Highly functional group compatible Rh-catalyzed addition of arylboroxines to activated N-tert-butanesulfinyl ketimines

Article abstract of DOI:10.1021/ol201438k

The rhodium-catalyzed addition of readily accessible arylboroxines to N-tert-butanesulfinyl ketimines derived from oxetan-3-one, N-Boc-azetidin-3-one, and isatins proceeds in high yields with excellent functional group compatibility. Moreover, high diastereoselectivities are observed for the additions to the N-sulfinyl ketimines derived from isatins.

Full text of DOI:10.1021/ol201438k

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3912–3915
Highly Functional Group Compatible
Rh-Catalyzed Addition of Arylboroxines to
Activated N-tert-Butanesulfinyl Ketimines
Hyung Hoon Jung, Andrew W. Buesking, and Jonathan A. Ellman*
Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107,
United States
jonathan.ellman@yale.edu
Received May 27, 2011
ABSTRACT
The rhodium-catalyzed addition of readily accessible arylboroxines to N-tert-butanesulfinyl ketimines derived from oxetan-3-one, N-Boc-azetidin-
3-one, and isatins proceeds in high yields with excellent functional group compatibility. Moreover, high diastereoselectivities are observed for the
additions to the N-sulfinyl ketimines derived from isatins.
The addition of nucleophiles to N-tert-butanesulfinyl
imines is one of the most extensively used approaches for
the asymmetric synthesis of amines1 and, increasingly, for
the synthesis of achiral amine products such as tertiary
carbinamines.2,3 N-tert-Butanesulfinyl imines show good
stability to hydrolysis and tautomerization and can readily
be prepared in a single step typically in high yields from
carbonyl compounds with diverse steric and electronic
properties. The low molecular weight and ease of removal
of the tert-butanesulfinyl amine protecting group further
contribute to the utility of this chemistry. The synthesis of
amines by the Rh-catalyzed addition of organoboron
reagents to N-tert-butanesulfinyl imines is particularly
useful due to both high functional group compatibility
and the very large number of commercially available, air
stable arylboronic acid reagents. The asymmetric syn-
thesis of a broad range of amines using this approach
has been achieved by the Rh-catalyzed addition of aryl4
and alkenyl5 boron reagents to N-tert-butanesulfinyl aldi-
mines, including aryl and alkyl aldimines,4a,b glyoxylate-
(3) For select applications of racemic sulfinamide in tertiary carbi-
namine synthesis, see: (a) Caldwell, J. J.; Collins, I. Synlett 2006, 2565.
(b) Nitta, A.; Fujii, H.; Sakami, S.; Nishimura, Y.; Ohyama, T.; Satoh,
M.; Nakaki, J.; Satoh, S.; Inada, C.; Kozono, H.; Kumagai, H.;
Shimamura, M.; Fukazawa, T.; Kawai, H. Bioorg. Med. Chem. Lett.
2008, 18, 5435. (c) Shao, P. P.; Ye, F.; Weber, A. E.; Li, X.; Lyons, K. A.;
Parsons, W. H.; Garcia, M. L.; Priest, B. T.; Smith, M. M.; Felix, J. P.;
Williams, B. S.; Kaczorowski, G. J.; McGowan, E. M.; Abbadie, C.;
Martin, W. J.; McMasters, D. R.; Gao, Y.-D. Bioorg. Med. Chem. Lett.
2009, 19, 5334. (d) Sealy, J. M.; Truong, A. P.; Tso, L.; Probst, G. D.;
Aquino, J.; Homa, R. K.; Jagodzinska, B. M.; Dressen, D.; Wonea,
D. W. G.; Brogley, L.; John, V.; Tung, J. S.; Pleiss, M. A.; Tucker, J. A.;
Konradi, A. W.; Dappen, M. S.; Toth, G.; Pan, H.; Ruslim, L.; Miller, J.;
Bova, M. P.; Sinha, S.; Quinn, K. P.; Sauer, J.-M. Bioorg. Med. Chem.
Lett. 2009, 19, 6386. (e) Shiau, T. P.; Houchin, A.; Nair, S.; Xu, P.; Low,
E.; Najafi, R.; Jain, R. Bioorg. Med. Chem. Lett. 2009, 19, 1110. (f) Low,
E.; Nair, S.; Shiau, T.; Belisle, B.; Debabov, D.; Celeri, C.; Zuck, M.;
Najafi, R.; Georgopapadakou, N.; Jain, R. Bioorg. Med. Chem. Lett.
2009, 19, 196.(g) Hamzik, P. J.; Brubaker, J. D. Org. Lett. 2010, 12, 1116.
(1) For reviews on tert-butanesulfinyl imine chemistry, see: (a) Robak,
M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600. (b)
Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna, A. Chem. Soc. Rev. 2009,
38, 1162.
(2) For the straightforward recycling of the tert-butanesulfinyl group
in applications of racemic tert-butanesulfinamide, see: Wakayama, M.;
Ellman, J. A. J. Org. Chem. 2009, 74, 2646.
r
10.1021/ol201438k
Published on Web 07/06/2011
2011 American Chemical Society

Table 1. Optimization of Reaction Conditionsa
entry
[Rh] catalyst
ligand
Ph[B] (equiv)
additive (equiv)
solvent
dioxane
temp (°C)
yieldb (%)
1
2
3
4
5
6
7
8
9
10
[Rh(acac)(coe)2]
[Rh(MeCN)2(cod)]BF4
[RhOH(cod)]2
[RhCl(cod)]2
dppbenz
À
PhB(OH)2 (2.0)
PhB(OH)2 (2.0)
PhBF3K (2.0)
PhB(OH)2 (2.0)
PhB(OH)2 (2.0)
(PhBO)3 (1.5)
(PhBO)3 (1.5)
(PhBO)3 (1.5)
(PhBO)3 (1.5)
(PhBO)3 (1.5)
Et3N (2.0)
70
rt
60
80
rt
rt
rt
rt
rt
rt
37c
10d
0d
Et3N (2.0)
1:2 dioxane/H2O
2:3 DMF/H2O
H2O
dppbenz
SSPhos
SSPhos
SSPhos
À
Et3N (2.0)
NaOH (1.2)
NaOEt (1.2)
NaOEt (1.2)
NaOEt (1.2)
NaOEt (1.2)
NaOEt (1.2)
NaOEt (1.2)
0d
[RhCl(cod)]2
EtOH
29e
70e
71e
84f
0
[RhCl(cod)]2
EtOH
[RhCl(cod)]2
EtOH
[RhCl(cod)]2
À
4:1 dioxane/EtOH
dioxane
[RhCl(cod)]2
À
[RhCl(cod)]2
dppbenz
4:1 dioxane/EtOH
quant
a General reaction conditions: 4 mol % of rhodium and 4 mol % of ligand were used. The reaction time was 18 h. b Yields were determined by
1H NMR of the crude material relative to 1,3,5-trimethoxybenzene as an external standard. c 9% of imine 1 remained. d Imine 1 was completely con-
sumed. e Ethoxy addition byproduct was observed in 20À30% yield. f Ethoxy addition product was observed in <5% yield.
derived aldimines,4c and trifluoroacetaldimines.4d How-
ever, to date the Rh-catalyzed addition of organoboron
reagents to N-sulfinyl ketimines has not been reported.6
We report here the highly functional group compatible
Rh-catalyzed addition of readily available arylboroxines to
activated N-tert-butanesulfinyl ketimines to provide 3-amino-
oxetanes,7,8 3-aminoazetidines,9 and 3-aminooxindole10
tertiary carbinamines. Notably, each of these pharmacophores
has seen recent and extensive use in drug candidates.7,10
We began our investigation by exploring a variety of
reaction conditions for phenyl boron reagent addition to
imine 1, which is activated by both ring strain and the
electronegative ring oxygen (Table 1). Under our pre-
viously developed reaction conditions for additions to
N-sulfinyl aldimines,4a a 37% yield of the desired product
2a was obtained (entry 1). Reported aqueous reaction
conditions4b,5,11 for organoboron reagent addition re-
sulted in complete consumption of imine 1, but little if
any desired product was observed (entries 2À4). However,
when the base and solvent were changed to NaOEt and
EtOH, respectively, a 29% yield of 2a was obtained even at
room temperature (entry 5). Because hydrolysis of 1 was
problematic, in order to exclude water, we next evaluated
arylboroxines, which are conveniently obtained by drying
commercially available arylboronic acids. Indeed, when
phenylboroxine was used, a considerable increase in pro-
ductyield was observed (entry 6). Significantly, the catalyst
in the absence ofthe sulfonatedS-Phosligandhadidentical
reactivity (entry 7), suggesting that this bulky monoden-
tate ligand was not participating in the active catalyst.
When EtOH was used as the sole solvent an ethoxy-
addition byproduct was formed in 20À30% yield (entries
5À7). This side reaction was minimized by using 20%
EtOH in dioxane (entry 8). In contrast, no reaction
occurred in the absence of EtOH (entry 9). Notably, addi-
tion of 1,2-bis(diphenylphosphino)benzene (dppbenz) to
air stable [RhCl(cod)]2 provided the product in quantita-
tive yield (entry 10).
(4) (a) Weix, D. J.; Shi, Y.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127,
1092. (b) Bolshan, Y.; Batey, R. A. Org. Lett. 2005, 7, 1481. (c) Beenen,
M. A.; Weix, D. J.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 6304.
(d) Truong, V. L.; Pfeiffer, J. Y. Tetrahedron Lett. 2009, 50, 1633.
(5) (a) Brak, K.; Ellman, J. A. J. Am. Chem. Soc. 2009, 131, 3850.
(b) Brak, K.; Ellman, J. A. J. Org. Chem. 2010, 75, 3147.
(6) Hayashi and co-workershave recently published on the first example
of Rh-catalyzed additions of organoboron reagents to ketimines with the
enantioselective catalytic addition of sodium tetraarylborates and potassium
aryltrifluoroborates to N-sulfonyl aromatic ketimines using chiral diene
ligands. (a) Shintani, R.; Takeda, M.; Tsuji, T.; Hayashi, T. J. Am. Chem.
Soc. 2010, 132, 13168. (b) Shintani, R.; Takeda, M.; Soh, Y.-T.; Ito, T.;
Hayashi, T. Org. Lett. 2011, 13, 2977.
(7) For recent reviews on the high level of utility of oxetanes in drug
discovery, including 3-amino derivatives, see: (a) Wuitschik, G.; Carreira,
E. M.;Wagner, B.; Fischer, H.; Parrilla, I.; Schuler, F.;Rogers-Evans, M.;
€
Muller, K. J. Med. Chem. 2010, 53, 3227. (b) Burkhard, J. A.; Wuitschik,
€
G.; Rogers-Evans, M.; Muller, K.; Carreira, E. M. Angew. Chem., Int. Ed.
2010, 49, 9052.
(8) For the preparation of 3-aminooxetanes by the addition of a
variety of organolithium reagents to N-sulfinyl imine 1 prepared from
oxetan-3-one, see ref 3g.
To establish the reaction scope, a variety of arylborox-
ines was explored (Scheme 1). Electron-rich arylboroxines
with para-andmeta-substituents were well tolerated (2bÀ2e).
However, the ortho-methylphenylboroxine resulted in a
poor conversion even at 60 °C (2f), presumably due to
ꢀ
(9) (a) Burkhard, J. A.; Guerot, C.; Knust, H.; Rogers-Evans, M.;
Carreira, E. M. Org. Lett. 2010, 12, 1944. (b) Burkhard, J. A.; Wagner,
€
B.; Fischer, H.; Schuler, F.; Muller, K.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2010, 49, 3524.
(10) For examples of drug candidates containing the 3-aminooxo-
indole pharmacophore, see: (a) Decaux, G.; Soupart, A.; Vassart, G.
Lancet 2008, 371, 1624. (b) Shimazaki, T.; Iijima, M.; Chaki, S. Eur. J.
Pharmacol. 2006, 543, 63. (c) Ochi, M.; Kawasaki, K.; Kataoka, H.;
Uchio, Y.; Nishi, H. Biochem. Biophys. Res. Commun. 2001, 283, 1118.
(11) White, J. R.; Price, G. J.; Plucinski, P. K.; Frost, C. G. Tetra-
hedron Lett. 2009, 50, 7365.
Org. Lett., Vol. 13, No. 15, 2011
3913

proceeded in high yield when the reaction temperature was
increased to 60 °C (2k). Additions to ketimine 3 prepared
from N-Boc-azetidin-3-one12 also proceeded cleanly and
in high yields (4aÀ4g). Most importantly, arylboroxines
with labile functional groups that are not compatible with
Grignard and organolithium reagents can be added to
both 1 and 3, including arylboroxines containing hydroxy
(2l), sulfonyl(2m), anilide (2n), ketone (2o), alkylester(4g),
and even activated aryl ester (4f) functionality.
Scheme 1. Oxetane and Azetidine Addition Reaction Scopea,b
Table 2. Optimization of Asymmetric Addition Reactiona
temp
yieldb
(%)
entry
imine
ligand
solvent
(°C)
drc
1
2
5
dppbenz
dioxane
dioxane
dioxane
dioxane
dioxane
CH2Cl2
THF
rt
rt
0
78
10e
97
99
99
99
17
99
99
À
À
2:1d
À
3
7
dppbenz
rt
4
À
À
À
À
À
À
À
rt
92:8
93:7
96:4
96:4
3:2d
97:3
97:3
5
0
6
0
7
0
8
toluene
CH2Cl2
THF
0
9
À20
10
À20
a General reaction conditions: 4 mol % of rhodium catalyst and/or
4 mol % of dppbenz were used. The reaction time was 18 h. b Yields were
determined by 1H NMR of the crude material relative to 1,3,5-
trimethoxybenzene as an external standard. c Diastereomeric ratio was
determined by HPLC unless otherwise specified. d Diastereomeric ratio
was determined by 1H NMR. e 15% of imine 7 remained.
Additions to imines 513 and 7 derived from protected
isatins also provide important classes of amine products
and allow exploration of the potential for asymmetric
induction (Table 2). When the previously optimized reac-
tion conditions from Table 1 were applied to the N-PMB-
protected imine 5 at room temperature, no conversion was
observed (entry 1). However, in the absence of dppbenz
the reaction proceeded readily albeit with poor diastereos-
electivity (entry 2). Next, because Hayashi and co-workers
had observed higher enantioselectivity for copper-
catalyzed asymmetric additions of arylboronates to
N-trityl-protected isatins relative to isatins with other
N-substituents,14 N-trityl-protected imine 7 was evaluated
as a substrate. Interestingly, both excellent conversion
to 8a and high diastereoselectivity was observed for
this substrate (entry 4). In addition, complete conversion
a See Supporting Information for reaction details. bIsolated yields
after chromatography. cReaction was run at 60 °C. No product was
observed at room temperature. dYields in parentheses were obtained
from the reaction in the absence of dppbenz. eReaction was run at 60 °C.
At room temperature, 50% yield of 2k was isolated. f3 equiv of NaOEt
was used. gReaction was run at 80 °C.
unfavorable steric interactions. All halogen atom-substituted
arylboroxines were well tolerated (2gÀ2j), although omis-
sion of the dppbenz ligand was required to minimize
cross-reactivity of the bromo substituent (2j). The addi-
tionofelectron-deficient4-trifluoromethylphenylboroxine
(13) For Grignard reagent addition to isatin imine 5, see: Lesma, G.;
Landoni, N.; Pilati, T.; Sacchetti, A.; Silvani, A. J. Org. Chem. 2009, 74,
4537.
ꢀ
(12) For a recent application of imine 3, see: Guerot, C.; Tchitchanov,
(14) Shintani, R.; Takatsu, K.; Hayashi, T. Chem. Commun. 2010, 46,
B. H.; Knust, H.; Carreira, E. M. Org. Lett. 2011, 13, 780.
6822.
3914
Org. Lett., Vol. 13, No. 15, 2011

10). Finally, solvent effects were evaluated. The use of toluene
as the cosolvent resulted in both poor conversion and
diastereoselectivity, while THF and CH2Cl2 provided high
yields and diastereoselectivity (entries 6À10).
a
c
À
Scheme 2. Reaction Scope of Asymmetric Additions
Under the optimized reaction conditions, different imine
substrates and arylboroxines were evaluated to define the
reaction scope (Scheme 2). Imine substrates that are
electron-neutral (entries 8aÀ8g), -rich (14a), and -deficient
(10a and 12a) all reacted with high yields and diastereos-
electivities. Electron-neutral and -rich arylboroxines also
added readily (e.g., 8a and 8b), while electron-deficient
arylboroxines displayed a modest decrease in yield (8g). As
expected, highly functionalized arylboroxines were well
tolerated under the reaction conditions (8eÀ8g). More-
over, in all cases, the diastereomerically pure major iso-
mer could be isolated by chromatography. Single-crystal
X-ray analysis of 8d established the sense of induction,
which, assuming the illustrated sulfinyl imine geometry
(Scheme 2), is consistent with the open transition state
previously proposed for Rh-catalyzed organoboron re-
agent additions to aldimines.
In summary, we have developed a highly functional
group compatible method for the rhodium-catalyzed ad-
dition of readily accessible arylboroxines to activated
N-tert-butanesulfinyl ketimines derived from oxetan-3-
one, N-Boc-azetidin-3-one, and isatins. The reactions occur
readily and in the case of isatin-derived N-tert-butanesulfinyl
ketimines also proceed with excellent diastereoselectivities.
The methods reported here should provide access to densely
functionalized tertiary carbinamines with considerable phar-
maceutical utility.
Acknowledgment. ThisworkwassupportedbytheNSF
(CHE-1049571). Additionally, we thank Dr. Chris Incar-
vito (Yale) for crystallographic analysis.
a See Supporting Information for reaction details. bIsolated yields of
the major diastereoisomer after chromatography. cDiastereomeric ratio
in parentheses was determined by HPLC from the crude products.
Supporting Information Available. Spectroscopic data
of all new compounds shown in Schemes 1 and 2, detailed
experimental procedures, and HPLC traces and X-ray
data for compound 8d are provided. This material is
available free of charge via the Internet at http://pubs.
acs.org.
continued to be observed at lower temperatures and resulted
in notably higher diastereomeric ratios (entries 5À7, 9, and
Org. Lett., Vol. 13, No. 15, 2011
3915