Synthesis of PdII complexes bearing an enantiomerically resolved seven-membered N-heterocyclic carbene ligand and initial studies of their use in asymmetric Wacker-type oxidative cyclization reactions

Article abstract of DOI:10.1016/j.tet.2009.04.072

The development of enantiomerically resolved, axially-chiral seven-membered N-heterocyclic carbene (⁷NHC) ligands for palladium is described. These ⁷NHC ligands are derived from enatiomerically pure 2,2′-diamino-6,6′-dimethylbiphenyl

Full text of DOI:10.1016/j.tet.2009.04.072

Tetrahedron 65 (2009) 5084–5092
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of PdII complexes bearing an enantiomerically resolved
seven-membered N-heterocyclic carbene ligand and initial studies of their
use in asymmetric Wacker-type oxidative cyclization reactions
Christopher C. Scarborough, Ana Bergant, Graham T. Sazama, Ilia A. Guzei, Lara C. Spencer,
*
Shannon S. Stahl
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The development of enantiomerically resolved, axially-chiral seven-membered N-heterocyclic carbene
(7NHC) ligands for palladium is described. These 7NHC ligands are derived from enatiomerically pure
2,20-diamino-6,60-dimethylbiphenyl, which is transformed via a synthetic sequence consisting of ortho-
arylation, N-alkylation, and cyclization to afford seven-membered-ring amidinium salts. Synthesis of the
seven-membered amidinium salts benefits from microwave irradiation, and in-situ metalation of the
amidinium salts yields 7NHC–PdII complexes. The chiral 7NHC–Pd complexes were examined as chiral
catalysts under aerobic conditions in two intramolecular oxidative amination reactions of alkenes. In one
case, enantioselectivities up to 63% ee were obtained, while the other substrate underwent cyclization to
afford essentially racemic products. The catalytic data compare favorably to results obtained with a PdII
catalyst bearing a chiral five-membered-ring NHC ligand and, thereby, highlight the potential signifi-
cance of this new class of chiral NHC ligands.
Received 16 February 2009
Received in revised form 9 April 2009
Accepted 20 April 2009
Available online 3 May 2009
Keywords:
N-Heterocyclic carbene
Palladium
Organometallic chemistry
Wacker oxidation
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
amination of chiral cyclophanes (Fig. 1, ligand L2)5,4 or by amination
of 1,2-diones with chiral amines (Fig. 1, ligands L3–L5).6–8 Although
Chiral monodentate N-heterocyclic carbenes (NHCs) have broad
potential utility in asymmetric catalysis, but successful applications
of such ligands remain somewhat limited.1,2 To our knowledge, only
six transformations have been reported in which chiral mono-
dentate NHC ligands have been employed to afford enantiose-
lectivities above 90% ee (for representative examples, see Fig. 1).
The transformations include olefin metathesis,3 1,4-addition of
arylboronic acids to enones,4 hydrosilylation of ketones,5 intra-
molecular alpha-arylation of amides,6,7 copper-catalyzed conjugate
addition to cycloheptenone with diethylzinc,8 and Ni-catalyzed
reductive coupling of 1,3-dienes and aldehydes with triethylsilane.9
All of these transformations utilize five-membered-ring NHC li-
gands. Two strategies have been employed in the design of chiral
monodentate five-membered NHCs: ‘chiral relay’ and the use of
chiral nitrogen substituents. In the first strategy, developed by
Grubbs and co-workers,3 chirality in the N-heterocycle induces an
asymmetric conformation of the nonsymmetrical (but achiral) ni-
trogen substituents (Fig. 1, ligand L1). In the second strategy, the
ligand chirality arises from the incorporation of chiral nitrogen
substituents into the ligand, for example, by Buchwald–Hartwig
attempts have been made to develop ligands that feature both
chiral relay and chiral nitrogen substituents, only modest success
has been achieved thus far.8,10
NHCs are excellent ligands for metal-catalyzed aerobic oxidation
reactions because metal–NHC complexes are oxidatively stable.11
NHC–Pd complexes have been employed as catalysts for aerobic oxi-
dation of alcohols,12 Wacker-type cyclization of ortho-allyl phenols,13
and intramolecular oxidative amination of olefins (Fig. 2a, b, and c,
respectively).14 We have been interested in the development of
enantioselective aerobicoxidativeaminationreactionsof alkenes, and
theuseofchiralNHC ligandswas alogicalstartingpoint. Inconnection
with these efforts, we have been exploring the development and ap-
plication of a new class of NHCs based upon a seven-membered het-
erocyclic framework (Fig. 3b).15,16 These seven-membered NHCs
(7NHCs) are attractive because they feature an axially-chiral hetero-
cyclic framework that provides an out-of-plane projection of the ni-
trogensubstituents (Fig. 3b). Thisnon-planaritycontrasts thein-plane
orientation of the nitrogen substituents in five-membered NHCs
(Fig. 3a), and we reasoned that increased enantioselectivity might be
achieved in asymmetric catalysis with 7NHCs. We have reported that
a racemic 7NHC–Pd complex is an active catalyst for the intra-
molecular aerobic oxidative amination of o-crotyl tosylanilide
(Fig. 2c),14 but, at the time of this work, we had not yet succeeded in
* Corresponding author.
E-mail address: stahl@chem.wisc.edu (S.S. Stahl).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.072

C.C. Scarborough et al. / Tetrahedron 65 (2009) 5084–5092
5085
Figure 1. Asymmetric catalysis with chiral monodentate NHCs giving >90% ee.
preparing enantiomerically resolved 7NHC–Pd complexes. Our initial
synthesis of 7NHC–Pd complexes15 is not amenable to the synthesis of
resolved analogs. Here, we describe the synthesis of enantiomerically
resolved seven-membered-ring amidinium salts, metalation of the
amidinium salts by PdII and the investigation of 7NHC–PdII complexes
in intramolecular aerobic oxidative heterocyclization reactions. The
Figure 2. Palladium-catalyzed aerobic oxidation reactions that have employed NHC ligands.

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C.C. Scarborough et al. / Tetrahedron 65 (2009) 5084–5092
(the 7NHC-precursor).18 We therefore focused our efforts on exe-
cuting the second strategy, which would allow many resolved 7NHC
complexes to be synthesized from a single stock of resolved diamine.
As we have reported previously,15a the use of 2,20-diamino-1,10-
binaphthyl (DABN) for the synthesis of resolved DABN-derived
seven-membered-ring amidinium salts was successful only with
neopentyl groups as nitrogen substituents (e.g., Fig. 4a); the cor-
responding amidinium salts bearing N-(2-adamantyl) or N-aryl
groups were not accessible (e.g., Fig. 4b).15,19 These observations
were problematic because palladium complexes bearing 7NHCs
with primary nitrogen substituents proved to be unstable. The in-
stability of 7NHC–Pd complexes bearing primary alkyl nitrogen
substituents appears to arise from decreased steric protection of
the carbene carbon relative to those with secondary nitrogen sub-
stituents. Based on this hypothesis, we reasoned that substituents
in the ortho-positions (i.e., the 3 and 30 positions of the biphenyl
moiety) could provide additional steric protection of the carbene
carbon and, thereby, permit primary alkyl nitrogen substituents to
be employed (Fig. 4c). Based on this proposal, we explored methods
to access ortho substituted biaryl diamines.
Figure 3. (a) Planarity of five-membered NHCs (5NHCs). (b) Non-planarity of seven-
membered NHCs (7NHCs).
enantioselectivity data from the catalytic reactions is modest (ꢀ63%
7
ee). Nevertheless, the NHC ligand proves to be substantially better
than one of the most successful known 5NHC ligands.
2. Results and discussion
2.1. Strategy
At the time this work began, there were only two reported ex-
amples of chiral monodentate 5NHCs employed in reactions that
achieved ee’s above 90%.3c,4 The chiral 5NHCs developed by Grubbs
and co-workers (L1, Fig. 1)3 were not useful for our goal of accessing
NHC–Pd(O2CR)2 catalysts for asymmetric aerobic Wacker-type oxi-
dation reactions because such catalysts were not synthetically ac-
cessible.17 The chiral 5NHCs developed by Andrus and co-workers
(L2, Fig. 1)4 proved to be prohibitively difficult to synthesize. Within
this context, we turned our attention to the development of new
chiral NHC ligands, and our efforts led to the 7NHC derivatives. After
achieving preliminary success in the preparation of racemic 7NHC–
Pd complexes,15 we envisioned two potential strategies to access
resolved derivatives of 7NHC ligands: (1) incorporation of sub-
stituents ortho to the nitrogens (the 3 and 30 positions of the biphenyl
moiety), and (2) use of resolved biphenyl diamines (i.e., biphenyl
diamines with substituents in the 6 and 60 positions). In the first
strategy, we reasoned (and obtained preliminary support from
computational modeling) that steric interactions between the ortho
groups and the nitrogen substituents should prevent racemization of
the 7NHC. This strategy proved unattractive, however, because it
would require independent resolution of each new amidinium salt
2.2. Development of the Daugulis–Zaitsev ortho-arylation for
the synthesis of m-quaterphenyl-20,200-diamines, and access to
resolved 7NHC–Pd complexes
Installation of steric bulk ortho to the nitrogen substituents of
biaryl diamines required an ortho functionalization strategy. We
recently reported that application of an ortho C–H arylation re-
action developed by Daugulis and Zaitsev20 provides ready access
to ortho diarylated biaryl diamines (Scheme 1).21 An important
result from this study is that the ortho-arylation reaction is more
effective for 2,20-diamino-6,60-dimethylbiphenyl (4) than for DABN,
and we therefore turned our attention completely to the resolved
diamine 4.22 We next examined the synthesis of [7NHC–H]þ salts
derived from these new resolved quaterphenyl diamines.
This synthetic access to ortho-functionalized biaryl diamines
enabled us to test the hypothesis that primary nitrogen substituents
could be used in the preparation of stable NHC–Pd complexes. Our
initial studies were carried out on the inexpensive and readily
available diamine 6, which was synthesized by acetylation, Dagulis–
Zaitsev arylation, and deacetylation of 2,20-diaminobiphenyl.21 Se-
quential addition of 1-naphthaldehyde and lithium aluminum
Figure 4. (a) Stable 7NHC–[M] complexes are not stable with primary alkyl nitrogen substituents. (b) Resolved 7NHC–HBF4 salts are not accessible with secondary alkyl nitrogen
substituents. (c) Proposed access to stable resolved 7NHC–[M] complexes.

C.C. Scarborough et al. / Tetrahedron 65 (2009) 5084–5092
5087
Scheme 1. Synthesis of resolved quaterphenyl diamines.
Scheme 2. Primary N-substituents with ortho-aryl groups afford a stable NHC–Pd complex.
hydride to the quaterphenyl diamine 621 furnished the di-N-alky-
lated quaterphenyl diamine 7 in high yield. Cyclization of this di-
amine afforded the desired amidinium tetrafluoroborate salt 8.
Addition of [Pd(allyl)Cl]2 and KOtBu to 8 furnished the stable NHC–
Pd(allyl)Cl complex 9, albeit in low yield (Scheme 2). The structure
of 9 was verified by X-ray crystallographic analysis (Fig. 5).23 Syn-
thesis of the stable NHC–Pd complex 9 bearing primary nitrogen
substituents supported our hypothesis that incorporation of steric
bulk in the ortho-positions of the biphenyl diamine could provide
steric protection of the NHC and permit the synthesis of stable NHC–
metal complexes bearing primary nitrogen substituents.
amination with cyclohexane carboxaldehyde and LiAlH4 to afford
(S)-10 in 94% yield (Scheme 3). Initial attempts to cyclize (S)-10
using published conditions15,24 with HC(OEt)3 and NH4BF4 to form
amidinium salt (S)-11 were largely unsuccessful, providing a thick
dark reaction mixture after prolonged reaction times, from which
only a small amount of nearly pure amidinium salt could be
extracted; shorter reaction times provided very low yields as well.
We ultimately found the cyclization reaction could be achieved by
employing microwave irradiation.25 The amidinium salt (S)-11 was
obtained in 38% yield, and workup of the crude mixture was not as
challenging. Metalation of amidinium salt (S)-11 with KOtBu and
[Pd(allyl)Cl]2 afforded the 7NHC–Pd(allyl)Cl complex (S)-12 in 29%
yield (Scheme 3). As NHC–Pd(carboxylate)2 complexes are of cata-
lytic relevance,11,12 we sought to make such a complex from (S)-12.
The next important challenge was to demonstrate that this
synthetic approach could be used with resolved biphenyl diamines.
Toward this end, (S)-5 was alkylated via sequential reductive
Figure 5. Solid-state molecular structure of 9. Hydrogen atoms are omitted for clarity. Only the preferred orientation of the disordered atom C2 is shown, which is disordered over
two positions in an 85:15 ratio. Thermal ellipsoids are shown at 30% probability.

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C.C. Scarborough et al. / Tetrahedron 65 (2009) 5084–5092
Scheme 3. Synthesis of the first resolved metal complexes bearing a chiral 7NHC.
Scheme 4. Synthesis of the catalytically relevant resolved 7NHC–Pd complex (S)-14.
Addition of ethereal HCl to (S)-12 to afford the [NHC-PdCl2]2 com-
plex (S,S)-13 followed by addition of AgO2CCF3 (AgTFA) afforded the
NHC–Pd(TFA)2(OH2) complex (S)-14 (Scheme 4). The molecular
structure of (S)-14 was confirmed in the solid-state by X-ray dif-
fraction analysis (Fig. 6).23 Unfortunately, the yields of amidinium
salt and NHC–Pd(allyl)Cl are quite low, despite extensive attempts
to improve them.26 Nonetheless, these results represented the first
successful preparation of resolved 7NHC complexes of this type.
2.3. Initial efforts to apply resolved 7NHC–Pd complexes to
asymmetric intramolecular aerobic oxidative amination of
alkenes
The [NHC-PdCl2]2 complex (S,S)-13 was first examined as a cat-
alyst for the asymmetric aerobic oxidative cyclization of substrate
15 (Table 1).27 This substrate was examined because it is the only
substrate reported to undergo palladium-catalyzed asymmetric
aerobic oxidative amination.28 Yang and co-workers achieved up to
86% ee in the oxidative cyclization of this substrate with a (ꢁ)-
sparteine-Pd catalyst. NHC ligands have not been tested previously
in this oxidative cyclization reaction. Representative screening data
in Table 1 reveal only modest success with the use of the 7NHC–Pd
complex (S,S)-13 as the catalyst. In the best case, the product 16 was
obtained in 63% ee, albeit in rather low yield (Table 1, entry 3).
Other conditions examined resulted in significantly lower ee or no
formation of 16. For example, base was shown to facilitate substrate
oxidation by PdII, but iPr2NEt was the only base among those tested
Table 1
Aerobic oxidative cyclization of substrate 15 catalyzed by (S,S)-13
Entry
AgX
Additive(s)
Yielda (%)
%eeb (%)
1
2c
3
4
5
6
7
AgTFA
AgTFA
AgTFA
AgOAc
AgoBz
AgOTs
Ag2CO3
iPr2NEt
24
25
35
w0
w0
w0
w0
27
20
63
d
d
d
d
iPr2NEt
iPr2NEt, 3Å MS
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
a
Yield determined by GC relative to internal standard.
% ee determined by GC or HPLC.
Reaction run at 80 ꢂC.
Figure 6. Solid-state molecular structure of (S)-14. Only one symmetry-independent
molecule is shown. All hydrogen atoms except those on the aqua ligand are omitted for
clarity. Thermal ellipsoids are shown at 30% probability.
b
c

C.C. Scarborough et al. / Tetrahedron 65 (2009) 5084–5092
5089
Table 2
Attempts at asymmetric aerobic oxidative cyclization of substrate 2 by (S,S)-13
Entry
Agx
Additive(s)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
AgOAc
AgOAc
AgOAc
AgTFA
AgTFA
AgTFA
AgTFA
d
BzOHc
Na2CO3
d
BzOHc
31
27
63
22
20
26
12
9
ꢁ3
2
1
1
d
d
Na2CO3
ꢁ7
iPr2NEt,d 3Å MS
0
a
Yield determined by GC relative to internal standard.
% ee determined by HPLC.
20 mol %.
b
c
d
2 equiv.
Figure 7. Solid-state molecular structure of 19. Hydrogen atoms are omitted for clarity.
Thermal ellipsoids are shown at 50% probability.
(including Na2CO3, NaOAc, NaO2CPh, MgO, Ca(OH)2, NEt3) that led
to even modest levels of catalytic turnover. The origin of these
observations is not currently known.
was unambiguously determined by X-ray diffraction analysis
(Fig. 7).23 Although complexes 19 and 20 were not the targeted NHC–
Pd(carboxylate)2 catalysts, we nonetheless tested these complexes as
catalysts for the oxidative cyclization reactions of substrates 2 and 15.
In the aerobic oxidative cyclization of substrate 15 with catalysts
19 and 20, improved yields could be obtained relative to those with
catalyst (S,S)-13; however, the product 16 was racemic in every case
(Table 3). The aerobic oxidative cyclization of 2 with catalysts 19
and 20 proceeded in excellent yield (Table 4), but, once again,
the product was always racemic. The improved yields with the
We nextturnedourattention tothe aerobicoxidativeamination of
substrate 2, which has been shown by us to be an effective substrate
for aerobic oxidative amination catalyzed by NHC–Pd complexes,
including one of our racemic 7NHC ligands (Fig. 2).14 The conditions
employed in entries 1–6 of Table 2 resemble the best conditions for
the reported racemic cyclization of 2,14 whereas the conditions
employedinentry7mirroredthebestconditionsforthecyclizationof
15. Although modest yields of product 3 were obtained, the cycliza-
tion product was nearly racemic in every case (Table 2).
Table 3
2.4. Use of a resolved 5NHC–Pd complex in asymmetric
aerobic oxidative Wacker-type cyclization reactions
Aerobic oxidative cyclization of substrate 15 catalyzed by 19 and 29
When the oxidative cyclization studies described above were
nearly complete, Ku¨ndig and co-workers reported the use of chiral
5NHC ligands in Pd-catalyzed intramolecular
a-arylation reactions
(Fig. 1d).6,7 The latter work, which provided the first highly-
enantioselective reaction (>90% ee) employing a chiral NHC–Pd
catalyst, prompted us to examine the most successful 5NHC ligand
from this work in Wacker-type oxidative cyclization reactions.
Synthesis of palladium complexes derived from the amidinium
iodide salt 1 (Fig. 1d) were carried out by combining 1 with [Pd(al-
lyl)Cl]2 and KOtBu to afford the NHC–Pd(allyl)Cl complex 17, followed
by protonolysis of the allyl ligand with ethereal HCl to afford the
[NHC–PdCl2]2 complex 18.29 Anion metathesis with silver(I)-carb-
oxylate salts did not furnish the desired NHC–Pd(carboxylate)2
complexes, but instead led to formation of the cyclometalated com-
plexes 19 and 20 (Scheme 5). The solid-state molecular structure of 19
Entry
Catalyst
Additive(s)
Yielda (%)
eeb (%)
1
2c
3
4
5
6
7
8
19
19
19
19
20
20
20
20
d
57
15
66
34
5
7
13
2
2
5
7
0
0
0
4
0
20% BzOH
2 equiv Na2CO3
2 equiv iPr2NEt, 3Å MS
d
20% BzOH
2 equiv Na2CO3
2 equiv iPr2NEt, 3Å MS
a
Yield determined by GC relative to internal standard.
% ee determined by HPLC.
Reaction run at 80ꢂC.
b
c
Scheme 5. Synthesis of catalytically relevant palladium complexes bearing Ku¨ ndig’s chiral NHC.

5090
C.C. Scarborough et al. / Tetrahedron 65 (2009) 5084–5092
were then vortexed for 18 h under 1 atm dioxygen at 80 ꢂC, after
which time the reactions were filtered over Celite and the solvent was
removed from each tube under reduced pressure prior to analysis by
1H NMR spectroscopy, gas chromatography, and/or HPLC.
Table 4
Aerobic oxidative cyclization of substrate 2 catalyzed by 19 and 20
4.3. Synthesis and characterization data
4.3.1. N,N0-Bis(1-naphthylmethyl)-20,200-diamino-
m,m-quaterphenyl (7)
Entry
Catalyst
Additive(s)
Yielda (%)
eeb (%)
1
2
3
4
5
6
19
19
19
20
20
20
d
BzOHc
Na2CO3
d
BzOHc
90%
91%
90%
82%
85%
83%
5%
4%
6%
5%
4%
0%
Diamine
6 (470 mg) was combined with 778 mL 1-naph-
d
thaldehyde and a few crystals of p-TsOH in w250 mL toluene. A
Dean–Stark apparatus was attached, and the reaction was heated to
reflux for 48 h. Solvent was then removed in vacuo and the residue
was taken up in 25 mL dry THF. 339 mg LiAlH4 (6.4 equiv) was added
slowly and the solution was heated to 50 ꢂC for 2 h. After cooling to
room temperature, the reactionwas carefully quenched by sequential
addition of 0.3 mL H2O, 0.6 mL 10% NaOH(aq), then 0.9 mL H2O. The
solid that formed was removed by filtration, and the filtrate was
concentrated in vacuo. Product was purified by column chromatog-
raphy (SiO2 packed with 5% NEt3 in toluene, then flushed with tolu-
ene before loading crude) using a gradient eluent (pure toluene to 1:1
toluene–EtOAc) to afford 605 mg 7 as a light yellow oil (70% yield).
HRMS: m/z (ESI) calculated [MH]þ¼617.2956, measured 617.2963
d
Na2CO3
a
Yield determined by GC relative to internal standard.
%ee determined by HPLC.
20 mol %.
b
c
d
2 equiv.
5NHC–Pd-catalysts may reflect the smaller size of the 5NHC ligand
compared to the 7NHC ligand.
3. Conclusions
(
D
¼1.1 ppm). 1H NMR (300 MHz, CDCl3) 3.99 (s, 4H) 6.90 (d, J¼6.0 Hz,
In this study, we have achieved preparation of the first enan-
tiomerically resolved 7NHC–Pd complexes and investigated their
reactivity in aerobic oxidative cyclization reactions of alkenes. The
7NHC-precursor amidinium salt is accessible through a sequence
involving a Pd-catalyzed ortho-arylation of the biaryl ring, in-
corporation of nitrogen substituents via reductive amination, and
cyclization using HC(OEt)3 and NH4BF4 under microwave irradia-
tion. The ortho-arylation reaction is critical to access stable 7NHC–
Pd complexes. These ligands were employed with mixed success in
Pd-catalyzed aerobic oxidative cyclization reactions. In one case, up
to 63% ee was achieved in a Pd-catalyzed intramolecular oxidative
amination reaction. Although this level of enantioselectivity is
relatively modest, the result is significantly better than that
obtained with Pd-catalysts bearing a chiral five-membered NHC
ligand (ꢀ7% ee). These observations highlight the prospects for the
use of chiral seven-membered NHCs of the type described here in
asymmetric catalysis.
2H), 7.01 (t, 7.5 Hz, 2H), 7.14–7.36 (m, 22H), 7.60 (d, J¼8.4 Hz, 2H), 7.69
(d, J¼9.0 Hz, 2H). 13C NMR (75 MHz, CDCl3) 50.6, 121.8, 123.6, 125.4,
125.6, 126.3, 127.2, 127.9, 128.5, 128.5, 129.4, 130.9, 131.1, 132.5, 133.8,
134.2, 135.6, 140.9, 145.0.
4.3.2. Amidinium salt 8
Diamine 7 (3.1 g) was combined with 560 mg NH4BF4 in 150 mL
HC(OEt)3. The reaction was heated to 130 ꢂC for 48 h. The reaction
was then concentrated in vacuo to a thick oil and taken up in minimal
methylene chloride. Excess hexanes were added to drive the product
out of solution, and the suspension was cooled in a freezer overnight.
Tan solid was collected by filtration and washed with pentane. The
solid was then taken up in minimal refluxing ethanol and cooled in
a freezer. The resultant powder was collected by filtration, washed
with pentane, and dried under high vacuum to afford 1.7 g pure 8 as
a tan solid (47% yield). HRMS: m/z (ESI) calculated [MH]þ¼627.2795,
measured 627.2805 (
D
¼1.6 ppm). 1H NMR (300 MHz, CDCl3) 4.35 (d,
J¼14.4 Hz, 2H), 4.82 (d, J¼14.4 Hz, 2H), 6.73 (br s, 4H), 7.04 (ddd, J¼8.1,
6.9, 1.2 Hz, 2H), 7.10–7.15 (m, 4H), 7.21 (ddd, J¼8.4, 6.9,1.2 Hz, 2H),
7.28–7.31 (m, 4H), 7.36–7.54 (m, 10H), 7.61 (d, J¼7.8 Hz, 2H), 7.68 (d,
J¼8.4 Hz), 9.49 (s, 1H). 13C NMR (75 MHz, CDCl3) 57.1, 122.2, 125.9,
126.0, 126.7, 128.0, 128.9, 129.1, 129.3, 129.6, 130.1, 130.2, 132.2, 132.4,
133.8, 134.3, 136.9, 137.2, 142.1, 179.1.
4. Experimental
4.1. General considerations
Solvents for reactions performed on the benchtop were dried
by passing them through
a
column of activated alumina,30
whereas solvents for reactions performed in a glove box were
dried over Na/benzophenone and distilled. 1H and 13C NMR
spectra were recorded on 300 or 500 MHz spectrometers. 1H
4.3.3. NHC–Pd(allyl)Cl complex 9
Compound 8 (756 mg, 1.06 mmol), KOtBu (132.2 mg, 1.1 equiv),
and [Pd(allyl)Cl]2 (230 mg, 0.60 equiv) were combined in 30 mL dry
THF in a glove box. The reaction was stirred at room temperature
for 20 h, after which it was removed from the glove box. The sus-
pension was filtered over Celite and the solvent removed in vacuo.
Compound 9 was purified by column chromatography (SiO2) using
a gradient eluent (40% Et2O in hexanes to pure Et2O) as a lightly
yellow solid (100 mg, 12% yield). The product is a 1.5:1 mixture of
allyl rotamers by 1H NMR spectroscopy. HRMS: m/z (ESI) calculated
chemical shifts (d) are reported in parts per million relative to
SiMe4 (0.0 ppm) while 13C chemical shifts are reported in parts
per million relative to deuterated solvent (77.23 ppm for CDCl3 or
128.06 for benzene-d6).
4.2. General screening conditions for oxidative Wacker-type
cyclization reactions
[M(ꢁCl)]þ¼771.2169, measured 771.2178 (
D
¼1.2 ppm). 1H NMR
Screening was conducted in disposable Borosilicate Heavy Wall
13ꢃ100 mm Culture Tubes (Fisherbrand). Catalyst and solid additives
were weighed into reaction tubes, which were then loaded onto
a custom 48-well parallel reactor mounted on a Large Capacity Mixer
(Glas-Col). The headspace was purged under a positive flow of
dioxygen with mild vortexing for 15 min. A stock solution of the
substrate in toluene (0.1 M) was added to the reaction tubes, which
(300 MHz, CDCl3) (all peaks are quite broad. Identity is known from
X-ray crystal structure, but NMR spectra are difficult to interpret)
1.64 (m, 1.5H), 2.25 (m, 1H), 2.38 (m, 1H), 2.84 (m, 1.5H), 3.31 (m,
2.5H), 4.29 (m, 1.5H), 4.72 (m, 1H), 5.00 (m, 1.5H), 5.24 (m, 1H),
6.94–7.64 (m, 45H). 13C NMR (75 MHz, CDCl3) 58.2 (br peak), 115.7,
116.4, 125.0, 125.7, 127.7, 127.9, 128.4, 129.1, 132.0, 133.4, 136.2, 140.1,
144.9 (br peak).

C.C. Scarborough et al. / Tetrahedron 65 (2009) 5084–5092
5091
4.3.4. (S)-N,N0-Bis(cyclohexylmethyl)-20,200-diamino-40,400-
dimethyl-m,m-quaterphenyl ((S)-10)
vacuo and dried under high vacuum to afford 195 mg of a bright
yellow compound, which reacts as the drawn compound when
combined with AgO2CCF3 (below). 1H NMR spectroscopy revealed
two large broad peaks, in the alkyl and aryl regions, but no distinct
peaks were observed. Peaks in NMR spectra are challenging to as-
sign, and this structure is assigned from previous precedent,15 and
from reactivity ((S)-14 is derived quantitatively from this species,
which has been fully characterized using ESI-MS, 1H and 13C NMR
spectroscopy, and single-crystal X-ray diffraction analysis).
Diamine (S)-5 (2.0 g) was combined with 1.7 mL cyclohexane
carboxaldehyde (2.5 equiv) and a few crystals of p-TsOH in 120 mL
toluene in a Dean–Stark apparatus. The reaction was heated to
reflux for 60 h, cooled to room temperature, and solvent was re-
moved in vacuo. The resultant residue was taken up in 50 mL dry
THF and 650 mg LiAlH4 was carefully added portionwise. The re-
action was stirred at 50 ꢂC for 2 h, cooled to room temperature, and
carefully quenched by sequential addition of 1 mL H2O, 2 mL 10%
NaOH(aq), and 3 mL H2O. The solid, which had crashed out was
removed by filtration, and solvent was removed from the filtrate in
vacuo to afford (S)-10 in 95% yield. HRMS: m/z (ESI) calculated
4.3.8. NHC–Pd(O2CCF3)2(OH2) complex (S)-14
Compound (S,S)-13 (83 mg, 0.056 mmol) was combined with
54.2 mg (4.4 equiv) AgO2CCF3 in dichloromethane. This reaction
mixture was stirred at room temperature for 1.5 h, during which time
a white solid was observed to have formed. Filtration over Celite and
removal of solvent under vacuum afforded (S)-14 as a tan-yellow
solid in quantitative yield. The identity of this species was confirmed
by X-ray crystallographic analysis (Fig. 6). ESI-MS: m/z (major peak
containing Pd) 707.7 ([NHC-Pd(OH2) (OH)]þ). 1H NMR (300 MHz,
CDCl3) 0.39–0.51 (m, 4H), 0.83–1.44 (m, 18H), 2.19 (s, 6H), 3.23 (dd,
J¼13.5, 5.1 Hz, 2H), 4.32 (dd, J¼13.2, 8.1 Hz, 2H), 7.18 (d, J¼7.5 Hz, 2H),
7.31 (d, J¼7.5 Hz, 2H), 7.46–7.52 (m, 10H). 13C NMR (75 MHz, CDCl3)
[MH]þ¼557.3891, measured 557.3883
(
D
¼1 ppm). 1H NMR
(300 MHz, CDCl3) 0.41 (br q, J¼12.3 Hz, 4H), 0.90–1.09 (m, 8H),
1.20–1.28 (m, 4H), 1.48–1.55 (m, 4H), 2.02 (s, 6H), 2.27 (m, 4H), 3.27
(br s, 2H), 6.87 (dd, J¼7.8, 0.8 Hz, 2H), 7.10 (d, J¼7.6 Hz, 2H), 7.27–
7.30 (m, 2H), 7.35–7.40 (m, 4H), 7.49–7.52 (m, 4H). 13C NMR
(75 MHz, CDCl3) 20.5, 26.1, 26.7, 30.9, 31.0, 38.8, 54.5, 121.9, 126.5,
127.6, 128.4, 129.1, 131.3, 137.1, 142.4, 145.8.
4.3.5. Amidinium salt (S)-11
Diamine (S)-10, NH4BF4 (1.3 equiv), and 100 mL HC(OEt)3 were
combined and subjected to microwave irradiation (equilibration
time to 100 ꢂC¼10 min, 2 h at 100 ꢂC, max power¼250 watts).
Concentration on a rotary evaporator, dissolving in minimal hot
toluene, and crashing out with hexanes afforded some powder and
a sticky orange semi-solid. The powder was filtered away, and the
semi-solid was again taken up in hot toluene and crashed out with
hexanes. This procedure was repeated as necessary until no more
powder formed. Dissolved filtered powder in dichloromethane and
filtered to remove excess NH4BF4. Removed solvent from filtrate to
afford a sticky solid, which was re-dissolved in minimal dichloro-
methane and added dropwise to a 250 mL graduated cylinder filled
with hexanes (powder forms immediately on addition of each
drop). After complete addition, let suspension sit for 30 min then
decanted the hexanes. Dissolved solid in dichloromethane and
transferred to a flask. Solvent was removed in vacuo to afford 38%
yield (1.35 g) of (S)-11 as a tan powder. HRMS: m/z (ESI) calculated
19.6, 25.5, 25.9, 26.1, 29.8, 30.8, 38.4, 60.3, 128.5, 128.6, 129.4, 129.7,
25
132.0, 133.3, 134.3, 137.6, 139.4, 145.1, 201.8. [
a
]
þ3.6 (c 5.5, CH2Cl2).
D
4.3.9. NHC–Pd(allyl)Cl complex 17
In a glove box, amidinium salt 1 (285 mg, 0.552 mmol), [Pd(al-
lyl)Cl]2 (131 mg, 0.65 equiv), and KOtBu (80 mg, 1.3 equiv) were
combined in 20 mL THF. The reaction stirred at room temperature
in the dark for 12 h, after which time the reaction flask was re-
moved from the glove box and exposed to ambient conditions.
Solvent was removed on a rotary evaporator, and product was
isolated by column chromatography (SiO2) using 1:1 Et2O–hexanes
as the eluent to afford a light tan solid with a 1H NMR spectrum,
which could be consistent with the drawn product, but was not
conclusive. Carried material forward without full characterization.
Identity is based on formation of 19 and 20.
4.3.10. [NHC-PdCl2]2 complex 18
[MH]þ¼567.3734, measured 567.3736
(
D
¼0.4 ppm). 1H NMR
To crude 17 was added 1 mL ethereal HCl (2.0 M, 3.6 equiv com-
pared to amidinium salt 1). The reaction was stirred at room temper-
ature for 2 h. Solvent was removed on a rotary evaporator to afford
141 mg 18 as an orange–brown solid in 45% yield over two steps. Again,
the 1H NMR spectra were consistent with the drawn product, but in-
conclusive. Assignment is based on formation of 19 and 20. 1H NMR
(300 MHz, CDCl3) (all peaks are broad) 1.06–1.16 (m, 36H), 3.29 (s, 6H),
3.34 (s, 6H), 6.92 (s, 2H), 7.07–7.23 (m, 12H), 7.38 (s, 2H), 7.66 (s, 4H).
(300 MHz, CDCl3) 0.39 (qd, J¼11.7 Hz, 2H), 0.52–0.71 (m, 4H), 0.81–
0.97 (m, 4H), 1.10–1.35 (m, 6H), 1.39–1.43 (m, 6H), 2.29 (s, 6H), 2.93
(dd, J¼13.8, 5.1 Hz, 2H), 3.37 (14.0, 6.1 Hz, 2H), 7.27–7.35 (m, 6H),
742–7.49 (m, 4H), 7.55–7.61 (m, 4H), 9.05 (s, 1H). 13C NMR (75 MHz,
CDCl3) 19.6, 25.6, 25.7, 25.8, 29.7, 30.0, 40.1, 61.4, 127.7, 128.9, 130.1,
131.0, 132.6, 132.8, 134.4, 137.6, 138.3, 145.4, 175.8.
4.3.6. NHC–Pd(allyl)Cl complex (S)-12
This complex was synthesized analogously to compound 9.
Product was purified by column chromatography (SiO2) using 1:1
Et2O–hexanes as the eluent. Product was isolated in 29% yield
(195 mg) as a lightly yellow solid. Peaks in NMR spectra are chal-
lenging to assign, and this structure is assigned from previous
precedent,15 1H NMR spectroscopy (dr w2.2:1), and from reactivity
((S)-14 is derived quantitatively from this species, which has been
fully characterized using ESI-MS, 1H and 13C NMR spectroscopy, and
single-crystal X-ray diffraction analysis). 1H NMR (300 MHz, CDCl3)
0.47–1.40 (m, 31.9H), 2.15–2.53 (m, 10.15H), 2.53–3.05 (m, 4.8H),
3.34–3.65 (m, 4.25H), 4.33 (m, 2H), 5.23 (m, 0.45H), 5.39 (m, 1H),
7.09–7.37 (m, 20.3H).
4.3.11. Pd complex 19
Compound 18 (81 mg, 0.072 mmol) was combined with 49 mg
AgOAc (4.1 equiv) in dichloromethane. The reaction stirred at room
temperature in the dark for 2 h, after which time the reaction was
filtered through Celite to remove the AgCl. Solvent was removed in
vacuo to afford 74 mg 6 (86% yield) as a brown solid. The structure of
19 was unambiguously assigned by X-ray diffraction analysis
(Fig. 4): X-ray-quality crystals were obtained from slow evaporation
of a CDCl3-solution of 6 in a round-bottom flask. An X-ray-quality
crystal of 6 was re-dissolved in CDCl3, and gave a 1H NMR spectrum,
which was identical to the bulk material. HRMS: m/z (ESI) calculated
[M–OAc]þ¼491.1836, measured 491.1830 (
D
¼1.0 ppm). 1H NMR
(300 MHz, CDCl3) 1.09 (s, 9H), 1.26 (s, 9H), 2.11 (br s, 6H), 2.32 (s,
3H), 2.94 (s, 3H), 5.13 (s, 1H), 6.26 (s, 1H), 6.79–6.99 (m, 2H), 6.99 (d,
J¼2.1 Hz, 1H), 7.10–7.16 (m, 4H), 7.37–7.48 (m, 2H), 7.49 (dd, J¼5.4,
4.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) 21.8, 22.1, 27.4, 29.3, 37.3, 37.7,
66.1, 71.8, 118.0, 123.0, 125.5, 126.1, 127.2, 127.8, 128.2, 131.4, 131.5,
134.0, 135.7, 136.4, 138.9, 139.2, 162.2, 174.2.
4.3.7. [NHC-PdCl2]2 complex (S,S)-13
Compound (S)-12 (195 mg, 0.26 mmol) was dissolved in 50 mL
Et2O, and 3.25 mL 2.0 M ethereal HCl (25 equiv) was added via
syringe. This mixture was stirred at room temperature for 6 h, over
which time the solution turned bright yellow. Removed solvent in

5092
C.C. Scarborough et al. / Tetrahedron 65 (2009) 5084–5092
10. (a) Zinner, S. C.; Herrmann, W. A.; Ku¨hn, F. E. J. Organomet. Chem. 2008, 693,
4.3.12. Pd complex 20
1543–1546; (b) Baskakov, D.; Herrmann, W. A.; Herdtweck, E.; Hoffmann, S. D.
Organometallics 2007, 26, 626–632; (c) Roland, S.; Audouin, M.; Mangeney, P.
Organometallics 2004, 23, 3075–3078.
Prepared from 18 analogously to the above synthesis of 19, using
AgO2CCF3 in place of AgOAc. Product was obtained in w100% yield
(67 mg) as a dark brown solid. HRMS: m/z (ESI) calculated
11. Rogers, M. M.; Stahl, S. S. Top. Organomet. Chem. 2007, 21, 21–46.
12. Sigman, M. S.; Jensen, D. R. Acc. Chem. Res. 2006, 39, 221–229.
13. Mun˜iz, K. Adv. Synth. Catal. 2004, 346, 1425–1428.
[M]þ¼491.3426, measured 491.3437
(D
¼2.2 ppm). 1H NMR
(300 MHz, CDCl3) (all peaks are rather broad) 1.03–1.29 (m, 36H),
2.33 (m, 6H), 2.51 (m, 6H), 5.84–5.92 (m, 4H), 7.03–7.91 (m, 16H),
8.89 (br s, 2H). 13C NMR (75 MHz, CDCl3) 15.5, 21.4, 21.7, 27.1, 27.4,
27.6, 28.2, 38.3, 39.4, 66.1, 66.9, 72.4, 118.7, 123.1, 124.7, 125.0, 127.3,
128.4, 129.3, 129.6, 132.0, 133.2, 134.1, 137.0, 137.3, 146.7, 147.4.
14. Rogers, M. M.; Wendlandt, J. E.; Guzei, I. A.; Stahl, S. S. Org. Lett. 2006, 8, 2257–2260.
15. (a) Scarborough, C. C.; Popp, B. V.; Guzei, I. A.; Stahl, S. S. J. Organomet. Chem.
2005, 690, 6143–6155; (b) Scarborough, C. C.; Grady, M. J. W.; Guzei, I. A.;
Gandhi, B. A.; Bunel, E. E.; Stahl, S. S. Angew. Chem., Int. Ed. 2005, 44, 5269–5272.
16. Such 7NHCs were first predicted in a computational study: Kastrup, C. J.; Old-
field, S. V.; Rzepa, H. S. J. Chem. Soc., Dalton Trans. 2002, 2421–2422.
17. The synthetic inaccessibility of such NHC–Pd(O2CR)2 complexes appears to
arise from ortho-metallation of the carboxylate complex. For a more detailed
discussion, see: Rogers, M. M. Ph.D. Thesis, University of Wisconsin-Madison,
Madison, WI, 2007.
Acknowledgements
18. Attempts to resolve amidinium salts with methyl groups in the 3 and 30 posi-
tions of the biphenyl moiety were unsuccessful. For further details, see: Scar-
borough, C.C. Ph.D. Thesis, University of Wisconsin-Madison, Madison, WI,
2008.
CCS is grateful to the American Chemical Society Division of
Organic Chemistry for a graduate fellowship. This work was funded
by the National Institutes of Health (R01 GM67173) and a UW-
Madison Graduate School Technology Transfer Grant.
19. Following our initial studies on 7NHCs, Herrmann and co-workers reported that
amidinium salts derived from BINAM could be accessed with secondary alkyl
and aryl nitrogen substituents when phosgene was added to the mono-for-
mylated diamine: Herrmann, W. A.; Baskakov, D.; Ruhland, K. J. Heterocycl.
Chem. 2007, 44, 237–239. In our hands, these amidinium salts were highly
unstable to water and difficult to work with.
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