Synthesis of Ester- and Phosphonate-Functionalized AuI–Imidazolylidene Chlorides through the Isonitrile Route

Article abstract of DOI:10.1002/chem.201700214

Starting from DMSAuCl, isonitriles and functionalized propargylammonium salts in the presence of simple trimethylamine as auxiliary base, unsymmetrically substituted ester- and phosphonate-functionalized Au^I–imidazolylidene complexes were synthesized in an easy-to-use modular one-pot template synthesis. In the course of the reaction, after the initial nucleophilic addition of the amine to the gold(I)-activated isonitrile, a Michael addition closes the N-heterocyclic carbene (NHC) ring. Then the remaining double bond migrates into the NHC ring, evidently a more stable position than the initial exocyclic double bond. These functional groups attached to the back bone of the NHC ligands represent ideal handles for a further modification of the system, for example an attachment to larger assemblies or heterogenization by an attachment to surfaces are conceivable.

Full text of DOI:10.1002/chem.201700214

A Journal of
Accepted Article
Title: Synthesis of Ester- and Phosphonate-Functionalized
Imidazolylidene Au(I) Chlorides via the Isonitrile Route
Authors: Thomas Wurm, Julius Hornung, Matthew O’Neil, Matthias
Rudolph, Frank Rominger, and A. Stephen K. Hashmi
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To be cited as: Chem. Eur. J. 10.1002/chem.201700214
Link to VoR: http://dx.doi.org/10.1002/chem.201700214
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Chemistry - A European Journal
10.1002/chem.201700214
Synthesis of Ester- and Phosphonate-Functionalized
Imidazolylidene Au(I) Chlorides via the Isonitrile Route
a
a
a
a
Thomas Wurm, Julius Hornung, Matthew O’Neil, Matthias Rudolph, Frank
a
a,b
Rominger, A. Stephen K. Hashmi *
[a] M. Sc. T. Wurm, M. Sc. J. Hornung, B. Sc. M. O’Neil, Dr. M. Rudolph, Dr. F.
[
+]
Rominger, Prof. Dr. A. S. K. Hashmi
Organisch-Chemisches Institut
Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)-6221-54-4205
E-mail: hashmi@hashmi.de
Homepage: http://www.hashmi.de
[b] Prof. Dr. A. S. K. Hashmi
Chemistry Department, Faculty of Science
King Abdulaziz University, Jeddah 21589, Saudi Arabia
[+] Crystallographic investigation
Keywords: NHC ligands, gold complexes, isonitriles, template synthesis
Abstract: Starting from DMSAuCl, isonitriles and functionalized propargylammonium
salts in the presence of simple trimethylamine as auxiliary base, unsymmetrically
substituted ester- and phosphonate-functionalized Au(I)-imidazolylidene complexes
were synthesized in an easy-to-use modular one-pot template synthesis. In the course
of the reaction, after the initial nucleophilic addition of the amine to the gold(I)-activated
isonitrile, a Michael addition closes the NHC ring. Then the remaining double bond
migrates into the NHC ring, obviously a more stable position than the initial exocyclic
double bond. These functional groups attached to the back bone of the NHC ligands
represent ideal handles for a further modification of the system, for example an
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Chemistry - A European Journal
10.1002/chem.201700214
attachment to larger assemblies or heterogenization by an attachement to surfaces
are conceivable.
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Chemistry - A European Journal
10.1002/chem.201700214
Introduction
[
1]
Soon after the isolation of the first free NHC by Arduengo, NHCs where introduced
as ancillary ligands in homogeneous catalysis. The major advantages of N-heterocyclic
carbenes, in contrast to ligands such as phosphanes, are their thermal stability, their
low toxicity, and their stability against oxidation. This enables the application of NHC-
[
2]
transition metal complexes in a manifold of different reactions. ꢀ
The established syntheses of NHC-based transition metal complexes start from
preformed NHC precursors like imidazolium salts.[3] After the synthesis of these
precursors they are transformed into the free carbenes, or synthons of the free carbene
(
e.g. Ag(I)-complexes)[4] and afterwards reacted with suitable metal complexes to
obtain the desired NHC-metal complexes.
Recently, an alternative strategy for the preparation of acyclic carbene-based catalysts
emerged. Based on the addition of amines to metal-coordinated isonitriles, a reactivity
pattern going back to the work of Tschugaeff and the correct structural assignment of
Shaw,[5] NAC complexes are accessible[6] and were recently tested in catalytic
applications with great success.[7]
[
8]
[9]
After the first synthesis of the Au(I) isonitrile complexes and Au(I) NAC complexes
the initial contributions in the field of gold catalysis were made by Espinet,[10]
Echavarren[10-11] and Hashmi.[12] Soon applications by Toste[13] and Slaughter[14]
followed. Finally, an extension on cyclic NHC ligands, based on the initial observations
by Michelin,[15] was developed by Hashmi et al. to a facile procedure for the synthesis
of symmetrilcally or unsymmetrically substituted NHC-complexes of Pd(II), Au(I) and
Pt(II).[16] In addition Hashmi et al. applied a variety of different functionalized amines
[
17]
[18]
[19]
(
aminoesters , Michael-acceptors
and acetal functionalities ) and thereby
obtained different classes of NHC-ligands which now all are accessible via this
convergent template synthesis (see Scheme 1).[20] In addition, Hashmi et al. were able
to generate anormal NHC Au(I) complexes from metal bound isonitriles through a 1,3-
dipolar cycloaddition (“anormal” with regard to the position of the C-metal bond, not a
mesoinionic complex).[21] Another remarkable contribution in this field was reported by
Bertrand et al. who were able to synthesize Au(I)-complexes of so called anti-Bredt
NHC-ligands by a related procedure.[22]
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Chemistry - A European Journal
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Previousꢀreports:
R'
N
Cl
H
N
NEt3,ꢀDCM,ꢀrt
2
N
N
N
N
C
R'
R'
R''
R''
+
Cl
R''
-ꢀHNEt Cl
3
Au
Au
Cl
Cl
R'
N
1.ꢀDCM,ꢀ
rt
O
H
N
+
+
C
2.ꢀH
O
R''
-ꢀ2ꢀMeOH
Au
Au
Cl
Cl
R'
O
O
O
N
C
DCM,ꢀrt
H
N
N
+
R'
R''
N
O
R''
Au
Cl
Au
Cl
ThisꢀWork:
EWG
R'
N
Cl
EWG
NEt ,ꢀDCM,ꢀrt
H
N
3
C
+
2
N
N
R'
R''
Au
R''
-ꢀHNEt Cl
3
Au
Cl
Cl
EWG:ꢀCOOR,ꢀPO(OR)2
Scheme 1: Synthesis of NHC-complexes from Au(I)-isonitrile complexes.
On the basis of this knowledge, the conversion of Au(I)-isonitriles with functionalized
propargylammonium salts for the preparation of imidazolylidene-Au(I) complexes with
an additional functionalization in the backbone was investigated (see in Scheme 1).
Results and Discussion
a) Synthesis of functionalized propargylammonium salts
To test our hypothesis, it was necessary to develop a simple access to the required
propargylamine derivatives. After several attempts the four step synthesis shown in
Scheme 2 appeared to be ideal.
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Chemistry - A European Journal
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Starting from commercially available propargylamine 1, a ketone (2a or 2b) and
NaHB(OAc) a reductive amination provided the alkylated propargylamine derivatives
a or 3b. These were converted to the corresponding carbamates 4a and 4b with di-
3
3
tert-butyldicarbonate. Subsequent deprotonation at the alkyne unit at -78 °C by n-BuLi
and treatment with the desired acid chloride delivered derivatives 5.
Finally, the BOC-protection was removed with an excess of HCl (4 N in 1,4-dioxane).
After one recrystallization, six representatives of the propargylammonium salts 6 were
obtained. 6b was synthesized by the analogous sequence using commercially
available N-methyl-N-propargylamine.
With the exception of 6b, all compounds shown in Scheme 2 are easy-to-handle, air-
stable, colorless solids which could conveniently be fully characterized. At -32 °C they
can be stored for several months without decomposition. In contact with air compound
6b decomposed rapidly and therefore was used directly for the subsequent complex
synthesis.
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Chemistry - A European Journal
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O
O
NH
N
O
NaHB(OAc)3
DCM,ꢀRT
Boc2O
NH2
+
kat.ꢀDMAP
n
2
2
a;ꢀnꢀ=ꢀ0
b;ꢀnꢀ=ꢀ2
3
3
a;ꢀnꢀ=ꢀ0
b;ꢀnꢀ=ꢀ2
4a; nꢀ=ꢀ0
4b;ꢀnꢀ=ꢀ2
1
2
.ꢀn-BuLi
THF,ꢀ-ꢀ78ꢀ°C
.ꢀEWG-Cl
O
Cl
HClꢀin
dioxaneꢀ4N
EWG
H
N
2
N
O
EWG
DCM,ꢀRT
n
O
O
O
Cl
Cl
Cl
H
N
O
2
O
H
O
H
N
N
;
ꢀyield:ꢀ22ꢀ%
;ꢀyield:ꢀ29ꢀ%
;ꢀyield:ꢀ51ꢀ%
O
Cl
O
O
P
Cl
Cl
H
N
O P
O
O
O
2
H
N
H
2
N
O
;
ꢀyield:ꢀ45ꢀ%
;ꢀyield:ꢀ41ꢀ%
;ꢀyield:ꢀ18ꢀ%
Scheme 2: Reaction sequence for the synthesis of functionalized propargylammonium salts.
During all efforts to deprotonate the isolated ammonium salts and to characterize the
1
free amines, the recorded H NMR spectra indicated a slow decomposition of the
material. This observation is not unexpected as the acceptor-substituted C-C triple
bond and the amine nucleophile can easily react in intra- or intermolecular reactions.
Only the protonation of the amine prevents this mode of decomposition.
Thus not the free amines but the ammonium salts 6 were used for the synthesis of the
target compounds and were deprotonated in situ by further added triethylamine.
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Chemistry - A European Journal
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b) Synthesis of the ester- and phosphonate-functionalized Au(I) imidazolylidene
complexes
The test reaction shown in Scheme 3 used 6a, the gold-isonitrile complex 7 and 1.2
eq. triethylamine as auxiliary base. The progress was monitored in every 30 minutes
by TLC. The continuous formation of the new compound 8a was detected, at the same
time 7 was consumed.
After a reaction time of 24 h no further conversion of the remaining starting material
was observed. The reason for the incomplete conversion probably is the competing
decomposition of the deprotonated building block 6a, thus further 0.2 eq. of 6a were
added.
Scheme 3: The synthesis of 8a as test reaction.
This indeed led to the complete conversion of the remaining 7. After column
chromatography pure 8a was isolated in 59 % yield.
After this test reaction with the preformed gold-isonitrile complex 7, a one pot synthesis
of 8a according to Scheme 4 starting from DMSAuCl, 2,6-diisopropylisonitrile and 6a
was explored.
To DMSAuCl as a suspension in dichloromethane 1.05 eq. of 2,6-diisoproylisonitrile
were added. During the addition the turbid suspension quickly turned to a clear
solution. After 15 minutes 6a and then triethylamine was added. Indeed, 8a was
obtained and the yield of 57 % is only a little lower than the yield obtained with
preformed 7.
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Using the one pot conditions from Scheme 4, eleven representatives of 8 could be
prepared in yields ranging from 70 to 34 %. The low yields of 8b, 8d and 8g originated
from the necessity of an additional step in the work up, after the column
chromatography for these three compounds still an impurity was present, only an
additional recrystallization from dichloromethane/pentane provided pure material.
EWG
EWG
R'
N
C
NEt3
S
+
+
Cl
R'
N
N
R''
Au
Cl
DCM,ꢀrt
H N
2
Au
Cl
R''
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
Au
Cl
Au
Cl
Au
Cl
Au
Cl
;ꢀyieldꢀ34ꢀ%
;
ꢀyield:ꢀ57ꢀ%ꢀ
;ꢀyield:ꢀ42ꢀ%ꢀ
;ꢀyieldꢀ70ꢀ%ꢀ
O
O
O
O
O
O
O
O
Ph
O
N
N
N
N
N
N
N
N
Au
Cl
Au
Cl
Au
Cl
Au
Cl
O
;ꢀyield:ꢀ69ꢀ%ꢀ
;ꢀyield:ꢀ58ꢀ%ꢀ
;ꢀyieldꢀ38ꢀ%ꢀ
;ꢀyieldꢀ69ꢀ%
O
O
O
O
O
O
P
P
P
O
O
O
Ph
N
N
N
N
N
N
Au
Cl
Au
Cl
Au
Cl
;ꢀyield:ꢀ70ꢀ%ꢀ
;ꢀyield:ꢀ66ꢀ%ꢀ
;ꢀyield:ꢀ58ꢀ%
Scheme 4: Synthesis of functionalized imidazolylidene Au(I) complexes.
The yields of 8a, 8c, 8e, 8f, 8h, 8i, 8j and 8k show that the method has a broad scope,
various substituents in the isonitrile component are tolerated. Even 8b, 8h and 8a with
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Chemistry - A European Journal
10.1002/chem.201700214
an increasing steric demand of the ortho-substituents at the phenyl group of the used
isonitriles provided yields of about 60-70 %.
8c and 8e show that the electronic influence of substituents at the isonitriles is
moderate, electron rich and thus less electrophilic 3,5-dimethoxyphenylisonitrile and
cyclohexylisonitrile could be used successfully.
8d and 8i delivered crystals suitable X-ray single crystal structure analysis (Figure
1
).[23] These confirmed the connectivity and showed that the nature of the functional
group on the substituent at the backbone barely influences the geometry of the NHC
ligand.[19-20] In addition, the comparison with known, unsubstituted NHC ligands also
shows no significant influence.
Thus the electronic and steric properties of the NHC ligands in 8 do not deviate of
these of the known NHC ligands, but at the same time provide functional groups for
the derivatization of these compounds and immobilization. Primary tests to proof the
catalytic activity of two representative complexes were conducted with furan-yne
substrate 9.[24] As expected up to 81% of phenol 10 (NMR yield) were obtained with 5
mol% of the functionalized complexes without optimization.
5
5
mol% [Au]
NTs
O
NTs
mol % AgNTf2
CDCl , rt, 8 h
OH
3
6
8
6% with
1% with
Scheme 5: Catalytic activity of the obtained complexes.
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Figure 1: Molecular structures of 8d (left) and 8i (right) in the solid state. 8d: d(CNHC-Au):
.979 Å, d(Au-Cl): 2.274 Å, d(CNHC-N): 1.354 Å, d(CNHC-N): 1.358 Å, (N-CNHC-N): 104.9 °; 8i:
d(CNHC-Au): 1.973 Å, d(Au-Cl): 2.275 Å, d(CNHC-N): 1.352 Å, d(CNHC-N): 1.356 Å, (N-CNHC-N):
04.7 °.
1
1
In analogy to the other modular NHC syntheses, it is reasonable to assume an initial
nucleophilic addition of the amine to the activated gold-isonitrile complex. Then another
nucleophilic addition of the new nitrogen nucleophile, the nitrogen atom derived from
the isonitrile, to the Michael acceptor will provide an NHC gold(I) complex with an
exocyclic double bond. Under the basic conditions by a deprotonation, reprotonation
sequence the double bond of these intermediates (conceivable are the intermediates
I-IV) isomerizes to the endocyclic position, providing the unsaturated NHC in the
products 8. Indeed, a computational study clearly confirmed a strong driving force for
such a double bond migration, for the simplified model compound with carboxylic ester
(
8m) and with phosphonate (8l) the energies of the isomers show that the more stable
exocyclic isomer is the (E)-isomer I/III (donor/acceptor trans at the double bond) while
the (Z)-isomer II/IV is significantly less stable. The most stable isomer is the
unsaturated NHC 8l/8m. The driving force for the isomerization reaction of I to 8l is G
=
-7.4 kcal/mol, for the isomerization of III to 8m is G = -10.6 kcal/mol. This explains
why 8 is the exclusive product of the reaction, no traces of the isomers (and
intermediates) I-IV are detected.
Table 1: Computed energies of the isomeric species I, II and 8 (B3LYP-D3(BJ), cc-
pVTZ, PCM).
I
II
8l
E (kcal/mol)
H (kcal/mol)
G (kcal/mol)
0.0
0.0
0.0
6.3
6.1
5.0
-8.7
-8.4
-7.4
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III
IV
8m
E (kcal/mol)
H (kcal/mol)
G (kcal/mol)
0.0
0.0
0.0
6.3
-11.7
-11.3
-10.6
5.3
11.7
Conclusion
In summary we developed a modular and flexible four step procedure for the synthesis
of functionalized propargylammonium salts. The synthesis enables the introduction of
ester as well as phosphonate functionalities.
These propargylammonium salts were successfully applied for the synthesis of eleven
ester- and phosphonate-functionalized imidazolylidene Au(I) complexes. A
comparison of the structural parameters of representative examples of the synthesized
complexes with literature data revealed that introduction of the functionalities has, as
desired, no strong influence on the bonding situation inside the NHC framework. Thus
this approach opens a fast access to libraries of functionalized NHC complexes which
can be further derivatized and for example be used for surface attachment. This is
subject of current investigations in the group. Furthermore, due to its convergent
synthetic strategy, this easy-to-use procedure is predestinated for the synthesis of
catalyst libraries.
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Chemistry - A European Journal
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