Steroid Derived Mesoionic Gold and Silver Mono- and Polymetallic Carbenes

Article abstract of DOI:10.1021/acs.inorgchem.5b01524

A two-step synthesis of gold mesoionic carbene complexes containing estrone moieties has been developed. The method uses the methylation of the triazole nucleus, followed by the treatment of the triazolium salt with Ag₂O and transmetalation wit

Full text of DOI:10.1021/acs.inorgchem.5b01524

Article
pubs.acs.org/IC
Steroid Derived Mesoionic Gold and Silver Mono- and Polymetallic
Carbenes
María Frutos and María C. de la Torre*
́ ́
Instituto de Química Organica General, Consejo Superior de Investigaciones Científicas (CSIC), Centro de Innovacion en Química
Avanzada (ORFEO-CINQA), Juan de la Cierva 3, 28006-Madrid, Spain
Miguel A. Sierra*
Departamento de Química Organ
́
ica, Facultad de Química, Universidad Complutense, Centro de Innovacion
́
en Química Avanzada
(
ORFEO-CINQA), 28040-Madrid, Spain
*
S Supporting Information
ABSTRACT: A two-step synthesis of gold mesoionic carbene
complexes containing estrone moieties has been developed.
The method uses the methylation of the triazole nucleus,
followed by the treatment of the triazolium salt with Ag O and
2
transmetalation with [AuCl(SMe )]. Mono-, bi-, tri-, and
2
tetrametallic gold complexes can be obtained depending on
the structure of the starting triazolium salts. Tetrametallic gold
carbene embedded in a macrocylic stereoidal cavity containing
four estrone nuclei has been also prepared. Additionally, the mono- and bimetallic silver carbene complexes containing triazole-
steroid ligands have been isolated and characterized. These complexes resulted to be stable and have been characterized by
spectroscopic and HRMS techniques. The gold and silver complexes having triazole-steroid ligands are unprecedented in the
literature and the method reported here to access to these compounds is easy and efficient. Preliminary results regarding the
catalytic activity of some of the gold-carbenes prepared in the insertion of diazoalkanes into alcohols are presented.
INTRODUCTION
with R PAuX. Some gold derivatives of bile acids have also
been described (Scheme 2). To the best of our knowledge, no
3
■
8
1
Beyond the now conventional Arduengo-type carbenes the
called abnormal or mesoionic carbenes (MIC) have emerged as
a powerful family of ligands whose use in synthesis and catalysis
is still in its first stages of development. Among the numerous
compounds included in this classification the derivatives of
,2,3-triazoles stand out since their seminal discovery by
Albrecht in 2008 because of their outstanding properties.
,2,3-triazoles are made by the Cu-catalyzed Huisgen cyclo-
biological data about the activity of such complexes is known.
In this context, it is surprising that steroid derivatives
containing 1,2,3-triazolylidene ligands and one or more metals
have not been yet reported. In our previous work we have
developed different approaches to prepare steroide, diterpene,
alkaloid and in general natural products derived structures
1
2
1
9
containing the 1,2,3-triazole moiety. Therefore, alkylation of
addition between a terminal alkyne and an azide in high yields
and with complete selectivities. This method is easy and highly
3
the triazole and subsequent treatment with Ag O and a Au(I)
2
tunable allowing for a diversification of the carbene structures,
which is difficult to achieve in other families of carbenes. The
standard protocol to form the metal-carbene complexes
source should lead to the corresponding 1,2,3-triazolylidene
gold complex. In optimum conditions even the silver carbene
complexes could be isolated and characterized. Moreover, since
steroid derivatives containing up to four 1,2,3-triazole nuclei are
easily available following our reported methodologies, in
principle up to tetracarbene derivatives can be accessed. Herein
we report a general and flexible approach to the synthesis of
gold and silver mesoinic carbene-steroid complexes having
highly symmetrical or macrocyclic steroid derived structures
containing up to four metals.
required alkylation of the 1,2,3-triazole, followed by treatment
4
with Ag O and the metal salt or complex. These smooth
2
conditions are compatible with sensitive functional groups
(Scheme 1).
Since the original report of steroid containing transition
5
metals in the early sixties, interest in these types of compounds
has steadily grown because of their potential applications in
6
medicine and biology. Since gold derivatives possess the ability
to inhibit the growth of tumors several gold−steroid complexes
7
have been described. Most of the reported gold derived steroid
complexes have the structure of Au-ethynylestrone and they
have been prepared by the reaction of the deprotonated alkyne
Received: July 9, 2015
Published: November 24, 2015
©
2015 American Chemical Society
11174
DOI: 10.1021/acs.inorgchem.5b01524
Inorg. Chem. 2015, 54, 11174−11185

Inorganic Chemistry
Article
Scheme 1
Scheme 2
N CCH), 114.8 (CH, C-4), 112.4 (CH, C-2), 62.2 (OCH ), 54.3
3
2
(
NCH ), 50.4 (CH, C-14), 48.1 (C, C-13), 44.0 (CH, C-9), 38.3 (CH,
2
C-8), 35.9 (CH , C-16), 31.6 (CH , C-12), 29.7 (CH , C-6), 26.6
2
2
2
(
CH , C-7), 25.9 (CH , C-11), 21.6 (CH , C-15), 13.9 (CH , C-18).
2 2 2 3
IR (KBr): νmax 3437, 2923, 1737, 1605, 1500, 1460, 1500, 1460, 1234,
1
for C H N O : 442.2489 [M + H] ; found 441.2490. mp: 163−165
°
055, 733. [α]D25 + 103.8 (c 0.295, CHCl ). MS (ES) m/z calculated
3
+
28
32
3
2
C.
Compound 6a. Following the general procedure a mixture of
bisazide (164 mg, 0.88 mmol, 1.00 equiv), alkyne 1 (542 mg, 1.76
mmol, 2.20 equiv), sodium (L)-ascorbate (70 mg, 0.35 mmol, 0.40
EXPERIMENTAL SECTION
■
equiv), and CuSO ·5H O (44 mg, 0.18 mmol, 0.20 equiv) in DMF
General Methods and Materials. Unless noted otherwise, all
manipulations were carried out under an argon atmosphere using
standard Schlenk techniques. DMF and MeCN were dried by passage
through solvent purification columns containing activated alumina.
CH Cl was stored in CaCl for 24 h and dried through a distillation
4
2
(
25 mL) was stirred under Ar at rt for 2.5 h. The resulting residue was
purified (SiO , Hex/AcOEt 1:1 to 1:9) to yield 6a as a white solid
2
1
(
489 mg, 69%). H NMR (400 MHz, CDCl ): δ 7.52 (s, 2H, N C
3
3
CH), 7.40−7.37 (m, 2H, Ar), 7.28−7.25 (m, 2H, Ar), 7.18 (d, J = 8.6
Hz, 2H, H-1), 6.76 (dd, J = 8.6 Hz, 2.6 Hz, 2H, H-2), 6.70 (d, J = 2.6
2
2
2
with CaH . Other solvents were HPLC grade and were used without
2
Hz, 2H, H-4), 5.63 (s, 4H, NCH ), 5.13 (s, 4H, OCH ), 2.88−2.85
further purification. Unless noted otherwise, all reagents were obtained
from commercial sources and used without further purification. Flash
column chromatography was performed using silica gel (Merk, no.
2
2
(
m, 4H, CH , H-6), 2.50 (dd, J = 18.8 Hz, 8.6 Hz, 2H), 2.41−2.32 (m,
2
2
H), 2.25−1.90 (m, 10H), 1.66−1.36 (m, 12H), 0.89 (s, 6H, H-18).
13
1
13
C NMR (100 MHz, CDCl ): δ 221.0 (2CO, C-17), 156.2 (2C, C-
9
3
385, 230−400 mesh). H and C NMR spectra were recorded at
3
1
13
00, 400, or 500 MHz ( H NMR) and at 75, 100, or 125 MHz ( C
3), 145.0 (2C, N
3
CCH), 138.0 (2C, C-5), 133.3 (2C, Ar), 132.8
NMR) using CDCl3 and DMSO-d6 as solvents with the residual
solvent signal as internal reference (CDCl , 7.26 and 77.2 ppm) and
(2C, C-10), 130.6 (2CH, Ar), 129.9 (2CH, Ar), 126.5 (2CH, C-1),
123.0 (2CH, N
CCH), 114.8 (2CH, C-4), 112.4 (2CH, C-2), 62.0
(2OCH ), 51.4 (2NCH ), 50.4 (2CH, C-14), 48.1 (2C, C-13), 44.0
(2CH, C-9), 38.4 (2CH, C-8), 35.9 (2CH , C-16), 31.6 (2CH , C-12),
29.7 (2CH , C-6), 26.6 (2CH , C-7), 26.0 (2CH , C-11), 21.7 (2CH
C-15), 13.9 (2CH , C-18). IR (KBr): νmax 3436, 2928, 1736, 1608,
1498, 1454, 1253, 1232, 1052, 753. [α]
3
3
(
DMSO-d , 2.50 and 39.5 ppm). The following abbreviations are used
2
2
6
to describe peak patterns when appropriate: s (singlet), d (doublet), t
triplet), q (quadruplet), m (multiplet), and br (broad). Mass spectra
2
2
(
2
2
2
,
2
were recorded using electrospray (ES) chemical ionization techniques
in its positive mode. IR spectra were obtained on a PerkinElmer 681
spectrophotometer. Optical rotations were measured on a 241 MC
polarimeter using a sodium lamp. Melting points were determined on
a Koffler block.
Azides, 3-O-propargylestrone 1, and macrocycle 18 were synthe-
sized by using an experimental procedure previously described.
Azides are potentially explosive materials, they must be prepared and
handled behind safety screens, and protected from light, shock, and
heat.
3
25
+ 111.75 (c 0.36, CHCl
).
H N O : 805.4436 [M + H] ; found
57 6 4
D
3
+
MS (ES) m/z calculated for C50
805.4462. mp: 125−128 °C.
Compound 6b. Following the general procedure a mixture of
bisazide (174 mg, 0.92 mmol, 1.50 equiv), alkyne 1 (627 mg, 2.03
mmol, 2.20 equiv), sodium (L)-ascorbate (73 mg, 0.37 mmol, 0.40
9
a
equiv), and CuSO
(25 mL) was stirred under Ar at rt for 4 h. The resulting residue was
purified (SiO , Hex/AcOEt 1:1 to 3:7) to yield 6b as a white solid
(665 mg, 90%). H NMR (400 MHz, CDCl
·5H O (44 mg, 0.18 mmol, 0.20 equiv) in DMF
4 2
2
1
General Procedure for the Synthesis of 1,2,3-Triazoles. A
mixture of organic azide (1.00 or 1.20 equiv), alkyne (1.00, 2.20, 3.30,
or 4.40 equiv), sodium (L)-ascorbate (0.20, 0.40, 0.60, or 0.80 equiv),
and CuSO ·5H O (0.10, 0.20, 0.30, or 0.40 equiv) in DMF was stirred
3
): δ 7.57 (s, 2H, N
CH), 7.37 (t, J = 8.1 Hz, 1H, Ar), 7.26−7.23 (m, 3H, Ar), 7.18 (d, J =
8.6 Hz, 2H, H-1), 6.76 (dd, J = 8.6 Hz, 2.8 Hz, 2H, H-2), 6.70 (d, J =
3
C
2.8 Hz, 2H, H-4), 5.50 (s, 4H, NCH
(m, 4H, CH , H-6), 2.49 (dd, J = 18.7 Hz, 8.6 Hz, 2H), 2.40−2.31 (m,
2H), 2.24−1.90 (m, 10H), 1.66−1.36 (m, 12H), 0.89 (s, 6H, H-18).
), 5.15 (s, 4H, OCH ), 2.89−2.85
4
2
2
2
under Ar at rt until completion of the reaction (TLC analysis). The
reaction was quenched with water at 0 °C and allowed to reach rt. The
mixture was extracted with DCM three times. The combined organic
extracts were washed with water (twice) and once with brine. The
2
1
3
C NMR (100 MHz, CDCl
): δ 221.0 (2CO, C-17), 156.3 (2C, C-
3
3), 145.0 (2C, N CCH), 138.0 (2C, C-5), 135.7 (2C, Ar), 132.8
3
organic layer was dried over MgSO and filtered, and the solvent was
(2C, C-10), 130.1 (CH, Ar), 128.4 (2CH, Ar), 127.6 (CH, Ar), 126.5
4
removed under vacuum to afford the corresponding reaction products,
which were purified through a short pad of SiO2.
(2CH, C-1), 122.8 (2CH, N CCH), 114.8 (2CH, C-4), 112.4
3
(2CH, C-2), 62.1 (2OCH ), 53.8 (2NCH ), 50.4 (2CH, C-14), 48.1
2
2
Compound 2. Following the general procedure a mixture of benzyl
azide (307 mg, 2.31 mmol, 1.50 equiv), alkyne 1 (474 mg, 1.54 mmol,
(2C, C-13), 44.0 (2CH, C-9), 38.4 (2CH, C-8), 35.9 (2CH , C-16),
2
31.6 (2CH , C-12), 29.7 (2CH , C-6), 26.6 (2CH , C-7), 26.0 (2CH ,
2
2
2
2
1
.00 equiv), sodium (L)-ascorbate (61 mg, 0.31 mmol, 0.20 equiv) and
C-11), 21.7 (2CH , C-15), 13.9 (2CH , C-18). IR (KBr): ν 3436,
2 3 max
25
CuSO ·5H O (38 mg, 0.15 mmol, 0.10 equiv) in DMF (25 mL) was
stirred under Ar at rt for 1 h. The resulting residue was purified (SiO ,
Hex/AcOEt 4:1 to 3:7) to yield 2 as a white solid (604 mg, 89%). H
2928, 1736, 1608, 1498, 1234, 1050. [α]D + 108.67 (c 0.39, CHCl ).
4
2
3
+
MS (ES) m/z calculated for C H N O : 805.4436 [M + H] ; found
2
50 57
6
4
1
805.4460. mp: 108−112 °C.
NMR (400 MHz, CDCl ): δ 7.43 (s, 1H, N CCH), 7.30−7.25 (m,
Compound 6c. Following the general procedure a mixture of
bisazide (194 mg, 1.03 mmol, 1.00 equiv), alkyne 1 (700 mg, 2.27
mmol, 2.20 equiv), sodium (L)-ascorbate (82 mg, 0.41 mmol, 0.40
equiv), and CuSO ·5H O (51 mg, 0.21 mmol, 0.20 equiv) in DMF
3
3
3
H, Ar), 7.18−7.16 (m, 2H, Ar), 7.09 (d, J = 8.6 Hz, 1H, H-1), 6.67
(
(
2
5
dd, J = 8.6 Hz, 2.8 Hz, 1H, H-2), 6.61 (d, J = 2.8 Hz, 1H, H-4), 5.42
s, 2H, NCH ), 5.05 (s, 2H, OCH ), 2.79- 2.76 (m, 2H, CH , H-6),
2
2
2
4
2
.38 (dd, J = 18.7 Hz, 8.6 Hz, 1H), 2.30−2.22 (m, 1H), 2.16−1.81 (m,
(32 mL) was stirred under Ar at rt for 3 h. The resulting residue was
13
H), 1.57−1.27 (m, 6H), 0.80 (s, 3H, H-18). C NMR (100 MHz,
purified (SiO , MeOH/DCM 2%) to yield 6c as a white solid (700
2
1
CDCl ): δ 221.0 (CO, C-17), 156.3 (C, C-3), 144.9 (C, N C
mg, 84%). H NMR (400 MHz, CDCl ): δ 7.54 (s, 2H, N CCH),
3
3
3
3
CH), 137.9 (C, C-5), 134.6 (C, Ar), 132.7 (C, C-10), 129.2 (2CH,
Ar), 128.9 (CH, Ar), 128.2 (2CH, Ar), 126.5 (CH, C-1), 122.6 (CH,
7.28 (s, 4H, Ar), 7.17 (d, J = 8.4 Hz, 2H, H-1), 6.75 (dd, J = 8.4 Hz,
2.7 Hz, 2H, H-2), 6.68 (d, J = 2.7 Hz, 2H, H-4), 5.50 (s, 4H, NCH2),
1
1175
DOI: 10.1021/acs.inorgchem.5b01524
Inorg. Chem. 2015, 54, 11174−11185

Inorganic Chemistry
Article
5
.13 (s, 4H, OCH ), 2.87−2.84 (m, 4H, CH , H-6), 2.47 (dd, J = 18.7
8H), 2.09−2.03 (m, 4H), 1.97−1.89 (m, 4H), 1.83−1.60 (m, 16H),
2
2
1
3
Hz, 8.5 Hz, 2H), 2.39−2.30 (m, 2H), 2.23−1.88 (m, 10H), 1.65−1.34
1.44−1.14 (m, 20H), 0.80 (s, 12H, H-18), 0.18 (s, 36H, OTMS). C
(
(
m, 12H), 0.89 (s, 6H, H-18). 13C NMR (100 MHz, CDCl ): δ 221.0
2CO, C-17), 156.3 (2C, C-3), 145.1 (2C, N CCH), 138.0 (2C,
NMR (100 MHz, CDCl ): δ 155.4 (4C, C-3), 145.5 (4C, N CCH),
3
3
3
137.9 (4C, C-5), 133.1 (4C, Ar), 132.8 (4C, C-10), 130.6 (4CH, Ar),
3
C-5), 135.3 (2C, Ar), 132.8 (2C, C-10), 128.9 (4CH, Ar), 126.5 (CH,
130.0 (4CH, Ar), 126.2 (4CH, C-1), 122.7 (4CH, N CCH), 115.4
3
C-1), 122.7 (2CH, N CCH), 114.8 (2CH, C-4), 112.4 (2CH, C-2),
(4CH, C-4), 112.2 (4CH, C-2), 85.0 (4C, CC), 81.3 (4C, C-17),
3
6
4
2.1 (2OCH ), 53.8 (2NCH ), 50.4 (2CH, C-14), 48.1 (2C, C-13),
71.2 (4C, CC), 61.9 (4OCH ), 51.3 (4NCH ), 49.3 (4CH, C-14),
2 2
2
2
4.0 (2CH, C-9), 38.4 (2CH, C-8), 35.9 (2CH , C-16), 31.6 (2CH ,
48.9 (4C, C-13), 44.3 (4CH, C-9), 40.0 (4CH, C-8), 39.4 (4CH , C-
2
2
2
C-12), 29.7 (2CH , C-6), 26.6 (2CH , C-7), 26.0 (2CH , C-11), 21.7
16), 33.2 (4CH , C-12), 29.9 (4CH , C-6), 27.4 (4CH , C-7), 26.5
2
2
2
2
2
2
(
1
2CH , C-15), 13.9 (2CH , C-18). IR (KBr): ν 3436, 2925, 1736,
(4CH , C-11), 23.2 (4CH , C-15), 13.1 (4CH , C-18), 1.8 (12CH ,
2
3
max
2 2 3 3
25
605, 1500, 1230, 1053, 817. [α]D + 96.26 (c 0.34, CHCl ). MS (ES)
OTMS). IR (KBr): νmax 3435, 2929, 1610, 1499, 1455, 1250, 1140,
3
+
25
m/z calculated for C H N O : 805.4436 [M + H] ; found 805.4436.
mp: 215−218 °C.
1109, 1088, 892, 842, 754. [α]D + 87.67 (c 0.57, CHCl ). MS (EI)
50
57
6
4
3
+
m/z calculated for C120H149N O Si : 1999.0720 [M + H] ; found
12
8
4
Compound 11. Following the general procedure a mixture of
trisazide (179 mg, 0.74 mmol, 1.00 equiv), alkyne 1 (749 mg, 2.43
mmol, 3.30 equiv), sodium (L)-ascorbate (87 mg, 0.44 mmol, 0.60
equiv), and CuSO ·5H O (55 mg, 0.22 mmol, 0.30 equiv) in DMF
1999.0735. mp = decomposes before melting.
General Procedure for the Synthesis of Triazolium Salts.
Triazole (1.00 equiv) and Meerwein’s salt (1.30 equiv per triazole)
were stirred under Ar at rt in CH Cl until the reaction was completed
4
2
2
2
1
(
30 mL) was stirred under Ar at rt for 3 h. The resulting residue was
( H NMR analysis). The reaction was quenched with methanol and
purified (SiO , MeOH/DCM 2%) to yield 11 as a white solid (790
filtered through a short pad of NaHCO . The solvent was removed
under vacuum to afford the corresponding reaction product without
further purification.
2
3
1
mg, 91%). H NMR (400 MHz, CDCl ): δ 7.58 (s, 3H, N CCH),
3
3
7
2
5
8
1
.18 (d, J = 2.8 Hz, 3H, H-1), 7.14 (s, 3H, Ar), 6.76 (dd, J = 8.6 Hz,
.8 Hz, 3H, H-2), 6.70 (d, J = 2.8 Hz, 3H, H-4), 5.46 (s, 6H, NCH2),
Compound 3. Following the general procedure a mixture of 2 (340
mg, 1.13 mmol, 1.00 equiv) and Me OBF (218 mg, 1.47 mmol, 1.30
.14 (s, 6H, OCH ), 2.89−2.85 (m, 6H, H-6), 2.49 (dd, J = 18.8 Hz,
2
3
4
.6 Hz, 3H), 2.40−2.31 (m, 3H), 2.24−1.89 (m, 15H), 1.66−1.35 (m,
equiv) in CH Cl (70 mL) was stirred under Ar at rt for 3 h. The
2 2
8H), 0.89 (s, 9H, H-18). 13C NMR (100 MHz, CDCl ): δ 221.0
reaction was quenched with methanol and filtered through a plug of
3
(
3CO, C-17), 156.2 (3C, C-3), 145.2 (3C, N CCH), 138.0 (3C,
NaHCO . The solvent was removed under vacuum to yield 5 as a
3
3
1
C-5), 136.9 (3C, Ar), 132.9 (3C, C-10), 127.7 (3CH, Ar), 126.5
white solid (605 mg, 98%). H NMR (400 MHz, CDCl ): δ 8.63 (s,
3
(
(
(
3CH, C-1), 123.0 (3CH, N CCH), 114.8 (3CH, C-4), 112.3
1H, N CCH), 7.48−7.44 (m, 2H, Ar), 7.40−7.36 (m, 3H, Ar), 7.17
3
3
3CH, C-2), 62.0 (3OCH ), 53.4 (3NCH ), 50.4 (3CH, C-14), 48.1
(d, J = 8.6 Hz, 1H, H-1), 6.74 (dd, J = 8.6 Hz, 2.7 Hz, 1H, H-2), 6.70
(d, J = 2.7 Hz, 1H, H-4), 5.64 (s, 2H, NCH ), 5.23 (s, 2H, OCH ),
2
2
3C, C-13), 44.0 (3CH, C-9), 38.4 (3CH, C-8), 35.9 (3CH , C-16),
2
2
2
3
1.6 (3CH , C-12), 29.7 (3CH , C-6), 26.6 (3CH , C-7), 26.0 (3CH ,
4.27 (s, 3H, NCH ), 2.86−2.83 (m, 2H, CH , H-6), 2.49 (dd, J = 18.9
2
2
2
2
3
2
C-11), 21.7 (3CH , C-15), 13.9 (3CH , C-18). IR (KBr): ν 3445,
Hz, 8.6 Hz, 1H), 2.37−2.28 (m, 1H), 2.20−1.88 (m, 5H), 1.65−1.32
2
3
max
2
[
928, 1736, 1608, 1498, 1454, 1253, 1232, 1052, 1007, 817, 752.
(m, 6H), 0.88 (s, 3H, H-18). 13C NMR (100 MHz, CDCl ): δ 220.9
3
α]D25 + 75.71 (c 0.55, CHCl ). MS (ES) m/z calculated for
(CO, C-17), 154.9 (C, C-3), 140.1 (C, N CCH), 138.6 (C, C-5),
3
3
+
C H N O : 1168.6383 [M + H] ; found 1168.6337. mp: 148−150
134.1 (C, Ar), 131.3 (C, C-10), 130.0 (2CH, Ar), 129.9 (CH, Ar),
72
82
9
6
°C.
129.6 (2CH, Ar), 129.5 (2CH, N CCH), 126.9 (CH, C-1), 114.7
3
Compound 13. Following the general procedure a mixture of
(CH, C-4), 112.3 (CH, C-2), 57.9 (OCH ), 57.6 (NCH ), 50.5 (CH,
2
2
tetraazide (110 mg, 0.37 mmol, 1.00 equiv), alkyne 1 (500 mg, 1.62
mmol, 4.40 equiv), sodium (L)-ascorbate (58 mg, 0.30 mmol, 0.80
equiv), and CuSO ·5H O (37 mg, 0.15 mmol, 0.40 equiv) in DMF
C-14), 48.0 (C, C-13), 44.0 (CH, C-9), 38.7 (CH, C-8), 38.3 (NCH3),
35.9 (CH , C-16), 31.6 (CH , C-12), 29.6 (CH , C-6), 26.5 (CH , C-
2
2
2
2
7), 25.9 (CH , C-11), 21.7 (CH , C-15), 13.9 (CH , C-18). IR (KBr):
4
2
2
2
3
2
5
(
23 mL) was stirred under Ar at rt for 2 h. The resulting residue was
νmax 3436, 2930, 1735, 1610, 1498, 1456, 1084, 1063, 710. [α]D
+
purified (SiO , MeOH/DCM 4%) to yield 14 as a white solid (534
87.88 (c 0.46, CHCl ). MS (ES) m/z calculated for C H N O :
2
3
29 34
3
2
1
+
mg, 94%). H NMR (400 MHz, CDCl ) δ 7.59 (s, 4H, N CCH),
456.2646 [M − BF ] ; found 456.2648. mp: 119−122 °C.
3
3
4
7
2
8
4
0
.16 (d, J = 8.6 Hz, 4H, H-1), 7.13 (s, 2H, Ar), 6.74 (dd, J = 8.6 Hz,
Compound 7a. Following the general procedure a mixture of 6a
.7 Hz, 4H, H-2), 6.69 (br s, 4H, H-4), 5.58 (s, 8H, NCH ), 5.10 (s,
(90 mg, 0.11 mmol, 1.00 equiv) and Me OBF (43 mg, 0.29 mmol,
2
3
4
H, OCH ), 2.87−2.83 (m, 8H, H-6), 2.49 (dd, J = 18.8 Hz, 8.6 Hz,
2.60 equiv) in CH Cl (14 mL) was stirred under Ar at rt for 19 h.
2
2 2
H), 2.36−2.33 (m, 4H), 2.22−1.89 (m, 20H), 1.65−1.33 (m, 24H),
The reaction was quenched with methanol and filtered through a plug
.88 (s, 12H, H-18). 13C NMR (100 MHz, CDCl ): δ 220.9 (4CO,
of NaHCO . The solvent was removed under vacuum to yield 7a as a
3
3
1
C-17), 156.2 (4C, C-3), 145.2 (4C, N CCH), 138.1 (4C, C-5),
white solid (103 mg, 90%). H NMR (400 MHz, CDCl ): δ 8.59 (s,
3
3
1
1
6
4
35.0 (4C, Ar), 132.9 (4C, C-10), 132.4 (2CH, Ar), 126.5 (4CH, C-
2H, N CCH), 7.41 (s, 4H, Ar), 7.16 (d, J = 8.5 Hz, 2H, H-1), 6.72
3
), 123.4 (4CH, N CCH), 114.8 (4CH, C-4), 112.4 (4CH, C-2),
(d, J = 8.5 Hz, 2H, H-2), 6.68 (br s, 2H, H-4), 5.84 (s, 4H, NCH ),
3
2
1.9 (4OCH ), 50.7 (4NCH ), 50.5 (4CH, C-14), 48.1 (4C, C-13),
5.18 (s, 4H, OCH ), 4.19 (s, 6H, NCH ), 2.85−2.82 (m, 4H, H-6),
2
2
2
3
4.0 (4CH, C-9), 38.4 (4CH, C-8), 35.9 (4CH , C-16), 31.7 (4CH ,
2.49 (dd, J = 18.8 Hz, 8.7 Hz, 2H), 2.35−2.27 (m, 2H), 2.17−1.90 (m,
2
2
13
C-12), 29.7 (4CH , C-6), 26.6 (4CH , C-7), 26.0 (4CH , C-11), 21.7
10H), 1.65−1.31 (m, 12H), 0.87 (s, 6H, CH ). C NMR (100 MHz,
2
2
2
3
(
1
4CH , C-15), 14.0 (4CH , C-18). IR (KBr): ν 3436, 2927, 1737,
608, 1575, 1498, 1454, 1232, 1157, 1053, 816, 752. [α]D + 126.54
CDCl ): δ 221.0 (2CO, C-17), 155.0 (2C, C-3), 140.3 (2C, N C
2
3
max
3
3
25
CH), 138.7 (2C, C-5), 134.2 (2C, Ar), 131.9 (2C, C-10), 131.1 (2CH,
(
c 0.56, CHCl ). MS (EI) m/z calculated for C H N O :
Ar), 130.8 (2CH, Ar), 130.2 (2CH, N CCH), 126.9 (2CH, C-1),
3
94 107 12
8
3
+
1
532.8361 [M + H] ; found 1532.8307. mp: 163−165 °C.
Compound 17. To a solution of the macrocycle 18 (151 mg, 0.09
mmol, 1.00 equiv) in 25 mL of CH Cl under Ar, triethylamine is
114.8 (2CH, C-4), 112.3 (2CH, C-2), 58.0 (2OCH ), 54.3 (2NCH ),
2
2
50.5 (2CH, C-14), 48.0 (2C, C-13), 44.0 (2CH, C-9), 38.9 (2NCH3),
38.3 (2CH, C-8), 36.0 (2CH , C-16), 31.6 (2CH , C-12), 29.6 (2CH ,
2
2
2
2
2
added (97 μL, 0.70 mmol, 8.00 equiv). The reaction is stirred for 15
min. We then add trimethylsilane triflate (97 μL, 0.52 mmol, 6.00
equiv) drop by drop. The mixture is stirred at rt for 1 h until the
reaction is complete (TLC analysis). The solvent is removed under
vacuum. 17 is obtained as a white solid. (We isolated the product from
C-6), 26.5 (2CH , C-7), 26.0 (2CH , C-11), 21.7 (2CH , C-15), 14.0
2 2 2
(2CH , C-18). IR (KBr): ν 3436, 2928, 1735, 1609, 1498, 1454,
3
max
3
0
1233, 1083, 1058, 750. [α]D + 91.53 (c 0.34, CHCl ). MS (ES) m/z
3
+
calculated for C H N O BF : 921.4865 [M − BF ] ; found
5
2
62
6
4
4
4
2
+
921.4915. For C H N O : 417.2411 [M − 2BF ] ; found
5
2
62
6
4
4
1
the trimethylammonium salt for its characterization). H NMR (400
417.2401. mp: 140−142 °C.
MHz, CDCl ): δ 7.39−7.35 (m, 4H, Ar), 7.25−7.20 (m, 4H, Ar), 7.16
Compound 7b. Following the general procedure a mixture of 6b
3
(
s, 4H, N CCH), 6.99 (d, J = 8.8 Hz, 4H, H-1), 6.59 (dd, J = 8.8
(90 mg, 0.11 mmol, 1.00 equiv) and Me OBF (43 mg, 0.29 mmol,
3
3
4
Hz, 2.8 Hz, 4H, H-2), 6.46 (d, J = 2.8, 4H, H-4), 5.57 (d, J = 4.2 Hz,
2.60 equiv) in CH Cl (14 mL) was stirred under Ar at rt for 1 h. The
2 2
8
H, NCH ), 5.15 (s, 8H, OCH ), 2.76−2.56 (m, 8H), 2.29−2.22 (m,
reaction was quenched with methanol and filtered through a plug of
2
2
1
1176
DOI: 10.1021/acs.inorgchem.5b01524
Inorg. Chem. 2015, 54, 11174−11185

Inorganic Chemistry
Article
NaHCO . The solvent was removed under vacuum to yield 7b as a
5.20 equiv) in CH Cl (53 mL) was stirred under Ar at rt for 24 h.
The reaction was quenched with methanol and filtered through a plug
3
2
2
1
white solid (105 mg, 95%). H NMR (400 MHz, CDCl ): δ 8.55 (s,
3
2
6
5
2
2
H, N CCH), 7.46−7.37 (s, 4H, Ar), 7.15 (d, J = 8.7 Hz, 2H, H-1),
of NaHCO . The solvent was removed under vacuum to yield 15 as a
3
3
1
.72 (dd, J = 8.7 Hz, 2.7 Hz, 2H, H-2), 6.68 (d, J = 2.7 Hz, 2H, H-4),
.64 (s, 4H, NCH ), 5.20 (s, 4H, OCH ), 4.23 (s, 6H, NCH ), 2.85−
white solid (436 mg, quantitative). H NMR (400 MHz, DMSO-d ): δ
6
9.05 (s, 4H, N CCH), 7.72 (s, 2H, Ar), 7.26 (d, J = 8.6 Hz, 4H, H-
2
2
3
3
.82 (m, 4H, H-6), 2.49 (dd, J = 18.6 Hz, 8.7 Hz, 2H), 2.31−2.29 (m,
1), 6.85 (br d, J = 8.5 Hz, 4H, H-2), 6.81 (br s, 4H, H-4), 6.09 (s, 8H,
NCH ), 5.41 (s, 8H, OCH ), 4.27 (s, 12H, NCH ), 2.85−2.83 (m,
H), 2.16−2.18 (m, 10H), 1.64−1.30 (m, 12H), 0.86 (s, 6H, CH ).
3
2
2
3
1
3
C NMR (100 MHz, CDCl ): δ 221.2 (2CO, C-17), 154.9 (2C, C-
8H, H-6), 2.47−2.32 (m, 8H), 2.21−2.18 (m, 4H), 2.12−2.03 (m,
4H), 1.97−1.94 (m, 8H), 1.77−1.73 (m, 4H), 1.63−1.36 (m, 24H),
3
3
), 140.3 (2C, N CCH), 138.6 (2C, C-5), 134.0 (2C, Ar), 132.8
3
0.83 (s, 12H, H-18). 13C RMN (100 MHz, DMSO-d
): δ 219.6 (4C
CCH), 138.0 (4C, C-5),
133.9 (2CH, Ar), 133.8 (4C, Ar), 133.5 (4C, C-10), 130.3 (4CH, C-
1), 126.6 (4CH, N
CCH), 114.5 (4CH, C-4), 112.4 (4CH, C-2),
58.2 (4OCH ), 52.8 (4NCH ), 49.5 (4CH, C-14), 47.3 (4C, C-13),
43.5 (4CH, C-9), 38.6 (4NCH ), 37.8 (4CH, C-8), 35.4 (4CH , C-
16), 31.3 (4CH , C-12), 29.2 (4CH , C-6), 26.0 (4CH , C-7), 25.5
(4CH , C-11), 21.2 (4CH , C-15), 13.5 (4CH , C-18). IR (KBr): νmax
3435, 2929, 1735, 1609, 1498, 1454, 1234, 1083, 1059, 846. [α]
108.60 (c 0.48, CHCl ). MS (ES) m/z calculated for
12: 1850.9330 [M − BF
decomposes before melting.
Compound 16. Following the general procedure a mixture of 17
(362 mg, 0.18 mmol, 1.00 equiv) and Me OBF (139 mg, 0.94 mmol,
5.20 equiv) in CH Cl (40 mL) was stirred under Ar at rt until
completion of the reaction (5 h 30 min). The reaction was quenched
with methanol and filtered through a plug of NaHCO . The solvent
was removed under vacuum, and the residue was precipitated in a
mixture of CHCl and methanol to remove the triethylammonium
formed in the previous step. 16 is obtained as a white solid (210 mg,
(
2C, C-10), 130.5 (2CH, Ar), 130.3 (CH, Ar), 130.1 (2CH, N C
6
3
CH), 129.5 (CH, Ar), 126.9 (2CH, C-1), 114.8 (2CH, C-4), 112.2
O, C-17), 155.0 (4C, C-3), 140.1 (4C, N
3
(
(
(
7
2CH, C-2), 57.6 (2OCH ), 56.8 (2NCH ), 50.4 (2CH, C-14), 48.1
2C, C-13), 44.0 (2CH, C-9), 38.7 (2NCH ), 38.3 (2CH, C-8), 36.0
2CH , C-16), 31.6 (2CH , C-12), 29.6 (2CH , C-6), 26.5 (2CH , C-
), 25.9 (2CH , C-11), 21.7 (2CH , C-15), 13.9 (2CH , C-18). IR
2 2
3
3
2
2
2
2
2
2
2
2
3
3
2
(
7
KBr): ν 3435, 2929, 1735, 1609, 1498, 1454, 1234, 1083, 1057,
2
2
2
max
56. [α]D25 + 69.77 (c 0.30, CHCl ). MS (ES) m/z calculated for
3
2
2
3
+
25
D
C H N O BF : 921.4865 [M − BF ] ; found 921.4895. For
+
5
2
62
6
4
4
4
2+
C H N O : 417.2411 [M − 2BF ] ; found 417.2449. mp: 124−
3
52
62
6
4
4
+
1
27 °C.
Compound 7c. Following the general procedure a mixture of 6c
375 mg, 0.47 mmol, 1.00 equiv) and Me OBF (179 mg, 1.21 mmol,
C
98
H
118
N
O
12
8
B
F
3
] ; found: 1850.9630. mp:
4
(
3
4
2.60 equiv) in CH Cl (60 mL) was stirred under Ar at rt for 19 h.
3
4
2
2
The reaction was quenched with methanol and filtered through a plug
of NaHCO . The solvent was removed under vacuum to yield 7c as a
white solid (437 mg, 92%). H NMR (500 MHz, DMSO-d ): δ 9.08
2
2
3
1
6
3
(
s, 2H, N CCH), 7.57 (s, 4H, Ar), 7.26 (d, J = 8.6 Hz, 2H, H-1),
3
6
5
2
2
1
.87 (dd, J = 8.6 Hz, 2.5 Hz, 2H, H-2), 6.83 (d, J = 2.5 Hz, 2H, H-4),
3
.92 (s, 4H, NCH ), 5.39 (s, 4H, OCH ), 4.29 (s, 6H, NCH ), 2.87−
2
2
3
1
.84 (m, 4H, H-6), 2.45 (dd, J = 18.8 Hz, 8.4 Hz, 2H), 2.38−2.34 (m,
H), 2.23−2.18 (m, 2H), 2.11−2.04 (m, 2H), 1.99−1.94 (m, 4H),
90% two steps). H NMR (400 MHz, DMSO-d
CCH), 7.53−7.49 (m, 4H, Ar), 7.43−7.38 (m, 4H, Ar), 7.08 (d, J
= 8.6 Hz, 4H, H-1), 6.75 (dd, J = 8.6 Hz, 2.7 Hz, 4H, H-2), 6.70 (d, J =
2.7 Hz, 4H, H-4), 6.03 (s, 8H, NCH ), 5.59 (s, 4H, OH), 5.46 (s, 8H,
OCH ), 4.28 (s, 12H, NCH ), 2.79−2.64 (m, 8H), 2.32−2.27 (m,
4H), 2.15−2.08 (m, 4H), 1.99−1.64 (m, 25H), 1.58−1.51 (m, 5H),
6
): δ 8.84 (s, 4H,
N
3
13
.81−1.74 (m, 2H), 1.62−1.33 (m, 12H), 0.83 (s, 6H, H-18).
C
NMR (125 MHz, DMSO-d ): δ 219.6 (2CO, C-17), 155.0 (2C, C-
2
6
3
), 140.1 (2C, N CCH), 137.9 (2C, C-5), 133.9 (2C, Ar), 133.4
2
3
3
(
2C, C-10), 129.8 (4CH, Ar), 129.6 (2CH, N CCH), 126.5 (CH,
3
13
C-1), 114.6 (2CH, C-4), 112.4 (2CH, C-2), 58.2 (2OCH ), 55.7
1.40−1.23 (m, 14H), 0.77 (s, 12H, H-18). C NMR (100 MHz,
DMSO-d ): δ 153.9 (4C, C-3), 140.3 (4C, N
CCH), 137.7 (4C, C-
5), 133.2 (4C, C−Ar), 131.7 (4C, C-10), 130.7 (4CH, Ar), 130.2
(4CH, Ar), 129.8 (4CH, N
CCH), 126.4 (4CH, C-1), 115.0 (4CH,
C-4), 112.3 (4CH, C-2), 85.1 (4C, CC), 78.8 (4C, C-17), 68.7 (4C,
CC), 57.7 (4OCH ), 53.3 (4NCH ), 49.6 (4CH, C-14), 47.7 (4C,
C-13), 45.8 (4CH, C-9), 43.8 (4CH, C-8), 38.8 (4NCH ), 38.5
, C-6), 26.9 (4CH , C-
, C-18). IR
2
(
(
2
2NCH ), 49.5 (2CH, C-14), 47.3 (2C, C-13), 43.4 (2CH, C-9), 38.4
2NCH ), 37.8 (2CH, C-8), 35.4 (2CH , C-16), 31.3 (2CH , C-12),
9.2 (2CH , C-6), 26.0 (2CH , C-7), 25.5 (2CH , C-11), 21.1 (2CH ,
6
3
2
3
2
2
2
2
2
2
3
C-15), 13.5 (2CH , C-18). IR (KBr) ν 3436, 2931, 1736, 1609,
3
max
2
5
1
498, 1455, 1233, 1083, 1059, 821. [α]D + 97.55 (c 0.20, MeCN).
2
2
+
MS (ES) m/z calculated for C H N O BF : 921.4865 [M − BF ] ;
found 921.4899. mp: 55−157 °C.
3
52
62
6
4
4
4
(4CH
7), 26.0 (4CH
, C-16), 33.0 (4CH
2
2
2
2
Compound 10. Following the general procedure a mixture of 11
2
, C-11), 22.4 (4CH
3
(
3
300 mg, 0.26 mmol, 1.00 equiv) and Me OBF (148 mg, 1.00 mmol,
(KBr): ν 3436, 2932, 1610, 1498, 1455, 1256, 1083, 1031, 819.
3
4
max
[α]D25 + 83.67 (c 0.54, MeOH). MS (ES) m/z calculated for
.90 equiv) in CH Cl (66 mL) was stirred under Ar at rt for 24 h.
2 2
+
The reaction was quenched with methanol and filtered through a plug
of NaHCO . The solvent was removed under vacuum to yield 10 as a
white solid (363 mg, 95%). H RMN (400 MHz, DMSO-d ) δ 9.07 (s,
C
112
H
128
N
12
O
B
8
3
F
12: 2029.0114 [M − BF
4
] ; found 2028.9998. mp:
184−187 °C.
3
1
General Procedure for the Synthesis of Gold Carbenes. In a
6
3
H, N CCH), 7.67 (s, 3H, Ar), 7.25 (d, J = 8.5 Hz, 3H, H-1), 6.86
Schlenk tube charged with 4 Å molecular sieves, a mixture of
3
(
(
(
dd, J = 8.5 Hz, 2.8 Hz, 3H, H-2), 6.82 (d, J = 2.8 Hz, 3H, H-4), 5.92
triazolium salt (1.00 equiv), NMe Cl (1.50 equiv per triazole) and
4
s, 6H, NCH ), 5.41 (s, 6H, NCH ), 4.30 (s, 9H, OCH ), 2.86−2.84
Ag O (0.75 equiv per triazole) was stirred at rt in dark in
2
2
3
2
1
m, 6H, H-6), 2.47−2.36 (m, 6H), 2.23−2.19 (m, 3H), 2.12−2.03 (m,
MeCN:CH Cl (1:1) until the formation of the silver carbene ( H
2
2
3
1
H), 1.99−1.91 (m, 6H), 1.81−1.73 (m, 3H), 1.62−1.46 (m, 9H),
NMR analysis). The [AuCl(SMe )] (1.00 equiv referred to the starting
2
13
.44−1.32 (m, 9H), 0.83 (s, 9H, H-18). C RMN (100 MHz, DMSO-
triazolium salt) was added and the reaction was stirred at rt until the
1
d ) δ 219.6 (3CO, C-17), 155.0 (3C, C-3), 140.1 (3C, N CCH),
reaction was completed ( H NMR analysis). The reaction was filtered
6
3
1
1
37.9 (3C, C-5), 134.4 (3C, Ar), 133.4 (3C, C-10), 130.4 (3CH, Ar),
through a pad of Celite and the solvent was removed under vacuum to
afford the corresponding reaction products, which were purified
through a short pad of SiO2.
30.0 (3CH, C-1), 126.6 (3CH, N CCH), 114.5 (3CH, C-4), 112.4
3
(
(
(
7
3CH, C-2), 58.2 (3OCH ), 55.5 (3NCH ), 49.5 (3CH, C-14), 47.3
3C, C-13), 43.4 (3CH, C-9), 38.5 (3NCH ), 37.8 (3CH, C-8), 35.4
3CH , C-16), 31.3 (3CH , C-12), 29.2 (3CH , C-6), 25.9 (3CH , C-
2
2
Compound 5. Following the general procedure a mixture of 3 (270
3
mg, 0.50 mmol, 1.00 equiv), NMe Cl (82 mg, 0.75 mmol, 1.50 equiv),
2
2
2
2
4
), 25.5 (3CH , C-11), 21.1 (3CH , C-15), 13.5 (3CH , C-18). IR
and Ag O (86 mg, 0.37 mmol, 0.75 equiv) in MeCN:CH Cl (26 mL)
2
2
3
2
2
2
KBr) ν 3435, 2926, 1736, 1610, 1498, 1454, 1234, 1083, 1057, 819.
was stirred under Ar at rt for 18 h. [AuCl(SMe )] (146 mg, 0.50
mmol, 1.00 equiv) was added, and the reaction mixture was stirred for
max
2
α]D25 + 65.06 (c 0.63, CHCl ). MS (ES) m/z calculated for
3
+
two more hours. The resulting residue was purified (SiO , Hex/AcOEt
75
90
9
6
2
8
4
2
2+
1
4:6) to yield 5 as a white solid (296 mg, 86%). H RMN (400 MHz,
75
90
9
6
4
4
3+
CDCl ) δ 7.56−7.52 (m, 2H, Ar), 7.38−7.36 (m, 3H, Ar), 7.21 (d, J =
75
90
9
6
4
3
8.5 Hz, 1H, H-1), 6.84 (d, J = 2.8 Hz, 1H, H-4), 6.78 (dd, J = 8.5 Hz,
Compound 15. Following the general procedure a mixture of 13
2.8 Hz, 1H, H-2), 5.62 (s, 2H, NCH ), 5.23 (s, 2H, OCH ), 4.17 (s,
2
2
(
320 mg, 0.21 mmol, 1.00 equiv) and Me OBF (161 mg, 1.09 mmol,
3H, NCH ), 2.93−2.89 (m, 2H, H-6), 2.50 (dd, J = 18.3 Hz, 8.3 Hz,
3
4
3
1
1177
DOI: 10.1021/acs.inorgchem.5b01524
Inorg. Chem. 2015, 54, 11174−11185

Inorganic Chemistry
Article
1
0
1
1
H), 2.40−2.35 (m, 1H), 2.28−1.90 (m, 5H), 1.68−1.25 (m, 6H),
(s, 4H, Ar), 7.22 (d, J = 8.6 Hz, 2H, H-1), 6.83 (d, J = 2.6 Hz, 2H, H-
.90 (s, 3H, H-18). 13C NMR (100 MHz, CDCl ): δ 221.0 (CO, C-
4), 6.79 (dd, J = 8.5 Hz, 2H, H-2), 5.59 (s, 4H, NCH ), 5.21 (s, 4H,
3
2
7), 159.8 (C, N CCAu), 154.9 (C, C-3), 142.5 (C, N CCAu),
OCH ), 4.21 (s, 6H, NCH ), 2.93−2.91 (m, 4H, H-6), 2.15 (dd, J =
3
3
2
3
38.6 (C, C-5), 133.9 (C, Ar), 133.4 (C, C-10), 129.4 (CH, Ar), 129.2
18.8 Hz, 8.6 Hz, 2H), 2.39−2.32 (m, 2H), 2.27−1.95 (m, 10 H),
13
(
1
2CH, Ar), 129.1 (2CH, Ar), 126.9 (CH, C-1), 114.7 (CH, C-4),
12.7 (CH, C-2), 59.7 (OCH ), 59.1 (NCH ), 50.5 (CH, C-14), 48.1
1.65−1.48 (m, 12H), 0.91 (s, 6H, H-18). C NMR (125 MHz,
CDCl ): δ 220.8 (2CO, C-17), 159.4 (2C, N CCAu), 154.8 (2C,
2
2
3
3
(
C, C-13), 44.1 (CH, C-9), 38.4 (NCH ), 37.8 (CH, C-8), 36.0 (CH ,
C-3), 142.6 (2C, N CCAu), 138.4 (2C, C-5), 134.4 (2C, Ar), 133.8
3
2
3
C-16), 31.7 (CH , C-12), 29.8 (CH , C-6), 26.6 (CH , C-7), 26.0
(2C, C-10), 129.6 (4CH, Ar), 126.8 (2CH, C-1), 114.5 (2CH, C-4),
112.5 (2CH, C-2), 59.6 (2OCH ), 58.2 (2NCH ), 50.4 (2CH, C-14),
2
2
2
(
CH , C-11), 21.7 (CH , C-15), 14.0 (CH , C-18). IR (KBr): ν
2 2 3 max
2
2
3
[
436, 2927, 1733, 1607, 1497, 1454, 1230, 1157, 1055, 1026, 750, 708.
48.0 (2C, C-13), 43.9 (2CH, C-9), 38.2 (NCH ), 37.8 (2CH, C-8),
3
α]D25 + 58.64 (c 0.22, CHCl ). MS (ES) m/z calculated for
35.8 (2CH , C-16), 31.5 (2CH , C-12), 29.7 (2CH , C-6), 26.4
3
2
2
2
+
C H N O AuCl: 688.2000 [M + H] ; found 688.1832. For
C H N O AuCl: 705.2265 [M + NH ] ; found 705.2298. For
C H N O AuClNa: 710.1819 [M + Na] ; found 710.1859. mp:
(2CH , C-7), 25.9 (2CH , C-11), 21.6 (2CH , C-15), 13.8 (2CH , C-
2
9
34
3
2
2 2 2 3
+
18). MS (ES) m/z calculated for C H N O Au Cl: 1261.3690 [M −
+
29
37
4
2
4
52 60
6
4
2
+
Cl] ; found 1261.3747. mp: decomposes before melting.
29
33
3
2
decomposes before melting.
Compound 8a. Following the general procedure a mixture of 7a
Compound 12. Following the general procedure a mixture of 10
(70 mg, 0.05 mmol, 1.00 equiv), NMe Cl (23 mg, 0.21 mmol, 4.50
4
(
35 mg, 0.03 mmol, 1.00 equiv), NMe Cl (11 mg, 0.10 mmol, 3.00
equiv), and Ag O (25 mg, 0.11 mmol, 2.25 equiv) in MeCN:CH Cl
4
2
2
2
equiv), and Ag O (12 mg, 0.05 mmol, 1.50 equiv) in MeCN:CH Cl
(48 mL) was stirred under Ar at rt for 3 days. [AuCl(SMe )] (42 mg,
0.14 mmol, 3.00 equiv) was added, and the reaction was stirred for two
2
2
2
2
(
8 mL) was stirred under Ar at rt for 3 days. [AuCl(SMe )] (20 mg,
2
0
.07 mmol, 2.00 equiv) was added, and the reaction mixture was
more hours. The resulting residue was purified (SiO , Hex/AcOEt,
1:9) to yield 12 as a white solid (27 mg, 30%). H NMR (400 MHz,
2
1
stirred for two more hours. The resulting residue was purified (SiO ,
MeOH/CH Cl , 1%) to yield 8a as a white solid (33 mg, 71%). H
NMR (500 MHz, CDCl ): δ 7.43 (s, 4H, Ar), 7.21 (d, J = 8.6 Hz, 2H,
2
1
CDCl ): δ 7.62 (s, 3H, Ar), 7.21 (d, J = 8.5 Hz, 3H, H-1), 6.84−6.80
2
2
3
(m, 6H, H-2 y H-4), 5.58 (s, 6H, NCH ), 5.30 (s, 6H, OCH ), 4.26 (s,
3
2
2
H-1), 6.83 (d, J = 2.7 Hz, 2H, H-4), 6.79 (dd, J = 8.6 Hz, 2.8 Hz, 2H,
9H, NCH ), 2.93−2.90 (m, 6H, H-6), 2.50 (dd, J = 18.9 Hz, 8.5 Hz,
3
H-2), 5.85 (s, 4H, NCH ), 5.26 (s, 4H, OCH ), 4.23 (s, 6H, NCH ),
3H), 2.40−2.33 (m, 3H), 2.27−1.91 (m, 15H), 1.67−1.38 (m, 18H),
2
2
3
2
.92−2.90 (m, 4H, H-6), 2.50 (dd, J = 18.8 Hz, 8.6 Hz, 2H), 2.40−
0.89 (s, 9H, H-18). 13C NMR (100 MHz, CDCl ): δ 221.0 (3CO,
3
2
.34 (m, 2H), 2.26−2.21 (m, 2H), 2.18−1.93 (m, 10 H), 1.67−1.39
C-17), 159.4 (3C, N CCAu), 155.2 (3C, C-3), 143.2 (3C, N C
3
3
(
(
m, 12H), 0.91 (s, 6H, H-18). 13C NMR (125 MHz, CDCl ): δ 220.8
CAu), 138.4 (3C, C-5), 135.6 (3C, Ar), 133.7 (3C, C-10), 128.9
(3CH, Ar), 126.8 (3CH, C-1), 114.8 (3CH, C-4), 112.7 (3CH, C-2),
59.9 (3OCH ), 57.7 (3NCH ), 50.5 (3CH, C-14), 48.1 (3C, C-13),
3
2CO, C-17), 160.1 (2C, N CCAu), 154.9 (2C, C-3), 142.8 (2C,
3
N CCAu), 138.4 (2C, C-5), 133.7 (2C, Ar), 131.9 (2C, C-10),
3
2
2
131.2 (2CH, Ar), 130.1 (2CH, Ar), 126.7 (2CH, C-1), 114.6 (2CH,
44.1 (3CH, C-9), 38.4 (3NCH ), 38.2 (3CH, C-8), 36.0 (3CH , C-
3
2
C-4), 112.6 (2CH, C-2), 59.8 (2OCH ), 56.1 (2NCH ), 50.4 (2CH,
16), 31.7 (3CH , C-12), 29.8 (3CH , C-6), 26.6 (3CH , C-7), 26.0
2 2 2
2
2
C-14), 48.0 (2C, C-13), 44.0 (2CH, C-9), 38.2 (NCH ), 38.0 (2CH,
(3CH , C-11), 21.7 (3CH , C-15), 14.0 (3CH , C-18). IR (KBr): ν
3
2 2 3 max
C-8), 35.8 (2CH , C-16), 31.5 (2CH , C-12), 29.6 (2CH , C-6), 26.4
3437, 2924, 1737, 1608, 1496, 1453, 1261, 1158, 1085, 1054, 1027,
2
2
2
(
1
1
2CH , C-7), 25.9 (2CH , C-11), 21.6 (2CH , C-15), 13.8 (2CH , C-
804. [α]D30 + 51.06 (c 0.63, CHCl ). MS (ES) m/z calculated for
2
2
2
3
3
+
8). IR (KBr): νmax 3436, 2926, 1736, 1611, 1496, 1453, 1230, 1163,
C H N O Au Cl : 1870.5147 [M − Cl] ; found 1870.5140. mp:
75
87
9
6
3
2
056, 1026, 751. [α]D25 + 62.89 (c 0.18, CHCl ). MS (ES) m/z
decomposes before melting.
3
+
calculated for C H N O Au Cl: 1261.3690 [M − Cl] ; found
1
Compound 14. Following the general procedure a mixture of 15
5
2
60
6
4
2
2+
261.3751. For C H N O Au : 613.1998 [M − 2Cl] ; found:
(200 mg, 0.10 mmol, 1.00 equiv), NMe Cl (68 mg, 0.62 mmol, 6.00
52
60
6
4
2
4
613.1979. mp: decomposes before melting.
equiv), and Ag O (72 mg, 0.31 mmol, 3.00 equiv) in MeCN:CH Cl
2
2
2
Compound 8b. Following the general procedure a mixture of 7b
(23 mL) was stirred under Ar at rt for 3 days. [AuCl(SMe )] (183 mg,
0.62 mmol, 6.00 equiv) was added, and the reaction was stirred for two
2
(
235 mg, 0.23 mmol, 1.00 equiv), NMe Cl (76 mg, 0.69 mmol, 3.00
4
equiv), and Ag O (81 mg, 0.35 mmol, 1.50 equiv) in MeCN:CH Cl
more hours. The resulting residue was purified (SiO , MeOH/CH Cl ,
0.5%) to yield 14 as a white solid (96 mg, 38%). H NMR (400 MHz,
2
2
2
2
2
2
1
(
50 mL) was stirred under Ar at rt for 3 days. [AuCl(SMe )] (135 mg,
2
0
.46 mmol, 2.00 equiv) was added and the reaction was stirred for two
CDCl ): δ 7.64 (s, 2H, Ar), 7.21 (d, J = 8.3 Hz, 4H, H-1), 6.83−6.81
3
more hours. The resulting residue was purified (SiO , CHCl ) to yield
(m, 8H, H-2 and H-4), 5.82 (s, 8H, NCH ), 5.33 (s, 8H, OCH ), 4.27
2
3
2
2
1
8
7
6
5
2
1
b as a white solid (273 mg, 91%). H NMR (400 MHz, CDCl ): δ
(s, 12H, NCH ), 2.93−2.90 (m, 8H, H-6), 2.51 (dd, J = 18.8 Hz, 8.6
3
3
.60 (s, 1H, Ar), 7.45−7.36 (m, 3H, Ar), 7.22 (d, J = 8.5 Hz, 2H, H-1),
Hz, 4H), 2.42−2.33 (m, 4H), 2.27−1.90 (m, 20H), 1.67−1.38 (m,
.87 (br s, 2H, H-4), 6.83 (br d, J = 2.8 Hz, H-2), 5.56 (s, 2H, NCH ),
24H), 0.90 (s, 12H, H-18). 13C RMN (100 MHz, CDCl ): δ 220.9
2
3
.41 (s, 2H, OCH ), 4.24 (s, 6H, NCH ), 2.94−2.90 (m, 4H, H-6),
(4CO, C-17), 159.9 (4C, N CCAu), 155.2 (4C, C-3), 143.5 (4C,
2
3
3
.50 (dd, J = 18.9 Hz, 8.6 Hz, 2H), 2.39−2.36 (m, 2H), 2.24−1.94 (m,
N CCAu), 138.5 (4C, C-5), 133.8 (4C, Ar), 133.5 (4C, C-10),
3
13
0 H), 1.67−1.24 (m, 12H), 0.90 (s, 6H, H-18). C NMR (100 MHz,
131.4 (2CH, Ar), 126.8 (4CH, C-1), 114.9 (4CH, C-4), 112.7 (4CH,
C-2), 60.0 (4OCH ), 54.4 (4NCH ), 50.5 (4CH, C-14), 48.1 (4C, C-
CDCl ) δ 221.0 (2CO, C-17), 159.9 (2C, N CCAu), 155.3 (2C,
3
3
2
2
C-3), 143.3 (2C, N CCAu), 138.4 (2C, C-5), 134.9 (2C, Ar), 133.6
13), 44.1 (4CH, C-9), 38.4 (4NCH and 4CH, C-8), 36.0 (4CH , C-
3
3
2
(
2C, C-10), 129.7 (CH, Ar), 128.2 (2CH, Ar), 126.8 (2CH, C-1),
16), 31.7 (4CH , C-12), 29.8 (4CH , C-6), 26.6 (4CH , C-7), 26.1
2 2 2
1
5
3
1
26.0 (CH, Ar), 114.9 (2CH, C-4), 112.7 (2CH, C-2), 60.0 (2OCH2),
(4CH , C-11), 21.7 (4CH , C-15), 14.0 (4CH , C-18). IR (KBr): ν
2 2 3 max
7.7 (2NCH ), 50.5 (2CH, C-14), 48.1 (2C, C-13), 44.1 (2CH, C-9),
3447, 2927, 1736, 1607, 1577, 1607, 1496, 1453, 1231, 1161, 1084,
2
8.4 (NCH ), 38.1 (2CH, C-8), 36.0 (2CH , C-16), 31.7 (2CH , C-
1055, 1026, 1007, 842. [α]D25 + 41.61 (c 0.31, CHCl ). MS (ES) m/z
3
2
2
3
+
2), 29.8 (2CH , C-6), 26.6 (2CH , C-7), 26.0 (2CH , C-11), 21.7
calculated for C H N O Au Cl : 2481.6612 [M − Cl] ; found
2
2
2
98 114 12
8
4
3
(
1
2CH , C-15), 14.0 (2CH , C-18). IR (KBr) ν 3436, 2925, 1736,
609, 1496, 1452, 1232, 1085, 753. [α]D + 37.08 (c 0.25, CHCl ).
2481.6749. mp: decomposes before melting.
2
3
max
25
Compound 19. Following the general procedure a mixture of 16
3
+
MS (ES) m/z calculated for C H N O Au Cl: 1261.3690 [M − Cl] ;
found 1261.3727. mp: decomposes before melting.
(100 mg, 0.05 mmol, 1.00 equiv), NMe Cl (31 mg, 0.14 mmol, 6.00
52
60
6
4
2
4
equiv) and Ag O (33 mg, 0.14 mmol, 3.00 equiv) in MeCN:CH Cl
2
2
2
Compound 8c. Following the general procedure a mixture of 7c
(11 mL) was stirred under Ar at rt for 3 days. [AuCl(SMe )] (55 mg,
0.19 mmol, 4.00 equiv) was added, and the reaction was stirred for two
2
(
200 mg, 0.198 mmol, 1.00 equiv), NMe Cl (65 mg, 0.59 mmol, 3.00
4
more hours. The resulting residue was purified (SiO , MeOH/CH Cl ,
0.5%) to yield 19 as a white solid (63 mg, 50%). H NMR (400 MHz,
2
2
2
2
2
2
1
0
.07 mmol, 2.00 equiv) was added, and the reaction was stirred for two
CDCl ): δ 7.37−7.31 (m, 8H, Ar), 7.10 (d, J = 8.6 Hz, 4H, H-1), 6.80
3
more hours. The resulting residue was purified (SiO , CHCl ) to yield
8
(dd, J = 8.6 Hz, 2.8 Hz, 4H, H-2), 6.75 (d, J = 2.8 Hz, 4H, H-4), 5.81
(d, 8H, NCH ), 5.25 (d, J = 3.2 Hz, 8H, OCH ), 4.23 (s, 12H,
2
3
1
c as a white solid (32 mg, 13%). H NMR (500 MHz, CDCl ): δ 7.45
3
2
2
1
1178
DOI: 10.1021/acs.inorgchem.5b01524
Inorg. Chem. 2015, 54, 11174−11185

Inorganic Chemistry
Article
Scheme 3
+
NCH ), 2.76−2.56 (m, 8H), 2.29−2.22 (m, 8H), 2.09−2.03 (m, 4H),
MS (ES) m/z calculated for C H N O Ag: 1019.4200 [M − BF ] ;
3
58 66
6
4
4
1
.97−1.89 (m, 4H), 1.83−1.60 (m, 20H), 1.44−1.14 (m, 20H), 0.80
found:1019.4216. mp: decomposes before melting.
Compound 9a. Following the general procedure, a mixture of 7a
(163 mg, 0.16 mmol, 1.00 equiv), NMe Cl (53 mg, 0.49 mmol, 3.00
equiv), and Ag O (56 mg, 0.24 mmol, 1.50 equiv) in MeCN:CH Cl
2
(17 mL) was stirred under Ar at rt for 3 days. The reaction was filtered
through a pad of Celite, and the solvent was removed under vacuum to
yield 9a as a white solid (76 mg, 46%). H NMR (300 MHz, CDCl ):
δ 7.47 (s, 8H, Ar), 7.21 (d, J = 8.1 Hz, 4H, H-1), 6.78−6.54 (m, 8H,
H-2 y H-4), 5.77 (s, 8H, NCH ), 5.21 (s, 8H, OCH ), 4.22 (s, 12H,
(
s, 12H, H-18). 13C NMR (100 MHz, CDCl ): δ 159.1 (4C, N C
3
3
CAu), 153.4 (4C, C-3), 142.8 (4C, N CCAu), 138.6 (4C, C-5),
4
3
1
1
1
1
32.5 (4C, C-10), 131.2 (4C, Ar), 130.3 (8CH, Ar), 126.8 (4CH, C-
), 116.3 (4CH, C-4), 113.2 (4CH, C-2), 83.7 (4C, CC), 80.7 (C-
7), 70.3 (4C, CC), 59.0 (4OCH ), 55.7 (4NCH ), 50.1 (4CH, C-
2
2
2
2
1
4), 48.2 (4C, C-13), 44.0 (4CH, C-9), 40.0 (4CH, C-8), 39.3 (4CH ,
3
2
C-16), 38.1 (4NCH ), 33.3 (4CH , C-12), 29.8 (4CH , C-6), 27.4
3
2
2
(
4CH , C-7), 26.3 (4CH , C-11), 22.8 (4CH , C-15), 12.3 (4CH , C-
2
2
2
2
2
3
NCH ), 2.92−2.88 (m, 8H, H-6), 2.51 (dd, J = 18.3 Hz, 8.4 Hz, 4H),
1
1
2
8). IR (KBr): νmax 3435, 2929, 1610, 1455, 1378, 1250, 1140, 1109,
3
2
.40−2.35 (m, 4H), 2.28−1.94 (m, 20H), 1.67−1.43 (m, 24H), 0.91
088, 1047, 842. MS (ES) m/z calculated for C112H124N O Au Cl :
12
8
4
3
+
(s, 12H, H-18). The compound was unstable and correct MS data
could not be registered.
657.7387 [M − Cl] ; found 2657.7465. mp: decomposes before
melting.
General Procedure for the Synthesis of Silver Carbenes. In a
Compound 9b. Following the general procedure, a mixture of 7b
250 mg, 0.25 mmol, 1.00 equiv), NMe Cl (81 mg, 0.74 mmol, 3.00
(
4
Schlenk tube charged with 4 Å molecular sieves a mixture of triazolium
equiv), and Ag O (86 mg, 0.15 mmol, 1.50 equiv) in MeCN:CH Cl
2
2
2
salt (1.00 equiv), NMe Cl (1.50 equiv per triazole) and Ag O (0.75
4
2
(
55 mL) was stirred under Ar at rt for 3 days. The reaction was filtered
equiv per triazole) was stirred at rt in dark in MeCN:CH Cl (1:1)
2
2
1
through a pad of Celite and the solvent was removed under vacuum to
until the reaction was completed ( H RMN analysis). The reaction
was filtered through a pad of Celite and the solvent was removed
under vacuum to afford the corresponding reaction products.
Compound 4. Following the general procedure, a mixture of 3 (270
yield 9b as a white solid (163 mg, 63%). 1H NMR (300 MHz,
CDCl ): δ 7.53 (s, 2H, Ar), 7.49−7.39 (m, 6H, Ar), 7.20 (d, J = 8.6
3
Hz, 4H, H-1), 6.81−6.72 (m, 8H, H-2 y H-4), 5.54 (s, 8H, NCH ),
2
5
2
2
.28 (s, 8H, OCH ), 4.23 (s, 12H, NCH ), 2.92−2.82 (m, 8H, H-6),
2
3
mg, 0.50 mmol, 1.00 equiv), NMe Cl (82 mg, 0.75 mmol, 1.50 equiv),
4
.51 (dd, J = 18.4 Hz, 8.2 Hz, 4H), 2.40−2.35 (m, 4H), 2.27−1.90 (m,
and Ag O (86 mg, 0.37 mmol, 0.75 equiv) in MeCN:CH Cl (26 mL)
13
2
2
2
0H), 1.68−1.35 (m, 24H), 0.90 (s, 12H, H-18). C NMR (100
was stirred under Ar at rt for 24 h. The reaction was filtered through a
MHz, DMSO-d ): δ 219.7 (4CO, C-17), 165.1 (4C, N CCAg)
6
3
pad of Celite, and the solvent was removed under vacuum to yield 4 as
1
55.3 (4C, C-3), 144.1 (4C, N CCAg), 137.6 (4C, C-5), 135.6 (4C,
1
3
a white solid (272 mg, 98%). H NMR (400 MHz, CDCl ): δ 7.37−
3
Ar), 132.8 (4C, C-10), 129.6 (2CH, Ar), 128.6 (6CH, Ar), 126.3
7
.30 (m, 10H, Ar), 7.18 (d, J = 8.4 Hz, 2H, H-1), 6.75 (dd, J = 8.4 Hz,
(
4CH, C-1), 114.8 (4CH, C-4), 112.6 (4CH, C-2), 60.2 (4OCH2),
7.7 (4NCH ), 49.6 (4CH, C-14), 47.3 (4C, C-13), 43.4 (4CH, C-9),
37.8 (4NCH ), 37.0 (4CH, C-8), 35.4 (4CH , C-16), 31.4 (4CH , C-
2), 29.2 (4CH , C-6), 26.0 (4CH , C-7), 25.5 (4CH , C-11), 21.2
2 2 2
4CH , C-15), 13.5 (4CH , C-18). IR (KBr): ν 3445, 2927, 1736,
1607, 1497, 1453, 1311, 1232, 1158, 1055, 818. [α]D + 53.19 (c 0.78,
CHCl ). MS (EI) m/z calculated for C H N O Ag: 939.3729 [M −
J = 2.9 Hz, 2H, H-2), 6.72 (d, J = 8.9 Hz, 2H, H-4), 5.54 (s, 4H,
NCH ), 5.15 (s, 4H, OCH ), 4.18 (s, 6H, NCH ), 2.88−2.85 (m, 4H),
5
2
2
2
3
3
2
2
2
.49 (dd, J = 18.8 Hz, J = 8.4 Hz, 2H), 2.38−2.33 (m, 2H), 2.23−1.88
1
13
(
m, 12H), 1.65−1.34 (m, 10H), 0.88 (s, 6H, H-18). C NMR (100
(
2 3 max
́
MHz, CDCl ): δ 220.9 (2CO,C-17), 166.5 (2C, N CCAg), 155.2
25
3
3
(
1
1
2C, C-3), 144.1 (2C, N CCAg), 138.4 (2C, C-5), 134.0 (2C, Ar),
3
3
52 60
6
4
+
33.7 (2C, C-10), 129.2 (5CH, Ar), 128.7 (5CH, Ar), 126.8 (2CH, C-
BF ] ; found 941.3720. mp: decomposes before melting.
4
), 114.8 (2CH, C-4), 112.5 (2CH, C-2), 60.6 (2OCH ), 59.6
Compound 9c. Following the general procedure, a mixture of 7c
(250 mg, 0.25 mmol, 1.00 equiv), NMe Cl (82 mg, 0.75 mmol, 3.00
2
(
(
2
2NCH ), 50.4 (2CH, C-14), 48.0 (2C, C-13), 44.0 (2CH, C-9), 38.3
2
4
2CH, C-8), 37.2 (2NCH ), 35.9 (2CH , C-16), 31.6 (2CH , C-12),
equiv), and Ag O (86 mg, 0.15 mmol, 1.50 equiv) in MeCN:CH Cl
3
2
2
2
2
2
9.7 (2CH , C-6), 26.5 (2CH , C-7), 25.9 (2CH , C-11), 21.6 (2CH ,
(55 mL) was stirred under Ar at rt for 3 days. The reaction was filtered
2
2
2
2
C-15), 13.9 (2CH , C-18). IR (KBr): ν 3437, 2927, 1736, 1607,
through a pad of Celite and the solvent was removed under vacuum to
3
max
2
5
1
1497, 1455, 1232, 1055, 819, 721. [α]D + 67.19 (c 0.775, CHCl3).
yield 9c as a white solid (243 mg, 95%). H NMR (400 MHz, CDCl ):
3
1
1179
DOI: 10.1021/acs.inorgchem.5b01524
Inorg. Chem. 2015, 54, 11174−11185

Inorganic Chemistry
Article
δ 7.44 (s, 8H, Ar), 7.21 (d, J = 8.4 Hz, 4H, H-1), 6.77−6.72 (m, 8H,
Scheme 4
H-2 y H-4), 5.54 (s, 8H, NCH ), 5.17 (s, 8H, OCH ), 4.20 (s, 12H,
2
2
NCH ), 2.91−2.88 (m, 8H, H-6), 2.50 (dd, J = 18.7 Hz, 8.6 Hz, 4H),
3
2
.40−2.33 (m, 4H), 2.26−1.91 (m, 20H), 1.67−1.37 (m, 24H), 0.90
(
1
s, 12H, H-18). 13C NMR (100 MHz, CDCl ): δ 221.0 (4CO, C-
3
7), 165.9 (4C, N CCAg), 155.3 (4C, C-3), 144.3 (4C, N C
3
3
CAg), 138.5 (4C, C-5), 135.1 (4C, C−Ar), 133.9 (4C, C-10), 129.9
(
8CH, Ar), 126.9 (4CH, C-1), 114.7 (4CH, C-4), 112.6 (4CH, C-2),
0.8 (4OCH ), 59.0 (4NCH ), 50.5 (4CH, C-14), 48.1 (4C, C-13),
2 2
4.1 (4CH, C-9), 38.4 (4NCH ), 37.4 (4CH, C-8), 36.0 (4CH , C-
3
2
6), 31.7 (4CH , C-12), 29.8 (4CH , C-6), 26.6 (4CH , C-7), 26.0
2
2
2
2 2 3 max
3
436, 2928, 1736, 1609, 1492, 1232, 1084, 1054, 949, 759. MS (EI)
+
accounting for the molecular formula C H N O AuCl, which
29 32 3 2
19
m/z calculated for C104H120N O Ag BF : 1965.7493 [M − BF ] ;
found 1965.7491. mp: decomposes before melting.
12
8
2
4
4
is in accordance with the proposed structure 5 (Scheme 4).
Having demonstrated the compatibility of the reaction
conditions to form both the silver and gold carbene complexes
with the steroid nucleus, the synthesis of bis-carbene complexes
was addressed next. Thus, bis-steroids 6a, 6b, and 6c tethered
by o-, m- and p-phenyl bis-triazole bridges were prepared and
subsequently dimethylated (Me OBF ) in essentially quantita-
General Procedure for Catalytic Studies. Gold carbene (0.002
mmol, 0.01 equiv) and AgSbF6 (0.002 mmol, 0.01 equiv) was
dissolved in 1 mL of the CDCl under Ar and stirred for 15 min at rt.
3
Alcohol (1.80 mmol, 10 equiv) was added followed by ethyl-
phenyldiazoacetate (0.18 mmol, 1.00 equiv) dissolved in 1 mL of
CDCl . The reaction mixture was stirred at rt.
3
3
4
Computational Details. All calculations were carried at the DFT
1
0
11
tive yields (Scheme 5). The dimethylated salts (7a−c) were
level using the M06 functional with an ultrafine grid as
12
reacted with Ag O (1.50 equiv) in the presence of NMe Cl in a
2
4
implemented in Gaussian09. This functional accounts for dispersion
mixture of MeCN:CH Cl (1:1). The putative silver carbene
interactions and performs with good accuracy in transition-metal
2
2
13
complexes were treated with 2 equiv of [AuCl(SMe )], forming
chemistry. The geometries of compounds 9a and 9a′ were optimized
2
using basis set I (BS-I). With BS-I, the non metal atoms were
the corresponding gold bis-carbenes (8a−c) in 71%, 63%, and
13% yields, respectively. While the yields in bis-carbenes 8a−b
were good, the yield of the p-tethered bis-carbene 8c drops
dramatically (13%). Compound 8c decomposes to form a
purple solid (that we preliminarily attribute to the formation of
gold nanoparticles). The reasons for this anomaly are still
unknown.
14
described with the 6-31G(d,p) basis set, whereas Ag and Au were
15
described with the SDD double-ζ basis set, complemented with a set
16
of f-polarization functions.
RESULTS AND DISCUSSION
■
To demonstrate the viability of preparing steroid based silver
and gold carbene complexes, the alkynyl derivative of estrone 1
was reacted with benzyl azide forming the triazole derivative 2
in 89% yield. Methylation (Me OBF ) occurred uneventfully in
The structures of the gold carbenes 8a−c were established
1
13
according to their NMR and MS spectra. H and C NMR
showed signals attributable to half of the molecule, which is a
consequence of their C2 symmetry. In addition to the
characteristic signals of the steroid fragments, signals for the
aromatic joint were observed (see Experimental Section). As in
the case of the simple gold monocarbene 5, with the exception
of those of the ketone group, carbons carrying the metal are the
most deshielded ones, appearing around 160 ppm. Finally, for
the three isomers, the HRMS spectra showed peaks
corresponding to the fragmentation of one Cl−Au bond, as
well as the double charged peaks as the result of the
fragmentation of the two Cl−Au bonds. Therefore, HRMS
analysis provides a molecular formula of C H N O Au Cl for
3
4
nearly quantitative yield at the N3 of the triazole nucleus, and
the resulting salt 3 was submitted to treatment with Ag O in
2
the presence of NMe Cl in a mixture of MeCN:CH Cl (1:1)
4
2
2
forming the silver bis-carbene 4 in 98% yield. Compound 4 was
1
13
unstable but it could be characterized ( H, C and HRMS, see
the Experimental Section). Silver carbene formation was
evidenced by the disappearance of the triazolium CH signal
1
in the H RMN spectra (3, δ = 8.63 ppm) and the appearance
1
3
of a low field shifted signal in the C NMR (3: δ = 129.5 ppm;
17
4
, δ = 166.5 ppm). HRMS obtained under ESI conditions
yield a peak at m/z = 1019.4216 which corresponds to the
52
62
6
4
2
2
+
molecular formula [C H N O Ag] . Besides the isotopic
the three isomers and supports the proposed structures 8a, 8b,
and 8c for these compounds (Scheme 5).
With the synthesis of gold bis-carbene complexes 8a−c
performed, we pursued the isolation and characterization of the
intermediate silver carbene complexes. Being aware of the
instability of such complexes o-, m-, and p-bridged bistriazole
5
8
66
6
4
composition of the molecular peak matches the theoretical
1
8
one. Therefore, the silver carbene 4 must be formed by two
estrone-derived triazolylidene fragments [(Trz )Ag], having the
2
structure represented by formula 4 (Scheme 3).
The stable gold monocarbene 5 was obtained in a one-pot
reaction without isolation of the intermediate silver carbene 4
by reacting salt 3 with Ag O in the presence of NMe Cl and 4
derivatives 7a−c were reacted in the dark with Ag O (1.5
2
equiv) in the presence of NMe Cl and 4 Å molecular sieves in a
2
4
4
Å MS, in a mixture of MeCN:CH Cl (1:1) with air exclusion,
mixture of CH CN:CH Cl (1:1), with exclusion of air. The
2
2
3
2
2
followed by treatment with [AuCl(SMe) ]. Compound 5 was
corresponding silver carbene complexes 9a−c were isolated in
2
obtained in 86% isolated yield (Scheme 4). The structure of
46%, 63% and 95% yields, respectively. Interestingly, except for
1
20
compound 5 was established by spectroscopic means. Its H
the ortho derivative 9a, which was unstable, carbenes 9b and
and 13C NMR spectra show signals attributable to the estrone
and benzylic fragments. The NMR spectra of complex 5 were
almost identical to the silver carbene 4, being the major
difference the chemical shift of the carbene carbon, which
appeared high field shifted with respect to silver carbene (5, δ =
9c were stable enough for full spectroscopic characterization
1
(Scheme 6). H NMR spectra of the silver carbenes were
devoid of signals attributable to any triazolium proton (7b, δ =
13
8.55 ppm; 7c, δ = 9.08 ppm), and the C NMR showed a new
signal (9b, δ = 165.2 ppm; 9c, δ = 165.9 ppm) identifiable to
the carbene carbon, instead of the signal due to the CH carbon
of the triazolium precursor (7b, δ = 130.1 ppm; 7c, δ = 129.6
1
59.8 ppm, Δδ = +6.7). In addition the HRMS spectra of 5
+
shows a molecular peak at m/z 688.1832 ([M + H] ),
1
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Article
Scheme 5
Scheme 6. Ratio of 9c/9c′ was 3/2 Determined by Analysis of the Molecular Cluster of the HRMS Spectra
ppm). Respecting to the coordination of the Ag(I) carbenes,
On the contrary, HRMS of the carbene 9c showed two peaks
HRMS of 9b showed a main fragment at m/z = 941.3720 [M-
in accordance with the existence of two species. One of them
+
BF ] , which is consistent for a monometallic charged silver
fits with the charged bimetallic carbene represented by
4
+
complex incorporating one molecule of bis-triazole, as
represented by formula 9b (Scheme 6).
structure 9c′, since one peak at m/z = 1965.7491 [M-BF ] ,
4
accounting for the molecular formula [C1 H N O Ag BF
04 120 12 8 2 4
1
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+
2+
Figure 1. Experimental (left) and theoretical (right) isotopical distribution of peaks [(steroid)Ag] /[(steroid) Ag ] of 9c:9c′ (3:2).
2
2
]+
m/z = 940.3802 [M-2BF ] , corresponding to the radical ion
was detected. In addition, a double charged peak appeared at
the triazole-Ag-triazole array (C−Ag−C = 173.57°), while
complex 9b′ shows a slightly distorted array with respect to 9b
for one triazole-Ag-triazole arrangement (C−Ag−C = 169.75°).
In addition, the array in the first triazole moiety imposes a bent
geometry for the second triazole-Ag-triazole array (C−Ag−C =
151.78°), which undoubtedly decreases the overall stability of
21
2
+
4
2
+
with molecular formula [C104H120N O Ag ] . Interestingly,
12
8
2
one additional cluster of peaks appeared at m/z = 941.3000,
which can be attributed to the single charged species
+
[
(
C H N O Ag] having the structure represented by 9c
52
60
6
4
22
2
1
the silver-steroid tretramer 9b′.
Scheme 6).
The theoretical isotopical distribution of the molecular
cluster of the ESI-HRMS for peaks corresponding to 9c
(estrone)Ag] and 9c′ [(estrone) Ag ] is shown in Figure 1.
As it can be clearly seen in Figure 1 the simulated molecular
cluster for a mixture 9c:9c′ (3:2) perfectly matches with the
experimental spectrum
An analogous DFT computational study carried out in the
gold complex 8a, now having an ortho-disposition, shows a
conventional structure in which each carbene is acting as a
ligand of the Au(I) nuclei (see Supporting Information).
The methodology developed above was next tested for C3-
symmetric tris-triazole and C -symmetric tetra-triazole estrone
+
2+
[
2
2
2
derivatives. Methylated tris-triazolylidene 10 was prepared from
triazole 11 by methylation under the usual conditions (to
complete the reaction 24 h were needed), and submitted to the
sequence Ag O/NMe Cl in a mixture of MeCN:CH Cl (1:1)
Computational calculations (DFT) were carried out to gain
some insight into the formation and the structure of the silver
complexes 9. Calculations were performed using the actual
monosilver 9b and bis-silver complexes 9b′ without simplifi-
cations in the steroidic ligand framework (see the Experimental
Section). It may look easier to form a dimeric dimetallic
carbene like 9b′ than the apparently distorted monometallic
2
4
2
2
followed by transmetalation with [AuCl(SMe )] (3 equiv). The
Au(I) tris-carbene complex 12 was obtained in 30% yield
2
(
Scheme 7).
The C
tetrametallic gold carbene 14 by the two-step procedure
Scheme 8). Methylation of 13 (Meerwein’s salt) yielded 15
2
1
tetra-triazole 13 yielded the corresponding
2
complex 9b. However, as it can be seen in Figure 2, the
monometallic carbene 9b shows a nearly linear arrangement for
(
quantitatively, yet longer reaction times were needed.
Submission of 15 to Ag O/NMe Cl in a mixture of
2
4
MeCN:CH Cl (1:1) followed by transmetalation with [AuCl-
2
2
(
SMe )] (4 equiv) afforded 14 in 38% yield (Scheme 8).
2
The crude products of the reactions for carbenes 12 and 14
1
show clean H NMR spectra attributable to the presence of
single products. However, extensive decomposition (with the
formation of black material, probably due to colloidal gold) was
1
13
observed during column chromatography. H and C NMR
spectra were in accordance with the proposed structures. In
addition the HRMS spectra showed peaks for the positively
charged radicals corresponding to the molecular formulas
+
+
[
C H N O Au Cl ] and [C H N O Au Cl ] for the tri-
75 87 9 6 3 2 98 114 12 8 4 3
and tetrametallic carbenes 12 and 14, respectively (Schemes 7
and 8). The experimental molecular clusters of the ESI-mass
spectra were congruent with the theoretical isotopical
distribution (see the Supporting Information).
Finally, the preparation of a giant macrocycle containing four
gold carbene ligands was attempted. Thus, compound 16 was
prepared by methylation of the per-O-silylated derivative 17,
since the direct methylation of 18 produced the concomitant
but not quantitative methylation of the hydroxy groups.
Compound 17 was accessed from 18 by reaction with
Figure 2. Computed structures of 9b and 9b′. Selected angles: (9)
C6−Ag63−C29 = 173.57°; (9b′) C100−Ag63−C12 = 169.75°; C76−
Ag64−C36 = 151.78°.
TMSOTf/Et N (quantitative yield). Methylation of 17 using
3
1
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Scheme 7. Preparation of C -Symmetric Tris-triazole Estrone Derivatives
3
Scheme 8. Preparation of C -Symmetric Tris-triazole
Estrone Derivatives
respectable 50% yield upon purification by flash chromatog-
raphy (Scheme 9). The structure of 19 was confirmed by
2
1
13
spectroscopic means. The H and C NMR spectra showed a
single set of signals for the estrone and the aromatic fragments.
In addition, the presence of the gold carbene moieties is
demonstrated by the absence of signals due to the triazolium
protons (16, δ = 8.84 ppm) and the presence of a signal in the
13
19
C NMR at 159.1 ppm. In addition, a peak at m/z =
2
657.7465 was detected in the HRMS spectra that matches the
+
molecular formula [C112H124N O Au Cl ] . Therefore, the
12
8
4
3
tetrametallic structure represented by 16 was assigned to the
macrocyclic tetrametallic carbene. To the best of our
knowledge this is the first macrocyclic structure based on
23
natural products containing a polymetallic carbene feature.
Once the methodology to obtain M-steroid derived (M = Ag,
Au) mono- and polymetallic 1,2,3-triazolylidene carbenes,
containing up to four metals in their structures and having
different geometries was established, their role as catalysts of
several model reactions was tested. It is well established that
Au-NHC catalyze the transfer of the carbene moiety of diazo
compounds to a nucleophile, avoiding the formation of the
24
homocoupling products. Therefore, we tested gold carbene 5
in the reactions of ethylphenyldiazoacetate and alcohols. Thus,
ethyl phenyldiazoacetate (1 equiv) was reacted with excess of
MeOH (10 equiv) in the presence of 1 mol % (related to the
the Meerwein’s salt proportionates the tetramethylated
tetrazolium salt having the free alcohol in 90% yield (two
25
ester) of gold-carbene 5 and 1 mol % of AgSbF
. The reaction
6
steps from 18). Again, submission of macrocycle 16 to Ag O/
occurs instantaneously yielding quantitatively ethyl α-methox-
2
26
NMe Cl followed by transmetalation with [AuCl(SMe )]
yphenylacetate. Unfortunately, HPLC analysis using a chiral
4
2
27
yielded the tetracarbenic macrocycle 19 as a white solid in a
column shows no ee in the product. Similar results were
1
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Scheme 9
Therefore, 1 mol % of AgSbF per mol of diazoester efficiently
6
catalyzes these reactions. This strong catalytic activity may be
behind the absence of enantioselection observed in the
28,29
presence of gold carbene 5.
Interestingly, silver carbenes
do not show any catalytic activity.
CONCLUSIONS
■
A two-step synthesis of steroid-derived gold triazolylidene
carbene complexes has been developed. The method uses the
methylation of the triazole nucleus, followed by the treatment
of the triazolium salt with Ag O and [AuCl(SMe )]. Depending
2
2
on the initial structure of the triazole, mono-, bi-, tri-, and
tetrametallic gold complexes can be obtained. These gold
complexes are highly symmetric. The modification of the nature
of the azide can easily modify the symmetries and nuclearities
of the products obtained. Moreover, a tetrametallic gold
carbene embedded in a macrocylic stereoidal cavity (containing
four estrone nuclei) is available in an acceptable 50% yield. All
these compounds have been fully characterized using
spectroscopic techniques and HRMS.
Additionally, the intermediate silver carbene complexes have
been isolated and characterized in some cases. Therefore, silver
monocarbene 4 having two triazole-steroid ligands and single
bis-steroid-monotriazole ligand 9b and 9c, as well as bimetallic
carbene complex 9c′ containing four steroid nuclei and four
triazole ligands (two for each silver nucleus) were obtained by
reaction of the corresponding triazolium salts and Ag O. These
2
complexes are stable and have been characterized by
spectroscopic and HRMS techniques. DFT computational
calculations show that the mononuclear silver complex 9b has a
slightly distorted N−Ag−N bond, while the binuclear complex
9
b′ shows two different N−Ag−N bonds, the first of them is
slightly distorted but imposing geometric constrains resulted in
a strong distortion to the second N−Ag−N bond.
Some of these compounds have been tested as catalysts in
the insertion of diazoalkanes into alcohols, demonstrating that
silver salt are much more active than the gold carbenes. These
preliminary results are promising and subsequent research to
use these complexes as chiral catalysts is underway in our
laboratories. Finally, the gold and silver complexes synthesized
through this work are unprecedented in the literature. Although
at this moment is speculative, the biological activity as tumor
grown inhibitors of these compounds might be interesting.
obtained when ethanol, isopropanol, tert-butanol, and ciclohex-
anol were used (Scheme 10).
The reaction of ethyl phenyldiazoacetate and MeOH (10
equiv) in the conditions used above but in the absence of the
gold carbene 5, also occurs instantaneously (Scheme 10).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.5b01524.
■
*
S
Computational details, and proton and carbon NMR
spectra for all synthesized compounds (PDF)
Scheme 10
AUTHOR INFORMATION
Corresponding Authors
E-mail: mc.delatorre@csic.es.
E-mail: sierraor@ucm.es.
■
*
*
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
1
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Article
A.; Mueller-Bunz, H.; Ohmatsu, K.; Ooi, T.; Albrecht, M. J. Am. Chem.
ACKNOWLEDGMENTS
■
Soc. 2013, 135, 13193.
Support for this work under grants (CTQ2013-46459-C2-01-P
to M.A.S., CTQ2013-46459-C2-02-P to M.C.T., and
CTQ2014-51912-REDC Programa Redes Consolider) from
the MINECO (Spain) is gratefully acknowledged. M.F.P.
thanks MINECO for a predoctoral FPI grant.
1
(20) For carbene 9a we could only get the H NMR spectrum.
(21) Crudden has reported the preparation of binuclear silver
mesoionic carbenes analogous to 9b′ and 9c′ containing two bis-
triazole ligands directly attached to the benzene ring in a meta
disposition. The absence of the methylene group favors the exclusive
formation of the symmetric dimeric structure having C−Ag−C bonds
of 173.9 (3). Obviously, the formation of structures referable to 9b or
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(
Ag(I) salts also catalyze the transfer ethylphenyldiazoacetate to
methanol in a 50% of conversion after 5 days of reaction at rt.
Again, no ee was obtained in these conditions.
(
(
(
5
(29) For a systematic study of the electronic and steric influence on
the catalytic activity of 1,3,4-trisubstituted-1,2,3-triazol-5-ylidene Au(I)
carbenes, see: Wright, J. R.; Young, P. C.; Lucas, N. T.; Lee, A.-L.;
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3
(
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(
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llwarth,
̈
(
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(
18) The comparison between the experimental and the simulated
molecular clusters for compounds 4, 5, 8a, 9b, 9c, 14, 15, and 19 can
be found in the Supporting Information.
(
19) (a) de Frem
́
ont, P.; Scott, M. N.; Stevens, E. D.; Nolan, S. P.
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ez, D.; Petronilho,
1
1185
DOI: 10.1021/acs.inorgchem.5b01524
Inorg. Chem. 2015, 54, 11174−11185