Enantioselective C-H amination using cationic ruthenium(II)-pybox catalysts

Article abstract of DOI:10.1002/anie.200801445

The whole pybox and dice: Highly enantioselective amination reactions of both allylic and benzylic C-H bonds are catalyzed by cationic ruthenium(II)-pybox complexes (see structure). A novel mode of stereocontrol, which is induced by the versatile pybox ligand, is proposed to account for the excellent enantioselectivity in these reactions. Boc = tert-butoxycarbonyl, pybox = pyridine bisoxazoline. (Chemical Equation Presented)

Full text of DOI:10.1002/anie.200801445

Angewandte
Chemie
DOI: 10.1002/anie.200801445
Asymmetric Catalysis
À
Enantioselective C H Amination Using Cationic Ruthenium(II)–
pybox Catalysts**
Erika Milczek, Nad›ge Boudet, and Simon Blakey*
À
C H bond amination has emerged as a powerful tool for the
synthesis of complex nitrogen-containing molecules. Follow-
ing the early discoveries by Breslow and Gellman,[1] Du Bois
and co-workers revolutionized this area of chemistry by
developing protocols for practical, efficient, and predictable
[2]
À
reactions for oxidative C H amination. Dirhodium(II)
tetracarboxylate catalysts were shown to be particularly
effective. Manganese– and ruthenium–porphyrin com-
plexes,[3] silver complexes,[4] and preoxidized nitrogen sources
have also been developed as catalysts to carry out this
important reaction.[5]
Despite these recent advances, general methods for both
À
enantioselective and intermolecular C H amination remain
elusive. Although chiral dirhodium(II) complexes have been
developed as catalysts for highly enantioselective metal-
locarbene reactions,[6] their application to C H amination
À
Scheme 1. Synthesis of ruthenium(II)–pyboxcomplexes.
chemistry is yet to produce the same spectacular results.[7] To
À
date, the most effective protocol for asymmetric C H
amination requires the combination of enantioenriched
sulfoxamines as chiral auxiliaries and a chiral dirhodium(II)
catalyst.[8] To address the challenge of catalytic asymmetric
À
Based on the study by Fiori and Du Bois, which demonstrates
À
that rhodium-catalyzed C H amination involves formation of
an electrophilic metallonitrene and a build up of positive
charge on the carbon center during the insertion process, we
rationalized that a cationic catalyst would be more reactive
than its neutral analogue.[2e] Halide abstraction from the
C H amination, we chose to study ruthenium(II)–pybox
(pybox = pyridine bisoxazoline) complexes (Scheme 1).
Despite reports that show complex 1 exhibited limited
reactivity and selectivity in C H amination reactions, we
felt that the modular nature of the ligand, and the fact that the
anionic ligands were independent of the chiral pybox ligand,
offered us an opportunity which had not been possible by
using either dirhodium(II)- or porphyrin-based catalyst
systems.
[3f]
À
Table 1: Reaction optimization studies.
Ruthenium(II)–pybox complexes 1–4 were readily pre-
pared by using the method developed by Nishiyama et al.
(Scheme 1).[9] In our initial study, the challenging test
substrate sulfamate ester 5[10] was treated with 1.1 equivalents
of the oxidant bis(acetoxy)iodobenzene and 5 mol% catalyst
Entry
Solvent
Additive[a]
Catalyst
Yield [%][b]
ee [%][b]
1
2
3
4
5
6
7
8
CH2Cl2
C6H6
Et2O
CH2Cl2
C6H6
Et2O
CH2Cl2
C6H6
Et2O
CH2Cl2
C6H6
Et2O
–
–
–
2
2
2
2
2
2
3
3
3
3
3
3
4
4
50
47
33
61
49
42
94
45
40
98
84
58
93
84
24
26
43
53
70
77
69
84
84
61
76
81
80
84
À
2 to give the desired product of C H insertion 6, albeit in
modest yield and enantiomeric excess (Table 1, entries 1–3).
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
[*] E. Milczek, Dr. N. Boudet, Prof. S. Blakey
Department of Chemistry
Emory University
1515 Dickey Drive, Atlanta, GA 30322 (USA)
Fax: ( +1)404-727-7586
E-mail: sblakey@emory.edu
Homepage: http://www.chemistry.emory.edu/faculty/blakey/
9
10[c,d]
11[c,d]
12[c,d]
13[c,d]
14[c,e]
C6H6
C6H6
[**] This work was supported by the ACS PRF (grant no. 47137-G1), the
Emory University Research Council, and the Emory University
College of Arts and Sciences.
[a] 5 mol% additive used; Tf=trifluoromethanesulfonyl. [b] The yields
and ee values were determined by HPLC on a chiral stationary phase.
[c] PhI(O2CtBu)2 was used in place of PhI(OAc)2. [d] Reaction conducted
at 228C. [e] Reaction conducted at 48C.
Supporting information (including experimental details, character-
ization data, and structural elucidation) for this article is available
on the WWW under http://dx.doi.org/10.1002/anie.200801445.
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À
Table 2: Asymmetric amination of benzylic and allylic C H bonds.
parent ruthenium(II)–pybox complex 2 using AgOTf gave
improved yields and selectivities in the solvents studied
(Table 1, entries 4–6). Other silver salts with noncoordinating
counterions (AgBF4, AgSbF6, AgPF6, AgBArF4) all gave
similar results. However, silver salts with coordinating
counterions (AgOAc and AgOCOCF3) were not effective.
The rigid indenyl-pybox ligand provided catalyst 3 which
showed improved conversion (94% yield in CH2Cl2; Table 1,
entry 7) and selectivity (84% ee; Table 1, entries 8 and 9). By
employing a more soluble oxidant (PhI(O2CtBu)2) the
reaction could be conducted at room temperature and the
yields of the amination product improved (Table 1,
entries 10–12). However, despite the lower reaction temper-
ature, a small decrease in enantioselectivity was observed.
The tunability of the [RuX2L(pybox)] catalyst framework is
demonstrated by the effects of replacing the chloride ligands
(3) with bromide (4). This change increased both the turnover
and selectivity, as well as allowing the reaction temperature to
Entry Substrate
Product
Yield ee
[%][a] [%][b]
1[c]
68
71
90
88
2
À
be lowered to 48C, thus producing the desired C H amination
product in good yield (84%) and enantioselectivity (84% ee;
Table 1, entry 14).
3[c]
60
56
88[d]
Several trends were observed in the optimization studies.
Reactions conducted in CH2Cl2 had the highest yields but the
lowest enantioselectivities, while reactions conducted in Et2O
had the best enantioselectivities but the lowest yields. A
control experiment revealed that the RuII complex 7 was a
4[e]
80
À
competent catalyst for the C H amination reaction in CH2Cl2
but was not effective in Et2O [Eq. (1)]. This observation led
5
6
58
60
92
89
7
8
42
14
75
us to speculate that the poor enantioselectivities in CH2Cl2
may arise from a catalytically active ruthenium species that is
released from the chiral pybox ligand. However, attempts to
improve the enantioselectivities in CH2Cl2 by conducting the
reaction in the presence of excess ligand led only to lower
yields. No improvement in the selectivity was observed.
n.d.
[a] Yield of isolated product. [b] The ee values were determined by HPLC
on a chiral stationary phase. [c] Reaction conducted at 48C. [d] The
absolute configuration determined by X-ray crystallography; other
configurations assigned by analogy. [e] After 16 h, additional catalyst
(5 mol%), AgOTf (5 mol%), and PhI(O2CtBu)2 were added. Boc=tert-
butyloxycarbonyl, n.d.=not determined.
À
The optimized reaction conditions allow asymmetric C H
À
amination of substrates with benzylic and allylic C H bonds
(Table 2). Both electron-donating and electron-withdrawing
substituents are tolerated on the aryl ring, and the products
are obtained with good yields and excellent enantioselectiv-
ities (88–92% ee; Table 2, entries 1–5). Notably, the catalyst
À
performs well on the ortho-substitued substrate 8, with the C
reaction of indole 9 (92% ee; Table 2, entry 5) as well as in
the allylic amination of 10 (89% ee; Table 2, entry 6).
The allylic amination reaction proceeds with complete
H insertion reaction proceeding in 71% yield and 88% ee
(Table 2, entry 2). This observation is in stark contrast to the
significant drop in reactivity seen when these substrates are
exposed to porphyrin-based RuII catalysts.[11] Additionally,
excellent enantioselectivity is observed for the insertion
À
selectivity for the C H insertion product. Under our reaction
conditions, we have not observed the competing aziridination
product, which is commonly generated when dirhodium(II)
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tetracarboxylate catalysts are used.[12] The preference for C
H insertion exhibited by the cationic ruthenium(II)–pybox
system is further highlighted by the reaction of cis-olefin 11
[Eq. (2)]. Under the standard reaction conditions, six- and
À
Table 3: Effect of the ancillary ligand on catalyst performance.
Entry
Catalyst
Yield [%][a]
ee [%][a]
1
2
3
4
12
13
84
62
80
84
83
82
À
nine-membered-ring products (resulting from C H insertion
[a] The yields and ee values were determined by HPLC on a chiral
stationary phase.
reactions) are produced, but no aziridination product was
observed. Although this substrate highlights the remarkable
chemoselectivity profile of this catalyst, the cis substituent on
the double bond disrupts the transition state and leads to
significantly lower enantioselectivity (50% ee).
The standard reaction conditions are capable of promot-
À
ing C H insertion reactions to form five-membered rings
(Table 2, entry 7), but they are ineffective for the amination of
straight-chain aliphatic substrates (Table 2, entry 8).
In considering the mechanism of this reaction, we note
that the five-coordinate [RuCl2(indenyl-pybox)] complex,
which lacks the ethylene ligand, leads to a lower yield and
selectivity with the test substrate 5 (32%, 59% ee; compare
with Table 3, entry 5). This observation suggests that the
ethylene group in catalyst 4 might remain bound to the
ruthenium center during the amination reaction, and there-
fore prompted us to further examine the role of this ancillary
ligand.[13]
Figure 1. Stereochemical model for the cationic ruthenium(II)–pybox-
À
catalyzed C H amination reaction.
Unfortunately, our attempts to replace the ethylene ligand
in catalyst 4 with alternative olefins, such as trans-2-butene or
trans-cyclooctene, were not successful, presumably because of
the steric hindrance imparted by both the indenyl-pybox and
bromide ligands.[14] However, we were able to synthesize
complexes 12 and 13 in which the olefin was replaced by
carbon monoxide and triphenylphosphine, respectively
(Table 3). When these new catalysts were tested under the
optimized reaction conditions we observed that the ancillary
ligand had an impact on the catalyst turnover number (TON);
however, the enantioselectivities were identical (within error;
Table 3, entries 1–3). These data indicate that while the
nature of the ancillary ligand is important for accessing the
active catalyst, in all likelihood the ancillary ligand dissociates
Halide abstraction from catalyst 4 provides a vacant coordi-
nation site cis to the pyridine ring of the pybox ligand to
enable metallonitrene formation.[15] Subsequent ethylene
dissociation and bromide isomerization provides a second
vacant coordination site cis to the pyridine ring, and a second
oxidation provides the active RuVI species. In the transition
state, the sulfamate ester wraps around into the vacant
quadrant created by the pybox ligand and the bulky aromatic
group points away from the ligand, thus resulting in one of the
two enantiotopic hydrogen atoms (Ha) pointing directly at the
reactive metallonitrene species. The reaction of this hydrogen
atom gives rise to products with the same absolute config-
À
À
before C H amination takes place and therefore the active
aminating species is identical for all three catalysts.
uration as observed in the C H amination protocol. Also, the
geometry of this transition state is consistent with an HC
Based on these data that indicates the necessity of
removing a halide ion from the RuII complex to achieve
good TON and selectivity as well as the studies of Che and co-
workers that show that the active aminating species in
ruthenium porphyrin complexes are bisimido–ruthenium(VI)
compounds,[3b,g] we propose that a C2-symmetric cationic
bisimido–ruthenium(VI) complex (14) is the active species for
the reaction conditions outlined in this study (Figure 1).
abstraction/radical rebound mechanism, which has been
À
observed for other ruthenium-catalyzed C H amination
processes.[3b]
In conclusion, we have developed an effective protocol for
À
the catalytic asymmetric amination of benzylic and allylic C
H bonds through the rational design of a cationic rutheniu-
m(II)–pybox catalyst. Studies to fully understand the role of
the ancillary ligands and to confirm the nature of the
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Communications
[5] H. Lebel, K. Huard, S. Lectard, J. Am. Chem. Soc. 2005, 127,
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remain a focus of our research.
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[10] At the time of this investigation, the best reported results for the
enantioselective cyclization of this substrate were 84% ee, 48%
yield; see Ref. [3].
[11] J. L. Liang, S. X. Yuan, J. S. Huang, C. M. Che, J. Org. Chem.
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[12] K. Guthikonda, P. M. When, B. J. Caliando, J. Du Bois, Tetrahe-
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[13] For a recent review on the use of olefins as ligands in transition-
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[14] trans-Cyclooctene has been used as a ligand in an analogous but
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1999, 5, 3509.
[15] For a similar model in the context of Ru-catalyzed cyclopropa-
nation, see: H. Nishiyama, Y, Itoh, Y. Sugiwara, H. Matsumoto,
K. Aoki, K. Itoh, Bull. Chem. Soc. Jpn. 1995, 68, 1247.
Received: March 27, 2008
Published online: July 21, 2008
À
Keywords: amination · asymmetric catalysis · C H activation ·
.
ruthenium
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