Chelated ester enolates as versatile nucleophiles for direct nucleophilic attack on aromatic nitro groups

Article abstract of DOI:10.1055/s-2006-944189

Chelated amino acid ester enolates react with aromatic nitro compounds at the nitrogen atom. Best results were obtained with TFA-protected glycinates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-944189

1616
LETTER
Chelated Ester Enolates as Versatile Nucleophiles for Direct Nucleophilic
Attack on Aromatic Nitro Groups
N
ucleophile
s
for
D
a
irec
t
N
ucle
n
ophilic
A
ttac
i
k on
A
e
romatic
N
i
l
tro Groups Stolz, Rigobert Pick, Uli Kazmaier*
Institut für Organische Chemie, Universität des Saarlandes, 66123 Saarbrücken, Germany
Fax +49(681)3022409; E-mail: u.kazmaier@mx.uni-saarland.de
Received 13 March 2006
Many years later Bartoli et al. reported an efficient synthe-
Abstract: Chelated amino acid ester enolates react with aromatic
nitro compounds at the nitrogen atom. Best results were obtained
with TFA-protected glycinates.
sis of 7-substituted indoles by addition of vinylmagne-
sium bromide towards substituted nitrobenzenes.11
Herein, the first step was a nucleophilic attack of the
Grignard reagent on the oxygen (and not on the nitrogen
as before) of the nitro group (Scheme 2). The labile O-
alkylated intermediate formed then underwent elimina-
tion of enolate giving rise to aromatic nitroso com-
pound.12 This was attacked a second time by the Grignard
reagent and the O-vinylhydroxylamine derivative formed
underwent a [3,3]sigmatropic rearrangement towards the
indole.
Key words: amino acids, chelates, enolates, nitroarenes
Nitro compounds play an important role as key intermedi-
ates in organic synthesis. Besides the very popular nitro
aldol reaction,1 especially the conversion of the nitro
group into other functionalities is of major interest. For
example, the nitro compounds can easily be reduced to
either amines,2 or nitroso, hydroxyamino and hydrazine
derivatives, depending on the pH value and the reducing
agent used.3 Dehydration of nitroalkanes allows the in situ
generation of nitrile oxides, reactive intermediates which
undergo rapid 1,3-dipolar cycloadditions.4 Very recently
Carreira’s group5 and our group6 reported independently
about a reductive conversion of nitro groups into nitriles.
H
NO2
3 equiv
MgBr
N
THF, –40 °C
67%
MgBr
MgBr
MgBr
By far much less investigated, but not less interesting, are
additions of C-nucleophiles to the nitro group.7 Already in
1935, Kursanov and Solodkov investigated the reaction of
nitrobenzene with an excess of phenylmagnesium chlo-
ride and obtained diphenylamine via the hydroxylamine
derivative A, which was reduced in situ by the excess of
the Grignard reagent (Scheme 1).8 Other Grignard re-
agents such as allylmagnesium halides attack the nitro
group also at the nitrogen,9 and the intermediate formed
can be converted into different products depending on the
reaction conditions used.10
OMgBr
NO
N
O
N
O
MgBr
OMgBr
Scheme 2
In principle, nitro groups can also be attacked by enolates,
as indicated by the conversion of B into C (Scheme 3).13
But to the best of our knowledge, no other examples of
such kind of additions are reported in the literature so far.
–
O
N
Ph
Ph
PhMgX
PhMgX
+
N
OMgX
Ph
OMgX
O
Ph NO2
OH
NaOH
Ph
A
EtOH, 25 °C
62%
NO2
N
OH
O
O
2 PhMgX
MgX2
B
C
Ph
Ph
Ph
NH
Ph
+
H3O
Scheme 3
N
MgX
+
+
+
MgO
Ph Ph
For several years our group has been investigating
reactions of chelated amino acid ester enolates as nucleo-
philes in several kinds of reactions.14 Based on their high
reactivity, these enolates react under very mild reaction
conditions to a wide range of unnatural amino acids. Very
recently, we reported the highly stereoselective 1,4-
addition of these enolates D towards nitroalkenes
(Scheme 4).15 Interestingly the nitronates formed as inter-
Scheme 1
SYNLETT 2006, No. 10, pp 1616–1618
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-944189; Art ID: G07306ST
© Georg Thieme Verlag Stuttgart · New York
2
1
.0
6
.2
0
0
6

LETTER
Nucleophiles for Direct Nucleophilic Attack on Aromatic Nitro Groups
1617
mediates could be trapped by acyl halides giving rise to
nitriles6 or different heterocycles,16 depending on the
reaction conditions and the protecting groups used.
Table 1 Addition of Chelated Enolates towards Nitroarenes
OH
Ot-Bu
NO2
N
COOt-Bu
+
N
O
TFA
H
N
Zn
NO2
R
R
TFA
Ot-Bu
1
2
3
NO2
R
R
N
O
Entry
Substrate
R
Product19
Yield (%)a
PG
–78 °C to r.t.
up to 97%
Zn
PGHN
COOt-Bu
38b
95
88
74
85
85
81
–
D
1
2
3
4
5
6
7
8
2a
2a
2b
2c
2d
2e
2f
Cl
3a
3a
3b
3c
3d
3e
3f
up to 97% ds
Cl
Scheme 4
Br
Therefore, we were interested to see what might happen
with aromatic nitro compounds, for example if nucleo-
philic attack on the aromatic ring is possible. Based on our
previous good results obtained with TFA-protected tert-
butyl glycinate, we used enolate 1 as nucleophile in the re-
action with p-chloro nitrobenzene 2a, and indeed, a reac-
tion was observed, but not at the aromatic ring system, but
at the nitro group, and the N-arylhydroxylamine 3a was
obtained in very moderate yield (<20%). During our at-
tempts to optimize the reaction conditions we found that
increasing the amount of nucleophile to 2.5 equivalents17
gave the expected product in a very clean reaction but
only 38% yield (Table 1, entry 1). This was quite surpris-
ing, because all starting material was consumed. With re-
spect to the structure of 3a, one might assume that the N-
hydroxylated aminal structure might be sensitive towards
hydrolysis, especially under acidic conditions. Therefore
we changed also the work-up protocol. Instead of hydro-
lyzing the reaction mixture with 1 N KHSO4 (as done be-
fore) we quenched the reaction with a buffer solution (pH
6). And indeed, under these conditions the expected
product could be obtained in nearly quantitative yield (en-
try 2). To prove the generality of this reaction, we subject-
ed several other nitroarenes to these optimized conditions
(entries 3–8).18 The yield depends obviously on the elec-
tronic nature of the aromatic ring system. With electron-
withdrawing substituents the yields were generally very
high and they decrease with decreasing electron-with-
drawing properties, as illustrated in the series of halogen
substituted derivatives 2a–c. Even with nitrobenzene the
yield was good, but no reaction was observed with
nitroanisole 2g, or other ‘electron-rich’ nitro derivatives.
I
CN
COOMe
H
2g
OCH3
3g
a Work-up conditions: quenching with NH4OAc/HOAc buffer (pH 6).
b Work-up conditions: quenching with 1 N KHSO4.
Next, we tried to trap the deprotonated 3, formed in the
addition step, by an intramolecular cyclization
(Scheme 6). And indeed, if o-substituted nitroarene 2h
was used, the cyclization product 3h was obtained directly
as sole product.
O
COOMe
NO2
Ot-Bu
O
N
COOt-Bu
+
N
O
TFA
65%
Zn
H
N
TFA
1
2h
3h
Scheme 6
In conclusion we could show that chelated enolates are
versatile nucleophiles for direct additions towards
aromatic nitro groups. Applications towards the synthesis
of more complex molecules and mechanistic studies are
currently under investigation.
To prove the influence of the attacking nucleophile, we
varied also the substitution pattern on the glycinate
(Scheme 5). However, in this reaction the TFA protecting
groups proved to be the best, with carbamates such as 4
the yields dropped dramatically, nearly independent of the
ester used.
Acknowledgment
Financial support by the Deutsche Forschungsgemeinschaft as well
as the Fonds der Chemischen Industrie is gratefully acknowledged.
References and Notes
(1) (a) Rosini, G.; Ballini, R. Synthesis 1988, 833. (b) Ono, N.
The Nitro Group in Organic Synthesis; VCH: New York,
2001. (c) Marcelli, T.; van der Haas, R. N. S.; Van
OH
OR'
NO2
N
COOR'
+
N
O
Maarseveen, J. H.; Hiemstra, H. Synlett 2005, 2817.
(d) Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Adv. Synth.
Catal. 2005, 347, 1643. (e) Marcelli, T.; van der Haas, R. N.
S.; Van Maarseveen, J. H.; Hiemstra, H. Angew. Chem. Int.
Ed. 2006, 45, 929; Angew. Chem. 2006, 118, 943.
Boc
H
N
Zn
R
R
Boc
2b R = Br
2d R = CN
5a R = Br, R' = Et
32%
4a R' = Et
5a R = CN, R' = t-Bu 28%
4b R' = t-Bu
Scheme 5
Synlett 2006, No. 10, 1616–1618 © Thieme Stuttgart · New York

1618
D. Stolz et al.
LETTER
mL) and hydrolyzed in an ice bath with NH4OAc/HOAc
buffer (pH 6, 10 mL). The layers were separated and the
aqueous layer was extracted twice with Et2O. The combined
organic layers were dried (Na2SO4) and the solvent was
evaporated in vacuo. The crude product was purified by
flash chromatography (silica, hexane–EtOAc).
(2) (a) Purushothama Chary, K.; Raja Ram, S.; Iyengar, D. S.
Synlett 2000, 683. (b) Shojiro, M.; Makiko, O.; Toshimichi,
M.; Takashi, H.; Haruki, N. Tetrahedron Lett. 2003, 44,
3717.
(3) (a) Rosso, J. A.; Bertolotti, S. G.; Braun, A. M.; Martire, D.
O.; Gonzalez, M. C. J. Phys. Org. Chem. 2001, 14, 300.
(b) Feng, S.-H.; Zhang, S.-J.; Yu, H.-Q.; Li, Q.-R. Chem.
Lett. 2003, 32, 718.
(4) (a) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82,
5339. (b) Torssell, K. Nitrile Oxides, Nitrones and
Nitronates in Organic Synthesis; VCH: New York, 1988.
(5) Czekelius, C.; Carreira, E. M. Angew. Chem. Int. Ed. 2005,
44, 612; Angew. Chem. 2005, 117, 618.
(6) Mendler, B.; Kazmaier, U. Org. Lett. 2005, 7, 1715.
(7) (a) Kharash, H. S.; Reimnuth, O. Grignard Reactions of
Nonmetallic Substances; Prentice-Hall: New York, 1954,
384. (b) Buck, P. Angew. Chem., Int. Ed. Engl. 1969, 8, 120.
(c) Nutzel, K. Methoden der Organischen Chemie (Houben-
Weyl), Vol. 13; Thieme: Stuttgart, 1973, 47.
(8) Kursanov, D. N.; Solodkov, P. A. Zh. Obshch. Khim., Ser. A
1935, 5, 1487; Chem. Abstr. 1936, 30, 2181.
(9) (a) Barboni, L.; Bartoli, G.; Marcantoni, E.; Petrini, M.;
Dalpozzo, R. J. Chem. Soc., Perkin Trans. 1 1990, 2133.
(b) Bartoli, G.; Palmieri, G.; Petrini, M.; Bosco, M.;
Dalpozzo, R. Gazz. Chim. Ital. 1990, 120, 247.
(10) (a) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.
Tetrahedron Lett. 1988, 29, 2251. (b) Bartoli, G.;
Marcantoni, E.; Petrini, M.; Dalpozzo, R. J. Org. Chem.
1990, 55, 4456.
(11) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R.
Tetrahedron Lett. 1989, 30, 2129.
(19) Selected Spectroscopic and Analytical Data.
tert-Butyl [(4-Chlorophenyl)(hydroxy)amino][(trifluoro-
acetyl)amino]acetate (3a).
Compound 3a was obtained from 2a (79 mg, 0.5 mmol) as a
colorless solid; yield 175 mg (0.47 mmol, 95%); mp 101 °C.
1H NMR (500 MHz, CDCl3): d = 1.40 (s, 9 H), 5.68 (d,
J = 7.9 Hz, 1 H), 5.90 (s, 1 H), 7.14 (d, J = 8.8 Hz, 2 H), 7.23
(d, J = 8.8 Hz, 2 H), 7.56 (d, J = 7.6 Hz, 1 H). 13C NMR (125
MHz, CDCl3): d = 27.8, 72.6, 84.8, 115.6 (q, JC,F = 286.1
Hz), 118.2, 128.7, 128.8, 147.4, 157.3 (q, JC,F = 37.2 Hz),
164.7. HMRS (CI): m/z [M]+ calcd for C14H16N2O4F3Cl:
368.0751. Found: 368.0746. Anal. Calcd for
C14H16N2O4F3Cl (368.77): C, 45.59; H, 4.38; N, 7.59.
Found: C, 45.28; H, 4.30; N, 7.57.
tert-Butyl [(4-Bromophenyl)(hydroxy)amino][(trifluoro-
acetyl)amino]acetate (3b).
Compound 3b was obtained from 2b (51 mg, 0.25 mmol) as
a colorless solid; yield 91 mg (0.22 mmol, 88%); mp 98 °C.
1H NMR (500 MHz, CDCl3): d = 1.39 (s, 9 H), 5.68 (d,
J = 8.0 Hz, 1 H), 6.16 (br s, 1 H), 7.06 (d, J = 8.5 Hz, 2 H),
7.35 (d, J = 8.5 Hz, 2 H), 7.56 (d, J = 7.0 Hz, 1 H). 13C NMR
(125 MHz, CDCl3): d = 27.8, 72.5, 84.9, 114.3, 116.2, 118.5,
131.7, 147.9, 157.4 (q, JC,F = 38.5 Hz), 165.0.
HMRS (CI): m/z [M]+ calcd for C14H16N2O4F3Br: 412.02.
Found: 412.0247. Anal. Calcd for C14H16N2O4F3Br
(413.19): C, 40.69; H, 3.90; N, 6.78. Found: C, 40.82; H,
3.80; N, 6.76.
(12) Bosco, M.; Dalpozzo, R.; Bartoli, G.; Palmieri, G.; Petrini,
M. J. Chem. Soc., Perkin Trans. 2 1991, 657.
(13) Dean, F. M.; Patampongse, C.; Podimuang, V. J. Chem.
Soc., Perkin Trans. 1 1974, 583.
tert-Butyl [(4-Cyanophenyl)(hydroxy)amino][(trifluoro-
acetyl)amino]acetate (3d).
(14) Reviews: (a) Kazmaier, U. Amino Acids 1996, 11, 283.
(b) Kazmaier, U. Liebigs Ann. Chem./Recl. 1997, 285.
(c) Kazmaier, U. Recent Res. Dev. Org. Chem. 1998, 2, 351.
(15) Mendler, B.; Kazmaier, U. Synthesis 2005, 2239.
(16) Mendler, B.; Kazmaier, U.; Huch, V.; Veith, M. Org. Lett.
2005, 7, 2643.
(17) Probably, attack of the glycine nucleophile occurs according
to Scheme 2 and one equiv of the enolate is necessary to
reduce the nitro group. Attempts to trap the oxidized glycine
species are currently under investigation.
Compound 3d was obtained from 2d (104 mg, 0.70 mmol)
as a colorless solid; yield 215 mg (0.60 mmol, 85%); mp
151 °C. 1H NMR (500 MHz, CDCl3): d = 1.35 (s, 9 H), 5.80
(d, J = 7.5 Hz, 1 H), 6.32 (s, 1 H), 7.31 (d, J = 9.0 Hz, 2 H),
7.56 (d, J = 8.5 Hz, 2 H), 7.67 (d, J = 7.0 Hz, 1 H). 13C NMR
(125 MHz, CDCl3): d = 27.8, 71.8, 85.1, 105.4, 116.2, 116.6,
119.0, 133.1, 152.9, 157.4 (q, JC,F = 39.9 Hz), 164.1. HMRS
(CI): m/z [M]+ calcd for C15H16N3O4F3: 359.1093. Found:
359.1082. Anal. Calcd for C15H16N3O4F3 (359.34): C, 50.14;
H, 4.50; N, 11.69. Found: C, 50.18; H, 4.55; N, 11.53.
Methyl 4-[{2-tert-Butoxy-2-oxo-1-[(trifluoroacetyl)ami-
no]ethyl}(hydroxy)amino]benzoate (3e).
(18) Additions of Chelated Enolates towards Nitroarenes –
General Procedure.
The base used for enolate formation was prepared directly
before use. In a Schlenk flask HMDS (428 mg, 2.65 mmol)
was dissolved in THF (2 mL) under N2. Then, n-BuLi (1.6
M, 1.64 mL, 2.63 mmol) was added dropwise at –20 °C and
the mixture was allowed to stir at r.t. for 10 min. After
cooling at –78 °C a solution of ZnCl2 (187 mg, 1.38 mmol,
dried previously in vacuo with a hot-air gun) was added with
the amino acid derivative (1.25 mmol) in THF (3 mL). The
suspension was stirred for further 30 min at –78 °C to form
the chelated ester enolate. After that the nitroarene (0.5
mmol) was added in THF (1 mL). The solution was allowed
to warm to r.t. overnight before it was diluted with Et2O (10
Compound 3e was obtained from 2e (18 mg, 0.10 mmol) as
a colorless solid; yield 33 mg (84.1 mmol, 85%); mp 114 °C.
1H NMR (500 MHz, CDCl3): d = 1.35 (s, 9 H), 3.86 (s, 3 H),
5.84 (d, J = 7.6 Hz, 1 H), 6.30 (br s, 1 H), 7.25 (d, J = 8.5 Hz,
2 H), 7.67 (d, J = 7.6 Hz, 1 H), 7.94 (d, J = 8.5 Hz, 2 H). 13
C
NMR (125 MHz, CDCl3): d = 27.8, 51.9, 72.0, 84.8, 115.5
(q, JC,F = 286.1 Hz), 115.5, 124.4, 130.7, 153.0, 157.1,
164.5, 166.9. HMRS (CI): m/z [M]+ calcd for C16H19N2O6F3:
392.1195. Found: 392.1201. Anal. Calcd for C16H19N2O6F3
(392.37): C, 48.98; H, 4.89; N, 7.14. Found: C, 49.17; H,
4.87; N, 7.10.
Synlett 2006, No. 10, 1616–1618 © Thieme Stuttgart · New York