A Chiral Disulfoxide Ligand for the Efficient Rhodium-Catalyzed 1,2-Addition of Arylboroxines to N-Tosylarylimines

Article abstract of DOI:10.1002/adsc.201500975

Enantiomerically pure diarylmethylamines are important building blocks in active pharmaceutical ingredients. Herein, we report a rhodium precatalyst with a chiral disulfoxide ligand that effects the 1,2-addition of arylboroxines to aromatic imines to give high yields and high enantioselectivities of these products. The present paper describes a system that is very simple, where the ease of synthesis of the chiral ligand is combined with low catalyst loadings and reaction conditions that do not need any additives or external base.

Full text of DOI:10.1002/adsc.201500975

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DOI: 10.1002/adsc.201500975
Very Important Publication
A Chiral Disulfoxide Ligand for the Efficient Rhodium-Catalyzed
1,2-Addition of Arylboroxines to N-Tosylarylimines
Guang-Zhen Zhao,a GellØrt Sipos,a Alvaro Salvador,a Arnold Ou,a Pengchao Gao,a
Brian W. Skelton,b and Reto Dortaa,*
a
School of Chemistry and Biochemistry, University of Western Australia, 35 Stirling Highway, 6009 Crawley, Western
Australia, Australia
Fax: (+61)-8-6488-7330; phone: (+61)-8-6488-3161; e-mail: reto.dorta@uwa.edu.au
Centre for Microscopy, Characterisation and Analysis, University of Western Australia, 35 Stirling Highway, 6009
b
Crawley, Western Australia, Australia
Received: October 22, 2015; Revised: November 23, 2015; Published online: January 26, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500975.
Abstract: Enantiomerically pure diarylmethylamines is very simple, where the ease of synthesis of the
are important building blocks in active pharmaceuti- chiral ligand is combined with low catalyst loadings
cal ingredients. Herein, we report a rhodium precata- and reaction conditions that do not need any addi-
lyst with a chiral disulfoxide ligand that effects the tives or external base.
1,2-addition of arylboroxines to aromatic imines to
give high yields and high enantioselectivities of these Keywords: 1,2-additions; chiral disulfoxide ligands;
products. The present paper describes a system that diarylmethylamines; rhodium catalysis
Introduction
These advantages make them, when paired with
(chiral) Rh and Pd catalysts, the most widely used
Chiral diarylmethylamines are molecular frameworks aryl sources for asymmetric arylation reactions of
that are frequently found in pharmacologically active imines.[11] To date, a wide range of chiral ligands have
compounds and their synthetic access in enantiopure been described in these reactions and include phos-
form is therefore of high interest.[1–5] One of the most phine(s), olefin(s), phosphoramidite(s), and phos-
successful strategies that has emerged to access these phate(s), which in conjunction with the appropriate
compounds is the arylation of aldimines. For example, rhodium precursor, give the corresponding chiral
the asymmetric addition of highly reactive organome- amine products in good yields and high enantiomeric
tallic reagents to imino compounds with enantioselec- excess.[12] It is therefore surprising to note that among
tivity controlled by chiral O/N-coordinating ligands[6] the impressive array of chiral ligand systems de-
or chiral auxiliaries[2b,c,4c,7] is a fast and reliable scribed for this important reaction, there are very few
method for asymmetric synthesis of this scaffold.[8] reports that work at catalyst loadings lower than
Useful chiral diarylmethylamines with high enantio- 1 mol%,[12h,p] which given the high price of the metal/
meric excess were successfully obtained with this ligand combinations used would be a prerequisite for
method, although it is normally more efficient for the successful applications on a larger scale. A possible
synthesis of dialkylmethylamine or alkylarylmethyla- problem that may be at least in part responsible for
mine synthesis.[9]
the lack of reactivity of most catalysts is the fact that
Asymmetric addition processes that employ chiral these reactions are oftentimes plagued by competing
transition metal catalysts represent another entry to imine hydrolysis.[12k]
these building blocks. As a main advantage to the
In 2008, our group showed that a chiral chelating
above-mentioned more traditional methods, they disulfoxide ligand can be employed successfully in
offer the possibility of using milder, less reactive ary- a Rh-catalyzed addition reaction, namely the 1,4-addi-
lation agents.[10] Among them, arylboron reagents are tion of boronic acids to a,b-unsaturated compounds
particularly appealing as they are readily available, (Hayashi–Miyaura reaction).[13] The ligand design was
highly functional group compatible, and much less based on a simple mimic of the very successful chiral
toxic and hazardous than other arylation reagents. binap ligand, where the two phosphine moieties were
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substituted by chiral sulfoxides. This work and follow- tiopure form, which renders ligand syntheses straight-
ing ligand designs by other groups all suggest that at forward, cheap and practical.
least for such rhodium-catalyzed addition reactions, S-
To extend the reactivity of our binaso-type family
bound, sulfinyl-based ligands can indeed be used suc- of disulfoxides, we herein report the employment of
cessfully in asymmetric catalysis.[14] Of the many these C2-symmetric S-chiral disulfoxide ligands in the
chiral ligand designs available, one of the main advan- 1,2-addition of arylboroxines to N-tosylaldimines. At
tages of using sulfoxides is their easy access in enan- the outset of this study, it was not clear whether these
ligands would be successful in the 1,2-addition, as it is
well known that ligand requirements between the 1,4-
Table 1. Asymmetric arylation of N-tosylimine 6 with aryl-
boroxine 7: optimization of reaction conditions.[a]
addition to a,b-unsaturated compounds and the 1,2-
addition to imines are different and distinct and very
few examples exist where the same ligand is able to
promote both these reactions.[12n,p,q,u] Indeed, the
report here is the first that shows that a disulfoxide
ligand system can be used in the 1,2-addition reaction.
A careful optimization study on the reaction condi-
tions also led to a system where hydrolysis was not
observed for the imine substrates,[11f,12k,15] while mild
reaction conditions in aqueous toluene were main-
tained giving high yields and enantioselectivities at
catalyst loadings that are among the lowest report-
ed.[16]
Results and Discussion
Initial studies were carried out with 4-methylbenzal-
dehyde N-tosylimine 6a and phenylboroxine 7a reac-
tants with rhodium catalysts containing various
binaso-type ligands under reaction conditions report-
ed in the literature that include using excess KF as
a base additive (Table 1, entries 1–4). The chloro-
bridged rhodium dimer [(L1)RhCl]2, which was suc-
cessfully utilized in our initial report on 1,4-addition
reactions,[13a] was tested first (entry 1) using a toluene/
water mixture (1:1) to which were added the catalyst
(2.5 mol% Rh) and KF (4 equivalents). The mixture
was heated to 358C for 18 h giving a high isolated
yield of phenyl(4-methylphenyl)methylamine tosyla-
mide 8aa (95% yield) after chromatography on silica
gel. Gratifyingly, the enantiomeric purity was deter-
mined to be 96% ee by HPLC analysis. Varying the
para-substituents of the phenyl group on the binaso li-
gands did not improve the outcome with 4-fluoro-sub-
[a]
Reaction conditions: imine 6 (0.30 mmol), boroxine 7
(0.6 mmol B), rhodium catalyst and additives were stirred
in toluene/H2O (2.0 mL/2.0 mL) for 12–18 h.
Isolated yields after column chromatography.
[b]
[c]
Determined by HPLC analysis; absolute stereochemistry
assigned by comparison with results reported in refs.[12g,l]
[d]
6 (0.45 mmol), 7 (0.9 mmol) in toluene/H2O (4.5 mL/
2.5 mL).
Toluene as solvent, no H2O.
1.4 equiv. B (0.42 mmol) were used.
6 (0.45 mmol), 7 (0.9 mmol) in toluene/H2O (6.0 mL/
[e]
[f]
[g]
1.0 mL).
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À
Figure 1. (a) Molecular structure of [{(M,S,S)-p-Tol-binaso}Rh(OH)]2 (30% probability ellipsoids; only O H hydrogen
atoms shown). Selected bond lengths (Š) and angles (deg): Rh1 O10’, 2.049(3) and 2.061(3); Rh1 S1, 2.1563(9); Rh1 S2,
À
À
À
À
À
À
À
À
À
À
À
À
2.1598(9); S1 O1, 1.477(3); S2 O2, 1.481(3); S1 Rh1 S2, 98.87(3); O10 Rh1 S2, 93.86(8); O10 Rh1 S2’, 168.61(8); O10
Rh1 S1, 166.31(8); O10 Rh1 S1’, 92.45(8); O10 Rh1 O10’, 74.75(14). The prime refers to the atom at x,1Ày,1/2Àz. (b):
Half-view, ball-and-stick model of the {(M,S,S)-p-Tol-binaso}[Rh] fragment.
À
À
À
À
À
stituted binaso L2 giving a slightly lower yield and ligand for these substrates (entry 10), and more im-
enantioselectivity (entry 2). Excellent enantiocontrol portantly, the bis-sulfoxide ligand (R,R)-1,2-bis(tert-
was observed when electron-donating 4-methoxy-sub- butylsulfinyl)benzene,[14c] reported by Liao as an ex-
stituted binaso L3 was used (97% ee), but the isolated cellent ligand in the 1,4-addition reaction, led to a cat-
yield dropped significantly (50% yield). When modi- alyst system that showed high enantioselectivity
fying the backbone structure of the ligand (L4), which (entry 11), but was not very active.
in our earlier studies on the 1,4-addition reaction led
In the hope to increase reactivity further and be-
to the most active and selective catalyst,[13b] 8aa was cause Hayashi et al. had previously established that
again obtained in good enantiomeric excess (95% ee) a relatively big reactivity difference existed between
but in just 50% yield (entry 4). This underlines the the dimeric Cl- and OH-bridged catalyst precursors in
fact that 1,4-addition and 1,2-addition reactions have the related 1,4-addition reaction,[17] we next set out to
distinct ligand requirements and indeed, classical synthesize [(L1)Rh(OH)]2. This new Rh complex was
chiral diphosphine binap, one of the preferred ligands obtained in high yield by treatment of the disulfoxide
for the 1,4-addition reaction, performs very poorly in coordinated Cl-bridged [(L1)RhCl]2 with potassium
the 1,2-addition reaction to imines (entry 5). Not sur- hydroxide in aqueous acetone at room temperature,
prisingly, omitting the catalyst does not lead to any which after appropriate washing and work-up gave
product formation (entry 6).
[(L1)Rh(OH)]2 as a well-divided orange powder.
After having identified L1 as the proper ligand, we When this new catalyst was tested in the model reac-
proceeded to optimize the reaction conditions using tion and compared to [(L1)RhCl]2, (entries 13 and 7,
benzaldehyde N-tosylimine 6b and arylboroxine 7c. respectively), we noted a cleaner reaction outcome re-
The choice of these substrates also highlights the fact sulting in increased yield of 8bc. More importantly, by
that both enantiomers of the amine product(s) may switching to the hydroxo-bridged precatalyst, addition
be synthesized using a single catalyst by simply of base was not necessary anymore and as an added
switching the two substrate components (entry 1 vs. bonus, reactivity was such that the reactions could be
entry 7). We began our optimization of the reaction run at ambient temperature (entry 15). Entries 16 and
conditions by testing different bases in the reaction, 17 show that reaction conditions that completely
as KF is relatively expensive, especially given the fact remove water did not lead to generation of the prod-
that a large amount (4 equiv.) is required. As a first uct in significant amounts. It should though be noted
attempt, we switched to stronger NaOH as a base, that the low product yield seen when using a higher
that even when used in catalytic amounts (entry 8) in- catalyst loading (entry 17) indicates that direct trans-
curred significant hydrolysis of the imine substra- metallation between the rhodium amido species and
te.[11f,12k] Gratifyingly, a catalytic amount of K3PO4 arylboroxine (avoiding the [Rh]-OH intermediates) is
(0.2 equiv.) gave a high yield of product (91% yield) indeed happening,[12b] albeit at a much slower rate
while maintaining the excellent selectivity seen with (see also discussion of Figure 2 below).
KF (96% ee, entry 9). Binap was again not a good
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Table 2. Asymmetric arylation of N-tosylimines 6 with aryl-
boroxines 7.[a]
Figure 2. Possible
[(L1)Rh(OH)]2.
catalytic
cycle
starting
from
When only 1.4 equivalents of the arylboroxine cou-
pling partner were employed (based on B), the reac-
tion still proceeded smoothly (entry 18). Finally, we
were able to lower the catalyst loading further by run-
ning the reaction under slightly more dilute condi-
tions (entry 19).
Having established the correct reaction conditions,
precatalyst [(L1)Rh(OH)]2 was then tested in the ary-
lation of N-tosylarylimines with a variety of arylbor-
oxines (Table 2). To our delight, the low catalyst load-
ings (0.25 mol%) and simple (no addition of base or
other additives) as well as mild reaction conditions
(room temperature) worked for a variety of substrates
as shown in Table 2. The recorded enantioselectivities
throughout are excellent, and the desired products
were all obtained in 94–99% ee. As can be seen, aryl-
boroxines bearing electron-donating or electron-with-
drawing groups are well tolerated for the arylation of
benzaldehyde N-tosylimine 6b with products obtained
in 58–99% yield with 95–99% ee (entries 1–9). Good
yields were also achieved when nucleophiles with
electron-withdrawing functional groups (4-Cl, 4-F)
were employed (entries 4–6). The para- and meta-sub-
stituted arylimines were all arylated with phenylbor-
oxine 7a to give the desired products in 77–98% yield
with 96–99% ee (entries 10, 11, 13–18). The ortho-
substituted arylimines 6e, 6l and 6o also reacted swift-
ly with different boroxines to give the corresponding
addition products in good yields and enantioselectivi-
ties (entries 12, 21, 23). Overall and as far as we are
aware, the catalytic results in Table 2 report a reaction
system that is among the simplest and most efficient
for the synthesis of chiral diarylmethylamines.
[a]
Reaction conditions: A mixture of 6 (0.45 mmol), 7
(0.9 mmol B) and [(L1)Rh(OH)]2 was stirred in toluene
(6.0 mL) and H2O (1.0 mL) at 258C for 14–15 h.
[b]
Isolated yields after column chromatography.
[c]
Determined by HPLC analysis; absolute stereochemistry
assigned by comparison with results reported in refs.[12g,l]
[d]
Reaction was run at 358C.
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Table 3. Asymmetric arylation of N-nosylimines 9 with aryl-
boroxines 7.
ingly, the dihedral angles of the two naphthyl units
À
À
and S Rh S bond angles in [(L1)Rh(OH)]2 are very
similar to the values measured for the previously re-
ported [(L1)RhCl]2 complex, with the main difference
between the two complexes being seen in the bond
À
À
lengths for Rh OH which is shorter than that of Rh
À
À
Cl [Rh OH, 2.049(3) and 2.061(3) Š; Rh Cl,
2.3650(12) and 2.3847(12) Š].
À
The Rh S bond lengths in [(L1)Rh(OH)]2 and
[(L1)RhCl]2 are very similar, with slightly shorter
values (on average, 0.033 Š shorter) for the OH-
bridged complex due to its lower trans influence. In
À
terms of overall Rh OH bond length, we compared
the values found for [(L1)Rh(OH)]2 with the other,
crystallographically characterized complexes of the
same type. Quite surprisingly, only 7 other compounds
have been characterized so far and include either
alkene or phosphorus coordinated (m-OH)2 bridged
square-planar rhodium(I) dimers (Cambridge Struc-
tural Database).[12k,21] Within this limited dataset, we
[a]
Reaction conditions: a mixture of 9 (0.45 mmol), 7
(0.9 mmol B) and rhodium complex was stirred in tolu-
ene (6.0 mL) and H2O (1.0 mL) at 258C for 14–15 h.
Isolated yields after column chromatography.
[b]
[c]
Determined by HPLC analysis; absolute stereochemistry
assigned by comparison with results reported in ref.[12m]
À
notice that the mean Rh OH bond length for our
sulfoxide bound complex [2.055(3) Š] is at the lower
limit of the range reported so far (2.047–2.116 Š).
The dihedral angle between the two coordination
While modern deprotection methods for the tosy- planes defined by two groups of O—Rh—O of the
lated products 8 shown in Table 2 are very mild and four-membered ꢁRhORhOꢂ ring is 120.1(1)8, which is
straightforward,[18] we deemed it important to extend the largest among the reported (m-OH)2 bridged rho-
our chemistry to the related 4-nitrophenylsulfonylaldi- dium(I) dimers. Accordingly, it possesses the smallest
mines. This was also done in view of the fact that ac- intermetallic separation [2.82960(5) Š].
cording to some previous reports, nosyl-protected
Again comparing the solid-state structure of
À
substrates do not behave analogously to the tosyl-pro- [(L1)Rh(OH)]2 with [(L1)RhCl]2, the S O bond
tected ones in these 1,2-addition reaction.[10a,12m,o] lengths of [(L1)Rh(OH)]2 are slightly longer [S O in
À
À
Under the exact same reaction conditions established free ligand, 1.4922(16) Š; S O in Cl-bridged complex,
above, we found that the products of representative 1.466(4) and 1.473(4) Š; S O in OH-bridged com-
substrates were transformed to the amine products plex, 1.477(3) and 1.481(3) Š], reflecting the s-donat-
with excellent enantioselectivities (91–98% ee) and ing properties of the hydroxo bridges.
À
yields (93–97%), outlining the excellent behaviour of
Most important to the discussion of possible reac-
tion pathways during catalysis and in line with what
the catalyst system for these reactions (Table 3).[19]
The very high activity and selectivity of the new we saw for [(L1)RhCl]2, the p-tolyl groups in
[(L1)Rh(OH)]2 precatalyst in these 1,2-addition reac- [(L1)Rh(OH)]2 that are connected to the sulfoxide
tions strongly indicate that a similar, unusual mecha- units are oriented parallel to the other half of the
nism to the 1,4-addition mechanism with [(L1)RhCl]2 naphthalenic backbone with bond lengths within the
takes place.[13c,d] There, we were able to show that the range of p–p stacking interactions. It therefore indi-
high reactivity was likely due to the fact that substrate cates again that the normal model for enantioselec-
approach and binding to the metal is less difficult tion, which assumes that the substrates approach the
than in other chiral chelating ligands because of the metal so as to minimize steric interactions with pro-
relative lack of bulk protruding from our ligand struc- truding groups placed on the chiral ligand, is not op-
ture, and where electronic factors originating from erative in this case.[22] As outlined in Figure 2, it is
the use of the sulfinyl moieties were at least partially most probable that enantioselection occurs at the sub-
responsible for transferring the chiral information to sequent insertion step, although favourable/unfavour-
the products. To test and underline the validity of able interactions between the tosyl group and the sul-
these arguments in the present system, the structure finyl moiety of the ligand during the imine approach
of the precatalyst was ascertained by an X-ray crystal might be operative in this case. Finally and as deter-
structure
analysis
of
suitable
crystals
of mined experimentally, the direct path depicted in the
[(L1)Rh(OH)]2 (Figure 1).[20] The Rh center adopts center of the catalytic cycle of Figure 2 is very minor.
the expected square planar geometry with the sulfur
atoms coordinated to the metal center. Not surpris-
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Conclusions
Typical Catalytic Procedure
A
stock solution of [{(M,SS,SS)-p-Tol-binaso}Rh(OH)]2
Herein, we have shown, for the first time, that
a chiral disulfoxide ligand can be used as an ancillary
ligand in the rhodium-catalyzed asymmetric 1,2-addi-
tion of arylboroxines to N-tosylarylimines. Results
gathered here show that the binaso ligand, as already
evidenced in the related 1,4-addition reaction, com-
bines excellent reactivity with high enantioselectivity
that compare very favourably with the best data avail-
able in the literature. Especially by introducing the
new m-OH-bridged rhodium complex of binaso, we
have been able to avoid complicated reaction condi-
tions and taken together with the fact that the chiral
ligand is very readily available (1 step synthesis from
commercially available starting materials), the results
presented here might well represent the simplest cata-
lytic system available for this important transforma-
tion.
(9 mg, 0.069 mmol) was stirred in toluene (18 mL) inside the
glove-box in a screw-cap vial. During the mixing time,
a septum-capped reaction vial was charged with imine 6 or 9
(0.45 mmol) and the corresponding arylboroxine
7
(0.30 mmol). To this vial was added the required amount of
the stock solution of the catalyst [2.9 mL containing 1.46 mg
(0.0011 mmol) for 0.25 mol% runs]. Then toluene (3.1 mL)
was added to make up for a total volume of 6 mL. After
this, a stir bar was added, the vial was sealed and was
brought out from the glove-box. H2O (1 mL, degassed,
Milli-Q) was then added with a syringe and the mixture was
stirred for 14 h. After this, the solvent was removed under
vacuum. The residue was dissolved in a minimum amount of
dichloromethane and charged on top of a silica gel column
and purified by column chromatography (hexane/ethyl ace-
tate or diethyl ether as eluent). Products 8 or 10 where then
dried under vacuum and analyzed.
Characterization data of the compounds can be found in
the Supporting Information of this article.
Acknowledgements
Experimental Section
RD thanks the Australian Research Council (ARC) for gen-
erous funding (FT130101713). GZZ, GS and PG thank the
University of Western Australia for an International Post-
graduate Research Scholarship, an Australian Postgraduate
Award and a Safety-Net Top-Up Scholarship. AS thanks the
Swiss National Science Foundation for a postdoctoral fellow-
ship. AO thanks the University of Western Australia for an
Australian Postgraduate Award and a Safety-Net Top-Up
Scholarship. The Centre for Microscopy, Characterisation &
Analysis at UWA is thanked for providing facilities and assis-
tance.
Preparation of [{(M,SS,SS)-p-Tol-binaso}-Rh(OH)]2:
A
solution of [{(M,SS,SS)-p-Tol-binaso}RhCl]2 (600 mg,
0.45 mmol) in acetone (60 mL) was prepared in a Schlenk
tube inside the glove-box. The Schlenk tube was taken out-
side, connected to a Schlenk line and aqueous KOH
(2.2 mL, 2.5M) was added under stirring. The solution was
stirred at room temperature for 1.5 h and then the solvent
was removed under vacuum. Dichloromethane (40 mL) was
added to the crude solid in the Schlenk flask, and the organ-
ic layer was washed and decanted with degassed water (3”
15 mL). Anhydrous Na2SO4 was added to the flask and the
organic layer was then concentrated to a small volume (~
1.5 mL). At this point, the Schlenk flask was reintroduced References
into the glove-box and the content was filtered through
Celiteꢃ and the cake was washed with a small amount of
CH2Cl2. Crystals were obtained by layering with THF
(20 mL) and cooling the mixture at À308C overnight. The
supernatant solution was decanted and the crystals were
washed with cold THF (2”4 mL). The burgundy crystals
were redissolved in 0.5 mL DCM and 10 mL pentane was
added drop by drop to precipitate the product, which was
dried under vacuum for 5 h to afford the corresponding
complex as an orange-red finely divided powder. The yield
of [{(M,SS,SS)-p-Tol-binaso}Rh(OH)]2 was 445 mg (76%)
after a second recrystallization/precipitation sequence of the
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1
mother liquor. H NMR (500 MHz, CD2Cl2): d=8.32 (d, J=
8.8 Hz, 4H), 8.06 (d, J=8.8 Hz, 4H), 8.02–7.77 (br, 8H),
7.74 (d, J=8.3 Hz, 4H), 7.37 (ddd, J=8.2, 6.9, 1.2 Hz, 4H),
6.96 (ddd, J=8.5, 6.8, 1.3 Hz, 4H), 6.58 (d, J=7.9 Hz, 8H),
6.33 (d, J=8.6 Hz, 4H), 2.00 (s, 12H), 0.22 (s, 2H);
13C NMR (126 MHz, CD2Cl2): d=145.61, 141.93, 141.59,
134.57, 131.91, 130.28, 129.09, 128.36, 127.55, 127.51, 127.48,
126.9–127.4 (br), 126.79, 121.07, 21.25; anal. calcd. for
C68H54O6Rh2S4: C 62.77, H 4.18; found: C 62.61, H 4.23;
[a]2D0: +295.45 (c 2.20, CDCl3).
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