Transition metal complexes in organic synthesis, part 74: Total synthesis of the marine alkaloid 6-chlorohyellazole

Article abstract of DOI:10.1055/s-2004-835646

A considerably improved iron-mediated synthesis leads to the marine carbazole alkaloid hyellazole on large scale in eight steps and 63% overall yield from 2,6-dimethoxytoluene. The first conversion of hyellazole into 6-chlorohyellazole has been achieved a

Full text of DOI:10.1055/s-2004-835646

LETTER
2705
Transition Metal Complexes in Organic Synthesis, Part 74:1 Total Synthesis
of the Marine Alkaloid 6-Chlorohyellazole
Total
S
ynthesis of
a
the Marine
n
A
lkaloid 6-C
s
hlorohye
-
llazole Joachim Knölker,* Wolfgang Fröhner, Renate Heinrich
Institut für Organische Chemie, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany
Fax +49(351)46337030; E-mail: hans-joachim.knoelker@chemie.tu-dresden.de
Received 15 September 2004
OCH3
CH3
Abstract: A considerably improved iron-mediated synthesis leads
to the marine carbazole alkaloid hyellazole on large scale in eight
steps and 63% overall yield from 2,6-dimethoxytoluene. The first
conversion of hyellazole into 6-chlorohyellazole has been achieved
along with remarkably regiospecific halogenation reactions.
+
(OC)3Fe
2
1
+
H2N
BF4
C6H5
3
4
Key words: alkaloids, cross-coupling, cyclizations, halogenation,
iron
Scheme 1 Retrosynthetic analysis of 6-chlorohyellazole (2)
and the first transformation of hyellazole (1) into 6-chlo-
rohyellazole (2). In the course of our investigations, we
found remarkably regiospecific halogenation reactions of
hyellazole (1).
The majority of the currently known naturally occurring
carbazoles has been isolated from terrestrial plants.1–6
Hyellazole (1) and 6-chlorohyellazole (2) were the first
carbazole alkaloids obtained from marine sources
(Figure 1). They were isolated in 1979 by Moore from the
blue-green alga Hyella caespitosa.7 In addition to their
different origin these two alkaloids are also structurally
unique having a phenyl group at the 1-position.
The iron complex salt 3 was prepared almost quantitative-
ly by azadiene-catalyzed complexation of cyclohexa-1,3-
diene with pentacarbonyliron followed by hydride ab-
straction with trityl tetrafluoroborate.18,19
OCH3
CH3
Cl
OCH3
CH3
OCH3
CH3
OCH3
CH3
Claycop, Et2O
10 equiv Ac2O, r.t., 1 h
94%
O2N
N
H
N
H
OCH3
OCH3
C6H5
C6H5
5
6
Hyellazole (1)
6-Chlorohyellazole (2)
OCH3
1.3 equiv AlCl3
Tf2O, Et3N
Figure 1 Carbazoles from the blue-green alga Hyella caespitosa
CH2Cl2, –20 °C
97%
CH2Cl2, r.t., 21 h
96%
O2N
CH3
OH
The interesting structures of the carbazole alkaloids 1 and
2 prompted several research groups to develop strategies
for their total synthesis. Thus, since the isolation in 1979
ten different total syntheses have been achieved for
hyellazole (1).8–17 However, only three total syntheses of
6-chlorohyellazole (2) were reported.8b,13,17 Surprisingly,
attempts to convert hyellazole (1) into 6-chlorohyellazole
(2) have not been described. Starting from the iron com-
plex salt 3 and the arylamine 4, we developed two routes
to hyellazole using either the iron-mediated quinone
imine or the iron-mediated arylamine cyclization as key
step (Scheme 1).14
7
OCH3
C6H5B(OH)2, 0.05 equiv Pd(PPh3)4
dioxane, K3PO4, 80 °C
87%
O2N
CH3
OTf
8
OCH3
CH3
OCH3
H2, Pd/C
MeOH, r.t.
100%
O2N
H2N
CH3
C6H5
C6H5
Herein, we describe a considerably improved route to the
arylamine 4, the key precursor to hyellazole (1), a novel
procedure for the iron-mediated arylamine cyclization,
9
4
Scheme 2 Five-step synthesis of the arylamine 4
Nitration of 2,6-dimethoxytoluene (5) using claycop20
afforded selectively 2,6-dimethoxy-3-nitrotoluene (6)
(Scheme 2). Regioselective cleavage of the methyl ether
SYNLETT 2004, No. 15, pp 2705–2708
Advanced online publication: 08.11.2004
DOI: 10.1055/s-2004-835646; Art ID: G36104ST
© Georg Thieme Verlag Stuttgart · New York
0
7
.1
2
.2
0
0
4

2706
H.-J. Knölker et al.
LETTER
ortho to the nitro group provided 3-methoxy-2-methyl-6- substitutions of carbazoles generally occur in the 3-posi-
nitrophenol (7). Transformation to the triflate 8 and tion and for a 3-substituted carbazole in the 6-position.
subsequent Suzuki–Miyaura cross-coupling reaction21 We have exploited this regioselectivity for our total syn-
with phenylboronic acid afforded the biaryl derivative 9. theses of carquinostatin A, lavanduquinocin, and ( )-neo-
Catalytic hydrogenation of 9 led to the arylamine 4. This carazostatin B.4,6 An attempt to convert hyellazole (1) to
improved route affords the arylamine 4 in five steps and 6-chlorohyellazole (2) by reaction with N-chlorosuccin-
76% overall yield (previous route: six steps, 18%).14,22
imide in the presence of a catalytic amount of hydrochlo-
ric acid led exclusively to 4-chlorohyellazole (11). On the
other hand, bromination of 1 using N-bromosuccinimide
and a catalytic amount of hydrobromic acid gave only the
expected 6-bromohyellazole (12). Both, bromination of
the former and chlorination of the latter product afforded
6-bromo-4-chlorohyellazole (13) and thus demonstrate
that the regioselectivities are complementary. The smooth
bromination of 6-bromohyellazole (12) to 4,6-dibromo-
hyellazole (14) shows that the observed regiospecificity
of the first halogenation of 1 can be explained by steric
effects. The transformation of the iron complex 10 into 6-
bromohyellazole (12) has also been achieved in a one-pot
process by reaction with an excess of N-bromosuccinim-
ide and switching from oxidative cyclization conditions
(basic reaction medium) to electrophilic substitution
conditions (acidic reaction medium).24 This procedure
provides a direct access to 6-bromocarbazoles, which
represent important precursors for the total synthesis of
further carbazole alkaloids.4,6
Electrophilic substitution of the arylamine 4 with the com-
plex salt 3 gave the iron complex 10 in 98% yield
(Scheme 3). The iron-mediated arylamine cyclization, by
oxidation with ferricenium hexafluorophosphate in the
presence of sodium carbonate, converts complex 10 into
hyellazole (1) in two steps and 84% yield.14 Taking the
improved synthesis of the arylamine 4 into account,
hyellazole (1) is obtained in eight steps and 63% overall
yield based on commercially available 2,6-dimethoxy-
toluene (5). The superiority of our iron-mediated ap-
proach is emphasized by comparison with the alternative
syntheses reported for hyellazole (1).8–13,15–17
The iron-mediated arylamine cyclization with concomi-
tant aromatization to the 9H-carbazole derivative is usual-
ly achieved with very active manganese dioxide, iodine in
pyridine or ferricenium hexafluorophosphate in the pres-
ence of sodium carbonate as oxidizing agents.23 Herein,
we describe a novel procedure for this transformation.
Treatment of the iron complex 10 with 3 equivalents of N-
bromosuccinimide in the presence of an excess of sodium
carbonate led to hyellazole (1) in 69% yield. Electrophilic
Finally, we could exploit the high regioselectivity ob-
tained in the bromination of 1 for a conversion of hyell-
azole (1) to 6-chlorohyellazole (2) by a halogen exchange
(OC)3Fe
OCH3
CH3
OCH3
+ 3, MeCN
1. Cp2FePF6, Na2CO3, 2. a) Me3NO, b) MeI, 84%
82 °C, 2.5 h
98%
or: 3 equiv NBS, MeCN, 10 equiv Na2CO3, r.t., 69%
CH3
H2N
H2N
C6H5
C6H5
4
10
1. 3 equiv NBS, 1 equiv Na2CO3, MeCN, r.t.
2. 1.2 equiv NBS, 0.45 equiv HBr, MeCN
69%
OCH3
OCH3
CH3
OCH3
CH3
Br
Cl
1.05 equiv NBS, cat. HBr
4 equiv CuCl, DMF
CH3
MeCN, r.t.
92%
153 °C, 6 h
96%
N
H
N
H
N
H
C6H5
C6H5
C6H5
Hyellazole (1)
6-Chlorohyellazole (2)
12
1.05 equiv NCS
90% cat. HCl
1.05 equiv NCS
1.05 equiv NBS, cat. HBr
MeCN, r.t.
96% cat. HCl
MeCN, r.t.
93%
MeCN, r.t.
Cl
Cl
Br
OCH3
CH3
OCH3
OCH3
CH3
Br
Br
1.05 equiv NBS, cat. HBr
CH3
MeCN, r.t.
98%
N
H
N
H
N
H
C6H5
C6H5
C6H5
11
13
14
Scheme 3 Iron-mediated synthesis of hyellazole (1), regiospecific halogenation reactions, and transformation into 6-chlorohyellazole (2)
Synlett 2004, No. 15, 2705–2708 © Thieme Stuttgart · New York

LETTER
Total Synthesis of the Marine Alkaloid 6-Chlorohyellazole
2707
reaction.25 Treatment of 6-bromohyellazole (12) with 4
equivalents of cuprous chloride in N,N-dimethylform-
amide (DMF) at reflux afforded almost quantitatively 6-
chlorohyellazole (2).26 The spectral data of our syn-
thetic 6-chlorohyellazole (mp 162–163 °C)26 are in full
agreement with those reported for the natural product
(mp 163–164 °C).7 Considering our excellent access to
hyellazole (1) described above, 6-chlorohyellazole (2) is
now available in only ten steps and 55% overall yield
based on commercial 2,6-dimethoxytoluene (5).
(19) (a) Fischer, E. O.; Fischer, R. D. Angew. Chem. 1960, 72,
919. (b) Knölker, H.-J.; Baum, G.; Foitzik, N.; Goesmann,
H.; Gonser, P.; Jones, P. G.; Röttele, H. Eur. J. Inorg. Chem.
1998, 993.
(20) (a) Cornélis, A.; Laszlo, P. Synthesis 1985, 909. (b) Laszlo,
P.; Pennetreau, P. J. Org. Chem. 1987, 52, 2407.
(c) Gigante, B.; Prazeres, A. O.; Marcelo-Curto, M. J.;
Cornélis, A.; Laszlo, P. J. Org. Chem. 1995, 60, 3445.
(21) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Miyaura, N. In Topics in Current Chemistry, Vol. 219;
Miyaura, N., Ed.; Springer: Berlin, 2002, 11.
(22) Azzena, U.; Melloni, G.; Pisano, L. Tetrahedron Lett. 1993,
34, 5635.
(23) For an overview on the different methods for iron-mediated
oxidative cyclizations to carbazoles, see: (a) Knölker, H.-J.
In Transition Metals for Organic Synthesis, Vol. 1; Beller,
M.; Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998, 534.
(b) Knölker, H.-J. Chem. Soc. Rev. 1999, 28, 151.
(24) Synthesis of 6-Bromohyellazole (12) by Oxidative
Cyclization of the Iron Complex 10 with Concomitant
Bromination Using NBS:
Acknowledgment
This work was supported by the Fonds der Chemischen Industrie.
We thank the BASF AG, Ludwigshafen, for a supply of penta-
carbonyliron.
References
Na2CO3 (27 mg, 255 mmol) was added to a solution of the
iron complex 10 (109 mg, 253 mmol) in MeCN (5 mL).
Subsequently, a solution of NBS (135 mg, 758 mmol) in
MeCN (2 mL) was added dropwise at r.t. to the intensely
stirred light yellow suspension. The resulting dark brown
mixture was stirred at r.t. for 1 h. After that period, conc.
HBr (48%, 12.8 ml, 19 mg, 113 mmol) and a solution of NBS
(54 mg, 303 mmol) in MeCN (4 mL) were added, and the
reaction mixture was stirred for additional 2.5 h. To this
mixture Na2CO3 (27 mg, 255 mmol) and silica gel (3 g) were
added. Removal of the solvent in vacuum and purification of
the residue by flash chromatography (hexane–EtOAc, 7:1)
on silica gel afforded 6-bromohyellazole (12) as colorless
crystals; yield: 64 mg (69%); mp 168–169 °C (cyclohexane).
UV (MeOH): l = 218, 242, 270 (sh), 310, 347, 360 nm. IR
(DRIFT): n = 3356 (br), 1585, 1503, 1485, 1457, 1414,
1286, 1204, 1145, 1126, 1023, 841, 801, 703 cm–1. 1H NMR
(500 MHz, CDCl3): d = 2.21 (s, 3 H), 3.99 (s, 3 H), 7.16 (d,
J = 8.6 Hz, 1 H), 7.39–7.42 (m, 3 H), 7.44–7.47 (m, 2 H),
(1) Part 73: Fröhner, W.; Krahl, M. P.; Reddy, K. R.; Knölker,
H.-J. Heterocycles 2004, 63, 2393.
(2) Chakraborty, D. P.; Roy, S. In Progress in the Chemistry of
Organic Natural Products, Vol. 57; Herz, W.; Grisebach,
H.; Kirby, G. W.; Steglich, W.; Tamm, C., Eds.; Springer:
Wien, 1991, 71.
(3) Chakraborty, D. P. In The Alkaloids, Vol. 44; Cordell, G. A.,
Ed.; Academic Press: New York, 1993, 257.
(4) Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
(5) Chakraborty, D. P.; Roy, S. In Progress in the Chemistry of
Organic Natural Products, Vol. 85; Herz, W.; Grisebach,
H.; Kirby, G. W.; Steglich, W.; Tamm, C., Eds.; Springer:
Wien, 2003, 125.
(6) Knölker, H.-J. Curr. Org. Synth. 2004, 1, 309.
(7) Cardellina, J. H.; Kirkup, M. P.; Moore, R. E.; Mynderse, J.
S.; Seff, K.; Simmons, C. J. Tetrahedron Lett. 1979, 4915.
(8) (a) Kano, S.; Sugino, E.; Hibino, S. J. Chem. Soc., Chem.
Commun. 1980, 1241. (b) Kano, S.; Sugino, E.; Shibuya, S.;
Hibino, S. J. Org. Chem. 1981, 46, 3856.
(9) Takano, S.; Suzuki, Y.; Ogasawara, K. Heterocycles 1981,
16, 1479.
(10) (a) Kawasaki, T.; Nonaka, Y.; Sakamoto, M. J. Chem. Soc.,
Chem. Commun. 1989, 43. (b) Kawasaki, T.; Nonaka, Y.;
Akahane, M.; Maeda, N.; Sakamoto, M. J. Chem. Soc.,
Perkin Trans. 1 1993, 1777.
7.54 (m, 2 H), 7.62 (br s, 1 H), 8.15 (d, J = 1.7 Hz, 1 H). 13
C
NMR and DEPT (125 MHz, CDCl3): d = 13.78 (CH3), 56.14
(CH3), 100.07 (CH), 111.62 (C), 112.06 (CH), 119.39 (C),
122.69 (CH), 124.89 (C), 125.52 (C), 125.78 (C), 127.71
(CH), 127.77 (CH), 129.06 (2 CH), 129.82 (2 CH), 133.72
(C), 137.23 (C), 138.04 (C), 153.00 (C). MS (110 °C): m/z
(%) = 365 (100) [M+], 350 (13), 286 (4), 271 (51), 270 (27),
242 (12), 241 (19). Anal. Calcd for C20H16BrNO: C, 65.59;
H, 4.40; N, 3.82. Found: C, 65.57; H, 4.46; N, 3.75.
(25) Gilbert, E. J.; Van Vranken, D. L. J. Am. Chem. Soc. 1996,
118, 5500.
(11) (a) Moody, C. J.; Shah, P. J. Chem. Soc., Perkin Trans. 1
1989, 376. (b) Moody, C. J.; Shah, P. J. Chem. Soc., Perkin
Trans. 1 1989, 2463.
(12) Danheiser, R. L.; Brisbois, R. G.; Kowalczyk, J. J.; Miller,
R. F. J. Am. Chem. Soc. 1990, 112, 3093.
(26) Transformation of 6-Bromohyellazole (12) into 6-
Chlorohyellazole (2):
(13) Beccalli, E. M.; Marchesini, A.; Pilati, T. J. Chem. Soc.,
Perkin Trans. 1 1994, 579.
DMF (25 mL) was added to a mixture of 6-bromohyellazole
(12) (505 mg, 1.38 mmol) and cuprous chloride (546 mg,
5.52 mmol). The resulting suspension was heated under
reflux for 6 h. The reaction mixture was cooled to r.t., H2O
(50 mL) and conc. HCl (25 mL) were added, and the aqueous
layer was extracted with Et2O (2 × 50 mL). The combined
organic layers were washed with H2O (2 × 50 mL) and dried
over Na2SO4. Evaporation of the solvent in vacuum and
purification of the residue by flash chromatography
(hexane–EtOAc, 4:1) on silica gel provided 6-chloro-
hyellazole (2) as colorless crystals, which were subsequently
recrystallized from MeOH at –30 °C; yield: 425 mg (96%);
mp 162–163 °C. UV (EtOH): l = 211 (sh), 221, 242, 265
(sh), 302 (sh), 310, 347, 361 nm. IR (DRIFT): n = 3358 (br),
(14) (a) Knölker, H.-J.; Baum, E.; Hopfmann, T. Tetrahedron
Lett. 1995, 36, 5339. (b) Knölker, H.-J.; Baum, E.;
Hopfmann, T. Tetrahedron 1999, 55, 10391.
(15) (a) Choshi, T.; Sada, T.; Fujimoto, H.; Nagayama, C.;
Sugino, E.; Hibino, S. Tetrahedron Lett. 1996, 37, 2953.
(b) Choshi, T.; Sada, T.; Fujimoto, H.; Nagayama, C.;
Sugino, E.; Hibino, S. J. Org. Chem. 1997, 62, 2535.
(16) Witulski, B.; Alayrac, C. Angew. Chem. Int. Ed. 2002, 41,
3281; Angew. Chem. 2002, 114, 3415.
(17) Duval, E.; Cuny, G. D. Tetrahedron Lett. 2004, 45, 5411.
(18) (a) Knölker, H.-J.; Baum, E.; Gonser, P.; Rohde, G.; Röttele,
H. Organometallics 1998, 17, 3916. (b) Knölker, H.-J.
Chem. Rev. 2000, 100, 2941.
Synlett 2004, No. 15, 2705–2708 © Thieme Stuttgart · New York

2708
H.-J. Knölker et al.
LETTER
124.12 (C), 124.97 (C), 125.44 (CH), 125.64 (C), 126.87
(C), 128.39 (CH), 129.70 (2 CH), 130.77 (2 CH), 135.16 (C),
138.41 (C), 139.63 (C), 153.62 (C). MS (105 °C):
m/z (%) = 321 (100) [M+], 306 (16), 271 (37), 270 (14), 242
(6), 241 (11). Anal. Calcd for C20H16ClNO: C, 74.65; H,
5.01; N, 4.35. Found: C, 74.71; H, 5.17; N, 4.32.
1586, 1503, 1486, 1452, 1416, 1286, 1205, 1145, 1064,
1023, 842, 803, 705 cm–1. 1H NMR (500 MHz, acetone-d6):
d = 2.14 (s, 3 H), 3.99 (s, 3 H), 7.27 (dd, J = 8.7, 2.1 Hz, 1
H), 7.40 (m, 3 H), 7.45 (m, 1 H), 7.53 (m, 2 H), 7.75 (s, 1 H),
8.13 (d, J = 2.1 Hz, 1 H), 9.66 (br s, 1 H). 13C NMR and
DEPT (125 MHz, acetone-d6): d = 14.06 (CH3), 56.31
(CH3), 101.13 (CH), 113.28 (CH), 120.21 (CH), 120.55 (C),
Synlett 2004, No. 15, 2705–2708 © Thieme Stuttgart · New York