Asymmetric Michael addition of formaldehyde N,N-dialkylhydrazones to alkylidene malonates

Article abstract of DOI:10.1039/b200209b

Enantiopure formaldehyde N,N-dialkylhydrazones 1 smoothly react with prochiral alkylidene malonates 2 in the presence of MgI₂ to afford the corresponding Michael adducts 3 in excellent yields and good diastereoselectivities; direct racemization

Full text of DOI:10.1039/b200209b

Asymmetric Michael addition of formaldehyde N,N-dialkylhydrazones to
alkylidene malonates
Juan Vázquez,a Auxiliadora Prieto,a Rosario Fernández,a Dieter Endersb and José M. Lassaletta*c
a Departamento de Química Orgánica, Universidad de Sevilla, Apdo de Correos No. 553, 41071 Seville,
Spain
b Institut für Organische Chemie, RWTH-Aachen, Professor Pirlet Strasse, 1, 52074 Aachen, Germany
c
Instituto de Investigaciones Químicas, c/ Americo Vespuccio s/n, 41092 Seville, Spain.
E-mail: jmlassa@cica.es
Received (in Cambridge, UK) 4th January 2002, Accepted 24th January 2002
First published as an Advance Article on the web 11th February
Enantiopure formaldehyde N,N-dialkylhydrazones
1
mixture of diastereomers. The optimized conditions were then
used for the addition of reagent 1B to several aliphatic and
aromatic alkylidene malonates 2b–g (Scheme 2, Table 1).∑
Regeneration of the formyl group to obtain aldehydes 6 was
accomplished by ozonolytic cleavage of the hydrazone CNN
double bond in moderate-to-good yields (60–87%), but the
products were found to racemize partially during the chromato-
graphic separation.** Even though the crude aldehydes were
obtained with a reasonable purity and could be eventually used
without purification at this step, alternative removals of the
auxiliary were also investigated. Fortunately, it was found that
the direct dithioketalization of the hydrazone moiety11 was a
suitable reaction to this aim. Thus, treatment of adducts 3 with
ethanedithiol in the presence of an excess of BF3·OEt2 (2.5–5
eq.) afforded the desired dithioketals 7 (Scheme 2, Table 2). The
enantiomeric purities of these adducts were independently
smoothly react with prochiral alkylidene malonates 2 in the
presence of MgI2 to afford the corresponding Michael
adducts 3 in excellent yields and good diastereoselectivities;
direct racemization-free BF3·OEt2-catalyzed thiolysis of the
hydrazone CNN bond affords the corresponding dithioketals
7 in optically pure or enantiomerically enriched form.
The asymmetric Michael addition of enolates,1 silylketene
acetals,2 enamines3 and aza-enolates from hydrazones4 to
alkylidene malonates has been successfully employed as the key
reaction for the synthesis of various 1,5-dicarbonyl compounds.
Use of an acyl (formyl) anion equivalent as the nucleophile in
the same reaction opens access to 4-oxoesters in a similar
manner. Though reports have been described for such a reaction
leading to racemates,5 examples of asymmetric nucleophilic
acylations of enoates are rare.6 On the other hand, SAMP-
derived formaldehyde N,N-dialkylhydrazone 1A had been
successfully used as a neutral formyl anion equivalent7 for the
asymmetric formylation of enones8 and a,b-unsaturated lac-
tones,9 but the extension of this methodology to a,b-unsaturated
esters was unsuccessful. The precedent of the addition of 1A to
nitroalkenes,10 which exhibit similar levels of reactivity to that
of alkylidene malonates,† suggested that the addition of
formaldehyde N,N-dialkylhydrazones to the latter should also
be possible under non-catalysed conditions, or, at least, under
mild conditions compatible with the hydrazone moiety. Results
collected on the basis of this hypothesis are given herein.
Unexpectedly, the addition of formaldehyde SAMP-hydra-
zone 1A to easily available dimethyl alkylidene malonates 2
was unsuccessfully essayed under a variety of uncatalysed
conditions. On the other hand, the selection of a suitable
promoter system for this reaction presented some difficulties.
For instance, activation of 2 by common Lewis acids, such as
ZnCl2, AlCl3, Ti(OiPr)4 or trialkylsilyl triflates, afforded the
expected hydrazono malonates 3, but glyoxal bis-hydrazone 4
was also isolated as an undesired by-product.‡ In the case of the
aromatic substrate 2d, benzaldehyde SAMP-hydrazone 5 was
also isolated as a by-product, even in dry media. Its formation
can be explained by a [2 + 2] cycloaddition of 1A to the
activated malonate followed by a retrocycloaddition to the
observed by-product and methylidene malonate, unstable
against polymerization. Finally, it was concluded that use of
stoichiometric amounts of freshly dried MgI2§ allowed the
establishment of the required equilibrium shown in Scheme 1,
while minimizing the side reactions mentioned above.
As use of the SAMP-hydrazone 1A afforded disappointing
diastereoselectivities, a second optimization study was required
in order to improve the stereochemical result. Therefore, several
formaldehyde hydrazones, carrying pyrrolidine-based auxilia-
ries as a common characteristic,¶ were prepared and reacted
with ethylidene derivative 2a as a model substrate in the
presence of MgI2 as the promoter (Scheme 2, R = Me). From
this study, (S)-1-methyleneamino-2-(1-methoxydiphenylme-
thyl)pyrrolidine (1B) emerged as the most convenient reagent,
affording the corresponding adduct 3a in 91% yield as a 89+11
Scheme 1
498
CHEM. COMMUN., 2002, 498–499
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ically enriched, 1,4-dicarbonyl derivatives. Extension of this
methodology to related substrates bearing two different elec-
tron–withdrawing groups on the same olefinic carbon is a
current object of study in our laboratories.
We thank the MCYT (Grants BQU2001-2376 and PPQ2000-
1341; fellowship to A. P.), and the Fonds der Chemischen
Industrie for financial support. The donation of chemicals by
Degussa AG, BASF AG, and Bayer AG is gratefully ac-
knowledged.
Notes and references
† As discussed in ref. 3, the electrophilic reactivity of nitroalkenes and
alkylidenemalonates can be a priori correlated with the pK values in
nonaqueous solvents of the anions generated upon addition. See also: W. N.
Olmstead and F. G. Bordwell, J. Org. Chem., 1980, 45, 3299.
‡ The formation of this product is consistent with activation of the reagent
1A by the Lewis acid, followed by nucleophilic attack of a second molecule
of free reagent. Air oxidation of the resulting a-hydrazinohydrazone finally
affords the undesired product 4.
§ Sub-stoichiometric amounts of MgI2 were also effective as catalyst, but
yields and selectivities were lower in this case. For instance, 3a was
obtained with 51% de and 77% yield by using 0.1 eq of MgI2 under the
conditions given Table 1. Drying of the catalyst (0.05 mbar, 40 °C, 5 h) is
essential in order to obtain reproducible results.
Scheme 2 Reagents and conditions: a: MgI2, CH2Cl2. b: HS(CH2)2SH (1.5
eq.), BF3·OEt2 (2.5–5 eq). c: O3, Me2S, 278 °C?rt. d: Ra-Ni, MeOH.
1
measured by HPLC or H NMR LIS experiments carried out
with Eu(hfc)3, thereby confirming the absence of racemization
in this reaction, even for the more sensitive aromatic sub-
strates.
As illustrative examples of another potentially useful trans-
formation, Ra-Ni mediated desulfuration of 7b,d,f was also
effected to afford malonates 8b (75%), 8d (70%), and 8f (71%),
respectively. Comparison of the optical rotation of (S)-8f with
literature data was used for the assignment of its absolute
configuration.†† As the transformations 3?7 and 7?8 are
assumed to proceed without inversion of neighbor stereogenic
centers, the (3S) configuration of 3f and 7f was deduced thereof.
The absolute configuration of all other products was assigned
by analogy.
¶ As in related enamines, the pyrrolidine ring confers high nucleophilicity
to the aza-enamine system: G. Häfelinger and H.-G. Mack, in The
Chemistry of Enamines, ed. S. Patai and Z. Rappoport, John Wiley & Sons,
New York, 1994, pp. 1–85.
∑ Synthesis of compounds 3. Method A. To a stirred, cooled solution of 2a–c
(1 mmol) and MgI2 (1 mmol) in dry CH2Cl2 (1 mL) was added a solution
of hydrazone 1B (1.5 mmol) in CH2Cl2 (1 mL) under an argon atmosphere.
The mixture was stirred until completion (TLC), diluted with more CH2Cl2
(10 mL), washed with H2O, dried (MgSO4), and purified by flash
chromatography. Method B. To a stirred, cooled solution of 2d–g (1 mmol)
and hydrazone 1B (2 mmol) in dry CH2Cl2 (1 mL) was added MgI2 (1
mmol) under an argon atmosphere. The mixture was then treated as
described above.
** Extensive racemization was observed starting from the sensitive
aromatic compound 3d in optically pure form, as determined by shift
experiments using Eu(hfc)3. A much higher stability was expected in the
aliphatic series, but, starting from optically pure 3a, a 5–20% racemization
was also observed after chromatographic purification.
†† (S)-8f: had [a]21D +44.3 (c 0.7, MeOH). Lit: [a]24D +45.0 (c 1, MeOH:
J.-Y. Legros, M. Toffano and J.-C. Fiaud, Tetrahedron, 1995, 51, 3235.
In summary, the MgI2-promoted Michael addition of enantio-
pure formaldehyde hydrazone 1B to alkylidene malonates 2
appear as a convenient method for the synthesis of enantiomer-
Table 1 Synthesis of hydrazono malonates 3a–g
Yielda
(%)
3
R
T (°C)
t (h)
deb
Conf.
a
b
c
d
e
f
Me
Et
CH2CH2Ph
Ph
p-NO2C6H4
2-Naphthyl
278
278
278
0
24
24
48
7
3
6
91
95
70
88
98
98
97
78c
(S,R)
(S,R)
(S,R)
(S,S)
(S,S)
(S,S)
(S,S)
1 K. Yasuda, M. Shindo and K. Koga, Tetrahedron Lett., 1997, 38,
3531.
2 D. A. Evans, T. Rovis, M. C. Kozlowski and J. S. Tedrow, J. Am. Chem.
Soc., 1999, 121, 1994.
3 S. J. Blarer and D. Seebach, Chem. Ber., 1983, 116, 2250; K. Tomioka,
K. Yasuda and K. Koga, Tetrahedron Lett., 1986, 27, 4611; J. Martens
and S. Lübben, Tetrahedron, 1991, 47, 1205; Catalytic version: J. M.
Betancort, K. Sakthivel, R. Thayumanavan and C. F. Barbas III,
Tetrahedron Lett., 2001, 42, 4441; W. Zhuang, T. Hansen and K. A.
Jørgensen, J. Chem. Soc. Chem. Commun., 2001, 347.
4 D. Enders, A. S. Demir and B. E. M. Rendenbach, Chem. Ber., 1987,
120, 1731; D. Enders, A. S. Demir, H. Puff and S. Franken, Tetrahedron
Lett., 1987, 28, 3795.
68c
70c
76 ( > 98)
80 ( > 98)
90 ( > 98)
79 ( > 98)
0
0
0
g
6
a Yield of isolated product. b Determined by 1H NMR analysis of the crude
reaction mixtures; in parenthesis: de of purified major diastereomer.
c Inseparable mixture of diastereomers.
5 For example see: H. Stetter and F. Jonas, Chem. Ber., 1981, 114, 564; H.
Cerfontain and P. C. M. van Noort, Synthesis, 1980, 490; H. Ahlbrecht
and H.-M. Komptes, Synthesis, 1983, 645.
6 D. Enders, P. Gerdes and H. Kipphardt, Angew. Chem., 1990, 102, 226;
Angew. Chem., Int. Ed. Engl., 1990, 29, 179 ; D. Enders, J. P. Shilvock
and G. Raabe, J. Chem. Soc., Perkin Trans. 1, 1999, 1617, and literature
cited therein.
7 R. Fernández and J. M. Lassaletta, Synlett, 2000, 1228.
8 J. M. Lassaletta, R. Fernández, E. Martín-Zamora and E. Díez, J. Am.
Chem. Soc., 1996, 118, 7002; E. Díez, R. Fernández, C. Gasch, J. M.
Lassaletta, J. M. Llera, E. Martín-Zamora and J. Vázquez, J. Org.
Chem., 1997, 62, 5144.
9 D. Enders and J. Vázquez, Synlett, 1999, 629; D. Enders, J. Vázquez and
G. Raabe, Chem. Commun., 1999, 701; D. Enders, J. Vázquez and G.
Raabe, Eur. J. Org. Chem., 2000, 893.
Table 2 Synthesis of dithioketals 7a–g
Yielda
7
R
t (h) (%)
ee
Conf. [a]24D (c, CH2Cl2)
a
b
c
d
e
f
Me
Et
CH2CH2Ph
Ph
p-NO2C6H4
2-Naphthyl
96
48
96
48
24
48
16
87
70
60
61
65
63
70
79b
70c
68b
(R)
(R)
(R)
(S)
(S)
(S)
(S)
+5.1 (1.1)
+11.8 (0.9)
+0.8 (1.0)
+6.6 (1.1)
22.1 (1.0)
+9.6 (1.2)
+28.1 (1.3)
> 98c
> 98b
97b
g
> 98b
10 D. Enders, R. Syrig, G. Raabe, R. Fernández, C. Gasch, J. M. Lassaletta
and J. M. Llera, Synthesis, 1996, 48.
11 E. Díez, A. M. López, C. Pareja, E. Martín-Zamora, R. Fernández and
J. M. Lassaletta, Tetrahedron Lett., 1998, 39, 7955.
a Yield of isolated product. b Determined by HPLC using a chiral stationary
phase column (Daicel Chiralpak AD). c Determined by 1H NMR shift
experiments using Eu(hfc)3.
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