Ruthenium-catalyzed cyclization of aromatic nitriles with alkenes: Stereoselective synthesis of (Z)-3-methyleneisoindolin-1-ones

Article abstract of DOI:10.1021/ol502375p

Aromatic nitriles underwent cyclization with activated alkenes in the presence of a ruthenium catalyst, AgSbF₆, and Cu(OAc)₂·H₂O providing substituted 3-methyleneisoindolin-1-ones with high Z-stereoselectivity. The Z-stereoselectivity of the 3-methyleneisoindolin-1-one moiety was controlled by the intramolecular hydrogen bonding.

Full text of DOI:10.1021/ol502375p

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed Cyclization of Aromatic Nitriles with Alkenes:
Stereoselective Synthesis of (Z)‑3-Methyleneisoindolin-1-ones
Mallu Chenna Reddy and Masilamani Jeganmohan*
Department of Chemistry, Indian Institute of Science Education and Research, Pune 411021, India
*
S Supporting Information
ABSTRACT: Aromatic nitriles underwent cyclization with acti-
vated alkenes in the presence of a ruthenium catalyst, AgSbF6,
and Cu(OAc) ·H O providing substituted 3-methyleneisoindolin-
2
2
1-ones with high Z-stereoselectivity. The Z-stereoselectivity of
the 3-methyleneisoindolin-1-one moiety was controlled by the
intramolecular hydrogen bonding.
soindolinone is a core structure unit present in various natural
products and biologically active molecules. In particular, the
-methyleneisoindolin-1-one structural motif is found in several
By using the traditional methods and metal-catalyzed reac-
1
3−7
I
tions,
isoindolinone and (E)-3-methyleneisoindolin-1-
one derivatives are efficiently prepared, but, Z-stereoselective
3-methyleneisoindolin-1-one synthesis is not well demonstrated8
because of the rapid Z to E stereoselective isomerization.
Herein, we report a ruthenium-catalyzed annulation of aro-
3
biologically active natural products and designed pharmaceutical
2
molecules. Traditionally, 3-methyleneisoindolin-1-ones are pre-
pared by the reaction of phthalimides with Wittig reagents and
nucleophilic addition of organometallic reagents into phthalimides
9
matic nitriles with activated alkenes to yield Z-stereoselective
3
followed by dehydration. Alternatively, it can also be prepared by
3-methyleneisoindolin-1-ones in good yields in a highly regio-
selective manner. In the reaction, Z-stereoselectivity was con-
trolled by the intramolecular hydrogen-bonding.
metal-catalyzed intramolecular cyclization ofo-alkynylbenzamides,
coupling of 2-halobenzamides with terminal alkynes, and inter-
molecular coupling of substituted ynamides or o-vinylbenzamides
Treatment of 3,4-dimethoxybenzonitrile (1a) with methyl ac-
4
rylate (2a) in the presence of [[RuCl (p-cymene)] ] (5.0 mol %),
with aromatic boronic acids. However, the control of regio- and
2
2
AgSbF (20 mol %), and Cu(OAc) ·H O (2.0 equiv) in acetic acid
stereoselectivity and the observation of competitive side products
are critical problems in these reactions. In addition, preactivated
halo-substituted aromatics are required to prepare the key starting
materials.
6
2
2
(
3
AcOH) at 120 °C for 36 h gave 3-methyleneisoindolin-1-one
aa in 75% isolated yield in a high Z-stereoselectivity (eq 1)
Recently, isoindolinone derivatives have been efficiently pre-
pared by metal-catalyzed oxidative cyclization of aromatic amides
with alkenes without having any preactivated species on the
5
,6
aromatic moiety via chelation-assisted C−H bond activation.
N-Aryl- or -tosylbenzamides reacted with alkenes in the presence
of palladium or rhodium catalysts yielding five-membered
(for detailed optimization studies, see the Supporting Information).
The Z-stereoselectivity of compound 3aa was controlled by the
intramolecular hydrogen bonding of the N−H group of 3aa to the
carbonyl group of the ester moiety of 3aa. The catalytic reaction is
also highly regioselective; the ortho C−H bond activation takes
place selectively at a less hindered side of aromatic 1a. It is im-
portant to note that until now methyleneisoindolin-1-ones have
been prepared from substituted benzamides or aromatic ketoximes
with alkenes. Here, we show the synthesis of methyleneisoindolin-
1-ones from easily available aromatic nitriles.
6
a−c
isoindolinones.
N-Alkoxybenzamides reacted with activated
alkenes in the presence of palladium catalyst yielding (E)-3-
6
d,e
methyleneisoindolin-1-one derivatives.
In the meantime, N-
methylsubstituted benzamide or primary benzamides reacted
6f
with n-butyl acrylate to afford 3-methyleneisoindolin-1-ones.
However, the corresponding reaction was studied with only two
primary benzamides and a single 3-methoxy-N-methylbenza-
mide, and the observed yield was also very low. In fact, N-alkyl-
substituted benzamides and primary benzamide are not suitable
substrates for the cyclization with alkenes because of their
sluggish reactivity. However, pyridine-substituted amides un-
derwent cyclization with alkenes efficiently in the presence of
rhodium catalyst affording cis and trans stereoisomeric mixtures
The scope of the cyclization reaction was examined with
various alkenes (Table 1). Ethyl acrylate (2b), n-butyl acrylate
(
2c), and cyclohexyl acrylate (2d) underwent cyclization with 1a,
yielding cyclization products 3ab−ad in 67%, 70%, and 74%
yields, respectively (entries 1−3). Interestingly, 2,2,2-trifluoroethyl
6g−i
of 3-methyleneisoindolin-1-ones.
Apart from the benza-
mides, aromatic ketoximes reacted with isocyanates to give a
mixture of cis and trans stereoisomeric 3-methyleneisoindolin-1-
ones.
Received: August 11, 2014
7
©
XXXX American Chemical Society
A
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Letter
a
a
Table 1. Scope of the Activated Alkenes 2b−g
Table 2. Cyclization of Nitriles 1 with Alkenes 2c or 2g
a
All reactions were carried out using 1a, alkenes 2b,c (4.0 equiv), 2d−f
3.0 equiv), and 2g (1.2 equiv), [{RuCl (p-cymene)} ] (5 mol %),
(
2
2
AgSbF6 (20 mol %), and Cu(OAc) .H O (2.0 equiv) in AcOH
2
2
b
(
3.0 mL) at 120 °C for 36 h. Isolated yield.
acrylate (2e) and 2-hydroxyethyl acrylate (2f) also efficiently
reacted with 1a giving cyclization products 3ae and 3af in 62%
and 61% yields, respectively (entries 4 and 5). In the product 3af,
a free hydroxy group was converted into acetate group in the
presence of AcOH. Surprisingly, vinyl sulfone (2g) also reacted
efficiently with 1a, providing cyclic compound 3ag in 65% yield,
respectively (entry 6). Next, the reaction was tested with other
alkenes such as methyl vinyl ketone, acrylonitrile, and styrenes.
However, in the reaction, no cyclization product was observed.
a
All reactions were carried out using 1a−o, alkene 2g (1.20 equiv) or
c (4.0 equiv), [{RuCl (p-cymene)} ] (5 mol %), AgSbF (20 mol %)
2
2
2
6
It seems a good coordinating group such as ester and SO Ph-
2
and Cu(OAc) ·H O (2.0 equiv) in acetic acid (3.0 mL) at 120 °C for
3
carried out for 39 h. Reaction was carried out for 45 h.
2
2
substituted alkenes were suitable for the reaction.
b
c
d
6 h. Isolated yield. Reaction was carried out for 42 h. Reaction was
e
The present catalytic reaction was also successfully ex-
tended with various substituted aromatic nitriles (Table 2).
Thus, electron-rich aromatic nitriles such as 4-hydroxy- (1b),
Scheme 1. Regioselective Studies
4-methoxy- (1c), and 4-methylbenzonitriles (1d) and benzoni-
trile (1e) efficiently reacted with phenyl vinyl sulfone (2g) to give
isoindolinone derivatives 3bg−eg in good to moderate yields in a
highly Z-stereoselective manner (entries 1−4). The structure of
compound 3cg was supported by a single-crystal X-ray diffraction
(
4
see the Supporting Information). Halogen groups such as
-iodo- (1f), 4-bromo- (1g), 4-chloro- (1h) and 4-fluorobenzoni-
triles (1i) were nicely involved in the reaction, providing cyclization
products 3fg−ig in good yields in a highly stereoselective manner
(
entries 5−8). Very interestingly, electron-deficient aromatic
nitriles such as 4-nitrobenzonitriles (1j), 4-methyl ester benzoni-
triles (1k), and 4-formylbenzonitriles (1l) nicely reacted with
phenyl vinyl sulfone (2g) affording products 3jg−lg in 61%, 56%,
and 52% yield, respectively, in a highly regio- and stereoselective
manner (entries 9−11). It is important to note that a free OH and
sensitive I, Br, ester, CHO, and NO groups were not affected.
2
Further, 4-(dimethylamino)benzonitrile (1m), sterically hindered
o-methoxybenzonitrile (1n), and 1-naphthonitrile (1o) reacted
with n-butyl acrylate (2c) providing cyclization products 3mc−oc
in 59%, 51%, and 56% yields, respectively (entries 12−14).
Next, the cyclization reaction was tested with unsymmetrical
aromatic nitriles such as m-bromobenzonitrile (1p), 2-naphthoni-
trile (1q), and 3,4-dimethylbenzonitrile (1r) with 2c or 2g
side, giving products 3pg−3rg in 45%, 59%, and 59% yields,
respectively (Scheme 1), whereas in the substrate 1s, the ortho C−
H bond activation takes place at the sterically hindered side,
providing cyclization product 3sg in 77% yield (Scheme 1).
Isoindolin-1-one derivatives are widely used as a fluorescent
2
marker for labeling biomolecules. To learn the optical behavior,
(
Scheme 1). In these substrates, two different regioselective pro-
we have performed the following reaction and monitored the
absorbance and fluorescence of the product (eq 2). Treatment of
pyrene-1-carbonitrile (1t) with 2g provided cyclization product
ducts are possible. However, the reaction is highly regioselective,
and the ortho C−H activation takes place at the less hindered
B
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Letter
reaction conditions, providing N-arylated product 7b in 95%
yield. Then, the ester group of compound 7b was converted into
COOH derivative 8 in 89% yield in the presence of 15% aqueous
K CO (2.0 mL) in MeOH at 80 °C for 4 h. It is known that the
2
3
compound 8 can be easily converted into the pharmaceutical
7
molecule 9 and 10.
A possible reaction mechanism is proposed in Scheme 3 to
5
−9
account for the present cyclization reaction.
Three different
3
tg in 32% yield. Compound 3tg shows absorbance at 415 nm
Scheme 3. Proposed Mechanism
and fluorescence at 470 nm (see the Supporting Information).
The starting material pyrene-1-carbonitrile (1t) shows absorb-
ance at 355 nm, and fluorescence shows three character-
istic bands at 383, 402, and 425 nm. After installation of the
isoindolin-1-one moiety, the fluorescence was enhanced 55 nm
and a broad single emission band with red shift was observed.
Next, the free N−H group of 3aa was attempted to protect
with di-tert-butyl dicarbonate (4) (2.0 equiv) in the presence
4
-(dimethylamino)pyridine (4-DMAP) (2.0 equiv) in CH CN at
3
room temperature for 1 h (eq 3). In the reaction, N-BOC-protected
catalytic reactions were involved in the reaction. In the first step,
Cu(OAc) likely acts as a Lewis acid to which the nitrile group of
2
benzonitrile 1 is coordinated to provide intermediate 11. In this
stage, the Lewis acid likely reduces the electron density of the
nitrile group followed by hydration, providing benzamide 12, and
compound 5 was observed in 97% yield. It is very interesting to
note that in the product 5 alkene Z-stereoselectivity was retained
(
NOE experiments, see the Supporting Information). Similarly,
the N−H group of 3ab was tried by arylating with iodobenzene
6a) in the presence of CuI (20 mol %) and K CO (3.0 equiv)
11a
regenerates the active Cu(OAc)2.
In the second catalytic cycle, AgSbF likely removes the chloride
6
(
2
3
ligand from [[RuCl (p-cymene)] ] complexfollowed by theligand
2
2
in DMF at 150 °C for 16 h (eq 4). In the reaction, N-arylated
product 7a was observed in 71% yield, in which alkene Z-stereo-
selectivity was also retained.
exchange with Cu(OAc) giving a cationic ruthenium species 13.
2
Coordination of the amide group of 12 into the ruthenium cationic
species 13 followed by the ortho-metalation provides a five
The N-arylation reaction prompted us to explore the pos-
sibility of preparation of pharmaceutical molecules 9 and 10
11b,c
membered ruthenacycle 14 and AcOH.
Coordinative insertion
7
,10
10
of alkene 2 into the Ru−carbon bond of ruthenacycle 14 affords
ruthenacycle intermediate 15. β-Hydride elimination of inter-
(
Scheme 2).
These molecules show sedative activity.
mediate 15 in the presence of Cu(OAc) provides alkenylated
2
Scheme 2. Synthesis of Sedative Active Molecules
product 16 and regenerates the active ruthenium species 13.
In the third catalytic cycle, the amide group of product 16
coordinates with ruthenium species 13 followed by the intra-
molecular coordination of double bond to afford intermediate
1
7 and AcOH. Intramolecular coordinative insertion of N−Ru
bond of intermediate 17 into the alkene moiety via aza-Michael
addition provides intermediate 18a. Subsequent β-hydride
elimination of intermediate 18a in the presence of Cu(OAc)2
provides product 3 and regenerates ruthenium species 16.
In fact, in the intramolecular insertion of N−Ru bond of
intermediate 17 into the double bond of alkene moiety, two
different diastereoselective intermediates such as the ester moiety
of alkene and cyclic tertiary C−N−H bond are syn to each other
(18a) and anti to each other (18b) via aza-Michael addition
(
Scheme 3, eq 5). These intermediates only decide the nature of
Treatment of 3,4-dimethylbenzonitrile (1r) with N-butylacrylate
2c) under the optimized reaction conditions provided cyclic
(
compound 3rc in 55% yield in a highly regio- and stereoselective
manner (Scheme 2). Later, the free N−H group of compound
3rc was arylated with 4-fluorophenyl iodide (6b) under similar
C
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Organic Letters
Letter
product. If ester and C−N−H are syn toeachother as intermediate
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8a, only Z-stereoselective product 3 would be formed. If both are
4
anti to each other as intermediate 18b, E-stereoselective product
3
′ would be expected. In the cyclization of aromatic nitrile 1 with
(
2, intermediate 18a was only formed (eq 5). This is mainly due to
4
1, 157. (f) Norman, M. H.; Minick, D. J.; Rigdon, G. C. J. Med. Chem.
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2c) under similar reaction conditions, providing product 3ac in
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2
2
mol %), AgSbF (20 mol %), and Cu(OAc) ·H O (1.5 equiv) in
6
2
2
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version did not proceed in the absence of ruthenium catalyst with
or without the Lewis acid.
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In conclusion, we have demonstrated a highly regio- and stereo-
selective synthesis of (Z)-3-methyleneisoindolin-1-ones in good to
moderate yields by a ruthenium-catalyzed annulation of aromatic
nitriles with activated alkenes. In the reaction, Z-stereoselectivity
was controlled by the intramolecular hydrogen bonding.
(f) Patureau, F. W.; Besset, T.; Glorius, F. Angew. Chem., Int. Ed. 2011,
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(
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8) Z-Stereoselective synthesis: (a) Lu, Y.; Wang, D.-H.; Engle, K. M.;
ASSOCIATED CONTENT
Supporting Information
■
*
S
(
General experimental procedure, starting materials preparation,
CIF, and characterization details. This material is available free of
charge via the Internet at http://pubs.acs.org.
Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 5916. (b) Li, J.; John, M.;
Ackermann, L. Chem.Eur. J. 2014, 20, 5403.
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9) Nitrile-directed reactions: alkoxylation and arylation: (a) Li, W.;
Sun, P. J. Org. Chem. 2012, 77, 8362. (b) Li, W.; Xu, Z.; Sun, P.; Jiang, X.;
Fang, M. Org. Lett. 2011, 13, 1286. Cyclization: (c) Reddy, M. C.;
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amide cyclization: (d) Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew.
Chem., Int. Ed. 2011, 50, 6379. (e) Ackermann, L.; Wang, L.; Wolfram,
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AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: mjeganmohan@iiserpune.ac.in.
Notes
The authors declare no competing financial interest.
(
g) Parthasarathy, K.; Senthilkumar, N.; Jayakumar, J.; Cheng, C.-H.
Org. Lett. 2012, 14, 3478. (h) Arockiam, P. B.; Fischmeister, C.;
Bruneau, C.; Dixneuf, P. H. Green Chem. 2011, 13, 3075. (i) Singh, K. S.;
Dixneuf, P. H. Organometallics 2012, 31, 7320.
ACKNOWLEDGMENTS
We thank the DST (SR/S1/OC-26/2011), India, for support of
this research. M.C.R. thanks the CSIR for a fellowship.
■
(
10) Kanamitsu, N.; Osaki, T.; Itsuji, Y.; Yoshimura, M.; Tsujimoto,
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3
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dx.doi.org/10.1021/ol502375p | Org. Lett. XXXX, XXX, XXX−XXX