Catalytic enantioselective addition of phenylboronic acid and phenylboroxine to N-tosylimines: PdII and RhI catalysis

Article abstract of DOI:10.1002/ejoc.200901139

This is the first account of a successful, Pd^II-catalysed enantioselective addition of phenylboronic acid to electron-deficient N-tosylarylimines by using chiral diphosphane ligands. A number of commercial diphosphane ligands were screened. Des

Full text of DOI:10.1002/ejoc.200901139

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901139
Catalytic Enantioselective Addition of Phenylboronic Acid and Phenylboroxine
II
I
to N-Tosylimines: Pd and Rh Catalysis
Carolina S. Marques[a,b] and Anthony J. Burke*[a,b]
Keywords: N-Tosylarylimines / Phenylboronic acid / Addition / Chiral amines / Enantioselective catalysis
II
This is the first account of a successful, Pd -catalysed enan- screened. Despite moderate to good yields, ee values of 99%
I
tioselective addition of phenylboronic acid to electron-de-
ficient N-tosylarylimines by using chiral diphosphane li-
gands. A number of commercial diphosphane ligands were
could be achieved with MeDuPhos. Novel Rh catalysts were
also screened, and ee values as high as 74% could be ob-
tained.
Introduction
Despite the attractiveness of this approach, catalytic
asymmetric imine arylations with boronic acids still have
yet to be fully exploited. In 2004, Tomioka and co-workers
reported the arylation of N-tosylimines with both aryl-
The formation of carbon–carbon single bonds is one of
the most fundamental, yet important reactions in organic
synthesis. The addition of specific carbon nucleophiles to
appropriate functionalities, like C=O, C=C and C=X is an
attractive synthetic methodology for forming C–C bonds.
In fact, the addition of arylboronic acids to arylimines in
the presence of appropriate catalysts, like (phosphane)rho-
dium(I) complexes is a very attractive method for forming
C–C bonds under very mild conditions, and at the same
time, introducing the amino functional group in the prod-
I
boronic acids and arylboroxines using Rh catalysts formed
from a variety of novel N-Boc--valine amidomonophos-
[3]
phanes and (S)-BINAP. The best result obtained was 92%
ee. (S)-BINAP could only afford a maximum ee of 34%. In
the same year, Hayashi’s group reported the arylation of N-
tosylimines with arylboroxines using chiral rhodium(I) cat-
[4]
alysts that contain C -symmetric bicyclo[2.2.2]octadienes;
2
ee values as high as 99% were obtained. It was demon-
strated that the ee values obtained with commercial chiral
diphosphane ligands, like (R)-BINAP (31% ee), (R)-
segphos (70% ee) and (S)-phosphoramidite (6% ee), were
lower. The main disadvantages of this method are that the
chiral diene must first be synthesised in order to prepare
[
1]
uct. Due to the large variety of arylboronic acids, which
are commercially available, a large array of α-arylamines
can be quickly assessed by using this method. Many α-aryl-
amines are known to be biologically active and are thus
present in a number of natural products and drugs. For in-
stance, (S)-ceterizine (Figure 1), an antihistaminic approved
drug to treat allergic symptoms, can be obtained by using
a diarylmethylamine precursor as a potential key intermedi-
ate.[
the chiral ligand, and toxic arylboroxines are used as rea-
[5a]
gents. Zhou and co-workers
demonstrated the highly
enantioselective addition of arylboronic acids to N-tosylar-
ylimines catalysed by Rh complexes containing a spiro
monophosphite ligand (S)-ShiP in aqueous media. The ad-
dition product was obtained in good yield (77%) and with
2]
[
5b]
high ee (93%). Gennari’s group
has reported the use of
chiral binaphtholic phosphate and phosphoramidite ligands
I
for the Rh -catalysed arylation of some N-tosylimines. The
best ee values (76–99%) were obtained with the former li-
gands.
Afterwards, Xu and co-workers[6a] developed and tested
Figure 1. (S)-Ceterizine (Zyrtec®).
a new type of C -symmetric chiral diene ligands, which
2
proved to be a remarkably efficient ligand for asymmetric
arylation of N-tosylarylimines using arylboronic acids.
They obtained excellent enantioselectivities (98%). Trin-
cado and Ellman later made some changes to the pro-
cedure and tested several known chiral phosphanes, of
which (R,R)-deguphos (5) (Figure 2) gave the best results.
They concluded that pre-incubating the ligand, the precata-
[
a] Departamento de Química, Universidade de Évora,
Rua Romão Ramalho 59, 7000 Évora, Portugal
Fax: +351-266744971
[
7]
E-mail: ajb@dquim.uevora.pt
[
b] Centro de Química de Évora, Universidade de Évora,
Rua Romão Ramalho 59, 7000 Évora, Portugal
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901139.
Eur. J. Org. Chem. 2010, 1639–1643
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1639

C. S. Marques, A. J. Burke
SHORT COMMUNICATION
Figure 2. Chiral phosphane ligands screened.
lyst and the arylboronic acid for 90 min prior to the ad-
dition of the substrate improved the yield, but, in some
cases decreased the enantioselectivity.
The application of palladium catalysts for catalytic asym-
metric imine arylation is very poorly developed, and there
are only a few reports in the literature as far as we are
aware. Shi and co-workers[ reported on the application of
8a]
2
+
C -symmetric cationic diaquo(NHC)Pd complexes, where
2
[
8c]
ee values of up to 94% have been achieved. Dai and Lu
Scheme 1. Asymmetric phenylation of N-tosylarylimine 1 with
reported the first application of the diphosphane ligands phenylboronic acid (2).
SEGPHOS and BINAP in an attempt to phenylate N-tosyl-
p-nitrophenylimine. However, the reaction failed. Besides
Table 1. Solvent screening reactions.
offering such versatility for carbon–carbon bond forma-
[
9]
η[a]
[%]
ee[b]
[%]
tion, Pd is a cheaper metal than rhodium and less toxic.
In this paper we wish to report our work with various
chiral Pd and Rh catalysts for the catalytic asymmetric aryl-
ation of selected N-tosylimines.
Entry
Solvent
Time
h]
[
1
2
3
4
5
6
7
dioxane
20
20
20
20
22
22
22
24
26
13
Ͻ10
30
26
10 (R)
17 (R)
45 (R)
Ͻ5 (R)
38 (R)
46 (S)
81 (R)
CHCl
3
MeOH
DMF
THF
Results and Discussion
CH
CH
2
Cl
CN
2
3
Ͻ5
Initially, we looked at the effect and potential of palla-
dium for this useful transformation. Lu and Dai have
shown that N-tosylarylimines with strong electron-with-
[
a] Isolated yields. [b] Determined by HPLC using an AD column,
n-hexane/2-propanol (90:10) at 0.7 mL/min, with wavelength detec-
tor at 230 nm.
[
5c]
drawing groups are the best substrates for this reaction.
For this reason we chose N-tosyl-o-chlorophenylimine as
our substrate. Pd(OAc) was used as the palladium source. the solvents, despite the ee increasing slightly for some sol-
2
We investigated the reaction of the N-tosyl-o-chloroaryl- vents, like MeOH, CH Cl and CH CN (Table 1, Entries 3,
2
2
3
imine 1 with phenylboronic acid (2) in the presence of 6 and 7, respectively). We believe that hydrolysis of the
[
5c]
Pd(OAc) (3 mol-%), Berens’ DIOP analogue 10 and a base tosylimine was the main side reaction,
which becomes
2
in toluene at 55 °C (Scheme 1). Berens’ DIOP analogue 10 kinetically more favourable in polar, coordinating solvents
has been studied in a number of catalytic asymmetric reac- like MeOH, DMF and CH CN. Toluene is therefore the
3
[
10a]
tions, like hydrogenation,
asymmetric allylic alkyl- solvent of choice. The switch in the configuration of the
[
10b]
[10c]
[10c]
ation,
hydroboration
and hydrosilylation.
Grati- major enantiomer to (S) on using CH Cl (Table 1, Entry 6)
2 2
fyingly as a first attempt, we could obtain the addition was surprising and implied a structural change in the active
product 3 in 77% yield and with an ee of 42% (Scheme 1). catalyst and/or the mechanism in this case.
The enantioselection favoured the (R) enantiomer.
A diverse range of diphosphane ligands were then
We conducted a solvent screening study to determine if screened (Figure 2). These included Trost’s ligands 4 and 6,
there were any solvent effects. The results are shown in which have been very successful in the palladium-catalyzed
[
11]
Table 1.
asymmetric allylic alkylation reaction,
(R,R)-Me-
This study showed that the reaction could be conducted DuPhos (8), which has also been very successful in the same
[
12,13]
in almost all the solvents described in Table 1, with the ex- reaction
and Berens’ ligand 10, which also has been
[
10b]
ception of CH CN and DMF. The yield decreased for all quite good for Pd-catalysed reactions.
3
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Eur. J. Org. Chem. 2010, 1639–1643

Addition of Phenylboronic Acid and Phenylboroxine to N-Tosylimines
We screened the ligands with both N-tosyl-o-chloroaryl- CH ) .
[
5a]
Berens’ ligand 10 gave moderate ee values of 42
2
2
imine 1 and N-tosyl-p-chloroarylimine 11 under the same and 41%, respectively (Table 2, Entries 12 and 13). Trost’s
conditions as described in Scheme 1.
ligands 4 and 6, which are excellent for palladium-catalyzed
By analysing the results obtained it could be seen that, allylic alkylations,[11] gave ee values of 82% and 69%,
generally speaking, the yields were moderate to good, with respectively (Table 2, Entries 1 and 4) with substrate 1.
a highest of 77% (isolated) achieved (Table 2, Entry 12).
We have proposed the following working model to ex-
The highest yields were achieved with 1, which indicated plain the resulting product configuration. This model was
[
8a]
that electronic effects were quite important. In fact, on based partly on information furnished in Shi’s paper.
I
using para substrate 11, the yields were very poor, see for Due to the overall configuration of the key Pd –aryl species
example Entry 3 (Table 2). containing Trost’s naphthyl ligand 6 or the DuPhos ligands
/8 or the BINAP ligand 9 (which are expected to coordi-
Table 2. Asymmetric phenylations of N-tosylimines 1 and 11 with nate with the arylimine in the mode suggested in Scheme 2)
7
phenylboronic acid and ligands 4–10.
the phenyl group will be delivered from the catalyst to the
imine via Re-face attack with preferential formation of the
(S)-amine enantiomer. Then delivery of the aryl group to
the imine will occur by Si-face attack resulting in the prefer-
ential formation of the (S)-amine enantiomer (Scheme 2).
In the case of Trost’s phenyl ligand 4, or the DeguPhos
ligand 5, or Berens’ ligand 10 the aryl group is expected to
be delivered by Si-face attack resulting in the preferential
formation of the (R)-amine enantiomer (Scheme 2).
Entry
Substrate
Ligand
Time
h]
η[a]
[%]
ee[b,c]
[%]
[
1
2
3
4
5
6
7
8
9
1
1
11
1
11
1
11
1
11
1
11
1
11
4
5
70
41
40
70
40
70
40
70
40
45
45
23
45
27
57
Ͻ10
22
16
21[
82 (R)
72 (R)
12 (R)
69 (S)
29 (S)
92 (S)
n.r.
Ͼ99 (S)
11 (S)
Ͻ5 (S)
Ͻ10 (S)
42 (R)
41 (R)
5
6
6
7
d]
7
n.r.
41
19
29
10
77
22
8
8
10
11
12
13
9
9
10
10
[
a] Isolated yields. [b] Determined by HPLC by using an AD col-
Scheme 2. Working model to explain the differential stereochemical
outcomes by using different diphosphane ligands.
umn, n-hexane/2-propanol (90:10) at 0.7 mL/min for substrate 1
and OD-H column, n-hexane/2propanol (93:7) at 0.7 mL/min for
substrate 11, both with wavelength detector at 230 nm. [c] The ab-
solute configurations were determined by comparing the data with
those already know in the literature. [d] No reaction.
In an attempt to block imine hydrolysis,[15] the phenyl-
boroxine 13 was investigated as the phenyl source. The re-
sults are highlighted in Table 3. Both 1 and 11 were used as
Regarding the enantioselectivity of these reactions. Some substrates and 7 and 10 as ligands.
very good to excellent ee values could be obtained. Overall
Concerning Berens’ ligand 10, the best result was
it was substrate 1, which gave the best ee values, and we achieved by using boroxine 13 and molecular sieves
attribute this to both electronic and sterochemical effects; (Table 3, Entry 5). Compared with Entry 12 (Table 2) this
for example, Ͼ99% ee with Me-DuPhos (8) (Table 2, En- method makes a significant difference, with both the yield
try 8) using 1 as substrate and 92% ee using iPr-DuPhos and the ee remarkably improved. Like in the case of using
(7) as ligand with the same substrate (Table 2, Entry 6). The phenylboronic acid (2) (Table 2, Entries 12 and 13) the aryl
fact that less bulkier 8 gave higher ee values than 7 might group is expected to be delivered by Si-face attack resulting
imply the intervention of a more compact Pd catalyst in the in preferential formation of the (R)-amine (Scheme 2).
former case. Surprisingly, although the phosphanes 7 and 8
It was found that the yields increased on using phenyl-
have the opposite absolute configurations, the major amine boroxine and molecular sieves as compared to using only
enantiomer had the (S) configuration in each case. In fact, phenylboroxine. With the bulkier iPr-DuPhos ligand (7) the
it was (S)-BINAP, which gave the lowest ee values, ac- yield increased for all the reactions, although the enantio-
companied by low yields. However, this would be expected selectivities remained quite low.
on the basis of Dai and Lu’s[ results with N-tosyl-p-nitro-
5c]
Using the method of Zhou
[5a]
we have also screened
phenylimine, and is in agreement with that of Zhou and co- some rhodium(I) catalysts with Berens’ ligand 10. Although
workers, who achieved an ee of 10% with 11 as substrate, the yields were quantitative, we could only achieve an ee
even though the pre-catalyst used was Rh(acac)(CH2- as high as 16% using [RhCl(COD)] with the N-tosyl-o-
2
Eur. J. Org. Chem. 2010, 1639–1643
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1641

C. S. Marques, A. J. Burke
SHORT COMMUNICATION
Table 3. Asymmetric phenylations of N-tosylimines 1 and 11 with Experimental Section
boroxine 13 and ligands 7 and 10.
General Remarks: All reactions were performed under an inert gas,
all the reagents were obtained from Aldrich, Fluka and Acros, and
all the solvents were dried by using standard laboratory methods.
The substrates 1 and 11 and phenylboroxine 13 were prepared by
using literature procedures.[
14,16]
Berens’ ligand 10 was provided by
ChiraTecnics, Lda. Racemic products for chiral HPLC analysis
were prepared from the corresponding N-tosylimines (0.5 mmol)
with phenylboronic acid (1.0 mmol) in the presence of Pd(OAc)
5 mol-%) and 2,2Ј-bypiridine (10 mol-%) in dioxane (1.5 mL) at
00 °C for 48–72 h.
2
(
1
Entry Substrate Ligand Mol. sieves (3 Å) Time η[a]
ee[b,c]
[
mg]
[h]
[%]
[%]
General Procedure for the Catalytic Asymmetric Arylation of N-
Tosylarylimines with Phenylboronic Acid or Phenylboroxine: Tolu-
ene (1.0 mL) was added to a round-bottom flask charged with
phenylboronic acid or phenylboroxine (0.4 mmol), pre-catalyst
(3 mol-%) and chiral ligand (3.3 mol-%) under nitrogen. The mix-
ture was heated to 55 °C and stirred for 30 min. N-Tosylarylimine
(0.2 mmol), toluene (1 mL) and NEt3 (0.4 mmol) were added se-
quentially. After the mixture was stirred for 55 °C during 24–48 h,
HCl (0.2 , 5 mL) was added to quench the reaction. The mixture
was extracted with EtOAc and washed with brine. The combined
1
2
3
4
5
6
7
8
1
11
1
11
1
11
1
11
10
10
7
none
none
none
none
200
200
200
200
44
44
44
44
64
64
64
64
Ͻ 10 36 (R)
27
27
40 (R)
38 (S)
7
Ͻ 10 Ͻ5 (R)
10
10
7
99
64
38
64 (R)
37 (R)
Ͻ5 (S)
7
29 Ͻ10 (R)
[
a] Isolated yields. [b] Determined by HPLC using an AD column,
n-hexane/2-propanol (90:10) at 0.7 mL/min for substrate 1 and OD-
organic phases were dried with MgSO and concentrated in vacuo.
The crude product was purified by silica gel column chromatog-
raphy to afford the desired diarylamine product.
4
H column, n-hexane/2-propanol (93:7) at 0.7 mL/min for substrate
1
1, both with wavelength detector at 230 nm. [c] The absolute con-
figurations were determined by comparing the data with those al-
ready know in the literature.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data.
chloroarylimine 1 and KF as base in toluene/water. How-
ever, when the reaction was conducted in the absence of
water (with toluene as solvent) and triethylamine as base
the ee dropped to 9% and the yield to 33%. This indicated
Acknowledgments
that the presence of water was important somewhere in the We are grateful for financial support from the Fundação para a
catalytic cycle. On turning to [Rh(COD) BF ] with trieth- Ciência e a Tecnologia (FCT) (project PPCDT/QUI/55779/2004)
2
4 2
through POCI 2010, supported by the European Community fund
FEDER. The FCT is also acknowledged for the award of a PhD
grant to C. S. M. (SFRH/BD/45132/2008). The personnel of the
NMR units of INETI (Lisbon, Portugal) and CACTI (Vigo, Spain)
are gratefully acknowledgment for NMR analysis.
ylamine as base in toluene, we could increase the ee up to
4%, despite obtaining a yield of only 14%. Analysis of the
7
Rh pre-catalyst showed that it contained approx. 5.5%
water, which was amassed during storage. When a fresh an-
hydrous sample of [Rh(COD) BF ] was used the ee was
2
4 2
only 6%, but the yield had increased to 34%. This result is
hard to explain, but implies that in the case of [Rh(COD)2-
BF ] substoichiometric quantities of water promote higher
enantioselection and at the same time, retard reaction effi-
ciency. The actual mechanism is currently under investiga-
tion.
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palladium-catalysed arylation of electron-deficient N-tosyl-
imines using both phenylboronic acid and phenylboroxine.
An ee of Ͼ99% could be obtained with Me-DuPhos. The
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Eur. J. Org. Chem. 2010, 1639–1643

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Received: October 8, 2009
[
Published Online: February 11, 2010
Eur. J. Org. Chem. 2010, 1639–1643
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1643