Biaryl-like CATPHOS diphosphines via double diels-alder cycloaddition between 1,4-bis(diphenylphosphinoyl)buta-1,3-diyne and anthracenes: Efficient ligands for the palladium-catalyzed amination of aromatic bromides and α-arylation of ketones

Article abstract of DOI:10.1021/om800118t

A mixture of palladium(0) and CATPHOS, the 1,3-butadiene-bridged diphosphine generated via double Diels-Alder cycloaddition between bis(diphenylphosphinoyl)buta-1,3-diyne and anthracene, catalyzes the amination of a range of aromatic bromides as well as the α-arylation of ketones, giving conversions that either rival or exceed those obtained with BINAP.

Full text of DOI:10.1021/om800118t

Organometallics 2008, 27, 1679–1682
1679
Biaryl-Like CATPHOS Diphosphines via Double Diels–Alder
Cycloaddition between 1,4-Bis(diphenylphosphinoyl)buta-1,3-diyne
and Anthracenes: Efficient Ligands for the Palladium-Catalyzed
Amination of Aromatic Bromides and r-Arylation of Ketones
Simon Doherty,* Julian G. Knight,* Catherine H. Smyth,* Ross W. Harrington, and
William Clegg
School of Natural Sciences, Chemistry, Bedson Building, Newcastle UniVersity,
Newcastle upon Tyne NE1 7RU, U.K.
ReceiVed February 9, 2008
lation of ketones,11 iridium- and rhodium-catalyzed chemo- and
regioselective intermolecular cyclotrimerization of terminal
alkynes,12 cycloaddition and cycloisomerization of 1,6-enynes,13
rhodium-catalyzed isomerization of secondary propargylic al-
cohols to R,ꢀ-enones,14 the palladium-catalyzed carbonylation
of heteroaromatic chlorides,15 and the iridium-catalyzed cross-
coupling of terminal alkynes with internal alkynes.16 Given the
effectiveness of biaryl-based diphosphines in platinum group
metal catalysis, there is likely to be considerable interest in the
development of alternative diphosphines which possess a similar
basic skeletal architecture, particularly if their synthesis is
operationally straightforward, modular, and more cost-effective.
Summary: A mixture of palladium(0) and CATPHOS, the 1,3-
butadiene-bridged diphosphine generated Via double Diels–
Alder cycloaddition between bis(diphenylphosphinoyl)buta-1,3-
diyne and anthracene, catalyzes the amination of a range of
aromatic bromides as well as the R-arylation of ketones, giVing
conVersions that either riVal or exceed those obtained with
BINAP.
Biaryl and biaryl-like diphosphines (Chart 1) have evolved
into a highly versatile class of ligand for a host of carbon-carbon
and carbon-heteroatom bond-forming reactions.1 While enan-
tiopure atropos biaryl-based diphosphines2 can be used directly
in asymmetric catalysis, their tropos counterparts can be resolved
only after coordination to a substitutionally inert metal.3 Even
so, BIPHEP, NUPHOS, and related tropos diphosphines (Chart
1) have been used to effect a host of platinum group metal
catalyzed asymmetric transformations, including Diels–Alder4
and hetero Diels–Alder reactions,5 the carbonyl-ene reaction,6
asymmetric hydrogenation,7 and rhodium-catalyzed ene-type
cyclizations,8 in the majority of cases with excellent levels of
enantiocontrol. In addition, biaryl diphosphines are also proving
to be the ligands of choice for a host of achiral transformations,
including the palladium-catalyzed inter- and intramolecular
amination of aryl halides9 and alkenyl bromides,10 the R-ary-
(6) (a) Mikami, K.; Yusa, Y.; Aikawa, K.; Hatano, M. Chirality 2003,
15, 105. (b) Mikami, K.; Kakuno, H.; Aikawa, K. Angew. Chem., Int. Ed.
2005, 44, 7257. (c) Doherty, S.; Goodrich, P.; Hardacre, C.; Luo, H.-K.;
Nieuwenhuyzen, M.; Rath, R. K. Organometallics 2005, 24, 5945. (d)
Doherty, S.; Knight, J. G.; Smyth, C. H.; Harrington, R. W.; Clegg, W. J.
Org. Chem. 2006, 71, 9751. (e) Doherty, S.; Knight, J. G.; Smyth, C. H.;
Harrington, R. W.; Clegg, W. Organometallics 2007, 26, 6453. (f) Doherty,
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(7) (a) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham, T.;
Noyori, R. Angew. Chem., Int. Ed. 1999, 38, 495. (b) Korenaga, T.; Aikawa,
K.; Terada, M.; Kawauchi, S.; Mikami, K. AdV. Synth. Catal. 2001, 343,
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K. Org. Lett. 2006, 8, 1517. (g) Mikami, K.; Wakabayshi, K.; Yusa, Y.;
Aikawa, K. Chem. Commun. 2006, 2365. (h) Jing, Q.; Sandoval, C. A.;
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6, 3699. (b) Mikami, K.; Kataoka, S.; Aikawa, K. Org. Lett. 2005, 7, 5777.
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J. Am. Chem. Soc. 2002, 124, 14104.
(1) (a) Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric
Catalysis: Wiley: New York, 1995. (b) Noyori, R. Asymmetric Catalysis
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(11) For a highly informative review see: (a) Culkin, D. A.; Hartwig, J.
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S. L. J. Am. Chem. Soc. 1997, 119, 11108. (c) Hamann, B. C.; Hartwig,
J. F. J. Am. Chem. Soc. 1997, 119, 12383.
(4) (a) Becker, J. J.; White, P. S.; Gagné, M. R. J. Am. Chem. Soc.
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Nieuwenhuyzen, M.; Knight, J. G. Org. Lett. 2003, 5, 3863. (c) Doherty,
S.; Goodrich, P.; Hardacre, C.; Luo, H.-K.; Rooney, D. W.; Seddon, K. R.;
Styring, P. Green Chem. 2004, 6, 63.
(12) (a) Tanaka, K.; Toyoda, K.; Wada, A.; Shirasaka, K.; Hirano, M.
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10.1021/om800118t CCC: $40.75
2008 American Chemical Society
Publication on Web 03/26/2008

1680 Organometallics, Vol. 27, No. 8, 2008
Communications
Chart 1. Selected atropos and tropos Diphosphines
In this regard, we report here that the 1,3-butadiene-bridged
diphosphine generated via double Diels–Alder cycloaddition
between bis(diphenylphosphinoyl)buta-1,3-diyne and anthracene
can be reduced under exceptionally mild conditions to afford
CATPHOS, a biaryl-like diphosphine that forms a highly
efficient catalyst for the amination of aryl bromides and the
R-arylation of ketones, giving conversions that either rival or
exceed those obtained with BINAP.
Figure 1. Molecular structure of [(CATPHOS)PdCl2] (5a) showing
the conformation of the 1,3-butadiene tether. Hydrogen atoms have
been omitted for clarity. Ellipsoids are at the 40% probability level.
Scheme 1
Our interest in bicyclic diphosphine 4 began after recognizing
the close similarity with the core structural architecture of
NUPHOS diphosphines17 (Chart 1): namely, two diphenylphos-
phino groups bridged by a substituted 1,3-butadiene tether.
While attempts to prepare 4 by direct cycloaddition of an-
thracene with diphosphine 1 proved unsuccessful, the phosphine
oxide 3 can be prepared in high yield via the thermal double
cycloaddition between bis(diphenylphosphinoyl)buta-1,3-diyne
and anthracene, as previously described (Scheme 1).18 Reduction
of 3 also proved to be extremely problematic, as the use of
trichlorosilane and trialkylamine at elevated temperature gave
a multitude of products, one of which was identified as
diphenylphosphine. After repeated modification of the reaction,
optimum conditions for the reduction were eventually identified
and mild heating (40 °C) of a mixed toluene-tetrahydrofuran
solution of 3 in the presence of trichlorosilane and triethyl
phosphite gave 4 in near-quantitative yield as a spectroscopically
and analytically pure white solid. The 31P NMR spectrum of 4
contains a single resonance at δ -15.3, while two sharp signals
structures of 5a,b were determined to compare these parameters
with the corresponding values for BIPHEP and related diphos-
phines. A perspective view of the molecular structure of 5a is
shown in Figure 1.19 The molecular structure of 5a shows that
the coordination around Pd is close to square planar with a
dihedral angle of 7.4° between the PdP2 and PdCl2 planes. The
natural bite angle of 94.27(3)° is comparable to that of 94.06(3)°
reported for [Pd{MeO-BIPHEP)Br(p-NCC6H4)]20 and is char-
acteristic of a diphosphine bridged by a four-carbon sp2-
hybridized tether. The dihedral angle of 21.1° between the least-
squares planes defined by the double bonds and their substituents,
C(1)C(2)C(5)C(12) and C(3)C(4)C(25)C(32), is markedly smaller
than those found in biaryl-based diphosphines, which are
typically much closer to 65–75°.
Since palladium(0)/BINAP is a highly effective catalyst for
the amination of a range of aryl bromides with primary
amines9a,b as well as the R-arylation of ketones,11b these two
transformations were considered ideal candidates with which
to undertake a comparative study between CATPHOS and
BINAP. Our preliminary evaluation focused on the amination
1
at δ 5.04 and 4.94 in the H NMR spectrum are characteristic
of the protons attached to the exo- and endo-bridgehead carbon
atoms. The identity of 4 was unequivocally established by a
single-crystal X-ray study, full details of which are provided in
the Supporting Information.
With a particular interest in using the CATPHOS diphosphine
4 as a surrogate for more conventional biaryl diphosphines, we
next investigated its platinum group metal coordination chem-
istry. Dropwise addition of a dichloromethane solution of 4 to
a dichloromethane solution of [(cycloocta-1,5-diene)MCl2] (M
) Pd, Pt) resulted in quantitative formation of [(CATPHOS)-
MCl2] (M ) Pd, 5a; M ) Pt, 5b). As the natural bite angle and
the dihedral angle of biaryl-based diphosphines are both believed
to influence catalyst performance, the X-ray single-crystal
(17) (a) Doherty, S.; Knight, J. G.; Robins, E. G.; Scanlan, T. H.;
Champkin, P. A.; Clegg, W. J. Am. Chem. Soc. 2001, 123, 5110. (b)
Doherty, S.; Robins, E. G.; Nieuwenhuyzen, M.; Knight, J. G.; Champkin,
P. A.; Clegg, W. Organometallics 2002, 21, 1383. (c) Doherty, S.; Newman,
C. R.; Rath, R. K.; van den Berg, J. A.; Hardacre, C.; Nieuwenhuyzen, M.;
Knight, J. G. Organometallics 2004, 23, 1055.
(19) Full details of the X-ray analysis of 5b are provided in the
Supporting Information. 5b is isostructural with 5a, and the detailed results
are given in the Supporting Information.
(20) Drago, D.; Pregosin, P. S.; Tschoerner, M.; Albinati, A. J. Chem.
Soc., Dalton Trans. 1999, 2279.
(18) Li, M.-X.; Li, J.-L.; Wang, Y.-M.; Meng, J.-B. Chin. J. Chem. 2000,
18, 373.

Communications
Organometallics, Vol. 27, No. 8, 2008 1681
Table 1. Comparative Study of the Palladium-Catalyzed Arylation
of Aniline Using Catalyst Generated from Pd2(dba)3 and either
rac-BINAP or CATPHOSa
Table 2. Palladium-Catalyzed Arylation of n-Hexylamine and
2-Aminopyridine Using Catalyst Generated from Pd2(dba)3 and
CATPHOSa
entry
diphosphine
aryl bromide
time (h)
conversn (%)b
1
2
3
4
5
6
7
8
BINAP
CATPHOS
BINAP
CATPHOS
BINAP
CATPHOS
BINAP
CATPHOS
BINAP
CATPHOS
BINAP
CATPHOS
BIPHEP
JOHNPHOS
BINAP
4-MeC6H4
4-MeC6H4
2-MeC6H4
2-MeC6H4
4-tert-BuC6H4
4-tert-BuC6H4
3,5-Me2-C6H3
3,5-Me2-C6H3
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-CNC6H4
4-CNC6H4
8
8
4.5
4.5
5
5
2
2
6
6
3
3
5
1
3
3
80
79
80
95
67
98
51
100
50
94
60
95
77
100
100
93
9
10
11
12
13
14
15
16
CATPHOS
a Reaction conditions: 1.0 equiv of Ar-Br, 1.1 equiv of amine, 1.4
equiv of NaO-t-Bu, 0.5 mol % Pd2(dba)3, 1.5 mol % BINAP, CATPHOS,
or JohnPhos, toluene (2 mL), 80 °C. b Conversions were determined by
GC analysis of the reaction mixture and are based on aryl bromide;
average of three runs.
a Reaction conditions: 1.0 equiv of Ar-Br, 1.1 equiv of amine, 1.4
equiv of NaO-t-Bu, 0.5 mol % Pd2(dba)3, 1.5 mol % BINAP, CATPHOS,
or JohnPhos, toluene (2 mL), 80 °C. b Conversions were determined by
GC analysis of the reaction mixture and are based on aryl bromide;
average of three runs.
of 4-bromotoluene with aniline using Pd2(dba)3/(diphosphine)
(1.0 mol % Pd) in toluene at 80 °C with NaO-t-Bu as base, full
details of which are given in Table 1. Under these conditions
the catalyst based on rac-BINAP gave 80% conversion after
8 h, compared to 79% for the corresponding CATPHOS-based
catalyst; both gave complete conversion within 20 h. Interest-
ingly, amination of the sterically more demanding 2-bromo-
toluene proceeded smoothly and more efficiently with the
Pd2(dba)3/CATPHOS combination, which gave 95% conversion
after 4.5 h compared to a conversion of only 80% obtained with
the corresponding BINAP-based catalyst (entries 3 and 4).
Having established that the catalyst based on palladium(0) and
CATPHOS can compete effectively with its BINAP counterpart,
the aminations were extended to include a range of electron-
deficient and electron-rich aryl bromides. As expected, good
conversions were obtained with electron-poor substrates, while
electron-rich substrates were markedly more challenging;
nevertheless, good conversions could be obtained after suf-
ficiently long reaction times. The difference in performance
between CATPHOS- and BINAP-based catalysts was most
evident in the amination of electron-rich substrates. For example,
reaction of 4-tert-butyl-1-bromobenzene with aniline using 1.0
mol % Pd(0)/CATPHOS gave 98% conversion after 5 h,
whereas its BINAP counterpart achieved only 67% conversion
in the same time (entries 5 and 6). Similarly, the corresponding
amination of 4-bromoanisole with Pd/CATPHOS gave 94%
conversion to the desired product after 6 h, compared to only
50% with Pd/BINAP (entries 9 and 10), while the reaction
between 3,5-dimethyl-1-bromobenzene and aniline catalyzed by
Pd/CATPHOS went to completion in 2 h but only reached 51%
conversion with Pd/BINAP (entries 7 and 8). The comparative
catalyst testing was extended to include systems based on
BIPHEP and 2-(di-tert-butylphosphino)biphenyl (JohnPhos), the
former because it belongs to the tropos class of biaryl diphosphine
and in this regard resembles CATPHOS, and the latter because it
forms a highly active catalyst for the room-temperature amination
and Suzuki coupling of aryl halides.21 In parallel experiments, the
reaction of 4-chloro-1-bromobenzene with aniline was investigated
with catalysts generated from BIPHEP and JohnPhos. Gratifyingly,
the Pd(0)/CATPHOS catalyst system was significantly more active
than its BIPHEP counterpart (entries 12 and 13). In contrast, Pd(0)/
JohnPhos was highly active and gave complete conversion within
1 h (entry 14), whereas Pd(0)/CATPHOS required 3 h to reach
95% conversion.
Encouraged by these conversions, catalyst testing was
extended to include the arylation of n-hexylamine and 2-ami-
nopyridine. As shown in Table 2, good conversions were
typically obtained with n-hexylamine within 4–8 h (entries 1–4),
whereas reactions involving 2-aminopyridine required signifi-
cantly longer times, reaching a similar level of conversion after
24–48 h with the same catalyst loading (entries 7–9). As
described above, a comparative study showed that Pd(0)/
CATPHOS gave much higher conversions than Pd(0)/BIPHEP
for the amination of 4-bromoanisole with n-hexylamine (entry
5). In contrast, most surprisingly, the same reaction only reached
67% conversion after 6 h using 1.0 mol % Pd(0)/JohnPhos (entry
7) compared with a conversion of 94% for the corresponding
CATPHOS system in the same time. However, further studies
are clearly required to fully evaluate the relative merits of
CATPHOS versus JohnPhos and related diphosphines. As found
for Pd(0)/BINAP, the ratio of monoarylated/bisarylated product
1
was typically greater than 30/1, as determined by H NMR
analysis of the crude reaction mixture.
The promising performance of Pd(0)/CATPHOS catalyst for
the amination of aryl bromides prompted us to extend our studies
(21) (a) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38,
2413. (b) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L.
J. Org. Chem. 2000, 65, 1158.

1682 Organometallics, Vol. 27, No. 8, 2008
Communications
Table 3. Palladium-Catalyzed r-Arylation of Ketones Using
version for use in asymmetric catalysis. To this end, the
corresponding Diels–Alder cycloaddition between 9,10-di-
methylanthracene22 and bis(diphenylphosphinoyl)buta-1,3-diyne
resulted in selective monocycloaddition to afford 6 in high yield
after 40 min with no evidence for any double cycloaddition
adduct even after heating for 24 h at 200 °C (eq 1). While 9,10-
dimethylanthracene appears to be sterically too demanding to
undergo double cycloaddition with 1, the corresponding reaction
between 9-methylanthracene and bis(diphenylphosphinoyl)buta-
1,3-diyne at 200 °C for 40 min results in highly regioselective
double cycloaddition to afford the C2-symmetric adduct 7 (eq
2), with the more bulky methyl-substituted bridgehead carbon
atoms attached to C2 and C3 of the 1,3-butadiene tether, as
confirmed by a single-crystal X-ray study.
Catalyst Generated from Pd2(dba)3 and CATPHOSa
(1)
(2)
a Reaction conditions: 1.0 equiv of Ar-Br, 1.2 equiv of ketone, 1.3
equiv of NaO-t-Bu, 1.5 mol % Pd2(dba)3, 3.6 mol % CATPHOS, THF
(3 mL), 70 °C. b Monoarylation-diarylation ratio determined by 1H NMR
spectroscopy. c Conversions were determined by GC analysis of the
reaction mixture and are based on aryl bromide; average of three runs.
d Catalyst generated from 1.5 mol % Pd2(dba)3 and 3.6 mol % rac-BINAP.
In conclusion, palladium(0) complexes of the inexpensive and
easy-to-prepare biaryl-like CATPHOS diphosphine, formed via
double Diels–Alder cycloaddition between bis(diphenylphos-
phinoyl)buta-1,3-diyne and 2 equiv of anthracene, are highly
efficient catalysts for the amination of aryl bromides as well as
the R-arylation of enolizable ketones. Comparative catalyst
testing with selected substrates revealed that Pd(0)/CATPHOS
either rivals or outperforms its BINAP counterpart. The corre-
sponding Diels–Alder reaction with 9-methylanthracene occurs
in a highly regioselective manner to afford a C2-symmetric
version (DM-CATPHOS) with the methyl-substituted bridge-
head carbon atoms located on C2 and C3 of the butadiene tether,
while the use of 9,10-dimethylanthracene results in selective
monocycloaddition. Studies are currently underway to investi-
gate the tropos/atropos character of these phosphines for
applications in asymmetric catalysis and to explore the range
of alkynylphosphines that undergo Diels–Alder cycloaddition
with the aim of preparing electron-rich monodentate derivatives
for use in palladium-catalyzed cross-couplings.
to include the R-arylation of enolizable ketones (Table 3), a
reaction that is efficiently catalyzed by a combination of
Pd2(dba)3 and Tol-BINAP or BINAP. Following a protocol
described by Buchwald,11b a THF solution of Pd2(dba)3,
CATPHOS, and NaO-t-Bu (3 mol % Pd) catalyzed the arylation
of cyclohexanone with 4-bromo-1-chlorobenzene at 70 °C to
give 84% conversion to the desired arylated ketone, which is
comparable to that of 87% obtained with the corresponding
BINAP system under the same conditions. As shown in Table
3, electron-rich and electron-poor aromatic bromides both couple
with cyclohexanone, acetophenone, and heteroaryl ketones with
good to excellent conversion to the desired R-arylated product.
For each pair of coupling partners, good conversions were
typically obtained within 1–5 h, with the exception of 2-acetyl-
furan, which required a reaction time of 24–48 h to reach an
acceptable level of conversion with the same catalyst loading.
For all substrates examined, the ratio of monoarylation to
diarylation was typically greater than 8:1 and ketones containing
R,R′-hydrogen atoms were regioselectively arylated at the least
hindered position, again with high selectivity for monoarylation.
For example, a 8:1 mixture of monoarylation-diarylation was
obtained from the reaction between cyclohexanone and 4-tert-
butylbromobenzene (entry 3), while the coupling of 3-methyl-
2-butanone with 4-bromo-1-chlorobenzene occurred exclusively
at the methyl carbon to afford a 12:1 ratio of monoarylated to
diarylated product (entry 11).
Acknowledgment. We gratefully acknowledge the EPSRC
for funding (CHS, Newcastle University) and Johnson
Matthey for generous loans of palladium salts.
Supporting Information Available: Text, figures, a table, and
CIF files giving full details of experimental procedures and
characterization data for all compounds, details of catalyst testing,
and, for compounds 4, 5a,b, and 7, details of crystal data, structure
solution and refinement, atomic coordinates, bond distances, bond
angles, anisotropic displacement parameters. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
As the parent CATPHOS diphosphine 4 is likely to be tropos
in nature, we reasoned that introduction of substituents at the
bridgehead carbon atoms would increase the barrier to rotation
about C2-C3 of the butadiene tether to afford an atropisomeric
OM800118T
(22) Duerr, B. F.; Chung, Y.-S.; Czarnik, A. W. J. Org. Chem. 1988,
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