Palladium(II)-catalyzed cyclization reaction of 2-(Alk-2'-ynyloxy) benzonitriles or 2-(Alk-2'-ynylamino)benzonitriles: A facile way to 2H-chromene and 1,2-dihydroquinoline derivatives

Article abstract of DOI:10.1002/adsc.201200445

An efficient synthesis of 2H-chromenes and 1,2-dihydroquinolines from palladium(II)-catalyzed tandem reactions of 2-(alk-2'-ynyloxy)benzonitriles or 2-(alk-2'-ynylamino)benzonitriles was developed. This tandem reaction involves an intermolecular trans-acetoxypalladation of an alkyne followed by an addition to the nitrile group to quench the carbon-palladium bond and complete the catalytic cycle without the necessity of a redox system.

Full text of DOI:10.1002/adsc.201200445

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DOI: 10.1002/adsc.201200445
Palladium(II)-Catalyzed Cyclization Reaction of 2-(Alk-2’-ynyl-
oxy)benzonitriles or 2-(Alk-2’-ynylamino)benzonitriles: A Facile
Way to 2H-Chromene and 1,2-Dihydroquinoline Derivatives
Guoqin Xia,a Xiuling Han,a,* and Xiyan Lua,*
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: xlhan@mail.sioc.ac.cn or xylu@mail.sioc.ac.cn
Received: May 20, 2012; Revised: July 12, 2012; Published online: October 5, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200445.
Abstract: An efficient synthesis of 2H-chromenes
and 1,2-dihydroquinolines from palladium(II)-cata-
lyzed tandem reactions of 2-(alk-2’-ynyloxy)benzo-
nitriles or 2-(alk-2’-ynylamino)benzonitriles was de-
veloped. This tandem reaction involves an intermo-
lecular trans-acetoxypalladation of an alkyne fol-
lowed by an addition to the nitrile group to quench
the carbon-palladium bond and complete the cata-
lytic cycle without the necessity of a redox system.
also a few examples of Pd(II)-catalyzed intermolecu-
lar additions to nitriles for the synthesis of aryl ke-
tones and aryl ketimines.[6] Recently, our group ex-
plored some palladium(II)-catalyzed tandem reactions
initiated by nucleopalladation of alkynes and quench-
ing of the carbon-palladium bond by its addition to
the carbon-heteroatom multiple bond followed by
protonolysis.[7] In these reactions, palladium(II) com-
plexes were used as catalysts and no redox system
was required. As part of ongoing efforts in developing
nucleophilic addition reactions of carbon-palladium
bonds to carbon-heteroatom multiple bonds, we set
out to explore the cyclization reactions of 2-(alk-2’-
ynyloxy)benzonitriles or 2-(alk-2’-ynylamino)benzoni-
triles initiated by acetoxypalladation. If it works,
some 2H-chromene and 1,2-dihydroquinoline deriva-
Keywords: cyclization; nitriles; oxypalladation; pal-
ladium; protonolysis
In recent years, the addition of carbon-transition tives will be obtained conveniently, and these kinds of
metal bonds to carbon-heteroatom multiple bonds has substructures frequently exist in natural products and
become a new strategy in carbon-carbon bond forma- pharmaceuticals.[8]
tion.[1] Compared to the reactions using Grignard re-
In the initial investigation, 2-(but-2’-ynyloxy)benzo-
agents and organolithium reagents, these reactions nitrile (1a) was chosen as a substrate to test the reac-
are generally catalytic, more tolerant for the function- tion conditions under the catalysis of Pd(OAc)2/bpy
AHCTUNGTRENNUNG
al groups, more atom economic and easier to handle. and the results are shown in Table 1. It was found
As to the carbon-heteroatom multiple bonds, the ni- that the cyclization of 1a proceeded smoothly in mod-
trile group is generally inert in organometallic reac- erate yield to produce 2H-chromene 2a at 808C using
tions, and compounds such as CH3CN or PhCN are dioxane/acetic acid as solvent, and the best amount of
usually used as solvents or ligands in many catalytic 2,2’-bipyridine was 10 mol% (Table 1, entries 1–3). No
reactions. In the literature, rhodium and nickel com- desired product was detected in the absence of
plexes have already been exploited to catalyze addi- Pd
tion reactions to the nitrile group, and many useful ligand (Table 1, entries 4 and 5). Other ligands such
products can be synthesized by this strategy.[2,3]
as substituted bipyridines, pyridine and dppp were
ACHTUNGRTENUN(NG OAc)2 as the catalyst or 2,2’-bipyridine as the
Palladium-catalyzed nucleophilic addition reactions also tested, but none of them could improve the yield
to polar carbon-heteroatom multiple bonds are an im- (see the Supporting Information). The yield of 2a de-
portant development of the traditional palladium creased when raising up or lowering down the reac-
chemistry,[4] and nitrile groups have also been studied. tion temperature (Table 1, entries 6 and 7). It was
Yang and Larock reported the Pd(0)-catalyzed intra- worth noting that the yield was decreased significantly
molecular addition reactions of nitriles to form the in the presence of 4 ꢁ molecular sieve (Table 1,
carbocycles,[5a–d] and Vicente studied the insertion of entry 8), indicating that water was crucial for the reac-
a nitrile into the carbon-palladium bond.[5e] There are tion. When some amount of water was added to the
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Guoqin Xia et al.
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Table 1. Optimization of the reaction conditions.[a]
Table 2. Substrate scope for the cyclization of 2-(alk-2’-
ynyloxy)benzonitriles.[a]
Entry Solvents
bpy
Yield
AHCTUNGTRENNUNG
[mol%] [%][b]
Entry
R1
R2
Yield [%][b]
1
2
3
4
dioxane/HOAc (2/0.5)
6
50
55
41
0
1
2
3
4
5
6
7
8
H
4-OMe
3-OMe
5-Me
5-t-Bu
4-NEt2
5-F
5-Cl
5-Br
4-NO2
H
H
Me (1a)
Me (1b)
Me (1c)
Me (1d)
Me (1e)
Me (1f)
Me (1g)
Me (1h)
Me (1i)
Me (1j)
H (1k)
64 (2a)
74 (2b)
70 (2c)
54 (2d)
58 (2e)
54 (2f)
62 (2g)
57 (2h)
47 (2i)
23 (2j)
0
58 (2l)
30 (2m)
61 (2n)
72 (2o)
76 (2p)
dioxane/HOAc (2/0.5)
dioxane/HOAc (2/0.5)
dioxane/HOAc (2/0.5)
dioxane/HOAc (2/0.5)
dioxane/HOAc (2/0.5)
dioxane/HOAc (2/0.5)
dioxane/HOAc (2/0.5)
dioxane/HOAc/H2O (2/0.5/0.1)
dioxane/HOAc/H2O (2/0.5/0.05) 10
dioxane/HOAc/H2O (2/0.5/0.25) 10
HOAc/H2O (2/0.5)
THF/HOAc/H2O (2/0.5/0.1)
toluene/HOAc/H2O (2/0.5/0.1)
DCE/HOAc/H2O (2/0.5/0.1)
MeCN/HOAc/H2O (2/0.5/0.1)
10
20
0
10
10
10
10
10
5[c]
6[d]
7[e]
8[f]
9
0
43
31
38
61
50
60
13
64
trace
62
34
9
10
11
12
13
14
15
16
10
11
12
13[c]
14
15
16
10
10
10
10
10
n-Pr (1l)
Ph (1m)
Me (1n)
Me (1o)
H
4,5-di-Me
4,5-methylenedioxy
(1p)[d]
[a]
[a]
Reaction conditions: 1a (0.3 mmol), PdACTHNURTGNENG(U OAc)2 (5 mol%)
and bpy (10 mol%) were dissolved in solvents as shown
in the Table, then the mixture was stirred for 15 h at
808C.
Reaction conditions: 1 (0.3 mmol), PdACTHNURTGNENG(U OAc)2 (5 mol%)
and bpy (10 mol%) were dissolved in THF (2 mL),
HOAc (0.5 mL) and H2O (0.1 mL), then the mixture was
stirred at 808C for 15 h.
Isolated yield.
The reaction time was 3 days.
[b]
[c]
[d]
[e]
[f]
[b]
[c]
[d]
Isolated yield.
Reaction was carried out in the absence of Pd
The reaction was conducted at 608C.
The reaction was conducted at 1008C.
4 ꢁ MS was added.
ACHTUNGERTN(NUNG OAc)2.
1p=b-(but-2-ynyloxy)-a-naphthonitrile.
system, the yield did improve (Table 1, entry 9).[9]
A
drawing group such as a nitro group gave a very poor
solvent screening showed that THF was most effec- yield (Table 2, entry 10). When the benzene ring was
tive, and other solvents such as MeCN, DCE and tolu- substituted with a halogen atom, the cyclization reac-
ene were ineffective or gave a lower yield of 2a tions can also proceed smoothly to get the corre-
(Table 1, entries 13–16). Then many kinds of additives sponding products in moderate yields (Table 2, en-
such as LiOAc and acetic anhydride were tried to im- tries 7–9). Then b-(but-2-ynyloxy)-a-naphthonitrile
prove the reaction further, but the yield of 2a was de- (1p) was tested under the same reaction conditions,
creased dramatically. Many Brønsted acids and Lewis a good yield was obtained (76%, Table 2, entry 16),
acids were also screened to activate the nitrile group and the structure of product 2p is the fundamental
(see the Supporting Information), but none of them skeleton of a chromene antibiotic.[8a] There was little
gave a better result. Finally, the following conditions influence when the substituent R2 was changed from
were chosen as being optimal for the reaction: 1a Me to n-Pr, but for a phenyl-substituted one, the yield
(0.3 mmol), PdACHTUNGTRENNUNG(OAc)2 (5 mol%), bpy (10 mol%) were of the product was only 30% even on prolonging the
dissolved in THF (2 mL), HOAc (0.5 mL), and H2O reaction time to 3 days. Terminal alkynes gave no
(0.1 mL), then the mixture was stirred at 808C for product in this reaction.
15 h.
In the cyclization reaction of 2-(but-2’-ynyloxy)ben-
Under the optimized conditions, a series of substi- zonitrile (1a), 2-hydroxybenzonitrile was found to be
tuted 2-(alk-2’-ynyloxy)benzonitriles was tested as a side product, indicating the instability of the sub-
shown in Table 2. Substrates with electron-donating strates under the reaction conditions. Thus, a relatively
groups such as methoxy or methyl on the benzene stable substrate 3 was used to test the reaction
ring provided good results (Table 2, entries 2–6, 14 (Scheme 1). Unfortunately, the yield was far from sat-
and 15), while substrates with a strong electron-with- isfactory.
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Palladium(II)-Catalyzed Cyclization Reaction of 2-(Alk-2’-ynyloxy)benzonitriles
as compared with their oxy-containing counterparts
(compare Table 2 and Table 3).
A proposed mechanism is outlined in Scheme 2.
First, the coordination of the palladium catalyst with
the substrate generates complex A, then trans-acet-
AHCTUNGTREGoNNUN xypalladation of A occurs to form the vinyl palladi-
um species B. The carbon-palladium bond in inter-
mediate B adds to the nitrile group intramolecularly
to produce the intermediate C. Protonolysis of C gen-
erates the imine D and Pd(II) catalyst. The attack of
protonated imine E by water results in the formation
of enamine F. Then, F undergoes an intermolecular
acetyl migration with E to generate the final product
G and regenerate another molecule of F. It is worth
Scheme 1. Cyclization of dimethyl 2-(but-2’-ynyl)-2-(o-cya-
nophenyl)malonate. Reaction conditions: (0.3 mmol),
Pd(OAc)2 (5 mol%) and bpy (10 mol%) were dissolved in
THF (2 mL), HOAc (0.5 mL) and H2O (0.1 mL), then the
mixture was stirred at 808C for 3 days.
3
ACHTUNGTRENNUNG
Generally, a heteroatom in the substrate is sup- noting that the ligand bipyridine is crucial to the cycli-
posed to coordinate with the palladium catalyst, zation reaction, possibly for its ability in stabilizing
which makes the reaction proceed smoothly. Then the the vinyl palladium intermediate that allows the cata-
substrate 2-(but-2’-ynylamino)benzonitrile (5a) which lytic reaction to proceed smoothly.[7a,10]
contains a nitrogen atom was tried. To our delight,
We have also tried this kind of cyclization reactions
under the same conditions as shown in Table 2, a 92% initiated by carbopalladation of alkynes using differ-
yield of product 6a was obtained. Subsequent investi- ent kinds of arylboronic acids, but none of them
À
gation of the substrate scope showed that a series of worked. It seems that only vinyl C Pd bonds generat-
substituted 2-(alk-2’-ynylamino)benzonitriles could ed by acetoxypalladation of alkynes can add to the ni-
give the corresponding cyclization products in good to trile groups successfully in our cyclization reactions.
excellent yields (Table 3).
One possible explanation is the effect of the lone pair
When the substituent on the nitrogen was a benzyl, of electrons on the oxygen atom of the acetoxy group
the reaction rate was faster as compared with sub- in intermediate B as shown in Scheme 2, which may
À
strate 5a, although the yield was slightly decreased make the C Pd bond more nucleophilic to add to the
(Table 3, entries 1 and 2). Chlorine or bromine atom nitrile group easily.
on the benzene ring of the substrates had no influence
In conclusion, we have developed an efficient way
on the yield of the reaction (Table 3, entries 5 and 6). for the synthesis of 2H-chromene and 1,2-dihydroqui-
It was obvious to see that the cyclization reactions of noline derivatives. This is a Pd(II)-catalyzed intramo-
2-(alkyl-2’-ynylamino)benzonitriles proceeded better lecular cyclization of 2-(alk-2’-ynyloxy)benzonitriles
or 2-(alk-2’-ynylamino)benzonitriles initiated by trans-
acetoxypalladation of the alkyne and quenching of
the carbon-palladium bond by the addition to the ni-
trile group followed by protonolysis without the ne-
cessity of a redox system. This strategy may find fur-
ther applications in the future for rapidly constructing
other useful heterocyclic compounds.
Table 3. Substrate scope for the cyclization of 2-(alk-2’-
ynylamino)benzonitriles.[a]
Experimental Section
Representative Procedure for the Synthesis of 2H-
Chromene 2a
Entry
R
R1
R2
Time [h]
Yield [%][b]
1
2
3
4
5
6
Ts
Bn
Ts
Ts
Ts
Ts
H
H
H
H
4-Cl
4-Br
Me (5a)
Me (5b)
n-Pr (5c)
Ph (5d)
Me (5e)
Me (5f)
20
14
48
96
20
16
92 (6a)
84 (6b)
86 (6c)
62 (6d)
85 (6e)
74 (6f)
A dried tube equipped with a condenser was charged with
substrate 1a (0.3 mmol), palladium acetate (3.4 mg, 5 mol%)
and bipyridine (4.7 mg, 10 mol%), then 2 mL of THF,
0.5 mL of acetic acid and 0.1 mL of water were added se-
quentially, the resulting mixture was refluxed for 15 h. Then
the solvents were evaporated under reduced pressure and
the residue was purified by flash column chromatography to
give the cyclization product 2a as a white solid; yield: 64%;
mp 190–1918C; 1H NMR (400 MHz, CDCl3): d=10.94 (s,
1H), 7.34–7.27 (m, 2H), 6.99–6.92 (m, 2H), 4.88 (s, 2H),
2.30 (s, 3H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
[a]
Reaction conditions: 5 (0.2 mmol), PdACTHNURTGNENG(U OAc)2 (5 mol%)
and bpy (10 mol%) were dissolved in THF (2 mL),
HOAc (0.5 mL) and H2O (0.1 mL), then the mixture was
stirred at 808C for the indicated time.
[b]
Isolated yield.
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Guoqin Xia et al.
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Scheme 2. A plausible mechanism for the palladium(II)-catalyzed tandem cyclization reaction.
197.9, 169.6, 156.5, 142.3, 132.4, 128.5, 121.2, 118.9, 116.8,
114.5, 65.2, 29.4, 24.8; IR (KBr): n=3271, 1671, 1652, 1600,
1500 cmÀ1; MS (70 eV, EI): m/z (%)=131 (M+), 188, 146,
91, 77, 43 (100); anal. calcd. for C13H13NO3: C 67.52, H 5.67,
N 6.06; found: C 67.48, H 5.76, N 5.94.
b) T. Miura, M. Murakami, Org. Lett. 2005, 7, 3339;
c) K. Ueura, S. Miyamura, T. Satoh, M. Miura, J. Orga-
nomet. Chem. 2006, 691, 2821; d) T. Miura, T. Haruma-
shi, M. Murakami, Org. Lett. 2007, 9, 741; e) H. Shimi-
zu, M. Murakami, Chem. Commun. 2007, 2855; f) G. C.
Tsui, Q. Glenadel, C. Lau, M. Lautens, Org. Lett. 2011,
13, 208.
[3] For nickel-catalyzed reactions, see: a) Y.-C. Wong, K.
Parthasarathy, C.-H. Cheng, Org. Lett. 2010, 12, 1736;
b) J. C. Hsieh, Y. C. Chen, A. Y. Cheng, H. C. Tseng,
Org. Lett. 2012, 14, 1282.
Acknowledgements
We thank the National Basic Research Program of China
(2011CB808706), National Natural Science Foundation of
China (20872158) and Chinese Academy of Sciences for fi-
nancial support.
[4] For recent reviews, see: a) J. Tsuji, Palladium in Organ-
ic Synthesis, Springer Verlag, Heidelberg, Berlin, 2005,
p 211; b) Y. Yamamoto, I. Nakamura, Top. Organomet.
Chem. 2005, 14, 211. and references cited therein.
[5] a) C. C. Yang, P. J. Sun, J. M. Fang, J. Chem. Soc.
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