Cyanation of N-acylhydrazones with trimethylsilyl cyanide promoted by a Bronsted base and a Lewis acid

Article abstract of DOI:10.1002/adsc.200505272

Cyanation of N-acylhydrazones using trimethylsilyl cyanide (TMSCN) proceeded well in the presence of an amine to afford the corresponding α-hydrazinonitriles in high yields. For less reactive substrates, the combined use of an amine and a catalytic amount

Full text of DOI:10.1002/adsc.200505272

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DOI: 10.1002/adsc.200505272
Cyanation of N-Acylhydrazones with Trimethylsilyl Cyanide
Promoted by a Brønsted Base and a Lewis Acid
Hideyuki Konishi, Chikako Ogawa, Masaharu Sugiura, and Shu¯ Kobayashi*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Phone: (þ81)-3-5841-4790, Fax: (þ81)-3-5684-0634, e-mail: skobayas@mol.f.u-tokyo.ac.jp
Received: July 9, 2005; Accepted: September 8, 2005
Abstract: Cyanation of N-acylhydrazones using tri-
methylsilyl cyanide (TMSCN) proceeded well in
the presence of an amine to afford the corresponding
a-hydrazinonitriles in high yields. For less reactive
substrates, the combined use of an amine and a cat-
alytic amount of scandium triflate [Sc(OTf)3] was ef-
fective to promote the reactions. The mechanistic
study suggested that the amine worked as a Brønsted
base.
acid catalyst. A mechanistic study to clarify the reaction
pathway is also described.
In the course of our investigations to examine effec-
tive Lewis base catalysts for cyanation of 3-phenylpro-
panal-derived N-benzoylhydrazone (1a) with trimethyl-
silyl cyanide (TMSCN), several Lewis bases
(5.0 equivs.), which we found to be effective for allyla-
tion using allyltrichlorosilanes,[6] were initially tested
(Table 1). However, dimethylformamide (DMF), di-
methyl sulfoxide (DMSO), pyridine N-oxide, and phos-
phine oxides were ineffective (entries 1–5). On the oth-
er hand, triethylamine, which was less effective for the
allylation, was found to promote the reaction well (en-
try 6). Triphenyl- or tributylphosphine, dimethyl sulfide,
and triphenylarsine were also examined, but only tribu-
tylphosphine showed a slight activity resulting in low
Keywords: amines; cyanides; hydrazones; Lewis
acids; nucleophilic addition; scandium
¼
Cyanation of C N double bonds is one of the most in- yield (entries 7–10).
vestigated reactions because it affords a variety of a-
Next, various amines were screened (Table 2). In gen-
amino acid derivatives. Intensive studies have led to de- eral, aliphatic tertiary amines gave the desired product
velopment of efficient reaction systems including cata- in high yields (entries 5, 6, 10 and 11), while primary or
lytic enantioselective versions.[1] Whereas preformed secondary amines were less effective (entries 1–4).[7]
imines are used as substrates in most cases, several 4-(Dimethylamino)pyridine (DMAP) and N-methylimid-
imines such as aliphatic aldehyde derivatives are often azole resulted in moderate to good yields, but pyridine
sensitive to hydrolysis. N-Acylhydrazones are advanta-
geous as imine equivalents, since they can easily be pre-
pared via condensation of the corresponding carbonyl
compounds and acylhydrazines, can often be purified
Table 1. Survey of effective bases.
by simple recrystallization, and are stable at ambient
temperature.[2] The cyanation of N-acylhydrazones af-
fords a-hydrazinonitriles, which can be converted into
a-amino acids via an N N bond cleavage[3] and hydrol-
ꢀ
ysis. a-Hydrazinonitriles are also an important class of
compounds. They can be easily hydrolyzed toa-hydrazi-
no acids, which consist of hydrazinopeptides and N-ami-
nopeptides as pseudo amino acid analogues.[4] It was re-
ported that N-acylhydrazones reacted with various nu-
cleophiles in the presence ofBrønsted acids, Lewis acids,
or Lewis bases to afford a wide variety of nitrogen-con-
taining compounds.[5] To the best of our knowledge,
however, catalysis by Brønsted bases has not been cov-
ered before. Here, we report the first example of the cy-
anation of N-acylhydrazones promoted by a Brønsted
base or the combination of a Brønsted base and a Lewis
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Hideyuki Konishi et al.
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sterically hindered pivalaldehyde derivative (1f) also re-
acted well (entry 7). It is noted that even aliphatic ke-
tone-derived hydrazones were successfully converted
into a,a-disubstituted hydrazinonitriles (entries 8 and
9). However, aromatic and a,b-unsaturated aldehyde-
derived hydrazones remained almost intact resulting in
recovery of the starting materials (entries 10–12).
In order to activate hydrazones with lower reactivities,
the simultaneous addition of triethylamine and Lewis
acid catalysts was next examined (Table 4). We previ-
ously reported that the cyanation of certain N-benzoyl-
hydrazones was catalyzed by a Lewis acid,[9] and Jacob-
sen et al. reported an enantioselective version using chi-
ral rare earth metal complexes.[10] To our delight, the
Table 2. Effect of amines.
combination of scandium triflate
[Sc(OTf)3,
0.20 equivs.] and triethylamine (1.0 equiv.) was found
to promote the reaction (entry 2), while Sc(OTf)3
(0.20 equivs.) alone afforded a trace amount of the prod-
uct (entry 1).[11] When the reaction was conducted for a
longer time, considerable amounts of side products were
formed and the yield of the desired product decreased
was poorly effective (entries 7–9). These results suggest (entry 3). The main side product provedto be adehydro-
that the basicities of the amines probably do not corre- genated product, [cyano(phenyl)methylene]benzohy-
spond to the promotional activities.[8]
drazide, whose structure was unambiguously deter-
Further optimization was conducted after choosing mined by X-ray analysis.[12] After several attempts, the
triethylamine as a promoter. After several attempts, it formation of side products was effectively prevented
was revealed that a slight excess amount of TMSCN by lowering the temperature (entries 4–6). Finally, a
and an equimolar amount of triethylamine were suffi- longer reaction time at ꢀ208C gave the best result (en-
cient to promote cyanation of 1a (Table 3, entry 1). We try 7).
then investigated the substrate scope under these condi-
With the optimal conditions in hand, cyanation of less
tions. Aliphatic aldehyde-derived hydrazones reacted reactive N-acylhydrazones was tried (Table 5). Aromat-
with TMSCN smoothly to afford the corresponding ic hydrazones with an electron-donating group at the
products in moderate to high yields (entries 1–7). A para or ortho position reacted smoothly to afford the
corresponding adducts in high yields (entries 2–4),
while electron-withdrawing groups retarded the reac-
tion (entry 5). a,b-Unsaturated substrates failed to
give the products (entries 6 and 7). Significantly, alkyl
Table 3. Substrate scope.
aryl ketone-derivatives could be converted well to the
products (entries 8–10). The combination of a catalytic
Table 4. Cyanation of benzaldehyde N-benzoylhydrazone
(1i).
1900
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Cyanation of N-Acylhydrazones with Trimethylsilyl Cyanide
Table 5. Cyanation using Sc(OTf)3 and NEt3.
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Scheme 1. Formation of the assumed intermediate O-Si-2a.
accompanied with regeneration of the amine. In fact,
the amine can be catalytic as demonstrated in Table 3,
entry 2. When N-acylhydrazones having no amide hy-
drogen (Figure 1) were subjected to the reaction, no
product was obtained at all. This strongly supports that
deprotonation of the amide hydrogen by a base is an in-
dispensable process in this reaction.
amount of Sc(OTf)3 and one equivalent of NEt3 acceler-
ated the reaction rate more than NEt3; the sterically hin-
dered pivalaldehyde-derived N-benzoylhydrazone 1f
gave a high yield after 24 h (entry 11).
To get mechanistic insights into the reaction pathway,
the reaction of 1a with TMSCN (1.0 equiv.) and NEt3
(1.0 equiv.) in deuterated dichloromethane at room
Figure 1. Unreactive N-acylhydrazones.
1
temperature was monitored by H NMR. As the reac-
tion proceeded, new quartet and doublet signals gradu-
ally appeared at 4.11 ppm and at 5.34 ppm, respectively.
In the case of aromatic aldehyde- or ketone-derived
After ca. 18 h, the reaction showed almost no change substrates, the addition of a catalytic amount of
and was quenched by deuterated methanol (CD3OD). Sc(OTf)3 was necessary to promote the reaction. This
These new two peaks were completely converted to a might be ascribed to the fact that the addition of cyanide
triplet at 4.08 ppm and a broad singlet at 5.32 ppm, re- requires deconjugation of the stable intermediates O-Si-
spectively. 13C NMR analysis of the reaction was also 1. Thus, Sc(OTf)3 might act as a Lewis acid to activate O-
conducted at the same time and a characteristic new Si-1 (Scheme 3). The higher reactivity of hydrazones
peak emerged at 51.1 ppm, which was shifted to with electron-donating substituents might be attributed
52.8 ppm when quenched by CD3OD. The initial prod- to facile protonation or Lewis acid coordination of O-Si-
uct could be assigned to an O-trimethylsilylated cyana- 1, which was possibly rate-determining.
tion product (O-Si-2a), whose structure was further con-
firmed by silylation of 2a with TMSCl and NEt3 and ketone-derived N-acylhydrazones reacted with
(Scheme 1). TMSCN to afford a-hydrazinonitriles in the presence
In summary, we have found that aliphatic aldehyde-
To account for the formation ofO-Si-2a and that gen- of an amine. In addition, a catalytic amount of Sc(OTf)3
eral Lewis bases such as phosphine oxides were ineffec- was found to promote the reaction of less reactive N-
tive for the current reaction, it is likely that triethyla- acylhydrazones in cooperation with the amine base. A
mine works as a Brønsted base. A possible mechanism mechanistic study indicated that the amine worked as
is shown in Scheme 2. The reaction is initiated by depro- a Brønsted base, which initiated the reaction by abstrac-
tonation of the amide hydrogen of an N-acylhydrazone, tion of the amide hydrogen of the substrate. This method
¼
while the oxy anion is trapped by TMSCN to release cy- is a rare example of the cyanation of C N bonds promot-
anide ion (CNꢀ). Then the O-silylated substrate O-Si-1 ed by both Brønsted base and Lewis acid.[13] Further in-
is attacked by CNꢀ and protonated by the ammonium vestigations to develop enantioselective versions of this
salt to form an O-silylated cyanation product (O-Si-2) reaction are now in progress.
Adv. Synth. Catal. 2005, 347, 1899 – 1903
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Hideyuki Konishi et al.
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Scheme 2. Assumed reaction mechanism.
General Procedure for Cyanation of N-
Benzoylhydrazones 1 using NEt3 and Sc(OTf)3
A
mixture of 1 (0.25 mmol) and Sc(OTf)3 (24.6 mg,
0.050 mmol) in dichloromethane (1.0 mL) was stirred at
room temperature for 15 min. NEt3 (35 mL, 0.25 mmol) was
added to the mixture and then the whole was cooled at
ꢀ208C. To the mixture was added dropwise TMSCN (50mL,
0.38 mmol) at ꢀ208C. After stirring at ꢀ208C for the indicat-
ed time, the reaction was quenched by adding saturated aque-
ous NH4Cl (3.0 mL). The organic layer was separated and the
aqueous layer was extracted with dichloromethane (three
times). The combined organic layers were dried over Na2SO4,
filtered, and concentrated under vacuum. The residue was pu-
rified by preparative TLC on silica gel to afford product 2.
Scheme 3. Plausible role of Sc(OTf)3.
Experimental Section
General Procedure for Cyanation of N-
Benzoylhydrazones 1 using NEt3
Acknowledgements
This work was partially supported by CREST,SORST,and
ERATO,Japan Science and Technology Agency (JST),and
Grant-in-Aid for Scientific Research from the Japan Society of
the Promotion of Sciences (JSPS).
To a mixture of 1 (0.25 mmol) and NEt3 (0.25 mmol) in di-
chloromethane (1.0 mL) was added TMSCN (50 mL,
0.38 mmol) at room temperature. After stirring at room tem-
perature for the indicated time, the reaction was quenched
by adding saturated aqueous NH4Cl (3.0 mL). The organic lay-
er was separated and the aqueous layer was extracted with di-
chloromethane (three times). The combined organic layers References and Notes
were dried over Na2SO4, filtered, and concentrated under vac-
uum. The residue was purified by preparative TLC on silica gel
to afford product 2.
¼
[1] Recent examples of cyanation of C N bonds, see: a) S.
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1902
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Adv. Synth. Catal. 2005, 347, 1899 – 1903

Cyanation of N-Acylhydrazones with Trimethylsilyl Cyanide
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[12] Crystallographic data (excluding structure factors) for
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with the Cambridge Crystallographic Data Centre as
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of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB21EZ, UK
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ccdc.cam.ac.uk].
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¼
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Adv. Synth. Catal. 2005, 347, 1899 – 1903
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1903