Metal-triflate-catalyzed synthesis of polycyclic tertiary alcohols by cyclization of γ-allenic ketones

Article abstract of DOI:10.1002/anie.201310724

It has been established that bismuth(III) triflate catalyzes the cyclization of γ-allenic ketones under mild reaction conditions. This reaction allows the selective formation of polycyclic tertiary alcohols from cyclic ketone derivatives. The resulting dienols can engage in stereoselective cycloadditions to efficiently afford complex polycyclic systems. Simply complex: The described catalytic carbonyl-ene reaction is efficiently performed under mild reaction conditions by using only 1 mol % of bismuth(III) triflate, thus affording functionalized molecular scaffolds. Complex polycyclic structures with a defined stereochemistry have been synthesized by using the carbonyl-ene products in a subsequent hydroxy-directed Diels-Alder reaction.

Full text of DOI:10.1002/anie.201310724

Angewandte
Chemie
DOI: 10.1002/anie.201310724
Synthetic Methods
Metal-Triflate-Catalyzed Synthesis of Polycyclic Tertiary Alcohols by
Cyclization of g-Allenic Ketones**
Ilhem Diaf, Gilles Lemiꢀre,* and Elisabet DuÇach*
Abstract: It has been established that bismuth(III) triflate
catalyzes the cyclization of g-allenic ketones under mild
reaction conditions. This reaction allows the selective forma-
tion of polycyclic tertiary alcohols from cyclic ketone deriv-
atives. The resulting dienols can engage in stereoselective
cycloadditions to efficiently afford complex polycyclic systems.
We first used the acyclic b-ketoester 1 bearing a pendant
trisubstituted allene as a model and assessed its reactivity
towards various metal triflate catalysts in nitromethane
(Table 1, entries 1–4). A rapid screening highlighted non-
expensive bismuth(III) triflate[9,10] as a very active catalyst at
low loading with the total conversion of 1 occurring at À208C.
Switching solvents from nitromethane to CH2Cl2 considerably
C
omplex polycyclic molecules have always fascinated
organic chemists, and their rapid, reliable, and efficient
synthesis constitutes a motivating challenge to accept. Cyclo-
isomerization reactions are undoubtedly powerful and pro-
vide a sustainable means to generate molecular complexity
with good control of selectivity.[1] In this context, the intra-
molecular carbonyl-ene reaction represents a very useful tool
for the efficient formation of substituted cyclohexanols,[2] and
has been widely used in natural product synthesis. Because of
the relatively high energetic barrier, carbonyl-ene processes
often require high temperatures or the employment of Lewis
acids, usually in excess (Prins reaction). Despite its reliability,
this reaction presents some important limitations, such as the
difficulty in forming five-membered rings because of the
higher cyclization energy requirement induced by geometric
factors. In addition, ketones are intrinsically much poorer
enophiles than aldehydes in these reactions. Cyclizations
involving ketone derivatives have been reported[3] and
include highly activated ketones such as trifluoromethylke-
tones[4] or a-ketoesters.[5]
Table 1: Metal-triflate-catalyzed cyclization of methyl ketone 1.[a]
Entry
Catalyst (mol%)
Solvent
t [h]
Yield [%][b]
1
2
3
4
5
6
7
Al(OTf)3 (5)
Fe(OTf)3 (5)
Cu(OTf)2 (5)
Bi(OTf)3 (5)
Bi(OTf)3 (1)
Bi(OTf)3 (1)
HOTf (1)
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH2Cl2
0.5
3
3
54
62
52
59[c]
88
31
20
12
0.5
0.5
0.5
toluene
CH2Cl2
[a] Reaction conditions: allenic ketone 1 (0.2–1 mmol) in solvent (0.1m)
and catalyst (1–5 mol%) stirred at room temperature, unless otherwise
stated [b] Combined yield of the isolated products 2b and 2c. [c] The
reaction was conducted at À208C.
The cyclization of carbonyl-allene compounds has been
mainly studied under thermal,[6] radical,[7] and transition-
metal-catalyzed[8] processes. Herein we present our results
concerning the metal-triflate-catalyzed cyclization of g-allenic
ketones. We anticipated that allenes could be used as ene
components to bias the geometric cyclization for the forma-
tion of five-membered rings. Moreover, the higher reactivity
of allenes, as compared to alkenes, should allow the reaction
with ketones to proceed under mild reaction conditions.
slowed down the reaction rate and led to the isolation of the
cyclopentadienes 2b and 2c in good yield (88%) at room
temperature by using only 1 mol% of bismuth(III) triflate
(entry 5). The formation of 2b could arise from the elusive
ene product 2a undergoing an elimination reaction. Hydra-
tion of compound 2b could lead to the tertiary alcohol 2c.
To prevent the elimination of the alcohol in 2a, a reaction
which is possibly favored by the position of OH group b to the
ester, the reactivity of the allenic cyclohexanone derivative 3
was examined (Scheme 1). In the presence of 1 mol% of
Bi(OTf)3, the bicyclic triene isomers 4a and 4b were
predominantly produced in 40% yield (Scheme 1). Remark-
ably, the related cyclopentanone derivative 5a behaved
differently under the same mild reaction conditions. Elimi-
nation of the tertiary alcohol did not occur and the substituted
cis-diquinane 6a was obtained in 85% yield as a single
diastereoisomer.
[*] I. Diaf, Dr. G. Lemiꢀre, Dr. E. DuÇach
Institut de Chimie de Nice UMR 7272
Universitꢁ de Nice Sophia-Antipolis, CNRS
Parc Valrose, 06108 Nice Cedex 2 (France)
E-mail: lemiere@unice.fr
dunach@unice.fr
[**] We acknowledge a scholarship to I.D. by the Algerian Ministry of
Research. This work was partially supported by the French Agence
Nationale de la Recherche (project ANR-ALEA 2013-BS07-0009-01),
the University of Nice-Sophia Antipolis, and the CNRS. We are
grateful to Dr. Fabien Fontaine-Vive for fruitful discussions on DFT
calculations.
The selectivity in favor of the bicyclic tertiary alcohol
seemed to be quite general for allene-derived cyclopenta-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310724.
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Table 3: Bismuth(III)-catalyzed cyclization of g-allenic ketones.[a]
Entry Substrate
t
Product
Yield [%][b]
1
15 min
86
2
3
4
2 h
8 h
2 h
87[c]
Scheme 1. Reactivity of cyclic allenic ketones.
nones bearing diverse functional groups (Table 2). For
instance, 5b and the nitrile-containing precursor 5c cyclized
smoothly to afford the desired bicyclic products 6b (84%)
and 6c (47%), respectively (Table 2, entries 2 and 3). The
63[d]
Table 2: Bismuth(III)-catalyzed cycloisomerization of allenic ketones.[a]
40
(52)[e]
Entry Substrate
R
t
Product Yield [%][b]
5
6
5 min
5 min
96
98
1
2
5a
5b
CO2Et
30 min
6a
6b
85
24 h
84[c]
3
4
5c
5d
CN
3 days
30 min
6c
6d
47[d]
83
5
6
7
5e
5 f
5g
H
Me
Ph
1 day
10 min
10 min
6e
6f
6g
–
50[e]
75[e]
[a] Reaction conditions as in Table 2. [b] Yield of isolated product. [c] The
reaction was conducted in toluene. [d] 5 mol% of catalyst was used.
[e] Yield based on the recovered starting material.
[a] Reaction conditions: allenic ketone 5 (0.2–1 mmol) in CH2Cl2 (0.1m)
and Bi(OTf)3 (1 mol%) were stirred at room temperature. [b] Yield of
isolated product. [c] A 1.4:1 isomer ratio was obtained. [d] 5 mol% of
catalyst was used. [e] Traces of diene isomers were also observed.
conditions, the fully substituted allene 5i, bearing an internal
phenyl group, was satisfactorily cyclized into 6i. It was
observed that 6i was more prone to elimination than previous
pentacyclic substrates. However, we were able to limit the
formation of this undesired by-product by conducting the
reaction in toluene instead of CH2Cl2, and the tertiary alcohol
was isolated with 87% yield (entry 2). Interestingly, the
hindered cyclopentanone 5j, having a gem-dimethyl group,
also reacted at room temperature under the standard reaction
conditions to afford the highly substituted alcohol 6j
(entry 3). Surprisingly, the less-reactive 1-indanone derivative
5k could also be cyclized in the presence of 1 mol% of
bismuth(III) triflate, and led to the allylic/benzylic alcohol 6k
in 40% yield upon isolation (entry 4). In addition, the 2-
indanone derivative 5l proved to be a particularly appropriate
substrate for this metal-catalyzed cycloisomerization, thus
leading efficiently to the polycylic alcohol 6l in almost
quantitative yield (entry 5). The allenic compound 5m,
having a strained cyclobutanone moiety,[11] was also cleanly
allenic substrate 5d, having a more elaborate ester group
featuring an additional terminal olefin, was chemoselectively
cyclized with a very good yield of 83%. Although low
conversion was observed with the allenic ketone 5e, this
cycloisomerization reaction was not restricted to b-carboxylic
acid derivatives. Indeed, the reaction also took place with the
substrates 5 f and 5g bearing a methyl and phenyl group,
respectively (entries 6 and 7), to afford the corresponding
tertiary alcohols with good yields.
These results point out that pentacyclic b-ketoesters are
particularly suitable substrates for the intramolecular car-
bonyl ene reaction with allenes. Therefore, a study involving
the modification of the cyclopentanone core and of the allene
substitution was undertaken to explore the reaction scope
(Table 3). The cyclohexyl derivative 5h was efficiently trans-
formed into the polycyclic alcohol 6h (entry 1). Although 1,3-
disubstituted allenes were not compatible with these catalytic
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transformed into the bicyclo[3.2.0]heptene 6m within a very
short reaction time and a nearly quantitative yield (entry 6).
A remarkable effect of the ring size of the starting cyclic
ketone on the product selectivity was observed (see
Scheme 1). This reactivity difference might be attributed to
the higher strain of the cyclopentane and cyclobutane rings,
and would thus slow down the elimination process. To confirm
this hypothesis, we performed DFT calculations[12] to evaluate
the Gibbs free energies corresponding to the elimination
processes for bicyclic systems with different ring sizes. As
shown in Table 4, dehydration is a highly endergonic process
Scheme 2. Diastereoselective transformation of diene products.
Table 4: Calculated Gibbs free energies for the alcohol elimination.[a]
were successfully isolated from substrates featuring four- and
five-membered cyclic ketones. This methodology provides
access to original and highly functionalized bicyclic alcohols
from readily available starting materials. Some preliminary
DFT calculations were performed to rationalize the remark-
able effect of the substrate ring size on the reaction outcome.
We confirmed that the elimination of the tertiary alcohol from
the final product was thermodynamically favored for cyclo-
pentenes fused to a cyclohexane ring. We showed that the
bicyclic dienol products successfully engaged in highly
selective Diels–Alder reactions, thus leading to more complex
polycyclic systems with complete control of the relative
stereochemistry of the four stereogenic centers.
Entry
Substrate
n
DG [kJmolÀ1
]
Product
1
2
3
A
B
C
0
1
2
+53.7
À20.5
À50.7
A’
B’
C’
[a] DFT calculations were performed at the B3LYP6-31+G(d,p) level of
theory. The effects of dichloromethane as solvent were taken into
account by using the polarizable continuum model (PCM).
Received: December 10, 2013
Revised: January 28, 2014
Published online: March 12, 2014
for the bicyclic alcohol A which contains a four-membered
ring (entry 1, DG =+ 53.7 kJmolÀ1). The reaction becomes
energetically favored for the analogous alcohol B which
contains a five-membered ring and has a dehydration energy
of À20.5 kJmolÀ1 (entry 2). As expected, the elimination is
highly favored in the case of the six-membered ring substrate
C with a calculated energy of À50.7 kJmolÀ1 (entry 3). The
trend observed from these calculations is in good agreement
with the experimental results and can explain the propensity
of the non-isolable hydrindenol derivative C to easily
eliminate in Lewis acid media.
Finally, we were interested in further synthetic applica-
tions and the dienol products were used in subsequent
selective cycloadditions to attain more complex polycyclic
structures. We were able to successfully perform highly
diastereoselective Diels–Alder reactions by reacting the
prepared bicyclic systems with methyl acrylate in the presence
of MgBr2 and lutidine at room temperature (Scheme 2).[13]
This methodology afforded the cycloaddition adducts 7 and 9
from conjugated the 1,3-dienes 6a and 8, respectively, as
single regio- and diastereoisomers.[14] No conversions were
detected in the absence of lutidine, and could indicate that
a possible hydroxy-directed[15] mechanism is involved. This
procedure constitutes a straightforward route to complex
polycyclic systems with a controlled stereochemistry.
Keywords: allenes · bismuth · cyclizations ·
.
homogeneous catalysis · synthetic methods
[1] a) M. Lautens, W. Klute, W. Tam, Chem. Rev. 1996, 96, 49 – 92;
b) I. Ojima, M. Tzamarioudaki, Z. Li, R. J. Donovan, Chem. Rev.
1996, 96, 635 – 662; c) B. M. Trost, M. J. Krische, Synlett 1998, 1 –
16; d) C. Aubert, O. Buisine, M. Malacria, Chem. Rev. 2002, 102,
813 – 834; e) G. C. Lloyd-Jones, Org. Biomol. Chem. 2003, 1,
215 – 236; f) Z. Zhang, G. Zhu, X. Tong, F. Wang, X. Xie, J.
Wang, L. Jiang, Curr. Org. Chem. 2006, 10, 1457 – 1478; g) E.
Jimꢀnez-NfflÇez, A. M. Echavarren, Chem. Rev. 2008, 108, 3326 –
3350; h) A. Fürstner, Chem. Soc. Rev. 2009, 38, 3208 – 3221; i) C.
Aubert, L. Fensterbank, P. Garcia, M. Malacria, A. Simonneau,
Chem. Rev. 2011, 111, 1954 – 1993; j) Y. Yamamoto, Chem. Rev.
2012, 112, 4736 – 4769.
[2] M. L. Clarke, M. B. France, Tetrahedron 2008, 64, 9003 – 9031.
[3] a) A. F. Thomas, M. Ozainne, Helv. Chim. Acta 1979, 62, 361 –
368; < lit b > B. M. Trost, P. G. McDougal, K. J. Haller, J. Am.
Chem. Soc. 1984, 106, 383 – 395; c) A. C. Jackson, B. E. Gold-
man, B. B. Snider, J. Org. Chem. 1984, 49, 3988 – 3994; d) P. A.
Wender, C. R. D. Correia, J. Am. Chem. Soc. 1987, 109, 2523 –
2525; e) P. Anastasis, R. Duffin, V. Matassa, K. H. Overton, J.
Chem. Soc. Perkin Trans. 1 1991, 1221 – 1224; f) M. Banwell, M.
McLeod, Chem. Commun. 1998, 1851 – 1852; g) M. G. Banwell,
P. Darmos, M. D. McLeod, D. C. R. Hockless, Synlett 1998, 897;
h) M. Banwell, D. C. R. Hockless, M. D. McLeod, New J. Chem.
2003, 27, 50 – 59.
In conclusion we have reported on the metal-triflate-
catalyzed cycloisomerization of g-allenic ketones. This car-
bonyl-ene reaction was efficiently performed under mild
reaction conditions by using only 1 mol% of the nontoxic,
relatively cheap, and easily recyclable bismuth(III) triflate.[10a]
The resulting acid-sensitive diene-containing tertiary alcohols
[4] a) C. Aubert, J.-P. Bꢀguꢀ, Tetrahedron Lett. 1988, 29, 1011 – 1014;
b) A. Abouabdellah, C. Aubert, J.-P. Bꢀguꢀ, D. Bonnet-Delpon,
J. Guilhem, J. Chem. Soc. Perkin Trans. 1 1991, 1397 – 1403.
Angew. Chem. Int. Ed. 2014, 53, 4177 –4180
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4179

.
Angewandte
Communications
[5] a) Y.-J. Zhao, B. Li, L.-J. S. Tan, Z.-L. Shen, T.-P. Loh, J. Am.
Chem. Soc. 2010, 132, 10242 – 10244; b) D. Yang, M. Yang, N.-Y.
Zhu, Org. Lett. 2003, 5, 3749 – 3752.
[6] a) M. Bertrand, M.-L. Roumestant, P. Sylvestre-Panthet, J.
Chem. Soc. Chem. Commun. 1979, 529 – 530; b) M. Bertrand,
M. L. Roumestant, P. Sylvestre-Panthet, Tetrahedron Lett. 1981,
22, 3589 – 3590; c) J. Jin, D. T. Smith, S. M. Weinreb, J. Org.
Chem. 1995, 60, 5366 – 5367.
[7] a) G. Pattenden, G. M. Robertson, Tetrahedron 1985, 41, 4001 –
4011; b) J. K. Crandall, M. Mualla, Tetrahedron Lett. 1986, 27,
2243 – 2246; c) D. Belotti, J. Cossy, J. P. Pete, C. Portella, J. Org.
Chem. 1986, 51, 4196 – 4200; d) T. Gillmann, Tetrahedron Lett.
1993, 34, 607 – 610; e) G. A. Molander, E. P. Cormier, J. Org.
Chem. 2005, 70, 2622 – 2626.
[8] a) S.-K. Kang, Y.-H. Ha, B.-S. Ko, Y. Lim, J. Jung, Angew. Chem.
2002, 114, 353 – 355; Angew. Chem. Int. Ed. 2002, 41, 343 – 345;
b) S.-K. Kang, S. K. Yoon, Chem. Commun. 2002, 2634 – 2635;
c) S.-K. Kang, K.-J. Kim, Y.-T. Hong, Angew. Chem. 2002, 114,
1654 – 1656; Angew. Chem. Int. Ed. 2002, 41, 1584 – 1586; d) S.-
K. Kang, S.-W. Lee, J. Jung, Y. Lim, J. Org. Chem. 2002, 67,
4376 – 4379; e) Y.-H. Ha, S.-K. Kang, Org. Lett. 2002, 4, 1143 –
1146; f) J. Montgomery, M. Song, Org. Lett. 2002, 4, 4009 – 4011;
g) S.-K. Kang, Y.-T. Hong, J.-H. Lee, W.-Y. Kim, I. Lee, C.-M.
Yu, Org. Lett. 2003, 5, 2813 – 2816; h) C.-M. Yu, Y.-T. Hong, J.-H.
Lee, J. Org. Chem. 2004, 69, 8506 – 8509; i) C.-M. Yu, J. Youn,
M.-K. Lee, Org. Lett. 2005, 7, 3733 – 3736; j) H. Tsukamoto, T.
Matsumoto, Y. Kondo, J. Am. Chem. Soc. 2008, 130, 388 – 389.
[9] For reviews on bismuth catalysis: a) T. Ollevier, Org. Biomol.
Chem. 2013, 11, 2740 – 2755; b) J. M. Bothwell, S. W. Krabbe,
R. S. Mohan, Chem. Soc. Rev. 2011, 40, 4649 – 4707; c) H.
Gaspard-Iloughmane, C. Le Roux, Eur. J. Org. Chem. 2004,
2517 – 2532.
[10] For recent organic transformations using Bi(OTf)3 as catalyst:
a) G. Lemi›re, B. Cacciuttolo, E. Belhassen, E. DuÇach, Org.
Lett. 2012, 14, 2750 – 2753; b) X. Li, X. Yang, H. Chang, Y. Li, B.
Ni, W. Wei, Eur. J. Org. Chem. 2011, 3122 – 3125; c) N. Kawai, R.
Abe, M. Matsuda, J. i. Uenishi, J. Org. Chem. 2011, 76, 2102 –
2114; d) K. Komeyama, N. Saigo, M. Miyagi, K. Takaki, Angew.
Chem. 2009, 121, 10059 – 10062; Angew. Chem. Int. Ed. 2009, 48,
9875 – 9878; e) B. D. Kelly, J. M. Allen, R. E. Tundel, T. H.
Lambert, Org. Lett. 2009, 11, 1381 – 1383; f) P. Rubenbauer, E.
Herdtweck, T. Strassner, T. Bach, Angew. Chem. 2008, 120,
10260 – 10263; Angew. Chem. Int. Ed. 2008, 47, 10106 – 10109;
g) K. Komeyama, K. Takahashi, K. Takaki, Org. Lett. 2008, 10,
5119 – 5122; h) M. Rueping, B. J. Nachtsheim, T. Scheidt, Org.
Lett. 2006, 8, 3717 – 3719; i) F. Mühlthau, O. Schuster, T. Bach, J.
Am. Chem. Soc. 2005, 127, 9348 – 9349.
[11] M. Presset, Y. Coquerel, J. Rodriguez, J. Org. Chem. 2009, 74,
415 – 418.
[12] Gaussian03, RevisionD.02, Frisch, M. J. et al., Gaussian, Inc.,
Wallingford CT, 2004.
[13] a) L. Barriault, J. D. O. Thomas, R. Clꢀment, J. Org. Chem. 2003,
68, 2317 – 2323; b) L. Barriault, P. J. A. Ang, R. M. A. Lavigne,
Org. Lett. 2004, 6, 1317 – 1319; c) R. Clꢀment, C. M. Grise, L.
Barriault, Chem. Commun. 2008, 3004 – 3006; d) R. L. Beingess-
ner, J. A. Farand, L. Barriault, J. Org. Chem. 2010, 75, 6337 –
6346; e) J. Ramharter, J. Mulzer, Org. Lett. 2011, 13, 5310 – 5313.
[14] The relative stereochemistry of 9 was confirmed by X-ray
diffraction (see the Supporting Information).
[15] a) D. E. Ward, M. S. Abaee, Org. Lett. 2000, 2, 3937 – 3940;
b) D. E. Ward, M. S. Souweha, Org. Lett. 2005, 7, 3533 – 3536.
4180 www.angewandte.org
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