Uncatalyzed Strecker-type reaction of N,N-dialkylhydrazones in pure water

Article abstract of DOI:10.1002/ejoc.200800297

Aldehyde and ketone N,N-dialkylhydrazones behave as a stable class of imine surrogates exhibiting a unique reactivity in the Strecker reaction with in situ generated HCN, that proceeds in pure water in the absence of co-solvents, catalysts or promoters. E

Full text of DOI:10.1002/ejoc.200800297

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800297
Uncatalyzed Strecker-Type Reaction of N,N-Dialkylhydrazones in Pure Water
Eugenia Marqués-López,[a] Raquel P. Herrera,[b][‡] Rosario Fernández,*[a] and
José M. Lassaletta*[b]
Keywords: Synthetic methods / Hydrazones / Nucleophilic addition / Water / Hydrazino nitriles
Aldehyde and ketone N,N-dialkylhydrazones behave as a
stable class of imine surrogates exhibiting a unique reactivity
in the Strecker reaction with in situ generated HCN, that pro-
ceeds in pure water in the absence of co-solvents, catalysts
or promoters. Experimental evidence suggests that the reac-
tion is assisted by an intramolecular activation of HCN by
the dialkyl amino lone pair.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
One of the limitations of the Strecker reaction is related
to the instability, difficult preparation and storage of the
imine substrates 1, in particular in the aliphatic series.
Thanks to their higher stability, N-acylhydrazones 2 and
N,N-dialkylhydrazones 3 (Figure 1) are privileged sub-
strates that have been used as imine surrogates in reactions
with cyanide, HCN, or TMSCN using a variety of catalysts
or promoters. For instance, compounds 2 have been acti-
vated by phase-transfer catalysts,[13] (PYBOX)lanthanide
complexes,[14] or a combination of a Brønsted base and a
Introduction
The development of environment-friendly organic reac-
tions (green chemistry) is a very active field of research,
emerged as a response to the increasing regulatory pressure
directed to the elimination/reduction of chemical waste.[1]
Implementation of methods that avoid the use of organic
solvents and/or metal-based catalysts are fundamental stra-
tegies in this field. Among the alternative reaction media,
reactions that can be performed in pure water are particu-
larly valuable,[2] also for the added economical benefit.
The Strecker reaction is an industrially relevant reaction
useful for the synthesis of α-amino nitriles, direct precursors
of α-amino acids.[3] Due to the limitations of the original
method, this reaction is generally carried out in organic sol-
vents, by the nucleophilic addition of HCN or TMSCN to
imines 1 (preformed or not) using different Lewis acid or
base catalysts.[4] There are also reports of Strecker reactions
performed in aqueous media,[5] including water-containing
DMF,[6] polyethylene glycol/water (2:1),[7] and β-cyclodex-
trin in water/methanol (9:1).[8] The Sc(OTf)3-catalyzed one-
pot Strecker reaction from aldehydes and benzhydrylamine
takes place in pure water, but toxic tributyltin cyanide is
required as the reagent.[9] Strecker-type reactions in ionic
liquids have also been recently reported,[10] but this ap-
proach has obvious economic disadvantages and ionic li-
quids are not free of toxicity[11] and biodegradability[12] is-
sues.
Lewis acid,[15] whereas compounds 3 react with TMSCN in
[16]
the presence of TiCl4
or concentrated LiClO4 in diethyl
ether solution.[17]
Figure 1. Imines 1, N-acylhydrazones 2 and N,N-dialkylhydrazones
3.
Results and Discussion
Recently, we started investigations directed to explore the
organocatalytic activation of N,N-dialkylhydrazones as im-
ine surrogates in the Strecker reaction. Preliminary screen-
ings were performed in CH2Cl2 as the solvent, with
TMSCN as the cyanide source and hydrazone 3a as a
[a] Departamento de Química Orgánica, Facultad de Química, model substrate. In the background studies, we realized that
Universidad de Sevilla,
the addition of MeOH or PhOH as additives proved to be
Apdo. de Correos No. 1203, 41071 Seville, Spain
beneficial for the reactivity, leading to partial conversions
after relatively short reaction times (Table 1, Entries 2, 3).
This is a surprising result because related Strecker-type ad-
ditions to different imine surrogates require the activation
by catalysts of diverse nature,[18] and it suggests that HCN,
produced in situ by the reaction of MeOH or PhOH with
TMSCN, spontaneously adds to the hydrazone C=N bond.
E-mail: ffernan@us.es
[b] Instituto de Investigaciones Químicas, CSIC-US,
c/ Américo Vespucio 49, Isla de la Cartuja, 41092 Seville, Spain
E-mail: jmlassa@iiq.csic.es
[‡] Present address: Dpto. de Química Orgánica, Instituto de Cien-
cia de Materiales de Aragón, CSIC-Univ. de Zaragoza, 50009
Zaragoza, Spain
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
Eur. J. Org. Chem. 2008, 3457–3460
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3457

E. Marqués-López, R. P. Herrera, R. Fernández, J. M. Lassaletta
SHORT COMMUNICATION
Table 1. Uncatalyzed Strecker reaction of 3a with TMSCN at room
More hindered dialkyl (3h–j) or aryl alkyl ketone hydra-
zones (3k), however, reacted at slower rates but also reached
high conversions of products 4h–k in reasonable reaction
times when 2–3 equiv. of TMSCN were employed (En-
tries 9–12). Though piperidine derivatives were initially cho-
sen as substrates for their poorer n–π conjugation with re-
spect to other hydrazones,[19] the simplest dimethylamino
aldehyde and ketone derivatives 3aЈ and 3kЈ showed a sim-
ilar reactivity (Entries 2 and 13).
temperature.[a]
Entry
Solvent
Additive Time [h] Conversion [%][b]
The unexpected reactivity of hydrazones was suspected
to be related with the presence of the dialkylamino group
as a differential structural motif. In order to gain a better
insight into the role of the N(sp3) lone pair in the observed
reactivity, N-acyl derivative 5 was also used as substrate un-
der the same reaction conditions (Scheme 1). In spite of the
similar stability and the higher electrophilicity provided by
the carbonyl group, this compound exhibited a very low
reactivity with TMSCN in water compared with the N-di-
alkyl analogues, affording a low conversion (Ͻ 5%) to
product 6[20] under the above conditions. This result indi-
cates that the availability of the N-lone pair is essential for
the reactivity.
1
2
3
4
5
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
H2O
–
18
3
3
3
3
4
14
31
97
Ͼ99
MeOH[c]
PhOH[c]
–
–
[a] Experimental conditions: TMSCN (0.2 mmol) was added to a
solution of hydrazone 3a (0.1 mmol) in 0.5 mL of solvent. [b] Cal-
culated by 1H NMR analysis of the crude reaction mixtures. [c]
0.2 mmol of additive.
Therefore, the reaction was performed in pure MeOH to
afford cleanly the addition product in excellent yield (En-
try 4). Disregarding eventual solubility issues, we decided
to look at the possibility of performing the uncatalyzed re-
action in pure water. Satisfyingly, the reaction also took
place smoothly in short reaction times to afford the product
4a in nearly quantitative yield (Entry 5).
The scope of the reaction was explored by using a variety
of aldehyde N,N-dialkylhydrazones 3a–g of diverse nature,
and, interestingly, even ketone derivatives 3h–k could be
used with the results collected in Table 2. These data indi-
cate that the reaction is highly efficient for all types of sub-
Scheme 1. Reactivity of N-acylhydrazone 5.
Two different mechanisms that explain the unexpected
strates. The more reactive aldehyde derivatives 3a–g react reactivity induced by the dialkylamino group can be pos-
in 5–8 h, requiring only a slight excess of reagent to reach tulated. first possibility considered (mechanism A,
complete conversions and providing adducts 4a–g in excel- Scheme 2) consists of the activation of the TMSCN reagent
lent yields (Entries 1, 3–8).
by attack of the silicon atom by the NR2 lone pair.[21] This
A
Table 2. Uncatalyzed Strecker reaction of N,N-dialkylhydrazones with TMSCN in water.[a]
Entry
Hydrazone
R1
R2
NR2
TMSCN [equiv.]
Product
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
3a
3aЈ
3b
3c
3d
3e
3f
3g
3h
3i
PhCH2CH2
PhCH2CH2
Me
H
H
H
H
H
H
H
H
piperidin-1-yl
NMe2
1.5
1.5
1.2
1.2
1.2
1.2
1.5
1.5
2
2
2
3
3
4a
4aЈ
4b
4c
4d
4e
4f
4g
4h
4i
7
7
7
8
7
5
7
7
15
15
18
17
72
90
90
90
89
95
92
91
90
94
piperidin-1-yl
piperidin-1-yl
piperidin-1-yl
piperidin-1-yl
piperidin-1-yl
piperidin-1-yl
piperidin-1-yl
piperidin-1-yl
piperidin-1-yl
piperidin-1-yl
NMe2
iPr
iBu
tBu
cyclohexyl
cyclopropyl
–(CH2)4–
tBu
cyclopropyl
Ph
Me
Me
Me
Me
90
3j
3k
3kЈ
4j
4k
4kЈ
93[c]
88[d]
71
Ph
[a] Experimental conditions: TMSCN was added to a mixture of hydrazone 3 (0.2 mmol) and H2O (0.5 mL). Product 4 was isolated by
extraction with AcOEt from the reaction media. [b] Isolated yield. [c] Contains 7% of unreacted ketone hydrazone. [d] Contains 9% of
unreacted ketone hydrazone.
3458
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3457–3460

Uncatalyzed Strecker-Type Reaction of N,N-Dialkylhydrazones in Pure Water
Scheme 2. Activation of cyanide for the addition to hydrazones.
leads to a pentavalent silicon transition state, in which the
nucleophilic addition of cyanide to the azomethine carbon
atom is intramolecularly assisted by the neighbouring
amino group, trough a transition state where the silicon
atom shifts to the nitrogen atom. In this scenario, a cooper-
ative activation of the C=N bond by water is postulated to
explain the absence of reactivity in other solvents under
non-catalyzed conditions. Alternatively, a second situation
Scheme 3. One-pot, direct synthesis of hydrazino nitriles 4 from
aldehydes.
(mechanism B) can be envisaged, in which a previous hy-
drolysis of TMSCN takes place to afford HCN that is then
“activated” in a similar way.[22]
Therefore, additional experiments were also carried out
by using a 1:1 mixture of AcOH/KCN for the in situ gener-
ation of HCN in the reaction media. The reaction also pro-
ceeds to give the same adducts in similar yields and with
the same reaction rates. This fact strongly suggests that a
previous hydrolysis of TMSCN occurs, thereby enabling the
reaction to progress through mechanism B.[23]
provided by the intramolecular activation of HCN, driving
the addition of cyanide to the neighbour azomethine car-
bon atom and making the use of external catalysts unneces-
sary.
Experimental Section
As mentioned above, stronger electrophiles containing
more polarized carbon–heteroatom bonds do not react with
TMSCN or HCN in the absence of catalysts. This circum-
stance makes it possible to perform the reaction in a one-
pot fashion starting from the aldehyde (not reactive), the
hydrazine and TMSCN in water (Scheme 3). By using these
conditions, hydrazones 3d and 3g afforded exclusively prod-
ucts 4d and 4g in 94 and 84% yield, respectively. The alter-
native in situ generation of HCN from AcOH and KCN is
also a suitable strategy for the one-pot synthesis of adducts
4d and 4g, obtained in similar 90 and 80% yield, respec-
tively.
General Procedure for the Synthesis of Hydrazino Nitriles 4a–k, 4aЈ,
and 4kЈ from Hydrazones 3: TMSCN (1.2–3.0 equiv.) was added to
a solution of hydrazone 3a–k, 3aЈ, or 3kЈ (0.2 mmol) in H2O
(0.5 mL, 0.4 ), and the mixture was stirred until total consump-
tion of starting material (5–72 h), diluted with satd. NaHCO3
(2 mL), extracted with AcOEt (3ϫ1 mL), dried (Na2SO4), filtered,
and concentrated to yield compounds 4 in pure form.
Direct Three-Component Reactions with TMSCN as the Cyanide
Source: A mixture of hydrazine (130 µL, 1.2 mmol) and isovaleral-
dehyde or cyclopropanecarbaldehyde (1 mmol) was stirred for
10 min. H2O (2.5 mL) and TMSCN (268 µL, 2 mmol) were then
added.[24] The mixture was stirred until total consumption of the
starting material (8 h), then satd. NaHCO3 (2 mL) was added, and
the mixture was extracted with AcOEt (3ϫ1 mL). The combined
organic phases were dried with Na2SO4, filtered, and concentrated
to afford compounds 4 in pure form.
Conclusions
The N-(dialkylamino) group in hydrazones plays a dual
role in that it allows their use as substrates for the uncata-
lyzed hydrocyanation in pure water: (a) stabilization of the
substrate related with the nǞπ conjugation that minimizes
Direct Three-Component Reactions with KCN as the Cyanide
Source: Hydrazine (130 µL, 1.2 mmol) and isovaleraldehyde or cy-
clopropanecarbaldehyde (1 mmol) were stirred for 10 min. H2O
(2.5 mL, 0.4 ), KCN (1.4 mmol or 2 mmol) and AcOH (1.4 mmol
the tendency to tautomerization, and (b) high reactivity or 2 mmol) were consecutively added.[23] The mixture was stirred
Eur. J. Org. Chem. 2008, 3457–3460
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3459

E. Marqués-López, R. P. Herrera, R. Fernández, J. M. Lassaletta
SHORT COMMUNICATION
[12]
N. Gathergood, M. Teresa Gascia, P. J. Scammells, Green
Chem. 2004, 6, 166–175.
T. Chiba, M. Okimoto, Synthesis 1990, 209–211.
J. M. Keith, E. M. Jacobsen, Org. Lett. 2004, 6, 153–155.
H. Konishi, C. Ogawa, M. Sugiura, S. Kobayashi, Adv. Synth.
Catal. 2005, 347, 1899–1903.
D. Enders, M. Moser, Tetrahedron Lett. 2003, 44, 8479–8481.
A. Heydari, R. Baharfar, M. Rezaie, S. M. Aslanzadeh, Chem.
Lett. 2002, 368–369.
until total consumption of the starting material (18 h), then satd.
NaHCO3 (2 mL) was added, and the mixture was extracted with
AcOEt (3ϫ1 mL). The combined organic phases were dried with
Na2SO4, filtered, and concentrated to afford compounds 4.
[13]
[14]
[15]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data for com-
[16]
[17]
1
pounds 3 and 4. H and 13C NMR spectra for new compounds.
[18]
[19]
For a remarkable exception, see: R. Martínez, D. J. Ramón, M.
Yus, Tetrahedron Lett. 2005, 46, 8471–8474.
Acknowledgments
The planar conformations required for the nǞπ conjugation
in the N–N=C system are efficiently inhibited in this case by
the strain associated with the loss of the preferred chair-like
conformation of the six-membered piperidine ring. This partic-
ularity increases the electrophilic character of the azomethine
carbon atom in these derivatives with respect to other N,N-
dialkylhydrazones.
We thank the Spanish Ministerio de Ciencia y Tecnología (grants
CTQ2007-61915, CTQ2007-60244, and predoctoral fellowship to
E. M.-L.) and the Junta de Andalucía (2005/FQM-658) for finan-
cial support. R. P. H. thanks the Consejo Superior de Investiga-
ciones Científicas for a postdoctoral contract.
[20]
[21]
After 7 h at room temp., the starting material remained essen-
tially unchanged. Only traces of product 6 were detected by 1H
NMR analysis {300 MHz, [D6]acetone: δ = 4.11 (dd, J = 6.9,
13.2 Hz, 1 H)} and MS-FAB (m/z = 266) of the crude reaction
mixture.
The activation of TMSCN by Lewis bases is well established:
a) S. Kobayashi, Y. Tsuchiya, T. Mukaiyama, Chem. Lett. 1991,
537–540; b) I. S. Kruchok, I. I. Gerus, V. P. Kukhar, Tetrahe-
dron 2000, 56, 6533–6539; c) T. Ishikawa, T. Isobe, Chem. Eur.
J. 2002, 8, 552–557; d) S. S. Kim, G. Rajagopal, D. W. Kim,
D. H. Song, Synth. Commun. 2004, 34, 2973–2980; e) A. Baeza,
C. Nájera, M. G. Retamosa, J. M. Sansano, Synthesis 2005,
2787–2797; f) B. M. Fetterly, J. G. Verkade, Tetrahedron Lett.
2005, 46, 8061–8066; g) J. J. Song, F. Gallou, J. T. Reeves, Z.
Tan, N. K. Yee, C. H. Senanayake, J. Org. Chem. 2006, 71,
1273–1276.
For a recent kinetic and computational study of a related terti-
ary amine assisted ketone cyanation, see: S. J. Zuend, E. N. Ja-
cobsen, J. Am. Chem. Soc. 2007, 129, 15872–15883.
As expected, no reaction takes place when KCN alone is added
to the hydrazone in water.
Reactions performed without a preliminary stirring of the alde-
hyde and the hydrazine also afforded products 4d or 4g, and no
cyanohydrin resulting from the hydrocyanation of the aldehyde
could be detected. The reactions, however, were not so clean
under these conditions and the yields were lower. This can be
attributed to a partial silylation or protonation of the hydraz-
ine.
[1] For a recent monograph, see: R. A. Sheldon, I. Arends, U.
Hanefeld in Green Chemistry and Catalysis, Wiley-VCH,
Weinheim, 2007.
[2] a) C.-J. Li, T.-H. Chan, Comprehensive Organic Reactions in
Aqueous Media, John Wiley & Sons, Inc., Hoboken, 2007; b)
Organic Reactions in Water – Principles, Strategies and Applica-
tions (Ed.: U. M. Lindström), Blackwell Publishing, Oxford,
2007; c) C.-J. Li, L. Chen, Chem. Soc. Rev. 2006, 35, 68–82.
[3] A. Strecker, Ann. Chem. Pharm. 1850, 75, 27–45.
[4] H. Groger, Chem. Rev. 2003, 103, 2795–2827.
[5] From the “green” point of view, reactions in water do not in-
clude reactions “in aqueous media” or “in the presence of
water”. For a critical essay, see: D. G. Blackmond, A. Arm-
strong, V. Coombe, A. Well, Angew. Chem. Int. Ed. 2007, 46,
3798–3800.
[6] E. Takahashi, H. Fujisawa, T. Yanai, T. Mukaiyama, Chem.
Lett. 2005, 34, 318–319.
[7] M. A. Kumar, M. F. S. Babu, K. Srinivasulu, Y. B. Kiran, C. S.
Reddy, J. Mol. Catal. A 2007, 265, 268–271.
[8] K. Surandra, N. S. Krishnaveni, A. Mahesh, K. R. Rao, J. Org.
Chem. 2006, 71, 2532–2534.
[9] S. Kobayashi, T. Busujima, S. Nagayama, Chem. Commun.
1998, 981–982.
[22]
[23]
[24]
[10] J. S. Yadav, B. V. S. Reddy, B. Eshwaraiah, M. Srinivas, P. Vish-
numurthy, New J. Chem. 2003, 27, 462–465.
[11] B. Jastorff, K. Mölter, P. Behrend, U. Bottin-Weber, J. Filser,
A. Heimers, B. Ondruschka, J. Ranke, M. Schaefer, H.
Schröder, A. Stark, P. Stepnowski, F. Stock, R. Störmann, S.
Stolte, U. Welz-Biermann, S. Ziegert, J. Thöming, Green Chem.
2005, 7, 362–372, and references therein.
Received: March 19, 2008
Published Online: June 3, 2008
3460
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3457–3460