Triarylborane ammonia complexes as ideal precursors for arylzinc reagents in asymmetric catalysis

Article abstract of DOI:10.1021/ol0515659

(Chemical Equation Presented) The value of arylboranes as precursors for arylzinc reagents in asymmetric catalysis is demonstrated. Kinetic studies on the transmetalation reaction with zinc reagents rationalize the observed differences of three classes of arylboranes in catalytic applications. By using the stable and easily accessible triarylborane ammonia complexes, an array of chiral diarylmethanols in high yield and enantioselectivity was synthesized.

Full text of DOI:10.1021/ol0515659

ORGANIC
LETTERS
2
005
Vol. 7, No. 21
597-4600
Triarylborane Ammonia Complexes as
Ideal Precursors for Arylzinc Reagents
in Asymmetric Catalysis
4
Stefan Dahmen* and Matthias Lormann
cynora GmbH, Kaiserstrasse 100, D-52134 Herzogenrath, Germany
dahmen@cynora.de
Received July 5, 2005
ABSTRACT
The value of arylboranes as precursors for arylzinc reagents in asymmetric catalysis is demonstrated. Kinetic studies on the transmetalation
reaction with zinc reagents rationalize the observed differences of three classes of arylboranes in catalytic applications. By using the stable
and easily accessible triarylborane ammonia complexes, an array of chiral diarylmethanols in high yield and enantioselectivity was synthesized.
3
4
Besides the transfer of alkyl, alkenyl, and alkynyl groups to
aldehydes, the addition of aromatic zinc reagents and in
particular diphenylzinc has attracted a lot of attention
recently. The products of this reaction are diarylmethanols,
some of which are important precursors for pharmacologi-
cally active compounds.2
hydrogenation or CBS-reduction ) resides in the possibility
of making products with electronically and sterically similar
aryl rings.
1
The first protocols for the phenyl transfer to aldehydes
relied on diphenylzinc as a phenyl source and required at
5
least 1 equiv of this expensive starting material for optimum
enantioselectivity. Pu et al. initially even used methanol as
an additive thus quenching a part of the reagent to obtain
The advantage of arylzinc additions to aldehydes over
other methods of making such diarylmethanol products (like
6
better results. An improvement in terms of efficiency was
7
made by adding diethylzinc to the reaction mixture. It was
(1) For a review on arylation reactions, see: (a) Bolm, C.; Hildebrand,
J. P.; Muniz, K.; Hermanns, N. Angew. Chem., Int. Ed. 2001, 40, 3284.
For recent additions to this field, see: (b) Ko, D.-H.; Kim, K. H.; Ha, D.-
C. Org. Lett. 2002, 4, 3759. (c) Fontes, M.; Verdagner, X.; Sol a` , L.; Peric a` s,
M. A.; Riera, A. J. Org. Chem. 2004, 69, 2532. (d) Ji, J.-X.; Wu, J.; Au-
Yeung, T. T.-L.; Yip, C.-W.; Haynes, R. K.; Chan, A. S. C. J. Org. Chem.
(3) (a) Okhuma, T.; Koizumi, M.; Ikehira, H.; Yokozawa, T.; Noyori,
R. Org. Lett. 2000, 2, 659. (b) Noyori, R.; Okhuma, T. Pure Appl. Chem.
1999, 71, 1493.
(4) (a) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1995, 36, 9153. (b)
Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837. (c) Corey, E.
J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 5675. (d) Corey, E. J.; Helal, C.
J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(5) Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62, 444.
(6) (a) Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem. 1999, 64, 5222.
(b) Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem. 1999, 64, 7940.
(7) Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Mu n˜ iz, K. Angew. Chem.,
Int. Ed. 2000, 39, 3465.
2
005, 70, 1093. (e) Braga, A. L.; L u¨ dtke, D. S.; Vargas, F.; Paix a˜ o, M. W.
Chem. Commun. 2005, 2512.
2) For selected active pharmaceutical ingredients (APIs), see: Cizolirtine
a) Torrens, A.; Castrillo, J. A.; Claparols, A.; Redondo, J. Synlett 1999, 6,
65. (b) Farr e´ , A. J.; Frigola, J. Drug. Future 2002, 27, 721. Carbinoxam-
(
(
7
ine: (c) Roszowski, A. P.; Govier, W. M. Pharmacologist 1959, 1, 60. (d)
Hunt, J. H. J. Chem. Soc. 1961, 2228. (e) Barouh, V.; Dall, H.; Patel, D.;
Hite, G. J. Med. Chem. 1971, 14, 834. (f) James, M. N. G.; Williams, G.
J. B. Can. J. Chem. 1974, 52, 1872.
1
0.1021/ol0515659 CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/23/2005

thus possible to reduce the necessary amount of diphenylzinc
to 0.65 equiv and still transfer both aryl groups to the
aldehyde. Mechanistic studies suggested that the active zinc
species is a mixed phenylzincethyl, which is less active than
diphenylzinc and thus more selective.8,1b However, the inter-
change of phenyl and ethyl groups in this reaction is con-
sistently difficult to monitor under relevant reaction condi-
tions. Three further improvements were recently made in this
field. The use of boronic acids as an aryl source enabled the
transfer of functionalized aryl rings to aldehydes.1 Triph-
Figure 1. Boron compounds as phenylzinc precursors.
c,9
1
0
enylborane was demonstrated to be a viable phenyl source
and finally, additives enabled the use of simple, commercially
mixture was quenched by addition of iodine in absolute
dichloromethane and analyzed by GC, using decane as
internal standard (see the Supporting Information).
1
1
available ligands for the triphenylborane protocol.
A serious drawback of all these protocols is in our eyes
still to be seen in the price and availability of the aryl sources.
While the expensive and sensitive diphenylzinc is only
available and reasonably employable for research purposes,
the arylboronic acid protocol calls for a huge excess of
diethylzinc (6 to 7 equiv) and drastic conditions for the
transmetalation step. Triphenylborane (1) on the other hand
is a reasonably priced but still a rather air sensitive and
flammable compound.
We therefore searched for other aryl sources for the
transmetalation step yielding active arylzinc reagents. Our
attention was first drawn to complexes of triphenylborane.
Triphenylborane sodium hydroxide complex is a com-
mercially available compound that is sold by DuPont as a
flame retardant. Various other complexes of triphenylborane
are known, many of which can easily be prepared by addition
of, e.g., a nitrogen nucleophile to the triphenylborane
solution. We chose to prepare the well-known ammonia
complex 2 via a simple protocol. Initial experiments showed
that this ammonia complex is an outstandingly stable,
versatile, and economic precursor for arylzinc reagents in
asymmetric catalysis. We here describe a detailed study on
its transmetalation behavior, as well as its application in
asymmetric catalysis.
To gain some understanding of the two occurring pro-
cesses, namely transmetalation and (enantioselective) 1,2-
addition of the intermediary formed active zinc reagent to
the aldehyde, we undertook kinetic studies of the ammonia
complex (2). Additionally, we studied the transmetala-
tion of diphenyl borinate (3) and triphenylborane (1) to
compare reactivity patterns and enantioselectivity of the
intermediary formed arylzinc reagents in addition reactions
to aldehydes.
The transmetalation reactions of compounds 1 to 3 were
studied at room temperature (20 °C) in toluene, the solvent
of choice for most reported enantioselective addition reac-
tions. After the given reaction time, a sample of the reaction
12
Figure 2. Transmetalation of boron compounds in toluene.
As it can be seen from Figure 2, the rate of the
transmetalation reaction of the three compounds is different.
While triphenylborane exchanges about 50% of its three
phenyl groups practically immediately (first sample was
taken after 1 min of reaction time), the two complexes take
longer. Borinate 3 shows a rather fast transmetalation
reaction, exchanging one of its two phenyl groups within
60 min. The rate of transmetalation for the ammonia complex
2
is decisively slower. However, after 60 min all three borane
compounds have exchanged about half of their available
phenyl groups. For triphenylborane and the borinate, the
amount of exchanged phenyl groups remains constant over
13
several hours. A slight decrease of active phenylzinc reagent
generated from ammonia complex 2 was observed in several
kinetic experiments and an experimental artifact can therefore
1
4
be ruled out.
The dissimilar transmetalation patterns should result in a
changed behavior in catalysis. To examine the catalytic
reaction, we performed the addition of phenylzinc generated
from the corresponding borane (1-3) to benzaldehyde in
(
8) Hermanns, N. Ph.D. Thesis, RWTH Aachen, Germany, 2002.
(9) (a) Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124, 14850. (b)
Rudolph, J.; Schmidt, F.; Bolm, C. Synthesis 2005, 840.
10) (a) Rudolph, J.; Hermanns, N.; Bolm, C. J. Org. Chem. 2004, 69,
(
3
8
997. (b) Rudolph, J.; Schmidt, F.; Bolm, C. AdV. Synth. Catal. 2004, 346,
67.
(13) Even after 16 h the amount of “active“ phenyl groups remains
unchanged.
(14) The formation of an equilibrium could be discussed giving rise to
an ammonia stabilized Ph2BEt + PhZnEt. It is unclear, however, which
process could lead to an intermediary higher level of detectable phenylzinc.
(
11) Rudolph, J.; Lormann, M.; Bolm, C.; Dahmen, S. AdV. Synth. Catal.
005, 347, 1361.
12) Layton, W. J.; Niedenzu, K.; Niedenzu, P. M.; Trofimenko, S. Inorg.
Chem. 1985, 24, 1454.
2
(
4598
Org. Lett., Vol. 7, No. 21, 2005

the presence of a chiral ligand. Previous experience had
shown that amino alcohol 5 is one of the most powerful
15
catalyst precursors for the envisaged reaction. A closely
related ligand structure was recently used by the group of
Chan for the addition of phenylzinc generated by the boronic
1
d
acid protocol. Although no chiral product is obtained in
these reactions, the reactivity pattern closely resembles that
of any other benzaldehyde substrate in the asymmetric variant
of this catalytic reaction. The kinetic profile with use of
triphenylborane is depicted in Figure 3.
Figure 4. Kinetic profile of catalysis with BPh
3
‚NH
3
(2).16
not readily exchange more than 55% of its three phenyl
groups. This results in lower overall conversion of aldehyde,
which freezes at 85%. Nevertheless, after 3 h, 14% phe-
nylzinc is detected. As this phenylzinc does not react with
the aldehyde, we assume it to be trapped in a coordination
complex of either the catalyst or the product.
However, the finding that only small amounts of the active
phenylzinc reagent are present during catalysis can be
essential for the enantioselectivity of the asymmetric variant.
This is because phenylzinc reagents are powerful nucleo-
philes which can result in a considerable (undirected)
background reaction diminishing the enantioselectivity. A
complete conversion of aldehyde is easily achieved by
adjustment of the stoichiometry (see below).
(1).16
3
Figure 3. Kinetic profile of catalysis with BPh
As already reported in the literature,8,1b the addition
reaction of phenylzinc is fast, giving complete conversion
to the desired product in 60 min. The stoichiometry chosen
for the reaction calls for the transfer of two out of three
phenyl groups (67%) of the triphenylborane. This is more
than the initially observed 45% of transmetalated groups
which are found in the absence of aldehyde and ligand. It is
also clear from the “PhZn” graph in Figure 2 that the required
phenylzinc reagent is generated rapidly from the excess
borane as no depletion of phenylzinc reagent is observed
during the catalysis. During the whole process, the amounts
of phenylzinc reagent and benzaldehyde are comparable. It
is also apparent that after consumption of aldehyde the level
of active phenylzinc does not rise above 11% although one
of three phenyl groups remains (representing a theoretical
amount of 33%).
The kinetic profile of the reaction with borinate 3 is also
very interesting (Figure 5). As could be expected from the
This picture is quite different for triphenylborane ammonia
complex 2 (Figure 4). While the overall reaction rate is
similar (85% conversion of aldehyde after 60 min), the
available amount of phenylzinc reagent during the catalysis
is much lower (usually below 5% during the reaction). This
can be explained by the much slower transmetalation rate
as described above. Additionally and in contrast to the free
triphenylborane, the triphenylborane ammonia complex does
Figure 5. Kinetic profile of catalysis with borinate (3).16
transmetalation reaction described above, generation of
phenylzinc and therefore overall reaction rate is high.
Compared to the two prior examples, the initial reaction rate
is even higher and over 40% conversion is reached after only
15 min at room temperature. After transfer of the first phenyl
(15) As a member of cynora’s screening library, the ligand has been
employed in various asymmetric reactions. In an internal ligand screening
it proved to be among the best N,O-ligands for this reaction. The synthesis
of this compound was first described in: Cimarelli, C.; Mazzanti, A.;
Palmieri, G.; Volpini, E. J. Org. Chem. 2001, 66, 4759.
Org. Lett., Vol. 7, No. 21, 2005
4599

group of the borinate, however, the reaction drastically slows
down but does not stop because after a reaction time of 19.5
h a conversion of 80% is achieved. This clearly shows that
although exchange of the second phenyl group of the borinate
is possible, it is much slower under the chosen reaction
conditions.
Table 2. Aryl Transfer to Aldehydesa
To compare the different phenylzinc sources in terms of
enantioselectivity, asymmetric catalyses were carried out with
ligand 5 and 4-chlorobenzaldehyde as substrate (Table 1).
arylborane
complex
(R′ ))
aldehyde
(R ))
yield
(%)
ee
(%)
entry
1
2
3
4
5
6
7
8
9
2-Br-C6H5
2-Me-C6H5
2-MeO-C6H5
3-Cl-C6H5
4-Cl-C6H5
4-Me-C6H5
4-MeO-C6H5
Ph
Ph
Ph
C6H11
n-heptyl
H
H
H
H
H
H
H
4-Me
4-Cl
4-MeO
H
96
94
89
93
94
97
91
92
91
86
88
85
98 (R)
98 (R)
92 (R)
95 (R)
97 (R)
98 (R)
95 (R)
94 (S)
95 (S)
96 (S)
70 (S)
71 (S)
Table 1. Comparison of Phenylzinc Sources and Optimization
of Ligand Loading
10
11
12
H
a
Conditions: ligand 5 (5 mol %), BPh3‚NH3 (2) (0.19 mmol), toluene
1.0 mL), aldehyde (0.25 mmol), diethylzinc (0.6 mmol, 0.6 mL, 1.0 M in
(
hexane), 10 °C, 12 h.
amount of 5
(mol %)
yield
(%)
ee
(%)
The catalytic system can also be employed for various other
aldehydes (Table 2). With benzaldehydes, very good enan-
tioselectivity could be achieved for all substitution patterns
entry
borane
1
2
3
4
5
6
1
2
3
2
2
2
5
5
5
1
2.5
10
95
97
94
89
91
96
36 (R)
97 (R)
87 (R)
78 (R)
92 (R)
97 (R)
(entry 1-7). The transfer of substituted aryl rings to
benzaldehyde can also be achieved with high enantioselec-
tivity (entries 8-10). Only aliphatic aldehydes resulted in
lower ee values with the chosen ligand.
In conclusion, we have demonstrated the value of arylbo-
rane conplexes as precursors for arylzinc reagents in asym-
metric catalysis. In a kinetic approach we were able to
monitor the transmetalation reaction and rationalize the
observed differences of the three classes of arylboranes in
catalytic applications. Using the stable and easily accessible
triarylborane ammonia complexes, we synthesized an array
of chiral diarylmethanols in high yield and enantioselectivity.
The simple reaction protocol and the ready availability of
substrates and ligand provide for the first time an excellent
opportunity for technical applications.
The obtained results reflect the expectations from the above-
described kinetic studies. The quickly transmetalating triph-
enylborane (1) gives 36% ee in the presence of 5 mol % of
ligand presumably due to the relatively large influence of
undirected background reaction. With the somewhat more
slowly transmetalating borinate 3, 87% ee is achieved while
the ammonia complex 2 gives rise to the product in 97% ee.
As can also been deduced from Table 1, a ligand loading
of 5 mol % is sufficient to obtain optimal enantioselectivity.
17
Supporting Information Available: Experimental pro-
cedures, HPLC analyses, and NMR characterization for
compounds 6. This material is available free of charge via
the Internet at http://pubs.acs.org.
(
16) Conditions: ligand 5 (2.5 mol %), borane or borinate (0.5 mmol),
benzaldehyde (1.0 mmol), decane (96 µL), toluene (2.0 mL), diethylzinc
1.75 mL, 1 M in hexane), 20 °C.
17) Especially the BPh3 system is highly sensitive to the quality of the
(
(
employed diethylzinc. Trace impurities which are contained in commercial
charges of diethylzinc can have significant influence on the enantioselectivity
of the catalysis.
OL0515659
4600
Org. Lett., Vol. 7, No. 21, 2005