Novel and versatile protocol for the preparation of functionalized benzocyclotrimers

Article abstract of DOI:10.1016/j.tetlet.2009.02.070

2-Bromo-3-(trimethylstannyl)cyclopenta-1,3-diene is the key-intermediate for the synthesis of vic-bromo(trimethylstannyl)bicycloolefins via Diels-Alder reaction with dienophiles. The cycloadducts can be cyclotrimerized by copper(I) 2-thiophenecarboxylate

Full text of DOI:10.1016/j.tetlet.2009.02.070

Tetrahedron Letters 50 (2009) 1989–1991
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel and versatile protocol for the preparation of functionalized
benzocyclotrimers
a
b
b,
*
Erdin Dalkılıç a, Murat Güney a, Arif Daßstan a, , Nurullah Saracoglu , Ottorino De Lucchi , Fabrizio Fabris
*
a Department of Chemistry, Atatürk University, TR-25240 Erzurum, Turkey
b Department of Chemistry, Università Ca’ Foscari di Venezia, Dorsoduro 72137, I-30123 Venezia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Bromo-3-(trimethylstannyl)cyclopenta-1,3-diene is the key-intermediate for the synthesis of vic-
bromo(trimethylstannyl)bicycloolefins via Diels–Alder reaction with dienophiles. The cycloadducts can
becyclotrimerized by copper(I) 2-thiophenecarboxylate(CuTC)to affordfunctionalizedbenzocyclotrimers.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 13 January 2009
Revised 9 February 2009
Accepted 10 February 2009
Available online 14 February 2009
Keywords:
Cyclotrimerization
Cycloaddition
Copper
Diels–Alder
Stereochemistry
Tetrazine
Highly functionalized benzocyclotrimers are valuable substrates
for supramolecular chemistry.1,2 Even though in recent years the
preparation of such molecules has been greatly improved, the syn-
thesis of precursors bearing the moieties able to impart supramo-
lecular behavior is sometimes troublesome. Cyclotrimerization of
vic-bromo(trimethyltin)olefins mediated by copper 2-thiophene-
carboxylate (CuTC)3 is the most general methodology to accomplish
this reaction.4 The alternative Heck-type methodology of bicyclic
vinyl iodides or bromides fails to afford cyclotrimers in the pres-
ence of further unsaturations.5 The key intermediate 1 for the
synthesis of a general class of substituted cyclotrimers 2 can be
ideally obtained from three approaches: (a) functionalization of
the cycloadduct of cyclopentadiene with the dienophile of interest,
and functionalization of the ethylidene moiety; (b) cycloaddition of
a synthetic equivalent of 1-bromo-2-(trimethyltin)ethyne with a
suitably substituted diene 5; (c) Diels–Alder reaction between a
in our laboratories.8 The last proposed retro-synthetic disconnec-
tion (c) is based on the availability of the key intermediate 7.9 In
this Letter, we describe a practical synthesis of 7 and its general
utility for the synthesis of variously substituted cyclotrimers.
X
X
3
a
SnMe3
X
X
X
SnMe3
X
X
c
SnMe3
Br
b
+
+
Br
Br
X
1
CuTC
5
7
6
4
suitable dienophile
6 and 2-bromo-3-(trimethylstannyl)cyclo-
penta-1,3-diene 7 (Fig. 1).
Strategy (a) provided a large number of cyclotrimers, but it
requires poorly selective reagents, such as bromine or strong bases,
consequently it is scarcely applicable to functionalized prod-
ucts.2c,4,6 1-Bromo-2-(trimethyltin)ethyne7 4, which is critical in
route (b), is a poor dienophile for Diels–Alder reactions, and the
design of an effective synthetic equivalent of 4 is object of research
X
X
X
X
X
X
2
* Corresponding authors. Tel.: +39 41 2348908; fax: +39 41 2348517.
E-mail address: fabrisfa@unive.it (F. Fabris).
Figure 1. Possible strategies leading to precursors of cyclotrimers.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.070

1990
E. Dalkılıç et al. / Tetrahedron Letters 50 (2009) 1989–1991
n
-BuLi,
t
-BuOK,
X
X
X
X
SnMe3
X
X
X
X
Br
Br
BrCH2CH2Br
n
-BuLi, Me3SnCl
THF
SnMe3
Br
CuTC
NMP
X
X
X
X
X
X
THF
+
Br
10
(95% yield)
8
9
(55% yield)
14, 15
Scheme 1. Synthesis of the stannylated precursor of cyclopentadiene 7.
MeOOC
COOMe
16: X-X =
(24% yield, 1:9 syn to anti)
N
N
17: X-X =
(4% yield, only anti)
O
O
COOMe
N
Ph
N
N
N
N
COOMe
COOMe
Scheme 4. Copper-mediated reactions leading to benzocyclotrimers.
SnMe3
Br
SnMe3
Br
N
N
N
N
COOMe
N
10
N
acting on the plane of the ethylidene fragment of the bicycle.17
More striking is the effect of the endo-cycloadduct of PTAD 15: in
this case, the sole anti-cyclotrimer 17 was obtained.
- N2
COOMe
COOMe
12
11
In conclusion, we proposed an original and versatile protocol for
the preparation of highly functionalized precursors of benzocyclo-
trimers. These compounds were submitted to standard procedure
for the cyclotrimerization, affording two original functionalized
benzocyclotrimers, which will be further investigated as supramo-
lecular scaffolds.
COOMe
25 °C
retro-Diels-Alder
SnMe3
Br
N
N
+
12
7
COOMe
13
Acknowledgments
Scheme 2. Tetrazine route leading to cyclopentadiene 7.
The authors are indebted to the Scientific and Technical Re-
search Council of Turkey (TUBITAK) and to Centro Nazionale Ricer-
che (CNR) (joined project No.: TBAG-107T874) for financial
supports. This work also was supported by the Turkish Academy
of Sciences, in the framework of the Young Scientist Award Pro-
gram (AD/TUBA-GEBIP/2001-1-3), Atatürk University, and Middle
East Technical University in Turkey and in Italy by MIUR (Rome)
within the national PRIN framework in Italy.
The protocol starts with the synthesis of the 2,3-dibromobicy-
clo[2.2.1]hepta-2,5-diene 9 from commercially available norborna-
diene 8, according to reported procedures based on the use of
potassium tert-butanolate/n-butyllithium super-base.10 The tri-
methyltin moiety is introduced at this stage, via a metal-halogen
exchange operated with n-butyllithium at À78 °C (Scheme 1).6b
The resulting vic-bromo(trimethyltin)norbornadiene 10 is
submitted to cycloaddition with dimethyl 1,2,4,5-tetrazine-3,6-
dicarboxylate,11 to afford cycloadduct 11 that undergoes facile
retro-Diels–Alder with loss of nitrogen to furnish intermediate 12
(Scheme 2).12 A second retro-Diels–Alder reaction spontaneously
occurs affording pyridazine 13 and substituted cyclopentadiene 7
which can be easily isolated.13
References and notes
1. Rieth, S.; Yan, Z.; Xia, S.; Gardlik, M.; Chow, A.; Fraenkel, G.; Hadad, C. M.;
Badjic´, J. D. J. Org. Chem. 2008, 73, 5100–5109; Yan, Z.; McCracken, T.; Xia, S.;
´
Maslak, V.; Gallucci, J.; Hadad, C. M.; Badjic, J. D. J. Org. Chem. 2008, 73, 355–
363; Yan, Z.; Xia, S.; Gardlik, M.; Seo, W.; Maslak, V.; Gallucci, J.; Hadad, C. M.;
Cyclopentadiene 7 cannot be stored for a prolonged time; there-
fore, after rapid isolation it is reacted with electron-poor olefins at
room temperature. The cycloaddition is generally smooth and exo-
thermic, furnishing the expected cycloadducts in a few hours
(Scheme 3).14
The PTAD cycloadduct 15 is crystalline and it is readily purified
by fractional crystallization, alternatively product 14 is isolated
after a fast filtration on a short silica-gel pad.15
Cyclotrimers 16 and 17 were obtained after reaction with CuTC
in dry NMP at À20 °C (Scheme 4).16 The syn to anti diastereoselec-
tivity and the yields of the products strictly reflect the steric hin-
drance of the substituents. In detail, 14 furnished a 1:9 syn to
anti mixture of 16: this unfavorable diastereomeric ratio is imput-
able to the steric repulsion between the carboxymethyl moieties
´
Badjic, J. D. Org. Lett. 2007, 9, 2301–2304; Maslak, V.; Yan, Z.; Xia, S.; Gallucci, J.;
´
Hadad, C. M.; Badjic, J. D. J. Am. Chem. Soc. 2006, 128, 5887–5894.
2. (a) Scarso, A.; Pellizzaro, L.; De Lucchi, O.; Linden, A.; Fabris, F. Angew. Chem.,
Int. Ed. 2007, 46, 4972–4975; (b) Fabris, F.; Pellizzaro, L.; Zonta, C.; De Lucchi, O.
Eur. J. Org. Chem. 2007, 283–291; (c) Zonta, C.; Cossu, S.; De Lucchi, O. Eur. J. Org.
Chem. 2000, 1965–1971.
3. Borsato, G.; De Lucchi, O.; Fabris, F.; Groppo, L.; Lucchini, V.; Zambon, A. J. Org.
Chem. 2002, 67, 7894–7897.
4. Borsato, G.; Brussolo, S.; Crisma, M.; De Lucchi, O.; Lucchini, V.; Zambon, A.
Synlett 2005, 1125–1128; De Lucchi, O.; Dasßtan, A.; Altundaßs, A.; Fabris, F.;
Balcı, M. Helv. Chim. Acta 2004, 87, 2364–2368; Dastan, A.; Uzundumlu, E.;
Balci, M.; Fabris, F.; De Lucchi, O. Eur. J. Org. Chem. 2004, 183–192; Dastan, A.;
Fabris, F.; De Lucchi, O.; Güney, M.; Balci, M. Helv. Chim. Acta 2003, 86, 3411–
3416; Borsato, G.; De Lucchi, O.; Fabris, F.; Lucchini, V.; Pasqualotti, M.;
Zambon, A. Tetrahedron Lett. 2003, 44, 561–563; Fabris, F.; Bellotto, L.; De
Lucchi, O. Tetrahedron Lett. 2003, 44, 1211–1213.
5. Higashibayashi, S.; Sakurai, H. J. Am. Chem. Soc. 2008, 130, 8592–8593; Amaya,
T.; Sakane, H.; Hirao, T. Angew. Chem., Int. Ed. 2007, 46, 8376–8379;
Higashibayashi, S.; Sakurai, H. Chem. Lett. 2007, 36, 18–19; Zambrini, L.;
Fabris, F.; De Lucchi, O.; Gardenal, G.; Visentin, F.; Canovese, L. Tetrahedron
2001, 57, 8719–8724; Cossu, S.; De Lucchi, O.; Paulon, A.; Peluso, P.; Zonta, C.
Tetrahedron Lett. 2001, 42, 3515–3518.
6. (a) Zonta, C.; Cossu, S.; Peluso, P.; De Lucchi, O. Tetrahedron Lett. 1999, 40,
8185–8188; (b) Durr, R.; Cossu, S.; Lucchini, V.; De Lucchi, O. Angew. Chem., Int.
Ed. 1997, 36, 2805–2807.
7. Zavgorodnii, V. S.; Petrov, A. A. Zh. Obshch. Khim. 1966, 36, 1480–1483;
Zavgorodnii, V. S.; Petrov, A. A. J. Gen. Chem. USSR (Engl. Transl.) 1966, 36, 1485;
Zavgorodnii, V. S.; Petrov, A. A. Zh. Obshch. Khim. 1965, 35, 931–932; J. Gen.
Chem. USSR (Engl. Transl.) 1965, 35, 936.
8. Padovan, P.; Tartaggia, S.; Lorenzon, S.; Rosso, E.; Zonta, C.; De Lucchi O.; Fabris
F., Tetrahedron Lett. 2009, 50, 1973–1976.
9. Zonta, C.; Fabris, F.; De Lucchi, O. Org. Lett. 2005, 7, 1003–1006. This approach
was successfully used in the case of 3-bromo-4-trimethystannyl-1-
(tosyl)pyrrole.
SnMe3
PTAD
DMAD
Br
O
SnMe3
Br
MeOOC
MeOOC
SnMe3
Br
7
N
N
Ph
N
O
14
(70% yield)
15
(82% yield)
Scheme 3. Diels–Alder reactions leading to cyclotrimerization precursors.

E. Dalkılıç et al. / Tetrahedron Letters 50 (2009) 1989–1991
1991
10. Borsato, G.; Linden, A.; De Lucchi, O.; Lucchini, V.; Wolstenholme, D.; Zambon,
A. J. Org. Chem. 2007, 72, 4272–4275; Peluso, P.; Greco, C.; De Lucchi, O.; Cossu,
S. Eur. J. Org. Chem. 2002, 4024–4031; Tranmer, G. K.; Yip, C.; Handerson, S.;
Jordan, R. W.; Tam, W. Can. J. Chem. 2000, 78, 527–535; Kenndoff, J.; Polborn,
K.; Szeimies, G. J. Am. Chem. Soc. 1990, 112, 6117–6118.
11. Boger, D. L.; Zhang, M. Dimethyl 1,2,4,5-Tetrazine-3,6-dicarboxylate. In
Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley: N.Y.,
1995; pp 2170–2174; Boger, D. L.; Panek, J. S.; Patel, M. Org. Synth. 1991, 70,
79–92.
4 h. Volatile materials were removed and the residue was purified by filtration
on florisil or silica-gel.
15. Compound 14: colorless oil. 1H NMR (200 MHz, CDCl3): d 4.00 (m, 1 H), 3.95
(m, 1 H), 3.79 (s, 3 H), 3.78 (s, 3 H), 2.25 (m, 2 H), 0.25 (s, 9 H). 13C NMR
(50 MHz, CDCl3): d 167.2, 166.3, 154.5, 152.6, 151.3, 148.8, 72.6, 65.0, 62.3,
54.0, 53.9, À7.3. Compound 15: mp = 157–159 °C (DCM/n-hexane). 1H NMR
(200 MHz, CDCl3): d 7.49–7.32 (m, 5 H), 5.10 (bs, 2 H), 2.22 (d, J = 9.1 Hz, 1 H),
2.17 (d, J = 9.1 Hz, 1 H), 0.26 (s, 9 H). 13C NMR (50 MHz, CDCl3): d 160.6, 159.5,
147.6, 133.5, 133.4, 131.0, 130.3, 127.4, 73.8, 72.1, 50.5, À7.5.
12. Saracoglu, N. Tetrahedron 2007, 63, 4199–4236; Boger, D. L.; Weinreb, S. M.
Hetero Diels–Alder Methodology in Organic Synthesis; Academic Press: FL, 1987;
Boger, D. L. Tetrahedron 1983, 39, 2869–2939.
16. anti-16: mp = 250–252 °C (EtOAc/cyclohexane). 1H NMR (400 MHz, CDCl3) d
(ppm): 4.35 (q, J = 1.7 Hz, 2 H), 4.34 (t, J = 1.5 Hz, 2 H), 4.29 (q, J = 1.7 Hz, 2 H),
3.78 (s, 6 H), 3.765 (s, 6 H), 3.760 (s, 6 H), 2.50 (dt, J = 8.0, 1.7 Hz, 2 H), 2.47 (dt,
J = 8.1, 1.7 Hz, 1 H), 2.13 (dt, J = 8.0, 1.7 Hz, 2 H), 2.12 (dt, J = 8.1, 1.7 Hz, 1 H);
13C NMR (100 MHz, CDCl3) d (ppm): 165.0, 164.9, 164.5, 150.3, 150.2, 149.6,
137.8, 137.7, 137.5, 64.9, 64.0, 52.1, 52.01, 52.00, 51.0, 50.9, 50.7. syn-16:
mp = 289–290 °C (DCM/cyclohexane), 7.2 mg (2% yield). 1H NMR (400 MHz,
CDCl3) d (ppm): 4.34 (t, J = 1.5 Hz, 6 H), 3.75 (s, 18 H), 2.57 (dt, J = 7.9, 1.5 Hz, 3
H), 2.17 (dt, J = 7.9, 1.5 Hz, 3 H); 13C NMR (100 MHz, CDCl3) d (ppm): 164.5,
149.7, 137.4, 66.7, 51.9, 50.9. anti-17: mp = >300 °C dec. (DCM/n-hexane). 1H
NMR (300 MHz, CDCl3) d (ppm): 7.38–7.30 (m, 3 H), 7.25–7.17 (m, 6 H), 7.07–
7.02 (m, 4 H), 6.86–6.80 (m, 2 H), 5.81 (br s, 2 H), 5.76 (br s, 2 H), 5.73 (br s, 2
H), 2.81 (dt, J = 10.5, 1.4 Hz, 1 H), 2.70 (dt, J = 10.2, 1.7 Hz, 2 H), 2.23 (dt, J = 10.5,
1.4 Hz, 1 H), 2.13 (dt, J = 10.2, 1.7 Hz, 2 H); 13C NMR (75 MHz, CDCl3) d (ppm):
158.5, 157.9, 156.3, 133.6, 133.4, 131.4, 130.9, 129.33, 129.31, 128.8, 128.4,
125.1, 124.7, 62.6, 62.6, 62.3, 50.6, 48.4.
13. Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (770 mg, 3.89 mmol) was added
to a solution of 10 (1.30 g, 3.89 mmol) in DCM (20 mL), and the mixture was
strirred for 15 min at room temperature. The solvent was removed in vacuum at
0 °C, n-hexane (50 mL) was added, and the resulting slurry was filtered, washing
the solid residue with n-hexane (2 Â 50 mL). The resulting solution was
concentrated at 0 °C to afford
7
(1.20 g, 100%): colorless oil. 1H NMR
(200 MHz, CDCl3): d 6.55 (m, 1 H), 6.45 (m, 1 H), 3.02 (m, 2 H), 0.30 (s, 9 H).
13C NMR (50 MHz, CDCl3): d 151.8, 146.8, 132.7, 129.0, 46.1, À7.0. GC-MS (70 eV)
m/z = 308 (M+, 5), 263 (6), 199 (20), 165 (100%). The intensity of 1H NMR signals
halved after 24 h at rt. This decrease was accompanied to the appearance of a
complex set of other signals that can be attributed to the tautomers resulting
from the [1,5]sigmatropic shift of the 1,3-cyclopentadienic skeleton. No
Diels–Alder dimeric products were detected by GC-MS in the mixtures.
14. General procedure for the cycloaddition of 7 to dienophiles. Freshly prepared 7
(500 mg, 1.62 mmol) was dissolved in DCM (15 mL), and the dienophile
(1.62 mmol) was added. The mixture was stirred at room temperature for 1–
17. Favorable diastereoisomeric ratio was observed when a coordinating group is
present in the apical position, presumably because of a template effect on the
cyclotrimerization reaction: Ref. 9.