A tandem cross-coupling/SNAr approach to functionalized carbazoles

Article abstract of DOI:10.1021/ol702274y

(Chemical Equation Presented) A novel route to functionalized carbazoles utilizing a tandem Suzuki cross-coupling/S_NAr protocol is described. This process was found to be compatible with a variety of electron-withdrawing groups including aldehy

Full text of DOI:10.1021/ol702274y

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4893-4896
A Tandem Cross-Coupling/SNAr
Approach to Functionalized Carbazoles
David J. St. Jean, Jr.,* Steve F. Poon, and Jamie L. Schwarzbach
Department of Medicinal Chemistry, Amgen, Inc., One Amgen Center DriVe,
Thousand Oaks, California 91320-1799
daVid.st.jean@amgen.com
Received September 17, 2007
ABSTRACT
A novel route to functionalized carbazoles utilizing a tandem Suzuki cross-coupling/SNAr protocol is described. This process was found to be
compatible with a variety of electron-withdrawing groups including aldehydes, esters, and sulfones. Using this method, a concise total synthesis
(four steps, 50% overall yield) of the carbazole alkaloid glycosinine was achieved.
The carbazole ring system is present in a variety of naturally
occurring medicinally active substances.1 Both synthetic and
natural carbazole derivatives have been shown to exhibit a
broad range of biological activity including the inhibition
of CDK-52 and antimicrobial/anti-inflammatory activities.3,4
Carbazole-containing molecules have also been widely used
as organic materials.5 Due to these interesting properties, a
number of synthetic approaches to the carbazole framework
have been described.6 To the best of our knowledge, there
exists only a single report where both a carbon-nitrogen
and carbon-carbon bond of a functionalized carbazole were
constructed in a one-pot tandem process.6b Although this
protocol proceeded in modest to high yields, it required
prolonged heating at elevated temperatures (3 h at 160 °C)
and was sometimes complicated by the formation of isomeric
products.
Prompted by the diverse biological activities, we aimed
to identify a novel metal-catalyzed microwave-assisted
protocol that would allow for the rapid entry into the
carbazole scaffold. Herein, we present a high yielding, one-
pot synthesis of functionalized carbazoles utilizing a tandem
Suzuki cross-coupling/SNAr strategy (CC-SNAr).
Our proposed approach is shown in Scheme 1. Cross-
coupling of an aniline-derived boronic ester (1) with an
appropriately substituted dihalide (2) using microwave-
assisted palladium catalysis would provide diaryl intermedi-
(6) (a) Yamamoto, M.; Matsubara, S. Chem. Lett. 2007, 36, 172. (b)
Bedford, R. B.; Betham, M. J. Org. Chem. 2006, 71, 9403. (c) Liu, C.-Y.;
Knochel, P. Org. Lett. 2005, 7, 2543. (d) Smitrovich, J. H.; Davies, I. W.
Org. Lett. 2004, 6, 533. (e) Kno¨lker, H.-J.; Wolpert, M. Tetrahedron 2003,
59, 5317 and references cited therein. (f) Bringmann, G.; Tasler, S.; Endress,
H.; Peters, K.; Peters, E. M. Synthesis 1998, 10, 1501. (g) Kuwahara, A.;
Nakano, K.; Nozaki, K.; J. Org. Chem. 2005, 70, 413. (h) Gilchrist, T. L.
Heterocyclic Chemistry; Pitman Publishing Ltd.: London, 1985. (i) Sun-
dberg, R. J. Comp. Heterocycl. Chem. II 1996, 2, 119. (j) Moody, C. J.
Synlett 1994, 681. (k) Bergman, J.; Pelcman, B. Pure Appl. Chem. 1990,
62, 1967. (l) Soderberg, B. C. G. Curr. Org. Chem. 2000, 4, 727. (m) Lin,
G.; Zhang, A. Tetrahedron Lett. 1999, 40, 341. (n) Pedersen, J. M.; Bowman,
W. R.; Elsegood, M. R. J.; Fletcher, A. J.; Lovell, P. J. J. Org. Chem.
2005, 70, 10615. (o) Larock, R. C.; Berrios-Pena, N.; Narayanan, K. J.
Org. Chem. 1990, 55, 3447. (p) Rocca, P.; Marsais, F.; Godard, A.;
Queguiner, G. Tetrahedron 1993, 49, 49. (q) Tsang, W. C. P.; Zheng, N.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560.
(1) (a) Kno¨lker, H.-J.; Reddy, K. R. Chem. ReV. 2002, 102, 4303. (b)
Kno¨lker, H.-J. Top. Curr. Chem. 2005, 244, 115.
(2) Potterat, O.; Puder, C.; Bolek, W.; Wagner, K.; Ke, C.; Ye, Y.;
Gillardon, F. Pharmazie 2005, 60, 637.
(3) Roy, M. K.; Thalang, V. N.; Trakoontivakorn, G.; Nakahara, K. Br.
J. Pharmacol. 2005, 145, 145.
(4) Hsu, M.-J.; Chao, Y.; Chang, Y.-H.; Ho, F.-M.; Huang, L.-J.; Huang,
Y.-L.; Luh, T.-Y.; Chen, C.-P.; Lin, W.-W. Biochem. Pharmacol. 2005,
70, 102.
(5) (a) Zhang, Y.; Wada, T.; Sasabe, H. J. Mater. Chem. 1998, 8, 809.
(b) Grazulevicius, J. V.; Strohriegl, P.; Pielichowski, J.; Pielichowski, K.
Prog. Polym. Sci. 2003, 28, 1297. (c) Thomas, K. R. J.; Lin, J. T.; Tao,
Y.-T.; Ko, C.-W. J. Am. Chem. Soc. 2001, 123, 9404. (d) D´ıaz, J. L.;
Dobarro, A.; Villacampa, B.; Velasco, D. Chem. Mater. 2001, 13, 2528.
10.1021/ol702274y CCC: $37.00
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Published on Web 10/16/2007

the possibility of in situ cyclization. To this end, our first
attempt involved using Boc derivative 1b; however, only
biaryl derivative 6 was observed (entry 2). Acetylated
derivatives (1c and 1d) were also subjected to the cross-
coupling procedure (entries 3 and 4). As with the Boc
derivative, the major products were derived from cross-
coupling (6); however, significant amounts of cleavage
products were also seen (i.e., 7). Since the hydrolysis of the
electron-withdrawing group was observed under these condi-
tions, we hypothesized that a more stable group would allow
for productive in situ cyclization. Indeed, when the meth-
ylsulfonyl (Ms) derivative 1e (entry 5) was exposed to 5,
carbazole 8 was formed in quantitative conversion.
Scheme 1. Proposed One-Pot CC-SNAr Route to Carbazoles
The generality of this method appears to be rather broad,
tolerating a wide variety of electron-withdrawing groups
(Table 2, entries 1-9).9 It was found that para-toluenesulfo-
ate 3. Intramolecular SNAr cyclization of intermediate 3
would provide carbazole 4.
Table 2. Pd(PPh3)4-Catalyzed CC-SNAr Approach to
Carbazoles
Initially, our efforts focused on the reaction of unsubsti-
tuted boronic ester 1a (Table 1) with 3-bromo-4-fluoro-
Table 1. Optimization of the Tandem CC-SNAr Protocol
yielda
(%)
entry
9
R1
X
R2
R3
R4
1
2
3
4
5
6
7
8
9
9a Ms
9b Ts
9c Ms
9d Ms
9e Ms
9f Ms
9g Ms
9h Ms
9i Ms
F
F
F
F
F
F
F
F
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CO2Me
H
COMe
COMe
CO2Me
CONMe2
CHO
95
86
88
47b
87
(E)-CHdCH-CO2Me 78
CN
NO2
SO2Me
COMe
H
90
96
81
29c
83
0
10 9a Ms Cl
H
CO2Me
H
11 9j Ts
12 9k Ms
13 9l Ms
F
F
F
H
H
entry
R1
6a
7a
8a
H
0d
1
2
3
4
5
H
Boc
Acb
COCF3
Ms
100
100
70
60
0
0
0
30
40
0
0
0
0
0
100
a Isolated yield, reported as an average of two runs. b Required an
additional 15 min at 170 °C. c The intermediate biaryl chloride was isolated
in 56% yield. d The intermediate biaryl fluoride was isolated in 93% yield.
a Ratios determined by HPLC. b The corresponding boronic acid was
used.
nyl (Ts) derivative (1f) also cleanly delivered the desired
carbazole (entries 2 and 11). Subjecting 3-bromo-4-chloro-
acetophenone to boronic ester 1a resulted in only a 29%
isolated yield, although significant amounts of the intermedi-
ate diaryl chloride were also observed (entry 10). While this
tandem process proceeded smoothly with an electron-
withdrawing group ortho to the fluoride (entry 11), the
acetophenone (5) using a microwave-assisted cross-coupling
protocol (5 mol % of Pd(PPh3)4, 3 equiv of K2CO3, 4:1 DME/
water, 140 °C, 15 min).7 Unfortunately, only cross-coupled
material was observed (i.e., 6/7) (Table 1, entry 1).8 We
rationalized that modulating the pKa of the aniline by the
addition of an electron-withdrawing group would increase
(8) A variety of conditions were employed including elevated temper-
atures (up to 200 °C for 30 min) and stronger bases (such as NaOH).
(9) This process is also compatible with conventional heating. Carbazole
9a was formed in 99% yield when boronic ester 1a was exposed to 3-bromo-
4-fluoroacetophenone at 90 °C for 12 h.
(7) Using these conditions, 3-bromoacetophenone underwent cross-
coupling with boronic ester 1a in quantitative yield.
4894
Org. Lett., Vol. 9, No. 23, 2007

corresponding meta isomer failed under the standard condi-
tions (entry 12).
Substituted pyridines were also subjected to the CC-SNAr
coupling protocol (Table 3). While both the 2- and 4-fluoro-
compound could be accessed by removal of the sulfonamide
functionality. For example, exposing tosylated carbazole 9b
to Cs2CO3 in a mixture of THF and MeOH provided 9m in
91% yield (Scheme 3).11,12
Scheme 3. Formation of Carbazole 9m
Table 3. CC-SNAr-Mediated Formation of Pyridoindoles
yielda
entry
10
X
Y
Z
(%)
1
2
3
10a
10b
10c
N
C
C
C
N
C
C
C
N
97b
trace
90c
To demonstrate the utility of this method in natural product
synthesis, we developed a facile route to the carbazole
alkaloid glycosinine (13) (Scheme 4).13 Methylation and
a Isolated yield, reported as an average of two runs. b The corresponding
bromofluoride was used. c The HCl salt of the iodofluoride and 4.0 equiv
of K2CO3 were used.
Scheme 4. Total Synthesis of Glycosinine
pyridine derivatives delivered the carbazoles in high yield
(Table 3, entries 1 and 3), the 3-fluoro isomer produced only
trace amounts (entry 2). These results, combined with data in
Table 2, demonstrate the need for an electron-withdrawing
group at either the ortho or para position relative to the
fluorine.
To further expand the potential utility of this method, the
coupling of fluorinated boronic esters with bromo anilines
(11 and 12) was investigated (Scheme 2). Unfortunately,
Scheme 2. Pd(OAc)2/SPhos-Catalyzed CC-SNAr Approach to
Carbazoles
bromination of 4-fluoro-2-hydroxybenzaldehyde delivered
14. Boronic ester 1f cleanly reacted with 14 using the general
Pd(PPh3)4 catalyzed CC-SNAr coupling protocol to deliver
the tosylated carbazole in near quantitative yield. Depro-
tection using Cs2CO3 produced glycosinine (13) (four
steps, 50% overall yield). This synthesis compares favorably to
the previously reported route (six steps, 19% overall yield).14
To the best of our knowledge, this process constitutes a
novel approach to the synthesis of functionalized carbazoles.
Given the high yield, short reaction times, operational
simplicity, and functional group compatibility, this protocol
will provide convenient access to a variety of carbazole-
containing molecules. Furthermore, using this method an
efficient total synthesis of the carbazole alkaloid glycosinine
was achieved.
exposure to the general CC-SNAr conditions failed to
produce synthetically useful quantities of the desired carba-
zole (presumably due to the electron poor nature of the
boronic ester). After exploring a variety of conditions, the
combination of 2 mol % of Pd(OAc)2 and 4 mol % of
2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos)
proved to be optimal.10 This catalytic system, in combination
with K2CO3 (3 equiv) and a toluene/water solvent mixture,
delivered carbazole 9a in 83% yield after only 15 min of
microwave irradiation.
(11) Bajwa, J. S.; Chen, G.-P.; Prasad, K.; Repie`, O.; Blacklock, T. J.
Tetrahedron Lett. 2006, 47, 6425.
(12) The methylsulfonyl group of 9a can also be removed, although it
required more forcing conditions (KOH, MeOH, 70 °C, 12 h).
(13) Lange, G. L.; Ruangrungsi, N.; Ariyaprayoon, J.; Lange, G. L.;
Organ, M. G. J. Nat. Prod. 1990, 53, 946.
(14) Kno¨lker, H.-J.; Go¨smann, H.; Hofmann, C. Synlett 1996, 8,
737.
Although the aniline boronic ester 1a (Table 1, entry 1)
failed to undergo the desired CC-SNAr coupling, the same
(10) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, 127, 4685.
Org. Lett., Vol. 9, No. 23, 2007
4895

Acknowledgment. J.L.S. gratefully acknowledges Am-
gen, Inc. for a summer internship.
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and NMR spectra
OL702274Y
4896
Org. Lett., Vol. 9, No. 23, 2007