Formation of 3,4-Diarylpyrrole- and Pyrrolocoumarin Core of Natural Marine Products via Barton–Zard Reaction and Selective O-Demethylation

Article abstract of DOI:10.1002/ejoc.202000099

A metal-free approach to 3,4-diarylpyrrole-2-carboxylate and pyrrolocoumarin cores of lamellarins and related natural products based on Barton–Zard reaction of nitrostilbenes with ethyl isocyanoacetate was developed. In the case of diarylpyrrole-2-carboxy

Full text of DOI:10.1002/ejoc.202000099

A Journal of
Accepted Article
Title: Formation of 3,4-Diarylpyrrole- and Pyrrolocoumarin Core of
Natural Marine Products via Barton-Zard Reaction and Selective
O-demethylation
Authors: Eugenia A. Silyanova, Alexander Samet, Lev K. Salamandra,
Victor N. Khrustalev, and Victor V. Semenov
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000099
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10.1002/ejoc.202000099
European Journal of Organic Chemistry
Formation of 3,4-Diarylpyrrole- and Pyrrolocoumarin Core of Natural Marine Products
via Barton-Zard Reaction and Selective O-demethylation
Eugenia A. Silyanova,[a] Alexander V. Samet,*[a] Lev K. Salamandra,[a] Victor N. Khrustalev,[a,b]
and Victor V. Semenov[a]
[a] N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky
Prospect, 119991 Moscow, Russian Federation
E-mail: sametav@ioc.ac.ru
[b] Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street,
117198 Moscow, Russian Federation
ABSTRACT
A metal-free approach to 3,4-diarylpyrrole-2-carboxylate and pyrrolocoumarin cores of
lamellarins and related natural products based on Barton-Zard reaction of nitrostilbenes with
ethyl isocyanoacetate was developed. In the case of diarylpyrrole-2-carboxylates with a 3-(o-
methoxyphenyl) fragment, treatment with 1 eq. BBr3 resulted in selective O-demethylation of the
ortho-methoxy group, while other methoxy groups in the molecule remained intact. The
resulting 3-(2-hydroxyphenyl)pyrrole-2-carboxylates underwent base-induced lactonization to
form the target pyrrolocoumarins.
INTRODUCTION
Since the first isolation of lamellarins in 1985, about 100 related naturally occurring
pyrrole-based alkaloids (in particular, ningalins and lukianols), have been isolated from diverse
marine organisms until 2012.[1] Almost all these compounds share a common 2-carboxy-3,4-
diarylpyrrole core, and most of them feature a pyrrolocoumarin fragment with multiple hydroxy
or methoxy substituents in benzene rings (Figure 1).
1
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10.1002/ejoc.202000099
European Journal of Organic Chemistry
Figure 1. Some natural marine products with 3,4-diarylpyrrole and pyrrolocoumarin cores
These lamellarin alkaloids have been found to exhibit a variety of biological activities
such as antitumor activity,[2] reversal of multidrug resistance;[3] as well as inhibiting HIV-1
integrase,[4] topoisomerase,[5] and various kinases.[6] Due to their novel molecular structures and
promising biological activity, the synthesis of lamellarins and their analogues continues to attract
considerable interest of chemists and was extensively reviewed during the last decade.[1,2,7]
These syntheses can be divided into two categories: one is the functionalization of a pre-
existing pyrrole, and the other is the formation of the pyrrole core as the key step. Syntheses of
the first category include successive introduction of aryl substituents into positions 3/4/5 of the
pyrrole ring (mostly by metal-catalyzed coupling reactions)[8] and introduction of a carboxy
group into position 2.[9] In the second approach the pyrrole ring is formed by various methods
such as Grob cyclization,[10] Paal-Knorr and Hantsch reactions,[11] interaction of α-aminoester or
α-aminonitrile with α,β-unsaturated carbonyl compounds,[12] [3+2] dipolar cycloaddition,[13]
metal-catalyzed [3+2] annulation,[14] or the reductive recyclization of pyridazines.[15]
The coumarin (lactone) fragment might be present in the molecule before the pyrrole ring
formation;[16] in some cases these two rings are closed simultaneously,[13,17] but more often the
lactone fragment is formed later than the pyrrole one – either from of O-aryl pyrrole-2-
carboxylates (by intramolecular oxidative coupling[8a] or Heck reaction[18]), or by intramolecular
2
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European Journal of Organic Chemistry
nucleophilic substitution of Br in 3-(2-bromophenyl)pyrrole-2-carboxylic acids,[9c,10c,12a] or by
intramolecular C-H/O-H oxidative coupling of 3-arylpyrrole-2-carboxylic acids.[9b,11b-d,12d]
However, the most ubiquitous approach consists in lactonization of 3-(2-hydroxyphenyl)pyrrole-
2-carboxylates, prepared from their O-protected derivatives (PG = MOM,[19] Bn,[10b,10e] i-
Pr,[12с,20] Ac,[9a] Ms[11е] (Scheme 1) (this usually implies an introduction of the protective group
as a separate step).
Scheme 1. Formation of the lactone fragment.
RESULTS AND DISCUSSION
An Approach to 3,4-Diarylpyrrole Core. Surprisingly, a Barton-Zard reaction[21] (that is, base-
catalyzed reaction of nitroalkenes with alkyl isocyanoacetate) has not yet been reported for
synthesis of the pyrrole core of lamellarins and related compounds,[22] though such reaction with
1,2-diaryl-1-nitroethylenes should be a straightforward way of accessing 3,4-diarylpyrrole-2-
carboxylates as key structural fragments of the lamellarins, ningalins and lukianols.
Recently, we reported a useful modification of the reaction conditions which enabled an
efficient synthesis of 3,4-diarylpyrrole-2-carboxylates from nitrostilbenes and helped us to
overcome a problem of low yields in this reaction in the case of highly oxygenated Ar
substituents.[23] This modification (that is, carrying out the reaction in ethanol as a solvent and
using K2CO3 as a base) was now applied for a synthesis of the target products.
3
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10.1002/ejoc.202000099
European Journal of Organic Chemistry
Thus, ethyl 3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylate 2а was prepared by this
method from nitrostilbene 1а and then demethylated under the action of BBr3 (3 eq.) to afford
lamellarin Q Et ester (Scheme 2):
Scheme 2. Synthesis of Lamellarin Q Et ester.
i: CNCH2COOEt, EtOH, K2CO3, 87%; ii: BBr3 (3 eq.), CH2Cl2, 0oC, 85%; iii: BBr3 (2 eq.), CH2Cl2, 0oC, 63%; iv: 4-
HOC6H4CHO, MeOH, MeNH2•HCl, NaHCO3; v: CNCH2COOEt, EtOH, K2CO3
Noteworthy, the reaction in the presence of 2 eq.BBr3[24] demonstrated a pronounced selectivity:
it produced a mixture of partially demethylated products 2b and 2c in ca. 1:4 ratio. The structure
of a minor product (2b) was confirmed by its alternative synthesis from 2-(4-hydroxyphenyl)-1-
(4-methoxyphenyl)-1-nitroethene 1b (Scheme 2) (the latter was, in turn, prepared by
condensation of 4-methoxyphenylnitromethane and 4-hydroxybenzaldehyde).
Demethylation of methyl 3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylate 3а with excess
BBr3 (3 eq.) furnished lamellarin Q (Scheme 3, Figure 2):
Scheme 3. Synthesis of Lamellarin Q.
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European Journal of Organic Chemistry
i: BBr3 (3 eq.), CH2Cl2, 0oC, 84%; ii: MeONa, reflux, 84%; iii: CNCH2COOEt, MeOH, K2CO3, 89%
Figure 2. Molecular structure of Lamellarin Q • MeCN (50% ellipsoids).
Methyl ester 3а could be prepared either by transesterification of the ethyl ester 2а, or directly
from the nitrostilbene 1а by reacting it with ethyl isocyanoacetate in MeOH instead of EtOH.
The latter approach gives lamellarin
Q
in only 3 steps (starting from 4-
methoxyphenylnitromethane and p-anisaldehyde) and total yield 35% (this is quite comparable
with the known syntheses of this compound, [25] cf. the most recent work[25a] – 20% in 7 steps).
An Approach to the Pyrrolocoumarin Core. Further experiments showed that Barton-Zard
reaction of nitrostilbene 4а (prepared by condensation of phenylnitromethane and 2-
methoxybenzaldehyde) furnished 3-(2-methoxyphenyl)pyrrole 5а, and demethylation of the
5
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10.1002/ejoc.202000099
European Journal of Organic Chemistry
latter with 1 eq. BBr3 produced 3-(2-hydroxyphenyl) derivative 6a in almost quantitative yield
(Table 1, entry 1). An attempt of preparing 6а directly from salicylaldehyde via the
corresponding nitrostilbene failed.
More careful investigation of this reaction revealed that various 3,4-diarylpyrrole-2-
carboxylates 5, containing an ortho-methoxy group in the 3-Ar moiety, upon treatment with 1 eq.
BBr3 underwent selective O-demethylation of this particular group to afford 3-(2-
hydroxyphenyl) derivatives 6 in high yields, while other alkoxy groups present in the molecule 5
remained intact (Scheme 4, Table 1):
Scheme 4. Selective O-demethylation of an o-methoxy group and subsequent lactonization.
i: CNCH2COOEt, EtOH, K2CO3; ii: BBr3 (1 eq.), CH2Cl2, 0oC; iii: NaOH, EtOH
Yields are somewhat lower for the compounds 5e,f,j,k – probably, methylenedioxy
fragment was attacked in these cases.
Obviously, this is a rare and interesting example of a selective O-demethylation induced
by a substituent remote from the reacting methoxy group – in this case by COOEt fragment in
the pyrrole ring (to the best of our knowledge, no such examples were reported for aryl-
substituted pyrrole carboxylates).[26,27] Moreover, such an approach allows one to avoid a
separate step of introducing O-protective groups, as discussed above (cf. Scheme 1).
Upon treatment with ethanolic NaOH at room temperature hydroxy derivatives 6 readily
undergo cyclization into lactones 7 in high yields (Table 1).
Table 1. Yields of selective demethylation products 6 and cyclization products 7
Entry
Starting
compound
Product 6 Product 7
(yield, %) (yield, %)
Ar
R1
R2
R3
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
H
OMe
H
H
H
OMe
H
H
H
H
OMe
OMe
6a (96)
6b (82)
6c (98)
6d (89)
6e (61)
6f (55)
6g (78)
6h (81)
6i (81)
6j (68)
6k (51)
6l (78)
7a (82)
7b (80)
7c (83)
7d (74)
7e (78)
7f (80)
7g (71)
7h (80)
7i (71)
7j (83)
7k (81)
7k (82)
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
OCH2O
OMe
H
H
H
OCH2O
OMe
H
Ph
OCH2O
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
2-MeO-5-MeC6H3
H
OMe
H
H
H
OMe
OMe
10
11
12
5j
5k
5l
OCH2O
H
Me
6
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European Journal of Organic Chemistry
Noteworthy, demethylation of an “almost symmetrical” pyrrole 5l[28] with two identical
2-methoxy-5-methylphenyl fragments in positions 3 and 4 selectively afforded 3-(2-hydroxy-5-
methyl)phenylpyrrole 6l, which produced lactone 7l upon treatment with the base (Table 1, entry
12). This control experiment provided additional evidence for a crucial role of COOEt as a
directing group in the selective O-demethylation process.
If the molecule 5 contains more than one methoxy group, treatment with an excess BBr3
could result in a complete О-demethylation[29] to produce the corresponding hydroxy derivatives
8 and 9 (Scheme 5, Table 2):
Scheme 5. Complete O-demethylation of methoxy groups and lactonization.
i: BBr3 (3-4 eq.), CH2Cl2, 0oC; iii: NaOH, EtOH
Table 2. Yields of products of complete demethylation 8 and cyclization products 9
Starting
compound
Product 8
(yield, %)
8a (74)
8b (87)
8c (79)
Product 9
(yield, %)
9a (80)
9b (84)
9c (76)
R
R1
R2
R3
H
H
OH
OH
OH
H
H
H
H
H
OH
H
H
OH
H
H
OH
H
H
OH
5c
5d
5g
5h
5i
8d (79)
8e (83)
9d (79)
9e (81)
Structure of the compound 9a was confirmed by X-ray diffraction study (see ESI):
CONCLUSION
Thus, an approach to 3,4-diarylpyrrole-2-carboxylate core of lamellarins and related natural
products via Barton-Zard reaction of 1,2-diaryl-1-nitroethenes with ethyl isocyanoacetate was
developed, and lamellarin Q was prepared by this method. In the case of pyrrole-2-carboxylates
with a 3-(2-methoxyphenyl) fragment, treatment with 1 eq. BBr3 resulted in selective O-
demethylation of the ortho-methoxy group, while other methoxy groups in the molecule
remained intact. Lactonization of the 3-(2-hydroxyphenyl)pyrrole-2-carboxylates thus formed
produced the target pyrrolocoumarin system. We hope that these results could serve as a useful
supplement to the known methods of lamellarin synthesis.
EXPERIMENTAL SECTION
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European Journal of Organic Chemistry
General Experimental
Melting points were measured on a Boetius melting point apparatus and were uncorrected.
1
Reaction mixtures were stirred magnetically. H NMR spectra were recorded on a Bruker AM-
300 (300.13MHz), Bruker DRX-500 (500.13 MHz) and Bruker AV-600 (600.13 MHz)
instruments. Chemical shifts are stated in parts per million (ppm) and referenced to the
appropriate NMR solvent peak(s). Spin-spin coupling constants (J) were reported in hertz (Hz).
13C NMR spectra were recorded on a Bruker DRX-500 (125.76 MHz) and Bruker AV-600
(150.9 MHz) instruments. Chemical shifts are stated in parts per million (ppm). Spin−spin
coupling constants were reported in hertz (Hz). Low resolution mass spectra (m/z) were recorded
on a Finnigan MAT/INCOS 50 mass spectrometer at 70 eV using direct probe injection.
Elemental analysis was performed on the automated PerkinElmer 2400 CHN microanalyzer.
Flash chromatography was carried out on silica gel (Acros, 0.035−0.070 mm, 60 Å). TLC was
performed on Merck 60 F254 plates. Anhydrous CH2Cl2 was obtained by distillation with P2O5.
The preparation and characteristics of nitrostilbenes 1a,[30a] 4e,[30b], 4j[23] and 3,4-diarylpyrrole-2-
carboxylates[23] 2a, 5e, 5j were identical to those reported earlier.
General Procedure for the Synthesis of 1,2-diarylnitroethylenes 1a, 4a-k. A mixture of
arylnitromethane (4.5 mmol), arylaldehyde (5 mmol), MeOH (7 ml), MeNH2•HCl (27 mg, 0.4
mmol), and NaHCO3 (17 mg, 0.2 mmol) was stirred at room temperature for 3-5 days (TLC
control). The resulting suspension was filtered, washed twice with cold methanol (3 ml) and
d/ried.
1-Nitro-1-(4-methoxyphenyl)-2-(2,5-dimethoxyphenyl)ethylene (4i): 700 mg, 61% yield,
yellow crystals, m.p. 121-122 °C. H NMR (500 MHz, CDCl3): δ = 8.56 (s, 1H; H-2), 7.26 (d, J =
8.8 Hz, 2H; Ar), 6.98 (d, J = 8.8 Hz, 2H; Ar), 6.85 (dd, J = 9.1 Hz, J = 2.9 Hz, 1H; Ar), 6.82 (d,
J = 9.1 Hz, 1H; Ar), 6.30 (d, J = 2.8 Hz, 1H; Ar), 3.86 (s, 3H; OCH3), 3.84 (s, 3H; OCH3), 3.34
ppm (s, 3H; OCH3); 13C NMR (125 MHz, CDCl3): δ = 161.2, 154.0, 153.2, 149.8, 132.6, 129.5,
123.5, 121.2, 119.5, 115.0, 114.4, 112.6, 56.6, 55.8, 55.6 ppm; MS (70 eV): m/z (%): 316 (6) [M
/+ H]+, 315 (36) [M]+, 254 (55), 239 (22), 211 (9), 168 (11), 152 (10), 139 (10), 127 (8), 121
(100), 77 (6), 28 (7), 15 (25); elemental analysis calcd (%) for C17H17NO5 (%): C 64.75, H 5.43,
N 4.44; found: C 64.55, H 5.29, N 4.58.
1-Nitro-1,2-bis(2-methoxy-5-methylphenyl)ethylene (4l). A suspension of AgNO2 (616 mg, 4
mmol) and iodine (1.027 g, 4 mmol) in THF (20 ml) was stirred for 45 min. and a solution of
2,2'-dimethoxy-5,5'-dimethylstilbene[31] (536 mg, 2 mmol) and pyridin (0.5 ml) in THF (10 ml)
was added. The mixture was stirred for 5 h, a resulting precipitate was filtered off and washed
with THF (3 ml). To the filtrate, Et3N (1 ml) was added, the solution was kept for 2 h and
evaporated to dryness. The residue was dissolved in CH2Cl2 (10 ml), washed successively with
8
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European Journal of Organic Chemistry
5% aq. Na2S2O3, 5% HCl and water, dried, and the solvent removed in vacuo. Column
chromatography of the residue on silica gel (eluent hexane-EtOAc 5:1) afforded 0.29 g of the
1
nitrostilbene 4l. 288 mg, 46% yield, yellow crystals, m.p. 106-107 °C. H NMR (500 MHz,
CDCl3): δ = 8.54 (s, 1H; H-2), 7.25 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H; Ar), 7.07 (dd, J = 8.4 Hz, J
= 2.1 Hz, 1H; Ar), 6.93 (d, J = 2.1 Hz, 1H; Ar), 6.91 (d, J = 8.4 Hz, 1H; Ar), 6.77 (d, J = 8.4 Hz,
1H; Ar), 6.56 (d, J = 2.0 Hz, 1H; Ar), 3.85 (s, 3H; OCH3), 3.76 (s, 3H; OCH3), 2.23 (s, 3H;
13
CH3), 1.97 ppm (s, 3H; CH3); C NMR (125 MHz, CDCl3): δ = 156.9, 156.1, 147.3, 132.6,
132.0, 131.9, 130.5, 130.4, 129.6, 129.3, 120.4, 120.3, 111.3, 110.7, 55.9, 55.8, 20.4, 20.3 ppm;
MS (70 eV): m/z (%): 314 (18) [M + H]+, 313 (100) [M]+, 267 (18), 252 (34), 237 (7), 165 (10),
145 (10), 135 (60), 119 (7), 105 (27); elemental analysis calcd (%) for C18H19NO4: C 68.99, H
6.11, N 4.47; found: C 69.24, H 6.01, N 4.63.
Ethyl 3,4-bis(4-hydroxyphenyl)-1H-pyrrole-2-carboxylate (lamellarin Q ethyl ester). To a
stirred solution of ethyl 3,4-bis(4-methoxyphenyl)-1H-pyrrolе-2-carboxylate 2a[23а] (175 mg, 0.5
mmol) in anhydrous CH2Cl2 (2 ml), BBr3 (1.5 ml 1M in CH2Cl2) was added dropwise at -5 °C.
The resulting solution was stirred for 90 min (TLC control), quenched with NaHCO3 (756 mg, 9
mmol) in H2O (5 ml), stirred for 1 min, diluted with water (25 ml), extracted with ethyl acetate
(3×7 ml). The extract was washed with water (2×5 ml), dried by filtration through cotton wool,
and evaporated in vacuo. Pure product was obtained after column chromatography (ethyl acetate
1
– heptane 1:2): 137 mg, 85% yield, white solid, m.p. 176-177 °C; H NMR (500 MHz,
[D6]DMSO): δ = 11.75 (s, 1H; NH), 9.24 (s, 1H; OH), 9.17 (s, 1H; OH), 7.07 (d, J = 3.2 Hz, 1H;
H-5), 6.93 (d, J = 8.5 Hz, 2H; Ar), 6.86 (d, J = 8.6 Hz, 2H; Ar), 6.65 (d, J = 8.5 Hz, 2H; Ar),
6.56 (d, J = 8.6 Hz, 2H; Ar), 4.06 (q, J = 7.1 Hz, 2H; CH2), 1.09 ppm (t, J = 7.1 Hz, 3H; CH3);
13C NMR (125 MHz, [D6]DMSO): δ = 160.6, 155.9, 155.4, 131.7, 128.9, 128.4, 125.7, 125.5,
125.1, 120.8, 118.9, 114.9, 114.3, 59.1, 14.1 ppm; MS (70 eV): m/z (%): 324 (12) [M + H]+, 323
(53) [M]+, 277 (100), 248 (7), 220 (10), 190 (5), 165 (17), 152 (6), 139 (8), 105 (7), 77 (6), 51
(5), 29 (28); elemental analysis calcd (%) for C19H17NO4: C 70.58, H 5.30, N 4.33; found: C
70.21, H 5.17, N 4.67.
Partial O-demethylation of 2a. To a stirred solution of ethyl 3,4-bis(4-methoxyphenyl)-1H-
pyrrolе-2-carboxylate 2a (175 mg, 0.5 mmol) in anhydrous CH2Cl2 (2 ml), BBr3 (1 ml 1M in
CH2Cl2) was added dropwise at -5 °C. The resulting solution was stirred for 90 min (TLC
control), quenched with NaHCO3 (504 mg, 6 mmol) in H2O (5 ml), stirred for 1 min, diluted
with water (25 ml), extracted with ethyl acetate (3×7 ml). The extract was washed with water
(2×5 ml), dried by filtration through cotton wool, and evaporated in vacuo. The residue was
chromatographed (ethyl acetate – heptane 1:2) to furnish an inseparable mixture of 2b and 2c in
9
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10.1002/ejoc.202000099
European Journal of Organic Chemistry
ca. 1:4 ratio (total yield 106 mg, 63%), as well as some amounts of the starting 2a (10 mg, 6%)
and lamellarin Q Et ester (21 mg, 13%).
Ethyl 3-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (2b), minor
1
component of the mixture: H NMR (500 MHz, [D6]DMSO): δ = 11.8 (s, 1H; NH), 9.26 (s,
1H; OH), 7.13 (d, J = 3.1 Hz, 1H; H-5), 6.99 (d, J = 8.6 Hz, 2H; Ar), 6.94 (d, J = 8.4 Hz, 2H;
Ar), 6.74 (d, J = 8.6 Hz, 2H; Ar), 6.66 (d, J = 8.4 Hz, 2H; Ar), 4.07 (q, J = 7.1 Hz, 2H; CH2),
3.68 (s, 3H; OCH3), 1.09 ppm (t, J = 7.1 Hz, 3H; CH3).
Ethyl 3-(4-methoxyphenyl)-4-(4-hydroxyphenyl)-1H-pyrrole-2-carboxylate (2c), major
1
component of the mixture: H NMR (500 MHz, [D6]DMSO): δ = 11.8 (s, 1H; NH), 9.18 (s,
1H; OH), 7.09 (d, J = 3.2 Hz, 1H; H-5), 7.06 (d, J = 8.6 Hz, 2H; Ar), 6.86 (d, J = 8.6 Hz, 2H;
Ar), 6.83 (d, J = 8.3 Hz, 2H; Ar), 6.56 (d, J = 8.6 Hz, 2H; Ar), 4.07 (q, J = 7.1 Hz, 2H; CH2),
3.75 (s, 3H; OCH3), 1.09 ppm (t, J = 7.1 Hz, 3H; CH3) (signals at 11.8, 4.07 and 1.09 coincide).
Alternative synthesis of the compound 2b. A mixture of 4-methoxyphenylnitromethane (388
mg, 2.3 mmol), 4-hydroxybenzaldehyde (312 mg, 2.6 mmol), MeOH (2 ml), MeNH2•HCl (13
mg, 0.2 mmol), and NaHCO3 (8 mg, 0.1 mmol) was stirred at room temperature for 5 days (TLC
control). The reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate
(3×5 ml). The extract was washed with water (2×3 ml), dried by filtration through cotton wool,
and evaporated in vacuo. Crude 1-nitro-1-(4-methoxyphenyl)-2-(4-hydroxyphenyl)ethylene 1b
(206 mg) was isolated by column chromatography (toluene) as an oil and used without further
purification.
Freshly calcined potassium carbonate (204 mg, 1.45 mmol) was added to a solution of the above
crude 1b (200 mg, 0.74 mmol) and ethyl isocyanoacetate (84 mg, 0.74 mmol) in ethanol (1 ml)
and the mixture stirred at room temperature until the disappearance of the starting nitrostilbene
(12 h, TLC control). The reaction mixture was diluted with water (up to 30 ml), neutralized with
HCl, extracted with ethylacetate (3×5 ml). The extract was washed with water (2×3 ml), dried by
filtration through cotton wool, and evaporated in vacuo. Pure product 2b (15 mg, 2% in 2 steps)
was obtained after column chromatography (ethyl acetate – hexane 1:3).
1
1-Nitro-1-(4-methoxyphenyl)-2-(4-hydroxyphenyl)ethylene (1b) (crude): yellow oil; H
NMR (500 MHz, CDCl3): δ = 8.16 (s, 1H; H-2), 7.24 (d, J = 8.5 Hz, 2H; Ar), 7.00-7.05 (m, 4H;
Ar), 6.69 (d, J = 8.2 Hz, 2H; Ar), 5.45 (s, 1H; OH), 3.88 ppm (s, 3H; OCH3).
Ethyl 3-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (2b): white
solid; m.p. 152-153 °C; 1H NMR spectrum is identical to that of the minor product in the mixture
of 2b and 2c (see above); MS (70 eV): m/z (%): 338 (10) [M + H]+, 337 (46) [M]+, 291 (100),
276 (21), 220 (17), 190 (9), 165 (18), 110 (13), 96 (9), 89 (9), 29 (33), 15 (13); elemental
analysis calcd (%) for C20H19NO4: C 71.20, H 5.68, N 4.15; found: 70.95; H 5.61; N 4.36.
10
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Methyl 3,4-bis(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (3a). Method 1. Solution of Na
(33 mg, 1.4 mmol) in methanol (2.5 ml) was added to suspension of ethyl 3,4-bis(4-
methoxyphenyl)-1H-pyrrolе-2-carboxylate 2a (50 mg, 0.14 mmol) in methanol (2 ml) and
refluxed for 90 min. The reaction mixture was neutralized with aq. HCl, filtered, washed with
water (2×3 ml) and dried. The resulting pyrrole was obtained in 84% yield. White solid, m.p.
175-176 °C (lit.22a 176-177 °C); 1H NMR (500 MHz, CDCl3): δ = 9.13 (s, 1H; NH), 7.19 (d, J =
8.6 Hz, 2H; Ar), 7.02 (m, Ar, 3H; H-5), 6.84 (d, J = 8.7 Hz, 2H; Ar), 6.75 (d, J = 8.7 Hz, 2H;
13
Ar), 3.82 (s, 3H; OCH3), 3.76 (s, 3H; OCH3), 3.73 ppm (s, 3H; OCH3); C NMR (125 MHz,
CDCl3): δ =161.5, 158.5, 157.9, 131.8, 129.4, 129.0, 127.1, 126.4, 120.0, 119.3, 113.6, 113.1,
55.1, 55.0, 51.2 ppm; MS (70 eV): m/z (%): 338 (18) [M + H]+, 337 (81) [M]+, 305 (100), 290
(21), 191 (21), 164 (15), 152 (16), 117 (12), 102 (12), 95 (12), 88 (13), 15 (60).
Method 2. Freshly calcined potassium carbonate (552 mg, 4 mmol) was added to a suspension of
1,2-bis(4-methoxyphenyl)-nitroethylene 1a[30а] (570 mg, 2 mmol) and ethyl isocyanoacetate (226
mg, 2 mmol) in methanol (4 ml) and the mixture stirred at room temperature until the
disappearance of the starting nitrostilbene (12 h, TLC control). The reaction mixture was diluted
with water (up to 30 ml), neutralized with HCl, filtered, washed wish water (3×5 ml) and dried.
The resulting pyrrole 3а was obtained in 89% yield.
Methyl 3,4-bis(4-hydroxyphenyl)-1H-pyrrole-2-carboxylate (lamellarin Q). To a stirred
solution of anhydrous CH2Cl2 (2 ml) and methyl 3,4-bis(4-methoxyphenyl)-1H-pyrrole-2-
carboxylate 3a (168 mg, 0.5 mmol) was added BBr3 (1.5 ml 1M in CH2Cl2) dropwise at -5 °C.
The resulting solution was stirred for 90 min (TLC control), quenched with NaHCO3 (756 mg, 9
mmol) in H2O (5 ml), stirred for 1 min, diluted with water (5 ml), extracted with ethyl acetate
(3×7 ml). The extract was washed with water (2×5 ml), dried by filtration through cotton wool,
and evaporated in vacuo. Pure product was obtained after column chromatography (ethyl acetate
– heptane 1:2): 84% yield, white solid, m.p. 226-227 °C (lit.[8d] 227-228 °C); 1H NMR (500 MHz
, [D6]DMSO): δ = 11.80 (s, 1H; NH), 9.26 (s, 1H; OH), 9.18 (s, 1H; OH), 7.07 (d, J = 3.2 Hz,
1H; H-5), 6.93 (d, J = 8.5 Hz, 2H; Ar), 6.85 (d, J = 8.6 Hz, 2H; Ar), 6.65 (d, J = 8.5 Hz, 2H; Ar),
13
6.56 (d, J = 8.6 Hz, 2H; Ar), 3.60 ppm (s, 3H; CH3); C NMR (125 MHz, [D6]DMSO): δ
=160.9, 155.9, 155.4, 131.6, 128.9, 128.5, 125.7, 125.3, 125.2, 120.9, 118.4, 114.9, 114.4, 50.7
ppm; MS (70 eV): m/z (%): 310 (12) [M + H]+, 309 (60) [M]+, 277 (100), 248 (9), 220 (13), 165
(19), 138 (8), 88 (9), 15 (5).
General Procedure for the Synthesis of Ethyl Pyrrole-2-carboxylates 2a, 5a-l. Freshly
calcined potassium carbonate (552 mg, 4 mmol) was added to a suspension of 1,2-
diarylnitroethylene 1a, 4a-l (2 mmol) and ethyl isocyanoacetate (226 mg, 2 mmol) in ethanol (4
11
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European Journal of Organic Chemistry
ml) and the mixture stirred at room temperature until the disappearance of the starting
nitrostilbene (12-36 h, TLC control). The reaction mixture was diluted with water (up to 30 ml),
neutralized with HCl, filtered, washed wish water (3×5 ml) and dried. 5a, 5c, 5d were extracted
with ethyl acetate (3×5 ml), the extract was washed with water (2×3 ml), dried by filtration
through cotton wool, and evaporated in vacuo.
Ethyl 3-(6,7-dimethoxy-2H-1,3-benzodioxol-5-yl)-4-phenyl-1H-pyrrole-2-carboxylate (5f):
1
727 mg, 92% yield, yellowish solid, m.p. 149-150 °C; H NMR (500 MHz, [D6]DMSO): δ =
11.99 (s, 1H; NH), 7.30 (d, J = 3.2 Hz, 1H; H-5), 7.19 (m, 4H; Ar), 7.10 (m, 1H; Ar), 6.30 (s,
1H; Ar), 6.01 (s, 1H; OCH2O), 5.98 (s, 1H; OCH2O), 4.05 (m, 2H; CH2CH3), 3.89 (s, 3H;
13
OCH3), 3.30 (s, 3H; OCH3), 1.06 ppm (t, J = 7.1 Hz, 3H; CH2CH3); C NMR (125 MHz,
[D6]DMSO): δ = 160.3, 144.5, 143.5, 136.9, 136.7, 135.0, 128.1, 126.7, 125.5, 124.8, 124.1,
122.2, 121.1, 120.3, 104.6, 101.2, 59.8, 59.7, 59.1, 13.9 ppm; MS (70 eV): m/z (%): 396 (25) [M
+ H]+, 395 (100) [M]+, 364 (4), 349 (22), 334 (9), 307 (12), 276 (7), 177 (3), 165 (5), 150 (3),
139 (3), 29 (19), 15 (6); elemental analysis calcd (%) for C22H21NO6: C 66.83, H 5.35, N 3.54;
found: C 66.61, H 5.42, N 3.64.
General Procedure for the Synthesis of 3-(2-Hydroxyaryl)-4-Arylpyrrole-2-carboxylates
6a-l. To a stirred mixture of anhydrous CH2Cl2 (2 ml) and ethyl 3-(2-methoxyaryl)-4-aryl-1H-
pyrrole-2-carboxylate 5a-l (0.5 mmol) was added BBr3 (0.5 ml 1M in CH2Cl2) dropwise at -5 °C.
The resulting solution was stirred for 30 min (TLC control), quenched with NaHCO3 (252 mg, 3
mmol) in H2O (5 ml), stirred for 1 min, diluted with water (25 ml), extracted with ethyl acetate
(3×7 ml). The extract was washed with water (2×5 ml), dried by filtration through cotton wool,
and evaporated in vacuo. Pure products were obtained after column chromatography (ethyl
acetate – heptane 1:2).
Ethyl
3-(2-hydroxy-5-methylphenyl)-4-(2-methoxy-5-methylphenyl)-1H-pyrrole-2-
1
carboxylate (6l): 142 mg, 78% yield, yellowish oil; H NMR (500 MHz, CDCl3): δ = 9.29 (s,
1H; NH), 7.18 (d, J = 3.1 Hz, 1H; H-5), 6.97 (dd, J = 8.3 Hz, J = 1.7 Hz, 1H; Ar), 6.93 (dd, J =
8.3 Hz, J = 1.9 Hz, 1H; Ar), 6.88 (d, J = 1.9 Hz, 1H; Ar), 6.82 (d, J = 8.3 Hz, 1H; Ar), 6.72 (d, J
= 1.7 Hz, 1H; Ar), 6.67 (d, J = 8.3 Hz, 1H; Ar), 5.52 (s, 1H; OH), 4.21 (q, J = 7.1 Hz, 2H; CH2),
3.52 (s, 3H; OCH3), 2.17 (s, 3H; CH3), 2.12 (s, 3H; CH3), 1.16 ppm (t, J = 7.1 Hz, 3H; CH3); 13C
NMR (125 MHz, CDCl3): δ = 161.4, 154.6, 151.5, 131.9, 131.7, 129.4, 129.2, 128.6, 128.5,
125.1, 123.9, 122.7, 122.6, 122.2, 120.2, 115.5, 110.6, 60.7, 55.2, 20.5, 20.4, 14.1 ppm; MS (70
eV): m/z (%): 366 (24) [M + H]+, 365 (100) [M]+, 319 (86), 304 (16), 290 (10), 276 (14), 149
(7), 29 (29); elemental analysis calcd (%) for C22H23NO4: C 72.31, H 6.34, N 3.83; found: C
72.62, H 6.19, N 3.63.
12
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European Journal of Organic Chemistry
General Procedure for the Synthesis of Polyhydroxyarylpyrrole-2-carboxylates 8a-e. To a
stirred mixture of anhydrous CH2Cl2 (2 ml) and ethyl polymethoxyaryl-1H-pyrrole-2-carboxylate
5c, d, g, h, i (0.5 mmol) was added BBr3 (1.5 ml for 5d,c; 2 ml for 5g,h,i 1M in CH2Cl2)
dropwise at -5 °C. The resulting solution was stirred for 30 min (TLC control), quenched with
NaHCO3 (756 mg (9 mmol) for 5d,c; 1008 mg (12 mmol) for 5g,h,i) in H2O (5 ml), stirred for 1
min, diluted with water (25 ml), extracted with ethyl acetate (3×7 ml). The extract was washed
with water (2×5 ml), dried by filtration through cotton wool, and evaporated in vacuo. Pure
products were obtained after column chromatography (ethyl acetate – heptane 1:2).
Ethyl 3-(2,4-dihydroxyphenyl)-4-(4-hydroxyphenyl)-1H-pyrrole-2-carboxylate (8d): 134
1
mg, 79% yield, white solid, m.p. 221-222 °C; H NMR (500 MHz, [D6]DMSO): δ = 11.65 (s,
1H; NH), 9.11 (s, 1H; OH), 9.02 (s, 1H; OH), 8.65 (s, 1H; OH), 7.08 (d, J = 3.1 Hz, 1H; H-5),
6.96 (d, J = 8.5 Hz, 2H; Ar), 6.61 (d, J = 8.2 Hz, 1H; Ar), 6.54 (d, J = 8.5 Hz, 2H; Ar), 6.26 (d, J
= 2.2 Hz, 1H; Ar), 6.11 (dd, J = 8.2 Hz, J = 2.2 Hz, 1H; Ar), 4.01 (m, 2H; CH2), 1.05 ppm (t, J =
13
7.1 Hz, 3H; CH3); C NMR (125 MHz, [D6]DMSO): δ = 160.7, 157.1, 156.1, 155.2, 132.1,
128.0, 126.5, 125.4, 124.9, 120.1, 114.8, 113.7, 105.7, 102.3, 58.9, 14.1 ppm; MS (70 eV): m/z
(%): 340 (19) [M + H]+, 339 (74) [M]+, 293 (100), 273 (3), 265 (6), 236 (4), 29 (7); elemental
analysis calcd (%) for C19H17NO5: C 67.25, H 5.05, N 4.13; found: C 67.51, H 5.14, N 3.83.
General Procedure for the Synthesis of Benzo[c]chromen-6-ones 7a-l, 9a-e. Solution of 3-(2-
hydroxyaryl)-4-aryl-1H-pyrrole-2-carboxylate (0.5 mmol) 6a-l, 8c,d,g,h,i in ethanol and 10%
NaOH (0.1 ml) was stirred at room temperature for 3 h, evaporated, diluted with water (20 ml),
filtered, washed with water (3×5 ml) and CH2Cl2 (3 ml) and dried.
1-(2-Methoxy-5-methylphenyl)-8-methylchromeno[3,4-b]pyrrole-4(3H)-one (7l): 131 mg,
1
82% yield, white solid, m.p. 247-248 °C; H NMR (500 MHz, [D6]DMSO): δ = 12.77 (s, 1H;
NH), 7.46 (s, 1H; H-2), 7.31 (d, J = 8.3 Hz, 1H; Ar), 7.26 (d, J = 8.0 Hz, 1H; Ar), 7.18 (m, 2H;
Ar), 7.12 (s, 1H; Ar), 7.07 (d, J = 8.3 Hz, 1H; Ar), 3.64 (s, 3H; OCH3), 2.32 (s, 3H; CH3), 2.18
13
ppm (s, 3H; CH3); C NMR (125 MHz, [D6]DMSO): δ = 155.1, 154.5, 148.7, 132.6, 132.2,
129.6, 129.2, 129.0, 128.2, 125.6, 123.2, 122.7, 118.3, 117.2, 116.5, 116.4, 111.1, 55.2, 20.6,
20.1 ppm; MS (70 eV): m/z (%): 320 (21) [M + H]+, 319 (100) [M]+, 304 (6), 276 (6), 233 (2),
212 (2), 189 (2); elemental analysis calcd (%) for C20H17NO3: C 75.22, H 5.37, N 4.39; found: C
75.03, H 5.30, N 4.53.
1-(4-Hydroxyphenyl)-8-hydroxychromeno[3,4-b]pyrrole-4(3H)-one (9e): 119 mg, 81% yield,
white solid, m.p. 327-328 °C; 1H NMR (500 MHz, [D6]DMSO): δ = 12.69 (s, 1H; NH), 9.55 (s,
1H; OH), 9.43 (s, 1H; OH), 7.38 (s, 1H; H-2), 7.28 (d, J = 8.0 Hz, 1H; Ar), 7.23 (d, J = 8.9 Hz,
13
1H; Ar), 7.04 (s, 1H; Ar), 6.88 (d, J = 8.0 Hz, 2H; Ar), 6.78 ppm (d, J = 8.9 Hz, 1H; Ar); C
13
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10.1002/ejoc.202000099
European Journal of Organic Chemistry
NMR (125 MHz, [D6]DMSO) δ 156.8, 154.6, 153.3, 144.0, 130.7, 128.4, 124.6, 124.2, 121.5,
118.8, 117.8, 116.8, 115.5, 115.3, 108.1 ppm; MS (70 eV): m/z (%): 294 (18) [M + H]+, 293
(100) [M]+, 264 (6), 236 (6), 152 (8), 89 (5), 63 (7), 55 (9), 39 (7), 28 (17); elemental analysis
calcd (%) for C17H11NO4: C 69.62, H 3.78, N 4.78; found: C 69.87, H 3.82, N 4.56.
X-ray structural study
X-ray diffraction data for Lamellarin Q and 9a were collected on a three-circle Bruker D8
QUEST PHOTON-III CCD diffractometer ((MoK)-radiation, T = 100 K, graphite
monochromator,  and  scan mode) and corrected for absorption using the SADABS
program.[32] The data were indexed and integrated using the SAINT program.[33]. The structures
were determined by direct methods and refined by full-matrix least squares technique on F2 with
anisotropic displacement parameters for non-hydrogen atoms. In the crystal of Lamellarin Q, a
solvate acetonitrile molecule was found in the asymmetric unit. The hydrogen atoms of the
amino and hydroxy groups were localized in the difference-Fourier map and refined isotropically
with fixed displacement parameters [Uiso(H) = 1.2Ueq(N) and 1.5Ueq(O)]. The other hydrogen
atoms were placed in calculated positions and refined within riding model with fixed isotropic
displacement parameters [Uiso(H) = 1.5Ueq(C) for the CH3-groups and 1.2Ueq(C) for the other
groups]. All calculations were carried out using the SHELXTL[34] program suite.
Crystallographic data for Lamellarin Q • MeCN and 9a have been deposited with the
Cambridge Crystallographic Data Center, CCDC 1964758 and CCDC 1964759, respectively.
Copies of this information may be obtained free of charge from the Director, CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (Fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk or
www.ccdc.cam.ac.uk).
Crystal structure determination was performed in the Department of Structural Studies of
Zelinsky Institute of Organic Chemistry, Moscow, Russia.
†Electronic supplementary information (ESI) available: X-ray data for Lamellarin Q • MeCN
1
13
and compound 9a; characterization and spectra for the compounds 4-9; copies of H and C
NMR spectra for all new compounds.
AKNOWLEDGEMENTS
This work was carried out with the the financial support of the Russian Science Foundation
(grant no. 18-13-00044). X-ray diffraction study was conducted by V.N.K. with the financial
14
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10.1002/ejoc.202000099
European Journal of Organic Chemistry
support from the Ministry of Education and Science of the Russian Federation (Project No.
4.1154.2017/4.6) and the “RUDN University Program 5-100”.
15
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European Journal of Organic Chemistry
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[19] MOM (methoxymethyl) is, by far, the most popular O-protective group in
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[21]
a) D. H. R. Barton, S. Z. Zard, J. Chem. Soc., Chem. Commun. 1985, 1098-1100;
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[22]
Similar reactions could proceed with cyano- and sulphonyl-substituted alkenes,
though usually under harsher conditions and in lower yields: a) J. L. Bullington, R. R.
Wolff, P. F. Jackson, J. Org. Chem. 2002, 67, 9439-9442; b) D. Mysꢀiwiec, B. Donnio, P.
J. Chmielewski, B. Heinrich, M. Stępieꢁ, J. Am. Chem. Soc. 2012, 134, 4822-4833; see
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a) E. A. Silyanova, A. V. Samet, V. V. Semenov, Russ. Chem. Bull. 2018, 67,
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A. V. Samet, E. A. Silyanova, V. P. Kislyi, A. S. Maksimenko, A. E. Varakutin, L. D.
Konyushkin, M. M. Raihstat, A. S. Kiselyov, V. V. Semenov, ACS Comb. Sci. 2018, 20,
700-721.
[24]
Using smaller amounts of BBr3 led to incomplete conversion, probably due to the
complexation, cf. P. R. Brooks, M. C. Wirtz, M. G. Vetelino, D. M. Rescek, G. F.
Woodworth, B. P. Morgan, J. W. Coe, J. Org. Chem. 1999, 64, 9719-9721.
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Selective O-demethylation with BCl3 and BBr3 in polymethoxy arenes directed by
an ortho- carbonyl substituent is well-documented: a) M. V. Bhatt, S. U. Kulkarni,
Synthesis 1983, 249-282 and references therein; b) F. M. Dean, J. Goodchild, L. E.
Houghton, J. A. Martin, R. B. Morton, B. Parton, A. W. Price, N. Somvichien,
18
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10.1002/ejoc.202000099
European Journal of Organic Chemistry
Tetrahedron Lett. 1966, 7, 4153-4159. In contrast, reports on such effects of the remote
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At the same time, a very recent work reported an interesting example of the
selective demethylation and subsequent lactonization in 3-(o-methoxyphenyl)pyrrole-2-
carbonyl iodide prepared in a few steps from the corresponding pyrrole-2-carboxylate:
R. Klintworth, C. B. de Koning, J. P. Michael, J. Org. Chem. 2020, 85, 1054-1061.
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Prepared from the corresponding symmetrical stilbene upon treatment with
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276-281. Of note, previously this procedure, initially developed for the nitration of
styrenes, was never used with stilbenes.
[29]
Interestingly, we were able to find only 2 examples where the pyrrolocoumarin
system was formed via BBr3-induced O-demethylation of 3-(o-methoxyphenyl)pyrrole-2-
carboxylates: Y. Furusho, A. Tsunoda, T. Aida, J. Chem. Soc. Perkin Trans. 1 1996, 183-
190; and ref. 22a.
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19
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000099
European Journal of Organic Chemistry
A metal-free approach to pyrrolocoumarin cores of lamellarins and related natural products
based on Barton-Zard reaction of nitrostilbenes with ethyl isocyanoacetate was developed.
Treatment of diarylpyrrole-2-carboxylates with 1 eq. BBr3 resulted in selective O-demethylation
of the ortho-methoxy group, while other methoxy groups remained intact. Subsequent base-
induced lactonization give target pyrrolocoumarins.
Keywords: lamellarin Q, natural products, Barton-Zard reaction, O-demethylation, total
synthesis
Key Topic: lamellarin synthesis
20
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