Electrophilic Amination of 4-Fluorophenol with Diazenes: A Complete Removal of the Fluorine Atom

Article abstract of DOI:10.1021/jo035856b

The electrophilic amination of 2-fluorophenol, 4-fluorophenol, and 2-chlorophenol was observed to occur as a result of their treatment with diazenes 1-4 under mild reaction conditions in the presence of ZrCl ₄. The products originating from the

Full text of DOI:10.1021/jo035856b

SCHEME 1
Electr op h ilic Am in a tion of 4-F lu or op h en ol
w ith Dia zen es: A Com p lete Rem ova l of th e
F lu or in e Atom †
Sergeja Bombek, Franc Pozˇgan, Marijan Kocˇevar, and
Slovenko Polanc*
Faculty of Chemistry and Chemical Technology,
University of Ljubljana, Asˇkercˇeva 5,
SI-1000 Ljubljana, Slovenia
drazides9 and other N-N-containing compounds,10 we
recently reported on the electrophilic amination of 4-h-
alophenols and 2,4-dihalophenols with diisopropyl diaz-
enedicarboxylate in the presence of ZrCl4 as a Lewis acid.
In several cases, the reactions led to a mixture of two
products that were aminated either at the ortho or at the
para position, with respect to the phenolic OH (Scheme
1).11 The formation of products bearing the corresponding
hydrazino functionality at position 4 indicated that the
slovenko.polanc@uni-lj.si
Received December 22, 2003
Abst r a ct : The electrophilic amination of 2-fluorophenol,
4-fluorophenol, and 2-chlorophenol was observed to occur as
a result of their treatment with diazenes 1-4 under mild
reaction conditions in the presence of ZrCl4. The products
originating from the 2-fluorophenol or 2-chlorophenol can
be considered as “normal” products of amination. On the
other hand, the 2-chloro-4-amino-substituted phenols ob-
tained from the 4-fluorophenol seem to be formed in a
process that involves an ipso amination, the complete
removal of the fluorine atom, and the introduction of the
chlorine atom.
(5) (a) Heiss, C.; Schlosser, M. Eur. J . Org. Chem. 2003, 447-451.
(b) Rausis, T.; Schlosser, M. Eur. J . Org. Chem. 2002, 3351-3358. (c)
Bobbio, C.; Schlosser, M. Eur. J . Org. Chem. 2001, 4533-4536. (d)
Schlosser, M.; Castagnetti, E. Eur. J . Org. Chem. 2001, 3991-3997.
(e) Mongin, F.; Marzi, E.; Schlosser, M. Eur. J . Org. Chem. 2001, 2771-
2777. (f) Marzi, E.; Bigi, A.; Schlosser, M. Eur. J . Org. Chem. 2001,
1371-1376. (g) Mongin, F.; Desponds, O.; Schlosser, M. Tetrahedron
Lett. 1996, 37, 2767-2770.
(6) See also: (a) Eskildsen, J .; Østergaard, N.; Vedsø, P.; Begtrup,
M. Tetrahedron 2002, 58, 7635-7644. (b) Sammakia, T.; Stangeland,
E. L.; Whitcomb, M. C. Org. Lett. 2002, 4, 2385-2388. (c) Lukevics,
E.; Arsenyan, P.; Belyakov, S.; Popelis, J .; Pudova, O. Tetrahedron Lett.
2001, 42, 2039-2041. (d) Collins, I. J . Chem. Soc., Perkin Trans. 1
2000, 2845-2861. (e) Mattson, R. J .; Sloan, C. P.; Lockhart, C. C.; Catt,
J . D.; Gao, Q.; Huang, S. J . Org. Chem. 1999, 64, 8004-8007. (f)
Consiglio, G.; Spinelli, D.; Dell’Erba, C.; Novi, M.; Petrillo, G. Gazz.
Chim. Ital. 1997, 127, 753-769. (g) Bjork, P.; Malm, J .; Hornfeldt, A.
B.; Gronowitz, S. Heterocycles 1997, 44, 237-253. (h) Giumanini, A.
G.; Verardo, G.; Geatti, P.; Strazzolini, P. Tetrahedron 1996, 52, 7137-
7148. (i) Frohlich, J .; Hametner, C.; Kalt, W. Monatsh. Chem. 1996,
127, 325-330. (j) Frohlich, J .; Hametner, C. Monatsh. Chem. 1996,
127, 435-443. (k) Frohlich, J . Bull. Soc. Chim. Belg. 1996, 105, 615-
634. (l) Comins, D. L.; Saha, J . K. Tetrahedron Lett. 1995, 36, 7995-
7998. (m) Belohradsky, M.; Holy, P.; Zavada, J . J . Chem. Soc., Perkin
Trans. 2 1995, 1853-1856. (n) Bury, P.; Hareau, G.; Kocien´ski, P.;
Dhanak, D. Tetrahedron 1994, 50, 8793-8808. (o) Hawkins, D. W.;
Iddon, B.; Longthorne, D. S.; Rosyk, P. J . J . Chem. Soc., Perkin Trans.
1 1994, 2735-2743.
It has been known for 50 years that a halogen atom
on the thiophene ring can migrate in the presence of a
strong base.1 A similar observation was reported for the
case of halogenated benzenes by Wotiz and Huba.2 This
transformation, also known as the “halogen dance”, was
later thoroughly investigated by several groups.3-6 In
contrast, acid-promoted halogen migration rarely occurs
with aromatic molecules and is limited to bromine7 and
iodine.8 As a part of our continuing interest in hy-
† Dedicated to Professor Sa´ndor Antus, University of Debrecen, on
the occasion of his 60th birthday.
(1) Vaitiekunas, A.; Nord, F. F. J . Am. Chem. Soc. 1953, 75, 1764-
1768.
(2) Wotiz, J . H.; Huba, F. J . Org. Chem. 1959, 24, 595-598.
(3) For reviews, see: (a) Schlosser, M. Eur. J . Org. Chem. 2001,
3975-3984. (b) Smith, M. B.; March, J . In March’s Advanced Organic
Chemistry: Reactions, Mechanisms, and Structures, 5th ed.; Wiley:
New York, 2001; p 735. (c) Que´guiner, G.; Marsais, F.; Snieckus, V.;
Epsztajn, J . Adv. Heterocycl. Chem. 1991, 52, 187-304. (d) Bunnett,
J . F. Acc. Chem. Res. 1972, 5, 139-147.
(4) (a) Lazaar, J .; Rebstock, A.-S.; Mongin, F.; Godard, A.; Tre´court,
F.; Marsais, F.; Que´guiner, G. Tetrahedron 2002, 58, 6723-6728. (b)
Toudic, F.; Ple, N.; Turck, A.; Que´guiner, G. Tetrahedron 2002, 58,
283-293. (c) Godard, A.; Rocca, P.; Guillier, F.; Duvey, G.; Nivoliers,
F.; Marsais, F.; Que´guiner, G. Can. J . Chem. 2001, 79, 1754-1761.
(d) Arzel, E.; Rocca, P.; Grellier, P.; Labae¨ıd, M.; Frappier, F.; Gue´ritte,
F.; Gaspard, C.; Marsais, F.; Godard, A.; Que´guiner, G. J . Med. Chem.
2001, 44, 949-960. (e) Arzel, E.; Rocca, P.; Marsais, F.; Godard, A.;
Que´guiner, G. Tetrahedron 1999, 55, 12149-12156. (f) Arzel, E.; Rocca,
P.; Marsais, F.; Godard, A.; Que´guiner, G. Heterocycles 1999, 50, 215-
226. (g) Arzel, E.; Rocca, P.; Marsais, F.; Godard, A.; Que´guiner, G.
Tetrahedron Lett. 1998, 39, 6465-6466. (h) Ple, N.; Turck, A.; Heyn-
derickx, A.; Que´guiner, G. Tetrahedron 1998, 54, 9701-9710. (i) Ple,
N.; Turck, A.; Heynderickx, A.; Que´guiner, G. Tetrahedron 1998, 54,
4899-4812. (j) Trecourt, F.; Gervais, B.; Mallet, M.; Que´guiner G. J .
Org. Chem. 1996, 61, 1673-1676. (k) Cochennec, C.; Rocca, P.; Marsais,
F.; Godard, A.; Que´guiner, G. Synthesis 1995, 321-324. (l) Guillier,
F.; Nivoliers, F.; Godard, A.; Marsais, F.; Que´guiner, G. Tetrahedron
Lett. 1994, 35, 6489-6492. (m) Ple, N.; Turck, A.; Couture, K.;
Que´guiner, G. Tetrahedron 1994, 50, 10299-10308. (n) Rocca, P.;
Cochennec, C.; Marsais, F.; Thomas-dit-dumont, L.; Mallet, M.; Godard,
A.; Que´guiner, J . Org. Chem. 1993, 58, 7832-7838. (o) Marsais, F.;
Pineau, P.; Nivolliers, F.; Mallet, M.; Turck, A.; Godard, A.; Que´guiner,
J . Org. Chem. 1992, 57, 565-573.
(7) (a) Giles, R. G. F.; Green, I. R.; Knight, L. S.; Son, V. R. L.; Yorke,
S. C. J . Chem. Soc., Perkin Trans. 1 1994, 865-873. (b) Giles, R. G.
F.; Green, I. R.; Knight, L. S.; Son, V. R. L.; Mitchell, P. R. K.; Yorke,
S. C. J . Chem. Soc., Perkin Trans. 1 1994, 853-857. (c) J acquesy, J .-
C.; J ouannetaud, M.-P. Tetrahedron Lett. 1982, 23, 1673-1676. (d)
Press, J . B.; Eudy, N. H. J . Heterocycl. Chem. 1981, 18, 1261-1262.
(e) Brittain, J . M.; de la Mare, P. B. D.; Newman, P. A. Tetrahedron
Lett. 1980, 21, 4111-4112.
(8) (a) Muramoto, Y.; Asakura, H.; Suzuki, H. Nippon Kagaku Kaishi
1992, 172-178. (b) Butler, A. R.; Sanderson, A. P. J . Chem. Soc., Perkin
Trans. 2 1972, 989-992.
(9) (a) Pozˇgan, F.; Polanc, S.; Kocˇevar, M. Synthesis 2003, 2349-
2352. (b) Pozˇgan, F.; Polanc, S.; Kocˇevar, M. Heterocycles 2001, 54,
1011-1019. (c) Kafka, S.; Trebsˇe, P.; Polanc, S.; Kocˇevar, M. Synlett
2000, 254-256. (d) Polanc, S. In Targets in Heterocyclic Systems.
Chemistry and Properties; Attanasi, O. A., Spinelli D., Eds.; Societa`
Chimica Italiana: Rome, 2000; Vol. 3 (1999), pp 33-91. (e) Sˇtefane,
B.; Kocˇevar, M.; Polanc, S. Tetrahedron Lett. 1999, 40, 4429-4432. (f)
Kepe, V.; Pozˇgan, F.; Golobicˇ, A.; Polanc, S.; Kocˇevar, M. J . Chem. Soc.,
Perkin Trans. 1 1998, 2813-2816. (g) Kocˇevar, M.; Mihorko, P.; Polanc,
S. J . Org. Chem. 1995, 60, 1466-1469.
(10) (a) Bombek, S.; Lenarsˇicˇ, R.; Kocˇevar, M.; Polanc, S. Synlett
2001, 1237-1240. (b) Sˇtefane, B.; Cˇ ernigoj, U.; Kocˇevar, M.; Polanc,
S. Tetrahedron Lett. 2001, 42, 6659-6662. (c) Kosˇmrlj, J .; Kocˇevar,
M.; Polanc, S. J . Chem. Soc., Perkin Trans. 1 1998, 3917-3919. (d)
Sˇtefane, B.; Kocˇevar, M.; Polanc, S. J . Org. Chem. 1997, 62, 7165-
7169. (e) Kosˇmrlj, J .; Kocˇevar, M.; Polanc, S. Synlett 1996, 652-654.
(11) Bombek, S.; Lenarsˇicˇ, R.; Kocˇevar, M.; Saint-J almes, L.;
Desmurs, J .-R.; Polanc, S. Chem. Commun. 2002, 1494-1495.
10.1021/jo035856b CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/24/2004
2224
J . Org. Chem. 2004, 69, 2224-2227

TABLE 1. Electr op h ilic Am in a tion of 2-F lu or op h en ol
TABLE 2. Electr op h ilic Am in a tion of 4-F lu or op h en ol
a n d 2-Ch lor op h en ol
timea
(h)
product(s)
(yield, %)b
entry
diazene
T (°C)
timea
(h)
product(s)
(yield, %)b
entry
phenol
diazene
T (°C)
1
2
3
4
1
2
3
4
4
4
4
-62
5 (83)
6 (89)
-62
1
2
3
4
4-Fc
4-F
4-F
4-F
1
2
3
4
4
4
4
-65
9 (66)
10 (60)
11 (41)
12a (58) and
12b (29)
9 (89)
-62
-45, rt
7 (86)
-62
6 + 15c
8a (34)d and
8b (36)d
-62
-15, rt
6 + 18d
a
b
The reactions were performed in CH2Cl2, under argon. Iso-
lated yields are given. c Reaction mixture was stirred for 6 h at
5
6
7
8
2-Cle
2-Cl
2-Cl
2-Cl
1
2
3
4
1.5
4
-42
-62
10 (95)
d
-45 °C, followed by 15 h at rt. Purified by radial chromatography
using petroleum ether-ethyl acetate (5:3).
4
-62
11 (78%
12a (36) and
12b (40)
6 + 18f
-45, rt
SCHEME 2
a
The reactions were performed in CH2Cl2, under argon. b Yields
obtained after radial chromatography using petroleum ether-ethyl
d
acetate (5:3) are given. c 4-F: 4-fluorophenol. Reaction mixture
was stirred for 6 h at -15 °C, followed by 18 h at rt. e 2-Cl:
2-chlorophenol. f Reaction mixture was stirred for 6 h at -45 °C,
followed by 18 h at rt.
SCHEME 3
amination was accompanied by a halogen substitution.
We found that the fluorine, the chlorine, the bromine, or
the iodine atom migrated under mild reaction conditions.
This type of halogen displacement during an electrophilic
amination has not been described previously, although
the reactions of haloarenes with dialkyl diazenedicar-
boxylates are well documented.12
an unsymmetrical diazene, namely the diazenecarboxa-
mide 4, where we isolated regioisomers 8a and 8b. It is
possible to differentiate between them on the basis of
their mass spectra, as we described previously for similar
trisubstituted semicarbazides.16
The electrophilic amination of 4-fluorophenol with the
diazenes 1-4 in the presence of ZrCl4 led to 4-aminated
2-chlorophenols 9-12 (Scheme 3, Table 2, entries 1-4).
Diazene 4 that reacted through either of the electrophilic
nitrogens to give the compounds 12a and 12b displayed
a certain level of regioselectivity (12a /12b ) 2:1). The
products 9-12 obviously originated from 4-fluorophenol
in a process that included fluorine substitution, followed
by the introduction of a chlorine atom. The same prod-
ucts, i.e., phenol derivatives 9-12, were also prepared
by a “normal” electrophilic amination from 2-chlorophenol
and diazenes 1-4 (Table 2, entries 5-8).17
The migration of fluorine on organic substrates has
been observed only rarely and has involved the use of
high energy intermediates or excited molecules.13 Soon
after our report,11 Avent and Taylor published a unique
1,3-shift of fluorine on fullerene C60F36 at room temper-
ature.14 In this paper, we present new results related to
fluorine removal that will provide some evidence for a
plausible reaction pathway. Three halophenols (2-fluo-
rophenol, 4-fluorophenol, and 2-chlorophenol) were used
in this study. When electrophilic aromatic substitution
is performed on these substrates, the new group is
directed primarily to the para position, with respect to
the phenolic OH, in 2-fluorophenol or 2-chlorophenol, and
to the ortho position, with respect to the phenolic OH, in
4-fluorophenol.15 Thus, the amination of 2-fluorophenol
with dialkyl diazenedicarboxylates 1-3 in the presence
of ZrCl4 resulted in the formation of 4-substituted 2-fluo-
rophenols 5-7 with high yields (Scheme 2, Table 1,
entries 1-3). The reaction is not regioselective in regard
to the aminating agent, as shown by the application of
To get a better insight into the amination process that
involved the removal of the fluorine atom we performed
several additional experiments. These experiments showed
(12) For recent reports, see: (a) Yadav, J . S.; Reddy, B. V. S.;
Veerendhar, G.; Rao, R. S.; Nagaiah, K. Chem. Lett. 2002, 318-319.
(b) Yadav, J . S.; Reddy, B. V. S.; Kumar, G. M.; Madan, C. Synlett
2001, 1781-1783. (c) Lee, K. Y.; Im, Y. J .; Kim, T. H.; Kim, J . N. Bull.
Korean Chem. Soc. 2001, 22, 131-132. (d) Dufresne, C.; Leblanc, Y.;
Berthelette, C.; McCooeye, C. Synth. Commun. 1997, 27, 3613-3624.
(e) Leblanc, Y.; Boudreault, N. J . Org. Chem. 1995, 60, 4268-4271.
(f) Mitchell, H.; Leblanc, Y. J . Org. Chem. 1994, 59, 682-687. (g)
Zaltsgendler, I.; Leblanc, Y.; Bernstein, M. A. Tetrahedron Lett. 1993,
34, 2441-2444.
(16) Lenarsˇicˇ, R.; Kocˇevar, M.; Polanc, S. J . Org. Chem. 1999, 64,
4, 2558-2563.
(17) The reaction yields of 4-fluorophenol with dialkyl diazenedi-
carboxylates 1-3 are lower than those of 2-chlorophenol with the same
diazenes. In the case of 2-chlorophenol, the reactions are typical
electrophilic aromatic substitutions while 4-fluorophenol follows the
reaction pathway proposed in Scheme 4. After radial chromatography
of the reaction mixtures, obtained from 4-fluorophenol and dialkyl
diazenedicarboxylates, a certain amount of an unidentified dark
residue (tar) remains at the baseline (sample line) of the silica gel plate.
This is the reason for lower yields of products 9-11 (Table 2, entries
1-3), prepared from 4-fluorophenol, compared to the yields of the same
products that were synthesized from 2-chlorophenol (Table 2, entries
5-7).
(13) Gakh, A. A.; Tuinman, A. A. Tetrahedron Lett. 2001, 42, 7137-
7139 and references therein.
(14) Avent, A. G.; Taylor, R. Chem. Commun. 2002, 2726-2727.
(15) Reference 3b, p 681.
J . Org. Chem, Vol. 69, No. 6, 2004 2225

SCHEME 4
products are formed on reactions of 4-chloro-, 4-bromo-,
and 4-iodophenol with diisopropyl diazenedicarboxylate.11
In conclusion, 2-fluorophenol, 4-fluorophenol, and 2-chlo-
rophenol reacted with diazenes in ZrCl4-promoted con-
versions that result in 4-aminated halophenols. The
electrophilic amination of 4-fluorophenol with either
dialkyl diazenedicarboxylates 1-3 or diazenecarboxam-
ide 4, which led to 4-aminated 2-chlorophenols, indicated
that this transformation was accompanied by the removal
of fluorine and the subsequent introduction of the chlo-
rine atom. A plausible reaction pathway for the above
process is proposed.
Exp er im en ta l Section
Typ ica l P r oced u r e for th e Electr op h ilic Am in a tion of
Ha lop h en ols Rep r esen ted by En tr y 2 of Ta ble 2. A solution
of diethyl diazenedicarboxylate (2, 175 µL, 1.1 mmol) and
4-fluorophenol (112 mg, 1 mmol) in CH2Cl2 (7 mL) was added
dropwise to a stirred suspension of ZrCl4 (260 mg, 1.1 mmol) in
CH2Cl2 (5 mL) at -62 °C under an argon atmosphere. After 4
h, the reaction mixture was quenched with water (5 mL) and
neutralized with a saturated aqueous solution of NaHCO3. The
two phases were separated, and the aqueous solution was
extracted with CH2Cl2 (4 × 10 mL). The combined extracts were
then dried over anhydrous Na2SO4 and evaporated to dryness.
The residue was purified by radial chromatography using
petroleum ether-ethyl acetate (5:3) as the eluent to give the
product 10 (182.2 mg, 60% yield).
the following: (i) 4-fluorophenol did not react with ZrCl4
in the absence of diazenes 1-4; (ii) 4-aminated 2-fluo-
rophenols 5-8 remained unchanged after being treated
with ZrCl4 in CH2Cl2 at temperatures and times required
for the synthesis of 9-12 from 4-fluorophenol and diaz-
enes 1-4 in the presence of ZrCl4. The above results allow
us to conclude that the substitution of the fluorine atom
did not take place either before or after the amination;
rather, it took place during this process.
Diisop r op yl 1-(3-flu or o-4-h yd r oxyp h en yl)-1,2-h yd r a -
A plausible reaction pathway that would lead from
4-fluorophenol and diazenes 1-4 to the products 9-12
is proposed in Scheme 4. In the first step, we assume
the formation of an ion pair intermediate I; similar
species containing electrophilic nitrogen were recently
proposed for the ZrCl4-mediated intramolecular migra-
tion of the imino group of O-arylketoximes.18 In the
second step, an ipso attack15 of the nitrogen electrophile
at position 4 would give II. This latter intermediate could
then eliminate ZrCl4F-, leading to III. An anion, ZrCl4F-,
may serve as the source of a chloride ion, this is because
the cleavage of the Zr-Cl bond is preferential to the
cleavage of the Zr-F bond (bond energies: Zr-Cl, 489.5
kJ mol-1; Zr-F, 646.8 kJ mol-1).19 Thus, the reaction of
the chloride ion with cation III would lead to the dienone
IV, a tautomer of the final product.20 Steric factors in an
ion pair intermediate I seem to regulate the outcome of
the amination. Thus, sterically hindered electrophilic
nitrogen attacks the para position that is occupied by a
small fluorine atom, rather than by the neighboring
zin ed ica r boxyla te11 (5): mp 126.3-128.5 °C (n-heptane-
diethyl ether); IR 3307, 2984, 1709, 1529, 1403, 1258, 1107 cm-1
;
1H NMR (CDCl3) δ 1.27 (d, J ) 6.2 Hz, 6H), 1.28 (d, J ) 6.2 Hz,
6H), 5.01 (m, 2H), 5.27 (s, 1H), 6.82 (s, 1H), 6.92 (m, 1H), 7.09
(m, 1H), 7.23 (m, 1H); 13C NMR (CDCl3) δ 21.84, 21.87, 70.4,
71.2, 112.8 (m), 117.0 (d, J ) 2.6 Hz), 121.0 (m), 134.1 (d, J )
8.4 Hz), 142.5 (d, J ) 13.7 Hz), 150.3 (d, J ) 239.8 Hz), 154.7,
156.1; MS (EI) m/z 314 (M+, 73), 228 (28), 186 (100), 141 (50),
61 (35). Anal. Calcd for C14H19FN2O5: C, 53.50; H, 6.09; N, 8.91.
Found: C, 53.76; H, 5.95; N, 8.68.
Dieth yl 1-(3-flu or o-4-h yd r oxyp h en yl)-1,2-h yd r a zin ed i-
ca r boxyla te (6): mp 101-103 °C (petroleum ether-diethyl
ether); IR 3229, 2988, 1720, 1682, 1526, 1259, 1069 cm-1 1H
;
NMR (CDCl3) δ 1.28 (t, J ) 7.1 Hz, 3H), 1.29 (t, J ) 7.1 Hz,
3H), 4.23 (q, J ) 7.1 Hz, 2H), 4.24 (q, J ) 7.1 Hz, 2H), 5.75 (s,
1H), 6.98 (s, 1H), 6.93 (m, 1H), 7.08 (m, 1H), 7.22 (m, 1H); 13C
NMR (CDCl3) δ 14.29, 14.30, 62.4, 63.2, 113.2 (m), 117.0 (d, J )
2.9 Hz), 121.4 (m), 134.0 (d, J ) 8.2 Hz), 142.7 (d, J ) 15.5 Hz),
150.3 (d, J ) 240.2 Hz), 155.2, 156.4; MS (EI) m/z 286 (M+, 45),
214 (96), 141 (100); HRMS calcd for C12H15FN2O5 286.0965,
found 286.0972. Anal. Calcd for C12H15FN2O5: C, 50.35; H, 5.28;
N, 9.79. Found: C, 50.11; H, 5.67; N, 9.98.
Dia llyl 1-(3-flu or o-4-h yd r oxyp h en yl)-1,2-h yd r a zin ed i-
ca r boxyla te (7): oil; IR 3296, 1707, 1519, 1448, 1391, 1323,
-
-OZrCl4 group hindered ortho position in I. It is in
agreement with our previous results showing that a para
attack of the electrophilic nitrogen becomes disfavored
if the bulkier halogen is attached in the place of the
fluorine atom. Indeed, predominantly ortho-aminated
1279, 1244 cm-1 1H NMR (CDCl3) δ 4.67 (m, 4H), 5.19-5.38
;
(m, 5H), 5.90 (m, 2H), 6.90-7.24 (m, 4H); 13C NMR (CDCl3) δ
66.8, 67.5, 113.4 (m), 117.1 (d, J ) 2.9 Hz), 118.2, 118.5, 121.5
(m), 131.5, 131.6, 133.6 (d, J ) 8.3 Hz), 143.0 (d, J ) 10.9 Hz),
150.3 (d, J ) 240.6 Hz), 155.0, 156.1; MS (EI) m/z 310 (M+, 37),
225 (88), 181 (75), 111 (100); HRMS calcd for C14H15FN2O5
310.0965, found 310.0970. Anal. Calcd for C14H15FN2O5: C,
54.19; H, 4.87; N 9.03. Found: C, 54.13; H, 5.01; N, 9.12.
Meth yl 2-[(2-ch lor oeth yl)a m in oca r bon yl]-2-(3-flu or o-4-
h yd r oxyp h en yl)h yd r a zin eca r boxyla te (8a ): mp 192-194.5
°C (chloroform-methanol); IR 3379, 3292, 1728, 1650, 1542,
(18) Kikugawa, Y.; Tsuji, C.; Miyazawa, E.; Sakamoto, T. Tetrahe-
dron Lett. 2001, 42, 2337-2339.
(19) King, R. B. In Encyclopedia of Inorganic Chemistry; Wiley:
Chichester, 1994; Vol. 1, p 303.
(20) The products 5-12 cannot be isolated from the reaction mixture
prior to treatment with water. The reason seems to be the formation
of 1:1 complex between the product and zirconium halide (ZrCl4 or
ZrCl3F). This is also in agreement with the fact that an equimolar
amount of ZrCl4 is always required for amination. All attempts to
isolate and characterized the above-mentioned complex from a gummy-
like material that was insoluble in CH2Cl2 failed. The product is easily
isolated after treatment of the reaction mixture with water. Under
these conditions the hydrolysis of zirconium halide (ZrCl4 or ZrCl3F)
takes place.
1514, 1443, 1373, 1254 cm-1 1H NMR (DMSO-d6) δ 3.33 (m,
;
2H), 3.59 (m, 2H), 3.61 (s, 3H), 6.90 (m, 2H), 7.13 (dd, J 1 ) 12.8
Hz, J 2 ) 2.5 Hz, 1H), 7.23 (broad s, 1H), 9.75 (s, 1H), 9.86 (s,
1H); 13C NMR (DMSO-d6) δ 42.0, 43.1, 52.2, 112.6 (m), 116.9 (d,
J ) 2.9 Hz), 120.4 (m), 134.1 (d, J ) 8.0 Hz), 142.4 (d, J ) 12.1
Hz), 149.9 (d, J ) 240.2 Hz), 155.9, 156.0; MS (EI) m/z 305 (M+,
3), 231 (2), 200 (100), 141 (62), 125 (37); HRMS (FAB) calcd for
2226 J . Org. Chem., Vol. 69, No. 6, 2004

C11H13ClFN3O4 305.0579, found 305.0583. Anal. Calcd for C11H13
ClFN3O4: C, 43.22; H, 4.29; N 13.75. Found: C, 43.32; H, 4.41;
N, 13.49.
-
(M+, 90), 241 (100), 197 (69), 127 (28); HRMS calcd for C14H15
ClN2O5 326.0669, found 326.0671. Anal. Calcd for C14H15
ClN2O5: C, 51.46; H, 4.63; N, 8.57. Found: C, 51.59; H, 4.89; N,
8.69.
-
-
Meth yl 2-[(2-ch lor oeth yl)a m in oca r bon yl]-1-(3-flu or o-4-
h yd r oxyp h en yl)h yd r a zin eca r boxyla te (8b): mp 142-145 °C
(chloroform-methanol); IR 3316, 1694, 1644, 1584, 1526, 1457,
Meth yl 2-[(2-ch lor oeth yl)a m in oca r bon yl]-2-(3-ch lor o-4-
h yd r oxyp h en yl)h yd r a zin eca r boxyla te (12a ): mp 167-170
°C (diethyl ether-ethyl acetate); IR 3392, 3242, 1741, 1665,
1624, 1542, 1510, 1285, 1256, 1058 cm-1; 1H NMR (DMSO-d6) δ
3.37 (m, 2H), 3.59 (m, 5H), 6.90 (d, J ) 8.8 Hz, 1H), 7.10 (dd, J 1
) 8.8 Hz, J 2 ) 2.6 Hz, 1H), 7.24 (broad t, 1H), 7.32 (d, J ) 2.6
Hz, 1H), 9.87 (s, 1H), 10.10 (s, 1H); 13C NMR (DMSO-d6) δ 42.0,
43.2, 52.2, 116.0, 118.7, 124.5, 126.2, 134.6, 150.8, 155.9, 156.0;
MS (EI) m/z 321 (M+, 20), 285 (4), 216 (100), 157 (61). Anal.
Calcd for C11H13Cl2N3O4: C, 41.01; H, 4.07; N, 13.04. Found:
C, 40.85; H, 4.26; N 12.99.
1
1379, 1321, 1239, 1109 m-1; H NMR (DMSO-d6) δ 3.35 (t, J )
6.3 Hz, 2H), 3.58 (t, J ) 6.3 Hz, 2H), 3.65 (s, 3H), 6.89 (m, 2H),
7.05 (m, 1H), 7.23 (m, 1H), 8.78 (s, 1H), 9.84 (s, 1H); 13C NMR
(DMSO-d6) δ 41.4, 43.7, 53.2, 112.7 (m), 116.8 (d, J ) 3.6 Hz),
120.6 (m), 134.3 (d, J ) 7.9 Hz), 142.9 (d, J ) 12.7 Hz), 149.8
(d, J ) 240.4 Hz), 155.4, 157.1; MS (EI) m/z 305 (M+, 10), 200
(13), 184 (14), 57 (100). Anal. Calcd for C11H13ClFN3O4: C, 43.22;
H, 4.29; N, 13.75. Found: C, 43.01; H, 4.21; N, 13.49.
Diisop r op yl 1-(3-ch lor o-4-h yd r oxyp h en yl)-1,2-h yd r a -
zin ed ica r boxyla te11 (9): mp 120.8-122.3 °C (n-heptane-
diethyl ether); IR 3295, 2984, 1707, 1518, 1431, 1291, 1272, 1108
Meth yl 2-[(2-ch lor oeth yl)a m in oca r bon yl]-1-(3-ch lor o-4-
h yd r oxyp h en yl)h yd r a zin eca r boxyla te (12b): mp 124-127
°C (n-heptane-ethyl acetate); IR 3312, 1693, 1643, 1582, 1516,
1
cm-1; H NMR (CDCl3) δ 1.26 (d, J ) 6.2 Hz, 6H), 1.28 (d, J )
1
1450, 1379, 1254, 1221, 1061 cm-1; H NMR (DMSO-d6) δ 3.35
6.2 Hz, 6H), 5.00 (m, 2H), 5.69 (s, 1H), 6.86 (s, 1H), 6.95 (d, J )
8.7 Hz, 1H), 7.24 (broad d, J ) 8.7 Hz, 1H), 7.44 (broad s, 1H);
13C NMR (CDCl3) δ 21.88, 21.92, 70.3, 71.2, 115.9, 119.5, 125.0,
125.7, 135.0, 150.1, 154.6, 156.0; MS (EI) m/z 330 (M+, 47), 244
(m, 2H), 3.58 (t, J ) 6.3 Hz, 2H), 3.64 (s, 3H), 6.90 (s, 1H), 6.91
(d, J ) 8.7 Hz, 1H), 7.20 (dd, J 1 ) 8.7 Hz, J 2 ) 2.6 Hz, 1H), 7.42
(broad s, 1H), 8.80 (s, 1H), 10.19 (s, 1H); 13C NMR (DMSO-d6) δ
41.4, 43.7, 53.2, 115.9, 118.7, 124.5, 126.4, 134.8, 151.3, 155.4,
157.1; MS (EI) m/z 321 (M+, 4), 285 (5), 216 (93), 157 (100);
HRMS calcd for C11H13Cl2N3O4 321.0283, found 321.0290. Anal.
Calcd for C11H13Cl2N3O4: C, 41.01; H, 4.07; N, 13.04. Found:
C, 41.27; H, 4.14; N 12.88.
(32), 202 (100), 157 (71), 141 (30). Anal. Calcd for C14H19
ClN2O5: C, 50.84; H, 5.79; N, 8.47. Found: C, 50.76; H, 5.94; N,
8.40.
-
Dieth yl 1-(3-ch lor o-4-h yd r oxyp h en yl)-1,2-h yd r a zin ed i-
ca r boxyla te (10): mp 83-86 °C (petroleum ether-diethyl
ether); IR 3292, 2986, 1713, 1514, 1429, 1381, 1287, 1250, 1055
1
cm-1; H NMR (CDCl3) δ 1.27 (t, J ) 7.1 Hz, 3H), 1.29 (t, J )
Ack n ow led gm en t. The Ministry of Education, Sci-
ence and Sport of the Republic of Slovenia is gratefully
acknowledged for its financial support (P1-0230-103).
We would like to thank Dr. Bogdan Kralj and Dr. Dusˇan
Zˇigon (Mass Spectrometry Center, J ozˇef Stefan Insti-
tute, Ljubljana, Slovenia) for recording the mass spec-
tra.
7.1 Hz, 3H), 4.23 (q, J ) 7.1 Hz, 2H), 4.24 (q, J ) 7.1 Hz, 2H),
5.62 (s, 1H), 6.94 (s, 1H), 6.97 (d, J ) 8.9 Hz, 1H), 7.25 (dd, J 1
) 8.9 Hz, J 2 ) 2.5 Hz, 1H), 7.45 (d, J ) 2.5 Hz, 1H); 13C NMR
(CDCl3) δ 14.25, 14.26, 62.4, 63.2, 116.0, 119.6, 125.3, 126.3,
134.5, 150.6, 155.2, 156.4; MS (EI) m/z 302 (M+, 33), 230 (60),
157 (100); HRMS calcd for
C12H15ClN2O5 302.0669, found
302.0672. Anal. Calcd for C12H15ClN2O5: C, 47.67; H, 5.00; N,
9.27. Found: C, 47.54; H, 5.32; N 9.58.
Dia llyl 1-(3-ch lor o-4-h yd r oxyp h en yl)-1,2-h yd r a zin ed i-
ca r boxyla te (11): oil; IR (NaCl) 3295, 2952, 1708, 1497, 1423,
1389, 1329, 1281, 1238, 1057 cm-1; 1H NMR (CDCl3) δ 4.67 (m,
4H), 5.18-5.40 (m, 4H), 5.64 (s, 1H), 5.90 (m, 2H), 6.97 (d, J )
8.9 Hz, 1H), 7.07 (s, 1H), 7.25 (m, J ) 1 Hz), 7.45 (broad s, 1H);
13C NMR (CDCl3) δ 66.7, 67.4, 116.1, 118.1, 118.4, 119.7, 125.4,
126.5, 131.4, 131.6, 134.2, 150.8, 155.0, 156.0; MS (EI) m/z 326
Su p p or tin g In for m a tion Ava ila ble: General Experi-
mental Section; synthesis and characterization data of the
diazene 4 and its precursor (the corresponding hydrazinecar-
boxylate). This material is available free of charge via the
Internet at http://pubs.acs.org.
J O035856B
J . Org. Chem, Vol. 69, No. 6, 2004 2227