Bis-sulfamyl imines: Potent substrates for asymmetric additions of arylboroxines under rhodium catalysis

Article abstract of DOI:10.1002/adsc.201000838

Bis-sulfamyl imines are shown to be potentially ideal substrates for rhodium-catalysed asymmetric additions of arylboron nucleophiles as they show: (i) near perfect enantioselectivities (11 examples, 98-99+% ee), (ii) good to excellent diastereoselectivities (10-32:1 rac:meso), and (iii) high functional group tolerance in removal of the low molecular weight protecting group via mild heating in aqueous pyridine.

Full text of DOI:10.1002/adsc.201000838

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DOI: 10.1002/adsc.201000838
Bis-Sulfamyl Imines: Potent Substrates for Asymmetric Additions
of Arylboroxines under Rhodium Catalysis
Rosemary Crampton,a Simon Woodward,a,* and Martin Foxb
a
School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, U.K.
Fax : (+44)-115-951-3564; e-mail: simon.woodward@nottingham.ac.uk
Chirotech Technology Ltd, A subsidiary of Dr. Reddyꢀs Laboratories (EU) Ltd, Unit 162 Cambridge Science Park,
b
Milton Road, Cambridge, CB4 0GH, U.K.
Received: November 10, 2010; Revised: January 11, 2011; Published online: April 12, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000838.
Abstract: Bis-sulfamyl imines are shown to be po-
tentially ideal substrates for rhodium-catalysed
asymmetric additions of arylboron nucleophiles as
they show: (i) near perfect enantioselectivities (11
examples, 98–99+% ee), (ii) good to excellent dia-
stereoselectivities (10–32:1 rac:meso), and (iii) high
functional group tolerance in removal of the low
molecular weight protecting group via mild heating
in aqueous pyridine.
enantiopurity, are needed for further synthesis – a
current need in our own groups.
In this context we were attracted to the under-uti-
lised bis-sulfamyl imines 1 of Davis (Scheme 1).[10] Or-
ganomagnesium and organolithium reagents were
added to 1 to give the sulfamides 2 as an intractable
mixture of diastereomers. This mixture was then de-
protected to give the rarely isolated free amines 3
themselves. We were attracted to applying this acti-
vating group to asymmetric rhodium-catalysed amine
synthesis as: (i) the effective MW of the protecting
group is only 32 per amine, (ii) the SO2 group is
cleaved under remarkably mild conditions (simple
warming in aqueous pyridine) which is compatible
with many functional groups, and (iii) an asymmetric
double addition strategy affords the possibility to
Keywords: asymmetric catalysis; boron; diarylme-
thylamines; protecting groups; rhodium
Chiral diarylmethylamines are valuable chemical attain very high enantioselectivities by statistical bias-
motifs occurring in pharmaceutical targets.[1] One key ing.
approach to diarylmethylamines is rhodium-catalysed
Bis-sulfamyl imine 1a was synthesised as described
asymmetric arylation of activated aldimines. The addi- by Davis[10] and a range of conditions for the addition
tions of arylstannane,[2a] aryltitanium,[2b] arylzinc[2c] of boron nucleophiles was screened. The addition
and arylboron reagents[3–7] have all been reported product was observed in good conversion with phe-
with good to excellent enantioselectivities. Arylboron nylboroxine 5a using the conditions and bicyclo-
reagents are of particular interest due to their com-
mercial availability, air and moisture stability, low tox-
icity and functional group tolerance.[8] The principle
issue in this area is attaining optimal synthetic utility
for the activating/protecting group: N-tosyl,[3] N-
nosyl,[4] N-diphenylphosphinoyl,[5] N-Boc[6] or N-for-
myl[2c] (the latter two as their PhSO2H imine adducts)
and N,N-dimethylsulfamoyl[7] have all been employed.
Shortcomings of these approaches include a poor
atom economy due to a high molecular weight (MW)
in the protecting group (and in some cases the neces-
sity of using PhSO2H imine adducts) and troublesome
deprotection (particularly for N-tosyl) which can
often be low yielding and incompatible with sensitive
functional groups.[3b,9] These protecting deficiencies
Scheme 1. Synthesis of racemic diarylmethylamines from
are particularly acute where the free amines, in high bis-sulfamyl imines.[10]
Adv. Synth. Catal. 2011, 353, 903 – 906
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Rosemary Crampton et al.
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Table 1. Optimisation of aryl addition.[a]
Entry
Nucleophile
mmol
T [8C]
Conversion [%][b]
ee [%][c]
dr[c]
1
2
3
4
5
6
7
8
9
10
N
0.6
2.5
1.8
0.6
0.6
0.6
60
80
60
60
93/77[d] (2a)
81/75[d] (2a)
0 (2a)
–
–
–
–
–
–
–
–
19:1
16:1
19:1
–
–
–
R
15 (2b)
80
66 (2b)
>99 (R,R)[f]
100
100
100
100
100
91/61[d] (2b)
78 (2b)
>99 (R,R)[f]
0.4[g]
0.2[g]
0.17[g]
1.8
>99 (R,R)[f]
24 (2b)
16 (2b)
16 (2b)
–
–
–
[a]
Reactions were carried out using imine 1a (0.25 mmol), nucleophile (as stated in table), [RhClACTHNUGTRNE(UNG C2H4)2]2 (3 mol%), 4
(6.6 mol%), 3.1M KOH(aq) (40 mol%) in dioxane (1.6 mL) for 3 h.
From crude H NMR.
[b]
[c]
[d]
[e]
[f]
1
Determined by chiral HPLC (see Supporting Information for conditions).
Isolated yield.
Prepared from bromobenzene.[11]
Stereochemistry determined by deprotection and comparison of the optical rotation with literature values.
3.1M KOH(aq) scaled down pro rata from 0.1 mmol (40 mol%) to 0.066, 0.083 or 0.028 mmol, respectively.
[g]
ACHTUNGTRENNUNG[2.2.2]octadiene ligand 4 developed by Hayashi
et al.[4b] (Table 1, entry 1). However, with the elec-
tron-deficient 4-chlorophenylboroxine 5b the conver-
sion dropped to 15% with mono-addition and hydrol-
ysis products observed (entry 4). Increasing the tem-
perature to 1008C raised the conversion to 91%
(entry 6). Lowering the amount of boroxine used had
a detrimental effect on the conversion (entries 7–9).
Lithium phenylboronate[11] could be added in place of
the boroxine, however with boronic acid and potassi-
um trifluoroborate nucleophiles little or no product
was observed (entries 3 and 10). Caesium fluoride
was found to be an acceptable base. However, in-
creasing the amount of potassium hydroxide and the
use of anhydrous conditions gave diminished conver-
sions (see Supporting Information).
Scheme 2. Synthesis of meso-diastereomer.
A range of substituted bis-sulfamyl imines and phe-
nylboroxines were prepared to test the scope of the
reaction. Aryl-Grignard addition to the imines gave a
1:1 mixture of diastereomers which could be separat- groups (entries 1 and 2, Table 2) and electron-donat-
ed by chiral HPLC but in most cases are identical by ing groups (entry 5) were tolerated. The enantiomeric
1H NMR. Synthesis of the achiral meso-diastereoiso- excess is excellent in most cases with the increased
mer via an N-sulfamoyloxazolidinone intermediate,[12] steric requirements of ortho-substituted 5e lowering
7 (Scheme 2) confirmed the identity of the three the result to 96% in entry 4.
peaks seen in the chiral HPLC chromatograph.
The substitution on the imine aryl group was inves-
Firstly, the unsubstituted imine 1a was reacted with tigated; again electron-withdrawing groups (entry 7)
a range of arylboroxines 5. Both electron-withdrawing and electron-donating groups (entry 10) were well tol-
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Bis-Sulfamyl Imines: Potent Substrates for Asymmetric Additions of Arylboroxines
Table 2. Scope of arylation.[a]
Entry
Ar1
Ar2
Yield [%][b]
ee [%][c]
dr[c]
1
2
3
4
5
6
7
8
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
4-FC6H4 (1c)
4-MeC6H4 (1d)
2-MeC6H4 (1e)
4-MeOC6H4 (1f)
3-MeC6H4 (1h)
4-BrC6H4 (1i)
4-FC6H4 (1c)
4-ClC6H4 (5b)
4-FC6H4 (5c)
4-MeC6H4 (5d)
2-MeC6H4 (5e)
4-MeOC6H4 (5f)
4-CO2EtC6H4 (5g)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
61 2b
69 2c
58 2d
71 2e
72 2f
37 2g
73 2c
73 2d
69 2e
69 2f
75 2h
62 2i
76 2j
>99 (R,R)[d]
>99 (R,R)
>99 (R,R)
96 (R,R)
>99 (R,R)
94 (R,R)[e]
>99 (S,S)
>99 (S,S)
98 (S,S)
>99 (S,S)
>99 (S,S)
>99 (S,S)[d]
98 (S,S)
16:1
32:1
~13:1[e]
~19:1[e]
12:1
32:1[f]
12:1
~12:1[e]
32:1
9
10
11
12
13
19:1
12:1
Ph (5a)
4-MeC6H4 (5d)
~10:1[e]
~10:1[e]
[a]
Reactions were carried out using imine 1 (0.25 mmol), boroxine 5 (0.6 mmol), [RhCl
3.1M KOH(aq) (40 mol%) in dioxane (1.6 mL) at 1008C for 3 h.
Isolated yield.
Determined by chiral HPLC (see Supporting Information for conditions).
Stereochemistry determined by deprotecting and comparing the optical rotation with literature values, other cases were
assigned by analogy.
ACHTUNGNERT(UNNG C2H4)2]2 (3 mol%), 4 (6.6 mol%),
[b]
[c]
[d]
[e]
[f]
Minimum dr, co-elution with traces of monoaryl addition product complicates analyses, see Supporting Information.
Calculated from ee of derived acetate 6g, a chiral HPLC method has yet to be found for 2g.
Table 3. Deprotection to free amine.
erated. ortho-Substitution on the imine (entry 9) had
a smaller impact on the enantiomeric excess than on
the boroxine. Unfortunately, thus far, although al-
ready high, the diastereomeric ratio could not be im-
proved by recrystallisation of 2.
Using the mild deprotection protocol described
above the chiral diarylmethylamines were isolated in
good yield and enantiomeric excess. The amines could
be isolated in near quantitative yield as their hydro-
gen sulfate salts, or as the free amine after a base
wash. In the case of the ethyl ester substituted 3g, the
free base was not isolated for fear of hydrolysis, but
the salt was used in the subsequent acetylation in
80% yield.
In some cases the ee values attained for the amine
3 in Table 3 are lower than that expected from the
precursor samples 2, analysed in Table 2. Traces of
monoaddition product (<5%, ee could not be deter-
mined) co-eluting with the meso-isomer account for
these observations. Nevertheless, the final free amines
are attained at synthetically useful ee values.
Entry Ar1
Ar2
Yield [%] ee [%][a]
1
Ph
4-ClC6H4
4-FC6H4
93 3b
80 3c
72 3d
76 3e
95 3f
87 (R)[b]
94 (R)
92 (R)
97 (R)
86 (R)
91 (R)
82 (S)
92 (S)
96 (S)
94 (S)
86 (S)
95 (S)[b]
92 (S)
2
Ph
3
Ph
4-MeC6H4
2-MeC6H4
4-MeOC6H4
4
Ph
5
Ph
6
Ph
4-CO2EtC6H4 99 3g[c]
7
8
9
4-FC6H4
4-MeC6H4
2-MeC6H4
Ph
Ph
Ph
79 3c
60 3d
74 3e
85 3f
73 3h
61 3i
99 3j
10
11
12
13
4-MeOC6H4 Ph
3-MeC6H4
4-BrC6H4
4-FC6H4
Ph
Ph
4-MeC6H4
[a]
Measured on acetamide derivative 6 by chiral HPLC
(see Supporting Information for conditions).
Stereochemistry determined by comparison of the optical
rotation with literature values, other cases were assigned
by analogy.
[b]
[c]
Isolated as the hydrogen sulfate salt.
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Experimental Section
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General Procedure for Rhodium-Catalysed
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A flame-dried Schlenk was charged with [RhClACTHNUGTRNE(UNG C2H4)2]2
(2.9 mg, 7.5 mmol, 3 mol%), 4 (5.5 mg, 16.5 mmol, 6.6 mol%)
and dioxane (0.4 mL), the orange solution was stirred at
room temperature for 10 min. Imine 1 (0.25 mmol), arylbor-
oxine 5 (0.6 mmol), 3.1M aqueous KOH (32.2 mL, 40 mol%)
and dioxane (1.2 mL) were added. The yellow solution was
stirred at 1008C for 3 h and became dark brown. Filtered
through a pad of silica, flushed with Et2O (20 mL), the fil-
trate was concentrated and purified by column chromatogra-
phy.
Deprotection to free amine (Table 3)
A solution of the sulfamide 2 in 5% H2O-pyridine (10 mL)
was stirred at reflux overnight. The pyridine was removed
under vacuum and the residue was partitioned between 1M
HCl (20 mL) and Et2O (20 mL). The aqueous layer was ba-
sified with 6M NaOH and extracted with Et2O (2ꢂ15 mL),
the organics were dried (Na2SO4) and concentrated to give
the product with no further purification necessary.
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Acknowledgements
Support from the Engineering and Physical Sciences Re-
search Council (EPSRC) and the FP7 programme of the Eu-
ropean Union through the COST-D40 programme is ac-
knowledged. One of us (RC) is grateful to the Engineering
and Physical Sciences Research Council, the University of
Nottingham and ChiroTech Technology Ltd. for the provi-
sion of a Ph.D. studentship.We thank the referees for impor-
tant suggestions regarding process optimisation and stereo-
chemical ratio determination.
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