Diels-Alder routes to angularly halogenated cis-fused bicyclic ketones: Readily accessible cyclynone intermediates

Article abstract of DOI:10.1016/j.tetlet.2010.06.135

We have developed an efficient Lewis acid-catalyzed Diels-Alder route to a series of cis-fused bicyclic ketones bearing quaternary halogenation at the angular position. We have also developed a Diels-Alder-based one-flask method for the regioselective pre

Full text of DOI:10.1016/j.tetlet.2010.06.135

Tetrahedron Letters 51 (2010) 4653–4654
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Tetrahedron Letters
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Diels–Alder routes to angularly halogenated cis-fused bicyclic ketones: readily
accessible cyclynone intermediates
b
a,b,
Jun Hee Lee a, , Woo Han Kim , Samuel J. Danishefsky
*
*
a Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, NY 10027, United States
b Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 June 2010
Accepted 29 June 2010
We have developed an efficient Lewis acid-catalyzed Diels–Alder route to a series of cis-fused bicyclic
ketones bearing quaternary halogenation at the angular position. We have also developed a Diels–
Alder-based one-flask method for the regioselective preparation of TBS-protected 6-hydroxy tetralone
and 5-hydroxy indanone derivatives.
Ó 2010 Elsevier Ltd. All rights reserved.
Our laboratory has a longstanding interest in expanding the
capacities of the Diels–Alder reaction to the synthesis of complex
and difficultly accessible molecular architectures. In this regard,
cis-fused bicyclic ketones of the type 3, bearing angular halogena-
R1
R4
O
R1
R4
O
X
R2
R3
R2
R3
[4+2]
X
+
( )n
( )n
H
tion
a to the carbonyl function, represent a valuable substructure
1
2
3
X = Cl, Br, I
n = 1, 0
in organic synthesis. In principle, Diels–Alder reaction of a 2-halo-
cycloalk-2-enone (cf. 1)1 with an appropriately substituted diene
(2) could serve as a strategically efficient means by which to access
this generic motif (Scheme 1). However, previous studies had indi-
cated that tin(IV) chloride-catalyzed Diels–Alder cycloaddition of
2-bromocyclohex-2-enone (1a) with various simple dienes, such
as 2,3-dimethyl-1,3-butadiene (2a) and isoprene (2b), proceeds
in low yields and with incomplete conversions, even following pro-
longed reaction times.2 In the case of diene 2a, product decompo-
sition served to further mitigate the reaction efficiency.
Accordingly, we sought to develop an improved Diels–Alder-based
Scheme 1.
Table 1
MeAlCl2-catalyzed Diels–Alder reaction of 1a and 2aa
O
O
Br
H
Me
Me
Me
Br
MeAlCl2
+
(cat.)
CH2Cl2
Me
2a
1a
3a
method which would provide for more ready access to
a-haloge-
nated bicyclic motifs of the type 3.3
Entry
MeAlCl2 (mol %)
Temperature (°C)
Yield (%)
In light of our recent successes in achieving MeAlCl2-catalyzed
Diels–Alder reactions of the parent compound, cyclohex-2-enone,
with a series of simple dienes,4 we hypothesized that the same cat-
alytic system might be applied to the target system at hand. We
note that each of the 2-halocycloalk-2-enone substrates (cf. 1)
were readily prepared according to standard procedures (see
Supplementary data for details). In preliminary explorations, we
observed that, in the presence of 20 mol % MeAlCl2 at 0 °C,
substrates 1a and 2a smoothly underwent the desired [4+2] addi-
tion to provide an adduct 3a in 74% yield (Table 1, entry 1).5 When
the catalyst loading was dropped to 10 mol % and the temperature
decreased to À10 °C, excellent yields of the cycloadduct were ob-
tained once more (entry 2). Importantly, this reaction could be
1
2
3
20
10
10
0
74
91
À10
À10
89 (gram-scale)b
a
Reactions were carried out using 4 equiv diene at 0.2 M in CH2Cl2 with respect
to enone.
b
Using 6.00 mmol (1.05 g) of 1a.
achieved even on a gram scale with comparable levels of efficiency
(entry 3).
We next sought to evaluate the scope of the Diels–Alder reac-
tion with respect to structural variations in both the diene and
the dienophile components. Thus, as outlined in Table 2, we were
pleased to find that our Diels–Alder conditions were able to accom-
modate a range of dienophile and diene-coupling partners. Thus,
cyclohex-2-enones bearing both
a-chloro (1b) and a-iodo (1c)
functionalities readily participate in the cycloaddition with 2,3-di-
methyl-1,3-butadiene to afford bicyclic products in excellent yields
* Corresponding authors. Tel.: +1 212 639 5501; fax: +1 212 772 8691 (S.J.D.).
E-mail address: s-danishefsky@ski.mskcc.org (S.J. Danishefsky).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.135

4654
J. H. Lee et al. / Tetrahedron Letters 51 (2010) 4653–4654
Table 2
O
NMe2
O
MeAlCl2-catalyzed [4+2] reaction of 2-halocycloalk-2-enonesa
toluene
Br
+
R1
O
R1
R4
100 ¼C
13 h
10 mol%
MeAlCl2
O
X
( )n
OTBS
( )n
OTBS
R2
R3
R2
R3
X
+
1a, n = 1
1d, n = 0
5a, n = 1, 72%
5b, n = 0, 72%
4
CH2Cl2
Š10 ¼ C
( )n
( )n
H
R4
1
2
3
Scheme 2.
Entry
1
Enone
Diene
Me
Product
Yield (%)
94
under thermal conditions, the Rawal diene (4)7 and bromocyclo-
hexenone 1a undergo cycloaddition followed by a spontaneous
elimination of the dimethylamine and hydrogen bromide moieties,
to cleanly deliver the aromatic bicyclic adduct 5a8 as a single reg-
ioisomer in 72% yield (Scheme 2). The bromocyclopentenone 1d
undergoes an analogous sequence to provide compound 5b. All at-
tempts to isolate the direct cycloaddition product were unsuccess-
ful, presumably due to its strong propensity to undergo
aromatization. Clearly, in couplings with electron-rich dienes of
O
O
Cl
Cl
Me
Me
Me
2a
2a
2a
1b
H
I
3b
O
O
Me
Me
O
Me
Me
I
2
3
4
5
6
7
90b
91
1c
H
3c
3d
3e
the type 4, the a-bromocyclenone can function as a readily avail-
Me
Me
O
O
Br
able equivalent of a cycloalkynone. We note that the original con-
cept of a cyclohexynone equivalent was articulated by Corey in
1981.9 In the Corey example, the cyclohexynone was of opposite
effective polarity to the cycloalkynones shown here. Not surpris-
ingly, this procedure gives rise to oxygenated tetralones with dif-
ferent structures from the Corey case.
Me
Me
Br
1d
H
O
O
Me
Me
Cl
Me
Me
Cl
72c
90
In conclusion, we have developed an operationally simple
method for the preparation of a series of cis-fused bicyclic ketone
2a
2b
1e
H
derivatives bearing angular
a-halogenation. We have also devel-
O
Br
oped a one-flask, highly regioselective method for the preparation
of TBS-protected 6-hydroxy tetralone and 5-hydroxy indanone
derivatives. Ongoing research in our laboratory is focused on fur-
ther adaptation of these functionalized Diels–Alder adducts.
Br
1a
Me
Me
H
3f
O
O
Me
O
O
Me
Br
Br
1a
Acknowledgments
70d
87e
This work was supported by the NIH (HL25848 to S.J.D.). We
thank Rebecca Wilson for continuing advice on the preparation
of the manuscript and Dr. Peter K. Park (Columbia University) for
several fruitful discussions. We also thank Dr. Yasuhiro Itagaki
(Mass Spectral Core Facility, Columbia University) for mass spec-
tral analysis.
2c
2d
H
3g
Br
Br
1a
H
3h
a
Unless otherwise indicated, the reactions were carried out at À10 °C for 2 h,
using 10 mol % MeAlCl2 and 4 equiv diene at 0.2 M in CH2Cl2 with respect to enone.
Supplementary data
b
Reaction was carried out in the dark, since cycloadduct 3c is light-sensitive.
Reaction was carried out at 0 °C for 1 h.
Reaction was carried out at À20 °C for 3.5 h; the exo-cycloadduct (not shown)
c
d
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.06.135.
was also isolated, in 12% yield.
e
Reaction was carried out at À7 °C for 6 h, using 30 mol % MeAlCl2.
References and notes
(entries 1 and 2). Moreover, 2-bromocyclopent-2-enone (1d) and
2-chlorocyclopent-2-enone (1e) display good levels of reactivity,
providing cycloadducts 3d and 3e in 91% and 72% yields, respec-
tively (entries 3 and 4). The reaction is also amenable to variation
in diene substitution. Thus, reaction of 1a with diene 2b delivered
the bicyclic adduct 3f as a single regioisomer (entry 5). Substrate
2c, bearing methyl substitution at the 1-position of the diene, also
participated in the cycloaddition with apparently complete regi-
oselectivity, although a mixture of endo:exo adducts (6:1) was ob-
served (entry 6). The two diastereomers were readily separated by
chromatographic means.6 Finally, even the relatively unreactive
butadiene (2d) effectively participated in the Diels–Alder reaction
with 1a, in the presence of 30 mol % MeAlCl2, to furnish adduct 3h
in 87% yield within 6 h (entry 7).
1. For the preparation of 2-halocycloalk-2-enones, see: (a) Krafft, M. E.; Cran, J. W.
Synlett 2005, 1263–1266; (b) Kim, K.-M.; Park, I.-H. Synthesis 2004, 2641–2644;
(c) Anderson, J. C.; Pearson, D. J. J. Chem. Soc., Perkin Trans. 1 1998, 2023–2029;
(d) Kim, K. M.; Chung, K. H.; Kim, E. K.; Ryu, E. K. Synthesis 1993, 283–284; (e)
Smith, A. B., III; Branca, S. J.; Pilla, N. N.; Guaciaro, M. A. J. Org. Chem. 1982, 47,
1855–1869.
2. (a) Liu, H.-J.; Shia, K.-S. Tetrahedron Lett. 1995, 36, 1817–1820; For an earlier
report on the Diels–Alder reaction of 1d with Dane’s diene under SnCl4 catalysis:
(b) Woski, S. A.; Koreeda, M. J. Org. Chem. 1992, 57, 5736–5741.
3. An elegant enantioselective version of the related reaction was reported during
the investigation of this work: Shibatomi, K.; Futatsugi, K.; Kobayashi, F.; Iwasa,
S.; Yamamoto, H. J. Am. Chem. Soc. 2010, 132, 5625–5627.
4. Lee, J. H.; Kim, W. H.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 5482–5484.
5. All the new compounds gave satisfactory analytical data (mp, IR, 1H NMR, 13C
NMR, and high resolution mass). See Supplementary data for experimental and
analytical details.
6. Relative stereochemistry of both cycloadducts was confirmed by extensive 1D
and 2D NMR analyses such as 1H, 13C, DEPT-135, DEPT-90, COSY, HSQC, and
NOESY. See Supplementary data for details.
Finally, having established the optimal conditions for the Diels–
Alder reaction of 2-halocycloalk-2-enones (1a–e) with simple
dienes (2a–d), we sought to evaluate the cycloaddition of this class
of dienophile with an electron-rich synergistic diene. Interestingly,
7. Kozmin, S. A.; Rawal, V. H. J. Org. Chem. 1997, 62, 5252–5253.
8. Hares, O.; Hobbs-Mallyon, D.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1 1993,
1481–1492.
9. Corey, E. J.; Estreicher, H. Tetrahedron Lett. 1981, 22, 603–606.