Unimolecular rearrangements of ketene-O,O-acetals and fragmentations occurring in the gas phase

Article abstract of DOI:10.1002/jms.1915

Gas phase skeletal rearrangements of regioisomeric 3-cyano-2-methoxy-3a- alkylfuro[2,3-b]- and [3,2-b]indoles were evidenced by product ions [M - 32]^+?, consistent with loss of methanol, on electron ionization in their mass spectra. The rearranged products occurring in gas phase were demonstrated to have elemental composition and fragmentation properties identical to those of authentic samples of 2-indolyl cyanomalonates. Isotopic labeling experiments support the formation mechanism of the [M - 32] ^+? ion. Additional thermal gas-phase reaction products were characterized by comparison with an authentic sample. Copyright

Full text of DOI:10.1002/jms.1915

Research Article
Received: 14 February 2011
Accepted: 15 March 2011
Published online in Wiley Online Library: 2011
(wileyonlinelibrary.com) DOI 10.1002/jms.1915
Unimolecular rearrangements
of ketene-O,O-acetals and fragmentations
occurring in the gas phase
a,b
Martha S. Morales-Ríos,a,b∗ Perla Y. Lopez-Camacho,
´
a,b
a
a
´
Carlos O. Jacobo-Cabral, Nadia A. Perez-Rojas, Joel J. Trujillo-Serrato,
Eleuterio Burgueno-Tapia, Oscar R. Suarez-Castillo
c
d
˜
´
and Pedro Joseph-Nathana,b
Gas phase skeletal rearrangements of regioisomeric 3-cyano-2-methoxy-3a-alkylfuro[2,3-b]- and [3,2-b]indoles were evidenced
by product ions [M−32]+•, consistent with loss of methanol, on electron ionization in their mass spectra. The rearranged
products occurring in gas phase were demonstrated to have elemental composition and fragmentation properties identical to
those of authentic samples of 2-indolyl cyanomalonates. Isotopic labeling experiments support the formation mechanism of
the [M−32]+• ion. Additional thermal gas-phase reaction products were characterized by comparison with an authentic sample.
c
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Keywords: ketene acetal; gas phase rearrangement; thermal decarbomethoxylation; indole; EI-ion trap
INTRODUCTION
EXPERIMENTAL
General
Unimolecular isomerizations involving sigmatropic ketene acetal
rearrangements occurring in condensed phase has been a topic
for extensive research, since they have found considerable
applications in the complex natural and unnatural product
synthesis.[1] However, contrary to the widely recognized [3,3]-
sigmatropic rearrangement of ketene acetals, the [1,3] process
is a rare event witnessed previously in few cases.[2–7] In a
recent article, we evidenced that regioisomeric α-cyano ketene-
O,O-acetals 1 and 2 can interconvert through the kinetically
significantintermediatescycloprop[b]indoles3viaconcerted[1,3]-
sigmatropic shifts,[8,9] with the ultimate quantitative formation of
thermodynamic 2-indolyl cyanomalonate isomers 4, arising from
a ring opening of 3 via [1,2]-hydrogen shift (Scheme 1).
Melting point was measured on a Fisher-Johns apparatus and
is uncorrected. NMR experiments were performed using Varian
Mercury spectrometers working at 300 and 75.4 MHz for 1H
and 13C, respectively, in acetone-d6 as a solvent. Chemical
shifts are reported in ppm downfield from tetramethylsilane.
IR spectrum was measured with a Perkin-Elmer 16 FPC FT infrared
spectrophotometer. All solvents and reagents were purchased
in the reagent grade quality and were used without further
purification, except as noted. Tetrahydrofuran (THF) and Et2O
weredistilledfromsodium/benzophenoneketylimmediatelyprior
to use. Solvents for chromatography were purified by distillation.
ColumnchromatographywasperformedonSilicaGel60(230–400
Kinetic studies determined in condensed phase also showed
that the ketene acetal rearrangement of 1a (R = t-Bu) to
4a required 25 kcal mol−1, whereas the rearrangement of the
sterically less demanding 1b (R = i-Pr) to 4b took place at
a lower barrier (23 kcal mol−1). These low activation barriers,
together with the fact that compounds 1a, 2a and 4a provided
similar mass spectral patterns during electron ionization-mass
spectrometry (EI-MS) analysis, allowed us to assume that in
the case of 1a and 2a, gas-phase rearrangements occurred.
In this respect, it has been known for several decades that EI
mass spectra of organic molecules could yield peaks arising by
sigmatropicrearrangementsduringfragmentionformation,[10–14]
generating a specific subject on studies in the gas phase by mass
spectrometry.[15–18] Herein, we report our work on gas-phase
skeletal rearrangements of ketene-O,O-acetals 1 and 2 (Table 1)
by EI-MS, to provide insight into the fundamental unimolecular
reactivity of such ketene-O,O-acetals from the point of view of
gas-phase ion chemistry.
∗
Correspondence to: Martha S. Morales-Ríos, Departamento de Química and
´
Programa dePosgrado en Farmacología, Centro deInvestigacion y deEstudios
´
´
Avanzados del Instituto Politecnico Nacional, Apartado 14-740, Mexico, D. F.,
07000 Mexico.
E-mail: smorales@cinvestav.mx
´
Departamento de Química Centro de Investigacion y de Estudios Avanzados
a
´
´
delInstitutoPolitecnicoNacional,Apartado14-740,Mexico,D.F.,07000Mexico
´
Programa dePosgrado en Farmacología, Centro deInvestigacion y deEstudios
b
´
´
Avanzados del Instituto Politecnico Nacional, Apartado 14-740, Mexico, D. F.,
07000 Mexico
´ ´
Departamento de Química Organica, Escuela Nacional de Ciencias Biologicas,
c
´
´
Instituto Politecnico Nacional, Prolongacion de Carpio y Plan de Ayala, Col.
´
´
Santo Tomas, Mexico, D. F., 11340 Mexico
´
´
´
d
Area Academica de Química, Universidad Autonoma del Estado de Hidalgo,
Mineral de la Reforma, Hidalgo, 42184 Mexico
c
J. Mass. Spectrom. 2011, 46, 489–495
Copyright ꢀ 2011 John Wiley & Sons, Ltd.

M. S. Morales-Ríos et al.
Scheme 1. Unimolecular rearrangements of kinetic intermediate cycloprop[b]indoles 3a–e.
Table 1. Characteristic m/z values (relative intensity, %) in EI-MS spectraa of 4a–e
Ion assignment
4a
4b
4c
4d
4e
M+•
328 (10)
296 (7)
281 (76)
272 (34)
240 (100)
269 (15)
237 (10)
–
314 (12)
282 (38)
267 (100)
–
362 (11)
330 (41)
315 (2)
–
300 (8)
268 (100)
253 (50)
–
286 (11)
254 (100)
239 (6)
–
[M–MeOH]+•
[M–MeOH–Me]+
[M–C4H8]+•
[M–C4H8 –MeOH]+•
[M–CO2Me]+
[M–MeOH–Me–CO2]+
[M–MeCO2CHCN]+
–
–
–
–
255 (40)
223 (36)
–
303 (22)
271 (21)
264 (100)
241 (91)
209 (27)
–
227 (50)
195 (12)
–
a By direct insertion probe at 280 ◦C.
mesh) from Aldrich. Ketene acetals 1a, 1b, 2a and 2b and 2-
indolyl cyanomalonates 4a–e were synthesized as described[8]
from the corresponding methyl 3-cyano-3a-alkyl-2-oxo-2,3,3a,8a-
tetrahydro-8H-furo[2,3-b]indole-8-carboxylates.[8,19,20]
(ddd, J = 8.2, 1.4, 0.7 Hz, 1H), 7.36 (td, J = 7.2, 1.3 Hz, 1H), 7.29 (td,
J = 7.2, 1.3 Hz, 1H), 4.53 (s, 2H), 4.15 (s, 3H), 1.67 (s, 9H); 13C NMR
(75 MHz, acetone–d6) δ 153.6, 137.8, 131.3, 130.0, 126.1, 125.2,
124.0 (2 C), 119.3, 117.1, 55.2, 32.5 (2 C), 19.1; IR (CHCl3): νmax 3010,
2259, 1734 cm−1; MS (EI) m/z 270 [M]+• (26), 255 (100), 228 (33),
211 (7), 195 (23); HRMS ESI/APCI m/z for C16H18N2O2 + H, calcd:
271.1447, found: 271.1445.
Preparation of deuterated compounds
Mixtures of mainly doubly (CHD2) and triply (CD3) deuterated
ketene acetal 1a-d2/d3 and 2-indolyl cyanomalonates 4a–e-d2/d3
were prepared in quantitative yields following the procedure
described in detail earlier for the protio-analogues,[8] using an
excess of freshly prepared ethereal solution of a mixture of
diazomethane-d1/d2.[21] The mixtures of deuterated compounds
1a-dn and 4a–e-dn were characterized by MS and 1H NMR
comparison with the corresponding protio-analogues 1a and
4a–e.[8]
GC-MS/MS analysis
The GC-MS analyses were performed using an ion-trap Varian
Saturn 2000 spectrometer. The GC conditions were as follows: split
injection mode; column, WCOT-fused silica (30 m × 0.25 mm I.D.,
0.25-µm film thickness); injection port temperature, 220 ◦C; carrier
gas, helium; flow rate, 1.0 ml/min; oven temperature, initially
70 ◦C, increased to 250 ◦C at 30 ◦C/min. The MS conditions were
as follows: direct insertion probe and transfer line heater, 280 ◦C;
ion source temperature, 220 ◦C; electron impact ionization mode;
ionization energy, 70 eV; electron multiplier voltage, 1800 V. The
typical mass spectrum was recorded by averaging 1200 scans
from m/z 20 to 650 at a scan rate of 1 s/scan. For multistage
sequencing MS2 –MS4, the compounds were introduced by direct
insertion probe and the precursor ions were selected within an
isolation width of 2 u. Exact mass measurements for the ions of
interest were recorded on Jeol JMS-GCMate II instrument with
internal perfluorokerosene calibration or on an Agilent LCTOF
spectrometer at the UCR Mass Spectrometry Facility, University
of California, Riverside, with an error less than 4 ppm for all ions
discussed.
Methyl 3-tert-butyl-2-(cyanomethyl)-1H-indole-1-carboxylate(6a)
A solution of 4a (200 mg, 0.61 mmol) in DMSO (1.6 ml) was added
to a solution of NaCN in H2O (0.15 ml, 6.0 mg). The reaction
mixture was stirred at 80 ◦C for 4 h, then concentrated under
vacuum. A saturated aqueous solution of NaCl was added (15 ml),
and the mixture was extracted with EtOAc (3 × 25 ml). The
combined organic layers were dried over MgSO4, filtered and
concentrated under vacuum. The residue was purified by column
chromatography (2 : 3 CH2Cl2/hexane) to afford 6a (64 mg, 39%)
as a white solid: mp 102–104 ◦C, Rf = 0.56 (CH2Cl2); 1H NMR
(300 MHz, acetone–d6) δ 8.18 (ddd, J = 8.2, 1.4, 0.7 Hz, 1H), 7.99
c
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J. Mass. Spectrom. 2011, 46, 489–495

Gas phase rearrangement of ketene acetals
Figure 1. MS1 (left side) and MS2 (right side) spectra of 4a–e obtained by direct insertion probe at 280 ◦C.
RESULTS AND DISCUSSION
throughout the indole and benzyl rings can confer a high
stability to the m/z 264 fragment ion (Fig. 2). The accurate
mass measurements confirmed the composition of the fragment
of interest at m/z 272.0797 for 4a (C14H12N2O4+•, −0.4 ppm)
and at m/z 264.1025 for 4c (C17H14NO2+, 1.1 ppm). Besides
the dominant fragmentations discussed above, an interesting
alternative fragmentation pathway occurs for all the studied
compounds 4a–e which could be connected with the cleavage of
the N–C carbamate bond[22,23] to give the [M−59]+ ion (Table 1).
The elemental compositions of these ions were also confirmed
using accurate mass measurements, which afforded relative errors
within the range −0.4 to 1.6 ppm.
Identification of 2-indolyl cyanomalonates 4 by EI MS/MS
To distinguish the product ion spectra of rearranged 2-indolyl
cyanomalonates 4, generated in the gas phase by EI of isomeric
ketene-O,O-acetals 1 and 2, the chemical structures of authentic
4a–e were initially characterized by tandem mass spectrometry
(MS/MS). Figure 1 illustrates MS1 and MS2 spectra obtained from
4a–e. These spectra are very alike, exhibiting common peaks that
correspond to losses of 32, 15 and 44 Da. The accurate mass
measurement and the stepwise fragmentation MS2 –MS4 analysis
of 4a–e revealed that such losses involved the gradual elimination
ofMeOH,Me•,andCO2 (Table 1).Forthesetofcompoundsstudied,
such consecutive losses represent the dominant fragmentation
pathway, except for 4a and 4c. Thus, the spectrum of 4a
also exhibits a significant peak at m/z 272 attributed to the
elimination of isobutene from the molecular ion induced by
the first fragmentation stage (MS2 experiment). The following
cleavage results in the peak at m/z 240 (MS3) which corresponds
to a typical difference of 32 Da (methanol), the most intense
peak in the MS1 ionization process (Fig. 1). In the case of 4c, the
elimination of a cyanomalonate radical and hydrogen transfer
from the benzyl (CH2) group to C2 can be proposed for the ion
formation at m/z 264, the most intense peak in the MS1 ionization
process(Fig. 1).Thechargedelocalizationandresonanceoccurring
Characterization of [M−32]+• ion
Among the representative product ions of the whole set of
studied compounds 4a–e, we were especially interested in
the [M−32]+• ion as diagnostic evidence for rearrangements
of ketene-O,O-acetals 1 and 2 to 2-indolyl cyanomalonates 4. The
accurate mass measurements confirmed the composition of t+h•e
fragments [M–MeOH]+• at m/z 296.1161 for 4a (C17H16N2O3
,
2.0 ppm), at m/z 282.1005 for 4b (C16H14N2O3+•, −1.1 ppm), at
m/z 330.1005 for 4c (C20H14N2O3+•, 0.9 ppm), at m/z 268.0848
for 4d (C15H12N2O3+•, −3.0 ppm) and at m/z 254.0691 for 4e
(C14H10N2O3+•, −0.8 ppm). The first reaction step in the formation
c
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M. S. Morales-Ríos et al.
Figure 2. Main fragmentation pathways of 4a–e. (i) The basic fragmentation pattern of 4a–e. (ii) The specific fragmentation pattern of 4a (R = t-Bu).
(iii) The specific fragmentation pattern of 4c (R = Bn).
4c (m/z 282 and 330) is in the range of 38–41% and corresponds
to the base peak in the spectra of 4d and 4e (m/z 268 and 254;
Table 1). This behavior highlights the importance of the coplanar
arrangement between the ketenium ion and the indole system
allowing a number of resonance structures that confer a higher
stability to the [M−32]+• ion. The elimination of methanol is a
typical fragmentation process undergone by methyl esters.[24–26]
The reason for the lack of [M–MeOH–CO]+• product ions might
be that neither the neighboring electronegative cyano group nor
the heteroaromatic π-system serve as sites of localization of a
positive charge, while other decomposition directions related to
cleavages of the carbamate group are much more favored.
The elimination process of methanol was confirmed using
selectivelylabeled2-indolylcyanomalonates4a–ewithdeuterium
atoms attached to the methyl ester group of the cyanomalonate
moiety. Mixtures of mainly doubly (CO2CHD2) and triply (CO2CD3)
deuterated indoles 4a–e-d2/d3 were obtained by treatment
Scheme 2. The proposed formation mechanism of the [M−32]+• ion.
of 2-oxofuroindolines 5a–e with in situ prepared deuterated
diazomethane[27] to give H/D isotopomeric mixtures of 1a–e,
followed by rearrangement in DMSO solution (Fig. 3).[8,9] The
mechanism of the [M−32]+• ion is proposed to be initiated by
identity of obtained deuterated indoles 4a–e-dn including the
position and the extent of deuterium content were confirmed
on the basis of 1H NMR and EI-MS analyses of the [M]+• isotope
pattern.
Compound 4a-dn was subjected to the EI-MS/MS experiments.
Its MS1 spectra presented in Fig. 3 indicate that elimination of
isobutene from the molecular ion, following the dominant frag-
mentation pathway (Fig. 2, path ii), does not remove deuterium
atoms from the molecule (i.e. 330-d2 → 274-d2). However, deu-
terium is completely removed after elimination of the methanol
proton transfer from the methine carbon chain onto the methyl
estergroupviaacyclicfour-memberedtransitionstate(Scheme 2).
The elimination of a methanol molecule gives rise to the ketenium
ion, which potentially can be stabilized by charge delocalization
through the indole framework. Atthis respect, a notable difference
in the relative [M−32]+• ion abundance was observed as function
of the bonded C3 alkyl substituent. The intensity of the [M−32]+•
ion expressively grows up within the succession t-Bu < i-Pr, Bn
< Et, Me. Thus, whereas the loss of methanol is only of 7% for
4a (m/z 296), the relative intensity of [M−32]+• ion for 4b and
c
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Gas phase rearrangement of ketene acetals
Figure 4. Chromatographic ion traces obtained from GC-MS analyses of
puret-Bu-substitutedisomersa(1, 2and4, up)andi-Pr-substitutedisomers
b (1, 2 and 4, down).
Figure 3. Preparation of deuterated indoles 4a–e-dn and EI-MS1 spectra
of 4a–c-dn.
Scheme 3. Thermal formation of 6a–6e.
molecule (i.e. 274-d2 → 240), in good agreement with the pro-
posed model. On the other hand, analysis of the fragmentation
of 4c-dn indicates that elimination of the cyanomalonate radical
removes deuterium atoms from the molecule (i.e. 364-d2 → 264).
In addition, the MS2 experiments of compounds 4a–e-dn demon-
strated that in all cases loss of methanol eliminates deuterium
atoms from the molecule, whereas the fragment ions [M−59]+
produced by carbomethoxyl loss (Table 1) still retain the deu-
teriumcontent,evidencingthatthisfragmentationroutedefinitely
originates from the N–C carbamate bond cleavage. Thus, the
N- and C-carbomethoxy groups are highly diagnostic, yielding
specific and distinctive fragmentation reactions for compounds
4a– e.
patterns were compared to those of 4a or 4b. In the second case,
ion chromatograms were generated to look for retention time
isomer differentiation.
The EI-MS of thermolabile compounds 1a, 1a-dn and 2a or
1b and 2b acquired in MS1 and MS2 modes revealed that the
fragmentionswereundistinguishablefromthosedescribedabove
for authentic indoles 4a, 4a-dn or 4b, respectively, evidencing that
rearrangements occur before ionization and cleavage processes.
With respect to GC-MS analyses of compounds 1a, 2a, 1b and
2b, the mass chromatograms (MCs) of the series of isomers a and
b were consistent sample-to-sample with a persistent small peak
∗
(indicated by in Fig. 4). The MC of isomers a show significant
differences that were traced to the presence of a couple of partially
coeluting peaks at 8.9 and at 9.0 min in 1a, whereas the MC of
2a is composed by a single peak with a shoulder at 9.0 min, while
that of 4a shows a single peak at 9.1 min. It is also worth noting
that the chromatographic peaks broaden significantly within the
succession 4a < 2a < 1a, with peak widths estimated at 50%
Rearrangement studies of ketene-O,O-acetals 1 and 2
Two procedures were used to analyze the rearrangements of
ketene-O,O-acetals 1 and 2. In the first case, the EI-MS of
compounds 1a, 2a, 1b and 2b admitted by direct insertion probe
were acquired under MS1 and MS2 modes, and the fragmentation
c
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M. S. Morales-Ríos et al.
height of 6, 12 and 15 s, respectively. As expected, variation REFERENCES
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in
Fig. 4). As expected, 6a was also produced during GC-MS
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Acknowledgement
Financial support by CONACYT Grant No. 81810 is gratefully
acknowledged.
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