A New approach to pyrrolocoumarin derivatives by palladium-Catalyzed reactions: Expedient construction of polycyclic lamellarin scaffold

Article abstract of DOI:10.1002/adsc.200900287

A new and efficient protocol for straightforward synthesis of chromeno[3,4-b]pyrrol-4(3H)-one derivatives by palladium-catalyzed sequential coupling/cyclization reactions has been developed. The key strategy relies on creation of pyrrole ring through pall

Full text of DOI:10.1002/adsc.200900287

FULL PAPERS
DOI: 10.1002/adsc.200900287
A New Approach to Pyrrolocoumarin Derivatives by Palladium-
Catalyzed Reactions: Expedient Construction of Polycyclic
Lamellarin Scaffold
Lei Chena and Ming-Hua Xua,b,*
a
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, Peopleꢀs
Republic of China
Fax : (+86)-21-5080-7388; e-mail: xumh@mail.shcnc.ac.cn
State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555
b
Zuchongzhi Road, Shanghai 201203, Peopleꢀs Republic of China
Received: April 22, 2009; Published online: August 5, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900287.
Abstract: A new and efficient protocol for straight- b]pyrrol-4(3H)-one product has been demonstrated
forward synthesis of chromenoACTHNUGRTENUNG[3,4-b]pyrrol-4(3H)- by the expedient synthesis of polycyclic lamellarin
one derivatives by palladium-catalyzed sequential scaffold in four steps. It provides a new entry to syn-
coupling/cyclization reactions has been developed. thesis of potentially valuable lamellarin analogues.
The key strategy relies on creation of pyrrole ring
through palladium-catalyzed intramolecular hydro-
ACHTUNGTRENNUNGamination of related acetylenic aminocoumarins. The Keywords: coumarin derivatives; cross-coupling; hy-
synthetic utility of the obtained chromenoACTHNUTRGENUGN[3,4- droamination; lamellarin; palladium
Introduction
modulatory activity.[4] Recently, we have become in-
terested in these polyheterocyclic natural products for
Coumarin derivatives are known as an important drug discovery and envisioned the possible structural
class of compounds and are present in a large number modification while preserving the common pyrrolo-
of naturally occurring substances as well as medicinal- coumarin nucleus to explore the structure-activity re-
ly useful agents. They often exhibit a broad range of lationship (SAR).
biological and pharmacological activities, such as anti-
Despite numerous studies on the synthesis of cou-
fungal, antibacterial, antitumor, anti-HIV, antibiotic, marin derivatives with broad structural diversity, syn-
antioxidant, and anti-inflammatory.[1] Therefore, the thetic methods for the efficient and straightforward
synthesis and screening of coumarin compounds has construction of chromenoACTHUNRTGNEUNG[3,4-b]pyrrol-4(3H)-one
been the subject of constant interest in the past sever- units have been scare. In ningalins and lamellarins
al decades, and tremendous efforts have been devoted syntheses, the strategies employed often involve the
by organic chemists to the development of new meth-
odologies for the synthesis of diverse coumarin deriv-
atives.[2] Among them, the construction of libraries of
coumarin compounds that are structurally related to
bioactive natural products has received particular at-
tention.[3] Ningalins and lamellarins are two important
families of marine alkaloids that both possess an in-
teresting pyrrolocoumarin (chromenoACTHNUGRTENUNG[3,4-b]pyrrol-
4(3H)-one) subunit, as represented by ningalin B and
lamellarin D in Figure 1. They have exhibited a
variety of potentially valuable biological properties
including cytotoxicity, HIV-1 integrase inhibition,
Figure 1. Natural products with chromenoACTHNUGRTENUNG[3,4-b]pyrrol-
multidrug resistance (MDR) reversal, and immuno- 4(3H)-one subunit.
Adv. Synth. Catal. 2009, 351, 2005 – 2012
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2005

Lei Chen and Ming-Hua Xu
FULL PAPERS
multi-step preparation of a highly functionalized pyr- marin went smoothly to give the corresponding 4-hy-
role core followed by lactonization.[5] To the best of droxy-3-nitrocoumarin product in high yield (90%).
our knowledge, there were only two reports employ- Unfortunately, triflation of 4-hydroxy-3-nitrocoumarin
ing the strategy of direct formation of the pyrrole ring with trifluoromethanesulfonic anhydride was found to
by classic Fischer indole synthesis[6] and Claisen rear- be unsuccessful, mostly probably due to the poor sta-
rangement[7] using simple 3-aminocoumarins as the bility of the resulting product containing two strong
starting point. Unfortunately, both methods suffered electron-withdrawing groups. We then decided to con-
from the inaccessibility of highly diversified vert the 4-hydroxy group into a halogen. Since there
chromenoACHTUNGTRENNUNG
[3,4-b]pyrrol-4(3H)-one products; new ap- are difficulties in preparing 4-bromocoumarins,[9] we
proaches with broader reaction generality are greatly turned our attention to 4-chloro-3-nitrocoumarin
desirable. Considering the remarkable development which could be easily accessed by the reaction of 4-
of transition metal-catalyzed coupling reactions on hydroxy-3-nitrocoumarin with POCl3 in DMF at room
the 3- or 4-position of coumarins in recent years,[8] we temperature.[10] In the past ten years, significant prog-
envisaged that the direct construction of the pyrrole ress has been made in the area of transition metal-cat-
ring could be expected to be achieved by cyclization alyzed coupling reactions of aryl chlorides.[11] Al-
of the key intermediate 4-acetylenyl-3-aminocoumar- though aryl chlorides, in general, are poorly reactive,
in, whereby this cyclization precursor should be readi- those very electron-deficient ones have been known
ly accessed after Sonogashira coupling and nitro re- to serve as suitable substrates for palladium-catalyzed
duction of the corresponding 3,4-disubstituted cou- coupling reactions. Accordingly, in our case of 4-
À
marin. Thus, diversification on the pyrrole ring could chloro-3-nitrocoumarin (1), the C Cl bond at the C-4
be efficiently realized by easily tuning the starting al- position on the coumarin ring could be activated by
kynes in the step of the Sonogashira reaction the strong electron-withdrawing effect of the neighbor-
(Scheme 1). In this paper, we wish to report our suc- ing nitro and ester carbonyl groups, thus enabling the
cessful development of such a new and straightfor- smooth Sonogashira cross-coupling with terminal al-
ward approach to the synthesis of chromenoACTHNUTRGENUG[N 3,4- kynes (Scheme 2).
b]pyrrol-4(3H)-one derivatives using a palladium-cat-
alyzed sequential coupling/cyclization strategy.
Under the conditions of a catalytic amount of
Pd(PPh3)2Cl2 and CuI, we examined the potential of
ACHTUNGTRENNUNG
Sonogashira reaction between 4-chloro-3-nitrocou-
marin (1) and hexyne in THF at room temperature.
With Et3N as the base, the result is disappointing and
no desired product was obtained (Table 1, entry 1). To
Results and Discussion
Following the above strategy, initial experiments were our delight, when K2CO3 was used as base, the cou-
carried out to synthesize the necessary 4-halogeno-3- pling reaction proceeded and gave the expected prod-
nitro- or 4-trifluoromethanesulfonyloxy-3-nitrocou- uct 2a in 45% yield in the presence of 20 mol% of
marin. Under the conditions of 67% HNO3/HOAc at Pd
ACHTUGNERTN(NUNG PPh3)2Cl2 and CuI (entry 2). Interestingly, a de-
808C, nitration of the readily available 4-hydroxycou- crease of the catalyst loading to 10 mol% led to a dra-
Scheme 1. New strategy for synthesis of chromenoACTHNUTRGNE[UNG 3,4-b]pyrrol-4(3H)-ones.
Scheme 2. Synthesis of 4-chloro-3-nitrocoumarin as coupling substrate.
2006
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A New Approach to Pyrrolocoumarin Derivatives by Palladium-Catalyzed Reactions
FULL PAPERS
Table 1. Screening of catalytic system for Sonogashira coupling.
Entry[a]
Catalytic system (mol%)
T [oC]
Base
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
U
r.t.
r.t.
r.t.
50
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
Et3N
24
24
24
12
48
24
48
48
48
48
0
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
45
79
35
46
50
48
24
23
trace
ACHTUNGTRENNUNG
[a]
Reaction was carried out with 1 (0.50 mmol) and hexyne (0.60 mmol) in freshly distilled THF (10 mL) under nitrogen at-
mosphere.
Isolated yield.
[b]
matic improvement of the reaction yield to a good
In order to extend the substrate generality of 4-ace-
level (79%, entry 3). Other attempts including the tylenylcoumarins, we decided to check the potential
change of palladium catalysts and increasing the reac- of another Sonogashira coupling of aromatic alkynes
tion temperature did not afford better results (en- with 4-ethynyl-3-aminocoumarin (4) that is readily
tries 4–10).
available by desilylation of compound 3d. Very grati-
With optimal reaction conditions identified, the fyingly, the cross-coupling took place smoothly when
scope of the methodology was further investigated by various aryl iodides were employed under the stan-
the coupling of coumarin chloride 1 with various al- dard
kynes. It was found that aliphatic alkynes including [Pd(PPh3)4/CuI/Et3N] in THF at room temperature
trimethylsilylacetylene could typically work well, but and was completed in 30 min, leading to a range of 4-
aromatic alkynes are unlikely to be proper substrates arylethynyl-3-aminocoumarins in high yields
Sonogashira
cross-coupling
conditions
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
probably due to the inefficient transmetallation of ar- (Table 2). Notably, no reaction occurred with aryl bro-
omatic copper(I) acetylide with Pd(0) species. To mides under similar conditions.
access the intermediates of 4-acetylenyl-3-aminocou-
With a variety of 4-acetylenyl-3-aminocoumarin
marins (3a–d), the obtained coupling products 2a–d compounds (3a–l) in hand, we moved on to the key
were treated with iron powder in HOAc/H2O at room cyclization for constructing the corresponding pyrro-
temperature to undergo
(Scheme 3).
a
successful reduction locoumarin framework. Intramolecular hydroamina-
tion of alkynes has become a promising method in or-
ganic chemistry that allows the straightforward syn-
Scheme 3. Sonogashira coupling with aliphatic alkynes and reduction.
Adv. Synth. Catal. 2009, 351, 2005 – 2012
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Table 2. Preparation of 4-arylethynyl-3-aminocoumarins.
Table 3. Screening of catalyst for intramolecular hydro-ami-
nation.
Entry[a]
Ar
3
Yield [%][b]
Entry[a] Catalyst
(mol%)
Solvent
T
t
Yield
[%][b]
1
2
3
4
5
6
7
8
C6H5
3e
3f
3g
3h
3i
3j
3k
3l
90
90
85
80
88
80
81
75
G
[oC]
[h]
4-MeOC6H4
4-EtO2CC6H4
2-MeC6H4
1-Naphthyl
4-Me2NC6H4
4-AcNHC6H4
4-PMBNHC6H4
1
2
3
Pd
Pd
Pd
N
–
reflux
reflux
5
8
5
8
8
60
20
49
40
30
–
–
–
–
–
4
5
PdCl2 (10)
CuI (20)
CH3CN reflux
DMF reflux
Toluene reflux
Toluene reflux NR
Toluene reflux NR
NMP
NMP
NMP
6
InBr3 (20)
[a]
7
In
U
Reaction was carried out with 4 (1.00 mmol), aryl iodide
(1.10 mmol), Pd(PPh3)4 (0.05 mmol), CuI (0.05 mmol),
8
Zn
U
AHCTUNGTRENNUNG
9
10
11
t-BuOK
NaH
KH
r.t.
r.t.
r.t.
NR
NR
NR
Et3N (0.2 mL) in freshly distilled THF (20 mL) under ni-
trogen atmosphere.
Isolated yield.
[b]
[a]
Reaction was carried out with 3e (0.50 mmol) in de-
gassed solvent (5 mL) under nitrogen atmosphere.
Isolated yield.
[b]
[c]
thesis of valuable nitrogen-containing heterocycles,
especially those indole-like compounds. In recent
years, great progress has been made in the develop-
ment of catalytic hydroaminations of alkynes; various
methods have been explored extensively.[12] Concern-
ing intramolecular hydroaminations,[12a,b] however, the
palladium catalyst is the most utilized. To find a good
reaction system, several different metallic catalysts
NR: No Reaction.
Table 4. Synthesis of chromenoACTHNUTRGNEUGN[3,4-b]pyrrol-4(3H)-one de-
rivatives.
such as PdACHTUNGTRENNUNG ACHTGNUTRENNUNG
(PPh3)2Cl2,[13a,b] Pd(OAc)2,[13c] PdCl2,[13d]
[13f] [13g]
CuI,[13e] InBr3,[13f] In
A
and Zn
A
were
evaluated with 4-phenylacetylenyl-3-aminocoumarin
3e. As indicated in Table 3, Pd(PPh3)2Cl2 emerged as
the best catalyst. In the presence of 10 mol% of
Pd(PPh3)2Cl2 in refluxing DMF, the expected hetero-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
annulation of the acetylenic amine 3e could be ach-
ieved in 60% yield. Other conditions including anion-
ic cyclization[14] with t-BuOK, NaH, or KH only re-
sulted in low yield or no reaction.
Upon establishing the reaction conditions of the
key cyclization step, we then investigated the sub-
strate scope of the methodology. A series of 4-acet-
Entry[a]
3
R
5
t [h]
Yield [%][b]
1
2
3
4
5
6
3a
3b
3c
3e
3f
3g
3h
3i
CH
BnOACHTGNURETNNU(G CH2)3
t-Bu
C6H5
4-MeOC6H4
4-EtO2CC6H4
2-MeC6H4
1-Naphthyl
4-Me2NC6H4
4-AcNHC6H4
(CH2)3
5a
5b
5c
5e
5f
5g
5h
5i
8
8
8
5
5
8
8
36
2
2
2
56
57
74
60
83
80
75
70
73
64
75
ACHTUNGTRENNUNG
7
8[c]
9
ACHTUNGTRENNUNG
sults are summarized in Table 4. In all cases, the de-
sired pyrrolocoumarin products could be obtained in
moderate to good yields. For arylacetylenic substrates
3j–l with strong electron-donating R, it was found
that the reaction proceeded very rapidly and was
completed in 2 h (entries 9–11). In contrast, for sub-
strate 3i with the bulky a-naphthyl group attached to
the triple bond, hydroamination proceeded very
3j
3k
3l
5j
5k
10
11
4-PMBNHC6H4 5l
[a]
Reaction was carried out with
Pd
3
(0.50 mmol),
N
under nitrogen atmosphere unless otherwise noted.
Isolated yield.
Reaction was carried out with 30% catalyst loading.
[b]
[c]
2008
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A New Approach to Pyrrolocoumarin Derivatives by Palladium-Catalyzed Reactions
FULL PAPERS
slowly even in the presence of 30 mol% of ent synthesis of the polycyclic lamellarins[4a] B, D, H,
Pd(PPh3)2Cl2 catalyst and a prolonged time of 36 h M, N, W, X scaffold (Scheme 4). Selective bromina-
ACHTUNGTRENNUNG
was needed (entry 8). It is interesting to note that the tion on the pyrrole ring of 2-phenylchromenoACHTUNGTRENNUNG[3,4-
structural X-ray investigation of 5a[15] indicates that b]pyrrol-4(3H)-one 5e with NBS at room temperature
two molecules form intermolecular hydrogen bond- simply afforded bromide 6 in 90% yield. Condensa-
À
ings between each carbonyl oxygen and pyrrole N H tion of 6 with bromoacetaldehyde diethyl acetal
(Figure 2).
(BDEA) in refluxing DMF gave the corresponding
acetal product 7, which was then efficiently cross-cou-
pled with phenylboronic acid via Suzuki coupling to
provide 8 in good yield. Ring closure of 8 by treat-
ment with CF3COOH/ACTHNUGTRNE(UNG CF3CO)2O under reflux ac-
cording to Nordlanderꢀs acetal indolization proce-
dure[16] successfully produced the polycyclic lamellarin
scaffold 9 in 73% yield. It is noteworthy that diverse
aryl groups for the E and F members could be readily
introduced during the preparations of 3 (as in
Table 2) and 8 via palladium-catalyzed Sonogashira
and Suzuki coupling, respectively.
Conclusions
In summary, we have successfully developed a new
and efficient protocol for the synthesis of an interest-
ing class of pyrrolocoumarin compounds – chromeno-
AHCTUNGTREG[NNUN 3,4-b]pyrrol-4(3H)-ones. The key strategy relies on
the creation of the pyrrole ring through palladium-
catalyzed intramolecular hydroamination of related
acetylenic aminocoumarins. It has been found that
readily available 4-chloro-3-nitrocoumarin could serve
as a suitable substrate to undergo smooth Sonogashira
cross-coupling with aliphatic alkynes. The preparation
of the corresponding arylacetylenylaminocoumarins
involves immediate nitro reduction and desilylation of
Figure 2. X-ray crystallography of 5a.
To further demonstrate the synthetic value of this 4-trimethylsilylacetylenyl-3-nitrocoumarin, followed
new methodology, we sought to explore the versatility by another Sonogashira cross-coupling with aryl io-
of chromenoACHTUNGTRENNUNG[3,4-b]pyrrol-4(3H)-one 5 for the expedi- dides. With the resulting chromenoACHTUNGTREN[NGUN 3,4-b]pyrrol-
Scheme 4. Expedient construction of polycyclic lamellarin scaffold.
Adv. Synth. Catal. 2009, 351, 2005 – 2012
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99.9, 114.4, 116.4, 116.8, 117.6, 123.1, 123.6, 124.3, 127.4,
128.0, 130.1, 142.4, 150.9, 153.9, 159.7; HR-MS: m/z=
291.0898, calcd. for C18H13NO3: 291.0895.
4(3H)-one product, an expedient construction of poly-
heterocyclic lamellarin scaffold could be achieved in
four steps. The method provides a useful option for
the rapid synthesis of potentially valuable lamellarin
analogues without pre-preparation of a highly func-
tionalized pyrrole core. Given the abundance of natu-
ral products and biologically active compounds that
contain the chromenoACTHNUGRTENUNG[3,4-b]pyrrol-4(3H)-one moiety,
this methodology should find wide applications in me-
dicinal chemistry. Access to more lamellarin ana-
Ethyl
4-(4-oxo-3,4-dihydrochromenoACHTGNUTERNNU[G 3,4-b]pyrrol-2-yl)
1
benzoate (5g): H NMR (300 MHz, DMSO-d6): d=1.30 (d,
J=6.9 Hz, 3H), 4.28 (d, J=6.9 Hz, 2H), 7.33–7.47 (m, 4H),
7.92–8.02 (m, 5H), 13.08 (bs, 0.31H); 13C NMR (100 MHz,
DMSO-d6): d=14.2, 60.8, 102.4, 116.8, 117.3, 118.0, 123.5,
124.4, 125.8, 128.1, 129.2, 129.6, 129.7, 134.8, 140.7, 150.9,
153.9, 165.3; HR-MS: m/z=334.1074, calcd. for C20H15NO4
[M+H]+: 334.1079.
2-o-Tolylchromeno
1
N
logues and evaluation of all these chromenoACTHNUGTRNEUNG[3,4-
(300 MHz, CDCl3): d=2.52 (s, 3H), 6.81 (s, 1H), 7.26–7.52
(m, 7H), 7.82 (d, J=7.2 Hz, 1H), 9.91 (s, 1H), 12.70 (bs,
1H); 13C NMR (100 MHz, CDCl3): d=20.6, 103.8, 116.3,
116.8, 117.7, 123.7, 124.3, 126.0, 128.0, 128.8, 129.4, 129.8,
130.8, 131.0, 136.1, 142.1, 150.9, 154.1; HR-MS: m/z=
275.0951, calcd. for C18H13NO2: 275.0946.
b]pyrrol-4(3H)-one derivatives for biological effects
are currently under way.
Experimental Section
2-(Naphthalen-1-yl)chromenoACTHNUTRGENUGN[3,4-b]pyrrol-4(3H)-one (5i):
General Procedure for Synthesis of Chromeno
N
1H NMR (300 MHz, DMSO-d6): d=7.22 (s, 1H), 7.32–7.75
(m, 3H), 7.58–7.73 (m, 4H), 8.01–8.18 (m, 4H); 13C NMR
(100 MHz, DMSO-d6): d=104.7, 116.7, 116.8, 117.7, 123.9,
124.4, 125.2, 125.5, 126.4, 127.1, 128.1 (2C), 128.5, 129.1,
129.2, 129.5, 130.8, 133.4, 141.0, 151.0, 154.1; HR-MS: m/z=
311.0945, calcd. for C21H13NO2: 311.0946.
b]pyrrol-4(3H)-ones (5)
Under a nitrogen atmosphere, a solution of 3 (0.5 mmol),
Pd(PPh3)2Cl2 (35 mg, 0.05 mmol) in DMF (5 mL) was stirred
ACHTUNGTRENNUNG
at reflux until TLC indicated completion of the reaction.
The reaction mixture was cooled to room temperature and
diluted with EtOAc. The organic layer was washed with
water and dried over Na2SO4. After being concentrated
under vacuum, the crude product was purified by column
chromatography on silica gel to afford 5.
2-(4-(Dimethylamino)chromenoACTHNUGTRNEUNG[3,4-b]pyrrol-4(3H)-one
1
(5j): H NMR (300 MHz, DMSO-d6): d=2.95 (s, 6H), 6.77
(d, J=8.7 Hz, 2H), 7.18 (s, 1H), 7.31–7.41 (m, 3H), 7.81 (d,
J=8.7 Hz, 2H), 7.95 (d, J=8.4 Hz, 1H), 12.63 (s, 1H);
13C NMR (100 MHz, DMSO-d6): d=39.8, 98.6, 112.1, 115.8,
116.7, 117.6, 118.0, 123.5, 124.1, 126.8, 127.8, 130.2, 143.6,
150.4, 151.0, 153.8; HR-MS: m/z=305.1284, calcd. for
2-ButylchromenoACHTUNGTRENNUNG
[3,4-b]pyrrol-4(3H)-one (5a): 1H NMR
(300 MHz, CDCl3): d=0.96 (t, J=7.5 Hz, 3H), 1.38–1.50
(m, 2H), 1.72–1.82 (m, 2H), 2.88 (t, J=7.2 Hz, 2H), 6.47 (s,
1H), 7.26–7.45 (m, 3H), 7.75 (d, J=7.8 Hz, 1H), 11.22 (s,
1H); 13C NMR (100 MHz, CDCl3): d=13.8, 22.2, 27.7, 31.2,
100.8, 115.6, 117.2, 118.1, 123.2, 124.1, 127.5, 130.9, 146.5,
151.2, 156.0; anal. calcd. for C15H15NO2: C 74.67, H 6.27, N
5.81; found: C 74.64, H 6.31, N 5.44.
C19H17N2O
N-[4-(4-Oxo-3,4-dihydrochromenoACHTNUGTRNE[NUG 3,4-b]pyrrol-2-yl)phe-
[M+H]+: 305.1290.
2ACHTUNGTRENNUNG
nyl]acetamide (5k): 1H NMR (300 MHz, DMSO-d6): d=
2.06 (s, 3H), 7.32–7.41 (m, 4H), 7.67 (d, J=8.7 Hz, 2H),
7.90–7.97 (m, 3H), 10.10 (s, 1H), 12.85 (s, 1H); 13C NMR
(100 MHz, DMSO-d6): d=24.1, 100.2, 116.8, 117.6, 119.1,
123.6, 124.4, 125.2, 126.5, 128.1, 130.1, 139.6, 139.7, 142.3,
151.0, 154.0, 168.6; HR-MS: m/z=319.1077, calcd. for
2-(3-(Benzyloxy)propyl)chromenoACHTUNTRGNEUNG[3,4-b]pyrrol-4(3H)-one
(5b): 1H NMR (300 MHz, CDCl3): d=2.04–2.13 (m, 2H),
2.97 (t, J=7.5 Hz, 2H), 3.58 (t, J=6.0 Hz, 2H), 4.55 (s, 2H),
6.45 (s, 1H), 7.26–7.42 (m, 8H), 7.74 (d, J=7.2 Hz, 1H),
10.67 (s, 1H); 13C NMR (100 MHz, CDCl3): d=25.0, 29.0,
69.1, 73.0, 101.2, 115.9, 117.3, 118.1, 123.2, 124.1, 127.7 (2C),
127.8, 128.4, 130.7, 138.1, 145.1, 151.3, 155.7; HR-MS: m/z=
334.1437, calcd. for C21H20NO3 [M+H]+: 334.1443.
C19H15N2O3ACTHNUTRGNEUNG
[M+H]+: 319.1083.
2-[4-(4-Methoxybenzylamino)phenyl]chromeno
pyrrol-4(3H)-one (5l): H NMR (300 MHz, DMSO-d6): d=
[3,4-b]-
1
3.70 (s, 3H), 4.23 (d, J=5.7 Hz, 2H), 6.59–6.60 (m, 1H),
6.64 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.1 Hz, 2H), 7.12 (s,
1H), 7.26–7.39 (m, 5H), 7.68 (d, J=8.1 Hz, 2H), 7.93 (d, J=
7.5 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d=45.6, 55.0,
98.3, 112.3, 113.7, 115.7, 116.7, 117.6, 117.9, 123.5, 124.1,
126.9, 127.8, 128.4, 130.2, 131.6, 143.9, 149.2, 150.9, 153.8,
158.2; HR-MS: m/z=397.1547, calcd. for C25H21N2O3 [M+
H]+: 397.1552.
2-tert-Butylchromeno
[3,4-b]pyrrol-4(3H)-one
(5c):
C 74.89, H 6.25, N 5.55.
1
2-Phenylchromeno
G
Synthesis of 1-Bromo-2-phenylchromenoACTHNUTRGENUG[N 3,4-b]-
pyrrol-4(3H)-one (6)
(300 MHz, DMSO-d6): d=7.32–7.50 (m, 7H), 7.97–8.00 (m,
3H); 13C NMR (100 MHz, DMSO-d6): d=100.9, 116.8,
117.2, 117.5, 123.5, 124.3, 125.8, 128.0, 128.6, 129.0, 129.9,
130.5, 142.3, 150.9, 154.0; HR-MS: m/z=261.0791, calcd. for
C17H11NO2: 261.0790.
To a flask was added 2-phenylchromenoACTHNUTRGNEUNG[3,4-b]pyrrol-4(3H)-
one 5e (65 mg, 0.25 mmol), NBS (89 mg, 0.5 mmol) and
THF (10 mL). The solution was stirred for 2 h and extracted
with EtOAc, washed with water. The organic layer was
dried over Na2SO4 and concentrated under vacuum. The
crude product was purified by column chromatography (pe-
troleum ether/acetone, 10/1) on silica gel to afford 6 as a
2-(4-Methoxyphenyl)chromenoACTHNUGTRNEUNG[3,4-b]pyrrol-4(3H)-one
1
(5f): H NMR (300 MHz, DMSO-d6): d=3.79 (s, 3H), 7.03
(d, J=8.7 Hz, 2H), 7.29–7.45 (m, 4H), 7.91–7.97 (m, 3H),
12.81 (bs, 0.18H); 13C NMR (100 MHz, DMSO-d6): d=55.3,
2010
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ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2005 – 2012

A New Approach to Pyrrolocoumarin Derivatives by Palladium-Catalyzed Reactions
FULL PAPERS
1
pale yellow solid; yield: 85 mg (90%); H NMR (300 MHz,
CDCl3): d=7.38–7.55 (m, 6H), 7.80 (d, J=6.9 Hz, 2H), 8.74
(d, J=7.5 Hz, 1H), 10.21 (s, 1H); 13C NMR (100 MHz,
CDCl3): d=90.6, 117.7 (2C), 118.0, 123.1, 124.6, 126.5,
129.0, 129.2, 129.4, 129.9, 130.3, 140.3, 152.1, 153.9; MS (EI):
m/z=339 (M+, 96.5), 341 (M+, 100).
128.7 (2C), 129.6, 129.9, 130.9, 134.1, 135.6, 151.7, 155.3;
HR-MS: m/z=361.1101, calcd. for C25H15NO2: 361.1103.
Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (20721003), the Shanghai Rising-Star Program
(08QH14027), the Chinese Academy of Sciences and State
key Laboratory of Drug Research, Shanghai Institute of Ma-
teria Medica is acknowledged.
Synthesis of 1-Bromo-3-(2,2-diethoxyethyl)-2-phenyl-
chromenoACHTUNGTRENNUNG[3,4-b]pyrrol-4(3H)-one (7)
To a flask was added 6 (50 mg, 0.15 mmol), Cs2CO3 (325 mg,
1.0 mmol), bromoacetaldehyde diethyl acetal (150 mL,
1.0 mmol) and DMF (5 mL). The solution was stirred at
reflux for 48 h until TLC indicated completion of reaction.
The mixture was cooled to room temperature and diluted
with EtOAc. The organic layer was washed with water and
dried over Na2SO4. After concentrated under vacuo, the res-
idue was purified by column chromatography (petroleum
ether/EtOAc, 40/1) on silica gel to afford 7 as a white solid;
References
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1
yield: 42 mg (62%); H NMR (300 MHz, CDCl3): d=1.09 (t,
J=6.9 Hz, 6H), 3.36–3.46 (m, 2H), 3.57–3.67 (m, 2H), 4.46
(d, J=5.4 Hz, 2H), 4.81 (t, J=5.4 Hz, 1H), 7.31–7.57 (m,
8H), 8.72 (d, J=7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d=15.2, 49.5, 64.0, 92.4, 102.1, 116.0, 117.1, 117.2, 123.0,
123.9, 126.6, 128.4, 128.5, 128.9, 129.5, 131.3, 144.6, 151.3,
154.5.
Synthesis of 3-(2,2-Diethoxyethyl)-1,2-diphenyl-
chromenoACHTUNGTRENNUNG[3,4-b]pyrrol-4(3H)-one (8)
Under a nitrogen atmosphere, a solution of 7 (26 mg,
0.058 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), phenylboronic
ACHTUNGTRENNUNG
acid (12 mg, 0.1 mmol) and K2CO3 in DMF (5 mL) was
stirred at reflux for 1 hour. The reaction mixture was cooled
to room temperature and diluted with EtOAc. The organic
layer was washed with water and dried over Na2SO4. After
concentrated under vacuum, the crude product was purified
by column chromatography (petroleum ether/EtOAc, 30/1)
on silica gel to afford 8 as a white solid; yield: 23 mg (90%);
1H NMR (300 MHz, CDCl3): d=1.12 (t, J=6.9 Hz, 6H),
3.39–3.49 (m, 2H), 3.60–3.70 (m, 2H), 4.51 (d, J=5.4 Hz,
2H), 4.92 (t, J=5.4 Hz, 1H), 6.99 (t, J=7.8 Hz, 1H), 7.20–
7.41 (m, 13H); 13C NMR (100 MHz, CDCl3): d=15.3, 48.8,
64.0, 102.5, 115.6, 117.1, 118.1, 119.9, 123.6, 123.7, 127.1,
127.3, 127.6, 128.1, 128.3, 128.5, 129.8, 131.0, 131.4, 134.2,
144.5, 151.4, 155.4.
Synthesis of the Lamellarin Scaffold (9)
A solution of 3-(2,2-diethoxyethyl)-1,2-diphenylchromeno-
A
8
(23 mg,
0.005 mmol)
in
(CF3CO)2O (1 mL) and CF3COOH (3 mL) under a nitrogen
atmosphere was stirred at reflux for 48 h. The excess anhy-
dride and acid were removed by distillation. The residue
was added Et3N (0.1 mL) and concentrated under vacuum.
The crude product was purified by column chromatography
(petroleum ether/EtOAc, 20/1) on silica gel to afford 9 as a
white solid; yield: 13 mg (73%); 1H NMR [300 MHz,
(CD3)2CO]: d=6.88–6.98 (m, 1H), 6.99–7.03 (m, 1H), 7.17–
7.23 (m, 1H), 7.25–7.35 (m, 3H), 7.38–7.65 (m, 7H), 7.77 (d,
J=7.8 Hz, 1H), 9.19 (d, J=7.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=109.3, 113.5, 114.3, 117.4, 117.9,
123.9, 124.1, 124.3, 124.4, 125.0, 127.3, 127.5, 128.2, 128.4,
Adv. Synth. Catal. 2009, 351, 2005 – 2012
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2011

Lei Chen and Ming-Hua Xu
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(2) K; wavelength: 0.71073 ꢅ.; crystal system: mono-
clinic, space group: P21/n; unit cell dimensions: a=
5.3392(6) ꢅ, b=11.0688(13) ꢅ, c=20.905(2) ꢅ, a=908,
b=90.745 (2)8, g=908; V=1235.3 (2) ꢅ3; Z=4; 1calcd.
=
1.297 Mg/m3; F
ACTHNUGTRNEN(UG 000)=512; final R indices [I>2s(I)]:
R1 =0.0563,wR2 =0.1444; R indices (all data), R1 =
0.0690, wR2 =0.1525; 6902 reflections measured, 2560
were unique (R(int) =0.0607). CCDC 726962 contains
the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
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asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2005 – 2012