Palladium-catalyzed arylative ring-opening reactions of norbornenols: Entry to highly substituted cyclohexenes, quinolines, and tetrahydroquinolines

Article abstract of DOI:10.1002/anie.201001752

(Figure Presented) Coing retro: Palladium-catalyzed retroallylations from norbornene-derived tertiary alcohols participate in coupling reactions with aryl- or vinylhalides to provide tetrasubstituted cyclohexenes with excellent regio- and diastereoselecti

Full text of DOI:10.1002/anie.201001752

Angewandte
Chemie
DOI: 10.1002/anie.201001752
Domino Reactions
Palladium-Catalyzed Arylative Ring-Opening Reactions of
Norbornenols: Entry to Highly Substituted Cyclohexenes, Quinolines,
and Tetrahydroquinolines**
Michael Waibel and Nicolai Cramer*
The development of efficient and sustainable procedures
towards the synthesis of complex molecules is an important
task for modern organic chemistry. Ways to improve effi-
ciency include the use of domino reactions that allow a rapid
increase in molecular complexity[1] and the discovery of novel
reactivity to address previously inert functionalities. A
challenging area of the latter approach are metal-catalyzed
[2]
À
activations of C C bonds. b-Carbon eliminations from
tertiary alcohols proceed relatively easily to produce C(sp)–
metal[3] and C(sp2)–metal species,[4] whereas related forma-
tions of C(sp3)–metal species usually require ring-strain
assistance.[5] In contrast, retro-allylation from bulky tertiary
homoallylic alcohols is a known reaction proceeding with a
range of transition and main group metals generating allyl
metal species that are arguably a highly versatile and valuable
reactive group in synthetic organic chemistry.[6] Yorimitsu,
Scheme 1. Palladium-catalyzed arylative ring-opening of norbornenols.
Oshima, and co-workers demonstrated in seminal contribu-
tions that allyl palladium species arising from such retro-
allylations are suitable for coupling reactions with aryl
halides.[7] Surprisingly, the concomitantly liberated carbonyl
group has never been addressed in subsequent transforma-
tions. In this respect, symmetrically substituted bicyclic
homoallylic alcohols represent an appealing substrate class.
the envisioned retro-allylation reactivity.[9] Subsequently, the
arising palladium(II) species 3, could either undergo reduc-
tive elimination, b-hydride elimination, or equilibration
reactions through s–p isomerizations. We speculated that
reductive elimination would be fast enough to maintain the
imprinted stereochemistry and allow access to the thermody-
namically less favorable cyclohexene isomer 4 having a
cis relationship of the two pairs of substituents.
À
Selective ring-opening by C C bond cleavage would simulta-
neously generate arrays of stereogenic centers, an acyl group,
and an allylic metal species. Subsequent trapping reactions
should allow access to biologically relevant heterocyclic
scaffolds with high efficiency.[8]
Initially, we explored the viability of the process with
norbornenol 1a and p-bromotoluene as a substrate. In the
presence of Pd(OAc)2 and tricyclohexylphosphine complete
conversion of 1a was observed and 40% of desired arylated
product 4 was formed (Table 1, entry 1). Although no other
isomers were detected, arene 6, arising from b-hydride
elimination of 3 into 5 and subsequent aromatization,
appeared in 43%. Lowering the temperature mostly sup-
pressed this process and increased the yield of desired product
4 to 72% (entry 2). Replacement of PCy3 by PtBu3·HBF4
slightly increased the yield of 4, whereas PPh3 gave more
aromatized product 6 (entries 3–4). In contrast, the use of
S-Phos (2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl)[10]
or X-Phos (2-dicyclohexylphosphino-2’,4’,6’-triisopropylbi-
phenyl)[11] additionally improved the yield of 4 (entries 5–6).
Dioxane or CPME can be used instead of toluene (entries 7–
8). Aryl chlorides and aryl iodides work with comparable
efficiency, whereas aryl triflates lead to significantly more of
the aromatization product 6 (entries 9–11).
Herein we report palladium-catalyzed arylative ring-
opening reactions of norbornene-derived tertiary alcohols
(1) to access highly substituted acyl cyclohexenes, quinolines,
and tetrahydroquinolines in a stereodefined fashion. The
proposed process is initiated by formation of an aryl
palladium(II) complex from aryl halides (Scheme 1). A
simultaneous coordination of this species to the hydroxy
group as well as to the double bond (2) is a requirement for
[*] Dr. M. Waibel, Dr. N. Cramer
Laboratory of Organic Chemistry, ETH Zurich
Wolfgang-Pauli-Strasse 10, HCI H 304, 8093 Zurich (Switzerland)
Fax: (+41)44-632-1328
E-mail: nicolai.cramer@org.chem.ethz.ch
Homepage: http://www.cramer.ethz.ch
[**] N.C. thanks the Fonds der Chemischen Industrie for a Liebig-
Fellowship. M.W. is a fellow of the Roche Research Foundation and a
Feodor-Lynen fellow of the Alexander von Humboldt Foundation.
We thank Prof. Erick M. Carreira for generous support.
We next explored the scope of the reaction. A variety of
aryl and vinyl bromides with different electronic and steric
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201001752.
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Table 1: Optimization of the arylative ring-opening of 1a.[a]
component to obtain an aniline-bearing cyclohexene 4. This
species could then undergo a dehydrative cyclization giving
imine 7 (Scheme 3). Although imine 7 could not be directly
Entry
L
Solvent
ArX
6 [%][b]
4 [%][b]
1[c]
2
3
4
5
6
7
8
9
PCy3
PCy3
xylene
4-BrTol
4-BrTol
4-BrTol
4-BrTol
4-BrTol
4-BrTol
4-BrTol
4-BrTol
4-ClTol
PhI
43
11
9
41
5
11
12
16
12
17
53
40 (4a)
72 (4a)
81 (4a)
49 (4a)
87 (4a)
82 (4a)
68 (4a)
66 (4a)
77 (4a)
67 (4b)
26 (4b)
toluene
toluene
toluene
toluene
toluene
dioxane
CPME
toluene
toluene
toluene
PtBu3·HBF4
PPh3
S-Phos
X-Phos
PCy3
PCy3
S-Phos
PCy3
Scheme 3. Domino cyclization of norbornenols 1 with o-bromoanilines.
10
11
PCy3
PhOTf
[a] Reaction conditions: 1a (0.05 mmol), ArX (4 equiv), Cs2CO3
(1.5 equiv), Pd(OAc)2 (5 mol%), L (12 mol%), 0.15m in the indicated
solvent, 1008C, 3–12 h. [b] Isolated product. [c] Run at 1208C. CPME=
cyclopentyl methyl ether, Cy=cyclohexyl, Tf=trifluoromethanesulfonyl.
tracked, its aromatization product 8 was isolated in moderate
yields.[13] The imine formation as well as the subsequent
oxidation is significantly accelerated by addition of acetic acid
and exposure of the reaction mixture to air, therefore
providing access to quinolines in good yields. This domino
sequence proved to be tolerant towards different substituents
on the bromoanilines yielding quinolines 8a–8i with a broad
substitution pattern (Scheme 4).
properties can be employed giving 4a–4k in high yields
(Scheme 2). The substitution pattern of norbornenol 1 can be
varied from cyclic derivatives with different ring sizes to
acyclic substrates (4l–4n). Notably, the diastereoselectivity is
maintained throughout all substrate combinations leading
exclusively to the depicted isomers.[12]
To take advantage of the concomitantly formed carbonyl
group, we envisioned using o-bromoaniline as the aryl halide
Scheme 4. Scope for quinolines 8. Reaction conditions: 1 (0.05 mmol),
ArBr (2 equiv), Cs2CO3 (1.5 equiv), Pd(OAc)2 (5 mol%), S-Phos
(12 mol%); 0.15m in toluene, 1008C, 12 h, then AcOH (15 equiv),
238C, 2 h.
To further capitalize upon intermediate imine 7 for an
increase in molecular complexity, we explored the incorpo-
ration of a reduction step into the domino process to access
tetrahydroquinolines 9 (Scheme 3). Addition of sodium
cyanoborohydride and acetic acid prompted a clean reduction
and gave tetrahydroquinolines 9a–9 f in good yields and
excellent diastereoselectivity for the created N-substituted
stereogenic center (Scheme 5). Once again, the process
proved to be compatible with a range of substituents. The
Scheme 2. Scope of norbornenol ring-opening reaction. Reaction con-
ditions: 1 (0.05 mmol), ArBr (4 equiv), Cs2CO3 (1.5 equiv), Pd(OAc)2
(5 mol%), S-Phos (12 mol%), 0.15m in toluene, 1008C, 3–12 h.
[a] Run with PCy3. [b] Run at 808C. [c] Used 4 equiv cyclohexenyl
triflate.
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In summary, we have disclosed palladium-catalyzed ring-
opening reactions of norbornene-derived tertiary alcohols.
The intermediates arising from this retro-allylative fragmen-
tation are trapped with aryl or vinyl halides in a highly regio-
and diastereoselective fashion leading to tetrasubstituted
cyclohexenes. This procedure can be extended to domino
reactions providing either access to highly functionalized
synthetically valuable quinolines or to tetrahydroquinolines.
Extension of the methodology to related substrate classes and
the development of asymmetric variants are in progress.
Experimental Section
Compound 1a (11.4 mg, 0.05 mmol), 4-bromotoluene (32.2 mg,
0.20 mmol), Pd(OAc)2 (0.56 mg, 2.50 mmol), S-Phos (2.46 mg,
6.00 mmol), and Cs2CO3 (24.4 mg, 0.075 mmol) were weighed into
an oven dried vial equipped with a magnetic stir bar, sealed with a
rubber septum, and flushed with nitrogen. After the addition of
0.25 mL of dry toluene, the reaction mixture was degassed by three
freeze-pump-thaw cycles, and immersed into a preheated oil bath
(1008C) for 12 h. After TLC analysis showed the complete con-
version, the reaction mixture was cooled to 238C and directly purified
on silica gel (10% EtOAc in pentane, Rf = 0.25) yielding 13.8 mg
(87%) of 4a as a colorless oil.
Scheme 5. Scope for tetrahydroquinolines 9. Reaction conditions: 1
(0.05 mmol), ArBr (2 equiv), Cs2CO3 (1.5 equiv), Pd(OAc)2 (5 mol%),
S-Phos (12 mol%); 0.15m in dioxane, 1008C, 3 h, then NaCNBH3
(3 equiv), AcOH (5 equiv), 238C, 2 h.
stereochemical outcome of the reduction and the relative
configuration of the tetrahydroquinolines was established by
the X-ray crystallographic analysis of derivative 9 f
(Figure 1).[14]
Received: March 24, 2010
Published online: May 17, 2010
À
Keywords: C C activation · domino reactions · heterocycles ·
palladium · ring-opening
.
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Angew. Chem. Int. Ed. 2010, 49, 4455 –4458
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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Communications
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10.1800(4) ꢀ, b = 90.893(3)8, V= 1772.60(12) ꢀ3, Z = 4, Dcalc
=
1.392 MgmÀ3, T= 123 K, reflections collected: 6890, independ-
ent reflections: 4014 (Rint = 0.078), R(all) = 0.0806, wR(gt) =
0.1411. CCDC 770255 contains the supplementary crystallo-
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[15] See the Supporting Information for determination of the
absolute configuration.
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