketed addition funnel (-78 °C),
and added dropwise to halobenzene 11d (13.6 g, 50 mmol) in
THF (110 mL) at -78 °C. After the mixture was stirred for 45
min, dry benzenediazonium tetrafluoroborate27 (11.5 g, 60.0
mmol) was added in small portions from an attached flask via
a flexible transfer tube over a 0.5-h period. The temperature
during addition was maintained at -78 °C. The mixture was
stirred at -78 °C for an additional 3 h, and was allowed to
warm to room temperature. A 6 M solution of HCl (30 mL)
was added. The volume of THF was reduced, and the mixture
was poured into water and extracted (CH2Cl2/hexanes, 1:7).
The combined extracts were dried (Na2SO4) and passed
through a short silica gel column (CH2Cl2/hexanes, 1:7). The
solvent was removed to give 18.2 g of crude material that
solidified upon standing. The material was dissolved in re-
fluxing MeOH and then allowed to cool to room temperature.
This produced 6.2 g of pure orange crystals that were filtered
and washed with cold MeOH. The mother liquor and washings
were concentrated and refluxed to redissolve the product and
placed in the freezer overnight to give an additional 3.2 g of
pure crystals. MeOH was removed from the filtrate and the
residue passed through a silica gel column to give an additional
4.6 g of the product. This gave the combined yield of 14.0 g or
74% of an isomeric mixture of 12d : EI-MS m/z 378, 376, 374
(M+, 8, 16, 8), 77 (100). Anal. Calcd for C12H6Br2F2N2: C, 38.33;
H, 1.61; N, 7.45. Found: C, 38.54; H, 1.57; N, 7.47.
A mixture of water (20 mL), reduced iron powder (250 mg),
and the crude azo acid 7 (2.19 g) was gently refluxed overnight.
Alternatively, crude acid 7 (5.5 g, 13.2 mmol) was reduced with
an alkaline solution (50 mL of 10% NaOH) of Na2S2O4 (6.07
g, 34.9 mmol). The mixture was stirred and heated until full
dissolution. After acidification the precipitate was filtered off.
The resulting crude acid was dissolved in a small amount of
CH2Cl2 and passed through a silica gel plug (CH2Cl2/acetone,
20:1). The solvent was removed and the crude product was
recrystallized twice (isooctane) to give pure acid 2b in about
40% yield based on 7 or 17% overall yield based on the starting
A sample of the mixture was separated by column chroma-
tography to give the trans isomer as the first fraction and cis
isomer as the second.
Trans isomer 12d was obtained as orange crystals (MeOH):
1
mp 77-78 °C; H NMR δ 7.46-7.51 (m, 3H), 7.72 (t, J ) 6.8
Hz, 1H), 7.85-7.89 (m, 2H); 13C NMR δ 105.4-105.8 (m),
2
123.3, 129.3, 132.6 (t, J CF ) 13 Hz), 132.8, 134.9, 151.3 (dd,
3
1J CF ) 260 Hz, J CF ) 4 Hz), 152.8; 19F NMR δ -114.4.
1
amino acid: mp 112-114 °C; H NMR δ 1.00 (t, J ) 7.3 Hz,
Cis isomer 12d was obtained as yellow-orange microcrystals
6H), 1.60 (sextet, J ) 7.3 Hz, 4H), 2.76 (t, J ) 7.2 Hz, 4H),
5.65 (br s, 2H), 8.09 (s, 2H); 13C NMR δ 13.3, 22.9, 37.0, 117.6,
117.9, 137.8, 154.0, 171.4; IR (KBr) 3462 and 3352 (N-H),
1669 (CdO), 1270 (C-O) cm-1. Anal. Calcd for C13H19NO2S2:
C, 54.71; H, 6.71; N, 4.91; S, 22.47. Found: C, 54.81; H, 6.72:
N, 4.91; S, 22.35.
1
(MeOH): mp 68-69 °C; H NMR δ 6.85 (d, J ) 7.1 Hz, 2H),
7.19-7.30 (m, 3H), 7.50 (t, J ) 6.8 Hz, 1H); 13C NMR δ 104.8-
2
105.1 (m), 118.5, 129.0, 129.2, 132.3 (t, J CF ) 22 Hz), 133.5,
1
3
146.4 (dd, J CF ) 251 Hz, J CF ) 5 Hz), 154.6; 19F NMR δ
-112.2.
1,3-Dib r om o-5-p h e n yld ia zo-4,6-b is(p r op ylt h io)b e n -
zen e (13d ). An isomeric mixture of azo derivative 12d (5.0 g,
3,5-Dibr om o-2,6-bis(p r op ylth io)a n ilin e (2d ). Crude azo
compound (13d , 6.5 g, 13.3 mmol) was dissolved in AcOH (80
mL), electrolytic grade iron (1 g) was added, and the reaction
was stirred at 90 °C overnight. The reaction mixture was
poured into water (300 mL) and extracted with CH2Cl2. The
(27) Furniss, B. S.; Hannaford, A. J .; Smith, P. W. G.; Tatchell, A.
R. Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Wiley: New
York, 1989; p 939.
1970 J . Org. Chem., Vol. 69, No. 6, 2004

1-Iodo-2,6-bispropylthiobenzenes
13.4 mmol) was dissolved in 95% EtOH (50 mL) with stirring
at 70 °C. A solution of NaOH (1.4 g, 35 mmol) and 1-pro-
panethiol (2.56 g, 34 mmol) in 95% EtOH (15 mL) was added,
and the reaction was stirred overnight at 80 °C. Most of the
EtOH was removed and 6 M HCl (40 mL) was added. The
mixture was poured into water (300 mL) and extracted with
CH2Cl2. The combined extracts were dried (Na2SO4) and
passed through a silica gel plug (CH2Cl2/hexane, 1:2). The
solvent was then removed to give 13d (6.5 g) as a red-orange
oil that was used without purification for the next step. An
analytical sample of 13d was obtained by column chromatog-
raphy (CH2Cl2/hexanes, 1:3): 1H NMR δ 0.79 (t, J ) 7.3 Hz,
6H), 1.38 (sextet, J ) 7.3 Hz, 4H), 2.58 (t, J ) 7.1 Hz, 4H),
7.46-7.51 (m, 3H), 7.85-7.89 (m, 3H); 13C NMR δ 13.3, 22.7,
38.4, 123.1, 126.9, 129.2, 132.1, 132.3, 134.7, 151.9, 163.1.
Anal. Calcd for C18H20Br2N2S2: C, 44.28; H, 4.13; N, 5.74.
Found: C, 44.48; H, 4.22; N, 5.76.
Ack n ow led gm en t. This project was supported in
part by NSF grants (CHE-9703002 and CHE-0096827).
We thank Dr. Vladimir Benin for his help with char-
acterization of acid 1b and Ms. Monika Sienkowska for
her technical assistance.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures, full experimental details, and characterization
for known compounds (3 (R ) COOH),28 11c,29 and 11d 24,30),
analogous compounds (1c, 2c, 12c, and 13c), and 8 and 9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(28) Horrom, B. W.; Lynes, T. E. J . Med. Chem. 1963, 6, 528-532.
(29) Vorozhtsov, N. N., J r.; Yakobson, G. G.; Krizhechkovskaya, N.
I. Khim. Nauka Promst. 1958, 3, 404-405; Chem Abstr. 1958, 52,
19987h.
(30) Nazarpack-Kandlousy, N.; Nelen, M. I.; Goral, V.; Eliseev, A.
V. J . Org. Chem. 2002, 67, 59-65.
J O0302399
J . Org. Chem, Vol. 69, No. 6, 2004 1971