Association of intramolecular furan Diels-Alder reaction and N-acyliminium alkylation for the synthesis of pentacyclic precursor of aromathecins

Article abstract of DOI:10.1055/s-0029-1218300

A new approach for the synthesis of isoindoloquinoline and aromathecin templates is presented. These were obtained in a few steps starting from inexpensive reagents by two different strategies. The key step for both sequences was the IMFDA reaction, leadi

Full text of DOI:10.1055/s-0029-1218300

3214
LETTER
Association of Intramolecular Furan Diels–Alder Reaction and N-Acylimin-
ium Alkylation for the Synthesis of Pentacyclic Precursor of Aromathecins
Synthesis of
P
r
e
ntacycli
é
c
Precurso
d
of
A
romath
é
ecins ric Pin, Sébastien Comesse, Adam Daïch*
Laboratoire de Chimie, URCOM, EA 3221, CNRS-INC3M FR3038, UFR des Sciences et Techniques, Université du Havre,
BP 540, 25 Rue Philipe Lebon, 76058 Le Havre Cedex, France
Fax +33(2)32744391; E-mail: adam.daich@univ-lehavre.fr
Received 29 May 2009
O
Abstract: A new approach for the synthesis of isoindoloquinoline
A
C
N
B
N
1a R = H: rosettacin
and aromathecin templates is presented. These were obtained in a
few steps starting from inexpensive reagents by two different strat-
egies. The key step for both sequences was the IMFDA reaction,
leading diastereoselectively to the formation of the unsaturated DE
ring system of the expected alkaloid skeletons.
D
1b R = Me: acuminatine
1c R = CH2OH: 22-hydroxyacuminatine
E
R
O
Key words: benzoindolizino[1,2-b]quinolinone, heterocycle, N-acyl-
iminium, a-amidoalkylation, Diels–Alder
2 Ar =
N
Ar
3 Ar =
O
Structures with the pentacyclic benzoindolizino[1,2-b]-
quinolinone nucleus such as in the alkaloids rosettacin
(1a), acuminatine (1b), and 22-hydroxyacuminatine (1c)
are scarce in literature. To date these are the only three ex-
amples that have been isolated (Figure 1). These systems
belong to the aromathecin family and are considered as
noncamptothecin topoisomerase-I inhibitors1 and have
been candidates for therapeutic development. In fact,
rosettacin (1a) and some analogues have been used2 as
camptothecin–luotonin A hybrids for binding to the topo-
I–DNA covalent binary complex. On the other hand 22-
hydroxyacuminatine (1c), isolated along with CPT from
C. accuminata in very low yield,3 has shown significant
cytotoxicity against murine leukaemia P-388 and KB cell
lines in vitro.4 The continuing interest surrounding these
unique subunits is aptly demonstrated by recent research
efforts for their construction5 and their biological evalua-
tion.6 In light of these reports, it seemed appropriate to de-
velop new synthetic methodology to obtain polycyclic
systems 2 and 3 (Figure 1) as valuable skeletons of these
alkaloids.
N
MeO2C
2, 3 our targets
Figure 1 Representative natural products containing pentacyclic
unit 1a–c and our scaffold targets 2 and 3
with the very popular intramolecular furan Diels–Alder
(IMFDA) reaction.8 While this cycloaddition has been
extensively exploited as the key step in the synthesis of
several synthetic and natural targets containing hexahy-
droindolinones,9 its use to obtain polyhydroisoquinolines
has not been extensively invistigated.10 Related work
based on a similar technique, but using ethylenic dipolaro-
philes and pyrone11 or oxazole12 nuclei as the diene, have
produced alkaloids belonging to the yohimbine and indolo-
pyridonaphthyridine families. In this context, we herein
disclose our exploratory results using this particular tech-
nique to provide polycyclic scaffolds 2 and 3 outlined in
Figure 1.
At the outset, we envisaged testing the feasibility of this
strategy in the isoindolinone series. For this purpose we
planned to employ key intermediate I for the construction
of the isoquinoline skeleton of product 2 (Scheme 1). The
required key I would be obtained from the N-acyliminium
In connection with our ongoing project aimed at the
synthesis of aromathecins,7 we became interested in the
exploration of N-acyliminium chemistry in association
O
O
O
ion N-acyliminium
chemistry
IMFDA
N
N
N
OAc
O
O
O
R1
R1
4
2
key I
Scheme 1 Retrosynthetic scheme leading to the tetracyclic target 2
SYNLETT 2009, No. 19, pp 3214–3218
x
x
.x
x
.2
0
0
9
Advanced online publication: 21.10.2009
DOI: 10.1055/s-0029-1218300; Art ID: D14109ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Pentacyclic Precursor of Aromathecins
3215
ion precursor 413 via the formation of the olefinic chain acids, AlCl3, BF3·OEt2, or Bi(OTf)3 were used in reflux-
and the subsequent introduction of a desired R1 group.
ing toluene, but only degradation of the reaction mixture
was observed with no recovery of starting material. Two
reasons can explain this lack of ability to react. Precursor
6 could be activated by the ester group. But more likely
the presence of the phenyl group at the b-position makes
the approach of the furan ring difficult due to steric hin-
drance. The problem with precursor 8 results, doubtless,
from a lack of activation of the olefin which has a LUMO
orbital energy too high for an IMFDA reaction with nor-
mal electron demand. We thus speculated that a terminal
electron-withdrawing group on an otherwise unsubstitut-
ed dienophilic double bond could decrease the energy of
the LUMO orbital and consequently facilitate the expect-
ed cycloaddition process.
Our study started with the synthesis of key intermediates
of type I (6 and 8 in Scheme 2 and 14 in Scheme 3) in or-
der to measure the impact of the dienophilic substituent on
both the reaction yield and the IMFDA reaction step of
these precursors. Access to 6 and 8 was easily accom-
plished in a few steps from the known acetoxy lactam 413
based on an a-amidoalkylation process via the stable N-
acyliminium cation followed by a Wittig–Horner reac-
tion.
As shown in Scheme 2, precursors 6 and 8 did not lead to
the formation of the desired oxabicyclic systems 7 and 9
under the experimental conditions used classically for this
transformation. In further efforts, 6 and 8 were heated in
refluxing toluene, mesitylene, or 1,2-dichlorobenzene for
12 hours, but in all cases starting material was recovered.
In attempts to facilitate the IMFDA process, three Lewis
In path A (Scheme 3), after saponification of the interme-
diate ester (e.g., K2CO3, MeOH–H2O), the hydroxy lac-
tam 10, subjected to Wittig–Horner reaction with ethyl
O
O
O
O
O
O
i
iv
N
N
N
64%
84%
OAc
Ph
4
O
5
8
ii 23%
O
iii
O
N
O
N
O
N
iii
O
O
Ph
Ph
EtO2C
CO2Et
H
6
( )-7
( )-9
Scheme 2 IMFDA reaction of olefinic intermediates 6 and 8. Reagents and conditions: (i) 1-phenyl-1-trimethylsiloxyethylene (1.2 equiv),
1 mol% Bi(OTf)3, MeCN, r.t., 12 h; (ii) triethyl phosphonoacetate, NaH, THF, reflux, 12 h; (iii) solvent (see text), reflux, 12 h; (iv) allyltri-
methylsilane (1.2 equiv), 1 mol% Bi(OTf)3, MeCN, r.t., 12 h.
O
O
O
O
O
O
i
v
N
N
N
86%
85%
path A
OH
R
14
vi 42%
10
11 R = CO2H
12 R = CH2OH
13 R = CHO
ii
CO2Et
58%
ref. 13
69%
iii
O
O
O
N
O
N
N
iv
or
76%
path B
H
H
O
O
EtO2C
EtO2C
( )-2A'
( )-2A
8
Scheme 3 Reagents and conditions: (i) (a) ethyl (triphenylphosphoranylidene)acetate, toluene, reflux, 24 h; (b) K2CO3, MeOH, H2O, reflux,
3 h; (ii) (COCl)2, CH2Cl2, r.t., 4 h; (b) NaBH4, DMF–THF (1:2), 0 °C, 1 h; (iii) (COCl)2, DMSO, Et3N, CH2Cl2, –60 °C to 0 °C; (iv) OsO4 (0.01
equiv), NaIO4 (3 equiv), THF–H2O (1:1), r.t., 2 h; (v) triethyl phosphonoacetate, NaH, THF, r.t., 1.30 h; (vi) CH2Cl2, reflux, 48 h.
Synlett 2009, No. 19, 3214–3218 © Thieme Stuttgart · New York

3216
F. Pin et al.
LETTER
(triphenylphosphoranylidene)acetate, led to the carboxy- stemming from the dialkylation process in 4:1 ratio in fa-
lic acid 11 in 86% yield for the two steps.14 The reduction vor of the desired product 19. No change in this ratio was
to alcohol 12 also took place in two steps with an overall observed whatever the number of equivalents of allyl bro-
yield of 58%. Finally, Swern oxidation of 12 provided the mide used, but 19 and 20 were easily separated by chro-
expected formyl derivative 13 in appreciable yield (69%). matography [SiO2, EtOAc–cyclohexane (1:4)].
For path B (Scheme 3), the oxidative cleavage of the ter-
minal olefin 8 was achieved using OsO4/NaIO4 (0.01:3) in
With olefin derivative 19 in hand, we set out to study its
IMFDA reaction under the conditions outlined above, and
THF–H2O (v/v = 1:1). Under these conditions, the ex-
in all cases the reaction failed as previously with the isoin-
pected aldehyde 13 was isolated in 76% yield after chro-
dolinone analogues.18 Again, conversion of olefin 19 into
matography on silica gel column with a mixture of
23 proved to be inefficient using the RCM reaction be-
CH2Cl2–cyclohexane as eluent.
tween 19 and ethyl acrylate with Grubbs I as catalyst.19 On
Aldehyde 13 was then subjected to the Wittig–Horner the other hand the a,b-unsaturated ester 23 was readily
reaction to generate the activated olefin 14 as the E-iso- prepared from the olefin 19 in two steps by initial oxida-
mer in 85% yield. The IMFDA of 14 was conducted in re- tion of the olefin with OsO4 (0.05 equiv) and NaIO4 (3
fluxing dichloromethane, and the expected product was equiv) in THF–H2O (1:1) to provide the aldehyde 22 in
isolated in acceptable 42% yield. This cycloaddition prod- 68% yield (Scheme 4). Installation of the ester function by
uct was also isolated as a single diasteroisomer (2A or the Wittig–Horner reaction with 22 using triethyl
2A¢)15 for which the relative configuration of asymmetric phosphonoacetate (e.g., NaH, THF, r.t., 1 h) then afforded
carbons has not yet been determined. Encouraged by the the desired a,b-unsaturated ester 23 (72%).
effectiveness of this IMFDA reaction, we next considered
its use in the pyrroloquinoline series to access the penta-
cyclic scaffold of the aromathecins. The synthetic strategy
As with its isoindolinone analogue, the a,b-unsaturated
ester 23 undergoes partial IMFDA reaction in a yield not
exceeding 13% under the conditions studied. In spite of
was thus modified to obtain the quinoline counterpart of
this mediocre yield, we isolated the expected cycloadduct
the IMFDA precursors bearing a nonactivated 19 or an ac-
320 as a single isomer. The results for the exploration of
tivated olefin 23 with an electron-withdrawing ester group
other reaction conditions in order to enhance of the reac-
tion yield are summarized in Table 1.
(Scheme 4).
For this purpose, chloromethylquinoline 17 was prepared
We did not succeed in crystallizing product 3 but, to our
satisfaction, COSY analysis allowed us to attribute every
proton and the NOESY experiment proved to have a piv-
otal role in the structure determination (Figure 2).
in two steps from aniline 15 (Scheme 4)16,17 Compound 17
was then treated with furfurylamine in ethanol at reflux to
lead to lactam 18 which was purified by recrystallization
from ethanol (78%). Due to the acidity of the protons at
Four diastereomers are possible according to the exo and
the a-position of the nitrogen amide of 18, 19 was ulti-
endo approaches of the trans-olefin (J = 15.6 Hz) during
mately reached by C-alkylation of 18 using allyl bromide
the IMFDA reaction (Scheme 5). A significant NOE be-
in the presence of NaH (3 equiv) as base (71%). Under
tween H6, H8, and one of the protons at C7-position. It
these conditions, precursor 19 was accompanied by 20,
O
O
O
O
CO2Et
O
O
CO2Et
Cl
2 steps
35%
ii
i
+
N
N
N
78%
71%
iv
4:1
N
N
NH2
N
N
O
19
20
15
16
17
18
Cl
iii
68%
v
O
O
O
O
O
O
O
vi
vii
or
O
N
N
N
N
N
72%
13%
N
N
N
N
N
( )-3A'
H
H
O
O
22
21
( )-3A
23
O
CO2Et
EtO2C
EtO2C
Scheme 4 Reagents and conditions: (i) furfurylamine, EtOH, reflux, 48 h; (ii) allyl bromide, NaH (3 equiv), DMF, 70 °C, 30 min; (iii) IMFDA
general conditions; (iv) Grubbs I catalyst (2 mol%), ethyl acrylate, toluene, 70 °C; (v) OsO4 (0.05 equiv), NaIO4 (3 equiv), THF–H2O (1:1),
r.t., 2 h; (vi) triethyl phosphonoacetate, NaH, THF, r.t., 1 h; (vii) toluene, reflux, sealed tube, 12 h.
Table 1 Conditions of IMFDA Reaction of Olefin 23 into 3
IMFDA conditions
CH2Cl2 reflux
Traces
Toluene reflux
6
Mesitylene reflux Toluene AlCl3 reflux Toluene sealed tube reflux
13
Yield of product 3 (%)
6
5
Synlett 2009, No. 19, 3214–3218 © Thieme Stuttgart · New York

LETTER
Synthesis of Pentacyclic Precursor of Aromathecins
3217
Figure 2 NOESY experiment for product 3A
means that H6 and H8 are close together and have the same of the reaction can explain the poor yields obtained, with
orientation on the D ring. Furthermore, H9 has an impor- an optimum yield of 13% in the case of ( )-3A.
tant interaction with the other proton at C7. Thus, we can
conclude that H9 a to the ester function adopts a position
opposite to H6 and H8. We can thus exclude compounds
( )-3B and ( )-3B¢ from the four structures presented in
Scheme 5.
In summary, polycyclic scaffolds 2 and 3 of alkaloids and
derivatives have been obtained using the IMFDA cy-
cloaddition of furfuryl and olefinic substituents attached
to isoindolinones and pyrroloquinolinones. All synthetic
steps of these sequences proceeded in good yields except
Distinguishing between compounds ( )-3A and ( )-3A¢ is the cycloaddition step leading to target 3. In addition, the
rather difficult because no NOE was observed for H10 stereogenic centers from the cycloaddition (exo approach)
apart with H9 and H11 at the neighboring carbons. Howev- were formed with high stereoselectivity. An application of
er, the absence of NOE with the H8 leads us to think that this strategy to the synthesis of aromathecins is currently
this proton and H10 are in opposite directions as for ( )- under way in our group, and the results will be reported in
3A. Furthermore, H10 is coupled with H9 with J = 3.9 Hz due course.
which remains an acceptable value for protons in a cis re-
lationship with an angle of 107°. With an angle of 43° as
for ( )-3A¢, a coupling constant of more than 5 Hz would
Acknowledgment
The authors wish to think the Region of ‘Haute Normandie-76,
France’ for a Regional Graduate Fellowship, attributed to Frédéric
Pin, and our colleague Dawn Hallidy for the English improvement.
be predicted. This suggests that the product formed was
( )-3A resulting from an exo approach with the IMFDA
reaction under a thermodynamic control. The reversibility
O
O
O
exo
attack
N
or
N
N
N
N
N
H
H
O
O
O
( )-3A
( )-3B
( )-14 ex
EtO2C
EtO2C
CO2Et
O
N
O
O
N
endo
attack
or
N
N
N
N
H
H
O
O
O
( )-14 en
( )-3A'
( )-3B'
CO2Et
EtO2C
EtO2C
Scheme 5 The four diastereomers possible according to the exo and endo approaches during the IMFDA reaction
Synlett 2009, No. 19, 3214–3218 © Thieme Stuttgart · New York

3218
F. Pin et al.
LETTER
(11) Martin, S. F.; Geraci, L. S. Tetrahedron Lett. 1988, 29, 6725.
(12) Ohba, M.; Kubo, H.; Natsutani, I. Tetrahedron 2007, 63,
12689; and references cited therein.
(13) Pin, F.; Comesse, S.; Garrigues, B.; Marchalín, Š.; Daïch, A.
J. Org. Chem. 2007, 72, 1181.
(14) (a) Ishihara, Y.; Kiyota, Y.; Goto, G. Chem. Pharm. Bull.
1990, 38, 3024. (b) Mali, R. S.; Yeola, S. N. Synthesis 1986,
755.
References and Notes
(1) Verma, R. P.; Hansch, C. Chem. Rev. 2009, 109, 213.
(2) (a) Cinelli, M. A.; Morrell, A.; Dexheimer, T. S.; Scher,
E. S.; Pommier, Y.; Cushman, M. J. Med. Chem. 2008, 51,
4609. (b) Cheng, K.; Rahier, N. J.; Eisenhauer, B. M.; Gao,
R.; Thomas, S. J.; Hecht, S. M. J. Am. Chem. Soc. 2005, 127,
838.
(3) Marchand, C.; Antony, S.; Kohn, K. W.; Cushman, M.;
Ioanoviciu, A.; Staker, B. L.; Burgin, A. B.; Stewart, L.;
Pommier, Y. Mol. Cancer Ther. 2006, 5, 287.
(4) Lin, L. Z.; Cordell, G. A. Phytochemistry 1989, 28, 1295.
(5) For the first synthesis of rosettacin 1a, see: Walraven, H. G.
M.; Pandit, U. K. Tetrahedron 1979, 36, 321.
(6) (a) Dai, X.; Cheng, C.; Ding, C.; Yao, Q.; Zhang, A. Synlett
2008, 2989. (b) Pin, F.; Comesse, S.; Sanselme, M.; Daïch,
A. J. Org. Chem. 2008, 73, 1975. (c) Zhou, H.-B.; Liu,
G.-S.; Yao, Z.-J. J. Org. Chem. 2007, 72, 6270.
(7) (a) Cinelli, M. A.; Morrell, A.; Dexheimer, T. S.; Scher,
E. S.; Pommier, Y.; Cushman, M. J. Med. Chem. 2008, 51,
4609. (b) Xiao, X.; Antony, S.; Pommier, Y.; Cushman, M.
J. Med. Chem. 2006, 49, 1408.
(8) (a) Brocksom, T. J.; Nakamura, J.; Ferreira, T. J.; Brocksom,
U. J. Braz. Chem. Soc. 2001, 12, 597. (b) Vogel, P.; Cossy,
J.; Plumet, J.; Arjona, O. Tetrahedron 1999, 55, 13521; and
references cited therein.
(15) Data for 2A
Mp 123 °C (white solid); Rf = 0.27 (cyclohexane–EtOAc =
1:1). IR: n = 1729 (C=O), 1684 (C=O), 1645 (C=C), 1444
(CH), 1426 (CH), 1290 (CO) cm–1. 1H NMR (200 MHz,
CDCl3): d = 1.12–1.24 (m, 1 H, H6a), 1.20 (t, 3 H, CH3CH2,
J = 7.0 Hz), 2.37–2.47 (m, 1 H, H7), 2.63–2.75 (m, 1 H, H6b),
2.68–2.75 (m, 1 H, H8), 3.70 (d, 1 H, H4a, J = 15.6 Hz), 4.10
(q, 2 H, CH3CH2, J = 7.0 Hz), 4.41 (dd, 1 H, H5, J = 12.5, 3.1
Hz), 4.90 (d, 1 H, H4b, J = 15.6 Hz), 5.10 (dd, 1 H, H1,
J = 4.7, 1.6 Hz), 6.28 (d, 1 H, H3, J = 5.5 Hz), 6.42 (dd, 1 H,
H2, J = 5.5, 1.6 Hz), 7.38–7.55 (m, 3 H, Har), 7.83 (d, 1 H,
Har, J = 7.0 Hz). 13C NMR (50 MHz, CDCl3): d = 14.4
(CH3), 36.6 (C6), 39.6 (C7), 41.1 (C4), 53.7 (C8), 57.5 (C5),
61.1 (CH2 ester), 80.1 (C1), 85.7 (Cq), 122.0 (CHar), 124.2
(CHar), 128.6 (CHar), 131.6 (CHar), 132.5 (Cq), 136.7 (C3),
137.7 (C2), 145.2 (Cq), 166.7 (C=O), 171.5 (C=O). Anal.
Calcd for C19H19NO4 (325.13): C, 70.14; H, 5.89; N, 4.31.
Found: C, 69.98; H, 5.66; N, 4.21.
(9) For the IMFDA approaches, see: (a) Boonsombat, J.;
Zhang, H.; Chughtai, M. J.; Hartung, J.; Padwa, A. J. Org.
Chem. 2008, 73, 3539. (b) Ikoma, M.; Oikawa, M.; Sasaki,
M. Tetrahedron 2008, 64, 2740. (c) Kachkovskyi, G. O.;
Kolodiazhnyi, O. I. Tetrahedron 2007, 63, 12576.
(d) Padwa, A.; Crawford, K. R.; Straub, C. S. J. Org. Chem.
2006, 71, 5432; and references cited therein.
(16) Anzini, M.; Cappelli, A.; Vomero, S.; Giorgi, G.; Langer, T.;
Bruni, G.; Romeo, M. R.; Basile, A. S. J. Med. Chem. 1996,
39, 4275.
(17) Roma, G.; di Braccio, M.; Balbi, A.; Mazzei, M.; Ermili, A.
J. Heterocycl. Chem. 1987, 24, 329.
(18) Only traces of product 24 were detected by 1H NMR.
(19) See, for example: Mentink, G.; Van Maarseveen, J. H.;
Hiemstra, H. Org. Lett. 2002, 4, 3497.
(10) In this area, see: (a) Varlamov, A. V.; Boltukhina, E. V.;
Zubkov, F. I.; Nikitina, E. V. J. Heterocycl. Chem. 2006, 43,
1479. (b) Namboothiri, I. N. N.; Ganesh, M.; Mobin, S. M.;
Cojocaru, M. J. Org. Chem. 2005, 70, 2235. (c) Zubkov,
F. I.; Nikitina, E. V.; Turchin, K. F.; Aleksandrov, G. G.;
Safronova, A. A.; Borisov, R. S.; Varlamov, A. V. J. Org.
Chem. 2004, 69, 432. (d) Zubkov, F. I.; Nikitina, E. V.;
Turchin, K. F.; Safronova, A. A.; Borisov, R. S.; Varlamov,
A. V. Russ. Chem. Bull., Int. Ed. 2004, 53, 860. (e) Tromp,
R. A.; Brussee, J.; Van Der Gen, A. Org. Biomol. Chem.
2003, 1, 3592. (f) Varlamov, A. V.; Nikitina, E. V.; Zubkov,
F. I.; Shurupova, O. V.; Chernyshev, A. I. Mendeleev
Commun. 2002, 12, 32. (g) Jacobi, P. A.; Li, Y. J. Am.
Chem. Soc. 2001, 123, 9307. (h) Padwa, A.; Brodney, M.
A.; Satake, K.; Straub, C. S. J. Org. Chem. 1999, 64, 4617.
(i) Padwa, A.; Brodney, M. A.; Liu, B.; Satake, K.; Wu, T.
J. Org. Chem. 1999, 64, 3595. (j) Lautens, M.; Fillion, E.
J. Org. Chem. 1998, 63, 647. (k) Padwa, A.; Dimitroff, M.;
Waterson, A. G.; Wu, T. J. Org. Chem. 1998, 63, 3986.
(l) Padwa, A.; Kappe, C. O.; Cochran, J. E.; Snyder, J. P.
J. Org. Chem. 1997, 62, 2786.
(20) Data for 3A
Mp 159 °C (white solid); Rf = 0.23 (cyclohexane–EtOAc =
2:3). IR: n = 2903 (CH), 1731 (C=O), 1692 (C=O), 1636
(C=N), 1508 (C=C) cm–1. 1H NMR (200 MHz, CDCl3): d =
1.21–1.31 (m, 1 H, H11a), 1.24 (t, 3 H, CH3CH2, J = 7.0 Hz),
2.42–2.53 (m, 1 H, H12), 2.77 (dd, 1 H, H13, J = 4.7, 3.9 Hz),
2.96–3.08 (m, 1 H, H11b), 3.77 (d, 1 H, H4a, J = 14.9 Hz),
4.10 (q, 2 H, CH3CH2, J = 7.0 Hz), 4.60 (dd, 1 H, H5,
J = 12.1, 2.7 Hz), 5.02 (d, 1 H, H4b, J = 14.9 Hz), 5.13 (dd, 1
H, H1, J = 3.9, 1.6 Hz), 6.30 (d, 1 H, H3, J = 6.3 Hz), 6.47
(dd, 1 H, H2, J = 6.3, 1.6 Hz), 7.62 (dd, 1 H, H8, J = 7.8, 7.0
Hz), 7.78–7.86 (m, 1 H, H7), 7.98 (d, 1 H, H9, J = 7.8 Hz),
8.14 (d, 1 H, H6, J = 8.6 Hz), 8.62 (s, 1 H, H10). 13C NMR (50
MHz, CDCl3): d 14.4 (CH3), 35.3 (C11), 39.6 (C12), 41.2 (C4),
53.7 (C13), 58.9 (C5), 61.1 (CH2 ester), 80.2 (C1), 85.5 (Cq),
123,8 (Cq), 127.3 (C8), 127.9 (Cq), 129.4 (C6), 129.8 (C9),
131.7 (C7), 133.2 (C10), 137.1 (C3), 137.4 (C2), 149.8 (Cq),
163.2 (C=N), 164.9 (C=O), 171.3 (C=O). Anal. Calcd for
C22H20N2O4 (376.41): C, 70.20; H, 5.36; N, 7.44. Found: C,
70.05; H, 5.16; N, 7.28.
Synlett 2009, No. 19, 3214–3218 © Thieme Stuttgart · New York