Synthesis of new γ-lactones from preactivated monosubstituted pyrazines and TMS-ketene acetals

Article abstract of DOI:10.1139/v2012-016

The double addition of bis(trimethylsilyl) ketene acetals (1a-1b, R ₁ = CH₃,-(CH₂)₅-) to 2-substituted pyrazines promoted by triflic anhydride leads to γ-lactones in a single step. A systematic study involving electron-withdrawing and electron-donating groups (R₂ = CN, COOMe, PhCH=CH, Cl, Me, OMe) in the pyrazine ring reveals a strong dependence of electronic effects on the regiochemistry of nucleophilic addition.

Full text of DOI:10.1139/v2012-016

469
Synthesis of new γ-lactones from preactivated
monosubstituted pyrazines and TMS–ketene
acetals
Azucena Garduño-Alva, M. Carmen Ortega-Alfaro, José G. López-Cortés,
Isabel Chávez, Joaquin Barroso-Flores, Rubén A. Toscano, Henri Rudler, and
Cecilio Álvarez-Toledano
Abstract: The double addition of bis(trimethylsilyl) ketene acetals (1a–1b, R1 = CH3, –(CH2)5–) to 2-substituted pyrazines
promoted by triflic anhydride leads to g-lactones in a single step. A systematic study involving electron-withdrawing and
electron-donating groups (R2 = CN, COOMe, PhCH=CH, Cl, Me, OMe) in the pyrazine ring reveals a strong dependence
of electronic effects on the regiochemistry of nucleophilic addition.
Key words: pyrazines, g-lactones, N-activation.
Résumé : La double addition des acétals de bis(trimethylsilyl) cétènes (1a–1b, R1 = CH3, –(CH2)5–) sur les pyrazines sub-
stituées en 2 et activées par l’anhydride triflique conduit à la formation de g-lactones en une seule étape. Une étude systé-
matique utilisant des substituants électro-attracteurs et des électro-donneurs (R2 = CN, COOMe, PhCH=CH, Cl, Me, OMe)
sur l’anneau de la pyrazine a révélé une forte dépendance des effets électroniques sur la régio-chimie de l’addition nucléo-
philique.
Mots‐clés : pyrazines, g-lactones, N-activation.
ences in their reactivity. When this reaction is extended to di-
azines such as pyrazine, quinoxaline, and pyrimidine, the
ring-closure reaction takes place in one step (Scheme 1).9–11
In continuation of our studies on the activation of different
diazaheterocyclic compounds and their reactivity towards nu-
cleophiles, we herein report the full details on the regiochem-
istry of the nucleophilic addition of bis(TMS)–ketene acetals
to different monosubstituted pyrazines previously activated
with triflic anhydride. This systematic study involves both
electron-withdrawing and electron-donating groups on the
pyrazine ring.
Introduction
Nitrogen heterocycles are abundant in nature and are of
great significance to life because their structural subunits ex-
ist in many natural products such as vitamins, hormones,
antibiotics, and alkaloids, as well as in pharmaceuticals, her-
bicides, and dyes.1,2 The functionalization of azaheterocycles
is therefore a powerful tool for synthesizing natural products
and bioactive substances. Among the synthetic strategies that
exist for carrying out such transformations, we have focused
our efforts on the activation of the aromatic substrates by co-
ordinating their double bonds to a transition metal and the
activation of the aza-aromatics that occurs through nitrogen
atoms via their pyridinium salts.3 Following these ap-
proaches, we and other research groups have described the
synthesis of functionalized g- and d-lactones via a double nu-
cleophilic addition of bis(TMS)–ketene acetals to chromium(0)
complexes,4 allyl acetates,5 tropylium ions,6 and some aza-
heterocycles using methyl chloroformate7 or triflic anhy-
dride8 as activating agents, and the appropriated halogen to
induce the formation of the corresponding halolactones.
In the case of diazaheterocycles, there are important differ-
Results and discussion
Reactivity of pyrazines containing electron-withdrawing
groups
We started our study by using substituted pyrazines con-
taining electron-withdrawing groups; thus, triflic anhydride
(2 equiv) was added by syringe to a solution of correspond-
ing pyrazine (2–5) in dry CH2Cl2 at –30 °C, followed by
2 equiv of bis(trimethylsilyl)ketene acetal 1; the reaction
Received 4 August 2011. Accepted 26 January 2012. Published at www.nrcresearchpress.com/cjc on 26 April 2012.
A. Garduño-Alva, J.G. López-Cortés, I. Chávez, R.A. Toscano, and C. Álvarez-Toledano. Instituto de Química-UNAM, Circuito
Exterior, Ciudad Universitaria, Coyoacán C. P. 04510, México, D. F.
M.C. Ortega-Alfaro. Instituto de Ciencias Nucleares-UNAM, Circuito Exterior, Ciudad Universitaria, Coyoacán C. P. 04510, México, D.
F.
J. Barroso-Flores. Centro Conjunto de Investigación en Química Sustentable UAEM-UNAM. Car. Toluca-Atlacomulco, Km 14.5 Unidad
San Cayetano. Personal de la UNAM. Toluca 50200, Estado de México, México.
H. Rudler. Institut Parisien de Chimie Moléculaire, UMR CNRS 7201, Université Pierre et Marie Curie, 4 place Jussieu, 75005 Paris
CEDEX 5, France.
Corresponding author: C. Alvarez-Toledano (e-mail: cecilio@unam.mx).
Can. J. Chem. 90: 469–482 (2012)
doi:10.1139/V2012-016
Published by NRC Research Press

470
Can. J. Chem. Vol. 90, 2012
Scheme 1.
a related g-lactone, using pyridazine as starting material and
triflic anhydride as the activating agent (Scheme 4).10
O
R
I
The IR spectrum of product 7a shows two absorption
bands at 1791 and 1705 cm–1, which indicates the presence
of two different carbonyl groups. This result was confirmed
in the 13C NMR spectrum by the signals at 176.1 and
176.9 ppm, assigned to a lactone and an amide group, re-
R
OH
R
1)
R
O
Activating agent
I2
2) R
OTMS
NaHCO3
N
N
O
N
A
A
R
OTMS
1
spectively. Two groups of signals shifted upfield in the H
NMR spectrum indicate the presence of four methyl groups,
two of them as singlets, and the others as doublets coupled
with a heptet signal shifted at 2.91 ppm, integration for one
proton, which suggests an isopropyl group. This was in ac-
cordance with the introduction of 2 equiv of (TMS)–ketene
acetal. The relative position of chlorine with respect to the
lactone ring was assigned by the long-distance interaction ob-
served in the HMBC experiment (Fig. 1).
The structure of 7a was fully established through an X-ray
diffraction analysis (Fig. 3) and confirmed that a g-lactone
cis-fused to a tetrahydropyrazine had been formed, one nitro-
gen bearing a trifluoromethanesulfonyl group, as expected
from the NMR spectroscopic data, and the other surprisingly
bearing an acyl group, which comes from an additional ke-
tene acetal moiety.10
A
N
N
N
O
1) Activating agent
O
2) R
OTMS
N
R
R
A
R
OTMS
= Tf O,
2
Activating agent
A = Tf, CO Me
ClCO Me
2
2
mixture was stirred for 12 h (Scheme 2). The results are
shown in Table 1. This reaction leads to the formation of
two regioisomers (A and A') depending on the nucleophilic
attack of the TMS–ketene acetal. As can be seen, the reaction
proceeds in a regioselective mode leading to products A.
This behavior includes pyrazines containing strongly or mod-
erated electron-withdrawing groups (Table 1, entries 1–8).
The assignment of the structure of all compounds was per-
Reactivity of pyrazines containing electron-donating
groups
To gain insight into the factor that controls the regiochem-
istry by electron-donating groups, we started screening this
reaction using 2-methylpyrazine (6) and the (TMS)–ketene
acetal 1a (Table 1, entry 9) under similar reaction conditions.
We obtained products A and A' in a 5:1 ratio, with a yield of
1
formed through spectroscopic methods. For example, the H
NMR spectrum of compound 2a (mp 173 °C) confirms the
double nitrogen activation and the ring closure in one step,
leading to a cis-g-lactone, which is consistent with two
coupled signals shifted at 6.69 ppm (H6) and 5.12 ppm (H5)
with J = 8 Hz. The 13C NMR spectrum displays representa-
tive signals at 174.4 (lactone C=O), 85.9 (C6), 68.6 (C5),
and 124.6 ppm (C3). Similar results were observed in the
case of 2b (mp 138 °C). Long-distance correlation (3J) be-
tween H6 with C2, C7, and C8, as well as H5 with C3 using
1
96%.12 The major product was identified as 6a, whose H
NMR spectrum showed two doublets at 6.53 and 4.79 ppm
for H6 and H5 with J = 8 Hz, corresponding to a cis-fused
lactone; this signal pattern concurs with previous results.
Structure 6a' was assigned to the minor product and, in this
case, the vinyl protons H5 and H6 were displayed as a multi-
ple signal with the integration of two protons. The 13C NMR
spectrum for this compound revealed a signal at 88.0 ppm
assigned to quaternary carbon C2, consistent with a nucleo-
philic addition of (TMS)–ketene acetal over C3 and C2 of 6.
Two-dimensional NMR experiments are in agreement with
the structure of 6a'.
a
heteronuclear multiple-bond correlation spectroscopy
(HMBC) experiment, provides evidence of the correct posi-
tion of the nitrile group, which is bonded to C2 (Fig. 1).
The structure of 4a was fully established through an X-ray
diffraction analysis (Fig. 2) and confirmed that a g-lactone
cis-fused to a tetrahydropyrazine had been formed.
In accordance with spectroscopic data, we can establish
that the first nucleophilic attack toward pyrazine occurs on
C5 once the nitrogen at position 4 has been activated, leading
to intermediate D. This regiospecific activation is due to the
fact that N4 is more basic as compared with N1, because of
the neighboring electron-withdrawing group. A second acti-
vation promoted by another triflic anhydride molecule then
takes place at N1, leading to E, which favors the ring-closure
reaction, to give 2a and 2b (Scheme 3).
The introduction of chlorine as a substituent on the pyra-
zine ring leads to different behavior (Table 1, entries 7 and
8). As can be seen, products 5a and 5b were formed in mod-
erate yield, and the new compounds 7a and 7b, containing an
amide group in their structure (B), were also obtained. This
is probably because the second nitrogen activation is not as
fast, leading to a side reaction between the acetal 1 and triflic
anhydride. The formation of 7a and 7b probably follows a
similar reaction mechanism, as previously proposed by us in
Similar to that observed for electron-withdrawing groups,
the first activation occurs at the N4 despite increasing basic
character in N1; we thought that the steric effect plays an im-
portant role in the first stage of the reaction. On the other
hand, a loss in the selectivity of nucleophilic addition is ob-
served and a mixture of products 6a and 6a' is obtained
when acetal 1a is used. When the same reaction was carried
out with acetal 1b, we only obtained the analogous com-
pound 6b. These results using the more sterically encum-
bered acetal substrate 1b suggest that steric hindrance
controls both the regioselectivity and yield of the nucleo-
philic addition product.
Finally, we carried out this reaction on 2-methoxypyrazine
(8), which, once activated with triflic anhydride, led to three
products after workup: two were identified as lactones 8' and
9 and the other as carboxylic acid 10 (Scheme 5). The three
products were formed by the regioselective nucleophilic addi-
tion of TMS–ketene acetal on C3, and in the case of 8' and 9
Published by NRC Research Press

Garduño-Alva et al.
471
Scheme 2.
R2
Tf
N
Tf
N
O
R1
R2
O
R1
6
5
R1
N
N
O
O
6
5
1) Tf2O
2) R2
R1
O
R2
N
2
3
2
3
6
5
O
R2
2
OTMS
OTMS
O
R2
N
N
3
R2
R2
N
R2
Tf
Tf
R2
Tf
1a: R2 = CH3
1b: R2 = -(CH2)5-
A
B
A'
2 R1 = CN
2a-b
3a-b
4a-b
5a-b
6a-b
2'a-b
3'a-b
4'a-b
5'a-b
6'a-b
3 R1 = COOMe
R1 = PhCH=CH
4
5 R1 = Cl
7a-b
6 R1 = Me
Table 1. Products obtained using 2-substituted pyrazines (2–6).
Product (yield, %)
Entry
1
2
3
4
5
6
7
8
R1
CN
CN
COOMe
COOMe
PhCH=CH
PhCH=CH
Cl
R2
Me
–(CH2)5–
Me
–(CH2)5–
Me
–(CH2)5–
Me
A
A'
—
—
—
—
B
2a (60)
2b (36)
3a (89)
3b (84)
4a (43)
4b (73)
5a (44)
5b (37)
6a (80)
6b (55)
—
—
—
—
—
—
6a' (16)
—
7a (37)
7b (25)
—
Cl
Me
Me
–(CH2)5–
Me
–(CH2)5–
9
10
—
gle crystal analysis (Fig. 5), which revealed that the first
activation occurs on N4 of pyrazine followed by nucleophilic
attack of the ketene acetal on C3; this compound is analo-
gous to the first intermediate proposed in the reaction mech-
anism (E) (Scheme 3).
Fig. 1. Heteronuclear multiple-bond correlation spectroscopy
(HMBC) correlation for 2a and 7a.
In accordance with the experimental results, a possible
mechanism for the formation of 8', 9, and 10 can be sug-
gested (Scheme 6): the first nitrogen activation occurs on the
nitrogen at the 4-position, then (TMS)–ketene acetal is nucle-
ophilic added at the 3-position, leading to F, which is the key
intermediate that gives rise to the three products. The hydrol-
ysis of F thus leads to 10. A subsequent nitrogen activation
of F with a second equivalent of triflic anhydride favors the
ring-closure reaction to 8'. Alternatively, F might react with a
second equivalent of ketene acetal, which is in excess, prob-
ably through a tandem reaction giving the amide 9, as we
have previously suggested.10
To understand the regiochemistry of the first nucleophilic
addition on the pyrazines with triflic anhydride (C), we cal-
culated the Fukui indices at the B3LYP/6–31G(d,p) level of
theory. Figure 6 shows f+ values for the substituted pyrazi-
nium ions CN (2C), Me (6C), and MeO (8C). Geometry op-
timizations were carried out for each triflated compound.
On the basis of the calculated values for 2C and 8C, nu-
cleophilic addition is carried out on C5 and C3, respectively.
However, in the case of 6C, we obtained close values of Fu-
kui indices in both carbon atoms, showing a similar probabil-
ity of nucleophilic attack by the TMS–ketene acetal. These
theoretical findings agree with the experimental results and
explain the loss of regioselectivity.
with a ring-closure on C2, which is evidenced by the signals
observed on the 13C NMR spectra of these compounds
around 100 ppm. These results reveal a high influence of the
methoxy group in modifying the reactivity of the pyrazine.
Additionally, a close relationship can be seen between the
structure of 9a–9b and the results obtained for compounds
7a–7b, where an N-trifluoromethanesulfonyl moiety is
bonded to an acyl group from 1 additional equiv of ketene
acetal. The IR spectra of 9 showed two absorption bands
around 1800 and 1700 cm–1, consistent with a lactone and
an amide group. The NMR spectroscopic data agree with
this assessment. We fully confirmed the structure of 9a
through X-ray diffraction analyses (Fig. 4).
The IR spectra of the more polar compounds 10a and 10b
showed the characteristic absorption band for the COOH
1
group, confirmed by the signals displayed in the H NMR
spectra at 10.70 and 10.08 ppm, respectively. We also ob-
served the signals for the carboxyl groups in the 13C NMR
spectra at 179.8 and 178.9 ppm, respectively. A final assess-
ment of the 10b structure was obtained through an X-ray sin-
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472
Can. J. Chem. Vol. 90, 2012
Fig. 2. ORTEP view of compund 4a. Thermal ellipsoids at 30% probability level.
Scheme 3.
Tf O Tf
1
SiMe3
NC
N
NC
N
2
-OTf
NC
N
6
5
6
5
-Me3SiOTf
O
1
5
R2
R2
O SiMe3
4
4
+
N
3
3
N
N
O
R2
R2
Tf
Tf
OSiMe3
Tf O Tf
D
C
Tf
N
–OTf
Tf
NC
6
5
O
SiMe3
NC
N
+
-Me3SiOTf
6
O
O
R2
N
N
O
R2
R2
R2
Tf
Tf
2a, b
E
Mechanism insight
only product obtained was 11c, which is formed through the
nucleophilic addition at the 3-position on preactivated pyra-
zine (Scheme 8 and Table 2, entry 1). The spectroscopic
data for 11c confirms this result. In particular, the protons of
the double bond gave the double signals at 6.37 and
6.09 ppm with J = 5 Hz and two singlets with the integration
of three protons assigned to the methyl groups observed in
In an attempt to trap the intermediates proposed in the
pathway to obtain 8–10, we carried out three experiments in
which we modified the stoichiometry of the ketene acetal as
well as its structure. In the first assay, we performed the reac-
tion using 1 equiv of triflic anhydride plus 2 equiv of ketene
acetal 1b. We obtained 10b as the only product in 98% yield,
thus confirming that F is the crucial intermediate in the reac-
tion (Scheme 7).
Since the course of the reaction involves the formation of
intermediate F as an initial step, we modified the structure
of the ketene acetal by selecting the O-(TMS) ester 1c.
When we used an equimolar amount of Tf2O and 1c, the
1
the H NMR spectrum. Furthermore, in the 13C NMR spec-
trum we observed two signals at 172.7 and 157.8 ppm, as-
signed to an ester group and N=C, respectively. If the same
reaction is carried out in a 2:1 ratio of Tf2O–1c (Scheme 8
and Table 2, entry 2), 11c, and 12c were obtained in nearly
equal amounts (38% and 48%, respectively). The IR spectrum
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Garduño-Alva et al.
473
Scheme 4.
Me3SiO
Me3SiO
Me
Me
Me3Si OTf
1
SiMe3
O
Cl
N
Cl
N
2
Cl
N
-OTf
6
5
1
O
5
4
4
+
N
Me
Me
O SiMe3
3
3
5
N
N
Me
Me
Tf
Tf
OSiMe3
Tf O Tf
5C
5D
5
Me
Me
Me
SiMe3
O
Me3SiO
Me3SiO
Cl
Me
O
H2O
Cl
N
O
N
1
1
O
Me
5
4
O
5
4
N
N
Me
Me
Tf
Me
Tf
7a
Fig. 3. ORTEP view of compound 7a. Only one of two independent molecules is displayed. Thermal ellipsoids are at the 30% probability
level.
of 12c displays two absorption bands for carbonyl groups. As
formation of intermediate F, after which a consecutive activa-
tion promoted by a second molecule of triflic anhydride can
promote the ring-closure reaction if a bis(TMS)–ketene acetal
is used as a nucleophile.
For 12c, we propose the following pathway (Scheme 9): as
in preceding cases, the first nitrogen activation occurs on the
nitrogen at the 4-position, then (TMS)–ketene acetal is
nucleophilic-added at the 3-position, leading to 11c, which
reacts with a second equivalent of triflic anhydride, giving
as a possible intermediate an iminiun salt that after work-up
1
characteristic signals in the H NMR spectrum, we observe
those corresponding to the double bond C=C and the methyl
group of the ester. The 13C NMR spectrum shows two quar-
tets with J = 323 Hz, indicating the presence of two different
CF3SO2 bonded to both nitrogen atoms, which concurs with
the mass spectrometry analysis. We can fully establish the
structure of 12c through X-ray diffraction analyses (Fig. 7).
These results confirm that the successive activation on the
pyrazine ring takes place in steps, the crucial step being the
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474
Can. J. Chem. Vol. 90, 2012
Scheme 5.
R2
O
R2
Tf
N
OMe
O
OMe
O
N
2
2
O
R2
O
1
3
3
R2
N
MeO
N
N
2
1) 2 equiv. Tf2O
R2
R2
Tf
R2
OTMS
OTMS
Tf
4
3
9a (20%)
9b (31%)
N
2) 2 equiv.
8a' (37%)
8b' (31%)
8
R2
N
2
3
OMe
O
1a: R2 = CH3
1b: R2 = -(CH2)5-
N
OH
R2
R2
Tf
10a
(22%)
10b (25%)
Fig. 4. ORTEP view of compound 9a. Thermal ellipsoids are at the 30% probability level.
leads to the hemiacetal G, which after hidrolysis is trans-
formed into the pyrazinone 12c.
the nucleophilic addition. Calculated Fukui indices reflect the
observed orientations upon the formation of the lactones
through nucleophilic addition of the nucleophiles employed.
Some suggested intermediates were trapped, which enabled
us to propose a reasonable mechanism.
Conclusions
In all cases it was possible to obtain the g-lactone through
a one-pot reaction. The first N-activation of the diazine takes
place on the nitrogen atom furthest from the substituent. This
behavior can be attributed to the steric effect of the activating
agent. The nucleophilic addition of the TMS–ketene acetal
over the pyrazinium ring strongly depends on the substitu-
ents. Electron-withdrawing groups thus favor the addition on
C5, even though strong donating groups such as methoxy
modify the regiochemistry to the C3-position. In the case of
the methyl group, we observe a loss of the regioselectivity of
Experimental section
Materials
Anhydrous solvents were obtained by distillation under an
inert atmosphere over sodium benzophenone for THF and
anhydrous CaCl2 for dichloromethane. Column chromatogra-
phy was performed using 70–230 mesh silica gel. All re-
agents and solvents were obtained from commercial suppliers
and used without further purification. All compounds were
Published by NRC Research Press

Garduño-Alva et al.
475
Fig. 5. ORTEP view of 10b. Thermal ellipsoids are at the 30% probability level.
Scheme 6.
Scheme 7.
-OTf
N
OMe
O
N
OMe
N
OMe
R2
MeO
N
N
1) 1 equiv.Tf2O
2) 2 equiv.1b
+
N
O SiMe3
N
OH
N
Tf
R2
OSiMe3
Tf
Tf O Tf
7
10b
(98%)
-Me3SiOTf
Scheme 8.
Tf
N
-OTf
Tf O Tf
Tf
N
OMe
O
O
MeO
N
N
1) Tf2O
2)
O
OMe
SiMe3
OMe
N
+
SiMe3
N
OMe
N
O
O
OMe
N
OMe
OTMS
Tf
Tf
N
O
N
O
R2
1c
R2
R2
R2
8
11c
12c
Tf
Tf
F
Table 2. Products obtained using 2-methoxy-
pyrazine.
-Me3SiOTf
H2O
Starting material
Yield (%)
Tf
OMe
O
N
OMe
O
Tf2O
Entry (equiv)
1c
(equiv)
N
11c
76
12c
—
O
R2
1
2
1
2
1.1
2
N
OH
R2
N
R2
38
48
Tf
R2
Tf
10
8'
all data are expressed in wavenumbers (cm–1). Melting
points were obtained on a Melt-Temp II apparatus and are
uncorrected. NMR spectra were measured with a JEOL
Eclipse +300 and a Varian Inova (500 MHz), using CDCl3
and acetonitrile-D3 as solvents. Chemical shifts are in ppm
(d) relative to TMS. The MS-FAB and MS-EI spectra were
obtained on a JEOL SX 102A. The ketene acetals 1a–1c
were prepared according to published methods.13
Fig. 6. Fukui f+ indices for the parent compounds. Hydrogen atoms
are omitted for clarity; only indexes for the ring-member atoms are
displayed.
Computational details
All computations were carried out using the Gaussian09
suite of programs.14 Natural population analyses were performed
with the NBO 3.1 program included in the aforementioned
characterized by IR spectra, recorded on a PerkinElmer
283B or 1420 spectrophotometer using the KBr technique;
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476
Can. J. Chem. Vol. 90, 2012
Fig. 7. ORTEP view of 12c. Thermal ellipsoids are at the 0% probability level.
Scheme 9.
Tf O Tf
N
N
N
OMe
OMe
MeO
-OTf
N
OMe
O
-Me3SiOTf
O
+
N
SiMe3
N
OMe
Tf
Tf
Tf O Tf
11c
1c
-TfO-
Tf
Tf
N
Tf
OH
OMe
N
O
N
+
OMe
O
O
O
H2O
-MeOH
N
OMe
N
OMe
N
OMe
Tf
Tf
Tf
12c
H
G
Gaussian09 suite. The Berny optimization algorithm was
employed in optimizing the geometry of all compounds. Fu-
kui indices were later calculated for all the molecules fol-
lowing the regular procedure,15 by using the results in the
Natural Population Analysis (NPA).16
compounds 4a, 7a, 9a, 10b, and 12c were mounted on a
glass fiber at room temperature. The crystals were then
placed on a Bruker SMART APEX CCD diffractometer,
equipped with Mo Ka radiation; decay was negligible in all
cases. Data collections for all crystals were obtained at room
temperature. Details of crystallographic data collected on
compounds 4a, 7a, 9a, 10b, and 12c are provided in Table 3.
Systematic absences and intensity statistics were used in
space group determination. The structures were solved using
direct methods.17 Anisotropic structure refinements were
Structure determination by X-ray crystallography
Suitable X-ray quality 4a, 7a, 9a, 10b, and 12c crystals
were grown through slow evaporation of a dichloromethane–
n-hexane solvent mixture at –5 °C. Single white crystals of
Published by NRC Research Press

Table 3. Crystal data and structure refinement parameters of 4a, 7a, 9a, 10b, and 12c.
Compound
Parameter
4a
7a
9a
10b
12c
Formula
C18H16F6N2O6S2
534.45
0.42×0.40×0.26
Colorless block
Monoclinic
P21/c
C13H16ClF3N2O5S
404.798
0.39×0.28×0.24
Colorless block
Triclinic
C14H19F3N2O6S
400.37
0.39×0.19×0.14
Colorless block
Monoclinic
P21/n
C13H17F3N2O5S
370.35
0.50×0.25×0.13
Colorless prism
Monoclinic
P21/c
C14H16F6N2O7S2
502.41
0.37×0.36×0.13
Colorless prism
Triclinic
MW (g mol–1)
Crystal size (mm)
Color
Crystalline system
Space group
Cell parameters
a (Å)
b (Å)
c (Å)
P-1
P-1
15.180(1)
11.218(1)
14.197(1)
90
107.859(1)
90
11.171(2)
11.550(2)
15.926(2)
97.247(2)
103.735(2)
110.879(2)
1814(1)
8.294(1)
7.654(1)
28.814(4)
90
93.174(2)
90
11.923(1)
7.894(1)
17.451(2)
90
95.063(2)
90
7.678(1)
9.173(1)
16.308(2)
75.703(2)
89.535(2)
66.402(2)
1014.5(2)
2
a (°)
b (°)
g (°)
V (Å3)
2301.0(3)
4
1826.3(5)
4
1636.1(3)
4
Z
4
Dcalcd (Mg m–3)
Reflections collected / Rs
Ind. reflections, Rint
Data/parameters
Final R, wR2[I > 2s(I)]
R1, wR2 (all data)
GoF on F2
1.543
1.482
1.456
1.504
1.645
18466 / 0.0267
4215, 0.0321
4215/309
0.0487, 0.1211
0.0636, 0.1313
1.031
24689 / 0.0254
6633, 0.0273
6633/551
0.0480, 0.1147
0.0637, 0.1237
1.024
14037 / 0.0393
3321, 0.0419
3321/240
0.0668, 0.1581
0.0877, 0.1694
1.054
12725 / 0.0217
2995, 0.0259
2995/257
0.0400, 0.1031
0.0470, 0.1087
1.028
13897 / 0.0228
3687, 0.0247
3687/337
0.0423, 0.1084
0.0511, 0.1144
1.026

478
Can. J. Chem. Vol. 90, 2012
achieved using full-matrix least-squares techniques on all
non-hydrogen atoms. All hydrogen atoms — except H2 in
compound 10b — were placed in idealized positions, based
on hybridization, with isotropic thermal parameters fixed at
1.2 or 1.5 times the value of the Ueq of the parent carbon
atom. Structure solutions and refinements were performed us-
ing SHELXTL v 6.10 (see the Supplementary data).18
133.8 (C3), 119 (q, CF3, J = 322 Hz), 119 (q, CF3, J =
320 Hz), 109.7 (CN), 103.0 (C2), 85.9 (C6), 68.6 (C5), 43.9
(C7), 24.3 (C9), 20.4 (C10). MS (EI+, 70 eV) m/z (%): 457
(50) M+, 324 (100) [M – 133]+. HR-MS(FAB+) calcd for
C11H9F6N3O6S2: 456.9837; found: 456.9845.
6’-Cyano-2’-oxo-4',7'-bis(trifluoromethanesulfonyl)spiro
[cyclohexane-1,3'-2',3',3a',4',7',7a'-hexahydrofuro[2,3-b]
pyrazine] (2b)
2-Benzylidene pyrazine (4) was prepared according to a
modification of the reported method19 as follows: In a
150 mL two-neck round-bottom flask fitted with a magnetic
stirrer and reflux condenser, 1 equiv of potassium tert-bu-
toxide (0.56 g, 5.5 mmol) was placed in 30 mL of anhydrous
THF under nitrogen. After that, 1 equiv of 2-methylpyrazine
(0.5 mL, 5.5 mmol) was added and the mixture was refluxed.
Then, a solution of 1 equiv of benzaldehyde (0.6 mL,
5.5 mmol) in 20 mL of anhydrous THF was slowly added.
The reaction mixture was refluxed for 24 h. Finally, 30 mL
of brine was added and the product extracted with CH2Cl2
(2 × 50 mL). The combined organic layers were dried with
anhydrous Na2SO4, and the solvent was removed in vacuo.
The product was purified by neutral alumina chromatogra-
phy. Elution with hexane – ethyl acetate (98:2). (C12H10N2,
M = 261 g/mol, white solid, mp 116–120 °C (0.68 g,
C14H13F6N3O6S2 (M = 497 g/mol) was prepared starting
from pyrazine 2-carbonitrile (0.3 mL, 3.35 mmol), trifluoro-
methanesulfonic anhydride (1.2 mL, 6.7 mmol), and 1b
(1.8 mL, 6.7 mmol) and was obtained as a white solid, mp
138 °C (0.60 g, 1.21 mmol, 36%). IR n (cm–1): 2240 (CN),
1
1798 (C=O lactone). H NMR (300 MHz, acetonitrile-D3) d:
7.60 (s, 1H, H3), 6.61 (d, 1H, H6, J = 8 Hz), 5.14 (d, 1H,
H5, J = 8 Hz), 2.00–1.20 (m, 10H, Hcyclohexyl). 13C NMR
(75 MHz, acetonitrile-D3) d: 173.8 (C=O lactone), 135.9
(C3), 119 (q, CF3, J = 322 Hz), 119 (q, CF3, J = 320 Hz),
110.4 (CN), 106.0 (C2), 87.7 (C6), 71.3 (C5), 46.4 (C7),
34.7, 30.1, 24.8 21.4, 21.0 (Ccyclohexyl). MS (EI+, 70 eV) m/z
(%): 497 (50) M+, 364 (100) [M– 133]+. HR-MS (FAB+)
calcd for C14H14F6N3O6S2: 498.0228; found: 498.0228.
1
3.74mmol,68%).IRn(cm–1):3031(=CH–),1630(–C=N–). H
Methyl 3,3-dimethyl-2-oxo-4,7-bis
NMR (300 MHz, CDCl3) d: 8.64 (s, 1H, H5), 8.54 (s, 1H,
H3), 8.40 (s, 1H, H6), 7.75 (d, 1H, H7 J = 16 Hz), 7.61–
7.33 (m, 5H, H arom.), 7.16 (d, 1H, H8 J = 16 Hz). 13C
NMR (75 MHz, CDCl3) d: 151.3 (C2), 144.5 (C6) 143.8
(C3), 142.8 (C5), 136.0 (C9), 135.2 (C8), 129.0 (C11),
128.9 (C12), 127.4 (C10) 124.0 (C7). MS (EI+, 70 eV) m/z
(%): 182 (10) [M+].
(trifluoromethanesulfonyl)-2,3,3a,4,7,7a-hexahydrofuro[2,3-
b]pyrazine-6-carboxylate (3a)
C12H12F6N2O8S2 (M = 490 g/mol) was prepared starting
from methyl 2-pyrazine carboxylate (0.3g, 2.17 mmol), tri-
fluoromethanesulfonic anhydride (0.73 mL, 4.34 mmol), and
1a (1.00 mL, 4.34 mmol) and was obtained as a white solid,
mp 176 °C (0.94 g, 1.91 mmol, 89%). IR n (cm–1): 2991,
2946, 2870 (CH, CH3), 1808 (C=O ester), 1747 (C=O lac-
tone), 1410 years 1227 (SO2), 1142 (CF3). 1H NMR
(400 MHz, CDCl3) d: 7.51 (s, 1H, H3), 6.59 (d, 1H, H6,
J = 8 Hz), 4.83 (d, 1H, H5, J = 8 Hz), 3.75 (s, 3H, H13),
1.35 (s, 3H, H9), 1.29 (s, 3H, H10).13C NMR (100 MHz,
CDCl3) d: 175.3 (C=O lactone), 159.6 (C=O ester), 131.3
(C3), 120.9 (C2), 119.2 (q, CF3, J = 321 Hz), 87.7 (C6),
70.5 (C5), 53.1 (C13), 44.7 (C7), 25.5 (Me), 21.2 (Me). MS
(IE+, 70 eV) m/z (%): 590 (15) M+, 357 (100) [M – 133]+.
General procedure
Synthesis of lactones
In a 100 mL flask fitted with a magnetic stirrer, the corre-
sponding monosubstituted pyrazine was dissolved in 30 mL
of anhydrous dichloromethane and placed under nitrogen
at –30 °C. After that 2 equiv of triflic anhydride were added,
showing the formation of a precipitate, and subsequently
2 equiv of bis(trimethylsilyl)–ketene acetal 1 was added. The
reaction mixture was allowed to reach room temperature and
left stirring for 12 h. Finally, 40 mL of distilled water was
added, the organic phase was recovered, and then dried with
anhydrous sodium sulfate and filtered. The solvent was
evaporated under vacuum. The products were purified using
silica gel column chromatography, eluting with hexanes –
ethyl acetate (98:2).
Methyl 2'-oxo-4',7'-bis(trifluoromethanesulfonyl)spiro
[cyclohexane-1,3'-2',3',3a',4',7',7a'-hexahydrofuro[2,3-b]
pyrazine]-6'-carboxylate (3b)
C15H16F6N2O8S2 (M = 530 g/mol) was prepared starting
from methyl 2-pyrazine carboxylate (0.3 g, 2.17 mmol), tri-
fluoromethanesulfonic anhydride (0.73 mL, 4.34 mmol), and
1b (1.18 mL, 4.34 mmol) and was obtained as a white solid,
mp 150 °C (0.97 g, 1.82 mmol, 84%). IR n (cm–1): 2959,
2941, 2870 (CH, CH2, CH3), 1798 (C=O ester), 1743 (C=O
lactone), 1410 and 1225 (SO2), 1150 (CF3). 1H NMR
(300 MHz, CDCl3) d: 7.56 (s, 1H, H3), 6.56 (d, 1H, H6,
J = 8 Hz), 4.84 (d, 1H, H5, J = 8 Hz), 3.87 (s, 3H, H17),
2.15–1.28 (m, 10H, Hcyclohexyl). 13C NMR (75 MHz, CDCl3)
d: 173.3 (C=O lactone), 159.7 (C=O ester), 131.7 (C3),
122.7 (C2), 119.4 (q, CF3, J = 322 Hz), 119.3 (q, CF3, J =
322 Hz), 88.1 (C6), 72.5 (C5), 53.3 (C17), 46.2 (C7), 35.3,
29.8, 24.4, 20.9, 20.5 (Ccyclohexyl). MS (IE+, 70 eV) m/z (%):
530 (30) M+, 109 (100) [M – 421]+. HR-MS (FAB+) calcd
for C15H16F6N2O8S2: 530.0252; found: 530.0252.
6-Cyano-3,3-dimethyl-2-oxo-4,7-bis
(trifluoromethanesulfonyl)-2,3,3a,4,7,7a-hexahydrofuro[2,3-
b]pyrazine (2a)
C11H9F6N3O6S2 (M = 457 g/mol) was prepared starting
from pyrazine 2-carbonitrile (0.3 mL, 3.35 mmol), trifluoro-
methanesulfonic anhydride (1.2 mL, 6.7 mmol), and 1a
(1.6 mL, 6.7 mmol) and was obtained as a white solid, mp
173 °C (0.92 g, 2.01 mmol, 60%). IR n (cm–1): 2238 (CN),
1
1795 (C=O lactone). H NMR (300 MHz, acetonitrile-D3) d:
7.58 (s, 1H, H3), 6.69 (d, 1H, H6, J = 8.2 Hz), 5.12 (d, 1H,
H5, J = 8.2 Hz), 1.39 (s, 3H, H9), 1.36 (s, 3H, H10). 13C
NMR (75 MHz, acetonitrile-D3) d: 174.4 (C=O lactone),
Published by NRC Research Press

Garduño-Alva et al.
479
6-(2-Phenyl-1E-ethenyl)-3,3-dimethyl-2-oxo-4,7-bis
(trifluoromethanesulfonyl)-2,3,3a,4,7,7a-hexahydrofuro[2,3-
b]pyrazine (4a)
6'-Chloro-2'-oxo-4'-7'-bis(trifluoromethanesulfonyl)spiro
[cyclohexane-1,3'-2',3',3a',4',7',7a'-hexahydrofuro[2,3-b]
pyrazine] (5b)
C18H16F6N2O6S2 (M = 534 g/mol) was prepared starting
from 2-benzylidene pyrazine (0.4 g, 2.2 mmol), trifluorometh-
anesulfonic anhydride (0.7 mL, 4.4 mmol), and 1a (1 mL,
4.4 mmol) and was obtained as a white solid, mp 160 °C
(0.51 g, 0.95 mmol, 43%). IR n (cm–1): 3105, 3085 (=C–H),
2985, 2920 (CH, CH2), 1785 (C=O lactone), 1411 and
1230 (SO2), 1017 (CF3). 1H NMR (400 MHz, CDCl3) d:
7.45–7.30 (m, 5H, CHarom.) 6.75 (d, 1H, H13), 6.71 (s,
1H, H3) 6.60 (d,1H, H6, J = 8 Hz), 6.50 (d, 1H, H14),
4.85 (d, 1H, H5, J = 8 Hz), 1.42(d, 6H, H9 and H10). 13C
NMR (100 MHz, CDCl3) d: 175.6 (C=O lactone), 135.4
(C14), 134.8 (C15), 131.9 (C2), 129.5, 128.9, 127.2
(Carom.), 120.9 (q, CF3 J = 320 Hz), 118.1 (C13), 117.7
(q, CF3 J = 320 Hz), 116.9 (C3), 87.8 (C6), 70.9 (C5),
44.4 (C7), 26.0, 21.0 (C9 and C10). MS (IE+, 70 eV) m/z
(%): 534 (5)[M], 401(15) [M – 133]+, 268 (15) [M – 133]+,
C13H13ClF6N2O6S2 (M = 506 g/mol) was prepared starting
from 2-chloropyrazine (0.3 mL, 3.4 mmol), trifluoromethane-
sulfonic anhydride (1.15 mL, 6.8 mmol), and 1b (1.85 mL,
6.8 mmol) and was obtained as a white solid, mp 142 °C
(0.505 g, 0.99 mmol, 37%). IR n (cm–1): 2947, 2861 (CH,
CH2), 1801 (C=O lactone), 1426 and 1229 (SO2), 1147
(CF3). 1H NMR (300 MHz, CDCl3) d: 6.66 (s, 1H, H3),
6.58 (d, 1H, H6, J = 7.4 Hz), 4.83 (d, 1H, H5, J = 7.4 Hz),
2.11–1.37 (m, 10H, Hcyclohexyl). 13C NMR (75 MHz, CDCl3)
d: 173.4 (C=O lactone), 126.56 (C2), 120.4 (C3), 119.7 (q,
CF3, J = 324 Hz), 118.8 (q, CF3, J = 321 Hz), 89.8 (C6),
72.6 (C5), 45.9 (C7), 35.6, 29.6, 24.5, 21.0, 20.4 (Ccyclohexyl).
MS (EI+, 70 eV) m/z (%): 506 (30) M+, 373 (100) [M – 133]+.
HR-MS (FAB+) calcd for C13H13ClF6N2O6S2: 505.9808;
found: 505.9812.
145 (100)[M
–
123]. HR-MS (FAB+) calcd for
7-Isobutyroyl-6-chloro-3,3-dimethyl-2-oxo-4-
trifluoromethanesulfonyl-2,3,3a,4,7,7a-hexahydrofuro[2,3-
C18H16F6N2O6S2: 534.0354; found: 534.0357.
b]pyrazine (7a)
6'(2-Phenyl-1E-ethenyl)-3',3'-dimethyl-2'-oxo-4',7'-bis
(trifluoromethanesulfonyl)spiro[cyclohexane-1,3'-
2',3',3a',4',7',7a'-hexahydrofuro[2,3-b]pyrazine (4b)
C13H16F3N2O5S (M = 404 g/mol) was prepared starting
from 2-chloropyrazine (0.3 mL, 3.4 mmol), trifluoromethane-
sulfonic anhydride (1.58 mL, 6.8 mmol), and 1a (1.85 mL,
6.8 mmol) and was obtained as a white solid, mp 140 °C
(0.567 g, 1.09 mmol, 32%). IR n (cm–1): 1791 (C=O lac-
C21H20F6N2O6S2 (M = 574 g/mol) was prepared starting
from 2-benzylidene pyrazine (0.4 g, 2.2 mmol), trifluorometh-
anesulfonic anhydride (0.7 mL, 4.4 mmol), and 1b (1.2 mL,
4.4 mmol) and was obtained as a white solid, mp 186 °C
(0.90 g, 1.56 mmol, 71%). IR n (cm–1): 3095, 3061 (=C–H),
2936, 2868 (CH, CH2), 1788 (C=O lactone), 1408 and
1212 (SO2), 1011 (CF3). 1H NMR (400 MHz, CDCl3) d:
7.43–7.33 (m, 5H, Harom.), 6.95 (d,1H, H16, J = 16 Hz),
6.65 (s,1H,H3), 6.56 (d, 1H, H6, J = 8 Hz), 6.49 (d,1H,
H17, J = 16 Hz), 4.84 (d, 1H, H5, J = 8 Hz), 1.90–1.60
(m, 10H, Hcyclohexyl). 13C NMR (100 MHz, CDCl3) d: 173.8
(C=O, lactone), 135.9 (C17), 134.7 (C18), 129.6 (C2),
128.9, 127.3, 127.2 (Carom.), 119.6 (q, CF3, J = 322 Hz),
119.1 (q, CF3, J = 322 Hz), 117.9 (C16), 116.7 (C3), 87.9
(C6), 72.3 (C5), 45.9 (C7), 35.5, 29.5, 24.5, 21.0, 20.4
(Ccyclohexyl). MS (IE+, 70 eV) m/z (%): 574 (40) [M+], 441
1
tone), 1705 (C=O ester). H NMR (300 MHz, CDCl3) d:
7.23 (d, 1H, H6, J = 7 Hz), 6.53 (s, 1H, H3), 4.65 (d, 1H,
H5, J = 7 Hz), 2.91 (h, 1H, H13, J = 6.5 Hz), 1.40 (s, 3H,
H9), 1.38 (s, 3H, H10), 1.28 (d, 3H, H14, J = 6.5 Hz), 1.17
(d, 3H, H15, J = 6.5 Hz). 13C NMR (75 MHz, CDCl3) d:
176.1 (C=O lactone), 175.9 (C=O amide), 127.4 (C2), 119.7
(q, CF3, J = 324 Hz), 118.8 (q, CF3, J = 321 Hz), 117.3
(C3), 85.6 (C6), 71.7 (C5), 44.9 (C7), 34.5 (C13), 25.8
(C9), 20.9 (C10), 19.4 (C14), 19.3 (C15). MS (EI+, 70 eV)
m/z (%): 404 (2) M+, 71 (100) [M – 333]+. HR-MS (FAB+)
calcd for C13H17ClF3N2O5S: 405.0499; found: 405.0495.
6'-Chloro-7'-cyclohexanecarbonyl-4'-
trifluoromethanesulfonyl-spiro[cyclohexane-1,3'-
(100) [M+ – 133], 308 (40) [M+ – 133], 181 (40)[M+
–
2',3',3a',4',7',7a'-hexahydrofuro[2,3-b]pyrazine] (7b)
C19H24ClF3N2O5S (M = 484 g/mol) was prepared starting
from 2-chloropyrazine (0.3 mL, 3.4 mmol), trifluoromethane-
sulfonic anhydride (1.15 mL, 6.8 mmol), and 1b (1.85 mL,
6.8 mmol) and was obtained as a white solid, mp 146 °C
(0.505 g, 0.844 mmol, 25%). IR n (cm–1): 1780 (C=O lac-
127]. HR-MS (FAB+) C21H20F6N2O6S2: 574.0667; found:
574.0659.
6-Chloro-3,3-dimethyl-2-oxo-4,7-bis
(trifluoromethanesulfonyl)-2,3,3a,4,7,7a-hexahydrofuro[2,3-
1
b]pyrazine (5a)
tone), 1703 (C=O ester). H NMR (300 MHz, CDCl3) d:
C10H9ClF6N2O6S2 (M = 466 g/mol) was prepared starting
from 2-chloropyrazine (0.3 mL, 3.4 mmol), trifluoromethane-
sulfonic anhydride (1.15 mL, 6.8 mmol), and 1a (1.58 mL,
6.8 mmol) and was obtained as a white solid, mp 144 °C
(0.35 g, 0.749 mmol, 22%). IR n (cm–1): 1795 (C=O lac-
7.09 (s, 1H, H3), 6.40 (d, 1H, H6, J = 8 Hz), 4.57 (d, 1H,
H5, J = 8 Hz), 2.44 (m, 1H, H16), 1.97–1.18 (m, 20H,
Hcyclohexyl). 13C NMR (75 MHz, CDCl3) d: 174.7 (C=O lac-
tone), 174.5 (C=O ester), 129.4 (C2), 117.4 (C3), 85.7
(C6), 72.7 (C5), 46.2 (C16), 44.7 (C7), 35.3, 29.6, 29.4,
25.4, 25.3, 25.2, 24.6, 21.1, 20.4 (Ccyclohexyl). MS (EI+,
70 eV) m/z (%): (IE, 70 eV) m/z (%): 484 (2) M+, 83
1
tone). H NMR (300 MHz, CDCl3) d: 6.71 (s, 1H, H3), 6.60
(d, 1H, H6, J = 7.5 Hz), 4.82 (d, 1H, H5, J = 7.5 Hz), 1.42
(s, 3H, H9), 1.40 (s, 3H, H10). 13C NMR (75 MHz, CDCl3)
d: 175.0 (C=O lactone), 124.6 (C2), 119.5 (q, CF3, J =
322 Hz), 118.7 (q, CF3, J = 319 Hz), 89.5 (C6), 71.3 (C5),
44.2 (C7), 25.9 (C9), 20.8 (C10). MS (EI+, 70 eV) m/z (%):
466 (8) M+, 69 (100) [M – 397]+. HR-MS (FAB+) calcd for
C10H9ClF6N2O6S2: 465.9495; found: 465.9491.
(100) [M
–
401]+. HR-MS (FAB+) calcd for
C19H25ClF3N2O5S: 485.1125; found: 485.1127.
3,3,6-Trimethyl-2-oxo-4,7-bis(trifluoromethanesulfonyl)-
2,3,3a,4,7,7a-hexahydrofuro[2,3-b]pyrazine (6a)
C11H12F6N2O6S2 (M = 446 g/mol) was prepared starting
Published by NRC Research Press

480
Can. J. Chem. Vol. 90, 2012
from 2-methylpyrazine (0.3 mL, 3.27 mmol), trifluorometh-
anesulfonic anhydride (1.1 mL, 6.6 mmol), and 1a
(1.53 mL, 6.6 mmol) and was obtained as a white solid, mp
104 °C (1.39 g, 3.13 mmol, 95%). IR n (cm–1): 1792 (C=O
170.2 (C=O lactone), 119.0 (q, CF3, J = 320 Hz), 112.9 and
107.4 (C5 and C6), 104.9 (C2), 64.3 (C3), 52.6 (C16), 47.3
(C7), 32.7, 27.7, 24.5, 21.0, 20.5 (Ccyclohexyl). MS (EI+,
70 eV) m/z (%): 502 (15) M+, 153 (100) [M – 349]+. HR-
MS (FAB+) calcd for C14H16F6N2O7S2: 502.0330; found:
502.0300.
1
lactone). H NMR (300 MHz, CDCl3) d: 6.53 (d, 1H, H6,
J = 7.6 Hz), 6.35 (s, 1H, H3), 4.79 (d, 1H, H5, J = 7.6 Hz),
2.09 (s, 3H, H13), 1.39 (s, 3H, H9), 1.37 (s, 3H, H10). 13C
NMR (75 MHz, CDCl3) d: 175.7 (C=O lactone), 131.5 (C3),
119.7 (q, CF3, J = 322 Hz), 118.9 (q, CF3, J = 320 Hz),
117.7 (C2), 88.0 (C6), 70.5 (C5), 44.2 (C7), 25.9 (C9), 20.7
(C10), 17.7 (C13). MS (EI+, 70 eV) m/z (%): 446 (30) M+,
7-Isobutyroyl-7a-methoxy-3,3-dimethyl-2-oxo-4-
trifluoromethanesulfonyl-2,3,3a,4,7,7a-hexahydrofuro[2,3-
b]pyrazine (9a)
C14H19F3N2O6S (M = 400 g/mol) was prepared starting
from 2-methoxypyrazine (0.3 mL, 3.1 mmol), trifluorometh-
anesulfonic anhydride (1.07 mL, 6.2 mmol), and 1a (1.4 mL,
6.2 mmol) and was obtained as a white solid, mp 170 °C
(0.238 g, 0.595 mmol, 20%). IR n (cm–1): 1813 (C=O lac-
313 (100) [M
C11H12F6N2O6S2: 446.0041; found: 446.0042.
–
133]+. HR-MS (FAB+) calcd for
6'-Methyl-2'-oxo-4',7'-bis(trifluoromethanesulfonyl)spiro
[cyclohexane-1,3'-2',3',3a',4',7',7a'-hexahydrofuro[2,3-b]
pyrazine] (6b)
C14H16F6N2O6S2 (M = 486 g/mol) was prepared starting
from 2-methylpyrazine (0.3 mL, 3.27 mmol), trifluorometh-
anesulfonic anhydride (1.1 mL, 6.6 mmol), and 1b (1.8 mL,
6.6 mmol) and was obtained as a white solid, mp 138 °C
(0.87 g, 1.79 mmol, 55%). IR n (cm–1): 1746 (C=O lactone).
1H NMR (300 MHz, CDCl3) d: 6.49 (d, 1H, H6, J = 7.6 Hz),
6.29 (s, 1H, H3), 4.81 (d, 1H, H5, J = 7.6 Hz), 2.09 (s, 3H,
C16), 2.00–1.61 (m, 10H, Hcyclohexyl). 13C NMR (75 MHz,
CDCl3) d: 174.0 (C=O lactone), 133.5 (C3), 119.8 (q, CF3,
J = 323 Hz), 118.9 (q, CF3, J = 320 Hz), 117.9 (C2), 88.3
(C6), 71.6 (C5), 45.9 (C7), 35.4, 29.3, 24.5, 21.0, 20.3
(Ccyclohexyl), 17.7 (C16). MS (EI+, 70 eV) m/z (%): 486 (20)
M+, 353 (100) [M – 133]+. HR-MS (FAB+) calcd for
C14H16F6N2O6S2: 486.0354; found: 486.0350.
1
tone), 1682 (C=O amide). H NMR (300 MHz, CDCl3) d:
6.97 (d, 1H, H5, J = 7 Hz), 6.06 (d, 1H, H6, J = 7 Hz),
4.58 (s, 1H, H3), 3.48 (s, 3H, H16), 3.19 (h, 1H, H13, J =
7 Hz), 1.46 (s, 3H, H9), 1.21 (d, 3H, H14, J = 7 Hz), 1.20
(d, 3H, H15, J = 7 Hz), 1.19 (s, 3H, H10). 13C NMR
(75 MHz, CDCl3) d: 175.5 (C=O lactone), 173.3 (C=O
amide), 119.0 (q, CF3, J = 323 Hz), 112.4 (C6), 104.8 (C2),
104.1 (C5), 61.2 (C3), 51.8 (C16), 45.1 (C7), 34.4 (C13),
24.2 (C9), 20.4 (C10), 19.9 (C14), 19.3 (C15). MS (EI+,
70 eV) m/z (%): 400 (5) M+, 243 (100) [M – 157]+. HR-MS
(FAB+) calcd for C14H19F3N2O6S: 400.0916; found:
400.0924.
7'-Cyclohexanecarbonyl-7a'-methoxy-4'-
trifluoromethanesulfonyl-spiro[cyclohexane-1,3'-
2',3',3a',4',7',7a'-hexahydrofuro[2,3-b]pyrazine] (9b)
C20H27F3N2O6S (M = 480 g/mol) was prepared starting
from 2-methoxypyrazine (0.3 mL, 3.1 mmol), trifluorometh-
anesulfonic anhydride (1.07 mL, 6.2 mmol), and 1b (1.7 mL,
6.2 mmol) and was obtained as a white solid, mp 144 °C
(0.465 g, 0.97 mmol, 31%). IR n (cm–1): 1799 (C=O lac-
7a-Methoxy-3,3-dimethyl-2-oxo-4,7-bis
(trifluoromethanesulfonyl)-2,3,3a,4,7,7a-hexahydrofuro[2,3-
b]pyrazine (8a')
C11H12F6N2O7S2 (M = 462 g/mol) was prepared starting
from 2-methoxypyrazine (0.3 mL, 3.1 mmol), trifluorometh-
anesulfonic anhydride (1.07 mL, 6.2 mmol), and 1a (1.4 mL,
6.2 mmol) and was obtained as a white solid, mp 114 °C
(0.535 g, 1.16 mmol, 37%). IR n (cm–1): 1817 (C=O lac-
1
tone), 1698 (C=O amide). H NMR (300 MHz, CDCl3) d:
6.98 (d, 1H, H6, J = 7 Hz), 6.06 (d, 1H, H5, J = 7 Hz),
4.46 (s, 1H, H3), 3.47 (s, 3H, H22), 2.88 (m, 1H, H16),
1.82–1.25 (m, 20H, Hcyclohexyl). 13C NMR (75 MHz, CDCl3)
d: 175.2 (C=O lactone), 171.4 (C=O amide), 119.0 (q, CF3,
J = 320 Hz), 113.0 and 104.3 (C5 and C6), 104.3 (C2), 61.9
(C3), 51.6 (C22), 47.3 (C7), 44.9 (C16), 32.5, 30.1, 29.9,
27.8, 25.9, 25.7, 25.6, 24.5, 21.2, 20.9 (Ccyclohexyl). MS (IE+,
70 eV) m/z (%): 480 (3) M+, 243 (100) [M – 237]+. HR-MS
(FAB+) calcd for C20H27F3N2O6S: 480.1542; found:
480.1545.
1
tone). H NMR (300 MHz, CDCl3) d: 6.26 (dd, 2H, H5 and
H6, J = 6.8 Hz), 4.53 (s, 1H, H3), 3.52 (s, 3H, H13), 1.48
(s, 3H, H9), 1.23 (s, 3H, H10). 13C NMR (75 MHz, CDCl3)
d: 172.4 (C=O lactone), 119.8 (q, CF3, J = 323 Hz), 119.4
(q, CF3, J = 322 Hz), 111.9 and 107.2 (C5 and C6), 105.1
(C2), 63.8 (C3), 52.8 (C13), 45.0 (C7), 24.5 (C9), 18.9
(C10). MS (EI+, 70 eV) m/z (%): 462 (80) M+, 301 (100)
[M – 161]+. HR-MS (FAB+) calcd for C11H12F6N2O7S2:
461.9990; found: 461.9977.
2-(3-Methoxy-1-trifluoromethanesulfonyl-1,2-
dihydropyrazin-2-yl)-2-methylpropionic acid (10a)
7a'-Methoxy-4',7'-bis(trifluoromethanesulfonyl)spiro
[cyclohexane-1,3'-2',3',3a',4',7',7a'-hexahydrofuro[2,3-b]
pyrazine] (8b')
C10H13F3N2O5S (M = 330 g/mol) was prepared starting
from 2-methoxypyrazine (0.3 mL, 3.1 mmol), trifluorometh-
anesulfonic anhydride (1.4 mL, 6.2 mmol), and 1a (1.7 mL,
6.2 mmol) and was obtained as a white solid, mp(dec) 128 °C
(0.23 g, 0.696 mmol, 22%). IR n (cm–1): 3200–3000 (OH),
C14H16F6N2O7S2 (M = 502 g/mol) was prepared starting
from 2-methoxypyrazine (0.3 mL, 3.1 mmol), trifluorometh-
anesulfonic anhydride (1.07 mL, 6.2 mmol), and 1b (1.7 mL,
6.2 mmol) and was obtained as a white solid, mp 114 °C
(0.485 g, 0.967 mmol, 31%). IR n (cm–1): 1812 (C=O lac-
1
1726 (C=O carboxylic acid). H NMR (300 MHz, CDCl3) d:
10.70 (s, 1H, OH), 6.36 (s, 1H, H5), 6.17 (s, 1H, H6), 4.79
(s, 1H, H3), 3.82 (s, 3H, H12), 1.34 (s, 3H, H9), 1.24 (s, 3H,
H10). 13C NMR (75 MHz, CDCl3) d: 179.8 (C=O carboxylic
acid), 158.0 (C2), 126.4 (C5), 120.0 (q, CF3, J = 323 Hz),
110.6 (C6), 60.1 (C3), 54.4 (C12), 47.2 (C7), 22.9 (C9),
1
tone). H NMR (300 MHz, CDCl3) d: 6.25 (dd, 2H, H5 and
H6, J = 7 Hz), 4.40 (s, 1H, H3), 3.51 (s, 3H, H16), 2.19–
1.25 (m, 10H, Hcyclohexyl). 13C NMR (75 MHz, CDCl3) d:
Published by NRC Research Press

Garduño-Alva et al.
481
20.7 (C10). MS (IE+, 70 eV) m/z (%): 330 (5) M+, 243 (100)
[M – 87]+. HR-MS (FAB+) calcd for C10H14F3N2O5S:
331.0576; found: 331.0574.
804200 (9a), CCDC 804201 (10b), and CCDC 804202
(12c) contain the X-ray data in CIF format for this manu-
script. These data can be obtained, free of charge, via http://
www.ccdc.cam.ac.uk/products/csd/request (Or from the Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033; or e-mail:
deposit@ccdc.cam.ac.uk).
1-(3-Methoxy-1-trifluoromethanesulfonyl-1,2-
dihydropyrazin-2-yl)-cyclohexane-1-carboxylic acid (10b)
C13H17F3N2O5S (M = 370 g/mol) was prepared starting
from 2-methoxypyrazine (0.3 mL, 3.1 mmol), trifluorometh-
anesulfonic anhydride (0.52 mL, 3.1 mmol), and 1b (1.7 mL,
6.2 mmol) and was obtained as a white solid, mp(dec) 120 °C
(0.282 g, 0.762 mmol, 25%). IR n (cm–1): 3100–3000 (OH),
Acknowledgments
The authors would like to acknowledge the technical assis-
tance provided by Rocio Patiño, Luis Velasco, and Javier
Perez. They would also like to thank the Dirección General
de Asuntos del Personal Académico - Programa de Apoyos a
1
1726 (C=O carboxylic acid). H NMR (300 MHz, CDCl3) d:
10.08 (s, 1H, OH), 6.39 (s, 1H, H5), 6.15 (s, 1H, H6), 4.54
(s, 1H, H3), 3.86 (s, 3H, H15), 2.19–1.62 (m, 10H, Hcyclohexyl).
Proyectos de Investigación
e
Innovación Tecnológica
13C NMR (75 MHz, CDCl3) d: 178.9 (C=O carboxylic
acid), 157.7 (C2), 126.9 (C5), 119.9 (q, CF3, J = 324 Hz),
110.6 (C6), 60.9 (C3), 54.5 C15), 51.9 (C7), 31.6, 30.2,
30.2, 25.0, 22.9 (Ccyclohexyl). MS (EI+, 70 eV) m/z (%): 370
(5) M+, 243 (100) [M – 127]+. HR-MS (FAB+) calcd for
C13H18F3N2O5S: 371.0889; found: 371.0574.
(DGAPA-PAPIT) IN201211 and the Consejo Nacional de
Cienca y Technología (CONACYT) 127796 projects and
CONACYT for the Ph.D. grant extended to A.G.-A.
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C14H19F3N2O5S (M = 384 g/mol) was prepared starting
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1
2.35 mmol, 76%). IR n (cm–1): 1734 (C=O ester). H NMR
(300 MHz, CDCl3) d: 6.37 (d, 1H, H5, J = 5 Hz), 6.09 (d,
1H, H6, J = 5 Hz), 4.48 (s, 1H, H3), 3.84 (s, 3H, H14),
3.67 (s, 3H, H16), 2.20–1.12 (m, 10H, Hcyclohexyl). 13C NMR
(75 MHz, CDCl3) d: 172.7 (C=O ester), 157.8 (C2), 126.4,
110.0 (C5, C6), 119.9 (q, CF3, J = 323 Hz), 61.0 (C3), 54.4
(C14), 52.4 C16), 51.8 (C7), 31.8, 30.4, 25.1, 23.1, 23.0
(Ccyclohexyl). MS (EI+, 70 eV) m/z (%): 384 (4) M+, 243
(100) [M – 141]. HR-MS (FAB+) calcd for C14H20F3N2O5S:
385.1045; found: 385.1050.
Methyl 1-(3-oxo-1,4-bis(trifluoromethanesulfonyl)-1,2,3,4-
tetrahydropyrazin-2-yl)-cyclohexane-1-carboxylate (12c)
C14H16F6N2O7S2 (M = 502 g/mol) was prepared starting
from 2-methoxypyrazine (0.3 mL, 3.1 mmol), trifluorometh-
anesulfonic anhydride (1.07 mL, 6.2 mmol), and 1c
(1.33 mL, 6.2 mmol) and was obtained as a white solid mp
108 °C (0.75 g, 1.49 mmol, 96%). IR n (cm–1): 1764 (C=O
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ester). H NMR (300 MHz, CDCl3) d: 6.57 (d, 1H, H5, J =
5.7 Hz), 6.23 (d, 1H, H6, J = 5.7 Hz), 4.57 (s, 1H, H3), 3.71
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502.0303; found: 502.0299.
Supplementary data
Supplementary data (proton and carbon labels used in
NMR characterization and complete tables with Fukui indi-
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