"On water" nucleophilic addition of formaldehyde N,N-dialkylhydrazones to α-keto esters

Article abstract of DOI:10.1002/asia.201100174

Water solves the problem: The use of pure water as the reaction mixture is key for the nucleophilic addition of formaldehyde hydrazones to α-keto esters, leading to highly functionalized carbinols in high yields and short reaction times. The need for heterogeneous conditions and the observed solvent kinetic isotope effect are in agreement with the proposed "on water" activation. Copyright

Full text of DOI:10.1002/asia.201100174

DOI: 10.1002/asia.201100174
“On Water” Nucleophilic Addition of Formaldehyde N,N-Dialkylhydrazones
to a-Keto Esters
Ana Crespo-PeÇa,[a] Eloꢀsa Martꢀn-Zamora,[b] Rosario Fernꢁndez,*[b] and
Josꢂ M. Lassaletta*[a]
In memory of Rafael Suau
The need for sustainable chemical production is increas-
ingly stimulating research in new methodologies designed to
achieve a smaller environmental impact.[1] Such processes, in
general associated with the reduction of large amounts of
hazardous waste, are the central objective of the discipline
coined “green chemistry”. The substitution/reduction of or-
ganic solvents by alternative reaction media has emerged as
one of the most-active lines of research in this context. The
use of water appears to be one of the most-attractive possi-
bilities in this field, combining the desired reduction of
waste with simpler procedures compared to alternatives
such as ionic liquids, supercritical CO2, and fluorous media.
An important additional advantage for the use of pure
Scheme 1. Formaldehyde N,N-dialkylhydrazones as neutral d1 synthons.
water is the obvious reduction of costs.[2,3]
We have been interested in the ambiphilic properties of
hydrazones, which allow them to react as electrophilic sub-
strates, but also as nucleophilic species depending on struc-
ture and conditions. Formaldehyde N,N-dialkylhydrazones
(FDAHs) posses an enhanced nucleophilic character that
has been exploited for the synthesis of a variety of bifunc-
tional compounds (Scheme 1). The availability of efficient
functional-group transformations makes these compounds
appear as formyl anion and/or cyanide equivalents.[4] In par-
ticular, it has been possible to perform addition reactions to
carbonyl compounds that take place either spontaneously in
the case of activated substrates, such as a-alkoxy-
(amino)aldehydes[5] or trifluoromethylketones,[6] or by acti-
ACHTUNGTRENNUNG
vation with Lewis acids in the case of less-reactive, unacti-
vated aldehydes.[7]
Herein, we report our results on the nucleophilic addition
of formaldehyde hydrazones to readily available a-keto
esters and the unexpected, dramatic effect that the use of
water has on the reaction rates.
Recently, we began to explore the organocatalytic activa-
tion of Michael acceptors for the nucleophilic addition of
formaldehyde N,N-dialkylhydrazones,[8] whilst independent
studies have demonstrated the suitability of organocatalytic
activation for the addition to imines.[9–11] In this context, we
wanted to study the unprecedented addition to a-keto esters
4 for the synthesis of highly functionalized quaternary carbi-
nols (5). Preliminary screenings, performed in dichlorome-
thane as the solvent and using the relatively hindered iso-
[a] A. Crespo-PeÇa, Dr. J. M. Lassaletta
Instituto de Investigaciones Quꢀmicas (CSIC-US)
Amꢁrico Vespucio 49, E-41092 Seville (Spain)
Fax : (+34)954460565
E-mail: jmlassa@iiq.csic.es
propyl-substituted derivative 4e as
a model substrate
[b] Prof. E. Martꢀn-Zamora, Prof. R. Fernꢂndez
Departamento de Quꢀmica Orgꢂnica
Universidad de Sevilla
(Scheme 2), showed that the nature of the N-dialkylamino
group had a dramatic influence on the reactivity of the hy-
drazone. Thus, neither hydrazones 1 nor 3, which contained
N-dimethylamino and piperidino groups, respectively, react-
ed with 4e even over prolonged reaction times (Table 1, en-
Profesor Garcꢀa Gonzꢂlez 1, E-41012, Seville, Spain
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100174.
Chem. Asian J. 2011, 6, 2287 – 2290
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2287

COMMUNICATION
The scope of the reaction was explored by using a variety
of a-keto esters 4a–i, including aliphatic (Table 2, entries 1,
3–9), trifluoromethyl-substituted (Table 2, entry 2), aromatic
(Table 2, entries 10–13) and heteroaromatic derivatives
(Table 2, entries 14 and 15). The collected data indicate that
the reaction is highly efficient for all types of substrate, with
the more-reactive 4a,b,d,e reacting at room temperature to
reach high conversions and yields of adducts 5a,b,d,e in
short reaction times (Table 2, entries 1,2,5, and 6, respective-
ly). In the case of less-reactive substrates 4c,f–i, longer reac-
tion times were required and poorer conversions and yields
were achieved (Table 2, entries 3, 8, 10, 12, and 14, respec-
tively). However, the addition of a catalytic amount of 6 sig-
nificantly improved the reactivity, leading to better yields of
products 5c,f–i in reduced reaction times (Table 2, entries 4,
9, 11, 13, and 15). Analytically pure samples were obtained
by chromatographic purification using organic solvents, but
a representative experiment was also performed to explore
the possibility of avoiding organic solvents: the model sub-
strate 4e was reacted with 1.3 equivalents of 2. As this re-
agent has a low boiling point (50–558C at 200 Torr),[6] the
slight excess of 2 was removed upon concentration and
drying of the product in vacuo (Table 2, entry 7). In this
way, nearly pure 5e (>90% by GC analysis, see the
1H NMR spectrum in the Supporting Information) was ob-
tained without using any organic solvents.
Scheme 2. Reactivity of FDAHs 1–3 toward a-keto ester 4e.
tries 1 and 2). Further activation of 4e by addition of 1,3-
bisACHTUNGTRENNUNG[3,5-bis(trifluoromethyl)phenyl]thiourea (6) as a catalyst
was also attempted unsuccessfully (Table 1, entry 3). In
sharp contrast, however, pyrrolidine derivative 2 exhibited,
as expected,[12]
a relatively higher reactivity (Table 1,
Table 1. Selected preliminary experiments.[a]
Entry
Solvent
Reagent
Cat. 6 [%]
t [h]
Conv. [%][b]
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
MeOH
1
3
1
2
2
2
2
2
2
2
2
2
2
–
–
10
–
–
–
10
–
–
168
168
168
72
24
24
72
3
3
24
3
3
24
<5
<5
<5
29
4
15
CH2Cl2
56
H2O[c]
>99
<5
15
<5
10
9
neat
neat
The significant increase in reactivity suggests the active
participation of water in the reaction mechanism, beyond
any hydrophobic effect or solvation phenomena that might
also be used to explain the above results. This hypothesis is
in agreement with the recently proposed acid-catalysis
mechanism,[15] and experimental support was also obtained
from the comparison of the reaction rates in pure water and
10
11
12
13
CH2Cl2/H2O[d]
THF/H2O[d]
THF/H2O[d]
–
–
–
52
[a] Experimental conditions: Hydrazone (0.5 mmol) was added to a solu-
tion of keto ester 4e (1 mmol) in 1.0 mL of solvent. [b] Determined by
1H NMR analysis of the crude reaction mixtures. [c] An emulsion was
formed. [d] 1:1 mixture. [e] Homogeneous reaction, 1:1 mixture.
1
deuterium oxide. Thus, monitoring the reaction by H NMR
spectroscopy revealed a considerable solvent kinetic isotope
entry 4). Further experiments were performed in toluene
and methanol to identify any relevant solvent effect
(Table 1, entries 5 and 6). However, these experiments indi-
cated a limited reactivity in most cases, with the reaction re-
quiring a long time to reach reasonable conversion rates.
The addition of 6 as the catalyst produced a noticeable im-
provement for the reaction performed in dichloromethane
(Table 1, entry 7), but the required reaction times were still
too long. Finally, we decided to explore the possibility of
performing the reaction “on water”, that is, exploiting the
rate acceleration observed for some organic reactions when
carried out in aqueous suspension.[13,14] To our delight, the
reaction of 4e with 2 performed using pure water as the re-
action medium reached complete conversion after only
3 hours at room temperature, without the need of any cata-
lyst or co-solvent (Table 1, entry 8). Further experiments
were conducted to understand the nature of the activation.
When the reaction was carried out in the absence of solvent
(Table 1, entries 9 and 10), in a 1:1 dichloromethane/water
mixture (Table 1, entry 11), and in other aqueous (yet homo-
geneous) conditions (Table 1, entries 12 and 13), the relative
lack of reactivity supported the proposed “on water” effect.
effect as estimated from the observed half-lives of 2 in its re-
action with 4e using H2O (t1/2 =82 min) and D2O (t1/2
=
140 min) as reaction media.
ꢀ
This fact reveals that the cleavage of at least one O H(D)
bond takes place in the rate-limiting step. On the other
hand, the poor reactivity observed in methanol could be ten-
tatively explained by an activation mechanism in which the
two protons of water are involved. In line with this analysis,
it can be tentatively proposed that water behaves as a cata-
lyst binding the two reagents together whilst acting as a
proton source for the acidic activation of the carbonyl
group, as depicted in Scheme 3. According to this model, a
ternary complex I would be initially formed, from which the
ꢀ
C C bond-formation takes place simultaneously with the
cleavage of a water molecule to yield a diazenium-hydroxide
intermediate II in the rate-limiting step. This zwitterionic in-
termediate, stabilized by a N,O electrostatic interaction,
would then easily afford product 5 after deprotonation of
the methylene group with the regeneration of a molecule of
water. The proposed association of water with the hydra-
zone sp2 N atom has been previously proposed to explain
the reactivity of related hydrazones in hydrocyanation reac-
2288
www.chemasianj.org
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2287 – 2290

“On Water” Nucleophilic Addition of Formaldehyde N,N-Dialkylhydrazones to a-Keto Esters
Table 2. Uncatalyzed and catalyzed nucleophilic addition of 2 to a-keto esters 4 in
asymmetric addition to g,d-unsaturated b-keto
esters.[8] The model is also consistent with the ex-
perimentally observed activation of the a-keto ester
4 by thiourea 6 as depicted in complex IB. It should
be stressed that hydrogen bonding to the sp2
N atom of the reagent does not interfere with the
n!p conjugation that makes the azomethine
carbon a nucleophilic center.
In order to demonstrate the synthetic utility of
adducts 5, representative compounds 5e–g were
transformed into highly functionalized cyanohydrins
7e–g by using magnesium monoperoxy phthalate
hexahydrate (MMPP·6H2O)[17] as the reagent
(Scheme 4).
pure water.[a]
Entry
Keto ester 4
Cat. 6
[mol%]
Product 5
t
Conversion Yield
[h] [%][b]
[%][c]
1
–
–
–
1
1
6
>99
>99
25
95
4a
4b
5a
5b
2
3
96
n.d.
In summary, the exceptional stability of formal-
dehyde hydrazones toward hydrolysis or polymeri-
zation makes it possible to perform reactions in
pure water. This reaction medium was shown to en-
hance the reactivity of the azomethine carbon for
nucleophilic addition to a variety of a-keto esters,
thus yielding highly functionalized tertiary carbinols
in good to excellent yields. A significant solvent ki-
netic isotope effect was observed, pointing to the
active participation of water as an acidic catalyst
for the reaction.
4c
4c
5c
5c
4
5
10
-
6
6
>99
97
78
85
4d
5d
6
–
–
3
>99
79
4e
4e
5e
5e
7[d]
5
>99
>99[e]
Experimental Section
8
1.3
80
77
General Procedure for the Uncatalyzed Addition of 1-
Methyleneaminopyrrolidine (2) to Ethyl 2-oxo-carboxylates 4
(Method A)
4 f
4 f
5 f
5 f
9
10
–
1.3 100
99
45
1-Methyleneaminopyrrolidine (2; 0.5 mmol, 53 mL) was added
to a suspension of keto ester 4 (1 mmol) in H2O (1 mL) and
the mixture was stirred at RT until completion (determined by
TLC analysis). The mixture was then diluted with H2O (5 mL)
and extracted with Et2O (3ꢄ5 mL). The organic layer was
dried (Na2SO4), concentrated, and the resulting residue was
purified by column chromatography on silica gel to yield pure
product 5.
10
8
48
4g
4g
5g
5g
11
12
10
–
8
1
88
37
82
n.d.
General Procedure for Catalyzed Reactions (Method B)
A mixture of a-keto ester 4 (1 mmol) and 1,3-bisACHTUNGTRENNUNG[3,5-bis(tri-
4h
4h
5h
5h
fluoromethyl)phenyl]thiourea (6; 0.05 mmol) in water (1 mL)
was stirred for 15 min at RT and then 1-methyleneamino pyr-
rolidine (2; 0.5 mmol, 53 mL) was added at once. After comple-
tion (determined by TLC analysis), the mixture was treated as
described in method A.
13
14
10
–
1
8
99
25
89
n.d.
General Procedure for the Synthesis of Cyanohydrins 7
4i
4i
5i
5i
15
10
8
72
63
Magnesium monoperoxy phthalate hexahydrate (MMPP
·6H2O) (1.1 mmol) was added to a stirred solution of hydra-
zone 5 (1 mmol) in CH2Cl2 (10 mL) and the mixture was
stirred at room temperature for 6 h. H2O (10 mL) and CH2Cl2
(10 mL) were added and the organic layer was washed with a
saturated solution of NaCl (3ꢄ10 mL), dried (Na2SO4), con-
centrated, and the resulting residue was purified by column
chromatography on silica gel to yield pure product 7.
[a] Reactions were performed at room temperature at 0.5 mmol scale. [b] Determined
by H NMR analysis of the crude reaction mixtures. [c] Yield of isolated product after
column chromatography on silica gel. [d] Reaction performed with 1.3 equiv of hydra-
zone 2. [e] Yield of crude product after removal of water in vacuo. Purity>90% (de-
termined by GC analysis).
1
Spectral and analytical data for compounds 5 and 7 are given
in the Supporting Information.
tions performed in pure water.[16] Moreover, a similar hydro-
gen-bonding interaction between 2 and a hydroxyl group of
a catalyst has been demonstrated to be essential in the
Chem. Asian J. 2011, 6, 2287 – 2290
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2289

R. Fernꢂndez, J. M. Lassaletta et al.
COMMUNICATION
[2] a) C.-J. Li, T.-H. Chan, Comprehensive Organic Reactions in Aque-
ous Media, Wiley, Hoboken, NJ, 2007; b) Organic Reactions in
Water Principles, Strategies and Applications (Ed.: U. M. Lindstrçm),
Blackwell Publishing, Oxford, UK, 2007; c) C.-J. Li, L. Chen, Chem.
Soc. Rev. 2006, 35, 68–82.
[3] For a critical review, see: D. G. Blackmond, A. Armstrong, V.
Coombe, A. Well, Angew. Chem. 2007, 119, 3872–3874; Angew.
Chem. Int. Ed. 2007, 46, 3798–3800.
[4] For reviews, see: a) D. Enders, M. Bolkenius, J. Vꢂzquez, J. M. Las-
saletta, R. Fernꢂndez, J. Prakt. Chem. 1998, 340, 281–285; b) R.
Fernꢂndez, J. M. Lassaletta, Synlett 2000, 1228–1240; c) R. Brehme,
D. Enders, R. Fernꢂndez, J. M. Lassaletta, Eur. J. Org. Chem. 2007,
5629–5660.
[5] a) J. M. Lassaletta, R. Fernꢂndez, E. Martꢀn-Zamora, C. Pareja, Tet-
rahedron Lett. 1996, 37, 5787–5790; b) R. Fernꢂndez, E. Martꢀn-
Zamora, C. Pareja J. M. Lassaletta, J. Org. Chem. 2001, 66, 5201–
5207.
[6] a) R. Fernꢂndez, E. Martꢀn-Zamora, C. Pareja, J. Vꢂzquez, E. Dꢀez,
A. Monge J. M. Lassaletta, Angew. Chem. 1998, 110, 3598–3600;
Angew. Chem. Int. Ed. 1998, 37, 3428–3430; b) C. Pareja, E. Martꢀn-
Zamora, R. Fernꢂndez, J. M. Lassaletta, J. Org. Chem. 1999, 64,
8846–8854.
Scheme 3. Proposed mode of activation “on water”.
[7] R. Fernꢂndez, E. Martꢀn-Zamora, C. Pareja, M. Alcarazo, J. Martꢀn,
J. M. Lassaletta, Synlett 2001, 1158–1160.
[8] R. P. Herrera, D. Monge, E. Martꢀn-Zamora, R. Fernꢂndez, J. M.
Lassaletta, Org. Lett. 2007, 9, 3303–3306.
[9] D. J. Dixon, A. L. Tillman, Synlett 2005, 2635–2638.
[10] M. Rueping, E. Sugiono, T. Theissmann, A. Kuenkel, A. Kockritz,
A. Pews-Davtyan, N. Nemati, M. Beller, Org. Lett. 2007, 9, 1065–
1068.
[11] T. Hashimoto, M. Hirose, K. Maruoka, J. Am. Chem. Soc. 2008, 130,
7556–7557.
[12] With regards to related enamines, the pyrrolidine ring in 2 confers a
higher nucleophilicity to the aza-enamine system. See Ref. [4] and
[8]. Also see: D. Monge, E. Martꢀn-Zamora, J. Vꢂzquez, M. Alcara-
zo, E. ꢈlvarez, R. Fernꢂndez, J. M. Lassaletta, Org. Lett. 2007, 9,
2867–2870.
[13] S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb, K. B.
Sharpless, Angew. Chem. 2005, 117, 3339–3343; Angew. Chem. Int.
Ed. 2005, 44, 3275–3279.
[14] A. Chanda, V. V. Fokin, Chem. Rev. 2009, 109, 725–748.
[15] J. K. Beattie, C. S. P. McErlean, C. B. W. Phippen, Chem. Eur. J.
2010, 16, 8972–8974.
[16] E. Marquꢁs-Lꢅpez, R. P. Herrera, R. Fernꢂndez, J. M. Lassaletta,
Eur. J. Org. Chem. 2008, 3457–3460.
Scheme 4. Oxidative cleavage of the hydrazone moiety in adducts 5.
Acknowledgements
We thank the Spanish Ministerio de Ciencia e Innovaciꢅn (grant numbers
CTQ2010-15297 and CTQ2010-14974), the European FEDER funds, and
the Junta de Andalucꢀa (grant numbers 2008/FQM-3833 and 2009/FQM-
4537) for financial support. A.C. thanks the ꢆAgencia Consejo Superior
de Investigaciones Cientꢀficasꢇ for a JAE predoctoral fellowship.
[17] R. Fernꢂndez, C. Gasch, J. M. Lassaletta, J. M. LLera, J. Vꢂzquez,
Tetrahedron Lett. 1993, 34, 141–144.
Keywords: hydrazones · kinetic isotope effect · synthetic
methods · nucleophilic addition · water
Received: February 21, 2011
Revised: May 24, 2011
Published online: July 26, 2011
[1] For a recent monograph, see: R. A. Sheldon, I. Arends, U. Hane-
feld, Green Chemistry and Catalysis, Wiley-VCH, Weinheim, 2007.
2290
www.chemasianj.org
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2287 – 2290