A novel, tandem construction of C-N and C-C bonds: Facile and one-pot transformation of the Baylis-Hillman adducts into 2-benzazepines

Article abstract of DOI:10.1039/b310550d

A novel reaction involving tandem construction of C-N and C-C bonds via the simultaneous Ritter and Houben-Hoesch reactions on Baylis-Hillman adducts leading to a convenient, one-pot synthesis of 2-benzazepine derivatives is described. A facile stereoselective transformation of the Baylis-Hillman adducts into (E)- and (Z)-allyl amides is also presented.

Full text of DOI:10.1039/b310550d

A novel, tandem construction of C–N and C–C bonds: facile and one-pot
transformation of the Baylis–Hillman adducts into 2-benzazepines†
Deevi Basavaiah* and Tummanapalli Satyanarayana
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
Received (in Cambridge, UK) 2nd September 2003, Accepted 12th November 2003
First published as an Advance Article on the web 28th November 2003
A novel reaction involving tandem construction of C–N and C–
C bonds via the simultaneous Ritter and Houben–Hoesch
reactions on Baylis–Hillman adducts leading to a convenient,
one-pot synthesis of 2-benzazepine derivatives is described. A
facile stereoselective transformation of the Baylis–Hillman
adducts into (E)- and (Z)-allyl amides is also presented.
mL) was treated with methanesulfonic acid (3 mL) at 110 °C for 5
h, thus providing methyl (2E)-2-acetylaminomethyl-3-phenylprop-
2-enoate (2a) in 72% isolated yield. We then prepared representa-
tive (E)-allyl amides (2b–f) via treatment of various Baylis–
Hillman adducts (1b–d) with aceto-, propio-, and acrylonitriles
(Scheme 2). With a view to understanding the stereochemical
directive effects of the cyano group we also examined the reaction
of 3-hydroxy-2-methylene-3-phenylpropanenitrile (3a) with acet-
onitrile under similar conditions, which provided (2Z)-2-acet-
ylaminomethyl-3-phenylprop-2-enenitrile (4a) in 82% isolated
yield. We then successfully transformed a representative class of
Baylis–Hillman adducts (3b, 3c) into the corresponding (Z)-allyl
amides (4b, 4c) (Scheme 2). This stereochemical reversal from
ester group to cyano group is consistent with earlier reports on
various transformations of the Baylis–Hillman adducts.9
At this stage it occurred to us that the presence of electron
donating group(s) on the aromatic ring might help in the
construction of the C–C bond (via the Houben–Hoesch reaction)
after construction of the C–N bond (via Ritter reaction) thus leading
to the formation of 2-benzazepine derivatives (Scheme 3).
Accordingly, we treated ethyl 3-hydroxy-2-methylene-3-(3-me-
thoxyphenyl)propanoate (1e), the Baylis–Hillman adduct obtained
from ethyl acrylate and 3-methoxybenzaldehyde, with acetonitrile
in the presence of methanesulfonic acid under various conditions.
We were pleased to isolate the expected 3-aza-2-methyl-5-ethoxy-
carbonyl-9-methoxybicyclo[5.4.0]undeca-1(7),2,5,8,10-pentaene
(5) in 55% yield when 1e (2 mmol) in acetonitrile (5 mL) was
The 2-benzazepine moiety is present in many pharmaceutically
active naturally occurring molecules such as galanthamine (one of
the most effective current drugs for Alzheimer’s disease), lycor-
amine, narwedine, montanine, coccinine, pancracine, brunsvigine,
ribasine, communesin A, communesin B, nomofungin, etc.1 and in
fact, several synthetic 2-benzazepines have also been found to
exhibit hypotensive, analgesic, antiarrhythmic activity and are also
useful for treatment of mental disorders and hypoxia.2 Therefore,
the development of simple and convenient procedures for the
synthesis of 2-benzazepine derivatives continues to be a challeng-
ing endeavor in synthetic organic chemistry.1a–d,3 In continuation
of our interest in the synthesis of heterocyclic molecules using
Baylis–Hillman chemistry,4 we herein describe a novel reaction
involving tandem construction of C–N and C–C bonds via the
simultaneous Ritter5 and Houben–Hoesch6 reactions on Baylis–
Hillman adducts leading to a convenient, one-pot synthesis of
2-benzazepine derivatives.
The Baylis–Hillman reaction is an emerging atom-economical
carbon–carbon bond forming reaction providing densely function-
alized molecules whose applications in many organic transforma-
tion methodologies have been well documented.4,7,8 During our
ongoing research program on the synthesis of useful and important
heterocyclic molecules,4 we required various 2-benzazepine deriv-
atives. We have envisioned that 2-benzazepine derivatives can in
principle be obtained from the Baylis–Hillman adducts via the
construction of a C–N bond through the Ritter reaction with
simultaneous construction of a C–C bond through the Houben–
Hoesch reaction as there would be a nitrilium ion intermediate
(Scheme 1).
Accordingly, we first selected methyl 3-hydroxy-2-methylene-
3-phenylpropanoate (1a), the Baylis–Hillman adduct obtained from
methyl acrylate and benzaldehyde, as a substrate for performing the
Ritter and Houben–Hoesch reactions with acetonitrile in the
presence of methanesulfonic acid under various conditions.
However this reaction did not proceed to the formation of the
desired 2-benzazepine derivative but stopped at the allyl amide
stage. The best results were obtained when methyl 3-hydroxy-
2-methylene-3-phenylpropanoate (1a) (1 mmol) in acetonitrile (5
Scheme 2 Stereoselective transformation of Baylis–Hillman adducts into
(E)-allyl amides (2a–f) and (Z)-allyl amides (4a–c) under Ritter condi-
tions.10,11
Scheme 1 Schematic representation of synthetic strategy for 2-benzazepine
derivatives.
† Electronic Supplementary Information (ESI) available: Experimental
procedures, analytical, spectral data for all 2-benzazepine derivatives
(5–15) and allyl amides (2a–f, 4a–c). Stereochemical assignment for 2a–f
and 4a–c. See http://www.rsc.org/suppdata/cc/b3/b310550d/
Scheme 3 Facile one-pot synthesis of 2-benzazepine derivatives (5–15)
involving novel tandem construction of C–N and C–C bonds.11
32
C h e m . C o m m u n . , 2 0 0 4 , 3 2 – 3 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

Table 1 Synthesis of 2-benzazepine derivatives (5–15)a
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Alcohol
(1e–m)
Product
R1 (alkyl) R (alkyl) (5–15) Yield (%)
1e
1e
1f
1g
1h
1i
1i
1j
1k
1l
1m
3-(MeO)Ph
3-(MeO)Ph
3-(MeO)Ph
3-(PrO)Ph
Et
Et
Me
Et
Me
Et
Me
Et
Et
Et
Et
Me
Et
Me
Et
Et
Et
5
6
7
8
9
10
11
12
13
14
15
55
67
44
58
65
70
74
72
33
48
46
3-(PrO)Ph
3,5-(MeO)2Ph
3,5-(MeO)2Ph
3,5-(MeO)2Ph
3,4,5-(OMe)3Ph Me
3,4-(OCH2O)Ph Et
3,4-(OCH2O)Ph Me
Et
Me
4 (a) D. Basavaiah and A. J. Rao, Chem. Commun., 2003, 604; (b) D.
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1639.
a All the reactions were carried out on 2 mmol scale of Baylis–Hillman
alcohols (1e–m) with methanesulfonic acid in alkanenitriles (5 mL) at 150
°C for 6 h. Yields are of the pure compounds obtained after column
chromatography. All the compounds were fully characterized.
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692; (b) K.-S. Yang, W.-D. Lee, J.-F. Pan and K. Chen, J. Org. Chem.,
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2003, 44, 937; (d) H. Kraiem, M. I. Abdullah and H. Amri, Tetrahedron
Lett., 2003, 44, 553; (e) M. Shi and Y-M. Xu, Angew. Chem., Int. Ed.,
2002, 41, 4507; (f) C. Yu and L. Hu, J. Org. Chem., 2002, 67, 219; (g)
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10 See ESI† for E/Z of the amides.
11 A plausible mechanism for the formation of allyl amides and
2-benzazepines is presented in the ESI†.
12 A temperature of 150 °C is necessary as at 110 °C 2-benzazepine (5) is
not formed. Also in the case of 1a, even at 150 °C there is no formation
of the corresponding 2-benzazepine derivative.
13 Crystal data for 13: C17H21NO5; M, 319.35; crystal colour, habit: light
yellow, rectangular; crystal dimensions, 0.5 3 0.48 3 0.24 mm; crystal
Fig. 1 ORTEP diagrams of (a) 13 and (b) 15.
treated with methanesulfonic acid (3 mL) at 150 °C for 6 h.12 We
then extended this strategy to representative Baylis–Hillman
adducts (1e–m) to provide the desired 2-benzazepine derivatives
(6–15) in moderate to good yields via reaction with aceto- and
propionitriles (Scheme 3, Table 1). The structures of 13 and 15
were also established by single crystal X-ray crystallography (Fig.
1).13
In conclusion, we have developed a novel strategy involving
tandem construction of C–N and C–C bonds leading to a
convenient one-pot procedure for the synthesis of 2-benzazepine
derivatives from the Baylis–Hillman adducts. We have also
described the stereoselective transformation of the Baylis–Hillman
adducts into (E) or (Z)-allyl amides, thus demonstrating the efficacy
of the Baylis–Hillman adducts as an important source for
exploration of new reactions and stereoselective transformation
methodologies.
We thank DST (New Delhi) for funding this project. We thank
UGC (New Delhi) for recognizing our University of Hyderabad as
a “University with Potential for Excellence (UPE)” and generous
funding and also for a Special Assistance Program in Organic
Chemistry in the School of Chemistry. TS thanks UGC (New
Delhi) for his research fellowship. We also thank the National
Single Crystal X-ray Facility in our School of Chemistry funded by
DST (New Delhi). We thank Professor T. P. Radhakrishnan for
helpful discussions regarding X-ray crystal structures.
system, monoclinic; lattice type, primitive; a
= 10.669(6), b =
Notes and references
13.041(8), c = 12.062(9) Å; b = 93.18(5)°; V = 1675.6(18) Å3; space
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44, 1203; (b) C. Guillou, J-L. Beunard, E. Gras and C. Thal, Angew.
Chem., Int. Ed., 2001, 40, 4745; (c) C-K. Sha, A-W. Hong and C-M.
Huang, Org. Lett., 2001, 3, 2177; (d) J. Jin and S. M. Weinreb, J. Am.
Chem. Soc., 1997, 119, 2050; (e) J. M. Boente, L. Castedo, R. Cuadros,
J. M. Saa, R. Suau, A. Perales, M. Martinez-Ripoll and J. Fayos,
Tetrahedron Lett., 1983, 24, 2029.
2 (a) R. E. Johnson and C. A. Busacca (Sterling drug, Inc.), US Pat.
5,098,901; Chem. Abstr., 1992, 117, 7949j; (b) P. Croisier and L.
Rodriguez (UCB S. A.), Ger. Offen. 2,733,868 and 2,733,869; Chem.
Abstr., 1978, 88, 152455g and 152456h; (c) J. A. Meschino (McNeil
group, P21/a : b3 (No. 14); Z = 4; m = 0.093 mm21; Dcalcd = 1.266 g
cm23; F000 = 680; l(Mo Ka) = 0.71073 Å; R = 0.0569, wR2
=
0.1845. Crystal data for 15: C15H15NO4; M, 273.28; crystal colour,
habit: light yellow, rectangular; crystal dimensions, 0.47 3 0.42 3 0.40
mm; crystal system, monoclinic; lattice type, primitive; a = 8.096(5),
b = 16.436(8), c = 10.159(8) Å; b = 98.73(5)°; V = 1336.1(15) Å3;
space group, P21/a : b3 (No. 14); Z = 4; m = 0.099 mm21; Dcalcd
=
1.359 g cm23; F000 = 576; l(Mo Ka) = 0.71073 Å; R = 0.0441, wR2
0.1081. CCDC 211673 and 211674. See http://www.rsc.org/
=
suppdata/cc/b3/b310550d/ for crystallographic data in CIF or other
electronic format.
C h e m . C o m m u n . , 2 0 0 4 , 3 2 – 3 3
33