Influences of Phenyl Rings on NHC Ligands with Bicyclic Architectures

Article abstract of DOI:10.1021/acs.joc.8b02480

In addition to phosphanes, olefins, amines, and amides, over the past two decades N-heterocyclic carbene (NHC) has emerged as a useful alternative ligand. Based on a number of derivatization studies on NHC ligands, imidazol-2-ylidene and imidazolin-2-ylidene became the standard heterocyclic form, and bulky substituents have commonly been introduced on the nitrogen(s) adjacent to carbenic carbons. Our group previously developed NHCs equipped with noncarbenic carbons with a bicyclic architecture that gives them unique steric properties that make them bulky but accessible. In this study, we synthesized a novel type of NHC ligand that possesses a bicyclo[2.2.1]heptane architecture, and we compared five derivatives using copper-catalyzed allylic arylations with aryl Grignard reagents. The regioselectivity of the substitution obviously indicates that a phenyl ring over an active site has a characteristic effect on the resultant copper catalysts when γ-substitution is the major pathway.

Full text of DOI:10.1021/acs.joc.8b02480

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Article
Influences of phenyl rings on NHC ligands with bicyclic architectures
Shin Ando, Ryota Miyata, Hirofumi Matsunaga, and Tadao Ishizuka
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02480 • Publication Date (Web): 04 Dec 2018
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Influences of phenyl rings on NHC ligands with bicyclic architectures
Shin Ando,* Ryota Miyata, Hirofumi Matsunaga, and Tadao Ishizuka*
Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi Chuo-ku, Kumamoto 862-0973,
Japan
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ando@gpo.kumamoto-u.ac.jp (S.A), tstone@gpo.kumamoto-u.ac.jp (T.I.)
Abstract
In addition to phosphanes, olefins, amines, and amides, over the past two decades N-heterocyclic
carbene (NHC) has emerged as a useful alternative ligand. Based on a number of derivatization studies
on NHC ligands, imidazol-2-ylidene and imidazolin-2-ylidene became the standard heterocyclic form,
and bulky substituents have commonly been introduced on the nitrogen(s) adjacent to carbenic carbons.
Our group previously developed NHCs equipped with non-carbenic carbons with a bicyclic
architecture that gives them unique steric properties that make them bulky but accessible. In this study,
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we synthesized a novel type of NHC ligand that possesses a bicyclo[2.2.1]heptane architecture, and we
compared five derivatives using copper-catalyzed allylic arylations with aryl Grignard reagents. The
regioselectivity of the substitution obviously indicates that a phenyl ring over an active site has a
characteristic effect on the resultant copper catalysts when -substitution is the major pathway.
Introduction
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The choice of a ligand for use as a transitional metal catalyst is crucial to an effective
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chemical transformation. In addition to electron-donating ability, Lewis basicity in other words, the
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steric bulkiness of the ligands is important in the obtainment of effective metal catalysts. Therefore, in
the development of an effective catalytic cycle, the steric properties of ligands are routinely tuned.
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a
2b
Some parameters such as cone angle and bite angle have been used to represent the steric demands
of phosphine ligands, and these factors have provided significant insight to an understanding of the
mechanism as well as to a prediction of reactivity.
Over the past two decades, N-heterocyclic carbenes (NHC) have become an alternative
ligand to phosphines, olefins, amines, or amides because of their unique binding nature that includes
strong -donation to bound transition metals that results in a remarkably strong and stable complex
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under aerial conditions. A number of heterocycles containing carbenic carbons with neighboring
nitrogen(s) have been studied, and imidazolin-2-yliden and imidazol-2-yliden have become the general
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ring system for NHC ligands. These structures possess two nitrogen elements adjacent to carbenic
carbons, where many functional groups have been introduced in order to study the steric and electronic
effects.4-5 As a result of these numerous derivations, the steric effects of the substituents on nitrogen
elements are recognized as stronger than the electronic effects. Furthermore, the substituents on
nitrogen elements structurally influence the environment around the bound metals on a much stronger
level than the substituents on non-carbenic carbons. Based on these facts, the steric variety in NHC
ligands is due mostly to nitrogen elements (Figure 1a).3b,6
Recently, our group developed original NHCs, which we refer to as DHASI, and discovered
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that DHASI ligands have particular steric properties. The non-carbenic carbons in this series of NHC
ligands have a bicyclic architecture, and an aromatic ring is rigidly fixed toward an active site that
results in effective steric shielding. Silver and copper complexes of DHASIiPr have isopropyl groups
on two nitrogen elements and can be isolated as air-stable crystals, but the copper complex ably
catalyzes the borylation of sterically hindered arylbromide, which is a reaction where ubiquitous NHC
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ligands are incompatible. It is worth noting that most imidazolinylidene ligands with N-alkyl groups
do not have a stabilizing effect sufficient to isolate air-stable copper complexes. The results of the
present study indicate that our bicyclic architecture is sufficiently bulky to stabilize the metal
complexes yet remains accessible even for sterically demanding substrates (Figure 1b). The DHASI
ligands are also useful to nickel catalysts for the Corriu-Kumada-Tamao coupling of tertiary alkyl
Grignard reagents7c and for Suzuki-Miyaura coupling between aryl/heteroaryl chlorides and
aryl/heteroarylboronic acids.7d
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Figure 1. Features of general NHC ligands (a) and of NHC ligands with bicyclic architectures (b).
DHASI ligands, which contain a bicyclo[2.2.2]octadiene system, are synthesized via a
Diels-Alder reaction between anthracene and N,N’-diacetyl-2-imidazolone with some subsequent
chemical transformations (Figure 2).7b,8 Although DHASI is a version of NHC ligands that shows
promise for the realization of unique metal catalysts, the substituents on the bicyclic structure are
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difficult to modify. As yet there has been no investigation into how the steric and electronic features of
a bicyclic architecture affect the functions of DHASI ligands. Through the development of finely
tunable NHC ligands with a bicyclic architecture, we intended to examine the effects that structural
change could exert on stabilizing ability as well as on the acceleration of reductive elimination during
catalysis. To perform these examinations, we designed a novel type of NHC ligand equipped with
another bicyclic ring system, bicyclo[2.2.1]heptane, via the use of cyclopentadiene as a diene in a
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Diels-Alder reaction. Here, we report the syntheses of NHC ligands with a bicyclo[2.2.1]heptane
framework, which include saturated alkyl, unsaturated olefin, exo,cis-dimethoxy groups,
endo,cis-dimethoxy groups, and a phenyl ring over active sites. The synthesized NHC ligands were
applied to a copper-catalyzed allylic arylation with PhMgBr in order to examine the effect of
accelerating the reductive elimination step. The introduced aromatic ring had a unique steric effect and
accelerated the reductive elimination step to predominantly produce the -product, which also was
observed in our previous study using DHASI ligands.
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O
DHASI Ligands
Derivatization of the aromatic ring is not straightforward.
Influences of structures to functions are unclear
R"
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NHCs w/ bicyclo[2.2.1]heptane framework (This work)
Finely tunable sites over an active site.
Investigations about how structural features affect functions
Figure 2. Designs of NHC ligands studied in previous work and in this study.
Results and discussion
Syntheses of novel types of NHC ligands with a bicyclo[2.2.1]heptane framework.
We began our syntheses of novel NHC ligands with a Diels-Alder reaction between freshly
cracked cyclopentadiene and N,N’-diacetyl-2-imidazolone to afford the known imidazolidinone 1
(
Scheme 1a).8-9 Imidazolidinone 1 has an olefin that allows the subsequent introduction of many types
of substituents, which should result in flexible modifications. In this context, we synthesized five
derivatives to observe the steric effect of the substituents when introduced on two carbons over an
active site.
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First, we developed a saturated N,N’-dimethyl-4,5-(cyclopentane-1,3-diyl)-imidazolinium
chloride 7 for use as an NHC precursor (Scheme 1a). We refer to this NHC motif as CPSI
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(
(cyclopentane-1,3-diyl)-imidazolinylidene). The synthesis of imidazolinium chloride 7 started from
the hydrogenation of an olefin using a Pd/C catalyst under a H balloon to obtain the saturated
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compound 2 in a quantitative yield. The acetyl groups of compound 2 were then cleaved by
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methanolysis in a quantitative yield. Following methylation of the nitrogen elements in a 95% yield,
cyclic urea 4 was reduced by LiAlH to afford imidazolidine 5 in an 87% yield. Imidazolidine 5 was
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treated with HCl in methanol to afford N,N’-dimethylethylenediamine 6 as a hydrochloride salt, and
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N,N’-dimethyl-4,5-(cyclopentane-1,3-diyl)-imidazolinium chloride 7 (CPSIMe•HCl).
Second, we synthesized N,N’-dimethyl-4,5-(cyclopent-1-ene-3,5-diyl)-imidazolinium
chloride 9 (CPESIMe•HCl) under the same synthetic route as CPSIMe•HCl 7 with the exception of
omitting hydrogenation of the olefin (Scheme 1b, in a 60% overall yield; see the experimental section
for details).
Scheme 1. Syntheses of the NHC precursors with cyclopentane-1,3-diyl and
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Third and fourth, we introduced two methoxy groups on the cis configurations
exo,cis-dimethoxy derivative 18 and endo,cis-dimethoxy derivative 24 (Scheme 2). We expected these
two isomers to provide information about the steric effects of the substituents that reside at different
distances
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The
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chloride
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(exo,cis-diMeO-CPSIMe•HCl) was started from the dihydroxylation of the olefin of compound 1
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catalyzed by OsO (0.5 mol%) with NMO as the terminal oxidant in a 92% yield. After a 97% yield
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of acetonide formation from the cis-dihydroxy groups, the NOE spectra of the acetonide 11 was
analyzed and 12.4% of it fell between a methyl group of the acetonide and one of the methylene
protons, which assured a exo,cis-configuration for the dihydroxy groups. The acetyl groups were
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cleaved by methanolysis to yield compound 12 in a quantitative yield, and the resultant free N-H
functionality was methylated to afford compound 13 in a 97% yield. At this point, acetonide was
deprotected in a 95% yield, and the methylation of the dihydroxy groups gave exo,cis-dimethoxy
compound 15 in a 95% yield. From compound 15, exo,cis-diMeO-CPSIMe•HCl 18 was synthesized via
a transformation similar to that described above, which amounted to a reduction of the urea moiety
(94%), methanolysis of aminal, and ring closure using (EtO) CH (98% over 2 steps, Scheme 2a). The
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endo,cis-dimethoxy functionality was achieved from the exo,cis-diol 14 via a three-step conversion that
1
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involved Swern oxidation to diketone 19 in a 69% yield, reduction with NaBH to endo,cis-dihydroxy
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compound 20 in a quantitative yield, and then methylation to afford endo,cis-dimethoxy compound 21
in a 79% yield. Compound 21 was also transformed to endo,cis-diMeO-CPSIMe•HCl 24 using the
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same synthetic route as other ligands for a 77% overall yield (Scheme 2b).
Scheme 2. Syntheses of the NHC precursors with cis-1,2-dimethoxy-cyclopentane-3,5-diyl groups
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Finally, we introduced an aromatic ring to the same framework based on another synthetic
strategy that involved the introduction of amino groups to the known compound 25,12 which was
synthesized in two steps from cyclopentadiene and benzyne formed in situ. This exo,cis-diol 25 was
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oxidized to diketone 26 under Swern oxidation conditions in a 96% yield, and then treated with
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NH OH•HCl to afford dioxime 27 in an 89% yield. The direct reduction of dioxime to diamine using
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nickel boride gave diamine hydrochloride 28 as a crude product, which was subsequently converted
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to bis(ethylcarbamate) 29. Carbamate 29 was reduced with LiAlH4 to afford
N,N’-dimethylethylenediamine 30 as a crude hydrochloride salt, which was then heated in (EtO) CH to
3
afford N,N’-dimethyl-4,5-(benzocyclopentane-3,4-diyl)-imidazolinium chloride 31 (BCPSIMe•HCl) in
a 23% overall yield from dioxime 27 (Scheme 3).
Scheme 3. Synthesis of the NHC precursor with a benzocyclopentane-3,5-diyl group
Structural alteration of NHC ligands and its influence on regioselectivity during
copper-catalyzed allylic arylations with aryl Grignard reagents
With the five novel NHC ligands in hand, we performed copper-catalyzed allylic arylations
of cinnamyl bromide with PhMgBr to investigate the steric effects of the structural differences in a
1
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bicyclic[2.2.1]heptane architecture (Table 1). The regioselectivity of this reaction is strongly affected
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4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
by the properties of ligands, and greater degrees of sterically hindered and electron-deficient ligands
will give the -product preferentially. On the other hand, the conjugation of an -product is longer than
that of a -substituted product, which results in the preferred -product, either without ligands or with
sterically less-hindered ligands.7a,16 To evaluate the steric effect that the substituents exert on
non-carbenic carbons, we used NHC ligands that were equipped with methyl groups on the nitrogen
elements, as shown in Table 1. As shown by entry 1, CPSIMe 7, which has a bicyclo[2.2.1]heptane
ring system, preferentially gave us the -product relative to the -product (/ = 2.38/1). Although the
-product was still the major yield, CPESIMe 9 gave a higher ratio of the -product (entry 2, / =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
.92/1). The introduction of exo,cis-dimethoxy groups on the ligand (exo,cis-diMeO-CPSIMe 18)
resulted in a significant increase in the -product (/ = 3.33/1). To our surprise, the
endo,cis-dimethoxy ligand (endo,cis-diMeO-CPSIMe 24), which has the closest site for substituents
from bound copper, did not heighten the -selectivity, which remained at the same level (/ = 2.12/1)
as the reaction with CPESIMe 9. A comparison of those results shows that the NHC ligand with a
1,2,3,4-tetrahydro-1,4-methano-naphthyl group (BCPSIMe 31) significantly affected the properties of
the copper catalyst and gave us the -product as the major yield (entry 5, / = 1/7.69), which also
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means the steric effect of BCPSIMe 31 was stronger than that of the DHASIMe ligand (32, entry 6, /
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
a
= 1/3.76). It is noteworthy that the two phenyl rings on the 1,2-diphenylethylenediamine-based NHC
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
33) showed no such steric effect (entry 7, / = 4.00/1).7a A comparison of the NHC ligands
synthesized in this study indicates that the phenyl ring fixed toward the active site would be the critical
element for the acceleration of the reductive elimination step in this reaction by DHASI ligands and by
16
BCPSIMe 31. We additionally attempted the allylic arylations using two other Grignard reagents
(
entries 8 to 11). Previous studies clearly established that the copper catalyzed allylic substitutions were
significantly affected by the electronic properties of substrates (see reference 16 and references cited
therein). The results suggested that the structural changes from DHASI to BCPSI influenced the
regio-selectivity regardless of the electronic properties of the nucleophile.
Table 1. Influences of the structures of NHC ligands with bicyclic architectures on
regio-selectivity during the copper-catalyzed allylic arylations of cinnamyl bromide with aryl
Grignard reagents a
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Entry Ligand
Ar
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Combined Yield (%) Ratio (:)b
1
7
84
95
92
86
92
98
99
2.38 : 1
1.92 : 1
3.33 : 1
2.12 : 1
1 : 7.69c
1 : 3.76c
4.00 : 1
1 : 2.81
2
9
3
18
24
31
327a
337a
32
4
5
6d
7d
8
4-Me-C H – 98
6
4
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31
32
31
4-Me-C H – 99
1 : 5.23
6
4
10
4-Cl-C H –
98
99
1 : 4.14
1 : 8.55
6
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
4-Cl-C H –
6 4
a
b
1
The NHC precursors were converted to the corresponding NHC ligands in situ. Calculated using H
c
d
NMR. The averages of two runs are shown. From reference 7a.
We also tried syntheses of silver complexes supported by these novel NHC ligands, and
isolation of a bench-top stable silver complex was successful only when we used BCPSIMe as a ligand.
The other four NHC ligands gave us highly hygroscopic unstable silver complexes; therefore, we could
17
not characterize these complexes for use as NHC transfer agents. In contrast, BCPSIMe-AgCl 34 was
successfully isolated in a 56% yield by a typical synthetic method with use of Ag O, as reported by Lin
2
1
7
7a
and co-workers. As we had previously reported, DHASIMe-AgCl complex 35 was also sufficiently
stable to allow isolation and characterization, which included crystallographic analysis, as well as for
storage under air on a bench. These observations suggested that phenyl rings installed in BCPSIMe and
DHASIMe were effective functional groups to stabilize the silver complexes, which allowed isolation
and storage under air on a bench. The silver complex 34 was also applied to the allylic arylations
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1
1
1
1
1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
shown in Table 1, and the results were comparable to the in situ procedure (Scheme 4), which
confirmed that the in situ formation of NHC-CuCl aptly worked during the reactions listed in Table 1.18
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. a) Synthesis of BCPSIMe-AgCl complex 34 b) Allylic arylations using a transmetallation
procedure from NHC-AgCl complexes
Structural analyses of some NHC precursors with bicyclic architectures
The structural similarities between BCPSIMe L5 and DHASIMe L6 notwithstanding,
bicyclo[2.2.1]heptene and bicyclo[2.2.2]octadiene are different bicyclic systems, which generate
different environments around a bound metal. To analyze these two structures in detail, we performed
X-ray crystallography of DHASIMe•HCl 32,7a which is the precursor of DHASIMe L6, and
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BCPSIMe•HCl 31. The ORTEP diagrams, the dihedral angles, and the distances between the
pre-carbenic carbon of the imidazolinium ring, C(1), and the centroid of the phenyl ring over the
imidazolinium ring are shown in Figure 3. Crystal analysis of 32 revealed two structures in the cell and
the means of the dihedral angles and distances are shown. The dihedral angle between the phenyl ring
and the imidazolinium ring (angle a) on compound 31 (Figure 3b) is ca. 6° smaller than that on
DHASIMe•HCl 32 (Figure 3a), and the distances between the carbon C(1) and the centroid of the
phenyl ring of compound 31 is ca. 0.15 Å shorter than that of compound 32. In addition to NHC
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
a
precursors 31 and 32, we used X-ray crystallography to analyze silver chloride complexes 34 and 35 .
The distances between silver and centroids of phenyl rings of each complex showed the same trends as
the precursors: 4.531 Å for complex 34 and 4.974 Å for complex 35. The dihedral angle between the
phenyl rings and the imidazolinylidene ring were 46.76° for complex 34 and 56.32° for complex 35,
which were smaller than for precursors 31 and 32. We also analyzed the steric map of these two
1
9
structures using SambVca 2.0 software developed by Cavallo and co-workers. The buried volume of
BCPSIMeAgCl was 28.4%, which was slightly higher than of DHASIMeAgCl (26.1%). The steric
maps also indicated a bit higher steric pressure from the phenyl ring for BCPSIMe than that for
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1
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1
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2
2
2
2
2
2
2
2
2
2
3
3
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5
5
5
5
6
DHASIMe (Figure 4). These steric differences could be the reason for the better -selectivity of the
allylic arylation with BCPSIMe compared with that with DHASIMe. The different environments on
these frameworks would be a useful steric variety of NHC ligands, and the N-substituents on these
NHCs leave room for the tuning of sterics. Moreover, the phenyl ring of the BCPSI core structure
could be derivatized with the use of substituted benzynes or other appropriate dienophiles for
Diels-Alder reactions with cyclopentadiene, and this structural flexibility is amenable to the
fine-tunings of the properties of NHCs with a bicyclic architecture.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
1
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8
9
0
1
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9
0
1
2
3
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0
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9
1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
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6
a)
b
a
Me
c
N
Me
N
N
3
.748Å
N
N(2)
C(1)
Mean of the value from
two structures.
Cl
Me
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
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1
2
3
4
5
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8
9
0
Cl
Me
N(1)
55.52° (a)
116.39° (b)
119.06° (c)
DHASIMe•HCl (32)
b)
b
a
Me
N
c
Me
N
N
Cl
N
3.592Å
N(2)
Me
49.38°(a)
09.22°(b)
120.16°(c)
Cl
Me
1
N(1)
BCPSIMe•HCl (31)
C(1)
c)
b
Me
N
a
Me
4.974Å
c
N
N(2)
C(1)
N
Ag
Cl
N
Ag
Me
Cl
N(1)
5
1
1
6.32° (a)
16.53° (b)
19.79° (c)
Me
DHASIMeAgCl (35)7a
d)
b
c
a
Me
N
Me
Ag
N
N
N(2)
Ag
N
4.531Å
N(1)
Me
Cl
4
6.76°(a)
107.08°(b)
119.68°(c)
Me
Cl
C(1)
BCPSIMeAgCl (34)
Figure 3. ORTEP diagrams, dihedral angles, and distances between C(1) and the centroids of the
phenyl rings of DHASIMe•HCl 32 (a), BCPSIMe•HCl 31 (b), DHASIMeAgCl 35 (c), and
BCPSIMeAgCl 34 (d). Selected bond length (Å) and angles (deg): Figure 3a (mean of 2 structures):
C(1)–N(1), 1.311; C(1)–N(2), 1.310; N(1)–C(1)–N(2), 113.63, Figure 3b: C(1)–N(1), 1.313; C(1)–N(2),
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2
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1
.313; N(1)–C(1)–N(2), 113.82, Figure 3c: C(1)–N(1), 1.326; C(1)–N(2), 1.326; N(1)–C(1)–N(2),
109.65, Figure 3d: C(1)–N(1), 1.331; C(1)–N(2), 1.326; N(1)–C(1)–N(2), 109.49.
0
1
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0
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9
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1
2
3
4
5
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7
8
9
0
a)
b)
7
a
Figure 4. Steric maps of a) DHASIMeAgCl (35) and BCPSIMeAgCl (34).
Conclusions
In this study, we synthesized five novel NHC ligand precursors, 7, 9, 18, 24, and 31,
equipped with bicyclo[2,2,1]heptane architectures on non-carbenic carbons. We applied these NHC
ligands to the copper-catalyzed allylic arylations of cinnamyl bromide with PhMgBr. Among the
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synthesized NHC ligands, only (benzocyclopentane-3,5-diyl)-NHC 31, which possesses a phenyl ring
fixed to the bound copper, produced the -product in a major yield. It must be emphasized here that
regioselectivity was not affected by the dimethoxy groups, even those in the endo,cis-configuration
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(24), which were arguably near enough to the bound copper to be expected to exert some steric effect.
DHASIMe 32, which also has a phenyl ring on a bicyclo[2.2.2]octadiene framework, had previously
7a
shown a preference similar to that of the -product in this reaction. These results obviously indicated
that the phenyl rings set over the bound copper caused a characteristic effect, that included an
acceleration of the reductive elimination step. X-ray diffraction studies of BCPSIMe•HCl 31 and
DHASIMe•HCl 32 verified the position of the phenyl ring of BCPSIMe as existing somewhat closer to
a bound metal than that of DHASIMe, which would be one reason that the -selectivity of BCPSIMe is
higher than that of DHASIMe. The established synthetic route enables the flexible derivatization of the
aromatic ring, which should be useful for tuning of the properties of NHC ligands. As we further
investigate the effects of the steric and electronic properties of the phenyl rings of NHCs with bicyclic
architectures in our laboratory, we will apply the novel NHCs synthesized in this study to the
development of useful metal catalysts.
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6
Experimental Section
General Procedure and Chemicals
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9
0
All reactions were carried out under an argon atmosphere with freshly distilled solvents
under anhydrous conditions, unless otherwise noted. Anhydrous CH Cl , DMSO, and THF were
2
2
purchased and used without further distillation. Et N was distilled from CaH . Other reagents were
3
2
1
used without further purification. Yields refer to chromatographically and spectroscopically ( H NMR)
1
13
homogeneous materials unless otherwise noted. H and C NMR spectra were recorded at 600 and 151
MHz, respectively. Chemical shifts are reported in δ ppm and reference either an internal
tetramethylsilane or solvent peaks. The following abbreviations are used to indicate the multiplicities: s
=
singlet; d = doublet; t = triplet; q = quartet; qt = quintet; sex = sextet; sept = septet dd = doublet of
doublets; ddd = doublet of doublet of doublets; dddd = doublet of doublet of doublet of doublets; dt =
doublet of triplets; app = apparent; m = multiplet; br = broad. Melting points were uncorrected.
High-resolution mass spectra were recorded on a double-focusing magnetic-sector mass analyzer
operating in a fast atomic bombardment (FAB) mode.
3aR,4S,7R,7aS)-1,3-Diacetyl-3a,4,7,7a-tetrahydro-4,7-methanobenzo[4,5-d]imidazol-2-one (1)8–10
(
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A mixture of 1,3-diacetylimidazolin-2-one (17.7 g, 105 mmol) and an excess of freshly cracked
cyclopentadiene (88.8 ml, 1.05 mol) in m-xylene (105 mL) was stirred in a sealed tube at 150°C for 72
h. The resultant mixture was then cooled to room temperature and concentrated under reduced pressure.
n-Hexane was added to the residue, and the crude precipitate was filtered and washed with n-hexane.
The crude solid containing the title product and a small amount of unreacted imidazolone was
dissolved in MeOH (250 mL), and 2M HCl aq. (250 mL) was added to the solution to decompose the
imidazolone. The resultant mixture was stirred at 25 °C for 30 min, and then MeOH was removed
under reduced pressure. The residual aqueous layer was extracted with CH Cl (200 mL × 3), and the
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
5
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5
5
5
5
5
5
5
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1
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8
9
0
1
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8
9
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1
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1
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
combined organic extracts were washed with brine (200 mL), dried over Na SO , and concentrated
2
4
under reduced pressure to afford the title compound 1 (13.3 g, 54%) as a white solid. mp 116–117 °C;
1
H NMR (600 MHz, CDCl , 298 K): δ = 6.04 (dd, J = 1.8, 1.8 Hz, 2H), 4.42 (dd, J = 1.8, 1.8 Hz, 2H),
3
3
.53 (sep, J = 1.8 Hz, 2H), 2.47 (s, 6H), 1.70 (ddd, J = 10.2, 1.8, 1.8 Hz, 1H), 1.39 (d, J = 10.2 Hz, 1H)
ppm. Other spectral data matched the reported data.8–10
(3aR,4R,7S,7aS)-1,3-Diacetylperhydro-4,7-methanobenzo[4,5-d]imidazol-2-one (2)
EtOAc (80 mL) was added to a flask charged with 10% Pd/C (70 mg) and a magnetic stirrer bar under
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Ar. A solution of diacetylimidazolidinone 1 (7.01 g, 30.0 mmol) and in EtOAc (20 mL) was added to
the resultant flask, and then the argon balloon was replaced with a hydrogen balloon. The reaction flask
was evacuated and backfilled with hydrogen, and this sequence was repeated three times. The resultant
reaction mixture was stirred at 25 °C under hydrogen atmosphere for 1 h, and the reaction mixture was
filtered through a Celite pad, washed with EtOAc (100 mL). The filtrate and washings were combined
and concentrated under reduced pressure to afford the title compound 2 (7.06 g, quantitative) as a white
0
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solid. The purity of the product was sufficient without further purification. mp 111−112 °C; H NMR
(600 MHz, CDCl , 296 K): δ = 4.21 (dd, J = 1.8, 1.8 Hz, 2H), 2.82 (sep, J = 1.8 Hz, 2H), 2.55 (s, 6H),
3
13
1
1
.56–1.54 (m, 2H), 1.43–1.40 (m, 1H), 1.18 (dd, J = 7.8, 7.8 Hz, 1H) ppm; C{ H} NMR (151 MHz,
CDCl , 302 K): δ = 170.9, 152.8, 55.6, 39.7, 36.1, 24.4, 21.4 ppm; IR (KBr pellet): ν = 1739 (C=O),
3
max
-1
+
1698 (C=O) cm ; HRMS (FAB+) m/z calcd. for C H N O [M + H] : 237.1239; found: 237.1220.
1
2
17
2
3
3aR,4R,7S,7aS)-Perhydro-4,7-methanobenzo[4,5-d]imidazol-2-one (3)10
(
MeOH (7 mL) and CH Cl (35 mL) were added to a flask charged with diacetylimidazolidinone 2 (1.92
2
2
g, 8.15 mmol) and a magnetic stir bar at 25 °C. After cooling to 0 °C in an ice bath, NaH (60% in
mineral oil, 163 mg, 4.07 mmol) was added to the resultant solution in small portions, and the reaction
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mixture was stirred at 25 °C for 4 h. The reaction was then quenched with sat. NH Cl aq. (30 mL) at
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0 °C and extracted with CH Cl (100 mL × 8). The combined organic extracts were washed with brine
2
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(
100 mL), dried over Na SO , and concentrated under reduced pressure. The residue was triturated with
2 4
n-hexane, and the solid precipitated was filtered, washed with n-hexane, and dried under reduced
pressure to afford the title compound 3 (1.25 g, quantitative) as a white powder. The purity of the
1
product was sufficient without further purification. H NMR (600 MHz, DMSO-d , 296 K): δ = 6.23 (s,
6
2
H), 3.71 (s, 2H), 2.14 (s, 2H), 1.52 (ddd, J = 6.0, 6.0, 1.8 Hz, 2H), 1.34–1.30 (m, 1H), 1.22–1.21 (m,
1
3
1
2H) ppm; C{ H} NMR (151 MHz, CDCl , 302 K): δ = 163.5, 57.0, 40.8, 36.2, 21.5 ppm. Other
3
spectral data matched the reported data.10
(3aR,4R,7S,7aS)-1,3-Dimethylperhydro-4,7-methanobenzo[4,5-d]imidazol-2-one (4)
A solution of imidazolidinone 3 (304 mg, 2.00 mmol) and MeI (0.50 mL, 8.00 mmol) in THF (10 mL)
was cooled to 0 °C in an ice bath. NaH (60% in mineral oil, 288 mg, 4.80 mmol) was added to the
solution in small portions at 0 °C, and the reaction mixture was stirred at 25 °C for 4 h. The reaction
was quenched with MeOH (0.4 mL) at 0 °C, and the resultant solution was stirred for 30 min at 25 °C.
Sat. NH Cl aq. (1.0 mL) and H O (8.0 mL) were added to this solution at 0 °C, and extracted with
4
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CH Cl (50 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over
2
2
Na SO , and concentrated under reduced pressure. The residue was purified by flash column
2
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chromatography (80% EtOAc/n-hexane) on silica gel (60 mL) to afford the title compound 4 (343 mg,
1
9
5%) as a yellow oil. H NMR (600 MHz, CDCl , 298 K): δ = 3.59 (dd, J = 1.8, 1.8 Hz, 2H), 2.74 (s,
3
6H), 2.41 (sep, J = 1.8 Hz, 2H), 1.49 (ddd, J = 10.8, 1.8, 1.8 Hz, 1H), 1.41 (ddd, J = 10.8, 1.8, 1.8 Hz,
13
1
1
2
H), 1.35–1.31 (m, 4H) ppm; C{ H} NMR (151 MHz, CDCl , 301 K): δ = 160.3, 60.1, 39.4, 35.9,
3
-1
9.4, 21.4 ppm; IR (film): νmax = 1679 (C=O) cm ; HRMS (FAB+) m/z calcd. for C H N O [M +
10
17
2
+
H] : 181.1341; found: 181.1334.
(3aR,4R,7S,7aS)-1,3-Dimethylperhydro-4,7-methanobenzo[4,5-d]imidazole (5)
THF (17.3 mL) was added to a flask charged with dimethylimidazolidinone 4 (623 mg, 3.46 mmol) and
a magnetic stir bar at 25 °C. After cooling to 0 °C in an ice bath, LiAlH (262 mg, 6.92 mmol) was
4
added to the resultant solution in small portions, and the reaction mixture was stirred at 50 °C for 2 h.
The reaction mixture was then cooled to 0 °C in an ice bath and diluted with 34 mL of THF. H O (0.26
2
mL), 15% NaOH aq. (0.26 mL), and H O (0.79 mL) were added to the mixture sequentially at the same
2
temperature. The resultant mixture was stirred at 25 °C for 30 min, and the solution was filtered
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through a Celite pad, washed with THF (20 mL × 3), and the combined filtrate and washings were
concentrated under reduced pressure. The crude residue was passed through a short pad of silica gel,
6
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eluted with EtOAc, and the eluent was concentrated under reduced pressure to afford the title
1
compound 5 (498 mg, 87%) as a yellow oil. H NMR (600 MHz, CDCl , 298 K): δ = 3.98 (d, J = 3.6
3
Hz, 1H), 3.01 (d, J = 3.6 Hz, 1H), 2.67 (s, 2H), 2.23 (s, 6H), 2.09 (sep, J = 1.8 Hz, 2H), 1.93 (d, J = 7.2
13
1
Hz, 2H), 1.50 (s, 2H), 1.28–1.24 (m, 2H) ppm; C{ H} NMR (151 MHz, CDCl , 302 K): δ = 85.3,
3
+
+
7
1.9, 40.1, 39.5, 39.4, 22.2 ppm; HRMS (FAB+) m/z calcd. for C H N [M + H] : 167.1548; found:
10 19 2
167.1553.
(4R,5S)-1,3-Dimethyl-4,5-(1R,3S-cyclopentane-1,3-diyl)-imidazolinium chloride (7)
Chlorotrimethylsilane (1.9 mL) was added to MeOH (5.0 mL) with stirring at 0 °C, and the resultant
solution was added to a flask charged with dimethylimidazolidine 5 and a magnetic stir bar. The
reaction solution was heated at 65 °C with a distillation apparatus until TMS−OMe was distilled off.
The distillation apparatus was removed, and equipped with a reflux condenser. The resultant mixture
was then heated at reflux for 19 h. The resultant solution was concentrated under reduced pressure to
afford the crude N,N’-dimethylethylenediamine hydrochloride 6. (EtO) CH (20.5 mL) was added to a
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flask charged with the crude 6, and the resultant suspension was heated at 100 °C in an oil bath for 20 h.
The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in
CH Cl , and Et O was added to precipitate the crude title compound 7. The precipitate was filtered,
0
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washed with a 1 : 1 mixture of CH Cl and Et O, and dried under reduced pressure to afford the title
2
2
2
1
compound 7 (350 mg, 85% over two steps) as an off-white powder. mp 247–249 °C (decomp.); H
NMR (600 MHz, CDCl , 298 K): δ = 10.3 (s, 1H), 4.24 (s, 2H), 3.27 (s, 6H), 2.69 (s, 2H), 1.64 (d, J =
3
1
1.4 Hz, 1H), 1.61 (d, J = 8.4 Hz, 2H), 1.54 (d, J = 11.4 Hz, 1H), 1.33 (dd, J = 8.4, 2.4 Hz, 2H) ppm;
1
3
1
C{ H} NMR (151 MHz, CDCl , 302 K): δ = 158.5, 68.6, 39.6, 37.2, 34.4, 21.7 ppm; IR (KBr pellet):
3
-1
+
+
νmax = 1653 (C=N) cm ; HRMS (FAB+) m/z calcd. for C H N [M - Cl] : 165.1392; found:
10
17
2
1
65.1397.
(3aR,4S,7R,7aS)-3a,4,7,7a-tetrahydro-4,7-methanobenzo[4,5-d]imidazol-2-one (8)10
MeOH (13.5 mL) and CH Cl (68.5 mL) were added to a flask charged with diacetylimidazolidinone 1
2
2
(3.80 g, 16.2 mmol) and a magnetic stir bar at 25 °C. After cooling to 0 °C in an ice bath, NaH (60% in
mineral oil, 325 mg, 8.10 mmol) was added to the resultant solution in small portions, and the reaction
mixture was stirred at 25 °C for 4 h. The reaction was quenched with sat. NH Cl aq. (50 mL) and
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extracted with CH Cl (100 mL × 8). The combined organic extracts were washed with brine (100 mL),
2
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7
8
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dried over Na SO , and concentrated under reduced pressure. The residue was triturated with n-hexane,
2
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and the solid precipitated was filtered, washed with n-hexane, and dried under reduced pressure to
1
afford the title compound 8 (2.31 g, 95%) as a white powder. mp 230–231 °C (decomp); H NMR (600
MHz, CDCl , 298 K): δ = 6.17 (dd, J = 1.8, 1.8 Hz, 2H), 4.67 (br s, 2H), 4.13 (s, 2H), 3.03 (sep, J = 1.8
3
Hz, 2H), 1.56 (ddd, J = 9.6, 1.8, 1.8 Hz, 1H), 1.19 (d, J = 9.6 Hz, 1H) ppm. Other spectral data
matched the reported data.10
(4R,5S)-1,3-Dimethyl-4,5-(3S,5R-cyclopent-1-ene-3,5-diyl)-imidazolinium chloride (9)
Imidazolidinone 8 was methylated in a 76% yield under the same reaction conditions as the synthesis
1
of dimethylimidazolidine 4. Data for the dimethylimidazolidinone S1: state: yellow oil; H NMR (600
MHz, CDCl , 299 K): δ = 6.01 (dd, J = 1.8, 1.8 Hz, 2H), 3.88 (dd, J = 1.8, 1.8 Hz, 2H), 3.14 (sep, J =
3
13
1
1
.8 Hz, 2H), 2.71 (s, 6H), 1.62 (ddd, J = 9.6, 1.8, 1.8 Hz, 1H), 1.22 (d, J = 9.6 Hz, 1H) ppm; C{ H}
NMR (151 MHz, CDCl , 302 K): δ = 160.3, 133.9, 59.8, 45.6, 44.3, 28.9 ppm; IR (film): ν = 1693
3
max
-1
+
(C=O) cm ; HRMS (FAB+) m/z calcd. for C H N O [M + H] : 179.1184; found: 179.1189.
1
0
15
2
Imidazolinium chloride 9 was synthesized via reduction of the cyclic urea moiety, methanolysis of the
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