Asymmetric intermolecular cyclopropanation of alkenes and N–H insertion of aminoesters by diazoacetylferrocene catalyzed by ruthenium and iron porphyrins

Article abstract of DOI:10.1016/j.poly.2021.115294

The asymmetric addition of diazoacetylferrocene to styrene derivatives to give optically active cyclopropyl acetylferrocenes (ee up to 96%) was carried out using chiral ruthenium porphyrins as homogeneous catalysts. Intermolecular N–H functionalization of

Full text of DOI:10.1016/j.poly.2021.115294

Polyhedron 205 (2021) 115294
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Asymmetric intermolecular cyclopropanation of alkenes and N–H
insertion of aminoesters by diazoacetylferrocene catalyzed by
ruthenium and iron porphyrins
⇑
Daniel Carrié, Thierry Roisnel, Gérard Simonneaux
Univ Rennes, CNRS, ISCR-UMR 6226, F-35000, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric addition of diazoacetylferrocene to styrene derivatives to give optically active cyclo-
propyl acetylferrocenes (ee up to 96%) was carried out using chiral ruthenium porphyrins as homoge-
neous catalysts. Intermolecular N–H functionalization of anilines and amino esters by means of
carbenoid-induced N–H insertion was also observed using tetraphenylporphyrin iron chloride as catalyst.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 26 April 2021
Accepted 23 May 2021
Available online 28 May 2021
Dedicated to Paul Le Maux for his large
contribution in porphyrin chemistry.
Keywords:
Diazoacetacetylferrocene
Ruthenium porphyrins
Optically active cyclopropyl ketone
NH insertion
Chiral porphyrins
1
. Introduction
Since ferrocene discovery in 1951 [1], the chemistry of this
diazoacetonitrile [12] can be quite also efficient for in asymmetric
cyclopropanation. Surprisingly, if many of these diazo derivatives
have been proven to be efficient for asymmetric cyclopropanation
of styrenes, they have not been extended to diazoacetylferrocene.
Consequently, we examined herein the uses of ruthenium com-
plexes of optically active porphyrins (Fig. 1) as catalysts for inter-
molecular asymmetric cyclopropanation of styrene derivatives
with diazoacetylferrocene. N–H insertion of amino esters by dia-
zoacetylferrocene catalyzed by iron porphyrins was also explored
as possible application for bioconjugation of proteins.
organometallic molecule has been intensively investigated with
many applications in synthesis, materials [2] and medecine [3].
Remarkably, diazoacetylferrocene, first prepared by Regitz in
1
968 [4] and later by Toma [5] has been used more recently for
the preparation of ferrocenylketene [6,7]. Many other reactions
such as C–H insertion [8], palladium-mediated polymerization
[
9] and unsaturated ester synthesis [10] have been also reported
with various diazoferrocene derivatives.
Recent growth in the area of transition metal porphyrin chem-
istry has, in part, been driven by the increased interest associated
with metal-catalyzed carbene transfer reactions using diazo
derivatives [11]. Both asymmetric cyclopropanation [12] and N–
H insertion reactions [13,14] using such catalyts and diazo com-
pounds are now well developed. However, the use of organometal-
lic diazo derivatives is a new challenge in this field of research
because of the presence of a metal complex in the reagent. In the
course of our work on synthetic application of chiral metallopor-
phyrins [15], we also found that rarely used diazo derivatives such
as diazomethylphosphonate [16], trifluorodiazoethane [17] and
2
. Experimental section
2.1. General
All reactions were performed under argon. Solvents were dis-
tilled from an appropriate drying agent prior to use: CH
CaH . Commercially available reagents were used without further
purification unless otherwise stated. All reactions were monitored
by TLC with Merck precoated aluminum foil sheets (Silica gel 60
with fluorescent indicator UV254). Compounds were visualized
with UV light at 254 nm. Column chromatographies were carried
2 2
Cl from
2
1
out using silica gel from Merck (0.063–0.200 mm). H NMR and
1
3
⇑
Corresponding author.
E-mail address: gerard.simonneaux@univ-rennes1.fr (G. Simonneaux).
C NMR in CDCl
3
were recorded using Bruker (Advance 400dpx
spectrometer) at 400 MHz and 125 MHz, respectively. High
https://doi.org/10.1016/j.poly.2021.115294
277-5387/Ó 2021 Elsevier Ltd. All rights reserved.
0

D. Carrié, T. Roisnel and Gérard Simonneaux
Polyhedron 205 (2021) 115294
CO
Ru
CO
Ru
N
N
N
N
N
N
N
N
A
B
Cl
N
N
N
Fe
N
C
Fig. 1. Tetramesitylporphyrin ruthenium carbon monoxide (TMP)Ru(CO) (A), Chiral Halterman ruthenium porphyrin (B) and tetraphenylporphyrin iron chloride (FeTPPCl)
C).
(
resolution mass spectra were recorded on a Thermo-Fisher Q-Exac-
tive (Q-Tof 2) spectrometer in ESI positive mode at the CRMPO at
Rennes. Enantiomeric excesses were determined by chiral HPLC
room temperature. The reaction was stirred for 12 h. The solvent
was then removed under vacuum and the residue was chro-
matographied on preparative silica plates (dichloromethane) to
give ferrocenyl 2-phenylcyclopropyl Ketone (13.6 mg, 0.04 mmol)
(
Chiralpak IE, 70/30 heptane/ethanol).
(
53% yield).
2.2. Diazoacetylferrocene preparation
A solution of 200
wise (30 min) to 87 mmol of ferrocene carboxylic acid suspended
in CCl under argon. The mixture was stirred for 12 h. The solvent
ll (2.5 eq) of oxalyl chloride was added drop-
4
was then evaporated under vacuum to give quantitatively the
known ferrocenylacetyl chloride [6]. The solid was dissolved in
5
4
ml of CH
eq of TMSCHN
3
CN in presence of 1 eq of triethylamine. To this solution,
in hexane (2 N solution in hexane) was added
2
dropwise at 0 °C and stirred for 2 h at 0 °C and then 12 h at room
temperature. After evaporation of the solvent under vacuum, the
residue was chromatographied on silica gel plates (CH
2 2
Cl as elu-
ent) to give 94.3 mg diazoacetylferrocene (43% yield).
2.3. Cyclopropanation reaction
A solution of diazoacetylferrocene (20.4 mg, 0.08 mmole) in
.5 ml was added dropwise (45 min) to a 1 ml dichloromethane
solution of complex B (0.5 mg) and styrene (42 mg, 0.4 mmol) at
0
Ferrocenyl 2-Phenylcyclopropyl Ketone: 1H NMR (400 MHz,
0
3
CDCl ): d 7.45–7.15 (m, 5H, H6-7-8-9-10); 4.87 (m, 2H, H2-2 );
2

D. Carrié, T. Roisnel and Gérard Simonneaux
Polyhedron 205 (2021) 115294
0
4
2
.53 (m, 2H, H3-3 ), 4.21 (s, 5H, Cp-H4); 2.73–2.70 (m, 1H, H
a
);
);1.55–1.45 (m,
2
): d 202.14 (CO); 140.98
2.4. Dimer formation
.52–2.45 (m, 1H, H
b
); 1.92–1.85 (m, 1H, H
c d
or H
). 13C NMR (400 MHz, CD
TMPRuCO (0.5 mg) and diazoacetylferrocene (109 mg,
3.5 mmol) were stirred in a solution of CH Cl at room tempera-
1
(
(
H, H or H
c
d
2
Cl
4
2
2
C5); 128.60 (2C, C6-10);126.46 (C, C8); 126.17 (2C, C7-9), 79.85
C, C1); 72.56 (C, C3 or C3 ); 72.51 (C, C3 or C3 ); 69.93 (5C, C4);
0
0
ture under argon for until complete consumption of diazo was evi-
dent by TLC (12 h). The solvent was then removed and the residue
was purified by column chromatography on silica gel (dichloro-
0
0
6
9.67 (C, C2 or C2 ); 69.46 (C, C2 or C2 ); 30.63 (CH
); 18.53 (CH ). HR-MS (m/z): calcd for C20
18O Na 56Fe (M
Na) : 353.05992. Found 353.0600.
b
); 29.05
(
CH
a
2
H
methane) to give the dimer (53 mg, 55% yield).
+
+
1
Ferrocenyl 2-p-Methylphenylcyclopropyl Ketone : 1H NMR
): d 7.25–6.98 (m, 4H, H4-7-9-10); 4.86 (m, 2H,
H NMR (400 MHz, CDCl
3
0
): d 6.77 (br, 2H, HC@); 4.78 (br, 4H,
0
13
H2-2 ); 4.61 (br, 2H, H3-3 ), 4.29 (br, 10H, Cp-H4).
C NMR
(
400 MHz, CDCl
3
0
0
3
(100 MHz, CDCl ): d 195.37 (CO); 134.12 (CH@); 78.89 (C-CO);
H2-2 ); 4.53 (m, 2H, H3-3 ), 4.21 (s, 5H, Cp-H4); 2.75–2.60 (m,
0
0
7
2.87 (C3 and C3 ); 70.13 (C4); 69.45 (C2 and C2 ). HR-MS (m/z):
1
1
H, H
H, H
): d 202.26 (CO); 137.89 (C5); 136.07 (C8); 129.27 (C6-10);
a
); 2.52–2.43 (m, 1H, H
b
); 2.36 (s, 3H, Me); 1.90–1.82 (m,
5
6
+
13
20 2 2
calcd for C24H O Na Fe (M+Na) : 475.00543. Found: 475.0052.
c
or H ); 1.52–1.43 (m, 1H, H
d
c d 2
or H ). C NMR (400 MHz, CD -
Cl
1
2
0
0
26.11 (C7-9); 79.88 (C1); 72.51 (C3 or C3 ); 72.45 (C3 or C3 );
2.5. General procedure for N–H insertion in organic solvent
0
0
6
9.92 (C4); 69.65 (C2 or C2 ); 69.45 (C2 or C2 ); 30.53 (CH
8.89 (CH ); 21.04 (CH ); 18.41 (CH ). HR-MS (m/z): calcd for
20O Na Fe (M + Na) : 367.07557. Found 367.0759.
Ferrocenyl 2-p-Methoxyphenylcyclopropyl Ketone: 1H NMR
): d 7.15 (d, 2H, H6-10, J = 8.13 Hz); 6.89 (d, 2H,
b
);
2
C
a
3
2
In a typical experiment, the
FeTPPCl (1.3 mg, 1.8 mmol) were placed in a Schlenk tube under
argon and dissolved in 2 ml of distilled CH Cl . NEt (0.27 mmol)
was added to the solution. Diazoacetylferrocene (0.18 mmol) was
then added at room temperature. After 2 min of stirring, the inser-
tion product was purified by column chromatography on silica gel
a-amino ester (0.18 mmol) and
5
6
+
21
H
2
2
3
(
400 MHz, CDCl
H7-9, J = 8.13 Hz); 4.87 (m, 2H, H2-2 ); 4.54 (m, 2H, H3-3 ); 4.22
s, 5H, Cp-H4); 2.74–2.60 (m, 1H, H ); 2.52–2.35 (m, 1H, H );
.92–1.77 (m, 1H, H or H );1.53–1.36 (m, 1H, H ). C NMR
100 MHz, CDCl
3
0
0
(
1
a
b
1
3
or H
d
(CH
N-acetylferrocene aniline: 1H NMR (400 MHz, CDCl
7.23 (m, 2H, HoPh); 6.80–6.68 (m, 3H, Hm+pPh); 4.93 (m, 2H, H2-
2 2
Cl /Methanol: 95/5).
c
d
c
(
1
7
3
): d 202.18 (CO); 150.33 (C8); 132.92 (C5);
3
): d 7.27–
0
27.30 (C6-10); 114.05 (C7-9); 79.80 (C1); 72.37 (C3 or C3 );
2.32 (C3 or C3 ); 69.81 (C4); 69.56 (C2 or C2 ); 69.32 (C2 or
0
0
0
0
2 ); 4.87 (bs, 1H, NH); 4.64 (m, 2H, H3-3 ); 4.36 (br, 2H, CH
4.27 (s, 5H, Cp-H4). 13C NMR (100 MHz, CDCl
): d 199.21 (CO);
147.56 (CNH); 129.23 (CoPh); 117.40 (CpPh); 112.89 (CmPh); 76.62
2
);
0
C2 ); 55.33 (OCH
(
3
3
); 30.38 (CH
b
); 28.59 (CH
a
); 18.25 (CH
2
). HR-MS
3
Na 5 Fe (M+Na) : 383.07049. Found
6
+
m/z): calcd for C21
83.0704.
Ferrocenyl 2-p-Chlorophenylcyclopropyl Ketone: 1H NMR
): d 7.36–7.05 (m, 4H, H6-7-9-10); 4.92–4.78 (m,
H, H2-2 ); 4.54 (m, 2H, H3-3 ); 4.21 (s, 5H, Cp-H4); 2.73–2.62
20 2
H O
0
0
(C1); 72.59 (C3 and C3 ); 70.07 (C4); 68.85 (C2 and C2 ); 50.63
17NO Na 56Fe (M
(
CH ). HR-MS (m/z): calcd for
2
18
C H
+
(
400 MHz, CDCl
3
+Na) :342.05517. Found: 342.0555.
0
0
-phenylalanine methyl ester: 1H NMR
2
N-Acetylferrocene
D
(
m, 1H, H
a
); 2.51–2.40 (m, 1H, H
);1.53–1.40 m, 1H, H
b
); 1.94–1.83 (m, 1H, H
c
or
): d
(400 MHz, CDCl ): d 7.42–7.20 (m, 5H, HPhAla); 4.77 (bs, 2H, H2-
3
13
H
d
c
or H
d
). C NMR (400 MHz, CD
2
Cl
2
0
0
2
); 4.54 (bs, 2H, H3-3 ); 4.22 (s, 5H, Cp-H4), 3.89–3.73 (2H, CH
CO); 3.71 (s, 3H, OCH ); 3.67 (t, 1H, CH-NH, J = 6.97 Hz); 3.14–
Ph). 13C NMR (100 MHz, CDCl
): d 201.04 (CO);
2
-
2
(
01.74 (CO); 139.53 (C5); 132.13 (C8); 128.72 (C7-9); 127.46
C6-10); 79.56 (C1); 72.54 (C3 or C3 ); 72.51 (C3 or C3 ); 69.84
3
0
0
2
.97 (2H, CH
2
3
0
0
(
C4); 69.58 (C2 or C2 ); 69.34 (C2 or C2 ); 30.55 (CH
CH ); 18.49 (CH ). HR-MS (m/z): calcd for C20
17O35ClNa 56Fe
M+Na) : 387.02095. Found 387.0206.
Ferrocenyl 2-p-Trifluoromethylphenylcyclopropyl Ketone: 1H
NMR (400 MHz, CDCl
d, 2H, H7-9, J = 7.88 Hz); 4.87 (m, 2H, H2-2 ); 4.57 (m, 2H, H3-
), 4.22 (s, 5H, Cp-H4); 2.80–2.70 (m, 1H, H
); 1.98–1.88 (m, 1H, H or H ); 1.56–1.47 (m, 1H, H
13C NMR (100 MHz, CDCl
): d 201.43 (CO); 145.24 (C5); 128.71
CF , q, J = 32.42 Hz); 126.32 (C6-10); 125.55 (C7-9); 122.85
C8); 79.44 (C1); 72.61 (C3 or C3 ); 72.59 (C3 or C3 ); 69.86 (C3
b
); 28.23
1
74.26 (OCO); 137.67 (Cq, CPh); 129.23 (CmPh);128.31 (CoPh);126.55
(
(
a
2
H
0
(
C
pPh); 76.80 (C1); 73.20 (C3 and C3 ); 69.98 (C4); 68.79 (C2 and
0
+
C2 ); 62.41 (CHAla); 54.03 (CH
2
CO); 51.62 (OCH
3
); 39.44 (CHCH
2
).
5
6
+
HR-MS (m/z) : calcd for C22
Found: 428.0922.
H
23NO
3
Na Fe (M+Na) : 428.09195.
3
): d 7.60 (d, 2H, H6-10, J = 7.88 Hz); 7.30
0
(
3
N-Acetylferrocene
CDCl ) : d 7.14 (d, 2H, HmPh, J = 7.68 Hz); 6.78 (d, 2H, HoPh
J = 7.68 Hz); 4.79 (br, 2H, H2-2 ); 4.57 (br, 2H, H3-3 ), 4.22 (s, 5H,
Cp-H4); 4.18 (q, 2H, CH O, J = 7.12 Hz); 3.90–3.78 (2H, CH CO);
.65 (t, 1H,CHCO, J = 6.66 Hz); 3.13–2.84 (2H, CH CH); 1.27 (t,
H, CH CH ) : d 201.37
, J = 7.12 Hz). 13C NMR (100 MHz, CDCl
L
-tyrosine ethyl ester : 1H NMR (400 MHz,
0
a
); 2.57–2.46 (m, 1H,
3
,
H
b
c
d
c
or H ).
d
0
0
3
2
2
(
(
3
1
3
3
2
0
0
0
0
0
2
3
3
b
or C3 ); 69.56 (C2 or C2 ); 69.39 (C2 or C2 ); 30.70 (CH ); 28.28
(
CO); 173.75 (OCO); 171.18 (COH); 130.39 (CmPh); 128.52 (C,
1
9
(
CH
a
); 18.71 (CH
2
).
F NMR (376.5 MHz, CDCl
3
): d ꢀ62.38
0
C
Ph); 115.41 (CoPh); 76.63 (C, C1); 72.56 (C3 and C3 ); 70.03 (C4);
5
6
+
(
CF
3
). HR-MS (m/z): calcd for
C
21
H17OF
3
Na
Fe (M+Na) :
0
6
8.87 (C2 and C2 ); 62.39 (CHTyr); 60.89 (OCH
2
); 53.95 (CH
2
-
4
21.04731. Found 421.0472.
Ferrocenyl 2-m-Trifluoromethylphenylcyclopropyl Ketone: 1
CO);38.42 (CH2Tyr); 14.04 (CH3). HR-MS (m/z) : calcd for
H
5
6
23 4
C H25NO Na Fe (M+Na) : 458.10252. Found : 458.1020.
NMR (400 MHz, CDCl
m, 2H, H2-2 ); 4.57 (m, 2H, H3-3 ), 4.23 (s, 5H, Cp-H4); 2.83–
3
): d 7.64–7.34 (m, 4H, H8-9-10); 4.89–4.86
1
0
0
N-Acetylferrocene
CDCl ) : d 4.81 (br, 2H, H2-2 ); 4.55 (br, 2H, H3-3 ); 4.25 (s, 5H, Cp-
H4); 3.80 (2H, CH CO); 2.99 (d, 1H, CHNH, J = 5.84 Hz); 2.10–1.90
(m, 1H, CHiPr); 1.52 (s, 9H, CH3tBu); 1.03 (d, 6H, CH3iPr, J = 6.82 Hz).
L-valine tert-butyl ester : H NMR (400 MHz,
(
2
H
0
0
3
.71 (m, 1H, H
); 1.57–1.47 (m, 1H, H
01.51 (CO); 142.04 (C5); 131.04 (CF
C9); 129.04 (C10); 125.44 (C7); 123.28 (C6); 122.63 (C8); 79.47
a
); 2.55–2.45 (m, 1H, H
b
); 1.97–1.86 (m, 1H, H
). C NMR (100 MHz, CDCl
, q, J = 32.42 Hz); 129.92
c
or
13
d
c
or H
d
3
): d
2
2
(
(
3
1
1
3
C NMR (100 MHz, CDCl ) : d 201.05 (CO); 173.76 (OCO); 80.79
3
0
0
0
C1); 72.58 (2C, C3 and C3 ); 69.85 (C4); 69.55 (C2 or C2 ); 69.41
CtBu);77.25 (C1) 72.21 (C3 and C3 ); 69.91 (C4); 68.78 (C2 and
0
). 19F NMR
0
(
C2 or C2 ); 29.71 (CH
b
); 28.19 (CH
): d ꢀ62.64 (CF ). HR-MS (m/z) : calcd for
Na Fe (M+Na) : 421.04731. Found 421.0471.
a
); 18.46 (CH
2
C2 ); 67.46 (CHNH); 54.98 (CH CO); 31.59 (CH ); 27.92 (CH3tBu);
2
iPr
18.36 (CH3iPr). HR-MS (m/z) : calcd for C21H29NO3 Na 56Fe (M
(
C
376.5 MHz, CDCl
3
3
5
6
+
21
H17OF
3
+Na) : 422.1389. Found : 422.1387.
3

D. Carrié, T. Roisnel and Gérard Simonneaux
Polyhedron 205 (2021) 115294
2.6. X-ray structure determination
rocene was obtained with 43% yield after 2 days together with a
1
0% yield of ferrocenecarboxylic anhydride [24]. To better charac-
Single crystals of the complexes of diazoacetylferrocene and
terize the diazo group, an X-ray structure determination was
undertaken. The diazoacetylferrocene was the first ferrocenic diazo
compound to have its structure investigated by X-ray diffraction
analysis (Fig. 2). The interatomic C–N (1.312(10) Å) and N–N
(1.113(9) Å) distances for the diazo compound are however quite
similar to the bond length distances for other diazoketones [25,26].
ferrocenyl 2-phenylcyclopropyl ketone were grown by slow diffu-
sion of hexane onto dichloromethane solutions. Data collection
was carried out at 250 K for diazoacetylferrocene and 296 K for fer-
rocenyl 2-phenylcyclopropyl ketone on a D8 Venture diffractome-
ter equipped with a (CMOS) Photon 100 detector, using Mo-K
a
radiation (k = 0.71073 Å), multilayer monochromator. The struc-
ture was solved by dual-space algorithm using the SHELXT pro-
gram [18] and then refined with full-matrix least-squares
methods based on F2 (SHELXL program) [19]. All non hydrogen
atoms were refined with anisotropic atomic displacement param-
3.2. Cyclopropanation reaction
meso-Tetramesitylporphyrin carbonyl ruthenium (TMP)Ru(CO)
(Fig. 1, compound A) catalyzed decomposition of diazoacetylfer-
rocene in the presence of styrene in dichloromethane resulted in
the formation of the corresponding cyclopropane in 61% yield
(Table 1) with a trans stereoselectivity (Scheme 2) and a moderate
amount of olefin resulting to the dimerization of the carbene (30%)
2
eters. For diazoacetylferrocene, a final refinement on F with
4
499 unique intensities and 290 parameters converged at xR
2
(
F ) = 0.0987 (R
F
= 0.0401) for 4240 observed reflections with
(
I > 2 ) and for ferrocenyl 2-phenylcyclopropyl ketone, a final
r
2
refinement on F with 2797 unique intensities and 200 parameters
2
converged at
reflections with (I > 2
Diazoacetylferrocene complex (C12
Crystal structure has been described in monoclinic symmetry and
P 2 (I.T.#4) acentric space group. Cell parameters have been
x
R(F ) = 0.1094 (R
F
= 0.0523) for 2288 observed
r
).
2
H10FeN O); M = 254.07.
1
refined as follows: a = 9.4037(9), b = 507292(6), c = 19.623(2) Å,
3
b = 90.141(4)°, V = 1057.18(18) Å . Number of formula unit Z is
equal to 4 and calculated density d and absorption coefficient m
ꢀ3
ꢀ1
values are 1.596 g.cm and 1.402 mm respectively.
Ferrocenyl 2-phenylcyclopropyl ketone complex (C20
H18FeO);
M = 330.19. Crystal structure has been described in monoclinic
symmetry and P 2 (I.T.#4) acentric space group. Cell parameters
1
have been refined as follows: a = 5.9391(5), b = 12.2635(16),
3
c = 10.7050(13) Å, b = 91.532(3)°, V = 779.41(15) Å . Number of for-
mula unit Z is equal to 2 and calculated density d and absorption
ꢀ3
ꢀ1
coefficient m values are 1.407 g.cm and 0.966 mm respectively.
Final atomic positional coordinates, with estimated standard
deviations, and bond lengths and angles have been deposited at
the Cambridge Crystallographic Data Centre.
3
. Results
3.1. Synthesis of diazoacetylferrocene and X-ray structure
determination
Fig. 2. ORTEP structure of diazoacetylferrocene.
For the synthesis of diazoacetylferrocene, it was first decided to
use trimethylsilyldiazomethane (TMSCHN
zomethane because the latter is not only highly toxic but also
explosive. TMSCHN has been previously used in the preparation
of a variety of diazoketones from the corresponding acyl chloride
by treatment with TMSCHN [20–23]. Herein, we successfully
2
) as a substitute of dia-
Table 1
2
Cyclopropanation of styrene derivatives with diazoacetylferrocene catalyzed by
TMPRuCO (catalyst A).
2
Entry
Alkene
Yield (%)
Dimer (%)
adapted this recent method with ferrocene acyl chloride that was
prepared from acid. Conversion of this acid to its acyl chloride with
thionyl chloride gave a quasi-quantitative yield. The ferrocene acyl
1
2
3
4
5
6
C
4-CH
4-CH OC H
4-CF
4-ClC
3-CF
6
H
5
61
48
41
29
35
39
30
32
33
31
32
41
3 6 4
C H
3
6
4
chloride was then allowed to react with 2 equivalents of TMSCHN
2
3 6 4
C H
6
H
4
in the presence of an excess of triethylamine dissolved in THF at
low temperature (0 °C) (Scheme 1). The expected diazoacetylfer-
3
C
H
6 4
Scheme 1. Synthesis of diazoacetylferrocene.
4

D. Carrié, T. Roisnel and Gérard Simonneaux
Polyhedron 205 (2021) 115294
H
N2
Catalyst A
+
O
2
CH Cl2
Fe
Fe
O
Argon
Scheme 2. Cyclopropanation catalyzed by ruthenium porphyrin.
To assure the absolute configuration, an X-ray structure deter-
mination of cyclopropyl ketone obtained from the styrene adduct
was undertaken. Although at the end of the cyclopropanation,
the ee was of only 74%, simple recrystallization of the product in
2 2
hexane/CH Cl easily raises the optical purity to nearly 100%. The
X-ray structure of monocrystals obtained from the styrene deriva-
tives confirms the 1S,2S configuration for the trans isomer (see
Fig. 3).
Scheme 3. Dimerization of diazoacetylferrocene catalyzed by ruthenium
porphyrin.
3.4. Dimerization
(
Scheme 3). To extend the scope of this cyclopropanation, the reac-
tion of a number of styrene derivatives with diazoacetylferrocene
in the presence of TMPRu(CO) at 25 °C in dichloromethane was
studied. The results are summarized in Table 1. In these experi-
ments, cyclopropanes are the major products, usually obtained
with carbene dimers as by-products. Electron-rich styrenes (4-
methoxy or 4-methyl styrene) are cyclopropanated more effi-
ciently than styrenes bearing electron-withdrawing groups (4-Cl
In ruthenium-porphyrin catalyzed cyclopropanation, the corre-
sponding carbene complexes which take octahedral coordination
in the presence of axial ligand (solvent) are considered as the
active intermediates. As an example, we reported the first X-ray
structure of a ruthenium porphyrin carbene complex with a
methanol as an axial ligand trans to the Ru-carbon bond [29]. Since
ketocarbenes are found to be easily inserted in metal-nitrogen
bond of iron porphyrin [30,31], preparation of the ruthenium keto-
carbene complex was undertaken. Thus, reaction of the carbonyl
ruthenium complex with excess of diazoacetylferrocene in dichlor-
omethane results in the displacement of the CO ligand and gener-
ation of a carbene complex. The carbene complex was not stable
or 4-CF
resulting from dimerization of the carbenes, was also detected
30–41%). With styrene bearing the trifluoromethyl group in meta
position, dimerization of the carbene is the main reaction.
3
). In the two later cases, a significant amount of olefins,
(
3.3. Asymmetric cyclopropanation
The asymmetric version was also tested using Halterman por-
phyrin [27] as chiral ligand (Fig. 1, compound B). To evaluate the
reactivity of the diazoacetylferrocene, its ruthenium-catalyzed
decomposition was examined in the presence of styrene in dichlor-
omethane at room temperature by using the chiral complex as cat-
alyst (Table 2). The cyclopropane was formed with 53% yield,
complete trans selectivity and 74% enantioselectivity for the trans
isomer (Table 2, entry 1). The presence of the cis isomer was not
detected after chromatography purification on silica gel. A small
amount (8%) of the dimer was also observed. We also investigated
the cyclopropanation of para-substituted styrenes (Table 2). As
shown in the Table 2, para-substitution (4-Y-styrene, 4 = MeO,
3
Br, CF and H) has a significant effect upon the enantioselectivity
of styrene cyclopropanation (74–96%).The best enantioselectivity
was obtained with para-methoxystyrene (ee = 96%). As previously
observed with other diazo derivatives [28], dimerization is less
prominent than cyclopropanation reaction with a bulky porphyrin
such as Halterman porphyrin.
Fig. 3. ORTEP structure of ferrocenyl 2-phenylcyclopropyl ketone.
Table 2
Cyclopropanation with diazoacetylferrocene catalyzed by RuHalt(CO) (catalyst B).
2
3a
Entry
Alkene
Yield (%)
% ee
Dimer (%)
[a]
D
1
2
3
4
5
6
C
4-CH
4-CH
4-CF
4-ClC
3-CF
6
H
5
53
69
72
53
78
30
74
79
96
86
83
76
8
133
152
154
111
135
82
3
C
6
H
4
12
10
12
11
35
3
OC
6
H
4
3
C
6
H
4
6
H
4
3
C
6
H
4
a
(
2 2
c 1.0, CH Cl ).
5

D. Carrié, T. Roisnel and Gérard Simonneaux
Polyhedron 205 (2021) 115294
enough to be purified by chromatography on silica gel but can be
characterized by HMBC NMR at low temperature (210 K). Analysis
of the NMR spectrum shows a low-field cross-peak between the
Table 3
Insertion in N–H bond of amino acid esters by diazoacetylferrocene catalyzed by
FeTPPCl (catalyst C).
carbene carbon at 213 ppm and the carbene proton at
Entry
Substrate
Aniline
Time
Yield (%)
1
1
4.28 ppm. The H chemical shift is in the range of those previously
1
2
1 h
1 h
87
82
reported for such Ru = CHR porphyrin complexes [11].
L
-Tyrosine ethyl ester
-Phenylalanine methyl ester
-Valine t-Butyl ester
Next, we also report that the tetramesitylporphyrin ruthenium
complex (Fig. 1, compound A) catalyzes the stereoselective decom-
position of diazoacetylferrocene to form cis olefinic products
3
4
D
1 h
1 h
88
85
L
(Scheme 3). This coupling reaction proceeds also through a metal-
locarbene intermediate to give a cis dimer (55% yield). It should be
emphasized that synthesis of cis-1,2-diferrocenoylethylene was
previously attempted from photo-oxidation of 2,5-diferrocenylfu-
ran but without success and it was considered that the cis-isomer
was isomerized into the trans-isomer by thermal condition [32].
Coll [41] using a ruthenium porphyrin catalyst. More recently,
asymmetric synthesis of optically active trifluoromethyl cyclo-
propane bearing a ferrocenyl group has been described by Iwasa
and Coll [42].
Iron porphyrin-catalyzed N–H insertions have been previously
studied in organic solvents [14,43,44] and in water [13,14]. This
paper suggests that diazo chemistry provides a powerful, attractive
alternative to conventional chemistry. As a method for applying
metal-catalyzed carbenoid transfer reactions for selective modifi-
cation of proteins, various amino esters were used as models for
NH insertion reactions by diaoacetylferrocene using a porphyrin
complex, TSPPFeCl. It also shows a total regioselectivity with tyro-
sine without O–H insertion. As previously observed with insulin
3.5. Insertion in N–H bond of amino acid esters by
diazoacetylferrocene
We then investigated the reaction of diazoacetylferrocene with
aniline and amino esters in organic solvent. In particular, we
wanted to check if these reactions can tolerate the presence of fer-
rocenyl group in the diazo compound. The insertion reactions are
shown in Scheme 4 and the results reported in Table 3. In these
case, the catalyst used for these reaction was FeTPPCl (Fig. 1C).
The reactions are fast (<1h). The yields obtained are quite high
[
2
13], insertion is regioselective onto the NH termini. The introduc-
tion of new functional groups on specific sites containing NH
groups can modify the stability of the macromolecules, their bio-
logical activity and the interactions between them. In the future,
the challenge is to optimize all the possible parameters in water
and in protic solvents using water-soluble iron porphyrins which
tolerate the different functions present on the protein.
(
87–88%) with the diazo ketone bearing the ferrocenyl group if
we except the results obtained with tyrosine (82%) probably due
to solubility difficulty in CH Cl . Aniline gave also a good yield
87%). As previously observed with ethyl diazoacetate [13], all
2
2
(
1
the insertion products into aminoesters were characterized by
NMR, showing also an AB system for CH group in alpha position
of the nitrogen (see experimental section).
H
2
5. Conclusion
The transition-metal-catalyzed asymmetric cyclopropanation
have become important enantioselective C–C bond-forming
approaches. By use of ruthenium complexes of chiral porphyrin
ligands, the formation of cyclopropyl ferrocenes has been accom-
plished with high enantioselectivity (ee up to 96%). The N–H inser-
tion of diazoacetylferrocene with aminoesters catalyzed by iron
porphyrins has high potential for wide application in bioconjuga-
tion of peptides and proteins, as previously reported by us [13]
and others [45] with water-soluble ruthenium porphyrins.
4
. Discussion
Chiral cyclopropyl ketones are a versatile yet underexploited
class of functionalized cyclopropanes with only rare isolated exam-
ples of enantioselective cyclopropanation involving a diazoketone
reagent [33–35]. However, it is now recognized that many func-
tional groups can be tolerated in the transition metal-catalyzed
reactions of
a-diazo compounds [36]. Consequently, it is possible
to design a diazo substrate bearing the necessary functional groups
for further use after cyclopropanation. An example is the fullerenes
functionalized with ferrocenes via the cyclopropanation reaction
which were reported by Tagliatesta [37] and Sokolov [38].
It should also be noted that synthesis of substituted cyclopropyl
ferrocenyl ketones have been previously reported by Horspool et al
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
[
39] and by Xu et al [40] using a sulfur ylide addition to the corre-
sponding chalcone-containing ferrocenes in solution or under solid
state reaction but without enantioselectivity. Cyclopropanation of
vinylferrocene is a different way to obtain cyclopropylferrocene.
An example of such reaction has been reported by Myamoto and
Appendix A. Supplementary data
CCDC 2062260 contains the supplementary crystallographic data
for diazoacetylferrocene and CCDC 2062261 contains the
H
O
R
O
O
OR
1
N2
R
1
Catalyst C
+
N
H
CH Cl2
O
2
H N
2
R
Fe
Fe
Argon
O
R = -CH Ph, -CH PhOH, i-Pr
2
2
R1 = Me, Et, t-Bu
Scheme 4. N–H insertion of diazoacetyl ferrocene catalyzed by FeTPPCl (catalyst C).
6

D. Carrié, T. Roisnel and Gérard Simonneaux
Polyhedron 205 (2021) 115294
supplementary crystallographic data for ferrocenyl 2-phenylcyclo-
propyl ketone. These data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: (+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.
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