Structure–enantioselectivity correlation in NHC–Au(I) catalysis for 1,6-enynecyclizations

Article abstract of DOI:10.1016/j.tetlet.2016.07.046

A direct correlation of the NHC ligand structure and the induced enantioselectivity has been uncovered for a series of new chiral gold(I) complexes. The Au(I)Cl complexes were identified by¹H,¹³C NMR spectroscopy, and X-ray structure analysis. The corresponding activated Au(I) catalysts with a phenyl nitrile dynamic ligand are prepared and used in the catalysis of 1,6-enyne cyclization reactions. High chemical yields and good enantioselectivity have been obtained with 6%?mol of the chiral NHC–Au(I) catalysts. The products in these reactions reach up to 75% ee. The structure of the chiral NHC ligand, where an ortho-biphenyl moiety is connected to the nitrogen atoms, the 3,5-dialkyl distal phenyl group plays a determining role in enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2016.07.046

Accepted Manuscript
Structure-enantioselectivity correlation in NHC-Au(I) catalysis for 1,6-enyne-
cyclizations
Benjamin W. Gung, Michael R. Holmes, Caleb A. Jones, Ruoyu Ma, Charles
L. Barnes
PII:
S0040-4039(16)30892-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.046
TETL 47908
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 June 2016
6 July 2016
12 July 2016
Please cite this article as: Gung, B.W., Holmes, M.R., Jones, C.A., Ma, R., Barnes, C.L., Structure-enantioselectivity
correlation in NHC-Au(I) catalysis for 1,6-enynecyclizations, Tetrahedron Letters (2016), doi: http://dx.doi.org/
1
0.1016/j.tetlet.2016.07.046
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Structure-enantioselectivity correlation in NHC-Au(I) catalysis for 1,6-
enynecyclizations
a
a
a
a
b
Benjamin W. Gung *, Michael R. Holmes , Caleb A. Jones , Ruoyu Ma , Charles L. Barnes
a
Department of Chemistry & Biochemistry, Miami University, Oxford, Ohio 45056
Elmer O. Schlemper X-Ray Diffraction Center, University of Missouri-Columbia, Columbia, MO 65211
b
Abstract: A direct correlation of the NHC ligand structure and the induced enantioselectivity has been
1
13
uncovered for a series of new chiral gold(I) complexes. The Au(I)Cl complexes were identified by H, C
NMR spectroscopy, and X-ray structure analysis. The corresponding activated Au(I) catalysts with a
phenyl nitrile dynamic ligand are prepared and used in the catalysis of 1,6-enyne cyclization reactions.
High chemical yields and good enantioselectivity have been obtained with 6% mol of the chiral NHC-
Au(I) catalysts. The products in these reactions reach up to 75% ee. The structure of the chiral NHC
ligand, where an ortho-biphenyl moiety is connected to the nitrogen atoms, the 3,5-dialkyl distal phenyl
group plays a determining role in enantioselectivity.
Key words:
NHC ligands
gold catalysis
cyclizations
enantioselectivity
Homogeneous catalysis by Au(I) complexes has emerged as a powerful tool for organic
1
-3
synthesis. The cationic Au(I) catalysts are π-acidic, which upon coordination to unsaturated bonds,
4
-7
especially alkynes, leads to nucleophilic attack and new bond formation. N-Heterocyclic (NHC) ligands
have been shown to have many advantages such as stability and structural variability to form transition
8
-10
metal complexes. However few effective chiral NHC ligands for gold complexes have been developed
1
1-14
despite a variety of NHC-other transition metal complexes have been reported.
It is a challenge to
develop highly enantioselective chiral NHC ligands for Au(I) complexes because of the propensity of
3,15
gold(I) to form linear two-coordinate complexes. The 1,6-intramolecular methoxy cyclization has been
16-17
used as a bench test for the catalytic activity of gold catalysts.
Ph Ph
Ar
N
N
Ar
Ar
N
N
Ar
R
R
Ar
Ar
1
Ar = substituted
phenyl
2 Ar = ph, Naph
R = i-Pr, t-Bu
Figure 1. Chiral N-heterocyclic carbene-gold complexes previously reported from Tomioka and Kundig's
groups, respectively.

Tomioka reported C
2
-symmetric NHC-Au(I) complexes (1) and induced up to 56% ee in enyne
18
cyclizations, Figure 1. Kundig reported similar enantioselective enyne cyclization reactions using chiral
NHC-Au(I) catalyst of similar to (2) resulting up to 72% ee, Figure 1. We wish to report new chiral
17
NHC-Au(I) catalysts that show strong catalytic activity and thermo-stability with up to 75% ee.
Recently we reported the synthesis and characterization of a family of new chiral NHC-Au(I)
19
complexes, Figure 2. In our design, we continued the application of the C -symmetry and the aryl-alkyl
2
combination at the chiral centers. In addition, we added an ortho-biphenyl structural moiety to the aryl
component. We have now performed enyne cyclization reactions with two different substrates using our
new chiral NHC-Au(I) complexes as catalysts. A clear correlation between the structure of the NHC
ligand and the enantioselectivity has been uncovered for these reactions. The results are described in this
report.
R'
R'
Ar =
N
N
Ar
Ar
R
R
3a b
c
4a b
c
5a b c
Au
Cl
R Me Me Me nPr nPr nPr iPr iPr iPr
R' H Me tBu H Me tBu H Me tBu
3
a-5c
Figure 2. Chiral N-heterocyclic carbene-gold complexes reported by us recently.
We have prepared three new complexes from the chiral amines shown in Figure 3 since our report
last year. These add to the systematic variations in structure to study the correlation between the chiral
NHC ligands and the enantioselectivity it can achieve in catalyzed cyclizations. The details of the chiral
ligand synthesis can be found in the supplemental information.
Me
Me tBu
tBu
NH2
NH2
NH2
Et
Et
Et
6
7
8
Figure 3. New chiral amines with o-biphenyl substituents.
The ligand chirality stems from the stereocenter where the nitrogen atom is connected. Our
recently reported gold complexes have the alkyl group varying in size from a methyl group to a propyl
group, and to an isopropyl. We have now prepared three new ligands with an ethyl group at the chiral
center, Figure 3.
The chiral Au(I) complexes 10a-c are prepared as shown in Scheme 1 following the procedure
reported by Nolan and coworkers for preparing imidazoliums with bulkyl substituents. The chiral amines
are converted to diimine intermediates by treating with glyoxal and formic acid. The resulting diimines

were converted to the imidazolium chlorides by treatment of ZnCl
dioxane. The chiral NHC- gold(I) complexes were obtained by stirring the imidazolium chloride with
Au[S(Me) ]Cl in acetone in the presence of K CO . The gold(I) complexes of 10a-c are stable and can be
2
and paraformaldehyde in acidic
2
2
3
1
13
purified by column chromatograph. Their structures are determined by H and C NMR spectroscopy.
Complex 10a and complex 10b were also characterized by X-ray diffraction analysis, Figure 4. Crystals
of 10a and 10b were grown by careful layering of hexane onto a saturated toluene solution (or
dichloromethane in the case of 10b) of the gold complex and allowed to stand for a few days at room
temperature. For details of the crystal structures, see supplemental information.
Scheme 1 Synthesis of Au(I) complexes 10a-c with variation at the aryl (Ar) group.
1
. glyoxal, CH Cl2
K2CO
3
Ar NH2
Et
2
Na SO , HCO H
Au[S(Me) ]Cl
2
4
2
2
N
N
N+
N
Ar
Ar
Acetone
70%
R'
2
. ZnCl , (CH O) Ar
Ar
Et
Et
2
2
n
Et
Cl-
Et
Au
Cl
Dioxane•HCl
THF, 70°C
6
,7,8
R'
9a-c
1
0a-c
72%
Ar =
a
b
c
R': = H, = Me, = tBu
Figure 4. X-ray determined structure of Au(I) complex 10a and 10b with the chiral NHC bearing ethyl
(R) and either phenyl (10a) or 3,5-dimethylphenyl (10b) groups.
Complex 10a presents the expected linear geometry with the C-Au-Cl angle of a perfect 180.0 
while 10b has a C-Au-Cl angle of 178.5 . The Au-Ccarbene distance for 10a is 1.989(3) Å and for 10b is
.985(4) Å. An apparent C symmetry is found for complex 10a, but the crystal structure of 10b shows a
1
2
more complicated pattern. The aromatic rings of 10b are clustered on one side with the methyl groups
being close to the face of the other phenyl rings.
2
0
From our recent study of Au(I)-catalyzed [3 + 2] cycloadditions, it is important to use
benzenenitrile as a dynamic ligand after the activation of the gold complexes by abstraction of the
chloride using AgSbF
and 10a-c were activated with AgSbF
6
. This study continues this practice. As shown in Scheme 2, gold complexes 3a-5c
and protected with a weak coordination ligand PhCN. The
6

resulting active catalysts 11a-15c are stable white solid and can be stored under nitrogen in the
refrigerator for weeks without losing activity.
Scheme 2 Activation of the gold complexes and protection of the cationic gold with PhCN.
SbF -
6
N
N
N
N
AgSbF , PhCN
6
R
R
Au+
N
R
R
Au
Cl
DCM
R'
R'
R'
R'
R'
R'
75-97%
R'
R'
Ph
3
4
5
1
a-c
a-c
a-c
11a 11b 11c 12a 12b 12c 13a 13b 13c 14a 14c 15c
R Me Me Me Et Et Et nPr nPr nPr iPr iPr Bu
R'
0a-c
H Me tBu H Me tBu H Me tBu H tBu tBu
The cyclization reactions gave universally high chemical yields and varying enantioselectivity
depending on the ligand structure and to a smaller degree the structure of the substrates. The distal aryl of
the biphenyl structure moiety in the chiral ligand plays a crucial role in the enantioaelectivity of the
cyclizations. In the three series where the alkyl groups are methyl, ethyl, and propyl groups (structures 11,
12, and 13 in Scheme 2), the values of ee% of the cyclization product increase as the aryl group changing
from a phenyl to a 3,5-dimethylphenyl, then to a 3,5-di-t-butylphenyl group. In other words, the
enantioselectivity of the reaction was proportional to the steric bulk of the distal aryl group.
The effect of the alkyl group is less profound. There is a small increase of enantioselectivity from
R = methyl to R = Et , then to R = n-propyl. However when R = isopropyl, the trend in the distal aryl
group no longer holds (see entries 10 and 11 in Table 1). When even greater R (t-butyl) was employed,
the catalyst became inactive (not shown).
The combination of R = n-propyl and the distal aryl group = 3,5-di-t-butyl (catalyst 13c, entry 9,
Table 1) gave the highest ee% for substrate 16 (75 ee%) in Table 1. But for substrate 18, catalyst 11c (R =
methyl, aryl = 3,5-di-t-butyl, Table 2), produced the highest enantioselectivity. Despite this slight
dependency on substrate structure, the steric size of the distal aryl group is the single most important
factor for this series of gold(I) catalysts. The alkyl group R cannot be too big. This point is demonstrated
by catalyst 14c, which has an isopropyl group and its enantioselectivity maxed out at 30-40%ee. One
possibility is the bulky alkyl group blocks the access of the substrate to such a degree as to lower the
enantioselectivity. It seems reasonable to suggest an improved design of these gold(I) catalysts by further
increasing the steric bulk of the distal aryl group. This should allow the aryl group to completely block
one enantiomeric face of the Au(I) catalyst and allow the alkyne substrate to coordinate from the side that
occupied by the alkyl group.

Table 1 1,6- Intramolecular Methoxy Enyne cyclizations of Substrate 16
MeO C
MeO C
2
2
6
% mol catalyst
MeO C
MeO C
2
2
MeOH, rt, 1-3 h
OMe
%ee
16
17
Entry
Catalyst %yield
[]
1.2
5.8
12.6
2.1
1
2
3
4
11a
11b
11c
12a
75
91
98
95
4
24
51
8.7
5
6
12b
12c
96
88
1.8
8
-15.9
64
7
8
9
13a
13b
13c
14a
14c
15c
63
85
67
94
87
82
0.8
3
-4.8
18.6
11.6
-8.2
-16.9
20
75
38
33
70
1
1
1
0
1
2
a.
16
Values of % ee were calculated from comparing to the literature value for the optical rotation [].
Table 2 1,6-Intramolecular Methoxy Enyne cyclizations of Substrate 18
H
MeO C
MeO C
OMe
Ph
2
6% mol cat.
2
MeO C
MeO C
2
2
MeOH, rt, 1-3 h
Ph
1
8
19
a
Entry
Catalyst
11a
% yield []
%ee
1
99
-0.5
1.0

2
3
4
5
6
7
8
9
1
1
11b
11c
12a
84
95
79
99
88
81
99
99
94
98
26.7
60.7
9.0
31.0
70.0
10.4
1.0
0.5
12b
12c
13a
13b
13c
14c
15c
33.6
10.2
-4.8
31.0
-6.7
-39.6
39.0
12.0
6.0
36.0
7.0
0
1
a.
46.0
Values of % ee were calculated from comparing
1
6
to the literature value for the optical rotation [].
In summary, it is well known that the linear two-coordinate complexes of Au(I) presents a great
3,21
challenge in developing enantioselective Au(I) catalysts. The reacting substrate is positioned away
from the source of the ligand-centered chirality. Previous and current results from 1,6-intramolecular
methoxy enyne cyclizations underscore such a challenge. However, this study highlights a direct
correlation of the NHC ligand structure and the induced enantioselectivity. The structure of the chiral
NHC ligand, where an ortho-biphenyl moiety is connected to the nitrogen atoms, the 3,5-dialkyl distal
phenyl group plays a determining role in enantioselectivity. Based on this observation, an improved
design of these gold(I) catalysts involves a further increase in the steric bulk of the distal aryl groups.
Work along this line is currently underway in our laboratories.
Acknowledgements
Financial support from Miami University in the form of a faculty research grant (CFR) and from NSF for
the NMR Facility are acknowledged. CAJ was a recipient of a Dean's Scholarship from the College of Arts &
Sciences.
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Highlights:




X-ray structures were obtained for two new chiral NHC-Au(I) complexes.
The products in the Au(I)-catalyzed reactions reach up to 75% ee.
A correlation of ligand structure and enantioselectivity has been uncovered.
The dialkyl phenyl group plays a determining role in enantioselectivity.