Enantioselective construction of indanones from cyclobutanols using a rhodium-catalyzed C-C/C-H/C-C bond activation process

Article abstract of DOI:10.1055/s-0029-1219959

Enantioselective rhodium(I)-catalyzed reactions of tert-cyclobutanols lead via consecutive C-C/C-H/C-C bond activations to indanones with quaternary stereogenic centers. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219959

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1699
Enantioselective Construction of Indanones from Cyclobutanols Using a
Rhodium-Catalyzed C–C/C–H/C–C Bond Activation Process
R
hodium-Cataly
o
ze
d
C–C/C–
b
H/C–C Bon
i
A
ctiv
a
ations s Seiser, Gino Cathomen, Nicolai Cramer*
Laboratorium für Organische Chemie, ETH Zürich, HCI H 304, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland
Fax +41(44)6321328; E-mail: Nicolai.cramer@org.chem.ethz.ch
Received 23 March 2010
were completely inert towards this second b-carbon elim-
ination and gave exclusively the expected indanols 7 (en-
tries 1 and 2). A furyl substituent allowed for the proposed
pathway leading to 6, although the major product was still
indanol 7 (entry 3). When the ligand was switched to
Josiphos (L4, Figure 1), indanone 6 became the dominant
product (entry 4). We observed that the selectivity of this
process could be additionally altered by the addition of in-
organic bases. For example, addition of cesium carbonate
enhanced the reactivity of the aryl b-carbon cleavage, and
with these conditions indanone 6 was formed predomi-
nantly with Binap (L1, entry 5). Further screening of elec-
Abstract: Enantioselective rhodium(I)-catalyzed reactions of tert-
cyclobutanols lead via consecutive C–C/C–H/C–C bond activations
to indanones with quaternary stereogenic centers.
Key words: rhodium, ring opening, quaternary stereogenic center,
C–C activation, C–H activation
The selective and catalytic functionalization of C–C sin-
gle bonds mediated by transition-metal complexes is a
fundamental challenge in organometallic chemistry. The
lack of prefunctionalized reactants makes this area com-
pelling and has broad implications for organic synthesis.1
However, unfavorable kinetics and thermodynamics for
the metal insertion and competing C–H activations make
such processes challenging, resulting in reactivity and se-
lectivity issues. Especially efficient enantioselective vari-
ants are scarce and mainly focus on strained substrates.2
The enantioselective activation of C–C s bonds of sym-
metrically substituted cyclobutanols via b-carbon cleav-
age recently came into our focus as attractive tool to
access quaternary stereogenic centers.3 In addition to the
formed quaternary stereocenter, this process generates an
alkyl-rhodium(I) intermediate that enjoys exceptional
high reactivity and participates in a host of synthetically
useful and mechanistically intriguing downstream reac-
tions.4,5 We6 and Murakami and coworkers7 recently re-
ported a process involving a 1,4-rhodium shift of such
intermediates, providing aryl-rhodium species 4 that adds
across the formed ketone to give rise to highly functional-
ized indanols 7 (Scheme 1). To expand the utility of this
reaction, we envisioned a further C–C activation of rhod-
ium alkoxide 5 prior to protonation. A b-aryl cleavage of
5 would lead to indanones 6 bearing quaternary stereogen-
ic centers. This process would represent an appealing ex-
ample of a C–C/C–H/C–C activation sequence. Such
metal-promoted b-aryl cleavages from tertiary alcohols
have been reported,8 and Hartwig and coworkers showed
that electron-rich aromatics are cleaved preferentially
from differentially substituted triarylmethanols.9
tron-rich aromatic substituents such as
a 2,4,6-
trimethoxyphenyl, 2-N-methylindolyl, and 2-thienyl
group confirmed the trend of a higher cleavage propensity
with increasing donating character of the aromatic substit-
uent (entries 6–8). Especially the 2-thienyl substituent re-
sulted in a clean and high-yielding reaction and was
therefore the substituent of choice.
OH
Ar
Ph
R
O
∗
1
R
[Rh]
6
this work:
– Ar-[Rh]
O[Rh]
Ar
Ph
R
β-carbon
cleavage
β-carbon
cleavage
2
Ar
O[Rh]
R
[Rh]
Ph
O
∗
∗
∗
Ar
R
3
ref. 6
Ar
5
OH
1,4-Rh
shift
Towards this goal, we examined the reactivity of different
aromatic groups on prototype cyclobutanols 1 for the b-
aryl cleavage (Table 1). Substrates 1 with a phenyl sub-
stituent or a more electron-rich p-methoxyphenyl group
∗
[Rh]
O
∗
addition
∗
R
Ar
R
7
4
Scheme 1 Proposed mechanism for the formation of indanone 6 by
a b-carbon cleavage, 1,4-Rh shift, 1,2-addition, and b-aryl cleavage
SYNLETT 2010, No. 11, pp 1699–1703
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x
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DOI: 10.1055/s-0029-1219959; Art ID: Y00210ST
© Georg Thieme Verlag Stuttgart · New York

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T. Seiser et al.
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Table 1 Optimization of the Second b-Carbon Cleavage Stepa
With (R)-Binap (L1), we obtained indanone 6a with an ee
value of 79% (entry 8). While the Josiphos ligand (L4) ex-
hibited the highest reactivity for the b-aryl cleavage, its
selectivity for the crucial enantiodetermining first b-car-
bon cleavage was very poor (<5% ee, entry 9). (R)-Seg-
phos (L2) gave an improved enantioselectivity and
yielded 6a with 88% ee (entry 10). While (R)-Difluorphos
(L3) induced the same enantioselectivity, its higher reac-
tivity allowed isolating indanone 6a in a virtually quanti-
tative yield (entry 11). Therefore L3 was chosen as the
standard ligand for this process.
HO
O
Ar
OH
Ar
Ph
R
[Rh], L
+
R
R
1
7
6
Entry
1
L
R
Ar
6/7b
Yield of 6 (%)c
L1
Me
<1:20 n.d.
O
O
F
F
2
L1
Me
<1:20 n.d.
O
O
O
O
PPh2
PPh2
PPh2
PPh2
PPh2
PPh2
OMe
F
F
3
L1
L4
L1
L1
Me
Me
Me
Et
1:9 n.d.
6:1 42
9:1 80
1:2 31
O
O
O
O
O
L1
L2
L3
4
OMe
Pt-Bu2
t-Bu
t-Bu
MeO
MeO
PAr2
PAr2
Ph2P
Fe
5e
6e
Ar =
L4
L5
OMe
Figure 1 Ligands employed in this study
MeO
OMe
With these optimized conditions, we explored the scope
of the process.10 The reactivity as well as the selectivity is
maintained throughout a range of different substituted cy-
clobutanols 1 (Table 2).11 Silyl groups, ester functional-
ities as well as aryl chlorides are well tolerated (entries 3–
7e
L1
Et
3:1 55
Me
N
8e
9e
L1
L4
L2
L3
Et
Et
Et
Et
>20:1 99 (79% ee)d
>20:1 48 (<5% ee)d
>20:1 74 (88% ee)d
>20:1 99 (88% ee)d
S
S
S
S
O
HO
[Rh], L3
Cl
toluene, 110 °C, 1 h
10e
11e
CO2Me
7e
77%, 99% ee, 5:1 dr
Cl
O
[Rh], L3
Cs2CO3
Cl
OH
xylenes
120 °C, 24 h
a Reaction conditions: 0.1 mmol 1, 2.5 mol% [Rh(OH)(cod)]2,
6.0 mol% L, 0.25 M in xylenes, 120 °C, 12 h.
b Ratios were determined by 1H NMR.
c Isolated yields.
CO2Me
MeO2C
O
6e
45%, 98% ee
1g
d The ee values were determined by HPLC with a chiral stationary
phase.
MeO2C
O
e With 1.5 equiv Cs2CO3.
O
[Rh], L5
toluene, 110 °C, 4 h
8). Coordinating heterocycles like pyridine do not inhibit
the reaction. Noteworthy, the electron-poor pyridine core
participates preferentially over a phenyl group in the 1,4-
rhodium shift, thus leading to the formation of aza-
indanone 6f in excellent enantioselectivity (entry 9).
8
Cl
72%, 95% ee
Scheme 2 Ligands and conditions adjustments steer the chemosel-
ectivity of the reaction {[Rh] = 2.5 mol% [Rh(OH)(cod)]2, 6 mol%
L*}
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Rhodium-Catalyzed C–C/C–H/C–C Bond Activations
1701
The importance of the ligand and the employed conditions In summary, we reported a C–C/C–H/C–C activation se-
for the reaction outcome is demonstrated for the furyl- quence of tert-cyclobutanols providing access to in-
substituted cyclobutanol 1g, allowing to selectively ad- danones with quaternary stereogenic centers in excellent
dress the formation of three different products enantioselectivities. This triple activation process extends
(Scheme 2). Difluorphos (L3), short reaction times, and the range of accessible and synthetically useful building
base-free conditions promote the selective formation of blocks from catalytic enantioselective C–C bond activa-
indanol 7e. The reaction leading to indanone 6e can be tions.
triggered by the addition of cesium carbonate in combina-
tion with prolonged reaction times. Sterically demanding
ligands like DTBM-MeOBiphep (L5) promote the cy-
clobutanol cleavage in excellent selectivity, but stop at the
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
stage of intermediate 3 or 4. The organorhodium species
undergoes instead protodemetalation giving ketone 8 with
an acyclic methyl quaternary stereocenter.4e
Table 2 Scope of the C–C/C–H/C–C Activation Reactiona
Entry
1
1
6
Yield (%)b
99
ee (%)c
88
cis-1a
6a
O
O
OH
OH
Et
Et
S
S
Et
Et
Me
Me
2d
trans-1a
cis-1b
6a
6b
98
97
86
88
3d
Cl
O
Cl
OH
Me
Bu
Bu
S
4d
cis-1c
6c
6c
99
99
80
93
OH
O
O
TBSO
Cl
Cl
S
OTBS
OTBS
Me
Me
Cl
Cl
5
trans-1c
OH
TBSO
Cl
S
6e
trans-1d
6d
73
89
O
Cl
OH
OPiv
Me
PivO
S
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T. Seiser et al.
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Table 2 Scope of the C–C/C–H/C–C Activation Reactiona (continued)
Entry
7d
1
6
Yield (%)b
94
ee (%)c
83
cis-1d
6d
6e
O
O
OH
PivO
Cl
S
OPiv
Me
Cl
Cl
8e
trans-1e
trans-1f
60
60
94
92
Cl
OH
CO2Me
Me
O
MeO2C
S
9d,f
6f
N
OH
Ph
S
Me
N
a Reaction conditions: 0.1 mmol 1, 2.5 mol% [Rh(OH)(cod)]2, 6.0 mol% L3, 1.5 equiv Cs2CO3, 0.25 M in xylenes, 120 °C, 12 h.
b Isolated yields.
c Determined by HPLC with a chiral stationary phase.
d With ent-L3.
e After 12 h, 2.5 mol% [Rh(OH)(cod)]2 and 6.0 mol% L4 were added.
f Aza-indanone 6f was formed preferentially over the indanone (2:1 selectivity).
(6) Seiser, T.; Roth, O. A.; Cramer, N. Angew. Chem. Int. Ed.
2009, 48, 6320.
(7) Shigeno, M.; Yamamoto, T.; Murakami, M. Chem. Eur. J.
Acknowledgment
We are grateful to the Swiss National Foundation (21-119750.01),
Solvias AG for Josiphos and MeOBiphep ligands, Takasago Inter-
national Corporation for Segphos ligands as well as Prof. E. M.
Carreira for generous support. The Fonds der Chemischen Industrie
is acknowledged for a Liebig-Fellowship (N.C.) and a Kekulé-
Fellowship (T.S.).
2009, 47, 12929.
(8) (a) Terao, Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M.
J. Am. Chem. Soc. 2001, 123, 10407. (b) Wakui, H.;
Kawasaki, S.; Satoh, T.; Miura, M.; Nomura, M. J. Am.
Chem. Soc. 2004, 126, 8658. (c) Nishimura, T.; Katoh, T.;
Hayashi, T. Angew. Chem. Int. Ed. 2007, 46, 4937.
(9) (a) Zhao, P.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem.
Soc. 2006, 128, 3124. (b) Zhao, P.; Hartwig, J. F.
Organometallics 2008, 27, 4749.
References and Notes
(1) For recent reviews, see: (a) Rybtchinski, B.; Milstein, D.
Angew. Chem. Int. Ed. 1999, 38, 871. (b) Murakami, M.;
Ito, Y. Top. Organomet. Chem. 1999, 3, 97.
(10) Typical Procedure for the Preparation of (S)-3-[(tert-
Butyldimethylsilyloxy)methyl]-6-chloro-3-methylindan-
1-one (6c)
(c) van der Boom, M. E.; Milstein, D. Chem. Rev. 2003, 103,
1759. (d) Jun, C.-H. Chem. Soc. Rev. 2004, 33, 610.
(e) Satoh, T.; Miura, M. Top. Organomet. Chem. 2005, 14, 1.
(2) Seiser, T.; Cramer, N. Org. Biomol. Chem. 2009, 7, 2835.
(3) (a) Douglas, J. C.; Overman, L. E. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5363. (b) Trost, B. M.; Jiang, D. C.
Synthesis 2006, 369. (c) Quaternary Stereocenters;
Christoffers, J.; Baro, A., Eds.; Wiley: Weinheim, 2005.
(4) (a) Matsuda, T.; Shigeno, M.; Makino, M.; Murakami, M.
Org. Lett. 2006, 8, 3379. (b) Matsuda, T.; Shigeno, M.;
Murakami, M. J. Am. Chem. Soc. 2007, 129, 12086.
(c) Seiser, T.; Cramer, N. Angew. Chem. Int. Ed. 2008, 47,
9294. (d) Seiser, T.; Cramer, N. Chem. Eur. J. 2010, 16,
3383. (e) Seiser, T.; Cramer, N. J. Am. Chem. Soc. 2010,
132, 5340.
tert-Cyclobutanol trans-1c (40.9 mg, 0.100 mmol),
[Rh(cod)(OH)]2 (1.14 mg, 2.50 mmol), (R)-Difluorphos (L3,
4.10 mg, 6.00 mmol), and Cs2CO3 (0.150 mmol, 48.9 mg)
were weighted into an oven-dried vial equipped with a
magnetic stir bar, capped with a septum, and purged with
nitrogen. Dry xylenes (0.5 mL) were added, and the mixture
was degassed with three freeze-pump-thaw cycles. The
mixture was stirred for 10 min at 23 °C and subsequently
immersed into a preheated oil bath (120 °C) for 12 h. After
TLC analysis showed the complete conversion, the reaction
mixture was cooled to 23 °C and directly purified on silica
gel (pentane–EtOAc 30:1, Rf = 0.18) giving 32.2 mg (99%,
93% ee) of indanone (S)-6c as colorless oil. 1H NMR (400
MHz, CDCl3): d = 7.71–7.60 (m, 1 H), 7.54 (dd, J = 8.2, 2.1
Hz, 1 H), 7.45 (dd, J = 8.2, 0.5 Hz, 1 H), 3.62–3.56 (m, 2 H),
2.75 (d, J = 18.7 Hz, 1 H), 2.41 (d, J = 18.7 Hz, 1 H), 1.40
(s, 3 H), 0.77 (s, 9 H), –0.06 (s, 3 H), –0.13 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): d = 204.0, 158.2, 138.5,
134.3, 134.1, 125.7, 122.9, 70.7, 48.5, 44.1, 25.6, 23.4, 18.1,
(5) For related palladium-catalyzed reactions, see:
(a) Nishimura, T.; Matsumura, S.; Maeda, Y.; Uemura, S.
Chem. Commun. 2002, 50. (b) Matsumura, S.; Maeda, Y.;
Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 2003, 125,
8862.
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Rhodium-Catalyzed C–C/C–H/C–C Bond Activations
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–5.7, –5.8. HRMS (EI+): m/z calcd for C13H16ClO2Si [M –
(11) The absolute configuration of compounds 6 were assigned in
C4H9]+: 267.0603; found: 267.0603. IR (ATR): 2955, 2929,
2885, 2856, 1720, 1602, 1470, 1254, 1236, 1180, 1109, 837,
777 cm–1. [a]D20 –21 (c 0.94, CHCl3).
analogy to the reported cleavage site. See ref. 4c,d, and 6.
Synlett 2010, No. 11, 1699–1703 © Thieme Stuttgart · New York