NH4OAc promoted cyclocondensation of 3-(o-allylphenyl)pentane-1, 5-diones: Synthesis of tetracyclic benzofused 1-azahomoisotwistanes

Article abstract of DOI:10.1021/ol301693s

A facile two-step synthetic route for preparing the novel tetracyclic skeleton of benzofused 2,6-diaryl-1-azahomoisotwistanes 2 had been developed. The route was carried out by a one-pot tandem cross-coupling reaction of o-allylbenzaldehydes 1 with aryl methyl ketones 3, and NH₄OAc mediated the cascade cyclocondensation reaction of the resulting 1,5-diketones 4 with the 3-o-allylphenyl group in good yield in two steps.

Full text of DOI:10.1021/ol301693s

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
NH4OAc Promoted Cyclocondensation
of 3‑(o‑Allylphenyl)pentane-1,5-diones:
Synthesis of Tetracyclic Benzofused
1‑Azahomoisotwistanes
Meng-Yang Chang,* Ming-Hao Wu, and Hang-Yi Tai
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University,
Kaohsiung 807, Taiwan
mychang@kmu.edu.tw
Received June 20, 2012
ABSTRACT
A facile two-step synthetic route for preparing the novel tetracyclic skeleton of benzofused 2,6-diaryl-1-azahomoisotwistanes 2 had been devel-
oped. The route was carried out by a one-pot tandem cross-coupling reaction of o-allylbenzaldehydes 1 with aryl methyl ketones 3, and NH4OAc
mediated the cascade cyclocondensation reaction of the resulting 1,5-diketones 4 with the 3-o-allylphenyl group in good yield in two steps.
For the preparation of the azaheterocyclic skeleton,
ammonium acetate (NH4OAc) has served as the nitrogen
source in countless synthetic protocols and applications,
for example, functionalized pyridines,1 pyrroles,2
homotropinones,3 pyrimidines,4 and imidazoles.5 In parti-
cular, the pyridine ring system is of immense interest
because of its synthetic approaches with diversified design,
which are often characterized by the number of atoms in
each fragment contributing to the six-membered skeleton,
including (5 þ 1), (4 þ 2), (3 þ 3), (3 þ 2 þ 1), or (2 þ 2 þ 2)
routes.6 Among the most synthetic approaches for the
formation of the pyridine framework, NH4OAc promoted
the one-pot tandem condensation of arylaldehyde with 2
equiv of aryl methyl ketone which is a well established
protocol under various conditions.7
In continuation of our recent investigation with
the syntheses of some benzannulated molecules
(1) For reviews on the synthesis of substituted pyridines, see: (a)
Kharchenko, V. G.; Markova, L. I.; Fedotova, O. V.; Pchelintseva,
N. V. Chem. Heterocycl. Compd. 2003, 39, 1121. (b) Hill, M. D. Chem.;
Eur. J. 2010, 16, 12052. (c) Henry, G. D. Tetrahedron 2004, 60, 6043.
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Hapke, M. Chem. Soc. Rev. 2007, 36, 1085.
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(b) Fatemeh, T.; Mahnaz, F. Synlett 2012, 1379.
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Chem. 2002, 67, 2197. (b) Donohoe, T. J.; Basutto, J. A.; Bower, J. F.;
Rathi, A. Org. Lett. 2011, 13, 1036. (c) Hu, J.; Zhang, Q.; Yuan, H.; Liu,
Q. J. Org. Chem. 2008, 73, 2442. (d) Thapa, P.; Karki, R.; Yun, M.;
Kadayat, T. M.; Lee, E.; Kwon, H. B.; Na, Y.; Cho, W.-J.; Kim, N. D.;
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Essawy, S. A. Synthesis 1999, 2114. For (3 þ 3) route, see: (g) Bagley,
M. C.; Glover, C.; Merritt, E. A. Synlett 2007, 2459. For (3 þ 2þ1)
route, see: (h) Aulakh, V. S.; Ciufolini, M. A. J. Org. Chem. 2009, 74,
5750. (i) Allais, C.; Constantieux, T.; Rodriguez, J. Chem.;Eur. J. 2009,
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2009, 11, 2161.
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Zhao, Z.; Lindsley, C. W. Org. Lett. 2004, 6, 1453. (b) Wang, J.; Dyers,
L.; Mason, R., Jr.; Amoyaw, P.; Bu, X. R. J. Org. Chem. 2005, 70, 2353.
(c) Kundu, N.; Bhattacharya, K.; Abtab, S. M. T.; Chaudhury, M.
Tetrahedron Lett. 2012, 53, 2719. (d) Hosseini-Zare, M. S.; Mahdavi,
M.; Saeedi, M.; Asadi, M.; Javanshir, S.; Shafiee, A.; Foroumadi, A.
Tetrahedron Lett. 2012, 53, 3448. (e) Khalili, B.; Tondro, T.; Hashemi,
M. M. Tetrahedron 2009, 65, 6882.
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Lett. 2005, 34, 732. (c) Adib, M.; Tahermansouri, H.; Koloogani, S. A.;
Mohammadi, B.; Bijanzadeh, H. R. Tetrahedron Lett. 2006, 47, 5957.
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r
10.1021/ol301693s
XXXX American Chemical Society

(e.g., tetrahydroanthracen-9-ones and isoquinolines),8 a
facile two-step synthetic route for preparing the novel
tetracyclic skeleton of benzofused 2,6-diaryl-1-azahomo-
isotwistane was studied next. Natural products with the
carbon structural framework of homoisotwistane
(tricyclo[5.3.1.03,8]undecane), such as seychellene, patchouli
alcohol and cannivonine, exhibited some interesting biolo-
gical activities and were prepared by unique synthetic
approaches as shown in Figure 1.9
Scheme 1. Synthetic Routes of 2,4,6-Triarylpyridine (Y = H)
and 2,6-Diaryl-1-azahomoisotwistane (Y = Allyl)
Figure 1. Natural products with the structural framework of
homoisotwistane.
In the NH4OAc mediated (5 þ 1) cyclocondensation re-
€
action, traditionally the Krohnke pyridine with a 2,4,6-
triaryl substitution pattern could be isolated under the
solvent-free, catalyst-free, or microwave irradiation con-
ditions via the intermediate of chalcone and 1,5-diketone
(Y = H) asshowninScheme 1.10 WithY changed fromhy-
drogen tothe allyl groupon thestartingarylaldehyde (Y =
allyl), the 1,5-diketone was isolated by a one-pot tandem
cross-coupling reaction11 (ClaisenꢀSchmidt condensation/
Michael addition) of o-allylbenzaldehyde with aryl methyl
ketone in acceptable yields. Surprisingly, when treatment
of 3-(o-allylphenyl)-1,5-diketone reacted with NH4OAc,
we observed that the novel tetracyclic benzofused skeleton
of 1-azahomoisotwistane replaced the expected pyridine
skeleton.12 So far, there is still no example to describe the
NH4OAc promoted straightforward cyclocondensation
reaction of 1,5-diketone with the 3-o-allylaryl substituent.
To initiate the synthetic work of skeleton 2, 3-(o-
allylphenyl)-1,5-diketone 4a was first prepared via the
one-pot tandem reaction of starting material 1a13 with 3a
(R1 = Ph) in a 92% yield under an alkaline aqueousꢀ
methanolic solution as shown in Scheme 2. Next, the tetra-
cyclic benzofused 2,6-diphenyl-1-azahomoisotwistane 2a was
formed via a one-pot cascade cyclocondensation reaction of
the resulting 1,5-diketone 4a with NH4OAc in 75% yield. By
the above-mentioned synthetic procedure, changing dif-
ferent analogues 3bꢀ3k, 1,5-diketones 4bꢀ4o (66ꢀ92%)
and 1-azahomoisotwistanes 2bꢀ2o (44ꢀ82%) were iso-
lated, respectively. Therefore, in the case of 4n and 4o
(R1 = Me), only one diastereoisomer was eluted, corre-
sponding to the steric effects; no other isomer was detected.14
Furthermore, 2a, 2c, 2j, and 2n were determined by
single-crystal X-ray crystallography. Structure 2a is shown
in Figure 2. We also challenged the one-pot synthesis of 2a
via a NaOH-mediated reaction of 1a and 3a, followed by
the addition of NH4OAc in an alkaline solution. However,
2a (48%) was only isolated by increasing the reaction time.
The formation of the tetracyclic adduct 2a was con-
firmed through spectral analysis. The 1H NMR spectrum
of 2a exhibited two doublets at δ 6.86 and 6.83 for
benzofused protons. Three CH protons appeared as two
doublets of H-3 (δ 3.48) and two multiplets of H-4 (δ 2.97)
and H-8 (δ 2.25). Three CH2 protons appeared as two
triplets of H-5 (δ 1.93) and two doublets of doublets of H-7
(δ 1.81 and 1.73) and H-9 (δ 3.07 and 2.91). The structure
of 2a was confirmed by HRMS, which showed a peak at
m/z 410.2125 [Mþ þ 1].
(8) (a) Chang, M.-Y.; Wu, M.-H. Tetrahedron Lett. 2012, 53, 3173.
(b) Chang, M.-Y.; Wu, M.-H.; Lee, N.-C.; Lee, M.-F. Tetrahedron Lett.
2012, 53, 2125.
(9) (a) Srikrishna, A.; Ravi., G. Tetrahedron 2008, 64, 2565.
(b) Srikrishna, A.; Satyanarayana, G. Tetrahedron: Asymmetry 2005,
16, 3992. (c) Evan, D. A.; Golob, A. M.; Mandel, N. S.; Mandel, G. S.
J. Am. Chem. Soc. 1978, 100, 8170. (d) Takaishi, N.; Inamoto, Y.;
Aigami, K. J. Org. Chem. 1980, 45, 2254.
€
(10) Krohnke, F.; Zecher, W. Angew. Chem., Int. Ed. 1962, 1, 626.
(11) (a) Yanagisawa, A.; Takahashi, H.; Arai, T. Tetrahedron 2007,
63, 8681. (b) Waldmann, H.; Karunakar, G. V.; Kumar, K. Org. Lett.
2008, 10, 2159.
(12) (a) Hartman, G. D.; Halczenko, W.; Phillips, B. T. J. Org. Chem.
1985, 50, 2427. (b) Hartman, G. D.; Halczenko, W.; Phillips, B. T.
J. Org. Chem. 1986, 51, 142. (c) Margrey, K. A.; Chinn, A. J.; Laws,
S. W.; Pike, R. D.; Scheerer, J. R. Org. Lett. 2012, 14, 2458.
(13) The starting skeleton 1 was provided from commercially avail-
able isovanillin in moderate overall yields in three steps according to the
reported procedures with the reaction sequence of O-allylation and
Claisen rearrangement followed by O-methylation.
(14) CCDC 883599 (2a), 883600 (2c), 887548 (2j), 887547 (2n),
883594 (4a), and 883595 (8) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge via www.
ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: 44ꢀ1223ꢀ336033; E-mail:
deposit@ccdc.cam.ac.uk).
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Synthesis of Skeleton 2
Scheme 3. Synthesis of 2,4,6-Triarylpyridines 5
of 1e (R2 = Ph) with 3a were unsuccessful due to the base-
induced olefinic migration between the two aryl groups of 1e.
How are skeletons 2 and 5 produced? As shown in
Scheme 4, the initial event may be considered as the
formation of intermediate A with the imine skeleton by
the NH4OAc mediated intermolecular dehydration of the
symmetrical 1,5-diketone 4. Intermediate B is afforded
from the intramolecularaddition followed by dehydration.
Afterthe six-memberedring of intermediateB isgenerated,
sequential intramolecular DielsꢀAlder cycloaddition of
intermediate B with the dehydropyridine skeleton affords
2 (R2 = H). When R2 is the methyl group, pyridine skel-
eton 5 is immediately formed via oxidative dehydrogena-
tion due to the repulsion hindrance between the diene and
dienophile with the R2 group of intermediate B. The results
suggested that the steric conformation derived from the
Scheme 4. Possible Mechanism for the NH4OAc Mediated
Annulation
Figure 2. X-ray structure of 2a.
To extend this protocol for the application of skeleton 4
with the 3-(2-butenylphenyl) group (4p or 4q was prepared
from the reaction of 1d with 3a or 3f in 87% or 78% yield), we
found that skeleton 5was easily formed as a sole isomer (60%
of 5a or 45% of 5b) under the NH4OAc mediated one-pot
conditions (Scheme 3). The possible explanation could be
that the 2-butenyl side chain (R2 = Me) of 4p or 4q inhibited
the formation of skeleton 2 by the inherent steric hindrance.
Therefore, the ring closure of 4p or 4q was then turned to
form skeleton 5. Other attempts to produce 4s by treatment
Org. Lett., Vol. XX, No. XX, XXXX
C

R2 group might have caused the preference of pyridine
formation rather than [4 þ 2] cycloaddition. Therefore, the
bridged skeleton 2 with three six-membered rings and the
symmetrical pyridine skeleton 5 with 2,4,6-triaryl groups
envisioned that the bulky group (R3 group) should be the
key factor affecting the Michael addition of the second
methylketone.
Using the facile route, the efficient transformation
from 1a to 8 could be performed in high yield and in two
steps. First, compound 7 was prepared in 88% yield from
the reaction of 1a with excess NaOH (10.0 equiv) by the
one-pot combination of ClaisenꢀSchmidt condensation/
Michael addition/olefin migration. Then, 1-azaisotwistane
8 was isolated in 87% yield by NH4OAc mediated cyclo-
condensation (Scheme 6). Furthermore, the structural
framework of 8 was determined by single-crystal X-ray
crystallography. X-ray diffraction analysis could be em-
ployed to prove the constitution and relative configuration.14
In summary, we have successfully presented a synthetic
methodology for the skeleton of tetracyclic 1-azahomoi-
sotwistane 2, which involved one-pot tandem cross-
coupling of o-allylbenzaldehyde 1 with aryl methyl ketone
3; NH4OAc promoted the cascade cyclocondensation of
the resulting 1,5-diketone 4 with the 3-o-allylphenyl group
in good yield in two steps. The novel strategy showed that
NH4OAc is an excellent nitrogen source with which to
promote the formation of the tricyclo[5.3.1.03,8]undecane
structure. Considering the utility of these polycyclic ben-
zofused compounds, the development of these general
synthetic approaches is significant.
Scheme 5. Reaction of 1a with 3lꢀ3n
Scheme 6. Synthesis of 8
Acknowledgment. The authors would like to thank the
National Science Council of the Republic of China for its
financial support.
are efficiently constructed, respectively, by the one-pot cas-
cade cyclocondensation reaction.
Supporting Information Available. Experimental pro-
cedures, characterization data, scanned photocopies of
1H and 13C NMR of new compounds, and crystallo-
graphic data of compounds 2a, 2c, 2j, 2n, 4a, and 8
(CIF) were supported. This material is available free of
charge via the Internet at http://pubs.acs.org.
Under similar conditions, reactions of 1a with 3lꢀ3n
were further studied, as shown in Scheme 5. By controlling
the bulky size of the R3 group (tert-butyl, 2-fluorenyl, or
9-anthracenyl), only the aldol skeleton 6 was isolated. By
increasing the reaction time (20 h), solely 6d with the (E)-
form olefin was obtained in 86% yield by the olefin migra-
tion under alkaline conditions. From the observation, we
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX