Enantioselective synthesis of indanols from tert-cyclobutanols using a rhodium-catalyzed C-C/C-H activation sequence

Full text of DOI:10.1002/anie.200903189

Communications
DOI: 10.1002/anie.200903189
Asymmetric Catalysis
Enantioselective Synthesis of Indanols from tert-Cyclobutanols Using a
ꢀ
ꢀ
Rhodium-Catalyzed C C/C H Activation Sequence**
Tobias Seiser, Olivia A. Roth, and Nicolai Cramer*
Reactions involving the selective catalytic functionalization
ꢀ
ꢀ
of C H and C C bonds by transition-metal complexes have
considerable synthetic potential because of their economic
and ecological advantages.[1] In the presence of palladium or
rhodium catalysts, it has been shown that tertiary alcohols can
undergo b-carbon eliminations, thus leading to an organome-
=
tallic species and a ketone in which the formation of the C O
bond is the main driving force for the reaction. Most studies
has concentrated on the generation of aryl[2] and alkynyl
metals[3] from simple tertiary alcohols, and in most cases the
ketone formed was not incorporated into the product. In stark
contrast, the corresponding alkyl metal intermediates that
would arise from such reactions have been studied less.[4,5a,b,e,h]
However, accessing difficult-to-obtain organometallics by
activating traditionally unreactive bonds is a promising
strategy to omit the use of prefunctionalized reactants. The
ꢀ
activation of the strained C C s-bond of small rings is a
versatile approach to generate such alkyl metal species that
are able to undergo further reactions.[5] Furthermore, an
enantioselective insertion of a chiral metal catalyst into one of
ꢀ
the two adjacent C C bonds (cleavage A or B) of a
symmetrically substituted tert-cyclobutanol gives the oppor-
tunity for formation of two enantiomeric organometallic
species (2 and ent-2) having a quaternary stereogenic center
[Eq. (1)].[6] As such, we have investigated the reactivity of
strained tertiary alcohols towards activation by transition
metals to capitalize on the alkyl metal species formed for
coupled downstream trapping reactions.[7] Herein, we report
an efficient rhodium(I)-catalyzed activation of tert-cyclo-
butanols that lead to substituted indan-1-ols with high
stereocontrol.
Scheme 1. Proposed catalytic cycle for the formation of indanol 7.
hydride elimination. If undesired pathways, for example,
proto-demetalation or other intermolecular reactions, are
slow we speculate on the possibility of relaying the metal
through a 1,4-rhodium shift[3g,8] to access the more stable aryl
rhodium intermediate 6. Such species would be predisposed
to add in an intramolecular fashion to the carbonyl group[9] to
furnish indanol 7.
The anticipated reaction pathway is initiated by the
formation of a rhodium alkoxide species 4 from the alcohol
3 (Scheme 1). A selective insertion into one of the enantio-
ꢀ
topic C C s-bonds of the cyclobutane ring should form the
primary alkyl rhodium species 5. This intermediate bears a
quaternary carbon in the a position, therefore blocking b-
A selective process would require the identification of
ligands that would not only promote the initial b-carbon
elimination in an enantioselective fashion, but also control
the facial selectivity of the carbonyl addition step to
selectively form one of the possible diastereomers. In this
respect, we initially turned our attention to substrates with
R’ = Me, thus allowing sole optimization of the selectivity of
the carbonyl addition. In an initial experiment, 1,3-diphenyl-
3-methyl-cyclobutanol (3a) was heated at reflux in toluene in
the presence of [{Rh(OH)(cod)}2] (2.5 mol%) and (R)-binap
(L1, 6 mol%). These reaction conditions efficiently promoted
the formation of the expected indanol 7a as the only
detectable product in 92% yield and with an ee value of
64% (Table 1, entry 1). A brief survey of chiral phosphine
ligands (Table 1, entries 2–5) revealed that the josiphos ligand
family (Table 1, entries 6–11) was particularly suited for this
[*] T. Seiser, O. A. Roth, Dr. N. Cramer
Laboratory of Organic Chemistry, ETH Zurich
Wolfgang-Pauli-Strasse 10, HCI H 304, 8093 Zurich (Switzerland)
Fax: (+41)44-632-1328
http://www.cramer.ethz.ch
E-mail: nicolai.cramer@org.chem.ethz.ch
[**] We thank the Swiss National Foundation (21-119750.01), Solvia-
s AG for the Josiphos ligands and Umicore AG & Co. KG for
rhodium salts and Prof. Dr. E. M. Carreira for generous support. The
Fonds der Chemischen Industrie is acknowledged for a Liebig
Fellowship (N.C.) and a Kekulꢀ Fellowship (T.S.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903189.
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Chemie
[a]
Table 1: Selected optimization studies.[a]
Table 2: Scope of the rhodium(I)-catalyzed C C/C H activation.
ꢀ
ꢀ
Entry
3
R
7(X)
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
3i
Ph
7a (H)
7b (H)
7c (H)
7d (H)
7e (H)
7 f (H)
7g (H)
7h (H)
7i (H)
7j (H)
7k (Cl)
94
87
88
79
98
75
96
95
88
99
99
96
96
94
88
94
91
90
93
91
94
90
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(R)
(R)
(R)
4-ClC6H4
4-MeOC6H4
1-naphth
2-naphth
(E)-styryl
Me
nBu
iPr
tBu
tBu
Entry
L*
Yield [%][b]
ee [%][c]
9
10
11
1
2
3
4
L1 ((R)-binap)
92
99
99
99
86
85
84
94
91
99
96
64
76
24
89
82
92
81
96
92
84
92
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
3j
3k
L2
L3
L4
L5
L6
L7
L8
L9
L8
L8
[a] Reaction conditions: 3 (0.1 mmol), toluene (0.20m), 5–12 h. [b] Yield
of isolated product 7. [c] Determined by HPLC on a chiral stationary
phase and the absolute configuration was assigned by analogy with 7k.
naphth=naphthalene.
5[d]
6
7
8
9
10[e]
11[f]
the two diastereomers 7l and 8m (Table 3, entry 1). Dehy-
dration of the indanol to the indene revealed that the initial
[a] Reaction conditions: 3a (0.1 mmol; mixture of cis/trans isomers),[10]
toluene (0.20m). [b] Yield of isolated product 7a. [c] Determined by
HPLC on a chiral stationary phase. [d] L5 (12 mol%) and [{Rh(OAc)-
(C2H4)2}2] (2.5 mol%). [e] Cs2CO3 (1.1 equiv); [f] [{Rh(OH)(cod)}2]
(0.25 mol%) and L8 (0.6 mol%), xylenes (1.0m), 1208C, 12 h. binap=
2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl, cod=1,5-cyclooctadiene,
Cy =cyclohexyl, DMM=3,5-dimethyl-4-methoxyphenyl, DTBM=3,5-di-
tert-butyl-4-methoxyphenyl.
ꢀ
C C cleavage step—responsible for the configuration of the
quaternary stereocenter—had proceeded almost with no
selectivity. Gratifyingly, the difluorphos ligand (L4) induced
useful selectivities in both stereodetermining steps, resulting
in an overall excellent ee value of 99% and a good diaste-
reomeric ratio of 20:1 (Table 3, entry 2). The corresponding
trans-configured cyclobutanol 3m provided the diastereomer
8m with the opposite configuration at C3 with comparable ee
and d.r. values (Table 3, entry 3). The scope of the reaction
was explored with diverse cyclobutanols having aromatic and
heteroaromatic substituents. By being exposed to this second
set of conditions, the cyclobutanols furnished the rearranged
products in excellent yields as well as diastereo- and
enantioselectivities (Table 3, entries 3–13). The 6-aza-inda-
nols 7t and 8u were selectively formed over the correspond-
ing indanols (Table 3, entry 10 (2:1) and entry 11 (8:1)), thus
suggesting that electron-poor aromatic compounds preferen-
tially participate in the 1,4-rhodium shift. Nevertheless,
electron-rich heteroaromatic substituents, like a thiophene
group, are well suited for the reaction (Table 3, entries 12 and
13).
task. Steric and electronic fine-tuning led to the identification
of L8, bearing electron-poor aryl groups on the phosphorous
atom of the ferrocene backbone, as the best performer and
afforded 7a in 94% yield and 96% ee (Table 1, entry 8). With
only a minor decrease of the ee value (92% ee; Table 1,
entry 11), the catalyst loading could be lowered from 5 to
0.5 mol% rhodium. Bases such as cesium carbonate signifi-
cantly increased the reaction rates, however, at the expense of
lower selectivity (Table 1, entry 10).
The scope of the rhodium-catalyzed rearrangement was
examined with the optimized reaction conditions (Table 2). In
general, different aromatic tertiary cyclobutanols were
afforded the corresponding indanols in good yields and high
selectivities (Table 2, entries 1–6). This selectivity was main-
tained for substrates with small alkyl substituents (Table 2,
entries 7 and 8) as well as for those with sterically more
demanding isopropyl or tert-butyl substituents (Table 2,
entries 9–11).
A cyclobutanol substrate with identical aryl groups in the
3-position (3x) offers the possibility to explore the feasibility
of an enantioselective version of the 1,4-rhodium shift
(Scheme 2). Indeed, synthetically useful selectivities were
observed with the difluorphos ligand L8 and 8x was formed in
96% yield, 92% ee, and with 4.5:1 d.r. Further screening
revealed that the Taniaphos ligand L10 is unique in prefer-
entially providing the opposite diastereomer 7x (9:1 d.r.),
however, only as a racemate.
The absolute configuration of the para-chlorophenyl
derivative 7k was established to be R by X-ray crystallo-
graphic analysis.[11]
We next turned our attention to substrates where R’ ¼ Me
(Table 3). However, exposure of 3l to the aforementioned
optimized reaction conditions resulted in a 1.2:1 mixture of
In conclusion, we have demonstrated an efficient protocol
for the activation of tert-cyclobutanols through an enantiose-
ꢀ
lective rhodium(I)-catalyzed insertion into the C C s-bond
leading to alkyl rhodium species. These reactive intermedi-
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Communications
Table 3: Scope of the diastereoselective reaction.[a]
lective manner. Studies focusing on
related activation/relaying modes
and on an expansion of the reaction
manifold are ongoing.
Experimental Section
Entry
3
R1
R2
R’
Major
7/8[c]
Yield
[%][d]
ee
1,3-Diphenyl-3-methyl-cyclobutanol
product[b] (X)
[%][e]
(3a,
23.8 mg,
0.10 mmol),
[{Rh-
1[f]
2
3l
3l
Ph
Ph
Et
Ph
CH2OBn
4-ClC6H4
CO2Me
4-ClC6H4
nBu
Et
Et
nBu
nBu
nBu
Ph
Ph
Ph
Ph
Et
Et
7l (H)
7l (H)
8m (H)
7n (H)
8o (H)
7p (Cl)
8q (Cl)
7r (Cl)
8s (Cl)
1.2:1
20:1
1:10
>20:1
1:12
9:1
1:4.5
20:1
1:6
94
95
98
97
91
90
90
93
95
97
99
99
97
97
99
99
96
99
(cod)(OH)}2] (1.14 mg, 2.50 mmol) and
(R,S)-Josiphos (L8, 4.07 mg, 6.00 mmol)
were weighed into an oven dried vial
equipped with a magnetic stirrer. The
3
3m
3n
3o
3p
3q
3r
Ph
CH2OBn
Ph
CO2Me
4-ClC6H4
nBu
4[g]
5[g]
6
vial was then sealed with
a rubber
septum and flushed with nitrogen.
After the addition of dry toluene
(0.4 mL), the reaction mixture was
degassed by three freeze-pump-thaw
cycles, stirred for 10 min at 238C and
subsequently immersed into a preheated
oil bath (1108C) for 5 h. After conver-
sion was complete (as evident by TLC),
the reaction mixture was cooled to 238C
and directly purified by column chroma-
tography on silica gel (pentane/
EtOAc 13:1, Rf = 0.42) to give indanol
(R)-7a (22.4 mg, 94% yield, 96% ee) as
a colorless oil.
7
8
9
3s
4-ClC6H4
10
11
12
13
3t
Ph
Et
10:1
74[h]
63[i]
90
96
99
99
96
3u
3v
3w
Ph
Et
1:6
3:1
Received: June 12, 2009
Published online: July 16, 2009
Et
nBu
nBu
Keywords: asymmetric catalysis ·
.
ꢀ
ꢀ
C C activation · C H activation ·
indanols · rhodium
Et
1:15
65
[a] Reaction conditions: 3 (0.1 mmol), toluene (0.20m). [b] Configuration assigned by analogy with 7k
and diagnostic nOe interactions. [c] Determined by 1H NMR spectroscopy of the crude reaction mixture.
[d] Yield of isolated product 7. [e] Determined by HPLC on a chiral stationary phase. [f] L8 (6.0 mol%).
[g] L2 (6.0 mol%). [h] 9% of the indanol was formed. [i] 32% of the indanol was formed. Bn=benzyl.
ꢀ
[1] Reviews on C H bond functional-
ization: a) G. Dyker, Angew. Chem.
1999, 111, 1808 – 1822; Angew.
Chem. Int. Ed. 1999, 38, 1698 –
1712; b) F. Kakiuchi, S. Murai,
Top. Organomet. Chem. 1999, 3,
47 – 79; c) V. Ritleng, C. Sirlin, M. Pfeffer, Chem. Rev. 2002,
102, 1731 – 1770; d) F. Kakiuchi, S. Murai, Acc. Chem. Res.
2002, 35, 826 – 834; e) M. Miura, M. Nomura, Top. Curr.
Chem. 2002, 219, 211 – 241; f) F. Kakiuchi, N. Chatani, Adv.
Synth. Catal. 2003, 345, 1077 – 1101; g) F. Kakiuchi, Top.
Organomet. Chem. 2008, 24, 1 – 33; h) I. V. Seregin, V.
Gevorgyan, Chem. Soc. Rev. 2007, 36, 1173 – 1193; i) J. C.
Lewis, R. G. Bergman, J. A. Ellman, Acc. Chem. Res. 2008,
41, 1013 – 1025; j) F. Kakiuchi, T. Kochi, Synthesis 2008,
ꢀ
3013 – 3039; reviews on C C bond activation: k) B. Rybtch-
inski, D. Milstein, Angew. Chem. 1999, 111, 918 – 932; Angew.
Chem. Int. Ed. 1999, 38, 870 – 883; l) M. Murakami, Y. Ito,
Top. Organomet. Chem. 1999, 3, 97 – 129; m) C.-H. Jun, C. W.
Moon, D.-Y. Lee, Chem. Eur. J. 2002, 8, 2423 – 2428; n) M. E.
van der Boom, D. Milstein, Chem. Rev. 2003, 103, 1759 –
1792; o) C.-H. Jun, Chem. Soc. Rev. 2004, 33, 610 – 618;
p) T. Satoh, M. Miura, Top. Organomet. Chem. 2005, 14, 1 –
20; q) T. Seiser, N. Cramer, Org. Biomol. Chem. 2009, 7,
2835 – 2840.
Scheme 2. Probing an enantioselective 1,4-rhodium shift. Reaction condi-
tions: 3x (0.1 mmol), [{Rh(OH)(cod)}2] (2.5 mol%), L* (6.0 mol%), tolu-
ene (0.20m), 1108C, 12 h.
ꢀ
ates lead (presumably by a C H activation pathway) to aryl
[2] a) Y. Terao, H. Wakui, T. Satoh, M. Miura, M. Nomura, J.
Am. Chem. Soc. 2001, 123, 10407 – 10408; b) Y. Terao, H. Wakui,
M. Nomoto, T. Satoh, M. Miura, M. Nomura, J. Org. Chem. 2003,
rhodium species that ultimately give access to highly sub-
stituted indanol derivatives in an enantio- and diastereose-
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68, 5236 – 5243; c) Y. Terao, M. Nomoto, T. Satoh, M. Miura, M.
Nomura, J. Org. Chem. 2004, 69, 6942 – 6944; d) H. Wakui, S.
Kawasaki, T. Satoh, M. Miura, M. Nomura, J. Am. Chem. Soc.
2004, 126, 8658 – 8659; e) T. Nishimura, T. Katoh, T. Hayashi,
Angew. Chem. 2007, 119, 5025 – 5027; Angew. Chem. Int. Ed.
2007, 46, 4937 – 4939; f) T. Uto, M. Shimizu, K. Ueura, H.
Tsurugi, T. Satoh, M. Miura, J. Org. Chem. 2008, 73, 298 – 300.
[3] a) H.-F. Chow, C.-W. Wan, K.-H. Low, Y.-Y. Yeung, J. Org.
Chem. 2001, 66, 1910 – 1913; b) C.-K. Choi, J.-W. Hong, I.
Tomita, T. Endo, Bull. Korean Chem. Soc. 2002, 23, 112 – 118;
c) T. Nishimura, H. Araki, Y. Maeda, S. Uemura, Org. Lett. 2003,
5, 2997 – 2999; d) A. Funayama, T. Satoh, M. Miura, J. Am.
Chem. Soc. 2005, 127, 15354 – 15355; e) A. Horitak, H. Tsurugi,
A. Funayama, T. Satoh, M. Miura, Org. Lett. 2007, 9, 2231 – 2233;
f) T. Nishimura, T. Katoh, K. Takatsu, R. Shintani, T. Hayashi, J.
Am. Chem. Soc. 2007, 129, 14158 – 14159; g) R. Shintani, K.
Takatsu, T. Katoh, T. Nishimura, T. Hayashi, Angew. Chem.
2008, 120, 1469 – 1471; Angew. Chem. Int. Ed. 2008, 47, 1447 –
1449.
[4] Examples for retroallylation of homoallylic tertiary alcohols:
a) T. Kondo, K. Kodoi, E. Nishinaga, T. Okada, Y. Morisaki, Y.
Watanabe, T.-A. Mitsudo, J. Am. Chem. Soc. 1998, 120, 5587 –
5588; b) D. Necas, M. Tursky, M. Kotora, J. Am. Chem. Soc.
2004, 126, 10222 – 10223; c) S. Hayashi, K. Hirano, H. Yorimitsu,
K. Oshima, J. Am. Chem. Soc. 2006, 128, 2210 – 2211; d) M.
Iwasaki, S. Hayashi, K. Hirano, H. Yorimitsu, K. Oshima, J. Am.
Chem. Soc. 2007, 129, 4463 – 4469; e) R. Shintani, K. Takatsu, T.
Hayashi, Org. Lett. 2008, 10, 1191 – 1193.
Reddy, Org. Lett. 2000, 2, 3325 – 3327; d) M. Murakami, T.
Itahashi, Y. Ito, J. Am. Chem. Soc. 2002, 124, 13976 – 13977; e) T.
Nishimura, Y. Nishiguchi, Y. Maeda, S. Uemura, J. Org. Chem.
2004, 69, 5342 – 5347; f) T. Matsuda, M. Makino, M. Murakami,
Angew. Chem. 2005, 117, 4684 – 4687; Angew. Chem. Int. Ed.
2005, 44, 4608 – 4611; g) M. Murakami, S. Ashida, T. Matsuda, J.
Am. Chem. Soc. 2006, 128, 2166 – 2167; h) M. Murakami, S.
Ashida, T. Matsuda, Tetrahedron 2006, 62, 7540 – 7546; i) M.
Murakami, M. Makina, S. Ashida, T. Matsuda, Bull. Chem. Soc.
Jpn. 2006, 79, 1315 – 1321.
[6] a) T. Nishimura, S. Matsumura, Y. Maeda, S. Uemura, Chem.
Commun. 2002, 50 – 51; b) S. Matsumura, Y. Maeda, T. Nishi-
mura, S. Uemura, J. Am. Chem. Soc. 2003, 125, 8862 – 8869; c) T.
Matsuda, M. Shigeno, M. Makino, M. Murakami, Org. Lett.
2006, 8, 3379 – 3381; d) T. Matsuda, M. Shigeno, M. Murakami, J.
Am. Chem. Soc. 2007, 129, 12086 – 12087; e) C. Winter, N.
Krause, Angew. Chem. 2009, 121, 2497 – 2499; Angew. Chem. Int.
Ed. 2009, 48, 2460 – 2462.
[7] T. Seiser, N. Cramer, Angew. Chem. 2008, 120, 9435 – 9438;
Angew. Chem. Int. Ed. 2008, 47, 9294 – 9297.
[8] Review: a) S. Ma, Z. Gu, Angew. Chem. 2005, 117, 7680 – 7685;
Angew. Chem. Int. Ed. 2005, 44, 7512 – 7517; recent examples:
b) T. Miura, T. Sasaki, H. Nakazawa, M. Murakami, J. Am.
Chem. Soc. 2005, 127, 1390 – 1391; c) T. Matsuda, M. Shigeno, M.
Murakami, J. Am. Chem. Soc. 2007, 129, 12086 – 12087.
[9] For a related palladium-catalyzed intramolecular addition to
ketones, see: G. Liu, X. Lu, J. Am. Chem. Soc. 2006, 128, 16504 –
16505.
[5] For examples, see: a) T. Nishimura, K. Ohe, S. Uemura, J. Am.
Chem. Soc. 1999, 121, 2645 – 2646; b) T. Nishimura, S. Uemura, J.
Am. Chem. Soc. 1999, 121, 11010 – 11011; c) R. C. Larock, C. K.
[10] Pure cis and trans isomers gave identical yields and selectivities.
[11] See the Supporting Information for details.
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