General one-pot method for the preparation of N-tert-butanesulfinylamine diastereomer mixtures as standards for stereoselectivity determinations

Article abstract of DOI:10.1021/jo900353p

The one-pot preparation of N-sulfinylamine diastereomers proceeds in excellent yields (84-98%) for a diverse set of N-sulfinyl imine addition products. The method is operationally simple and extractive isolation provides analytically pure mixtures of dias

Full text of DOI:10.1021/jo900353p

SCHEME 1. Proposed Mechanism of Acid-Catalyzed
Cleavage of 1 in Hydroxylic versus Aprotic Solvents
General One-Pot Method for the Preparation of
N-tert-Butanesulfinylamine Diastereomer
Mixtures as Standards for Stereoselectivity
Determinations
Katrien Brak, Kimberly T. Barrett, and Jonathan A. Ellman*
Department of Chemistry, UniVersity of California,
Berkeley, California 94720
jellman@berkeley.edu
ReceiVed February 17, 2009
herein a general and easy-to-perform one-pot method for the
preparation of N-tert-butanesulfinylamine diastereomer mixtures.
The HCl-mediated cleavage of the tert-butanesulfinyl group
is thought to proceed by an acid-base reaction to provide 2,
followed by attack of chloride anion at the electrophilic sulfur
to produce the configurationally unstable tert-butanesulfinyl
chloride (3) (Scheme 1).4 The deprotection of an N-sulfinylamine
1 to provide the amine hydrochloride 5 is generally carried out
in the presence of a hydroxylic cosolvent, which reacts rapidly
in situ with the sulfinyl chloride to give sulfinate ester 4 as a
byproduct.3a However, we have recently demonstrated that by
carrying out the HCl-mediated cleavage in an aprotic solvent,
racemic sulfinyl chloride 3 is generated in near quantitative
yield.4 Upon the basis of this observation, we envisioned that
authentic diastereomers of N-tert-butanesulfinylamines could
readily be formed in one pot by HCl-mediated sulfinyl group
cleavage in an aprotic solvent followed by addition of base to
the same reaction vessel without any workup to achieve
resulfinylation of the amine.
To explore this hypothesis, N-sulfinylamine 1a was treated
with HCl at room temperature followed by addition of triethy-
lamine at -78 °C (Table 1, entry 1). Gratifyingly, the
N-sulfinylamine diastereomer mixture 6a was obtained in
quantitative yield and with 65:35 dr. Furthermore, it was found
that cooling the reaction mixture prior to the addition of base
was unnecessary, with a high yield and an approximate 1:1
mixture of N-sulfinylamine diastereomers obtained at room
temperature (entry 2). While the reaction proceeded in high yield
(77-99%) in a range of aprotic solvents (entries 2-5),
dichloromethane was chosen for subsequent reactions due to
its greater ability to solubilize a wide range of amine hydro-
chloride salts.
The one-pot preparation of N-sulfinylamine diastereomers
proceeds in excellent yields (84-98%) for a diverse set of
N-sulfinyl imine addition products. The method is operation-
ally simple and extractive isolation provides analytically pure
mixtures of diastereomers as standards for the rapid and
accurate determination of N-sulfinylamine diastereomeric
purity.
The asymmetric synthesis of chiral, R-branched amines is
an important and heavily pursued endeavor due to the high
frequency with which this structural motif occurs in drugs and
natural products.1 Additions of nucleophiles to enantiomerically
pure N-tert-butanesulfinyl imines are among the most popular
approaches for the asymmetric synthesis of amines.2 However,
to rigorously determine the diastereoselectivity of the nucleo-
philic addition step, further derivatization of the product is often
necessary to obtain standards for the analysis of stereoisomeric
purity. Typically, cleavage of the tert-butanesulfinyl group is
followed by isolation and then reaction of the resulting amine
with a derivatization reagent such as racemic sulfinyl chloride
or both (R)- and (S)-R-methoxy-R-(trifluoromethyl)phenylacetyl
chloride.3 These multistep procedures are tedious and require
the use of expensive reagents of limited stability. We report
A variety of bases for the resulfinylation reaction were next
evaluated. Hu¨nig’s base provided a moderate yield of the sulfinyl
diastereomers (entry 6). Proton sponge provided a comparably
high yield relative to triethylamine (entry 7); however, its
separation from the product by simple extractive techniques was
(1) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Kesseler, M.; Sturmer,
R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788–824.
(2) For reviews on the asymmetric synthesis of amines via N-tert-butane-
sulfinyl imines, see: (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem.
Res. 2002, 35, 984. (b) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62,
8869. (c) Ferreira, F.; Botuha, C.; Chemla, F.; Pe´rez-Luna, A. Chem. Soc. ReV.
2009, 38, 1162.
(3) For representative examples of diastereomer analysis after 1,2-nucleophilic
additions to N-tert-butanesulfinyl imines, see: (a) Cogan, D. A.; Liu, G.; Ellman,
J. Tetrahedron 1999, 55, 8883. (b) Tang, T. P.; Ellman, J. A. J. Org. Chem.
2002, 67, 7819. (c) Weix, D. J.; Shi, Y.; Ellman, J. A. J. Am. Chem. Soc. 2005,
127, 1092. (d) Beenen, M. A.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 6304.
(e) Beenen, M. A.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6910.
(4) (a) Wakayama, M.; Ellman, J. A. J. Org. Chem. 2009, 74, 2646. (b)
After submission of this manuscript another report on the formation of tert-
butanesulfinyl chloride, 3, by HCl-mediated deprotection of 1 in aprotic solvents
appeared. Aggarwal, V. K.; Barbero, N.; McGarrigle, E. M.; Mickle, G.; Navas,
R.; Ramon, J.; Unthank, M. G.; Yar, M. Tetrahedron Lett. 2009, Article in Press,
DOI: 10.1016/j.tetlet.2009.03.020.
3606 J. Org. Chem. 2009, 74, 3606–3608
10.1021/jo900353p CCC: $40.75 2009 American Chemical Society
Published on Web 04/07/2009

TABLE 1. Reaction Optimization
TABLE 2. Preparation of Diastereomer Mixtures from Various
N-tert-Butanesulfinylamines
entry solvent
base
base addition temp yield (%)a drb
1
2
3
4
5
6
7
8
THF
THF
triethylamine
triethylamine
-78 °C
99
90
77
99
86
50
85
0
65:35
54:46
57:43
58:42
60:40
54:46
58:42
rt
rt
rt
rt
rt
rt
rt
EtOAc triethylamine
Dioxane triethylamine
CH2Cl2 triethylamine
CH2Cl2 Hu¨nig’s basec
CH2Cl2 proton sponged
CH2Cl2 pyridine
a
1
Yields were determined by H NMR relative to 3,5-dimethoxytoluene.
b Diastereomeric ratio was determined by NMR analysis. c N,N-Diiso-
propylethylamine. d 1,2-Bis(dimethylamino)naphthalene.
unsuccessful. As might be expected from its decreased basicity,
pyridine failed to provide any product (entry 8).
To demonstrate the generality of the method, a variety of
N-sulfinyl imine addition products were prepared and evaluated
under the optimal reaction conditions (Table 2). R-Branched
benzylic amines provided an approximate 3:2 ratio of N-sulfiny-
lamine diastereomers despite the structural dissimilarity of the two
R-substituents (entry 2). Sterically encumbered tertiary carbi-
namines required slightly longer times for the deprotection of the
tert-butanesulfinyl group (1 h versus 0.5 h), but still provided a
mixture of diastereomers in high yield (entry 3). ꢀ-Amino esters
(entry 4) and R-branched allylic amines (entry 5) are also competent
substrates for the reaction sequence. Notably, a simple extractive
isolation provided analytically pure material in all cases.
Diastereomerically pure N-sulfinylamines generally did not
provide a 1:1 mixture of diastereomers upon resulfinylation with
sulfinyl chloride 3 (Table 2). This could be the result of either
incomplete sulfinyl chloride racemization or dynamic resolution
of the sulfinyl chloride under the reaction conditions.6 The
incomplete racemization of sulfinyl chloride was ruled out by
subjecting diastereomerically pure (RS,S) and (RS,R) N-sulfiny-
lamines to the reaction conditions. As long as the N-sulfiny-
lamine starting material is completely deprotected and the
intermediate sulfinyl chloride 3 fully racemizes, the same
diastereomeric ratio should be obtained independent of the
relative configurations of the sulfinyl and R-stereocenters.
Indeed, both (RS,S) and (RS,R) N-sulfinylamines provided a
diastereomeric ratio of 62:38 (Table 3). As predicted, both
reactions provided the same major diastereomer as opposite
enantiomers: (SS,S) for the (RS,S) starting amine 1b and (RS,R)
for the (RS,R) starting amine 1f. Therefore, the ∼3:2 ratio of
diastereomers is the result of dynamic resolution of sulfinyl
chloride under the reaction conditions.6
a Yields were determined by mass balance of analytically pure
material. b Diastereomeric ratio was determined by NMR analysis.
c Diastereomeric ratio was determined by NMR and HPLC analysis.
d The HCl-mediated N-tert-butanesulfinyl deprotection was performed
for 1 h.
TABLE 3. Evidence for Complete Racemization of Sulfinyl
Chloride 3 under the Reaction Conditions
diastereopure
N-sulfinylamine 1
N-sulfinylamine
entry
diastereomer mixture 6a
62:38
6b
1
2
1b (RS,S)
1f (RS,R)
(SS,S):(RS,S)
62:38
6f
(RS,R):(SS,R)
In conclusion, a one-pot method has been developed for the
preparation of authentic diastereomers of N-tert-butanesulfiny-
lamines. This straightforward method, which proceeds in high
yields for a broad range of N-sulfinylamines, should be
extremely useful for obtaining N-sulfinylamine diastereomer
a Diastereomeric ratio was determined by NMR and HPLC analysis.
mixtures as standards for the rapid and accurate determination
of diastereomeric purity.
Experimental Section
(5) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119,
9913.
(6) The dynamic resolution of sulfinyl chloride with chiral amine nucleophiles
has previously been reported: Dragoli, D. R.; Burdett, M. T.; Ellman, J. A. J. Am.
Chem. Soc. 2001, 123, 10127.
General Procedure for Preparing an Authentic Mixture of
N-tert-Butanesulfinylamines. The N-sulfinylamine 1 (1.0 equiv)
dissolved in CH2Cl2 (0.16 M) in an oven-dried vial equipped with
J. Org. Chem. Vol. 74, No. 9, 2009 3607

a Teflon coated stir bar under nitrogen was placed in an ambient
water bath. HCl (4.4 M) in dioxane (2.2 equiv) was added dropwise
to this solution, and the reaction mixture was stirred at rt for 0.5-1
h. NEt3 (2.4 equiv) was then added dropwise and the resulting
mixture was stirred at rt for 1 h. The reaction mixture was diluted
with EtOAc and washed successively with 1 N NaHSO4, saturated
NaHCO3, and brine. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure to provide
an authentic mixture of N-sulfinylamine diastereomers. The extrac-
tive isolation provided analytically pure material.
mmol), 4.4 M HCl dioxane (85 µL, 0.37 mmol), and NEt3 (57 µL,
0.41 mmol) in CH2Cl2 (1.1 mL) to afford 39.1 mg (98% yield) of
6b as a mixture of diastereomers (62:38; SS,S:RS,S). The reaction
mixture was stirred for 0.5 h after the HCl addition and for 1 h
after the NEt3 addition. The diastereomeric ratio was determined
by both 1H NMR and HPLC analysis. HPLC analysis (silica column,
hexanes:EtOH 97:3, 1.0 mL/min, λ ) 210 nm) tminor ) 10.6 min,
1
tmajor ) 12.2 min. H NMR (500 MHz, CDCl3) δ 0.79 (t, 1.9H, J
) 7.3 Hz), 0.84 (t, 1.1H, J ) 7.3 Hz), 1.18 (s, 3.4H), 1.23 (s, 5.6H),
1.71-1.91 (m, 1.4H), 2.00-2.11 (m, 0.62H), 3.41 (s, 1H),
1
4.25-4.32 (m, 1H), 7.24-7.38 (m, 5H). The H NMR shifts of
N-(1-Ethyl-2-methylpropyl)-tert-butanesulfinylamine (6a). The
general procedure was followed with N-sulfinylamine 1a (20 mg,
0.097 mmol), 4.4 M HCl dioxane (48 µL, 0.21 mmol), and NEt3
(32 µL, 0.23 mmol) in CH2Cl2 (0.61 mL) to afford 17.2 mg (86%
yield) of 6a as a mixture of diastereomers (60:40; SS,S:RS,S). The
reaction mixture was stirred for 0.5 h after the HCl addition and
for 1 h after the NEt3 addition. The diastereomeric ratio was
the (RS,S) diastereomer correspond to the literature data and those
of the (SS,S) diastereomer correspond to the literature data for its
(RS,R) enantiomer.5 MS (ESI) m/z 240 [MH]+. Anal. Calcd for
C13H21NOS: C, 65.23; H, 8.84; N, 5.85. Found: C, 64.96; H, 9.07;
N, 5.70.
1
1
Acknowledgment. This work was supported by the NSF
(CHE-0742565). K.B. is a recipient of the 2008-2009 ACS-
DOC fellowship sponsored by Wyeth Pharmaceuticals.
determined by H NMR analysis. H NMR (500 MHz, CDCl3) δ
0.82-0.98 (m, 9H), 1.208 (s, 5.4H), 1.212 (s, 3.6H), 1.33-1.44
(m, 0.6H), 1.47-1.64 (m, 1.4H), 1.75-1.83 (m, 0.4H), 1.89-1.99
(m, 0.6H), 2.84 (d, 0.4H, J ) 6.9 Hz), 2.92-2.99 (m, 1H), 3.06
(d, 0.6H, J ) 6.9 Hz). The 1H NMR shifts of the (RS,S) diastereomer
correspond to the literature data and those of the (SS,S) diastereomer
correspond to the literature data for its (RS,R) enantiomer.5 MS (ESI)
m/z 206 [MH]+. Anal. Calcd for C10H23NOS: C, 58.49; H, 11.29;
N, 6.82. Found: C, 58.13; H, 10.91; N, 6.50.
Supporting Information Available: General experimental
1
methods; specific reaction conditions for 6c-f; copies of H
NMR of 6a-f, 13C NMR of 6d-e, and HPLC traces of 6b,e-f.
This material is available free of charge via the Internet at
http://pubs.acs.org.
N-(1-Phenylpropyl)-tert-butanesulfinylamine (6b). The general
procedure was followed with N-sulfinylamine 1b (40 mg, 0.17
JO900353P
3608 J. Org. Chem. Vol. 74, No. 9, 2009