Sterically demanding, bioxazoline-derived N-heterocyclic carbene ligands with restricted flexibility for catalysis

Article abstract of DOI:10.1021/ja045349r

A unique family of N-heterocyclic carbenes derived from bioxazolines (IBiox) suitable for application in transition-metal catalysis is described. The ligands are electron rich, sterically demanding, and have restricted flexibility. Their usefulness has been demonstrated in the Suzuki-Miyaura cross-coupling of sterically hindered aryl chlorides and boronic acids. For the first time, tetraortho-substituted biaryls with methyl and larger ortho-substituents have been synthesized from aryl chlorides using the Suzuki-Miyaura method.

Full text of DOI:10.1021/ja045349r

Published on Web 10/28/2004
Sterically Demanding, Bioxazoline-Derived N-Heterocyclic
Carbene Ligands with Restricted Flexibility for Catalysis
Gereon Altenhoff, Richard Goddard, Christian W. Lehmann, and Frank Glorius*
Contribution from the Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1,
45470 Mu¨lheim an der Ruhr, Germany
Received August 2, 2004; E-mail: glorius@mpi-muelheim.mpg.de
Abstract: A unique family of N-heterocyclic carbenes derived from bioxazolines (IBiox) suitable for
application in transition-metal catalysis is described. The ligands are electron rich, sterically demanding,
and have restricted flexibility. Their usefulness has been demonstrated in the Suzuki-Miyaura cross-coupling
of sterically hindered aryl chlorides and boronic acids. For the first time, tetraortho-substituted biaryls with
methyl and larger ortho-substituents have been synthesized from aryl chlorides using the Suzuki-Miyaura
method.
Introduction
cross-couplings was not feasible. Instead, more costly and less
readily available aryliodides and arylbromides had to be used.
The Suzuki-Miyaura cross-coupling reaction has become an
attractive standard process for biaryl formation.1 Its popularity
results from the wide functional group tolerance, as well as the
low toxicity and robustness of the reagents involved. Many
catalyst systems have been developed to increase the scope of
this important transformation and allow the reaction to proceed
under milder conditions.1-10 For a long time, the use of
unactivated aryl chlorides as substrates in Suzuki-Miyaura
Buchwald4 and Fu5 were the first to independently develop
catalyst systems based on electron-rich, sterically demanding
phosphine ligands, which allow the Suzuki-Miyaura cross-
coupling of many unactivated aryl chlorides. The application
of N-heterocyclic carbene (NHC)11 ligands in the reaction was
first reported by Herrmann in 1998.7 Subsequently, palladium
complexes of many N-heterocyclic carbene (NHC)11 ligands
were found to be competent catalysts for the Suzuki-Miyaura
coupling of unactivated aryl chlorides,7-10 with sterically
demanding ligands, such as IMes or IAd, being especially useful.
Ortho-substituted biaryls are important substructures of
biologically active compounds and organic functional materials.1
Unfortunately, the linking of sterically hindered carbon centers
is notoriously difficult and the formation of multi-ortho-
substituted biaryls under mild conditions has remained elusive.12
Recently, we described the IBiox6 ligand, a bioxazoline-derived
NHC, which contains a tricyclic, rigid backbone as the key
structural element and substituents next to the nitrogen atoms
(1) (a) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359. (b) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron
2002, 58, 9633. (c) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(d) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (e) Miyaura, N. Top.
Curr. Chem. 2002, 219, 11.
(2) For a review on Pd-catalyzed cross-coupling reactions of aryl chlorides,
see: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(3) For a survey of the rational design of catalysts for the Suzuki-Miyaura
coupling, see: Miura, M. Angew. Chem., Int. Ed. 2004, 43, 2201.
(4) For the use of unactivated aryl chlorides, see: (a) Old, D. W.; Wolfe, J.
P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722. (b) Wolfe, J. P.;
Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413. (c) Wolfe, J. P.;
Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
9550. (d) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 116, 1907. For the use of aryl tosylates, see:
(e) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 11818. For the use of aryl bromides in the asymmetric synthesis of
axially chiral biaryls, see: (f) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc.
2000, 122, 12051. For the use of aryl bromides in the synthesis of tetraortho-
substituted biaryls, see: (g) Yin, J.; Rainka, M. P.; Zhang, X.-X.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 1162.
(5) For the use of unactivated aryl chlorides in biaryl formations, see: (a) Littke,
A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387. (b) Littke, A. F.;
Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020. (c) Liu, S.-Y.;
Choi, M. J.; Fu, G. C. Chem. Commun. 2001, 2408.
(6) For other catalysts based on phosphine ligands, see, for example: (a) Shen,
W. Tetrahedron Lett. 1997, 38, 5575. (b) Bei, X.; Turner, H. W.; Weinberg,
W. H.; Guram, A. S.; Petersen, J. L. J. Org. Chem. 1999, 64, 6797. (c)
Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000, 39, 4153.
(d) Bedford, R. B.; Cazin, C. S. J.; Hazelwood, S. L. Angew. Chem., Int.
Ed. 2002, 41, 4120. (e) Stambuli, J. P.; Kuwano, R.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2002, 41, 4746.
(8) (a) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem. 1999,
64, 3804. (b) Grasa, G. A.; Viciu, M. S.; Huang, J.; Zhang, C.; Trudell, M.
L.; Nolan, S. P. Organometallics 2002, 21, 2866. (c) Hillier, G. A.; Grasa,
G. A.; Viciu, M. S.; Lee, H. M.; Yang, C.; Nolan, S. P. J. Organomet.
Chem. 2002, 653, 69. (d) Viciu, M. S.; Kelly, R. A., III; Stevens, E. D.;
Naud, F.; Studer, M.; Nolan, S. P. Org. Lett. 2003, 5, 1479. (e) Navarro,
O.; Kelly, R. A., III; Nolan, S. P. J. Am. Chem. Soc. 2003, 125, 16194.
(9) Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. Angew. Chem.,
Int. Ed. 2003, 42, 3690.
(10) For other catalysts based on NHC ligands, see, for example: (a) Zhang,
C.; Trudell, M. L. Tetrahedron Lett. 2000, 41, 595. (b) Fu¨rstner, A.; Leitner,
A. Synlett 2001, 290. (c) Magill, A. M.; McGuinness, D. S.; Cavell, K. J.;
Britovsek, G. J. P.; Gibson, V. C.; White, A. J. P.; Williams, D. J.; White,
A. H.; Skelton, B. W. J. Organomet. Chem. 2001, 617, 546. (d) Zhao, Y.;
Zhou, Y.; Ma, D.; Liu, J.; Li, L.; Zhang, T. Y.; Zhang, H. Org. Biomol.
Chem. 2003, 1, 1643. (e) Wang, A.-E.; Zhong, J.; Xie, J.-H.; Li, K.; Zhou,
Q.-L. AdV. Synth. Catal. 2004, 346, 595.
(7) (a) Herrmann, W. A.; Reisinger, C.-P.; Spiegler, M. J. Organomet. Chem.
1998, 557, 93. (b) Weskamp, T.; Bo¨hm, V. P. W.; Herrmann, W. A. J.
Organomet. Chem. 1999, 585, 348. (c) Bo¨hm, V. P. W.; Gsto¨ttmayr, C.
W. K.; Weskamp, T.; Herrmann, W. A. J. Organomet. Chem. 2000, 595,
186. (d) Herrmann, W. A.; Bo¨hm, V. P. W.; Gsto¨ttmayr, C. W. K.; Grosche,
M.; Reisinger, C.-P.; Weskamp, T. J. Organomet. Chem. 2001, 617, 616.
(e) Gsto¨ttmayr, C. W. K.; Bo¨hm, V. P. W.; Herdtweck, E.; Grosche, M.;
Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1363.
(11) For excellent reviews on the use of NHC ligands in catalysis, see: (a)
Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1291. (b) Herrmann,
W. A.; Ko¨cher, C. Angew. Chem., Int. Ed. Engl. 1997, 36, 2162. See also:
(c) Arduengo, A. J., III; Krafczyk, R. Chem. Unserer Zeit 1998, 32, 6. (d)
Bourissou, D.; Guerret, O.; Gabba¨ı, F. P.; Bertrand, G. Chem. ReV. 2000,
100, 39.
(12) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., de Meijere, A.,
Eds.; John Wiley & Sons: New York, 2004.
9
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J. AM. CHEM. SOC. 2004, 126, 15195-15201
15195

A R T I C L E S
Altenhoff et al.
Scheme 3. Synthesis of the IBiox‚HOTf Saltsa
a (a) Toluene, 80 °C; (b) SOCl2, toluene, 90 °C; (c) NaOH, THF, EtOH,
80 °C; (d) AgOTf, chloromethyl pivalate, CH2Cl2; 1, 40 °C.
Figure 1.
IBiox5‚HOTf (two cyclopentyl rings) to IBiox12‚HOTf (two
cyclododecyl rings) (Figure 1). We also prepared the open-chain
tetramethyl-substituted ligand IBioxMe4‚HOTf for comparison.
The ligands were all synthesized from the corresponding readily
available amino alcohols.15 Amide formation of the amino
alcohols with diethyl oxalate, followed by chlorination and base-
mediated cyclization, gave the bioxazolines16 1 in good overall
yield of around 75% (Scheme 3). Purification of the products
is simply achieved by washing or crystallization. Early on, we
realized that standard methods for imidazolium salt formation,
as used for bisimines, are not applicable to bioxazolines.17 We
found that bioxazolines could be successfully converted into
imidazolium salts by using a combination of AgOTf and
chloromethyl pivalate. It is also worth noting that the use of
AgOTf also facilitates the formation of other imidazolium salts
such as IMes‚HOTf.18 Optimum results for the imidazolium
system were obtained by preforming the alkylating reagent from
AgOTf and chloromethyl pivalate, and by removal of the AgCl
formed. Under the optimized protocol, AgOTf and chloromethyl
pivalate were stirred in CH2Cl2 for 45 min in the dark, followed
by filtration, and subsequent addition of the filtrate to the
bioxazolines 1. Subsequently, the reaction mixture was stirred
for 24 h at 40 °C, resulting in yields above 60% (Scheme 3).
Overall, this method has proven to be very reliable for the
cyclization of bioxazolines, imineoxazolines, and bisimines. It
has the advantage that it leads to the formation of the triflate
salts, which are soluble in CH2Cl2 and THF, and can be
chromatographed. This is in stark contrast to the much less
soluble standard imidazolium chlorides.
Scheme 1. Suzuki-Miyaura Couplings of Sterically Hindered
Substrates at Ambient Temperature
Scheme 2. Reasonable Conformations of IBiox6‚HOTf;
Conformations a and b Were Proven by NMR/X-ray Analysis
placed in close proximity to a carbene-coordinated metal that
determine its catalytic properties (Figure 1). Using this ligand,
we were able to form di- and triortho-substituted biaryls at
ambient temperature with nonactivated aryl chlorides as sub-
strates (Scheme 1).9,13
NMR and X-ray structural analysis showed that IBiox6‚HOTf
exists in the form of at least two different conformers which
rapidly interconvert at room temperature (Scheme 2). We
reasoned that the flexible steric bulk caused by chair flipping
of the cyclohexyl rings proves beneficial in the catalytic cycle
of the Suzuki-Miyaura coupling reaction and that the sterically
more demanding conformations would favor the formation of
a catalytically active monoligated Pd(IBiox6)1 species.14 How-
ever, while IBiox6‚HOTf was successfully employed for the
synthesis of many different biaryls, the challenging formation
of tetraortho-substituted biaryls remained out of reach. Here,
we report the synthesis of a family of differently substituted
IBiox ligands, the investigation of their electronic and steric
properties, as well as their successful application in the formation
of tetraortho-substituted biaryls from aryl chlorides.
The substitution pattern of the 4,5-dialkoxy-substituted 1,3-
disubstituted imidazolium salts has important implications, both
sterically and electronically (Figure 2).
First, the NHC ligands have an unambiguous binding mode.
Because the imidazolium core of the IBiox‚HOTf is tetrasub-
stituted, only C2 of the imidazolium ring is accessible for
coordination to a metal. A number of recent publications report
the possibility of the involvement of NHC binding modes other
than through C2.19
(15) The amino alcohols were prepared starting from the commercially available
ketones by formation of the corresponding hydantoins, hydrolysis ((a)
Palacin, S.; Chin, D. N.; Simanek, E. E.; MacDonald, J. C.; Whitesides,
G. M.; McBride, M. T.; Palmore, G. T. R. J. Am. Chem. Soc. 1997, 119,
11807), and reduction ((b) Aurich, H. G.; Biesemeier, F.; Geiger, M.;
Harms, K. Liebigs Ann. Chem. 1997, 423. (c) Abiko, A.; Masamune, S.
Tetrahedron Lett. 1992, 33, 5517). This method allows the convenient
synthesis of large gram quantities of amino alcohol.
Results and Discussion
The investigation began with the synthesis of a series of IBiox
ligands, with differing carbocycle ring sizes, ranging from
(13) Subsequently, two other catalyst systems have been reported for Suzuki-
Miyaura reactions of sterically hindered aryl chlorides at ambient temper-
ature, the latter being exceptionally practical and general: refs 8e and 4d.
However, none of these systems has been reported to allow the successful
formation of tetraortho-substituted biaryls from aryl chlorides.
(14) The importance of monoligated Pd(0) complexes as catalytically active
species in Suzuki-Miyaura cross-coupling has been proposed. See, for
example: (a) ref 5b; (b) ref 6e; (c) Hu, Q.-S.; Lu, Y.; Tang, Z.-Y.; Yu,
H.-B. J. Am. Chem. Soc. 2003, 125, 2856. For the successful application
of an interesting sterically demanding NHC ligand in a difficult Sonogashira
coupling, see: (d) Ma, Y.; Song, C.; Jiang, W.; Wu, Q.; Wang, Y.; Liu,
X.; Andrus, M. B. Org. Lett. 2003, 5, 3317.
(16) (a) Mu¨ller, D.; Umbricht, G.; Weber, B.; Pfaltz, A. HelV. Chim. Acta 1991,
74, 232. (b) Helmchen, G.; Krotz, A.; Ganz, K.-T.; Hansen, D. Synlett
1991, 257.
(17) Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C. Chem. Commun. 2002,
2704.
(18) The reaction of the corresponding bisimine with AgOTf (1.2 equiv) and
chloromethyl-ethyl ether (1.4 equiv) in CH2Cl2 (0.17 M) at 40 °C leads to
the smooth formation of IMes‚HOTf in 83%. Related systems react equally
well.
(19) (a) Lebel, H.; Janes, M. K.; Charette, A. B.; Nolan, S. P. J. Am. Chem.
Soc. 2004, 126, 5046. (b) Chianese, A. R.; Kovacevic, A.; Zeglis, B. M.;
Faller, J. W.; Crabtree, R. H. Organometallics 2004, 23, 2461.
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Bioxazoline-Derived N-Heterocyclic Carbene Ligands
A R T I C L E S
Table 1. Vibrational CO Frequencies and Calculated21 TEP for
(IBiox)Ir(CO)2Cl-Complexes (TEP ) 0.722[νaverage(CO)] + 593 cm-1
)
1
1
1
ligand
ν
(CO) [cm-
]
ν
(CO) [cm-
]
TEP [cm-
]
IBioxMe4
IBiox6
IBiox8
1982
1982
1981
1980
2066
2065
2064
2064
2054
2054
2053
2053
IBiox12
Table 2. Selected 1H and 13C NMR Data (in ppm) for the
Bioxazoline-Derived Imidazolium Triflates
Figure 2. Characteristics of the IBiox ligand system.
C2
−H
OCH2
C2
OCN
Cquart
OCH2
IBioxMe4‚HOTf
IBiox5‚HOTf
IBiox6‚HOTf
IBiox7‚HOTf
IBiox8‚HOTf
IBiox12‚HOTf
8.71
8.83
8.93
8.83
8.82
8.71
4.76
4.83
4.82
4.75
4.78
4.73
112.4
112.6
113.2
112.4
113.0
114.5
125.2
125.7
124.8
124.9
125.0
125.2
64.6
73.6
67.5
71.3
71.5
70.9
88.4
87.6
85.9
87.1
87.6
87.3
the electronic character of the IBiox ligands is largely inde-
pendent of the substitution pattern. Similar chemical shifts are
obtained for key groups of the bioxazoline-derived imidazolium
cores (Table 2).
The uniformity of the IR and NMR data within the series
means that the steric bulk of the ligand can be varied without
affecting the electronic character. It is important to note that
this is not the case for most other monodentate ligand systems.
For example, increasing the size of a trialkyl phosphine ligand
significantly changes both its steric and its electronic properties
(e.g., for PEt3, PiPr3, PtBu3: Tolman’s cone angle ) 132°, 160°,
182° and TEP ) 2061.7, 2059.2, 2056.1 cm-1, respectively).20
In addition, the IBiox ligands have a rigid tricylic core, which
presents a highly anisotropic face to the metal. To estimate the
steric demand of the IBiox ligands, X-ray quality crystals were
grown and structurally analyzed for all IBiox‚HOTf salts
prepared (Figure 4). Comparison of the structures reveals that,
whereas the central imidazolium ring is strictly planar, the
oxazolium five-membered rings can take up slightly different
conformations in which the methylene groups C3 and C6 lie
slightly ((0.2 Å) out of the plane of the central ring. The
differences are so small that the tricycle can be largely
considered rigid. Figure 4 gives an indication of some of the
conformations available to the cycloalkyl substituents. For all
salts, the arrangements of the R-C atoms with respect to the
central tricycle are almost identical. The arrangement of the
remaining atoms is constrained by spiro attachment to the central
core and the ring nature of the substituents. It is likely that,
when a metal is bonded to the C2 of the imidazolium ring, the
cycloalkyl rings of the ligands surround and influence the
coordination sphere of the metal, the effect increasing with the
size of the cycloalkyl group. It is important to note that, whereas
the cycloalkyl rings are constrained close to the IBiox ligand
core, further away they can exist in several favorable conforma-
tions. This can be clearly seen in the structures of IBiox5‚HOTf,
IBiox6‚HOTf, and IBiox12‚HOTf, where the cycloalkyl rings
adopt different conformations on either side of the imidazolium
salt. It is tempting to suggest that while shielding the metal the
IBiox ligands are adaptable, allowing the coordination sphere
of the metal to expand or contract.22
Figure 3. X-ray structure of (IBiox6)Ir(CO)2Cl. Selected distances (Å)
and angles (deg): Ir-C1 2.072(3), Ir-C18 1.897(4), Ir-C19 1.892(3), Ir-
Cl 2.351(1), plane(Ir, C1, C18, C19, Cl)/plane(Ir, C1, N1, N2, C4, C5)
89.9(1)°.
Scheme 4. Synthesis of the (IBiox6)IrCl(CO)2 Complex
The 4,5-dioxygen substitution also has an influence on the
electronic properties of the ligands. According to Crabtree, the
average carbonyl stretching frequency of Ir(CO)2Cl(L) com-
plexes can be used as a measure of the electron-donor power
of ligands, quantified in terms of Tolman’s electronic parameter
(TEP).20 We first looked at IBiox6. The (IBiox6)Ir(CO)2Cl-
complex was synthesized in 46% overall yield and was shown
by X-ray analysis to contain a cis and a trans coordinated CO
group (Scheme 4, Figure 3). The IR spectrum of (IBiox6)Ir-
(CO)2Cl (measured in CH2Cl2) shows two CO stretching bands
(2065 and 1982 cm-1) of similar intensity, consistent with this.
The average ν(CO) (2024 cm-1) corresponds to a TEP of 2054
cm-1, following Crabtree’s linear fit procedure.21 This puts
IBiox6 electronically close to electron-rich phosphines, such as
PtBu3 (TEP ) 2056.1 cm-1),20 and shows them to be a little
less electron rich than standard NHC ligands (TEP ) 2050
cm-1). Three further (IBiox)Ir(CO)2Cl-complexes were pre-
pared, and similar values were obtained (Table 1). Thus, it seems
that the oxygen atoms cause a slight electron-withdrawing effect,
at least as far as the metal is concerned, and that this is
independent of the length of the alkyl substituents. The 1H and
13C NMR spectra of the IBiox‚HOTf salts also indicate that
To investigate this further, we compared the effectiveness of
the IBiox ligands in the challenging Suzuki-Miyaura coupling
(20) Tolman, C. A. Chem. ReV. 1977, 77, 313.
(21) Chianese, A. R.; Li, X.; Janzen, M. C.; Faller, J. W.; Crabtree, R. H.
Organometallics 2003, 22, 1663. See also: ref 19b.
(22) Burgess, K. Chem. Ind. 2003, 32 (17th November).
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A R T I C L E S
Altenhoff et al.
Scheme 5. Synthesis of [(IBiox7)PdCl2]2
product formation. Gratifyingly, still more product was formed
by using the IBiox12 ligand (96%). It is important to note that
under the same conditions IMes‚HOTf and IAd‚HOTf failed
to provide substantial amounts of product (Figure 5).
To demonstrate the efficacy and generality of this catalytic
system, we prepared several biaryl derivatives from sterically
hindered aryl chlorides and aryl boronic acids. In all cases,
around 3% homocoupling of the boronic acid was obtained,
presumably originating from the reduction of the Pd(II) pre-
catalyst. Whereas water was tolerated and sometimes even
beneficial in the synthesis of di- and triortho-substituted biaryls
at ambient temperature,9 the use of strictly anhydrous conditions
was found to be important for tetraortho-substituted biaryls,
because it minimized the competing protodeboronation of the
aryl boronic acid.24 Thus, the use of dry reagents such as finely
ground, flame-dried K3PO4 gave optimum results.25 As shown
in Table 3, IBiox12 proved to be an excellent ligand for the
synthesis of tetraortho-substituted biaryls in good yields. Many
different ortho-substituents, including methyl, ethyl, fluorine,
and methoxy, can be accommodated. These results represent
the first Suzuki-Miyaura cross-coupling of aryl chlorides to
give tetraortho-substituted biaryls with ortho-substituents that
are methyl or larger. A phosphine-based catalyst system for the
synthesis of tetraortho-substituted biaryls by Suzuki-Miyaura
cross-coupling has only recently been reported by Buchwald,
but only aryl bromides and anthracenyl chloride have been
successfully used as substrates.4d,g
To shed some light onto the mode of action of the IBiox
ligands, we looked at the formation of catalytically active
monocarbene-palladium complexes. Many standard methods
were screened, such as heating IBiox‚HOTf salts with Pd(OAc)2
and Na(OAc)2 in DMSO, or treating the preformed carbene with
palladium complexes. However, optimum results were obtained
by heating the IBiox7‚HOTf together with Pd(OAc)2 and an
excess of LiCl in THF to 100 °C for 2 days (Scheme 5).
[(IBiox7)PdCl2]2 was cleanly formed in 91% yield. X-ray
structural analysis of the complex clearly reveals that IBiox7 is
a sterically demanding ligand and that it surrounds the metal
like an oyster shell, while leaving enough space for the coor-
dination plane of palladium (Figure 6). As is usually observed,
palladium adopts a square-planar coordination, and two Pd
complexes are bridged by two chlorine atoms. Interestingly, the
(IBiox12)Pd-complex could not be prepared in an analogous
method. Instead, it was best prepared in 45% yield by heating
a dioxane solution of IBiox12‚HOTf, Pd(OAc)2, Cs2CO3, and
an excess of LiCl at 100 °C for 24 h. X-ray structural analysis
of this complex showed the same binding motif for IBiox12 as
for IBiox7 (Figures 6, 7). As for the IBiox7 complex, the large
Figure 4. X-ray structures of the IBiox triflate salts.
of 1-chloro-2,6-dimethylbenzene and 2,4,6-trimethylbenzene-
boronic acid. Preliminary experiments identified two useful
solvent/base systems: dioxane/Cs2CO3 and toluene/K3PO4, with
the latter combination generally giving slightly superior results.
Using the toluene/K3PO4 system and an excess of the aryl
boronic acid (1.5 equiv), a combination of Pd(OAc)2 and
IBioxMe4‚HOTf, IBiox5‚HOTf, or IBiox6‚HOTf gave only
small amounts of the desired cross-coupled product (Figure 5).
In these cases, the main product was 2,4,6-trimethylbenzene
formed by protodeboronation, which is a well-known side
reaction of sterically demanding substrates.23 Use of IBiox7‚
HOTf and IBiox8‚HOTf resulted in significantly increased
(23) For example, see: (a) Cammidge, A. N.; Cre´py, K. V. L. Chem. Commun.
2000, 1723. (b) Wallow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59, 5034.
(c) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207.
(24) Cammidge, A. N.; Cre´py, K. V. L. J. Org. Chem. 2003, 68, 6832.
(25) Commercial sources provide boronic acids of substantially different dryness.
Recrystallization may be advisable in some cases.
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Bioxazoline-Derived N-Heterocyclic Carbene Ligands
A R T I C L E S
Figure 5. Screening of ligands for Suzuki-Miyaura cross-coupling of sterically hindered substrates.
Figure 7. X-ray structure of [(IBiox12)PdCl2]2, showing one of the
conformations of the disordered cyclododecyl rings. Selected distances (Å)
and angles (deg): Pd-C1 1.944(5), Pd-Cl1 2.285(1), Pd-Cl2 2.337(1),
Pd-Cl2* 2.415(1), C8‚‚‚Pd 3.627(6), plane(Pd, C1, Cl1, Cl2, Cl2*)/plane-
(Pd, C1, N1, N2, C4, C5) 85.5(1)°.
Figure 6. X-ray structure of [(IBiox7)PdCl2]2. Selected distances (Å) and
angles (deg): Pd-C1 1.943(2), Pd-Cl1 2.2856(4), Pd-Cl2 2.3344(4), Pd-
Cl2* 2.4201(4), C8‚‚‚Pd 3.673(2), plane(Pd, C1, Cl1, Cl2, Cl2*)/plane(Pd,
C1, N1, N2, C4, C5) 83.4(1)°.
formation of coordinatively unsaturated metal species. The
catalytically active metal is shielded, but not completely,
allowing space within the coordination sphere of the metal. In
the case of nickel complexes, the influence of sterically
demanding NHC ligands on the coordination number has been
demonstrated.26 However, while electron richness and sterical
bulk are important, a certain degree of ligand flexibility seems
to be the key to successful application in the Suzuki-Miyaura
transformation, because classical rigid ligands such as IAd‚HOTf
failed to provide the desired products. Flexible steric bulk allows
the ligands to adapt to the changing needs of the catalytic cycle.
Thus, whereas a less sterically demanding ligand is favorable
for oxidative addition and transmetalation, reductive elimination
should benefit from more demanding conformations around the
metal center.
cycloalkyl rings substantially shield the metal. However, because
the cyclododecyl rings are significantly larger, the two IBiox12
ligands in the dimer are not independent of each other and one
of the cyclododecyl rings of each IBiox ligand moves toward
its NHC backbone to prevent unfavorable steric interaction. This
difference in conformation strikingly demonstrates the flexibility
of the cycloalkyl rings. Furthermore, one of the conformations
found for IBiox12 in [(IBiox12)PdCl2]2 resembles conformation
b of imidazolium salt IBiox6‚HOTf (Scheme 2) and the
conformation proposed for its catalytically active palladium
complex.9 It is interesting to note that there is a relatively short
Pd‚‚‚C contact (3.6 Å) between the nondisordered â C atom
(C8 in Figure 7) of the cyclododecyl ring and the metal,
indicative of a weak C-H‚‚‚Pd interaction. Most importantly,
both complexes were found to be catalytically active (3 mol
%, entries 3,4 of Table 3).
Conclusions
We have demonstrated the usefulness of a new class of
bioxazoline-derived NHC ligands, IBiox. These ligands are
Many beneficial features for catalysis can be attributed to
the IBiox ligand system. The ligands are electron rich, facilitat-
ing the oxidative addition of the metal complex with aryl
chlorides. The ligands are sterically demanding, favoring the
(26) Dorta, R.; Stevens, E. D.; Hoff, C. D.; Nolan, S. P. J. Am. Chem. Soc.
2003, 125, 10490.
9
J. AM. CHEM. SOC. VOL. 126, NO. 46, 2004 15199

A R T I C L E S
Altenhoff et al.
Table 3. Suzuki-Miyaura Couplings of Aryl Chlorides Resulting in
easily prepared, electron rich, and sterically demanding as a
consequence of their characteristic tricyclic backbone, while
being flexible, with restricted degrees of freedom. These
favorable characteristics should render them attractive for
application in many transition-metal-catalyzed processes. These
ligands have been successfully employed in the Suzuki-
Miyaura cross-coupling of sterically hindered aryl chlorides and
aryl boronic acids to give tetraortho-substituted biaryls.
Tetraortho-Substituted Biarylsa
Experimental Section
General Remarks. The solvents used were purified by distillation
over the drying agents indicated and were transferred under argon:
tetrahydrofuran (THF) (Na), CH2Cl2 (P4O10), toluene (Na/K). For flash
chromatography, Merck silica gel 60 (230-400 mesh) was used. All
commercially available compounds were used as received. All reactions
were set up under an atmosphere of argon; K3PO4 was ground with a
mortar and flame-dried. Noncommercial aryl boronic acids were
synthesized from the corresponding aryl Grignard by quench with
B(OMe)3 and acidic hydrolysis. Noncommercial aryl chlorides were
synthesized by Br/Cl-exchange with stoichiometric amounts of CuCl
in refluxing DMF.
General Procedure for the Synthesis of the Imidazolium Triflates.
To a suspension of AgOTf (1.45 equiv) in CH2Cl2 (0.3 M) was added
chloromethyl pivalate (1.45 equiv), and the resulting suspension was
stirred for 45 min. The supernatant was transferred via syringe to the
bioxazoline (1 equiv), and the resulting solution was stirred in a sealed
tube in the dark at 40 °C for 20 h. After the solution was cooled to
room temperature, the reaction was quenched with methanol and the
solvent evaporated in vacuo. The resulting oil was chromatographed
on silica gel (CH2Cl2/MeOH). Subsequent crystallization from CH2-
Cl2/diethyl ether gave the imidazolium triflate as colorless crystals.
IBiox12‚HOTf. Following the general procedure gave IBiox12‚
HOTf (4.5 g, 60%) as colorless crystals after chromatography on silica
(CH2Cl2 to CH2Cl2/MeOH ) 100/12) and crystallization.
1
Rf ) 0.53 (EtOAc); H NMR (400 MHz, CD2Cl2) δ 8.71 (s, 1H,
NCHN), 4.73 (s, 4H, CCH2O), 2.29-2.17 (m, 4H, CH2), 1.92-1.70
(m, 4H, CH2), 1.69-1.55 (m, 4H, CH2), 1.55-1.23 (m, 34H, CH2);
13C NMR (100 MHz, CD2Cl2) δ 125.2 (ONC), 121.0 (q, J1 ) 324
CF
Hz), 114.5 (NCHN), 87.3 (OCH2), 70.9 (C(CH2)2), 30.8 (CH2), 25.9
(CH2), 22.3 (CH2), 21.9 (CH2), 19.5 (CH2); 19F NMR (282 MHz, CD2-
Cl2) δ -78.8; IR (KBr) 3094, 2934, 2862, 1773, 1516, 1472, 1447,
1333, 1262, 1224, 1154, 1031, 1000, 965, 943, 903, 828, 748, 726,
637, 572, 517 cm-1. MS (EI), m/z (%) 457 (100), 278 (12), 206 (62),
100 (5), 97 (6), 95 (7), 83 (6), 81 (9), 69 (9), 55 (12), 41 (5); HRMS
(EI) calcd for C29H49N2O2 457.3794, found 457.3785. Crystal data for
IBiox12‚HOTf: [C29H49N2O2]+[CF3O3S]-‚CH2Cl2, from dichloromethane/
heptane, Mr ) 691.70, crystal size: 0.05 × 0.05 × 0.06 mm;
a ) 14.6777(4), b ) 25.7698(7), c ) 9.1906(2) Å, V ) 3476.3(2) Å3,
T ) 150 K, orthorhombic, space group Pnma (No. 62), Z ) 4, Fcalcd
)
1.322 g cm-3, F(000) ) 1472, Nonius KappaCCD diffractometer, λ(Mo
KR) ) 0.71073 Å, µ ) 0.30 mm-1, 51 282 measured and 3038
independent reflections (Rint ) 0.099), 1890 with I > 2σ(I), θmax
)
24.81°, Tmin ) 0.998, Tmax ) 1.00 (multiscan absorption correction),
direct methods (SHELXS-97) and least-squares refinement (SHELXl-
2
97) on Fo , both programs from G. Sheldrick, University of Go¨ttingen,
1997; 388 parameters. The structure is twinned (Pna21 emulating Pnma,
twinning law: [1 0 0, 0-1 0, 0 0 1]); two crystals were investigated,
and both were similarly twinned. The structure was refined in the
centrosymmetric space group Pnma, with 50:50 disorder about the
psuedo mirror plane perpendicular to the b axis. Dichloromethane solute
in crystal, H atoms riding except on solute, Chebyshev weights, R1 )
0.0640 (I > 2σ(I)), wR2 ) 0.1701 (all data), ∆Fmax/min ) 0.220/-0.203
a Reaction conditions: 1.0 mmol of ArX, 1.5 mmol of Ar′B(OH)2, 3
mmol of K3PO4, 3.6 mol % of IBiox12 (from IBiox12‚HOTf, KH, cat.
KOtBu), 3 mol % of Pd(OAc)2 in THF, toluene (3 mL), 110 °C, 16 h;
yield of isolated products. b 3 mol % of complex [(IBiox7)PdCl2]2. c 3 mol
% of complex [(IBiox12)PdCl2]2. d 0.5 mmol scale.
e Å-3
.
General Procedure for the Suzuki-Miyaura Cross-Coupling
Reactions. Preparation of the catalyst solution: In a glovebox, a mixture
9
15200 J. AM. CHEM. SOC. VOL. 126, NO. 46, 2004

Bioxazoline-Derived N-Heterocyclic Carbene Ligands
A R T I C L E S
of IBiox12‚HOTf (109 mg, 0.18 mmol), KH (10 mg, 0.25 mmol), and
KOtBu (3 mg, 0.03 mmol) was stirred in THF (0.5 mL) until hydrogen
evolution ceased. The resulting suspension was filtered through a short
pad of sand, and the vial was washed with THF to give 2 mL of filtrate.
Finally, the filtrate was mixed with Pd(OAc)2 (27 mg, 0.12 mmol) to
give the catalyst solution.
romethane/hexane/ethyl acetate, Mr ) 987.47, crystal size: 0.16 ×
0.33 × 0.40 mm; a ) 13.2368(2), b ) 11.6748(1), c ) 13.6306(1) Å,
â ) 97.3395(4), V ) 2089.17(4) Å3, T ) 100 K, monoclinic, space
group P21/n (No. 14), Z ) 2, Fcalcd ) 1.570 g cm-3, F(000) ) 1008,
Nonius KappaCCD diffractometer, λ(Mo KR) ) 0.71073 Å, µ ) 1.16
mm-1, 35 433 measured and 6612 independent reflections (Rint
)
Aryl boronic acid (1.5 mmol) and K3PO4 (3.0 mmol) were dissolved
in 2.5 mL of solvent and were stirred vigorously for 5 min. Aryl halide
(1.0 mmol) was added, followed by the addition of 0.5 mL of a
previously prepared catalyst solution. After 16 h at 110 °C, the solvent
was removed in vacuo and the residue was chromatographed on silica
gel giving the corresponding biaryl products.
0.039), 6088 with I > 2σ(I), θmax ) 31.01°, Tmin ) 0.678, Tmax ) 0.804,
direct methods (SHELXS-97) and least-squares refinement (SHELXl-
2
97) on Fo , both programs from G. Sheldrick, University of Go¨ttingen,
1997; 235 parameters, H atoms riding, Chebyshev weights, R1 ) 0.0282
(I > 2σ(I)), wR2 ) 0.0687 (all data), ∆Fmax/min ) 1.371 [0.77 Å from
Pd]/-0.692 e Å-3
.
General Procedure for the Formation of (IBiox)Ir(CO)2Cl. CO
gas was passed through an ice-cold solution of (IBiox)Ir(COD)Cl in
CH2Cl2 (5 mL) for 15 min. Solvent was evaporated at 0 °C, and the
residue was washed several times with cold pentane to give (IBiox)-
Ir(CO)2Cl as a light yellow solid.
[(IBiox12)PdCl2]2. IBiox12‚HOTf (50 mg, 0.08 mmol), Pd(OAc)2
(20 mg, 0.09 mmol), LiCl (100 mg, 2.38 mmol), and Cs2CO3 (26 mg,
0.08 mmol) were suspended in dioxane (3 mL) and stirred for 24 h at
100 °C. The solvent was removed, and the residue was extracted with
DCM/water. Concentration of the organic layer and drying in high
vacuum gave the complex as an orange solid (23 mg, 45%).
(IBiox6)Ir(CO)2Cl. Light yellow solid (54 mg, 95%). IR (CH2Cl2)
ν(CO) 2065, 1982; IR (KBr) 2940, 2061, 1965, 1754, 1455, 1430, 1358,
IR (KBr) 2928, 2861, 1759, 1470, 1444, 1422, 1364, 1292, 1210,
;
954, 860, 731 cm-1 1H NMR (400 MHz, CDCl3) δ 4.58 (bs, 8H,
1
1340, 1218, 986, 924, 859, 684, 653, 618 cm-1; H NMR (400 MHz,
CDCl3) δ 4.63 (ABq, VA ) 4.64, VB ) 4.62, J ) 8.7 Hz, 4H, OCH2),
2.71-2.54 (m, 4H, (CH2)cyclohexyl), 1.98-1.84 (m, 8H, (CH2)cyclohexyl),
1.69 (m, 2H, (CH2)cyclohexyl), 1.43-1.10 (m, 6H, (CH2)cyclohexyl); 13C NMR
(100 MHz, CDCl3) δ 181.0, 168.2, 149.5, 124.9 (ONC), 84.1 (OCH2),
64.9 (C(CH3)2), 36.0, 35.1, 24.3, 23.8 ((CH2)cyclohexyl); MS (EI), m/z
(%) 572 (28), 570 (14), 544 (13), 542 (11), 516 (26), 514 (88), 512
(100), 510 (34), 476 (38), 474 (28), 95 (16), 91 (6), 67 (14), 55 (10),
41 (9); HRMS (EI) calcd for C19H24ClIrN2O4 572.1057, found 572.1055.
Crystal data for (IBiox6)Ir(CO)2Cl: [C19H24ClIrN2O4], from d6-benzene,
Mr ) 572.05, crystal size: 0.05 × 0.10 × 0.18 mm; a ) 13.1029(2),
b ) 9.5315(1), c ) 16.4726(2) Å, â ) 105.399(1), V ) 1983.41(4)
Å3, T ) 100 K, monoclinic, space group P21/n (No. 14), Z ) 4,
OCH2), 3.01-2.50 (bs, 8H, (CH2)cylcododecyl), 2.30 (bs, 8H, (CH2)cylcododecyl),
1.92-1.11 (m, 72H, (CH2)cyclododecyl); 13C NMR (100 MHz, CDCl3) δ
127.7, 113.2, 84.6 (OCH2), 69.7 (C(CH3)2), 35.2 (bs), 26.2 (bs), 24.6,
24.4 (bs), 23.9 (bs), 21.9 (bs)((CH2) cyclododecyl); MS (ESIpos/MeCN)
638 ((IBiox12)PdCl+MeCN), 561 ((IBiox12)PdCl-HCl), 457 (IBiox12).
Crystal data for [(IBiox12)PdCl2]2‚1.3(C6H14): [C58H96Cl4N4O4Pd2]‚
1.3[C6H14], from dichloromethane/hexane, Mr ) 1382.97, crystal size:
0.08 × 0.06 × 0.08 mm; a ) 31.189(2), b ) 8.7086(4), c ) 23.904(1)
Å, â ) 94.711(2), V ) 6470.7(5) Å3, T ) 100 K, monoclinic, space
group C2/c (No. 15), Z ) 4, Fcalcd ) 1.420 g cm-3, F(000) ) 2923,
Nonius KappaCCD diffractometer, λ(Mo KR) ) 0.71073 Å, µ ) 0.771
mm-1, 30 015 measured and 10 693 independent reflections (Rint
)
F
calcd ) 1.916 g cm-3, F(000) ) 1112, Nonius KappaCCD diffractom-
0.053), 6676 with I > 2σ(I), θmax ) 31.50°, Tmin ) 0.842, Tmax ) 1.00
eter, λ(Mo KR) ) 0.71073 Å, µ ) 6.89 mm-1, 32 725 measured and
6221 independent reflections (Rint ) 0.041), 5445 with I > 2σ(I),
θmax ) 30.97°, Tmin ) 0.335, Tmax ) 0.720, direct methods (SHELXS-
(multiscan absorption correction), direct methods (SHELXS-97) and
2
least-squares refinement (SHELXl-97) on Fo , both programs from G.
Sheldrick, University of Go¨ttingen, 1997; 340 parameters. The two
cyclododecyl rings of the ligand are disordered and were modeled by
C atoms with isotropic displacement parameters. The crystal also
contains disordered hexane solute, which was similarly treated. Due
to the extent of the disorder, no H atoms were included in the
refinement. Chebyshev weights, R1 ) 0.0820 (I > 2σ(I)), wR2 ) 0.2211
2
97) and least-squares refinement (SHELXl-97) on Fo , both programs
from G. Sheldrick, University of Go¨ttingen, 1997; 244 parameters, H
atoms riding, Chebyshev weights, R1 ) 0.0226 (I > 2σ(I)), wR2 )
0.0685 (all data), ∆Fmax/min ) 1.277/-1.165 e Å-3
.
[(IBiox7)PdCl2]2. IBiox7‚HOTf (1.12 g, 24.0 mmol), Pd(OAc)2 (537
mg, 24.0 mmol), and LiCl (2.0 g) were suspended in THF (10 mL)
and stirred at 100 °C in a sealed tube. Within 16 h, the color of the
suspension changed from brown to yellow. The solvent was removed,
and the residue was extracted with DCM/water. Concentration of the
organic layer and drying in vacuo gave the complex as an orange solid
(1.10 g, 92%).
(all data), ∆Fmax/min ) 3.343 [1.0 Å from Pd]/-0.961 e Å-3
.
Acknowledgment. We thank Prof. A. Fu¨rstner for generous
support and constant encouragement, the BMBF, the Fonds der
Chemischen Industrie (Liebig scholarship to F.G.), as well as
the Deutsche Forschungsgemeinschaft for financial support.
IR (KBr) 2923, 2853, 1752, 1495, 1421, 1280, 1212, 998, 946, 917,
1
856, 804, 671 cm-1; H NMR (400 MHz, CDCl3) δ 4.51 (ABq, VA
)
Supporting Information Available: Experimental procedures
and characterization data for all unknown compounds. Crystal-
lographic information files (CIF) are available for IBioxMe4‚
HOTf, IBioxn‚HOTf (n ) 5,7,8,12), (IBiox6)Ir(CO)2Cl, [(IBiox7)-
PdCl2]2, and [(IBiox12)PdCl2]2. This material is available free
of charge via the Internet at http://pubs.acs.org.
4.52, VB ) 4.49, J ) 8.2 Hz, 8H, OCH2), 3.14-2.71 (m, 12H,
(CH2)cycloheptyl), 2.71-2.48 (m, 4H, (CH2)cycloheptyl), 2.03-1.84 (m, 16H,
(CH2)cycloheptyl), 1.84-1.49 (m, 16H, (CH2)cycloheptyl); 13C NMR (100
MHz, CDCl3) δ 127.4, 112.0, 84.8 (OCH2), 69.4 (C(CH3)2), 37.6, 37.0,
30.1, 29.8, 24.3, 24.1 ((CH2)cycloheptyl); MS (ESIpos/MeCN) 500
((IBiox7)PdCl+MeCN), 412 ((IBiox7)PdCl-HCl), 315 (IBiox7). Crys-
tal data for [(IBiox7)PdCl2]2: [C38H56Cl4N4O4Pd2], from dichlo-
JA045349R
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J. AM. CHEM. SOC. VOL. 126, NO. 46, 2004 15201