An efficient synthesis of Baylis-Hillman adducts of acrylamide: Pd-catalyzed hydration of Baylis-Hillman adducts of acrylonitrile

Article abstract of DOI:10.1016/j.tetlet.2009.08.127

An efficient palladium-catalyzed two-step protocol for the synthesis of Baylis-Hillman adducts of acrylamide was developed. The method involved the preparation of Baylis-Hillman adducts of acrylonitrile and a Pd-catalyzed hydration of nitrile with acetald

Full text of DOI:10.1016/j.tetlet.2009.08.127

Tetrahedron Letters 50 (2009) 6286–6289
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An efficient synthesis of Baylis–Hillman adducts of acrylamide:
Pd-catalyzed hydration of Baylis–Hillman adducts of acrylonitrile
*
Eun Sun Kim, Hyun Seung Lee, Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient palladium-catalyzed two-step protocol for the synthesis of Baylis–Hillman adducts of acryl-
amide was developed. The method involved the preparation of Baylis–Hillman adducts of acrylonitrile
and a Pd-catalyzed hydration of nitrile with acetaldoxime.
Received 3 August 2009
Revised 28 August 2009
Accepted 31 August 2009
Available online 4 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Baylis–Hillman adducts
Palladium
Nitrile
Hydration
Amide
Acetaldoxime
The Baylis–Hillman reaction, which involves the coupling of
activated vinylic systems with electrophiles under the catalytic
influence of a tertiary amine, gives rise to adducts, so called Bay-
lis–Hillman adducts, with a new stereocenter and has proven to
be a very useful carbon–carbon bond-forming method in the syn-
thesis of highly functionalized molecules.1
ous problem in many cases under the conventional hydration con-
ditions.7 Some useful methods for the selective hydration of nitrile
to amide have been developed including the use of TFA/H2SO47a or
the use of H2O2/K2CO3/DMSO at low temperature.7b Recently, tran-
sition metal-catalyzed selective hydration of nitriles has also been
reported involving the use of Rh,8a,b Pt,8c,d Ru,8e–h Ir,8i Mo,8j and
Co.8k,l Very recently, we reported an efficient Pd-catalyzed hydra-
tion method of nitriles to amides with the aid of acetaldoxime
(Scheme 1).9 In these contexts, synthesis of Baylis–Hillman
adducts of acrylamide could be realized in high yields via the indi-
rect way combining the synthesis of Baylis–Hillman adducts of
acrylonitrile and the following conversion of nitrile into amide
functionality.
As the activated vinyl compounds, various compounds have
been used in the Baylis–Hillman reaction including acrylates, acry-
lonitrile, vinyl ketones, vinyl sulfones, and acrylamides.1 However,
among the activated vinyl compounds acrylamide has not been
used much for the synthesis of the corresponding Baylis–Hillman
adducts due to its sluggish reactivity.1–3 The use of polar solvent
in combination with 1.0 equiv of amine catalyst2a–e or expensive
catalyst2c,d,f showed marginal success. In addition, most of the con-
ditions can be applied to only reactive aldehydes like 4-nitrobenz-
aldehyde and pyridine 2-carboxaldehyde.2b,c As an example, the
yield of Baylis–Hillman adducts of p-anisaldehyde and acrylamide
remained maximum 21% up to date.2a An enzymatic hydration of
Baylis–Hillman adduct of acrylonitrile to the corresponding amide
derivative has been examined;4 however, an efficient access to
Baylis–Hillman adducts of acrylamide is highly required based on
the usefulness of these compounds in organic synthesis.5
Thus we examined the feasibility for the synthesis of 2a from 1a
under Pd-catalyzed hydration conditions using acetaldoxime.9 For-
tunately, compound 2a was obtained in high yield (81%) as shown
in Scheme 2.10 As a comparison experiment, we examined the
hydration of 1a under different conditions including the use of
MeOH/H2SO4,5f TFA/H2SO4,5a,b,7a and H2O2/K2CO3/DMSO.7b Treat-
ment of 1a with MeOH/H2SO4 (rt to 50 °C) showed the formation
of rearranged alcohol 4, methoxy derivative 6, and dimeric ether
compound 7 in variable yields (see Fig. 1). We did not observe the
5a,b,7a
The hydration of nitriles to the corresponding amides is very
important in view of its broad industrial and pharmacological
applications.6–8 Hydrolysis of amides to carboxylic acids is a seri-
formation of any trace amounts of 2a. The use of TFA/H2SO4
showed the formation intractable complex mixtures and we did
not observe the formation of 2a again. The use of H2O2/K2CO3 in
aqueous DMSO showed sluggish reactivity and we observed the
formation of compound 2a in trace amounts. However we could
not improve the conditions. The use of FeCl3/AcOH (reflux)5g
* Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.127

E. S. Kim et al. / Tetrahedron Letters 50 (2009) 6286–6289
6287
CN
CONH2
Pd(OAc)2 / PPh3
+
CH3CH=NOH
aq EtOH, reflux, 3 h
Scheme 1.
O
Pd(OAc)2 (10 mol%)
PPh3 (20 mol%)
OH
OH
O
CN
R
NH2
O N
+
CH3CH=NOH
(2.0 equiv)
+
R
R
NH2
aq EtOH, reflux, 3-5 h
1a-k
Me
2a-k
3 (trace)
Scheme 2.
Ph
OH
CN
Ph
OAc
Ph
OMe
Ph
O
Ph
CN
CN
CN
CN
4
5
6
7
Figure 1.
Table 1
Pd-catalyzed hydration of Baylis–Hillman nitrile to the corresponding amide derivatives
Entry
Nitrile 1
Conditionsa (h)
Amide 2 (%)
OH
OH
CONH2
CN
1
3
1a
2a (81)
OH
OH
CONH2
CN
2
3
4
5
6
3
3
4
4
4
O2N
O2N
Cl
1b
2b (82)
Cl
OH
OH
CONH2
CN
1c
2c (84)
OH
OH
CONH2
CN
MeO
MeO
1d
2d (71)
OMe OH
OMe OH
CN
CONH2
2e (77)
1e
OH
OH
CN
CONH2
2f (70)b,c
1f
Me
Me
OH
OH
CONH2
CN
7
8
5
4
2g (75)c
1g
OH
OH
CN
CONH2
2h (70)c
1h
(continued on next page)

6288
E. S. Kim et al. / Tetrahedron Letters 50 (2009) 6286–6289
Table 1 (continued)
Entry
Nitrile 1
Conditionsa (h)
Amide 2 (%)
OH
OH
OH
CN
CONH2
2i (75)c
CONH2
2j (84)
9
10
11
12
5
N
N
1i
OH
CN
4
4
N
N
1j
HO
HO
CN
O
CONH2
O
N
N
H
2k (60)c
1k
H
COOMe
COOMe
3
CONH2
CN
1l
2l (92)
aConditions: Nitrile (1.0 mmol), Pd(OAc)2 (10 mol %), PPh3 (20 mol %), and CH3CH@NOH (2.0 equiv), aq EtOH, reflux.
bOxime ether 3 (3%) was isolated as a syn/anti (1:1) mixture.
cTrace amounts of starting materials were recovered (5–8%).
showed the formation of rearranged acetate 5 and intractable polar
side products.
Acknowledgments
Encouraged by the results, we prepared various Baylis–Hillman
adducts of acrylonitrile 1b–k according to the known method1 in
good to high yields (69–98%). Pd-catalyzed hydration of 1b–k
was carried out under the influence of Pd(OAc)2 (10 mol %), PPh3
(20 mol %), and CH3CH@NOH (2.0 equiv) in refluxing aqueous EtOH
for 3–5 h, and the results are summarized in Table 1.
As shown in Table 1, the yields of amides 2b–k were good to
high in all cases (60–84%) including the Baylis–Hillman adducts
of 4-methoxy (entry 4, 71%), 2-methoxy (entry 5, 77%), and 3-pyr-
idyl (entry 9, 75%). It is interesting to note that the yield of 4-meth-
oxy derivative 2d reached 71%. This compound was synthesized in
a very low yield (21%) via the direct Baylis–Hillman reaction ap-
proach with acrylamide (vide supra).2a In addition, the reaction
of 3-pyridyl derivative 1i under the same reaction conditions pro-
vided 2i in 75% yield. Synthesis of this compound failed completely
by the Baylis–Hillman reaction of acrylamide and pyridine-3-
carboxaldehyde.2b,11
This work was supported by National Research Foundation of
Korea Grant funded by the Korean Government (2009-0070633).
Spectroscopic data was obtained from the Korea Basic Science
Institute, Gwangju branch.
References and notes
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Fleming, E. M.; Connon, S. J. J. Org. Chem. 2004, 69, 6496–6499; (b) Yu, C.; Hu, L.
J. Org. Chem. 2002, 67, 219–223; (c) Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J.
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844–848; (e) Radha Krishna, P.; Manjuvani, A.; Sekhar, E. R. ARKIVOC 2005(iii),
99–109; (f) Tang, X.; Zhang, B.; He, Z.; Gao, R.; He, Z. Adv. Synth. Catal. 2007, 349,
2007–2017; (g) Radha Krishna, P.; Manjuvani, A.; Kannan, V.; Sharma, G. V. M.
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Khanna, A.; Chander, R.; Dikshit, M. Bioorg. Med. Chem. 2003, 11, 2269–2276.
3. For the formation of non-Baylis–Hillman adducts from acrylamide, see:
Bussolari, J. C.; Beers, K.; Lalan, P.; Murray, W. V.; Gauthier, D.; McDonnell, P.
Chem. Lett. 1998, 787–788.
4. For the biotransformation of nitriles to amides, see: (a) Wang, M.-X.; Wu, Y.
Org. Biomol. Chem. 2003, 1, 535–540; (b) Kubac, D.; Kaplan, O.; Elisakova, V.;
Patek, M.; Vejvoda, V.; Slamova, K.; Tothova, A.; Lemaire, M.; Gallienne, E.;
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Hillman adducts, see: (a) Singh, V.; Yadav, G. P.; Maulik, P. R.; Batra, S.
Tetrahedron 2006, 62, 8731–8739; (b) Singh, V.; Yadav, G. P.; Maulik, P. R.;
Batra, S. Tetrahedron 2008, 64, 2979–2991; (c) Nag, S.; Yadav, G. P.; Maulik, P.
R.; Batra, S. Synthesis 2007, 911–917; (d) Singh, V.; Pathak, R.; Batra, S. Catal.
The Baylis–Hillman adducts of aliphatic aldehyde (entry 8) and
isatin (entry 11) showed the same reactivity. Cinnamonitrile deriv-
ative 1l (entry 12), prepared from Baylis–Hillman adduct produced
the corresponding amide 2l in 92%. It is interesting to note that
oxime ether derivative 3 was isolated as a side product (3%, see
Scheme 2) in the reaction of m-methyl derivative 1f (entry 6). This
compound must be formed from the product 2f by further reaction
with acetaldoxime. The yield of 3 was increased up to 9% when we
ran the reaction of 1f with 5.0 equiv of acetaldoxime. This type of
side product was observed in other cases also in trace amounts,
but we did not isolate them in most cases. Starting material re-
mained in some cases even after 3–5 h (5–8% for entries 6–9 and
11); however, when we allowed the reaction mixture to run for a
longer time the amount of side product 3 increased.
In summary, we developed an efficient palladium-catalyzed
two-step protocol for the synthesis of Baylis–Hillman adducts of
acrylamide. The method involved the preparation of Baylis–Hill-
man adducts of acrylonitrile and the following Pd-catalyzed hydra-
tion of nitrile with acetaldoxime.

E. S. Kim et al. / Tetrahedron Letters 50 (2009) 6286–6289
6289
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synthesized similarly and the representative spectroscopic data of unknown
compounds (2f, 2h, 2i, 2k, and 2l) are as follows. Known compounds were
identified by their melting points and 1H NMR spectra by comparison with the
reported data, 2a,2a,2c,4a 2b,2b,2c 2c,4a 2d,4a 2e,2a,4a 2g,2a 2j.2bCompound 2f: 70%;
6. (a) Thallaj, N. K.; Przybilla, J.; Welter, R.; Mandon, D. J. Am. Chem. Soc. 2008, 130,
2414–2415; (b) Larock, R. C. Comprehensive Organic Transformations, 2nd ed.;
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Chem. Rev. 2002, 102, 1771–1802. and further references cited therein.
7. For the hydration of nitriles to amides catalyzed by acid or base, see: (a)
Moorthy, J. N.; Singhal, N. J. Org. Chem. 2005, 70, 1926–1929. and further
references cited therein; (b) Katritzky, A. R.; Pilarski, B.; Urogdi, L. Synthesis
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Org. Chem. 1971, 36, 3048–3050; (h) Merchant, K. J. Tetrahedron Lett. 2000, 41,
3747–3749.
white solid, mp 110–112 °C; IR (film) 3326, 3189, 1668, 1624, 1590 cmÀ1 1H
;
NMR (CDCl3, 300 MHz) d2.30 (s, 3H), 4.47 (br s, 1H), 5.41 (s, 1H), 5.44 (s, 1H),
5.91 (s, 1H), 6.06 (br s, 1H), 6.55 (br s, 1H), 7.05–7.22 (m, 4H); 13C NMR (CDCl3,
75 MHz) d 21.44, 74.30, 122.59, 123.21, 126.83, 128.36, 128.55, 138.16, 140.66,
144.46, 169.64; TSIMS m/z 192 (M++1). Anal. Calcd for C11H13NO2: C, 69.09; H,
6.85; N, 7.32. Found: C, 69.13; H, 7.02; N, 7.24.Compound 2h: 70%; white solid,
mp 86–88 °C; IR (KBr) 3376, 3189, 2929, 1655, 1630, 1604 cmÀ1 1H NMR
;
(CDCl3, 300 MHz) d 0.81 (t, J = 6.6 Hz, 3H), 1.22–1.39 (m, 6H), 1.51–1.67 (m,
2H), 3.39 (d, J = 5.4 Hz, 1H), 4.25–4.32 (m, 1H), 5.43 (s, 1H), 5.82 (s, 1H), 5.96
(br s, 1H), 6.68 (br s, 1H); 13C NMR (CDCl3, 75 MHz) d 13.96, 22.52, 25.57, 31.53,
35.59, 73.54, 121.24, 144.73, 169.87; TSIMS m/z 172 (M++1). Anal. Calcd for
C9H17NO2: C, 63.13; H, 10.01; N, 8.18. Found: C, 63.42; H, 10.27; N, 8.03.
Compound 2i: 75%; pale yellow solid, mp 113–115 °C; IR (KBr) 3316, 3179,
2924, 1670, 1592 cmÀ1 1H NMR (DMSO-d6, 300 MHz) d 5.53 (s, 1H), 5.70 (s,
;
8. For the transition metal-catalyzed hydration of nitriles to amides, see: (a) Goto,
A.; Endo, K.; Saito, S. Angew. Chem., Int. Ed. 2008, 47, 3607–3609; (b) Djoman, M.
C. K.-B.; Ajjou, A. N. Tetrahedron Lett. 2000, 41, 4845–4849; (c) Jiang, X.-b.;
Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. J. Org. Chem. 2004, 69, 2327–2331;
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7627; (e) Fung, W. K.; Huang, X.; Man, M. L.; Ng, S. M.; Hung, M. Y.; Lin, Z.; Lau,
C. P. J. Am. Chem. Soc. 2003, 125, 11539–11544; (f) Oshiki, T.; Yamashita, H.;
Sawada, K.; Utsunomiya, M.; Takahashi, K.; Takai, K. Organometallics 2005, 24,
6287–6290; (g) Yamaguchi, K.; Matsushita, M.; Mizuno, N. Angew. Chem., Int.
Ed. 2004, 43, 1576–1580; (h) Cadierno, V.; Francos, J.; Gimeno, J. Chem. Eur. J.
2008, 6601–6605; (i) Takaya, H.; Yoshida, K.; Isozaki, K.; Terai, H.; Murahashi,
S.-I. Angew. Chem., Int. Ed. 2003, 42, 3302–3304; (j) Breno, K. L.; Pluth, M. D.;
Tyler, D. R. Organometallics 2003, 22, 1203–1211; (k) Kim, J. H.; Britten, J.; Chin,
J. J. Am. Chem. Soc. 1993, 115, 3618–3622; (l) Chin, J.; Kim, J. H. Angew. Chem.,
Int. Ed. 1990, 29, 523–525.
9. Kim, E. S.; Kim, H. S.; Kim, J. N. Tetrahedron Lett. 2009, 50, 2973–2975.
10. Typical procedure for the conversion of 1a to 2a: A mixture of Baylis–Hillman
adduct 1a (159 mg, 1.0 mmol), acetaldoxime (118 mg, 2.0 mmol), Pd(OAc)2
(22.5 mg, 10 mol %), and PPh3 (52.5 mg, 20 mmol %) in aqueous EtOH (H2O/
EtOH, 1:4, 3 mL) was heated to reflux for 3 h under nitrogen atmosphere. The
reaction mixture was diluted with EtOH (5 mL), filtered through a Celite pad,
and washed with EtOH and CH2Cl2. After the removal of solvent and column
chromatographic purification process (hexanes/EtOAc/CHCl3, 1:1:1) compound
2a was obtained as a white solid, 144 mg (81%). Other compounds were
1H), 5.85 (br s, 1H), 5.87 (s, 1H), 7.01 (br s, 1H), 7.32 (dd, J = 7.8 and 4.8 Hz, 1H),
7.52 (br s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 8.43 (d, J = 4.8 Hz, 1H), 8.50 (s, 1H); 13C
NMR (DMSO-d6, 75 MHz) d 69.12, 117.70, 123.23, 134.29, 138.61, 146.71,
148.21, 148.40, 168.42; ESIMS m/z 179 (M++1). Anal. Calcd for C9H10N2O2: C,
60.66; H, 5.66; N, 15.72. Found: C, 60.54; H, 5.87; N, 15.49.
Compound 2k: 60%; pale yellow solid, mp 181–183 °C; IR (KBr) 3322, 3272,
3199, 1716, 1666, 1621 cmÀ1 1H NMR (DMSO-d6, 300 MHz) d 6.00 (s, 1H), 6.05
;
(s, 1H), 6.23 (s, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.82 (br s, 1H), 6.85 (td, J = 7.5 and
1.2 Hz, 1H), 6.95 (d, J = 6.6 Hz, 1H), 7.15 (td, J = 7.5 and 1.5 Hz, 1H), 7.58 (br s,
1H), 10.10 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) d 75.67, 109.29, 119.75,
120.87, 123.20, 128.86, 132.38, 143.23, 144.08, 167.57, 177.30; TSIMS m/z 219
(M++1). Anal. Calcd for C11H10N2O3: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.63;
H, 4.76; N, 12.55.Compound 2l: 92%; white solid, mp 128–130 °C; IR (KBr)
3315, 3172, 1711, 1661 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.46 (s, 2H), 3.85 (s,
;
3H), 5.98 (br s, 1H), 6.25 (br s, 1H), 7.34–7.45 (m, 3H), 7.57–7.60 (m, 2H), 7.93
(s, 1H); 13C NMR (CDCl3, 75 MHz) d 35.29, 52.40, 125.58, 128.61, 129.28,
129.60, 134.45, 143.06, 168.64, 172.71; ESIMS m/z 220 (M++1). Anal. Calcd for
C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.79; H, 6.07; N, 6.15.
11. Although Radha Krishna et al. reported the synthesis of 2i in 62% yield,2e we
could not obtain the compound in any trace amounts under the reported
2b
conditions, very unfortunately. Although they suggested Ref.
as the
2b
reference of compound 2i without spectroscopic data, the authors of Ref.
described that they failed to prepare compound 2i.