Enantioselective Rh-catalyzed addition of arylboronic acids to N-tosylarylimines

Article abstract of DOI:10.1055/s-2007-985570

A highly enantioselective rhodium-catalyzed addition of arylboronic acids to N-tosylarylimines is described, using chiral binaphtholic phosphite and phosphoramidite ligands. The best ee values (76-99%), associated with moderate to good chemical yields, we

Full text of DOI:10.1055/s-2007-985570

LETTER
2213
Enantioselective Rh-Catalyzed Addition of Arylboronic Acids to
N-Tosylarylimines
Enantioselective
h
i
dAryla
a
tionof
N
-
T
r
osylaryli
a
mine
s
Marelli,a Chiara Monti,b Cesare Gennari,*b Umberto Piarulli*a
a
Dipartimento di Scienze Chimiche e Ambientali, Università degli Studi dell’Insubria, Via Valleggio 11, 22100 Como, Italy
Fax +39(031)2386449; E-mail: umberto.piarulli@uninsubria.it
b
Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Via G. Venezian 21, 20133 Milano, Italy
Fax +39(02)50314072; E-mail: cesare.gennari@unimi.it
Received 13 June 2007
N,N-dimethylsulfamoylarylimines, using monodentate
Abstract: A highly enantioselective rhodium-catalyzed addition of
arylboronic acids to N-tosylarylimines is described, using chiral
binaphtholic phosphite and phosphoramidite ligands. The best ee
values (76–99%), associated with moderate to good chemical
yields, were obtained with binaphtholic phosphoramidite ligands
containing a bulky chiral amine.
phosphoramidite ligands.10
In our laboratories, a number of chiral tropos phosphorus
ligands, based on a flexible biphenol unit and a chiral P-
bound alcohol (phosphites) or secondary amine (phos-
phoramidites), were recently synthesized and used (indi-
vidually or as a binary mixture) in the Rh-catalyzed
asymmetric hydrogenation of functionalized olefins,11
and in the Rh-catalyzed conjugate addition of aryl boronic
acids to enones and enoates.12
Key words: arylations, arylboronic acids, asymmetric catalysis,
imines, rhodium
Enantiopure diarylmethylamines represent an interesting
synthetic target due to the presence of this substructure in
a variety of pharmacologically active compounds.1 In
recent years, considerable progress has been achieved in
the catalytic enantioselective arylation of imines as an
effective methodology for the synthesis of these important
substrates.2 Excellent enantioselectivities have been
reported for the addition of arylzinc,2 aryltin3 and
aryltitanium4 reagents. More recently, arylboron reagents
have received increasing attention because of their avail-
ability, stability, low toxicity, and compatibility with a
wide range of functional groups.5 So far, only a few re-
ports have been published on the rhodium(I)-catalyzed
asymmetric addition of arylboron reagents to imines. To-
mioka and co-workers described the first enantioselective
addition of arylboronic acids and arylboroxines to N-tos-
ylarylimines using a chiral amidophosphane ligand.6
Enantiomeric ratios above 95:5 were obtained through
steric tuning of both the imine and the boron reagent.
Hayashi and co-workers reported excellent enantioselec-
tivities for the addition of arylboroxines to N-tosyl- and N-
nosylarylimines employing chiral diene ligands.7 Ellman
and co-workers reported an example of high enantio-
selectivity in the addition of arylboronic acids to N-di-
phenylphosphinoylarylimines using deguphos as chiral
ligand.8 More recently, monodentate phosphite ligands
have been used by Zhou and co-workers in the highly
enantioselective (85–96% ee) addition of arylboronic
acids to N-tosylarylimines,9 while the group of de Vries,
Feringa and Minnaard reported good enantioselectivities
(82–94% ee) in the rhodium-catalyzed arylation of
In this letter, we report our findings in the rhodium-cata-
lyzed enantioselective addition of arylboronic acids to N-
tosylarylimines, using monodentate biphenolic and bi-
naphtholic phosphites and phosphoramidites as chiral
ligands.
A small library13 of chiral biphenolic and binaphtholic
phosphites and phosphoramidites (1–11, Figure 1)14 was
initially screened in the Rh-catalyzed addition of phenyl-
boronic acid to N-tosyl-p-tolylaldehyde imine, using the
conditions reported by Zhou and co-workers9 (Scheme 1).
The ligands were tested either individually (Table 1, en-
tries 1–11) or as binary combinations (La/Lb 1:1, 3 mol%
each)11,12 (Table 1, entries 12–16).
Rh(acac)(C2H4)2 (3 mol%)
Ph
La/Lb (1–11) (6 mol%)
PhB(OH)2 (13) (5 equiv)
Ts
Ts
N
N
H
KF (2 equiv)
toluene–H2O (1:1), 35 °C
12
14
Scheme 1 Enantioselective addition of phenylboronic acid to N-to-
syl-p-tolylaldehyde imine: preliminary screening (see Table 1)
In general, phosphoramidites were more selective than
phosphites: good enantiomeric excesses were obtained
with binaphtholic phosphoramidite ligands containing a
bulky chiral amine (i.e. ligands 9 and 11; entries 9 and 11).
Unfortunately, the yields were only moderate for most of
the ligands (good yields were obtained with the binaphth-
olic phosphite 7 and Monophos® (8), entries 7 and 8).
When binaphtholic phosphite 7 [yield: 87%, ee: 40% (S);
entry 7] and Monophos® (8) [yield: 90%, ee: 27% (S); en-
try 8] were used in combination, a small cooperative ef-
fect was observed [yield: 95%, ee: 50% (S); entry 12].
Although the increase of ee obtained by the combination
SYNLETT 2007, No. 14, pp 2213–2216
0
3
.0
9
.2
0
0
7
Advanced online publication: 13.08.2007
DOI: 10.1055/s-2007-985570; Art ID: G18607ST
© Georg Thieme Verlag Stuttgart · New York

2214
C. Marelli et al.
LETTER
Ph
N
O
P
O
O
O
O
O
O
O
P
P
O
P
O
O
1
2
3
4
Ph
N
Ph
N
O
O
O
O
O
O
P
OPh
N
P
P
P
O
O
Ph
Ph
5
6
7
8
Ph
N
Ph
N
Ph
O
O
O
O
P
P
N
P
O
O
Ph
Ph
Ph
9
10
11
Figure 1 Library of chiral biphenolic and binaphtholic phosphite and phosphoramidite ligands
Table 1 Screening of Ligands 1–11 and of Some Ligand Binary
Mixtures in the Addition of Phenylboronic Acid to N-Tosyl-p-tolyl-
aldehyde Iminea
of these two ligands is only marginal and not synthetically
useful, it implies that both ligands are present in the
rhodium complex during the enantiodiscriminating step
of the reaction.
Entry
1
La
1
Lb
–
–
–
–
–
–
–
–
–
–
–
8
9
1
4
6
Conversionb (%)
eec (%)
3 (R)
8 (S)
Encouraged by the ee values obtained with ligands 9 and
11, we decided to screen different reaction conditions
(solvent, base and temperature) using ligand 9, in order to
improve the yields of the reaction. While no improvement
was observed using numerous solvent–base combinations
[anhyd toluene, acetone, THF–H2O (1:1), dioxane–H2O
(10:1), dioxane–H2O (1:2) as solvents, with LiF, KF,
KOH, Et3N as bases], good yields and ee values were
finally obtained using anhydrous dioxane with LiF as
base.15
42
79
19
50
33
61
87
90
45
0
2
2
3
3
7 (S)
4
4
23 (S)
22 (R)
80 (S)
40 (S)
27 (S)
90 (S)
–
5
5
6
6
7
7
A small sublibrary of phosphoramidite ligands was then
tested under these optimized conditions in the addition of
phenylboronic acid to N-tosyl-p-tolylaldehyde imine, in-
cluding also ligand 15 (the diastereomer of 11) and bi-
naphtholic phosphoramidite 16 derived from bis(1-
naphthylethyl)amine (Figure 2 and Table 2).
8
8
9
9
10
11
12
13
14
15
16
10
11
7
25
95
17
50
56
55
93 (S)
50 (S)
49 (S)
61 (S)
0
7
9
Ph
O
O
O
O
7
P
N
P
N
8
24 (S)
Ph
a Reaction conditions: phenylboronic acid (5 equiv), N-tosyl-p-tolyl-
aldehyde imine (1 equiv), Rh(acac)(C2H4)2 (3 mol%), L (6 mol%),
toluene–H2O (1:1) with KF (2 equiv), 35 °C, 24 h.
15 (Ra,S,S)
16 (Sa,S,S)
b Calculated by 1H NMR analysis of the crude reaction mixture.
c Both the ee values and the absolute configurations were determined
by HPLC using a Chiralcel OD-H column (see ref. 9).
Figure 2 Structure of ligands 15 and 16 used in the screening under
optimized reaction conditions
Synlett 2007, No. 14, 2213–2216 © Thieme Stuttgart · New York

LETTER
Enantioselective Rh-Catalyzed Arylation of N-Tosylarylimines
2215
Table 3 Asymmetric Arylation of N-Tosylarylimines with Aryl-
Table 2 Addition of Phenylboronic Acid to N-Tosyl-p-tolylalde-
boronic Acids:18 Scope of the Reaction
hyde Iminea
Entry Ar
Ar1
L
Conver- eeb (%)
siona (%)
Entry
L
Conversionb (%)
eec (%)
87 (S)
33 (R)
90 (S)
86 (S)
84 (S)
76 (R)
1
2
3
4
5
6
9
60
21
93
82
65
15
1
2
2-MeC6H4
2-MeC6H4
Ph
Ph
9
54
42
40
70
40
32
16
30
88
80
60
85
78 (S)
71 (S)
89 (S)
81 (S)
99 (S)
51 (S)
89 (S)
87 (S)
87 (R)
87 (R)
68 (R)
76 (R)
10
11
15
6
11
9
3
4-OMeC6H4 Ph
4-OMeC6H4 Ph
4
11
9
5
1-naphthyl
1-naphthyl
4-BrC6H4
4-BrC6H4
Ph
Ph
16
6
Ph
11
9
a Reaction conditions: phenylboronic acid (5 equiv), N-tosyl-p-tolyl-
aldehyde imine (1 equiv), Rh(acac)2 (C2H4) (3 mol%), L (6 mol%),
anhyd dioxane with LiF (10 equiv), 50 °C, 24 h.
7
Ph
8
Ph
11
9
b Calculated by 1H NMR analysis of the crude reaction mixture.
c Both the ee values and the absolute configurations were determined
by HPLC using a Chiralcel OD-H column (see ref. 9).
9
4-MeC6H4
4-MeC6H4
4-OMeC6H4
10
11
12
Ph
11
9
Ph
A clear matched combination of the binaphthol chiral axis
and of the amine stereocenters is observed for phosphor-
amidite 9 (Sa,S,S) [yield: 60%, ee: 87% (S); entry 1] with
respect to 10 (Ra,S,S) [yield: 21%, ee: 33% (R); entry 2].
On the contrary, in the case of 11 (Sa,S,S) and 15 (Ra,S,S),
which also share the same enantiomer of the amine moi-
ety, the opposite enantiomer of the binaphthol chiral axis
plays only a very marginal role [ee: 90% (S) vs. ee: 86%
(S), entries 3 and 4]. The importance of the 2,5-di-
phenylpyrrolidine moiety is further confirmed by the 84%
ee in favor of the S-enantiomer (entry 5) obtained using
ligand 6, which is devoid of the chiral axis. Ligands 11
and 6 have already been used by us11,12 and others16 as
very effective ligands in different reaction processes.
Ligand 16 (Sa,S,S),17 which contains a bulkier amine sub-
stituent, showed a reduced yield and a reversed enantio-
facial selectivity [yield: 15%, ee: 76% (R); entry 6]. This
result might indicate that a different mechanism is operat-
ing in this case: possibly the active Rh complex contains
only one ligand.
Ph
4-OMeC6H4 11
a Calculated by 1H NMR analysis of the crude reaction mixture.
b Both the ee values and the absolute configurations were determined
by HPLC using a Chiralcel OD-H column (see ref. 9).
Good to excellent ee values (76–99%) were obtained in
the arylation of differently substituted N-tosylarylimines,
containing either electron-donating or electron-withdraw-
ing substituents, while the catalytic efficiency was moder-
ate in most cases, as witnessed by the conversions. An
excellent ee (99%; entry 5) was obtained with N-tosyl-1-
naphthaldehyde imine using ligand 9, while only a mod-
erate enantioselectivity (ee: 51%; entry 6) was observed
with ligand 11. Electron-rich substrates gave generally
higher yields (entries 1–4), while a slower addition reac-
tion, associated with lower overall yields, occurred with
electron-poor substrates (entries 7 and 8). Electron-rich
arylboronic acids (entries 9–12) gave generally good
yields in the addition to N-tosylbenzaldimine, associated
with moderate to good ee values.
Having established the optimal synthetic protocol, the
scope of this arylation reaction was examined, testing
several aromatic imines and arylboronic acids, and using
our best ligands 9 and 11 (Scheme 2 and Table 3).
Diarylmethylamines can be obtained from their N-tosyl
derivatives by removal of the N-tosyl group, in high yields
and without loss of enantiomeric purity, by reaction with
SmI2.19
Rh(acac)(C2H4)2 (3 mol%)
L (6 mol%)
Ar1B(OH)2 (5 equiv)
Ar1
In summary, we have described a highly enantioselective
arylation of N-tosylarylimines with arylboronic acids cat-
alyzed by rhodium complexes of chiral bulky binaphtho-
lic phosphoramidite ligands. In particular, ligand 9, which
gave high ee values and reasonable yields, can be easily
prepared from commercially available starting materials.
We are currently exploring the applicability of this proce-
dure to differently protected/activated arylimines (with
more easily cleavable activating/protecting groups) and to
ketimines.
Ts
Ts
Ar
N
Ar
N
H
LiF (10 equiv)
dioxane, 50 °C, 24 h
Scheme 2 Asymmetric arylation of N-tosylarylimines with aryl-
boronic acids: scope of the reaction
Synlett 2007, No. 14, 2213–2216 © Thieme Stuttgart · New York

2216
C. Marelli et al.
LETTER
(11) (a) Monti, C.; Gennari, C.; Piarulli, U. Tetrahedron Lett.
Acknowledgment
2004, 45, 6859. (b) Monti, C.; Gennari, C.; Piarulli, U.; de
Vries, J. G.; de Vries, A. H. M.; Lefort, L. Chem. Eur. J.
2005, 11, 6701.
We thank the European Commission for financial support [Folda-
mers, MEST-CT-2004-515968 and (R)Evolutionary Catalysis
MRTN-CT-2006-035866]. We also like to thank the Ministero
dell’Università e della Ricerca (PRIN prot. 2006030449) for finan-
cial support and for a postdoctoral fellowship (Assegno di ricerca)
to C. Monti. C. Marelli thanks the Dipartimento di Chimica
Organica e Industriale for the hospitality (2006).
(12) (a) Monti, C.; Gennari, C.; Piarulli, U. Chem. Commun.
2005, 5281. (b) Monti, C.; Gennari, C.; Piarulli, U. Chem.
Eur. J. 2007, 13, 1547.
(13) For recent reviews on combinatorial ligand libraries and
high-throughput experimentation in homogeneous catalysis,
see: (a) Gennari, C.; Piarulli, U. Chem. Rev. 2003, 103,
3071. (b) de Vries, J. G.; de Vries, A. H. M. Eur. J. Org.
Chem. 2003, 799. (c) Satyanarayana, T.; Kagan, H. B. Adv.
Synth. Catal. 2005, 347, 737. (d) De Vries, J. G.; Lefort, L.
Chem. Eur. J. 2006, 12, 4722. (e) Jäkel, C.; Paciello, R.
Chem. Rev. 2006, 106, 2912.
(14) (a) For the synthesis of ligands 1–6, see ref. 11. (b) For the
synthesis of ligand 7, see: Reetz, M. T.; Mehler, G. Angew.
Chem. Int. Ed. 2000, 39, 3889. (c) For the synthesis of
ligands 8–10, see: Feringa, B. L.; Pineschi, M.; Arnold, L.
A.; Imbos, R.; de Vries, A. H. M. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2620. (d) For the synthesis of ligand 11, see:
Choi, Y. H.; Choi, J. Y.; Yang, H. Y.; Kim, Y. H.
Tetrahedron: Asymmetry 2002, 13, 801.
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(18) General Procedure for the Arylation of N-Tosylaryl-
imines: In a flame-dried Schlenk tube flushed with nitrogen,
Rh(acac)(C2H4)2 (1.2 mg, 4.65 mmol, 3 mol%) and the ligand
(9.30 mmol, 6 mol%) were dissolved in anhyd dioxane (0.75
mL). After stirring for 30 min at r.t., LiF (1.5 mmol) and the
substrate (0.15 mmol) were added followed by the
appropriate arylboronic acid (0.75 mmol). The resulting
mixture was stirred at 50 °C for 24 h, quenched with H2O
(3 mL) and extracted with CH2Cl2 (3 mL). The organic phase
was dried over Na2SO4 and the solvent was evaporated under
vacuum. The residue was purified by flash chromatography
on silica gel (n-hexane–EtOAc, 7:3) affording the N-tosyl-
diarylmethylamine as a white solid.
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Synlett 2007, No. 14, 2213–2216 © Thieme Stuttgart · New York

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