RH-catalyzed animation of ethereal Cα-H bonds: A versatile strategy for the synthesis of complex amines

Article abstract of DOI:10.1002/anie.200460791

Intramolecular C-H insertion with sulfamates catalyzed by rhodium complexes offers an effective method for the preparation of N,O-acetals, which function as iminium ion precursors and undergo smooth diastereoselective coupling with nucleophiles under Lewi

Full text of DOI:10.1002/anie.200460791

Angewandte
Chemie
N,O-Acetals
a
À
H
Rh-Catalyzed Amination of Ethereal C
Bonds: AVersatile Strategy for the Synthesis of
Complex Amines**
Kristin Williams Fiori, James J. Fleming, and
Justin Du Bois*
The recent advancement of highly selective catalytic methods
À
for the amination of C H bonds has inspired novel
approaches to complex natural products.[1] Our efforts to
expand this chemistry further have led to the identification of
a distinct class of 1,2,3-oxathiazinane-2,2-dioxide heterocycles
2, made accessible through sulfamate ester 1 insertion into
a
[2,3]
À
ethereal C H centers (Scheme 1).
Herein, we demon-
Scheme 1. Oxathiazinane N,O-acetals as iminium ion equivalents.
strate a simple and effective method, which capitalizes on
À
catalyst-controlled regioselective C H oxidation, for assem-
bling these unique N,O-acetals 2. Such compounds display
exceptional versatility as iminium ion equivalents, coupling
smoothly and with high diasteroinduction to allyl silanes, enol
ethers, silyl ketene acetals, and, as reported previously,
alkynyl zinc reagents.[2] From these studies has evolved a
broadly predictive stereochemical model for nucleophilic
addition reactions with 2. In all, the stereoselective assembly
of functionalized oxathiazinanes through this efficient two-
À
step sequence opens untapped possibilities for C H amina-
tion in synthesis.[4]
Metal–carbene and metal–nitrene oxidants display a high
a
[5]
À
proclivity for insertion into ethereal C H bonds. In
principle, this bias can be exploited to direct site selectivity
in amination reactions of substrates that possess multiple
À
reactive C H centers. Such conjecture is readily tested with
sulfamates 4–7 (Scheme 2). Each of these compounds can
[*] K. Williams Fiori, J. J. Fleming, Prof. Dr. J. Du Bois
Department ofChemistry
Stanford University
Stanford, CA 94305-5080 (USA)
Fax: (+1)650-725-0259
E-mail: jdubois@stanford.edu
[**] We thank the National Institutes ofHealth (NINDS, R01
NS045684), Abbott Laboratories, Amgen, Boehringer Ingelheim,
Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Merck, Pfizer, and
Roche of r support ofour program. K.W.F. is the recipient ofa
National Science Foundation Predoctoral Fellowship. J.J.F. is
grateful to Amgen for a Graduate Fellowship Award.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200460791
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proceeds in high yield and in almost all cases with
excellent diastereocontrol (Table 1).[10] These data
constitute the first report of allyl additions to such
starting materials.
The uniqueness and utility of the allylated
oxathiazinane products (Table 1) merits discus-
sion. Preparation of these compounds through the
direct insertion of an appropriately substituted
sulfamate is limited by aziridine formation and
poor product yields [Eq. (1)]. As such, our two-
a
À
step protocol involving ethereal C H amination
makes available functionalized oxathiazinanes that
are otherwise difficult to access. Further manipu-
lation of these structures is facilitated through
nucleophilic ring opening of the oxathiazinane
core and/or alkene functionalization.[11,12] Such
compounds should thus find service for the assem-
bly of stereochemically complex amines.
Table 1: Coupling ofan allyl silane with heterocyclic N,O-acetals. [a]
À
Scheme 2. Catalyst-controlled regioselectivity in C H amination reactions.
Entry Substrate
1
Major product
d.r.[b] Yield [%][c]
20:1 71[d]
furnish two isomeric oxathiazinane products, as well as the
smaller 5-membered ring sulfamidates. Under [Rh2(OAc)4]
catalysis, sulfamates 4 and 5 show only a slight preference for
a
À
20:1 75[d,e]
10:1 60
insertion into a C H bond of the ether. These data indicate
À
that the relative rates of ethereal, benzylic, and tertiary C H
2
3
20:1 60[d,f]
amination are in fact comparable. Nonetheless, the regiose-
lectivity is improved substantially when [Rh2(O2CCPh3)4] is
used in place of the tetraacetate complex.[6,7] As a general
rule, we have found that the bulky Rh–triphenylacetate
20:1 78[d]
À
catalyst disfavors insertion into sterically crowded C H bonds
and is particularly disinclined towards reaction at benzylic
sites. This latter conclusion is nicely illustrated with sulfa-
mates 4 and 6.[8] When more complex substrates, such as 7, are
employed, the choice of [Rh2(O2CCPh3)4] also proves opti-
4
5
20:1 72
1.5:1 81
À
mal, and formation of the undesired C5 H-insertion product
is avoided. In contrast, the reaction of 7 with [Rh2(OAc)4] is
complicated by sulfamidate production. Collectively, these
findings offer compelling support for a Rh-bound nitrene-
type oxidant and provide an attractive strategy for the
regioselective assembly of oxathiazinane N,O-acetals.
6
7
20:1 89
2.5:1 82
Access to structurally complex N,O-acetals has furthered
our efforts to develop these compounds as iminium ion
precursors.[9] Initially, this work was hampered by the
instability of certain N,O-acetal derivatives towards silica
gel, which often complicated their purification. The efficiency
and high regioselectivity observed in the amination reaction
have made it possible, however, to employ N,O-acetal
products without recourse to chromatography. Following
this new protocol, the reaction mixture is filtered after the
oxidation to remove MgO, and the unpurified material is
treated with BF3·OEt2 and allyltrimethylsilane. The coupling
[a] Sulfamate oxidation: [Rh2(OAc)4] (2 mol%), PhI(OAc)2 (1.1 equiv),
MgO (2.3 equiv); coupling reaction: Me3SiCH2CH CH2 (4 equiv),
=
BF3·OEt2 (1.5 equiv); BF3·OEt2 was added dropwise over 75 min to a
solution ofthe allylsilane and the oxathiazinane; see Supporting
Information for details. [b] Diastereomeric ratios were determined by
1H NMR spectroscopy. [c] Combined yield ofthe two diastereomers over
two steps. [d] [Rh2(O2CCPh3)4] was employed in place of[Rh 2(OAc)4].
[e] Bn=benzyl. [f] NHP =NHCO2CH2CCl3.
=
of Me3SiCH2CH CH2 to a range of substituted heterocycles
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Conversely, the anti-configured sulfamates (Table 1, entries 5,
7) can not adopt a conformation that satisfies both models
simultaneously (Scheme 5). As a result, diastereoinduction is
greatly diminished in the allylsilane coupling reaction.
Although these TS designs are speculative, their predictive
power should prove beneficial for synthesis development.
The addition of allylsilanes to oxathiazinane N,O-acetals 2
has proven highly diastereoselective and has enabled the
refinement of a predictive transition-state model for this
process. Our original investigations demonstrated that
alkynyl zinc reagents couple to 2 with a strong bias for the
formation of the 4,5-syn product 10 (Scheme 3).[2] To ration-
Scheme 4. Highly selective addition to 5,6-syn-substituted iminium
ions.
Scheme 5. Selectivity erodes with 5,6-anti-configured substrates.
An interest in examining further the validity of the
iminium ion stereochemical model combined with the suc-
cessful addition of allyltrimethylsilane to N,O-acetals 2
prompted investigations with alternative nucleophiles
(Scheme 6, Table 2). Reactions of 2 with silyl enol ethers
Scheme 3. Stereochemical models for iminium ion additions.
alize these data, the work of Stevens was considered.[13] In this
context, the expected result of axial attack by the zinc reagent
on the twist-chair form of iminium ion 8 was consistent with
the observed stereochemical outcome. This proposal also
accounts for the anti selectivity observed in allylsilane
reactions with C6-branched N,O-acetals, as highlighted in
entry 1 of Table 1. For C5-substituted oxathiazinanes
(Table 1, entry 2), however, the analysis becomes more
complex. Iminium intermediates generated from such starting
materials can adopt either conformation 8 or 9 with minimal
energetic cost, as 1,3-trans diaxial interactions are virtually
absent in 9. Observed formation of the 4,5-anti oxathiazinanes
in entry 2 is consistent with allylsilane coupling along a
pathway in which the substituent at C5 is aligned axially. Such
a model parallels that of Felkin, Anh, and Eisenstein for
nucleophilic additions to carbonyl groups.[14,15] Accordingly,
the transition state (TS) leading from 9 minimizes steric and
torsional strain in the developing product and, in certain cases
(e.g. R = NHCO2CH2CCl3, OH), profits from stereoelec-
tronic stabilization.[16]
Scheme 6. Coupling with a silyl ketene O,S-acetal under catalytic con-
ditions.
and ketene acetals would furnish Mannich-type products
conveniently disposed for an assortment of subsequent trans-
formations.[17] These reagents, however, were unstable to
stoichiometric amounts of BF3·OEt2 at ambient temperature,
conditions utilized previously for the allylsilane additions. Not
surprisingly, initial test reactions to condense 12 with 13
afforded oxathiazinane 14 in poor yields (Scheme 6). Guided
by notable reports of Mannich additions catalyzed by metal
triflates, we identified Sc(OTf)3 as an exceptionally effective
agent.[18,19] An optimized protocol thus employs Sc(OTf)3
(10 mol%) in CH3CN to promote efficient and diastereose-
lective coupling of silyl enol ethers and ketene acetals with
structurally disparate N,O-acetals (Table 2).[10,20] The proce-
dure is straightforward and does not require purification of
the intermediate oxathiazinane. Importantly, the sense and
degree of induction recorded for these addition reactions is
5,6-Disubstituted
oxathiazinane
acetals
(Table 1,
entries 3–7) were used to test further the proposed TS
model. In these examples, the configuration of the vicinal
C5,C6 centers can reinforce or oppose the Felkin–Anh
preferred arrangement. Sulfamate esters with a 5,6-syn
substitution pattern (Table 1, entries 3, 4, 6) are in consonance
with both the Stevens and Felkin–Anh constructs, and thus
the allylsilane adds with excellent selectivity (Scheme 4).
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Table 2: Sc(OTf)3-catalyzed Mannich reactions ofN,O-acetals. [a]
[1] a) P. M. Wehn, J. Du Bois, J. Am. Chem. Soc. 2002, 124, 12950;
b) B. M. Trost, J. L. Gunzner, O. Dirat, Y. H. Rhee, J. Am. Chem.
Soc. 2002, 124, 10396; c) H. Huang, J. S. Panek, Org. Lett. 2003,
5, 1991; d) K. A. Parker, W. Chang, Org. Lett. 2003, 5, 3 891; e) A.
Hinman, J. Du Bois, J. Am. Chem. Soc. 2003, 125, 11510.
[2] J. J. Fleming, K. Williams Fiori, J. Du Bois, J. Am. Chem. Soc.
2003, 125, 2028.
[3] Compounds 2 and 3 are known generally as 1,2,3-oxathiazinane-
2,2-dioxides or as 2,2-dioxotetrahydro-1,2,3-oxathiazines. We
refer to such structures as oxathiazinanes or oxathiazinane N,O-
acetals for convenience.
Entry Nucleophile
1
Major product
d.r.[b] Yield [%][c]
20:1 80
À
[4] For recent reviews on C H amination, see: a) P. Dauban, R. H.
2
3
4
20:1 68[d]
20:1 60[d]
20:1 65
Dodd, Synlett 2003, 1571; b) P. Müller, C. Fruit, Chem. Rev. 2003,
103, 2905.
[5] a) P. Wang, J. Adams, J. Am. Chem. Soc. 1994, 116, 3296; b) G. A.
Sulikowski, S. Lee, Tetrahedron Lett. 1999, 40, 8035.
[6] For the original description of the use of [Rh2(OCCPh3)4], see:
S.-i. Hashimoto, N. Watanabe, S. Ikegami, Tetrahedron Lett.
1992, 33, 2709.
[7] For excellent discussions on the influence of the metal catalyst
À
on C H insertion reactions of carbenes, see: a) A. Padwa, D. J.
Austin, Angew. Chem. 1994, 106, 1881; Angew. Chem. Int. Ed.
Engl. 1994, 33, 1797; b) M. P. Doyle, T. Ren, Prog. Inorg. Chem.
2001, 49, 113; c) D. F. Taber, P. V. Joshi, J. Org. Chem. 2004, 69,
4276.
5
6
2.5:1 76
20:1 72[d]
À
[8] Benzylic C H insertion in such substrates is highly diastereose-
lective (ꢀ 10:1) under [Rh2(OAc)4] catalysis. Interestingly, this
selectivity is diminished in reactions conducted with
[Rh2(O2CCPh3)4]. For a detailed account of amination reactions
with chiral sulfamates, see: P. M. Wehn, J. Lee, J. Du Bois, Org.
Lett. 2003, 5, 4823.
[a] Sulfamate oxidation: [Rh2(OAc)4] (2 mol%), PhI(OAc)2 (1.1 equiv),
MgO (2.3 equiv); coupling reaction: nucleophile (4 equiv), Sc(OTf)3
(0.1 equiv); see Supporting Information for details. [b] Diastereomeric
ratios determined by H NMR spectroscopy. [c] Combined yield ofthe
two diastereomers over two steps. [d] [Rh2(O2CCPh3)4] was employed in
[9] For reviews on addition reactions to iminium ions, see: a) S. M.
Weinreb, Top. Curr. Chem. 1997, 190, 131; b) D. Enders, U.
Reinhold, Tetrahedron: Asymmetry 1997, 8, 1895; c) R. Bloch,
Chem. Rev. 1998, 98, 1407.
1
[10] The stereochemistry of the product was determined by 1H NMR
spectroscopy (a combination of coupling-constant and NOE
data); see the Supporting Information for details.
place of[Rh 2(OAc)4]. Tf=trifluoromethanesulfonyl.
[11] C. G. Espino, P. M. Wehn, J. Chow, J. Du Bois, J. Am. Chem. Soc.
2001, 123, 6935.
[12] R. E. Melꢀndez, W. D. Lubell, Tetrahedron 2003, 59, 2581.
[13] R. V. Stevens, Acc. Chem. Res. 1984, 17, 289.
[14] a) N. T. Anh, O. Eisenstein, Nouv. J. Chim. 1977, 1, 61; b) N. T.
Anh, Top. Curr. Chem. 1980, 88, 145.
entirely consistent with the Stevens/Felkin–Anh TS analysis
outlined above.
À
Methods for the oxidation of C H bonds are finding ever-
increasing application to problems in synthesis. The continued
evolution of such work is contingent upon the ability to
À
[15] A. Mengel, O. Reiser, Chem. Rev. 1999, 99, 1191.
[16] Addition reactions to oxocarbenium ions derived from 1,3-
dioxanes may also conform to this model; see: a) S. Uehira, Z.
Han, H. Shinokubo, K. Oshima, Org. Lett. 1999, 1, 1383; b) N. A.
Powell, S. D. Rychnovsky, J. Org. Chem. 1999, 64, 2026.
[17] Silyl enol ethers and ketene acetals were prepared following
established protocols; see: a) D. A. Evans, T. Rovis, M. C.
Kozlowski, C. W. Downey, J. S. Tedrow, J. Am. Chem. Soc.
2000, 122, 9134; b) A. Fettes, E. M. Carreira, J. Org. Chem. 2003,
68, 9274.
[18] S. Kobayashi, M. Sugiura, H. Kitagawa, W. W.-L. Lam, Chem.
Rev. 2002, 102, 2227, and references therein.
[19] Although Sc(OTf)3 will catalyze the addition of allyltrimethylsi-
lane to N,O-acetals, reaction times are typically quite long (48 h),
and product yields are diminished.
functionalize with high precision specific C H centers in
structurally intricate substrates. We have shown that the
architecture of the Rh catalyst and the reactivity of ethereal
a
À
C
H bonds can be used in combination to direct the
regioselective amination of substituted sulfamate starting
materials. These findings make available a novel class of
heterocyclic N,O-acetals that function proficiently as iminium
ion equivalents. High-yielding nucleophilic addition to these
latent electrophiles is now possible with allylsilanes, silyl enol
ethers, and ketene acetals, as well as alkynyl zinc reagents.[2]
Predictable and, in most cases, marked levels of diastereose-
lectivity underscore the addition process. Thus, with the
ability to assemble an impressive range of chiral oxathiazi-
À
nane derivatives, catalytic C H amination appears as a
forefront strategy for accessing nitrogen-containing products.
[20] Similar reaction conditions were described recently for the
addition of silyl enol ethers to 2-methoxy- and 2-acyloxypiper-
idines; see: O. Okitsu, R. Suzuki, S. Kobayashi, J. Org. Chem.
2001, 66, 809; see also: M. Yamanaka, A. Nishida, M. Nakagawa,
J. Org. Chem. 2003, 68, 3112.
Received: May 26, 2004 [Z460791]
À
Keywords: amination · C H insertion · N,O-acetals · rhodium ·
sulfamates
.
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