Practical and stereoselective synthesis of β-amino sulfones from alkyl phenyl sulfones and N-(tert-butylsulfinyl) aldimines

Article abstract of DOI:10.1039/c1ob05992k

A practical and straightforward approach for the highly stereoselective synthesis of β-amino sulfones was developed. With lithium bis(trimethylsilyl)amide as the base, the corresponding sulfone-stabilized carbanion derived from alkylphenyl sulfone can be

Full text of DOI:10.1039/c1ob05992k

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Practical and stereoselective synthesis of b-amino sulfones from alkyl phenyl
sulfones and N-(tert-butylsulfinyl) aldimines†
Hua Zhang,a,b Ya Li,b Wei Xu,c Wenrui Zheng,b Pei Zhou*d and Zhihua Sun*b
Received 20th June 2011, Accepted 1st August 2011
DOI: 10.1039/c1ob05992k
A practical and straightforward approach for the highly stere-
oselective synthesis of b-amino sulfones was developed. With
lithium bis(trimethylsilyl)amide as the base, the correspond-
ing sulfone-stabilized carbanion derived from alkylphenyl
sulfone can be transferred to N-(tert-butylsulfinyl) aldimines
in excellent yields and with high diastereoselectivity.
(S)-1-amino-2-methoxymethylpyrrolidine (SAMP) or (R,R,R)-2-
amino-3-methoxymethyl-azabicyclo-[3.3.1]octane (RAMBO) to
alkenyl sulfones to provide a novel access to enantiopure b-
amino sulfones.12 Despite the prominence of this reaction, the
relatively expensive chiral auxiliary SAMP or RAMBO limits its
practical uses in organic synthesis. Also, this reaction suffers from
low yield and diastereoselectivity. Ideally, we can envision that
a more straightforward (arylsulfonyl)alkylation of chiral imines
with alkylaryl sulfone would provide a highly attractive route to
the target structures. However, this approach appears to be under-
utilized: only scattered examples of direct (arylsulfonyl)alkylation
of imines as synthetic steps towards constructing nitrogen hetero-
cycles have been described with most of the reports dating back to
ten years ago.13 Furthermore, the sulfone-containing nucleophile
was limited to allylphenyl sulfone (or its derivatives), which is
a relatively easy case due to the aryl and allyl groups’ dual
stabilizing effects on the corresponding carbanion. To the best
of our knowledge, there is no general and solid study available
for the highly stereoselective synthesis of b-amino sulfones using a
direct (arylsulfonyl)alkylation strategy, and the practical and direct
asymmetric synthesis of b-amino sulfones remains challenging.
As part of our continuing efforts in the development of efficient
methodologies for synthesis of diverse chiral amines,14 herein we
report the practical synthesis of b-amino sulfones using readily ac-
cessible alkylphenyl sulfone and N-(tert-butylsulfinyl) aldimines.15
First, we choose methylphenyl sulfone 1, the simplest
alkylphenyl sulfone, as the nucleophile. It is worthwhile to note that
while the addition reaction of compound 1 to carbonyl compounds
has been well documented,16 commonly carried out with n-BuLi as
The b-amino sulfone motif is a predominant substructure of many
bioactive compounds,1 and it was found to play important roles
in a variety of enzyme inhibitors such as novel HIV protease
inhibitors2 and matrix metalloproteinase inhibitors,3 among oth-
ers. Additionally, b-amino sulfones are valuable intermediates in
the preparation of cyclic and acyclic nonproteinogenic a-amino
acids,4 amino alcohols,5 alkaloids,6 carbohydrate derivatives,7 and
nitrogen heterocycles,8 taking advantage of the basis that sulfones
can be involved in versatile synthetic transformations,9 such as
electrophilic substitution in the a-position, replacement of the
sulfone group with other functional groups, and reductive cleavage
of the sulfone group.
Despite its importance for applications related to the life
sciences, the synthesis of chiral b-amino sulfones has not been
well explored. Currently, the commonly used method involves
a synthetic sequence starting from natural amino acids,10 which
represents a viable approach to construct enantiopure b-amino
sulfones. However, tedious multi-step transformations did not
allow for a rapid and green synthesis of this kind of compounds.
The other synthetic strategy involves asymmetric aza-Michael
addition to alkenyl sulfones.11 For example, Enders reported
the conjugate addition of an enantiopure ammonia equivalent
-
the base to pre-generate the corresponding carbanion PhSO2CH2 ,
its direct (phenylsulfonyl)methylation to imines has not been
disclosed. By using imine 2a as the model compound, we examined
the (phenylsulfonyl) alkylation reaction between 1 and 2 in
different reaction conditions.‡ After screening several parameters
(e.g., solvent, base, and temperature), a reaction system comprising
lithium bis(trimethylsilyl)amide (LiHMDS) as base, and THF as
solvent proved to be efficient. Further study demonstrated that the
base solution added slowly to the reaction mixture of compound
1 and imine 2a in THF can give better results than that with
aSchool of Environment Science and Engineering, Shanghai Jiaotong Uni-
versity, Shanghai, 200240, China
bCollege of Chemistry and Chemical Engineering, Shanghai University of En-
gineering Science, Shanghai, 201600, China. E-mail: sungaris@gmail.com;
Fax: +86 21 6779 1432; Tel: +86 21 6779 1432
cDepartment of Biology, Texas A&M University, College Station, Texas,
77843, USA
dKey Laboratory of Urban Agriculture (South), School of Agriculture
College and Biology, Ministry of Agriculture, Shanghai Jiaotong University,
Shanghai, 200240, China. E-mail: peizhousjtu@163.com; Fax: +86 21 3420
5762; Tel: +86 21 3420 5762
-
pre-generated carbanion PhSO2CH2 .
† Electronic supplementary information (ESI) available: Experimental
details, characterization data, and copies of the 1H and 13C NMR
spectra of the new compounds. CCDC reference number 830371. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob05992k
Eventually, the above conditions were applied to a wide array of
structurally diverse imines as summarized in Table 1. A remarkable
feature of this reaction is that it can be applied to non-enolizable,
enolizable, aromatic, and heterocyclic imines alike. Also, this
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Table 1 (Phenylsulfonyl)methylation of N-(tert-butylsulfinyl) aldimines 2
Entry
1
Sulfinylimine 2
Product 3
Yield (%)a
93
drb
99 : 1
2
92
36 : 1
3
4
95
91
30 : 1
99 : 1
5
85
99 : 1
6
7
90
93
35 : 1
35 : 1
8
9
92
75
18 : 1
7 : 1
a Yields of isolated pure material. b Diastereomeric ratios were determined by HPLC–MS and 1H NMR spectroscopy on the crude reaction mixture. For
more details, see the ESI.†
addition reaction is compatible with a variety of functional groups.
High diastereoselectivity was observed in each case, excellent
yields were obtained with both non-enolizable (Table 1, entries
1–7) and enolizable imines that have one or two a-hydrogen
atom(s) (entries 8 and 9). Note that the position and electronic
withdrawing/donating nature of the substitution group(s) on the
aromatic rings had no detectable effect on both the yield and
diastereoselectivity. We also tried the same reaction conditions to
N-(tert-butylsulfinyl)trifluroethanimine 2i. Gratifying, the corre-
sponding fluorinated b-aminosulfones 3i can be obtained in very
good yield. It should be pointed out that previous preparation
of this compound starts from fluorinated imidoyl chlorides, which
involves fluorinated N-aryl b-imido sulfone as a key intermediate.17
Reduction of the latter compound usually required a very long
reaction time (two to several days) and gave the correspond-
ing b-aminosulfones in only moderate diastereoselectivity which
required chromatographic separation to get the predominant
diastereoisomer. Our highly stereoselective one-step procedure
to prepare b-aminosulfones in conjunction with commercially
available tert-butanesulfinamide, presented herein, represents an
advantage over the previous reported methods, making it highly
practical for organic synthesis.
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Table 2 (Phenylsulfonyl)alkylation of N-(tert-butylsulfinyl) aldimines 2
Entry
1
Imine 2
PhSO2R
Product 3
Facial selectivitya
16 : 1
Isomer ratioa 5 : 5¢
Yieldb 5
82
2a
N/A
2
3
4
2b
2a
2b
27 : 1
60 : 1
75 : 1
N/A
80
60
61
3 : 1
5 : 1
a Facial selectivity and isomer ratio were determined by HPLC–MS and 1H NMR spectroscopy on the crude products. For more details, see the ESI.†
b Isolated yield of 5.
Next, we turned our attention to the scope of other alkylphenyl
sulfones. As shown in Table 2, sterically hindered iso-propylphenyl
sulfone 4a can react with imines smoothly and these transfor-
mations provided the expected products 5 in good yield with
excellent diastereoselectivity. When iso-butylphenyl sulfone 4b
was applied to this reaction, the facial selectivities, i.e., the
diastereoselectivity during the nucleophilic addition of in situ
generated anion into imine functionality of 2, were excellent
(99 : 1). Interestingly, moderate to good stereoselectivity was
observed during the formation of another neighboring stereogenic
center (the carbon adjacent to the phenylsulfonyl group) and
the major diasteromers 5c and 5d can be separated in good
yield (56% and 63% respectively). Compared to that widely used
reaction of (phenylsulfonyl)methylation to aldehydes and ketones,
this reaction showed some interesting chemical properties: when
carbonyl compounds such as benzaldehyde 6 was subject to the
above optimized reaction conditions, no product was obtained and
the starting materials can be recovered completely, which indicates
that the electrophilicity and hard-/softness of aldehyde/imine
electrophiles can substantially affect the overall chemical outcome.
To further demonstrate the practical use of this direct (phenyl-
sulfonyl)alkylation reaction, the experiment was conducted with
compound 1 and imine 2a at 0.5 mol scale under the above
conditions. This reaction proceeded smoothly and completed in
normal time. After the usual work-up, the crude product can be
obtained, and NMR and HPLC–MS analysis indicated that the
diastereoselectivity was comparable to that at the small scale (1.0
mmol). Pure product 3a can be obtained in 85% yield after simple
recrystallization from ethyl acetate/hexane.
b-amino sulfone 3 showed some interesting chemical properties:
when compound 3a was treated with 2.0 equivalent NaH, alkenyl
sulfone 6 can be obtained in exclusively E form. The tert-butyl
sulfinamide group acted as a leaving group in this reaction, which
was not observed in previous related studies.13,15
Scheme 1 Conversion of 3a to compound 6.
The absolute configuration of sulfinamide 5c was determined
by single-crystal X-ray analysis (see Fig. 1a), and the facial selec-
tivity was consistent with our prediction based on a commonly
used non-chelation-controlled transition-state mode to give the
Cram products (Fig. 1b), in which tert-butyl group adopts the
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extracted three times with ethyl acetate. The combined organic layers were
dried over anhydrous MgSO4. Evaporation of the solvent afforded the
crude product, which was subject to flash chromatography to give the
corresponding sulfonamide 3a.
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Based on computational studies (see the ESI† for details), the
observed diastereoselectivity can also be rationalized by involving
a six membered cyclic boat-like transition state (Fig. 1c), wherein
Li+ chelates with one of the sulfonyl oxygens and the sulfinylimine
nitrogen atom, which directs the aryl group to the equatorial
position thus allowing the sulfonyl carbanion to attack exclusively
from the si face on the C N bond. We tentatively assume that
one or both transition-state modes are involved in this addition
reaction. The configurations of 3a–3i and 5a–5d were assigned by
analogy.
In summary, we have successfully developed a highly stereos-
elective and practical approach to b-amino sulfones. Not only
methylphenyl sulfone, but also sterically hindered alkylphenyl
sulfone can react with structurally diverse N-(tert-butylsulfinyl)
aldimines, delivering the corresponding b-amino sulfones in good
to excellent yields with high diastereoselectivities. Starting from
cheap and commercially available starting materials, our described
one-step procedure allows for large scale synthesis of this kind of
compounds, thus making it highly practical for organic synthesis.
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Acknowledgements
We thank the National Department Public Benefit Research
Foundation China (No. 200903056) for financial support.
Notes and references
‡ General procedure for (phenylsulfonyl)methylation of N-(tert-
butylsulfinyl) aldimines 2: LiHMDS (1.3 equiv, 1.3 ML, 1.0 mol L-1) was
added to a mixture of the imine 2a (1 mmol) and methylphenyl sulfone
1 (1.3 equiv, 1.3 mmol) in THF (5 mL) at -70 ◦C. Reaction mixtures
were stirred over 1 h. Then half-saturated NH4Cl-H2O solution (2 mL)
was added at lower temperature and the quenched reaction mixture was
17 S. Fustero, J. Garc´ıa Soler, A. Bartolome´ and M. S. Rosello´, Org. Lett.,
2003, 5, 2707–2710.
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6502–6505 | 6505
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