Synthesis of α-hydroxyhydrazones from aldehydes

Article abstract of DOI:10.1055/s-2001-15139

The 1,2-addition of formaldehyde N,N-dialkylhydrazones to simple aldehydes takes place in the presence of ZnCl₂ or Et₂AlCl to afford the corresponding α-hydroxyhydrazones. More reactive aldehydes undergo addition of these reagents in the absence of promoters. Use of (S)-1-methyleneamino-2-(diphenylmethoxymethyl) pyrrolidine as the reagent afforded separable mixtures of diastereoisomers, thereby allowing for the isolation of optically pure adducts in a single step.

Full text of DOI:10.1055/s-2001-15139

1158
LETTER
Synthesis of -Hydroxyhydrazones from Aldehydes
Rosario Fernández,*a Eloísa Martín-Zamora,a Carmen Pareja,a Manuel Alcarazo,b Jesús Martín,a José M. Lassaletta*b
a Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado de Correos No. 553, E-41071, Seville, Spain
b Instituto de Investigaciones Químicas, CSIC-USe, c/ Americo Vespuccio s/n, Isla de la Cartuja, E-41092 Seville, Spain
Fax +34 954460565; E-mail: jmlassa@cica.es
Received 30 April 2001
R1R2N
R1R2N
Abstract: The 1,2-addition of formaldehyde N,N-dialkylhydra-
zones to simple aldehydes takes place in the presence of ZnCl2 or
Et2AlCl to afford the corresponding -hydroxyhydrazones. More
reactive aldehydes undergo addition of these reagents in the absence
of promoters. Use of (S)-1-methyleneamino-2-(diphenyl-
methoxymethyl) pyrrolidine as the reagent afforded separable mix-
tures of diastereoisomers, thereby allowing for the isolation of
optically pure adducts in a single step.
R
retro-[2+2]
O
[2+2]
O
N
N
O
H
R
3
H
R
H
H
2
NR1R2
N
Key words: diastereoselectivity, hydroxyhydrazones, nucleophilic
addition
R1R2N
H
R1R2N
H
H
N
N
1
LA
H
N
NR1R2
H
H
N
H
NR1R2
1
α-Hydroxy-N,N-dialkylhydrazones are useful compounds
not only as protected forms of α-hydroxyaldehydes, but
also as versatile intermediates for the synthesis of α-
alkoxy carbonyl compounds,1 cyanohydrins,2 and many
other compounds resulting from C–C bond-forming
radical3 or anionic4 additions to their C=N bond. The nu-
cleophilic properties of formaldehyde N,N-dialkylhydra-
zones 1, associated to their enhanced aza-enamine
character, has allowed their use as d1 reagents toward sev-
eral electrophilic substrates.5 Thus, the Michael addition
to several electrophilic alkenes such as nitroalkenes,6 con-
jugated enones,7 and unsaturated lactones,8 has served for
the synthesis of several kinds of bifunctional compounds.
These precedents stimulated studies on the 1,2-addition of
these reagents to carbonyl compounds for the synthesis of
the title compounds. The first findings on this topic re-
vealed that the inductive effects operating in carbohy-
drate-derived alkoxyaldehydes2a or trifluoromethyl
ketones2b enhance the carbonyl reactivity up to the level
required for the spontaneous addition of these reagents. In
this paper, we wish to report on a broader scope of this re-
action, given by the 1,2-addition of formaldehyde N,N-di-
alkylhydrazones to several types of aldehydes.
4
O
R1R2N
H
H
R
N
2
OH
R
5
Scheme 1
Fortunately, it was finally possible to obtain the desired
11
adducts 5a-f in variable yields by using ZnCl2 or
Et2AlCl12 as suitable promoters. 1-Methyleneaminopyrro-
lidine 1a, readily available from commercial N-nitrosopy-
rrolidine,2c was the reagent of choice, giving better yields
of adducts and faster reactions than the simplest formalde-
hyde N,N-dimethylhydrazone 1b (Scheme 2, Table 1).
N
N
N
O
N
CH2Cl2
+
R
ZnCl2 or Et2AlCl
H
R
H
Preliminary experiments demonstrated that simple ali-
phatic and aromatic aldehydes 2a-f do not react spontane-
ously with formaldehyde N,N-dialkylhydrazones 1.
Attempts to activate the substrates by several Lewis acids
(BF3·Et2O, R3SiOTf, SnCl4, ZnBr2) led mainly to the for-
mation of undesired hydrazono transfer products 3,
which, in the absence of moisture, are presumably formed
via [2+2] and retro-[2+2] cycloadditions.9 Variable
amounts of compounds 4 were also isolated from the re-
action mixtures; their formation can be explained as an
oxidative dimerization of 1 via α-hydrazinoacetaldehyde
hydrazone.10 Therefore, only small amounts of the
desired products 5 were detected under these conditions
(Scheme 1).
H
H
OH
2a-g
1a
5a-g
Scheme 2
Noteworthy, p-nitrobenzaldehyde 2g also reacted with 1a
in the absence of any promoter to give the corresponding
1,2-adduct 5g, though in a lower 33% yield than that ob-
tained (81%) for the ZnCl2-promoted reaction (entries 7
and 8). This last result and the above-mentioned
precedents2a,b prompted us to investigate the uncatalyzed
addition of reagents 1 to more reactive substrates. Thus,
Synlett 2001, No. 7, 1158–1160 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of -Hydroxyhydrazones from Aldehydes
1159
Table 1 Addition of 1-methyleneaminopyrrolidine (1a) to alde-
hydes 2a-g.
previous treatment. Additionally, pentafluorobenzalde-
hyde 2m, chosen as representative of aromatic aldehydes,
behaves also as substrate for the spontaneous addition of
1a, affording the corresponding adduct 5m in 60% yield.
The development of an asymmetric version of these un-
catalyzed additions was also studied with limited success.
Thus, the addition of chiral reagents as 1-(methyleneami-
no)-2-(methoxymethyl)pyrrolidine 1c6c or the D-manni-
tol-derived C2-symmetric hydrazone 1d14 (Figure) to
aldehydes 2h-m proceeded with very low asymmetric in-
duction, affording the corresponding adducts in high
yields, but as unseparable mixtures of diastereoisomers in
all cases. On the other hand, the addition of (S)-1-methyl-
eneamino-2-(diphenylmethoxymethyl)pyrrolidine 1e2c to
aldehydes 2h-m took place with similar yields and selec-
tivities, but in this case the resolving properties of the aux-
iliary allowed an easy chromatographic separation of the
(2R/S) diastereomeric mixtures. In this reaction, com-
pound 1e plays two roles: it serves as a d1 reagent and as
a resolving agent at once, thereby allowing the obtention
of enantiomerically pure (R)- and (S)-6h-m adducts in a
single operation (Scheme 3). The results for the addition
of 1e to aldehydes 2h-m are collected in Table 3.
aThe amounts of promoter and reaction temperatures as indicated in
footnotes 11 and 12, unless otherwise specified. b Isolated yield after
chromatography. c-78 °C→r.t. (2 h) and then 2 h at r.t. d2.4 mmol of
promoter were used. e3g (R1R2N = pyrrolidin-1-yl, R = p-O2NC6H4)
was isolated as by-product in 30% yield.
α-monoalkoxy (2h,i) and α,α-dialkoxy (2j) aldehydes, as
well as chloral (2k) and fluoral (2l) also reacted with 1a in
the absence of promoters to afford the corresponding α-
hydroxyhydrazones 5h-l in good to excellent yields (Ta-
ble 2).13 As expected, the observed aldehyde reactivities
were strongly dependent on the substitution pattern. Nev-
ertheless, reasonable reaction rates were observed for all
substrates at room temperature, except for α-benzyloxy-
acetaldehyde 2h, which required heating at 60 °C for 18 h
for completion (Table 2, entry 1).
Ph
O
MeO
O
N
N
O
N
N
Ph
H
H
O
H
H
1c
1d
Figure Chiral hydrazones from L-proline and D-mannitol
OMe
Table 2 Uncatalyzed addition of methyleneaminopyrrolidine (1a)
to aldehydes 2h-m.
OMe
OMe
Ph
Ph
Ph
Ph
Ph
Ph
O
N
H
CH2Cl2
N
H
N
H
+
N
+
N
N
R
H
R
R
H
2h-m
OH
OH
1e
(R)-6h-l
(S)-6m
(S)-6h-l
(R)-6m
Scheme 3
Summarizing, the nucleophilic addition of formaldehyde
N,N-dialkylhydrazones to aldehydes represents a conve-
nient, single step method for the synthesis of a variety of
synthetically useful α-hydroxyhydrazones.
a At room temperature, unless otherwise specified. b Isolated yield af-
ter chromatography. c At 60 °C.
Acknowledgement
Interestingly, the commercial forms of dimethoxyacetal-
dehyde 2j (60% in H2O), chloral 2k (monohydrate), and
fluoral 2l (ethyl hemiacetal) could be used without any
We thank the Spanish 'Ministerio de Educación y Cultura' (Grants
PB 97-0747 and PPQ2000-1341) and the 'Junta de Andalucía' for fi-
nancial support.
Synlett 2001, No. 7, 1158–1160 ISSN 0936-5214 © Thieme Stuttgart · New York

1160
R. Fernández et al.
LETTER
(9) For a related reaction see: Gautier, A.; Renault, J. Bull. Soc.
Chim. Fr. 1963, 33, 1555. Such a mechanism is also in
agreement with ab initio MO calculations: Pappalardo, R.R.;
Muñoz, J.M.; Fernández, R.; Lassaletta, J.M., unpublished
results.
Table 3 Uncatalyzed addition of 1e to aldehydes 2h-m.
(10) The mechanism of the acid-catalyzed dimerization of
formaldehyde dimethylhydrazone has been studied in detail:
Condon, F.E.; Farcasiu, D. J. Am. Chem. Soc. 1970, 92, 6625.
(11) Typical procedure: To a cooled (0 C) solution of 1 (2 mmol)
and 2 (1 mmol) in dry CH2Cl2 (7 mL) was added 1M ZnCl2 in
Et2O (4 mmol). After completion, the mixture was washed
with sat. NaHCO3 and H2O, concentrated and purified by
column chromatography (petroleum ether-ethyl acetate).
Representative characterization data for 5g (oil): 1H NMR
(300 MHz, CDCl3) 1.87-1.94 (m, 4H), 3.14-3.20 (m, 4H),
4.05 (bs, 1H), 5.39 (d, 1H, J = 3.5 Hz), 6.45 (d, 1H, J = 3.5
Hz), 7.40-8.32 (m, 4H); 13C NMR (75 MHz, CDCl3) 23.2,
51.0, 72.6, 123.7, 126.8, 132.2, 147.2, 149.4; IR (film, cm-1)
3358-3298 br, 1581; MS (EI) 249 (M+, 24), 231 (80), 99 (66),
70 (100); HRMS m/z calcd. for C12H15N3O3: 249.1113; found
249. 1106.
aAt room temperature. bIsolated yield. cMixture fully separable by
flash chromatography. dAt 50 °C. eMixture separable after benzyl-
ation.
(12) Typical procedure: To a cooled (-78 C) solution of 1 (2
mmol) and 2 (1 mmol) in dry THF (4 mL) was added dropwise
1M Et2AlCl in hexane (1.5 mmol). After completion, 5M
NaOH (1 mL) was added and the mixture stirred for 30 min.
at r.t. H2O (10 mL) was added and the mixture was extracted
with Et2O (3 10 mL). The organic layer was washed with
brine, dried (Na2SO4), concentrated, and purified by column
chromatography (petroleum ether-ethyl acetate).
References and Notes
(1) (a) Enders, D.; Reinhold, U. Synlett 1994, 792. (b) Enders, D.;
Reinhold, U. Liebigs Ann. 1996, 11.
(2) (a) Lassaletta, J.M.; Fernández, R.; Martín-Zamora, E.;
Pareja, C. Tetrahedron Lett. 1996, 37, 5787. (b) Fernández,
R.; Martín-Zamora, E.; Pareja, C.; Vázquez, J.; Díez, E.;
Monge, A.; Lassaletta, J.M. Angew. Chem. Int. Ed. Engl.
1998, 37, 3428. (c) Pareja, C.; Martín-Zamora, E.; Fernández,
R.; Lassaletta, J.M. J. Org. Chem. 1999, 64, 8846. (d) Cerè,
V.; Peri, F.; Pollicino, S.; Ricci, A. Tetrahedron 1999, 55,
1087.
(2) For a related reaction see: Gautier, A.; Renault, J. Bull. Soc.
Chim. Fr. 1963, 33, 1555. Such a mechanism is also in
agreement with ab initio MO calculations: Pappalardo, R.R.;
Muñoz, J.M.; Fernández, R.; Lassaletta, J.M., unpublished
results.
Representative characterization data for 5e: mp 46-48 °C, 1H
NMR (300MHz, CDCl3) 1.84-1.92 (m, 4H), 3.12-3.19 (m,
4H), 3.87 (bs, 1H), 5.28 (d, 1H, J = 3.5 Hz), 6.57 (d, 1H,
J = 3.5 Hz), 7.31-7.40 (m, 5H); 13C NMR (75 MHz, CDCl3)
23.1, 51.2, 73.4, 126.3, 127.5, 128.2, 135.1, 152.6; IR (film,
cm-1) 3381-3230 br, 1601; MS (EI) 204 (M+, 10), 186 (100).
Anal. Calcd. for C12H16N2O: C, 70.56; H, 7.89; N, 13.71.
Found: C, 70.25; H, 7.90; N, 13.70.
(13) Typical procedure: A mixture of 1a or 1e (1 mmol) and
2h-m (2-5 mmol) in CH2Cl2 (4 mL) was allowed to react until
completion, concentrated, and purified by column
chromatography (petroleum ether-ethyl acetate).
Representative characterization data for 5m: mp 82-83 °C, 1H
NMR (300MHz, CDCl3) 1.88-1.92 (m, 4H), 3.17-3.24 (m,
4H), 3.85 (bs, 1H), 5.65 (d, 1H, J = 3.4 Hz), 6.55 (d, 1H,
J = 3.4 Hz); 13C NMR (75 MHz, CDCl3) 23.2, 50.9, 65.1,
128.8, 135.8, 139.1, 143.4, 146.7; IR (film, cm-1) 3300-3000
br, 1505; MS (EI) 294 (M+, 35), 276 (15), 70 (100). Anal.
Calcd. for C12H11F5N2O: C, 48.99; H, 3.77; N, 9.52. Found: C,
(3) (a) Friestad, G.K. Org. Lett. 1999, 1, 1499. (b) El Kaim, L.;
Gacon, A.; Perroux, A. Tetrahedron Lett. 1998, 39, 371.
(c) Miyata, O.; Muroya, M.; Koide, J.; Naito, T. Synlett 1998,
271.
(4) (a) Claremon, D.A.; Lumma, P.K.; Phillips, B.T. J. Am. Chem.
Soc. 1986, 108, 8265. (b) Baker, W.R.; Condon, S.L. J. Org.
Chem. 1993, 58, 3277. (c) Enders, D.; Reinhold, U. Angew.
Chem. 1995, 34, 1219. (d) Nicaise, O.; Denmark, S. Bull. Soc.
Chim. Fr. 1997, 134, 395. (e) Cerè, V.; Peri, F.; Pollicino, S.;
Ricci, A. Synlett 2000, 1585.
49.18; H, 3.83; N, 9.39. Data for 6l (major isomer): [ ]28
D
-156.0 (c 1.1, CH2Cl2); 1H NMR (CDCl3, 300 MHz) 0.12-
0.36 (m, 1H), 1.41-1.52 (m, 1H), 1.96-2.13 (m, 2H), 2.64-2.74
(m, 1H), 2.78-2.86 (m, 1H), 2.97 (s, 3H), 3.63 (d, 1H, J = 5.2
Hz), 4.40-4.44 (m, 1H), 4.77 (dd, 1H, J = 2.9, 8.3 Hz), 6.21 (d,
1H, J = 2.9 Hz), 7.31-7.61 (m, 10H); 13C NMR (75 MHz,
CDCl3) 21.3, 25.8, 49.3, 51.6, 68.0, 69.3 (q, J = 31.7 Hz),
85.6, 119.6, 123.9 (q, J = 281 Hz), 127.2, 127.6, 129.4, 129.8,
129.9, 138.4, 140.2; IR (film, cm-1) 3439, 1590; MS (EI) 392
(M+, 1), 195 (100). Anal. Calcd for C21H23F3N2O2: C, 64.27;
H, 5.90; N, 7.14. Found: C, 64.62; H, 5.99; N, 7.28.
(5) Short review: Fernández, R.; Lassaletta, J.M. Synlett 2000,
1228.
(6) (a) Lassaletta, J.M.; Fernández, R. Tetrahedron Lett. 1992, 33,
3691. (b) Lassaletta, J.M.; Fernández, R.; Gasch, C.; Vázquez,
J. Tetrahedron 1996, 52, 9143. (c) Enders, D.; Syrig, R.;
Raabe, G.; Fernández, R.; Gasch, C.; Lassaletta, J.M.; Llera,
J.M. Synthesis 1996, 48.
(7) (a) Lassaletta, J.M.; Fernández, R.; Martín-Zamora, E.; Díez,
E. J. Am. Chem. Soc. 1996, 118, 7002. (b) Díez, E.; Fernández,
R.; Gasch, C.; Lassaletta, J.M.; Llera, J.M.; Martín-Zamora,
E.; Vázquez, J. J. Org. Chem. 1997, 62, 5144.
(14) Fernández, R.; Ferrete, A.; Lassaletta, J.M.; Llera. J.M.;
Monge, A. Angew. Chem. Int. Ed. 2000, 39, 2893.
(8) (a) Enders, D.; Vázquez, J. Synlett 1999, 5, 629. (b) Enders,
D.; Vázquez, J.; Raabe, G. Chem. Commun. 1999, 701. (c)
Enders, D.; Vázquez, J.; Raabe, G. Eur. J. Org. Chem. 2000,
893.
Article Identifier:
1437-2096,E;2001,0,07,1158,1160,ftx,en;D06201ST.pdf
Synlett 2001, No. 7, 1158–1160 ISSN 0936-5214 © Thieme Stuttgart · New York