Sequential Cu(I)/Pd(0)-catalyzed multicomponent coupling and annulation Protocol for the synthesis of indenoisoquinolines

Article abstract of DOI:10.1021/ol802755z

Copper-catalyzed coupling of imines, vinylstannanes, or alkynes and o-bromoaroyl chlorides followed by Pd(0)-catalyzed annulations afforded indenoisoquinolines. Protocols requiring minimal purifications were developed, providing new methods for the construction of combinatorial libraries.

Full text of DOI:10.1021/ol802755z

ORGANIC
LETTERS
2009
Vol. 11, No. 4
815-818
Sequential Cu(I)/Pd(0)-Catalyzed
Multicomponent Coupling and
Annulation Protocol for the Synthesis of
Indenoisoquinolines
Thiruvellore Thatai Jayanth, Lei Zhang, Thomas S. Johnson,†
and Helena C. Malinakova*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045, and the Center for Methodology and Library DeVelopment
at the UniVersity of Kansas, 2121 Simons DriVe, Lawrence, Kansas 66047
hmalina@ku.edu
Received November 28, 2008
ABSTRACT
Copper-catalyzed coupling of imines, vinylstannanes, or alkynes and o-bromoaroyl chlorides followed by Pd(0)-catalyzed annulations afforded
indenoisoquinolines. Protocols requiring minimal purifications were developed, providing new methods for the construction of combinatorial
libraries.
The prevalance of N-heterocycles among established phar-
maceutical agents1 continues to inspire the development of
new synthetic methods. We have been exploring a protocol
based on an assembly of R-N-substituted amides followed
by various intramolecular cyclizations,2 opening up access
to combinatorial libraries of hexahydro-1H-isoindolones
(Figure 1).3
Herein, we describe a powerful novel combination of the
Cu(I)-catalyzed three-component coupling and an intramo-
lecular Pd(0)-catalyzed 1,2-bisarylation of an olefin or an
alkyne in amides IV and V to deliver substituted indenoiso-
quinolines VI and VII (Figures 1 and 2). The protocol allows
a rapid increase in molecular complexity in only two steps.
Figure 1. General strategy.
† Undergraduate research participant (NSF-REU), Grinnell College.
(1) ComprehensiVe Medicinal Chemistry II; Taylor, J. B., Triggle, D. J.,
Eds.; Elsevier: Amsterdam, Boston, 2007.
Structurally related indenoisoquinolines have been shown
to possess potent biological activities.4 Our protocol provides
a more efficient alternative to the established preparations
of indenoisoquinolines, particularly those substituted at the
angular position or the benzylic carbon in the indene ring.5
(2) Martin, S. F.; Sunderhause, J. D.; Dockendorff, C. Org. Lett. 2007,
9, 4223.
(3) (a) Zhang, L.; Lushington, G. H.; Neuenswander, B.; Hershberger,
J. C.; Malinakova, H. C. J. Comb. Chem. 2008, 10, 285. (b) Zhang, L.;
Malinakova, H. C. J. Org. Chem. 2007, 72, 1484.
10.1021/ol802755z CCC: $40.75
Published on Web 01/21/2009
2009 American Chemical Society

Scheme 1. Protocol Utilizing an Isolated Amide
that an intramolecular Heck reaction would afford intermedi-
ate VIII poised for electrophilic arylation to yield dihydroin-
deno[1,2-c]isoquinolines VI (Figure 2).10 The treatment of
amide 4a with Pd(OAc)2 (5%) and NaOAc (1 equiv) afforded
the indenoisoquinoline 5a in a 93% yield as a single
diastereomer (Scheme 1).11
Figure 2. Strategy toward indenoisoquinolines.
The method reported herein opens up a modular access to
indenoisoquinolines and is well amenable to automation.
Initial studies were focused on extending the scope of the
known Cu(I)-catalyzed coupling6 to o-bromoaroyl chlorides
III as well as to 1,1-disubstituted vinylstannanes II (Figure
2). We were able to decrease the molar excess of stannane
3a7 from 2.0 to 1.5 equiv8 and realize the coupling to imine
1a and aroyl chloride 2a providing amide 4a in good yields
(Scheme 1). An increase in the CuCl catalyst load improved
the yield of amide 4a from 67% (with 10 mol % CuCl) to
82% (with 20 mol % CuCl, Scheme 1).9 Next, the Pd-
catalyzed cyclization of amide 4a was explored, anticipating
Aiming to establish a protocol amenable to automated
synthesis, we sought to eliminate chromatographic purifica-
tion of amide 4a. The addition of solid KF and small
quantities of water, followed by filtration, was employed to
remove tin residues from the reaction mixtures. The resulting
crude amide 4a was treated with Pd(OAc)2 catalyst under
conditions reported in Scheme 1 to afford indenoisoquinoline
5a in 75% yield over two steps (entry 1, Table 1, Method
A). A brief survey revealed that sodium acetate was the
optimum base for the Pd-catalyzed cyclization.10 The
replacement of NaOAc with Na2CO3/n-Bu4NCl applying
modified Jeffery’s conditions12 (compare Methods A and B,
entries 1, 3, and 4, Table 1) resulted in a decrease in the
reaction yields, particularly severe for the electronically
deactivated imines 1c (R2 ) H) and 1d (R2 ) Cl) (entries 3
and 4, Method B, Table 1). Overall, the optimized sequential
protocol afforded the corresponding indenoisoquinolines
5a-5e in 38-75% yields over two steps (entries 1-5, Table
(4) Ryckebusch, A.; Garcin, D.; Lansiaux, A.; Goossens, J.-F.; Baldey-
rou, B.; Houssin, R.; Bailly, C.; Henichart, J.-P. J. Med. Chem. 2008, 51,
3617. (b) Teicher, B. A. Biochem. Pharmacol. 2008, 75, 1262. (c) Antony,
S.; Agama, K. K.; Miao, Z.-H.; Takagi, K.; Wright, M. H.; Robles, A. I.;
Varticovski, L.; Nagarajan, M.; Morrell, A.; Cushman, M.; Pommier, Y.
Cancer. Res. 2007, 67, 10397.
(5) (a) D’Souza, D. M.; Kiel, A.; Herten, D.-P.; Rominger, F.; Mu¨ller,
T. J. J. Chem. Eur. J. 2008, 14, 529. (b) Morrell, A.; Placzek, M.; Parmley,
S.; Grella, B.; Antony, S.; Pommier, Y.; Cushman, M. J. Med. Chem. 2007,
50, 4388. (c) D’Souza, D. M.; Rominger, F.; Mu¨ller, T. J. J. Angew. Chem.,
Int. Ed. 2005, 44, 153. (d) Xiao, X.; Miao, Z.-H.; Antony, S.; Pommier,
Y.; Cushman, M. Bioorg. Med. Chem. Lett. 2005, 15, 2795. (e) Jagtap,
P. G.; Baloglu, E.; Southan, G.; Williams, W.; Roy, A.; Nivorozhkin, A.;
Landrau, N.; Desisto, K.; Saltzman, A. L.; Szabo, C. Org. Lett. 2005, 7,
1753. (f) Xiao, X.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M.
Bioorg. Med. Chem. 2004, 12, 5147. (g) Fox, B. M.; Xiao, X.; Antony, S.;
Kohlhagen, G.; Pommier, Y.; Staker, B.; Stewart, L; Cushman, M. J. Med.
Chem. 2003, 46, 3275. (h) Cho, W.-J.; Park, M.-J.; Imanishi, T.; Chung,
B.-H. Chem. Pharm. Bull. 1999, 47, 900.
(6) Black, D. A.; Arndtsen, B. A. J. Org. Chem. 2005, 70, 5133.
(7) For the preparation of 3a via hydrostannylation, see: Darwish, A.;
Lang, A.; Kim, T.; Chong, J. M. Org. Lett. 2008, 10, 861.
(8) Compare to our original method reported in ref 3a.
(9) Variations in the CuCl load and the excess of stannane 3a in reactions
under the conditions described in Scheme 1affected the yields of amide
4a: (i) 20 mol % CuCl, 2.0 equiv 3a gave 4a in 80% yield; 20 mol %
CuCl, 1.0 equiv 3a gave 4a in 62% yield; (iii) 10 mol % CuCl, 1.5 equiv
3a gave 4a in 67% yield.
(10) (a) Zeni, G.; Larock, R. C. Chem. ReV. 2000, 100, 3009. (b) Brown,
D.; Grigg, R.; Sridharan, V.; Tambyrajah, V. Tetrahedron Lett. 1995, 8137.
For a review on the synthesis of heterocycles via transition metal catalysis,
see: (c) D’Souza, D. M.; Mu¨ller, T. J. J. Chem. Soc. ReV. 2007, 36, 1095.
(11) 1H NMR analysis of the crude reaction mixtures indicated the
presence of traces of a diastereomeric indenoisoquinoline. Isolation via
chromatography followed by trituration from hexanes afforded a pure single
diastereomer 5a. The relative stereochemistry was asssigned based on the
comparison of the spectroscopic data with the spectroscopic data recorded
for heterocycle 5j, the structure of which was established by X-ray
crystallography (vide infra).
(12) (a) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667. (b) Jeffery, T.
J. Chem. Soc., Chem. Commun. 1984, 1287.
816
Org. Lett., Vol. 11, No. 4, 2009

substituents. Indenoisoquinolines 5k-5o were obtained in
good yields (59-76%) over two steps (Table 2). Hetero-
Table 1. Angularly Substituted Indenoisoquinolines
Table 2. Diversification of Additional Building Blocks
entry
R1
R2
R3
productb
yieldc (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
OMe
H
OMe
Me
H
Cl
COOMe
OMe
-OCH2CH2O-
OMe OMe
NMe2
H
H
H
H
H
OMe
5a
5b
5c
5d
5e
5f
75 (71)d
69
entry
R1
R2
R3
R4
productb
yieldc (%)
1
2
3
4
5
Me
OMe
F
H
H
H
H
F
H
H
H
COOEt
COOEt
Me
Ph
Me
5k
5l
5m
5n
5o
62
76
68
59
54
67 (17)d
49 (11)d
38
OMe
OMe
OMe
Me
77
71
64
59
5ge
5h
5i
a Reaction conditions: (i) CuCl (20%), MeCN/ CH2Cl2, 45 °C, 6 h, imine/
acyl chloride/stannane ) 1.0: 1.2: 1.5 (mol); (ii) treatment with aqueous
KF, filtration, evaporation; (iii) Pd(OAc)2 (5%), NaOAc (1.0 equiv), DMF,
120 °C, 24 h. b Single diastereomer was isolated. c Isolated yield of
heterocycles 5 calculated per imine as the limiting reagent.
H
10
thiophene-2-yl
5j
74
a Method A was used for all the entries: (i) CuCl (20%), MeCN/CH2Cl2,
45 °C, 6 h, imine/acyl chloride/stannane ) 1.0:1.2:1.5 (mol); (ii) aqueous
KF, filtration, evaporation; (iii) Pd(OAc)2 (5%), NaOAc (1.0 equiv), DMF,
120 °C, 24 h. b With one exception, a single diastereomer was isolated.
c Isolated yield of heterocycles 5 obtained via Method A calculated per
imine as the limiting reagent. d Yield of heterocycle 5 obtained by Method
B is given in parentheses. Method B: same as Method A, but substituting
Na2CO3 (1.0 equiv)/n-Bu4NCl (1.0 equiv) for NaOAc. e Product was isolated
as a 4:1 mixture of diastereomers (by 1H NMR), the major diastereomer is
shown.
cycles 5k-5o were isolated as single diastereomers following
chromatography and trituration of the crude products. The
relative stereochemistry in heterocycles 5 (R4 ) COOEt and
Ph, Tables 1 and 2) was assigned based on analogy with
indenoisoquinolines 5j and 5n, the structure of which was
elucidated via single crystal X-ray crystallographic analyses.
The relative stereochemistry in products 5m and 5o (R4 )
Me) was assigned via spectroscopic methods.14
To access a distinct substitution pattern in the indenoiso-
quinolines, propargyl amide 7a was prepared from imine 1a,
aroyl chloride 2a, and alkyne 6a in a good yield (54%) using
conditions reported by Arndtsen15 (Scheme 2). We envi-
sioned that Pd-catalyzed intramolecular bisfunctionalization
of the alkyne16 would proceed via intermediate IX to afford
indenoisoquinolines VII (Figure 2). Conceivably, a 1,3-shift
of the allylic hydrogen in the intermediate IX would provide
an organopalladium intermediate poised for the terminal
electrophilic palladation.
1, Method A). The lower yields of the electronically
deactivated chloro- and ester-substituted indenoisoquinolines
5d and 5e are in agreement with the proposed involvement
of electrophilic palladation in the key step, although the less
facile iminolysis of the acyl chlorides may also be a
contributing factor. The 3,4-disubstituted imines 1f and 1g
afforded single regioisomers of heterocycles 5f (77%) and
5g (71%) arising from palladation at the least hindered
position in the aromatic ring (entries 6 and 7, Table 1). A
contiguous 1,2,3,4,5-substitution pattern was achieved in an
activated imine, yielding indenoisoquinoline 5h in 64% yield
(entry 8, Table 1). Efficient preparation of indenoisoquino-
lines 5i and 5j demonstrated the compatibility of the method
with heteroatoms other than oxygen (entries 9 and 10, Table
1).
To expand the reaction scope, imines 1a and 1b were
coupled to substituted aroyl chlorides 2b,c and vinylstannanes
3a and 3b,c13 bearing aliphatic (Me) and aromatic (Ph)
(13) For the preparation of the stannanes, see: Darwish, A.; Chang, J. M.
J. Org. Chem. 2007, 72, 1507.
Indeed, the treatment of amide 7a with Pd(OAc)2 catalyst
and Na2CO3/n-Bu4NCl additive mixture for a prolonged time
period (36 h at 120 °C in DMF) afforded the corresponding
indenoisoquinoline 8a in an excellent yield (91%) (Scheme
(14) The relative stereochemistry in heterocycle 5o was established via
1H NMR NOE study, and the structure of 5m was assigned accordingly.
For details see Supporting Information.
(15) Black, D. A.; Arndtsen, B. A. Org. Lett. 2004, 6, 1107.
Org. Lett., Vol. 11, No. 4, 2009
817

Scheme 2
.
Protocol Utilizing an Isolated Propargyl Amide
Table 3. Indenoisoquinolines with a Benzylic Substituent
entry
R1
R2 (aryl)
C6H5-
C6H5-
C6H5-
p-CH3C6H4-
p-FC6H4-
productb
yieldc (%)
1
2
3
4
5
OMe
Me
8a
8b
8c
8d
8e
66
51
68
63
57
thiophene-2-yl
OMe
OMe
2). Ultimately, the isolation of amide 7a was avoided,
limiting the purification of the crude reaction mixtures to
the removal of excess alkyne via filtration through a short
plug of silica. The resulting crude product was directly
subjected to Pd-catalysis, affording indenoisoquinoline 8a
in a good yield (66%) over two steps (entry 1, Table 2).
This protocol was then applied to the coupling of imines
1a, 1b, and 1j with aroyl chloride 2a and aryl acetylenes
6a-6c to provide indenoisoquinolines 8a-8e in good yields
(51-68%) over two steps (Table 2). Single crystal X-ray
crystallographic studies on heterocycle 8c unequivocally
established the structure, including the position of the double
bond within the isoquinoline ring.17
a Reaction conditions: (i) CuCl (20%), i-PrEt2N (1.5 equiv) MeCN, rt,
1 h, imine/acyl chloride/alkyne ) 1.0:1.2:1.5 (mol); (ii) treatment with
aqueous KF, filtration, evaporation; (iii) Pd(OAc)2 (5%), Na2CO3 (1.0 equiv),
n-Bu4NCl (1.0 equiv), DMF, 120 °C, 36 h. b Single diastereomer was
isolated. c Isolated yield of heterocycles 8 calculated per imine as the limiting
reagent.
modular strategy is particularly well suited for the construc-
tion of combinatorial libraries of indenoisoquinolines.
Acknowledgment. Support for this work from the Na-
tional Institutes of Health (KU Center for Methodology and
Library Development, Grant P 50 GM069663) is gratefully
acknowledged. We thank our colleague Dr. Victor W. Day
for his assistance with the X-ray crystallographic analyses.
The new synthetic protocol described here rapidly and
efficiently assembles indenoisoquinolines with distinct sub-
stitution patterns from three simple building blocks. The
Supporting Information Available: Description of the
synthesis and characterization of all new compounds, and
X-ray crystallographic analyses of compounds 5j, 5n, and
8c. This material is available free of charge via the Internet
at http://pubs.acs.org.
(16) Grigg, R.; Loganathan, V.; Sridharan, V. Tetrahedron Lett. 1996,
37, 3399.
(17) Structures of all the remaining indenoisoquinolines were assigned
accordingly. The structure assignment is also supported by 2D NMR and
1
NOE H NMR spectral studies performed on heterocycles 8c and 8d (see
Supporting Information).
OL802755Z
818
Org. Lett., Vol. 11, No. 4, 2009