Synthesis of 1(2H)-isoquinolones by the nickel-catalyzed denitrogenative alkyne insertion of 1,2,3-benzotriazin-4(3H)-ones

Article abstract of DOI:10.1021/ol8010826

(Chemical Equation Presented) 1,2,3-Benzotriazin-4(3H)-ones reacted with internal and terminal alkynes in the presence of a nickel(0)/phosphine catalyst to give a wide range of substituted 1(2H)-isoquinolones in high yield. The reaction proceeded through denitrogenative activation of the triazinone moiety and the following insertion of alkynes.

Full text of DOI:10.1021/ol8010826

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3085-3088
Synthesis of 1(2H)-Isoquinolones by the
Nickel-Catalyzed Denitrogenative Alkyne
Insertion of 1,2,3-Benzotriazin-4(3H)-ones
Tomoya Miura, Motoshi Yamauchi, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto UniVersity,
Katsura, Kyoto 615-8510, Japan
murakami@sbchem.kyoto-u.ac.jp
Received May 10, 2008
ABSTRACT
1,2,3-Benzotriazin-4(3H)-ones reacted with internal and terminal alkynes in the presence of a nickel(0)/phosphine catalyst to give a wide range
of substituted 1(2H)-isoquinolones in high yield. The reaction proceeded through denitrogenative activation of the triazinone moiety and the
following insertion of alkynes.
The 1(2H)-isoquinolone ring system is one of the basic units
often found in the structures of plant alkaloids1 and
pharmacologically valuable compounds.2 Therefore, the
development of efficient methods for their synthesis is of
great importance.3 Whereas transition-metal-based catalysis
has often been utilized for the synthesis of various hetero-
cyclic compounds,4 only limited examples applicable to the
synthesis of 1(2H)-isoquinolones have appeared.5 On the
other hand, a rhodium-catalyzed extrusion reaction of a
molecular dinitrogen from pyridotriazoles was utilized for
construction of a new heterocyclic system by Gevorgyan and
co-workers.6 We report herein a nickel-catalyzed denitro-
genative alkyne insertion reaction of 1,2,3-benzotriazin-
4(3H)-ones, which presents a new synthetic approach to
substituted 1(2H)-isoquinolones.
1,2,3-Benzotriazin-4(3H)-ones can be readily prepared
from anthranilic acid derivatives.7 Initially, the possibility
to activate the triazinone moiety was examined using
nickel(0)/phosphine complexes;8 3-phenyl-1,2,3-benzotriazin-
4(3H)-one (1a, 1.0 equiv) was treated with dec-5-yne (2a,
1.1 equiv) in the presence of a nickel(0) catalyst generated
(5) (a) Hudlicky, T.; Olivo, H. F. J. Am. Chem. Soc. 1992, 114, 9694.
(b) Grigg, R.; Sridharan, V.; Xu, L.-H. J. Chem. Soc., Chem. Commun.
1995, 1903. (c) Mahanty, J. S.; De, M.; Kundu, N. G. J. Chem. Soc., Perkin
Trans. 1 1997, 2577. (d) Sashida, H.; Kawamukai, A. Synthesis 1999, 1145.
(e) Batchu, V. R.; Barange, D. K.; Kumar, D.; Sreekanth, B. R.; Vyas, K.;
Reddy, E. A.; Pal, M. Chem Commun. 2007, 1966. (f) During the preparation
of our manuscript, Matsubara and co-workers reported a nickel-catalyzed
decarbonylative alkyne insertion of phthalimides: Kajita, Y.; Matsubara,
S.; Kurahashi, T J. Am. Chem. Soc. 2008, 130, 6058.
(1) (a) Lewis, J. R. Nat Prod. Rep. 1994, 11, 329. (b) Gonza´lez, M. C.;
Zafra-Polo, C.; Bla´zquez, A.; Serrano, A.; Cortes, D. J. Nat. Prod. 1997,
60, 108. (c) Chen, C.-Y.; Chang, F.-R.; Pan, W.-B.; Wu, Y.-C. Phytochem-
istry 2001, 56, 753. (d) Zhang, Z.; Li, S.; Zhang, S.; Liang, C.; Gorenstein,
D.; Beasley, R. S. Planta Med. 2004, 70, 1216.
(2) (a) Nagarajan, M.; Morrell, A.; Fort, B. C.; Meckley, M. R.; Antony,
S.; Kohlhagen, G.; Pommier, Y.; Cushman, M. J. Med. Chem. 2004, 47,
5651. (b) Ruchelman, A. L.; Houghton, P. J.; Zhou, N.; Liu, A.; Liu, L. F.;
LaVoie, E. J. J. Med. Chem. 2005, 48, 792. (c) Cappelli, A.; Mohr, G. P.;
Giuliani, G.; Galeazzi, S.; Anzini, M.; Mennuni, L.; Ferrari, F.; Makovec,
F.; Kleinrath, E. M.; Langer, T.; Valoti, M.; Giorgi, G.; Vomero, S J. Med.
Chem. 2006, 49, 6451.
(6) Chuprakov, S.; Hwang, F. W.; Gevorgyan, V. Angew. Chem., Int.
Ed. 2007, 46, 4757.
(7) Clark, A. S.; Deans, B.; Stevens, M. F. G.; Tisdale, M. J.;
Wheelhouse, R. T.; Denny, B. J.; Hartley, J. A. J. Med. Chem. 1995, 38,
1493.
(3) For a review, see: Glushkov, V. A.; Shklyaev, Y. V. Chem.
Heterocycl. Compd. 2001, 37, 663.
(8) For thermolysis of 3-aryl-1,2,3-benzotriazin-4(3H)-ones, see: (a) Hey,
D. H.; Rees, C. W.; Todd, A. R. J Chem. Soc. C 1968, 1028. (b) Barker,
A. J.; Paterson, T. M.; Smalley, R. K.; Suschitzky, H. J Chem. Soc., Perkin
Trans 1. 1979, 2203. (c) Cirrincione, G.; Almerico, A. M.; Dattolo, G.;
Aiello, E.; Diana, P.; Mingoia, F. J. Heterocycl. Chem. 1992, 29, 1309.
(4) For reviews, see: (a) Varela, J. A.; Saa´, C. Chem ReV. 2003, 103,
3787. (b) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (c)
Alonso, F.; Beletskaya, I. P.; Yus, M. Chem ReV 2004, 104, 3079. (d)
Cacchi, S.; Fabrizi, G. Chem ReV. 2005, 105, 2873.
10.1021/ol8010826 CCC: $40.75
Published on Web 06/18/2008
2008 American Chemical Society

benzyl- and methyl-substituted benzotriazinones 1e and 1f
required heating at higher temperatures (entries 4 and 5).
On the other hand, simple unprotected benzotriazinone 1g
failed to react with 2a even at 100 °C (entry 6).11
Scheme 1
Various internal alkynes 2 were subjected to the denitro-
genative insertion reaction with benzotriazinones 1a and 1b
(Table 2). Symmetrical internal alkynes such as diphenyl-
Table 2. Ni(0)-Catalyzed Insertion of Internal Alkyne 2a
entry
1
2 (R1, R2)
2b (Ph, Ph)
2c (CH2OBn, CH2OBn)
2d (Me, Ph)
2e (Me, p-CF3C6H4)
2f (Me, p-MeOC6H4)
2g (i-Pr, Me)
2h (n-Pr, CO2Et)
2i (n-Bu, Bpin)
3
yield (%)b
in situ from Ni(cod)2 (5 mol %, cod ) cycloocta-1,5-diene)
and PPh3 (20 mol %) at room temperature in THF. The
substrate 1a was consumed in 10 h, and subsequent
chromatographic isolation on silica gel afforded 3,4-dibutyl-
2-phenyl-1(2H)-isoquinolone (3aa) in 91% yield (Scheme
1). Substitution of PMe3 (10 mol %) for PPh3 resulted in a
faster reaction, which was completed in 3 h affording 3aa
in 93% isolated yield. We assume that the reaction is initiated
by insertion of nickel(0) into the N-N linkage of 1a, which
prompts extrusion of a molecular dinitrogen giving aza-
nickelacycle A.5f,9 Subsequent insertion of the alkyne into
the nickel-carbon bond leads to the seven-membered-ring
nickelacycle B.10 Finally, reductive elimination affords 3aa,
regenerating the nickel(0) catalyst.
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1b
1b
1b
1b
1b
3ab
3ac
3bd
3be
3bf
3bg
3bh
3bi
98
94
99 (86:14)
99 (73:27)
99 (89:11)
97 (58:42)
99 (92:8)c
93 (98:2)d,e
94 (99:1)e
2j (TMS, Bpin)
3bj
a Conditions: 1 (0.2 mmol), 2 (0.22 mmol), Ni(cod)2 (10 µmol, 5 mol
%), and PMe3 (20 µmol, 10 mol %) in THF (1 mL) at rt for 3-12 h under
N2 unless otherwise noted. b Combined yield of regioisomers unless
otherwise noted. Numbers in parentheses describe the regioselectivity. c 2
(0.4 mmol) and PPh3 (40 µmol, 20 mol %) at 60 °C. d Isolated yield of the
major regioisomer. e 60 °C.
The effect of the substituent on the nitrogen of the
benzotriazinone was examined (Table 1). Whereas both
ethyne (2b) and 1,4-dibenzyloxybut-2-yne (2c) reacted with
1a to give 3ab and 3ac in 98 and 94% yields, respectively
(entries 1 and 2). With unsymmetrical internal alkynes, the
regioselectivity of the insertion reaction was examined
wherein 3-tolyl-1,2,3-benzotriazin-4(3H)-one (1b) was used
in order to assign the regiochemistry of the products by NOE
experiments.12 1-Phenylprop-1-yne (2d) reacted smoothly
with 1b to provide 3bd in 99% yield in a fairly regioselective
fashion (86:14, entry 3). In the major product, the phenyl
group is bound to C(3) next to nitrogen.13 The regioselec-
tivity was enhanced by the presence of electron-donating
Table 1. Ni(0)-Catalyzed Alkyne Insertion: Scope of Substituent
on Nitrogen 1a
entry
1 (R)
3
T °C)
yieldb (%)
(9) For precedence of an intermediacy of a similar azanickelacycle, see:
(a) Takahashi, T.; Tsai, F.-Y.; Li, Y.; Wang, H.; Kondo, Y.; Yamanaka,
M.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 2002, 124, 5059. (b)
Duong, H. A.; Louie, J. J. Organomet. Chem. 2005, 690, 5098. (c) Duong,
H. A.; Louie, J. Tetrahedron 2006, 62, 7552.
1
2
3
4
5
6
1b (4-MeC6H4)
1c (4-MeOC6H4)
1d (4-CF3C6H4)
1e (Bn)
1f (Me)
1g (H)
3ba
3ca
3da
3ea
3fa
rt
rt
rt
60
80
100
98
95
99
96c
95d
0d
(10) For a previous example of alkyne insertion into a related seven-
membered ring nickelacycle intermediate, see: Korivi, R. P.; Cheng, C.-H.
Org. Lett. 2005, 7, 5179. The authors assumed that a carbon-carbon triple
bond can insert into both carbon-nickel and nitrogen-nickel linkages
depending on alkynes. The regiochemistry observed in the present reaction
using ethyl hex-2-ynoate (2h) suggests that a carbon-nickel linkage react
with 2h. In the reaction of other alkynes such as terminal alkynes, however,
insertion into a nitrogen-nickel linkage cannot be ruled out.
3ga
a Conditions: 1 (0.2 mmol), 2 (0.22 mmol), Ni(cod)2 (10 µmol, 5 mol
%), and PPh3 (40 µmol, 20 mol %) in THF (1 mL) for 12 h unless otherwise
noted. b Isolated yield. c PMe3 (20 µmol, 10 mol %). d PMe3 (20 µmol, 10
mol %) in toluene (1 mL).
(11) The benzotriazinone 1g was recovered.
(12) See the Supporting Information for details.
(13) Although a similar regiochemical preference was explained by
assuming stabilization of a partial negative charge on the carbon R to nickel
in ref 9b, the effect of the aryl substituent observed with the present reaction
is inconsistent with this explanation. Further studies including a theoretical
one are necessary for elucidation of the mechanistic and regiochemical issue.
electron-donating and -accepting aryl-substituted substrates
underwent the denitrogenative insertion reaction in a similar
way at room temperature (entries 1-3), the reaction of
3086
Org. Lett., Vol. 10, No. 14, 2008

Scheme 2
Table 3. Ni(0)-Catalyzed Insertion of Terminal Alkyne 2a
entry
2 (R1)
3
yieldb (%)
1
2
3
4
5
6
2k (n-Hex)
2k (n-Hex)
2l (c-Pent)
2m (t-Bu)
2n (TMS)
2o (n-Bu3Sn)
3bk
3bk
3bl
3bm
3bn
3bo
98 (73:27)c
99 (98:2)
98 (99:1)
99 (>99:1)e
94 (99:1)d,e
92 (99:1)d,f
a Conditions: 1b (0.2 mmol), 2 (0.22 mmol), Ni(cod)2 (10 µmol, 5 mol
%), and DPPF (20 µmol, 10 mol %) in THF (1 mL) at rt for 3-12 h under
N2 unless otherwise noted. b Combined yield of regioisomers unless
otherwise noted. Numbers in parentheses describe the regioselectivity.
c PMe3 (20 µmol, 10 mol %). d Isolated yield of the major regioisomer.
e 60 °C. f Ni(cod)2 (20 µmol, 10 mol %) and DPPF (40 µmol, 20 mol %)
at 60 °C. DPPF ) 1,1′-bis(diphenylphosphino)ferrocene.
groups at the para position of the aryl group (entries 4 and
5). In the case of alkynoate 2h, the regiochemistry of the
major isomer was consistent with the electronic demand
expected in the carbometalation step (i.e., A f B), although
an excess amount of 2h and the use of PPh3 were required
to get a high yield (entry 7).14 The high regioselectivity
observed with boryl-substituted alkynes15 can also be
understood on similar electronic grounds, which assume
stabilization of a partial negative charge on the carbon R to
boron by the electron-accepting character of boron (entries
8 and 9).16
corresponding products 3bl-3bo in yields ranging from 92%
to 99% (entries 3-6). In the case of phenylethyne (2p),
however, different regioisomers were preferentially obtained
depending on the ligand employed, although the selectivity
was modest (eq 1).
We then examined the reaction of terminal alkynes with
1b (Table 3). Although oct-1-yne (2k) is capable of under-
going a self-oligomerization reaction, it instead reacted via
the insertion reaction giving 3bk in 98% yield with the
Ni(0)/PMe3 catalyst (entry 1). However, the regioselectivity
was modest (73:27). Several phosphine ligands of nickel(0)
were tested to improve the selectivity in this case. To our
delight, the bidentate phosphine ligand, 1,1′-bis(diphenyl-
phosphino)ferrocene (DPPF), afforded very high regioselec-
tivity (98:2, entry 2).17,18 This catalyst system proved to be
general, catalyzing the insertion reaction of other terminal
alkynes 2l-2o with similarly high regioselectivity giving the
However, employing the densely functionalized products
3bj and 3bo, it was possible to prepare both isomers, 3bp
and 3bp′, with high regioselectivity (Scheme 2). Starting with
compound 3bj, the silyl group was selectively removed by
treatment with trifluoroacetic acid (TFA) at room tempera-
ture, giving 3-boryl-1(2H)-isoquinolone 4bj in 87% yield.
A subsequent palladium-catalyzed cross-coupling reaction
of 4bj with iodobenzene (5) afforded 3-phenyl-1(2H)-
isoquinolone 3bp′ (92% yield). On the other hand, an
analogous cross-coupling reaction performed directly on the
stannyl-substituted 3bo with 5 furnished the other regioiso-
mer, 4-phenyl-1(2H)-isoquinolone 3bp in 95% yield. Thus,
4bj and 3bo provide synthetic platforms for the preparation
of a wide variety of 3- and 4-substituted 1(2H)-isoquinolone.
(14) The major undesired process under the standard conditions using
PMe3 was self-oligomerization of 2h.
(15) For examples of the regioselective formation of R-boryl-substituted
metalacycle intermediates, see: (a) Quntar, A. A. A.; Srebnik, M. Org. Lett.
2004, 6, 4243. (b) Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2005, 127,
3252. (c) Nishihara, Y.; Miyasaka, M.; Okamoto, M.; Takahashi, H.; Inoue,
E.; Tanemura, K.; Takagi, K. J. Am. Chem. Soc. 2007, 129, 12634. (d)
Geny, A.; Lebœuf, D.; Rouquie´, G.; Vollhardt, K. P. C.; Malacria, M.;
Gandon, V.; Aubert, C. Chem. Eur. J. 2007, 13, 5408.
Finally, we examined the reaction of functionalized
triazinones 1h and 1i with 2a (Scheme 3). Methoxy ether
and ester functionalities were tolerated on the aryl group
of 1.
In conclusion, we have demonstrated a facile approach
for the preparation of substituted 1(2H)-isoquinolones. A
wide variety of alkyne substrates including borylalkynes were
(16) For a similar stabilization by a silyl substituent, see: Buchwald,
S. L.; Nielsen, R. B. J. Am. Chem. Soc. 1989, 111, 2870.
(17) Representative results (regioisomers ratio) with other phosphine
ligands: PMe2Ph (75:25), PMePh2 (87:13), P(n-Bu)3 (85:15), DPPPen (92:
8), DPEphos (88:12), XANTPHOS (93:7).
(18) The reaction of internal alkynes was retarded when dppf was used
in place of PMe3 as the ligand. For example, the reaction of 1-phenylprop-
1-yne using dppf required heating at 80 °C in toluene, giving inferior
regioselectivity of 65:35.
Org. Lett., Vol. 10, No. 14, 2008
3087

into the reaction mechanism and synthetic applications are
underway.
Scheme 3
Acknowledgment. We thank Mr. H. Fujita (Kyoto Uni-
versity) for his assistance in the structural determination by
NMR. This work was supported in part by Grant-in-Aid for
Scientific Research (A) (No. 19205013) from the Ministry
of Education, Culture, Sports, Science and Technology of
Japan. M.Y. acknowledges the financial support by the
Global COE Program “Integrated Materials Science” (No.
B-09).
Supporting Information Available: Experimental details
and spectra data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
regioselectively incorporated into 1,2,3-benzotriazin-4(3H)-
ones with loss of a dinitrogen molecule. Further investigation
OL8010826
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Org. Lett., Vol. 10, No. 14, 2008