Regioselective C-H bond functionalizations of acridines using organozinc reagents

Article abstract of DOI:10.1039/c1cc16582h

Despite the recent advance in C-H bond functionalization chemistry, the C-H bonds in the acridine ring system, which is an important scaffold in medicinal and material science, have met with limited success, due, in part, to the lack of activated C-H bonds adjacent to the ring nitrogen atom. Herein, several protocols that can effect the regioselective arylation and alkylation of acridines at the C-4 and C-9 positions are described.

Full text of DOI:10.1039/c1cc16582h

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COMMUNICATION
Regioselective C–H bond functionalizations of acridines using organozinc
reagentswz
Isao Hyodo,a Mamoru Tobisu*ab and Naoto Chatani*a
Received 24th October 2011, Accepted 8th November 2011
DOI: 10.1039/c1cc16582h
Despite the recent advance in C–H bond functionalization
chemistry, the C–H bonds in the acridine ring system, which is
an important scaffold in medicinal and material science, have met
with limited success, due, in part, to the lack of activated C–H
bonds adjacent to the ring nitrogen atom. Herein, several protocols
that can effect the regioselective arylation and alkylation of
acridines at the C-4 and C-9 positions are described.
the C-9 arylated acridine 3 was formed when a catalytic
amount of copper, iron, and indium salts was added (entries
2–4). Phosphine-ligated palladium (entry 5) and nickel-based
(entry 6) catalysts were also found to be active. Interestingly,
C-4 phenylated acridine was the major product in the case of
the nickel catalyst (vide infra for further optimization of this C-4
arylation). Finally, it was found that the use of a [RhCl(cod)]2
catalyst resulted in the cleanest reaction, and the desired
product 3 was obtained in 82% yield by increasing the catalyst
loading, the amount of 2, and the reaction temperature (entry 9).
Consequently, the conditions shown in entry 9 were identified
optimal for further exploration.
The acridine scaffold displays a range of distinctive biological
activities, thus serving as kinase inhibitors,1a antiviral1b and
anti-prion1c agents, DNA intercalators1d and others. In particular,
high affinity of the acridine scaffold for DNA and RNA has often
rendered it a key component in the field of chemical biology.2
Despite the broad-spectrum utility of this motif, the synthesis
of functionalized acridines greatly depends upon de novo ring
construction from acyclic components that bear the desired
substituents, and only a few catalytic methods exist for the direct
functionalization of preformed acridine frameworks.3 Herein,
we report on some methodology that permits the arylation and
alkylation of acridine in a regioselective manner.
Rhodium-catalyzed reactions of several substituted acridine
derivatives with diphenylzinc (2) afforded the corresponding
C-9 arylated product (Table 2). Introduction of strongly
electron-donating morpholyl groups into the acridine ring
decreased the yield of the C-9 arylated product significantly,
indicating that the electrophilicity of C-9 is a determining
factor for an efficient reaction, as we envisioned (entry 5).
Diarylzinc reagents prepared from Grignard reagents and
Zn(OMe)2 were also applicable to this reaction to deliver the
corresponding C-9 arylated acridines (entry 6).9,10
Remarkable progress made in the catalytic C–H bond
functionalization of aromatic and heteroaromatic rings4 has
allowed applications to pyridines, which have been traditionally
notorious substrates to deal with.4e,5–7 However, these methods
are not readily translated into acridines, since acridines are
lacking in relatively activated C–H bonds, such as those at the
2-position of pyridines.5 A notable exception to this is Chang’s
recent work, in which Rh(II)-catalyzed C-4 arylation of acridine
is demonstrated.3 Our approach to this problem involves the use
of organozinc reagents,5g since we envisioned that their nucleophilic
character would direct the carbon–carbon bond formation to
proceed at the most electrophilic C-9 position.8 We initially
examined the reaction of acridine (1) with diphenylzinc (2) in
the presence of various metal catalysts (Table 1). As expected,
Table 1 C-9 arylation of acridines: catalyst screena
Entry
Catalyst
Ligand
Yieldb (%)
1
2
3
4
5
6
None
None
None
None
None
PCy3
PCy3
PCy3
PCy3
PCy3
0
35
35
35
Cu(OTf)2
FeCl3
lnCl3
Pd(OAc)2
Ni(cod)2
[RhCl(cod)]2
[RhCl(cod)]2
[RhCl(cod)]2
11
10c
38
7
a Department of Applied Chemistry, Faculty of Engineering,
Osaka University, Suita, Osaka 565-0871, Japan.
8d
9e
75
85 (82)f
E-mail: chatani@chem.eng.osaka-u.ac.jp
a
b Center for Atomic and Molecular Technologies, Graduate School of
Engineering, Osaka University, Suita, Osaka 565-0871, Japan.
E-mail: tobisu@chem.eng.osaka-u.ac.jp
Reaction conditions: 1 (0.25 mmol), Ph2Zn (0.38 mmol), catalyst
(0.0125 mmol), PCy3 (0.025 mmol), when added, and toluene (1 mL)
in a screw-capped vial under N2 at 130 1C for 20 h unless otherwise
b
c
w This article is part of the ChemComm ‘Advances in catalytic
C–C bond formation via late transition metals’ web themed issue.
z Electronic supplementary information (ESI) available: Preparative
and spectroscopic data. See DOI: 10.1039/c1cc16582h
noted. NMR yields based on 1. C-4 phenylated acridine was also
d
obtained (30%). Run for 72 h. Run using [RhCl(cod)]2 (0.025 mmol),
e
f
PCy3 (0.05 mmol) and 2 (1.0 mmol) at 160 1C. Isolated yield.
c
308 Chem. Commun., 2012, 48, 308–310
This journal is The Royal Society of Chemistry 2012

Table 2 Substrate scope for C-9 arylationa
Table 3 Substrate scope of C-9 alkylation of acridinesa
Entry
R
Ar
Yield (%)
1
2
3
4
5
6
Phenyl
Ph
Ph
Ph
Ph
Ph
2-Tolylb
66
77
54
51
18
54
4-n-Butyl-C6H4
3,5-Dimethyl-C6H4
3-Isopropoxy-C6H4
Morpholyl
H
a
Reaction conditions: acridine derivative (0.25 mmol), Ar2Zn
(1.0 mmol), [RhCl(cod)]2 (0.025 mmol), PCy3 (0.05 mmol) and toluene
(2 mL) in a screw-capped vial under N2 at 130 1C for 20 h unless
b
otherwise noted. (2-Tolyl)2Zn prepared from 2-tolylMgBr and
Zn(OMe)2 was used.
a
Reaction conditions: (1) acridine derivative (0.25 mmol), R0 Zn
2
On the other hand, the reaction of acridine with diisopropylzinc
(4) in the presence of a Rh(I) catalyst afforded 9-isopropyl-
9,10-dihydroacridine (5), an addition product, in quantitative
yield. In contrast to the catalytic arylations using diarylzinc,
in situ aromatization did not proceed.11 Further investigations
revealed that the addition of 4 proceeds, even in the absence of
transition metal catalyst. (eqn (1)).
(0.5 mmol), and toluene (2 mL) in a screw-capped vial under N2 at
70 1C for 20 h. (2) K3[Fe(CN)6] (0.7 mmol), KOH (2.1 mmol), CH2Cl2
(5 mL), and H2O (0.4 mL) in a flask under air at rt for 20 h unless
otherwise noted. Isolated yield based on acridine substrate was shown.
b
c
The first reaction was run at 100 1C. R0 Zn prepared from R0MgBr
2
(1.0 mmol) and ZnCl2 (0.5 mmol) was used.
Table 4 Reaction optimization of C-4 arylationa
ð1Þ
Although it is well known that strong nucleophiles, such as
Grignard and organolithium reagents, add to acridines,8 the
corresponding reaction using organozinc reagents has never
been reported, to the best of our knowledge. The subsequent
treatment of dihydroacridine 5 with an appropriate oxidant
afforded the aromatized product in excellent yield. Thus, the
overall transformation can be viewed as the alkylation of
acridine at the C-9 position (Table 3). Functional groups
including trifluoromethyl (7), alkoxy (9) and fluoro (10)
groups were tolerated under these conditions. Importantly,
an ester was also compatible with this alkylation reaction,
which offers an advantage over the reactions using organo-
lithium and -magnesium reagents.8 Moreover, dialkylzincs
prepared by reacting alkyl Grignard reagents with ZnCl2 can
participate in this formal C-9 alkylation reaction. Various
secondary alkyl groups can be introduced, as in 12 and 13.
In contrast, primary alkylzinc reagents, such as Me2Zn, Et2Zn,
Entry
Ligand
Baseb
Yield (%)
1
2
3
4
PCy3
None
None
None
16
0
0
0
0
21
45
68
PtBu3
PMe3
lMesꢀHCl
lPrꢀHCl
SlPrꢀHCl
SlPrꢀHCl
SlPrꢀHCl
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
5
6
7c
8d
a
Reaction conditions: 3 (0.25 mmol), 2 (0.38 mmol), Ni(cod)2
(0.0125 mmol), ligand (0.025 mmol), and toluene (1.5 mL) in a
screw-capped vial under N2 at 130 1C for 20 h unless otherwise noted.
b
c
NaOtBu (0.025 mmol) was added, when indicated. Run using
NaOtBu (0.50 mmol). Run using Ni(cod)2 (0.050 mmol), SIPrꢀHCl
(0.10 mmol), NaOtBu (0.50 mmol), and 2 (1.0 mmol) at 160 1C.
d
observed when SIPr was used as a ligand to furnish 4-phenylated
product 14 in 21% yield (entry 6). Finally, the yield of 14
was increased to 68% by using NaOtBu (2 equiv.), Ni(cod)2
(20 mol%), SIPr (40 mol%), and 2 (4 equiv.).12
n
and Bu2Zn, did not form the alkylated products.
As shown in entry 6 of Table 1, the use of a nickel-based
catalyst afforded a C-4 phenylated acridine as a major product.
Intrigued by the unique selectivity using a nickel catalyst, we
attempted to further optimize the C-4 arylation of acridine.
9-Phenylacridine (3) was used as a substrate to avoid the
competitive C-9 arylation (Table 4). The use of other alkyl
phosphines (entries 2 and 3) did not afford any desired
product, and the starting material was recovered. While IMes
and IPr were ineffective, comparative catalytic activity was
An array of acridine derivatives can be arylated at the
4-position under these conditions (Table 5). The electronic
nature of the C-9 substituent had little impact on the efficiency
of the reaction, and the corresponding C-4 arylated product
was consistently produced. Although an excess amount of 2 was
required for the reaction to proceed, no diarylated product was
observed. It should be noted that a methoxy group remained
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 308–310 309

Table 5 Substrate scope for C-4 arylationa
Eur. J. Med. Chem., 2011, 46, 2917; (d) L. Janovec, M. Kozurkova
D. Sabolova, J. Ungvarsky, H. Paulıkova, J. Plsıkova, Z. Vantova
and J. Imrich, Bioorg. Med. Chem., 2011, 19, 1790.
´
,
´
´
´
´
´
´
´
2 For example, see: (a) L. A. Howell, R. Gulam, A. Mueller,
M. A. O’Connell and M. Searcey, Bioorg. Med. Chem. Lett.,
2010, 20, 6956; (b) K. Zelenka, L. Borsig and R. Alberto, Biocon-
jugate Chem., 2011, 22, 958; (c) G. W. Collie, S. Sparapani,
G. N. Parkinson and S. Neidle, J. Am. Chem. Soc., 2011, 133, 2721.
3 J. Kwak, M. Kim and S. Chang, J. Am. Chem. Soc., 2011, 133, 3780.
4 Recent reviews on catalytic C–H functionalization of heteroarenes:
(a) G. P. McGlacken and L. M. Bateman, Chem. Soc. Rev., 2009,
38, 2447; (b) F. Bellina and R. Rossi, Tetrahedron, 2009, 65, 10269;
(c) L. Ackerman, R. Vicente and A. R. Kapdi, Angew. Chem., Int.
Ed., 2009, 48, 9792; (d) K. Hirano and M. Miura, Synlett, 2011,
294; (e) Y. Nakao, Synthesis, 2011, 3209.
5 Majority of catalytic functionalization of pyridines occurs at the
2-position. For selected examples, see: (a) R. F. Jordan and
D. F. Taylor, J. Am. Chem. Soc., 1989, 111, 778; (b) E. J. Moore,
W. R. Pretzer, T. J. O’Connell, J. Harris, L. LaBounty, L. Chou and
S. S. Grimmer, J. Am. Chem. Soc., 1992, 114, 5888; (c) M. Murakami
and S. Hori, J. Am. Chem. Soc., 2003, 125, 4720; (d) J. C. Lewis,
R. G. Bergman and J. A. Ellman, J. Am. Chem. Soc., 2007,
129, 5332; (e) A. M. Berman, J. C. Lewis, R. G. Bergman and
J. A. Ellman, J. Am. Chem. Soc., 2008, 130, 14926; (f) Y. Nakao,
K. S. Kanyiva and T. Hiyama, J. Am. Chem. Soc., 2008, 130, 2448;
(g) M. Tobisu, I. Hyodo and N. Chatani, J. Am. Chem. Soc., 2009,
131, 12070; (h) S. Yotphan, R. G. Bergman and J. A. Ellman, Org.
Lett., 2010, 12, 2978; (i) A. M. Berman, R. G. Bergman and
J. A. Ellman, J. Org. Chem., 2010, 75, 7863.
6 Catalytic C-3 or C-4 functionalization of pyridines without direct-
ing groups: (a) C.-C. Tsai, W.-C. Shih, C.-H. Fang, C.-Y. Li,
T.-G. Ong and G. P. A. Yap, J. Am. Chem. Soc., 2010, 132, 11887;
(b) Y. Nakao, Y. Yamada, N. Kashihara and T. Hiyama, J. Am.
Chem. Soc., 2010, 132, 13666; (c) B.-J. Li and Z.-J. Shi, Chem. Sci.,
2011, 2, 488; (d) M. Ye, G.-L. Gao and J.-Q. Yu, J. Am. Chem.
Soc., 2011, 133, 6964; with directing groups: (e) M. Wasa,
B. T. Worrell and J.-Q. Yu, Angew. Chem., Int. Ed., 2010,
49, 1275; (f) P. Guo, J. M. Joo, S. Rakshit and D. Sames, J. Am.
Chem. Soc., 2011, 133, 16338.
7 Radical and related arylation methods can be applied to pyridine
derivatives, although the regioselectivity is relatively low.
(a) S. Yanagisawa, K. Ueda, T. Taniguchi and K. Itami, Org. Lett.,
2008, 10, 4673; (b) O. Kobayashi, D. Uraguchi and T. Yamakawa,
Org. Lett., 2009, 11, 2679; (c) M. Li and R. Hua, Tetrahedron Lett.,
2009, 50, 1478; (d) J. Wen, S. Qin, L.-F. Ma, L. Dong, J. Zhang,
S.-S. Liu, Y.-S. Duan, S.-Y. Chen, C.-W. Hu and X.-Q. Yu, Org.
Lett., 2010, 12, 2694; (e) I. B. Seiple, S. Su, R. A. Rodriguez,
R. Gianatassio, Y. Fujiwara, A. L. Sobel and P. S. Baran, J. Am.
Chem. Soc., 2010, 132, 13194; (f) Y. Ji, T. Brueckl, R. D. Baxter,
Y. Fujiwara, I. B. Seiple, S. Su, D. G. Blackmond and P. S. Baran,
Proc. Natl. Acad. Sci. U. S. A., 2011, 108, 14411.
Entry
1
R
Yield (%) Entry
R
Yield (%)
55
68
55
6
7
2
3
55
64
63
8
4
5
59
55
9
52
52
10b
a
Reaction conditions: 9-substituted acridine (0.25 mmol), 2 (1.0 mmol),
Ni(cod)2 (0.050 mmol), SIPrꢀHCl (0.1 mmol), NaOtBu (0.5 mmol) and
toluene (2 mL) in a screw-capped vial under N2 at 160 1C for 20 h unless
b
otherwise noted. (2-Tolyl)2Zn prepared from (2-tolyl)MgBr and
Zn(OMe)2 was used.
untouched (entries 5 and 6), while nickel-catalyzed C–O bond
cleavage using organozinc reagents has been reported to occur.13
Similar to the C-9 arylation reaction, Ar2Zn prepared from
ArMgX and Zn(OMe)2 was found to participate in this nickel-
catalyzed C-4 arylation reaction (entry 10).
In summary, regioselective functionalizations of acridine
derivatives using organozinc reagents are described. With a
nickel based catalyst, the reaction proceeded at the 4-position,
whereas C-9-selective functionalization took place with a
rhodium catalyst. Moreover, the overall C-9 alkylation of
acridine can be accomplished by the non-catalytic addition
of a dialkylzinc/oxidation sequence. Straightforward synthesis
of acridine derivatives can be expected through the present
C–H bond functionalization protocols.
8 Addition of reactive nucleophiles, such as Grignard and organo-
lithium reagents, occurs at the C-9 position of acridines to afford
dihydroacridines: (a) B. Dutta, G. K. Kar and J. K. Ray, Tetrahedron
Lett., 2003, 44, 8641; (b) E. Hayashi, S. Ohsumi and T. Maeda,
Yakugaku Zasshi, 1959, 7, 969.
9 A. Cote and A. B. Charette, J. Am. Chem. Soc., 2008, 130, 2771.
10 The use of diarylzincs prepared by the reaction of ArMgX or ArLi
and ZnCl2 afforded only the traces of an arylated product,
probably due to the inhibiting effect of residual metal salts. ArZnX
was also ineffective.
11 Treatment of 5 with 2 equivalents of 2 at 130 1C for 20 h did not
promote an aromatization leading to 9-isopropylacridine (11). In
contrast, 9-phenyl-9,10-dihydroacridine could be aromatized to
afford 3 by the treatment with 2. From these results, the ease of
aromatization of the dearomatized intermediate by an organozinc
reagent is likely to determine the course of the reaction.
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas ‘‘Molecular Activation Directed
toward Straightforward Synthesis’’ from MEXT, Japan. We also
thank the Instrumental Analysis Center, Faculty of Engineering,
Osaka University, for assistance with the HRMS analyses.
M.T. acknowledges the Novartis Foundation (Japan) for the
Promotion of Science for their financial support. I.H. thanks the
GCOE Program of Osaka University and JSPS.
Notes and references
1 Selected recent biological studies of acridines: (a) X. Luan, C. Gao,
N. Zhang, Y. Chen, Q. Sun, C. Tan, H. Liu, Y. Jin and Y. Jiang,
Bioorg. Med. Chem., 2011, 19, 3312; (b) M. Tonelli, G. Vettoretti,
B. Tasso, F. Novelli, V. Boido, F. Sparatore, B. Busonera, A. Ouhtit,
P. Farci, S. Blois, G. Giliberti and P. La Colla, Antiviral Res., 2011,
91, 133; (c) T. Nguyen, Y. Sakasegawa, K. Doh-ura and M.-L. Go,
12 Under these conditions, 1 afforded 3 (10%), 4-phenylacridine
(18%) and 14 (15%).
13 B.-J. Li, Y.-Z. Li, X.-Y. Lu, J. Liu, B.-T. Guan and Z.-J. Shi,
Angew. Chem., Int. Ed., 2008, 47, 10124.
c
310 Chem. Commun., 2012, 48, 308–310
This journal is The Royal Society of Chemistry 2012