Aromatic nitro groups and their reactions with chelated ester enolates

Article abstract of DOI:10.1055/s-2006-950228

Chelated amino acid ester enolates react with aromatic nitro compounds in a 1,3-addition mode at the nitro group giving amino acids bearing an aryl(hydroxy)amino side chain. Best results were obtained with trifluoroacetyl-protected glycinates. Two equivalents of enolate are necessary for complete conversion, because one equivalent is oxidized during the reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950228

SPECIAL TOPIC
3341
Aromatic Nitro Groups and Their Reactions with Chelated Ester Enolates
Aromatic
N
itro Gr
a
oups and
T
n
heir
R
eaction
i
s
w
ith
e
ChelatedE
l
ster
E
nolatesStolz, Uli Kazmaier,* Rigobert Pick
Institut für Organische Chemie, Universität des Saarlandes, 66123 Saarbrücken, Germany
Fax +49(681)3022409; E-mail: u.kazmaier@mx.uni-saarland.de
Received 1 May 2006
–
O
Ph
Ph
Abstract: Chelated amino acid ester enolates react with aromatic
PhMgX
PhMgX
+
N
OMgX
Ph
N OMgX
nitro compounds in a 1,3-addition mode at the nitro group giving
amino acids bearing an aryl(hydroxy)amino side chain. Best results
were obtained with trifluoroacetyl-protected glycinates. Two equiv-
alents of enolate are necessary for complete conversion, because
one equivalent is oxidized during the reaction.
Ph NO2
Ph
A
2 PhMgX
Ph
Ph
Ph
H3O+
Key words: amino acids, chelates, enolates, nitroarenes, ni-
trosoarenes
N
MgX
Ph Ph
+
+
+
MgX2 + MgO
NH
Ph
Bu
1) BuMgBr
2) H3O+
Nitro compounds play an important role as key intermedi-
ates in organic synthesis. Besides the very popular nitro
aldol reaction,1 of major interest is the conversion of the
nitro group into other functionalities. For example, nitro
compounds can easily be reduced either to amines2 or to
nitroso, hydroxyamino, and hydrazino derivatives, de-
pending on the pH and the reducing agent.3 Dehydration
of nitroalkanes allows the in situ generation of nitrile ox-
ides, reactive intermediates which undergo rapid 1,3-di-
polar cycloaddition.4 Very recently Carreira’s5 and our
own group6 reported independently a reductive conver-
sion of nitro groups into nitriles.
Bu
NO2
NO2
NO2
H
N
NO2
3 equiv
MgBr
THF, –40 °C
67%
MgBr
MgBr
MgBr
OMgBr
NO
N
O
N
Less investigated, but not of less interest, are additions of
C-nucleophiles to the nitro group.7 In 1927 Gilman and
McCracken,8 and a little later Kursanov and Solodkov9 in-
vestigated the reaction of nitrobenzene with an excess of
phenylmagnesium chloride and obtained diphenylamine
via the hydroxylamine derivative A, which was reduced in
situ by excess Grignard reagent (Scheme 1). Other Grig-
nard reagents such as benzyl- and allylmagnesium halides
also attack the nitro group at nitrogen (1,2-addition),10 and
the intermediates formed can be converted into different
products depending on the reaction conditions used.11 In-
terestingly, alkyl Grignard reagents show different reac-
tion behavior; they preferentially undergo conjugate
addition at the aromatic ring system (Scheme 1).12
O
MgBr
E
OMgBr
D
B
C
Scheme 1
undergoes a [3,3]-sigmatropic rearrangement to give the
indole (Scheme 1).
In principle, nitro groups can also be attacked by enolates,
as indicated by the conversion of chalcone F into ben-
zopyranone G (Scheme 2).15 But, to the best of our knowl-
edge, no other examples of this type of addition have been
reported in the literature.
In 1989 Bartoli et al. reported an efficient synthesis of 7-
substituted indoles by addition of vinylmagnesium bro-
mide to substituted nitrobenzenes.13 The first step is nu-
cleophilic attack of the Grignard reagent on the oxygen
(and not on the nitrogen) of the nitro group. The resulting
labile O-alkylated intermediate B then undergoes elimina-
tion of enolate C, giving an aromatic nitroso compound
D.14 This is attacked a second time by the Grignard re-
agent and the O-vinylhydroxylamine derivative E formed
For several years our group has been investigating the re-
actions of chelated amino acid ester enolates as nucleo-
philes in various types of reactions.16 Based on their high
reactivity, these enolates react under very mild reaction
O
OH
NaOH
EtOH, 25 °C
62%
NO2
N
OH
O
O
SYNTHESIS 2006, No. 19, pp 3341–3347
Advanced online publication: 04.09.2006
x
x.
x
x
.
2
0
0
6
F
G
DOI: 10.1055/s-2006-950228; Art ID: C04706SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

3342
D. Stolz et al.
SPECIAL TOPIC
–O
O–
+
NO2
OR
N
NO2
R'
H3O+
R'
R'
N
O
Tfa
–78 °C to r.t.
–
Zn
TfaN
COOR
TfaHN
COOR
H
I
ClCO2Me
SnCl2
MeO
O
O
N
N
O
R'
R
'
F3C
N
COOR
TfaHN
COOR
L
K
Scheme 3
conditions to give a wide range of unnatural amino acids. 3b, respectively). With respect to the structure of 3a, the
Very recently, we reported the highly stereoselective 1,4- N-hydroxylated aminal structure may be sensitive to-
addition of these enolates H towards nitroalkenes wards hydrolysis, especially under acidic conditions.
(Scheme 3).17 Interestingly, the nitronates I, formed as in- Therefore we also changed the workup protocol.
termediates, could be trapped not only by hydrogen chlo-
Frequently, we used 1 M potassium hydrogen sulfate so-
lution to keep the organic layer neutral to avoid deprotec-
tion of the tert-butyl ester and to suppress acid-catalyzed
elimination of water from the addition product; obviously,
ride but also by acyl halides giving nitriles K6 or different
heterocycles such as L18 depending on the reaction condi-
tions and protecting groups used.
Therefore, we have focused our interest on the reactions these conditions were not sufficiently mild. However,
of aromatic nitro compounds (Figure 1), because we were when a buffer solution (pH ~6) was used instead, the ex-
interested to see if these substrates also react in a conju- pected product 3a was obtained in near quantitative yield
gate fashion via nucleophilic attack of the enolate H on (Table, entry 1). To prove the generality of this reaction,
the aromatic ring (a), or if reaction occurs directly on the we subjected several other nitroarenes to these optimized
nitro group (b).19
conditions (entries 2–8).
The yield obviously depends on the electronic nature of
the aromatic ring system. With electron-withdrawing sub-
stituents the yields were generally very high and they de-
crease slightly with decreasing electron-withdrawing
properties, as illustrated in the series of halogen-substitut-
ed derivatives (Table 1, entries 1–3). Several other func-
tionalities such as cyano or ester groups are tolerated as
well (entries 4 and 5), because obviously the attack on the
b
NO2
RO
a
O
NTfa
Zn
H
Figure 1 Nucleophilic attack of chelated enolates on nitroarenes.
OH
Based on our previous good results obtained with trifluo-
roacetyl-protected tert-butyl glycinate,16 we used enolate
1 as the nucleophile in the reaction with 1-chloro-4-ni-
trobenzene (2a). Indeed, a reaction was observed, howev-
er, it was not at the aromatic ring system but at the nitro
group, and the N-arylhydroxylamine 3a was obtained in
very moderate yield (<20%). In addition, the yield varied
strongly from reaction to reaction, hence, we attempted to
optimize the reaction conditions. During these investiga-
tions we found, that increasing the amount of nucleophile
to 2.5 equivalents gave the expected product in a very
clean reaction, but still only 38% yield (Scheme 4). This
was quite surprising, because all the starting material was
consumed. In contrast, methyl 2-nitrobenzoate (2b) gave
a much higher yield of addition product. In this case, the
hydroxylamine derivative 3b was not obtained, the prod-
uct was the lactonization product 4b, which was not unex-
pected. We assumed that the cyclized product 4b is more
stable compared to the primary addition products 3a (or
N
COOt-Bu
38%
NO2
2a
Cl
1)
H
N
2) KHSO4
Cl
Tfa
Ot-Bu
3a
O–
N
N
O
MeOOC
Tfa
Zn
COOt-Bu
Tfa
COOMe
NO2
1
H
N
2b
3b
KHSO4 – MeOH
O
O
N
COOt-Bu
65%
H
N
Tfa
4b
Scheme 4
Synthesis 2006, No. 19, 3341–3347 © Thieme Stuttgart · New York

SPECIAL TOPIC
Aromatic Nitro Groups and Their Reactions with Chelated Ester Enolates
3343
_
Table 1 Addition of Chelated Enolates to Various Nitroarenes
O
O
+
N
Ot-Bu
Ot-Bu
OH
+
N
O
N
O
Tfa
2.5 equiv Tfa
N
COOt-Bu
Tfa
Zn
Zn
Ar
1
ArNO2
1
2h
1,3-addition
H
N
3
THF, –78 °C to r.t.
1,2-addition
2
_
TfaN
COOt-Bu
Entry
Substrate Ar
Product
3a19
3c19
3d
Yielda (%)
_
COOt-Bu
NHTfa
XZnO
O
O
N
N
1
2
3
4
5
6
7
8
2a
2c
2d
2e
2f
4-ClC6H4
4-BrC6H4
4-IC6H4
95
88
74
85
85
60b
81
77
XZnO
+
O
M
4-MeO2CC6H4
4-NCC6H4
5-quinolyl
Ph
3e19
3f19
3g
– XZnOH
_
TfaN
COOt-Bu
OZnX
COOt-Bu
NHTfa
O
N
_
2g
2h
2i
O
P
N
+
3h
H3O+
O
2-Cl-5-MeOC6H3
3i
N
a Workup conditions: NH4OAc/AcOH buffer (pH 6).
b Starting material (31%) recovered.
CF3
1
NH2
Reduction by 1
+
COOt-Bu
nitro group is much faster than the attack on these, also
well-activated, functionalities. Even with nitrobenzene
the yield was good (entry 7), but no reaction was observed
with 4-nitroanisole and other ‘electron-rich’ nitro deriva-
tives, as well as pyridine N-oxides. Introduction of one ad-
ditional electron-withdrawing group, as in 2i, resulted
again in a good yield of product 3i (entry 8).
COOt-Bu
NHTfa
COOt-Bu
N
NHTfa
O
HO
OH
Q
N
3h
3h
To show the influence of the attacking nucleophile, we
also varied the substitution pattern on the glycinate
(Scheme 5). This showed that in this reaction the trifluo-
roacetyl protecting group is superior, because with car-
bamates such as 5 the yields dropped dramatically, and
this decrease was nearly independent of the ester used.
Scheme 6
giving nitrone N. Such a mechanism was proposed by
Bartoli for the benzyl and allyl Grignard addition,10,11 but
we were not able to detect any nitrone intermediate. On
the other hand, if the enolate attacks in a 1,3-fashion on
the oxygen of 2h, one might expect an intermediate O,
which eliminates deprotonated a-hydroxyglycine P giv-
ing nitrosobenzene, which can also be attacked by the sec-
ond equivalent of enolate with formation of the expected
product 3h.
OH
OR'
NO2
N
COOR'
+
N
O
Boc
HN
Zn
R
R
Boc
2c R = Br
2f R = CN
6a R = Br, R' = Et
32%
5a R' = Et
To gain evidence for the 1,3-addition, we investigated the
reaction of nitrosobenzene with enolate 1 under the same
reaction conditions as the corresponding nitro compound
2h (Scheme 7), although only a slight excess of the eno-
late 1 (1.2 equiv) was used. Indeed, the reaction gave the
same product 3h and the yield was very close to that ob-
6b R = CN, R' = t-Bu 28%
5b R' = t-Bu
Scheme 5
Interestingly, good yields were only obtained if at least
two equivalents of the enolate were used. This indicates
that in this case one equivalent may act as the nucleophile
and the second equivalent may act as the reducing agent,
comparable to the Grignard additions shown in Scheme 1.
In the respect that the nucleophilic attack on the nitro
group can occur either on nitrogen (1,2-addition) or on
oxygen (1,3-addition), one can in principle propose two
mechanistic scenarios (Scheme 6). If the attack occurs di-
rectly at the nitrogen of 2h (1,2-addition), an intermediate
M should be formed which can eliminate zinc hydroxide
COOt-Bu
O
N
Ot-Bu
HO
N
NHTfa
N
O
1
1.2 equiv
Tfa
Zn
THF, –78 °C to r.t.
77%
3h
Scheme 7
Synthesis 2006, No. 19, 3341–3347 © Thieme Stuttgart · New York

3344
D. Stolz et al.
SPECIAL TOPIC
tained starting from the nitro compound 2h (Table 1, entry agent (3 equiv) both acidic positions can be allylated.22
7).
Product 8 thus obtained was subsequently subjected to
ring-closing metathesis using the Hoveyda–Blechert cata-
lyst 9, providing cyclic derivative 10.
We also attempted to detect the corresponding oxidation
products. Looking closely at intermediate P, one might
expect that this hemiaminal intermediate will either de- In conclusion, we have shown that chelated enolates are
compose directly in solution, or, at the very least, during versatile nucleophiles for direct addition to aromatic nitro
acidic workup. Therefore, we took sample probes during groups. The first step of the reaction is a reduction of the
the reaction, quenched them with 1 M potassium hydro- nitro group by the enolate to the corresponding nitroso
gen sulfate solution and analyzed them by GC/MS and compound, which is attacked by a second equivalent of
NMR. After 1 minute at –78 °C the glyoxylate Q could al- the enolate. Therefore, in principle, the reaction products
ready be unambiguously detected, what clearly indicates 3 can be obtained from either aromatic nitro or nitroso de-
that nucleophilic attack on the nitro group is a very rapid rivatives, but in general nitro compounds are more easily
process and that the reaction proceeds via this second 1,3- available.
addition pathway.
Of course, we were also interested to see if it is possible
to further modify the hydroxylamine derivatives 3. First
we attempted to trap the deprotonated intermediates di-
rectly with alkylation agents such as methyl iodide or ben-
zyl bromide, but no alkylation was observed under these
conditions. Therefore, we investigated the palladium-cat-
alyzed allylic alkylation (Scheme 8). During our studies
All reactions were carried out in oven-dried glassware (100 °C) un-
der argon. All solvents were dried before use. THF was distilled
from LiAlH4. The products were purified by flash chromatography
on silica gel (32–63 mm). Mixtures of EtOAc and hexanes were gen-
erally used as eluents. TLC: commercially precoated Polygram SIL-
G/UV254 plates (Macherey–Nagel). Visualization was accom-
plished with UV light and KMnO4 soln. Melting points were deter-
mined on a Büchi melting point apparatus and are uncorrected. 1H
on the application of this important reaction to the synthe- and 13C NMR were obtained on a Bruker DRX-500 spectrometer.
sis of amino acids,20 we observed that slightly acidified al-
HRMS were recorded on a Finnigan MAT 90 (CI) mass spectrom-
eter. Elemental analysis was carried out at the department of chem-
cohols can be allylated under nearly neutral conditions
istry, University of Saarbrücken.
with allylic carbonates.21 Using these allylic substrates,
the alcoholate is formed in situ during p-allyl complex
Additions of Chelated Enolates to Nitroarenes; General Proce-
formation, and this base then deprotonates the acidified
alcohol functionality, generating the required nucleophile.
One might expect that this protocol should also operate
with the hydroxylamine derivatives 3 and 6. Indeed, the
O-allylation of 3c worked very well at room temperature
giving monoallylated product 7. In principle, further pal-
ladium-catalyzed transformations should be possible at
the aryl halide moiety. Interestingly, no N-allylation was
observed under these mild reaction conditions. But under
more drastic conditions and with an excess of allylation
dure
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. 1.6 M n-BuLi (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. The mixture was cooled to –78 °C and a soln 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 at –78 °C for further 30 min to
form the chelated ester enolate. The nitroarene (0.5 mmol) was then
added in THF (1 mL). The soln was allowed to warm to r.t. over-
night and then diluted with Et2O (10 mL) and hydrolyzed in an ice
bath with NH4OAc/AcOH buffer (pH 6, 10 mL). The layers were
separated and the aqueous layer was extracted with Et2O (2 ×). The
combined organic layers were dried (Na2SO4) and the solvent was
evaporated in vacuo. The crude product was purified by flash chro-
matography (silica, hexane–EtOAc).
NHTfa
O
EtOOCO
N
COOt-Bu
NHTfa
COOt-Bu
HO
78%
N
7
tert-Butyl [(4-Chlorophenyl)(hydroxy)amino][(trifluoro-
acetyl)amino]acetate (3a)
Br
OCOOEt
)
Starting from 2a (79 mg, 0.5 mmol), 3a was obtained as a colorless
solid; yield: 175 mg (95%); mp 101 °C.
1H NMR (500 MHz, CDCl3): d = 1.40 [s, 9 H, OC(CH3)3], 5.68 (d,
J = 7.9 Hz, 1 H, NCHCO), 5.90 (s, 1 H, NOH), 7.14 (d, J = 8.8 Hz,
2 H, ArH), 7.23 (d, J = 8.8 Hz, 2 H, ArH), 7.56 (d, J = 7.6 Hz, 1 H,
NHCO).
4%
Pd(PPh
THF,
NTfa
∆
, 8 h
Br
O
N
COOt-Bu
3c
73%
NTfa
COOt-Bu
13C NMR (125 MHz, CDCl3): d = 27.8 [OC(CH3)3], 72.6 (NCH-
CO), 84.8 [OC(CH3)3], 115.6 (q, JC,F = 286.1 Hz, COCF3), 118.2
(ArC), 128.7 (ArC), 128.8 (ArC), 147.4 (ArC), 157.3 (q, JC,F = 37.2
Hz, COCF3), 164.7 (CO).
8
Br
O
N
N
N
Mes
Cl
Mes
Ru
O
Cl
80%
HMRS (CI): m/z [M]+ calcd for C14H16ClF3N2O4: 368.0751; found:
368.0746.
Br
10
9
Anal. Calcd for C14H16ClF3N2O4 (368.77): C, 45.59; H, 4.38; N,
7.59. Found: C, 45.28; H, 4.30; N, 7.57.
Scheme 8
Synthesis 2006, No. 19, 3341–3347 © Thieme Stuttgart · New York

SPECIAL TOPIC
Aromatic Nitro Groups and Their Reactions with Chelated Ester Enolates
3345
tert-Butyl [(4-Bromophenyl)(hydroxy)amino][(trifluoro-
acetyl)amino]acetate (3c)
119.0 (ArC), 133.1 (ArC), 152.9 (CN), 157.4 (q, JC,F = 39.9 Hz,
COCF3), 164.1 (CO).
Starting from 2c (51 mg, 0.25 mmol), 3c was obtained as a colorless
solid; yield: 91 mg (88%); mp 98 °C.
1H NMR (500 MHz, CDCl3): d = 1.39 [s, 9 H, OC(CH3)3], 5.68 (d,
J = 8.0 Hz, 1 H, NCHCO), 6.16 (br s, 1 H, NOH), 7.06 (d, J = 8.5
Hz, 2 H, ArH), 7.35 (d, J = 8.5 Hz, 2 H, ArH), 7.56 (d, J = 7.0 Hz,
1 H, NHCO).
13C NMR (125 MHz, CDCl3): d = 27.8 [OC(CH3)3], 72.5 (NCH-
CO), 84.9 [OC(CH3)3], 115.5 (q, JC,F = 286 Hz, COCF3), 116.1
(ArC), 118.5 (ArC), 131.7 (ArC), 147.9 (ArC), 157.3 (q, JC,F = 38.1
Hz, COCF3), 164.7 (CO).
HMRS (CI): m/z [M]+ calcd for C15H16F3N3O4: 359.1093; found:
359.1082.
Anal. Calcd for C15H16F3N3O4 (359.34): C, 50.14; H, 4.50; N,
11.69. Found: C, 50.18; H, 4.55; N, 11.53.
tert-Butyl [(Hydroxy)(5-quinolyl)amino][(trifluoroacetyl)ami-
no]acetate (3g)
Starting from 2g (87 mg, 0.50 mmol), 3g was obtained as a yellow
salt; yield: 116 mg (60%); mp 122 °C.
1H NMR (500 MHz, CDCl3): d = 1.29 [s, 9 H, OC(CH3)3], 5.96 (d,
J = 8.0 Hz, 1 H, NCHCO), 7.30 (dd, J = 4.0, 8.5 Hz, 1 H, ArH), 7.61
(d, J = 2.0 Hz, 1 H, ArH), 7.67 (dd, J = 2.0, 9.5 Hz, 1 H, ArH), 7.73
(d, J = 7.5 Hz, 1 H, NHCO), 7.96 (d, J = 9.5 Hz, 1 H, ArH), 8.05 (d,
J = 8.5 Hz, 1 H, ArH), 8.63 (d, J = 4.0 Hz, 1 H, ArH), 9.85 (br s, 1
H, NH).
HMRS (CI): m/z [M]+ calcd for C14H16BrF3N2O4: 412.02; found:
412.0247.
Anal. Calcd for C14H16BrF3N2O4 (413.19): C, 40.69; H, 3.90; N,
6.78. Found: C, 40.82; H, 3.80; N, 6.76.
tert-Butyl [(Hydroxy)(4-iodophenyl)amino][(trifluoro-
acetyl)amino]acetate (3d)
Starting from 2d (125 mg, 0.5 mmol), 3d was obtained as a yellow
13C NMR (125 MHz, CDCl3): d = 27.8 [OC(CH3)3], 72.0 (NCH-
CO), 84.3 [OC(CH3)3], 111.7 (ArC), 115.4 (q, JC,F = 286 Hz,
COCF3), 121.5 (ArC), 121.6 (ArC), 128.8 (ArC), 129.0 (ArC),
136.3 (ArC), 143.9 (ArC), 147.9 (ArC), 148.1 (ArC), 157.2 (q,
JC,F = 37.8 Hz, COCF3), 164.9 (CO).
HMRS (CI): m/z [M + H]+ calcd for C17H19F3N3O4: 386.1283;
found: 386.1315.
solid; yield: 171 mg (74%); mp 115 °C.
1H NMR (500 MHz, CDCl3): d = 1.38 [s, 9 H, OC(CH3)3], 5.68 (d,
J = 7.5 Hz, 1 H, NCHCO), 6.45 (br s, 1 H, NOH), 6.91 (d, J = 8.5
Hz, 2 H, ArH), 7.50 (d, J = 8.5 Hz, 2 H, ArH), 7.59 (d, J = 7.5 Hz,
1 H, NHCO).
tert-Butyl [(Hydroxy)(phenyl)amino][(trifluoroacetyl)ami-
no]acetate (3h)
Starting from 2h (62 mg, 0.50 mmol), 3h was obtained as a color-
13C NMR (125 MHz, CDCl3): d = 27.9 [OC(CH3)3], 72.4 (NCH-
CO), 84.8 [OC(CH3)3], 86.5 (ArC), 116.6 (q, JC,F = 285.6 Hz,
COCF3), 118.8 (ArC), 137.6 (ArC), 148.7 (ArC), 157.3 (q,
JC,F = 38.0 Hz, COCF3), 164.7 (CO).
HMRS (CI): m/z [M]+ calcd for C14H16F3IN2O4: 460.0107; found:
460.0072.
less liquid; yield: 135 mg (81%).
1H NMR (500 MHz, CDCl3): d = 1.38 [s, 9 H, OC(CH3)3], 5.76 (d,
J = 8.0 Hz, 1 H, NCHCO), 6.28 (br s, 1 H, NOH), 6.99 (dd, J = 7.5
Hz, 1 H, ArH), 7.17 (d, J = 7.5 Hz, 2 H, ArH), 7.24 (dd, J = 7.5 Hz,
2 H, ArH), 7.59 (d, J = 7.5 Hz, 1 H, NHCO).
13C NMR (125 MHz, CDCl3): d = 27.7 [OC(CH3)3], 72.6 (NCH-
CO), 84.5 [OC(CH3)3], 116.6 (q, JC,F = 286 Hz, COCF3), 116.8
(ArC), 123.4 (ArC), 128.7 (ArC), 148.6 (ArC), 157.2 (q, JC,F = 37.9
Hz, COCF3), 165.1 (CO).
Anal. Calcd for C14H16F3IN2O4 (460.22): C, 36.53; H, 3.51; N, 6.09.
Found: C, 35.89; H, 3.43; N, 6.12.
tert-Butyl {(Hydroxy)[4-(methoxycarbonyl)phenyl]amino}[(tri-
fluoroacetyl)amino]acetate (3e)
Starting from 2e (18 mg, 99.4 mmol), 3e was obtained as a colorless
solid; yield: 33 mg (85%); mp 114 °C.
HMRS (CI): m/z [M + H]+ calcd for C14H18F3N2O4: 335.1174;
found: 335.1165.
1H NMR (500 MHz, CDCl3): d = 1.35 [s, 9 H, OC(CH3)3], 3.86 (s,
3 H, OCH3), 5.84 (d, J = 7.6 Hz, 1 H, NCHCO), 6.30 (br s, 1 H,
NOH), 7.25 (d, J = 8.5 Hz, 2 H, ArH), 7.67 (d, J = 7.6 Hz, 1 H, NH-
CO), 7.94 (d, J = 8.5 Hz, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 27.8 [OC(CH3)3], 51.9 (OCH3),
72.0 (NCHCO), 84.8 [OC(CH3)3], 115.5 (q, JC,F = 286.1 Hz,
COCF3), 115.5 (ArC), 124.4 (ArC), 130.7 (ArC), 153.0 (ArC),
157.1 (COCF3), 164.5 (CHCO), 166.9 (CO2CH3).
tert-Butyl [(2-Chloro-5-methoxyphenyl)(hydroxy)amino][(tri-
fluoroacetyl)amino]acetate (3i)
Starting from 2i (94 mg, 0.50 mmol), 3i was obtained as a colorless
solid; yield: 153 mg (77%); mp 97 °C.
1H NMR (500 MHz, CDCl3): d = 1.46 [s, 9 H, OC(CH3)3], 3.71 (s,
3 H, OCH3), 5.96 (d, J = 9.5 Hz, 1 H, NCHCO), 6.43 (dd, J = 3.0,
8.5 Hz, 1 H, ArH), 6.91 (d, J = 8.5 Hz, 1 H, ArH), 7.03 (d, J = 3.0
Hz, 1 H, ArH), 7.37 (d, J = 9.5 Hz, 1 H, NHCO), 7.44 (s, 1 H,
NOH).
HMRS (CI): m/z [M]+ calcd for C16H19F3N2O6: 392.1195; found:
392.1201.
13C NMR (125 MHz, CDCl3): d = 27.7 [OC(CH3)3], 55.4 (OCH3),
69.7 (NCHCO), 84.6 [OC(CH3)3], 106.9 (ArC), 112.3 (ArC), 115.5
(q, JC,F = 286 Hz, COCF3), 115.6 (ArC), 130.1 (ArC), 144.9 (ArC),
156.8 (q, JC,F = 37.8 Hz, COCF3), 158.5 (ArC), 165.3 (CO).
HMRS (CI): m/z [M – C4H8]+ calcd for C11H10ClF3N2O5: 342.0186;
found: 342.0238.
Anal. Calcd for C16H19F3N2O6 (392.37): C, 48.98; H, 4.89; N, 7.14.
Found: C, 49.17; H, 4.87; N, 7.10.
tert-Butyl [(4-Cyanophenyl)(hydroxy)amino][(trifluoro-
acetyl)amino]acetate (3f)
Starting from 2f (104 mg, 0.70 mmol), 3f was obtained as a color-
less solid; yield: 215 mg (85%); mp 151 °C.
1H NMR (500 MHz, CDCl3): d = 1.35 [s, 9 H, OC(CH3)3], 5.80 (d,
J = 7.5 Hz, 1 H, NCHCO), 6.32 (s, 1 H, NOH), 7.31 (d, J = 9.0 Hz,
2 H, ArH), 7.56 (d, J = 8.5 Hz, 2 H, ArH), 7.67 (d, J = 7.0 Hz, 1 H,
NHCO).
tert-Butyl (3-Oxo-1,2-dihydro-2,1-benzisoxazol-1-yl)[(trifluoro-
acetyl)amino]acetate (4b)
Starting from 2b (91 mg, 0.50 mmol), 4b was obtained as a yellow
solid; yield: 118 mg (65%); mp 126 °C.
13C NMR (125 MHz, CDCl3): d = 27.8 [OC(CH3)3], 71.8 (NCH-
CO), 85.1 [OC(CH3)3], 105.4 (ArC), 116.2 (ArC), 116.6 (COCF3),
1H NMR (500 MHz, CDCl3): d = 1.29 [s, 9 H, OC(CH3)3], 6.08 (d,
J = 7.9 Hz, 1 H, NCHCO), 7.33 (dd, J = 7.6 Hz, 1 H, ArH), 7.41 (d,
Synthesis 2006, No. 19, 3341–3347 © Thieme Stuttgart · New York

3346
D. Stolz et al.
SPECIAL TOPIC
J = 7.9 Hz, 1 H, ArH), 7.66 (d, J = 7.6 Hz, 1 H, ArH), 7.73 (dd,
J = 7.7 Hz, 1 H, ArH), 7.83 (d, J = 7.9 Hz, 1 H, NHCO).
HMRS (CI): m/z [M]+ calcd for C21H28BrF3N2O4: 508.1185; found:
508.1164.
13C NMR (125 MHz, CDCl3): d = 27.5 [OC(CH3)3], 68.3 (NCH-
CO), 85.9 [OC(CH3)3], 112.5 (ArC), 113.5 (ArC), 115.3 (q,
JC,F = 285 Hz, COCF3), 125.4 (ArC), 125.7 (ArC), 135.7 (ArC),
154.7 (ArC), 157.3 (q, JC,F = 39.1 Hz, COCF3), 162.1 (CO2N),
166.9 (CHCO).
Anal. Calcd for C21H28BrF3N2O4 (509.36): C, 49.52; H, 5.54; N,
5.50. Found: C, 49.74; H, 5.82; N, 4.92.
tert-Butyl [(Allyl)(trifluoroacetyl)amino][(allyloxy)(4-bromo-
phenyl)amino]acetate (8)
To a stirred soln of 3c (300 mg, 0.73 mmol) in anhyd THF (3 mL)
was added Pd(PPh3)4 (33.6 mg, 4 mol%) and allyl ethyl carbonate
(285 mg, 2.19 mmol) in THF (3 mL); the mixture was refluxed for
8 h. Subsequently, the solvent was evaporated and the crude product
was directly purified by flash chromatography (silica, hexane) to
give 8 as a yellow oil; yield: 261 mg (73%).
1H NMR (500 MHz, CDCl3): d = 1.44 [s, 9 H, OC(CH3)3], 4.04–
4.44 (m, 4 H, CH2=CHCH2), 5.10–5.28 (m, 4 H, CH2=CH), 5.49 (br
s, 0.35 H, NCHCO), 5.73–5.83 (m, 2 H, CH2=CH), 6.12 (br s, 0.65
H, NCHCO), 6.95 (m, 2 H, ArH), 7.40 (m, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 27.8 [OC(CH3)3], 48.7
(CHCH2N), 75.1 (CHCH2O), 76.3 (NCHCO), 83.7 [OC(CH3)3],
116.0 (q, JC,F = 287 Hz, COCF3), 116.3 (ArC), 117.9
(CH2=CHCH2O), 118.9 (CH2=CHCH2N), 122.2 (ArC), 131.9
(ArC), 132.0 (CHCH2N), 133.2 (CHCH2O), 146.2 (ArC), 163.6
(CO).
HMRS (CI): m/z [M]+ calcd for C15H15F3N2O5: 360.0933; found:
360.0899.
Anal. Calcd for C15H15F3N2O5 (360.32): C, 49.99; H, 4.20; N, 7.78.
Found: C, 49.75; H, 4.18; N, 7.83.
Ethyl [(4-Bromophenyl)(hydroxy)amino][(tert-butoxycarbon-
yl)amino]acetate (6a)
Starting from 2c (101 mg, 0.50 mmol), 6a was obtained as a pale
yellow oil; yield: 63 mg (32%).
1H NMR (500 MHz, CDCl3): d = 1.14 (t, J = 7.0 Hz, 3 H, CH2CH3),
1.33 [s, 9 H, OC(CH3)3], 4.13 (q, J = 7.0 Hz, 2 H, CH2CH3), 5.59 (d,
J = 8.0 Hz, 1 H, NHCO), 5.91 (d, J = 8.5 Hz, 1 H, NCHCO), 6.82
(br s, 1 H, NOH), 7.04 (d, J = 8.0 Hz, 2 H, ArH), 7.29 (d, J = 8.5 Hz,
2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 14.1 (CH2CH3), 28.2
[OC(CH3)3], 62.1 (CH2CH3), 73.4 (NCHCO), 80.6 [OC(CH3)3],
115.4 (ArC), 118.8 (ArC), 131.4 (ArC), 148.4 (ArC), 155.7
(NCO2), 167.4 (CHCO).
HRMS (CI): m/z [M]+ calcd for C20H24BrF3N2O4: 492.0872; found:
492.0849.
tert-Butyl (Z)-2-(4-Bromophenyl)-4-(trifluoroacetyl)-3,4,5,8-
tetrahydro-2H-1,2,4-oxadiazocin-3-carboxylate (10)
tert-Butyl [(tert-Butyloxycarbonyl)amino][(4-cyanophenyl)(hy-
droxy)amino]acetate (6b)
Starting from 2f (74 mg, 0.50 mmol), 6b was obtained as a tough
yellow oil; yield: 50 mg (28%).
1H NMR (500 MHz, CDCl3): d = 1.29 [s, 9 H, CHCO2(CH3)3], 1.42
[s, 9 H, NHCO2(CH3)3], 5.61 (br s, 1 H, NHCO), 6.03 (br s, 1 H,
NCHCO), 6.37 (br s, 1 H, NOH), 7.28 (d, J = 8.0 Hz, 2 H, ArH),
7.53 (d, J = 8.5 Hz, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 27.8 [CCO2C(CH3)3], 28.2
[NCO2C(CH3)3], 73.5 (NCHCO), 81.1 [NCO2C(CH3)3], 83.8
[CCO2C(CH3)3], 106.4 (ArC), 116.8 (ArC), 119.2 (ArC), 133.6
(ArC), 152.5 (CN), 155.7 (NCO2), 167.7 (CHCO).
To a stirred soln of 8 (126 mg, 0.26 mmol) in anhyd CH2Cl2 (4 mL)
was added a soln of Hoveyda–Blechert catalyst 9 (16 mg, 10 mol%)
in anhyd CH2Cl2 (2 mL) at r.t. and the mixture was stirred over-
night. The solvent was evaporated in vacuo and the crude product
was purified by flash chromatography (silica, hexane–EtOAc) to
give 9 as a wax-like colorless solid; yield: 95 mg (80%).
1H NMR (500 MHz, CDCl3): d = 1.30 [s, 9 H, OC(CH3)3], 4.18 (dd,
J = 8.0, 16.0 Hz, 1 H, CHCH2N), 4.25 (d, J = 17.5 Hz, 1 H,
CHCH2O), 4.55 (d, J = 17.5 Hz, 1 H, CHCH2O), 4.61 (dd, J = 8.0,
16.0 Hz, 1 H, CHCH2N), 5.60 (m, J = 11.0 Hz, 1 H, OCH2=CH),
5.86 (m, J = 8.0, 11.0 Hz, 1 H, NCH2=CH), 6.40 (s, 1 H, NCHCO),
6.97 (d, J = 9.0 Hz, 2 H, ArH), 7.42 (d, J = 9.0 Hz, 2 H, ArH).
13C NMR (125 MHz, CDCl3): d = 27.8 [OC(CH3)3], 41.2
(CHCH2N), 71.3 (CHCH2O), 74.7 (NCHCO), 83.8 [OC(CH3)3],
115.3 (ArC), 115.8 (COCF3), 117.7 (ArC), 123.5 (CHCH2N), 130.9
(CHCH2O), 132.0 (ArC), 147.2 (ArC), 157.7 (q, JC,F = 36.6 Hz,
COCF3), 164.0 (CO).
tert-Butyl {(4-Bromophenyl)[(E)-5-methylhex-2-enyloxy]ami-
no}[(trifluoroacetyl)amino]acetate (7)
To a stirred soln of 3c (50 mg, 121 mmol) in anhyd THF (1.5 mL)
was added Pd(PPh3)4 (5.6 mg, 4 mol%) and ethyl 1-vinyl-3-methyl-
butyl carbonate (23 mg, 121 mmol) at r.t. After 30 min the red soln
was diluted with Et2O (10 mL) and hydrolyzed with 1 M KHSO4
(10 mL). The layers were separated, the aqueous layer was extract-
ed with Et2O (2 ×) and the combined organic layers were dried
(Na2SO4). The solvent was evaporated and the crude product was
purified by flash chromatography (silica, hexane–EtOAc) to give 7
as a pale yellow oil; yield: 48 mg (78%).
1H NMR (500 MHz, CDCl3): d = 0.82 (d, J = 2.5 Hz, 3 H, CH3),
0.84 (d, J = 2.5 Hz, 3 H, CH3), 1.39 [s, 9 H, OC(CH3)3], 1.57 [m, 1
H, CH(CH3)2], 1.88 (dd, J = 7.0 Hz, 2 H, CH2CH=CH), 4.16 (m, 2
H, CH=CHCH2O), 5.46 (m, J = 7.0, 15.0 Hz, 1 H, CH2CH=CH),
5.57 (d, J = 7.5 Hz, 1 H, NCHCO), 5.65 (m, J = 7.0, 15.0 Hz, 1 H,
CH=CHCH2O), 7.08 (d, J = 8.5 Hz, 2 H, ArH), 7.40 (d, J = 9.0 Hz,
2 H, ArH), 7.54 (br s, 1 H, NHCO).
MS (CI): m/z (%) = 465 (15), 409 (19), 363 (100), 279 (23).
Acknowledgment
Financial support by the Deutsche Forschungsgemeinschaft as well
as the Fonds der Chemischen Industrie is gratefully acknowledged.
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SPECIAL TOPIC
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Synthesis 2006, No. 19, 3341–3347 © Thieme Stuttgart · New York