Enantioselective synthesis of 3,4-dihydroisoquinolin-1(2H)-ones by nickel-catalyzed denitrogenative annulation of 1,2,3-benzotriazin-4(3H)-ones with allenes

Article abstract of DOI:10.1021/ja909603j

(Chemical Equation Presented) A denitrogenative annulation reaction of 1,2,3-benzotriazin-4(3H)-ones with allenes catalyzed by a nickel-phosphine complex to produce a variety of substituted 3,4-dihydroisoquinolin-1(2H)-ones in a regioselective manner is described. A highly enantioselective version, as well as structural evidence for the mechanistic course of this reaction, is also presented.

Full text of DOI:10.1021/ja909603j

Published on Web 12/15/2009
Enantioselective Synthesis of 3,4-Dihydroisoquinolin-1(2H)-ones by
Nickel-Catalyzed Denitrogenative Annulation of 1,2,3-Benzotriazin-4(3H)-ones
with Allenes
Motoshi Yamauchi, Masao Morimoto, Tomoya Miura, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto UniVersity, Katsura, Kyoto 615-8510, Japan
Received November 11, 2009; E-mail: murakami@sbchem.kyoto-u.ac.jp
Table 1. Ni(0)-Catalyzed Annulation of
Transition-metal-catalyzed annulation reactions continue to
provide many powerful synthetic methodologies for the construction
of heterocyclic compounds.1 Heterometalacyclic complexes often
act as key intermediates, which subsequently incorporate unsaturated
compounds through insertion and reductive elimination to afford
heterocyclic skeletons. It has been reported that heterocyclic
compounds such as triazoles,2 phthalimides,3a phthalic anhydride,3b
and isatoic anhydrides3c can be exploited as the precursory platform
to generate heterometalacyclic intermediates through oxidative
addition to a low-valent transition metal and subsequent extrusion
of gaseous molecules such as N2, CO, and CO2.4 We recently
developed a Ni-catalyzed denitrogenative annulation of 1,2,3-
benzotriazin-4(3H)-ones (1) with alkynes.5 A five-membered aza-
nickelacycle was postulated as the intermediate. Our continued
investigations have led us to isolate and characterize the postulated
azanickelacycle complex. Herein, we report on its stoichiometric
reaction with allenes, which has successfully been extended to a
catalytic asymmetric denitrogenative annulation of 1,2,3-benzotriazin-
4(3H)-ones.
N-Aryl-1,2,3-benzotriazin-4(3H)-ones 1 with Nona-1,2-diene (3a)a
entry
1
R1
R2
R3
4
5
% yieldb
1
2
3
4
5
6
7
1a Tol
1b Ph
1c 4-MeOC6H4
1d 4-ClC6H4
H
H
H
H
H
H
4aa 5aa 94 (94:6)c
4ba 5ba 90 (91:9)d
4ca 5ca 76 (94:6)e
4da 5da 83 (93:7)f,h
H
H
H
H
4ea 5ea 94 (95:5)c i
,
1e 2-MeOC6H4
79 (95:5)c j
,
1f
Ph
MeO MeO
H
4fa
5fa
1g Ph
CO2Me 4ga 5ga 88 (85:15)g
a Conditions: 1 (0.2 mmol), 3a (0.3 mmol), Ni(cod)2 (5 mol %), and
PMe3 (20 mol %) in THF (2 mL) at 60 °C for 3-16 h. b Total yield of
isomers; the 4/5 ratio is given in parentheses. c Z/E > 95:5. d Z/E )
78:22. e Z/E ) 83:17. f Z/E ) 86:14. g Z/E ) 80:20. h Using dioxane (2
mL) at 80 °C. i Using 10 mol % Ni(cod)2 and 40 mol % PMe3. j Using
10 mol % Ni(cod)2 and 40 mol % PMe3 in dioxane (2 mL) at 80 °C.
N-Tolyl-1,2,3-benzotriazin-4(3H)-one (1a)6 was treated with
equimolar amounts of Ni(cod)2 and 1,2-bis(diphenylphosphino)ben-
zene (Dppbenz) in THF at room temperature for 3 h. Recrystalli-
zation of the reaction mixture from CH2Cl2/hexane afforded
azanickelacycle 2 as dark-brown crystals in 79% yield (eq 1): The
The possibility of developing a catalytic reaction incorporating
allenes was then pursued (Table 1). When a mixture of 1a and 3a
(1.5 equiv) in THF was heated at 60 °C for 3 h in the presence of
a Ni catalyst (5 mol %) prepared from Ni(cod)2 and PMe3 (Ni/P )
1:4), the product 4aa resulted in preference to 5aa (94%, 4aa/5aa
) 94:6; entry 1). Other phosphine ligands such as PCy3, Pt-Bu3,
PPh3, and Dppbenz gave inferior results. Under the conditions
involving PMe3 as the ligand, a wide variety of aryl substituents
on the N atom afforded the corresponding 3,4-dihydroisoquinolin-
1(2H)-ones 4ba-ea in yields ranging from 76 to 94% with high
regioselectivities, suggesting less steric and electronic impact of
the aryl group (R1) (entries 2-5). The 4-methoxyphenyl group of
4ca was readily removed by treatment with cerium ammonium
nitrate to furnish the nonprotected 3,4-dihydroisoquinolin-1(2H)-
one.7 Benzotriazinones 1f and 1g having electron-donating and
-withdrawing ring substituents also participated in the reaction
(entries 6 and 7).
Terminal allenes having a variety of R substituents were
subjected to the annulation reaction of 1a. The regioselectivity was
significantly affected by the sterics of the R substituent (Table 2).
As with simple nona-1,2-diene 3a, functionalized allenes 3b-e
having one primary substituent exhibited good regioselectivity to
give the corresponding 3,4-dihydroisoquinolin-1(2H)-ones 4ab-ae
in good yields (entries 1-4). On the other hand, cyclohexylpropa-
1,2-diene (3f) afforded a mixture of regioisomers 4af and 5af in a
55:45 ratio (entry 5).8 Allene 3g bearing a tert-butyl group gave
the insertion products in favor of 5ag (4ag/5ag ) 18:82; entry 6),
and complete regioselectivity for 5 was observed with trialkylsilyl-
substituted allene 3h (entry 7). Whereas reductive elimination at
five-membered cyclic structure of 2 was unambiguously determined
by single-crystal X-ray analysis. Ni(II) complex 2 has square-planar
geometry, and the N atom of the amidate moiety is bound to the
Ni center in an η1 fashion. Presumably, oxidative insertion of Ni(0)
into the N-N(tolyl) bond of 1a and subsequent retroinsertion of
N2 furnished 2.
Next, we examined the reactivity of azanickelacycle 2, which
led us to discover that allene functionality was successfully
incorporated into the precursory skeleton. Thus, when 3 equiv of
nona-1,2-diene (3a) was reacted with 2 in THF at 60 °C, an isomeric
mixture of 3,4-dihydroisoquinolin-1(2H)-ones 4aa and 5aa in a 54:
46 ratio was obtained (99% total yield; eq 2):
9
54 J. AM. CHEM. SOC. 2010, 132, 54–55
10.1021/ja909603j  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Ni(0)-Catalyzed Annulation of
Table 3. Ni(0)-Catalyzed Enantioselective Annulation Reaction of
N-Aryl-1,2,3-benzotriazin-4(3H)-ones 1 with Allenes 3a
N-Tolyl-1,2,3-benzotriazin-4(3H)-one (1a) with Allenes 3a
entry
3
R
4
5
% yieldb
91 (94:6)c e
81 (93:7)c
76 (91:9)d
95 (92:8)c
,
1
2
3
4
5
6
7
3b
3c
3d
3e
3f
3g
3h
(CH2)2OBn
(CH2)2OSit-BuMe2
(CH2)2OH
(CH2)3CN
c-Hex
4ab
4ac
4ad
4ae
4af
4ag
4ah
5ab
5ac
5ad
5ae
5af
5ag
5ah
89 (55:45)c f
99 (18:82)c
82 (0:100)c
,
t-Bu
Sit-BuMe2
a The reaction conditions were the same as those in Table 1. b Total
yield of isomers; the 4/5 ratio is given in parentheses. c Z/E > 95:5. d Z/
E ) 67:23. e Using dioxane (2 mL) at 80 °C. f Using 10 mol % Ni(cod)2
and 40 mol % PMe3.
the more-substituted carbon is generally preferred for electronic
reasons, the steric bulk of the tert-butyl and trialkylsilyl groups
favors reductive elimination at the less-substituted carbon.
The use of 1,3-disubstituted allenes was also examined. To our
surprise, the product outcome varied with the ligand employed.
Thus, whereas the use of PMe3 furnished the imino ester 6ai in
75% yield,9 the bidentate phosphine ligand (R,R)-Me-DuPhos
afforded 4ai as the sole product in 99% yield at 100 °C (eq 3):10,11
a Conditions: 1 (0.2 mmol), 3 (0.3 mmol), Ni(cod)2 (10 mol %), and
chiral ligand (20 mol %) in THF (2 mL) for 12 h. b Total yield of
isomers; the 4/5 ratio is given in parentheses. c Determined by HPLC analysis
using a chiral column. d Using CH3CN. e Using 20 mol % Ni(cod)2.
of Ni(II) complex 2 (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
References
Next, the catalytic reaction was extended to an asymmetric
version, and various chiral ligands were examined using 1a and
3a (Table 3). Whereas bidentate phosphine ligands such as (R,R)-
Me-DuPhos and (S,S,R,R)-TangPhos exhibited reasonable enanti-
oselectivities, the regioselectivities were poor (entries 1 and 2). The
regio- and enantioselectivities both became acceptable when the
phosphino-oxazoline ligand (S,S)-i-Pr-FOXAP was employed (entry
3).12 Lowering the reaction temperature to 60 °C led to the best
result (96%, 90% ee, 4aa/5aa ) 98:2; entry 4). The asymmetric
process worked well with a sterically and electronically diverse
array of N-aryl substituents (entries 5-11). The reaction tolerated
the presence of a variety of functional groups (entries 12-19).
In summary, a denitrogenative annulation reaction of 1,2,3-
benzotriazin-4(3H)-ones with allenes provides a unique method for
the regio- and enantioselective synthesis of substituted 3,4-
dihydroisoquinolin-1(2H)-ones, which are found in a wide variety
of plant alkaloids and bioactive compounds.13 Further studies to
expand the reaction scope are in progress.
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(6) We developed a facile route to 1 from N-H-1,2,3-benzotriazin-4(3H)-one, which
is commercially available. For details of the Ullmann-type coupling reaction with
aryl halides, see the Supporting Information.
(7) See the Supporting Information for details.
(8) Lu, G.; Malinakova, H. C. J. Org. Chem. 2004, 69, 8266.
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(10) The enantiomeric excess of 4ai was low (19% ee).
(11) Treatment of 6ai with Ni(cod)2 (10 mol %) and (R,R)-Me-DuPhos (20 mol %) in
toluene at 100 °C caused isomerization to 4ai (97% yield), indicating that 4ai is
the thermodynamically more stable isomer.
(12) (S,S)-i-Pr-FOXAP ) (S,S)-[2-(4′-isopropyloxazolin-2′-yl)ferrocenyl]diphe-
nylphosphine. See: Miyake, Y.; Nishibayashi, Y.; Uemura, S. Synlett 2008, 1747.
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Acknowledgment. This work was supported in part by MEXT,
the Mitsubishi Chemical Corporation Fund, the Sumitomo Founda-
tion, and the Astellas Award in Synthetic Organic Chemistry, Japan.
Supporting Information Available: Experimental procedures,
spectral data for the new compounds, and details of the X-ray analysis
JA909603J
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