Intramolecular Povarov reactions involving 3-aminocoumarins

Article abstract of DOI:10.1039/c1ob05867c

A series of pentacyclic heterocyclic systems (15 examples, 69-89%) have been synthesized using intramolecular Povarov reactions involving 3-aminocoumarins and O-cinnamylsalicylaldehydes. The Povarov adducts are formed with high selectivity for the trans,trans relative stereochemistry in the newly-formed [6,6] fused ring system. One example of a Povarov adduct featuring a new [6,5] fused ring system is reported. In this case, cis,trans relative stereochemistry was preferred.

Full text of DOI:10.1039/c1ob05867c

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PAPER
Intramolecular Povarov reactions involving 3-aminocoumarins†
Amit A. Kudale,a David O. Miller,b Louise N. Dawea,b and Graham J. Bodwell*a
Received 1st June 2011, Accepted 18th July 2011
DOI: 10.1039/c1ob05867c
A series of pentacyclic heterocyclic systems (15 examples, 69–89%) have been synthesized using
intramolecular Povarov reactions involving 3-aminocoumarins and O-cinnamylsalicylaldehydes. The
Povarov adducts are formed with high selectivity for the trans,trans relative stereochemistry in the
newly-formed [6,6] fused ring system. One example of a Povarov adduct featuring a new [6,5] fused ring
system is reported. In this case, cis,trans relative stereochemistry was preferred.
two-step sequence or a multicomponent reaction, there are three
Introduction
points of diversity, which renders the Povarov reaction well-suited
to diversity-oriented synthesis.3 Over the past decade, various
advances in the Povarov reaction have been reported,4 including
the broadening of its scope (with respect to all three components
and the nature of the catalyst), progress toward the understanding
of its mechanism and its application in total synthesis.5
We recently reported that 3-aminocoumarin (4) can function as
the “aniline” component of the Povarov reaction, thereby giving
rise to the formation of 1,2,3,4-tetrahydropyrido[2,3-c]coumarins
such as 5 (Scheme 1).6 We now report an intramolecular version of
this reaction, which results in the efficient formation of pentacyclic
heteroaromatic systems.
In its original form, the Povarov reaction involved a BF3·OEt2-
catalysed formal inverse electron demand Diels–Alder (IEDDA)
reaction between an aniline-derived imine 1 (a 2-azadiene) and a
vinyl ether, followed by a double bond migration within the initial
adduct 2 to afford a 1,2,3,4-tetrahydroisoquinoline 3 (Scheme 1).1
Despite its impressive productivity (two new C–C bonds, one new
ring and up to three new stereogenic centres are formed), it received
only sporadic attention from the time of its discovery (1960s) until
the 1990s, when a one-pot, three-component version involving in
situ generation of the 2-azadiene 1 was developed.2 Either as a
Results and discussion
The Povarov reaction can be rendered intramolecular by the
tethering any two of the three components, or all three of them.
To date, all reported intramolecular Povarov reactions involve the
tethering of the dienophile and the aldehyde.5b,7 However, as in
the case of the intermolecular Povarov reaction, aromatic amines
other than anilines have been used infrequently.5b The focus of this
work was also the tethering of the aldehyde component and the
dienophile component, but 3-aminocoumarins8 were to be used
as the aromatic amine. As such, it was envisioned that aldehydes
of the general structure 6 would condense with 3-aminocoumarin
(4) to afford 2-azadienes 7 bearing a pendant dienophile and then
undergo a Type 1 intramolecular IEDDA reaction to afford, after
double bond migration, polycyclic products 9 (Scheme 2).
Scheme
3-aminocoumarin (4).
1
The Povarov reaction and examples involving
aDepartment of Chemistry, Memorial University, St. John’s, NL, Canada,
A1B 3X7. E-mail: gbodwell@mun.ca; Fax: +1-709-864-3702; Tel: +1-709-
864-8406
For initial studies, 2-(allyloxy)benzaldehyde (11),9 which was
prepared in 87% yield by the O-alkylation of salicylaldehyde (10)
with allyl bromide in the presence of anhydrous K2CO3 (Scheme 3),
was chosen. Enal 11 was then subjected to reaction with 3-
aminocoumarin8 (4) in the presence of 5 mol% Yb(OTf)3. No
reaction was evident at room temperature (tlc analysis). This was
not surprising because the C C bond in the allyl group is electron
neutral and would therefore not be expected to easily take part in
an IEDDA reaction, even an intramolecular one. However, upon
bCREAIT Network, Memorial University, St. John’s, NL, P.O. Box 4200,
Canada, A1C 5S7. E-mail: dmiller@mun.ca; Fax: +1-709-864-4569;
Tel: +1-709-864-8000
† Electronic supplementary information (ESI) available: experimental
procedures and characterization data for compounds 23, 32, 33, 35, 37, 54,
59 and 60; 1H and 13C spectra of all new compounds; CIF for 39; COSY
and HMQC spectra for compound 39. CCDC reference number 828370.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c1ob05867c
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the double bond in the allyl group is such a poor dienophile for the
IEDDA reaction. Mechanistically, it is more likely that the IEDDA
step of the Povarov reaction proceeds in a concerted fashion rather
than a stepwise manner because the stepwise mechanism would
require the intermediacy of a primary carbocation.
It was anticipated that the use of an alkyne-based dienophile for
the intramolecular IEDDA reaction would more easily afford aro-
matized products because the Povarov adduct 18 (or the IEDDA
adduct that precedes it) would only need to undergo one transfer
hydrogenation step. Accordingly, 2-(propargyloxy)benzaldehyde
(16)12 was reacted with 3-aminocoumarin (4) in the presence
of 5 mol% Yb(OTf)3 in acetonitrile at reflux (Scheme 4). The
reaction was sluggish, but the aromatized product 14 was isolated
in 47% yield after 9 days of reaction. A substantial amount of 3-
aminocoumarin (4) (19%) was recovered, but no reduced product
corresponding to 15 was isolated. This may indicate that the
oxidation of 18 (or the IEDDA adduct that precedes it) occurs
by a process other than transfer hydrogenation.
Scheme
3-aminocoumarin (4).
2
Planned intramolecular Povarov reactions involving
Scheme 4 Povarov reaction of 3-aminocoumarin (4) and ynal 16.
With the intention of facilitating the IEDDA step, aldehyde 20,13
which bears a pendant phenylethynyl dienophile, was synthesized
in two steps from 3-phenylprop-2-yn-1-ol (19)14 (Scheme 5). Ynol
19 was first converted into the corresponding bromide upon
Scheme 3 Povarov reaction of 3-aminocoumarin (4) and enal 11.
heating at reflux (CH3CN, 19 h), three new products were isolated
along with 23% recovery of 3-aminocoumarin (4) (Scheme 3).
One of these new products was determined to be the Povarov
adduct 13 (17%). The cis relative stereochemistry was assigned on
the basis of the small value of the coupling constant JH(7a),H(13a)
(H(7a) is observed as a somewhat broad singlet, d = 4.53) in
conjun◦ction with the value of the AM1-calculated dihedral angle
(45–46 ) for H(7a)–C(7a)–C(13a)–H(13a).10 As described below,
related systems with trans relative stereochemistry have coupling
constants of ca. 11 Hz.
15
treatment with CBr4/PPh3 and the crude product was used to
The other two products, 14 (19%) and 15 (39%), were deter-
mined to be an aromatized (dehydrogenated) version of 13 and
a reduced form of the in situ-generated imine 12, respectively.
The observed 1 : 2 ratio for the yields of 14 and 15 is consistent
with the notion that these two products are the result of trans-
fer hydrogenation reactions from Povarov adduct 13 to the in
situ-generated imine 12. Similar transfer hydrogenations during
Povarov reactions of aniline-derived 2-azadienes were reported
recently.11 Although the Povarov adduct 13 was isolated in only
17% yield, this result was encouraging, especially considering that
Scheme 5 Synthesis of aldehyde 20 and its Povarov reaction with
3-aminocoumarin (4).
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O-alkylate salicylaldehyde (10). This afforded aldehyde 20 in 72%
yield over 2 steps. Reaction of 20 with 3-aminocoumarin (4) in the
presence of 10 mol% Yb(OTf)3 resulted in no reaction after 3 h at
room temperature (tlc analysis), so the reaction was heated. After
72 h at reflux, the aromatized product 21 (43%) was isolated along
with 27% of recovered 3-aminocoumarin (4). No reduced product
resulting from transfer hydrogenation was obtained.
Despite the very limited benefit of adding a phenyl group to an
acetylenic dienophile, the same tactic was used for the correspond-
ing olefinic dienophile. This was predicated on the observation
that, during our investigations on the intermolecular Povarov
reactions,6 styrenes were found to react well with preformed
coumarin-fused 2-azadienes at room temperature with moderate
to good levels of endo/exo selectivity.
2-(Cinnamyloxy)benzaldehyde (23) was prepared by the O-
alkylation of salicylaldehyde (10) with cinnamyl bromide (22)15
(Scheme 6). When 23 was subjected to reaction with 3-
aminocoumarin (4) in the presence of 5 mol% Yb(OTf)3 in
acetonitrile at room temperature, pentacyclic Povarov adduct
24 was isolated in 56% yield after just 1 h. The yield could
be improved to 85% by using 10 mol% of the catalyst. This
reaction also had the practical advantage that the 24 precipitated
as the reaction progressed. As a result, it could be isolated simply
by suction filtration. The magnitude of the coupling constants
around the newly-formed six-membered ring (JH(7a),H(13a) = 11.1 Hz,
JH(13a),H(14) = 11.0 Hz) were key indicators of the trans,trans relative
stereochemistry. Traces of what may be another diastereomer were
observed in the 1H NMR spectrum of the crude reaction mixture,
but attempts to isolate this compound by flash chromatography
were unsuccessful.
Scheme 7 Synthesis of aldehydes 32, 33, 35 and 37.
36 (Scheme 7). Although also commercially available, cinnamyl
bromide (22) was prepared in two steps from ethyl cinnamate
using literature procedures.16 Cinnamyl bromides 30 and 31 were
prepared from 4-bromobenzaldehyde and 4-nitrobenzaldehyde,
respectively, in three steps using published procedures.16,17,18
The results of the intramolecular Povarov reactions are summa-
rized in Table 1. As with the parent reaction (Scheme 6 and Table 1,
Entry 1), the reaction between 3-aminocoumarin (4) and aldehyde
32 (Table 1, Entry 2) proceeded smoothly at room temperature to
afford 38 as a single diastereoisomer (84%). The slightly longer
reaction time is consistent with the mild electron withdrawing
effect of the bromo group on any developing positive charge
at the transition state of the IEDDA step. By the same token,
the replacement of the bromo substituent with a much stronger
electron withdrawing group (NO2) (Table 1, Entry 3) caused the
reaction time to increase to 5 days with a small decrease in the
yield (39, 72%). When the reaction of 4 and nitroaldehyde 33 was
conducted at reflux, the starting materials were consumed after
16 h and 39 was isolated in 49% yield.
A single crystal X-ray structure determination of 39 confirmed
the NMR-based assignment of the trans,trans relative stereochem-
istry. The pentacyclic skeleton is relatively flat and the molecules
are grouped into hydrogen bonded pairs of enantiomers (Fig. 1).
More specifically, the H–N–C–C O unit of one enantiomer
hydrogen bonds in a complementary fashion with that of its
antipode. In the resulting box-like arrangement of the interacting
Scheme 6 Synthesis of aldehyde 23 and its Povarov reaction with
3-aminocoumarin (4).
As in the case of the intermolecular Povarov reaction, the
intramolecular version described above offers three points of
diversity, i.e. the 3-aminocoumarin unit, the salicyclaldehyde unit
that connects the dienophile to diene and the cinnamyl unit
(the dienophile). As described below, a series of pentacyclic
heterocycles was generated using 3-aminocoumarins 4 and 25–
29, which were available from previous work in our group,8
and aldehydes 23, 32, 33, 35 and 37 (Scheme 7). Aldehydes
32, 33, 35 and 37 were synthesized in good to excellent yields
using O-alkylation reactions involving cinnamyl bromides 22, 30
and 31 and commercially available salicylaldehydes 10, 34 and
˚
O and H atoms, the intermolecular O–H distances (2.29(3) A) are
˚
almost the same as the intramolecular O–H distances (2.38(3) A).
The N(1)–H(1)–O(2¢) bond angle is 167(3)◦.
Aldehydes 35 and 37, which bear substituents on the benzalde-
hyde moiety, reacted with 3-aminocoumarin (4) to afford Povarov
adducts 40 (Table 1, Enty 4, 89%) and 41 (Table 1, Entry 5, 69%),
respectively. A series of 3-aminocoumarin derivatives 25–29 was
then reacted with aldehydes 23 and 35 to afford Povarov adducts
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Table 1 Intramolecular Povarov reactions leading to pentacyclic compounds 24 and 38–51a
Entry
1
Reactants
Time (h)
1
Product
Yield (%)b
85
4, 23
2
3
4
4, 32
4, 33
4, 35
2
84
72c
89
120c
1
5
6
4, 37
2
2
69
87
25, 23
7
8
25, 35
26, 23
2
2
84
84
9
10
26, 35
27, 23
2
1
85
78
11
12
27, 35
28, 23
1
0.5
75
82
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Table 1 (Contd.)
Entry
Reactants
Time (h)
Product
Yield (%)b
13
14
28, 35
29, 23
0.5
2
78
86
15
29, 35
2
86
a See Scheme 6 for reaction conditions. b Isolated yields. c 16 h reaction time and 49% yield when conducted at reflux.
this case, a stepwise mechanism is reasonable because it involves
the intermediacy of a secondary benzylic carbocation.
In all of the above examples, a new fused [6,6] ring system
is formed. To gain access to fused [6,5] ring systems, diene–
dienophile combinations with a one atom shorter tether would
be required. Accordingly, pyrrole-based aldehyde 5320 was N-
alkylated with cinnamyl bromide (22) in the presence of NaH in
DMF at 0 ◦C to afford ketoaldehyde 54 (64%) (Scheme 8). Inferior
results were obtained using other base/solvent combinations, i.e.
KOH/CH2Cl2, reflux, 72 h (10%); NaH/THF, reflux, 4 h (16%);
KOH/DMF, r.t., 24 h (33%).
Fig. 1 ORTEP representation (50% thermal ellipsoids) of 39 in the
crystal. C(3), C(11) and C(12) (crystallograhpic numbering) correspond
to C(7a), C(13a) and C(14), respectively (systematic numbering).
42–51 (Table 1, Entries 6–15) in 75–87% yield. As before, the
trans,trans product could be isolated by suction filtration of the
reaction mixture. On only one occasion, very small amounts of
two minor products were isolated by flash chromatography of the
filtrate (Entry 8). One of these products was identified (1H NMR,
IR, MS) as the aromatized product 52 (2%). A 13C NMR spectrum
of this compound could not be obtained due to its low solubility
in common organic solvents. Only traces (<1 mg, <1%) of the
other product were isolated. LC–MS (APCI(+)) analysis (m/z =
412, M+ + 1) suggested that it was an isomer of 44.
Scheme 8 Synthesis of ketoaldehyde 54 and its intramolecular Povarov
reaction with 3-aminocoumarin (4).
Reaction of ketoaldehyde 54 with 3-aminocoumarin (4) under
the standard Povarov reaction conditions was slow at room
temperature, but went to completion upon heating at reflux for
18 h. Povarov adduct 55 was isolated in 49% yield (Scheme 8). In
contrast to all of the previous examples, which have trans,trans
relative stereochemistry, 55 has cis,trans21 relative stereochemistry.
The stereochemical outcome is consistent either with a concerted
IEDDA step, in which the endo/exo selectivity19 is opposite to that
of the previous examples, or a stepwise ring closure leading to the
most stable product (see below).
The cis,trans relative stereochemistry in 55 was assigned on the
basis of AM1-calculated structures of modelsystem 56 (compound
55 without the acetyl group) and the observed values of the
coupling constants around the newly-formed six-membered ring
(Table 2). Of the four possible diastereomers of 56,21 cis,trans-56
With regard to the mechanism, the trans,trans relative stere-
ochemistry of the products is consistent with either a highly
endo/exo-selective,19 concerted IEDDA step or a stepwise ring
closure that leads very selectively to the most stable product. In
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Table 2 AM1-calculated relative energies of the four possible diastereomers of 56
Dihedral Angles (◦)
Isomer
Relative Energy (kcal mol-1)
H(7a)–C(7a)–C(11a)–H(11a)
H(11a)–C(11a)–C(12)–H(12)
0.0
-12.6
-91.4
5.4
9.1
9.8
19.6
-28.6
165.0
164.0
50.5
173.7
is about 5 kcal mol-1 lower in energy than cis,cis-56 and 9–10
kcal mol-1 lower in energy than trans,cis-55 and trans,trans-56.
The calculated H(7a)–C(7a)–C(11a)–H(11a) and H(11a)–C(11a)–
C(12)–H(12) dihedral angles (-12.6◦ and -91.4◦, respectively) for
cis,trans-56 are much more consistent with the observed coupling
constants (JH(7a),H(11a) = 5.4 Hz and JH(11a),H(12) ª 0 Hz) than for any
of the other three isomers of 56.
As a final avenue of investigation, the possibility of con-
ducting intramolecular Povarov reactions with electron deficient
dienophiles was investigated. This was prompted by the observa-
tion that aldehyde 33, which has a somewhat electron deficient
dienophile, still participated in the Povarov reaction, albeit slowly.
2-Formylphenyl cinnamate (59), which differs from 33 by virtue
of the carbonyl group adjacent to the double bond, was selected
for initial studies. It was synthesized (90%) from salicylaldehyde
(10) and trans-cinnamic acid (56) using slightly modified literature
conditions (Scheme 9),22 but its reaction with 4 did not show any
signs of progress after 3 h at room temperature. After heating the
reaction at reflux for 60 h, tlc analysis showed the presence of traces
of a new compound and a small amount of a white precipitate had
formed. LC–MS (APCI(+)) analysis of this precipitate (~5 mg)
showed a peak (m/z = 395) corresponding to the molecular ion of
the expected Povarov adduct 61, but the 1H NMR spectrum of this
precipitate was complicated due to the apparent presence of more
than one compound. Nevertheless, it clearly showed the presence
Scheme 9 Attempted intramolecular Povarov reaction of aldehydes 59
and 60 with 3-aminocoumarin (4).
of signals attributable to the expected Povarov adduct 61 with
trans,trans relative stereochemistry. The characteristic signals in
the 1H NMR spectrum were observed at d 5.56 (s, 1H), 4.99 (d, J =
10.0 Hz, 1H), 4.45 (d, J = 10.9 Hz, 1H) and 3.18 (m, 1H). Attempts
to purify this poorly-soluble compound were unsuccessful.
In an effort to facilitate the IEDDA step of the Po-
varov reaction and also enhance the solubility of the prod-
uct, 2,3-dimethoxycinnamic acid (58) was converted into its
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2-formylphenyl ester 60 upon reaction with salicylaldehyde (10),
albeit at low yield (Scheme 9). However, the presence of the
methoxy groups did not appear to have any beneficial effect
on the attempted Povarov reaction. As before, the reaction did
not show any signs of progress at room temperature and, after
heating at reflux for 72 h, only traces of a new product were
observed (tlc analysis). It may be that any benefit from the electron-
donating methoxy groups may be mitigated to some extent by
steric crowding. A small amount (~5 mg) of a poorly-soluble white
product was again isolated by suction filtration and it showed LC–
The solvent was removed under reduced pressure and the yellow
residue was subjected to flash chromatography (0–10% ethyl
acetate/petroleum ether) to afford 15 (0.061 g, 39%) as a pale
yellow gum, 13 (0.026 g, 17%) as an off-white solid, 14 (0.029 g,
19%) as a white solid and recovered 25 (0.014 g, 17%) as an
off-white solid.
15: dH(CDCl3) = 7.29–7.24 (m, 4H), 7.22–7.15 (m, 2H), 6.95–
6.90 (m, 2H), 6.38 (s, 1H, H-4), 6.13–6.06 (m, 1H, H-9¢), 5.44 (dd,
J = 16.8, 1.3 Hz, 1H, H-10¢ trans to H-9¢), 5.36 (br s, 1H, H-1¢),
5.31 (dd, J = 10.8, 1.7 Hz, 1H, H-10¢ cis to H-9¢), 4.62 (dd, J = 3.6,
1.8 Hz, 2H, H-2¢), 4.43 (d, J = 5.6 Hz, 2H, H-8¢) ppm; dC(CDCl3) =
159.9 (C-6), 156.5, 148.1, 133.3, 133.2, 128.94, 128.89, 125.8, 125.2,
124.7, 122.0, 121.0, 117.8, 116.2 (C-4), 111.9, 105.5, 69.0 (C-2¢),
42.7 (C-8¢) ppm; IR n = 3412 (w), 1705 (s), 1627 (m), 1602 (w),
1574 (w), 1504 (m), 1456 (m), 1355 (w), 1287 (m), 1239 (m), 1167
(m), 1117 (w) cm-1; MS m/z (relative intensity) = 308 (M++1, 21),
147 (M+-160, 100); HRMS [M+] calcd for C19H17NO3 307.1208
found 307.1211. 13: mp = 212–214 ◦C (ethyl acetate/hexanes);
dH(CDCl3) = 7.38–7.37 (m, 1H), 7.29–7.25 (m, 3H), 7.24–7.21 (m,
2H), 6.93 (t, J = 7.0 Hz, 1H), 8.87 (d, J = 8.0 Hz, 1H), 5.07 (s, 1H,
H-7), 4.53 (s, 1H, H-7a), 4.22–4.14 (m, 2H, H-13), 3.03 (dd, J =
18.3, 6.8 Hz, 1H, H-14b), 2.72 (dd, J = 18.5, 4.5 Hz, 1H, H-14a),
2.68–2.64 (m, 1H, H-13a) ppm; dC(CDCl3) = 158.3 (C-6), 153.9,
148.1, 129.9, 129.1, 126.5, 126.2, 124.8, 122.6, 121.5, 121.3, 121.1,
117.1, 116.7, 114.6, 66.7 (C-13), 47.5 (C-7a), 28.7 (C-14), 22.8 (C-
13a) ppm; IR n = 3331 (m), 1701 (s), 1612 (w), 1578 (m), 1501 (w),
1484 (m), 1469 (w), 1431 (m), 1339 (w), 1322 (w), 1289 (m), 1255
(m), 1232 (m), 1195 (s), 1127 (w), 1074 (w), 1029 (m), 1009 (w)
cm-1; MS m/z (relative intensity) = 307 (M++2, 21), 306 (M++1,
100), 304 (14), 302 (72), 174 (17); HRMS [M+] calcd for C19H15NO3
305.1052 found 305.1048. 14: mp = 222–224 ◦C; dH(DMSO-d6) =
8.79 (s, 1H), 8.30 (m, 1H), 8.24 (dd, J = 7.6, 1.0 Hz, 1H), 7.64–7.61
(m, 1H), 7.48–7.46 (m, 3H), 7.21 (t, J = 8.0 Hz, 1H), 7.07 (d, J =
8.0 Hz, 1H), 5.50 (s, 2H) ppm; dC(DMSO) = 157.9 (C-6), 156.6,
150.5, 149.1, 137.3, 132.6, 132.1, 131.2, 130.8, 127.6, 124.8, 123.8,
122.6, 121.6, 117.3, 117.1, 116.9, 67.2 (C-13) ppm; IR n = 1742
(s), 1608 (m), 1509 (s), 1432 (m), 1339 (s), 1177 (w), 1026 (s) cm-1;
MS m/z (relative intensity) = 303 (M++2, 23), 302 (M++1, 100);
HRMS [M+] calcd for C19H11NO3 301.0739 found 301.0741.
1
MS (APCI(+)) (m/z = 455) and H NMR signals (4.75 (d, J =
10.0 Hz), 4.44 (d, J = 10.0 Hz) and 3.39 (br m) that are consistent
with the expected Povarov adduct 62 with trans,trans relative
stereochemistry. The low solubility again precluded purification.
Conclusions
Intramolecular Povarov reactions involving a variety of 3-
aminocoumarins and benzaldehydes bearing a pendant dienophile
were found to proceed under mild conditions and with high
endo/exo selectivity. Using this methodology, fifteen new hete-
rocycles with a common pentacyclic core were synthesized.
Experimental section
General methods
All reactions were carried out without inert gas protection,
unless otherwise mentioned. THF was dried and distilled over
sodium/benzophenone. All other chemicals, including solvents,
were used as received, without further purification. Thin layer
chromatography (tlc) was performed on MN PolyGram precoated
silica gel plates using 254 nm UV visualization. Flash chromatog-
raphy was performed on silica gel columns. Melting points were
recorded on Fisher–Johns apparatus and are uncorrected. All
proton and carbon assignments are based on 2-D experiments
(COSY, HMQC, HMBC, see ESI for a representative example).
1H and 13C NMR spectra were recorded on Bruker AVANCE
spectrometer at 500.133 MHz and 125.770 MHz, respectively.
Peaks reported are relative to internal standards: TMS (d = 0.00)
1
2. Synthesis of 5,6,12,13-tetrahydro-5,12-dioxa-7-azadibenzo-
[a,h]anthracen-6-one (14). To a clear, colorless solution of 3-
aminocoumarin (4) (0.161 g, 1.00 mmol) in acetonitrile (10.0 mL)
was added ynal 16 (0.168 g, 1.05 mmol) followed by Yb(OTf)3
(0.031 g, 5 mol%). The reaction mixture was heated at reflux for
9 d, during which time the reaction mixture became a yellow sus-
pension. After cooling to room temperature, the reaction mixture
was subjected to suction filtration and the solids were washed with
cold dichloromethane and air-dried to afford 14 as a yellow solid
(0.111 g, 37%). The filtrate was concentrated and purified by flash
chromatography on silica gel (20% ethyl acetate/light petroleum
ether) to afford a second batch of 14 (0.029 g, 10%) as an off-white
solid and recovered 3-aminocoumarin (4) (0.030 g, 19%) as an
off-white solid. Combined yield of 14 = 0.140 g (47%).
for H and CDCl3 (d = 77.23), CD2Cl2 (d = 54.00) or DMSO-d6
(d = 39.51) for 13C spectra. Reported multiplicities are apparent.
Infrared spectra were obtained on Bruker Tensor 27 instrument
using neat samples. Low-resolution mass spectra were obtained
using Agilent 1100 series LC/MS chromatographic system and
high-resolution mass spectra were obtained using a Waters GCT
Permier Micromass mass spectrometer using neat samples. The
X-ray crystal structure of 39 was obtained on an AFC8-Saturn
single crystal X-ray diffractometer.
1. Synthesis of 3-(2-Allyloxybenzylamino)chromen-2-one
(15), (7aS*,13aR*)-5,6,7,7a,12,13,13a,14-octahydro-5,12-dioxa-
7-azadibenzo[a,h]anthracen-6-one (13) and 5,6,12,13-tetrahydro-
5,12-dioxa-7-azadibenzo[a,h]anthracen-6-one (14). To a clear,
colorless solution of enal 11 (0.087 g, 0.54 mmol) in acetonitrile
(5.0 mL) was added 3-aminocoumarin (4) (0.082 g, 0.51 mmol) at
room temperature followed by the addition of Yb(OTf)3 (0.016 g,
0.026 mmol). The clear, colorless solution turned into a clear
yellow solution instantaneously. The reaction mixture was stirred
at room temperature for 3 h and then heated at reflux for 19 h.
3. Synthesis of 14-Phenyl-5,6,12,13-tetrahydro-5,12-dioxa-7-
azadibenzo[a,h]anthracen-6-one (21). To a clear, colorless solu-
tion of 3-aminocoumarin (4) (0.081 g, 0.50 mmol) in acetonitrile
(5.0 mL) was added ynal 20 (0.125 g, 0.525 mmol) and Yb(OTf)3
(0.031 g, 10 mol%). The resulting yellow suspension was stirred
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at room temperature for 3 h. The reaction mixture was then
heated at reflux for 72 h. The mixture was cooled to room
temperature. The precipitate was isolated by suction filtration,
washed with acetonitrile and air-dried to afford 21 as a white
H-13a), 4.10 (t, J = 10.4 Hz, 1H, H-13b), 3.97 (d, J = 10.9 Hz,
1H, H-14), 2.41–2.34 (m, 1H) ppm; due to very low solubility of
this compound, a satisfactory 13C NMR spectrum could not be
obtained; the following major signals were observed: dC(CD2Cl2) =
141.7, 132.6, 132.0, 129.5, 126.8, 125.4, 124.5, 124.4, 121.3, 117.3,
116.8, 66.7 (C-13), 51.9 (C-7a), 44.9 (C-13a), 43.4 (C-14) ppm; IR
n = 3389 (w), 1704 (s), 1628 (m), 1555 (w), 1462 (m), 1457 (w),
1428 (w), 1346 (m), 1322 (w), 1281 (w), 1260 (w), 1238 (m), 1189
(m), 1172 (m), 1051 (m) cm-1; HRMS [M+] calcd for C25H18NO3Br
459.0470, found 459.0471.
◦
solid (0.085 g, 43%). mp = 277–279 C (decomp); dH(CD2Cl2) =
8.35 (d, J = 7.8 Hz, 1H), 7.55–7.54 (m, 3H), 7.32 (t, J = 7.5 Hz,
1H), 7.28–7.27 (m, 2H), 7.23–7.22 (m, 2H), 7.10 (t, J = 7.2 Hz,
1H), 6.88 (d, J = 7.7 Hz, 1H), 6.77–6.72 (m, 2H), 4.94 (s, 2H)
ppm; dC(CD2Cl2) = 159.3 (C-6), 157.2, 151.6, 150.2, 144.6, 139.2,
136.8, 133.2, 131.6, 130.9, 130.8, 130.0, 129.5, 128.5, 127.9, 126.3,
124.3, 123.3, 122.6, 118.3, 118.1, 117.5, 66.7 (C-13) ppm; MS m/z
(relative intensity) = 379 (M++2, 29), 378 (M++1, 100); HRMS
[M+] calcd for C25H15NO3 377.1052 found 377.1049.
7. Synthesis of (7aR*,13aR*,14S*)-14-(4-nitrophenyl)- 5,6,7,
7a,12,13,13a,14-octahydro-5,12–dioxa-7-azadibenzo[a,h]anthra-
cen-6-one (39). According to the general procedure, 3-
aminocoumarin (4) (0.055 g, 0.34 mmol), enal 33 (0.10 g,
0.36 mmol) and Yb(OTf)3 (0.021 g, 10 mol%) afforded 39 as a
pale yellow solid (0.104 g, 72%). mp = 239–240 ◦C; dH(CD2Cl2) =
8.17 (m, 2H), 7.43–7.41 (m, 3H), 7.34 (d, J = 7.4 Hz, 1H), 7.25–
7.18 (m, 2H), 7.04 (t, J = 7.5 Hz, 1H), 6.94 (t, J = 7.2 Hz, 1H),
6.84 (d, J = 7.7 Hz, 2H), 5.55 (s, 1H, H-7), 4.45 (d, J = 10.7 Hz,
1H, H-7a), 4.29 (dd, J = 10.3, 3.2 Hz, 1H, H-13a), 4.13–4.09 (m,
2H), 2.39–2.35 (m, 1H, H-13a) ppm; dC(CD2Cl2) = 159.0 (C-6),
154.4, 150.5, 149.2, 147.9, 132.7, 129.9, 129.6, 127.2, 125.7, 125.0,
124.7, 124.3, 121.7, 121.2, 120.4, 119.5, 117.6, 117.2, 66.7 (C-12),
52.1 (C-7a), 44.9 (C-13a), 44.0 (C-14) ppm; IR n = 3401 (w), 1705
(s), 1629 (m), 1552 (m), 1489 (m), 1448 (w), 1431 (m), 1327 (w),
1277 (w), 1258 (w), 1236 (m), 1181 (m), 1176 (w), 1042 (m) cm-1;
HRMS [M+] calcd for C25H18N2O5 426.1216, found 426.1211.
4. Synthesis of (7aR*,13aR*,14S*)-14-phenyl-5,6,7,7a,12,13,
13a,14-octahydro-5,12-dioxa-7-azadibenzo[a,h]anthracen-6-one
(24). To a clear colorless solution of 3-aminocoumarin (4)
(0.097 g, 0.60 mmol) in acetonitrile (6.0 mL) was added enal 23
(0.15 g, 0.63 mmol) followed by Yb(OTf)3 (0.037 g, 10 mol%). The
resulting clear yellow solution was stirred at room temperature
for 1 h. The reaction turned into a pale yellow suspension over
the course of the reaction. The product was isolated by suction
filration to afford 24 as a white solid (0.195 g, 85%). mp = 268–
269 ◦C; dH(CD2Cl2) = 7.36 (d, J = 7.7 Hz, 1H), 7.30–7.28 (m, 2H),
7.27–7.26 (m, 2H), 7.25–7.23 (m, 3H), 7.21–7.19 (m, 1H), 7.07–
7.05 (m, 1H), 6.98–6.95 (m, 2H), 6.85 (d, J = 7.4 Hz, 1H), 5.49
(s, 1H, H-7), 4.42 (d, J = 11.1 Hz, 1H, H-7a), 4.36 (dd, J = 10.6,
3.1 Hz, 1H, H-13a), 4.11 (t, J = 10.6 Hz, 1H, H-b), 3.98 (d, J =
11.0 Hz, 1H, H-14), 2.44–2.39 (m, 1H, H-13a) ppm; dC(CD2Cl2) =
159.1 (C-6), 154.4, 150.5, 149.0, 142.5, 132.1, 129.5, 129.4, 129.1,
126.7, 125.7, 125.5, 124.7, 124.2, 121.5, 121.2, 120.8, 117.3, 116.7,
66.9 (C-12), 52.0 (C-7), 45.0 (C-13a), 44.0 (C-14) ppm; IR n =
3334 (m), 1702 (s), 1618 (w), 1581 (w), 1492 (m), 1475 (w), 1445
(w), 1347 (m), 1322 (m), 1287 (w), 1252 (m), 1229 (m), 1191 (s),
1129 (w), 1116 (w), 1074 (w), 1050 (m), 1028 (w), 1012 (w) cm-1;
MS m/z (relative intensity) = 383 (M++2, 14), 382 (M++1, 53),
380 (29), 379 (29), 378 (100); HRMS [M+] calcd for C25H19NO3
381.1365, found 381.1371.
8. Synthesis of (7aR*,13aR*,14S*)-11-methoxy-14-phenyl-5,
6,7,7a,12,13,13a,14-octahydro-5,12-dioxa-7-azadibenzo[a,h]anth-
racen-6-one (40). According to the general procedure, 3-
aminocoumarin (4) (0.040 g, 0.25 mmol), enal 35 (0.070 g,
0.26 mmol) and Yb(OTf)3 (0.016 g, 10 mol%) afforded 40 as a
white solid (0.092 g, 89%). mp = 261–262 ◦C; dH(CD2Cl2) = 7.30–
7.27 (m, 3H), 7.26–7.24 (m, 1H), 7.22–7.19 (m, 3H), 7.01–6.96
(m, 4H), 6.88 (d, J = 6.9 Hz, 1H), 5.42 (s, 1H, H-7), 4.42–4.38
(m, 2H, H-7a, H-13a), 4.06 (t, J = 11.0 Hz, 1H, H-13b), 3.94
(d, J = 11.1 Hz, 1H, H-14), 3.79 (s, 3H, C-11-OCH3), 2.41–2.35
(m, 1H, H-13a) ppm; dC(CD2Cl2) = 159.3 (C-6), 149.23, 149.21,
144.2, 142.6, 132.4, 129.6, 128.7, 127.8, 126.8, 124.9, 124.4, 122.3,
121.3, 121.1, 121.0, 117.2, 116.9, 111.7, 67.2 (C-13), 56.4 (C-11-
OCH3), 52.2 (C-7a), 45.1 (C-13a), 44.2 (C-14) ppm; IR n = 3396
(w), 1717 (s), 1616 (w), 1598 (w), 1580 (w), 1494 (m), 1483 (m),
1457 (m), 1442 (m), 1342 (m), 1269 (m), 1216 (m), 1198 (m), 1181
(m), 1130 (m), 1115 (w), 1091 (m), 1063 (m) cm-1; MS m/z (relative
intensity) = 413 (M++2, 24), 412 (M++1, 97), 411 (42), 410 (100);
HRMS [M+] calcd for C26H21NO4 411.1471 found 411.1461.
5. General procedure for the intramolecular Povarov reactions.
To a solution of 3-aminocoumarin in acetonitrile (~0.1 M solution)
was added enal (1.05 equiv) and Yb(OTf)3 (10 mol%) at room tem-
perature. The resulting mixture was stirred at room temperature
or heated at reflux as specified until complete consumption of the
starting material (3-aminocoumarin) was observed by tlc analysis.
The resulting slurry was subjected to suction filtration and the
solids were washed with cold acetonitrile and air-dried to afford
the product. The filtrate was subjected to flash chromatography
depending upon the result of LC/MS analysis.
9. Synthesis of (7aR*,13aR*,14S*)-9-bromo-14-phenyl-5,
6,7,7a,12,13,13a,14-octahydro-5,12-dioxa-7-azadibenzo[a,h]anth-
racen-6-one (41). According to the general procedure, 3-
aminocoumarin (4) (0.040 g, 0.25 mmol), enal 37 (0.082 g,
0.26 mmol) and Yb(OTf)3 (0.016 g, 10 mol%) afforded 41 as a
white solid 0.10 g, 89%). mp = 271–272 ◦C; dH(CDCl3) = 7.51 (s,
1H), 7.32–7.23 (m, 5H), 7.19–7.13 (m, 3H), 6.97–6.90 (m, 2H),
6.71 (d, 1H, J = 8.8 Hz), 5.41 (s, 1H, H-7), 4.44–4.33 (m, 2H,
H-7a, H-13a), 4.05 (t, J = 10.7 Hz, 1H, H-13b), 3.90 (d, J =
10.6 Hz, 1H, H-14), 2.40–2.11 (m, 1H, H-13a) ppm; dC(CDCl3) =
159.0 (C-6), 153.1, 148.7, 141.7, 132.2, 131.4, 129.4, 128.0, 127.6,
6. Synthesis of (7aR*,13aR*,14S*)-14-(4-bromophenyl)- 5,6,
7,7a,12,13,13a,14-octahydro-5,12-dioxa-7-azadibenzo[a,h]anth-
racen-6-one (38). According to the general procedure, 3-
aminocoumarin (4) (0.135 g, 0.840 mmol), enal 32 (0.28,
0.88 mmol) and Yb(OTf)3 (0.052 g, 10 mol%) afforded 38 as a
◦
white solid (0.32 g, 84%). mp = 276–278 C; dH(CD2Cl2) = 7.48
(d, J = 7.1 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 7.8 Hz,
1H), 7.26–7.22 (m, 2H), 7.16–7.15 (m, 2H), 7.07 (t, J = 6.9 Hz,
1H), 7.01–6.98 (m, 2H), 6.87 (d, J = 7.1 Hz, 1H), 5.51 (s, 1H, H-7),
4.43 (d, J = 10.8 Hz, 1H, H-7a), 4.34 (dd, J = 10.4 Hz, 2.7 Hz, 1H,
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126.7, 124.5, 124.2, 123.0, 121.2, 120.2, 119.0, 116.6, 113.1, 66.7
(C-13), 51.4 (C-7a), 44.2 (C-13a), 43.8 (C-14) ppm (one carbon
signal fewer than expected); IR n = 3357 (w), 1720 (s), 1630
(m), 1602 (w), 1501 (m), 1484 (m), 1461 (m), 1451 (s), 1404 (w),
1367 (m), 1322 (m), 1292 (w), 1256 (m), 1234 (m), 1198 (s), 1176
(m), 1137 (w), 1116 (w), 1091 (w), 1072 (w), 1047 (m), 1034 (s)
cm-1; MS m/z (GC-MS) (relative intensity) = 461 (M+(81), 94), 459
(M+(79), 100); HRMS [M+] calcd for C25H18BrNO3 459.0470 found
459.0476.
0.40 mmol), enal 23 (0.10 g, 0.42 mmol) and Yb(OTf)3 (0.025 g,
10 mol%) afforded 44 as an off-white solid (0.14 g, 84%).
Additionally, flash chromatography (ethyl acetate) of the filtrate
afforded 52 as a white solid (0.003 g, 2%). 44: mp = 228–229 ◦C.
dH(CD2Cl2) = 7.41 (d, J = 7.1 Hz, 1H, H-8), 7.35–7.32 (m, 2H),
7.28 (d, J = 7.0 Hz, 1H), 7.26–7.20 (m, 3H), 7.17 (d, J = 8.8 Hz,
1H, H-4), 7.02 (t, J = 7.4 Hz, 1H, H-9), 6.82 (d, J = 8.4 Hz, 1H,
H-11), 6.73 (dd, J = 8.9, 2.1 Hz, 1H, H-3), 6.42 (d, J = 2.0 Hz, 1H,
H-1), 5.49 (s, 1H, H-7), 4.41 (d, J = 10.2 Hz, 1H, H-7a), 4.32 (dd,
J = 10.7, 3.0 Hz, 1H, H-13a), 4.07 (t, J = 11.1 Hz, 1H, H-13b),
3.91 (d, J = 11.3 Hz, 1H, H-14), 3.42 (s, 3H, C-2-OCH3), 2.41 (m,
1H, H-13a) ppm; dC(CD2Cl2) = 159.3 (C-6), 156.2, 154.6, 143.5,
142.7, 132.5, 129.7, 129.6, 128.7, 127.9, 125.6 (C-8), 121.6, 121.5
(C-9), 121.4, 120.9, 117.7, 117.5 (C-11), 114.4 (C-3), 107.9 (C-1),
67.2 (C-13), 55.9 (C-2-OCH3), 52.1 (C-7a), 44.8 (C-14), 44.4 (C-
13a) ppm; IR n = 3360 (w), 1702 (s), 1614 (w), 1560 (w), 1499
(m), 1467 (w), 1451 (w), 1426 (w), 1343 (m), 1319 (w), 1282 (w),
1258 (w), 1234 (w), 1187 (m), 1170 (m), 1050 (m) cm-1; MS m/z
(relative intensity) = 413 (M++2, 30), 412 (M++1, 100), 411 (39),
410 (69), 408 (65). HRMS [M+] calcd for C26H21NO4 411.1471,
found 411.1465. 52: mp = 273–274 ◦C (decomp); dH(CDCl3) =
8.54 (dd, J = 7.6, 2.4 Hz, 1H), 7.68–7.65 (m, 2H), 7.59 (d, J =
7.3 Hz, 1H), 7.40–7.38 (m, 1H), 7.35 (d, J = 6.5 Hz, 1H), 7.27–
7.26 (m, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.94–6.90 (m, 2H), 6.47
(d, J = 7.0 Hz, 1H), 4.98 (s, 2H), 3.29 (s, 3H) ppm; dC(CDCl3) =
due to small quantity and low solubility of this compound, 13C
NMR data could not be obtained. IR n = 1734 (s), 1597 (w), 1561
(w), 1499 (m), 1465 (s), 1431 (m), 1376 (m), 1294 (m), 1252 (m),
1215 (s), 1190 (m), 1153 (s), 1110 (m), 1085 (w), 1061 (w), 1039 (s),
1020 (m) cm-1; MS m/z (relative intensity) = 409 (M++2, 26), 408
(M++1, 100); HRMS [M+] calcd for C26H17NO4 407.1158, found
407.1160
10. Synthesis of (7aR*,13aR*,14S*)-2-methyl-14-phenyl-5,6,
7,7a,12,13,13a,14-octahydro-5,12-dioxa-7-azadibenzo[a,h]anthra-
cen-6-one (42). According to the general procedure, 3-amino-
6-methylcoumarin (25) (0.105 g, 0.600 mmol), enal 23 (0.15 g,
0.63 mmol) and Yb(OTf)3 (0.037 g, 10 mol%) afforded 42 as an
off-white solid (0.206 g, 87%). mp = 228–229 ◦C; dH(CD2Cl2) =
7.24–7.21 (m, 2H), 7.19–7.17 (m, 2H), 7.15–7.11 (m, 3H), 7.10–
7.07 (m, 1H), 6.94–6.91 (m, 1H), 8.86–6.83 (m, 1H), 6.62 (d, J =
8.4 Hz, 1H), 5.43 (s, 1H, H-7), 4.34 (d, J = 10.8 Hz, 1H, H-7a),
4.29 (dd, J = 10.7, 3.5 Hz, 1H, H-13a), 3.96 (t, J = 11.0 Hz,
1H, H-13b), 3.88 (d, J = 11.1 Hz, 1H, H-14), 2.32–2.24 (m, 1H,
H-13a), 2.23 (s, 3H, C-2-CH3) ppm; dC(CD2Cl2) = 159.4 (C-6),
152.3, 149.3, 142.7, 132.4, 130.9, 130.3, 129.6, 128.7, 127.8, 126.8,
125.9, 124.9, 124.4, 121.4, 121.2, 121.0, 117.2, 116.9, 67.1 (C-13),
52.2 (C-7a), 45.3 (C-13a), 44.3 (C-14), 20.8 (C-2-CH3) ppm; IR
n = 3366 (w), 1727 (s), 1699 (w), 1684 (w), 1652 (w), 1628 (m), 1558
(m), 1541 (w), 1499 (s), 1465 (m), 1340 (m), 1323 (m), 1287 (w),
1257 (m), 1222 (m), 1192 (m), 1180 (m), 1117 (m), 1073 (w), 1048
(m), 1036 (m) cm-1; MS m/z (relative intensity) = 397 (M++2, 28),
396 (M++1, 100), 395 (16), 394 (22), 392 (47). HRMS [M+] calcd
for C26H21NO3 395.1521 found 395.1520.
11. Synthesis of (7aR*,13aR*,14S*)-11-methoxy-2-methyl-14-
phenyl-5,6,7,7a,12,13,13a,14-octahydro-5,12-dioxa-7-azadiben-
zo[a,h]anthracen-6-one (43). According to the general procedure,
3-amino-6-methylcoumarin (0.044 g, 0.25 mmol) (25), enal 35
(0.070 g, 0.26 mmol) and Yb(OTf)3 (0.016 g, 10 mol%) afforded
43 as a white solid (0.089 g, 84%). mp = 230–232 ◦C; dH(CD2Cl2) =
7.24 (t, J = 7.0 Hz, 2H), 7.18 (d, J = 6.8 Hz, 1H), 7.14–7.13 (m,
2H), 7.06 (d, J = 8.4 Hz, 1H), 6.94–6.87 (m, 3H), 6.77 (d, J =
7.8 Hz, 1H), 6.73 (s, 1H), 5.32 (s, 1H, H-7), 4.33 (dd, J = 11.3,
3.5 Hz, 1H, H-13a), 4.30 (d, J = 10.9 Hz, 1H, H-7a), 3.98 (t, J =
11.5 Hz, 1H, H-13b), 3.84 (d, J = 10.8 Hz, 1H, H-14), 3.72 (s, 3H,
C-11-OCH3), 2.31 (m, 1H, H-13a), 2.00 (s, 3H, C-2-CH3) ppm;
dC(CD2Cl2) = 159.5 (C-6), 149.2, 147.3, 144.2, 142.7, 134.0, 132.3,
129.6, 128.7, 127.8, 125.1, 122.4, 121.5, 121.1, 120.6, 117.2, 116.5,
111.7 (C-10), 67.2 (C-13), 56.4 (C-11-OCH3), 52.1 (C-7a), 44.8 (C-
13a), 44.1 (C-14), 28.6 (C-2-CH3) ppm (one carbon signal fewer
than expected); IR n = 3358 (w), 1701 (s), 1678 (w), 1650 (w), 1613
(m), 1501 (s), 1469 (m), 1345 (w), 1312 (w), 1281 (w), 1252 (m),
1219 (m), 1191 (m), 1172 (w), 1119 (m), 1065 (w), 1033 (m) cm-1;
MS m/z (relative intensity) = 427 (M++2, 30), 426 (M++1, 100),
425 (18), 424 (32), 422 (11); HRMS [M+] calcd for C27H23NO4
425.1627, found 425.1623.
13. Synthesis of (7aR*,13aR*,14S*)-2,11-dimethoxy-14-phe-
nyl-5,6,7,7a,12,13,13a,14-octahydro-5,12-dioxa-7-azadibenzo-
[a,h]anthracen-6-one (45). According to the general procedure,
3-amino-6-methoxycoumarin (0.048 g, 0.25 mmol) (26), enal 35
(0.070 g, 0.26 mmol) and Yb(OTf)3 (0.016 g, 10 mol%) afforded
45 as a white solid (0.094 g, 85%). mp = 258–260 ◦C; dH(CD2Cl2) =
7.25 (t, J = 7.4 Hz, 2H), 7.19 (d, J = 7.4 Hz, 1H, H-4), 7.09–7.08
(m, 2H), 7.08 (d, J = 9.1 Hz, 1H), 6.93–6.87 (m, 2H), 6.76 (d, J =
7.7 Hz, 1H, H-10), 6.64 (dd, J = 9.0, 3.1 Hz, 1H, H-3), 6.34 (d,
J = 2.9 Hz, 1H, H-1), 5.37 (s, 1H, H-7), 4.34–4.30 (m, 2H, H-7a,
H-13a), 3.97 (t, J = 11.1 Hz, 1H, H-13b), 3.83 (d, J = 10.2 Hz,
1H, H-14), 3.71 (s, 3H, C-11-OCH3), 3.33 (s, 3H, C-2-OCH3),
2.32 (m, 1H, H-13a) ppm; dC(CD2Cl2) = 159.3 (C-6), 156.2, 149.2,
144.2, 143.5, 142.7, 132.5, 129.7, 128.7 (C-4), 127.9, 122.3, 121.5,
121.1, 120.8, 117.6, 117.2, 114.3 (C-3), 111.7 (C-10), 107.9 (C-1),
67.2 (C-13), 56.4 (C-11-OCH3), 55.9 (C-2-OCH3), 52.1 (H-7a),
44.7 (H-13a), 44.4 (H-14) ppm; IR n = 3365 (w), 1699 (s), 1619
(w), 1555 (m), 1501 (m), 1468 (w), 1421 (m), 1329 (m), 1302 (w),
1285 (w), 1257 (w), 1232 (m), 1182 (m), 1169 (m), 1029 (m) cm-1;
MS m/z (relative intensity) = 443 (M++2, 32), 442 (M++1, 100),
441 (24), 440 (48), 438 (26); HRMS [M+] calcd for C27H23NO5
441.1576, found 441.1577.
12. Synthesis of (7aR*,13aR*,14S*)-2-methoxy-14-phenyl-5,
6,7,7a,12,13,13a,14-octahydro-5,12-dioxa-7-azadibenzo[a,h]anth-
racen-6-one (44) and 2-methoxy-14-phenyl-5,6,12,13-tetrahydro-
5,12-dioxa-7-azadibenzo[a,h]anthracen-6-one (52). According to
the general procedure, 3-amino-6-methoxycoumarin (26) (0.076 g,
14. Synthesis of (7aR*,13aR*,14S*)-2-bromo-14-phenyl-5,6,
7,7a,12,13,13a,14-octahydro-5,12-dioxa-7-azadibenzo[a,h]anthra-
cen-6-one (46). According to the general procedure, 3-amino-
6-bromocoumarin (27) (0.072 g, 0.30 mmol), enal 23 (0.075 g,
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0.32 mmol) and Yb(OTf)3 (0.019 g, 10 mol%) afforded 46 as a
white solid (0.11 g, 78%). mp = 273–274 ◦C; dH(DMSO-d6) = 7.68
(dd, J = 7.2, 2.6 Hz, 1H, H-3), 7.40–7.37 (m, 3H), 7.34–7.30 (m,
4H), 7.24 (m, 1H), 7.22–7.21 (m, 1H), 7.19 (dd, J = 7.8, 2.8 Hz,
1H), 6.68 (d, J = 8.4 Hz, 1H, H-11), 6.08 (s, 1H, H-7), 4.42 (d, J =
10.2 Hz, 1H, H-7a), 4.29–4.04 (m, 3H), 2.13–2.05 (m, 1H, H-13a)
ppm; dC(CD2Cl2) = 159.1 (C-6), 154.5, 150.4, 149.2, 147.9, 131.6,
130.0, 129.7, 127.2, 125.6, 125.0, 124.8, 124.4, 121.6, 121.3 (C-9),
120.4, 119.6, 117.5, 117.2 (C-11), 66.7 (13), 52.1 (C-7a), 44.9 (C-
14), 44.0 (C-13a) ppm; IR n = 3392 (w), 1703 (s), 1620 (m), 1595
(w), 1583 (w), 1559 (w), 1488 (s), 1458 (m), 1410 (m), 1343 (s), 1310
(m), 1275 (m), 1254 (w), 1230 (w), 1217 (m), 1201 (s), 1137 (w),
1077 (m), 1048 (s), 1024 (m), 1009 (m) cm-1; HRMS [M+] calcd for
C25H18NO3Br 459.0470, found 459.0468.
(0.070 g, 0.26 mmol) and Yb(OTf)3 (0.016 g, 10 mol%) afforded
49 as a pale yellow solid (0.089 g, 78%). mp = 257–259 ◦C;
dH(CD2Cl2) = 7.89 (dd, J = 8.7, 2.3 Hz, 1H), 7.82 (d, J = 2.7 Hz,
1H), 7.29–7.26 (m, 3H), 7.21–7.19 (m, 3H), 6.93–6.89 (m, 2H), 6.78
(dd, J = 7.2, 1.5 Hz, 1H), 5.53 (s, 1H, H-7), 4.41 (d, J = 10.7 Hz,
1H, H-7a), 4.31 (dd, J = 10.7 Hz, 3.2 Hz, 1H, H-13a), 3.98 (t,
J = 11.5 Hz, 1H, H-13b), 3.90 (d, J = 11.3 Hz, 1H, H-14), 3.72 (s,
3H, C-11-OCH3), 2.36 (m, 1H, H-13a) ppm; dC(CD2Cl2) = 163.2
(C-6), 158.1, 152.4, 149.3, 144.5, 144.3, 141.4, 133.2, 130.0, 128.3,
121.74, 121.67, 121.4, 121.3, 120.7, 119.2, 117.8, 117.0, 111.9, 67.1
(C-13), 56.5 (C-11-OCH3), 52.1 (C-7a), 44.5 (C-13a), 44.1 (C-14)
ppm; IR n = 3395 (w), 1725 (s), 1629 (m), 1560 (m), 1499 (m), 1467
(w), 1451 (w), 1426 (w), 1343 (m), 1319 (w), 1282 (w), 1258 (w),
1234 (w), 1187 (m), 1170 (m), 1050 (m) cm-1; MS m/z (relative
intensity) = 457 (M++1, 14), 456 (M+, 52), 455 (100), 419 (26), 214
(56); HRMS [M+] calcd for C26H20N2O6 456.1321 found 456.1325.
15. Synthesis of (7aR*,13aR*,14S*)-2-bromo-11-methoxy-14-
phenyl-5,6,7,7a,12,13,13a,14-octahydro-5,12-dioxa-7-azadiben-
zo[a,h]anthracen-6-one (47). According to the general procedure,
3-amino-6-bromocoumarin (0.060 g, 0.25 mmol) (27), enal 35
(0.070 g, 0.26 mmol) and Yb(OTf)3 (0.016 g, 10 mol%) afforded
47 as an off-white solid (0.092 g, 75%). mp = 253–255 ◦C;
dH(CD2Cl2) = 7.28–7.26 (m, 2H), 7.22 (m, 1H), 7.17 (dd, J = 9.2,
1.8 Hz, 1H, H-3), 7.13 (m, 2H), 7.07 (d, J = 8.1 Hz, 1H, H-4), 7.02
(d, J = 2.1 Hz, 1H, H-1), 6.93–6.88 (m, 2H), 6.78 (d, J = 7.4 Hz,
1H, H-10), 5.44 (s, 1H, H-7), 4.35 (d, J = 11.5 Hz, 1H, H-7a), 4.31
(dd, J = 10.9 Hz, J = 3.9 Hz, 1H, H-13a), 3.97 (t, J = 11.3 Hz, 1H,
H-13b), 3.80 (d, J = 11.1 Hz, 1H, H-14), 3.72 (s, 3H, C-11-OCH3),
2.31 (m, 1H, H-13a) ppm; dC(CD2Cl2) = 158.7 (C-6), 149.3, 148.0,
142.2, 141.9, 132.8, 129.8, 129.3 (C-3), 128.1, 127.5 (C-1), 122.9,
122.0, 121.2, 119.4, 118.5 (C-4), 117.2, 117.1, 111.8 (C-10), 67.2
(C-13), 56.4 (C-11-OCH3), 52.1 (C-7a), 44.8 (C-13a), 44.1 (C-14)
ppm (one carbon signal fewer than expected); IR n = 3351 (m),
1710 (s), 1614 (w), 1584 (w), 1497 (m), 1482 (s), 1455 (m), 1407
(w), 1345 (m), 1316 (w), 1263 (s), 1229 (s), 1214 (m), 1203 (m),
1122 (w), 1091 (w), 1077 (w), 1059 (w), 1037 (s) cm-1; HRMS [M+]
calcd for C26H20BrNO4 489.0576, found 489.0574.
18. Synthesis of (7aR*,13aR*,14S*)-4-Methoxy-14-phenyl-
5,6,7,7a,12,13,13a,14-octahydro-5,12-dioxa-7-azadibenzo[a,h]-
anthracen-6-one (50). According to the general procedure, 3-
amino-8-methoxycoumarin (0.076 g, 0.40 mmol) (29), enal 23
(0.10 g, 0.42 mmol) and Yb(OTf)3 (0.025 g, 10 mol%) afforded
50 as an off-white solid (0.141 g, 86%). mp = 276–278 ◦C;
dH(CD2Cl2) = 7.33 (d, J = 7.6 Hz, 1H), 7. 23 (m, 2H), 7.16 (m, 1H),
7.12 (m, 3H), 6.93 (t, J = 7.3 Hz, 1H), 6.78 (t, J = 7.8 Hz, 1H), 6.74
(d, J = 7.8 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.51 (d, J = 8.3 Hz,
1H), 5.37 (s, 1H, H-7), 4.30 (d, J = 10.3 Hz, 1H, H-7a), 4.24 (dd,
J = 10.7, 3.3 Hz, 1H, H-13a), 3.98 (t, J = 11.0 Hz, 1H, H-13b),
3.84 (d, J = 10.5 Hz, 1H, H-14), 3.83 (s, 3H, C-4-OCH3), 2.29 (m,
1H, H-13a) ppm; dC(CD2Cl2) = 158.9 (C-6), 154.6, 147.8, 142.9,
138.8, 132.5, 129.6, 128.7, 127.8, 125.7, 124.1, 121.8, 121.7, 121.6,
121.4, 117.5, 116.7, 109.4, 67.1 (C-13), 56.7 (C-4-OCH3), 52.2 (C-
7a), 45.2 (C-13a), 44.4 (C-14) ppm (one carbon signal fewer than
expected) ppm; IR n = 3332 (m), 1682 (s), 1622 (w), 1600 (w), 1575
(m), 1483 (m), 1452 (m), 1345 (m), 1281 (m), 1260 (w), 1223 (m),
1212 (m), 1197 (m), 1179 (s), 1133 (w), 1108 (w), 1063 (w), 1050
(w), 1028 (m), 1003 (m) cm-1; MS m/z (relative intensity) = 413
(M++2, 27), 412 (M++1, 100), 411 (25), 410 (48), 408 (43); HRMS
[M+] calcd for C26H21NO4 411.1471, found 411.1474.
16. Synthesis of (7aR*,13aR*,14S*)-2-nitro-14-phenyl-5,6,
7,7a,12,13,13a,14-octahydro-5,12-dioxa-7-azadibenzo[a,h]anth-
racen-6-one (48). According to the general procedure, 3-amino-
6-nitrocoumarin (28) (0.062 g, 0.30 mmol), enal 23 (0.075 g,
0.32 mmol) and Yb(OTf)3 (0.019 g, 10 mol%) afforded 48 as a
pale yellow solid (0.105 g, 82%). mp = 262–263 ◦C; dH(CD2Cl2) =
8.00 (dd, J = 9.0 Hz, 1.8 Hz, 1H, H-3), 7.82 (d, J = 2.4 Hz, 1H,
H-1), 7.41–7.36 (m, 4H), 7.33–7.18 (m, 4H), 7.04 (t, J = 7.8 Hz,
1H, H-10), 6.82 (t, J = 7.3 Hz, 1H, H-9), 5.61 (s, 1H, H-7), 4.49 (d,
J = 10.4 Hz, 1H, H-7a), 4.29 (dd, J = 10.3, 3.2 Hz, 1H, H-13a),
4.04 (t, J = 10.3 Hz, 1H, H-13b), 3.99 (d, J = 10.6 Hz, 1H, H-14),
2.48–2.40 (m, 1H, H-13a) ppm; dC(CD2Cl2) = 158.7 (C-6), 152.3
151.2, 144.0, 140.9, 132.4, 130.0, 129.8, 128.4, 128.3, 128.0, 125.4,
121.6, 121.5, 120.5, 120.4, 119.4, 119.2, 117.5, 67.8 (C-13), 52.2
(C-7a), 42.1 (C-13a), 41.9 (C-14) ppm; IR n = 3354 (m), 1718 (s),
1583 (w), 1527 (s), 1490 (s), 1336 (s), 1254 (m), 1234 (w), 1185
(m), 1105 (w), 1049 (m) cm-1; HRMS [M+] calcd for C25H18N2O5
426.1216, found 426.1215.
19. Synthesis of (7aR*,13aR*,14S*)-4,11-dimethoxy-14-phe-
nyl-5,6,7,7a,12,13,13a,14-octahydro-5,12-dioxa-7-azadibenzo-
[a,h]anthracen-6-one (51). According to the general procedure,
3-amino-8-methoxycoumarin (0.048 g, 0.25 mmol) (29), enal 35
(0.070 g, 0.26 mmol) and Yb(OTf)3 (0.016 g, 10 mol%) afforded
51 as an off-white solid (0.095 g, 86%). mp = 265–266 ◦C;
dH(CD2Cl2) = 7.31–7.29 (m, 2H), 7.26–7.23 (m, 1H), 7.19–7.18
(m, 2H), 7.01 (d, J = 7.8 Hz, 1H), 6.97 (t, J = 8.3 Hz, 1H), 6.87–
6.84 (m, 2H), 6.77 (d, J = 7.5 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 5.43
(s, 1H, H-7), 4.41–4.37 (m, 2H, H-7a, H-13a), 4.05 (t, J = 11.0 Hz,
1H, H-13b), 3.92–3.91 (m, 4H, H-14), 3.79 (s, 3H), 2.36 (m, 1H,
H-13a) ppm; dC(CD2Cl2) = 158.8, 149.2, 147.8, 144.2, 142.8, 138.7,
132.5, 129.6, 128.6, 127.7, 124.0, 122.3, 121.8, 121.5, 121.1, 117.2,
116.7, 111.7, 109.3, 67.1, 56.7, 56.4, 52.1, 45.1, 44.3 ppm; IR n =
3345 (m), 1681 (s), 1602 (w), 1576 (m), 1558 (w), 1483 (m), 1439
(m), 1337 (m), 1258 (m), 1205 (s), 1175 (s), 1133 (m), 1109 (m),
1090 (m), 1064 (s) cm-1; MS m/z (relative intensity) = 443 (M++2,
32), 442 (M++1, 100), 440 (12); HRMS [M+] calcd for C27H23NO5
441.1576 found 441.1583.
17. Synthesis of (7aR*,13aR*,14S*)-11-methoxy-2-nitro-14-
phenyl-5,6,7,7a,12,13,13a,14-octahydro-5,12-dioxa-7-azadiben-
zo[a,h]anthracen-6-one (49). According to the general procedure,
3-amino-6-nitrocoumarin (0.052 g, 0.25 mmol) (28), enal 35
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20. Synthesis of (7aS*,11aS*,12R*)-9-acetyl-12-phenyl-7,7a,
10a,11,11a,12-hexahydro-6H-chromeno[3,4-b]pyrrolizino[2,1-e]-
pyridin-6-one (55). According to the general procedure, 3-
aminocoumarin (4) (0.040 g, 0.25 mmol), enal 54 (0.066 g,
0.26 mmol) and Yb(OTf)3 (0.016 g, 10 mol%) were reacted at
rt for 6 h and then heated at reflux for 18 h. The precipitate was
suction filtered and the solids were washed with cold acetonitrile
to afford 55 as a pale yellow solid (0.038 g, 38%). The solvent was
removed from filtrate under reduced pressure and the residue was
subjected to flash chromatography (30% ethyl acetate/hexanes) to
afford 55 as a pale yellow solid (0.011 g, 11%). Combined yield =
0.049 g, 49%. mp = 265–266 ◦C; dH(CDCl3) = 7.36–7.33 (m, 4H),
7.30–7.26 (m, 2H), 7.24 (s, 1H), 7.22–7.18 (m, 2H), 7.12–7.08 (m,
1H), 6.47 (s, 1H), 4.93 (s, 1H, H-7), 4.65 (d, J = 5.4 Hz, 1H, H-7a),
4.30 (s, 1H, H-12), 4.23 (dd, J = 10.8, 7.4 Hz, 1H, H-11a), 3.84 (t,
J = 10.8 Hz, 1H, H-11b), 3.40–3.35 (m, 1H, H-11a), 2.35 (s, 3H,
COCH3) ppm; dC(CDCl3) = 193.4 (COCH3), 158.2 (C-6), 148.0,
142.5, 138.7, 129.8, 129.5, 128.5, 127.8, 127.5, 126.2, 124.9, 121.6,
120.8, 116.7, 112.0, 102.3, 50.1 (C-11), 49.4 (C-11a), 46.7 (C-7a),
38.9 (C-12), 27.2 (COCH3) ppm; MS m/z (relative intensity) =
400 (M++2, 21), 399 (100); HRMS [M+] calcd for C25H20N2O3
396.1474 found 396.1479.
E. Maruthi, V. Reddy and J. S. Yadav, Synth. Commun., 2003, 33, 3063;
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9 S. S. Mathur and H. Suschitzky, J. Chem. Soc., Perkin Trans. 1, 1975,
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10 A conformer with H(7a) axial and H(13a) equatorial was calculated to
have a dihedral angle of 44.6◦. A conformer with H(7a) equatorial and
H(13a) axial was calculated to have a dihedral angle of 46.0◦. The latter
conformer was calculated to be 0.9 kcal mol-1 lower in energy than the
former.
11 N. Shindoh, H. Tokuyama, Y. Takemoto and K. Takasu, J. Org. Chem.,
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19 Attributing the descriptors endo and exo to the possible transition
states and the products that arise from them is tricky. If the position
of the phenyl group (the one attached to the dienophile) with respect
to the diene is used to determine whether a transition state is endo
or exo, then cis relative stereochemistry between C(14) and C(14a)
in the product is the result of an endo transition state. However, the
double bond migration that completes the Povarov reaction destroys
the stereochemistry at C(14a) so the relative stereochemistry between
C(7a) and C(13a) can be consulted. Here, an endo transition state gives
rise to a trans relationship. Under this scenario, all of the products
presented in Table 1 are endo adducts. In the case of compound 13,
which has no phenyl substituent on the dienophile, only the position of
the alkyl substituent with respect to the diene can be used to assign endo
and exo. Now a cis relationship between C(7a) and C(13a) arises from
an endo transition state. The apparent inconsistency arises in IMDA
reactions in which the dienophile is trans-configured. The designation
of endo and exo is dependent upon which end of the dienophile is
considered. This problem does not arise in the case of cis-configured
dienophiles.
Notes and references
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Ishitani and S. Nagayama, Chem. Lett., 1995, 423; (g) S. Kobayashi,
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20 H. J. Anderson, C. E. Loader and A. Foster, Can. J. Chem., 1980, 58,
2527.
21 The first descriptor refers to the C(7a)–C(13a) relative stereochemistry
and the second descriptor refers to the C(13a)–C(14) relative stereo-
chemistry.
22 M. R. Spaller, W. T. Thielemann, P. E. Bennan and P. A. Bartlett, J.
Comb. Chem., 2002, 4, 516.
7206 | Org. Biomol. Chem., 2011, 9, 7196–7206
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©