Total synthesis of murrayanine involving 4,5-dimethyleneoxazolidin-2-ones and a palladium(0)-catalyzed diary insertion

Article abstract of DOI:10.1002/hlca.200790148

A new total synthesis of the natural carbazole murrayanine (1) was developed by using the 4,5-dimethyleneoxazolidin-2-one 12 as starting material. The latter underwent a highly regioselective Diets - Alder cycloaddition with acrylaldehyde (= prop-2-enal;

Full text of DOI:10.1002/hlca.200790148

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Total Synthesis of Murrayanine Involving 4,5-Dimethyleneoxazolidin-2-ones
and a Palladium(0)-Catalyzed Diaryl Insertion
by Pablo Bernal and Joaquín Tamariz*
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Departamento de Química Organica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico
´
Nacional. Prol. Carpio y Plan de Ayala, 11340 Mexico, D.F. Mexico
(phone: (þ 5255)5729-6300/62411; fax: (þ 5255)5729-6300/46211;
e-mail: jtamariz@woodward.encb.ipn.mx)
A new total synthesis of the natural carbazole murrayanine (1) was developed by using the 4,5-
dimethyleneoxazolidin-2-one 12 as starting material. The latter underwent a highly regioselective Diels –
Alder cycloaddition with acrylaldehyde (¼ prop-2-enal; 13) to give adduct 14 (Scheme 3). Conversion of
this adduct into diarylamine derivative 9 was carried out via hydrolysis and methylation (Scheme 4).
Differing from our previous synthesis, in which such a diarylamine derivative was transformed into 1 by a
PdII-stoichiometric cyclization, this new approach comprised an improved cyclization through a more
efficient Pd0-catalyzed intramolecular diaryl coupling which was applied to 9, thus obtaining the natural
carbazole 1 in a higher overall yield.
1. Introduction. – Murrayanine (1) was the first naturally occurring carbazole
alkaloid to be isolated [1]. It was extracted from Murraya koenigii Spreng (Rutaceae)
[2] but later also from other species of the genus Murraya and Clausena [3]1), and
shows significant biological activity [4]. For instance, it has proved to potently inhibit
platelet aggregation [3b], act as an antibacterial and antifungal agent [2b][2c], and
have cytotoxic activity [3f]. As a result, several total [5] and partial [6] syntheses have
been carried out. Interestingly, owing to the fact that carbazole 1 bears a formyl group
at C(3), it can be converted into a series of other analogous carbazoles such as
koenoline (2) [1][2a][5c][5d], mukoeic acid (3) [2a], murrayafoline A (4) [2a], and
murrayaquinone A (5) [4][5d], through common functional-group manipulations.
1
)
From C. lansium, see [3a]; from M. euchrestifolia, see [3b]; from C. heptaphylla, see [3c]; from C.
excavata, see [3d,e]; From C. dunniana, see [3f]; from M. kwangsiensis, see [3g].
ꢀ 2007 Verlag Helvetica Chimica Acta AG, Zürich

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Recently, we have described a total synthesis of carbazole 1 [7] following our
general synthetic approach for the preparation of the carbazole scaffold [8]. This
approach was based on the regioselective Diels – Alder cycloaddition of the 4,5-
dimethyleneoxazolidin-2-one 6 [9], whose adduct 7 was transformed into diarylamine
derivative 8 through a two-step methodology (Scheme 1). The latter was converted into
the natural carbazole by a stoichiometric palladium(II) insertion in a 36% overall yield.
In fact, the closure of substituted diarylamines to yield the natural carbazole framework
by a PdII-mediated oxidative cyclization has been widely applied in the past [10]. In
contrast, the Pd0-catalyzed insertion process [11] has been useful for the construction of
both unsubstituted [12] and substituted carbazoles [13] although it is limited for the
total synthesis of natural carbazoles [10][11]. This is probably due to the difficulty in
preparing the diarylamine derivative with both the appropriate functionalization and
the presence of a halogen atom at a proper position of the arene rings for a feasible
intramolecular Heck coupling [11].
Scheme 1
With the aim of improving our general synthetic approach to carbazoles and, in
particular, our synthesis of murrayanine (1), we herein present the preparation of 1 by a
Pd0-catalyzed insertion of the properly substituted diarylamine derivative
9
(Scheme 2).
Scheme 2
2. Results and Discussion. – 2.1. Preparation of Dimethyleneoxazolidinone 12 and its
Regioselective Diels – Alder Addition to Acrylaldehyde (13). To achieve the appro-
priate functionalization of diarylamine derivative 9, we prepared the (2-bromophenyl)-
substituted dimethyleneoxazolidinone 12 and evaluated its regioselectivity in the
Diels – Alder reaction with acrylaldehyde (¼ prop-2-enal; 13) to give the key adduct 14
(Scheme 3). Compound 12 has been previously prepared by condensing butane-2,3-
dione (10) with isocyanate 11 in the presence of Et3N, lithium carbonate, and dioxane as
the solvent [9]. Similarly to the preparation of adduct 7, the Diels – Alder reaction of 12
with 13 occurred satisfactorily by carrying out the process under Lewis-acid catalysis.

Helvetica Chimica Acta – Vol. 90 (2007)
1451
Thus, upon addition of BF3 · Et2O to the reaction mixture at ꢀ 788, the starting
materials were completely consumed after 25 min, to provide the desired adduct 14 in
high yield (90%), as a single regioisomer. Notably, this cycloaddition was slightly more
selective than that between dimethyleneoxazolidinone 6 and 13 [7], but was still much
more regioselective than the cycloadditions between 6 and methyl vinyl ketone (¼ but-
3-en-2-one) or methyl propiolate (¼ methyl prop-2-ynoate) [9] under the same
conditions of Lewis-acid catalysis and temperature.
Scheme 3
2.2. Aromatization of Adduct 14 and its Transformation into the Natural Carbazole
Murrayanine (1). The cyclohexene moiety of adduct 14 was aromatized by using DDQ
(¼4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile) in refluxing benzene,
to give 2-oxo-1,3-benzoxazol-6-carboxaldehyde 15 in 65% yield (Scheme 4). Differing
from the previous synthetic route, where diarylamine derivative 8 was prepared from 7
by a two-step procedure through isolation of its hydrolysis precursor, hydroxydiaryl-
amine derivative 16 was not isolated after hydrolysis of 15 but converted directly into
the methoxydiarylamine derivative 9 (Scheme 4); otherwise, the yield was largely
decreased. Thus, after hydrolysis of 15 under smooth basic conditions (KOH, EtOH/
H2O, 258, 18 h), the crude mixture was treated with MeI in acetone and the base K2CO3
to give 9 in 90% yield.
Scheme 4
Finally, murrayanine (1) was efficiently prepared by a Pd0-catalyzed insertion of the
bromodiarylamine derivative 9. The best conditions furnishing 1 in 85% yield from 9
(1mol-equiv.) were achieved with 0.02 mol-equiv. of [Pd(PPh 3)4] catalyst [14] in the
presence of Na2CO3 (2.0 mol-equiv.) and LiCl (1.0 mol-equiv.) [15] in MeCN under

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reflux for 48 h. Spectral and physical data of the product 1 were in agreement with those
reported for the natural product [2a][3a]. 2D NMR Experiments (HMQC and
HMBC) were performed to assign the signals of the 13C-NMR spectrum of 1 (see
Exper. Part).
3. Conclusions. – A new total synthesis of the naturally occurring carbazole alkaloid
murrayanine (1) through a four-step route was described, starting from the (2-
bromophenyl)-substituted 4,5-dimethyleneoxazolidin-2-one 12 and achieving a 45%
overall yield. The highly regioselective Diels – Alder reaction of 12 with acrylaldehyde
(13) provided the key adduct 14, which was efficiently converted into diarylamine
derivative 9. In contrast to our previous procedure, the ring-closure process to give the
carbazole framework of 1 was accomplished by a Pd0-catalyzed reaction of the
precursor 9, demonstrating the utility of this methodology for the preparation of
natural carbazoles. The application of this approach for the synthesis of other natural
carbazoles is currently under investigation, and the results will be described in due
course.
´
We thank Fabiola Jimenez for her help in spectrometric measurements. J. T. is grateful to SIP/IPN
(grants 20050151 and 20060583) and CONACYT (grant 43508-Q) for financial support. P. B. thanks
CONACYT for a scholarship, and SIP/IPN for a scholarship complement. J. T. is a fellow of the EDI-IPN
and COFAA-IPN programs.
Experimental Part
General. All air-moisture-sensitive reactions were carried out under N2 in oven-dried glassware.
Benzene was freshly distilled from Na, and CH2Cl2 and MeCN from CaH2. Li2CO3 and Na2CO3 were
dried overnight at 1208 prior to use. Et3N was distilled from NaOH. All other reagents were used without
further purification. Compound 12 was prepared as reported [9]. Anal. TLC: E. Merck silica gel 60 F254
-
coated plates; visualization by a long- and short-wavelength UV lamp. CC ¼ Column chromatography.
M.p.: uncorrected; Electrothermal capillary melting-point apparatus. IR Spectra: Perkin-Elmer 1600
spectrophotometer; in cmꢀ1 1H- (300 MHz) and 13C-NMR (75.4 MHz) Spectra: Varian Mercury-300
.
instrument; in CDCl3 with Me4Si as internal standard; d in ppm, J in Hz. MS: EI mode (70 eV); Thermo-
Finnigan Polaris Q spectrometer. HR-MS: FAB mode (mNBA); Jeol JMS-AX-505-HA spectrometer.
3-(2-Bromophenyl)-2,3,4,5,6,7-hexahydro-2-oxobenzoxazol-6-carboxaldehyde (14). To a stirred
soln. of 12 (0.5 g, 1.9 mmol) and prop-2-enal (13; 0.32 g, 5.7 mmol) in anh. CH2Cl2 (50 ml) at ꢀ 788
under N2, BF3 · Et2O (0.081g, 0.57 mmol) was added dropwise, and the mixture was stirred for 25 min at
ꢀ 788. The mixture was diluted with CH2Cl2 (15 ml) and added to H2O (10 ml). The aq. layer was washed
with CH2Cl2 (3 ꢁ 15 ml), the combined org. phase washed with 5% aq. NaHCO3 soln. (3 ꢁ 15 ml) and
5% aq. NH4Cl soln. (2 ꢁ 15 ml) and dried (Na2SO4), the solvent evaporated, and the residue purified by
CC (silica gel (20 g), hexane/AcOEt 8 :2): 0.54 g (90%) of 14. Pale redish oil. TLC (hexane/AcOEt, 7:3):
Rf 0.27. IR (film): 1767, 1716, 1485, 1399, 1176, 1054, 981, 765, 727. 1H-NMR (300 MHz, CDCl3): 1.88 –
2.02 (m, 1 HꢀC(5), 1H ꢀC(7)); 2.04 – 2.34 (m, 2 HꢀC(4), 1H ꢀC(5)); 2.71– 2.92 ( m, HꢀC(6),
1 HꢀC(7)); 7.22 – 7.48 (m, HꢀC(4’), HꢀC(5’), HꢀC(6’)); 7.67 – 7.74 (m, HꢀC(3’)), 9.74 (d, J ¼ 0.8,
CHO). 13C-NMR (75.4 MHz, CDCl3): 18.2 (C(4)); 20.7 (C(7)); 21.4 (C(5)); 45.6 (C(6)); 121.7 (C(3a));
123.1 (C(2’)); 128.6 (C(5’)); 130.3 (C(6’)); 130.9 (C(4’)); 132.6 (C(7a) or C(1’)); 133.2 (C(1’) or C(7a));
133.7 (C(3’)); 154.5 (C(2)); 201.5 (CHO). EI-MS (70 eV): 323 (4, Mþ (81Br)), 321(4, Mþ (79Br)), 295
(18), 293 (20), 251 (26), 249 (25), 214 (20), 197 (20), 186 (80), 170 (100), 156 (30), 142 (22), 130 (18), 115
(12). HR-FAB-MS: 320.9998 (Mþ, C14H12BrNO3þ ; calc. 321.0001).
3-(2-Bromophenyl)-2,3-dihydro-2-oxobenzoxazol-6-carboxaldehyde (15). To a stirred soln. of 14
(0.50 g, 1.55 mmol) in anh. benzene (15 ml) under reflux and N , DDQ (0.44 g, 1.94 mmol) was added,
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Helvetica Chimica Acta – Vol. 90 (2007)
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and the suspension was stirred for 12 h under reflux. Then, more DDQ (0.44 g, 1.94 mmol) was added,
and the reflux was maintained for 12 h. The mixture was filtered over Celite, the solvent evaporated, and
the residue purified by CC (silica gel (20 g), hexane/CH2Cl2 1:1): 0.32 g (65%) of 15. White solid. TLC
(hexane/AcOEt 7:3): Rf 0.42. M.p. 150 – 1518 (hexane/CH2Cl2 7:3). IR (KBr): 1791, 1691, 1606, 1500,
1478, 1450, 1380, 1354, 1287, 1252, 1156, 983, 765, 715. 1H-NMR (300 MHz, CDCl3): 6.86 (d, J ¼ 7.8,
HꢀC(4)); 7.43 – 7.60 (m, HꢀC(4’), HꢀC(5’), HꢀC(6’)); 7.74 (dd, J ¼ 7.8, 1.2, HꢀC(5)); 7.82 (dd, J ¼ 8.2,
1.2, HꢀC(3’)); 7.83 (d, J ¼ 1.2, HꢀC(7)); 9.98 (s, CHO). 13C-NMR (75.4 MHz, CDCl3): 109.5 (C(4));
110.1 (C(7)); 122.5 (C(2’)); 128.2 (C(5)); 129.2 (C(5’)); 130.0 (C(6’)); 131.5 (C(1’)); 131.8 (C(4’)); 132.4
(C(6)); 134.4 (C(3’)); 136.4 (C(3a)); 143.0 (C(7a)); 156.7 (C(2)); 190.3 (CHO). EI-MS (70 eV): 238 (100,
[M ꢀ HBr]þ), 209 (8), 181 (6), 166 (20), 140 (6), 126 (2). HR-FAB-MS: 317.9772 ([M þ 1]þ,
C14H979BrNOþ3 ; calc. 317.9766).
4-[(2-Bromophenyl)amino]-3-methoxybenzaldehyde (9). A mixture of 15 (0.28 g, 0.88 mmol) and
KOH (0.197 g, 3.52 mmol) in EtOH/H2O 7:3 (5 ml) at 208 was stirred for 18 h. The mixture was
neutralized with 5% aq. HCl soln., the solvent evaporated, the residue dissolved in CH2Cl2 (10 ml), and
H2O (5 ml) added. The aq. layer was washed with CH2Cl2 (3 ꢁ 10 ml), the combined org. phase dried
(Na2SO4) and the solvent evaporated. The residue was dissolved in acetone (10 ml), and K2CO3 (0.304 g,
2.20 mmol) and MeI (0.374 g, 2.63 mmol) were added. The mixture was heated under reflux for 12 h and
then filtered over Celite washing with acetone (3 ꢁ 10 ml), and the solvent was evaporated. The residue
was purified by CC (silica gel (28 g), hexane/AcOEt 9 :1): 0.24 g (90%) of 9. White solid. TLC (hexane/
AcOEt 4 :1): Rf 0.40. M.p. 95 – 968 (hexane/AcOEt/CH2Cl2 8 :1:1). IR (KBr): 3391, 1678, 1579, 1527,
1488, 1462, 1354, 1294, 1261, 1157, 1129, 1032, 749. 1H-NMR (300 MHz, CDCl3): 4.00 (s, MeO); 6.92 (br.
s, NH); 6.95 (td, J ¼ 7.8, 1.6, HꢀC(4’)); 7.23 (d, J ¼ 8.2, HꢀC(5)); 7.30 (td, J ¼ 7.8, 1.6, HꢀC(5’)); 7.37 (dd,
J ¼ 8.2, 1.6, HꢀC(6)); 7.42 (d, J ¼ 1.6, HꢀC(2)); 7.51( dd, J ¼ 7.8, 1.6, HꢀC(6’)); 7.62 (dd, J ¼ 7.8, 1.6,
HꢀC(3’)); 9.79 (s, CHO). 13C-NMR (75.4 MHz, CDCl3): 55.9 (MeO); 108.0 (C(2)); 111.1 (C(5)); 116.3
(C(2’)); 120.8 (C(6’)); 124.2 (C(4’)); 127.3 (C(6)); 128.1 (C(5’)); 128.7 (C(1)); 133.4 (C(3’)); 138.1 (C(1’));
138.7 (C(4)); 147.7 (C(3)); 190.3 (CHO). EI-MS (70 eV): 307 (10, Mþ (81Br)), 305 (10, Mþ (79Br)), 211
(100), 182 (10), 154 (6). HR-FAB-MS: 305.0051 (Mþ, C14H1279BrNO2þ ; calc. 305.0051).
Murrayanine (¼1-Methoxy-9H-carbazole-3-carboxaldehyde; 1). A mixture of 9 (0.07 g, 0.23 mmol),
[Pd(PPh3)4] (0.0053 g, 0.0046 mmol), Na2CO3 (0.048 g, 0.45 mmol), and LiCl (0.00978 g, 0.23 mmol), in
dry MeCN (1ml) was stirred and heated under reflux and N 2 for 48 h. The mixture was diluted with
MeCN (10 ml) and filtered, and the residue on the filter was washed with MeCN (10 ml). The solvent was
evaporated and the residue purified by CC (silica gel (10 g), hexane/AcOEt, 9 :1): 0.044 g (85%) of 1.
White solid. TLC (hexane/AcOEt 7:3): Rf 0.42. M.p. 167 – 1688 ([3a][7]: 167 – 1688; [2a]: 1688; [5a]:
1
166.58). IR (KBr): 3165, 1659, 1608, 1579, 1500, 1451, 1342, 1239, 1140, 846, 726. H-NMR (300 MHz,
CDCl3): 4.05 (s, MeO); 7.32 (ddd, J ¼ 7.8, 7.2, 1.6, HꢀC(6)); 7.45 (br. s, HꢀC(2)); 7.46 – 7.55 (m, HꢀC(7),
HꢀC(8)); 8.10 (br. d, J ¼ 7.8, HꢀC(5)); 8.18 (br. s, HꢀC(4)); 8.72 (br. s, NH); 10.04 (s, CHO). 13C-NMR
(75.4 MHz, CDCl3): 55.7 (MeO); 103.4 (C(2)); 111.5 (C(8)); 120.5 (C(4)); 120.6 (C(5), C(6)); 123.5
(C(4a) or C(4b)); 123.6 (C(4b) or C(4a)); 126.6 (C(7)); 130.0 (C(3)); 134.0 (C(9a)); 139.4 (C(8a)); 146.0
(C(1)); 192.0 (CHO). EI-MS (70 eV): 225 (3, Mþ), 210 (5), 182 (4), 154 (100), 139 (9), 128 (26), 127
(18), 73 (26).
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Received March 27, 2007