Palladium catalyzed intramolecular acylcyanation of alkenes using α-iminonitriles

Article abstract of DOI:10.1039/c4cc04068f

Reported here is a palladium catalyzed intramolecular acylcyanation of alkenes using α-iminonitriles. Through this method, highly functionalized indanones are synthesized in moderate to high yields using Pd(PPh ₃)₄, without need for any additional ligands, and a common Lewis acid (ZnCl₂). Additionally, the reaction tolerates substitution at various positions on the aromatic ring including electron donating and electron withdrawing groups. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc04068f

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Palladium catalyzed intramolecular acylcyanation
of alkenes using a-iminonitriles†
Cite this: Chem. Commun., 2014,
50, 8974
Naveen R. Rondla, Jodi M. Ogilvie, Zhongda Pan and Christopher J. Douglas*
Received 27th May 2014,
Accepted 17th June 2014
DOI: 10.1039/c4cc04068f
www.rsc.org/chemcomm
Reported here is a palladium catalyzed intramolecular acylcyanation
of alkenes using a-iminonitriles. Through this method, highly
functionalized indanones are synthesized in moderate to high
yields using Pd(PPh3)4, without need for any additional ligands,
and a common Lewis acid (ZnCl2). Additionally, the reaction tolerates
substitution at various positions on the aromatic ring including
electron donating and electron withdrawing groups.
Transition metal catalyzed carbon–carbon (C–C) sigma bond
activation and subsequent addition across olefins is a powerful tool
in organic synthesis.1 This process produces highly functionalized
products, which can be difficult to synthesize by traditional routes.2
Among methods involving C–C sigma bond activation, C–CN sigma
bond activation and addition across double bonds has emerged
as powerful strategy for chemical synthesis (Scheme 1). Recent
discoveries include arylcyanation, allyl cyanation, alkylcyanation,
cyanoamidation, and cyanoesterification of olefins.3–7 Although
cyanoesterification and cyanoamidation install vicinal cyano and
ester or amide groups respectively, the corresponding chemistry
to install vicinal cyano and keto groups, acylcyanation, is under-
developed. Herein we present a method for intramolecular
acylcyanation of alkenes.
Scheme 1 Addition reactions via C–CN bond activation.
Metal catalyzed C–CN activation of acylnitriles is rare because
they have strong tendency to undergo de-carbonylation after
activation (Scheme 2, challenge 1).8 Takaya reported a formal
acylcyanation using benzoyl cyanides and terminal alkynes
(Scheme 2, challenge 2).9 Mechanistic studies showed that the
reaction occurs via alkyne acylation followed by hydrocyanation
of an intermediate ynone and subsequent alkene isomerisation.
Due to this pathway, the reaction scope is limited to terminal
alkynes and the E/Z product ratio is determined by the thermo-
Scheme 2 Challenges for direct acylcyanation.
dynamic stability of the isomers. These results indicate that direct nitrile is challenging. At high temperatures (greater than
migratory insertion of an unsaturated moiety into an acyl-palladium 100 1C), the acylnitrile decomposes. At low temperatures (below
100 1C), direct migratory insertion is not favorable, even with a
terminal alkyne. We envisioned that these challenges could be
overcome by using a-iminonitriles as an acylnitrile surrogate.
Department of Chemistry, University of Minnesota, 207 Pleasant Street, SE,
Minneapolis, Minnesota, 55455, USA. E-mail: cdouglas@umn.edu
Iminonitriles cannot undergo decarbonylation, yet can yield a
carbonyl group after hydrolysis upon workup. We chose to
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc04068f
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examine intramolecular reactions of alkenes, reasoning that mixture. Subsequent attempts to isolate imine 4a by chromato-
intramolecularity would speed migratory insertion. The activation of graphic methods were unsuccessful. Instead, indanone 3a was
C–CN bonds is a valuable process as the resulting products isolated in 55% yield. An a-iminonitrile-containing by-product
retain the nitrile functional group, which is useful in industrial, resulting from alkene isomerisation of 2a was isolated in 23%
pharmaceutical and academic research and can be converted to yield. In subsequent preparative acylcyanation reactions, hydro-
variety of other functional groups like aldehydes, ketones, carboxylic lysis of the imine to the indanone was performed after a solvent
acids and amines.10
exchange, using acetic acid in a THF–water mixture before
Zhu and co-workers reported the synthesis of a-iminonitriles purification of the desired indanone. During optimization
in one step from the corresponding aldehydes.11 However, Zhu however, NMR yields of imine 4a could be measured without
reports that the a-iminonitriles are acid-sensitive, making it hydrolysis of the imine.
necessary to purify the compounds by chromatography on costly
Various attempts were made to improve the yield of 3a and
silanized silica gel. In our experience, a modification of Zhu’s avoid double bond isomerization. Increasing the amount of
procedure involving treatment of a mixture 2-phenethylamine BPh3 to 50 mol% (entry 3) did not have a positive effect on the
and benzaldehyde 1a with TMSCN, followed by in situ oxidation yield and 3a was isolated in 51% yield. Use of a stronger Lewis
of the Strecker product with IBX and tetrabutylammonium acid B(C6F5)3 resulted in decomposition of a-iminonitrile 2a
1
bromide produced a-iminonitrile 2a. We were able to isolate and no product was detected by H NMR (entry 4). Changing
2a in 62% yield after chromatography on alumina (eqn (1), see the source of palladium to Pd2(dba)3 in the presence of PPh3
ESI† for additional details).
(20 mol%) and BPh3 (20 mol%) only resulted in a decreased
yield of 4a (as determined by 1H NMR, entry 5). Addition of
ZnCl2 (20 mol%) improved the yield of the product to 65%
(entry 6). A stronger zinc Lewis acid, Zn(OTf)2, proved ineffective
and no 3a was detected (entry 7). Changing from m-xylene to a
more polar solvent, 1,4-dioxane, lead to incomplete conversion of
the starting material and only 26% of the product observed by
1H NMR (entry 8). Other polar solvents had the same negative effect
on reaction yield (not shown). Gratifyingly, lowering the tempera-
ture to 130 1C slightly improved the yield of the reaction (entry 9).
Further decrease in the temperature in m-xylene did not improve
the yield (not shown). Lowering the reaction temperature to 120 1C
and using toluene, combined with an increase catalyst loading to
15 mol% significantly enhanced the yield of the reaction and
indanone 3a was isolated in 82% yield (entry 10) after hydrolysis
of 4a with acetic acid in THF–H2O. Control experiments indicated
that both ZnCl2 and Pd(PPh3)4 are necessary for acylcyanation
(entries 11 and 12).
(1)
Using our optimized procedure, a-iminonitrile 2a was prepared
on preparative scale (4300 mg), allowing us to explore C–CN sigma
bond activation and (Table 1).
Our investigations into the proposed acylcyanation reaction
began using Pd(PPh3)4 in m-xylene at 140 1C (entry 1), however,
no desired product was detected under these conditions. We
then examined Lewis acid additives, which have been reported
to significantly improve the yields in arylcyanation of alkenes
via C–CN activation of aryl nitriles.4 With BPh3 (20 mol%) as the
additive (entry 2), signals attributable to the imine 4a were
assigned in the 1H NMR spectrum of the crude reaction
With optimized conditions in hand, we studied the scope of
the reaction by changing the substitution at various positions
of the aromatic ring and olefin (Fig. 1). A set of a-iminonitriles
2b–k was prepared via the corresponding benzaldehydes. In
some cases, minor impurities in the a-iminonitrile persisted
after chromatography. These were carried into the C–CN bond
activation reactions and could be removed afterwards without
incident (see ESI† for details). A low yield of the desired
indanone was obtained for o-fluoro substrate 3b at the optimized
temperature, but upon increasing the reaction temperature to
130 1C, the reaction proceeded smoothly and the corresponding
indanone 3b was isolated in 73% yield. The 3,5-difluoro-4-
trimethylsilyl substrate gave corresponding indanone 3g in 75%
yield, indicating that the reaction also tolerates tri-substitution on
the aromatic ring. The reaction proceeds with substitution at meta
positions with 3,5-difluoro substrate yielding 64% of the corres-
ponding indanone 3c. Substitution at para position is also allowed
with p-methyl and p-fluoro substrates providing corresponding
indanones 3d and 3e in 81% and 85% respectively. Interestingly,
the reaction also tolerates p-chloro substitution on the phenyl
Table 1 Reaction conditions for acylcyanation
Catalyst (mol%) Lewis acid (mol%) Solvent (0.2 M) t (1C) 3aa (%)
1
2
3
4
5
6
7
8
9
Pd(PPh3)4(10)
Pd(PPh3)4(10)
Pd(PPh3)4(10)
Pd(PPh3)4(10)
Pd2(dba)3(5)b
Pd(PPh3)4(10)
Pd(PPh3)4(10)
Pd(PPh3)4(10)
Pd(PPh3)4(10)
—
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
1,4-Dioxane
m-Xylene
PhMe
140
140 55
140 51
0
BPh3(20)
BPh3(50)
B(C6F5)3(20)
BPh3(20)
ZnCl2(20)
Zn(OTf)2(20)
ZnCl2(20)
ZnCl2(20)
ZnCl2(20)
—
140
0
140 23c
140 65
140
0
120 26c,d
130 68
120 82
10 Pd(PPh3)4(15)
11 —
PhMe
120
120
0
0
12 —
ZnCl2(20)
PhMe
a
b
Isolated yield of indanone 3a. PPh3 (20 mol%) was added as ligand.
c
NMR yield of the intermediate imine 4a calculated using p-methoxy
d
acetophenone as internal standard. 65% of starting material detected. ring and the corresponding indanone 3f was isolated in 79% yield.
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Fig. 1 Substrate scope. Isolated yield of indanones after column chromato-
graphy on silica gel. Unless otherwise noted, all reactions run at 120 1C with
a
15 mol% of Pd(PPh3)4 and 20 mol% of ZnCl2. Please refer to ESI† for the
hydrolysis conditions for each substrate. b C–CN activation reaction was run at
c
130 1C. C–CN activation reaction was run at 130 1C with 20 mol% of
Pd(PPh3)4.
We also examined the effect different substituents on the aromatic
ring with varying electron density have on the efficiency of the
reaction. A substrate possessing a strong electron-withdrawing
group, such as the p-CF3, allowed the preparation of indanone 3i
in an excellent yield of 90%. Substrates possessing electron-
donating groups, such as p-tBu and p-OMe, were less reactive and
low conversion was observed under the optimized conditions. For
these substrates, an increase in the catalyst loading to 20 mol% and
an increase in the reaction temperature to 130 1C led to complete
conversion and indanones 3j and 3k were isolated in 77% and 60%
yields respectively. This indicates that electron-withdrawing groups
on the aryl ring provide an accelerating effect on the reaction. Next
the effect of changing substitution on the double bond was
examined. After increasing the reaction temperature from 120 1C
to 130 1C, a non-terminal alkene with an ethyl substitution was fully
consumed and the corresponding indanone 3h was isolated in 76%
yield. No indanone was detected when an unsubstituted allyl
substrate (R1 = R2 = H) was subjected to reaction conditions,
possibly due to b-hydride elimination.
Scheme 3 Crossover experiment.
mechanism depicted in Scheme 4. Oxidative addition into the
C–CN sigma bond of the a-iminonitrile 2a by the Pd(0) catalyst
is the first step. The Lewis acid ZnCl2 could assist this step by
binding to the nitrogen of the nitrile, imine, or both, thereby
making the a-iminonitrile more electrophilic and therefore
more prone to oxidative addition. Similarly, the effect of
electron withdrawing groups on the aryl ring may also increase
the rate of oxidative addition. Upon oxidative addition, Pd(II)
complex I is formed. After coordination of the internal olefin to
the metal center, complex I would then undergo migratory
insertion leading to complex II. The higher reaction tempera-
tures necessary for substrate 3h, which has an ethyl substituent
With the presence of Lewis acid being critical to the reaction, we
were interested to examine whether binding of ZnCl2 leads to
cleavage of the presumptive [Pd]–CN bond during the catalytic cycle.
To test this hypothesis, a mixture of 13C labeled a-iminonitrile 2l and
unlabelled a-iminonitrile 2d were subjected to the optimized reac-
tion conditions. If binding of ZnCl2 leads to cleavage of [Pd]–CN
bond during catalytic cycle, crossover products, e.g. 3m and 3a,
Scheme 3, would be observed. If binding of ZnCl2 solely leads to
activation of the bond without cleavage, no crossover products would
be observed. For this experiment, only indanones 3l and 3d were
obtained after hydrolysis and no crossover products (3m and 3a)
were observed. This indicates that ZnCl2 likely does not facilitate
[Pd]–CN cleavage during catalytic cycle.
Based on the above observations and previous studies4 of
similar systems we believe that the reaction proceeds via the
Scheme 4 Mechanistic hypothesis.
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on the olefin, relay the impact of sterics on migratory insertion. In Notes and references
other instances, the reaction temperature needs to be increased
1 (a) M. Murakami and Y. Ito, Activation of Unreactive Bonds and
due to the presence of an electron-donating group on the phenyl
ring, which presumably slows down oxidative addition. These
results might indicate that the rate-limiting step is substrate
dependant. Similar observations have been made in carboacylation
reactions of unstrained C–C bonds with 8-acyl quinoline directing
groups.12 From intermediate II, reductive elimination leads to
imine 4a and regeneration of the active Pd(0) catalyst.
´
Organic Synthesis, Springer-Verlag, New York, 1999; (b) C. Najera
and J. M. Sansano, Angew. Chem., Int. Ed., 2009, 48, 2452.
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7 Recently metal catalyzed O–CN and N–CN bond activations have
also been reported: alkene oxycyanation: (a) D. C. Koester,
M. Kobayashi, D. B. Werz and Y. Nakao, J. Am. Chem. Soc., 2012,
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N. Ohta, K. Semba and Y. Nakao, J. Am. Chem. Soc., 2014, 136, 3732;
alkene aminocyanation without transistion metals: (d) Z. Pan,
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In summary we have reported the first metal catalyzed
acylcyanation of alkenes. We overcame the challenge of decarbo-
nylation by using a-iminonitriles as a surrogate for acyl nitriles.
These a-iminonitriles are stable to chromatography using alumina
and directly prepared from the corresponding benzaldehydes. The
C–CN bond activation and alkene addition reaction proceeds in
good to excellent yields using a commercially available palladium
source (Pd(PPh3)4) and a common Lewis acid (ZnCl2) and without
the use of complex ligands or expensive additives. A crossover
experiment gives evidence that the reaction proceeds in an intra-
molecular fashion, with the nitrile likely bound to the metal during
catalytic cycle. Work on an asymmetric version as well as an
intermolecular variant of the reaction is currently underway in
our laboratory.
We thank National Institute of Health (1R01 GM095559) for
financial support, the Research Corporation for Science
Advancement for a Cottrell Scholar Award (C.J.D.). We thank
Sean Murray (UMN) for assistance with HRMS and Kenneth
Tritch (UMN) and Prof. Wayland E. Noland for technical advice 12 (a) A. M. Dreis and C. J. Douglas, J. Am. Chem. Soc., 2009, 131, 412;
(b) J. P. Lutz, C. M. Rathbun, S. M. Stevenson, B. M. Powell,
T. S. Boman, C. E. Baxter, J. M. Zona and J. B. Johnson, J. Am. Chem.
Soc., 2012, 134, 715; (c) C. M. Rathbun and J. B. Johnson, J. Am.
on Sandmeyer reactions. NMR spectra were recorded on an
instrument purchased with support from the National Institute
of Health (S10 OD011952).
Chem. Soc., 2011, 133, 2031.
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