Diastereoselective intramolecular Diels-Alder reactions of masked o-benzoquinones: A short entry to highly functionalized tricyclic [m.2.2.0] ring systems

Article abstract of DOI:10.1039/b103440p

Masked o-benzoquinones bearing a chiral center in the carbon-tether with a terminal olefin underwent diastereoselective intramolecular Diels-Alder reactions resulting in highly functionalized tricyclic ring systems.

Full text of DOI:10.1039/b103440p

Diastereoselective intramolecular Diels–Alder reactions of masked
o-benzoquinones: a short entry to highly functionalized tricyclic
[m.2.2.0] ring systems
Yua-Kuang Chen, Rama Krishna Peddinti and Chun-Chen Liao*
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 300.
E-mail: ccliao@mx.nthu.edu.tw; Fax: +886-3-5728123
Received (in Cambridge, UK) 18th April 2001, Accepted 12th June 2001
First published as an Advance Article on the web 4th July 2001
Masked o-benzoquinones bearing a chiral center in the
carbon-tether with a terminal olefin underwent diaster-
eoselective intramolecular Diels–Alder reactions resulting in
highly functionalized tricyclic ring systems.
furnished the single diastereomers 7c and 8c resulting from
IMDA reaction of MOBs 7b and 8b in very good yields (entries
4 and 5). The reaction of bromophenol 9a (n = 3) proceeded
slowly and afforded only 4% of the seven-membered ring
annulated cycloadduct 9c in 12 h.
The intramolecular Diels–Alder (IMDA) reaction is a powerful
tool for the rapid construction of highly substituted polycyclic
carbon skeletons.1 Milder reaction conditions and superior
reactivity and selectivities are often experienced as a result of
the entropy factor in IMDA reactions in comparison to
bimolecular Diels–Alder reactions. Recently, we have reported
the IMDA reactions of masked o-benzoquinones (MOBs)2 and
masked p-benzoquinones (MPBs)3 producing functionalized
ring systems. Herein, we report our preliminary results
regarding the diastereoselective IMDA reactions of MOBs
bearing a chiral centre in the carbon-tether with a terminal olefin
leading to highly functionalized tricyclic ring systems.
To ascertain whether the protection of the hydroxy function
at the tetrahedral carbon of 4a–9a has influenced the ster-
eochemical outcome of the reaction, we have prepared their
tert-butyldimethylsilyl derivatives 10a–15a and evaluated the
IMDA reaction of MOBs 10b–15b (Scheme 2). Gratifyingly,
the 2-methoxyphenols 10a, 11a and 13a–15a furnished a single
diastereomer in each case with an improved chemical yield. The
reaction of phenol 12a at either room temperature or reflux
temperature failed to produce the cycloadduct. These results are
summarized in Table 1.
Given the success in the IMDA reactions of in situ generated
MOBs, it seemed to us that a related process could be used for
the more stable MOBs to synthesize the tricyclic ring skeletons.
To test this proposition, phenols 16a–18a were synthesized
from 3. From our previous work, it was found that MOBs
bearing substituents at C-5 are quite stable and could be
isolated.7 Likewise, 16a–18a were oxidized with DAIB in
MeOH to the MOBs 16b–18b in excellent to quantitative yields
(Scheme 3). Interestingly, the IMDA reaction of 16b (n = 1)
proceeded in toluene at reflux temperature to furnish the endo-
diastereomeric adducts 16c,d in 38 and 15%, respectively, in
addition to 19% of exo-isomer 16e. Nevertheless, the 17b
reacted intramolecularly in THF at reflux temperature to afford
six-membered ring annulated adducts 17c and 17d in 93 and 4%
yield, respectively, with complete endo-selectivity, albeit with
longer reaction time. Similarly, 18b (n = 3) when heated at
reflux in mesitylene for 24 h, produced IMDA adducts 18c and
18d in rather poor yields. The MOB 19b formed from TBS
protected phenol 19a, upon reflux in toluene produced quantita-
tively endo-19c and exo-19e in 3+2 ratio. In contrast, a single
Masked o-benzoquinones,4 a highly reactive class of 6,6-di-
alkoxycyclohexa-2,4-dienones, can be easily generated in situ
by the oxidation of the corresponding 2-methoxyphenols with
hypervalent iodine reagents in MeOH. The in situ generated
MOBs undergo facile Diels–Alder reactions with a wide variety
of dienophiles.5 When the oxidation was carried out in the
presence of an alkenol, MOBs undergo IMDA reactions via a
tandem oxidative acetalization process.2 It was envisioned that
if MOBs bearing a chiral center in the alkenyl-tether undergo
intramolecular cycloaddition, easy access to highly substituted
tricyclic ring systems that are precursors for several linear and
angular tricyclic skeletons (Scheme 1), could be achieved.
The substrates required for this strategy were prepared from
benzaldehydes 1, 2 and 3. The Grignard reaction of 1 and 2 with
alkenylmagnesium reagents of varying chain length afforded
2-methoxyphenols 4a–9a, having a chiral center in the alkenyl-
tether, in 80–92% yield. The oxidation of 4a in MeOH to the
corresponding MOB 4b via the slow addition of diacetoxy-
iodobenzene (DAIB) at room temperature (Method A) did not
give satisfactory results. However, the slow addition of DAIB to
a methanolic solution of 4a (n = 1) at reflux temperature
(Method B) afforded IMDA adducts 4c and 4d of five-
membered ring annulation via transiently generated 4b, in 51
and 6% chemical yield, respectively, resulting from endo-
addition, in addition to 17% of a mixture of dimers (Scheme 2,
Table 1).† Similar results were obtained when the chain length
was increased by one carbon (n = 2) (entry 2). However, when
the reaction conditions were extended to 6a (n = 3), only a
mixture of dimers of MOB 6b were obtained. To prevent the
dimerization,6,7 we have examined the reaction of 4-bromophe-
nols 7a and 8a with DAIB in MeOH at room temperature, which
Scheme 2 Reagents and conditions: (i) CH2CH(CH2)n + 1 MgBr, THF, rt
(80–92%); (ii) TBSOTf, 2,6-lutidine, CH2Cl2, 210 °C (89–100%); (iii)
DAIB, MeOH (Methods A and B).
Scheme 1
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Chem. Commun., 2001, 1340–1341
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b103440p

Table 1 IMDA reactions of MOBs 4b–21b generated from phenols 4a–21a
Method/
timea
DA adduct(s)
(Yield %)c
Entry
Phenol
MOB
Timeb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
4a (X = H, R = H, n = 1)
5a (X = H, R = H, n = 2)
6a (X = H, R = H, n = 3)
7a (X = Br, R = H, n = 1)
8a (X = Br, R = H, n = 2)
9a (X = Br, R = H, n = 3)
10a (X = H, R = TBS, n = 1)
11a (X = H, R = TBS, n = 2)
12a (X = H, R = TBS, n = 3)
13a (X = Br, R = TBS, n = 1)
14a (X = Br, R = TBS, n = 2)
15a (X = Br, R = TBS, n = 3)
16a (R = H, n = 1)
B/2 h
B/2 h
B/2 h
A/1.5 h
A/1 h
A/2 h
B/1.5 h
B/2 h
B/2 h
A/1 h
A/1 h
B/2 h
C
4b
5b
6b
7b
8b
0.5 h
0.5 h
0.5 h
3.5 h
1 h
12 h
1 h
0.5 h
0.5 h
1.5 h
2 h
1 h
7.5 h
6 d
24 h
4 h
20 h
18 h
4c (51), 4d (6)
5c (46), 5d (2)
6c —
7c (80)
8c (71)
9c (4)
10c (53)
11c (73)
12c —
13c (90)
14c (95)
15c (15)
16c (38), 16d (15), 16e (19)
17c (93), 17d (4)
18c (12), 18d (3)
19c (60), 19e (40)
20c (98)
9b
10b
11b
12b
13b
14b
15b
16b
17b
18b
19b
20b
21b
17a (R = H, n = 2)
18a (R = H, n = 3)
19a (R = TBS, n = 1)
20a (R = TBS, n = 2)
C
C
C
C
21a (R = TBS, n = 3)
C
21c (10)
a Time during which DAIB was added. DAIB in MeOH was added to the phenol in MeOH at either rt (Method A) or reflux temperature (Method B). In
Method C, MOB was isolated and the IMDA reaction was carried out at reflux temperature in a solvent (toluene for entries 13, 16 and 17; THF for entry
14; and mesitylene for entries 15 and 18). b The reaction time after the addition of DAIB in entries 1–12. c Yields are of pure and isolated adducts.
Financial support from the National Science Council (NSC)
of the Republic of China is sincerely acknowledged. We thank
Mr G.-H. Lee of NTU and Mrs F.-L. Liao of NTHU for X-ray
diffraction studies. R. K. P. thanks NSC for a postdoctoral
fellowship.
Notes and references
† All the new compounds were charaterized by IR, 1H (400 MHz), and 13
C
NMR (100 MHz), DEPT, and low and high resolution MS analyses.
‡ Crystal data for 5cA: C21H22N2O9, M = 446.41, triclinic, a = 6.3649(3),
b = 9.8499(4), c = 17.6830(7) Å, a = 82.19, b = 85.9730(10), g =
72.0600(10)°, V = 1044.45(8) Å3, T = 293(2) K, space group P1, Z = 2,
m(Mo-Ka)
=
0.112 mm21. 10153 reflections collected, independent
reflections 4527 (Rint = 0.0384), final R indices [I > 2s(I)] R1 = 0.0523,
wR2 = 0.1102. CCDC 160765. See http://www.rsc.org/suppdata/cc/b1/
b103440p/
Scheme 3 Reagents and conditions: (i) CH2CH(CH2)n + 1 MgBr, THF, rt
(71–77%); (ii) TBSOTf, 2,6-lutidine, CH2Cl2, 210 °C (89–99%); (iii)
DAIB, MeOH, rt; (iv) solvent, reflux (Method C).
Crystal data for 7c: C13H17BrO4, M = 317.18, triclinic, a = 7.9569(2),
b = 12.4857(4), c = 14.1058(3) Å, a = 82.922(1), b = 83.764(1), g =
77.597(1)°, V = 1353.35(6) Å3, T = 295(2) K, space group P1, Z = 4,
m(Mo-Ka)
=
3.041 mm21. 13761 reflections collected, independent
endo-diastereomer 20c was produced in near quantitative yield
from MOB 20b (Scheme 3, Table 1).
reflections 5460 (Rint = 0.0324), final R indices [I > 2s(I)] R1 = 0.0488,
wR2 = 0.1096. CCDC 160763.
Crystal data for 16c: C13H18O4, M = 238.27, monoclinic, a = 6.7251(2),
b = 24.8959(4), c = 7.5943(3) Å, a = 90, b = 109.260(2), g = 90°, V =
1200.33(6) Å3, T = 295(2) K, space group Cc, Z = 4, m(Mo-Ka) = 0.097
The stereoselectivity of the cycloadduct of each successful
case is completely analogous to the first example (entry 1), with
the major, or sole, diastereomer arising from an approach in
which all three rings adopt conformations of endo-mode with a-
OH or a-OTBS in the transition state. The stereochemistries of
5cA (3,5-dinitrobenzoate of 5c), 7c, 16c and 16eA (3,5-dini-
trobenzoate of 16e) were confirmed from their X-ray struc-
tures‡ and that of the other adducts were confirmed by chemical
correlation and/or by comparing 1H NMR data.
The IMDA reactions of the MOBs with 4-Br substitution
proceeded in a highly diastereoselective manner leading to a
single endo-, a-OR isomer. With one exception (19b), all the
MOBs having OTBS functionality at the chiral center provided
a single diastereomer (endo-, a-OTBS). The reduced reactivity
of IMDA reactions with increased tether length as reflected in
seven-membered ring annulations (n = 3) has been previously
recorded.8 However, the yields of these reactions (n = 3) were
partially improved (6c: 28; 9c: 25; 15c: 59%) by the pyrolysis of
the crude mixture which contains dimers, obtained after
oxidation in mesitylene.
mm21. 3372 reflections collected, independent reflections 2080 (Rint
=
0.0187), final R indices [I > 2s(I)] R1 = 0.0412, wR2 = 0.1070. CCDC
160762.
Crystal data for 16eA: C20H20N2O9, M = 432.38, monoclinic, a =
20.8010(1), b = 12.5757(2), c = 15.9854(2) Å, a = 90, b = 112.123(1),
g = 90°, V = 3873.72(8) Å3, T = 295(2) K, space group P21/c, Z = 8,
m(Mo-Ka)
=
0.119 mm21. 18200 reflections collected, independent
reflections 7835 (Rint = 0.0254), final R indices [I > 2s(I)] R1 = 0.0502,
wR2 = 0.1174. CCDC 160764.
1 For recent reviews see: W. R. Roush, in Comprehensive Organic
Synthesis, Vol. 5, ed. B. M. Trost and I. Fleming, Pergamon, New York,
1991, pp. 513–550; D. Craig, in Stereoselective Synthesis, ed. G.
Helmchen, R. W. Hoffmann, J. Mulzer and E. Schaumann, Thieme,
Stuttgardt, 1996, Vol. E21c, pp. 2872–2904.
2 P.-Y. Hsiu and C.-C. Liao, Chem. Commun., 1997, 1085; C.-S. Chu,
T.-H. Lee, P. D. Rao, L.-D. Song and C.-C. Liao, J. Org. Chem., 1999,
64, 4111.
3 Y.-F. Tsai, R. K. Peddinti and C.-C. Liao, Chem. Commun., 2000, 475.
4 S. Quideau and L. Pouysegu, Org. Prep. Proced. Int., 1999, 31, 617.
5 S.-Y. Gao, S. Ko, Y.-L. Lin, R. K. Peddinti and C.-C. Liao, Tetrahedron,
2001, 57, 297 and references therein.
6 C.-H. Lai, Y.-L. Shen and C.-C. Liao, Synlett, 1997, 1351.
7 C.-F. Yen, R. K. Peddinti and C.-C. Liao, Org. Lett., 2000, 2, 2909.
8 For reactions of tethered 1,2,4-triazines see: J.-H. Li and J. K. Snyder,
J. Org. Chem., 1993, 58, 516 and references therein.
In summary, we have demonstrated here that masked o-
benzoquinones bearing a chiral center in the carbon-tether
underwent IMDA reactions to provide densely substituted
tricyclic ring systems. Transformation of these adducts to linear
and angular tricyclic skeletons, and the asymmetric version of
the present protocol are under active investigation.
Chem. Commun., 2001, 1340–1341
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