Metallo-Aldehyde Enolates via Enal Hydrogenation: Catalytic Cross Aldolization with Glyoxal Partners As Applied to the Synthesis of 3,5-Disubstituted Pyridazines

Article abstract of DOI:10.1021/jo030310a

Aldehyde enolates generated through rhodium-catalyzed enal hydrogenation are subject to electrophilic trapping by exogenous glyoxal partners to afford β-hydroxy-γ-keto-aldehyde products, which upon exposure to hydrazine afford 3,5-disubstituted pyridazine

Full text of DOI:10.1021/jo030310a

dolizations of this type have only been achieved indirectly
through the use of preformed enol silanes and directly
with iminium ion-enamine catalysis.7 Here, we report
that aldehyde enolates generated via rhodium-catalyzed
enal hydrogenation are subject to electrophilic trapping
by exogenous glyoxal partners to afford â-hydroxy-γ-keto-
aldehyde products, which upon exposure to hydrazine
provide pyridazines in moderate yield in a two-step, one-
pot sequence.
Meta llo-Ald eh yd e En ola tes via En a l
Hyd r ogen a tion : Ca ta lytic Cr oss
Ald oliza tion w ith Glyoxa l P a r tn er s As
Ap p lied to th e Syn th esis of
3,5-Disu bstitu ted P yr id a zin es
Gwendolyn A. Marriner, Susan A. Garner,
Hye-Young J ang, and Michael J . Krische*
Department of Chemistry and Biochemistry,
University of Texas at Austin, Austin, Texas 78712
mkrische@mail.utexas.edu
Received October 8, 2003
Abstr a ct: Aldehyde enolates generated through rhodium-
catalyzed enal hydrogenation are subject to electrophilic
trapping by exogenous glyoxal partners to afford â-hydroxy-
γ-keto-aldehyde products, which upon exposure to hydrazine
afford 3,5-disubstituted pyridazines in moderate yield in a
two-step, one-pot sequence.
To explore the applicability of catalytic hydrogenation-
aldolization methodology vis-a`-vis aldehyde enolate gen-
eration, acrolein was hydrogenated in the presence of
various aldehyde partners with Rh(COD)2OTf as pre-
catalyst. Whereas hydrogenation of acrolein in the pres-
ence of various electron-deficient aldehydes, for example,
p-nitrobenzaldehyde and chlorodifluoroacetaldehyde mono-
hydrate, was unproductive, condensation with phenyl
glyoxal monohydrate affords the corresponding aldol
product in 52% isolated yield as a 1:1 mixture of diaster-
eomers. Suspecting that the modest yield of aldol product
stems from the well-documented instability of the â-hy-
droxy aldehyde product,7a,8 a method for in situ trapping
of the aldol was sought. Accordingly, it was found that
upon complete consumption of phenyl glyoxal 1a , the
addition of methanolic hydrazine to the reaction mixture
results in rapid condensation to afford 3-methyl-5-phe-
nylpyridazine 1b in 62% isolated yield. This protocol for
tandem catalytic reductive aldol condensation-pyridazine
formation proved general for the condensation of acrolein
with aromatic and heteroaromatic glyoxals 1a -4a (Table
1, entries 1-4). As demonstrated by the conversion of
crotonaldehyde to pyridazines 5b and 6b, â-substituted
enals are also viable pronucleophiles (Table 1, entries 5
and 6).
As part of a program in catalytic reaction development
focused on the use of enones as latent enolates, rhodium-
catalyzed inter- and intramolecular reductive aldol cou-
pling of enones to aldehydes and ketones under the
conditions of hydrogenation was recently reported from
our lab.1,2 Subsequently, related catalytic C-C bond-
forming hydrogenations involving the reductive coupling
of dienes and diynes with R-keto aldehydes were devel-
oped.3 A unifying feature of these transformations relates
to the heterolytic activation of elemental hydrogen by
cationic rhodium catalysts, i.e., H2 + Rh+X- f Rh-H +
HX.4,5 Heterolytic activation of hydrogen promotes mono-
hydride-based catalytic cycles, which attenuate simple
hydrogenation pathways by disabling alkyl-hydrogen
reductive elimination manifolds. Efficient aldolization
under the mild conditions of hydrogenation (ambient
temperature and pressure) suggests the feasibility of a
hitherto elusive variant of the aldol reaction involving
the use of metallo-aldehyde enolates. Aldolizations in-
volving the use of alkali aldehyde enolates typically suffer
from polyaldolization, product dehydration, and competi-
tive Tishchenko-type processes.6 To date, catalytic al-
A mechanism accounting for the formation of aldol
products under hydrogenation conditions invokes hetero-
lytic activation of elemental hydrogen to form a Rh(I)-
monohydride.3,4 Enal hydrometallation affords Rh(I)-
enolate I, which upon glyoxal addition provides the Rh(I)
aldolate II. Oxidative addition of elemental hydrogen to
(1) Rhodium-catalyzed reductive aldol condensation employing hy-
drogen as the terminal reductant: (a) J ang, H.-Y.; Huddleston, R. R.;
Krische, M. J . J . Am. Chem. Soc. 2002, 124, 15156. (b) Huddleston, R.
R.; Krische, M. J . Org. Lett. 2003, 5, 1143.
(2) Rhodium-catalyzed reductive aldol condensation employing si-
lane as the terminal reductant: (a) Revis, A.; Hilty, T. K. Tetrahedron
Lett. 1987, 28, 4809. (b) Matsuda, I.; Takahashi, K.; Sata, S. Tetrahe-
dron Lett. 1990, 31, 5331. (c) Taylor, S. J .; Morken, J . P. J . Am. Chem.
Soc. 1999, 121, 12202. (d) Taylor, S. J .; Duffey, M. O.; Morken, J . P. J .
Am. Chem. Soc. 2000, 122, 4528.
(6) (a) Heathcock, C. H. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Heathcock, C. H., Eds. Pergamon Press: New York,
1991; Vol. 2, p 133. (b) Alcaide, B.; Almendros, P. Angew. Chem., Int.
Ed. 2003, 42, 858.
(3) (a) J ang, H.-Y.; Huddleston, R. R.; Krische, M. J . Angew. Chem.,
Int. Ed. 2003, 42, 4074. (b) Huddleston, R. R.; J ang, H.-Y. Krische, M.
J . J . Am. Chem. Soc. 2003, 125, 11488.
(4) For a review of the heterolytic activation of elemental hydrogen,
see: Brothers, P. J . Prog. Inorg. Chem. 1981, 28, 1.
(5) Mild basic additives induce heterolytic activation of hydrogen
via deprotonation of cationic rhodium dihydride intermediates: (a)
Schrock, R. R.; Osborn, J . A. J . Am. Chem. Soc. 1976, 98, 2134. (b)
Schrock, R. R.; Osborn, J . A. J . Am. Chem. Soc. 1976, 98, 2143. (c)
Schrock, R. R.; Osborn, J . A. J . Am. Chem. Soc. 1976, 98, 4450.
(7) ) (a) Denmark, S.; Ghosh, S. K. Angew. Chem., Int. Ed. 2001,
40, 4759. (b) Northrup, A. B.; MacMillan, D. W. C. J . Am. Chem. Soc.
2002, 124, 6798. (c) Pidathala, C.; Hoang, L.; Vignola, N.; List, B.
Angew. Chem., Int. Ed. 2003, 42, 2785.
(8) â-Hydroxy aldehydes predominately exist as dimers: Rychnovsky,
S. D.; Salitzky, D. J . J . Org. Chem. 1992, 57, 2336 and references
therein.
10.1021/jo030310a CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/22/2004
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J . Org. Chem. 2004, 69, 1380-1382

TABLE 1. Ta n d em Ca ta lytic Red u ctive Ald ol
Con d en sa tion to P yr id a zin es
SCHEME 1. P r op osed Ca ta lytic Cycle for th e
Red u ctive Ald ol Con d en sa tion of En a ls w ith
Glyoxa l P a r tn er s
deuterium atom in a manner consistent with the pro-
posed mechanism.
In summary, catalytic enal hydrogenation represents
a viable method for the reductive generation of metallo-
aldehyde enolates, as demonstrated by catalytic cross
aldol condensation with aromatic and heteroaromatic
glyoxal partners. Future studies will be devoted to the
development of related catalytic C-C bond-forming
hydrogenations.
a
Procedure: To a flame-dried 50-mL round-bottomed flask
Exp er im en ta l Section
under an atmosphere of Ar (g) charged with Rh(COD)2OTf (4.7
mg, 0.01 mmol, 1 mol %) and Ph3P (6.3 mg, 0.024 mmol, 2.4 mol
%) was added DCE (10 mL, 0.1 M). The resulting solution was
stirred for 5 min at which point KOAc (98.2 mg, 1 mmol, 100 mol
%), glyoxal monohydrate (1 mmol, 100 mol %), and then the enal
(5 mmol, 500 mol %) were added. The system was flushed with
hydrogen and stirred under 1 atm of H2 at ambient temperature
until complete consumption of the glyoxal was observed, at which
point hydrazine (314 µL, 10 mmol, 1000 mol %) was added as a
methanolic solution (10 mL, 1 M) and the reaction mixture was
allowed to stir for 45 min. Evaporation of the reaction mixture
onto silica gel and purification by silica gel chromatography
5-Meth yl-3-p h en ylp yr id a zin e (1b). The title compound was
prepared in accordance with the procedure described in Table
1. The title compound was obtained in 62% yield as a yellow
solid, identical in all respects with previously reported material.9
5-Meth yl-3-n a p h th a len -2-ylp yr id a zin e (2b). The title com-
pound was prepared in accordance with the procedure described
in Table 1. The title compound was obtained in 59% yield as a
yellow solid. Mp 137-140 °C. 1H NMR (400 MHz, CDCl3) δ 8.96
(d, J ) 1.7 Hz, 1H), 8.50 (d, J ) 1.0 Hz, 1H), 8.19 (dd, J ) 8.7,
1.9 Hz, 1H), 7.94 (d, J ) 8.5 Hz, 1H), 7.92 (m, 1H), 7.86 (m,
1H), 7.72 (m, 1H), 7.51 (m, 2H), 2.38 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 158.5, 151.5, 137.8, 133.9, 133.6, 133.2, 128.6, 128.6,
127.6, 126.9, 126.9, 126.4, 124.2, 124.2, 18.4. FTIR (film) 1636
cm-1. HRMS calcd for C15H13N2 (M + 1) 221.1079, found
221.1083.
5-Meth yl-3-th iop h en -2-ylp yr iza d in e (3b). The title com-
pound was prepared in accordance with the procedure described
in Table 1. The title compound was obtained in 31% yield as an
orange solid. Mp 118-120 °C. 1H NMR (400 MHz, CDCl3) δ 8.87
(d, J ) 1.4 Hz, 1H), 7.65 (dd, J ) 3.8, 1.0 Hz, 1H), 7.57 (d, J )
1.0 Hz, 1H), 7.47 (dd, J ) 5.0, 0.9 Hz, 1H), 7.14 (dd, J ) 5.1, 3.8
Hz, 1H), 2.38 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 154.4, 151.4,
140.6, 137.8, 129.0, 128.0, 126.0, 122.4, 18.4. FTIR (film) 3039
(w), 1596 (m), 1448 (w) cm-1. HRMS calcd for C9H9N2S (M + 1)
177.0486, found 177.0489.
b
provides pyridazines 1b-6b. The glyoxal was not used as the
crystalline monohydrate, but was purified via Ku¨gelrohr distilla-
tion prior to use and was added to the reaction mixture along with
an equimolar quantity of water. c For this singular example, a 3
mol % loading of Rh(COD)2OTf and a 7.2 mol % loading of Ph3P
d
were used. Reactions performed with crotonaldehyde were con-
ducted in THF (0.05 M) at 40 °C with a 5 mol % loading of
Rh(COD)2OTf and a 12 mol % loading of Ph3P.
the Rh(I) aldolate II gives the Rh(III) dihydride III, which
upon oxygen-hydrogen reductive elimination provides
the aldol product with concomitant regeneration of the
starting Rh(I) monohydride (Scheme 1).
5-Meth yl-3-(1-m eth yl-1H-p yr r ol-2-yl)p yr id a zin e (4b). The
title compound was prepared in accordance with the procedure
described in Table 1. The title compound was obtained in
To corroborate the proposed mechanism, the catalytic
reductive aldol condensation of acrolein with phenyl
glyoxal monohydrate was performed under 1 atm of
elemental deuterium. Exposure of the aldol product to
excess hydrazine in situ results in the formation of the
pyridazine deuterio-1b, which incorporates precisely one
1
30% yield as a yellow oil. H NMR (CDCl3, 400 MHz) δ 8.81 (d,
(9) South, M. S.; J akuboski, T. L.; Westmeyer, M. D.; Dukesherer,
D. R. J . Org. Chem. 1996, 61, 8921.
J . Org. Chem, Vol. 69, No. 4, 2004 1381

J ) 2.1 Hz, 1H), 7.48 (q, J ) 0.91 Hz, 1H), 6.80 (m, 1H), 6.64
(m, 1H), 6.22 (dd, J ) 2.4, 1.4 Hz, 1H), 4.09 (s, 3H), 2.35 (s, 3H).
13C NMR (CDCl3, 100 MHz) δ 154.1, 150.0, 137.2, 128.9, 127.8,
Mp 87-88 °C. 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J ) 2.0 Hz,
1H), 8.04 (dd, J ) 8.0, 1.5 Hz, 2H), 7.63 (m, 1H), 7.48 (m, 3H),
2.38 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 151.6, 136.4, 129.8,
128.9, 127.1 124.2, 18.3 (m). FTIR (film) 3039 (w), 1595 (m).
HRMS calcd for C11H10DN2 (M + 1) 172.0985, found 172.0980.
124.4, 112.0, 108.0, 37.8, 18.3. FTIR (film) 2957,1601 cm-1
.
HRMS calcd for C10H12N3 (M + 1) 174.1031, found 174.1032.
5-Eth yl-3-p h en ylp yr id a zin e (5b). The title compound was
prepared in accordance with the procedure described in Table
1. The title compound was obtained in 47% yield as a yellow
solid, identical in all respects with previously reported material.9
Ack n ow led gm en t. We thank the Robert A. Welch
Foundation (F-1466), the NSF-CAREER program
(CHE0090441), the Herman Frasch Foundation (535-
HF02), the NIH (RO1 GM65129-01), donors of the
Petroleum Research Fund, administered by the Ameri-
can Chemical Society (34974-G1), the Research Corpo-
ration Cottrell Scholar Award (CS0927), the Alfred P.
Sloan Foundation, the Camille and Henry Dreyfus
Foundation, and Eli Lily for partial support of this
research.
5-Eth yl-3-n a p h th a len -2-yl-p yr id a zin e (6b). The title com-
pound was prepared in accordance with the procedure described
in Table 1. The title compound was obtained in 50% yield as a
yellow solid. Mp 102-104 °C. 1H NMR (CDCl3, 400 MHz) δ 9.03
(s, 1H), 8.53 (s, 1H), 8.22 (dd, J ) 8.5, 1.4 Hz, 1H), 7.96 (m, 2H),
7.88 (d, J ) 5.1 Hz, 1H), 7.78 (s, 1H), 7.53 (m, 2H), 2.74 (q, J )
7.6 Hz, 2H), 1.35 (t, J ) 7.7 Hz, 3H). 13C NMR (CDCl3, 100 MHz)
δ 158.8, 150.8, 143.4, 133.9, 133.7, 133.2, 128.7, 128.6, 127.6,
126.9, 126.8, 126.4, 124.2, 122.9, 25.8, 13.7. FTIR (film) 2970
(w), 1642 (m) cm-1. HRMS calcd for C16H15N2 (M + 1) 235.1235,
found 235.1227.
Su p p or tin g In for m a tion Ava ila ble: Tabulated spectral
data (1H NMR, 13C NMR, HRMS, IR) and scanned images of
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
5-d 1-Meth yl-3-p h en ylp yr id a zin e (d eu ter io-1b). The title
compound was prepared in accordance with the procedure
described in Table 1, substituting deuterium for hydrogen gas.
J O030310A
1382 J . Org. Chem., Vol. 69, No. 4, 2004