Oxaziridine-mediated amination of branched allylic sulfides: Stereospecific formation of allylic amine derivatives via [2,3]-sigmatropic rearrangement

Article abstract of DOI:10.1021/jo060369s

Reaction of branched allylic sulfides with the N-Bocoxaziridine 1 results in [2,3]-sigmatropic rearrangement of the intermediate allylic N-Boc-surfimides with a high level of chirality transfer. The first example of formation of a quaternary stereocenter

Full text of DOI:10.1021/jo060369s

SCHEME 1
Oxaziridine-Mediated Amination of Branched
Allylic Sulfides: Stereospecific Formation of
Allylic Amine Derivatives via [2,3]-Sigmatropic
Rearrangement
Alan Armstrong,*,† Lee Challinor,† Richard S. Cooke,†
Jennifer H. Moir,‡ and Nigel R. Treweeke†
Department of Chemistry, Imperial College London,
South Kensington, London SW7 2AZ, U.K., and
Organon Newhouse, Lanarkshire ML1 5SH, Scotland
bearing radical-stabilizing groups (e.g., R2 ) CO2Me) due to
competing homolytic cleavage of the allylic C-S bond.4
Pleasingly, these substrates gave good results with oxaziridine
1.1a Bach also made interesting stereochemical observations
when using branched allylic sulfides (2, R1 * H). While the
[2,3]-sigmatropic rearrangement would be expected to proceed
with a high degree of chirality transfer,5 as has been observed
with N-sulfonylallylic sulfimides,6 Bach obtained products of
eroded ee when enantiomerically pure branched allylic sulfides
were used in his BocN3/FeCl2 system (Scheme 1). While the
poor ee of 3a could be rationalized by possible product
epimerization, this explanation is unlikely for 3b; furthermore,
it was discovered that recovered starting material 2b had a
deteriorated enantiopurity (75% ee). In addition to partial
substrate racemization, Bach postulated that the stereogenic
center at sulfur in the intermediate N-Boc-allylic sulfimides may
influence the stereochemical outcome of the reactions. As our
oxaziridine system is mechanistically distinct to Bach’s Fe-
catalyzed chemistry, we were interested in testing these more
demanding branched substrates in order to determine whether
efficient and stereocontrolled rearrangement would be possible.
Our initial studies focused on reactions of racemic R-branched
phenyl sulfides 2a and 2b. In view of the high chemoselectivity
observed earlier with unbranched phenylsulfides 2 (R1 ) H)
with 1,1a we were initially surprised that attempted amination-
rearrangement of rac-2a led not only to the expected allylic
amine derivative rac-3a (30%), but also to large quantities of
sulfoxide (60%, mixture of diastereomers). A relatively low
yield (55%) was also obtained for amination/rearrangement of
rac-2b. The low level of chemoselectivity is most likely due to
steric factors: Collet has demonstrated that increasing the size
of the oxaziridine N-substituent generally leads to higher levels
of oxidation versus amination,7 and it is reasonable to expect
that steric hindrance in the substrate would have the same effect.
In line with this idea, we found that while phenyl ethyl sulfide
a.armstrong@imperial.ac.uk
ReceiVed February 22, 2006
Reaction of branched allylic sulfides with the N-Boc-
oxaziridine 1 results in [2,3]-sigmatropic rearrangement of
the intermediate allylic N-Boc-sulfimides with a high level
of chirality transfer. The first example of formation of a
quaternary stereocenter using this transformation is reported.
We have recently developed the novel oxaziridine reagent 1
and demonstrated that it will effect efficient conversion of
sulfides to N-Boc-sulfimides under metal-free conditions.1,2
Reagents which, like 1, efficiently transfer electrophilic nitrogen
with a carbamate protecting group are rare.3 We have also shown
that this reagent will effect amination of allylic sulfides, leading
to allylic amine products via [2,3]-sigmatropic rearrangement
of the intermediate allylic sulfimide (Scheme 1).1a These results
extended the scope of the rearrangement since the only prior
report of the N-carbamate variant of this chemistry, from Bach’s
group and using BocN3/FeCl2, gave poor yields with substrates
(3) For reviews of electrophilic amination, see: (a) Erdik, E.; Ay, M.
Chem. ReV. 1989, 89, 1947. (b) Greck, C.; Genet, J. P. Synlett. 1997, 741.
(c) Mulzer, J.; Altenbach, H. J. In Organic Synthesis Highlights; VCH:
Weinheim, 1991; p 45. (d) Dembach, P.; Seconi, G.; Ricci, A. Chem. Eur.
J. 2000, 6, 1281. (e) Modern Amination Methods; Ricci, A., Ed.; Wiley-
VCH: Weinheim, 2000. (f) Erdik, E. Tetrahedron 2004, 60, 8747. (g) Greck
C, Drouillat B, Thomassigny, C. Eur. J. Org. Chem. 2004, 7, 1377. For a
recently reported catalytic method for preparing N-(trifluoroacetyl)sulfim-
ides, see: (e) Tomooka, C. S.; LeCloux, D. D.; Sasaki, H.; Carreira, E. M.
Org. Lett. 1999, 1, 149.
(4) (a) Bach, T.; Ko¨rber, C. Eur. J. Org. Chem. 1999, 1033. (b) Bach,
T.; Ko¨rber, C. J. J. Org. Chem. 2000, 65, 2358.
(5) (a) Bravermann, S. Int. J. Sulfur Chem. 1971, C6, 149. (b) Hoffmann,
R. W. Angew. Chem., Int. Ed. Engl. 1979, 18, 563.
* To whom correspondence should be addressed. Fax: +44 (0) 20 75945804.
Tel: +44 (0) 20 75945876.
† Imperial College London.
‡ Organon Newhouse.
(1) (a) Armstrong, A.; Cooke, R. S. Chem. Commun. 2002, 904. (b)
Armstrong, A.; Cooke, R. S.; Shanahan, S. E. Org. Biomol. Chem. 2003,
1, 3142. (c) Armstrong, A.; Jones, L. H.; Knight, J. D.; Kelsey, R. D. Org.
Lett. 2005, 7, 713.
(2) For reviews of sulfimide chemistry, see: (a) Taylor, P. C. Sulfur
Rep. 1999, 21, 241. (b) Gilchrist, T. L.; Moody, C. J. Chem. ReV. 1977,
77, 409. For some recent examples of sulfimidation, see: (c) Marzinzik,
A. L.; Sharpless, J. Org. Chem. 2001, 66, 594 and references therein. (d)
Takada, H.; Nishibashi, Y.; Ohe, K.; Uemura, S.; Baird, C. P.; Sparey, T.
J.; Taylor, P. C. J. Org. Chem. 1997, 62, 6512.
(6) (a) Dolle, R. E.; Osifo, K. I.; Li, C.-S. Tetrahedron Lett. 1991, 32,
5029. (b) Dolle, R. E.; Li, C.-S.; Novelli, R.; Kruse, L. I.; Eggleston, D. J.
Org. Chem. 1992, 57, 128.
(7) Vidal, J.; Damestoy, S.; Guy, L.; Hannachi, J.-C.; Aubry, A.; Collet,
A. Chem. Eur. J. 1997, 3, 1691.
10.1021/jo060369s CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/28/2006
4028
J. Org. Chem. 2006, 71, 4028-4030

SCHEME 2 a
SCHEME 5 a
a Reagents and conditions: (a) (i) DIBAL-H, CH2Cl2, -78 °C, (ii)
(EtO)2P(O)CH(Me)CO2Et, BuLi, 80%; (b) 1, -78 °C to rt, CH2Cl2, 77%;
(c) Raney Ni (W-2), EtOH, reflux, 74%; (d) (i) 4.0 N HCl in dioxane, (ii)
2 equiv of NEt3, AcCl, 100%.
a Reagents and conditions: (a) TsCl, NEt3, DMAP, CH2Cl2, 74%;
(b) HexSH, K2CO3, MeCN, 86%; (c) Dibal-H, CH2Cl2; (d) (EtO)2P(O)-
CH2CO2Me, 83%; (e) Dibal-H, CH2Cl2, 81%; (f) (i) Py‚SO3, THF, 0 °C;
(ii) LiAlH4, THF, reflux, 71%.
minimizing racemization of the intermediate aldehyde. Column
chromatography allowed separation of the alkene isomers giving
E-9 (Scheme 5). Treatment of E-9 with oxaziridine 1 gave the
rearrangement product 10 of 94% ee, again demonstrating a
high level of chirality transfer. The product configuration was
proved by conversion to the known N-acetyl aminoester 11 and
comparison of optical rotation data.9
SCHEME 3
We have shown that ketomalonate-derived N-Boc-oxaziridine
1 effects efficient amination of branched allylic hexyl sulfides
and that the rearrangement proceeds with a high level of chirality
transfer. The reagent therefore expands the scope of the
N-carbamate-protected allylic sulfimide rearrangement chemistry
relative to the previously reported4 BocN3/FeCl2 amination
system.10 Additionally, we have described the first example of
formation of a quaternary stereocenter using the sulfimide
rearrangement process. Overall, the simple and metal-free nature
of the reaction conditions is an attractive feature, and allows
for the synthesis of a range of sulfimide and allylic amine
products for further synthetic applications.
SCHEME 4
gave exclusively sulfimide on reaction with 1, phenyl isopropyl
sulfide afforded a 2.4:1 ratio of sulfimide/sulfoxide. We there-
fore reasoned that replacement of the sulfur phenyl substituent
in 2 with an unbranched alkyl group may restore the re-
quired chemoselectivity. n-Hexyl was chosen because the thiol
required to synthesize this substrate is relatively nonvolatile.
After initial experiments with racemic material indicated that
the desired chemoselectivity was indeed restored, we prepared
the hexyl sulfides 6a-c in enantiomerically pure form from
S-methyl lactate (Scheme 2) by a route analogous to that
developed by Bach for the phenylsulfide series.4b When these
enantiopure substrates were reacted with 1, we were able to
establish that the amination/rearrangement proceeded with
essentially complete transfer of chirality (Scheme 3). The
product configuration is depicted based on the expectation of
suprafacial rearrangement and was proven in the case of 7a by
conversion to the known8 amino acid 8 and comparison of its
optical rotation to literature values (Scheme 4). Unless amination
of sulfides 6 proceeds with complete diastereoselectivity, the
diastereomeric intermediate sulfimides must rearrange to give
the same product enantiomer.
Experimental Section
General Procedure for the [2,3] Rearrangement of Allylic
Sulfides (Schemes 3 and 5). To a stirred solution of oxaziridine 1
(1.05 equiv) in CH2Cl2 (0.18 M) at -78 °C under N2 was added
allylic sulfide 6 (1.0 equiv) in CH2Cl2 (0.16 M) dropwise. The
resulting solution was allowed to warm to room temperature over
30 min, after which time the solvent was removed under reduced
pressure. Column chromatography on silica afforded the sulfena-
mide products. Data for products are given below.
(R)-N-tert-Butoxycarbonyl-N-[(E)-1-methoxycarbonyl-2-bute-
nyl]hexylsulfenamide 7a. Rearrangement of 6a (190 mg, 0.823
mmol) upon chromatography (petrol/EtOAc 20:1) yielded 7a (205
mg, 72%) as a colorless oil: [R]23 +31 (c 0.2, CHCl3); HPLC
D
flow rate 1 mL/min; 100% hexane; 30 °C, chiral AD column;
detection at 254 nm gave ee of 95.6%; tR 19.4 min (major), 23.5
min (minor); νmax(film)/cm-1 1750 (CdO), 1162 (COC), 860 (SN),
1
752 (SC); H NMR (250 MHz, CDCl3, δ) 0.88 (t, J ) 6.7, 3H),
1.46 (s, 9H), 1.21-1.63 (m, 8H), 1.77 (d, J ) 4.9, 3H), 2.81 (t, J
) 7.3, 2H), 3.72 (s, 3H), 4.87 (d, J ) 6.1, 1H), 5.67-5.84 (m,
2H); 13C NMR (100 MHz, CDCl3, δ) 14.0, 18.0, 22.5, 27.2, 28.0,
28.5, 31.5, 39.2, 52.2, 67.6, 81.9, 125.1, 131.8, 156.4, 171.2; m/z
(CI) 346 (MH+ 41%); found MH+ 346.2053, C17H32NO4S requires
346.2052.
Our work with unbranched allylic sulfides1a indicated that
quaternary centers could be formed efficiently by sulfimide
rearrangement onto trisubstituted alkenes. However, there appear
to be no examples in the literature to date of using chirality
transfer from branched allylic sulfides to generate quaternary
stereocenters. To test this possibility, we prepared sulfide 9 from
S-lactate. After some experimentation, we were able to effect
olefination to give 9 in good yield and E/Z ratio (9:1) while
(9) Tanaka, M.; Oba, M.; Tamai, K.; Suemune, H. J. Org. Chem. 2001,
66, 2667.
(10) A complementary approach involves asymmetric sulfimidation of
achiral allylic sulfides. See ref 2d and also: Murakami, M.; Katsuki, T.
Tetrahedron Lett. 2002, 43, 3947. Murakami, M.; Uchida, T.; Saito, B.;
Katsuki, T. Chirality 2003, 15, 116.
(8) Mulzer, J.; Funk, G. Synthesis 1995, 101.
J. Org. Chem, Vol. 71, No. 10, 2006 4029

(R)-N-tert-Butoxycarbonyl-N-[(E)-1-hydroxymethyl-2-butenyl]-
hexylsulfenamide 7b. Rearrangement of 6b (17 mg, 0.080 mmol)
upon chromatography (petroleum ether/EtOAc 20:1) yielded 7b
followed by chromatography (petroleum ether/EtOAc 30:1) yielded
the title compound (41 mg, 77%) as a colorless oil: [R]27D -28 (c
1.9, CH2Cl2); HPLC flow rate 1 mL/min; hexane/IPA 0.5%; 23
°C, chiral OD-H; detection at 215 nm gave ee of 94%; tR 15.8 min
(major), 21.6 min (minor); νmax(film)/cm-1 1744 (CdO), 1163
(COC), 772 (SC); 1H NMR (500 MHz, CDCl3, δ) 0.89 (t, J ) 6.9,
3H), 1.23 (t, J ) 7.1, 3H), 1.22-1.37 (m, 6H), 1.50 (s, 9H), 1.58
(m, 2H), 1.59 (s, 3H), 1.74 (dd, J ) 6.5 and 0.1 3H), 2.78 (s, 1H),
4.13 (q, J ) 7.1, 2H), 5.56 (m, 1H), 5.88 (d, J ) 15.6, 1H); 13C
NMR (500 MHz, CDCl3, δ) 14.0, 17.9, 22.5, 23.1, 27.0, 28.1, 28.6,
30.9, 31.5, 40.0, 61.0, 68.6, 81.8, 125.4, 131.7, 156.6, 173.0; m/z
(20.2 mg, 76%) as a colorless oil: [R]20 -6.7 (c 0.3, CHCl3);
D
>95% ee according to 19F NMR analysis of its Mosher’s ester
(see the Supporting Information); νmax(film)/cm-1 3463 (OH), 1752
(CdO), 1164 (COC); 1H NMR (300 MHz, CDCl3, δ) 0.89 (t, J )
6.6, 3H), 1.50 (s, 9H), 1.29-1.58 (m, 8H), 1.73 (d, J ) 6.9, 3H),
1.93 (br s, 1H), 2.74-2.82 (m, 2H), 3.65-3.82 (m, 2H), 4.67 (dd,
J ) 13.2 and 7.6, 1H), 5.51-7.75 (m, 2H); 13C NMR (75 MHz,
CDCl3, δ) 14.0, 18.0, 22.4, 27.0, 28.1, 28.5, 31.4, 39.5, 63.9, 64.0,
81.5, 127.1, 130.0, 157.7; m/z (CI) 318 (MH+ 100); found MH+
318.2106, C16H32NO3S requires 318.2103.
+
(CI) 374 (MH+, 53), 335 (MNH4 - tBu, 100); found MH+
374.2365, C19H36NO4S requires 374.2365.
(S)-N-tert-Butoxycarbonyl-N-[(E)-1-methyl-2-butenyl]hexyl-
sulfenamide 7c. Rearrangement of 6c (30 mg, 0.16 mmol) upon
chromatography (petroleum ether/EtOAc 10:1) yielded 7c (33.4 mg,
Acknowledgment. We thank the EPSRC (GR/M54668) and
Organon (CASE award to L.C.) for their support of this work
and Bristol-Myers Squibb, Pfizer, and Merck Sharpe and Dohme
for generous unrestricted funding.
69%) as a colorless oil: [R]25 -25 (c 1.3, CHCl3); >95% ee as
D
determined by cleavage of the N-S bond with P(OEt)3, acidic Boc
deprotection, and 19F NMR analysis of the Mosher’s amide (see
the Supporting Information); νmax(film)/cm-1 1696 (CdO), 1168
(COC), 752 (SC); 1H NMR (250 MHz, CDCl3, δ) 0.88 (t, J ) 7.0,
3H), 1.48 (s, 9H), 1.24-1.69 (m, 14H), 2.71-2.78 (m, 2H), 4.71-
4.81 (m, 1H), 5.46-5.64 (m, 2H); 13C NMR (75 MHz, CDCl3, δ)
13.0, 16.8, 18.1, 21.5, 26.1, 27.2, 27.6, 30.5, 39.1, 55.6, 79.9, 125.0,
131.2, 156.0; m/z (CI) 302 (MH+, 20), 263 (MNH4+ - t-Bu, 100);
found MH+ 302.2146, C16H32NO2S requires 302.2154.
Supporting Information Available: Experimental procedures
for the preparation of allylic sulfide substrates, for the conversion
1
of 7a to 8, and for the conversion of 10 to 11. Copies of H and
13C NMR spectra of all new compounds. Details of ee determination
for 6a-c, 7a-c, and 10 (HPLC traces and copies of relevant
spectra). This material is available free of charge via the Internet
at http://pubs.acs.org.
(R)-N-tert-Butoxycarbonyl-N-[(E)-2-ethoxycarbonyl-3-pente-
nyl]hexylsulfenamide 10. Rearrangement of 9 (37 mg, 0.14 mmol)
JO060369S
4030 J. Org. Chem., Vol. 71, No. 10, 2006