Enantioselective synthesis of 3,4-chromanediones via asymmetric rearrangement of 3-allyloxyflavones

Article abstract of DOI:10.1021/jo100889c

(Figure presented) Asymmetric scandium(III)-catalyzed rearrangement of 3-allyloxyflavones was utilized to prepare chiral, nonracemic 3,4-chromanediones in high yields and enantioselectivities. These synthetic intermediates have been further elaborated to novel heterocyclic frameworks including angular pyrazines and dihydropyrazines. The absolute configuration of rearrangement products was initially determined by a nonempirical analysis of circular dichroism (CD) using time-dependent density functional theory (TDDFT) calculations and verified by X-ray crystallography of a hydrazone derivative. Initial studies of the mechanism support an intramolecular rearrangement pathway that may proceed through a benzopyrylium intermediate.

Full text of DOI:10.1021/jo100889c

pubs.acs.org/joc
Enantioselective Synthesis of 3,4-Chromanediones via Asymmetric
Rearrangement of 3-Allyloxyflavones
†
Jean-Charles Marie, Yuan Xiong, Geanna K. Min, Adam R. Yeager, Tohru Taniguchi,
†
†
‡
ꢀ †
Nina Berova,‡ Scott E. Schaus,*,† and John A. Porco, Jr.*,†
†Center for Chemical Methodology and Library Development (CMLD-BU), Boston University,
590 Commonwealth Avenue, Boston, Massachusetts 02215, and ‡Department of Chemistry,
Columbia University 3000 Broadway MC 3114, New York, New York 10027
seschaus@bu.edu; porco@bu.edu.
Received May 6, 2010
Asymmetric scandium(III)-catalyzed rearrangement of 3-allyloxyflavones was utilized to prepare
chiral, nonracemic 3,4-chromanediones in high yields and enantioselectivities. These synthetic
intermediates have been further elaborated to novel heterocyclic frameworks including angular
pyrazines and dihydropyrazines. The absolute configuration of rearrangement products was initially
determined by a nonempirical analysis of circular dichroism (CD) using time-dependent density
functional theory (TDDFT) calculations and verified by X-ray crystallography of a hydrazone
derivative. Initial studies of the mechanism support an intramolecular rearrangement pathway that
may proceed through a benzopyrylium intermediate.
Introduction
Enantioselective construction of quaternary stereogenic
carbons is a significant challenge in organic chemistry.1 As
part of our investigations concerning novel scaffolds, we
encountered an interesting chemotype bearing two adjacent,
fully substituted carbon centers present in cytotoxic, pre-
nylated flavonoids including sanggenon A (1) and sanggenol
F (2) (Figure 1).2 Further examination of their structures
inspired the development of metal-catalyzed, asymmetric
rearrangement3,4 of 3-allyloxyflavones 3 to 2-substituted
FIGURE 1. Structures of sanggenon A and sanggenol F.
(1) (a) Steven, A.; Overman, L. E. Angew. Chem., Int. Ed. 2007, 46, 5488–
5508. (b) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007,
36, 5969–5994.
(2) (a) Hano, Y.; Kanzaki, R.; Fukai, T.; Nomura, T. Heterocycles 1997,
45, 867–874. (b) Shi, Y.-Q.; Fukai, T.; Ochiai, M.; Nomura, T. Heterocycles
2001, 55, 13–20.
FIGURE 2. Asymmetric rearrangement of 3-allyloxyflavones.
(3) For catalytic, asymmetric Claisen (CAC) rearrangements, see:
(a) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 2000, 122, 3785–
3786. (b) Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew. Chem., Int.
Ed. 2001, 40, 4700–4703. (c) Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc.
2008, 130, 9228–9229. (d) Linton, E. C.; Kozlowski, M. C. J. Am. Chem. Soc.
2008, 130, 16162–16163. (e) Rehbein, J.; Leick, S.; Hiersemann, M. J. Org.
Chem. 2009, 74, 1531–1540. (f) Rehbein, J.; Hiersemann, M. J. Org. Chem.
2009, 74, 4336–4342.
3,4-chromanediones 45 (Figure 2). Herein, we report the
development of methodology to prepare chiral, nonracemic
(5) (a) Vinot, N.; Maitte, P. J. Heterocycl. Chem. 1989, 26, 1013–1021.
(b) Brown, P. E.; Clegg, W.; Islam, Q.; Steele, J. E. J. Chem. Soc., Perkin
Trans. 1 1990, 139–144. (c) Hegab, M. I.; Abdel-Megeid, F. M. E.; Gad,
F. A.; Shiba, S. A.; Sotofte, I.; Moller, J.; Senning, A. Acta Chem. Scand.
1999, 53, 284–290.
(4) For attempted [3,3] rearrangements of flavone allyl ethers, see:
€
Heimann, W.; Bar, H. Chem. Ber. 1965, 98, 114–119.
4584 J. Org. Chem. 2010, 75, 4584–4590
Published on Web 06/07/2010
DOI: 10.1021/jo100889c
r
2010 American Chemical Society

ꢀ
Marie et al.
JOCArticle
TABLE 1. Lewis Acid-Catalyzed Rearrangementa
entry
catalyst
equiv (mol %)
ligand
allyloxy flavone
% conversion (isolated yield of 7)b
erc
1
2
3
4
5
6
7
8
9
Lu(OTf)3
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
10
10
10
10
10
10
10
30
30
30
none
none
8a
8b
9
10
none
none
10
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
16
50
60
d
d
d
38
98 (95)
100 (98)
82 (57)
90:10
97:3
98:2
10
a
10
˚
Reaction conditions: (a) 0.16 mmol of 3-allyloxyflavone, 0.02-0.05 mmol of catalyst, 0.02-0.05 mmol of chiral ligand, and 250 mg of activated 4 A
MS in DCE (0.04 M) for 12 h under Ar at 35 °C; (b) 0.40 mmol of 1,2-ethylenediamine at rt for 2 h. bConversion determined by crude 1H NMR analysis
and isolated yields after column chromatography on silica gel. cDetermined by chiral HPLC analysis.7 dNo product isolated after column
chromatography.
TABLE 2. Rearrangement Substrate Scopea
chromanediones using metal-catalyzed rearrangements6 of
3-allyloxyflavones and our initial studies to probe the reac-
tion mechanism.
Results and Discussion
We began our investigation by evaluating reaction of
3-allyloxyflavone 5a with a series of Lewis acids (Table 1).
Among a panel of metals evaluated, trifluoromethanesulfo-
nate salts of Lewis acidic metals were found to catalyze the
reaction of 5a to chromanedione 6a in low to moderate yields
employing 10 mol % of catalyst (entries 1, 2, and 7). How-
ever, complete conversion of allyloxy flavone 5a was ob-
served when 30 mol % of Sc(OTf)3 was employed (entry 8).
For purification purposes, the reactive 1,2-dicarbonyls 6a
were condensed with 1,2-ethylenediamine to afford dihydro-
pyrazines 7.7
Encouraged by these preliminary results, we investigated
use of chiral ligands for Sc(OTf)3 in the rearrangement. We
found that the complex prepared using (R)-Ph-Pybox 10 as
ligand8 led to good conversions and enantioselectivities to
afford dihydropyrazines 7a,b when the internal position of
the olefin was substituted with a hydrogen (Table 1, entry 9)
or methyl group (entry 10). In preliminary studies, flavone
ether substrates bearing disubstituted alkenes (e.g., Z or E
crotyl ethers) were found to be sluggish in rearrangements in
entry substituents R1, R2 diamine % yield b product
er
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H, H (5a)
H, H (5a)
H, H (5a)
H, H (5a)
22a
22b
22c
23
22c
22c
24
24
24
24
24
78
98
93
86
91
90
93
88
96
94
94
86
93
92
80
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
93:7
d
93:7
>98:2c
97:3
e
90:10
96:4
95:5
98:2
96:4
95:5
91:9
96:4
96:4
5-OMe, H (11)
6-OMe, H (12)
7-OMe, H (13)
6-Me, H (14)
H, 20-MeO (15)
H, 40-MeO (16)
H, 40-Me (17)
H, 40-CF3 (18)
H, 40-Br (19)
H, 40-NO2 (20)
H, 20-MeO-40-Br (21)
24
24
24
24
(6) For asymmetric Nazarov cyclizations using scandium-Pybox com-
plexes, see: Liang, G.; Trauner, D. J. Am. Chem. Soc. 2004, 126, 9544–9545.
(7) See the Supporting Information for complete experimental details.
(8) (a) Fukuzawa, S.-I.; Matsuzawa, H.; Metoki, K. Synlett 2001, 5, 709–
711. (b) Sauerland, S. J. K.; Kiljunen, E.; Koskinen, A. M. P. Tetrahedron
Lett. 2006, 47, 1291–1293. (c) Evans, D. A.; Fandrick, K. R.; Song, H.-J.;
Scheidt, K. A.; Xu, R. J. Am. Chem. Soc. 2007, 129, 10029–10041.
(d) Desimoni, G.; Faita, G.; Toscanini, M.; Boiocchi, M. Chem.;Eur. J.
2007, 13, 9478–9485.
aReaction conditions: 0.16 mmol of 3-allyloxyflavone, 0.05 mmol of
˚
catalyst, 0.05 mmol of (R)-Ph-Pybox, and 250 mg of activated 4 A MS in
DCE (0.04 M) for 12 h under Ar at 35 °C, followed by reaction with 0.40
mmol of diamine at rt for 2 h. bIsolated yields after column chromato-
graphy on SiO2. cdr value provided. dSeparation of enantiomers via
HPLC was not accomplished. eNot determined.
J. Org. Chem. Vol. 75, No. 13, 2010 4585

ꢀ
Marie et al.
JOCArticle
contrast to catalytic asymmetric Claisen rearrangements of
2-alkoxycarbonyl-substituted allyl vinyl ethers reported by
Hiersemann and co-workers.3e,f Unfortunately, rearrange-
ments did not proceed when different substituents including
bromine, phenyl, or carboxylates occupied the 2-position of
the olefin.7 Furthermore, complexes of ligands 8 and 9 with
Sc(OTf)3 were found to be ineffective for the rearrangement.
Substrate Scope
Asymmetric rearrangement of a number of 3-allyloxyfla-
vone substrates with diverse aryl substituents is shown in
Table 2. Neither the position nor the electronic nature of
substituents affected yields and enantioselectivities of reac-
tions. For example, an electron-rich substituted allyloxy-
flavone (p-MeO, entry 10) afforded the same selectivity and
yields as an electron-poor substrate (p-NO2, entry 14).
Regarding the position of the substituents on the C-2 aryl
ring, we found that the rearrangement tolerated the presence
of electron-donating groups at C-20 (entries 9 and 15). Use of
1,2-diamines that differed structurally and electronically in
the condensation with the intermediate 3,4-chromanediones
facilitated access to various heterocyclic structures including
dihydropyrazines and pyrazines.
FIGURE 3. Analysis of the absolute configuration of (-)-25. Top:
the most stable conformer of (S)-25. Bottom: comparison of the
calculated and the observed CD spectra of 25. (a) Calculated CD
spectra at the TDDFT/B3LYP/6-31G(d) for (S)-25. The Boltzmann
populations of each conformer are shown in parentheses. (b) The
observed CD and (c) UV spectrum obtained as an acetonitrile
solution (0.04 mM). The observed CD spectrum is normalized to
100% ee. UV λmax (ε): 225 (54000), 268 (25000), 382 (18900). CD λext
(Δε): 236 (-12.0), 258 (-25.1), 278 (þ6.7), 327 (þ14.8), 382 (-14.5).
[R]25D = -284.9 (c = 1.2, CHCI3).7
FIGURE 4. Proposed transition-state model.
SCHEME 1. Synthesis and X-Ray Crystal Structure Analysis of Pyrazine Hydrazone 42
4586 J. Org. Chem. Vol. 75, No. 13, 2010

ꢀ
Marie et al.
JOCArticle
FIGURE 5. Deuterium-labeled substrates and crossover experiment.
(Scheme 1)7 independently confirmed the absolute configuration
of rearrangement products as determined by CD calculations.
Mechanistic Studies
To rationalize the observed enantioselectivity, we modeled
the transition state of the presumed octahedral intermediate
obtained by bidentate coordination of the 3,4-chromane-
dione to the scandium(III)-(R)-Ph-Pybox (Figure 4).10 The
transition model suggests that the rearrangement occurs on
the Re-face of the double bond due to steric hindrance of the
phenyl groups of the Ph-Pybox ligand (Figure 4). Further
experiments were conducted using the deuterium-labeled
substrate 3-(1,1-dideuteuroallyloxy)chromen-4-one 43. When
3-allyloxyflavone 43 was submitted to scandium(III)-catalyzed
rearrangement, complete transfer of the deuterium to the ter-
minal position of the olefin occurred. After condensation of
the intermediate 3,4-chromanedione 44 with 1,2-dianiline 22a,
the deuterated dihydropyrazine 45 was produced (eq 1, Figure 5).
This result indicates that the rearrangement process proceeds via
an intramolecular pathway.
In order to rule out the existence of an intermolecular
reaction pathway, a crossover experiment was also con-
ducted (Figure 5, eq 2).7 A 1:1 mixture of nonlabeled ally-
loxyflavone 5a and deuterated 6-OMe derivative 46 subjected
to the reaction conditions led to sole production of pyrazines
27 and 47. The absence of any observed allyl crossover is
consistent with an intramolecular rearrangement process.
We also performed experiments to investigate possible
mechanistic pathways. Crossover and deuterium-labeling
experiments are consistent with asymmetric [3,3]-sigmatro-
pic rearrangement3 of the scandium(III)-complexed flavone
ether 48 to afford 3,4-chromanedione 44 (Figure 6). In an
alternative pathway, the corresponding benzopyrylium11 49
FIGURE 6. Mechanistic alternatives for the asymmetric rearrange-
ment.
Absolute Configuration Assignment and Rationale
The absolute configuration of dichloropyrazine 25 was
established by a nonempirical analysis of circular dichroism
(CD) using time-dependent density functional theory
(TDDFT) calculations.9 Prior to calculation of CD spectra,
a conformational search using the MMFF94 was conducted
on an arbitrarily chosen S absolute configuration of 25. The
resulting 12 conformers within a 10 kcal/mol energy window
were optimized at the DFT/B3LYP/6-31G(d) level of theory,
leading to three stable conformers within 1.5 kcal/mol
(Figure 3).7 CD theoretical calculations were carried out for
these three conformers at the TDDFT/B3LYP/6-31G(d) level
of theory, and the final spectrum was obtained as the weighted
average based on Boltzmann populations (Figure 3). The
theoretical and observed CD spectra showed good agreement
including a negative band at around 390 nm and a positive
band at around 330 nm, thus unambiguously establishing the
absolute configuration of 25 as S. The absolute configuration of
7b produced from asymmetric rearrangement was studied in a
similar manner (Table 1, entry 10).7 X-ray crystal structure
analysis of a pyrazine-hydrazone 42 derived from (S)-(-)-27
(10) CAChe 6.1.12.33 was used to perform MM2/MM3 energy minimi-
zations. For related models, see: (a) Evans, D. A.; Masse, C. E.; Wu, J. Org.
€
Lett. 2002, 4, 3375–3378. (b) Abraham, L.; Korner, M.; Schwab, P.;
Hiersemann, M. Adv. Synth. Catal. 2004, 346, 1281–1294. (c) Desimoni,
G.; Faita, G.; Mella, M.; Piccinini, F.; Toscanini, M. Eur. J. Org. Chem.
2007, 9, 1529–1534.
(11) Moncada, M. C.; Pina, F.; Roque, A.; Parola, A. J.; Maestri, M.;
Balzani, V. Eur. J. Org. Chem. 2004, 2, 304–312.
(9) (a) Diedrich, C.; Grimme, S. J. Phys. Chem. A 2003, 107, 2524–2539.
(b) Stephens, P. J.; Devlin, F. J.; Gasparrini, F.; Ciogli, A.; Spinelli, D.;
Cosimelli, B. J. Org. Chem. 2007, 72, 4707–4715. (c) Bringmann, G.; Bruhn,
T.; Maksimenka, K.; Hemberger, Y. Eur. J. Org. Chem. 2009, 17, 2717–2727.
J. Org. Chem. Vol. 75, No. 13, 2010 4587

ꢀ
Marie et al.
JOCArticle
FIGURE 7. Overlay of fluorescence spectra of 51, 52, 53, and Sc(OTf)3 (3.0 ꢀ 10-4 M in CH2Cl2).
FIGURE 8. Overlay of NMR spectra of 53, 51, and 52 in CD2Cl2 (for 52, 4% by volume HFIP added for solubility).
derived from delocalization of the positive charge and aro-
matization may undergo a [2,3] sigmatropic rearrange-
ment12 to 50 followed by a stereospecific [1,2]-allyl shift.13,14
In the latter case, the deuterium atoms would also be located
on the terminal position of the double bond. In order to
(12) For [2,3]-Wittig rearrangement of silyl enol ethers derived from
3-allyloxy-4-chromanones, see: Sato, Y.; Fujisawa, H.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 2006, 8, 1275–1287.
(13) Drutu, I.; Krygowski, E. S.; Wood, J. L. J. Org. Chem. 2001, 66,
7025–7029.
(14) An alternative mechanism involving Prins cyclization of 49 is also
possible but is less likely based on benzopyrylium stability and reversibility of
the reaction; see: Olier, C.; Kaafarani, M.; Gastaldi, S.; Bertrand, M. P.
Tetrahedron 2010, 66, 413–445.
4588 J. Org. Chem. Vol. 75, No. 13, 2010

ꢀ
Marie et al.
JOCArticle
probe the latter mechanism, we prepared 4-siloxy-1-benzo-
pyrylium salt 51 by treatment of 3-methoxyflavone with
TBSOTf15 and determined that it has a characteristic fluores-
cence emission (450 nm) upon excitation at 410 nm16
(Figure 7). Similar fluorescence emissions observed for the
Sc(OTf)3-3-methoxyflavone complex 52 (excitation 400 nm)
as well as the corresponding complex derived from 3-allylox-
yflavone 5a7 support the involvement of benzopyrylium
intermediates after Lewis acid activation and a plausible
alternative to the [3,3] mechanism for rearrrangement of
3-allyloxyflavones. Comparison of 13C NMR spectra of 51
and complex 52 (Figure 8) also shows comparable downfield
shifts for C-2 (3-methoxyflavone: 156 ppm; 51: 162 ppm; 52:
165 ppm), further supporting likely involvement of benzo-
pyrylium intermediates in the asymmetric rearrangement of
3-allyloxyflavones.7
prestirred solution of Sc(OTf)3 (23 mg, 0.05 mmol, 0.30 equiv)
and (R,R)-(þ)-2,6-bis(4-phenyl-2-oxazolinyl)pyridine 10 (20 mg,
0.05 mmol, 0.33 equiv) in DCE (3 mL). After the suspension was
stirredat rt for2 h, a solutionofallyloxyflavone5a (0.16mmol, 1.0
equiv) in DCE (2 mL) was slowly added via cannula. The mixture
was stirred at room temperature for 30 min and stirred overnight
at 35 °C. 1,2-Ethylenediamine 24 (27 μL, 0.40 mmol, 2.50 equiv)
was added in one portion, and the mixture was allowed to stir for
an additional 2 h at room temperature. After removal of the
molecular sieves by filtration of the crude mixture through a pad
of Celite, the solvent was evaporated in vacuo and the pyrazines 25
or dihydropyrazines 7 and 28 were isolated by flash column
chromatography on silica gel.
(S)-5-Allyl-5-phenyl-3,5-dihydro-2H-chromeno[4,3-b]pyrazine
(7a). Purification on silica gel (petroleum ether/ethyl acetate =
80:20) afforded dihydropyrazine 7a as a bright yellow oil (47 mg,
25
0.16 mmol, 98%): [R]D (c 1.0, CHCl3) = þ52.3; er = 93:7
(ChiralCel OD 1% IPA in hexane, retention time 4.58:5.47 min,
major/minor); 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 7.9,
1.5 Hz, 1H), 7.38 (ddd, J = 8.3, 7.2, 1.7 Hz, 1H), 7.30-7.15 (m,
5H), 7.13 (d, J = 8.3 Hz, 1H), 6.95 (app t, J = 7.6 Hz, 1H),
5.94-5.81 (m, 1H), 5.06 (app d, J = 15.9 Hz, 1H), 5.05 (app d,
J = 10.6 Hz, 1H), 4.14-3.95 (m, 2H), 3.49-3.25 (m, 2H), 3.13
Conclusion
In summary, the asymmetric, scandium-catalyzed rear-
rangement of 3-allyloxyflavones has been utilized to prepare
chiral, nonracemic 3,4-chromanediones in high yield and
enantioselectivity. These reactive intermediates have been
further elaborated to novel frameworks including angular
pyrazines and dihydropyrazines. Initial mechanism studies
support an intramolecular rearrangement pathway that may
proceed through a benzopyrylium intermediate. Further
applications of the methodology in both diversity- and
target-oriented synthesis are currently under investigation
and will be reported in due course.
(dd, J = 14.7, 6.6 Hz, 1H), 2.92 (dd, J = 14.7, 7.4 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 159.0, 156.0, 149.6, 139.3, 133.1,
132.6, 128.4 (2C), 127.7, 126.0 (2C), 124.9, 122.0, 119.9, 118.4,
118.3, 85.6, 45.9, 44.4, 43.7; IR νmax (film) 3074, 2943, 2841,
1608, 1593, 1461, 1384, 1330, 1220, 1118, 993, 914, 703 cm-1
;
HRMS (ESIþ) m/z calcd for C20H19N2O 303.1497, found
303.1492 (M þ H).
(S)-5-(2-Methylallyl)-5-phenyl-3,5-dihydro-2H-chromeno[4,3-b]-
pyrazine (7b). Dihydropyrazine 7b was obtained from the rearran-
gement of the methallyloxyflavone 5b (47 mg, 0.16 mmol, 1.0 equiv)
after condensation of the intermediate 3,4-chromanedione 6b with
1,2-ethylenediamine 24 (27 μL, 0.40 mmol, 2.5 equiv). Purification
on silica gel (petroleum ether/ethyl acetate = 80:20) afforded the
title compound 7b as a bright yellow oil (290 mg, 0.09 mmol, 57%):
[R]D25 (c 0.5, CHCl3) = þ16.8; er = 98:2 (ChiralPak AD 1% IPA
Experimental Section
3-(Allyloxy)-2-phenyl-4H-chromen-4-one (5a). To a suspen-
sion of commercially available 3-hydroxyflavone (1.00 g, 4.20
mmol, 1.0 equiv) in dry acetone (100 mL) was added at room
temperature allyl bromide (0.54 mL, 6.30 mmol, 1.5 equiv,
filtered through a plug of basic alumina) followed by K2CO3
(870.0 mg, 6.30 mmol, 1.5 equiv). The temperature was slowly
increased to 65 °C, and the reaction mixture was stirred over-
night. The mixture was then cooled to room temperature, and
30 mL of Et2O was added. After filtration of the salts through a
pad of Celite, the solvent was removed in vacuo, and the crude
product was purified by column chromatography on silica gel.
The allyloxyflavone 5a was obtained as a white solid (1.14 g, 4.10
mmol, 97%) after flash chromatography on silica gel (petroleum
ether/ethyl acetate = 90:10): mp (petroleum ether/Et2O) =
1
in hexane, retention time 6.05:7.26 min, major/minor); H NMR
(400 MHz, CDCl3) δ 7.83 (br d, J = 7.5 Hz, 1H), 7.39 (app t, J =
7.8 Hz, 1H), 7.30-7.16 (m, 5H), 7.13 (d, J = 8.3 Hz, 1H), 6.96 (app
t, J = 7.6 Hz, 1H), 4.79 (br s, 1H), 4.57 (br s, 1H), 4.07 (ddd, J =
16.1, 5.2, 4.0 Hz, 1H), 3.96 (ddd, J = 15.3, 4.4, 1.8 Hz, 1H), 3.42
(ddd, J = 16.9, 15.2, 4.9 Hz, 1H), 3.30 (ddd, J = 16.8, 15.5, 4.9 Hz,
1H), 3.08 (d, J = 14.4 Hz, 1H), 2.95 (d, J = 14.4 Hz, 1H), 1.67 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 159.1, 155.9, 149.5, 140.5,
139.1, 133.0, 128.2 (2C), 127.5, 126.2 (2C), 124.9, 121.9, 120.0,
118.2, 115.7, 86.1, 46.2, 45.8, 44.6, 24.7; IR νmax (film) 3070, 2944,
2845, 1609, 1593, 1461, 1328, 1219, 1118, 994, 895, 699 cm-1
;
HRMS (ESIþ) m/z calcd for C21H21N2O 317.1654, found
1
53-54 °C; H NMR (400 MHz, CDCl3) δ 8.27 (dd, J = 8.0,
317.1679 (M þ H).
1.7 Hz, 1H), 8.14-8.09 (m, 2H), 7.68 (ddd, J = 8.6, 7.1, 1.7 Hz,
1H), 7.56-7.49 (m, 4H), 7.41 (ddd, J = 8.1, 7.2, 1.0 Hz, 1H),
5.94 (tdd, J = 16.4, 10.3, 6.1 Hz, 1H), 5.28 (dd, J = 17.2, 1.5 Hz,
1H), 5.15 (dd, J = 10.3, 1.2 Hz, 1H), 4.65 (d, J = 6.1 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 175.1, 156.0, 155.2, 139.9, 133.5,
133.4, 131.0, 130.6, 128.7 (2C), 128.4 (2C), 125.8, 124.6, 124.1,
118.5, 118.0, 73.2; IR νmax (film) 3062, 2937, 1640, 1614, 1467,
1393, 1236, 1200, 1145, 993, 691 cm-1; HRMS (ESIþ) m/z calcd
for C18H15O3 279.1021 found 279.1016 (M þ H).
(S)-6-Allyl-9,10-dichloro-6-phenyl-6H-chromeno[3,4-b]quinox-
aline (25). Pyrazine 25 was obtained using 4,5-dichloro-o-pheny-
lenediamine 22a (71 mg, 0.40 mmol, 2.5 equiv) for the condensa-
tion step. Purification on silica gel (petroleum ether/dichloro-
methane = 80:20) afforded the pyrazine 25 as a light yellow
powder (52 mg, 0.12 mmol, 78%): mp (petroleum ether/CH2-
25
Cl2) = 159-160 °C; [R]D (c 1.2, CHCl3) = -245.0; er = 93:7
(ChiralCel OD 0% IPA in hexane, retention time 9.78:12.26 min,
major/minor); 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H),
8.24 (dd, J = 7.8, 1.7 Hz, 1H), 8.22 (s, 1H), 7.45 (ddd, J = 8.3,
7.3, 1.7 Hz, 1H), 7.37-7.31 (m, 2H), 7.25-7.12 (m, 4H), 7.09
(ddd, J =7.8, 7.3, 1.1 Hz, 1H), 5.91 (app tdd, J = 17.1, 10.2, 6.9
Hz, 1H), 5.18 (dd, J=17.2, 1.8 Hz, 1H), 5.06 (dd, J = 10.2, 2.0 Hz,
1H), 3.55 (dd, J = 14.6, 6.9 Hz, 1H), 3.23 (dd, J = 14.6, 7.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 156.1, 152.3, 144.5, 141.3,
141.0, 140.2, 134.6, 133.5 (2C), 132.8, 130.0, 129.7, 128.2 (2C),
127.6, 125.9 (2C), 125.7, 122.6, 120.7, 119.0, 118.3, 85.5, 45.5; IR
General Procedure for Sc(OTf)3-(R)-Pybox-Ph-Mediated Re-
˚
arrangement. To a suspension of molecular sieves (4 A, 250.0
mg, flame-dried under high vacuum) was added, via cannula, a
(15) Lee, Y. G.; Ishimaru, K.; Iwasaki, H.; Ohkata, K.; Akiba, K. J. Org.
Chem. 1991, 56, 2058–2066.
(16) Fluorescence emission of benzopyryliums: (a) Alluis, B.; Dangles, O.
Helv. Chim. Acta 1999, 82, 2201–2212. (b) Drabent, R.; Pliszka, B.; Huszcza-
Ciokowska., G.; Smyk, B. Spectrosc. Lett. 2007, 40, 165–182.
J. Org. Chem. Vol. 75, No. 13, 2010 4589

ꢀ
Marie et al.
JOCArticle
νmax (film) 3076, 2918, 1609, 1586, 1560, 1486, 1467, 1453, 1339,
1223, 1182, 1152, 1108, 1028, 908, 884, 731, 700 cm-1;HRMS(ESIþ)
m/z calcd for C24H17Cl2N2O 419.0718, found 419.0676 (M þ H).
(6S,7aS,11aS)-6-Allyl-6-phenyl-7a,8,9,10,11,11a-hexahydro-6H-
chromeno[3,4-b]-quinoxaline (28). Dihydropyrazine 28 was ob-
tained using (1S,2S)-cyclohexane-1,2-diamine 23 (46 mg, 0.40
mmol, 2.5 equiv) for the condensation step. Purification on silica
gel (petroleum ether/ethyl acetate = 90:10) afforded the title com-
pound 28 as a bright yellow oil (49 mg, 0.14 mmol, 86%): 1H NMR
analysis of the crude showed only one diastereomer; [R]D25 (c 1.2,
CHCl3) = -103.1; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=7.8
Hz, 1H), 7.37 (app t, J=7.8 Hz, 1H), 7.23 (s, 2H), 7.22 (d, J = 3.4
Hz, 2H), 7.21-7.15 (m, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.93 (app t,
J=7.6 Hz, 1H), 5.88 (dddd, J= 17.0, 10.5, 7.4, 6.6 Hz, 1H), 5.04 (d,
J = 17.0 Hz, 1H), 5.03 (d, J = 10.4 Hz, 1H), 3.14 (dd, J = 14.6, 6.5
Hz, 1H), 2.95 (dd, J = 14.6, 7.4 Hz, 1H), 2.86 (dd, J = 11.6, 4.1 Hz,
1H), 2.76 (ddd, J=15.2, 11.0, 4.1 Hz, 1H), 2.53 (br d, J = 13.2 Hz,
1H), 2.41 (br d, J=11.3 Hz, 1H), 1.98-1.84(m, 2H), 1.69-1.57 (m,
1H), 1.55-1.39 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 157.9,
156.1, 149.2, 139.2, 132.9 (2C), 128.3 (2C), 127.6, 126.0 (2C), 125.0,
121.8, 119.9, 118.3, 118.1, 85.5, 60.4, 59.1, 43.6, 33.9, 33.7, 25.6 (2C);
IR νmax (film) 3073, 2933, 2857, 1606, 1589, 1574, 1462, 1448, 1321,
1257, 1221, 1055, 993, 916, 710 cm-1; HRMS (ESIþ) m/z calcd for
C24H25N2O 357.1967, found 357.1971 (M þ H).
General Procedure for the Preparation of Deuterated Allylox-
yflavones 43 and 46. To a solution of commercially available
3-hydroxyflavone (1.00 g, 4.20 mmol, 1.0 equiv) and allyl-1,1-d2
alcohol19 (378 mg, 6.30 mmol, 1.50 equiv) in dry THF (15 mL)
was added triphenylphosphine (1.32 g, 5.04 mmol, 1.20 equiv).
After complete dissolution of the phosphine, the temperature
was brought to 0 °C, and diisopropyl azodicarboxylate (DIAD,
1.0 mL, 5.04 mmol, 1.20 equiv) was added dropwise to the
mixture via syringe. The reaction was stirred overnight at room
temperature and quenched with satd NaHCO3 solution. After
separation of the layers and extraction of the aqueous phase with
ether, the combined organic layers were washed with brine, dried
over MgSO4, filtered, and concentrated. The crude was purified
by column chromatography on silica gel (petroleum ether/ether
=50: 50) to afford deuterated allyloxy flavone 43 as a white solid
(565 mg, 2.01 mmol, 48%). Following the same procedure, the
methoxy derivative 46 was prepared starting from commercially
available 6-methoxyflavonol (536 mg, 2.00 mmol, 1.0 equiv) and
was isolated as a white powder (186 mg, 0.60 mmol, 30%) after
purification on silica gel (petroleum ether/ether = 50:50).
3-Methoxy-2-phenyl-4H-chromen-4-one (53). To a solution of
3-hydroxyflavone (150 mg, 0.06 mmol) in dry acetone (6 mL)
were added dimethyl sulfate (0.10 mL, 0.09 mmol) and K2CO3
(131 mg, 0.09 mmol), and the reaction mixture was refluxed over-
night. The mixture was cooled to room temperature and filtered
through a pad of Celite. The solvent was removed in vacuo, and
the crude product purified by column chromatography on silica
(S)-2-(6-Phenyl-6H-chromeno[4,3-b]quinoxalin-6-yl)acetalde-
hyde (40). Following a procedure published in the literature,17
aldehyde 40 was synthesized starting from pyrazine 27 (52 mg, 0.15
mmol, 1.0 equiv) and was obtained as a colorless oil (51 mg, 0.14
mmol, 97%) after purification on silica gel (petroleum ether/Et2O
1
gel: H NMR (400 MHz, CD2Cl2) δ 8.21 (d, J =8.1 Hz, 1H),
8.13-8.07 (m, 2H), 7.70 (dd, J=8.6, 1.5 Hz, 1H), 7.59-7.50 (m,
4H), 7.41 (dd, J = 7.8 Hz, 1H), 3.89 (s, 3H); 13C (400 MHz,
CD2Cl2) δ 175.3, 156.0, 155.8, 142.0, 134.0, 131.6, 131.2, 129.0,
129.0, 126.0, 125.2, 124.8, 118.6, 60.4. IRmax (film) 1640, 1614,
1467, 1383, 1213, 1147, 897, 759 cm-1; HRMS (ESIþ) m/z calcd
for C16H13O3 253.0865, found 253.0857 (M þ H).
25
1
=70:30): [R]D (c 1.0, CHCl3)=-180.0; H NMR (400 MHz,
CDCl3) δ 9.86 (dd, J = 2.9, 1.9 Hz, 1H), 8.33 (d, J =7.8 Hz, 1H),
8.17-8.12 (m, 2H), 7.83-7.73 (m, 2H), 7.43 (app t, J = 7.3 Hz,
1H), 7.31 (d, J=7.7 Hz, 2H), 7.24-7.16 (m, 2H), 7.20 (d, J = 7.8
Hz, 2H), 7.12 (app t, J = 7.4 Hz, 1H), 3.88 (dd, J = 16.7, 1.9 Hz,
1H), 3.47 (dd, J= 16.6, 2.9 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 199.5, 155.2, 149.9, 143.4, 142.5, 141.2, 140.6, 133.0, 130.5, 129.6,
129.4, 129.3, 128.5 (2C), 128.1, 125.9 (2C), 125.7, 123.0, 121.5,
118.3, 83.5, 53.6; IR νmax (film) 3061, 2842, 2744, 1725, 1607, 1491,
1460, 1346, 1225, 1070, 704 cm-1; HRMS (ESIþ) m/z calcd for
C23H17N2O2 353.1290, found 353.1261 (M þ H).
4-(tert-Butyldimethylsilyloxy)-3-methoxy-2-phenylchromeny-
lium Triflate Salt (51)20. To a solution of 3-methoxy-2-phenyl-
4H-chromen-4-one 53 (10.0 mg, 0.04 mmol) in CD2Cl2 (1.0 mL)
was added TBSOTf (9.6 μL, 0.04 mmol). The reaction mixture
was stirred at 40 °C for 0.5 h. The crude mixture was directly
used for NMR and UV/fluorescence studies without further
purification: 1H NMR (500 MHz, CD2Cl2) δ 8.38 (dd, J = 8.2,
1.6 Hz, 1H), 8.25 (d, J = 7.1 Hz, 2H), 7.95 (dd, J = 7.5 Hz, 1H),
7.82 (d, J = 8.4 Hz, 1H), 7.69-7.59 (m, 4H), 3.86 (s, 3H), 1.00
(s); 0.88 (s) (9H total), 0.46, 0.03 (s, 6H); 13C (500 MHz, CD2Cl2)
δ 174.8, 162.0, 156.3, 140.9, 136.7, 133.5, 130.0, 129.8, 127.4,
126.1, 121.5, 119.1, 61.7, 26.0, 25.0, 18.6, -2.7, -4.0; IRmax
(S)-4-Benzyl-3-((E)-2-((S)-6-phenyl-6H-chromeno[4,3-b]quinox-
alin-6-yl)ethylideneamino)oxazolidin-2-one (42). Pyrazine hydra-
zone 42 was prepared according to a procedure published in the
literature18 starting from pyrazine aldehyde 40 (51 mg, 0.14 mmol,
1.0 equiv) and hydrazine 41 (55 mg, 0.29 mmol, 2.0 equiv). After
silica gel chromatography (petroleum ether/ethyl acetate = 60:40),
the title compound was obtained as colorless crystals (75 mg, 0.14
mmol, 99%): mp (petroleum ether/Et2O) = 162-164 °C; [R]D25 (c
1.2, CHCl3) = -83.1; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J =
7.9 Hz, 1H), 8.19 (d, J= 7.6 Hz, 1H), 8.13 (d, J= 7.8 Hz, 1H), 8.06
(app t, J = 5.4 Hz, 1H), 7.81-7.71 (m, 2H), 7.42 (app t, J = 7.3
Hz, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.25-7.13 (m, 5H), 7.18 (d, J =
7.5 Hz, 2H), 7.10 (app t, J = 7.5 Hz, 1H), 6.90 (d, J = 7.3 Hz, 2H),
4.22 (dd, J = 8.2, 3.9 Hz, 1H), 4.18 (dd, J = 16.2, 7.9 Hz, 1H), 4.04
(dd, J = 8.2, 4.2 Hz, 1H), 3.93 (dd, J = 15.1, 5.0 Hz, 1H), 3.74 (dd,
J = 14.8, 6.5 Hz, 1H), 2.91 (dd, J = 13.9, 2.8 Hz, 1H), 2.60 (dd,
J = 13.9, 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 155.4,
153.9, 150.8, 150.3, 143.3, 142.4, 141.4, 140.9, 134.9, 133.0, 130.4,
129.4 (2C), 129.2, 129.1 (2C), 128.7 (2C), 128.4 (2C), 127.9, 127.1,
126.0 (2C), 125.6, 122.8, 121.3, 118.3, 84.7, 65.5, 56.8, 44.8, 36.1; IR
(film) 3452 (br), 1736, 1245, 1186, 1029, 640 cm-1
.
Acknowledgment. Financial support from the National
Institutes of Health (P50 GM067041) and AstraZeneca is
gratefully acknowledged. We thank Prof. John Snyder and
Drs. Baudouin Gerard and Joshua Giguere (Boston
University) for helpful discussions, Drs. John Goodell, Aaron
Beeler, andMs. SusanCunningham for assistance with UPLC
analysis, and Dr. Emil Lobkovsky (Cornell University) for
X-ray crystal structure analysis. We are grateful to the
National Science Foundation (CHE 0443618) for funding the
Waters high resolution mass spectrometer used in this work.
ν
max (film) 3058, 3015, 2921, 1771, 1604, 1555, 1491, 1459, 1401,
Supporting Information Available: Complete experimental
procedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
1347, 1211, 1087, 1029, 704 cm-1; HRMS (ESIþ) m/z calcd for
C33H27N4O3 527.2083, found 527.2102 (M þ H).
ꢀ
(19) Krompiec, S.; Kuznik, N.; Urbala, M.; Rzepa, J. J. Mol. Catal. A:
(17) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217–
3219.
Chem. 2006, 198–209.
(20) Lee, Y. G.; Ishimaru, K.; Iwasaki, H.; Ohkata, K.; Akiba, K. J. Org.
Chem. 1991, 56, 2058–2066.
ꢀ
(18) Friestad, G. K.; Marie, J.-C.; Suh, Y.; Qin, J. J. Org. Chem. 2006, 71,
7016–7027.
4590 J. Org. Chem. Vol. 75, No. 13, 2010