One-pot synthesis of substituted tetrahydrocyclobuta[a]naphthalenes by domino aldol condensation/olefin migration/electrocyclization

Article abstract of DOI:10.1021/ol401152w

A facile one-pot synthetic route for preparing the novel benzofused tricyclic skeleton of 1,2,2a,8b-tetrahydrocyclobuta[a]naphthalenes 5 is developed. The route was realized by a NaH-mediated tandem aldol condensation/olefin migration/electrocyclization of o-allylbenzaldehydes 1 with cinnamyl sulfones 3 in good yields.

Full text of DOI:10.1021/ol401152w

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
One-Pot Synthesis of Substituted
Tetrahydrocyclobuta[a]naphthalenes
by Domino Aldol Condensation/Olefin
Migration/Electrocyclization
Meng-Yang Chang,* Ming-Hao Wu, and Yeh-Long Chen
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University,
Kaohsiung 807, Taiwan
mychang@kmu.edu.tw
Received April 24, 2013
ABSTRACT
A facile one-pot synthetic route for preparing the novel benzofused tricyclic skeleton of 1,2,2a,8b-tetrahydrocyclobuta[a]naphthalenes 5 is
developed. The route was realized by a NaH-mediated tandem aldol condensation/olefin migration/electrocyclization of o-allylbenzaldehydes 1
with cinnamyl sulfones 3 in good yields.
The domino reaction is a useful synthetic tool for con-
structing diversified frameworks; it has been successfully
applied to different synthetic fields.1 Most notably, it has
been found that a one-pot, well- designed reaction sequence
is the key combination to shortening reaction time and
increasing synthetic efficiency. Because the synthetic ap-
proaches for domino types are currently in vogue, many
catalyst-mediated one-pot reactions have been developed.2
In continuation of our recent investigation on the structure
of o-allylbenzaldehyde 1A for synthesizing benzannulated
molecules (e.g., homoisotwistanes 2A and tetrahydroanthra-
cen-9-ones 2B) using the facile condensation/cycloaddition
strategy;3,4 a one-pot synthetic route for preparing tricyclic
benzofused tetrahydrocyclobuta[a]naphthalenes 2C was stu-
died. As shown in Scheme 1, the o-allyl functional group plays
an important role in enabling different carbonꢀcarbon bond
formations to be useful substituent during the tandem
sequence. The introduction of an o-allyl substituent is expected
to shorten the synthetic step of targets by utilizing a simple
tandem design without transition metal manipulation. The
cyclobutanated naphthalene and its carbon allotropes have
received considerable attention from theorists and synthetic
chemists, because they can be used as the spacer or building
blocks for functionalized organic electrical materials and
potential agents.5 However, only limited methods are known
(1) For reviews on the synthesis of tandem reactions, see: (a) Tietze,
L. F. Chem. Rev. 1996, 96, 115. (b) Parsons, P. J.; Penkett, C. S.; Shell,
A. J. Chem. Rev. 1996, 96, 195. (c) Wasilke, J. C.; Obrey, S. J.; Baker,
R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001. (d) Posner, G. H. Chem.
Rev. 1986, 86, 831. (e) Bunce, R. A. Tetrahedron 1995, 48, 13103.
(2) (a) Hong, B.-C.; Liao, W.-K.; Dange, N. S.; Liao, J.-H. Org. Lett.
2013, 15, 468. (b) Enders, D.; Grossmann, A.; Gieraths, B.; Duzdemir, M.;
Merkens, C. Org. Lett. 2012, 14, 4254. (c) Dong, L. J.; Fan, T.-T.; Wang, C.;
Sun, J. Org. Lett. 2013,15, 204. (d) Lefranc, A.; Guenee, L.; Alexakis, A. Org.
Lett. 2013, 15, 2172. (e) Morten, C. J.; Byers, J. A.; Jamison, T. F. J. Am.
Chem. Soc. 2011, 133, 1902. (f) Jiang, K.; Jia, Z.-J.; Yin, X.; Wu, L.; Chen,
Y. C. Org. Lett. 2010, 12, 2766. (g) Nazef, N.; Davies, R. D. M.; Greaney,
M. F. Org. Lett. 2012, 14, 3720. (h) Hayashi, Y.; Toyoshima, M.; Gotoh, H.;
Ishikawa, H. Org. Lett. 2009, 11, 45. (i) Saanchez-Larios, E.; Holmes, J. M.;
Daschner, C. L.; Gravel, M. Org. Lett. 2010, 12, 5772.
(3) Chang, M.-Y.; Wu, M.-H.; Tai, H.-Y. Org. Lett. 2012, 14, 3936.
(4) Chang, M.-Y.; Wu, M.-H. Tetrahedron Lett. 2012, 53, 3173.
(5) (a) Zhang, W.; Koehler, K. F.; Harris, B.; Skolnick, P.; Cook,
J. M. J. Med. Chem. 1994, 37, 745. (b) Gu, Z.; Boursalian, G. B.;
Gandon, V.; Padilla, R.; Shen, H.; Timofeeva, T. V.; Tongwa, P.;
Vollhardt, K. P. C.; Yakovenko, A. A. Angew. Chem., Int. Ed. 2011,
50, 9413. (c) Schmidt, A. H.; Kircher, G.; Zylla, J.; Veit, S. J. Chem. Soc.,
Perkin Trans. 1 1999, 409.
(6) (a) Burdett, K. A.; Ikeler, T. J.; Swenton, J. S. J. Am. Chem. Soc.
1973, 95, 2702. (b) Matuszak, C. A.; Dickson, L. J. Org. Chem. 1972, 37,
3345. (c) Braun, A. M. J. Org. Chem. 1970, 35, 1208. (d) Mehta, G.;
Kotha, S. Tetrahedron 2001, 57, 625. (e) Trahanovsky, W. S.; Arvidson,
K. B. J. Org. Chem. 1996, 61, 9528. (f) Chen, C.; Xi, C.; Liu, Y.; Hong, X.
J. Org. Chem. 2006, 71, 5373and references cited therein.
r
10.1021/ol401152w
XXXX American Chemical Society

for establishing core structures, including the Birch reduction
of biphenylene, thermolyic rearrangement of tetrahydrobiphe-
nylene, photolytic irradiation of homobenzotropilidene and
metal complex-mediated cross-coupling routes.6 New routes
with this specific substitution pattern are needed.
Table 1. One-Pot Synthetic Route toward 1,2,2a,
8b-Tetrahydrocyclobuta[a]naphthalenes 5a,b
Scheme 1. Application of o-Allylbenzaldehyde 1A
aldehydes
sulfones
products
entry
1 (Y, Z)
3 (X, R)
5 yield (%)
1
1a, MeO, MeO
1a, MeO, MeO
1a, MeO, MeO
1a, MeO, MeO
1b, BnO, MeO
1b, BnO, MeO
1b, BnO, MeO
1b, BnO, MeO
1c, c-C5H9O, MeO
1c, c-C5H9O, MeO
1c, c-C5H9O, MeO
1c, c-C5H9O, MeO
1d, MeO, H
3a, Tol, Ph
5a, 75
5b, 82
5c, 80
5d, 78
5e, 76
5f, 84
2
3b, Tol, 4-FPh
3c, Tol, 3,4-CH2O2Ph
3d, Tol, 4-MeOPh
3a, Tol, Ph
3
To trigger the one-pot tandem synthesis of 1,2,2a,
8b-tetrahydrocyclobuta[a]naphthalenes 5, o-allylbenzal-
dehyde 1a and cinnamyl sulfone 3a were chosen as the
starting substrates in the investigation of the one-pot and
domino aldol condensation/olefin migration/intramolecu-
lar electrocyclization under various basic conditions (see
Table 1). Compound 1a can be prepared from isovanillin
or 3-hydroxybenzaldehyde via a three-step procedure of
O-allylation, Claisen rearrangement and O-alkylation.3,4
Compound 3a was prepared from the nucleophilic sub-
stitution of cinnamyl chloride with toluenesulfinic sodium
salt. Next, when we initially employed NaH as the base for
the intermolecular aldol reaction of compounds 1a and
3a in refluxing toluene, compound 5a was obtained at a
75% yield.
4
5
6
3b, Tol, 4-FPh
3c, Tol, 3,4-CH2O2Ph
3d, Tol, 4-MeOPh
3a, Tol, Ph
7
5g, 78
5h, 80
5i, 75
8
9
10
11
12
13
14
15
16
17
3b, Tol, 4-FPh
3c, Tol, 3,4-CH2O2Ph
3d, Tol, 4-MeOPh
3a, Tol, Ph
5j, 79
5k, 84
5l, 80
5m, 84
5n, 87
5o, 79
5p, 84
complex
1b, BnO, MeO
1b, BnO, MeO
1b, BnO, MeO
1a, MeO, MeO
3e, Ph, Ph
3f, Me, Ph
3h, Tol, Me
3g, Tol, H
a The reactions were run on a 0.3 mmol scale with skeletons 1 and 3
in toluene (10 mL). b The product was >95% pure as determined by
1H NMR analysis.
For the possible mechanism of cycloadduct 5, the for-
mation of intermediate A was first proposed. After the
olefin migration of o-allylbenzaldehyde on intermediate A,
intermediate B with a (E,Z,E)-triene motif exhibited a
stronger repulsion with steric hindrance than did inter-
mediate C. For intermediate C, the orientation of the
o-styrenyl group and the sulfonyl group on the central
alkene was trans-configured to one another (E-orientation).
Under thermal conditions, the preferred intermediate C
with a fully (E,E,E)-conjugated skeleton advanced an
intramolecular cascade stereospecific 8π-electrocyclic con-
rotatory ring closure to generate two adjacent stereogenic
centers with trans-configuration on intermediate D.7 After
the sequential formation of a 6π-electrocyclic disrotatory
ring closure on intermediate D, two contiguous cis-stereo-
genic centers were also formed via the cyclooctatriene
system.
As shown in the experimental results of the Frontier
molecular orbital theory,8 a tricyclic skeleton of tetra-
hydrocyclobuta[a]naphthalene 5 was isolated as a sole
isomer. Several tricyclic benzannulated compounds 5bꢀp
were efficiently constructed in good yields (75ꢀ87%) by
the above-mentioned one-pot facile, efficient and cascade
reaction of four o-allylbenzaldehydes 1aꢀd (Y/Z = H,
OMe, OBn, OC5H9) and eight cinnamyl sulfones 3aꢀf and
3h (X = R = Me/Ar). The results clearly show benzalde-
hyde component of skeleton 1 must be electron-rich and the
sulfonyl substituent of skeleton 3 with electron-withdrawing
(8) (a) Beaudry, C. M.; Trauner, D. Org. Lett. 2002, 4, 2221. (b)
Parker, K. A.; Wang, Z. Org. Lett. 2006, 8, 3553. (c) Webster, R.;
Gaspar, B.; Mayer, P.; Trauner, D. Org. Lett. 2013, 15, 1866. (d) Garcia-
Rubin, S.; Varela, J. A.; Castedo, L.; Saa, C. O. Org. Lett. 2009, 11, 983.
(e) Kim, K.; Lauher, J. W.; Parker, K. A. Org. Lett. 2012, 14, 3138. (f)
Lim, C. H.; Kim, S. H.; Kim, K. H.; Kim, J. N. Tetrahedron Lett. 2013,
54, 2476. (g) Woodward, R. B.; Hoffmann, R. J. Am. Chem. Soc. 1965,
87, 2511.
(7) (a) Beaudry, C. M.; Malerich, J. F.; Trauner, D. Chem. Rev. 2005,
105, 4757. (b) Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E. J. Am. Chem.
Soc. 1982, 104, 5560. (c) Nicolaou, K. C. J. Org. Chem. 2009, 74, 951.
B
Org. Lett., Vol. XX, No. XX, XXXX

group also play a key factor to initiate the formation of
skeleton 5 via the delocalized electron pushꢀpull conju-
gated relationship. However, NaH-mediated treatment of
compound 1a with compound 3g in refluxing toluene
provided a complex mixture due to the relative equilibrium
of carbanion in compound 3g, producing a competitive
nucleophilic substitution between R-attack (SN2) and
γ-attack (SN20). Furthermore, the structure of compound 5e
was determined by single-crystal X-ray crystallography.9
The proposed mechanism was shown in Scheme 2.10 The
tetracyclic bridged structural framework of compound 6
with a three-membered ring was established by a one-pot
cascade reaction, including the following: (i) an intermo-
lecular aldol condensation of compound 1d with 3a, (ii) an
intramolecular 6π-electrocyclization of intermediate E,
(iii) sequential generation of benzylic diradicals, and (iv)
followed by a self-coupling of two benzylic radicals on
intermediate F. The structure of compound 6 was deter-
mined by single-crystal X-ray crystallography.9
In the next work, the one-pot NaH-mediated reaction of
compounds 1e,f and 3a in refluxing toluene was examined,
as shown in Scheme 3. However, two skeletons of 1-ally-
loxy-6-phenylnaphthalene 7 (72%) and 3-allyloxy-5-phe-
nylnaphthalene 8 (82%) were isolated as the sole products,
and no desired tricyclic compounds 5q,r were detected.11
The exact skeleton of compound 7 was determined by
single-crystal X-ray crystallography.9 A plausible explana-
tion for the efficient formation of compound 7 or 8 could
be that intermediate G1 or G2 was generated first via an
intermolecular NaH-mediated nucleophilic substitution of
compounds 1e (benzaldehyde) or 1f (benzophenone) with the
carbanion of compound 3a. Then, an intramolecular proton
exchange of intermediate G1 or G2 occurred. Furthermore,
excess NaH deprotonated the hydroxyl group to form
dianion intermediate H1 or H2. After removal of compound
3a, compound 7 or 8 was accomplished by an intramolec-
ular cyclodehydration of the carbanion of intermediate
Table 2. Reaction Conditions of Compounds 3a and 1a or 1da,b
substrate (1a, 1d/3a),
base (equiv), solvent (mL),
products 4a/5m/6
entry
temp (°C), time (h)
yield (%)
1
2
3
4
5
6
1a/3a, NaH (10), THF, 25, 20
1a/3a, NaH (10), THF, 67, 6
65/ꢀ/ꢀ
71/ꢀ/ꢀ
80/ꢀ/ꢀ
67/ꢀ/ꢀ
65/ꢀ/ꢀ
ꢀ/46/30
1a/3a, NaH (10), THF, 67, 20
1a/3a, t-BuOK (10), THF, 67, 20
1a/3a, LDA (1.0 M, 10), THF, 67, 20
1d/3a, Na (25), xylene (10), 139, 20
a The reactions were run on a 0.3 mmol scale with 1a or 1b and 3a in
THF or xylene (10 mL). b The product was >95% pure as determined by
1H NMR analysis.
Scheme 3. Synthesis of Compounds 7 and 8
Changing the base to NaH, t-BuOK, or LDA (from 25
to 67 °C) in THF for the reaction of compound 1a and 3a
(see Table 2), we found that compound 4a was obtained
with a range of yields from 65ꢀ80% via a process of aldol
condensation and olefin migration (an interrupted Julia
olefination). Under the refluxing THF conditions with
different bases, no skeleton for compound 5a was observed.
According to these phenomena, we envisioned that the
refluxing temperature of the reaction solvent is a key factor
controlling the formation of intramolecular electrocycliza-
tion, and affecting the distribution of the product. Further-
more, when the base and solvent were replaced with Na
(10 equiv) and xylene (10 mL) in the one-pot domino
reaction of compound 1d with 3a, the isolated yield of the
compound 5m was decreased to 46% and the unexpected
compound 6 was isolated at a 30% yield. This is an interest-
ing phenomenon for the formation of compound 6.
Scheme 2. Possible Mechanism
Org. Lett., Vol. XX, No. XX, XXXX
C

I1 or I2. For the reaction mechanism of compound 7, we
envisioned that the stable carbanion of intermediate I1 was
easily delocalized on the 1,3-diarylpropene system such that it
was not easy to trigger the occurrence of aldol condensation.
At this stage, the oxy-anion could easily eliminate fragment
3a. In the mechanism of compound 8, when the carbanion of
intermediate I2 had not yet proceeded to aldol condensation,
the oxy-anion on the quaternary carbon center was preferred
to eliminate fragment 3a. Therefore, by changing the sub-
stituent from allyl to styryl group (for 1e) and replacing the
group of aldehyde with phenylketone (H fPh, for 1f), aone-
pot NaH-mediated tandem cyclodehydration of compounds
1e and 1f with compound 3a provided the one-pot synthetic
route toward a naphthalene skeleton at good yields.
found that complex mixture was observed for the reaction
of compounds 1a and 3i or 3j.13 From the results, we
envisioned that the sulfonyl group should be the key
substituent affecting aldol condensation.
In summary, we have successfully presented a synthetic
method for producing a tricyclic skeleton of 1,2,2a,8b-tetra-
hydrocyclobuta[a]naphthalene 5, which involves a one-pot
intermolecular aldol condensation/olefin migration/intra-
molecular electrocyclization of o-allylbenzaldehydes 1 with
cinnamyl sulfones 3. The substituent effect of skeletons 1and 3
and various reaction conditions were well-investigated. The
one-pot synthetic route of a naphthalene skeleton was also
examined. The structures of key products were confirmed
by X-ray crystal analysis. The one-pot synthetic approach
begins with simple starting materials and reagents, and
provides a potential methodology for the synthetic research.
Considering the utility of these polycyclic benzofused
compounds, the development of these general synthetic
approaches of o-allylbenzaldehydes is significant.
To extend this one-pot domino protocol for the applica-
tion of cinnamyl azide (3i) or cinnamyl nitrile (3j),12 we
(9) CCDC 934886 (5e), 934884 (6), and 923281 (7) contain the
supplementary crystallographic data for this paper. This 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: 44-
1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
(10) (a) Ng, S. M.; Beaudry, C. M.; Trauner, D. Org. Lett. 2003, 5,
1701. (b) Marvell, E. N.; Seubert, J.; Vogt, G.; Zimmer, G.; Moy, G.;
Siegmann, J. R. Tetrahedron 1978, 34, 1307.
Acknowledgment. We thank the National Science Coun-
cil of the Republic of China for financial support.
(11) (a) De Koning, C. B.; Michael, J. P.; Rousseau, A. L. Tetra-
hedron Lett. 1997, 38, 893. (b) De Koning, C. B.; Michael, J. P.;
Rousseau, A. L. J. Chem. Soc., Perkin Trans. 1 2000, 787. (c) De Koning,
C. B.; Manzini, S. S.; Michael, J. P.; Mmutlane, E. M.; Tshabidi, T. R.;
Van Otterlo, W. A. L. Tetrahedron 2005, 61, 555.
(12) Kanai, T.; Kanagawa, Y.; Ishii, Y. J. Org. Chem. 1990, 55, 3274.
(13) No condensation products were observed for the NaH-mediated
reaction of compound 1a with 3i or 3j.
Supporting Information Available. Experimental data
1
and scanned photocopies of H and 13C NMR spectral
data are provided. This information is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX