Enantioselective Rh(I)-catalyzed cyclization of arylboron compounds onto ketones

Article abstract of DOI:10.1021/ol300845q

Rhodium complexes based upon chiral sulfinamide-alkene, TADDOL-derived phosphoramidite, or diene ligands catalyze cyclizations of arylboron compounds onto ketones, generating a variety of products containing five-, six-, or seven-membered rings with good

Full text of DOI:10.1021/ol300845q

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2548–2551
Enantioselective Rh(I)-Catalyzed
Cyclization of Arylboron
Compounds onto Ketones
Darryl W. Low,† Graham Pattison,† Martin D. Wieczysty,† Gwydion H. Churchill,‡ and
Hon Wai Lam*,†
EaStCHEM, School of Chemistry, University of Edinburgh, The King’s Buildings, West
Mains Road, Edinburgh, EH9 3JJ, United Kingdom, and AstraZeneca Process Research
and Development, Charter Way, Silk Road Business Park, Macclesfield, Cheshire, SK10
2NA, United Kingdom
h.lam@ed.ac.uk
Received April 3, 2012
ABSTRACT
Rhodium complexes based upon chiral sulfinamideÀalkene, TADDOL-derived phosphoramidite, or diene ligands catalyze cyclizations of
arylboron compounds onto ketones, generating a variety of products containing five-, six-, or seven-membered rings with good yields and high
enantioselectivities.
Enantioenriched chiral tertiary benzylic alcohols are
building blocks of broad utility, and of the various meth-
ods available to access these structures,1 the catalytic
asymmetric arylation of ketones2 stands out as being
particularly attractive. Due to their availability, relative
insensitivity to air and moisture, high functional group
tolerance, and generally low toxicity, arylboron reagents
are attractive nucleophiles for these reactions. However,
compared with the large body of work describing catalytic
enantioselective arylations of aldehydes with arylboron
reagents,3À8 the corresponding reactions with ketones are
much less developed.9
† University of Edinburgh.
‡ AstraZeneca
(1) These methods include asymmetric additions of various carbon
nucleophiles to aromatic ketones and asymmetric dihydroxylation of
styrene derivatives. For relevant reviews, see: (a) Shibasaki, M.; Kanai,
M. Chem. Rev. 2008, 108, 2853–2873. (b) Hatano, M.; Ishihara, K.
Synthesis 2008, 2008, 1675. (c) Noe, M. C.; Letavic, M. A.; Snow, S. L.
Org. React. 2005, 66, 109–625.
The reason for this disparity is that ketones are more
challenging substrates for enantioselective addition
(4) Using cobalt catalysis: Karthikeyan, J.; Jeganmohan, M.; Cheng,
C.-H. Chem.;Eur. J. 2010, 16, 8989–8992.
~
(2) For relevant reviews, see: (a) Bolm, C.; Hildebrand, J. P.; Muniz,
K.; Hermanns, N. Angew. Chem., Int. Ed. 2001, 40, 3284–3308. (b)
Betancort, J. M.; Garcia, C.; Walsh, P. J. Synlett 2004, 749–760. (c)
Hatano, M.; Ishihara, K. Chem. Rec. 2008, 8, 143–155.
(5) Using nickel catalysis: (a) Arao, T.; Kondo, K.; Aoyama, T.
Tetrahedron Lett. 2007, 48, 4115–4117. (b) Yamamoto, K.; Tsurumi, K.;
Sakurai, F.; Kondo, K.; Aoyama, T. Synthesis 2008, 3585–3590. (c)
Sakupai, F.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2009, 57, 511–
512. (d) Sakurai, F.; Kondo, K.; Aoyama, T. Tetrahedron Lett. 2009, 50,
6001–6003.
(6) Using copper catalysis: Tomita, D.; Kanai, M.; Shibasaki, M.
Chem. Asian J. 2006, 1, 161–166.
(7) Using ruthenium catalysis: (a) Yamamoto, Y.; Kurihara, K.;
Miyaura, N. Angew. Chem., Int. Ed. 2009, 48, 4414–4416. (b)Yamamoto,
Y.; Shirai, T.; Watanabe, M.; Kurihara, K.; Miyaura, N. Molecules
2011, 16, 5020–5034. (c) Yamamoto, Y.; Shirai, T.; Miyaura, N. Chem.
Commun. 2012, 48, 2803–2805.
(3) Using rhodium catalysis: (a) Sakai, M.; Ueda, M.; Miyaura, N.
Angew. Chem., Int. Ed. 1998, 37, 3279–3281. (b) Focken, T.; Rudolph, J.;
Bolm, C. Synthesis 2005, 429–436. (c) Suzuki, K.; Ishii, S.; Kondo, K.;
Aoyama, T. Synlett 2006, 648–650. (d) Suzuki, K.; Kondo, K.; Aoyama,
T. Synthesis 2006, 1360–1364. (e) Arao, T.; Suzuki, K.; Kondo, K.;
Aoyama, T. Synthesis 2006, 3809–3814. (f) Duan, H. F.; Xie, J. H.; Shi,
W. J.; Zhang, Q.; Zhou, Q. L. Org. Lett. 2006, 8, 1479–1481. (g) Jagt,
R. B. C.; Toullec, P. Y.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J.
€
Org. Biomol. Chem. 2006, 4, 773–775. (h) Noel, T.; Vandyck, K.; Van der
Eycken, J. Tetrahedron 2007, 63, 12961–12967. (i) Nishimura, T.;
Kumamoto, H.; Nagaosa, M.; Hayashi, T. Chem. Commun. 2009,
€
5713–5715. (j) Clarke, E. F.; Rafter, E.; Muller-Bunz, H.; Higham,
(8) Using palladium catalysis: Zhang, R.; Xu, Q.; Zhang, X.; Zhang,
T.; Shi, M. Tetrahedron: Asymmetry 2010, 21, 1928–1935.
L. J.; Gilheany, D. G. J. Organomet. Chem. 2011, 696, 3608–3615.
r
10.1021/ol300845q
Published on Web 04/27/2012
2012 American Chemical Society

reactionsthanaldehydes; notonlyare ketoneslessreactive,
they also possess a smaller difference in steric proper-
ties between the two carbonyl flanking substituents, which
renders effective enantiofacial discrimination more diffi-
cult. Although enantioselective rhodium- or copper-cata-
lyzed intermolecular additions of arylboron reagents to
highly activated ketones such as isatins,9aÀc trifluoro-
methyl ketones,9d R-ketoesters,9eÀg and 1,2-diketones9g,h
have been reported, effective corresponding methods for
ketones lacking strong electron-withdrawing groups have
yet to be devised.10,11
One method to compensate for the lower reactivity of
unactivated ketones is to tether the ketone to the arylboron
compound, which would result in highly valuable cyclic
tertiary-alcohol-containing products.12 Catalytic enantio-
selective cyclizations of arylboron compounds onto ke-
tones have been described by Lin and Lu using a PdÀ
bisphosphine complex13 and by Kanai, Shibasaki, and
co-workers using a chiral CuÀbisphosphine complex.14
Very recently, the Sarpong group reported the enantiose-
lective synthesis of indanols using rhodiumÀbisphosphine-
catalyzed intramolecular hydroarylations of ketones.15
It should also be mentioned that Yin, Kanai, and Shibasaki
recently reported the intramolecular palladium-catalyzed
enantioselective hydroarylation of R-ketoamides using aryl
triflates.16
cyclizations to form six-membered rings were significantly
less selective (46À69% ee).13a,14,15a,16 Second, in the work
of Lu13a and Sarpong,15a only examples containing rela-
tively unhindered ketones were described; no examples
containing sterically hindering substituents such as ortho-
substituted aromatics or branched alkyl groups were re-
ported. While the work of Kanai and Shibasaki included
examples of sterically hindering ortho-substituted aryl
groups on the ketone, the cyclizations are restricted to
the use of highly activated R-ketoamides.14,16 Therefore,
there remains a clear need to address gaps in current
methods to enable access to a greater diversity of products,
which would further increase the value of metal-catalyzed
intramolecular ketone hydroarylation in synthesis.
We therefore recently initiated a program with these con-
siderations in mind, and herein we describe enantioselective
rhodium-catalyzed cyclizations of arylboronic esters and acids
onto ketones that result in diverse aza-, oxa-, and carbocycles
in good yields and high enantioselectivities. The reactions
proceed under mild conditions using chiral sulfinamideÀ
alkene, TADDOL-derived phosphoramidite, or diene ligands.
Thisstudy began withevaluation of chiralligands for the
enantioselective cyclization of substrate 1a containing an
arylpinacolboronic ester tethered to a methyl ketone via a
nitrogen linkage (Table 1). Reactions were performed
Although these methods successfully demonstrate the
concept of enantioselectivemetal-catalyzed intramolecular
ketone hydroarylation, challenges remain. First, in all of
these examples, only products containing five-membered
rings were prepared with high enantioselectivities;
Table 1. Evaluation of Chiral Ligands for Cyclization of 1a
(9) (a) Shintani, R.; Inoue, M.; Hayashi, T. Angew. Chem., Int. Ed.
2006, 45, 3353–3356. (b) Toullec, P. Y.; Jagt, R. B. C.; de Vries, J. G.;
Feringa, B. L.; Minnaard, A. J. Org. Lett. 2006, 8, 2715–2718. (c)
Shintani, R.; Takatsu, K.; Hayashi, T. Chem. Commun. 2010, 46,
6822–6824. (d) Martina, S. L. X.; Jagt, R. B. C.; de Vries, J. G.; Feringa,
B. L.; Minnaard, A. J. Chem. Commun. 2006, 4093–4095. (e) Duan,
H. F.; Xie, J. H.; Qiao, X. C.; Wang, L. X.; Zhou, Q. L. Angew. Chem.,
Int. Ed. 2008, 47, 4351–4353. (f) Cai, F.; Pu, X.; Qi, X.; Lynch, V.;
Radha, A.; Ready, J. M. J. Am. Chem. Soc. 2011, 133, 18066–18069. (g)
Zhu, T.-S.; Jin, S.-S.; Xu, M.-H. Angew. Chem., Int. Ed. 2012, 51, 780–
783. (h) Feng, X.; Nie, Y.; Yang, J.; Du, H. Org. Lett. 2012, 14, 624–627.
(10) Recently, the efficient but modestly enantioselective rhodium-
catalyzed addition of arylboronic acids to simple unactivated ketones
was reported: Korenaga, T.; Ko, A.; Uotani, K.; Tanaka, Y.; Sakai, T.
Angew. Chem., Int. Ed. 2011, 50, 10703–10707.
(11) For catalytic asymmetric arylations of unactivated ketones with
arylzinc species produced from the transmetalation of arylboron com-
ꢀ
pounds with diethylzinc, see: (a) Prieto, O.; Ramon, D. J.; Yus, M.
Tetrahedron: Asymmetry 2003, 14, 1955–1957. (b) Forrat, V. J.; Prieto,
O.; Ramon, D. J.; Yus, M. Chem.;Eur. J. 2006, 12, 4431–4445. (c)
Hatano, M.; Gouzu, R.; Mizuno, T.; Abe, H.; Yamada, T.; Ishihara, K.
Catal. Sci. Technol. 2011, 1, 1149–1158.
(12) For related catalytic enantioselective cyclizations of alkenylrho-
dium species onto aldehydes or ketones, see: (a) Shintani, R.; Okamoto,
K.; Otomaru, Y.; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127,
54–55. (b) Shintani, R.; Okamoto, K.; Hayashi, T. Chem. Lett. 2005, 34,
1294–1295.
(13) (a) Liu, G. X.; Lu, X. Y. J. Am. Chem. Soc. 2006, 128, 16504–
16505. (b) Liu, G. X.; Lu, X. Y. Tetrahedron 2008, 64, 7324–7330.
(14) Tomita, D.; Yamatsugu, K.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2009, 131, 6946–6948.
entry
ligand
conversion (%)a
ee (%)b
1c
2c
3
L1
L2
L3
L4
L5
L6
>95
>95
>95
>95
89
À10
0
À8
À34
À66
84
4
5
6
>95
(15) (a) Sarpong, R.; Gallego, G. L. Chem. Sci. 2012, 3, 1338–1342.
For application of a diastereoselective rhodium-catalyzed intramolecu-
lar hydroarylation of a ketone in total synthesis, see: (b) Larson, K. K.;
Sarpong, R. J. Am. Chem. Soc. 2009, 131, 13244–13245.
(16) Yin, L.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2011,
50, 7620–7623.
a Determined by 1H NMR analysis of the unpurified reaction
mixtures. b Determined by chiral HPLC analysis. c Using 5 mol % of
[Rh(C2H4)2Cl]2, 12 mol % of ligand, and 0.6 equiv of KOH. PMP =
para-methoxyphenyl.
Org. Lett., Vol. 14, No. 10, 2012
2549

using [Rh(C2H4)2Cl]2 (2.5 or 5 mol %) as the precatalyst
along with the chiral ligand (6 or 12 mol %, respectively) in
9:1 THF/H2O at 80 °C for 18 h in the presence of KOH.
While bisphosphines such as BINAP or SEGPHOS led to
efficient cyclizations (>95% conversion), enantioselectiv-
ities were low or non-existent (entries 1 and 2). Chiral
dienes, which have provided excellent results in various
enantioselective rhodium-catalyzed reactions,17 were in-
vestigated next. Unfortunately, R-phellandrene-derived
ligands L318 and L419 provided the product in low en-
antioselectivities (entries 3 and 4). Improved results were
observed using TADDOL-derived phosphoramidite L5,20
with ent-2a2122b being obtained in 89% conversion and
66% ee (entry 5). Chiral sulfinylÀalkenes have recently
emerged as a promisingclass ofligands for enantioselective
rhodium-catalyzed additions of arylboron reagents.9g,h,22
However, applications to intramolecular reactions have
not yet been described, and we were therefore delighted to
discover that sulfinamideÀalkene L622b,23 provided the
best results among all chiral ligands tested, delivering 2a
in >95% conversion and 84% ee (entry 6).
Figure 1 presents the scope of this process using ligand
L6. For substrate 1a, a further increase in enantioselec-
tivity was obtained by performing the cyclization at 50 °C
in 30:1 THF/H2O with a slight increase in rhodium loading
(6 mol %) in the presence of K3PO4 (0.5 equiv) as the base,
which provided 2a in 82% isolated yield and 89% ee.
Under these conditions, a range of other substrates
1bÀ1i24 underwent cyclization to give tetrahydroisoquino-
lin-4-ols 2bÀ2i in good to excellent yields and generally
high enantioselectivities (80À92% ee). In addition to
methyl ketones (products 2a, 2h, and 2i) and unhindered
aryl ketones (products 2c and 2f), the process was tolerant
of a sterically demanding tert-butyl ketone (product 2b)
and ortho-substituted aryl ketones (products 2d, 2e, and
2g). Substrate 1h containing a p-nitrile-substituted aryl-
boronic ester also underwent smooth cyclization, and
replacement of the nitrogen substituent from p-methoxy-
phenyl to p-chlorophenyl was also tolerated (product 2i).
Figure 1. Catalytic enantioselective synthesis of 1,2,3,4-tetrahy-
droisoquinolin-4-ols. Cited yields are of isolated material. En-
antiomeric excesses were determined by chiral HPLC analysis.
PMP = para-methoxyphenyl. a Reaction time of 6 h.
Scheme 1 illustrates an empirical stereochemical model
that might rationalize the sense of enantioinduction ob-
served in the reactions in Figure 1.21 First, by comparison
with a reported X-ray structure of a chiral sulfinami-
deÀalkeneÀrhodium complex, it can be predicted that L6
will bind to rhodium through the sulfur lone pair and the re
face of the vinyl group. Second, transmetalation of the
arylboronic ester in the substrate to rhodium is likely to
position the aryl group trans to the vinyl group, which has
the higher trans effect of the two ligand donor sites.25 Third,
(17) For reviews of chiral diene ligands, see: (a) Feng, C.-G.; Xu,
M.-H.; Lin, G.-Q. Synlett 2011, 1345–1356. (b) Shintani, R.; Hayashi, T.
Aldrichimica Acta 2009, 42, 31–38. (c) Johnson, J. B.; Rovis, T. Angew.
Chem., Int. Ed. 2008, 47, 840–871. (d) Defieber, C.; Grutzmacher, H.;
Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 4482–4502.
(18) Okamoto, K.; Hayashi, T.; Rawal, V. H. Chem. Commun. 2009,
4815–4817.
Scheme 1. Possible Stereochemical Model for the Formation
of 2
(19) Pattison, G.; Piraux, G.; Lam, H. W. J. Am. Chem. Soc. 2010,
132, 14373–14375.
(20) For a review of TADDOL-derived phosphoramidites in asym-
metric catalysis, see: Lam, H. W. Synthesis 2011, 2011–2043.
(21) The absolute configurations of the products obtained in Tables 1 and
Figure 1 were assigned by analogy with that of 2d, which was determined by
X-ray crystallography. See Supporting Information for details.
(22) (a) Thaler, T.; Guo, L.-N.; Steib, A. K.; Raducan, M.;
Karaghiosoff, K.; Mayer, P.; Knochel, P. Org. Lett. 2011, 13, 3182–
3185. (b) Feng, X.; Wang, Y.; Wei, B.; Yang, J.; Du, H. Org. Lett. 2011,
13, 3300–3303. (c) Qi, W.-Y.; Zhu, T.-S.; Xu, M.-H. Org. Lett. 2011, 13,
3410–3413. (d) Jin, S.-S.; Wang, H.; Xu, M.-H. Chem. Commun. 2011,
7230–7232. (e) Chen, G.; Gui, J.; Li, L.; Liao, J. Angew. Chem., Int. Ed.
2011, 50, 7681–7685. (f) Xue, F.; Li, X.; Wan, B. J. Org. Chem. 2011, 76,
7256–7262.
(23) Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883–
8904.
(24) See Supporting Information for the structures of 1bÀ1i.
2550
Org. Lett., Vol. 14, No. 10, 2012

arylrhodation of the ketone should proceed via conforma-
tions where the arylÀrhodium bond is aligned with the
carbonyl group. Two conformations fulfilling these condi-
tions are depicted in Scheme 1. In conformation A, the tether
connecting the aryl group to the ketone suffers an unfavor-
able steric interaction with the sulfinyl tert-butyl group.
However, in conformation B, the tether lies on the opposite
side of the tert-butyl group with respect to the Rh(I) square
plane, and reaction through this conformation explains the
observed stereochemical outcome.
Although the cyclization of substrate 1b containing
a tert-butyl ketone produced 2b in 80% ee under standard
conditions (Figure 1), use of TADDOL-derived phos-
phoramidite L5 in place of ligand L6 under slightly
modified conditions (KOH instead of K3PO4 and a reac-
tion temperature of 80 °C) led to a marked improvement in
enantioselectivity, giving ent-2bin 97% ee (eq 1). However,
the superior enantioselectivity afforded by L5 compared
with L6 in the cyclization of 1b was not replicated in the
other examples in Figure 1, and L6 remains the best ligand
overall for this substrate class.
In conclusion, highly enantioselective rhodium-catalyzed
cyclizations of arylboron compounds onto ketones have
been developed. The process allows the synthesis of
various five-, six-, and seven-membered aza-, oxa-, and
carbocycles and illustrates the utility of sulfinamideÀ
alkene, TADDOL-derived phosphoramidites, and dienes
as chiral ligands for rhodium-catalyzed intramolecular
additions of arylboron compounds.
The process is not limited to the production of six-
membered azacycles; cyclization of substrate 3 using phos-
phoramidite L5 provided seven-membered dihydro-
dibenzo[b,e]azepin-11-ol 4 in 84% yield and 97% ee
(eq 2).26 Oxacycle synthesis is also possible, as demon-
strated by the cyclization of boronic acid 5 containing a
highly sterically congested tert-butyl ketone. Using L6,
dihydrobenzofuranol 6 was obtained in a modest 66% ee,
but a new isopropenyl-substituted sulfinamide ligand L7
gave 6 in 94% yield and 97% ee (eq 3).27 Finally, the
process is applicable to the synthesis of carbocycles.
Using a new chiral diene L8, 1,3-diketone 7 underwent
an enantioselective desymmetrization to give tricycle 8
in 94% yield and 84% ee (eq 4).28
Acknowledgment. This work was supported by the
University of Edinburgh, AstraZeneca, Pfizer, and the
EPSRC (studentship to D.W.L. and Leadership Fellow-
ship to H.W.L.). Syngenta and AllyChem are gratefully
acknowledged for donations of tert-butane sulfinamide and
B2(pin)2. Samantha Brogan, Iain D. Roy, and Alan R.
Burns at the University of Edinburgh are thanked for
assistance in the preparation of chiral ligands. Gary S.
Nichol at the University of Edinburgh is thanked for
X-ray crystallography. We thank the EPSRC National
Mass Spectrometry Service Centre at the University of
Wales, Swansea, for high-resolution mass spectra.
(25) For reviews of the trans effect, see: (a) Appleton, T. G.; Clark,
H. C.; Manzer, L. E. Coord. Chem. Rev. 1973, 10, 335–422. (b) Hartley,
F. R. Chem. Soc. Rev. 1973, 2, 163–179. (c) Yatsimirskii, K. B. Pure
Appl. Chem. 1974, 38, 341–61.
(26) The absolute configuration of 4 was determined by X-ray
crystallography. See Supporting Information for details.
(27) It should be noted that L7 was inferior to L6 for substrates
1aÀ1j. For example, cyclization of 1a under the standard conditions
employed in Figure 1 but using L7 in place of L6 gave 2a in >95%
conversion but in 56% ee.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(28) Cyclization of 7 with L6 gave 8 with >95% conversion but in
<50% ee under a range of conditions.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
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