Organic base-mediated condensation of pyridinecarboxaldehydes to azachalcones

Article abstract of DOI:10.1002/adsc.200404318

A DBU-mediated aldol condensation-dehydration sequence has been used to prepare a series of synthetically important substituted 2- and 3-azachalcones. Michael products that typically accompany this sequence with inorganic bases were not observed in this p

Full text of DOI:10.1002/adsc.200404318

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Organic Base-Mediated Condensation of
Pyridinecarboxaldehydes to Azachalcones
Laura E. Downs, Derek M. Wolfe, Peter R. Schreiner*
Institute of Organic Chemistry, Justus-Liebig-University, Heinrich-Buff-Ring 58, 35392 Giessen, Germany
Fax: (þ49)-641-9934-300, e-mail: prs@org.chemie.uni-giessen.de
Department of Chemistry, The University of Georgia, Athens, Georgia 30602-2556, USA
E-mail: prs@chem.uga.edu
Received: October 14, 2004; Accepted: December 17, 2004
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A DBU-mediated aldol condensation-de-
hydration sequence has been used to prepare a series
of synthetically important substituted 2- and 3-aza-
chalcones. Michael products that typically accompa-
ny this sequence with inorganic bases were not ob-
served in this protocol of high practical value.
enone a better Michael acceptor (Scheme 2). Only the
Michaeladducts (e.g., 13 and 14) were isolated from con-
densations using 2 and 2-quinolinecarboxaldehyde. The
study showed that the reaction of 2-quinolinecarboxal-
dehyde could be stopped at the dehydration product
by applying stoichiometric amounts of pyridine to bind
the metal ion. The same approach, however, did not pre-
vent Michael addition in reactions involving 2.
Keywords: aldol reaction; azachalcones; chemoselec-
tivity; organic catalysis; pyridinecarboxaldehydes
In order to circumvent all of the problems noted
above, we considered application of an organic base to
eliminate the metal ion from the reaction mixture. We
chose 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as
the base because it is readily available, highly basic,
Azachalcones are valuable intermediates for Diels–Al- and of low nucleophilicity.[8] In our continuing interest
der and Michael reactions as well as many other conver- with organocatalysis and specifically the use of thioureas
sions.[1] Although there are many ways to prepare aza- to catalyze Diels–Alder reactions, we sought a series of
chalcones (Scheme 1),[2–4] none appear universally ap- substituted azachalcones that would elucidate the bind-
plicable to synthesize a wide variety of azachalcones us- ing mechanism of thiourea catalysts.[9] Since these cata-
ing a common synthetic protocol. All current ap- lysts are believed to activate dienophiles through hydro-
proaches suffer from subsequent Michael addition to gen bonding, azachalcones present the potential for ac-
the desired azachalcone to varying degrees. In one tivation by bidentate chelation.
case, the precipitate isolated from the condensation of
For comparison with literature data, we first prepared
2 and acetophenone was actually an oily mixture of 4–8 using published protocols,[3] but we favored a chro-
the Michael adduct 13 or 14 and the desired azachalcone matography step over crystallization. We have been un-
(9 or 10).[2] In condensations of 1 and several substituted able to prepare 9–12 and 18–23 similarly although the
benzaldehydes, cyclic products (e.g., 15) were reported- condensation products of 2-acetylpyridine (1) and 2-
ly isolated regardless of the stoichiometry used.[5] These and 3-pyridinecarboxaldehyde (2 and 3, respectively)
compounds form in high yields under conditions identi- have been prepared under almost identical conditions
cal to those suggested for the synthesis of the azachal- (Scheme 1). As in the study by Wachter-Jurcsak, we iso-
cones, and their structures were confirmed using X-ray lated the Michael adduct as the major product in con-
crystallography. Aryl-substituted oligopyridines (17) densations of pyridinecarboxaldehydes 2 and 3.[7] Con-
are isolated in 40% yield via the Krçhnke methodology densations of 2 using pyridine as an ion scavenger still
by using Michael adduct 16, generated under conditions yielded only the Michael product. Condensations of 3
identical to those used to prepare the azachalcones.[6]
reliable preparation of azachalcones therefore necessi- cone and its Michael adduct.
A
and pyridine gave inseparable mixtures of the azachal-
tates the prevention of the Michael pathway.
The DBU-mediated condensation of 2 with acetophe-
A recent study by Wachter-Jursczak and co-workers none was optimized using quantitative GC analyses (Ta-
proposed that the Michael pathway is favored by coordi- ble 1 and Supporting Information). The optimized pro-
nation of the metal ion to the azachalcone through an in- tocol was extended to all azachalcone targets. The
teraction with the nitrogen.[7] The cation withdraws elec- DBU protocol reliably effects condensations of 2 and
tron density from the conjugated system, making the 3 in yields comparable to or better than those reported
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DOI: 10.1002/adsc.200404318
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Laura E. Downs et al.
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Scheme 1. Condensation products of reactions using 2-acetylpyridine (1) and 2- and 3-pyridinecarboxaldehyde (2 and 3).
separated from all mixtures left longer than 32 hours.
These data indicate that DBU cannot be used in catalyt-
ic amounts. Reactions employing a two-fold excess in 2
or a five-fold excess in DBU each showed a large
amount of side product formation indicated by GC,
leading us to believe that the side product incorporates
the aldehyde and DBU, but we were unable to obtain
this side product in pure form. Upon heating, the side re-
Scheme 2. Metal ion coordination activating the Michael ac-
ceptor.
action overtook the desired transformation, and the im-
purity appeared in significant amounts after only ten mi-
nutes. Attempts to accelerate the DBU reaction by heat-
for the aqueous protocols (Table 2). However, we reiter- ing were abandoned.
ate that the synthesis of 2- and 3- azachalcones is only
The present DBU-mediated condensation succeeds
possible with the DBU protocol (Scheme 3). The cur- with both electron-donating and electron-withdrawing
rent limitation ofthis protocolis that it fails to effect con- substituents for the aldehydes studied and shows no for-
densations of the less reactive ketone 1.
mation of the Michael addition product that is common
Our mechanistic proposal (Scheme 4) suggests that when metal-containing inorganic bases are used for
these reactions could in principle be catalytic in DBU al- these condensations. This finding reinforces and super-
though an uncharacterized side product suggests that cedes the conclusions of Wachter-Jurcsak and co-work-
DBU is consumed in a separate side reaction. Indeed, ers that the metal cation promotes the Michael pathway
the reaction using 0.1 mol equivalents of DBUproduced in the condensations towards azachalcones. The utility
the azachalcone in only 7% yield, and a dark red layer of the organobase-mediated approach makes it an at-
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Adv. Synth. Catal. 2005, 347, 235–238

Condensation of Pyridinecarboxaldehydes to Azachalcones
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Table 1. Parameters and yields for optimizing the DBU protocol.
2 [mol]
Acetophenone [mol]
DBU [mol]
GC Yield [%]
Time [h]
Temperature [ 8C]
1
1
2
1
1
2
1
2
1
1
1
1
1
1
1
0.1
5
40
53
90
7
36
54
50
27.5
32
24
7.5
3
25
25
25
25
25
Reflux
1
Table 2. Yield comparison for DBU protocol versus reported
syntheses.
Compound
Yield [%]
DBU Protocol
Ref.[2]
Ref.[5]
9
10
11
12
18
19
20
21
22
23
73
98
90
65
69
63
31
85
38
38
42
–
40
–
–
–
–
–
–
–
35
85
40
63
86
–
–
63
–
–
Scheme 4. Proposed mechanistic pathway for DBU catalysis
in the present aldol/dehydration sequence.
inecarboxaldehyde were dissolved in 80 mL of dry THF. This
mixture was stirred at room temperature for 36 hours. The
THF was then removed, and the residual oil was purified by
flash column chromatography with 2:1 petroleum ether:ether
as the mobile phase. These solids were then crystallized from n-
heptane. Yields of isolated pure products are given below; all
compounds are known and gave NMR spectral data identical
to literature data (see cited references):
Scheme 3. Base-mediated protocol for condensations of 2-
and 3- pyridinecarboxaldehydes.
9: 73%; 1H NMR (400 MHz, CDCl3): d¼8.73 (d, 1H), 8.13
(m, 3H), 7.82 (d, 1H), 7.77 (dd, 1H), 7.63 (t, 1H), 7.54 (M,
3H), 7.34 (dd, 1H); 13C NMR (100 MHz, CDCl3): d¼124.45,
125.43, 125.50, 128.66, 128.73, 133.09, 136.90, 137.80, 142.80,
150.18, 153.17, 190.45.
tractive alternative to aqueous protocols that suffer
from accompanying Michael additions. We are currently
investigating ways to increase yields of the nitro-substi-
tuted azachalcones and the application of the DBU pro-
tocol to condensations using 2-acetylpyridine and N-
acetyloxazolidinone.
10: 98%; 1H NMR (400 MHz, CDCl3): d¼8.70 (d, 1H), 8.06
(m, 3H), 7.74 (m, 3H), 7.48, (d, 2H), 7.32 (m, 1H); 13C NMR
(100 MHz, CDCl3): d¼124.62, 124.89, 125.67, 128.98, 130.14,
136.12, 136.96, 139.55, 143.19, 150.22, 152.94, 189.09.
11: 90%; 1H NMR (200 MHz, CDCl3): d¼8.67 (d, 1H), 8.64
(dd, 1H), 8.03 (dd, 2H), 7.96 (dt, 1H), 7.80 (d, 1H), 7.56 (m, 4H),
7.36 (q, 1H); 13C NMR (50 MHz, CDCl3): d¼123.74, 124.16,
128.59, 130.82, 133.06, 134.55, 137.96, 140.90, 150.02, 121.15,
189.86.
Experimental Section
Compounds 9–12, 18, 19, 21, 22
12: 65%; 1H NMR (400 MHz CDCl3): d¼7.38 (m, 1H), 7.55
(m, 3H), 7.80 (d, 1H), 7.98 (m, 3H), 8.63 (d, 1H), 8.88 (s, 1H).
18: 69%; 1H NMR (400 MHz, CDCl3): d¼8.72 (d, 1H), 8.16
(d, 1H), 8.05 (d, 2H), 7.79 (m, 2H), 7.51 (d, 1H), 7.33 (m, 3H),
2.46 (s, 3H); 13C NMR (100 MHz, CDCl3): d¼21.72, 124.35,
These compounds were synthesized using the optimized DBU-
catalyzed aldol condensation/dehydration procedure (see Sup-
porting Informationfor the optimizationprotocol): 32 mmol of
the acetophenone, 32 mmol of DBU, and 64 mmol of 2-pyrid-
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Laura E. Downs et al.
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125.41, 125.55, 128.90, 129.36, 135.29, 136.89, 142.37, 144.00,
150.15, 153.31, 189.91.
References
19: 63%; 1H NMR (400 MHz, CDCl3): d¼8.71 (d, 1H), 8.16
(m, 3H), 7.78 (m, 2H), 7.50 (d, 1H), 7.32 (m, 1H), 7.01 (d, 2H),
3.92 (s, 3H); 13C NMR (100 MHz, CDCl3): d¼55.52, 113.86,
124.30, 125.43, 127.92, 130.82, 131.12, 136.92, 141.96, 150.12,
153.363, 163.65, 188.67.
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21: 85%; 1H NMR (200 MHz, CDCl3): d¼2.43 (s, 3H), 7.32
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The nitro-substituted compounds showed some evidence of
polymerization as the reaction mixture turned from an orange
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above. For 23, the product precipitated from the reaction mix-
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action time explains the lower isolated yields; all compounds
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22: 38%; 1H NMR (400 MHz, CDCl3): d¼3.90 (s, 3H), 7.00
(d, 2H), 7.36 (t, 1H), 7.61 (d, 1H), 7.78 (d, 1H), 7.94 (d, 1H), 8.05
(d, 2H), 8.62 (d, 1H), 8.86 (d, 1H); 13C NMR (100 MHz,
CDCl3): d¼55.55, 114.02, 123.74, 123.83, 130.93, 134.55,
140.09, 149.91, 150.96, 163.74, 188.04.
23: 38%; 1H NMR (400 MHz, CDCl3): d¼7.43 (m, 1H), 7.58
(d, 1H), 7.85 (d, 1H), 8.02 (d, 1H), 8.19 (d, 2H), 8.39 (d, 2H),
8.69 (d, 1H), 8.92 (s, 1H).
Acknowledgements
This work was supported by The University of Georgia and the
Justus-Liebig University Giessen.
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