Chiral spiro-β-lactams from 6-diazopenicillanates

Article abstract of DOI:10.1016/j.tet.2012.03.022

Chiral spiro-β-lactam derivatives have been prepared via stereoselective 1,3-dipolar cycloaddition of 6-diazopenicillanates. Using dipolarophiles such as acrylonitrile, acrylates or methyl vinyl ketone spiro-2-pyrazoline-β-lactams were obtained, whereas t

Full text of DOI:10.1016/j.tet.2012.03.022

Tetrahedron 68 (2012) 3729e3737
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Chiral spiro-b-lactams from 6-diazopenicillanates
*
Bruna S. Santos, Sandra C.C. Nunes, Alberto A.C.C. Pais, Teresa M.V.D. Pinho e Melo
University of Coimbra, Department of Chemistry, 3004-535 Coimbra, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral spiro-
diazopenicillanates. Using dipolarophiles such as acrylonitrile, acrylates or methyl vinyl ketone spiro-
2-pyrazoline- -lactams were obtained, whereas the cycloaddition with N-substituted-maleimides af-
forded spiro-1-pyrazoline- -lactams. 6-Diazopenicillanates also reacted with electron-deficient alkynes
to give the corresponding spiro-3H-pyrazole- -lactam as single product. The observed stereoselectivity
can be explained considering that the major product results from the addition to the less sterically
hindered -side of the -lactam. Microwave-induced denitrogenation of spiro-1-pyrazoline- -lactams
allowed the stereoselective synthesis of novel spirocyclopropyl- -lactams. The rationalization of the
observed selectivity was supported by electronic structure calculations.
Ó 2012 Elsevier Ltd. All rights reserved.
b-lactam derivatives have been prepared via stereoselective 1,3-dipolar cycloaddition of 6-
Received 6 February 2012
Received in revised form 2 March 2012
Accepted 6 March 2012
b
b
Available online 12 March 2012
b
ꢀ
Dedicated to Professor Antonio M. d’A.
Rocha Gonsalves
a
b
b
b
Keywords:
1,3-Dipolar cycloaddition
Ring contraction
6-Diazopenicillanates
Spiro-2-pyrazoline-
b
-lactams
-lactams
Spiro-1-pyrazoline-
b
Spiro-3H-pyrazole-b-lactams
Spirocyclopropyl-b-lactams
1. Introduction
The -lactam ring is the core structure of important pharma-
cologically active compounds, such as penicillins and cephalospo-
rins. On the other hand, penicillin resistance is often caused by the
Spirocyclopropylpenicillanates have also been prepared via rho-
dium-catalyzed cyclopropanation of a 6-diazopenicillanate sulfo-
ne5a and by the Cu(I) catalyzed reaction of 6-bromopenicillanoyl
b
magnesium bromide with a,b
-unsaturated esters.5b
In this context, the 1,3-dipolar cycloaddition of 6-diazopeni-
cillanates was further explored as well as the ring contraction of
spiropyrazolinepenicillanates to spirocyclopropylpenicillanates,
aiming to evaluate the scope and selectivity of these approaches to
action of enzymes known as
active -lactam bond of the antibiotic making it ineffective.
Therefore, compounds containing the -lactam ring are potential
lactamase inhibitors.1
-Lactams can be used as synthetic in-
termediates in organic synthesis, providing routes to - and
amino acids and peptides.2 Spiro-
-lactams are also interesting
b-lactamases, which cleave the re-
b
b
b-
b
spiro-b-lactams.
a
b-
b
2. Results and discussion
target molecules since some derivatives exhibit relevant biological
properties, namely, cholesterol absorption inhibition, antibacterial
activity and antiviral activity.3 In peptidomimetic chemistry, spiro-
6-Diazopenicillanates have been previously prepared mainly
by the diazotization of 6-aminopenicillanates with nitrous acid or
b b-
-turn mimetics.4 Thus, the search for new
by treatment of 6-b
-N-nitrosoamidopenicillanates with pyridine.6
b
-lactams are used as
lactam derivatives is a relevant research target.
We observed that an easier and efficient synthesis of 6-
diazopenicillanates 2 is achieved by reacting the corresponding
It has been previously shown that spiro-2-pyrazolinepenicilla-
nates can be obtained from the 1,3-dipolar cycloaddition of
6-diazopenicillanates with acrylamide, acrylonitrile and acryl-
ates.3e,g On the other hand, spiro-1-pyrazolinepenicillanates,
obtained from the addition of diphenyldiazomethane to the less
6-b
-aminopenicillanate 1a7 or 1b6a with ethyl nitrite at room
temperature. The diazo compounds are isolated in high yield by
removing the solvent, without need of further purification
(Scheme 1). In the case of 2b, the compound was also recrystallized.
The chemical behaviour of 6-diazopenicillanates 2 in the pres-
ence of a range of dipolarophiles was studied (Table 1). Initially, we
looked again into the previously reported cycloadditions of 6-
diazopenicillanates with acrylonitrile and ethyl acrylate.3e The
hindered
a-side of 6-alkylidenepenicillanates, undergo thermal
induced ring contraction to afford spirocyclopropylpenicillanates.3e
* Corresponding author. E-mail address: tmelo@ci.uc.pt (T.M.V.D. Pinho e Melo).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.022

3730
B.S. Santos et al. / Tetrahedron 68 (2012) 3729e3737
H
H
N
H
N
The reactivity of 6-diazopenicillanates 2 towards electron-
deficient alkynes was explored and led to the selective synthesis
of spiro- -lactams 5 incorporating a 3H-pyrazole ring (Table 2). In
N2
O
S
S
H2N
EtONO, CH2Cl2
rt, 6 h
b
O
CO2R
CO2R
fact, the cycloaddition at room temperature of benzyl 6-
diazopenicillanate (2a) and benzhydryl 6-diazopenicillanate (2b)
with dimethyl acetylenedicarboxylate gave spiro-b-lactams 5a
1a R = Bn
1b R = CHPh2
2a R = Bn
2b R = CHPh2
90%
80%
(15%) and 5c (55%), respectively (entries 1 and 6). It was again
observed that the process is more efficient starting from
Scheme 1. Synthesis of 6-diazopenicillanates 2.
Table 1
Reaction of 6-diazopenicillanates 2 with alkenes
R2
a R1 = Bn; R2 = CN
3,4
b R1 = Bn; R2 = CO2Et
N
R2
NH H
H
N
H
N
R2
N2
c R1 = Bn; R2 = CO2Me
S
S
S
HN
d R1 = Bn, R2 = COMe
N
N
e R1 = CHPh2; R2 = CN
O
O
O
CO2R1
CO2R1
CO2R1
f
R1 = CHPh2; R2 = CO2Et
2a R1 = Bn
3
g R1 = CHPh2; R2 = CO2Me
h R1 = CHPh2; R2 = COMe
4
2b R1 = CHPh2
Entry
R1
R2
Dipolarophile (equiv)
Reaction conditions
Yield (3/4)a
1
2
3
4
5
6
7
8
Bn
Bn
Bn
Bn
Bn
Bn
CHPh2
CHPh2
CHPh2
CHPh2
CHPh2
CN
CO2Et
1.5
1.5
1.5
2.5
3.0
3.0
1.5
1.5
1.5
3.0
3.0
rt, 16 h, DCM
rt, 16 h, DCM
rt, 18 h, DCM
57% (76:24)
34% (79:21)
d
CO2Me
CO2Me
COMe
COMe
CN
CO2Et
CO2Me
COMe
COMe
MW, 80 ꢀC, 1 min, Toluene
rt, 24 h, DCM
33% (80:20)
54% (83:17)
58% (83:17)
85% (88:12)
73% (85:15)
62% (85:15)
82% (83:17)
78% (83:17)
MW, 80 ꢀC, 1 min, toluene
rt, 16 h, DCM
rt, 16 h, DCM
rt, 18 h, DCM
rt, 24 h, DCM
45 ꢀC, 3 h, DCM
9
10
11
a
Isolated yield; ratio of diastereosiomers determined by 1H NMR.
reaction at room temperature of benzyl 6-diazopenicillanate (2a)
with acrylonitrile gave a (76:24) mixture of compounds 3a and 4a,
in 57% overall yield (entry 1). On the other hand, starting with
benzhydryl ester 2b the corresponding cycloadducts 3e and 4e
were obtained in significantly higher yield (85%) with a similar
stereoselectivity (entry 7). It should be noted that the reported
reaction of trichloroethyl 6-diazopenicillanate with acrylonitrile
gave the 1,3-dipolar cycloadducts in 82% overall yield.3e Thus, we
can conclude that the nature of the ester significantly influences
the yields of the isolated products. In fact, it was observed that 6-
diazopenicillanate 2a reacted with ethyl acrylate to give a (79:21)
mixture of cycloadducts 3b and 4b in 34% yield (entry 2) whereas
starting from 6-diazopenicillanate 2b, the corresponding isomeric
6-diazopenicillanate 2b. However, the yield of 5a was improved to
39% by carrying out the reaction with dimethyl acetylenedi-
carboxylate at 45 ꢀC for 3 h (entry 2). Under microwave irradiation
at 80 ꢀC for 2 min,
The
b
-lactam 5a was obtained in low yield (entry 3).
b
-lactams 5b (14%) and 5d (63%) were also prepared as single
products, from the reaction of the corresponding 6-
diazopenicillanates 2 with methyl propiolate carried out at the
reaction at room temperature (entries 4 and 8). Heating at 45 ꢀC for
3 h cycloadducts 5b (37%) and 5d (73%) were obtained in higher
yields (entries 5 and 9). In the NOESY spectrum of compound 5b, 5-
H shows connectivity with 40-H, but does not show connectivity
with the protons of the methyl ester group. Thus, we could con-
clude that the cycloaddition of 6-diazopenicillanates with methyl
propiolate occurs in a regio- and stereoselective manner.
spiro-b-lactams 3f and 4f were obtained in 73% yield (entry 8). The
observed stereoselectivity can be explained considering that the
major product results from the addition to the less sterically hin-
dered a-side of the b-lactam.
The reactivity of 6-diazopenicillanates 2 with N-substituted-
maleimides was also studied (Table 3). Particularly interesting was
to observe that the 1,3-dipolar cycloaddition of compounds 2b with
N-methyl- and N-phenylmaleimides gave a mixture of the corre-
sponding compounds 7 and 8, from which b-lactams 7 could be
isolated in pure form by crystallization. Starting from 6-
diazopenicillanate 2a the reaction with N-phenylmaleimide (6a)
led to the diastereoisomeric mixture of b-lactams 7a and 8a and it
was again observed that the major product 7a could be isolated in
pure form by crystallization. However, the cycloaddition of 6-
diazopenicillanate 2a with N-methylmaleimide (6b) afforded
a mixture of cycloadducts 7b and 8b that could not be separated. It
The work was then extended to the cycloaddition of 6-
diazopenicillanates 2 with other dipolarophiles (Table 1). Surpris-
ingly, attempts to carry out the reaction of benzyl 6-
diazopenicillanate (2a) with methyl acrylate at room temperature
were unsuccessful (entry 3). However, under microwave irradiation
at 80 ꢀC for 1 min the expected products 3c and 4c were obtained in
moderate yield (entry 4). In contrast with these observations, 6-
diazopenicillanate 2b reacted with methyl acrylate at room tem-
perature to afford the expected spiro-b-lactams 3g and 4g in good
yield (entry 9). 6-Diazopenicillanates 2 also participate in the 1,3-
dipolar cycloaddition with methyl vinyl ketone, efficiently giving
should be noted that in these reactions spiro-b-lactams in-
corporating a 1-pyrazoline heterocycle were obtained in contrast
with the products resulting from the cycloaddition of 6-
diazopenicillanates with alkenes such as acrylonitrile, acrylate
and methyl vinyl ketone, which led to derivatives bearing a 2-
pyrazoline unit (see Table 1). This observation is in agreement
with the known reactivity pattern of diazo compounds towards
the corresponding chiral
6, 10 and 11). The best results were achieved carrying out the
cycloaddition of -lactams 2a and 2b at room temperature, the
b-lactams with good selectivity (entries 5,
b
corresponding cycloadducts being obtained in 58% and 82%,
respectively (entries 5 and 10).

B.S. Santos et al. / Tetrahedron 68 (2012) 3729e3737
3731
Table 2
Reaction of 6-diazopenicillanates 2 with alkynes
R2
R3
H
4'
5'
N2
5a R1 = Bn; R2 = R3 = CO2Me
R2
R3
S
H
1
N
5b R1 = Bn; R2 = CO2Me, R3 = H
5c R1 = CHPh2; R2 = R3 = CO2Me
5d R1 = CHPh2; R2 = CO2Me, R3 = H
S
1'
2
N
O
N
6
7
5
2'
3
N
4
CO2R1
O
CO2R1
2a R1 = Bn
5
2b R1 = CHPh2
Entry
R1
R2
R3
Dipolarophile (equiv)
Reaction conditions
Isolated yield (%)
1
2
3
4
5
6
7
8
9
Bn
Bn
Bn
Bn
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
H
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
rt, 16 h, DCM
15
39
16
14
37
55
51
63
73
45 ꢀC, 3 h, DCM
MW, 80 ꢀC, 2 min, toluene
rt, 3 h, DCM
Bn
H
45 ꢀC, 3 h, DCM
rt, 16 h, DCM
CHPh2
CHPh2
CHPh2
CHPh2
CO2Me
CO2Me
H
45 ꢀC, 3 h, DCM
rt, 16 h, DCM
H
45 ꢀC, 3 h, DCM
Table 3
Reaction of 6-diazopenicillanates 2 with N-substituted-maleimides
R2
N
O
O
H
N
O
N
O
N2
O
O
H
N
H
S
N
N
7,8 a R1 = Bn; R2 = Ph
b R1 = Bn; R2 = CH3
c R1 = CHPh2; R2 = Ph
rt or MW
S
S
R2
N
+
N
R2
N
N
CO2R1
O
O
O
CO2R1
CO2R1
d R1 = CHPh2; R2 = CH3
2a R1 = Bn
6a R2 = Ph
6b R2 = Me
7
8
2b R1 = CHPh2
Entry
R1
R2
Dipolarophile (equiv)
Reaction conditions
Yield (7/8)a
1
2
3
4
5
Bn
Bn
Bn
CHPh2
CHPh2
Ph
Ph
CH3
Ph
CH3
1.6
1.1
1.6
1.6
1.6
rt, 6 h, DCM
39% (77:23)
12% (66:34)
25% (82:18)
76% (86:14)
58% (80:20)
MW, 80 ꢀC, 3 min, toluene
rt, 6 h, DCM
rt, 6 h, DCM
rt, 6 h, DCM
a
Isolated yield; ratio of diastereosiomers determined by 1H NMR.
dipolarophiles. In fact, diazo compounds react with
a
,
b
-un-
proton having a chemical shift of 6.21 ppm. In the HMBC spectrum,
50-H correlates with carbon 5-C (71.2 ppm), with 6-C (109.2 ppm)
and with the carbonyl carbons (7-C, 60-C and 80-C). The NOESY
spectrum showed cross peaks between 50-H and 10-H but no con-
nectivity was observed between 50-H and 5-H.
saturated carbonyl compounds to give 1-pyrazolines, which typi-
cally undergo isomerization to give the conjugated 2-pyrazolines.8
On the other hand, diazo compounds participate in cycloaddition
reactions with N-substituted-maleimides affording 1-pyrazolines.9
The reaction at room temperature of 6-diazopenicillanate 2a with
6-Diazopenicillanates 2 also reacted with N-methylmaleimide
N-phenylmaleimide gave spiro-
b-lactams 7a and 8a in 39% overall
to give the expected spiro-b-lactams (entries 3 and 5). It was again
yield whereas the microwave induced cycloaddition was less effi-
cient (entries 1 and 2). Starting from 6-diazopenicillanate 2b the
expected cycloadducts were obtained in 76% yield (entry 4). The
assignment of the structure of compound 7a (Fig. 1) was made on
the basis of two-dimensional NOESY, HMQC and HMBC spectra
(400 MHz). From the HMQC spectrum, it was established that the
carbon with the 43.5 ppm chemical shift corresponds to 50-C since
it shows connectivity with the proton having a chemical shift of
3.73 ppm. On the other hand, the carbon with 96.7 ppm chemical
shift corresponds to 10-C since it shows connectivity with the
observed that the 1,3-dipolar cycloaddition of benzhydryl
6-diazopenicillanate (2b) with N-substituted-maleimides led to
the target compounds in significantly higher yield than the corre-
sponding cycloaddition starting from benzyl 6-diazopenicillanate
(2a).
The formation of spiro-b-lactams 7 as the major product in the
cycloaddition of 6-diazopenicillanates 2 with N-substituted-mal-
eimides can be explained considering that the addition of the
dipolarophile occurs selectively to the less sterically hindered
a-side of the
b-lactam, which is also characterized by endo
selectivity.
Ph
Mete et al. reported that the 1,3-dipolar cycloaddition of 3-
diazo-piperidin-2-one with methyl methacrylate affords the cor-
responding spiro-1-pyrazolines whereas in the reaction with
methyl acrylate, methyl vinyl ketone and acrolein spiro-2-
pyrazolines are obtained. Both types of cycloadducts extruded ni-
trogen under thermolysis to give spirocyclopropyl derivatives effi-
ciently, although the ring contraction of the 2-pyrazoline
derivatives required higher temperature (dioxane, reflux, 20 min vs
8'
O
N
6'
7'
O
1'
5'
1
N
2'
S
2
N
5
6
3
3'
N
4
7
O
CO2Bn
Fig. 1. Structure of compound 7a.

3732
B.S. Santos et al. / Tetrahedron 68 (2012) 3729e3737
1,2-dichlorobenzene, reflux, 20 min).10 These observations led us to
study the thermolysis of spiro-2-pyrazoline- -lactams 3d, 4d under
the latter reaction conditions. However, no reaction was observed
leading only to the recover of the starting -lactam (43%). Similar
Molecular mechanics (MM) and quantum chemical calculations
have been carried out in order to determine the optimized geom-
etries of the low energy conformers of spirocyclopropane-b-lac-
b
b
tams 9a and 10a. A preliminary conformational search of different
starting structures generated in the Avogadro package12 for each
stereoisomer was performed, with molecular mechanics, resorting
to the UFF force-field. The conformational search employed random
rotor search and subsequent full minimization of every internal
coordinate, producing 10,000 conformations. The MM lowest en-
ergy conformations obtained in each case were refined at the PM3
level and subsequently, the lowest energy conformation obtained
for each stereoisomer was further refined using the B3LYP hybrid
functional13e15 and the 6-31G(d) basis set (Fig. 2).
result was obtained carrying out the thermolysis of compounds 3d,
4d in dioxane under microwave irradiation at 110 ꢀC for 3 min.
In contrast with the less common conversion of 2-pyrazolines to
cyclopropane derivatives, the synthesis of cyclopropanes via ring
contraction of 1-pyrazolines is well-known.11 Under thermal con-
ditions the elimination of nitrogen from 1-pyrazolines can lead to
the competitive formation of alkenes. The nature of the mechanism
involved in the cyclopropane formation is controversial since some
reactions are stereospecific, others show high stereoselectivity and
yet others are not selective. These observations led to different
mechanistic proposals. Thus, in some cases a concerted process has
been suggested whereas in other cases a stepwise cleavage of the 1-
pyrazolines ring via biradical or zwitterionic intermediates fol-
lowed by ring closure has been proposed.
In the NOESY spectrum of 9a, 5-H shows connectivity with the
proton having a 3.25 ppm chemical shift, but not with the proton
with a 3.16 ppm chemical shift. This observation is in agreement
with the structural parameters obtained for c0ompound 9a, which is
ꢁ
characterized by a distance for hydrogens 5 -H/5-H of 2.87 A and
0
ꢁ
It has been reported that 7-substituted-6,8-dioxo-2,3,7-
triazabicyclo[3.3.0]oct-2-enes, resulting from the cycloaddition of
diazo compounds with N-substituted-maleimides, undergo ther-
mal decomposition to give the corresponding cyclopropanes, 3-
azabicyclo[3.1.0]hexane derivatives.9,11m
3.59 A for hydrogens 1 -H/5-H. Thus, the signals at 3.25 ppm and
3.16 ppm can be assigned to protons 50-H and 10H, respectively. On
the other hand, the optimized structure for compound 10a presents
0
ꢁ
ꢁ
much larger distances, 3.83 A and 4.38 A for hydrogens 5 -H/5-H
and 10-H/5-H, respectively, and consequently no NOE effects
should be observed.
In this context, we decided to study the chemical behaviour of
spiro-
b
-lactams 7c and 7d, incorporating a 7-substituted-6,8-
The synthesis of cyclopropanes via ring contraction of spiro-1-
dioxo-2,3,7-triazabicyclo[3.3.0]oct-2-ene ring system, under ther-
mal conditions (Scheme 2). Attempts to carry out the nitrogen
extrusion from compound 7c by thermolysis in toluene (130 ꢀC for
30 min) were unsuccessful. However, under microwave irradiation
pyrazoline-b-lactams 7 was not stereospecific, which is an in-
dication that a stepwise mechanism must be involved. In fact,
considering the cleavage of the 1-pyrazoline ring leading to an
open-chain biradical followed by the cyclopropane ring closure,
a mixture of diastereoisomers would be expected (Scheme 3).
The stereoselectivity observed in the synthesis of spi-
at 250 ꢀC for 2 min, a solution of the spiro-
b
-lactam 7c in 1,2,4-
trichlorobenzene afforded a (77:23) mixture of cyclopropanes 9a
and 10a in 94% yield. Interestingly, spirocyclopropane- -lactam 9a
b
rocyclopropyl-b-lactams has also been rationalized by means of
could be isolated from this mixture in pure form by crystallization.
The ring contraction reaction of compound 7d was also achieved
under microwave irradiation at 250 ꢀC for 2 min, to give a (72:28)
mixture of cyclopropanes 9b and 10b in 64% yield.
theoretical calculations. The optimization of structures 9a and 10a
at the DFT level revealed that stereoisomer 10a is the most stable
but the energy difference between 9a and 10a is only 0.93 kcal/mol.
Thus, in order to explain the formation of stereoisomer 9a as the
R
O
N
O
O
R
O
R
H
5'
H
N
H
N
MW
H
N
H
H
N
N
250°C, 2 min
S
S
S
O
O
N
1'
5
N
1,2,4-Trichlorobenzene
H
O
O
O
CO2CHPh2
CO2CHPh2
CO2CHPh2
9a R = Ph
9b R = Me
9a/10a 94% (77:23)
9b/10b 64% (72:28)
10a R = Ph
10b R = Me
7c R = Ph
7d R = Me
Scheme 2. Synthesis of spirocyclopropyl-b-lactams via denitrogenation of spiro-1-pyrazoline-b-lactams 7c and 7d.
Fig. 2. Optimized geometries (DFT level) of the low energy conformers of compounds 10a (panel a) and 9a (panel b). Colour code: grey refers to carbon, red to oxygen, white to
hydrogen, blue to nitrogen and yellow to sulfur atoms.

B.S. Santos et al. / Tetrahedron 68 (2012) 3729e3737
3733
R
N
O
N
R
O
H
O
N
H
O
N
H
O
H
N
H
H
N
O
S
- N2
S
S
R
N
N
H
O
O
O
CO2CHPh2
CO2CHPh2
CO2CHPh2
11
11'
O
O
R
R
H
H
N
H
N
H
H
N
S
S
O
O
H
N
O
O
CO2CHPh2
CO2CHPh2
9a R = Ph
9b R = Me
10a R = Ph
10b R = Me
Scheme 3. Mechanism proposal for the ring contraction of spiro-1-pyrazoline-b-lactams.
major product it is necessary to analyze the conversion of the ini-
tially formed biradical 11 into 110, the rotational isomer, which
undergoes cyclization to give compound 10a (Scheme 3).
The precursor 7c, used in the synthetic route, was optimized and
the respective structure transformed into the biradical, which
served as an additional input for optimization at the PM3 level. The
final structure obtained was that of stereoisomer 9a. This prompted
the calculation of the energy profile presented in Fig. 3, with a scan
performed on the relevant dihedral of the biradical. It shows that
the formation of the structure 9a is favoured being the energy
penalty for the formation of the structure 10a ca. 1.7 kcal/mol. Both
stereoisomers are, thus, allowed.
3. Conclusion
Herein, we report the 1,3-dipolar cycloaddition of 6-
diazopenicillanates as a route to the selective formation of new
chiral spiro-
azolinepenicillanates to spirocyclopropylpenicillanates.
6-Diazopenicillanates, prepared from 6- -aminopenicillanates
by an easy and efficient methodology, reacted with acrylonitrile,
acrylates and methyl vinyl ketone to give spiro-2-pyrazoline-
b-lactams as well as the ring contraction of spiropyr-
b
b
-
lactam derivatives. 6-Diazopenicillanates also participated in the
1,3-dipolar cycloaddition with N-substituted-maleimides to afford
spiro-1-pyrazoline-
leading to the corresponding spiro-3H-pyrazole-
b
-lactams and with electron-deficient alkynes
-lactams as the
b
single product. The 1,3-dipolar cycloaddition was stereoselective,
the major cycloadduct being the result of the dipolarophile addition
to the less sterically hindered
Stereoselective synthesis of spirocyclopropyl-
crowave-induced denitrogenation of spiro-1-pyrazoline-
a
-side of the
b
-lactam.
-lactams via mi-
-lactams
b
b
was also achieved. Computational studies corroborated the
rationalization of the stereoselectivity observed in this ring con-
traction reaction.
The studied reactions were more efficient starting from benz-
hydryl 6-diazopenicillanate rather than benzyl diazopenicillanate,
indicating that the nature of the ester group influences significantly
the yields of the isolated products.
4. Experimental
4.1. General methods
1H NMR spectra were recorded on an instrument operating at
400 MHz. 13C spectra were recorded on an instrument operating at
100 MHz. The solvent is deuteriochloroform except where other-
wise indicated. IR spectra were recorded on a Perkin Elmer
1720X FTIR spectrometer. Optical rotations were measured on an
Optical Activity AA-5 electrical polarimeter. Melting points were
recorded on a Reichert hot stage and are uncorrected. Flash column
chromatography was performed with Merck 9385 silica as the
stationary phase. Mass spectra were recorded on an instrument
operating in ESI mode. Microwave reactions were carried out in
a microwave reactor CEM Focused Synthesis System, Discover
Fig. 3. Potential energy profile as a function of the relevant dihedral in the biradical
structure, using a step size of 10ꢀ. At each point all the internal coordinates were re-
laxed (relaxed scan) at the MM level using the UFF force-field. The biradical structure
obtained after the optimization of structure 7c at the PM3 level was used as starting
structure for the scan. The stereoisomer obtained upon optimization at the PM3 level
of the biradical structure with the corresponding dihedral is also indicated for each
data point.
S-Class. Benzyl 6-b b-
-aminopenicillanate (1a)7 and benzhydryl 6-
aminopenicillanate (1b)6a were prepared as described in the
literature.

3734
B.S. Santos et al. / Tetrahedron 68 (2012) 3729e3737
4.2. General procedure for the synthesis of 6-
diazopenicillanates
(1H, s, 3-H), 5.12 (2H, s, CH2Ph), 5.25 (1H, s, 5-H), 7.18e7.30 (5H,
m, Ph); dC 24.7, 32.4, 37.8, 63.2, 66.7, 67.6, 80.9, 112.4, 120.6, 127.7,
127.8, 127.9, 133.5, 166.1, 170.2; MS (ESI) m/z 393 (MNaþ, 100%),
358 (20), 330 (44); HRMS (ESI) m/z 393.09963 (C18H18N4NaO3S
[MNaþ], 393.09918).
Ethyl nitrite (1.80 g, 24.0 mmol) was added to a solution of the
appropriate 6-b-aminopenicillanate (10.9 mmol) in dichloro-
methane (110 mL). The resulting mixture was stirred for 6 h at
room temperature and the solvent was removed under reduced
pressure (without heat).
4.3.2. Benzyl spiro[penicillanate-6,50-(3-ethoxycarbonyl-2-
pyrazoline)] 3b and 4b. Prepared by method
A from 6-
diazopenicillanate 2a (184 mg, 0.58 mmol) and ethyl acrylate
(86 mg, 0.86 mmol). The reaction mixture was stirred for 16 h and
purification by flash column chromatography [ethyl acetate/hexane
(1:2)] afforded a (79:21) mixture of compounds 3b and 4b as
a yellow oil (82 mg, 0.29 mmol, 34%). Benzyl spiro[penicillanate-6,50-
(3-ethoxycarbonyl-2-pyrazoline)] 3b. nmax/cmꢁ1 (film) 3343 (NH),
4.2.1. Benzyl 6-diazopenicillanate (2a). Prepared from ethyl nitrite
(1.80 g, 24.0 mmol) and 6-
10.9 mmol). Compound 2a was obtained as a brown oil (3.11 g,
9.81 mmol, 90%). nmax/cmꢁ1 (film) 2083 (N]N), 1748 (
-lactam),
1701 (ester); dH 1.37 (3H, s, 2 -Me), 1.62 (3H, s, 2 -Me), 4.40 (1H, s,
b-aminopenicillanate 1a (3.33 g,
b
a
b
3-H), 5.18 (2H, s, CH2Ph), 6.17 (1H, s, 5-H), 7.37 (5H, m, Ph); dC 25.8,
34.0, 62.9, 64.2, 67.3, 69.0, 70.1, 128.6, 128.7, 134.9, 166.4, 167.9; MS
(ESI) m/z 318 (MHþ, 45%), 308 (36), 293 (21), 280 (100), 265 (26),
250 (55), 227 (39); HRMS (ESI) m/z 318.09024 (C15H16N3O3S [MHþ],
318.09069).
1781 (
CH2CH3), 1.31 (3H, s, 2
b
-lactam), 1740 and 1704 (esters); dH 1.27 (3H, t, J¼7.2 Hz,
a
-Me), 1.42 (3H, s, 2 -Me), 3.22 (1H, d,
b
J¼18.8 Hz, 40-H), 3.57 (1H, d, J¼18.8 Hz, 40-H), 4.23 (1H, q, J¼7.2 Hz,
CH2CH3), 4.41 (1H, s, 3-H), 5.10 (1H, d, J¼12.4 Hz, CH2Ph), 5.14 (1H,
d, J¼12.4 Hz, CH2Ph), 5.25 (1H, s, 5-H), 6.97 (1H, s, NH), 7.30 (5H, br
s, Ph); dC 14.3, 25.8, 33.4, 37.3, 53.4, 61.5, 63.9, 67.6, 68.6, 82.6, 128.7,
128.8, 128.8, 134.6, 140.9, 161.6, 167.3, 172.4; MS (ESI) m/z 418 (MHþ,
82%), 390 (100), 336 (13), 280 (10); HRMS (ESI) m/z 418.14167
(C20H24N3O5S [MHþ], 418.14312).
4.2.2. Benzhydryl 6-diazopenicillanate (2b). Prepared from ethyl
nitrite (1.87 g, 24.9 mmol) and 6-b-aminopenicillanate 1b (4.32 g,
11.3 mmol). Recrystallization from ether/petroleum ether afforded
2b as a yellow solid (3.54 g, 9.0 mmol, 80%). Mp 91e92 ꢀC (lit.6a
93.0e94.0 ꢀC) (from diethyl ether/petroleum ether); nmax/cmꢁ1
4.3.3. Benzyl spiro[penicillanate-6,50-(3-methoxycarbonyl-2-
(KBr) 2081 (N]N), 1743; dH 1.23 (3H, s, 2
a
-Me), 1.62 (3H, s, 2
b
-Me),
pyrazoline)] 3c and 4c. Prepared by method B from 6-
4.46 (1H, s, 3-H), 6.19 (1H, s, 5-H), 6.92 (1H, s, CHPh2), 7.30e7.36
(10H, m, 2ꢂPh); dC 25.6, 34.2, 63.1, 64.3, 69.1, 70.2, 78.3, 127.1, 127.5,
128.2, 128.3,128.6, 128.6, 139.2,139.3, 166.4,167.2; MS (ESI) m/z 394
(MHþ, 100%), 366 (10), 326 (43); HRMS (ESI) m/z 394.12077
(C21H20N3O3S [MHþ], 394.12199).
diazopenicillanate 2a (179 mg, 0.56 mmol) and methyl acrylate
(121 mg, 1.4 mmol). The solution was irradiated for 1 min and pu-
rification by flash column chromatography [ethyl acetate/hexane
(1:2)] afforded a (80:20) mixture of compounds 3c and 4c as
a yellow oil (75 mg, 0.19 mmol, 33%). Benzyl spiro[penicillanate-6,50-
(3-methoxycarbonyl-2-pyrazoline)] 3c. nmax/cmꢁ1 (film) 3337 (NH),
4.3. General procedure for the 1,3-dipolar cycloaddition of 6-
diazopenicillanates
1781 (
(3H, s, 2
b-lactam), 1740 and 1700 (esters); dH 1.33 (3H, s, 2a-Me), 1.42
b
-Me), 3.23 (1H, d, J¼18.8 Hz, 40-H), 3.58 (1H, d, J¼18.8 Hz,
40-H), 3.77 (3H, s), 4.42 (1H, s, 3-H), 5.11 (2H, br s, CH2Ph), 5.22 (1H,
s, 5-H), 6.99 (1H, s, NH), 7.30 (5H, br s, Ph); dC 24.7, 32.4, 36.2, 51.4,
52.4, 62.9, 66.6, 67.6, 81.6, 127.5, 127.6, 127.7, 127.8, 133.6, 139.4,
161.4, 161.0, 166.3, 171.4; MS (ESI) m/z 404 (MHþ, 100%), 392 (41),
376 (86), 293 (32), 280 (20), 268 (26); HRMS (ESI) m/z 404.12560
(C19H22N3O5S [MHþ], 404.12747).
Method A: To a mixture of the appropriate 6-diazopenicillanate
(0.50 mmol) in dichloromethane (5 mL) a solution of the corre-
sponding dipolarophile in dichloromethane (2 mL) was added. The
reaction mixture was stirred at room temperature under nitrogen.
The solvent was removed under reduced pressure and the crude
product was purified by flash column chromatography [ethyl ace-
tate/hexane] or by recrystallization, as indicated for each case.
Method B: A suspension of the appropriate 6-diazopenicillanate
(0.50 mmol) and the corresponding dipolarophile in toluene
(2 mL) was irradiated in the microwave reactor with the temper-
ature set to 80 ꢀC. The solvent was removed under reduced pres-
sure and the crude product was purified by flash column
chromatography [ethyl acetate/hexane] or by recrystallization, as
indicated for each case.
Method C: To a solution of the appropriate 6-diazopenicillanate
(0.50 mmol) in dichloromethane (5 mL) a solution of the corre-
sponding dipolarophile in dichloromethane (2 mL) was added. The
reaction mixture was stirred at 45 ꢀC under nitrogen. The solvent
was removed under reduced pressure and the product was purified
by flash column chromatography [ethyl acetate/hexane].
4.3.4. Benzyl spiro[penicillanate-6,50-(3-acetyl-2-pyrazoline)] 3d and
4d. Prepared by method A from 6-diazopenicillanate 2a (220 mg,
0.69 mmol) and methyl vinyl ketone (147 mg, 2.1 mmol). The re-
action mixture was stirred for 24 h and purification by flash column
chromatography [ethyl acetate/hexane (1:2)] afforded a (83:17)
mixture of compounds 3d and 4d as a orange oil (143 mg,
0.37 mmol, 54%). The products were also prepared by method B
from 6-diazopenicillanate 2a (184 mg, 0.58 mmol) and methyl vinyl
ketone (126 mg, 1.8 mmol). The solution was irradiated for 1 min
and purification by flash column chromatography [ethyl acetate/
hexane (1:2)] afforded a (83:17) mixture of compounds 3d and 4d
(130 mg, 0.34 mmol, 58%). Benzyl spiro[penicillanate-6,50-(3-acetyl-
2-pyrazoline)] 3d. nmax/cmꢁ1 (film) 3337 (NH),1779 (
(ester),1666; dH 1.40 (3H, s, 2 -Me),1.48 (3H, s, 2 -Me), 2.40 (3H, s),
b-lactam),1744
a
b
3.21 (1H, d, J¼18.8 Hz, 40-H), 3.61 (1H, d, J¼18.8 Hz, 40-H), 4.49 (1H,
s, 3-H), 5.17 (1H, d, J¼12.4 Hz, CH2Ph), 5.21 (1H, d, J¼12.4 Hz,
CH2Ph), 5.33 (1H, s, 5-H), 7.04 (1H, s, NH), 7.37 (5H, br s, Ph); dC 25.5,
25.7, 33.5, 35.8, 60.4, 63.9, 67.6, 68.5, 82.8, 128.7, 128.8, 128.8, 134.6,
148.5, 167.3, 172.6, 193.6; MS (ESI) m/z 388 (MHþ, 100%), 376 (16),
360 (70); HRMS (ESI) m/z 388.13330 (C19H22N3O4S [MHþ],
388.13255).
4.3.1. Benzyl spiro[penicillanate-6,50-(3-cyano-2-pyrazoline)] 3a and
4a. Prepared by method A from 6-diazopenicillanate 2a (172 mg,
0.54 mmol) and acrylonitrile (43 mg, 0.81 mmol). The reaction
mixture was stirred for 16 h and purification by flash column
chromatography [ethyl acetate/hexane (1:2)] afforded a (76:24)
mixture of compounds 3a and 4a as a yellow oil (115 mg,
0.31 mmol, 57%). Benzyl spiro[penicillanate-6,50-(3-cyano-2-
pyrazoline)] 3a. nmax/cmꢁ1 (film) 3337 (NH), 2225 (CN), 1784 (
b
-
4.3.5. Benzhydryl
spiro[penicillanate-6,50-(3-cyano-2-pyrazoline)]
lactam), 1734 (ester); dH 1.33 (3H, s, 2
a
-Me), 1.40 (3H, s, 2
b
-Me),
3e and 4e. Prepared by method A from 6-diazopenicillanate 2b
(158 mg, 0.40 mmol) and acrylonitrile (32 mg, 0.60 mmol). The
3.18 (1H, d, J¼18.4 Hz, 40-H), 3.54 (1H, d, J¼18.4 Hz, 40-H), 4.42

B.S. Santos et al. / Tetrahedron 68 (2012) 3729e3737
3735
reaction mixture was stirred for 16 h and purification by flash
column chromatography [ethyl acetate/hexane (1:3)] afforded
a (88:12) mixture of compounds 3e and 4e as a yellow solid
(150 mg, 0.34 mmol, 85%). Benzhydryl spiro[penicillanate-6,50-(3-
cyano-2-pyrazoline)] 3e. nmax/cmꢁ1 (film) 3345 (NH), 2225 (CN),
68.6, 77.6, 78.7, 82.8, 127.0, 127.7, 128.3, 128.5, 128.6, 128.7, 139.0,
148.5, 166.6, 172.7, 193.6; MS (ESI) m/z 464 (MHþ, 100%), 436 (16),
369 (53), 340 (13); HRMS (ESI) m/z 464.16256 (C25H26N3O4S [MHþ],
464.16385).
1782 (
b
-lactam), 1744 (ester); dH 1.28 (3H, s, 2
a
-Me), 1.48 (3H, s, 2
b
-
4.3.9. Benzyl
spiro[penicillanate-6,30-(4,5-dimethoxycarbonyl-3H-
Me), 3.27 (1H, d, J¼18.4 Hz, 40-H), 3.62 (1H, d, J¼18.4 Hz, 40-H), 4.56
(1H, s, 3-H), 5.31 (1H, s, 5-H), 6.94 (1H, s, CHPh2), 7.01 (1H, s, NH),
7.34e7.35 (10H, m, 2ꢂPh); dC 25.5, 33.7, 38.9, 64.4, 68.8, 78.9, 81.9,
113.3,121.8,127.0,127.7,128.4,128.6,128.7,128.7,138.8,166.3,171.2;
MS (ESI) m/z 469 (MNaþ, 36%), 434 (21), 406 (100), 366 (27),
348 (19); HRMS (ESI) m/z 469.13027 (C24H22N4NaO3S [MNaþ],
469.13048).
pyrazole)] (5a). Prepared by method A from 6-diazopenicillanate
2a (157 mg, 0.49 mmol) and dimethyl acetylenedicarboxylate
(105 mg, 0.74 mmol). The reaction mixture was stirred for 16 h and
purification by flash column chromatography [ethyl acetate/hexane
(1:2)] afforded compound 5a as a yellow oil (33 mg, 0.072 mmol,
15%). The product was also prepared by method B from 6-
diazopenicillanate 2a (178 g, 0.56 mmol) and dimethyl acetylene-
dicarboxylate (119 mg, 0.84 mmol). The solution was irradiated for
2 min and purification by flash column chromatography [ethyl ac-
etate/hexane (1:2)] afforded compound 5a (42 mg, 0.091 mmol,
16%). Finally, 5a could also be prepared by method C from 6-
diazopenicillanate 2a (167 mg, 0.53 mmol) and dimethyl acetyle-
nedicarboxylate (113 mg, 0.80 mmol). The reaction mixture was
stirred for 3 h and purification by flash column chromatography
[ethyl acetate/hexane (1:2)] afforded compound 5a (95 mg,
4.3.6. Benzhydryl spiro[penicillanate-6,50-(3-ethoxycarbonyl-2-
pyrazoline)] 3f and 4f. Prepared by method
A
from 6-
diazopenicillanate 2b (159 mg, 0.40 mmol) and ethyl acrylate
(60 mg, 0.60 mmol). The reaction mixture was stirred for 16 h and
purification by flash column chromatography [ethyl acetate/hexane
(1:3)] afforded a (85:15) mixture of compounds 3f and 4f as a yel-
low solid (144 mg, 0.29 mmol, 73%). Benzhydryl spiro[penicillanate-
6,50-(3-ethoxycarbonyl-2-pyrazoline)] 3f. nmax/cmꢁ1 (KBr) 3324
0.21 mmol, 39%). nmax/cmꢁ1 (film) 1791 (
1591 (N]N); dH 1.40 (3H, s, 2 -Me),1.44 (3H, s, 2b
b
-lactam), 1746 (ester),
-Me), 3.79 (3H, s),
(NH), 1782 (
b
-lactam), 1742 and 1708 (esters); dH 1.27 (3H, s, 2
a
-
a
Me), 1.35 (3H, t, J¼7.2 Hz, CH2CH3), 1.50 (3H, s, 2
b
-Me), 3.31 (1H, d,
3.90 (3H, s), 4.68 (1H, s, 3-H), 5.15 (1H, d, J¼12.0 Hz, CH2Ph), 5.22
(1H, d, J¼12.0 Hz, CH2Ph), 6.41 (1H, s, 5-H), 7.28e7.31 (5H, m, Ph);
dC 25.0, 31.5, 51.4, 52.0, 59.9, 60.7, 67.0, 68.0, 109.3, 127.7, 127.8,
127.9, 133.4, 147.8, 149.2, 149.4, 159.0, 160.0, 166.3; MS (ESI) m/z 460
(MHþ, 100%), 266 (6); HRMS (ESI) m/z 460.11605 (C21H22N3O7S
J¼18.8 Hz, 40-H), 3.66 (1H, d, J¼18.8 Hz, 40-H), 3.31 (1H, q, J¼7.2 Hz,
CH2CH3), 4.55 (1H, s, 3-H), 5.32 (1H, s, 5-H), 6.93 (1H, s, CHPh2), 6.97
(1H, s, NH), 7.30e7.36 (10H, m, 2ꢂPh); dC 14.3, 25.5, 33.5, 37.3, 61.5,
64.1, 68.7, 77.7, 78.8, 82.6, 127.0, 127.7, 128.3, 128.5, 128.6, 128.7,
138.9, 141.0, 161.6, 166.6, 172.4; MS (ESI) m/z 469 (MHþ, 100%), 466
(7), 369 (6), 326 (5); HRMS (ESI) m/z 494.17374 (C26H28N3O5S
[MHþ], 494.17442).
[MHþ], 460.11730); [
a
]
20 þ240 (c 1, CH2Cl2).
D
4.3.10. Benzyl spiro[penicillanate-6,30-(5-methoxycarbonyl-3H-pyr-
azole)] (5b). Prepared by method A from 6-diazopenicillanate 2a
(157 mg, 0.49 mmol) and methyl propiolate (62 mg; 0.74 mmol).
The reaction mixture was stirred for 3 h and purification by flash
column chromatography [ethyl acetate/hexane (1:2)] afforded
compound 5b as a yellow oil (27 mg, 0.067 mmol, 14%). The
product was also prepared by method C from 6-diazopenicillanate
2a (145 mg, 0.46 mmol) and methyl propiolate (57 mg;
0.67 mmol). The reaction mixture was stirred for 3 h and purifi-
cation by flash column chromatography [ethyl acetate/hexane
(1:2)] afforded 5b (67 mg, 0.016 mmol, 37%). nmax/cmꢁ1 (film)
4.3.7. Benzhydryl spiro[penicillanate-6,50-(3-methoxycarbonyl-2-
pyrazoline)] 3g and 4g. Prepared by method
A from 6-
diazopenicillanate 2b (132 mg, 0.34 mmol) and methyl acrylate
(44 mg, 0.51 mmol). The reaction mixture was stirred for 18 h and
purification by flash column chromatography [ethyl acetate/hexane
(1:3)] afforded a (85:15) mixture of compounds 3g and 4g as
a yellow solid (99 mg, 0.21 mmol, 62%). Benzhydryl spiro[pen-
icillanate-6,50-(3-methoxycarbonyl-2-pyrazoline)] 3g. nmax/cmꢁ1
(film) 3328 (NH), 1782 (
b-lactam), 1742 and 1712 (esters); dH 1.25
(3H, s, 2 -Me), 1.50 (3H, s, 2
a
b
-Me), 3.30 (1H, d, J¼18.8 Hz, 40-H),
1786 (
b
-lactam), 1744 (ester), 1566 (N]N); dH 1.41 (3H, s, 2
a-Me),
3.65 (1H, d, J¼18.8 Hz, 40-H), 3.84 (3H, s), 4.55 (1H, s, 3-H), 5.29 (1H,
s, 5-H), 6.93 (1H, s, CHPh2), 6.93 (1H, s, NH), 7.29e7.35 (10H, m,
2ꢂPh); dC 25.6, 33.3, 37.3, 52.4, 64.1, 68.7, 77.6, 78.8, 82.6, 126.9,
127.7, 128.3, 128.5, 128.6, 128.7, 138.9, 140.3, 162.0, 167.0, 172.6; MS
(ESI) m/z 480 (MHþ, 100%), 452 (9), 369 (4), 326 (3); HRMS (ESI) m/z
480.15715 (C25H26N3O5S [MHþ], 480.15877).
1.49 (3H, s, 2
b
-Me), 3.89 (3H, s), 4.67 (1H, s, 3-H), 5.16 (1H, d,
J¼12.0 Hz, CH2Ph), 5.21 (1H, d, J¼12.0 Hz, CH2Ph), 6.28 (1H, s, 5-
H), 6.78 (1H, s, 40-H), 7.30e7.32 (5H, m, Ph); dC 25.1, 30.9, 51.2,
59.3, 61.1, 66.9, 68.0, 103.3, 127.8, 127.8, 127.9, 133.5, 144.6, 148.4,
150.6, 160.8, 166.4; MS (ESI) m/z 402 (MHþ, 100%), 302 (5); HRMS
20
(ESI) m/z 402.11112 (C19H20N3O5S [MHþ], 402.11182); [
(c 1 CH2Cl2).
a
]
þ295
D
4.3.8. Benzhydryl
spiro[penicillanate-6,50-(3-acetyl-2-pyrazoline)]
3h and 4h. Prepared by method A from 6-diazopenicillanate 2b
(137 mg, 0.35 mmol) and methyl vinyl ketone (76 mg, 1.1 mmol).
The reaction mixture was stirred for 24 h and purification by flash
column chromatography [ethyl acetate/hexane (1:3)] afforded
a (83:17) mixture of compounds 3d and 4d as a yellow oil (133 mg,
0.29 mmol, 82%). The products were also prepared by method C
from 6-diazopenicillanate 2b (150 mg, 0.38 mmol) and methyl vi-
nyl ketone (84 mg, 1.2 mmol). The reaction mixture was stirred for
3 h and purification by flash column chromatography [ethyl ace-
tate/hexane (1:3)] afforded a (83:17) mixture of compounds 3h and
4h (137 mg, 0.30 mmol, 78%). Benzhydryl spiro[penicillanate-6,50-(3-
4.3.11. Benzhydryl spiro[penicillanate-6,30-(4,5-dimethoxycarbonyl-
3H-pyrazole)] (5c). Prepared by method from 6-
A
diazopenicillanate 2b (156 mg, 0.40 mmol) and dimethyl acetyle-
nedicarboxylate (85 mg, 0.60 mmol). The reaction mixture was
stirred for 16 h and purification by flash column chromatography
[ethyl acetate/hexane (1:3)] afforded compound 5c as a brown oil
(117 mg, 0.22 mmol, 55%). Compound 5c was also prepared by
method C from 6-diazopenicillanate 2b (154 mg, 0.39 mmol) and
dimethyl acetylenedicarboxylate (85 mg, 0.60 mmol). The reaction
mixture was stirred for 3 h and purification by flash column chro-
matography [ethyl acetate/hexane (1:3)] afforded compound 5c
acetyl-2-pyrazoline)] 3h. nmax/cmꢁ1 (film) 3326 (NH), 1780 (
b-lac-
(109 mg, 0.20 mmol, 51%). nmax/cmꢁ1 (film) 1789 (
(ester),1588 (N]N); dH 1.25 (3H, s, 2 -Me),1.45 (3H, s, 2b
b
-lactam), 1733
-Me), 3.78
tam), 1745 (ester), 1666; dH 1.28 (3H, s, 2
a
-Me), 1.48 (3H, s, 2
b
-Me),
a
2.39 (3H, s), 3.21 (1H, d, J¼18.8 Hz, 40-H), 3.61 (1H, d, J¼18.8 Hz, 40-
H), 4.55 (1H, s, 3-H), 5.34 (1H, s, 5-H), 6.94 (1H, s, CHPh2), 7.16 (1H,
br s, NH), 7.34e7.35 (10H, m, 2ꢂPh); dC 25.5, 25.5, 33.6, 35.8, 64.0,
(3H, s), 3.89 (3H, s), 4.74 (1H, s, 3-H), 6.40 (1H, s, 5-H), 6.93 (1H, s,
CHPh2), 7.18e7.29 (10H, m, 2ꢂPh); dC 24.8, 31.4, 51.4, 52.0, 59.9,
60.9, 68.1, 78.1, 109.3, 125.9, 126.7, 127.3, 127.6, 126.6, 127.7, 137.7,

3736
B.S. Santos et al. / Tetrahedron 68 (2012) 3729e3737
147.8, 149.2, 149.4, 159.0, 159.9, 165.6; MS (ESI) m/z 436 (MHþ,
165.8, 167.0, 170.3; MS (ESI) m/z 451 (MNaþ, 100%), 431 (4); HRMS
(ESI) m/z 451.10511 (C20H20N4NaO5S [MNaþ], 451.10466).
100%), 383 (10), 342 (13); HRMS (ESI) m/z 536.14744 (C27H26N3O7S
20
[MHþ], 536.14860); [
a]
þ255 (c 1, CH2Cl2).
D
4.3.15. Benzhydryl
spiro[penicillanate-6,40-(7-phenyl-6,8-dioxo-
4.3.12. Benzhydryl spiro[penicillanate-6,30-(5-methoxycarbonyl-3H-
pyrazole)] (5d). Prepared by method A from 6-diazopenicillanate
2b (151 mg, 0.38 mmol) and methyl propiolate (48 mg;
0.57 mmol). The reaction mixture was stirred for 16 h and pu-
rification by flash column chromatography [ethyl acetate/hex-
ane (1:3)] afforded compound 5d as a yellow solid (115 mg,
0.24 mmol, 63%). Compound 5d was also prepared by method C
from 6-diazopenicillanate 2b (159 mg, 0.40 mmol) and methyl
propiolate (50 mg; 0.59 mmol). The reaction mixture was stir-
red for 3 h and purification by flash column chromatography
[ethyl acetate/hexane (1:3)] afforded 5d (138 mg, 0.29 mmol,
73%). Mp 60e61 ꢀC (from ethyl acetate/hexane); nmax/cmꢁ1
2,3,7-triazabicyclo[3.3.0]oct-2-ene)] 7c and 8c. Prepared by method
A from 6-diazopenicillanate 2b (100 mg, 0.25 mmol) and N-phe-
nylmaleimide (71 mg, 0.41 mmol). The reaction mixture was stirred
for 6 h and purification by flash column chromatography [ethyl
acetate/hexane (1:3)] afforded a (86:14) mixture of compounds 7c
and 8c as a yellow oil(110 mg, 0.19 mmol, 76%). Crystallization from
ethyl acetate/hexane gave 7c in pure form as a white solid. Benz-
hydryl spiro[penicillanate-6,40-(7-phenyl-6,8-dioxo-2,3,7-triazabicy
clo[3.3.0]oct-2-ene)] 7c. mp 191e192 ꢀC (from ethyl acetate/hex-
ane); nmax/cmꢁ1 (KBr) 1778 (
(CO), 1595 (N]N); dH 1.36 (3H, s, 2
b
-lactam), 1756 (ester), 1735 (CO), 1724
-Me), 1.80 (3H, s, 2 -Me), 3.69
a
b
(1H, d, J¼8.0 Hz, 11-H), 4.73 (1H, s, 3-H), 5.93 (1H, s, 5-H), 6.13 (1H,
d, J¼8.0 Hz, 10-H), 7.00 (1H, s, CHPh2), 7.25e7.47 (15H, m, 2ꢂPh); dC
26.0, 33.9, 42.6, 66.5, 70.0, 70.9, 78.8, 94.9, 110.5, 126.5, 127.2, 127.5,
128.4, 128.5, 128.7, 128.7, 129.3, 129.4, 130.8, 138.9, 163.7, 166.1,
(KBr) 1785 (
b-lactam), 1734 (ester), 1496 (N]N); dH 1.33 (3H, s,
2
a
-Me), 1.57 (3H, s, 2b-Me), 3.96 (3H, s), 4.81 (1H, s, 3-H), 6.34
(1H, s, 5-H), 6.85 (1H, s, CHPh2), 7.01 (1H, s, 40-H), 7.32e7.38
(10H, m, 2ꢂPh); dC 25.9, 31.9, 52.6, 60.4, 62.3, 69.1, 79.0, 104.3,
127.0, 127.7, 128.3, 128.6, 128.7, 128.7, 138.9, 45.6, 149.5, 151.7,
166.7, 170.7; MS (ESI) m/z 567 (MHþ, 100%), 391 (11), 213 (14);
HRMS (ESI) m/z 567.16873 (C31H27N4O5S [MHþ], 567.16967); [
ꢁ85 (c 1, CH2Cl2).
a]
20
D
161.8, 166.8; MS (ESI) m/z 478 (MHþ, 100%), 340 (2); HRMS (ESI)
m/z 478.14308 (C25H24N3O5S [MHþ], 478.14312); [
a
]
þ225 (c 1,
20
D
CH2Cl2).
4.3.16. Benzhydryl
spiro[penicillanate-6,40-(7-methyl-6,8-dioxo-
2,3,7-triazabicyclo[3.3.0]oct-2-ene)] 7d and 8d. Prepared by method
A from 6-diazopenicillanate 2b (158 mg, 0.40 mmol) and N-meth-
ylmaleimide (71 mg, 0.64 mmol). The reaction mixture was stirred
for 6 h and purification by flash column chromatography [ethyl
acetate/hexane (1:3)] afforded a (80:20) mixture of compounds 7d
and 8d as a yellow oil (118 mg, 0.23 mmol, 58%). Crystallization
from ethyl acetate/hexane gave 7d in pure form as a white solid.
Benzhydryl spiro[penicillanate-6,40-(7-methyl-6,8-dioxo-2,3,7-triaz
abicyclo[3.3.0]oct-2-ene)] 7d. Mp 171e172 ꢀC (from ethyl acetate/
4.3.13. Benzyl spiro[penicillanate-6,40-(7-phenyl-6,8-dioxo-2,3,7-
triazabicyclo[3.3.0]oct-2-ene)] 7a and 8a. Prepared by method A
from 6-diazopenicillanate 2a (177 mg, 0.56 mmol) and N-phe-
nylmaleimide (150 mg, 0.87 mmol). The reaction mixture was
stirred for 6 h and purification by flash column chromatography
[ethyl acetate/hexane (1:2)] afforded a (77:23) mixture of com-
pounds 7a and 8a as a yellow oil (106 mg, 0.22 mmol, 39%). The
products were also prepared by method
B
from 6-
diazopenicillanate 2a (178 mg, 0.56 mmol) and N-phenyl-
maleimide (105 mg, 0.60 mmol). The reaction mixture was irra-
diated for 3 min and purification by flash column chromatography
[ethyl acetate/hexane (1:2)] afforded a (66:34) mixture of com-
pounds 7a and 8a (34 mg, 0.069 mmol, 12%). Crystallization from
ethyl acetate/hexane gave 7a in pure form as a white solid. Benzyl
spiro[penicillanate-6,40-(7-phenyl-6,8-dioxo-2,3,7-triazabicyclo[3.3
.0]oct-2-ene)] 7a. Mp 194e195 ꢀC (from ethyl acetate/hexane);
hexane); nmax/cmꢁ1 (KBr) 1774 (
1494 (N]N); dH 1.36 (3H, s, 2 -Me),1.83 (3H, s, 2
b-lactam), 1745 (ester), 1710 (CO),
a
b-Me), 3.01 (3H, s),
3.60 (1H, d, J¼8.0 Hz, 11-H), 4.73 (1H, s, 3-H), 5.85 (1H, s, 5-H), 5.97
(1H, d, J¼8.0 Hz, 10-H), 6.99 (1H, s, CHPh2), 6.90e7.37 (10H, m,
2ꢂPh); dC 25.5, 25.8, 33.9, 42.4, 66.3, 70.0, 71.0, 78.8, 95.0, 109.5,
127.2, 127.5, 128.4, 128.5, 128.7,128.7, 138.9, 163.7,166.1,167.8,171.2;
MS (ESI) m/z 505 (MHþ, 100%), 464 (7), 402 (9), 241 (7); HRMS (ESI)
20
m/z 505.15385 (C26H25N4O5S [MHþ], 505.15402); [
CH2Cl2).
a]
þ20 (c 1,
D
nmax/cmꢁ1 (KBr) 1781 (
b
-lactam), 1747 (ester), 1735 (CO), 1723
(CO), 1500 (N]N); dH (DMSO-d6) 1.44 (3H, s, 2a-Me), 1.69 (3H, s,
2
b
-Me), 3.73 (1H, d, J¼7.2 Hz, 50-H), 4.86 (1H, s, 3-H), 5.28 (2H, br
4.4. General procedure for the synthesis of spirocyclopropyl-
s, CH2Ph), 5.74 (1H, s, 5-H), 6.21 (1H, d, J¼7.2 Hz, 10-H), 7.21e7.23
b-lactams 9 and 10
(2H, m), 7.43e7.49 (8H, m); dC (DMSO-d6) 25.6 (2a-Me), 33.2 (2b-
Me), 43.5 (C-11), 64.0 (C-2), 67.0, 69.1(C-3), 71.2 (C-5), 96.7 (C-10),
109.2 (C-6), 126.7, 128.4, 128.5, 128.6, 128.8, 129.1, 131.4, 135.1,
164.9, 167.0, 168.2, 171.7; MS (ESI) m/z 491 (MHþ, 100%), 466 (9),
A suspension of the appropriate spiro-b-lactam 7 (50 mg) in
1,2,4-trichlorobenzene (1 mL) was irradiated in the microwave re-
actor with the temperature set to 250 ꢀC for 2 min. The crude
product was purified by flash column chromatography [hexane
then ethyl acetate/hexane (1:2)].
326 (4), 280 (5), 213 (5); HRMS (ESI) m/z 491.13711 (C25H23N4O5S
20
[MHþ], 491.13837); [
a
]
ꢁ125 (c 1, CH2Cl2).
D
4.3.14. Benzyl spiro[penicillanate-6,40-(7-methyl-6,8-dioxo-2,3,7-
triazabicyclo[3.3.0]oct-2-ene)] 7b and 8b. Prepared by method A
from 6-diazopenicillanate 2a (174 mg, 0.55 mmol) and N-meth-
ylmaleimide (98 mg, 0.88 mmol). The reaction mixture was stir-
red for 6 h and purification by flash column chromatography
[ethyl acetate/hexane (1:2)] afforded a (82:18) mixture of com-
pounds 7b and 8b as a yellow oil (60 mg, 0.14 mmol, 25%). Benzyl
spiro[penicillanate-6,40-(7-methyl-6,8-dioxo-2,3,7-triazabicyclo[3.3.
4.4.1. Benzhydryl spiro[penicillanate-6,60-(3-phenyl-2,4-dioxo-3-
azabicyclo[3.1.0]hexane)] 9a and 10a. Prepared from 7c (53 mg,
0.094 mmol). Purification by flash column chromatography affor-
ded a (77:23) mixture of compounds 9a and 10a as a brown oil
(47 mg, 0.088 mmol, 94%). Crystallization from ethyl acetate/hex-
ane gave 9a in pure form as a white solid. Benzhydryl spiro[pen-
icillanate-6,60-(3-phenyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane)] 9a.
Mp 232e233 ꢀC (from ethyl acetate/hexane); nmax/cmꢁ1 (film) 1786
0]oct-2-ene)] 7b. nmax/cmꢁ1 (film) 1794 (
1713 (CO), 1540 (N]N); dH 1.41 (3H, s, 2
b
a
-lactam), 1743 (ester),
-Me), 1.74 (3H, s, 2
(b-lactam), 1735 (ester), 1719 (CO); dH 1.22 (3H, s, 2a-Me), 1.54 (3H,
b
-
s, 2
b
-Me), 3.16 (1H, d, J¼5.6 Hz, 10-H), 3.25 (1H, d, J¼5.6 Hz, 50-H),
Me), 2.91 (3H, s), 3.53 (1H, d, J¼8.0 Hz, 50-H), 4.60 (1H, s, 3-H),
5.12e5.21 (2H, m, CH2Ph), 5.74 (1H, s, 5-H), 5.91 (1H, d, J¼8.0 Hz,
10-H), 7.29e7.31 (5H, m, Ph); dC 24.5, 25.0, 32.8, 41.4, 65.0, 66.7,
68.8, 69.9, 94.0, 108.5, 127.5, 127.6, 127.7, 127.7, 127.8, 133.5, 162.7,
4.60 (1H, s, 3-H), 5.43 (1H, s, 5-H), 6.87 (1H, s, CHPh2), 7.18e7.39
(15H, m, 2ꢂPh); dC 24.1, 29.8, 29.8, 33.1, 54.1, 63.7, 68.4, 69.5, 77.6,
126.0, 126.1, 126.5, 127.3, 127.5, 127.6, 127.7, 127.8, 128.1, 130.3, 138.0,
165.3, 167.8, 168.1, 170.4; MS (ESI) m/z 561 (MNaþ, 21%), 513 (14),

B.S. Santos et al. / Tetrahedron 68 (2012) 3729e3737
3737
ꢀ
97e104; (c) Perez-Llarena, F. J.; Bou, G. Curr. Med. Chem. 2009, 16, 3740e3765;
(d) Fisher, J. F.; Meroueh, S. O.; Mobashery, S. Chem. Rev. 2005, 105, 395e424; (e)
Bebrone, C.; Lassaux, P.; Vercheval, L.; Sohier, J.-S.; Jehaes, A.; Sauvage, E.;
Galleni, M. Drugs 2010, 70, 651e679.
366 (24), 326 (100), 282 (10), 213 (7); HRMS (ESI) m/z 561.14397
20
(C31H26N2NaO5S [MNaþ], 561.14546); [
Benzhydryl spiro[penicillanate-6,60-(3-phenyl-2,4-dioxo-3-azabicyclo
[3.1.0]hexane)] 10a. dH 1.19 (3H, s, 2 -Me), 1.51 (3H, s, 2 -Me), 3.09
a
]
D
þ135 (c 1, CH2Cl2).
2. (a) Ojima, I. Acc. Chem. Res. 1995, 28, 383e389; (b) Alcaide, B.; Almendros, P.;
Aragoncillo, C. Chem. Rev. 2007, 107, 4437e4492; (c) Szakonyi, Z.; Fulop, F.
Amino Acids 2011, 41, 597e608; (d) Kiss, L.; Forro, E.; Martinek, T. A.; Bernath, T.
A.; De Kimpe, N.; Fulop, F. Tetrahedron 2008, 64, 5036e5043; (e) Gyonfalvi, S. ,;
Szakonyi, Z.; Fulop, F. Tetrahedron: Asymmetry 2003, 14, 3965e3972; (f) Lee-
mans, E.; D’hooghe, M.; Dejaegher, Y.; Tarnroos, K. W.; De Kimpe, N. Eur. J. Org.
Chem. 2010, 352e358.
3. (a) Bari, S. S.; Bhalla, A. Top. Heterocycl. Chem. 2010, 22, 49e99; (b) Singh, G. S.;
D’hooghe, M.; De Kimpe, N. Tetrahedron 2011, 67, 1989e2012; (c) Chen, L.-Y.;
Zaks, A.; Chackalamannil, S.; Dugar, S. J. Org. Chem. 1996, 61, 8341e8343; (d)
Wu, G.; Tormos, W. J. Org. Chem. 1997, 62, 6412e6414; (e) Sheehan, J. C.; Chacko,
E.; Lo, Y. S.; Ponzi, D. R.; Sato, E. J. Org. Chem. 1978, 43, 4856e4859; (f) Skiles, J.
W.; McNeil, D. Tetrahedron Lett. 1990, 31, 7277e7280; (g) Campbell, M. M.;
Harcus, R. G.; Ray, S. J. Tetrahedron Lett. 1979, 20, 1441e1444.
4. (a) Alonso, E.; Lopez-Ortiz, F.; Del Pozo, C.; Peralta, E.; Macías, A.; Gonzalez, J. J.
Org. Chem. 2001, 66, 6333e6338; (b) Bittermann, H.; Gmeiner, P. J. Org. Chem.
2006, 71, 97e102.
a
b
€ €
(1H, d, J¼5.6 Hz), 3.33 (1H, d, J¼5.6 Hz), 4.57 (1H, s, 3-H), 5.46 (1H, s,
ꢀ
ꢀ
5-H), 6.88 (1H, s, CHPh2), 7.18e7.39 (15H, m, 2ꢂPh).
€ €
ꢀ
€ €
4.4.2. Benzhydryl spiro[penicillanate-6,60-(3-methyl-2,4-dioxo-3-
azabicyclo[3.1.0]hexane)] 9b, 10b. Prepared from 7d (46 mg,
0.091 mmol). Purification by flash column chromatography affor-
ded a (72:28) mixture of compounds 9b and 10b as a brown oil
(28 mg, 0.058 mmol, 64%). Benzhydryl spiro[penicillanate-6,60-(3-
methyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane)] 9b. nmax/cmꢁ1 (film)
ꢂ
1786 (
(3H, s, 2
b-lactam), 1735 (ester), 1711 (CO); dH 1.20 (3H, s, 2a-Me), 1.51
b
-Me), 2.84 (3H, s), 3.02 (1H, d, J¼5.6 Hz, 10-H), 3.12 (1H, d,
ꢀ
ꢀ
J¼5.6 Hz, 50-H), 4.56 (1H, s, 3-H), 5.38 (1H, s, 5-H), 6.85 (1H, s,
CHPh2), 7.12e7.28 (10H, m, 2ꢂPh); dC 24.8, 25.1, 30.4, 30.5, 34.1,
55.3, 64.6, 69.5, 70.4, 78.6, 127.0, 127.1, 127.5, 127.6, 128.3, 128.4,
128.6, 128.7, 139.0, 166.3, 169.7, 170.1, 171.5; MS (ESI) m/z 499
(MNaþ, 100%); HRMS (ESI) m/z 499.13084 (C26H24N2NaO5S [MNaþ],
499.12981). Benzhydryl spiro[penicillanate-6,60-(3-methyl-2,4-dioxo-
5. (a) Sandanayaka, V. P.; Prashad, A. S.; Yang, Y.; Thomas Williamson, R.; Lin, Y. I.;
Mansour, T. S. J. Med. Chem. 2003, 46, 2569e2571; (b) Arrowsmith, J. E.;
Greengrass, C. W.; Newman, M. J. Tetrahedron 1983, 39, 2469e2475.
6. (a) Sheehan, J. C.; Commons, T. J. J. Org. Chem. 1978, 43, 2203e2208; (b)
€
Sheehan, J. C.; Lo, Y. S.; Loliger, J.; Podewell, C. C. J. Org. Chem. 1974, 39,
1444e1445.
7. Manhas, M. S.; Gala, K.; Bari, S. S.; Bose, A. K. Synthesis 1983, 7, 549e552.
8. (a) Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577e6605; (b) Galley, G.; Patzel,
3-azabicyclo[3.1.0]hexane)] 10b. dH 1.17 (3H, s, 2a-Me), 1.55 (3H, s,
€
2
b
-Me), 2.81 (3H, s), 2.96 (1H, d, J¼5.6 Hz), 3.18 (1H, d, J¼5.6 Hz),
M.; Jones, P. G. Tetrahedron 1995, 51, 1631e1640; (c) Jung, M. E.; Min, S.-J.; Ess,
D. J. Org. Chem. 2004, 69, 9085e9089; (d) Simovic, D.; Di, M.; Marks, V.;
Chatfield, D. C.; Rein, K. S. J. Org. Chem. 2007, 72, 650e653.
9. Molchanov, A. P.; Diev, V. V.; Kostikov, R. R. Russ. J. Org. Chem. 2002, 38,
259e263.
10. Hutchinson, I. S.; Matlin, S. A.; Mete, A. Tetrahedron 2002, 58, 3137e3143.
11. (a) Brandi, A.; Goti, A. Chem. Rev. 1998, 98, 589e635; (b) Engel, P. S. Chem. Rev.
1980, 80, 99e150; (c) McGreer, D. E.; McKinley, J. W. Can. J. Chem. 1971, 49,
4.52 (1H, s, 3-H), 5.26 (1H, s, 5-H), 6.88 (1H, s, CHPh2), 7.19e7.28
(10H, m, 2ꢂPh).
4.5. Computational details
All the calculations were performed using the Gaussian 03
program package,16 except for the conformational search that was
performed with the Avogadro package.12 Graphical representations
were produced with Gaussview.
ꢀ
ꢀ
105e117; (d) Toth, G.; Levai, A.; Dinya, Z.; Snatzke, G. Tetrahedron 1991, 47,
8119e8132; (e) McElwee-White, L.; Dougherty, D. A. J. Am. Chem. Soc. 1984, 106,
3466e3474; (f) Tomilov, Yu. V.; Shulishov, E. V.; Yargin, S. A.; Nefedov, O. M.
Russ. Chem. Bull. 1995, 44, 2109e2113; (g) Clarke, T. C.; Wendling, L. A.; Berg-
man, R. G. J. Am. Chem. Soc. 1977, 99, 2740e2750; (h) Bartels, A.; Liebscher, J.
Tetrahedron: Asymmetry 1994, 5, 1451e1452; (i) Garcia Ruano, J. L.; Peromingo,
M. T.; Rosario Martin, M.; Tito, A. Org. Lett. 2006, 8, 3295e3298; (j) Cruz Cruz,
D.; Yuste, F.; Rosario Martin, M.; Tito, A.; Garcia Ruano, J. L. J. Org. Chem. 2009,
74, 3820e3826; (k) Van Auken, T. V.; Rinrhart, K. L., Jr. J. Am. Chem. Soc. 1962, 84,
3736e3743; (l) Hamaguchi, M.; Nakaishi, M.; Nagai, T.; Tamura, H. J. Org. Chem.
2003, 68, 9711e9722; (m) Nakano, Y.; Hamaguchi, M.; Nagai, T. J. Org. Chem.
1989, 54, 1135e1144.
Acknowledgements
ˇ
~
Thanks are due to Fundac¸ ao para a Ciencia e a Tecnologia (FCT)
(Grant SFRH/ BD/63622/2009; Project PEst-C/QUI/UI0313/2011),
FEDER, COMPETE and QREN for financial support. The authors
acknowledge the Nuclear Magnetic Resonance Laboratory of the
Coimbra Chemical Centre (www.nmrccc.uc.pt), University of
Coimbra for obtaining the NMR spectroscopic data and AtralCipan
for having provided the 6-aminopenicillanic acid.
12. Avogadro: an open-source molecular builder and visualization tool. Version 1.0.0.
13. Becke, A. D. Phys. Rev. A 1988, 38, 3098e3100.
14. Becke, A. D. J. Chem. Phys. 1993, 98, 5648e5652.
15. Lee, C. T.; Yang, W. T.; Parr, R. G. Phys. Rev. B 1988, 37, 785e789.
16. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G.; Robb, M. A.; Cheeseman,
J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.;
Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega,
N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.;
Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannen-
berg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.;
Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen,
W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision D.01; Gaussian:
Wallingford, CT, 2004.
Supplementary data
1H and 13C NMR spectra of selected compounds. Supplementary
data associated with this article can be found in the online version,
at doi:10.1016/j.tet.2012.03.022.
References and notes
1. (a) Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven,
E. F. V., Eds.; Elsevier: Oxford, 1996; (b) Knowles, J. R. Acc. Chem. Res. 1985, 18,