Enantioselective α-arylation of aldehydes via organo-SOMO catalysis. An ortho-selective arylation reaction based on an open-shell pathway

Article abstract of DOI:10.1021/ja9026902

(Chemical Equation Presented) The intramolecular-arylation of aldehydes has been accomplished using singly occupied molecular orbital (SOMO) catalysis. Selective oxidation of chiral enamines (formed by the condensation of an aldehyde and a secondary amine catalyst) leads to the formation of a 3π-electron radical species. These chiral SOMO-activated radical cations undergo enantioselective reaction with an array of pendent electron-rich aromatics and heterocycles thus efficiently providing cyclic α-aryl aldehyde products (10 examples: ≥70% yield and ≥90% ee). In accordance with our radical mechanism, when there is a choice between arylation at the ortho or para position of anisole substrates, we find that arylation proceeds selectively at the ortho position.

Full text of DOI:10.1021/ja9026902

Published on Web 07/29/2009
Enantioselective r-Arylation of Aldehydes via Organo-SOMO Catalysis. An
Ortho-Selective Arylation Reaction Based on an Open-Shell Pathway
Jay C. Conrad, Jongrock Kong, Brian N. Laforteza, and David W. C. MacMillan*
Merck Center for Catalysis at Princeton UniVersity, Princeton, New Jersey 08544
Received April 3, 2009; Revised Manuscript Received July 15, 2009; E-mail: dmacmill@princeton.edu
Table 1. Development of Organo-SOMO Aldehyde R-Arylation
Driven primarily by advances in transition metal chemistry, the
catalytic union of enolates with aryl halides has become a mainstay
transformation in asymmetric synthesis.1 In particular, the pioneering
work of Buchwald and Hartwig has provided a number of enantiose-
lective enolate R-arylations that allow the catalytic formation of
R-stereogenic carbonyls that are non-enolizable (e.g., quaternary carbon
centers).2-4 Recently, our laboratory introduced a new mode of
organocatalytic activation, termed SOMO catalysis, that is founded
upon the mechanistic hypothesis that a 3π-radical cation species (e.g.,
1) can readily participate in a range of unique asymmetric bond
constructions.5 As part of these studies, we documented the first direct
and enantioselective R-allylic alkylation,5b R-enolation,5c and
R-vinylation5d of aldehydes, three protocols that were not previously
known. Continuing this theme, we recently questioned whether the
R-arylation of aldehydes might also be accomplished via SOMO
catalysis to build and maintain enantioenriched benzylic stereocenters
(eq 1). Herein, we describe the enantioselective intramolecular aldehyde
R-arylation, a transformation that allows the highly efficient production
of enolizable R-formyl-R-aryl substrates without postreaction epimer-
ization or quaternary carbon formation.6 Moreover, this protocol is
highly ortho-selective using 1,3-disubstituted aryl rings, a finding that
is consistent with a radical based (open-shell) arylation mechanism.7
entry
oxidant
catalyst (Ar)
% yielda
% eeb
1
2
3
4
5
CAN
Ph, 2 (30 mol %)
63
60
85
61
70
80
84
92
92
90
97
98
[Fe(phen)3] · (PF6)3
[Fe(phen)3] · (PF6)3
[Fe(phen)3] · (PF6)3
[Fe(phen)3] · (PF6)3
[Fe(phen)3] · (PF6)3
Ph, 2 (30 mol %)
c
Ph, 2 (30 mol %)
Ph, 2 (20 mol %)
1-Naphth, 5 (20 mol %)
1-Naphth, 5 (20 mol %)
c
c
c d
,
6
a Isolated yields of the corresponding alcohol. b Enantiomeric excess
determined by chiral HPLC. c 30 mol % pivalic acid. d 50 mol % H2O.
bicyclic radical cation 3 that upon further oxidation would generate a
dienyl cation 4 (eq 2). At this stage, we presumed that rearomatization
via proton loss would be facile while hydrolysis of the iminium species
would reconstitute the catalyst and deliver the desired formyl R-ary-
lation product. Given the predilection of electron-rich aryl rings to
undergo ortho-selective addition to radical cations,7 we presumed that
high levels of regiochemical control should be possible if a traditional
SOMO catalysis mechanism is operative. Moreover, we presumed that
the activated radical DFT-1 would position the 3π-electron system
away from the bulky tert-butyl group, while the benzyl group on the
imidazolidinone framework effectively shields the Re-face leaving
the Si-face open to enantioselective arylation.
Our intramolecular aldehyde R-arylation was first evaluated using
3-anisole pentanaldehyde, catalyst 2 or 5, and a selection of oxidants
(Table 1). Initial experiments with ceric ammonium nitrate (CAN)
revealed that the proposed transformation was possible; however
reaction efficiency and enantioselectivity levels were found to be
moderate. Not satisfied with the general utility of these reaction
conditions, we sought to find a superior catalyst/oxidant combination.
As revealed in Table 1, use of [Fe(phen)3]·(PF6)3 as a single electron
oxidant allowed for a significant increase in enantiocontrol while
application of a recently designed imidazolidinone catalyst 5 enabled
optimal reaction efficiency and a further increase in stereocontrol (with
20 mol % catalyst). High-throughput experiments using a robotic
platform (see Supporting Information) revealed that tightly controlled
quantities of additives such as pivalic acid and water could also be
employed to boost efficiency (entries 3-6). Given the notable
selectivities achieved with both amines 2 and 5, we selected both
catalysts for further exploration.
As highlighted in Table 2, a wide array of aryl and heteroaryl ring
systems readily participate as SOMOphiles in this intramolecular
R-aldehyde coupling. For example, anisole, naphthylene, indole,
pyrrole, thiophene, and furan ring systems all function well9 in this
new enantioselective ring forming reaction. Moreover, aldehydes that
incorporate nitrogen, oxygen, or carbonyl containing tethers worked
well in this protocol (entries 2, 4, 5, and 10, catalyst 5: 93-96% ee).
Design Plan. In accord with our previous SOMO-catalysis studies,5
we reasoned that exposure of an aryl-tethered aldehyde to amine
catalyst 2 in the presence of a suitable oxidant would render the radical-
cation 1 (DFT-1). Rapid and enantioselective addition of the pendent
aryl ring system to the 3π-electron species would then provide a
9
11640 J. AM. CHEM. SOC. 2009, 131, 11640–11641
10.1021/ja9026902 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Organo-SOMO Intramolecular R-Arylation
We have been able to combine our novel SOMO R-arylation
reaction into a two-step organocatalytic sequence that first involves a
Hantzsch ester hydride (HEH) reduction11 of an anisole tethered R,ꢀ-
unsaturated aldehyde followed by the protocol described herein. As
shown in eq 4, this sequence provides the resulting bicyclic ring system
as a single (anti) diastereomer in 70% yield and 98% ee.
We have also been able to apply this new carbonyl R-arylation
technology toward the total synthesis of (-)-tashiromine.12 As outlined
in eq 5, exposure of the pyrrole amide tethered aldehyde 6 to this new
catalytic procedure provides the desired [6,5]-bicyclic ring system in
72% yield and in 93% ee. The resulting amide was then reduced in
the presence of AlCl3 with LiAlH4 in 83% yield prior to exhaustive
pyrrole hydrogenation using catalytic Rh/Al2O3 to provide (-)-
tashiromine in 62% isolated yield.
Acknowledgment. Financial support was provided by NIHGMS
(R01 GM078201-01-01) and kind gifts from Merck. J.C.C. thanks
NSERC for a postdoctoral fellowship.
Supporting Information Available: Experimental procedures and
spectral data are provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
(1) (a) Muratake, H.; Nakai, H. Tetrahedron Lett. 1999, 40, 2355. (b) Martín,
R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 7236. (c) Vo, G. D.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2008, 47, 2127.
(2) (a) Liao, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 195.
(b) Garc´ıa-Fortanet, J.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
8108.
a Conditions, entries 1-2: [Fe(phen)3]·(PF6)3, NaHCO3, HOPiv, -20 °C
MeCN; entries 3-5: [Fe(phen)3]·(PF6)3, Na2HPO4, -30 °C acetone; entries
6-10: CAN, NaHCO3, NaO2CCF3, -30 °C acetone. b Isolated yields after
NaBH4 reduction. c Determined by chiral HPLC of corresponding alcohols.
(3) This racemization has been exploited for dynamic kinetic resolutions: Xie, J.-H.;
Zhou, Z.-T.; Kong, W.-L.; Zhou, Q.-L. J. Am. Chem. Soc. 2007, 129, 1868.
(4) With quinone Michael acceptors: (a) Alema´n, J.; Cabrera, S.; Maerten, E.;
Overgaard, J.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 5520.
(5) (a) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C.
Science 2007, 316, 582. (b) Jang, H.-Y.; Hong, J.-B.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2007, 129, 7004. (c) Kim, H.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2008, 130, 398. (d) Graham, T. H.; Jones, C. M.; Jui, N. T.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 16494.
(6) Details of this work were described at the ACS Centennial Symposium: MacMillan,
David W. C. Abstracts of Papers, 236th ACS National Meeting, Philadelphia, PA,
United States, August 17-21, 2008 (2008), ORGN-545. CODEN: 69KXQ2 AN
2008:954577 CAPLUS.
(7) For ortho-selective radical additions to anisole, see: Tiecco, M.; Testaferri, L. In
ReactiVe Intermediates, Vol. 3; Abramovitch, R. A., Ed.; Plenum Press:
New York, 1983; p 61.
(8) (a) Nicolaou, K. C.; Reingruber, R.; Sarlah, D.; Bra¨se, S. J. Am. Chem.
Soc. 2009, 131, 2086. (b) A correction for ref 8a was submitted on the same
day as the original version of this manuscript (which also noted the mischarac-
terizations of ref 8a): J. Am. Chem. Soc. 2009, 131, 6640. While the authors of
refs 8a and 8b did not provide experimental verification of the reassigned structures,
our submission did so; see Supporting Information.
(9) It should be noted that Nicolaou and co-workers observed para-selectivity with
highly electron-rich 1,3,4-trisubstituted aryl rings (see ref 8a).
(10) An open-shell, radical pathway is also consistent with the successful addition of
highly electron-deficient styrenes to radical cations such as 1 (see ref 5d).
(11) (a) Ouellet, S. G.; Walji, A. M.; MacMillan, D. W. C. Acc. Chem. Res.
2007, 40, 1327. (b) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 32.
(12) Banwell, M. G.; Beck, D. A. S.; Smith, J. A. Org. Biomol. Chem. 2004, 2,
157.
JA9026902
As is clearly shown in Table 2, the imidazolidinone catalyst 5 is far
superior to amine 2 with respect to enantioselectivity and cyclization
efficiency. It is also important to note that these electron-rich aryl ring
systems are completely tolerant to the mild oxidative conditions
employed in this study. Furthermore, substrates that have the potential
for aromatic substitution at two regiochemical positions (ortho or para)
were in fact highly selective for ortho-functionalization (entries 1-5,
ortho-substitution only).10 Such regioselectivity provides further
evidence that a radical-mediated addition pathway is operative, as
proposed in eq 2. It should be noted that a cationic Friedel-Crafts
mechanism was recently proposed for a similar arylation reaction using
our imidazolidinone catalyst 2,8 a mechanistic interpretation based on
the exclusive observation of para-selective products. However, the
authors have subsequently issued a correction8b that several of their
adducts were in fact formed with ortho-selectivity (Table 2, entries
1 and 3). As such, given (i) our previous mechanistic studies into
SOMO-activation, wherein an open-shell pathway was definitively
shown using a radical-clock probe,5a and (ii) the observation of only
ortho-selective products using 1,3-disubstituted aryl rings, we presume
that a radical cyclization is operative for the substrates described in
this manuscript.9,10
9
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