Diastereoselective Aza-Mislow–Evans Rearrangement of N-Acyl tert-Butanesulfinamides into α-Sulfenyloxy Carboxamides

Article abstract of DOI:10.1002/anie.201809551

A diastereoselective [2,3] rearrangement of O-silyl N-sulfinyl N,O-ketene acetals derived from chiral N-acyl tert-butanesulfinamides was developed, giving α-sulfenyloxy carboxamides with excellent enantioselectivity. Enolization and subsequent silylation of N-acyl tert-butanesulfinamides initiate this aza variant of the Mislow–Evans rearrangement, in which the chirality at the sulfur atom in the rearrangement precursors is faithfully transferred to the α-carbon stereocenter of the products. The Ellman sulfinamide, often used as a chiral ammonia equivalent, can serve in this rearrangement as a chiral precursor for the asymmetric synthesis of α-oxygen-functionalized carboxamides.

Full text of DOI:10.1002/anie.201809551

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Accepted Article
Title: Diastereoselective Aza-Mislow-Evans Rearrangement of N-Acyl-
tert-Butanesulfinamides into α-Sulfenyloxy Carboxamides
Authors: Fan Tang, Yun Yao, Yan-Jun Xu, and Chong-Dao Lu
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10.1002/anie.201809551
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Diastereoselective Aza-Mislow-Evans Rearrangement of N-Acyl-
tert-Butanesulfinamides into α-Sulfenyloxy Carboxamides
Fan Tang,[b], [c] Yun Yao,[a] Yan-Jun Xu,[b] and Chong-Dao Lu* [a], [b]
Abstract: A diastereoselective [2,3]-rearrangement of O-silyl N-
sulfinyl N,O-ketene acetals derived from chiral N-acyl-tert-
butanesulfinamides
was
developed,
giving
α-sulfenyloxyl
carboxamides with excellent enantioselectivities. Enolization and
subsequent silylation of N-acyl-tert-butanesulfinamides initiate the
aza-variant of Mislow-Evans rearrangement, in which the chirality of
the sulfur in the rearrangement precursors is faithfully transferred to
the α-carbon stereocenter of the products. Ellman's sulfinamide,
often used as a chiral ammonia equivalent, can serve in this
rearrangement as a chiral precursor for the asymmetric synthesis of
α-oxygen-functionalized carboxamides.
[2,3]-Sigmatropic rearrangement is
transformation in organic synthesis.
a
fundamental
Mislow-Evans
rearrangement,[1] also known as Mislow−Braverman−Evans
rearrangement,[2] is a reversible [2,3]-sigmatropic rearrangement
involving conversion between an allylic sulfoxide and sulfenate
ester, in which the reaction is generally shifted toward the
sulfoxide. Sulfoxide−sulfenate rearrangement in the presence of
a thiophile leads to SO bond cleavage of the sulfenate ester,
generating allylic alcohols (Scheme 1a). This process has been
used to diastereoselectively construct allylic alcohol subunits in
bioactive complex molecules such as ()-doxycycline.[3] Recent
studies of Mislow–Evans rearrangement have focused on
incorporating
the
rearrangement
into
sequential
transformations,[4] thereby expanding synthetic applications.[5] In
addition, replacing the sulfoxide oxygen with a functionalized
nitrogen atom has expanded the substrate scope to include
allylic sulfimides.[6] However, relatively few sigmatropic
rearrangement reactions involving sulfinamides have been
reported,[7] in contrast to widespread use of rearrangements
involving functionalized allylic sulfoxides.
Scheme 1. [2,3]-Rearrangement of N-Acyl-tert-Butanesulfinamides via O-Silyl
N-Sulfinyl N,O-Ketene Acetal Intermediates.
Here we report an unprecedented [2,3]-rearrangement of N-
acylsulfinamides. We envisioned that enolization and
subsequent silylation of N-acyl sulfinamides[8] would afford O-
silyl N-sulfinyl N,O-ketene acetal intermediates that could
undergo [2,3]-rearrangement and provide α-sulfenyloxy
carboxamides (Scheme 1b). This transformation can be viewed
as an aza-variant of the Mislow-Evans rearrangement, and its
path to ketene acetal formation is reminiscent of the well-known
Ireland-Claisen rearrangement,[9] in which a silyl ketene acetal
derived from an allylic ester undergoes an oxa-variant of the
[a]
[b]
[c]
Dr. Y. Yao, Prof. C.-D. Lu
School of Chemical Science and Technology
Yunnan University
No.2 North Cuihu Road, Kunming 650091, China
E-mail: clu@ms.xjb.ac.cn
F. Tang, Prof. Y.-J. Xu, Prof. C.-D. Lu
Key Laboratory of Plant Resources and Chemistry of Arid Zones
Xinjiang Technical Institute of Physics and Chemistry, Chinese
Academy of Sciences
Cope
[3,3]-rearrangement.
In
the
aza-Mislow-Evans
rearrangement proposed here, the chirality of the sulfur in the
sulfinyl group is transferred to the α-position of the carboxamide
products; subsequent cleavage of the SO bond yields
enantioenriched α-hydroxyl carboxamides (Scheme 1b). In this
way, carboxamides are α-hydroxylated asymmetrically without
the need for oxidant.[10] The chiral sulfinyl group in the
rearrangement precursors serves as a potential hydroxyl group,
and the sulfinyl group can be conveniently introduced into
rearrangement precursors by using chiral sulfinamides as
starting materials. Ellman’s tert-butanesulfinamide,[11] commonly
No. 40-1 South Beijing Road, Urumqi 830011, China
F. Tang
University of Chinese Academy of Sciences
Beijing 100049, China
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201809551
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used as a chiral ammonia equivalent, was chosen for our
experiments because of its low molecular weight and low cost,
and because both enantiomers can easily be obtained on the kg
scale. This facilitates economical installation of an α-sulfenyloxyl
functional group in the R or S configuration.
Table 1. Substrate Scope[a]
Entry
N-Acyl-tert-
butanesulfinamides
R’)
Product
Yield
(%)[b]
Enantiomeric
ratio[c]
(R,
We initially examined the feasibility of the rearrangement
using N-allyl-N-acyl-(RS)-sulfinamide 1a. Deprotonation of 1a
with lithium hexamethyldisilazide (LiHMDS) at 78 oC and
subsequent silylation at 35 oC with chlorotrimethylsilane
(TMSCl) led to the proposed rearrangement (Scheme 2).
Workup with aqueous ammonium chloride afforded the
rearrangement product α-sulfenyloxy carboxamide 2a in 90%
yield with an enantiomeric ratio of 97:3. For reproducible results,
TMSCl had to be added to the reaction at 35 oC, and this
temperature had to be maintained throughout the reaction. In
contrast, when TMSCl was added to the reaction mixture at 78
oC and the reaction mixture was warmed quickly to room
temperature, substantial byproducts sometimes formed. These
byproducts may have arisen through competitive intermolecular
nucleophilic addition of the lithiated enolate intermediate to the
sulfinyl group of another N-acyl-sulfinamide before its
silylation.[12] In the absence of silylation reagent, the reaction
afforded no rearrangement product, even at room temperature.
Replacing LiHMDS with NaHMDS or KHMDS resulted in low
isolated yield and obvious byproduct formation. Swapping the
allyl substitution on the nitrogen atom of 1a to benzyl (Bn) or
para-methoxyphenyl (PMP) did not interfere with intramolecular
rearrangement, affording the corresponding products 2b and 2c
in high yields and excellent enantiomeric ratios. The
rearrangement precursor of N-phenylacetyl-sulfinamide 1d also
led to highly efficient transformation with 74% yield and an
enantiomeric ratio of 99:1. Gram-scale preparation of 2d gave
good yield of 80% while slightly decreasing enantioselectivity
(~97:3 er). The structures of 2a-d were confirmed using single-
crystal x-ray diffraction analysis.[13] The absolute configuration of
2a and 2b was assigned as (2R) based on x-ray
crystallography,[14] and that of 2d was also assigned as (2R)
based on comparison between the optical rotation of the SO
bond cleavage product of 2d and the optical rotation of the
synthetic α-hydroxyl amide sample prepared from (R)-mandelic
acid.
1
1e (4-MeC6H4, PMP)
1f (3-MeC6H4, PMP)
1g (2-MeC6H4, PMP)
1h (4-FC6H4, PMP)
1i (4-ClC6H4, PMP)
1j (4-BrC6H4, PMP)
1k (PMP, PMP)
2e
2f
69
91
77
70
86
81
87
83
89
35
90
95
45
93
96
60
53
97:3
2
98.5:1.5
98.5:1.5
98:2
3
2g
2h
2i
4
5
97:3
6
2j
98:2
7
2k
2l
95:5
8
1l (iPr, PMP)
98:2
9
1m (cyclopropyl, PMP)
1n (tBu, PMP)
2m
2n
2o
2p
2q
2r
98.5:1.5
95:5
10d
11
12
13d
14
15
16e, f
17d, e
1o (Bn, PMP)
99:1
1p (allyl, PMP)
98.5:1.5
98.5:1.5
98.5:1.5
99:1
1q (HC≡C(CH2)3, PMP)
1r (BnO(CH2)3, PMP)
1s (ClCH2(CH2)2, PMP)
2s
2t
1t (MeO2C(CH2)2, PMP)
99:1
1u ((Me)PhNC(O)(CH2)2,
PMP)
2u
98:2
18
19
20
21
22
23e
24i
1v (Me, Me)
2vg
2w
88
98
93
86
85
65
94
98:2
1w (Me, Ph)
99:1
1x (Me, 4-MeC6H4)
1y (Me, 4-FC6H4)
1z (Me, 2-naphthyl)
1za (Me, 4-MeC(O)C6H4)
ent-1c (Me, PMP)
2x
98:2
2y
98.5:1.5
99:1
2z
2zah
ent-2c
98:2
95:5
[a] Reaction conditions: 1 (0.30 mmol) and LiHMDS (0.36 mmol) in anhydrous
THF (3.0 mL) at 78 oC for 15 min and then 35 oC for 10 min, followed by
addition of chlorotrimethylsilane (0.60 mmol) at 35 oC unless otherwise noted.
PMP = 4-methoxyphenyl. [b] Isolated yield after silica gel chromatography. [c]
Enantiomeric ratios were determined using HPLC and a chiral stationary
phase. [d] Incomplete conversion of the starting material. [e] 2.4 equiv of base
and 4.0 equiv of TMSCl were used in this case. [f] Complete conversion of the
starting material but substantial uncharacterized byproducts were observed.
[g] Yield and enantiomeric ratio refer to the α-hydroxyl product after treatment
of the rearrangement product with P(OMe)3. [h] The acyl group at the para-
position of the phenyl ring was simultaneously converted to silyl enol ether [4-
CH2=C(OTMS)C6H4)]. [i] The (S)-enantiomer of N-tert-butanesulfinamide was
used.
Scheme 2. Initial Results of Chiral N-Acyl-tert-Butanesulfinamide
Rearrangement via O-Silyl N-Sulfinyl N,O-Ketene Acetal Intermediates.
Next we examined the substrate scope for the
diastereoselective rearrangement of chiral N-acylsulfinamides
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10.1002/anie.201809551
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(Table 1). The N-arylacetyl sulfinamides 1ek bearing ortho-,
meta-, and para-substituted aryl groups (R = Ar) smoothly
underwent rearrangement, giving the corresponding α-
sulfenyloxy carboxamides 2ek (entries 17) in good yields
(6991%) with excellent enantiomeric ratios (95:598.5:1.5).
Reactions of N-acylsulfinamides derived from α-branched
Grignard reagent MeMgBr effectively promoted bond cleavage
at 78 oC (eq. 2). In both cases, enantiomeric ratio was
maintained.[16] Under thio-Arbuzov reaction conditions (BnBr),[17]
the expected α-bromo amide product derived from 2c did not
form; instead, the SO bond cleavage product 5 was obtained in
76% yield with excellent enantiomeric ratio (eq. 3), indicating
that the secondary alcohol-derived sulfenate ester 2c is
unsuitable for the thio-Arbuzov transformation. Adjustment of
reaction conditions permitted selective oxidation of tert-
butanesulfenate ester 2d to the corresponding sulfonate ester 6
or sulfinate ester 7 (eq. 4).
We rationalize the observed enantioselectivity at the newly-
formed stereocenter as follows. Mislow-Evans rearrangement is
commonly thought to involve 5-membered cyclic endo transition
states.[18] However, a bulky substituent at C-2 in the allylic
system of rearrangement precursors can destabilize the endo
transition state and thereby facilitate exo rearrangement.[19] We
hypothesize that in this case, rearrangement occurs
preferentially via an exo transition state TS-1 in order to avoid
interactions in the endo transition state TS-2 between the tBu
group on the sulfur with the silyloxyl group at C-2 or with the R
group at C-3 in the 1-aza-allylic system. The (Z)-enolate forms
preferentially over the (E)-enolate because of severe steric
repulsion between the bulky N-substituted sulfinamide group
and the R group at the α-position in the (E)-enolate. This aza-
variant of the Mislow-Evans rearrangement does not suffer the
i
t
aliphatic acids (entries 810, R = Pr, cyclopropyl, and Bu)
provided rearrangement products 2ln with good yields and
enantioselectivity (95:598:2). The exception was the low yield
(35%) of 2n, which was due to low conversion of substrate 1n
(with a bulky α-substituent) under standard reaction conditions.
Conducting enolization at higher temperatures did not improve
yield of 2n. A range of α-linear alkyl-substituted acylated
sulfinamides containing aryl, vinyl, alkynyl, chloroalkyl, ester, or
amide groups gave generally excellent enantiomeric ratios
(>98:2, entries 1117). Even single α-sulfenyloxylation of
dicarboxylic derivatives was achieved (entries 1617),[15] albeit
in moderate yields. This reaction involved migration of the SO
moiety loaded onto one of the two carboxylic functionalities (1t
and 1u). Like N-acyl-sulfinamides containing N-ally, benzyl, and
PMP groups (Scheme 2), precursors with N-methyl, phenyl, and
functionalized phenyl groups underwent rearrangement to
construct diverse N-substituted α-sulfenyloxy amides with
excellent enantioselectivities (entries 1823). Using the (SS)-
enantiomer of N-acyl-sulfinamides as starting material reversed
the enantiomeric ratio for α-sulfenyloxy amide products. For
example, the rearrangement reaction of ent-1c gave the
enantioenriched (2S)-2c in excellent yield with good
enantiocontrol (entry 24).
racemization sometimes observed
in the traditional
rearrangement during chirality transfer from sulfur to carbon.
Such racemization arises in the traditional rearrangement
because of its reversibility.[20] It does not appear to be a problem
in the aza-rearrangement because quenching the reaction at low
temperature triggers desilylation that quickly transforms O-silyl
imidate to stable carboxamide.[21]
Rearrangement products were subsequently manipulated
(Scheme 3). The common thiophile P(OMe)3 easily cleaved the
SO bond of rearrangement product 2d in methanol at room
temperature, yielding α-hydroxyl amide 3 in 90% yield (eq. 1).
O
O
O
Ph
Ph
S
ref 16
CAN
conditions
Ph
NH
(1)
NH
NH2
tBu
OH PMP
O
PMP
OH
3
4
2d (99:1 er)
P(OMe)3, MeOH, rt (90% yield, 98:2 er)
MeMgBr, THF, 78 oC (77% yield, 97.5:2.5 er)
O
O
Me
BnBr, CH3NO2, 70 oC, 10 h
Me
NH
NH
(2)
(3)
tBu
O
PMP
OH
PMP
S
76%
5 (99:1 er)
2c (99:1 er)
O
Ph
S
2.4 equiv m-CPBA, THF, rt, 1 h
NH
2d
tBu
O
PMP
85%
99:1 er
O
O
6 (95:5 er)
O
1.0 equiv m-CPBA, THF
78 oC, 20 min
Ph
NH
(4)
2d
tBu
O
PMP
90%
S
99:1 er
7 (~3:1 dr)
O
Scheme 4. Rationalization of Observed Absolute Stereochemistry.
Scheme 3. Cleavage of the SO Bond of α-Sulfenyloxy Amides and Oxidation
of tert-Butanesulfenate ester.
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10.1002/anie.201809551
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sulfoximines to allylic sulfinamides, see: f) H.-J. Gais, M. Scommoda, D.
In summary, we have developed an aza-variation of the
Mislow-Evans rearrangement that relies on formation of
rearrangement precursors reminiscent of Ireland-Claisen
rearrangement. Enolization and subsequent silylation of chiral N-
Lenz, Tetrahedron Lett. 1988, 35, 7361−7364.
[7]
For
a
report on [3,3]-sigmatropic rearrangement reactions
involvingsulfinamides, see: T. Moragas, R. M. Liffey, D. Regentová, J.-
P. S. Ward, J. Dutton, W. Lewis, I. Churcher, L. Walton, J. A. Souto, R.
A. Stockman, Angew. Chem. 2016, 128, 10201–10205; Angew. Chem.
Int. Ed. 2016, 55, 10047–10051.
acyl-tert-butanesulfinamides
initiate
a
[2,3]-sigmatropic
rearrangement with faithful chiral transfer from the sulfur of the
sulfinyl group to the α-carbon of the amide. This rearrangement
efficiently generates a range of α-sulfenyloxy amides with
excellent enantioselectivities, allowing oxidant-free asymmetric
functionalization of carboxamides on the α-oxygen.
[8]
[9]
For alkylation reaction of the lithiated enolate intermediate of N-acyl
(RS)-sulfinamides, see: B. J. Backes, D. R. Dragoli, J. A. Ellman, J. Org.
Chem. 1999, 64, 5472–5478.
Reviews: a) H. Ito, T. Taguchi, Chem. Soc. Rev. 1999, 28, 43–50; b) A.
M. Martín Castro, Chem. Rev. 2004, 104, 2939–3002; c) E. A. Ilardi, C.
E. Stivala, A. Zakarian, Chem. Soc. Rev. 2009, 38, 3133–3148.
[10] a) G. M. Coppola, H. F. Schuster, α-Hydroxy Acids in Enantioselective
Syntheses; Wiley-VCH: Weinheim, 1997; b) B.-C. Chen, P. Zhou, F. A.
Davis, E. Ciganek In Organic Reactions (Eds.: L. E. Overman), John
Wiley & Sons, Inc.: New York, 2003, Vol. 62, pp 1−356.
Acknowledgements
[11] Reviews: a) J. A. Ellman, T. D. Owens, T. P. Tang, Acc. Chem. Res.
2002, 35, 984−995; b) M. T. Robak, M. A. Herbage, J. A. Ellman, Chem.
Rev. 2010, 110, 3600−3740.
This work was supported by the National Natural Science
Foundation of China (21871292, U1403301 and 21572262), the
Recruitment Program of Global Experts (Xinjiang Program) and
the Director Foundation of XTIPC (2015RC014).
[12] On the high electrophilic reactivity of N-acylsulfinamides serving as
sulfinylating agents, see: J. L. Garcia-Ruano, R. Alonso, M. M. Zarzuelo,
P. Noheda, Tetrahedron: Asymmetry 1995, 6, 1133–1142.
[13] Crystal structures of 2a-d (CCDC 1859325–1859328) are provided in
the Supporting Information.
Keywords: diastereoselective • rearrangement • asymmetric •
N-acyl-tert-butanesulfinamides •α-sulfenyloxy amides
[14] X-ray crystallography studies showed respective Flack parameters x(u)
of 0.016(17) and 0.003(9) for highly enantioenriched samples 1a and
1b. We consider the assignment of absolute configuration 1a and 1b
based on these Flack parameters to be conclusive because of the
sufficiently small standard uncertainty (u < 0.04) and the closeness of
the Flack parameter to zero within three standard uncertainties (|x|/u <
3.0). For the use of the Flack parameter for absolute configuration
determination, see: a) H. D. Flack, G. Bernardinelli, J. Appl. Cryst. 2000,
33, 1143–1148; b) H. D. Flack, G. Bernardinelli, Chirality 2008, 20,
681–690.
[1]
[2]
a) P. Bickart, F. W, Carson, J. Jacobus, E. G. Miller, K. Mislow, J. Am.
Chem. Soc. 1968, 90, 4869−4876; b) R. Tang, K. Mislow, J. Am. Chem.
Soc. 1970, 92, 2100−2104; c) D. A. Evans, G. C. Andrews, Acc. Chem.
Res. 1974, 7, 147−155; d) C. M. Rojas In Molecular Rearrangements in
Organic Synthesis (Ed.: Rojas, C. M.), John Wiley & Sons: Hoboken,
NJ, 2016; pp. 569−625.
a) S. Braverman, Y. Stabinsky, Chem. Commun. 1967, 270−271; b) S.
Braverman In The Chemistry of Sulphones and Sulphoxide (Eds.: S.
Patai, Z. Rappoport, C. J. M. Stirling), John Wiley: London, 1988;
Chapter 14; c) I. Colomer, M. Velado, R. Fernández de la Pradilla, V.
Viso, Chem. Rev. 2017, 117, 14201−14243.
[15] For recent reports of selective oxidation of amides to α-hydroxy amides
in the presence of other carbonyl groups, see: A. de la Torre, D. Kaiser,
N. Maulide, J. Am. Chem. Soc. 2017, 139, 6578−6581.
[3]
[4]
M. G. Charest, C. D. Lerner, J. D. Brubaker, D. R. Siegel, A. G. Myers,
Science 2005, 308, 395−398.
[16] For removal of the p-methoxyphenyl group on the nitrogen in 3 using
ceric ammonium nitrate (CAN), see: N. Kambe, T. Inoue, T. Takeda, S.-
i. Fujiwara, N. Sonoda, J. Am. Chem. Soc. 2006, 128, 12650−12651.
[17] M. Kersten, E. Wenschuh, Phosphorus, Sulfur Silicon Relat. Elem.
1993, 80, 81–84.
Selected examples: a) J. G. Miller, W. Kurz, K. G. Untch, G. Stork, J.
Am. Chem. Soc. 1974, 96, 6774−6775; b) R. L. Halcomb, S. H. Boyer,
M. D. Wittman, S. H. Olson, D. J. Denhart, K. K. C. Liu, S. J.
Danishefsky, J. Am. Chem. Soc. 1995, 117, 5720−5749; c) K. M.
Engstrom, M. R. Mendoza, M. Navarro-Villalobos, D. Y. Gin, Angew.
Chem. 2001, 113, 1162-1164; Angew. Chem. Int. Ed. 2001, 40,
1128−1130; d) C. He, C. Zhu, Z. Dai, C.-C. Tseng, H. Ding, Angew.
Chem. 2013, 125, 13498–13502; Angew. Chem. Int. Ed. 2013, 52,
13256−13260.
[18] a) D. K. Jones-Hertzog, W. L. Jorgensen, J. Am. Chem. Soc. 1995, 117,
9077–9078; b) R. W. Hoffmann, Angew. Chem. 1979, 91, 625–634;
Angew. Chem. Int. Ed. 1979, 18, 563−572.
[19] a) R. W. Hoffmann, S. Goldmann, R. Gerlach, N. Maak, Chem. Ber.
1980, 113, 845−855; b) S. Goldmann, R. W. Hoffmann, N. Maak, K.-J.
Geueke, Chem. Ber. 1980, 113, 831−844. For an early report on the
preferred exo transition states for both geometric isomers of cis- and
trans-butenyl p-toluenesulfenates, see: c) V. Rautenstrauch, J. Chem.
Soc. D 1970, 526−527.
[5]
Tandem Claisen-Mislow-Evans rearrangement: a) M. J. Pelc, A.
Zakarian, Org. Lett. 2005, 7, 1629−1631; b) M. J. Pelc, A. Zakarian,
Tetrahedron Lett. 2006, 47, 7519−7523; Tandem Knoevenagel
condensation/Mislow−Evans rearrangement (APAC reaction): c) Z. Du,
T. Kawatani, K. Kataoka, R. Omatsu, J. Nokami, Tetrahedron 2012, 68,
2471−2480. d) J. de Vicente, J. R. Huckins, S. D. Rychnovsky, Angew.
Chem. 2006, 118, 7416–7420; Angew. Chem. Int. Ed. 2006, 45,
7258−7262; e) B. M. Trost, L. Dong, G. M. Schroeder, J. Am. Chem.
Soc. 2005, 127, 10259−10268. For other tandem processes involving
Mislow-Evans rearrangement, see ref 2c.
[20] a) P. Bickart, F. W. Carson, J. Jacobus, E. G. Miller, K. Mislow, J. Am.
Chem. Soc. 1968, 90, 4869−4876; b) D. A. Evans, G. C. Andrews, J.
Am. Chem. Soc. 1972, 94, 3672−3674; c) R. W. Hoffmann, N. Maak,
Tetrahedron Lett. 1976, 17, 2237−2240.
[21] Control experiments indicated that treatment of α-sulfenyloxy
carboxamide 2d in THF with LiHMDS at 78 oC for 15 min and then 35
oC for 60 min resulted in complete SO bond cleavage (Note: if the
reaction was quenched at this stage, α-hydroxyl amide 3 was isolated
in 81% yield). Subsequent addition of TMSCl to the reaction mixture led
to silylation of the α-hydroxy group of 3.
[6]
a) T. L. Gilchrist, C. J. Moody, Chem. Rev. 1977, 77, 409−435; (b) R. D.
Baechler, M. Blohm, K. Rocco, Tetrahedron Lett. 1988, 29, 5353−5354;
c) A. Armstrong, R. S. Cook, Chem. Commun. 2002, 904−905; d) A.
Armstrong, L. Challinor, R. S. Cooke, J. H. Moir, N. R. Treweeke, J.
Org. Chem. 2006, 71, 4028−4030; e) A. Armstrong, D. P. G. Emmerson,
Org. Lett. 2009, 11, 1547−1550. For rearrangement of allylic
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10.1002/anie.201809551
Angewandte Chemie International Edition
COMMUNICATION
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COMMUNICATION
Fan Tang, Yun Yao, Yan-Jun Xu,
Chong-Dao Lu*
OSiMe3
O
O
O
R
R'
R
R'
[2,3]-shift
then H+
R
S
1) LiN(SiMe3)2
2) Me3SiCl
N
S
N
S
NH
R'
Page No. – Page No.
tBu
O
O
Diastereoselective Aza-Mislow-Evans
Rearrangement of N-Acyl-tert-
Butanesulfinamides into α-
28 examples
up to 98% yield
up to 99:1 er
Aza-variation of the Mislow-Evans rearrangement that relies on formation of
rearrangement precursors reminiscent of Ireland-Claisen rearrangement was
developed. Enolization and subsequent silylation of chiral N-acyl-tert-
butanesulfinamides initiate a [2,3]-sigmatropic rearrangement with faithful chiral
transfer from the sulfur of the sulfinyl group to the α-carbon of the amide.
Sulfenyloxy Carboxamides
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