Synthesis of multi-functionalized chromeno[2, 3-c]pyrrol-9(2H)-ones: Investigation and application of Baker-Venkataraman rearrangement involved reactions catalyzed by 4-(Dimethylamino)pyridine

Article abstract of DOI:10.1002/ejoc.201100435

An efficient one-pot synthesis of multi-functionalized chromeno[2, 3-c]pyrrol-9(2H)-ones from 1, 3-diaryl-1, 3-diket-ones and amino acids is described. The synthesis is based on the 4-(dimethylamino)pyridine-catalyzed Baker-Venkatara-man rearrangement and

Full text of DOI:10.1002/ejoc.201100435

FULL PAPER
DOI: 10.1002/ejoc.201100435
Synthesis of Multi-Functionalized Chromeno[2,3-c]pyrrol-9(2H)-ones:
Investigation and Application of Baker–Venkataraman Rearrangement Involved
Reactions Catalyzed by 4-(Dimethylamino)pyridine
Yanjun Yu,[a] Yun Hu,[a] Weiyan Shao,[a] Jianing Huang,[a] Yinglin Zuo,[a] Yingpeng Huo,[a]
Linkun An,[a] Jun Du,[a] and Xianzhang Bu*[a]
Keywords: Chromenopyrrolones / Baker–Venkataraman rearrangement / Amino acids / Synthesis design
An efficient one-pot synthesis of multi-functionalized
chromeno[2,3-c]pyrrol-9(2H)-ones from 1,3-diaryl-1,3-diket-
ones and amino acids is described. The synthesis is based on
the 4-(dimethylamino)pyridine-catalyzed Baker–Venkatara-
man rearrangement and subsequent reactions.
Introduction
forth;[6] or etherification of benzophenone intermediates[7]
Chromone (4H-1-benzopyran-4-one) containing com- under various conditions. In addition, the Baker–Venkatar-
pounds constitute a wide variety of naturally occurring and aman (B–V) rearrangement,[8] accomplished with oxidative
synthetic products. Representative analogues – flavones, or acidic catalytic cyclization,[9] has also been revealed to
xanthones, and their various derivatives – have shown be an efficient method for chromone formation (Scheme 1,
broad pharmacological activities, such as anticancer,[1] an- paths A1–A3).
ticardiovascular,[2] and anti-inflammatory,[3] and therefore,
Classic B–V rearrangement is a base-induced (typically
have useful medicinal applications. Syntheses of these chro- NaH, K2CO3 KOH, and NaOH) acyl transfer reaction of
mone analogues have been approached in various ways, al- 2-acetylphenyl carboxylate, resulting in a 1,3-diketone with
though in most of them the formation of the chromone a free o-hydroxy group. In some cases,[10] acylation of the
moiety as intermediates or reactants was involved. Typical free o-hydroxy group by carboxylic anhydride in the pres-
syntheses of chromone analogues include catalytic Sonoga- ence of alkali compounds under reflux could give 2-alkyl-
shira[4] and carbonylative annulation;[5] intramolecular Frie- 3-aroylchromones by another B–V reaction (Scheme 1,
del–Crafts acetylation of 2-phenyloxybenzoate ester, and so path B). Extensive results have been obtained by acylation
Scheme 1. Chromone formation reactions involving B–V rearrangement.
of 2,6-dihydroxyacetophenone with cinnamoyl chloride at
[a] School of Pharmaceutical Sciences, Sun Yat-Sen University,
high temperature in K2CO3/acetone media, affording
3-cinnamoyl-2-styrylchromone analogues. In this multistep
procedure, two B–V rearrangements are involved
(Scheme 1, path C1–C2).[11] Recently, Waldvogel and co-
Guangzhou 510275, China
Fax: +86-20-39943054
E-mail: phsbxzh@mail.sysu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100435.
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workers reported an optimized one-pot protocol for the
After 1a–g were obtained, model reactions were con-
synthesis of 3-cinnamoyl-2-styrylchromone analogues via ducted with 1a and acetic anhydride in Py with or without
α,α-dicinnamoylated acetophenone intermediates non-nucleophilic base to find an efficient catalyst for chro-
(Scheme 1, path D).[12] These works inspired the possibility mone formation. Briefly, 1a (120 mg) and Ac2O (75 mg)
to develop a new synthetic strategy to produce highly func- were dissolved in Py (1.5 mL); four parallel reactions were
tionalized chromone analogues, which would facilitate the conducted at 25 °C with or without the addition of
discovery of new bioactive molecules by organic and medic- DMAP, diisopropylethylamine (DIEA), or triethylamine
inal chemists. Herein, we describe the synthesis of 1,3-sub- (0.2 equiv.). After stirring for 1 h, the reaction mixture was
stituted chromeno[2,3-c]pyrrol-9(2H)-ones from diaryl-1,3- acidified with 10% HCl and extracted with EtOAc. The
diketones and amino acids, based on 4-(dimethylamino)- EtOAc layer was analyzed with DIONEX Ultimate 3000
pyridine (DMAP) catalyzed B–V rearrangement and subse- HPLC by using purified 1a, 2a, and 3a as references (Fig-
quent reactions under mild conditions.
ure 1). The results in Figure 1 suggested that the esterifica-
tions proceeded quickly in Py, affording the ester intermedi-
ate 2a in high yield (Table 2); the addition of DMAP
(0.2 equiv.) resulted in complete consumption of 1a, and the
chromone 3a appeared as the main product in the reaction
mixture. Replacement of DMAP by DIEA or NEt3 led to
little chromone 3a formation, with ester 2a as the main
product. Similarly, the Py-only system resulted in 2a as the
Results and Discussion
In our search for potent anticancer molecules, we pro-
posed a chromone-based compound library with new struc-
tures and high diversity. As mentioned above, acylation of
o-hydroxylated diaryl 1,3-diketones followed by a B–V re-
arrangement would be a promising way to achieve diversity
expansion. However, the previously reported conditions
usually required strong bases and high temperatures, and
therefore, would hinder the introduction of a susceptive
moiety. Direct acylation of 2,6-dihydroxyacetophenone with
cinnamoyl chloride or other acylation reagents under basic
catalysis at reflux is also deficient owing to the limitation
of the 2,6-dihydroxy requirement,[11–12] which would restrict
diversity expansion during library construction. Consider-
ing this information, we sought to find mild conditions for
the formation of the chromone moiety in our current work.
Our route started with the synthesis of 1,3-diaryl-1,3-di-
ketones 1 through esterifications and classical B–V re-
arrangements from 2-hydroxyacetophenones and aromatic
acyl chlorides. In this way, o-acylated phenol esters 1aЈ–gЈ
were obtained in 86–94% isolated yields through treatment
of 2-hydroxyacetophenones with different aromatic acyl
chlorides in pyridine (Py) at 25 °C. Subsequently, B–V re-
arrangements were induced by treating 1aЈ–gЈ with K2CO3
(1 equiv.) in Py at 75 °C to give 1a–g in 70–83% yields
(Table 1).
Table 1. Synthesis and structural information of 1aЈ–gЈ and 1a–g.
Entry
R1
R2
X
Ester
(yield [%])
Diketone
(yield [%])
1
2
3
4
5
6
7
H
H
H
H
H
OCH3
H
H
H
OCH3
CH3
H
H
CH3
CH=CH
1aЈ (90)
1bЈ (89)
1cЈ (87)
1dЈ (94)
1eЈ (86)
1fЈ (89)
1gЈ (90)
1a (72)
1b (83)
1c (70)
1d (77)
1e (79)
1f (71)
1g (76)
O
O
O
S
S
S
Figure 1. HPLC analysis of the reaction of 1a and Ac2O in Py
with or without DMAP, DIEA, or Et3N. Samples were diluted with
CH3CN. Column: DIONEX C18, 5 μm, 120 Å, 4.6ϫ250 mm; flow
rate: 1 mLminϪ1. 5 μL of sample was eluted with a gradient of 30–
95% CH3CN in double-deionized H2O over 35 min by using UV
detection at 254 nm.
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Multi-Functionalized Chromeno[2,3-c]pyrrol-9(2H)-ones
Table 2. Synthesis and structural information of 2a–g and 3a–g.
Entry
R1
R2
X
In Py
Ester (yield [%])
In DMAP (0.2 equiv.)/Py
Chromone (yield [%])
1
2
3
4
5
6
7
H
H
H
H
H
OCH3
H
H
H
OCH3
CH3
H
H
CH3
CH=CH
2a (93)
2b (90)
2c (95)
2d (74)
2e (84)
2f (79)
2g (75)
3a (89)
3b (85)
3c (91)
3d (69)
3e (81)
3f (73)
3g (67)
O
O
O
S
S
S
main product with only a trace amount of 3a. In Table 2,
the production data from reactions of more diketones 1b–g
with Ac2O in Py or Py/DMAP is also summarized. These
results revealed that DMAP was good at promoting the for-
mation of chromones under mild conditions.
Then, we examined the possibility of extending the above
finding to the synthesis of new chromone analogues. Acetic
anhydride was replaced by natural amino acid anhydrides.
We chose amino acids because they are biological molecules
with various side chains, which would be beneficial in tun-
ing the structures of the final products during bioactivity
evaluation. To avoid unexpected side reactions, the α-amino
groups of the amino acids were protected with 9-fluorenyl-
Scheme 2. Synthesis of 5a.
methyloxycarbonyl (Fmoc); this group is commonly of 1a with Fmoc-Leu-OH were therefore investigated to op-
adopted in peptide synthesis. In addition, the active side timize the reaction. Compound 1a (0.5 mmol) was acylated
chains of the amino acids were also protected with different in Py (exactly 10 mL)/DMAP (0.6 equiv.) either by using
protective reagents, depending on the nature of the active excess pre-prepared symmetric Fmoc-Leu anhydride or by
group. The α-amino group and side-chain-protected amino excess Fmoc-Leu-OH/DCC directly, while different reaction
acids are commercially available.
times and temperatures were applied. In brief, compound
In our first attempt, protected lysine, Fmoc-Lys(Boc)- 1a was acylated at 15 °C by using different reagents first,
OH (Boc = tert-butoxycarbonyl), was treated with dicyclo- and after 1a disappeared (about 30 min), as determined by
hexylcarbodiimide (DCC) in CH2Cl2 to form the symmetric TLC, the reaction mixture was stirred under various time
amino acid anhydrides as the main substrates for acti- and temperature conditions (Table 3). Next, the reaction
vation.[13] After filtering off the insoluble byproduct dicy- mixture was centrifuged, and 80 μL of the supernatant was
clohexylurea (DCU), CH2Cl2 was evaporated to give a resi- removed and diluted to 1.0 mL with acetonitrile for HPLC
due that was mixed with 1a in DMAP (0.2 equiv)/Py to analysis. Signals of 5 μL of sample were recorded with a
initiate the reaction. Compound 1a disappeared quickly as UV detector at 390 nm to avoid noise from byproducts, and
expected, and a major yellow spot could be observed by the product peak areas were calculated by integration.
TLC after 5 h. This product was therefore isolated and Meanwhile, the final product 5b (see Table 4 below for
purified by column chromatography to give a yellow structure information) was purified by column chromatog-
powder. Unexpectedly, instead of the target amino acid resi- raphy and characterized. A standard curve was obtained by
due, functionalized 3-benzoyl-4H-chromen-4-one (4a, plotting the peak area versus the mass of 5 μL of purified
Scheme 2), this product was identified as 3-(N-Boc-4-ami- 5b with various concentrations in acetonitrile, and was ana-
nobutyl)-1-phenylchromeno[2,3-c]pyrrol-9(2H)-one
(5a, lyzed with linear regression to give a standard equation A
Scheme 2) based on the analysis of HRMS, 1H and 13C = 98.34M, in which A is the obtained peak area in
NMR spectroscopy, HMBC, and HSQC data. Further- mAumin, mAu is the Absorbance unit ϫ 1/1000), M is the
more, we obtained single crystals of 5a, and its structure determined mass of 5 μL of sample in mg, and the constant
was confirmed by X-ray analysis (Figure 2).[14]
98.34 is the slope, k, for 5b from the general standard curve
This interesting result suggested that 1,3-disubstituted equation A = kM. The HPLC yield was calculated accord-
chromeno[2,3-c]pyrrol-9(2H)-ones could be synthesized in ing to YHPLC = 100%ϫ[Mϫ(1.0 mL/0.08 mL)ϫ10 mL]/N
the presence of DMAP. Several conditions for the reaction = 100%ϫ125A/kN, in which N is the theoretical yield in
Eur. J. Org. Chem. 2011, 4551–4563
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Figure 2. X-ray structures of 5a (left) and 5o (right).
Table 3. Synthesis of 5b under various conditions.
[a]
Entry
Reaction conditions
YHPLC [%]
Base
Acylation
Conditions
1
2
3
4
5
6
7
8
DMAP/Py
DMAP/Py
DMAP/Py
DMAP/Py
DMAP/Py
DIEA/Py
NEt3/Py
Leu anhydride
Leu anhydride
DCC + Leu
DCC + Leu
DCC + Leu
DCC + Leu
DCC + Leu
DCC + Leu
15 °C 30 min, then 15 °C for further 5 h
15 °C 30 min, then 15 °C for further 5 h, then 40 °C 2 h
15 °C 30 min, then 15 °C for further 5 h
15 °C 30 min, then 15 °C for further 5 h, then 40 °C for 2 h
15 °C 30 min, then 40 °C for 2 h
7.6
64.0
23.3
97.1
95.9
1.3
15 °C 30 min, then 40 °C for 2 h
15 °C 30 min, then 40 °C for 2 h
15 °C 30 min, then 40 °C for 2 h
7.4
0.77
Py
[a] Determined by HPLC. Column: DIONEX C18, 5 μm, 120 Å, 4.6ϫ250 mm; flow rate: 1 mLminϪ1. A 5 μL sample was eluted with a
gradient of 55–99% CH3CN in double-deionized H2O over 30 min by using UV detection at 390 nm.
mg, (here 158.5 mg, calculated based on 0.5 mmol of start- g; 0.5 mmol), and the reaction mixtures were stirred at
ing material 1a). The results are summarized in Table 3 (En- 15 °C until the 1,3-diketones 1 had disappeared, as moni-
tries 1–5).
tored by TLC. Each reaction mixture was then warmed to
The data in Table 3 indicated that the direct acylation of 40 °C for 2–4 h, then 80 μL of the supernatant was removed
1a with leucine/DCC followed by 2 h of stirring at 40 °C for HPLC analysis, according to the procedure described
would be the most efficient conditions (Table 3, Entry 5) for above. After that, the Py was evaporated from the rest of
the synthesis of 5b. More reactions were therefore carried the mixture to give a residue, which was purified by column
out under these conditions by replacing DMAP with NEt3 chromatography to give the final product. Eighteen new
or DIEA, or simply by removing DMAP for comparison 1,3-substituted chromeno[2,3-c]pyrrol-9(2H)-ones (5a–r,
purposes. As expected, these conditions only led to the for- Table 4) were successfully obtained in 44–89% yields, which
mation of 5b in very low yields (Table 3, Entries 6–8), re- were characterized by using IR spectroscopy, HRMS and
vealing the important contribution of DMAP in 1,3-disub- NMR spectroscopy. Furthermore, single crystals of 5o were
stituted chromeno[2,3-c]pyrrol-9(2H)-one formation.
also isolated and analyzed by using X-ray diffraction[14]
Encouraged by these results, we adopted the optimized (Figure 2). Each standard curve of the obtained pure prod-
conditions (Table 3, Entry 5) for the diversity expansion of ucts 5a–r was determined and used to calculate overall
chromeno[2,3-c]pyrrol-9(2H)-ones. To investigate the scope yields, YHPLC, according to the above-described procedure.
and generality of this one-pot procedure, different β-diket- Moderate to high production rates of 5a–r were obtained,
one intermediates 1a–g with various amino acids, including and both the isolated yields and HPLC yields are listed in
lysine, aspartic acid, alanine, leucine, phenylalanine, tyr- Table 4.
osine, and methionine, with different side chains were used.
Based on the above results, we propose a mechanism for
Briefly, different amino group and side-chain-protected the formation of 1,3-substituted chromeno[2,3-c]pyrrol-
amino acids (0.75 mmol), DMAP (0.3 mmol), and DCC 9(2H)-ones, in which a DMAP-catalyzed B–V rearrange-
(0.9 mmol) were dissolved in Py (exactly 10 mL) and mixed ment and subsequent reactions are involved. In the first
with different o-hydroxylated 1,3-diaryl-1,3-diketones (1a– step, a DMAP-catalyzed B–V rearrangement occurs soon
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Multi-Functionalized Chromeno[2,3-c]pyrrol-9(2H)-ones
Table 4. Synthesis and structural information of 5a–r.
Entry
Product
R1
R2
R3
X
Retention time
[min]
k[a]
Yield [%]
[b]
YHPLC
Yisolated
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
H
H
H
H
H
H
H
H
H
H
H
OCH3
H
H
OCH3
H
OCH3
H
H
H
H
H
H
H
H
H
CH3
OCH3
H
H
H
H
H
CH3
H
H
CH2(CH2)3NHCOOtBu
CH2CH(CH3)2
CH=CH
CH=CH
CH=CH
CH=CH
CH=CH
CH=CH
CH=CH
12.63
14.92
10.69
12.17
8.49
62.62
98.34
40.44
26.71
90.51
80.99
55.61
23.95
46.91
73.57
73.82
114.9
37.25
38.20
85.92
51.39
93.61
54.14
90.4
95.9
91.4
82.9
88.1
63.1
92.3
82.4
77.3
98.7
60.7
95.8
92.3
73.7
57.1
80.2
67.9
102
76
81
80
75
77
51
78
71
63
86
47
79
77
61
44
69
54
89
CH2CH2SCH3
CH2COOtBu
CH3
CH2C6H5
CH2C6H4(p-OtBu)
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
13.47
18.02
13.91
14.14
16.87
14.21
13.21
11.63
13.99
11.26
14.06
16.29
10.07
O
O
O
S
S
O
S
S
S
S
S
CH2CH(CH3)2
CH2(CH2)3NHCOOtBu
CH2(CH2)3NHCOOtBu
CH2(CH2)3NHCOOtBu
CH2(CH2)3NHCOOtBu
CH2C6H4(p-OtBu)
CH2CH2SCH3
[a] Slope of the standard curve equation A = kM of each compound. [b] Determined by HPLC. Column: DIONEX C18, 5 μm, 120 Å,
4.6ϫ250 mm; flow rate: 1 mLminϪ1. Gradient: 55–99% CH3CN in double-deionized H2O over 30 min by using UV detection at 390 nm.
after the esterification of 1, leading to the chromone inter-
mediate 4 (Scheme 3). The achieved regioselectivity should
result from the conjugation effect of the aromatic ring,
which decreases the electropositivity of the adjacent car-
bonyl carbon atom. On the other hand, although the pro-
tective Fmoc group is generally cleaved at room tempera-
ture by piperidine (20% or higher) in peptide chemistry, our
results strongly suggest that Fmoc can be removed by
DMAP under the current conditions, which are consistent
with those previously reported.[15] Once the amino group of
4 is liberated, a subsequent intramolecular carbonyl ad-
dition by the adjacent free amino group occurs and is fol-
lowed by elimination to afford the final products 5a–r
(Scheme 3).
To verify the formation of intermediate 4, Fmoc-Lys-
(Boc)-OH was replaced by Boc-Lys(Boc)-OH, and the reac-
tion was conducted under the same conditions. As ex-
pected, chromone product 4aЈ was obtained in high yield
(Scheme 4). Furthermore, to identify possible intermediates
and byproducts, the reaction mixture from the synthesis of
5a obtained by the unoptimized anhydride method was an-
alyzed by using HPLC and LC–MS, and reaction interme-
Scheme 3. Proposed mechanism for 1,3-substituted chromeno[2,3-
c]pyrrol-9(2H)-one formation.
diates such as ester intermediates 4a and Fmoc-cleaved 4a
were detected in addition to target 5a and cleaved Fmoc
species[15] (Figures S4 and S5 in the Supporting Infor-
mation), without the observation of other side products.
Noticeably, although they could be detected, chromone in- stability in the reaction mixture. These results support the
termediate 4a and Fmoc-cleaved 4a were difficult to sepa- assumption that final products 5a–r are formed via chro-
rate for further analysis owing to their low content and in- mone intermediate 4, as shown in Scheme 3.
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L. An, X. Bu et al.
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were protected with Fmoc, the side chains of lysine were protected
with Boc, and the side chains of aspartic acid and tyrosine were
protected as tBu. Reactions were monitored by TLC on glass plates
coated with silica gel with fluorescent indicator (GF254). Flash
chromatography was performed on silica gel H. Melting points
were determined by using an XT-4 apparatus. NMR spectra were
recorded with a Bruker Avance III (400 MHz for 1H, 100 MHz for
13C) instrument in the indicated solvent. Chemical shifts are re-
ported as parts per million (ppm) relative to the signal for internal
tetramethylsilane (δ = 0 ppm for 1H) for solutions in CDCl3. 1H
NMR spectroscopic data are reported in chloroform (δ
=
7.26 ppm), methanol (δ = 3.30 ppm), and DMSO (δ = 2.50 ppm).
13C NMR spectroscopic data are reported in chloroform (δ =
77.0 ppm) and DMSO (δ = 39.5 ppm). Multiplicities are reported
by the following abbreviations: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; J, coupling constants in Hz. HRMS spectra
were recorded with an LCMS-IT-TOF (SHIMADZU) instrument.
IR data were recorded with a Bruker FTIR spectrometer. HPLC
analyses were performed with a DIONEX Ultimate 3000 chroma-
tograph; HPLC conditions were as follows: DIONEX C18, 5 μm,
120 Å, 4.6ϫ250 mm column; flow rate: 1 mLminϪ1. For each test,
5 μL of sample was used and eluted in different gradients, using a
UV monitor at 254 or 390 nm detection wavelengths, depending on
the analytical requirements.
Scheme 4. Synthesis of 4aЈ.
Conclusions
A new mild synthetic method for the synthesis of 1,3-
substituted chromeno[2,3-c]pyrrol-9(2H)-ones was discov-
ered from an unexpected one-pot reaction of 2Ј-hydroxy-
1,3-diaryl-1,3-diketones with various amino acids. This pro-
cedure is based on DMAP-catalyzed B–V rearrangements
and subsequent Fmoc cleavage, cyclization, and elimi-
nation. As isosteres of xanthones, nitrogen-containing het-
erocyclochromones, such as pyrrolidine,[16] Py,[17] and lac-
tam-fused chromones,[18] have attracted much attention in
the design of drugs[17a,19] and fluorescent labels for bio-
logical substrates.[17b–17f] However, compared with the ex-
tensive studies of these azacyclochromones, there have been
few reports of pyrroles fused to chromones. Although Kelly
and Moiseyeva have reported the total synthesis of two
benzopyrano[2,3-b]pyrrol-4(1H)-ones, which are aglycones
of the natural antibiotics pyralomicins,[20] and a few synthe-
ses of N-alkylated benzopyranopyrrolone analogues have
been reported,[21] these procedures usually require harsh
conditions and/or long reaction sequences. Based on the
finding that chromone moieties could be formed by
DMAP-catalyzed B–V rearrangements, our work has estab-
lished a facile way to synthesize new chromeno[2,3-c]pyrrol-
9(2H)-ones under mild conditions. A variety of rings and
substitution patterns (amino acids with various active side
chains) were examined and proven to be well tolerated un-
der our reaction conditions. Among the obtained com-
pounds, 3c–d, 3f, and 5a–r were identified as new chromone
derivatives. Noticeably, the resulting new compounds have
multiple substituents and could be easily modified by using
various starting materials. We believe that our findings will
benefit organic and medicinal chemists to expand the diver-
sity of chromeno[2,3-c]pyrrol-9(2H)-one derivatives for fur-
ther biological activity screening, and such work is being
actively undertaken in our group.
Synthesis of 2-Acetylphenyl Benzoate (1aЈ): 2-Hydroxyaceto-
phenone (10.0 mmol, 1.36 g) and benzoyl chloride (12.0 mmol,
1.68 g) were dissolved in Py (25 mL) and stirred at 25 °C. When 2-
hydroxyacetophenone was consumed, in about 3 h as determined
by using TLC, a large excess of water was added, and then the pH
of the solution was adjusted to 5.0 with 10% HCl. The product
precipitated and was collected by filtration, giving 1aЈ as a white
1
powder (2.16 g, 90%). H NMR (400 MHz, CDCl3): δ = 8.22 (dd,
J = 8.3, 1.2 Hz, 2 H, Ar-H), 7.87 (dd, J = 7.8, 1.6 Hz, 1 H, Ar-H),
7.66 (t, J = 7.5 Hz, 1 H, Ar-H), 7.61–7.56 (m, 1 H, Ar-H), 7.53 (t,
J = 7.7 Hz, 2 H, Ar-H), 7.37 (td, J = 7.7, 1.1 Hz, 1 H, Ar-H), 7.24
(dd, J = 8.1, 0.9 Hz, 1 H, Ar-H), 2.55 (s, 3 H, CH3) ppm.
2-Acetylphenyl Furan-2-carboxylate (1bЈ): 2-Hydroxyacetophenone
(10 mmol, 1.36 g) and furoyl chloride (12.0 mmol, 1.56 g) were dis-
solved in Py (25 mL) and stirred at 25 °C. When 2-hydroxyace-
tophenone was consumed, in about 5 h as determined by using
TLC, a large excess of water was added, and then the pH of the
solution was adjusted to 5.0 with 10% HCl. The solution was ex-
tracted with EtOAc (50 mL) three times, and then the organic lay-
ers were combined and washed with water to pH = 7.0, dried with
MgSO4, and evaporation of EtOAc gave 1bЈ as a white powder
1
(2.05 g, 89%). H NMR (400 MHz, CDCl3): δ = 7.85 (dd, J = 7.8,
1.7 Hz, 1 H, Ar-H), 7.70 (dd, J = 1.6, 0.8 Hz, 1 H, Ar-H), 7.62–
7.55 (m, 1 H, Ar-H), 7.42 (dd, J = 3.5, 0.7 Hz, 1 H, Ar-H), 7.37
(td, J = 7.6, 1.1 Hz, 1 H, Ar-H), 7.26 (dd, J = 8.1, 1.0 Hz, 1 H,
Ar-H), 6.62 (dd, J = 3.5, 1.7 Hz, 1 H, Ar-H), 2.57 (s, 3 H, CH3)
ppm.
2-Acetyl-4-methoxyphenyl Furan-2-carboxylate (1cЈ): 2-Hydroxy-5-
methoxyacetophenone (10.0 mmol, 1.66 g) and furoyl chloride
(12.0 mmol, 1.56 g) were treated by the same procedure as that used
for the synthesis of 1aЈ, except for the reaction time (4 h), giving
1
1cЈ as a salmon-pink powder (2.26 g, 87%). H NMR (400 MHz,
CDCl3): δ = 7.88 (d, J = 8.8 Hz, 1 H, Ar-H), 7.69 (dd, J = 1.7,
0.8 Hz, 1 H, Ar-H), 7.42 (dd, J = 3.5, 0.7 Hz, 1 H, Ar-H), 6.87
(dd, J = 8.8, 2.5 Hz, 1 H, Ar-H), 6.74 (d, J = 2.5 Hz, 1 H, Ar-H),
6.62 (dd, J = 3.5, 1.7 Hz, 1 H, Ar-H), 3.87 (s, 3 H, OCH3), 2.52 (s,
3 H, CH3) ppm.
Experimental Section
General: All reagents were commercially available. Solvents were
treated by using standard techniques. All amino acids were used as
the following protected forms: α-amino groups of all amino acids
2-Acetyl-4-methylphenyl Furan-2-carboxylate (1dЈ): 2-Hydroxy-5-
methylacetophenone (10.0 mmol, 1.50 g) and furoyl chloride
4556
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4551–4563

Multi-Functionalized Chromeno[2,3-c]pyrrol-9(2H)-ones
(12.0 mmol, 1.56 g) were treated by using the same procedure as
1-(Furan-2-yl)-3-(2-hydroxy-5-methoxyphenyl)propane-1,3-dione
that used for the synthesis of 1aЈ, giving 1dЈ as a salmon-pink pow-
der (2.29 g, 94%). H NMR (400 MHz, CDCl3): δ = 7.69 (dd, J =
1.7, 0.8 Hz, 1 H, Ar-H), 7.64 (d, J = 1.9 Hz, 1 H, Ar-H), 7.41 (dd, as a yellow powder (1.46 g, 70%). H NMR (400 MHz, CDCl3): δ
(1c): Above-obtained 1cЈ (8.0 mmol, 2.08 g) was treated by using
1
the same procedure as that used for the synthesis of 1a, giving 1c
1
J = 3.5, 0.8 Hz, 1 H, Ar-H), 7.37 (dd, J = 8.0, 2.4 Hz, 1 H, Ar-H),
7.13 (d, J = 8.2 Hz, 1 H, Ar-H), 6.61 (dd, J = 3.5, 1.7 Hz, 1 H, Ar-
H), 2.55 (s, 3 H, CH3), 2.41 (s, 3 H, CH3) ppm.
= 15.19 (s, 1 H, OH), 11.64 (s, 1 H, OH), 7.62 (d, J = 0.9 Hz, 1 H,
Ar-H), 7.20 (d, J = 3.0 Hz, 1 H, Ar-H), 7.19 (dd, J = 3.5, 0.5 Hz,
1 H, Ar-H), 7.10 (dd, J = 9.0, 3.0 Hz, 1 H, Ar-H), 6.94 (d, J =
9.0 Hz, 1 H, Ar-H), 6.72 (s, 1 H, C=CH), 6.61 (dd, J = 3.5, 1.7 Hz,
1 H, Ar-H), 3.84 (s, 3 H,OCH3) ppm.
2-Acetylphenyl Thiophene-2-carboxylate (1eЈ): 2-Hydroxyaceto-
phenone (10.0 mmol, 1.36 g) and thenoyl chloride (12.0 mmol,
1.75 g) were treated by using the same procedure as that used for
the synthesis of 1bЈ, giving 1eЈ as a stramineous powder (2.12 g,
1-(Furan-2-yl)-3-(2-hydroxy-5-methylphenyl)propane-1,3-dione (1d):
Above-obtained 1dЈ (8.0 mmol, 1.95 g) was treated by using the
same procedure as that used for the synthesis of 1a, giving 1d as a
yellow powder (1.50 g, 77%). 1H NMR (400 MHz, CDCl3): δ =
15.16 (s, 1 H, OH), 11.88 (s, 1 H, OH), 7.62 (dd, J = 1.6, 0.7 Hz,
1 H, Ar-H), 7.54 (s, 1 H, Ar-H), 7.30–7.27 (m, 1 H, Ar-H), 7.18
(dd, J = 3.5, 0.6 Hz, 1 H, Ar-H), 6.90 (d, J = 8.5 Hz, 1 H, Ar-H),
6.77 (s, 1 H, C=CH), 6.60 (dd, J = 3.5, 1.7 Hz, 1 H), 2.34 (s, 3 H,
CH3) ppm.
1
86%). H NMR (400 MHz, CDCl3): δ = 8.01 (dd, J = 3.8, 1.2 Hz,
1 H, Ar-H), 7.86 (dd, J = 7.8, 1.7 Hz, 1 H, Ar-H), 7.70 (dd, J =
5.0, 1.2 Hz, 1 H, Ar-H), 7.62–7.55 (m, 1 H, Ar-H), 7.37 (td, J =
7.7, 1.1 Hz, 1 H, Ar-H), 7.26 (dd, J = 8.1, 1.0 Hz, 1 H, Ar-H), 7.20
(dd, J = 5.0, 3.8 Hz, 1 H, Ar-H), 2.58 (s, 3 H, CH3) ppm.
2-Acetyl-5-methoxyphenyl Thiophene-2-carboxylate (1fЈ): 2-Hy-
droxy-4-methoxyacetophenone (10.0 mmol, 1.66 g) and thenoyl
chloride (12.0 mmol, 1.75 g) were treated by using the same pro-
cedure as that used for the synthesis of 1aЈ, except for the reaction
time (5 h), giving 1fЈ as a stramineous powder (2.46 g, 89%). 1H
NMR (400 MHz, CDCl3): δ = 8.01 (dd, J = 3.8, 1.3 Hz, 1 H, Ar-
H), 7.89 (d, J = 8.8 Hz, 1 H, Ar-H), 7.69 (dd, J = 5.0, 1.3 Hz, 1
H, Ar-H), 7.20 (dd, J = 5.0, 3.8 Hz, 1 H, Ar-H), 6.87 (dd, J = 8.8,
2.5 Hz, 1 H, Ar-H), 6.74 (d, J = 2.5 Hz, 1 H, Ar-H), 3.87 (s, 3 H,
OCH3), 2.52 (s, 3 H, CH3) ppm.
1-(2-Hydroxyphenyl)-3-(thiophen-2-yl)propane-1,3-dione (1e):
Above-obtained 1eЈ (8.0 mmol, 1.97 g) was treated by using the
same procedure as that used for the synthesis of 1a, giving 1e as a
yellow powder (1.55 g, 79%). 1H NMR (400 MHz, CDCl3): δ =
15.66 (s, 1 H, OH), 11.96 (s, 1 H, OH), 7.79 (dd, J = 3.8, 1.1 Hz,
1 H, Ar-H), 7.73 (dd, J = 8.1, 1.5 Hz, 1 H, Ar-H), 7.61 (dd, J =
5.0, 1.0 Hz, 1 H, Ar-H), 7.49–7.43 (m, 1 H, Ar-H), 7.18 (dd, J =
4.9, 3.9 Hz, 1 H, Ar-H), 7.00 (dd, J = 8.4, 0.8 Hz, 1 H, Ar-H),
6.96–6.89 (m, 1 H, Ar-H), 6.70 (s, 1 H, C=CH) ppm.
2-Acetyl-4-methylphenyl Thiophene-2-carboxylate (1gЈ): 2-Hydroxy-
5-methylacetophenone (10.0 mmol, 1.50 g) and thenoyl chloride
(12.0 mmol, 1.75 g) were treated by using the same procedure as
that used for the synthesis of 1aЈ, except for the reaction time (5 h),
giving 1gЈ as a stramineous powder (2.34 g, 90%). 1H NMR
(400 MHz, CDCl3): δ = 8.00 (dd, J = 3.8, 1.2 Hz, 1 H, Ar-H), 7.69
(dd, J = 5.0, 1.2 Hz, 1 H, Ar-H), 7.64 (d, J = 1.9 Hz, 1 H, Ar-H),
7.37 (dd, J = 8.3, 2.1 Hz, 1 H, Ar-H), 7.19 (dd, J = 5.0, 3.8 Hz, 1
H, Ar-H), 7.13 (d, J = 8.2 Hz, 1 H, Ar-H), 2.55 (s, 3 H, CH3), 2.41
(s, 3 H, CH3) ppm.
1-(2-Hydroxy-4-methoxyphenyl)-3-(thiophen-2-yl)propane-1,3-dione
(1f): Above-obtained 1fЈ (8.0 mmol, 2.21 g) was treated by using
the same procedure as that used for the synthesis of 1a, giving 1f
1
as a yellow powder (1.57 g, 71%). H NMR (400 MHz, CDCl3): δ
= 15.45 (s, 1 H, OH), 12.47 (s, 1 H, OH), 7.75 (dd, J = 3.8, 1.1 Hz,
1 H, Ar-H), 7.64 (d, J = 8.9 Hz, 1 H, Ar-H), 7.57 (dd, J = 5.0,
1.1 Hz, 1 H, Ar-H), 7.16 (dd, J = 5.0, 3.8 Hz, 1 H, Ar-H), 6.57 (s,
1 H, C=CH), 6.48 (dd, J = 8.9, 2.5 Hz, 1 H, Ar-H), 6.45 (d, J =
2.5 Hz, 1 H, Ar-H), 3.85 (s, 3 H, OCH3) ppm.
1-(2-Hydroxy-5-methylphenyl)-3-(thiophen-2-yl)propane-1,3-dione
(1g): Above-obtained 1gЈ (8.0 mmol, 2.08 g) was treated by using
the same procedure as that used for the synthesis of 1a, giving 1g
1-(2-Hydroxyphenyl)-3-phenylpropane-1,3-dione
(1a):
K2CO3
(1.10 g, 8.0 mmol) was added to a solution of above-obtained 1aЈ
(8.0 mmol, 1.92 g) in Py (40 mL). The resulting mixture was heated
to 75 °C overnight. When the reaction was finished, as monitored
by using TLC, a large excess of water was added, and the pH of
the solution was adjusted to 5.0 with 10% HCl. The mixture was
extracted with EtOAc (50 mL) three times, then the organic layers
were combined and washed with water to neutral pH, dried with
MgSO4, and then EtOAc was evaporated to give the crude product,
which was purified by recrystallization from alcohol to give 1a as
1
as a yellow powder (1.58 g, 76%). H NMR (400 MHz, CDCl3): δ
= 15.74 (s, 1 H, OH), 11.75 (s, 1 H, OH), 7.80 (dd, J = 3.8, 1.1 Hz,
1 H, Ar-H), 7.61 (dd, J = 5.0, 1.0 Hz, 1 H, Ar-H), 7.49 (d, J =
1.3 Hz, 1 H, Ar-H), 7.29–7.26 (m, 1 H, Ar-H), 7.18 (dd, J = 4.9,
3.9 Hz, 1 H, Ar-H), 6.90 (d, J = 8.5 Hz, 1 H, Ar-H), 6.68 (s, 1 H,
C=CH), 2.34 (s, 3 H, CH3) ppm.
Determination of Effects of Non-Nucleophilic Base on Chromone 3a
Formation: Compound 1a (120 mg, 0.5 mmol) and Ac2O (75 mg,
0.75 mmol) were added to four 10 mL round-bottomed flasks
equipped with magnetic stirrers, and dissolved with Py (1.5 mL);
parallel reactions were conducted at 25 °C with or without the ad-
dition of DMAP, DIEA, or NEt3, respectively, (0.2 equiv.). After
stirring for 1 h, the reaction mixture was acidified with 10% HCl
and extracted with EtOAc, 0.1 mL of the EtOAc layer was taken
and diluted to 1.0 mL with CH3CN. Samples were analyzed by
using DIONEX Ultimate 3000 HPLC at 254 nm with a gradient
of 30–95% CH3CN in double-deionized H2O over 35 min, using
the synthesized and purified 1a, 2a, and 3a as references.
1
a yellow powder (1.38 g, 72%). H NMR (400 MHz, CDCl3): δ =
15.54 (s, 1 H, OH), 12.09 (s, 1 H, OH), 7.94 (dd, J = 7.1, 1.5 Hz,
2 H, Ar-H), 7.79 (dd, J = 8.1, 1.6 Hz, 1 H, Ar-H), 7.59–7.43 (m, 4
H, Ar-H), 7.01 (dd, J = 8.4, 0.9 Hz, 1 H, Ar-H), 6.95–6.90 (m, 1
H, Ar-H), 6.85 (s, 1 H, C=CH) ppm.
1-(Furan-2-yl)-3-(2-hydroxyphenyl)propane-1,3-dione (1b): Above-
obtained 1bЈ (8.0 mmol, 1.84 g) was treated by the same procedure
as that used for the synthesis of 1a, giving 1b as a yellow powder
(1.53 g, 83%). 1H NMR (400 MHz, CDCl3): δ = 15.08 (s, 1 H,
OH), 12.07 (s, 1 H, OH), 7.78 (dd, J = 8.1, 1.5 Hz, 1 H, Ar-H),
7.61 (d, J = 1.0 Hz, 1 H, Ar-H), 7.49–7.43 (m, 1 H, Ar-H), 7.18 2-(3-Oxo-3-phenylpropanoyl)phenyl Acetate (2a): Compound 1a
(d, J = 3.5 Hz, 1 H, Ar-H), 6.99 (dd, J = 8.4, 0.8 Hz, 1 H, Ar-H), (240.0 mg, 1.0 mmol) and Ac2O (1.5 mmol, 150.0 mg) were mixed
6.94–6.88 (m, 1 H, Ar-H), 6.78 (s, 1 H, C=CH), 6.60 (dd, J = 3.5, with Py (2.5 mL) and stirred at 25 °C for 1 h, and then the pH of
1.7 Hz, 1 H, Ar-H) ppm.
the resulting mixture was adjusted to 5.0 with 10% HCl, and it was
Eur. J. Org. Chem. 2011, 4551–4563
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4557

L. An, X. Bu et al.
extracted with EtOAc three times. After that, the organic layers 8.8 Hz, 1 H, Ar-H), 7.75 (dd, J = 3.8, 1.1 Hz, 1 H, Ar-H), 7.61
FULL PAPER
were combined and washed with water three times, and then dried
with MgSO4. The evaporation of EtOAc resulted in a crude prod-
uct, which was purified by column chromatography to give 2a as a
yellow powder (268.0 mg, 95%). 1H NMR (400 MHz, CDCl3): δ =
(dd, J = 4.9, 1.1 Hz, 1 H, Ar-H), 7.15 (dd, J = 4.9, 3.8 Hz, 1 H,
Ar-H), 6.87 (dd, J = 8.8, 2.5 Hz, 1 H, Ar-H), 6.66 (d, J = 2.5 Hz,
1 H, Ar-H), 6.55 (s, 1 H, C=CH), 3.86 (s, 3 H, OCH3), 2.34 (s, 3
H, CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 181.6, 180.7,
7.99–7.92 (m, 2 H, Ar-H), 7.80 (dd, J = 7.8, 1.6 Hz, 1 H, Ar-H), 169.0, 163.1, 150.5, 141.7, 132.2, 130.9, 130.1, 128.3, 120.8, 112.2,
7.59–7.46 (m, 4 H, Ar-H), 7.36 (td, J = 7.6, 1.1 Hz, 1 H, Ar-H),
7.16 (dd, J = 8.1, 1.0 Hz, 1 H, Ar-H), 6.70 (s, 1 H, C=CH), 2.32
(s, 3 H,CH3) ppm.
109.4, 95.9, 55.7, 21.1 ppm. HRMS (ESI–TOF): calcd. for
C16H13O5S [M Ϫ H]– 317.0484; found 317.0480.
4-Methyl-2-[3-oxo-3-(thiophen-2-yl)propanoyl]phenyl Acetate (2g):
Compound 1g (260.0 mg, 1.0 mmol) was treated by using the same
procedure as that used for the synthesis of 2a, except for the reac-
2-[3-(Furan-2-yl)-3-oxopropanoyl]phenyl Acetate (2b): Compound
1b (230.0 mg, 1.0 mmol) was treated by using the same procedure
as that used for the synthesis of 2a, giving 2b as a yellow powder
(244.8 mg, 90%). H NMR (400 MHz, CDCl3): δ = 15.95 (s, 1 H, 75%). H NMR (400 MHz, CDCl3): δ = 16.10 (s, 1 H, OH), 7.77
tion time (2 h), giving 2g as a yellow viscous liquid (226.5 mg,
1
1
OH), 7.83 (dd, J = 7.8, 1.7 Hz, 1 H, Ar-H), 7.61 (dd, J = 1.7,
0.7 Hz, 1 H, Ar-H), 7.55–7.50 (m, 1 H, Ar-H), 7.35 (td, J = 7.6,
(dd, J = 3.8, 1.1 Hz, 1 H, Ar-H), 7.63 (dd, J = 4.9, 1.1 Hz, 1 H,
Ar-H), 7.59 (d, J = 1.8 Hz, 1 H, Ar-H), 7.31 (dd, J = 8.2, 2.1 Hz,
1.2 Hz, 1 H, Ar-H), 7.23 (dd, J = 3.6, 0.7 Hz, 1 H, Ar-H), 7.14 (d, 1 H, Ar-H), 7.16 (dd, J = 4.9, 3.8 Hz, 1 H, Ar-H), 7.03 (d, J =
J = 1.1 Hz, 1 H, Ar-H), 6.64 (s, 1 H, C=CH), 6.59 (dd, J = 3.6, 8.2 Hz, 1 H, Ar-H), 6.54 (s, 1 H, C=CH) 2.40 (s, 3 H, CH3), 2.31
1.7 Hz, 1 H, Ar-H), 2.34 (s, 3 H, CH3) ppm. 13C NMR (101 MHz, (s, 3 H, CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 182.4, 180.2,
CDCl3): δ = 181.7, 177.1, 169.1, 150.6, 148.7, 146.2, 132.5, 129.5,
128.5, 126.2, 123.7, 116.0, 112.7, 96.2, 21.0 ppm. HRMS (ESI–
TOF): calcd. for C15H12O5 [M + H]+ 273.0763; found 273.0753.
169.3, 146.4, 141.7, 136.0, 133.0, 132.7, 130.4, 129.8, 128.3, 127.9,
123.7, 96.8, 21.0, 20.7 ppm. HRMS (ESI–TOF): calcd. for
C16H13O4S [M Ϫ H]– 301.0535; found 301.0530.
2-[3-(Furan-2-yl)-3-oxopropanoyl]-4-methoxyphenyl Acetate (2c): 3-Benzoyl-2-methyl-4H-chromen-4-one (3a): Compound 1a
Compound 1c (260.0 mg, 1.0 mmol) was treated by using the same
procedure as that used for the synthesis of 2a, giving 2c as a yellow
powder (287.0 mg, 95%). H NMR (400 MHz, CDCl3): δ = 15.96
(s, 1 H, OH), 7.61 (d, J = 0.8 Hz, 1 H, Ar-H), 7.33 (d, J = 2.1 Hz,
1 H, Ar-H), 7.24 (d, J = 3.5 Hz, 1 H, Ar-H), 7.05 (d, J = 2.8 Hz,
(240.0 mg, 1.0 mmol), DMAP (24.5 mg, 0.2 mmol), and Ac2O
(150.0 mg, 1.5 mmol) were stirred at 25 °C for 1 h. Then, the pH
of the resulting mixture was adjusted to 5.0 with 10% HCl, and
extracted with EtOAc three times. The organic layer was then com-
bined and washed with water and dried with MgSO4. EtOAc was
1
2 H, Ar-H), 6.65 (s, 1 H,C=CH), 6.59 (dd, J = 3.5, 1.6 Hz, 1 H, evaporated, resulting in a crude product, which was purified by
Ar-H), 3.86 (s, 3 H, OCH3), 2.32 (s, 3 H, CH3) ppm. 13C NMR column chromatography to give 3a as a white powder (235.0 mg,
1
(101 MHz, CDCl3): δ = 181.4, 177.1, 169.6, 157.3, 150.7, 146.3, 89%). H NMR (400 MHz, CDCl3): δ = 8.19 (dd, J = 8.0, 1.5 Hz,
142.2, 129.1, 124.6, 118.2, 116.1, 113.8, 112.7, 96.3, 55.7, 21.0 ppm.
HRMS (ESI–TOF): calcd. for C16H14O6 [M + H]+ 303.0869; found
303.0869.
1 H, Ar-H), 7.92 (dd, J = 8.4, 1.3 Hz, 2 H, Ar-H), 7.71 (ddd, J =
8.7, 7.2, 1.7 Hz, 1 H, Ar-H), 7.62–7.56 (m, 1 H, Ar-H), 7.51–7.40
(m, 4 H, Ar-H), 2.39 (s, 3 H, CH3) ppm.
2-[3-(Furan-2-yl)-3-oxopropanoyl]-4-methylphenyl Acetate (2d):
Compound 1d (244.0 mg, 1.0 mmol) was treated by using the same
3-(Furan-2-carbonyl)-2-methyl-4H-chromen-4-one (3b): Compound
1b (230.0 mg, 1.0 mmol) was treated by using the same procedure
procedure as that used for the synthesis of 2a, except for the reac-
tion time (2 h), giving 2d as a yellow powder (211.6 mg, 74%). H (216.0 mg, 85%). H NMR (400 MHz, CDCl3): δ = 8.20 (dd, J =
as that used for the synthesis of 3a, giving 3b as a brown powder
1
1
NMR (400 MHz, CDCl3): δ = 15.97 (s, 1 H,OH), 7.62 (dd, J = 6.6,
1.7 Hz, 2 H, Ar-H), 7.32 (dd, J = 8.2, 1.6 Hz, 1 H, Ar-H), 7.23 (d, H), 7.63 (d, J = 1.0 Hz, 1 H, Ar-H), 7.47 (d, J = 8.4 Hz, 1 H, Ar-
J = 3.6 Hz, 1 H, Ar-H), 7.03 (d, J = 8.2 Hz, 1 H, Ar-H), 6.63 (s, 1 H), 7.46–7.40 (m, 1 H, Ar-H), 7.22 (d, J = 3.6 Hz, 1 H, Ar-H),
7.9, 1.6 Hz, 1 H, Ar-H), 7.71 (ddd, J = 8.7, 7.2, 1.7 Hz, 1 H, Ar-
H, C=CH), 6.59 (dd, J = 3.5, 1.7 Hz, 1 H, Ar-H), 2.40 (s, 3 H, 6.57 (dd, J = 3.6, 1.7 Hz, 1 H, Ar-H), 2.43 (s, 3 H, CH3) ppm.
CH3), 2.33 (s, 3 H, CH3) ppm. 13C NMR (101 MHz, CDCl3): δ =
181.8, 177.0, 169.4, 150.7, 146.5, 146.2, 136.0, 133.1, 129.8, 128.0,
3-(Furan-2-carbonyl)-6-methoxy-2-methyl-4H-chromen-4-one (3c):
Compound 1c (260.0 mg, 1.0 mmol) was treated by using the same
123.4, 115.9, 112.6, 96.1, 20.9, 20.7 ppm. HRMS (ESI–TOF):
procedure as that used for the synthesis of 3a, giving 3c as a yellow
calcd. for C16H14O5 [M + H]+ 287.0919; found 287.0912.
powder (258.0 mg, 91%). 1H NMR (400 MHz, CDCl3): δ = 7.63
2-[3-Oxo-3-(thiophen-2-yl)propanoyl]phenyl Acetate (2e): Com-
pound 1e (246.0 mg, 1.0 mmol) was treated by using the same pro-
cedure as that used for the synthesis of 2a, giving 2e as a yellow
(d, J = 1.5 Hz, 1 H, Ar-H), 7.56 (d, J = 3.1 Hz, 1 H, Ar-H), 7.41
(d, J = 9.1 Hz, 1 H, Ar-H), 7.27–7.30 (m, 1 H, Ar-H), 7.21 (d, J =
3.6, Hz, 1 H, Ar-H), 6.57 (dd, J = 3.6, 1.7 Hz, 1 H, Ar-H), 3.89 (s,
3 H, OCH3), 2.41 (s, 3 H, CH3) ppm. 13C NMR (101 MHz,
CDCl3): δ = 180.8, 175.3, 165.7, 157.1, 152.9, 150.6, 147.4, 124.0,
123.9, 121.7, 120.0, 119.2, 112.6, 105.1, 55.9, 19.0 ppm. IR (KBr):
1
viscous liquid (242.0 mg, 84%). H NMR (400 MHz, CDCl3): δ =
16.09 (s, 1 H, OH), 7.79 (dd, J = 7.8, 1.7 Hz, 1 H, Ar-H), 7.76 (dd,
J = 3.8, 1.1 Hz, 1 H, Ar-H), 7.63 (dd, J = 4.9, 1.1 Hz, 1 H, Ar-H),
7.51 (td, J = 7.8, 1.7 Hz, 1 H, Ar-H), 7.34 (td, J = 7.7, 1.1 Hz, 1
H, Ar-H), 7.17–7.13 (m, 2 H, Ar-H), 6.55 (s, 1 H, C=CH), 2.33 (s,
3 H, CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 182.5, 180.2,
169.1, 148.7, 141.7, 132.8, 132.4, 130.5, 129.5, 128.5, 128.4, 126.3,
123.7, 96.9, 21.1 ppm. HRMS (ESI–TOF): calcd. for C15H11O4S
[M Ϫ H]– 287.0378; found 287.0365.
ν
= 3122, 1658, 1627, 1484, 1028, 829, 786 cm–1. HRMS (ESI–
˜
max
TOF): calcd. for C16H12O5 [M + H]+ 285.0763; found 285.0749.
3-(Furan-2-carbonyl)-2,6-dimethyl-4H-chromen-4-one (3d): Com-
pound 1d (244.0 mg, 1.0 mmol) was treated by using the same pro-
cedure as that used for the synthesis of 3a, except for the reaction
time (2 h), giving 3d as a brown powder (185.0 mg, 69%). 1H NMR
(400 MHz, CDCl3): δ = 7.98 (d, J = 1.0 Hz, 1 H, Ar-H), 7.62 (dd,
J = 1.6, 0.6 Hz, 1 H, Ar-H), 7.50 (dd, J = 8.6, 2.0 Hz, 1 H, Ar-H),
7.36 (d, J = 8.5 Hz, 1 H, Ar-H), 7.21 (d, J = 4.1 Hz, 1 H, Ar-H),
6.56 (dd, J = 3.6, 1.7 Hz, 1 H, Ar-H), 2.46 (s, 3 H, CH3), 2.41 (s,
3 H, CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 180.6, 175.4,
5-Methoxy-2-[3-oxo-3-(thiophen-2-yl)propanoyl]phenyl Acetate (2f):
Compound 1f (276.0 mg, 1.0 mmol) was treated by using the same
procedure as that used for the synthesis of 2a, except for the reac-
tion time (2 h), giving 2f as yellow viscous liquid (251.2 mg, 79%).
1H NMR (400 MHz, CDCl3): δ = 16.32 (s, 1 H, OH), 7.79 (d, J =
4558
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4551–4563

Multi-Functionalized Chromeno[2,3-c]pyrrol-9(2H)-ones
165.6, 154.0, 152.8, 147.3, 135.3, 135.1, 125.1, 122.9, 122.1, 120.0,
due was then mixed with 1a (240.0 mg, 1.0 mmol) and DMAP
(0.2 mmol) in Py (10 mL). A major yellow spot could be observed
in 5 h, and a large excess of water was added and the pH of the
mixture was adjusted to neutral with 10% HCl. The product was
then extracted with EtOAc, washed with water three times, and
dried with MgSO4. The evaporation of EtOAc resulted in a crude
product, which was purified by column chromatography to give 5a
as a yellow powder (185.7 mg, 43%). M.p. 156.9–158.8 °C. 1H
NMR (400 MHz, CDCl3): δ = 9.98 (s, 1 H, N-H), 8.32 (dd, J =
7.9, 1.6 Hz, 1 H, Ar-H), 8.04 (d, J = 7.6 Hz, 2 H, Ar-H), 7.55–7.61
(m, 1 H, Ar-H), 7.42 (t, J = 7.7 Hz, 2 H, Ar-H), 7.36 (d, J = 8.3 Hz,
1 H, Ar-H), 7.30 (t, J = 7.4 Hz, 1 H, Ar-H), 7.23 (d, J = 7.9 Hz, 1
H, Ar-H), 4.75 [s, 1 H, (C=O)-N-H], 3.24 (dd, J = 13.0, 6.5 Hz, 2
H, CH2), 2.94 (t, J = 7.1 Hz, 2 H, CH2), 1.79–1.70 (m, 2 H, CH2),
1.62–1.56 (m, 2 H, CH2), 1.34 (s, 9 H, CH3) ppm. 13C NMR
(101 MHz, CDCl3): δ = 175.8, 156.8, 142.1, 133.4, 131.3, 128.3
(3ϫ), 123.0 (2ϫ), 127.7, 127.1, 122.6, 122.4, 117.3, 113.7, 108.1,
117.5, 112.5, 20.8, 18.9 ppm. IR (KBr): ν
= 3122, 1632, 1568,
˜
max
1463, 1016, 818, 774 cm–1. HRMS (ESI–TOF): calcd. for C16H12O4
[M + H]+ 269.0814; found 269.0805.
2-Methyl-3-(thiophene-2-carbonyl)-4H-chromen-4-one (3e): Com-
pound 1e (246.0 mg, 1.0 mmol) was treated by using the same pro-
cedure as that used for the synthesis of 3a, giving 3e as a brown
powder (218.7 mg, 81%). 1H NMR (400 MHz, CDCl3): δ = 8.21
(dd, J = 7.9, 1.5 Hz, 1 H, Ar-H), 7.75–7.68 (m, 2 H, Ar-H), 7.62
(dd, J = 3.8, 1.0 Hz, 1 H, Ar-H), 7.48 (d, J = 8.2 Hz, 1 H, Ar-H),
7.46–7.41 (m, 1 H, Ar-H), 7.12 (dd, J = 4.8, 3.9 Hz, 1 H, Ar-H),
2.42 (s, 3 H, CH3) ppm.
7-Methoxy-2-methyl-3-(thiophene-2-carbonyl)-4H-chromen-4-one
(3f): Compound 1f (276.0 mg, 1.0 mmol) was treated by using the
same procedure as that used for the synthesis of 3a, except for the
reaction time (2 h), giving 3f as a yellow powder (219.0 mg, 73%).
1H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 8.9 Hz, 1 H, Ar-H),
7.72 (dd, J = 4.9, 1.2 Hz, 1 H, Ar-H), 7.62 (dd, J = 3.8, 1.1 Hz, 1
H, Ar-H), 7.11 (dd, J = 4.9, 3.9 Hz, 1 H, Ar-H), 6.99 (dd, J = 8.9,
2.4 Hz, 1 H, Ar-H), 6.87 (d, J = 2.4 Hz, 1 H, Ar-H), 3.93 (s, 3 H,
OCH3), 2.38 (s, 3 H, CH3) ppm. 13C NMR (101 MHz, CDCl3): δ
= 185.5, 174.8, 164.5, 164.3, 157.6, 144.3, 135.1, 134.8, 128.3, 127.3,
79.6, 39.0, 29.1, 28.3 (3ϫ), 26.0, 22.2 ppm. IR (KBr): νmax = 3337,
˜
3227, 2967, 1684, 1619, 1475, 1282, 1169, 745 cm–1. HRMS (ESI–
TOF): calcd. for C26H28N2O4 [M Ϫ H]– 431.1971; found 431.1944.
Reaction Optimization: Reaction optimization was carried out by
using the reaction of 1a with Fmoc-Leu-OH as a model. Taking
account of the contribution of DMAP in Fmoc cleavage, DMAP
(0.6 equiv.) was used during the reaction. Several conditions were
applied. Method I: Fmoc-Leu-OH (530 mg, 1.5 mmol) was dis-
solved in CH2Cl2 (20 mL), and then DCC (0.9 mmol) was added,
and the mixture was stirred at 15 °C until the amino acid disap-
peared. After filtering off the insoluble side product, DCU, CH2Cl2
was evaporated to give a viscous residue; the freshly obtained resi-
due was then mixed with 1a (120.0 mg, 0.5 mmol) and DMAP
(0.3 mmol) in Py (exactly 10 mL). The reaction mixture was either
stirred at 15 °C for 5 h, or warmed to 40 °C for another 2 h after
5 h of stirring at 15 °C. Method II: Fmoc-Leu-OH (265 mg,
0.75 mmol), 1a (0.5 mmol, 120 mg), and DMAP (0.3 mmol,
36.6 mg) were dissolved in Py (exactly 10 mL). Then, DCC
(0.9 mmol, 185.4 mg) was added, and the mixture was kept stirring
at 15 °C until 1a disappeared, as monitored by using TLC (about
30 min). After that, the reaction mixture was either stirred at 15 °C
for 5 h, or warmed to 40 °C for another 2 h after 5 h of stirring at
15 °C, or directly warmed to 40 °C for 2 h soon after the disappear-
ance of 1a. Then, each reaction mixture was centrifuged and 80 μL
of the supernatant was taken and diluted to 1.0 mL with acetoni-
trile for HPLC analysis and YHPLC calculation, according to pro-
cedures described above. In further investigations, more reactions
were carried out by replacing DMAP with NEt3 or DIEA, or sim-
ply by removing DMAP under conditions of direct acylation of 1a
with leucine/DCC followed with 2 h of stirring at 40 °C. The HPLC
yields were determined as well.
123.1, 117.1, 114.6, 100.2, 55.8, 19.0 ppm. IR (KBr): ν
= 3091,
˜
max
1637, 1601, 1406, 1237, 840, 771 cm–1. HRMS (ESI–TOF): calcd.
for C16H12O4S [M + H]+ 301.0535; found 301.0535.
2,6-Dimethyl-3-(thiophene-2-carbonyl)-4H-chromen-4-one
(3g):
Compound 1g (260.0 mg, 1.0 mmol) was treated by using the same
procedure as that used for the synthesis of 3a, except for the reac-
tion time (2 h), giving 3g as a yellow powder (190 mg, 67%). 1H
NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 1.4 Hz, 1 H, Ar-H),
7.72 (dd, J = 4.9, 1.1 Hz, 1 H, Ar-H), 7.61 (dd, J = 3.8, 1.1 Hz, 1
H, Ar-H), 7.51 (dd, J = 8.6, 2.2 Hz, 1 H, Ar-H), 7.37 (d, J = 8.5 Hz,
1 H, Ar-H), 7.11 (dd, J = 4.9, 3.9 Hz, 1 H, Ar-H), 2.46 (s, 3 H,
CH3), 2.40 (s, 3 H, CH3) ppm.
Determination of the Standard Curves and the HPLC Yields: Series
of solutions of purified 5a–r in acetonitrile were prepared at the
following concentrations: for 5a, 5e–g, 5j–k, and 5n–q, 2.5, 1.25,
0.625, 0.313, and 0.156 mgmLϪ1; for 5c, 2.2, 1.1, 0.55, 0.275, and
0.138 mgmLϪ1; for others, 2.0, 1.0, 0.5, 0.25, and 0.125 mgmLϪ1
.
For each compound, 5 μL sample was used and eluted with a linear
gradient of 55–99% CH3CN in double-deionized H2O over 30 min,
using UV detection at 390 nm. The standard curve was plotted with
the peak area versus the mass of 5 μL of purified 5a–r at various
concentrations, and was analyzed with linear regression to give a
standard equation, A = kM, in which A is the obtained peak area
in mAumin, mAu is the Absorbance unit ϫ 1/1000, M is the deter-
mined mass of 5 μL sample in mg, and k is the slope. To determine
the HPLC yield (YHPLC), the reaction mixture was centrifuged, and
80 μL of the supernatant was taken and diluted to 1.0 mL with
acetonitrile for HPLC analysis. Signals of 5 μL of sample were re-
corded on a UV detector at 390 nm to avoid the noise from byprod-
ucts, and the product peak area was calculated by integration. The
Synthesis of 5a–r under the Optimized Conditions
tert-Butyl [4-(9-Oxo-1-phenyl-2,9-dihydrochromeno[2,3-c]pyrrol-3-
yl)butyl]carbamate (5a): Compound 1a (120.0 mg, 0.5 mmol),
Fmoc-Lys(Boc)-OH (352 mg, 0.75 mmol), and DMAP (36.6 mg,
0.3 mmol) were dissolved in Py (10 mL), and then DCC (0.9 mmol,
185.4 mg) was added. The mixture was stirred at 15 °C until 1a
disappeared, as monitored by using TLC. Then, the reaction tem-
perature was raised to 40 °C for 3 h, and a major yellow spot could
be observed by TLC. The reaction mixture was then centrifuged,
HPLC yield was calculated according to YHPLC
=
100%ϫ[Mϫ(1.0 mL/0.08 mL)ϫ10 mL]/N = 100%ϫ125 A/kN,
in which N is the theoretical yield in mg.
Reaction Optimization and Synthesis of 5a–r
First Synthesis of 5a: Fmoc-Lys(Boc)-OH (1.41 g, 3.0 mmol) was and 80 μL of the supernatant was taken and diluted to 1.0 mL with
dissolved in CH2Cl2 (20 mL), and then DCC (1.8 mmol) was
added. The mixture was stirred at 25 °C until the amino acid disap-
peared. After filtering off the insoluble byproduct, DCU, CH2Cl2
was evaporated to give a viscous residue; the freshly obtained resi-
acetonitrile for HPLC analysis and YHPLC calculation, according
to the procedures described above. The rest of the supernatant was
concentrated under reduced pressure to remove Py, giving a residue
that could be purified by column chromatography to give 5a as a
Eur. J. Org. Chem. 2011, 4551–4563
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4559

L. An, X. Bu et al.
FULL PAPER
yellow powder (164.2 mg, 76%). The characterization data are
listed above.
3-Benzyl-1-phenylchromeno[2,3-c]pyrrol-9(2H)-one (5f): Compound
1a (120.0 mg, 0.5 mmol) and Fmoc-Phe-OH (290 mg, 0.75 mmol)
were treated by using the same procedure as that used for 5a, except
for the reaction time (40 °C for 4 h), giving 5f as a yellow powder
(89.5 mg, 51 %). M.p. 151.8–154.6 °C. 1H NMR (400 MHz,
MeOD): δ = 8.13 (dd, J = 8.0, 1.6 Hz, 1 H, Ar-H), 7.88 (d, J =
1.3 Hz, 1 H, Ar-H), 7.86 (s, 1 H, Ar-H), 7.60–7.54 (m, 1 H, Ar-H),
7.33 (dd, J = 8.0, 6.7 Hz, 4 H, Ar-H), 7.25 (d, J = 7.4 Hz, 1 H, Ar-
H), 7.22 (d, J = 0.8 Hz, 1 H, Ar-H), 7.21–7.18 (m, 4 H, Ar-H),
4.13 (s, 2 H, CH2) ppm. 13C NMR (101 MHz, CDCl3): δ = 175.8,
156.8, 142.5, 138.5, 133.5, 130.9, 128.8, 128.7 (2ϫ), 128.4 (4ϫ),
128.0, 127.6 (2ϫ), 127.0, 126.7, 122.6, 122.5, 117.3, 112.1, 108.2,
3-Isobutyl-1-phenylchromeno[2,3-c]pyrrol-9(2H)-one (5b): Com-
pound 1a (120.0 mg, 0.5 mmol) and Fmoc-Leu-OH (265 mg,
0.75 mmol) were treated by using the same procedure as that used
for 5a, except for the reaction time (40 °C for 2 h), giving 5b as a
yellow powder (128.4 mg, 81%). M.p. 146.7–148.6 °C. 1H NMR
(400 MHz, MeOD): δ = 8.16 (dd, J = 8.0, 1.6 Hz, 1 H, Ar-H), 7.94
(d, J = 1.3 Hz, 1 H, Ar-H), 7.92 (s, 1 H, Ar-H), 7.61 (ddd, J = 8.6,
7.2, 1.7 Hz, 1 H, Ar-H), 7.42–7.35 (m, 3 H, Ar-H), 7.29 (t, J =
7.4 Hz, 1 H, Ar-H), 7.23 (t, J = 7.5 Hz, 1 H, Ar-H), 2.68 (d, J =
7.2 Hz, 2 H, CH2), 2.03 (dt, J = 13.6, 6.8 Hz, 1 H,CH), 0.96 (d, J
= 6.6 Hz, 6 H, CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 175.9,
157.0, 142.6, 133.5, 131.2, 128.5 (2ϫ), 127.9, 127.8, 127.6 (2ϫ),
127.0, 122.6, 122.4, 117.3, 113.3, 108.3, 33.4, 29.0, 22.3 (2ϫ) ppm.
30.0 ppm. IR (KBr): ν
= 3416, 1611, 1475, 1323, 745 cm–1
.
˜
max
HRMS (ESI–TOF): calcd. for C24H17NO2 [M Ϫ H]– 350.1181;
found 350.1174.
= 3263, 2950, 1638, 1478, 1328, 1222, 754 cm–1.
3-[4-(tert-Butoxy)benzyl]-1-phenylchromeno[2,3-c]pyrrol-9(2H)-one
(5g): Compound 1a (120.0 mg, 0.5 mmol) and Fmoc-Tyr(p-OtBu)-
OH (345 mg, 0.75 mmol) were treated by using the same procedure
as that used for 5a, giving 5g as a red powder (165.0 mg, 78%).
IR (KBr): ν
˜
max
HRMS (ESI–TOF): calcd. for C21H19NO2 [M Ϫ H]– 316.1338;
found 316.1335.
1
3-[2-(Methylthio)ethyl]-1-phenylchromeno[2,3-c]pyrrol-9(2H)-one
(5c): Compound 1a (120.0 mg, 0.5 mmol) and Fmoc-Met-OH
(283 mg, 0.75 mmol) were treated by using the same procedure as
that used for 5a synthesis, giving 5c as a yellow powder (134.0 mg,
80%). M.p. 1146.0–149.2 °C. 1H NMR (400 MHz, MeOD): δ =
8.16 (dd, J = 8.0, 1.6 Hz, 1 H, Ar-H), 7.94 (dd, J = 7.1, 5.8 Hz, 2
H, Ar-H), 7.62 (ddd, J = 8.6, 7.1, 1.7 Hz, 1 H, Ar-H), 7.39 (t, J =
7.6 Hz, 3 H, Ar-H), 7.30 (dd, J = 8.3, 6.4 Hz, 1 H, Ar-H), 7.26–
7.21 (m, 1 H, Ar-H), 3.10 (t, J = 7.5 Hz, 2 H,CH2), 2.84 (t, J =
7.5 Hz, 2 H, CH2), 2.10 (s, 3 H, CH3) ppm. 13C NMR (101 MHz,
CDCl3): δ = 175.8, 156.8, 142.4, 133.6, 131.1, 128.5 (2ϫ), 128.4,
128.0, 127.6 (2ϫ), 127.0, 122.6 (2ϫ), 117.3, 112.4, 108.0, 33.9, 23.2,
M.p. 146.6–149.8 °C. H NMR (400 MHz, CDCl3): δ = 8.12 (d, J
= 8.0 Hz, 1 H, Ar-H), 7.90–7.86 (m, 2 H, Ar-H), 7.56 (t, J = 7.7 Hz,
1 H, Ar-H), 7.32 (dd, J = 12.7, 5.0 Hz, 3 H, Ar-H), 7.24 (t, J =
7.4 Hz, 1 H, Ar-H), 7.19 (t, J = 7.5 Hz, 1 H, Ar-H), 7.11 (d, J =
8.3 Hz, 2 H, Ar-H), 6.83 (d, J = 8.4 Hz, 2 H, Ar-H), 4.08 (s, 2 H,
CH2), 1.28 (s, 9 H, CH3) ppm. 13C NMR (101 MHz, CDCl3): δ =
175.7, 156.9, 154.2, 142.5, 133.6, 133.0, 131.0, 128.9 (2ϫ), 128.6,
128.5 (2ϫ), 128.1, 127.6 (2ϫ), 127.1, 124.5 (2ϫ), 122.6, 122.6,
117.3, 112.2, 108.4, 78.5, 29.4, 28.8 (3ϫ) ppm. IR (KBr): ν
=
˜
max
3416, 3220, 2932, 2382, 2293, 1609, 1471, 1158 cm–1. HRMS (ESI–
TOF): calcd. for C28H25NO3 [M Ϫ H]– 422.1756; found 422.1761.
15.4 ppm. IR (KBr): νmax = 3063, 1608, 1456, 1306, 1187, 770 cm–1.
1-(Furan-2-yl)-3-isobutylchromeno[2,3-c]pyrrol-9(2H)-one (5h):
Compound 1b (115.0 mg, 0.5 mmol) and Fmoc-Leu-OH (265 mg,
0.75 mmol) were treated by using the same procedure as that used
for 5a, giving 5h as a red powder (109.0 mg, 71%). M.p. 143.0–
˜
HRMS (ESI–TOF): calcd. for C20H17NO2S [M Ϫ H]– 334.0902;
found 334.0892.
1
tert-Butyl 2-(9-Oxo-1-phenyl-2,9-dihydrochromeno[2,3-c]pyrrol-3-
yl)acetate (5d): Compound 1a (120.0 mg, 0.5 mmol) and Fmoc-
Asp(tBu)-OH (310 mg, 0.75 mmol) were treated by using the same
procedure as that used for 5a, except for the reaction time (40 °C
for 4 h), giving 5d as a red powder (140.6 mg, 75%). M.p. 167.2–
168.9 °C. 1H NMR (400 MHz, MeOD): δ = 8.12 (dd, J = 8.0,
1.6 Hz, 1 H, Ar-H), 7.88–7.91 (m, 2 H, Ar-H), 7.57 (ddd, J = 8.6,
7.1, 1.7 Hz, 1 H, Ar-H), 7.35 (dd, J = 10.2, 4.7 Hz, 3 H, Ar-H),
7.25 (t, J = 7.4 Hz, 1 H, Ar-H), 7.22–7.17 (m, 1 H, Ar-H), 3.73 (s,
2 H, CH2), 1.38 (s, 9 H, CH3) ppm. 13C NMR (101 MHz, CDCl3):
δ = 175.4, 170.2, 156.6, 142.9, 133.5, 131.0, 129.0, 128.5 (2ϫ),
128.1, 127.6 (2ϫ), 127.1, 122.7, 122.6, 117.1, 108.0, 105.5, 82.4,
145.1 °C. H NMR (400 MHz, [D6]DMSO): δ = 12.36 (s, 1 H, N-
H), 8.16 (dd, J = 7.9, 1.5 Hz, 1 H, Ar-H), 7.80 (d, J = 0.9 Hz, 1
H, Ar-H), 7.72 (d, J = 3.3 Hz, 1 H, Ar-H), 7.69 (dd, J = 11.2,
4.3 Hz, 1 H, Ar-H), 7.46 (d, J = 8.2 Hz, 1 H, Ar-H), 7.33 (t, J =
7.2 Hz, 1 H, Ar-H), 6.67 (dd, J = 3.3, 1.8 Hz, 1 H, Ar-H), 2.66 (d,
J = 7.1 Hz, 2 H, CH2), 2.09–2.01 (m, 1 H, CH), 0.93 (d, J = 6.6 Hz,
6 H, CH3) ppm. 13C NMR (101 MHz, [D6]DMSO): δ = 173.6,
156.3, 146.2, 142.3, 141.3,133.9, 126.2, 122.7, 122.0,117.7, 117.4,
113.6, 112.2, 109.0, 106.4, 32.5, 28.4, 22.0 (2ϫ) ppm. IR (KBr):
ν
= 3231, 2956, 1646, 1616, 1463, 1317, 919, 757 cm–1. HRMS
˜
max
(ESI–TOF): calcd. for C19H17NO3 [M Ϫ H]– 306.1130; found
306.1121.
30.0, 28.1 (3ϫ) ppm. IR (KBr): ν
= 3367, 1713, 1656, 1477,
˜
max
1-(Furan-2-yl)-3-isobutyl-7-methylchromeno[2,3-c]pyrrol-9(2H)-one
(5i): Compound 1d (122.0 mg, 0.5 mmol) and Fmoc-Leu-OH
(265 mg, 0.75 mmol) were treated by using the same procedure as
that used for 5a, except for the reaction time (40 °C for 4 h), giving
5i as a red powder (101.1 mg, 63%). M.p. 142.3–144.4 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 12.30 (s, 1 H, N-H), 7.93 (d, J =
1.5 Hz, 1 H, Ar-H), 7.78 (d, J = 1.0 Hz, 1 H, Ar-H), 7.72 (d, J =
1322, 1154, 757 cm–1. HRMS (ESI–TOF): calcd. for C23H21NO4
[M Ϫ H]– 374.1392; found 374.1368.
3-Methyl-1-phenylchromeno[2,3-c]pyrrol-9(2H)-one (5e): Com-
pound 1a (120.0 mg, 0.5 mmol) and Fmoc-Ala-OH (233 mg,
0.75 mmol) were treated by using the same procedure as that used
for 5a synthesis, giving 5e as a yellow powder (105.9 mg, 77%).
M.p. 156.1–158.4 °C.1H NMR (400 MHz, [D6]DMSO): δ = 12.21 3.4 Hz, 1 H, Ar-H), 7.47 (dd, J = 8.5, 2.1 Hz, 1 H, Ar-H), 7.32 (d,
(s, 1 H, N-H), 8.16 (dd, J = 7.9, 1.5 Hz, 1 H, Ar-H), 8.10 (d, J =
7.4 Hz, 2 H, Ar-H), 7.73–7.68 (m, 1 H, Ar-H), 7.47 (dd, J = 14.7, (d, J = 7.1 Hz, 2 H, CH2), 2.38 (s, 3 H, CH3) 2.03 (m, 1 H, CH),
7.8 Hz, 3 H, Ar-H), 7.35 (d, J = 7.3 Hz, 1 H, Ar-H), 7.31 (d, J =
0.91 (d, J = 6.6 Hz, 6 H, CH3) ppm. 13C NMR (101 MHz, [D6]-
7.1 Hz, 1 H, Ar-H), 2.41 (s, 3 H, CH3) ppm. 13C NMR (101 MHz, DMSO): δ = 173.7, 154.5, 146.3, 142.3, 141.4, 134.8, 131.8, 125.7,
J = 8.5 Hz, 1 H, Ar-H), 6.66 (dd, J = 3.4, 1.8 Hz, 1 H, Ar-H), 2.64
[D6]DMSO): δ = 174.0, 155.9, 141.4, 133.6, 131.0, 127.9 (2ϫ), 127.4
(2ϫ), 127.2, 126.7, 126.3, 122.4, 121.9, 117.1, 109.5, 107.3, 8.6 ppm.
121.7, 117.6, 117.3, 113.5, 112.2, 108.9, 106.5, 32.5, 28.4, 22.1 (2ϫ),
20.3 ppm. IR (KBr): ν
= 3208, 2956, 1644, 1468, 1307, 1218,
˜
max
IR (KBr): ν
= 3213, 1626, 1473, 1285, 750 cm–1. HRMS (ESI–
815, 742 cm–1. HRMS (ESI–TOF): calcd. for C20H19NO3
˜
max
TOF): calcd. for C18H13NO2 [M Ϫ H]– 274.0868; found 274.0872.
[M Ϫ H]– 320.1287; found 320.1278.
4560
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4551–4563

Multi-Functionalized Chromeno[2,3-c]pyrrol-9(2H)-ones
1-(Furan-2-yl)-3-isobutyl-7-methoxychromeno[2,3-c]pyrrol-9(2H)-
one (5j): Compound 1c (130.0 mg, 0.5 mmol) and Fmoc-Leu-OH
(265 mg, 0.75 mmol) were treated by using the same procedure as
tert-Butyl (4-{9-Oxo-1-(thiophen-2-yl)-2,9-dihydrochromeno[2,3-
c]pyrrol-3-yl}butyl)carbamate (5n): Compound 1e (123.0 mg,
0.5 mmol) and Fmoc-Lys(Boc)-OH (351 mg, 0.75 mmol) were
treated by using the same procedure as that used for 5a, giving 5n
that used for 5a, giving 5j as a yellow powder (144.9 mg, 86%).
1
M.p. 140.5–142.7 °C. H NMR (400 MHz, [D6]DMSO): δ = 12.35 as a yellow powder (133.6 mg, 61 %). M.p. 163.1–165.7 °C. 1H
(s, 1 H, N-H), 7.80 (s, 1 H, Ar-H), 7.72 (d, J = 3.3 Hz, 1 H, Ar- NMR (400 MHz, CDCl3): δ = 9.74 (s, 1 H, N-H), 8.32 (d, J =
H), 7.58 (d, J = 3.1 Hz, 1 H, Ar-H), 7.42 (d, J = 9.1 Hz, 1 H, Ar-
H), 7.29 (dd, J = 9.1, 3.1 Hz, 1 H, Ar-H), 6.66 (dd, J = 3.1, 1.7 Hz,
7.0 Hz, 1 H, Ar-H), 8.00 (d, J = 2.6 Hz, 1 H, Ar-H), 7.58 (dd, J =
11.2, 4.1 Hz, 1 H, Ar-H), 7.34 (d, J = 8.3 Hz, 1 H, Ar-H), 7.30 (d,
1 H, Ar-H), 3.84 (s, 3 H, OCH3), 2.65 (d, J = 7.1 Hz, 2 H, CH2), J = 5.0 Hz, 1 H, Ar-H), 7.24 (d, J = 7.6 Hz, 1 H, Ar-H), 7.10–7.07
2.04 (m, 1 H, CH), 0.92 (d, J = 6.6 Hz, 6 H, CH3) ppm. 13C NMR
(101 MHz, [D6]DMSO): δ = 173.4, 154.6, 150.8, 146.3, 142.2,
141.5, 122.3, 118.8, 117.3, 113.3, 112.2, 108.8, 106.9, 106.2, 55.5,
(m, 1 H, Ar-H), 4.72 [s, 1 H, (C=O)-N-H], 3.24 (d, J = 6.0 Hz, 2
H, CH2), 2.91 (t, J = 7.1 Hz, 2 H, CH2), 1.77–1.72 (m, 2 H, CH2),
1.62–1.57 (m, 2 H, CH2), 1.41 (s, 9 H, CH3) ppm. 13C NMR
(101 MHz, CDCl3): δ = 175.5, 156.9, 141.7, 133.5, 133.4, 127.4,
126.9, 126.3, 125.2, 122.5, 122.5, 122.4, 117.3, 113.5, 108.0, 79.5,
32.5, 28.4, 22.1 (2ϫ) ppm. IR (KBr): ν
= 3153, 3041, 2953,
˜
max
1608, 1468, 1301, 776, 732 cm–1. HRMS (ESI–TOF): calcd. for
C20H19NO4 [M Ϫ H]– 336.1236; found 336.1206.
39.3, 29.2, 28.3 (3ϫ), 26.0, 22.6 ppm. IR (KBr): νmax = 3415, 3227,
˜
2935, 1685, 1618, 1473, 1283, 1171, 922, 755 cm–1. HRMS (ESI–
TOF): calcd. for C24H26N2O4S [M Ϫ H]– 437.1535; found
437.1496.
3-Isobutyl-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one (5k):
Compound 1e (123.0 mg, 0.5 mmol) and Fmoc-Leu-OH (265 mg,
0.75 mmol) were treated by using the same procedure as that used
for 5a, except for the reaction time (40 °C for 4 h), giving 5k as
a yellow powder (75.9 mg, 47%). M.p. 160.8–162.6 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 12.08 (s, 1 H, N-H), 8.16 (dd, J = 7.9,
1.4 Hz, 1 H, Ar-H), 8.01 (d, J = 3.6 Hz, 1 H, Ar-H), 7.73–7.66 (m,
1 H, Ar-H), 7.54 (d, J = 5.0 Hz, 1 H, Ar-H), 7.45 (d, J = 8.3 Hz,
1 H, Ar-H), 7.32 (t, J = 7.5 Hz, 1 H, Ar-H), 7.17–7.12 (m, 1 H,
Ar-H), 2.67 (d, J = 7.2 Hz, 2 H, CH2), 2.06 (m, 1 H, CH), 0.95 (d,
J = 6.6 Hz, 6 H, CH3) ppm. 13C NMR (101 MHz, [D6]DMSO): δ
= 173.9, 156.1, 141.3, 133.9, 133.3, 127.3, 126.3, 126.0, 122.7, 121.9,
121.3, 117.4, 113.5, 106.9, 32.6, 28.4, 22.1 (2ϫ) ppm. IR (KBr):
tert-Butyl (4-{6-Methoxy-9-oxo-1-(thiophen-2-yl)-2,9-dihydro-
chromeno[2,3-c]pyrrol-3-yl}butyl)carbamate (5o): Compound 1f
(138.0 mg, 0.5 mmol) and Fmoc-Lys(Boc)-OH (351 mg,
0.75 mmol) were treated by using the same procedure as that used
for 5a, giving 5o as a yellow powder (102.9 mg, 44%). M.p. 143.8–
145.1 °C. 1H NMR (400 MHz, CDCl3): δ = 9.58 (s, 1 H, N-H),
8.22 (d, J = 8.8 Hz, 1 H, Ar-H), 7.98 (d, J = 3.1 Hz, 1 H, Ar-H),
7.28 (dd, J = 5.1, 0.9 Hz, 1 H, Ar-H), 7.07 (dd, J = 5.0, 3.8 Hz, 1
H, Ar-H), 6.82 (dd, J = 8.8, 2.4 Hz, 1 H, Ar-H), 6.77 (d, J = 2.4 Hz,
1 H, Ar-H), 4.72 [s, 1 H, (C=O)-N-H], 3.90 (s, 1 H, OCH3), 3.23
ν
= 3201, 2954, 1611, 1476, 1224, 919, 753 cm–1. HRMS (ESI– (dd, J = 12.9, 6.4 Hz, 2 H, CH2), 2.88 (t, J = 7.2 Hz, 2 H, CH2),
˜
max
TOF): calcd. for C19H17NO2S [M Ϫ H]– 322.0902; found 322.0898.
1.76–1.71 (m, 2 H, CH2), 1.61–1.56 (m, 2 H, CH2), 1.41 (s, 9 H,
CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 175.1, 164.2, 158.7,
142.0, 133.5, 128.4, 127.4, 126.2, 125.1, 122.2, 116.5, 113.4, 111.2,
108.0, 100.2, 79.6, 55.7, 39.4, 29.3, 28.4 (3ϫ), 26.1, 22.7 ppm. IR
3-Isobutyl-6-methoxy-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-
one (5l): Compound 1f (138.0 mg, 0.5 mmol) and Fmoc-Leu-OH
(265 mg, 0.75 mmol) were treated by using the same procedure as
that used for 5a, giving 5l as a yellow powder (139.4 mg, 79%).
(KBr): νmax = 3261, 3073, 2971, 2929, 1680, 1641, 1475, 1271, 1168,
˜
833, 780 cm–1. HRMS (ESI–TOF): calcd. for C25H28N2O5S [M Ϫ
1
M.p. 110.6–111.4 °C. H NMR (400 MHz, [D6]DMSO): δ = 12.01
H]– 467.1641; found 467.1623.
(s, 1 H, N-H), 8.04 (d, J = 8.8 Hz, 1 H, Ar-H), 8.01–7.98 (m, 1 H,
Ar-H), 7.53 (d, J = 5.0 Hz, 1 H, Ar-H), 7.13 (dd, J = 4.9, 3.8 Hz,
tert-Butyl (4-{7-Methyl-9-oxo-1-(thiophen-2-yl)-2,9-dihydro-
1 H, Ar-H), 6.95 (d, J = 2.3 Hz, 1 H, Ar-H), 6.89 (dd, J = 8.8, chromeno[2,3-c]pyrrol-3-yl}butyl)carbamate (5p): Compound 1g
2.3 Hz, 1 H, Ar-H), 3.88 (s, 3 H, OCH3), 2.64 (d, J = 7.2 Hz, 2 H, (130.0 mg, 0.5 mmol) and Fmoc-Lys(Boc)-OH (351 mg,
CH2), 2.05 (m, 1 H, CH), 0.94 (d, J = 6.6 Hz, 6 H, CH3) ppm. 13
C
0.75 mmol) were treated by using the same procedure as that used
NMR (101 MHz, [D6]DMSO): δ = 173.4, 163.8, 158.0, 141.6, for 5a, giving 5p as a yellow powder (155.9 mg, 69%). M.p. 152.4–
1
133.4, 127.6, 127.2, 125.8 (2ϫ), 121.0, 115.7, 113.5, 111.6, 106.8, 153.3 °C. H NMR (400 MHz, [D6]DMSO): δ = 12.09 (s, 1 H, N-
100.1, 55.8, 32.6, 28.4, 22.1 (2ϫ) ppm. IR (KBr): ν
= 3414,
H), 7.99 (d, J = 3.1 Hz, 1 H, Ar-H), 7.94 (s, 1 H, Ar-H), 7.54 (d,
J = 5.0 Hz, 1 H, Ar-H), 7.51 (dd, J = 8.5, 1.6 Hz, 1 H, Ar-H), 7.37
(d, J = 8.4 Hz, 1 H, Ar-H), 7.11–7.17 (m, 1 H, Ar-H), 6.78 [s, 1 H,
(C=O)-N-H], 2.97 (d, J = 6.1 Hz, 2 H, CH2), 2.77 (t, J = 7.3 Hz,
2 H, CH2), 2.40 (s, 3 H, CH3), 1.64–1.71 (m, 2 H, CH2), 1.41–1.48
(m, 2 H, CH2), 1.35 (s, 9 H, CH3) ppm. 13C NMR (101 MHz,
[D6]DMSO): δ = 175.7, 155.1, 141.9, 134.6, 133.5, 132.0, 127.4,
126.5, 126.2, 125.2, 122.3, 122.2, 117.0, 113.3, 108.1, 79.5, 39.4,
˜
max
3171, 2952, 1608, 1473, 1286, 829, 772 cm–1. HRMS (ESI–TOF):
calcd. for C20H19NO3S [M Ϫ H]– 352.1007; found 352.0981.
tert-Butyl [4-(1-(Furan-2-yl)-9-oxo-2,9-dihydrochromeno[2,3-c]pyr-
rol-3-yl)butyl]carbamate (5m): Compound 1b (115.0 mg, 0.5 mmol)
and Fmoc-Lys(Boc)-OH (351 mg, 0.75 mmol) were treated by
using the same procedure as that used for 5a, giving 5m as a yellow
powder (162.5 mg, 77 %). M.p. 145.4–147.7 °C. 1H NMR
(400 MHz, CDCl3): δ = 9.57 (s, 1 H, N-H), 8.31 (dd, J = 7.9,
1.5 Hz, 1 H, Ar-H), 7.85 (d, J = 3.3 Hz, 1 H, Ar-H), 7.56–7.61 (m,
1 H, Ar-H), 7.41 (d, J = 0.9 Hz, 1 H, Ar-H), 7.34 (d, J = 8.3 Hz,
1 H, Ar-H), 7.29–7.23 (m, 1 H, Ar-H), 6.54 (dd, J = 3.3, 1.7 Hz, 1
29.2, 28.4 (3ϫ), 26.1, 22.7, 20.7 ppm. IR (KBr): νmax = 3389, 3248,
˜
2930, 1680, 1617, 1478, 1292, 1165, 824, 773 cm–1. HRMS (ESI–
TOF): calcd. for C25H28N2O4S [M + H]+ 453.1848; found
453.1839.
H, Ar-H), 4.67 [s, 1 H, (C=O)-N-H], 3.24 (d, J = 6.1 Hz, 2 H, 3-[4-(tert-Butoxy)benzyl]-6-methoxy-1-(thiophen-2-yl)chromeno-
CH2), 2.90 (t, J = 7.4 Hz, 2 H, CH2), 1.78–1.73 (m, 2 H, CH2), [2,3-c]pyrrol-9(2H)-one (5q): Compound 1f (138.0 mg, 0.5 mmol)
1.61–1.56 (m, 2 H, CH2), 1.46 (s, 9 H, CH3) ppm. 13C NMR and Fmoc-Tyr(p-OtBu)-OH (345 mg, 0.75 mmol) were treated by
(101 MHz, CDCl3): δ = 175.1, 157.0, 146.3, 141.6, 141.4, 133.5, using the same procedure as that used for 5a, giving 5q as a yellow
126.8, 122.7, 122.5, 119.1, 117.4, 113.1, 112.4, 109.8, 107.4, 79.4,
powder (123.9 mg, 54 %). M.p. 166.5–168.7 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 12.28 (s, 1 H, N-H), 8.08 (d, J =
8.9 Hz, 1 H, Ar-H), 8.06 (d, J = 3.6 Hz, 1 H, Ar-H), 7.56 (d, J =
4.9 Hz, 1 H, Ar-H), 7.20 (d, J = 8.4 Hz, 2 H, Ar-H), 7.17–7.14 (m,
39.4, 29.5, 28.4 (3ϫ), 26.1, 22.9 ppm. IR (KBr): νmax = 3333, 3166,
˜
2930, 1689, 1620, 1465, 1280, 918, 746 cm–1. HRMS (ESI–TOF):
calcd. for C24H26N2O5 [M ϪH]– 421.1763; found 421.1742.
Eur. J. Org. Chem. 2011, 4551–4563
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4561

L. An, X. Bu et al.
FULL PAPER
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1 H, Ar-H), 6.95 (d, J = 2.2 Hz, 1 H, Ar-H), 6.93 (s, 1 H, Ar-H),
6.92–6.89 (m, 2 H, Ar-H), 4.12 (s, 2 H, CH2), 3.88 (s, 3 H,
OCH3),1.25 (s, 9 H,CH3) ppm. 13C NMR (400 MHz, [D6]DMSO):
δ = 173.3, 163.9, 157.9, 153.3, 141.6, 134.0, 133.3, 128.5 (2ϫ),
127.7, 127.3, 126.1 (2ϫ), 123.8 (2ϫ), 121.7, 115.7, 112.6, 111.6,
[2]
[3]
107.0, 100.2, 77.6, 55.8, 28.5 (3ϫ), 28.4 ppm. IR (KBr): ν
=
˜
max
2973, 1609, 1475, 1271, 1162, 925, 777 cm–1. HRMS (ESI–TOF):
calcd. for C27H25NO4S [M Ϫ H]– 458.1426; found 458.1387.
3-[2-(Methylthio)ethyl]-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-
9(2H)-one (5r): Compound 1e (123.0 mg, 0.5 mmol) and Fmoc-
Met-OH (278 mg, 0.75 mmol) were treated by using the same pro-
cedure as that used for 5a, giving 5r as a yellow powder (151.7 mg,
89%). M.p. 143.6–145.6 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
12.20 (s, 1 H, N-H), 8.16 (d, J = 7.9 Hz, 1 H, Ar-H), 8.02 (d, J =
3.4 Hz, 1 H, Ar-H), 7.71 (t, J = 7.0 Hz, 1 H, Ar-H), 7.57 (d, J =
4.7 Hz, 1 H, Ar-H), 7.49 (d, J = 8.3 Hz, 1 H, Ar-H), 7.33 (t, J =
7.4 Hz, 1 H, Ar-H), 7.18–7.14 (m, 1 H, Ar-H), 3.07 (t, J = 7.5 Hz,
2 H, CH2), 2.86 (t, J = 7.5 Hz, 2 H, CH2), 2.13 (s, 3 H, CH3) ppm.
13C NMR (101 MHz, [D6]DMSO): δ = 173.8, 156.0, 141.4, 134.0,
133.2, 127.3, 126.2 (3ϫ), 122.8, 121.9, 121.7, 117.4, 112.5, 106.9,
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32.6, 23.7, 14.5 ppm. IR (KBr): ν
= 3142, 2972, 1642, 1479,
˜
[7]
[8]
max
1219, 823, 756 cm–1. HRMS (ESI–TOF): calcd. for C18H15NO2S2
[M Ϫ H]– 340.0466; found 340.0412.
Synthesis of 4aЈ: The synthesis of 4aЈ was performed under similar
conditions as those used to synthesize 5a–r. Boc-Lys(Boc)-OH
(0.75 mmol, 0.26 g), 1a (0.5 mmol, 120 mg), and DMAP
(0.3 mmol, 36.6 mg) were dissolved in Py (10 mL). Then, DCC
(0.9 mmol, 185.4 mg) was added, and the mixture was stirred at
15 °C until 1a disappeared, as monitored by using TLC (about
30 min). After that, the reaction mixture was warmed to 40 °C for
2 h. Then, the reaction mixture was filtered, and the filtrate was
concentrated under reduced pressure to remove the Py, giving a
residue that could be purified by column chromatography to give
[9]
[10]
1
4aЈ as an off-white powder (210 mg, 76.3%). H NMR (400 MHz,
CDCl3): δ = 8.15 (dd, J = 7.9, 1.3 Hz, 1 H, Ar-H), 7.91 (s, 1 H,
Ar-H), 7.89 (d, J = 1.2 Hz, 1 H, Ar-H), 7.74–7.68 (m, 1 H, Ar-H),
7.55 (t, J = 7.4 Hz, 1 H, Ar-H), 7.51 (d, J = 8.2 Hz, 1 H, Ar-H),
7.45–7.38 (m, 3 H, Ar-H), 5.02 [s, 1 H, (C=O)-N-H], 4.69 [s, 1 H,
(C=O)-N-H], 4.64 (td, J = 8.6, 5.4 Hz, 1 H, CH), 3.08 (d, J =
5.0 Hz, 2 H, CH2), 2.00–1.84 (m, 2 H, CH2), 1.51–1.45 (m, 4 H,
CH2), 1.42 (s, 9 H, tBu), 1.20 (s, 9 H, tBu) ppm. 13C NMR
(101 MHz, CDCl3): δ = 194.0, 176.3, 167.6, 156.0, 155.7, 154.6,
137.1, 134.1, 133.5, 129.4 (2ϫ), 128.5 (2ϫ), 125.9, 125.5, 123.3,
121.8, 117.9 (2ϫ), 79.8, 78.9, 52.8, 39.8, 34.5, 28.3, 27.9, 22.9 ppm.
ESI-MS: calcd. for C31H38N2O7 [M Ϫ H]– 550.3; found 549.3.
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CCDC-763383 (5a) and -763950 (5o) contain the supplemen-
tary crystallographic data for this paper. These data can be
obtainedfreeofchargefromThesedatacanbeobtainedfreeofcharge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): X-ray data, HPLC analysis and spectroscopic data for all new
compounds.
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E. Atherton, C. J. Logan, R. C. Sheppard, J. Chem. Soc. Perkin
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Acknowledgments
a) A. G. P. R. Figueiredo, A. C. Tome, A. M. S. Silva, J. A. S.
Cavaleiro, Tetrahedron 2007, 63, 910–917; b) . J. Morris, D. G.
Wishka, R. M. Jensen, J. Org. Chem. 1993, 58, 7277–7280.
a) A. Rampa, A. Bisi, P. Valenti, M. Recanatini, A. Cavalli, V.
Andrisano, V. Cavrini, L. Fin, A. Buriani, P. Giusti, J. Med.
Chem. 1998, 41, 3976–3986; b) F. Kielar, C. P. Montgomery,
E. J. New, D. Parker, R. A. Poole, S. L. Richardson, P. A. Sten-
son, Org. Biomol. Chem. 2007, 5, 2975–2982; c) B. S. Murray,
E. J. New, R. Pal, D. Parker, Org. Biomol. Chem. 2008, 6, 2085–
2094; d) F. Kielar, G. L. Law, E. J. New, D. Parker, Org. Biomol.
Chem. 2008, 6, 2256–2258; e) G. L. Law, R. Pal, L. O. Palsson,
We are indebted to the National High-tech R&D 863 Program (no.
2008AA02Z304), and the National Science Fund of China (no.
30973619) for financial support. We also thank Prof. Xiaopeng Hu
of Sun Yat-Sen University for his kind help in X-ray data analysis.
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