Mechanistic elucidation of ketenimine-butynoate cycloaddition reaction: role of biradical intermediates in isotopomeric purity of benzyl (1,1a,6,6a-13C4)-6-methyl anthranilic ester

Article abstract of DOI:10.1016/j.tet.2010.03.035

Thermal Diels-Alder reaction of vinyl ketenimines with ¹³C-labeled 2-butynoate, efficiently prepared from ¹³C₄-acetoacetate via the enol triflate, rendered at 160 °C the corresponding methylanthranilic ester isotopomerically pure. However, when the reaction was run at 100 °C, 7% of isotope exchange between C^6a and C⁵ was observed. This result is explained through a base-like catalyzed isomerization of the alkyne to the corresponding allene. Combined DFT and coupled-cluster computations show the feasibility of this mechanistic proposal. Better agreement between DFT and coupled-cluster activation and reaction energies is observed for the meta-GGA MPWB1K functional as compared to previous B3LYP results.

Full text of DOI:10.1016/j.tet.2010.03.035

Tetrahedron 66 (2010) 3855–3860
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Mechanistic elucidation of ketenimine–butynoate cycloaddition reaction: role of
biradical intermediates in isotopomeric purity of benzyl (1,1a,6,6a-13C4)-6-methyl
anthranilic ester
a
,
b
,
a
,
,b
*
´
´ ´
Armando Navarro-Vazquez
, Jose-Lorenzo Alonso-Gomez b, Johan Lugtenburg a
,
a,b,
*
´
Marıa-Magdalena Cid
a
´
´
´
Departamento de Quımica Organica, Facultade de Quımica, Universidade de Vigo, Campus Lagoas-Marcosende, 36310 Vigo, Spain
b Leiden Institute of Chemistry, Gorlaeus Laboratory, Leiden University, P O Box 9502, 2300 RA Leiden, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Thermal Diels–Alder reaction of vinyl ketenimines with 13C-labeled 2-butynoate, efficiently prepared
from 13C4-acetoacetate via the enol triflate, rendered at 160 ꢀC the corresponding methylanthranilic ester
isotopomerically pure. However, when the reaction was run at 100 ꢀC, 7% of isotope exchange between
C6a and C5 was observed. This result is explained through a base-like catalyzed isomerization of the
alkyne to the corresponding allene. Combined DFT and coupled-cluster computations show the feasi-
bility of this mechanistic proposal. Better agreement between DFT and coupled-cluster activation and
reaction energies is observed for the meta-GGA MPWB1K functional as compared to previous B3LYP
results.
Article history:
Received 5 January 2010
Received in revised form 12 February 2010
Accepted 10 March 2010
Available online 15 March 2010
Keywords:
Ketenimines
Diels–Alder
Biradicals
Ó 2010 Elsevier Ltd. All rights reserved.
DFT
Isotopic labeling
1. Introduction
Consequently, the conjunction of labeled metabolites and NMR and
MS techniques would be a useful tool to provide a macroscopic
The study and analysis of all metabolites in an organism
(metabolome) have recently drawn great attention due to their
utility in the study of genes functions.1 Anthranilic acid (1a), first
dubbed as vitamin L1, is a metabolite found in the biosynthetic
pathway of tryptophan in plants, yeast, and bacteria. The enzyme
anthranilate synthase catalyzes the conversion of chorismate into
anthranilate in the first reaction leading from the common aro-
matic amino acid pathway toward the biosynthesis of tryptophan
and is subjected to feedback inhibition.2 However, little is known
about the mechanisms that couple regulation of secondary meta-
bolic pathways to the synthesis of primary metabolic precursors.3
In fact, labeled anthranilic acids were already used to clarify the
biosynthetic origin of sweet odorous 2-aminobenzaldehyde in
Hebeloma sacchariolens.4
view of the metabolome,8 and to elucidate the mechanisms of
action of such compounds.
As a part of our work in the preparation of 13C-labeled vitamins,
we envisioned that 13C4-6-methylantranilic ester 2 could be
a suitable precursor to prepare the aromatic core of tetralabeled a-
tocopherol, the most important fat-soluble antioxidant in tissues
and also an essential nutritional supplement (Fig. 1).9
Moreover, several anthranilate derivatives, including the food
flavor 6-methylanthranilate (1b), have shown interesting biological
activities, i.e., anti-inflammatory,5 anti-proliferative,6 and herbi-
cidal,7 although the mode of action is not fully understood.
Figure 1. Anthranilic acid derivatives.
We have reported the preparation of benzyl (1,1a,6,6a-13C4)-6-
methylanthranilate (2) through a Diels–Alder reaction between
vinyl ketenimine 3 and benzyl 2,3-butadienoate. Interestingly, we
observed by 1H and 13C NMR spectroscopy that the product of the
reaction suffered partial 13C isotope exchange between position 5
* Corresponding authors. Tel.: þ34 986813563; fax: þ34 986812262; e-mail
addresses: armando.navarro@uvigo.es (A. Navarro-Va´zquez), mcid@uvigo.es (M.-M.
Cid).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.035

´
A. Navarro-Vazquez et al. / Tetrahedron 66 (2010) 3855–3860
3856
and the methyl group at position 6.10 The scrambling of 13C-label
was evident by carrying out the reactions with isotopically labeled
reagents. This exchange was explained through the reversible for-
mation of a cyclobutane intermediate that strongly supported
a stepwise cyclization mechanism. Generally, it is difficult to prove
the existence of a stepwise pathway in Diels–Alder reactions, par-
ticularly when biradical intermediates are involved, since evidence
for such biradical mechanism arises mainly from the loss of ste-
reochemical integrity. However, complete stereospecificity does
not necessary mean a concerted mechanism as stereochemistry
retention can arise from a very fast coupling of biradical in-
termediates. Most of the information on these biradical pathways
comes from ab initio computations, which in general agree that the
archetypal butadiene/ethylene Diels–Alder reaction takes place
CO Bn
*
*
*
*
2
OTf
*
O
*
O
*
O
*
NaH, Tf2O
Et2O, 93%
Et3N
THF, 77%
OBn
OBn
*
*
*
*
5
6
4
i
NH
NH
Pr3Si
i
i
i
Pr3Si
CO2Bn
*
Pr3Si
CO2Bn
*
.
NSiPr3
3
*
*
*
+
*
*
CH3
CH3
toluene, 160 º-C
*
7b
7a
NH2
NH2
CO2Bn
*
CO2Bn
KF, HCl
69%
*
*
*
*
+
*
*
through
a concerted transition state of synchronous nature,
CH3
CH3
*
whereas a stepwise biradical mechanism lies between 2.3 and
7.7 kcal/mol over the transition state (TS) for a concerted reaction.11
Note, however, that this difference is not so high and appropriate
structural modifications could make both mechanisms competitive.
In our previous synthesis we observed a 91:9 ratio between both
anthranilate isotopomers, a fact that can hamper further metabolic
routes investigations. In this way, we present here a novel synthesis
based on a ketenimine–alkyne Diels–Alder cycloaddition to pre-
pare isotopomerically purer (1,1a,6,6a)-13C4-6-methylanthranilate
2, along with a computational study of ketenimine–alkyne and
ketenimine–allene cycloadditions by means of combined DFT and
coupled-cluster computations.
2b
2
a
b
c
NaH, Tf2O, Et2O, 93%; Et3N, THF, 77%; toluene, 160 ºC; KF, HCl, 69%.
Scheme 2. Synthesis of benzylanthranilate 2.
reaction of benzyl 2,3-butadienoate, allene 8,10 product 2b was still
observed in the reaction of alkyne 4. As it is shown in Table 1, the
ratio between 2/2b was dependent on the temperature and on the
ketenimine 3/alkyne 4 ratio.
H
H
H
*
* *
•
*
CO2Bn
8
2. Results and discussion
Table 1
Reaction conditions for 3þ4/2þ2b
The here presented synthesis of anthranilate 2 involved a Diels–
Alder reaction between ketenimine 3 and benzyl (1,2,3,4-13C4)-
butynoate (4) (Scheme 1). Although 2 with three labeled positions
would be sufficient for most of the biochemical studies, we decided
to prepare the tetralabeled analogue because ethyl (1,2,3,4-13C4)-
acetoacetate is commercially available at reasonable prices and
could work as a precursor to compound 4.
Entry
3 (mol %)
T (ꢀC)
2/2ba
Yieldb (%)
1
2
3
4
5
6
7
110
70
100
140
140
160
160
160
160
93:7
97:3
93:7
93:7
99:1
99:1
99:1
45
25c
51
140
120
150
160
200
27d
40c
52
69
a
Ratio measured by 1H NMR integration.
Isolated yields.
Alkyne 4 was recovered.
Allene 8 was recovered.
b
c
i
NSiPr3
.
NH2
CO Bn
*
*
*
*
2
d
CO2Bn
*
*
*
i
Pr3Si
+
*
CH3
The data summarized in Table 1 show that when the Diels–Alder
2
3
4
reaction between ketenimine 3 and alkyne 4 was run at 100 ꢀC 7%
of isotope labeling exchange was observed. The highest isotopomer
ratio 2/2b (99:1) was obtained at 160 ꢀC and at least 150% excess of
ketenimine 3 was necessary due to its inherent thermal instability.
Higher excesses of 3 led to higher reaction yields.
Scheme 1. Retrosynthetic analysis of methylanthranilate 2.
Ethyl (1,2,3,4-13C4)-acetoacetate was first converted into the
corresponding benzyl ester 5 through a transesterification with
benzyl alcohol12 in order to make it more manageable (Scheme 2).
The conversion of the acetoacetate into the corresponding inner
alkyne 4 turned out to be a difficult task and deprotonation at the
less hindered allylic position gave rise to the allene instead. In-
spired by a method described for the decarboxylative elimination of
enoltriflates,13 we successfully prepared the desired alkyne through
base elimination of the corresponding enoltriflate 6. Thus, treat-
ment of 5 with NaH in Et2O followed by addition of triflic anhydride
and subsequent elimination of trifluoromethanesulfate with Et3N
in THF at 80 ꢀC, gave benzyl (1,2,3,4-13C4)-but-2-ynoate (4) in high
yield with total incorporation of 13C-label at each position. Kete-
nimine 3 was efficiently prepared from crotononitrile by reaction
with LDA and triisopropylsilyl chloride following a previously de-
scribed procedure.14
As we have already reported, a reversible [2þ2] cycloaddition
between allene 8 and ketenimine 3 is responsible for the observed
labeling exchange and, as this is not possible for the alkyne, the now
observed exchange strongly indicates a previous alkyne–allene
isomerization. A solution containing only alkyne 4 was heated at
160 ꢀC over 48 h. 1H NMR monitoring did not show any evidence of
isomerization to allene. This suggests the presence of a base-
catalyzed alkyne–allene isomerization process or intramolecular
rearrangements of reaction intermediates. In addition, the labeling
exchange decreases with higher reaction temperature and keteni-
mine excess. This fact suggests that isomerization is a slow process as
compared to cycloaddition and if enough ketenimine is present in
thereactionmixture thealkyne cleanlyundergoes the[4þ2] process.
In order to gain more insight into this type of processes, we have
examined both concerted and stepwise reaction pathways for the
cycloaddition reaction between butynal, 4c,15 and vinyl ketenimine,
3c (Scheme 3a). Our previous B3LYP studies10 showed that in the
Then, Diels–Alder reaction of alkyne 4 with bis(triisopropyl)-
ketenimine 3 rendered intermediates 7a/7b, that after tautomeriza-
tion and silyl groups deprotection rendered 13C-methylanthranilate
2/2b in 52–69% yield. Surprisingly, as in the case of the Diels–Alder

´
A. Navarro-Vazquez et al. / Tetrahedron 66 (2010) 3855–3860
3857
NH
NH
·
a)
·
NH
O
O
O
NH
O
O
NH
·
11
17
15
+
NH
O
9
4c
3c
13
NH
NH
·
b)
NH
O
·
O
O
O
H
NH
O
NH
·
H
18
12
16
+
·
H
NH
O
10
8c
3c
14
Scheme 3. Comparison of mechanisms for cycloaddition reactions of alkyne 4 (a) and allene 8 (b).
cycloaddition reaction between ketenimine 3c15 and allene 8c15
a biradical pathway, initiated by the formation of the bond be-
tween allene-C3 and ketenimine-C4, is energetically feasible. In fact,
MPWB1K computations place the transition state for the biradical
formation, 16, 2.1 kcal/mol over the transition state for the con-
certed process, 14, lending support to the existence of the stepwise
pathway (Scheme 3b).
As it is shown in Figure 2, the alkyne cycloaddition reaction
shows a higher barrier for the concerted pathway compared to the
allene cycloaddition (43.5 vs 37.8 kcal/mol, MPWB1K). Computa-
tions indicate that the stepwise and concerted pathways are en-
ergetically closer for the alkyne (43.5 vs 44.0 kcal/mol at MPWB1K),
than for the allene case, even though intermediate biradical 11 is
much higher in energy than the corresponding allyl biradical 12
(Fig. 2). Note that both biradicals, 11 and 12, are more stabilized in
the DFT UBS computations than in the single point BD(T) results.
According to the less stable character of biradical intermediate 11 as
compared to 12, the MPWB1K geometry for the concerted transi-
tion structure 13 shows that the reaction of alkyne 4c is more
synchronous than that of allene 8c, with C5–C6 and C1–C2 forming
bond distances of 2.084 and 2.379 Å vs 1.981 and 2.907 Å in 14,
respectively.
It is worth to note the good agreement between the MPWB1K
DFT and the coupled-cluster computations for both activation and,
particularly, reaction energies, although caveat should be taken in
computation of energies of intermediates with very strong biradical
character. This fact promotes the meta-GGA hybrid MPWB1K, in
conjunction with an UBS scheme, as a better choice than standard
B3LYP functional for studies on cycloaddition reactions involving
not only closed-shell concerted transition states but also open-shell
singlet biradical intermediates and biradicaloid transition states
(see Scheme 3 and Table 2). Further computational studies should
NH
·
NH
·
NH
O
NH
O
NH
O
O
O
NH
·
15
16
13
14
17
NH
O
O
O
O
NH
·
11
37.8
H
H
18
+
+
43.5
36.1
·
44.0
39.8
38.9
24.4
H
8c
3c
4c
18.3
·
NH
O
NH
NH
O
O
12
10
9
Figure 2. Comparative energy profile for the cycloaddition reaction of 3c with 4c or 8c.

´
A. Navarro-Vazquez et al. / Tetrahedron 66 (2010) 3855–3860
3858
Table 2
Free energies, DG423.15 K (kcal/mol), for computed species
Species
13
15
11
17
9
D
D
Ga,c
Ga,d
43.5
41.2
44.0
42.6
36.1
44.2
38.9
42.9
ꢁ51.6
ꢁ53.3
Species
14
16
12
18
10
19
20
21
D
D
D
Gb,c
Gb,e
Gb,d
37.8
38.9
36.5
39.8
37.9
38.7
18.3
22.1
25.8
24.4
29.3
25.4
ꢁ38.0
ꢁ14.9
ꢁ3.7
28.1
31.5
27.2
27.3
30.6
26.7
ꢁ25.4
ꢁ42.4
ꢁ12.8
a
Relative to 3cþ4c.
Relative to 3cþ8c.
MPWB1K/6-311þG**
b
c
.
d
e
BD(T)/cc-pVDZ//MPWB1K/6-311þG**
.
B3LYP/6-31þG with MPWB1K/6-311þG** thermochemical contributions.
*
help to better evaluate the performance of meta-GGA functionals
for this kind of cycloadditions.
Scheme 5. Plausible mechanism for the formation of allene 8 from alkyne 4 (via bir-
adical 11).
BD(T)//MPWB1K computations have been also performed for
the alternative [2þ2] cycloaddition reaction, responsible for isotope
exchange, between allene 8c and ketenimine 3c. Computations put
the transition state 20 for [2þ2] biradical collapse higher in energy
than the alternative [4þ2] TS 18 being the BD(T) predicted gap
(1.8 kcal/mol) small enough to be compatible with the experi-
mental observation of label scrambling (Scheme 4).
a base-catalyzed process, either caused by ketenimine itself or by
traces of amine-like side products generated in the reaction
medium.
3. Conclusions
We have developed an efficient synthetic procedure for fully
labeled butynoate 4 from commercially available ethyl 13C4-ace-
toacetate without any labeling loss or any isotope scrambling. Di-
els–Alder reaction of alkyne 4 and vinyl ketenimine 3 furnished
isotopomerically pure methylanthranilate 2. Temperatures higher
than 150 ꢀC are needed in order to avoid labeling scrambling. As an
explanation for this observed behavior, we propose a base-cata-
lyzed isomerization of the butynoate 4 to the more stable allene 8,
which is the ultimate responsible for the label-exchange. When
single point BD(T) computations were taken as reference, the
computational studies showed that DFT modeling of these re-
actions using a hybrid meta-GGA functional MPWB1K provides
a more consistent description as compared to B3LYP. This study
shows the value of 13C-labeled compounds combined with com-
putational methods in revealing hidden mechanistic details.
4. Experimental section
4.1. General
Scheme 4. Stepwise [2þ2] cycloaddition.
It should be noted the much better agreement of MPWB1K
computed energies for cyclization products 10 and 19 with the
BD(T) results as compared to the B3LYP computations, see Table 2,
which severely underestimated the exothermicity of the processes,
due to the deficient treatment of medium range correlation by this
functional.16
Although computations placed biradical 11 quite high in energy,
we still considered the possibility that the unexpected alkyne–
allene isomerization could be caused by a series of rearrangements
between biradical intermediates present during a stepwise [4þ2]
process. A possible mechanistic pathway is the conversion of the
biradical 11 into the vinyl–allyl radical 22 through a [1,4]-hydrogen
shift. Subsequent [1,4]-H shift on this intermediate gives bisallyl
biradical 12, which dissociates to the corresponding allene 8 and
the starting ketenimine 3 (Scheme 5). A further Diels–Alder re-
action between allene 8 and ketenimine 3 would account for the
label-exchange, as we have already demonstrated.10
Reagents and solvents were purchased as reagent-grade and
used without further purification unless otherwise stated. Solvents
were dried according to published methods and distilled before
use. All reactions were performed in oven-dried or flame-dried
glassware under an inert atmosphere of Ar unless otherwise
stated. NMR spectra were recorded in
(400.13 MHz and 100.61 MHz for proton and carbon, respectively)
spectrometer at 298 K with residual solvent peaks as internal ref-
a Bruker AMX400
erence and the chemical shifts are reported in
d [ppm], coupling
constants J are given in Hz and the multiplicities expressed as fol-
lows: s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet.
Electronic impact ionization (EI) mass spectra were recorded on
a VG-Autospec M instrument.
4.2. Benzyl (1,2,3,4-13C4)-3-trifluoromethanesulfonyloxybut-
2-enoate (6)
However, the MPWB1K computed reaction barrier (DG423.15 K),
for the conversion of biradical 11 into 22 through [1,4]-H shift is as
high as 32.1 kcal/mol, clearly ruling out this possibility, as 11 has to
surmount a very low barrier (2.8 kcal/mol at MPWB1K) to collapse
to adduct 9. Consequently, alkyne isomerization is very probably
Benzyl (1,2,3,4-13C4)-acetoacetate (5)10 (196 mg, 1 mmol) in dry
Et2O (7 mL) was added to a prewashed suspension of NaH (60%)
(82 mg, 2.04 mmol) in Et2O (4 mL) at 0 ꢀC and stirred for 1.5 h.

´
A. Navarro-Vazquez et al. / Tetrahedron 66 (2010) 3855–3860
3859
Triflic anhydride (1.05 g, 3.67 mmol) was then added and the re-
action mixture was stirred for 1 h more. The mixture was allowed
to warm to 25 ꢀC and stirred for 1 h. Satd aq ammonium chloride
solution was added followed by extraction with CH2Cl2. The organic
fractions were washed with 1 M hydrochloric acid solution and
brine, dried (Na4SO4), and concentrated under reduced pressure.
The residue was purified by column chromatography (SiO2, Hex-
ane/EtOAc, 83:17) to render the enoltriflate 6 (302 mg, 93%). nmax
(film)/cmꢁ1 1684; dH (400 MHz, CDCl3, TMS) 2.16 (ddd, J¼4.8, 6.9,
130.6 Hz, 3H), 5.22 (d, J¼3.3 Hz, 2H), 5.80 (ddd, J¼2.5, 7.9, 164.8 Hz,
1H), 7.37 (s, 5H) ppm; dC (101 MHz, CDCl3, TMS) 20.90 (ddd, J¼5.2,
5.8, 51.2 Hz, CH3, C4), 66.75 (s, CH2), 112.3 (ddd, J¼5.8, 78.1, 85.1 Hz,
CH, C2), 118.3 (q, J¼319.7 Hz, CF3), 128.4 (s, 2ꢂCH), 128.6 (s, CH),
135.2 (d, J¼1.5 Hz, C), 155.7 (ddd, J¼1.5, 51.2, 85.1 Hz, C3), 162.0
(ddd, J¼1.5, 5.2, 78.1 Hz, C1) ppm; dF (376 MHz, CDCl3, TMS)
ꢁ74.6 ppm; HRMS (FAB) m/z 329.0482 (C813C4H12F3O5S requires
329.0492).
MPWB1K20 functional, which has previously shown good perfor-
mance in the determination of saddle-point geometries and acti-
vation energies, for modeling of reactions involving biradical
intermediates. Thus, geometry optimizations were carried out us-
ing this functional and the 6-311þG** basis set. Harmonic fre-
quencies were computed for all optimized species in order to
characterize stationary points and to compute thermal contribu-
tions to free energies, which were computed at 34.7 atm (1 M
standard state) and 423.15 K. Wavefunction stability check has been
performed for species with potential biradical character.21
Coupled-cluster BD(T) single point energy computations were
performed using the frozen core approximation where core orbitals
are excluded from cluster expansion and the cc-pVDZ22 basis set in
its spherical harmonics expression (5d). All computations were
done with the Gaussian03 package.23
Acknowledgements
4.3. Benzyl (1,2,3,4-13C4)-but-2-ynoate (4)
We thank CESGA for allocation of computer time and Xunta de
Galicia INCITE08PXIB383129PR for financial support. J.-L.A.-G
thanks Xunta de Galicia for a research contract under the Isidro
Parga Pondal program. A.N.-V thanks Xunta de Galicia and Spanish
Ministerio de Innovacion y Ciencia for research contracts under the
A solution of the triflate 6 (820 mg, 2.4 mmol) in Et2O (70 mL)
and Et3N (4.2 mL, 30 mmol) was stirred at 80 ꢀC for 24 h. The sol-
vent was evaporated and the residue was purified (SiO2, hexane/
EtOAc, 84:16) to give the pure but-2-ynoate 4 (330 mg, 77% yield).
nmax (film)/cmꢁ1 2157, 1664; dH (400 MHz, CDCl3, TMS) 2.03 (dddd,
J¼1.8, 4.6, 10.7, 132.8 Hz, 3H), 5.18 (d, J¼3.4 Hz, 2H), 7.38–7.33 (m,
5H); dC (101 MHz, CDCl3, TMS) 3.7 (ddd, J¼1.8, 11.2, 65.9 Hz, CH3),
67.3 (t, J¼1.8 Hz, CH2), 72.1 (ddd, J¼11.2, 127.7, 182.7 Hz, C), 86.0
(ddd, J¼20.8, 65.9,182.7 Hz, C),128.39 (CH),128.42 (CH),128.5 (CH),
135.1 (s, C),153.4 (ddd, J¼1.8, 20.8, 127.7 Hz, C); HRMS m/z 179.0886
(C713C4H11O2 requires 179.0893).
´
Isidro Parga Pondal and Ramon y Cajal programs respectively.
Supplementary data
Cartesian coordinates for all computed structures; tables with
absolute, ZPVE energies, imaginary frequencies and representation
of associated vectors; 1H and 13C NMR spectra of 2, 4, and 5. Sup-
plementary data associated with this article can be found in online
version, at doi:10.1016/j.tet.2010.03.035.
4.4. Benzyl (1,1a,6,6a-13C4)-2-amino-6-methyl-benzoate (2)
References and notes
In a Schlenk tube ketenimine 3 (170 mg, 0.82 mmol) was diluted
in toluene (0.2 mL) under argon atmosphere. To this solution,
butynoate 4 (45 mg, 0.25 mmol) was added and the mixture was
heated at 160 ꢀC for 24 h. After removal of the toluene under re-
duced pressure, the residue was taken up in MeOH (5.0 mL). Next,
KF (160 mg, 2.76 mmol) and a solution of concentrated HCl (0.3 mL,
3.6 mmol) were added and the mixture was refluxed for 2 h. Then,
water was added and the solution was neutralized with satd aq
NaHCO3 solution. The water layer was extracted with Et2O; the
combined organic layers were washed with brine, dried (Na2SO4),
and the solvent removed in under reduced pressure. The residue
was purified by column chromatography (SiO2, 100% CH2Cl2)
affording 2 as a light yellow oil (42 mg, 69%). nmax (film)/cmꢁ11646;
dH (400 MHz, CDCl3, TMS) 2.43 (ddd, J¼4.0, 5.9, 128.0 Hz, CH3), 5.13
(br s, 2H, NH2), 5.37 (d, J¼3.1 Hz, 2H, CH2), 6.53 (m, 2H, H3þH5), 7.08
(m, 1H, H4), 7.33–7.47 (m, 5H); dC (101 MHz, CDCl3, TMS) 23.2 (ddd,
J¼1.0, 2.1, 43.5 Hz, CH3, C6a), 66.5 (CH2), 113.8 (ddd, J¼1.7, 61.9,
74.5 Hz, C1), 114.6 (m, CH, C3), 120.4 (dd, J¼4.5, 58.5 Hz, CH, C5),
128.2 (CH), 128.4 (CH), 128.5 (CH), 132.0 (t, J¼5.4 Hz, CH, C4), 135.8
(d, J¼2.1 Hz, C), 140.2 (ddd, J¼2.1, 43.5, 61.9 Hz, C6), 149.2 (dt, J¼2.6,
64.4 Hz, C2), 168.9 (ddd, J¼1.0, 2.1, 74.5 Hz, C1a); MS (EIþ) m/z (%)
246 (Mþþ1, 0.1), 245 (Mþ, 0.7), 91 (100); HRMS m/z 245.1239
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4.5. Computational details
Since the mechanisms proposed here involve many open-shell
singlet biradical species, we follow a well-established17 technique,
which requires geometry optimization at the DFT level of theory
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´
A. Navarro-Vazquez et al. / Tetrahedron 66 (2010) 3855–3860
3860
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