Formal synthesis of nitidine and NK109 via palladium-catalyzed domino direct arylation/N-arylation of aryl triflates

Article abstract of DOI:10.1021/ol200174g

The use of aryl triflates as reaction partners in a palladium-catalyzed domino direct arylation/N-arylation provides a great advantage due to the availability of starting materials. Furthermore, it allows expedient access to biologically interesting benzo

Full text of DOI:10.1021/ol200174g

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1486–1489
Formal Synthesis of Nitidine and NK109
via Palladium-Catalyzed Domino Direct
Arylation/N-Arylation of Aryl Triflates
Mathieu Blanchot, David A. Candito, Florent Larnaud, and Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto,
Toronto, Ontario, Canada, M5S 3H6
mlautens@chem.utoronto.ca
Received January 19, 2011
ABSTRACT
The use of aryl triflates as reaction partners in a palladium-catalyzed domino direct arylation/N-arylation provides a great advantage due to the
availability of starting materials. Furthermore, it allows expedient access to biologically interesting benzo[c]phenanthridine alkaloids.
The phenanthridine core is an important substructure
that is often found in natural products, particularly, the
benzo[c]phenanthridine alkaloids. Members of this family
have demonstrated antitumor, antimicrobial, and antiviral
properties (Figure 1).1
The synthesis of these compounds is not trivial, and
many studies have been directed toward their preparation
and the synthesis of derivatives. Traditional syntheses
often suffer from long synthetic pathways or are limited
because of their lack of generality and functional group
tolerance.2 Other alternatives using palladium-catalyzed
approaches have shown increasing popularity in recent
(1) (a) Makhey, D.; Gatto, B.; Yu, C.; Liu, L.; Liu, F.; LaVoie, E. J.
Bioorg. Med. Chem. 1996, 4, 781. (b) Lynch, M. A.; Duval, O.;
Sukhanova, A.; Devy, J.; MacKay, S. P.; Waigh, R. D.; Nabiev, I.
Figure 1. Biologically relevant benzo[c]phenanthridinium
Bioorg. Med. Chem. Lett. 2001, 11, 2643. (c) Fang, S. D.; Wang, L. K.;
alkaloids.
Hecht, S. M. J. Org. Chem. 1993, 58, 5025. (d) Janin, Y. L.; Croisy, A.;
Riou, J. F.; Bisagni, E. J. Med. Chem. 1993, 36, 3686.
r
10.1021/ol200174g
Published on Web 02/24/2011
2011 American Chemical Society

years since they offer the advantages of relatively mild
reaction conditions and high functional group tolerance.3
Methods employing direct arylation allow the use of
simplified starting materials and offer a more atom eco-
nomical approach relative to traditional metal-catalyzed
cross-coupling reactions.4
Our group and that of Catellani have been engaged in
studying a reaction manifold involving a sequence of
domino ortho-functionalization followed by terminal
cross-coupling processes for the synthesis of diversely
substituted aromatic compounds.5 Recently, we disclosed
the first example of palladium-catalyzed synthesis of phe-
nanthridine derivatives employing N-unsubstituted or
N-silylimines and aryl iodides as coupling partners. Using
this method, a number of diversely substituted phenan-
thridine derivatives were synthesized in good to excellent
yields.6
We sought to validate the utility of our method by
applying it to the synthesis of members of the benzo-
[c]phenanthridine alkaloid family of natural products.
However, the synthesis of the requisite aryl iodide reaction
partners proved to be inefficient. We recognized that the
use of readily available aryl triflates could provide a
potential solution to this problem. Significantly, aryl tri-
flates were found to be unsuitable reaction partners in
previous studies involving norbornene mediated C-H
functionalization. Herein we report that aryl triflates can
be utilized instead of aryl halides for the rapid construction
of diversely substituted phenanthridines and outline the
formal synthesis of the natural product Nitidine and
NK109.
As a starting point we chose to study the reaction shown
in Table 1. Combinations of several palladium precursors
with phosphine ligands in acetonitrile at 90 °C gave low
conversion (entries 1-4). Cleavage of the triflate to the
phenol competed with the main reaction; organic bases
such as DABCO or DMAP were found to eliminate this
side reaction, but conversions were low (entries 5 and 6).
Reducing the amount of cesium carbonate and increasing
the amount of the imine employed proved to be effective at
increasing the yield (entry 7). With these conditions pro-
duct 3a could be obtained in 85% yield.
Wenexttestedthegeneralityof thisprotocol byapplying
it to the synthesis of diversely substituted phenanthridines
and benzo[c]phenanthridines. A wide range of aryl tri-
flates, easily generated from the corresponding commer-
cially available phenols, could be successfully employed
(Table 2).
Aryl triflates bearing chloro, methoxy, and alkyl sub-
stituents reacted smoothly with the N-silylaldimine 2a
(entries 1-4) to form the corresponding phenanthridine.
The only apparent requirement is that aryl triflate must be
ortho-substituted. On the other hand, a range of imines,
including N-silylaldimines, and unsubstituted ketimines
reacted in good to moderate yields (entries 5-13).
Finally, based on the promising results of this investiga-
tion, we decided to test its applicability to the synthesis of
more complicated structures (Scheme 1). Triflate 1a was
easily prepared in three steps from commercially available
dibromide 4. Slow addition of n-BuLi to dibromide 4 at
-78 °C generated an aryne intermediate, which underwent
(2) Recent synthetic studies aimed at benzo[c]phenanthridines, see:
(a) Korivi, R. P.; Cheng, C.-H. Chem.;Eur. J. 2010, 16, 282. (b) Abe,
H.; Kobayashi, N.; Takeuchi, Y.; Harayama, T. Heterocycles 2010, 80,
873. (c) Kohno, K.; Azuma, S.; Choshi, T.; Nobuhiro, J.; Hibino, S.
Tetrahedron Lett. 2009, 50, 590. (d) Ramani, P.; Fontana, G. Tetrahe-
dron Lett. 2008, 49, 5262. (e) Sanz, R.; Fernandez, Y.; Castroviejo, M. P.;
Perez, A.; Fananas, F. J. Eur. J. Org. Chem. 2007, 62. (f) Luo, Y.; Mei,
Y.; Zhang, J.; Lu, W.; Tang, J. Tetrahedron 2006, 62, 9131. (g) Le, T. N.;
Gang, S. G.; Cho, W.-J. J. Org. Chem. 2004, 69, 2768. (h) Harayama, T.;
Sato, T.; Nakano, Y.; Abe, H.; Takeuchi, Y. Heterocycles 2003, 59, 293.
(i) Watanabe, T.; Ohashi, Y.; Yoshino, R.; Komano, N.; Eguchi, M.;
Sakiko, M.; Ishikawa, T. Org. Biomol. Chem. 2003, 1, 3024. (j)
Harayama, T.; Akiyama, T.; Akamatsu, H.; Kawano, K.; Abe, H.;
Takeuchi, Y. Synthesis 2001, 444. (k) Nakanishi, T.; Suzuki, M. Org.
Lett. 1999, 1, 985. (l) Geen, G. R.; Mann, I. S.; Mullane, M. V.;
McKillop, A. Tetrahedron 1998, 54, 9875. (m) Sotomayor, N.;
Dominguez, E.; Lete, E. J. Org. Chem. 1996, 61, 4062. (n) Seraphin,
D.; Lynch, M. A.; Duval, O. Tetrahedron Lett. 1995, 36, 5731. (o)
Maestri, G.; Larraufie, M.-H.; Derat, E.; Ollivier, Fensterbank, L.;
Table 1. Optimizationa
^
Lacote, E.; Malacria, M. Org. Lett. 2010, 12, 5692.
(3) Palladium-catalyzed approaches for the synthesis of phenanthri-
dines: (a) Catellani, M.; Motti, E.; Della Ca’, N. Top. Catal. 2010, 53,
991. (b) Gerfaud, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2009,
48, 572. (c) Bowman, W. R.; Lyon, J. E.; Pritchard, G. J. Synlett 2008,
2169. (d) Sripada, L.; Teske, J. A.; Deiters, A. Org. Biomol. Chem. 2008,
6, 263. (e) Della Ca’, N.; Motti, E.; Catellani, M. Adv. Synth. Catal. 2008,
350, 2513.
yield
(%)b
Pd source
ligand
base
(4) Reviews: (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev.
2007, 107, 174. (b) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006,
1253. (c) Miura, M.; Satoh, T. Top. Organomet. Chem. 2005, 14, 55.
(d) Wolfe, J. P.; Thomas, J. S. Curr. Org. Chem. 2005, 9, 625. (e) Ritleng,
V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731. (f) Modern
Arylation Methods; Ackermann, L.; Wiley-VCH: Weinheim, 2009. (g)
Handbook of C-H Transformations; Dyker, G., Ed.; Wiley-VCH: Wein-
heim, 2005.
(5) Reviews: (a) Tietze, L. F.; Brasche, G. ; Gericke, K. M. Domino
Reaction in Organic Synthesis; Wiley-VCH: Weinheim, 2006. (b) Chiusoli,
G. P.; Catellani, M.; Costa, M.; Motti, E.; Della Ca', N.; Maestri, G. Coord.
Chem. Rev. 2010, 254, 456. (c) Lautens, M.; Alberico, D.; Bressy, C.;
Fang, Y.-Q.; Mariampillai, B.; Wilhelm, T. Pure Appl. Chem. 2006, 78,
351.
1
2
3
4
5
6
7
Pd(OAc)2
PdCl2
PPh3
PPh3
TFP
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMAP
48
14
e5
0
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
P(t-Bu)3
PPh3
PPh3
PPh3
0
DABCO
Cs2CO3
11
85c
a Reaction conditions: aryl triflate (0.2 mmol, 1.0 equiv), imine (1.1
equiv), Pd source (10 mol %), Ligand (25 mol %), Base (3 equiv), and
norbornene (8.0 equiv) in MeCN (0.05 M) were heated in a sealed tube at
90 °C for 16 h. b NMR yield using mesitylene as an internal standard.
c Imine (2.0 equiv), Cs2CO3 (1.5 equiv).
(6) Candito, D. A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48,
6713.
Org. Lett., Vol. 13, No. 6, 2011
1487

Table 2. Substrate Scope of the Palladium-Catalyzed Domino
Direct Arylation/N-Arylationa
Scheme 1. Formal Synthesis Nitidine and NK109
a Pd(OAc)2 (20 mol %), PPh3 (50 mol %), and Cs2CO3 (3 equiv) were
used. bAryl triflate (5.3 mmol, 1.0 equiv).
a Diels-Alder reaction with furan to furnish the oxabi-
cycle 5 in 95% yield. Treatment of 5 with catalytic PTSA
(4-methylbenzenesulfonicacid) led tothe naphthol6which
could be readily converted to triflate 1a using triflic
anhydride and pyridine. The imines were easily prepared
by treatment of the corresponding aldehydes with
LiHMDS. Aldehyde 8 is commercially available, and
aldehyde 9 and 10 can be prepared in four straightforward
steps from o-vanillin. Purification of the imines proved to
bedifficult, and thus the crude imineswereused directly for
the reaction. 1a could be reacted with imines 2j-l under
our developed conditions to afford products 3n-p in 40%,
66%, and 88% yield, respectively. Significantly, the synthe-
sis of 3p was performedon a gram scale. The outlined route
constitutes a formal syntheses of Nitidine7 and NK109,8
respectively.
It is anticipated that this process follows a similar
catalytic cycle to that of other norbornene mediated
C-H functionalizations (Scheme 2).9 Oxidative addition
of the aryl triflate, carbopalladation of norbornene, and
electrophilic metalation followed by deprotonation can
yield palladacyclic intermediate I. Then the palladacycle
(7) Zee-Cheng, K. Y.; Cheng, C. C. J. Heterocycl. Chem. 1973, 10, 85.
(8) Nakanishi, T.; Suzuki, M.; Mashiba, A.; Ishikawa, K.;
Yokotsuka, T. J. Org. Chem. 1998, 63, 4235.
(9) (a) Faccini, F.; Motti, E.; Catellani, M. J. Am. Chem. Soc. 2004,
ꢀ
126, 78. (b) Barluenga, J.; Aznar, F.; Valdes, C. Angew. Chem., Int. Ed.
2004, 43, 343. (c) Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.;
Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6367. (d) Mann, G.;
Hartwig, J. F.; Driver, M. S.; Fernandez-Rivas, C. J. Am. Chem. Soc.
1998, 120, 827. (e) Bolm, C.; Hildebrand, J. P. J. Org. Chem. 2000, 65,
169. (f) Roesch, K. R.; Larock, R. C. J. Org. Chem. 1998, 63, 5306.
(g) Cardenas, K. R. D. J.; Martin-Matute, B.; Echavarren, A. M. J. Am.
a Reaction conditions: Aryl triflate (0.2 mmol, 1.0 equiv), imine (2
equiv), Pd(OAc)2 (10 mol %), PPh3 (25 mol %), Cs2CO3 (1.5 equiv), and
norbornene (8.0 equiv) in MeCN (0.05 M) were heated in a sealed tube at
90 °C for 16 h. b Isolated.
ꢀ
Chem. Soc. 2006, 128, 5033. (h) Cardenas, D. J.; Martı
´
n-Matute, B.;
Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 5033.
1488
Org. Lett., Vol. 13, No. 6, 2011

can go on to react with the imine to yield Pd(IV) inter-
mediate II. Chemoselective reductive elimination followed
by decarbopalladation can yield intermediate III. This inter-
mediate can then produce intermediate IV which reductively
eliminates to yield the desired phenanthridines, 3.
Scheme 2. Proposed Mechanism
In conclusion, this new protocol for the palladium-cata-
lyzed domino direct arylation/N-arylation using aryl triflates
represents a powerful strategy for heterocycle synthesis. The
ability to use aryl triflates has overcome previous limitations
and made this reaction more practical. A concise synthesis of
Nitidine and NK109 has been demonstrated, opening new
opportunities for biological studies of this substrate class.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council (NSERC), the Merck
Frosst Centre for Therapeutic Research, and the Univer-
sity of Toronto for financial support. D.A.C. thanks
NSERC for a PGS M scholarship and Dr. Robert Webster
(University of Toronto) for helpful discussions.
Supporting Information Available. Experimental pro-
cedure, characterization data, and NMR spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 6, 2011
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