A Practical Oxidative Method for the Cleavage of Hydrazide N-N Bonds

Article abstract of DOI:10.1002/chem.200305501

The selective N-oxidation of the most nucleophilic amino nitrogen atom in hydrazides is central to the development of an unprecedented methodology for the cleavage of their N-N bonds under oxidative conditions. Treatment of a series of hydrazides 1-9 with peracids such as magnesium monoperoxyphtalate hexahydrate (MMPP·6H₂O) or meta-chloroperbenzoic acid (m-CPBA) afforded the corresponding amides 10-16 in good-to-excellent yields (80-92%). The extension of the methodology to carbamate-like substrates such as 17 and 18 was also investigated, but in this case the process is synthetically useless in view of the low yields observed of carbamates 19 and 20 (≈ 15%). Experiments carried out with equivalent amounts of oxidant produced nitrones, such as 26, proceeding from the dialkylamino moiety, and ¹H NMR experiments indicated that this product is formed by fast conversion of the parent hydrazide, without detection of the expected hydrazide N-oxides. In addition, the over oxidation of 26 into nitronate 25 proceeds through an unknown intermediate. This oxidative N-N bond cleavage by peracids is an alternative method for the deamination of hydrazides, and constitutes the only solution compatible with substrates carrying functionalities sensitive to reducing conditions.

Full text of DOI:10.1002/chem.200305501

FULL PAPER
A Practical Oxidative Method for the Cleavage of Hydrazide NÀN Bonds
Rosario Fernµndez,[b] Ana Ferrete,[b] Josÿ M. Llera,[c] Antonio Magriz,[a]
EloÌsa MartÌn-Zamora,[b] Elena DÌez,[b] and Josÿ M. Lassaletta*[a]
Abstract: The selective N-oxidation of
the most nucleophilic amino nitrogen
atom in hydrazides is central to the de-
velopment of an unprecedented meth-
odology for the cleavage of their NÀN
bonds under oxidative conditions.
Treatment of a series of hydrazides
1 9 with peracids such as magnesi-
um monoperoxyphtalate hexahydrate
(MMPP¥6H2O) or meta-chloroperben-
zoic acid (m-CPBA) afforded the cor-
responding amides 10 16 in good-to-
excellent yields (80 92%). The exten-
sion of the methodology to carbamate-
like substrates such as 17 and 18 was
also investigated, but in this case the
process is synthetically useless in view
of the low yields observed of carba-
mates 19 and 20 (ꢀ15%). Experiments
carried out with equivalent amounts of
oxidant produced nitrones, such as 26,
proceeding from the dialkylamino
cated that this product is formed by
fast conversion of the parent hydrazide,
without detection of the expected hy-
drazide N-oxides. In addition, the over
oxidation of 26 into nitronate 25 pro-
ceeds through an unknown intermedi-
ate. This oxidative NÀN bond cleavage
by peracids is an alternative method
for the deamination of hydrazides, and
constitutes the only solution compati-
ble with substrates carrying functionali-
ties sensitive to reducing conditions.
1
moiety, and H NMR experiments indi-
Keywords: cleavage reactions
¥
hydrazides ¥ oxidation ¥ pericyclic
reactions ¥ synthetic methods
Introduction
routes and therefore, the cleavage of the NÀN bond appears
as a key transformation. Several reductive methods have
been used for this cleavage. The most widely used are 1)
Zn/H+,[9] 2) catalytic hydrogenation by Raney-Ni,[10] PtO2,[11]
or Pd-based catalysts,[12] 3) Na(Li)/NH3,[13] 4) SmI2,[14] and 5)
BH3¥THF.[15] Though these methods give satisfactory results
in general, there are limitations and difficulties in many
cases, mainly related with the harsh acidic or basic condi-
tions required, the lack of reactivity, and/or the partial race-
mization of neighboring stereogenic centers. Finally, it
should be noted that all available methods require strong re-
ducing conditions that are incompatible with a number of
functionalities or protecting groups.
Hydrazines or their acyl-protected forms are common inter-
mediates obtained in a growing number of synthetic routes.
Remarkable recent examples of such methods are the anion-
ic[1] or radical[2] additions to the C=N bond of hydrazones,
the electroreductive coupling of ketones with hydrazones,[3]
the addition of carbon nucleophiles to acylhydrazonium
salts,[4] the addition of N-aminolactams to Michael accept-
ors,[5] the aza-Michael addition of hydrazines to electrophilic
alkenes,[6] the radical cyclisation of N-allyl-a-perchlorohy-
drazides,[7] and the 1,3-dipolar cycloaddition of azomethine
imines to dipolarophiles (see Scheme 1).[8]
In most cases, obtaining the corresponding free amines or
acyl-protected derivatives is the main application for these
In fact, it was during our previous work on the Stauding-
er-like [2+2] cycloaddition of N,N-dialkylhydrazones with
functionalized ketenes (Scheme 2) that we faced serious dif-
ficulties with the reductive deamination of the resulting 1-di-
alkylamino azetidin-2-ones;[16] from the above-mentioned
variety of methods, only large excesses of SmI2 in the pres-
ence of hexamethylphosphoramide (HMPA) as co-solvent
afforded the desired products. Moreover, these inconvenient
conditions gave only low to moderate yields (42 65%).
Therefore, we were forced to study alternative methodolo-
gies suitable for the cleavage of the NÀN bond. In this
paper, we report in full on the unprecedented oxidative
cleavage of N,N-dialkylhydrazides by peracids.
[a] A. Magriz, Dr. J. M. Lassaletta
Instituto de Investigaciones QuÌmicas (CSIC-USe)
c/Americo Vespuccio s/n, Isla de la Cartuja
41092 Seville (Spain)
Fax : (+34)954-460-565
E-mail: jmlassa@cica.es
[b] Dr. R. Fernµndez, Dr. A. Ferrete, Dr. E. MartÌn-Zamora, Dr. E. DÌez
Dpto. de QuÌmica Orgµnica
Universidad de Sevilla (Spain)
[c] Dr. J. M. Llera
Dpto. de QuÌmica Orgµnica y Farmacÿutica
Universidad de Sevilla (Spain)
737
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DOI: 10.1002/chem.200305501
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FULL PAPER
Scheme 1. Hydrazide intermediates in organic synthesis: selected examples.
Abstract in Spanish: La N-oxidaciÛn selectiva del nitrÛgeno
amÌnico de hidrazidas constituye la estrategia clave para el
desarrollo de una nueva metodologÌa para la rotura del
enlace NÀN en estos compuestos en condiciones oxidantes.
El tratamiento de una serie de hidrazidas 1 9 con perµcidos
como MMPP¥6H2O Û m-CPBA conduce a las correspon-
dientes amidas 10 16 con rendimientos de buenos a excelen-
tes (80 92%). Se investigÛ ademµs la extensiÛn de la metodo-
logÌa a sustratos de tipo carbamato como 17 Û 18, pero los
rendimientos, muy inferiores (ꢀ15%) en este caso, hacen el
procedimiento inadecuado en sÌntesis. En experimentos lleva-
dos a cabo sin exceso de oxidante se obtuvieron nitronas
como 26 como el producto procedente del fragmento dialqui-
Scheme 2. [2+2] cycloaddition of N,N-dialkylhydrazones with ketenes.
The quaternization of a nitrogen atom is a central strategy
used to weaken a CÀN bond. Classic applications of this are
the Cope elimination of tertiary amine oxides,[17] the Hof-
mann degradation of quaternary ammonium salts,[18] the Ste-
vens rearrangement,[19] the Sommelet Hauser rearrange-
ment,[20] the [2,3]-sigmatropic rearrangement of allylic nitro-
gen ylides,[21] and the Meisenheimer rearrangement of terti-
ary amine oxides.[22] There are also known reactions in
which the quaternization of one of the nitrogen atoms of an
NÀN bond results in its cleavage. The Benzidine rearrange-
ment,[23] the Fischer indole synthesis,[24] the aza-Cope elimi-
nation from hydrazones to nitriles,[25] the acid-promoted re-
arrangement of aryl triazenes,[26] and the rearrangement of
N-nitroso aryl amines (Fisher Hepp)[27] belong to this group.
Surprisingly, and in spite of the many known precedents,
1
lamino, y en experimentos de H RMN se pudo comprobar
que este producto se forma rµpidamente a partir de la hidra-
zida de partida, sin que se detecten N-Ûxidos de hidrazida
como intermedios. Se pudo establecer ademµs que la oxida-
ciÛn de 26 a 25 transcurre a travÿs de una especie intermedia
no identificada. Este procedimiento de rotura oxidativa de
enlaces NÀN por perµcidos representa una metodologÌa alter-
nativa para la desaminaciÛn de hidrazidas, y constituye la
Çnica soluciÛn disponible para sustratos sensibles a condicio-
nes reductoras.
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Chem. Eur. J. 2004, 10, 737 745

Oxidative Method for the Cleavage of Hydrazide NÀN Bonds
737 745
there are no reports on the application of a related strategy
for the deamination of hydrazides.
The extension of the method to the deamination of carba-
mate-like derivatives 17 and 18[29] was also studied. Unfortu-
nately, the N-oxidation of this kind of substrate afforded the
desired products 19 20 in low yields, along with ketones 21
22 as the major products of the reactions. The formation of
the latter can be explained by aza-Cope elimination reac-
tions from N-oxide intermediates to imine derivatives, such
as 23, which easily hydrolyze to the corresponding ketone
under the reaction conditions. Supporting this hypothesis,
imine 23 (n=1) was detected as an intermediate in the oxi-
dation of 17 when m-CPBA was used in the presence of
NaHCO3 (Scheme 5).
Results and Discussion
The selective quaternization of the most nucleophilic amino
nitrogen of hydrazide A can be achieved by reaction with
several types of electrophilic reagents to afford compounds
of general structure B, according to the reaction depicted in
Scheme 3.
The presence of sensitive functionalities in the chlorinated
substrates 6 9 made cleavage under reductive conditions un-
successful. In addition, these oxidative conditions, reported
in our earlier work,[16] have been applied by Enders and co-
workers[30] as the only suitable procedure for the deamina-
tion of optically pure 1-dialkylaminoisoindolones.
Scheme 3. Quaternization of hydrazide amino nitrogens.
Due to the novelty of the reaction, we were also interest-
ed in its mechanism, therefore experiments were carried out
to gain useful information about the reaction course. Firstly,
the isolation and characterization of the product(s) derived
from the amine fragment were required. In the initial ex-
periments using excess oxidant and proline-derived hydra-
zides like 1 (entry 1, Scheme 6), nitrone 24 was obtained as
a byproduct, but the isolated yields of this compound were
repeatedly lower than 50%. Therefore, the question above
was not fully answered.
Among other possibilities (N-alkylation, N-acylation, N-
nitrosation, etc.) the N-oxidation of the amino nitrogen was
considered the most promising approach for our purposes
on the basis of the following considerations: 1) Mild condi-
tions and available reagents such as peracids are used. 2)
Neutral, easy to handle and easily characterized intermedi-
ates are expected. 3) The cleavage of the expected hydra-
zide N-oxides could proceed by thermal activation like the
closely related Meisenheimer rearrangement.
Attempts to isolate or detect any other reaction products
were unsuccessful. In addition, the over oxidation of 24 to
afford highly polar, low-molecular-weight byproducts was
considered, but this was ruled out after proving the stability
of 24 against excess of MMPP under the reaction conditions.
In the case of the mannitol-derived hydrazide 2, any frag-
ment proceeding from the dialkylamino moiety was lost
during workup. Finally, the cleavage of hydrazides 3 and 4
afforded cyclic nitronate 25 in low yields (13 26%) as the
only isolable byproduct. Though an excess of reagent was
necessary for the deamination of hindered substrates such as
1 or 2 (entries 1 and 2), in the case of 2,5-dimethylpyrroli-
dine derivatives, such as 3 or 4, the use of stoichiometric
amounts of MMPP or m-CPBA sufficed to achieve clean
and high-yielding transformations. In this case however, a
different byproduct, nitrone 26, was isolated from the amino
moiety in a yield of 75 80%, which was for the first time
high enough to understand the mass balance in the reaction
(Scheme 7).
Considering the experimental simplicity and based on our
[28]
previous experience[25a]
,
with these types of reagents, we
decided to start the experiments using magnesium mono-
peroxyphtalate hexahydrate (MMPP¥6H2O) or meta-chloro-
perbenzoic acid (m-CPBA) as the N-oxidation agents. It was
a pleasant surprise to observe that the reaction of several
[16]
substrates 1 9[7]
,
with these reagents proceeded smoothly
at room temperature to afford the desired deamination
products 10 16 directly, without detection of any intermedi-
ates (Scheme 4). Comparison of this behavior with that of
amine oxides suggests a lower thermal stability for hydra-
zide amine oxides, which are assumed to be the primary in-
termediates formed.
Taken together, the above results and considerations sug-
gest that the reaction proceeds through the spontaneous
cleavage of intermediate hydrazide N-oxides into the deami-
nated amide fragment (10 16) and a nitrone formed from
the dialkylamino moiety, which is then further oxidized by
an excess of oxidant. This last hypothesis was independently
confirmed by the controlled transformation of 26 into 25 by
addition of equivalent amounts of MMPP¥6H2O or m-
Scheme 4. Deamination of hydrazides by peracids.
The results in Table 1 show the efficiency of this sponta-
neous process. The procedure is effectively applied to the
deamination of a variety of hydrazides 1 9 carrying diverse
N-dialkylamino moieties including dimethylamino (en-
tries 6 8), pyrrolidin-1-yl (entry 5), pyperidin-1-yl (entry 9),
and more complex structures like the chiral derivatives of
prolinol (entry 1), mannitol (entry 2), or 2,5-dimethylpyrroli-
dine (entries 3 and 4).
1
CPBA under the reaction conditions. Additionally, H NMR
monitoring was conducted for the oxidation reactions of 4
by using 1 or 2 equivalents of dried m-CPBA in CDCl3
(Figure 1). Due to the simplicity of spectra of the chosen
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J. M. Lassaletta et al.
FULL PAPER
Table 1. Oxidative deamination of hydrazides
Entry
Hydrazide
MMPP [equiv]
t [h]
Product
Yield[a] [%]
1
6
4
88
2
12
6
82
3
1.1
2
91
4
5
6
7
1.1
0.5
0.5
0.5
2
82
82
80
82
3
3
3
8
3
0.5
92
740
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Oxidative Method for the Cleavage of Hydrazide NÀN Bonds
737 745
Table 1. (Continued)
Yield[a] [%]
Entry
Hydrazide
MMPP [equiv]
t [h]
Product
9
3
0.5
89
10
11
6
6
24
24
15[b]
15[c]
[a] Isolated yield. [b] Ketone 21 was isolated as major product in 60% yield. See text and Scheme 5. [c] Ketone 22 was isolated as major product in 65%
yield. See text and Scheme 5.
tion of the starting material
into the products 12 and 26; no
signals assignable to the pro-
posed hydrazide N-oxide inter-
mediate could be identified
(Figure 1, spectrum 1). When
the reactions were performed
with a twofold excess of oxi-
dant, a complex mixture was
observed after a short reaction
time (spectrum 2). In this spec-
trum, it was also possible to
identify peaks corresponding to
the deaminated product 12 and
the nitrone 26, but other signals
corresponding to the nitronate
Scheme 5. Oxidation of methoxycarbonyl derivatives 17 and 18.
25 and an unknown intermedi-
ate were also identified. The
spectra recorded at longer reac-
tion times (spectrum 3) indicated a smooth evolution of 26
into 25 through the mentioned intermediate, which was
completed after 1.5 h at room temperature (spectrum 4). In
the case of substrate 1, it seems reasonable to assume that
the corresponding over oxidation of 24 is strongly hindered
for steric reasons.
Assuming that the N-oxidation of the amine is the first
step of the reaction, it follows that the resulting hydrazide
N-oxides are unstable compounds that spontaneously react
Scheme 6. Cleavage of proline derivative 1 by excess of MMPP.
to afford the final products. According to this hypothesis, a
substrate and the clean reaction achieved under these condi-
tions, the spectra recorded at different reaction times could
be easily analyzed. The reaction performed with equivalent
amounts of oxidant indicated a fast and clean transforma-
search in literature databases reveals that these products are
not known.
The collected information made us consider two possible
reaction mechanisms:
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J. M. Lassaletta et al.
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1) Homolytic NÀN bond cleav-
age in the intermediate hy-
drazide N-oxides to afford
relatively stable amidyl and
nitroxide
free
radicals,
which give final products
after an intermolecular radi-
cal quench (Scheme 8).
2) A pericyclic process that
can be viewed as the con-
certed retro-1,2-addition of
the enolic form of the
amide to the nitrone
(Scheme 9).
We tentatively propose this
second mechanism on the basis
of three considerations.
Scheme 7. Cleavage of trans (R,R)-2,5-dimethylpyrrolidin-1-yl derivatives.
The first consideration is that
bicyclic substrates 27 and 28[8]
were transformed into the cor-
responding N-oxides 29 and 30
(Scheme 10), which were isolat-
ed as crystalline, stable com-
pounds. Attempts to promote
the thermal rearrangement of
29 or 30 into compounds 31 or
32 were unsuccessful. The un-
usual stability of these com-
pounds can be explained if, ac-
cording to the proposed pericy-
clic mechanism, they are
unable to reach the conforma-
tion required for the NÀN bond
cleavage, while their relative
stability would be difficult to
explain if the homolytic NÀN
bond cleavage mechanism is as-
sumed.
The second consideration is
that if a radical mechanism op-
erates, it would constitute a
kind of aza-Meisenheimer[22] re-
action and, accordingly, similar
radical recombinations and side
reactions would be expected.
Moreover, a partial dispropor-
tion of nitroxide radicals into
nitrone and hydroxylamine is
well established.[31] However,
no traces of hydroxylamines
were detected in the reaction
mixtures.
Finally the different behavior
of amide-like (1 9) and carba-
mate-like substrates (17, 18)
suggests that the nature of the
carbonyl strongly influences the
course of the reaction, a fact
Figure 1. 1H NMR experiments for the oxidation of 4 by m-CPBA.
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Chem. Eur. J. 2004, 10, 737 745

Oxidative Method for the Cleavage of Hydrazide NÀN Bonds
737 745
100 mA, an accelerating voltage of 4 kV, and a resolution of 1000 or
10000 (10% valley definition). The reactions were monitored by TLC.
Purification of the products was carried out by chromatography (silica
gel). The boiling range of the light petroleum ether was 40 658C.
General procedure for NÀN bond cleavage of hydrazides: MMPP¥6H2O
(0.55 6 mmol) was added to a solution of hydrazide 1 9, 17, or 18
(1 mmol) in methanol (5 mL); this mixture was stirred at room tempera-
ture until TLCindicated total consumption of the starting material. The
mixture was then diluted with H2O (10 mL) and extracted with CH2Cl2
(4î10 mL). The organic layer was washed with saturated NaHCO3 solu-
tion, dried (MgSO4), and concentrated, and the residue purified by flash
chromatography. Eluants, yields, and spectral and analytical data for
compounds 10 16, 19, and 20 are as follows.
(3R,4S)-3-Benzyloxy-4-isopropylazetidin-2-one (10) and 5-(1-ethyl-1-me-
thoxypropyl)-3,4-dihydro-2H-pyrrole 1-oxide (24): From 1, flash chroma-
tography (3:1 toluene/AcOEt) gave 193 mg (88%) of crystalline 10. M.p.
Scheme 8. Homolytic cleavage of the NÀN bond.
1
85 868C ; [a]2D6 =+120.4 (c=1.1 in CH2Cl2); H NMR (300 MHz, CDCl3):
d=0.94 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 1.9 2.1 (m, 1H),
3.35 (dd, J=4.9, 9.2 Hz, 1H), 4.67 (dd, J=2.9, 4.9 Hz, 1H), 4.72 (d, J=
11.9 Hz, 1H), 4.94 (d, J=11.9 Hz, 1H), 6.41 (brs, 1H), 7.2 7.4 ppm (m, 5
H); 13CNMR (75 MHz, CDCl 3): d=18.8, 18.9, 28.0, 60.8, 72.5, 81.9,
127.5, 127.6, 128.3, 137.3, 169.3 ppm; IR (film): n˜ =3262, 1760 cmÀ1; MS
(CI): m/z (%): 220 (60) [M++1], 192 (21), 91 (100); elemental analysis
calcd (%) for C13H17NO2: C71.20, H 7.81, N 6.39; found: C71.16, H
8.00, N 6.46.
Further elution with 20:1 CH2Cl2/MeOH afforded 24 mg (43%) of ni-
trone 24. 1H NMR (300 MHz, CDCl3): d=0.75 (t, J=7.4 Hz, 6H), 1.68
(dq, J=7.4, 14.8 Hz, 2H), 1.97 2.08 (m, 2H), 2.49 (dq, J=7.4, 14.8 Hz, 2
H), 2.79 2.84 (m, 2H), 3.11 (s, 3H), 4.01 4.08 ppm (m, 2H); 13CNMR
(75 MHz, CDCl3): d=7.9, 16.7, 22.8, 32.9, 47.4, 64.4, 81.9, 150.9 ppm; IR
(KBr): n˜ =2966, 1739, 1647 cmÀ1; MS (EI): m/z (%): 185 (5) [M+], 168
(32), 156 (100); HRMS calcd for C10H19NO2: 185.1416; found: 185.1413.
Scheme 9. NÀN bond cleavage through a pericyclic mechanism.
which is easier to understand assuming the proposed mecha-
nism.
Benzyl ester of (S)-benzyl-(2-oxoazetidin-3-yl)carbamic acid (11): From 2
(0.3 mmol), flash chromatography (7:1 toluene/acetone) gave 76 mg (82
1
%) of 12. [a]2D2 =À8.8 (c=1 in C HCl2); H NMR (500 MHz, [D6]DMSO,
2
908C): d=3.14 (dd, J=2.9, 5.5 Hz, 1H), 3.31 (t, J=5.5 Hz, 1H), 4.49 (d,
J=15.9 Hz, 1H), 4.61 (d, J=15.9 Hz, 1H), 4.90 (dd, J=2.9, 3.5 Hz, 1H),
5.12 (d, J=12.6 Hz, 1H), 5.16 (d, J=12.6 Hz, 1H), 7.40 (brs, 1H), 7.22
7.34 ppm (m, 10H); 13CNMR (125 MHz, [D 6]DMSO, 908C): d=47.0,
55.6, 70.2, 72.2, 132.2, 132.3, 132.7, 132.9, 133.4, 141.0, 143.5, 160.5,
172.0 ppm; IR (KBr): n˜ =3299, 1771, 1708 cmÀ1; MS (CI): m/z (%): 311
(68) [M++1], 283 (6), 239 (7), 221 (5), 91 (100); elemental analysis calcd
(%) for C18H18N2O3: C69.66, H 5.85, N 9.03; found: C69.59, H 6.19, N
9.11.
Conclusion
In summary, the unprecedented strategy outlined for the ox-
idative NÀN bond cleavage of hydrazides by peracids could
be successfully applied for the deamination of a variety of
substrates under mild conditions. In practice, this methodol-
ogy provides not only an efficient solution for particular sys-
tems where other methods fail[16] or produce undesired race-
mizations,[30] but appears as the only solution compatible for
substrates carrying functionalities sensitive to reducing con-
ditions.
3,6-Dimethyl-5,6-dihydro-4H-[1,2]oxazine 2-oxide (25): From
3 and
MMPP (3 mmol), flash chromatography (3:1 toluene/AcOEt) gave
193 mg (88%) of crystalline 10 and 17 mg (13%) of nitronate 25. 1H
NMR (300 MHz, CDCl3): d=1.32 (d, J=6.6 Hz, 3H), 1.94 2.01 (m, 1H),
2.08 2.14 (m, 1H), 2.14 (s, 3H), 2.46 2.48 (m, 2H), 5.28 5.31 ppm (m, 1
H); 13C NMR (75 MHz, CDCl3): d=16.7, 26.7, 29.7, 39.4, 62.3,
206.7 ppm; IR (KBr): n˜ =2928, 2856, 1641 cmÀ1; MS (CI): m/z (%): 130
(100) [M++1], 114 (72), 112 (98); HRMS calcd for C6H12NO2: 130.0868;
found: 130.0867.
Experimental Section
(R)-3-Benzyloxyazetidin-2-one (12) and (R)-2,5-dimethyl-3,4-dihydro-
2H-pyrrole 1-oxide (26): From 4 (0.3 mmol), flash chromatography (3:2
General methods: Melting points were determined by means of a metal
block and are uncorrected. Optical rotations were measured at room
temperature. FT-IR spectra were recorded for KBr pellets or films. EI-
mass spectra were recorded at 70 eV, by using an ionizing current of
toluene/AcOEt) gave 146 mg (82%) of crystalline 12. M.p. 80 828C;
1
[a]2D2 =+54.9 (c=1 in C HCl2); H NMR (500 MHz, CDCl3): d=3.28 (dd,
2
J=2.2, 4.9 Hz, 1H), 3.47 (t, J=4.9 Hz, 1H), 4.67 (d, J=11.6 Hz, 1H),
Scheme 10. Oxidation of bicyclic substrates 27 and 28.
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J. M. Lassaletta et al.
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4.81 4.84 (m, 1H), 4.86 (d, J=11.6 Hz, 1H), 5.93 (brs, 1H), 7.3 7.4 ppm
(m, 5H); 13CNMR (125 MHz, CDCl 3): d=44.1, 72.2, 82.5, 128.1, 128.5,
136.9, 168.3 ppm; IR (KBr): n˜ =3311, 1731, 1461 cmÀ1; MS (CI): m/z (%):
178 (100) [M++1], 150 (31), 91 (84); elemental analysis calcd (%) for
C10H11O2N: C67.78, H 6.23, N 7.90; found: C67.45, H 6.25, N 7.90.
3H), 4.51 (brs, 1H), 7.0 7.4 ppm (m, 5H); 13CNMR (75 MHz, CDCl 3):
d=2.8, 4.1, 16.8, 28.0, 35.8, 36.1, 52.2, 55.9, 126.0, 128.5, 128.6, 142.5,
157.0 ppm; HRMS calcd for C15H22NO2: 248.1650; found: 248.1648.
Dimethyl ester of (4R,6R,7R,8R)-1-oxo-5-oxy-4,6-diphenyltetrahydropyr-
azolo[1,2-c][1,3,4]oxadiazine-7,8-dicarboxylic acid (29): From 27
(0.1 mmol), flash chromatography (4:1 toluene/AcOEt) afforded 40 mg
(94%) of 29. [a]2D5 =À82.2 (c=0.96 in CH2Cl2); 1H NMR (500 MHz,
CDCl3): d=0.42 (t, 3H, J=7.2 Hz), 0.6 1.4 (m, 6H), 3.71 (s, 3H), 3.74 (s,
3H), 3.87 (dd, J=10.8, 9.4 Hz, 1H), 4.18 (ddd, J=10.8, 9.2, 2.6 Hz, 1H),
4.36 (dd, J=11.7, 3.5 Hz, 1H), 4.93 (d, J=9.4 Hz, 1H), 5.13 (dd, J=3.5,
11.8 Hz, 1H) 5.58 (t, J=11.8, 1H), 7.8 7.3 ppm (m, 10H); 13CNMR
(75 MHz, CDCl3): d=48.4, 51.9, 52.3, 58.2, 67.5, 79.0, 84.4, 129.1, 129.4,
130.1, 130.4, 131.3, 132.0, 132.4, 133.3, 151.9, 171.3, 172.1 ppm; MS (CI):
m/z (%): 427 (88) [M++1], 411 (100), 397 (62); elemental analysis calcd
(%) for C22H22N2O7: C61.97, H 5.20, N 6.57; found: C61.88, H 5.32, N
6.47.
Further elution with 20:1 CH2Cl2/MeOH afforded 41 mg (72%) of ni-
trone 26. [a]2D5 =+13.7 (c=1.1 in CH2Cl2); 1H NMR (300 MHz, CDCl3):
d=1.46 (d, J=6.7 Hz, 3H), 1.67 1.79 (m, 1H), 2.06 (dd, J=3.1, 1,5 Hz, 3
H), 2.27 2.39 (m, 1H), 2.65 2.71 (m, 2H), 4.09 4.19 ppm (m, 1H); 13C
NMR (75 MHz, CDCl3): d=12.9, 18.5, 25.0, 30.9, 67.9, 143.5 ppm; IR
(KBr): n˜ =2983, 1683, 1381 cmÀ1; MS (EI): m/z (%): 113 (100) [M+], 98
(62), 71 (19); HRMS calcd for C6H11NO: 113.0841; found: 113.0843.
3-Chloro-3-methyl-4-chloromethyl-2-pyrrolid-2-one
(14):
From
6
(1 mmol), flash chromatography (diethyl ether/petroleum ether 9:1) gave
146 mg (80%) of crystalline 14. M.p. 89 908C; 1H NMR (300 MHz,
CDCl3): major diasteroisomer: d=1.77 (s, 3H), 2.60 2.70 (m, 1H), 3.19
(dd, J=9, 10 Hz, 1H), 3.55 3.61 (m, 1H), 3.71 (dd, J=9, 11 Hz, 1H),
3.84 (dd, J=5, 11 Hz, 1H), 6.91 ppm (brs, 1H); minor diasteroisomer:
d=1.63 (s, 3H), 3.01 3.07 (m, 1H), 3.25 3.30 (m, 1H); 3.48 (m, 1H),
3.71 (m, 1H), 3.77 (m, 1H); 6.99 ppm (br, 1H); 13CNMR (75 MHz,
CDCl3): major diasteroisomer: d=24.6, 42.1, 43.5, 49.7, 67.8, 174.4 ppm;
minor diasteroisomer: d=21.1, 41.9, 43.0, 50.5, 67.0, 174.6 ppm; IR
(KBr): n˜ =3410, 3327, 1710 cmÀ1; MS (EI): m/z (%):185 (8) [M+], 183
(43) [M+], 181 (59) [M+], 91 (55), 89 (100); HRMS calcd for
C6H9Cl2NO: 181.0061; found: 181.0067.
Dimethyl ester of (4R,6S,7R,8R)-(1-oxo-5-oxy-4-phenyl-6-propyltetrahy-
dropyrazolo[1,2-c][1,3,4]oxadiazine-7,8-dicarboxylic acid (30): From 28
(0.1 mmol), flash chromatography (6:1 toluene/AcOEt) afforded 35 mg
(90%) of 30. [a]2D5 =À32.6 (c=0.6 in CH2Cl2); 1H NMR (500 MHz,
CDCl3): d=0.49 (t, J=7.3 Hz, 3H), 0.5 1.0 (m, 4H), 3.71 (s, 3H), 3.75 (s,
3H), 3.87 (dd, J=9.4, 10.8 Hz, 1H), 4.18 (ddd, J=2.6, 9.2, 10.8 Hz, 1H),
4.36 (dd, J=3.5, 11.7 Hz, 1H), 4.93 (d, J=9.4 Hz, 1H), 5.13 (dd, J=3.5,
11.8 Hz, 1H), 5.58 (t, J=11.8 Hz, 1H), 7.3 8.0 ppm (m, 5H); 13CNMR
(75 MHz, CDCl3): d=13.7, 18.6, 29.5, 31.0, 49.3, 52.9, 23.0, 59.1, 66.9,
78.8, 81.3, 128.1, 128.4, 128.9, 131.0, 149.1, 168.2, 168.7 ppm; MS (CI):
m/z (%): 393 (16) [M++1], 375 (20), 216 (100); elemental analysis calcd
(%) for: C19H24N2O7 C58,16, H 6,16, N 7,14; found: C57.94, H 6.22, N
7.00.
3,3-Dichloro-4-chloromethylpyrrolid-2-one (15): From 7 (1 mmol), flash
chromatography (diethyl ether/petroleum ether 9:1) gave 164 mg (82%)
of crystalline 15. M.p. 95 968C; 1H NMR (300 MHz, CDCl3): d=3.13
3.23 (m, 1H), 3.28 (dd, J=8.3, 10 Hz, 1H), 3.61 3.74 (m, 1H), 3.75 (dd,
J=10, 11.4 Hz, 1H), 4.00 (dd, J=4.2, 11.4 Hz, 1H), 6.91 ppm (br, 1H);
13CNMR (75 MHz, CDCl 3): d=40.8, 43.5, 53.5, 82.9, 169.0 ppm; IR
(KBr): n˜ =3423, 1729 cmÀ1; MS (EI): m/z (%): 205 (9) [M+], 203 (29)
[M+], 201 (31) [M+], 162 (14) [M+], 160 (42), 158 (45), 113 (10), 111
(65), 109 (100); HRMS calcd for C5H3Cl3NO: 200.9515; found: 200.9516.
Acknowledgments
3,3-Dichloro-4-(1-chlorobutyl)pyrrolid-2-one (16): From 8 (1 mmol), flash
chromatography (diethyl ether/petroleum ether 3:1) gave 223 mg (92%)
of crystalline 16. M.p. 83 848C; 1H NMR (300 MHz, CDCl3, 258C): d=
0.99 (t, J=7.3 Hz, 3H), 1.52 1.57 (m, 1H), 1.70 1.89 (m, 2H), 2.22 2.38
(m, 1H), 3.04 3.13 (m, 1H), 3.25 (dd, J=9.0, 10.5 Hz, 1H), 3.68 3.75 (m,
We thank the DirecciÛn General de InvestigaciÛn CientÌfica y Tÿcnica
(grant no. BQU2001-2376), the European Commission (RTN-2001-
00244,) and the Junta de AndalucÌa for financial support. A.F. thanks the
Ministerio de EducaciÛn y Ciencia for a doctoral fellowship. We also
thank Prof. Franco Gheli for a generous gift of compounds 6 9, and Prof.
H.-P. Husson and Dr. L. Micouin for samples of compounds 27 and 28.
1H), 4.25 4.33 (m, 1H), 7.58 ppm (br, 1H); 13CNMR (75 MHz, CDCl
,
3
TMS): d=13.2, 18.9, 37.3, 44.3, 56.4, 61.6, 82.8, 169.1 ppm; IR (KBr): n˜ =
3420, 1715 cmÀ1; MS (70 eV, EI): m/z (%): 245 (8) [M+], 243 (11) [M+],
208 (14), 104 (75) , 55 (100); HRMS calcd for C8H12Cl3NO: 242.9984;
found: 242.9977. Starting from 9, the same product was obtained in 89%
yield, and had identical characterization data.
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Methyl ester of (S)-(1-cyclopropyl-3-phenylpropyl)carbamic acid (19)
and 1-cyclopropyl-3-phenylpropan-1-one (21): From 17 (0.5 mmol), flash
chromatography (10:1 hexane/AcOEt) gave 52 mg (60%) of 21. 1H
NMR (300 MHz, CDCl3): d=0.7 0.9 (m, 2H), 0.9 1.0 (m, 2H), 1.8 2.0
(m, 3H), 2.8 3.0 (m, 4H), 7.1 7.4 ppm (m, 5H); 13CNMR (75 MHz,
CDCl3): d=10.9, 20,8, 30.9, 45.3, 126.1, 128.6, 128.8, 141.1, 210.5 ppm;
HRMS calcd for C12H14O: 174.1045; found: 174.1048.
Eluted second crystalline 19 (17.5 mg, 15%). M.p. 73 758C ; [a]2D3 =À0.9
(c=1.1 in CHCl3); 1H NMR (400 MHz, CDCl3): d=0.15 0.7 (m, 4H),
0.7 0.9 (m, 1H), 1.7 2.0 (m, 2H), 2.68 (t, J=7.0 Hz, 2H), 3.1 (brs, 1H),
3.65 (s, 3H), 4.65 (brs, 1H), 7.1 7.4 ppm (m, 5H); 13CNMR (100 MHz,
CDCl3): d=2.6, 3.8, 16.6, 32.3, 37.6, 52.0, 55.6, 125.8, 128.3, 128.4, 141.9,
155.7 ppm; elemental analysis calcd (%) for C14H19NO2: C72.07, H 8.21,
N 6.00; found: C71.78, H 8.21, N 6.11.
Methyl ester of (S)-(1-cyclopropyl-4-phenylbutyl)carbamic acid (20) and
1-cyclopropyl-4-phenylbutan-1-one (22): From 18 (0.5 mmol), flash chro-
matography (10:1 hexane/AcOEt) gave 61 mg (65%) of 22 as an oil. 1H
NMR (300 MHz, CDCl3): d=0.7 0.9 (m, 2H), 0.9 1.0 (m, 2H), 1.8 2.0
(m, 3H), 2.55 (t, J=8.5 Hz, 2H), 2.65 (t, J=8.2 Hz, 2H), 7.1 7.4 ppm (m,
5H); 13C NMR (75 MHz, CDCl3): d=10.9, 11.1, 20.7, 25.7, 35.4, 42.9,
126.1, 128.6, 128.7, 142.0, 211.0 ppm; HRMS calcd for C13H16O: 188.1201;
found: 188.1196.
Eluted second crystalline 20 (19 mg, 15%). M.p. 73 758C ; a[ ]2D3 =À44.7
(c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.15 0.55 (m, 4H),
0.7 0.8 (m, 1H), 1.5 1.7 (m, 4H), 2.5 2.7 (m, 2H), 2.99 (brs, 1H), 3.63 (s,
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Received: September 1, 2003 [F5501]
745
Chem. Eur. J. 2004, 10, 737 745
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim