Nucleophilic halogenations of diazo compounds, a complementary principle for the synthesis of halodiazo compounds: Experimental and theoretical studies

Article abstract of DOI:10.1021/jo401050c

Three new protocols for the nucleophilic halogenations of diazoesters, diazophosphonates, and diazopiperidinylamides as complementary methods to our previously reported electrophilic halogenations are presented for the first time. On the basis of hyperval

Full text of DOI:10.1021/jo401050c

Article
pubs.acs.org/joc
Nucleophilic Halogenations of Diazo Compounds, a Complementary
Principle for the Synthesis of Halodiazo Compounds: Experimental
and Theoretical Studies
Christian Schnaars, Martin Hennum, and Tore Bonge-Hansen*
Department of Chemistry, University of Oslo, Sem Sælands vei 26, N-0315 Oslo, Norway
S
* Supporting Information
ABSTRACT: Three new protocols for the nucleophilic halogenations of diazoesters, diazophosphonates, and diazopiper-
idinylamides as complementary methods to our previously reported electrophilic halogenations are presented for the first time.
On the basis of hypervalent α-aryliodonio diazo triflate salts 1A, 2A, and 3A, the corresponding halodiazo compounds are
generated via nucleophilic halogenations with tetrabutylammonium halides or potassium halides. The products from subsequent
catalytic intermolecular cyclopropanations of the halodiazoesters and halodiazophosphonates and thermal intramolecular C−H
insertion of the brominated diazopiperidinylamide are obtained in moderate to good yields after two steps. DFT calculations are
presented for the diazoesters to give insight into the mechanism and transition states of the nucleophilic substitutions with the
neutral nucleophiles dimethyl sulfide and triethylamine and the bromination with Br−.
diazoester triflate 1A was followed by nucleophilic substitution
with the neutral nucleophiles NEt3, SMe2, pyridine, AsPh3, and
SbPh3 to generate the corresponding α-onium triflate salts
(Scheme 1). This alternative approach to the electrophilic
substitution has to the best of our knowledge not found
applications for the synthesis of other diazo compounds, but
has a great potential given the large amount of nucleophiles
available. We wanted to apply this methodology in nucleophilic
halogenations11 on different classes of diazo compounds as an
alternative method to the electrophilic halogenations and
looked to gain insight into the mechanism of the nucleophilic
substitutions by DFT calculations.
INTRODUCTION
■
Diazo compounds are valuable organic compounds for several
transformations,1 among which their ability to generate
carbenoids in combination with an appropriate transition-
metal catalyst has found wide applications.2 These carbenoids
can undergo important reactions3 such as cyclopropanations,4
C−H insertions,5 and ylide transformations,6 among others.
Several methods for the synthesis of diazo compounds are
known, and the majority consist of introducing the diazo
functionality into a prefunctionalized starting material.7 The
inherent instability of the diazo compounds, however, often is a
limitation to the reaction conditions that can be applied.
Methods for direct functionalizations of diazo compounds at
the diazo carbon under preservation of the diazo group, on the
other hand, are scarce and only the electrophilic substitution in
which the diazo compound reacts as a nucleophile has been
thoroughly explored.8 We have previously shown that the
synthesis of thermally unstable halodiazo compounds can be
achieved in a mild and efficient way via a deprotonation−
electrophilic halogenation sequence with N-halosuccinimides
and DBU or NaH as a base.9 The availability of reagents for the
transfer of atoms or groups as electrophiles, however, is limited,
especially with regard to the transfer of heteroatoms.
RESULTS AND DISCUSSION
■
α-Onium diazoester triflates 1A, 1B, and 1C were prepared
according to the described literature procedure10 starting from
ethyl diazoacetate (EDA) to prepare α-aryliodonio diazoacetate
triflate 1A, followed by nucleophilic substitutions of 1A with
dimethyl sulfide (1B) or triethylamine (1C), respectively,
which occur readily at room temperature (Scheme 2a; the
corresponding phosphonates and amides will be discussed later
in the paper). The X-ray crystal structure of α-aryliodonio
diazoacetate triflate 1A was reported by Weiss et al.,10 and we
were able to obtain X-ray crystal structures of the α-
A complementary direct functionalization of diazo com-
pounds was reported by Robert Weiss et al.10 in 1994 in which
a nucleophilic substitution on diazoesters was performed for
the first time. The preparation of hypervalent α-aryliodonio
Received: May 14, 2013
Published: July 2, 2013
© 2013 American Chemical Society
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Scheme 1. Nucleophilic Substitution with α-Aryliodonio Diazoester 1A by Weiss et al.10
Scheme 2. Preparation of α-Onium Diazoesters 1A−1C, α-Onium Diazophosphonates 2A−2C, and α-Onium
Diazopiperidinylamides 3A−3C
dimethylsulfonium diazoacetate triflate 1B and α-triethylam-
monium diazoacetate triflate 1C.12
After the biphasic reaction mixture containing KX (X = I, Br,
Cl) and 1A was stirred at 0 °C (10 min for X = I and Br and 30
min for X = Cl), the organic phase was separated and passed
through a Celite/MgSO4 plug into a flask containing toluene at
0 °C, and the dichloromethane was removed in vacuo at 0 °C.
Following addition of styrene and Rh2(esp)2 to the residual
toluene solution, the catalytic cyclopropanation gave the same
yields of 66% for 1D and 1E (X = I and Br) and a lower yield of
26% for 1F (X = Cl) compared to method 1 (Table 1, method
2). The 1H NMR spectra of the crude reaction mixture
contained less impurities compared to those for method 1
because the byproducts potassium triflate, iodobenzene, and
styrene could be easily removed by phase separation and
evaporation in vacuo.
α-Aryliodonio diazoacetate triflate 1A was chosen as the
substrate for the nucleophilic halogenations because iodoben-
zene is the best and most inert leaving group compared to
dimethyl sulfide and triethylamine. Furthermore, dimethyl
sulfide and triethylamine could coordinate and deactivate the
catalyst in the following cyclopropanation step and could also
undergo unwanted side reactions, such as C−H insertions or
ylide formations. However, investigation of the reactivities of
compounds 1B and 1C in catalytic carbenoid reactions are
ongoing in our laboratories. Compound 1C formally contains
an amino acid fragment, which makes this compound
particularly interesting.
To develop a new route to halogenated diazo compounds,
initial nucleophilic halogenation experiments were performed
with tetrabutylammonium halides (TBAX, X = I, Br, Cl) as the
halide sources (method 1). Addition of TBAX to 1A in
dichloromethane at 0 °C showed rapid conversion to the
corresponding bromo- and iododiazoacetates 1A-Br and 1A-I
and slower conversion to the chlorodiazoacetate 1A-Cl
As a third method, a one-phase system with 1,4,7,10,13,16-
hexaoxacyclooctadecane (18-crown-6) solubilized potassium
halides in dichloromethane was tested. The yield of the
bromocyclopropyl ester 1E increased to 77%, whereas the yield
for iodocyclopropyl ester 1D decreased to 49%. Unfortunately,
no chlorinated diazo compound was obtained due to
insolubility of the potassium chloride in dichloromethane
with 18-crown-6 (Table 1, method 3).
13
1
(monitored by TLC analysis and H NMR, Scheme 3a).
Fluorination with TBAF was also attempted, but no conversion
was detected, probably due to the low nucleophilicity of the
fluoride ion.
Among the three protocols developed for the nucleophilic
halogenations, the highest yields for the iodocyclopropyl ester
1D were achieved with methods 1 and 2 (65% and 66%), for
the bromocyclopropyl ester 1E with method 3 (77%), and for
the chlorocyclopropyl ester 1F with method 1 (50%). The
diastereoselectivity was >7:1 in favor of the trans diastereomer
for all products. Thus, three new protocols for the nucleophilic
halogenations of diazoesters were developed for the first time
and added as alternative methods to the generation of
halodiazoacetates.
Having demonstrated that the nucleophilic halogenation of
diazoesters is a complementary synthetic method to the
electrophilic halogenation, we performed DFT calculations to
understand the mechanism and describe the transition states of
the nucleophilic substitutions with dimethyl sulfide, triethyl-
amine, and bromide and to support our experimental
observations.
Having demonstrated the nucleophilic halogenation to be a
new method to generate the corresponding halogenated
diazoesters, we investigated their dirhodium(II)-catalyzed
intermolecular cyclopropanation. Styrene and 2 mol %
14
Rh2(esp)2 in toluene as the solvent was chosen as a test
system, since it was most efficient in our previously reported
electrophilic halogenations.9 The corresponding halocycloprop-
yl esters 1D−1F were obtained in moderate yields of 50−67%
over two steps and good diastereomeric ratios in favor of the
trans diastereomer (Table 1, method 1). Although the yields of
the isolated cyclopropanes were lower compared to those
obtained with the electrophilic halogenation, a convenient
alternative method for the nucleophilic halogenation of diazo
esters was achieved for the first time and opens numerous
possibilities for further investigations.
Calculations were performed on the Gaussian 09 program
package16 using the hybrid density functional B3LYP.17 All
atoms except iodine were described by the 6-31+g(d,p) basis
set.18 Iodine was described by the LanL2DZ basis set.19 All
calculations were performed using the continuum solvation
After these initial results we wanted to test alternative
procedures for the nucleophilic halogenations. Potassium
halides were chosen as halide sources and a biphasic system
with water and dichloromethane as the reaction medium.15
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Scheme 3. Nucleophilic Halogenations of α-Aryliodonio Diazoacetate 1A and α-Aryliodonio Diazophosphonate 2A with
a
Methods 1−3 and the Following Catalytic Intermolecular Cyclopropanation
a
The phosphonates will be discussed later in the paper.
Table 1. Isolated Yields of Halocyclopropyl Esters 1D−1F from 1A with Methods 1−3
a
b
yield (%) (dr (trans:cis))
c
d
e
entry
X, 1A
product
method 1
method 2
method 3
electrophilic9b−d
1
2
3
I
1D
1E
1F
65 (8:1)
67 (8:1)
50 (7:1)
66 (8:1)
66 (8:1)
49 (9:1)
77 (7:1)
85 (9:1)
91 (9:1)
87 (7:1)
Br
Cl
26 (7:1)
a
b
Isolated yields of both diastereomers after two steps after column chromatography. Estimated by 1H NMR spectra of the crude product mixture.
c
Reagents and conditions: 1A (0.1−0.2 mmol) dissolved in dry CH2Cl2 (1−2 mL), 0 °C, TBAX (1.5 equiv) added, 1 h at 0 °C, SiO2 plug optional,
d
CH2Cl2 exchange with dry toluene (0 °C, 2 mL), styrene (5 equiv), 2 mol % Rh2(esp)2 (1 mL of dry toluene), 0 °C to rt. Reagents and conditions:
1A (0.1−0.2 mmol) dissolved in dry CH2Cl2 (1 mL), 0 °C, KX (1.5 equiv) in H2O (1 mL) added, 0 °C for 10−30 min, MgSO4/Celite plug
(CH2Cl2, −30 °C), CH2Cl2 exchange with dry toluene (0 °C, 2 mL), styrene (5 equiv), 2 mol % Rh2(esp)2 (1 mL of dry toluene), 0 °C to rt.
e
Reagents and conditions: KX (1.5 equiv) and 18-crown-6 (2 equiv) dissolved in dry CH2Cl2 (1 mL), 0 °C, 1A (0.1−0.2 mmol) added, 0 °C for 1 h,
CH2Cl2 exchange with dry toluene (2 mL), styrene (5 equiv), 2 mol % Rh2(esp)2 (1 mL of dry toluene), 0 °C to rt.
model CPCM with dichloromethane as the solvent.20 All
structures were fully optimized without any geometry or
symmetry constraints. Each stationary point was identified as
either a minimum or a saddle point by analytical calculation of
the frequencies. The connectivity between different structures
was verified by following the intrinsic reaction coordinates
(IRCs) from each saddle point.
The nucleophilic substitutions of α-aryliodonio diazoacetate
triflate 1A with SMe2 to the α-dimethylsulfonium diazoacetate
triflate 1B and with NEt3 to the α-triethylammonium
diazoacetate triflate 1C proceed via calculated energy-
minimized transition states TS-1B‡ and TS-1C‡ (Figure 1) at
room temperature. The energy of transition state TS-1B‡ is
calculated to be 19.4 kcal mol−1 and the energy for TS-1C‡ 18.9
kcal mol−1, and the relative energies of the products are −32.2
kcal mol−1 for 1B and −39.3 kcal mol−1 for 1C, which explains
the high driving force for the reaction. The substitution of α-
dimethylsulfonium diazoacetate triflate 1B with triethylamine,
however, would proceed via transition state TS-1BC‡ with an
energy barrier of 39.3 kcal mol−1 relative to 1B, which is twice
as high as for the two other transition states and confirmed the
experimental result that no reaction of 1B with NEt3 was
observed at room temperature.
For the bromination of 1A with TBAB an ion exchange from
triflate to bromide prior to the nucleophilic substitution step is
assumed (1ABr). An energy gain of 5.9 kcal mol−1 for 1ABr
results, and the transition state TS-1A-Br‡ is calculated to have
an energy barrier of 29.3 kcal mol−1 relative to 1ABr. The α-
bromodiazoacetate 1A-Br is 25.7 kcal mol−1 lower in energy
relative to 1ABr and 31.6 kcal mol−1 in relation to the triflate
salt 1A (Figure 2).
In the case of the α-dimethylsulfonium diazoacetate triflate
1B an energy barrier of 35.7 kcal mol−1 for the nucleophilic
bromination results in an impractical reaction rate at room
temperature. Furthermore, the energy difference of 1BBr and
product 1A-Br would be positive, 2.1 kcal mol−1 (energy profile
shown in the Supporting Information). The barrier for the
nucleophilic bromination of α-triethylammonium diazoacetate
triflate 1C would be even higher, 43.3 kcal mol−1, and the
product 1A-Br 8.6 kcal mol−1 higher in energy compared to
1CBr. Both theoretical results correspond to the experimental
observation that no bromination with 1B and 1C occurred.
The geometries of the energy-minimized calculated transition
states TS-1B‡, TS-1C‡, and TS-1A-Br‡ are depicted in Figure 3.
The bond distances of the nucleophile−carbon bond (Nu−C,
Nu = SMe2, NEt3, Br−) and leaving group−carbon bond (LG−
C, LG = IPh) are displayed. In all transition states the bond
distances of the developing Nu−C bond and the breaking LG−
C bond are lengthened compared to those of the starting
material 1A and the corresponding products.21 In TS-1B‡ the
LG−C bond difference is Δ(LG−C)1B = 0.45 Å (21%)
compared to the starting material 1A (2.10 Å in 1A compared
to 2.55 Å in TS-1B‡) and the Nu−C bond difference is Δ(Nu−
C)1B = 1.03 Å (59%) (Nu = SMe2) compared to the product
1B (2.79 Å in TS-1B‡ compared to 1.76 Å in 1B). For TS-1C‡
the Δ(LG−C)1C of 0.44 Å (21%) is similar to that in TS-1B‡,
but the Δ(Nu−C)1C (Nu = NEt3) of 1.22 Å (82%) is
significantly higher compared to that of TS-1B‡. In the case of
the bromination, the bond difference Δ(LG−C)1A‑Br in TS-1A-
Br‡ is 0.36 Å (17%) compared to 1ABr and Δ(Nu−C)1A‑Br
=
0.75 Å (40%) compared to the bromodiazoacetate 1A-Br (2.64
Å compared to 1.89 Å in 1A-Br). The differences Δ(Nu−C) in
all transition states are significantly larger than the differences
for the LG−C bonds, Δ(LG−C), compared to the
corresponding starting materials and products. This indicates
asynchronous, reactant-like transition states, which is in
accordance with the Hammond postulate22 for an exergonic
reaction.
The Nu−C−LG angle of attack in TS-1B‡ (Nu = SMe2) is
almost linear at 161.2°, and the angle of attack on the diazo
carbon (Nu−C−N) is 89.4°. The Nu−C−LG angle in TS-1C‡
(Nu = NEt3) of 163.1° is similar to that in TS-1B‡; the angle of
attack on the CN bond, however, is smaller, only 83.5°. In
TS-1A-Br‡, for the bromination, the Nu−C−LG (Nu = Br−)
angle of 83.2° is significantly smaller compared to those in TS-
1B‡ and TS-1C‡, which could result from stronger Coulomb
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Figure 1. Energy profile for the nucleophilic substitutions of 1A with SMe2 and NEt3 to 1B and 1C at room temperature. The energies are relative
energies with 1A as the zero point and are reported in kilocalories per mole.
Figure 2. Energy profile for the nucleophilic bromination of 1A with TBAB at room temperature. Energies are reported in kilocalories per mole.
interactions between the bromide and the partially positively
charged iodine atom. The Nu−C−N angle of attack of the
bromide on the CN bond of 102° is significantly larger than
the angles of the incoming SMe2 and NEt3. For the nucleophilic
substitutions of 1A with Me2S and Et3N the transition states
resemble an SN2-type mechanism, whereas for the bromination
a tetrahedral-like transition state indicates a carbonyl-like
addition−elimination reaction mechanism.
The obtained computational results are in agreement with
the experimental observations and give insight into the
mechanism of the nucleophilic substitutions of the prepared
α-onium diazoester 1A as concerted, asynchronous, and
dependent on the leaving group and nucleophile.
Having shown the possibility of nucleophilic halogenations of
diazoesters, we wanted to extend and apply this methodology
to other classes of diazo compounds. Diazophosphonates23 are
another widely used class of diazo compounds, and we recently
reported their electrophilic halogenations.9a The phosphonate
analogues 2A, 2B, and 2C were prepared in a manner similar to
that of the esters 1A−1C in good to excellent yields (Scheme
2b). α-Aryliodonio diazophosphonate triflate 2A, however, is
thermally less stable than the corresponding ester 1A and had
to be kept below 5 °C to avoid thermal decomposition by loss
of iodobenzene.24 Compound 2A is a yellow solid, whereas the
α-dimethylsulfonium diazophosphonate triflate 2B and the α-
triethylammonium diazophosphonate triflate 2C are oils which
were thermally more stable than 2A. With these new
compounds in hand, we investigated the nucleophilic
halogenations of 2A followed by cyclopropanation of 2A-X in
analogy to the ester 1A (Scheme 3b).
The cyclopropanations with the halogenated diazophospho-
nates 2A-X via the tetrabutylammonium halides (method 1)
gave medium yields of the corresponding halocyclopropyl-
phosphonates 2D−2F, with the brominated product 2E formed
in the highest yield of 71%. The chlorinated cyclopropane 2F
was obtained in 63% yield and the iodocyclopropylphosponate
2D in 66% yield (Table 2, method 1).
Changing to the biphasic method 2 increased the yield of the
iodocyclopropylphosphonate 2D slightly to 70% with a
decrease in yield for the brominated analogue 2E to 55%.
The chlorocyclopropylphosphonate 2F, as in the case of the
diazoester, was only obtained in a low yield.
Method 3 gave a yield of 66% of 2E and a lower yield of 49%
for 2D. As for the ester 1A, no chlorination with KCl could be
achieved with this method.
The isolated yields of the halocyclopropylphosphonate 2D−
2F via the nucleophilic halogenation were approximately 10%
lower than the yields obtained with our previously reported
electrophilic halogenations. However, we have demonstrated
for the first time that the nucleophilic halogenation can be
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Figure 3. Geometries of calculated transition states TS-1B‡ (left), TS-1C‡ (middle), and TS-1A-Br‡ (right) and relevant bond lengths in angstroms
and angles (Nu = SMe2, NEt3, Br−, LG = IPh).
Table 2. Isolated Yields of Halocyclopropylphosphonate 2D−2F with Methods 1−3
a
b
yield (%) (dr (trans:cis))
c
d
e
entry
X, 2A
product
method 1
method 2
method 3
electrophilic9a
1
2
3
I
2D
2E
2F
66 (12:1)
71 (12:1)
63 (12:1)
70 (12:1)
55 (12:1)
49 (13:1)
66 (11:1)
77 (16:1)
82 (12:1)
77 (12:1)
Br
Cl
<10
a
b
Isolated yields of both diastereomers after two steps after column chromatography. Measured by 1H NMR spectra of the crude product mixture.
c
Reagents and conditions: 2A (0.1−0.2 mmol) dissolved in dry CH2Cl2 (2 mL) at 0 °C, TBAX (1.5 equiv) added, 1 h at 0 °C, CH2Cl2 exchange
d
with dry toluene (0 °C, 2 mL), styrene (5 equiv), 2 mol % Rh2(esp)2 (1 mL of dry toluene), 0 °C to rt. Reagents and conditions: 2A (0.1−0.2
mmol) dissolved in dry CH2Cl2 (1 mL), 0 °C, KX (1.5 equiv) in H2O (1 mL) added, 0 °C for 30 min to 1 h, MgSO4/Celite plug (CH2Cl2, −30 °C),
e
CH2Cl2 exchange with dry toluene (0 °C, 2 mL), styrene (5 equiv), 2 mol % Rh2(esp)2 (1 mL of dry toluene), 0 °C to rt. Reagents and conditions:
KX (1.5 equiv) and 18-crown-6 (2 equiv) dissolved in dry CH2Cl2 (1 mL), 0 °C, 2A (0.1−0.2 mmol) added, 0 °C for 1 h, CH2Cl2 exchange with dry
toluene (2 mL), styrene (5 equiv), 2 mol % Rh2(esp)2 (1 mL of dry toluene), 0 °C to rt.
applied and extended to the diazophosphonates in addition to
the diazoesters.
the nucleophilic bromination, but only 3% via the electrophilic
bromination in relation to cis/trans-3D. The highest isolated
yield of 51% for 3D was achieved with method 3 by dropwise
addition of a solution of KBr and 18-crown-6 in dichloro-
methane to 3A at −30 °C. While the reaction temperature for
methods 1 and 3 had to be kept at or below −30 °C to avoid
decomposition of 3A, the biphasic procedure had to be done at
0 °C due to the aqueous phase. This may have caused some
decomposition of 3A prior to addition of the potassium
bromide in H2O, although it was done immediately after 3A
was dissolved. In contrast to the diazoester 1A and
diazophosphonate 2A, the organic phase did not have to be
separated and dried before the second step because no catalyst
was involved in the thermal intramolecular C−H insertion.
Interestingly, only traces of overhalogenated products were
detected for the diazoester 1A and diazophosphonate 2A,
which showed greater tolerance to the concentration and halide
equivalents. Also, elemental iodine was formed in the
attempted iodinations with all methods, and its formation
could not be avoided.
Having demonstrated that the nucleophilic halogenation can
be applied to three major classes of diazo compounds, we
wanted to study and compare the experimental properties and
reactivities of the prepared diazo triflate salts 1A−C, 2A−C,
and 3A−C.27 Nucleophilic substitutions of α-aryliodonio diazo
triflates 1A−3A with dimethyl sulfide and triethylamine
proceeded readily at room temperature to the corresponding
substituted α-onium diazo triflate salts 1B−3B and 1C−3C. A
1H NMR experiment of 1A (0.05 M in CDCl3) with 2 equiv of
SMe2 at room temperature showed full conversion to 1B after
20 min. The substitution of the analogous diazophosphonate
2A with SMe2 gave 2B quantitatively after 3 min, and the
diazopiperidinylamide 3A reacted instantaneously to the
corresponding α-dimethylsulfonium diazopiperidinylamide tri-
As a third class of diazo compounds, we prepared the
diazopiperidinylamide triflates 3A−3C in good to high yields
(Scheme 2c). The synthesis of the α-aryliodonium diazopiper-
idinylamide triflate 3A had to be done at −40 °C to avoid
decomposition by loss of iodobenzene. Compound 3A is the
thermally least stable of all synthesized diazo compounds 1A−
1C, 2A−2C, and 3A−3C and had to be kept and stored below
−30 °C.25 α-Dimethylsulfonium and α-triethylammonium
diazopiperidinylamide triflates 3B and 3C are significantly
more stable than 3A and can be kept at room temperature for
several hours without decomposition. The bromodiazopiper-
idinylamide 3A-Br gave a high yield (84%) of the α-bromo-β-
lactam 3D in a thermal intramolecular C−H insertion via the
electrophilic bromination and was therefore chosen as the
substrate.9e
Nucleophilic brominations of 3A with methods 1−3 led to
rapid extrusion of iodobenzene and a color change to red at
temperatures at or below 0 °C (see the Supporting Information
for kinetic measurements). Upon being warmed to room
temperature, the red reaction mixture decolorized, and the
corresponding α-bromo-β-lactam 3D was obtained in a
maximum 51% yield (method 3), along with byproducts from
di- and tribromination and dimerization (3E, 3F, and 3G,
Scheme 4). Unfortunately, it was difficult to obtain
reproducible high yields of lactam 3D, and the product
distributions varied with the conditions (Table 3). A low
concentration of the reaction mixture with respect to 3A
(0.02−0.04 M) and dropwise addition of 1.0−1.1 equiv of a
solution of the bromide source instead of bulk addition
decreased overbromination reactions, but formation of by-
products 3E−3G could never be completely avoided.26 An
average of 18% dibrominated byproduct 3E was obtained via
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Scheme 4. Nucleophilic Bromination of α-Aryliodonio Diazopiperidinylamide Triflate 3A and the Following Thermal
Intramolecular C−H Insertion to α-Bromo-β-lactam 3D with Formation of Byproducts 3E, 3F, and 3G
flate 3B. Nucleophilic halogenations with the tetrabutylammo-
nium halides showed quantitative loss of iodobenzene for 1A
after 35 min with chloride, for the bromination after 14 min,
and for the iodination after 1 min, which indicates a direct
dependence on the nucleophile. In the case of the bromination
and iodination, the corresponding halodiazoesters 1A-Br and
1A-I could be detected in the 1H NMR spectra, whereas for the
chlorination, overlapping signals, probably from dimerizations,
resulted. Thus, iodobenzene was chosen as a reliable indicator
to compare the nucleophilic substitution rates.
no nucleophilic substitution was achieved with the dimethyl-
sulfonium diazo triflates 1B−3B and triethylamine, which was
confirmed by the computational calculations. Furthermore,
nucleophilic halogenations were achieved only with the α-
aryliodonio diazo triflates 1A−3A; no halogenations were
observed with the α-dimethylsulfonium and α-triethylammo-
nium analogues 1B−3B and 1C−3C.
CONCLUSION
■
We have shown that the nucleophilic halogenation of α-
aryliodonio diazoacetate triflate, as well as the corresponding α-
aryliodonio diazophosphonate and α-aryliodonio diazopiper-
idinylamide, is an alternative method to the electrophilic
halogenation for the synthesis of halodiazo compounds. Three
different methods for the nucleophilic halogenations are
presented employing different halide sources. Subsequent
dirhodium(II)-catalyzed intermolecular cyclopropanation of
the halodiazoester and halodiazophosphonate and thermal
intramolecular C−H insertion of the bromodiazopiperidinyla-
mide gave the halocyclopropylesters and halocyclopropylphos-
phopnates and the α-bromo-β-lactam in medium to good
yields. DFT calculations have been performed, the experimental
results were confirmed, and the geometries of the transition
states could be obtained.
Table 3. Obtained Product Distributions and Yields of the
Thermal Intramolecular C−H Insertions with α-
Bromodiazopiperidinylamide 3A-Br
a
yield of 3D
nucleophilic
electrophilic9e
b
b
(cis + trans) (%) cis-3D:trans-3D:3E cis-3D:trans-3D:3E
c
method 1
method 2
method 3
45
40
51
1:6:1.5
1:5:1
84%, 1:6:0.2
d
e
1:6.3:1.3
a
Isolated yields of both diastereomers after two steps after column
b
chromatography. Determined by 1H NMR of crude reaction mixture.
c
Reagents and conditions: 3A (0.1−0.2 mmol) dissolved in dry
CH2Cl2 (3−5 mL) at −30 °C, TBAB (1.05 equiv) in dry CH2Cl2 (3−
5 mL) added dropwise over 15 min, −30 °C for 15 min, −30 °C to rt.
d
Reagents and conditions: 3A (0.1−0.2 mmol) dissolved in dry
CH2Cl2 (3−5 mL), 0 °C, KBr (1.0−1.1 equiv) in H2O (1−2 mL)
added, 0 °C for 15 min, 0 °C to rt. Reagents and conditions: KBr
e
EXPERIMENTAL SECTION
■
General Procedures. 1H NMR spectra were recorded at 500, 400,
and 200 MHz, decoupled 13C NMR spectra at 125 and 100 MHz, and
decoupled 31P NMR spectra at 162 MHz at the given temperatures.
Chemical shifts (δ) are reported in parts per million and referenced to
the residual solvent peak, and J values are given in hertz. Assignments
of protons and carbon atoms have been performed according to
COSY45SW as well as DEPT135 and HMQC NMR spectra. HRMS-
ESI spectra were measured with a QTOF instrument. Flash
chromatography was performed with silica gel (60 Å, 35−70 μm).
Ethyl acetate (EtOAc), diethyl ether (Et2O), and distilled n-hexane
were used as eluents. X-ray diffraction crystallography was performed
at room temperature. Structures have been deposited in the
Cambridge Crystallographic Data Base. Melting points (°C) for all
thermally stable new solid compounds are reported or, if measurable,
decomposition temperatures. Physical data of known compounds were
(1.0−1.1 equiv) and 18-crown-6 (1.5−2.0 equiv) dissolved in dry
CH2Cl2 (5 mL) at rt, added dropwise to a solution of 3A (0.1−0.2
mmol) in dry CH2Cl2 (5 mL) at −30 °C, 15 min at −30 °C, −30 °C
to rt.
Decomposition experiments of 1A, 2A, and 3A in CDCl3 at
room temperature showed quantitative loss of iodobenzene
within 75 min for the diazopiperidinylamide 3A and after 4
days for the diazophosphonate 2A. The diazoester 1A showed
no decomposition even after several days. This indicates a
direct influence of the electron-withdrawing group on the
leaving group activity of iodobenzene. The ester, being the
strongest electron-withdrawing group, deactivates, whereas the
less electron-withdrawing amide has a less stabilizing effect on
the leaving group iodobenzene. The triethylammonium diazo
triflates 1C−3C could only be synthesized from the α-
aryliodonio diazo compounds 1A−3A at room temperature;
1
in agreement with previously published data, and H NMR data are
given. For new compounds synthetic procedures and full character-
izations are reported. (See the Supporting Information for spectra and
graphical plots.)
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The Journal of Organic Chemistry
Article
Preparation and Characterization of Diazo Compounds 1A−
3C. Compounds 1A, 1B, and 1C have been prepared according to the
literature procedure by Weiss et al.10
MHz, CDCl3, 23 °C): δ = 4.26 (dq, J = 14.3 Hz, 7.1 Hz, 4H, CH2),
3.32 (s, 6H, CH3), 1.41 (t, J = 7.1 Hz, 6H, CH3). 13C NMR (125
1
MHz, CD2Cl2, −50 °C): δ = 120.3 (q, J(C,F) = 320 Hz, CF3), 64.4
2
1
(1-Diazo-2-ethoxy-2-oxoethyl)(phenyl)iodonium Triflate
(d, J(C,P) = 4.8 Hz, CH2), 42.0 (d, J(C,P) = 213 Hz, CN2), 28.9
(CH3), 15.9 (d, 3J(C,P) = 7.9 Hz, CH3). 31P NMR (162 MHz, CDCl3,
(1A). Yellow crystalline solid. Yield: 10.45 g (22.4 mmol, 86%).
1
23 °C): δ = 7.87. IR (solution, DCM, cm−1): v = 2130, 1286, 1028,
Decomposition temperature: 80 °C. H NMR (400 MHz, CDCl3, 23
̃
751, 640, 595. MS (ESI): m/z (rel intens) 239.1 (100) [M+]. HRMS
(ESI): m/z calcd for C7H16N2O3PS+ 239.0619, found 239.0615 (1.7
ppm).
°C): δ = 8.08 (d, J = 8.0 Hz, 2H, ArH), 7.65 (t, J = 7.3 Hz, 1H, ArH),
7.49 (t, J = 7.6 Hz, 2H, ArH), 4.32 (q, J = 7.0 Hz, 2H, CH2), 1.30 (t, J
= 7.0 Hz, 3H, CH3). 13C NMR (125 MHz, CD2Cl2, −50 °C): δ =
161.8 (CO), 135.4 (CHAr), 133.2 (CHAr), 131.9 (CHAr), 119.6 (q,
1J(C,F) = 320 Hz, CF3), 116.8 (C), 64.3 (CH2), 41.7 (CN2), 14.1
N-(Diazo(diethoxyphosphoryl)methyl)-N,N-diethylethana-
minium Triflate (2C). 2A (0.487 g, 0.91 mmol, 1.0 equiv) was
dissolved in dry CH2Cl2 (15 mL) at 0 °C. To this solution was added
triethylamine (0.134 mL, 0.097 g, 1.05 mmol, 1.05 equiv). The mixture
was strirred at 0 °C for 1 h and then concentrated in vacuo at 20 °C.
The residue was dried in high vacuum to afford 0.275 g (0.646 mmol,
71%) of 2C as a yellow oil. The product was kept in the refrigerator
(CH ). IR (solution, DCM, cm−1): v = 2110, 1706, 1280, 1024, 637.
̃
3
MS (ESI): m/z (rel intens) 317.0 (100) [M+]. HRMS (ESI): m/z
+
calcd for C10H10IN2O2 316.9787 [M+], found 316.9793 (1.9 ppm).
(1-Diazo-2-ethoxy-2-oxoethyl)dimethylsulfonium Triflate
(1B). White crystalline solid. Yield: 1.269 g (3.9 mmol, 89%). Mp:
1
1
76 °C. H NMR (400 MHz, CDCl3, 23 °C): δ = 4.35 (q, J = 7.1 Hz,
below 5 °C without decomposition. H NMR (400 MHz, CDCl3, 23
2H, CH2), 3.32 (s, 6H, CH3), 1.34 (t, J = 7.1 Hz, 3H, CH3). 13C NMR
°C): δ = 4.36−4.23 (m, 4H, CH2), 3.75 (q, J = 7.1 Hz, 4H, CH2), 3.17
(qd, J = 7.3 Hz, 5.0 Hz, 2H, CH2), 1.48 (t, J = 7.1 Hz, 6H, CH3),
1.45−1.34 (m, 9H, CH3); the three CH2 groups and the CH3 groups
of the NEt3 unit are unequal and split into two signals of four and two
protons and three and six protons, respectively (identified by COSY).
13C NMR (100 MHz, CDCl3, 23 °C): δ = 120.8 (q, 1J(C,F) = 320 Hz,
CF33), 65.6 (d, 2J(C,P) = 6.4 Hz, CH2), 57.2 (CH2), 47.0 (CH2), 16.3
(d, J(C,P) = 6.4 Hz, CH2), 8.8 (CH3), 8.4 (CH3). 31P NMR (162
1
(125 MHz, CD2Cl2, −50 °C): δ = 160.4 (CO), 120.3 (q, J(C,F) =
320 Hz, CF3), 63.4 (CH2), 26.6 (CH3), 14.00 (CH3). 13C NMR (100
MHz, CDCl , 23 °C): δ = 55.2 (CN ). IR (solution, DCM, cm−1): v =
̃
3
2
2151, 1710, 1282, 1032, 751, 640. MS (ESI): m/z (rel intens) 175.0
(100) [M+]. HRMS (ESI): m/z calcd for C6H11N2O2S+ 175.0541,
found 175.0546 (2.9 ppm). Assignment and structure elucidation are
supported by an X-ray crystallographic structure.
1-Diazo-2-ethoxy-N,N,N-triethyl-2-oxoethanaminium Tri-
flate (1C). Light yellow crystalline solid. Yield: 0.361 g (0.99 mmol,
51%). Mp: 88 °C. 1H NMR (400 MHz, CDCl3, 23 °C): δ = 4.35 (q, J
= 7.1 Hz, 2H, CH2), 3.86 (q, J = 7.1 Hz, 6H, CH2), 1.44 (t, J = 7.1 Hz,
9H, CH3), 1.34 (t, J = 7.1 Hz, 3H, CH3). 13C NMR (100 MHz,
MHz, CDCl , 23 °C): δ = 7.20. IR (solution, DCM, cm−1): v = 2085,
̃
3
1285, 1027, 640. MS (ESI): m/z (rel intens) 278.2 (100) [M+].
HRMS (ESI): m/z calcd for C11H25N3O3P+ 278.1634, found 278.1630
(1.4 ppm).
(1-Diazo-2-oxo-2-(piperidin-1-yl)ethyl)(phenyl)iodonium
Triflate (3A). Diacetoxyiodobenzene (0.603 g, 1.87 mmol, 1.0 equiv)
was dissolved in dry CH2Cl2 (10 mL) and the solution cooled to −40
°C. To this solution was added (TMS)OTf (0.361 mL, 1.87 mmol, 1.0
equiv) in one portion, followed by dropwise addition of 2-diazo-1-
(piperidin-1-yl)ethanone (0.287 g,1.87 mmol, 1.0 equiv) dissolved in
dry CH2Cl2 (5 mL). The mixture turned red, and some gas evolution
occurred. The red solution was stirred at −40 °C for 15 min. Et2O was
added until the mixture became cloudy. At this point the temperature
was raised to 0 °C, and more Et2O was added in small portions until
precipitation occurred. The mixture was stirred at 0 °C for 15 min and
then cooled again to −40 °C to complete precipitation. The solid was
filtered off quickly with suction and washed with −40 °C cooled Et2O
to afford 0.611 g (1.21 mmol, 65%) of 3A as an orange solid. The
product has to be kept below −20 °C to avoid thermal decomposition.
1H NMR (500 MHz, CD2Cl2, −18 °C): δ = 8.18−8.10 (m, 2H, ArH),
1
CDCl3, 23 °C): δ = 160.0 (CO), 120.9 (q, J(C,F) = 320 Hz, CF3),
63.5 (CH2), 56.4 (CH2), 14.3 (CH3), 8.49 (CH3), CN2 could not be
detected. IR (solution, DCM, cm−1): v = 2103, 1713, 1255, 1031, 639.
̃
MS (ESI): m/z (rel intens) 214.2 (100) [M+]. HRMS (ESI): m/z
+
calcd for C10H20N3O2 214.1556, found 214.1558 (0.9 ppm).
Assignment and structure elucidation are supported by an X-ray
crystallographic structure.
(Diazo(diethoxyphosphoryl)methyl)(phenyl)iodonium Tri-
flate (2A). Diacetoxyiodobenzene (1.496 g, 4.64 mmol, 1.0 equiv)
was dissolved in dry CH2Cl2 (30 mL) at room temperature. To this
solution was added trimethylsilyl trifluoromethanesulfonate, (TMS)-
OTf (0.9 mL, 4.64 mmol, 1.0 equiv), in one portion, followed by
dropwise addition of diethyl diazomethanephosphonate, EDP (0.827
g, 4.64 mmol, 1.0 equiv), dissolved in dry CH2Cl2 (2 mL). The
mixture became orange, and some gas evolution occurred. The orange
solution was stirred at room temperature for 15 min, and then Et2O
was added until the mixture became cloudy and precipitation occurred.
The mixture was cooled to 0 °C with an ice bath and stirred for 30 min
to complete precipitation. The solid was filtered off with suction and
washed with cold Et2O to afford 1.755 g (3.3 mmol, 72%) of 2A as a
yellow amorphous solid. The product has to be kept below 5 °C to
avoid thermal decomposition. 1H NMR (500 MHz, CD2Cl2, −50 °C):
δ = 8.10 (d, J = 7.8 Hz, 2H, ArH), 7.69 (t, J = 7.5 Hz, 1H, ArH), 7.51
(t, J = 7.8 Hz, 2H, ArH), 4.01−3.86 (m, 2H, CH2), 3.86−3.69 (m, 2H,
CH2), 1.11 (t, J = 7.1 Hz, 6H, CH3). 13C NMR (125 MHz, CD2Cl2,
−50 °C): δ = 135.4 (CHAr), 133.3 (CHAr), 131.9 (CHAr), 119.7 (q,
7.71−7.65 (m, 1H, ArH), 7.54−7.48 (m, 2H, ArH), 3.40−3.35 (m,
4H, CH2), 1.65−1.56 (m, 2H, CH2), 1.56−1.46 (m, 4H, CH2). 13C
NMR (125 MHz, CD2Cl2, −50 °C): δ = 159.2 (CO), 135.8 (CHAr),
1
133.2 (CHAr), 131.8 (CHAr), 119.8 (q, J(C,F) = 320 Hz, CF3),
115.9 (C), 46.7 (CN2), 25.4 (CH2), 24.0 (CH2). 13C NMR (125
MHz, CD Cl , −18 °C): δ = 47.6 (CH ). IR (solution, DCM, cm−1): v
̃
2
2
2
= 2075, 1642, 1023, 638. MS (ESI): m/z (rel intens) 356.0 (18) [M+],
328 (100) [M+ − N2], 245 (95), 201 (32). HRMS (ESI): m/z calcd
for C13H15IN3O+ 356.0260, found 356.0267 (2.0 ppm).
(1-Diazo-2-oxo-2-(piperidin-1-yl)ethyl)dimethylsulfonium
Triflate (3B). 3A (0.046 g, 0.092 mmol, 1.0 equiv) was dissolved in
dry CH2Cl2 (2.5 mL) at −30 °C. To this solution was added dimethyl
sulfide (8.1 μL, 6.9 mg, 0.111 mmol, 1.2 equiv) with stirring in one
portion. The mixture changed from orange to light yellow and was
strirred at −30 °C for 1 h and then concentrated in vacuo at 0 °C. The
residue was dried in high vacuum to afford 32.9 mg (0.090 mmol,
98%) of 3B as a light yellow amorphous solid. The product was kept in
2
1J(C,F) = 320 Hz, CF3), 117.1 (C), 64.3 (d, J(C,P) = 5.0 Hz, CH2),
25.3 (d, 1J(C,P) = 217 Hz, CN2), 15.8 (d, 3J(C,P) = 7.9 Hz, CH3). 31
P
NMR (162 MHz, CDCl3, 23 °C): δ = 9.61. IR (solution, DCM,
cm−1): v = 2090, 1261, 1023, 638. MS (ESI): m/z (rel intens) 381.0
̃
(100) [M+]. HRMS (ESI): m/z calcd for C11H15IN2O3P+ 380.9865,
found 380.9878 (3.4 ppm).
(Diazo(diethoxyphosphoryl)methyl)dimethylsulfonium Tri-
flate (2B). 2A (0.621 g, 1.17 mmol, 1.0 equiv) was dissolved in dry
CH2Cl2 (15 mL) at 0 °C. To this solution was added dimethyl sulfide
(0.215 mL, 0.182 g, 2.93 mmol, 2.5 equiv) with stirring. The mixture
decolorized and was strirred at 0 °C for 1 h and then concentrated in
vacuo at 20 °C. The residue was dried in high vacuum to afford 0.445
g (1.146 mmol, 98%) of 2B as a colorless oil. The product was kept in
1
the freezer below −20 °C without decomposition. Mp: 63 °C. H
NMR (400 MHz, CDCl3, 23 °C): δ = 3.50−3.39 (m, 4H, CH2), 3.34
(s, 6H, CH3), 1.72−1.64 (m, 2H, CH2), 1.64−1.55 (m, 4H, CH2). 13
C
NMR (100 MHz, CDCl3, 23 °C): δ = 159.2 (CO), 120.7 (q, 1J(C,F) =
320 Hz, CF3), 54.1 (CH2), 46.8 (CN2), 28.2 (CH3), 25.8 (CH2), 24.3
(CH ). IR (solution, DCM, cm−1): v = 2115, 1638, 1165, 1031, 751,
̃
2
1
the refrigerator below 5 °C without decomposition. H NMR (400
639. MS (ESI): m/z (rel intens) 214.1 (100) [M+], 186 (33) [M+ −
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The Journal of Organic Chemistry
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N2]. HRMS (ESI): m/z calcd for C9H16N3OS+: 214.1014, found
214.1018 (1.9 ppm).
for 1 h. Dry toluene (2 mL) was added and the CH2Cl2 removed in
vacuo at 0 °C. The residual was redissolved by addition of a minimum
amount of dry CH2Cl2 at 0 °C, and styrene (5 equiv), followed by a
solution of Rh2(esp)2 (2 mol %) in dry toluene (1 mL), was added.
The mixture was allowed to warm to room temperature, stirred for 1 h,
and then concentrated in vacuo. The product was purified by flash
column chromatography with n-hexane/EtOAc (100:0 to 5:1) for the
esters and n-hexane/EtOAc (100:0 to 2:1) for the phosphonates to
afford the halocyclopropylesters 1D and 1E in 49−77% isolated yields
and the halocyclopropanephosphonates 2D and 2E in 49−66%
isolated yields as a mixture of both diastereomers.
General Procedure for the Thermal Intramolecular C−H
Insertion of Brominated 3A: Method 1. 3A (0.1−0.2 mmol, 1
equiv) was dissolved in dry CH2Cl2 (3−5 mL) at −30 °C. To this
solution was added dropwise tetrabutylammonium bromide (1.05
equiv) in dry CH2Cl2 (3−5 mL) over 15 min. The red solution was
stirred at −30 °C for a further 15 min, then allowed to warm to room
temperature, and left with or without stirring until full decolorization
(30−60 min). The reaction mixture was left at room temperature for
an additional 1 h and then concentrated in vacuo. The product was
purified by flash column chromatography with n-hexane/Et2O (95:5 to
1:1 to 0:100) to afford 45% α-bromo-β-lactam 3D as a mixture of both
diastereomers.
General Procedure for the Thermal Intramolecular C−H
Insertion of Brominated 3A: Method 2. 3A (0.1−0.2 mmol, 1
equiv) was dissolved in dry CH2Cl2 (3−5 mL) at 0 °C. A solution of
KBr (1.0−1.1 equiv) in distilled H2O (1−2 mL) was added in one
portion immediately thereafter with stirring. The organic phase turned
red immediately, and the biphasic solution was stirred at 0 °C for 15
min and then allowed to warm to room temperature. Decolorization of
the organic phase occurred within ca. 30 min, and the mixture was
stirred for another 30 min at room temperature. The organic phase
was then separated and the aqueous phase diluted with H2O (2 mL)
and extracted with dry CH2Cl2 (3 mL). The combined organics were
dried over MgSO4, filtered, and concentrated in vacuo. The remaining
crude oil was purified by flash column chromatography with n-hexane/
Et2O (95:5 to 1:1 to 0:100) to afford 40% α-bromo-β-lactam 3D as a
mixture of both diastereomers.
General Procedure for the Thermal Intramolecular C−H
Insertion of Brominated 3A: Method 3. KBr (1.0−1.1 equiv) and
18-crown-6 (1.5−2.0 equiv) were stirred in dry CH2Cl2 (5 mL) at
room temperature until fully dissolved. This mixture was then added
dropwise over 15 min to a solution of 3A (0.1−0.2 mmol) in dry
CH2Cl2 (5 mL) at −30 °C. The deep red mixture was stirred for an
additional 15 min at −30 °C and then allowed to warm to room
temperature. Full decolorization occurred after 30 min, and the
mixture was then concentrated in vacuo at 20 °C. The remaining solid
was treated with a 1:3 mixture of Et2O/n-hexane (3 mL) and CH2Cl2
(0.5 mL) and the undissolved solid (18-crown-6) filtered off. The
remaining solution was purified by flash column chromatography with
n-hexane/Et2O (95:5 to 1:1 to 0:100) to afford 51% α-bromo-β-lactam
3D as a mixture of both diastereomers.
1-Diazo-N,N,N-triethyl-2-oxo-2-(piperidin-1-yl)ethanamin-
ium Triflate (3C). 3A (0.1135 g, 0.224 mmol, 1.0 equiv) was
dissolved in dry CH2Cl2 (5 mL) at 0 °C. To this solution was added
triethylamine (31.2 μL, 22.7 mg, 0.224 mmol, 1.0 equiv). The solution
changed from orange to yellow and was strirred at 0 °C for 30 min.
Et2O was added until the mixture became cloudy, and then the mixture
was warmed to room temperature until the solution became clear
again. Et2O was added until the mixture became cloudy again, and
precipitation occurred upon cooling to 0 °C. The mixture was stirred
at that temperature for 30 min. The obtained solid was filtered with
suction to afford 3C as a yellow, amorphous, sticky solid. The solid
product was collected from the filter paper, with the remaining solid
dissolved in CH2Cl2 and concentrated in vacuo at room temperature
to afford a second batch of a yellow oil of 3C with an overall yield of
54.0 mg (0.134 mmol, 60%). 3C was stored in the freezer below −20
°C but can also be handled at higher temperatures without
1
decomposition. H NMR (500 MHz, CD2Cl2, −50 °C): δ = 3.76
(q, J = 7.2 Hz, 6H, CH2), 3.44−3.33 (m, 4H, CH2), 1.70−1.60 (m,
2H, CH2), 1.60−1.46 (m, 4H, CH2), 1.37 (t, J = 7.2 Hz, 9H, CH3).
13C NMR (125 MHz, CD2Cl2, −10 °C): δ = 158.7 (CO), 121.0 (q,
1J(C,F) = 320 Hz, CF3), 77.1 (CN2), 56.1 (CH2), 46.9 (CH2), 25.7
(CH ), 24.4 (CH ), 8.5 (CH ). IR (solution, DCM, cm−1): v =
̃
2
2
3
2077,1639, 1257, 1032, 761, 707, 639. MS (ESI): m/z (rel intens)
253.3 (33) [M+], 225.3 (100) [M+ − N2], 142 (18). HRMS (ESI): m/
z calcd for C13H25N4O+ 253.2028, found 253.2021 (2.8 ppm).
General Procedure for the Intermolecular Cyclopropana-
tions of Halogenated 1A and 2A: Method 1. α-Aryliodonium
diazoacetate triflate 1A or phosphonate 2A (0.1−0.2 mmol, 1.0 equiv)
was dissolved in dry CH2Cl2 (1−2 mL) at 0 °C. Tetrabutylammonium
halide, TBAX (X = I, Br, Cl, 1.5 equiv), was added in one portion. The
mixture was stirred for 1 h at 0 °C, and then dry toluene (2 mL) was
added and the CH2Cl2 removed in vacuo at 0 °C. To the residue was
added styrene (5 equiv) at 0 °C followed by a solution of Rh2(esp)2 (2
mol %) in dry toluene (1 mL). The mixture was allowed to warm to
room temperature and stirred for 1 h. The mixture was concentrated
in vacuo and the product purified by flash column chromatography
with n-hexane/EtOAc (100:0 to 5:1) for the esters and n-hexane/
EtOAc (100:0 to 2:1) for the phosphonates to afford the
halocyclopropyl esters 1D−1F in 50−67% isolated yields and the
halocyclopropanephosphonates 2D−2F in 63−71% isolated yields as a
mixture of both diastereomers.
General Procedure for the Intermolecular Cyclopropana-
tions of Halogenated 1A and 2A: Method 2. α-Aryliodonium
diazoacetate triflate 1A or phosphonate 2A (0.1−0.2 mmol, 1.0 equiv)
was dissolved in dry CH2Cl2 (1 mL) at 0 °C. A solution of potassium
halide, KX (X = I, Br, Cl, 1.5 equiv), in distilled H2O (1 mL) was
added in one portion. The biphasic mixture was stirred at 0 °C for 10
min for X = I and Br and 30 min for X = Cl. The organic phase was
then separated and passed through a MgSO4/Celite plug with −30 °C
cooled CH2Cl2 as the eluent into a flask containing dry toluene (2
mL) at −30 °C. The remaining aqueous residue was extracted twice
with 0 °C cooled CH2Cl2, and the organic phases were also passed
through the MgSO4/Celite plug. The CH2Cl2 was removed in vacuo at
0 °C, and to the residual reaction mixture was added styrene (5 equiv)
followed by a solution of Rh2(esp)2 (2 mol %) in dry toluene (1 mL)
at 0 °C. The mixture was allowed to warm to room temperature and
stirred for 1 h. The mixture was concentrated in vacuo and the product
purified by flash column chromatography with n-hexane/EtOAc
(100:0 to 5:1) for the esters and n-hexane/EtOAc (100:0 to 2:1)
for the phosphonates to afford the halocyclopropyl esters 1D−1F in
26−66% isolated yields and the halocyclopropanephosphonates 2D
and 2E in 55−70% isolated yields as a mixture of both diastereomers.
General Procedure for the Intermolecular Cyclopropana-
tions of Halogenated 1A and 2A: Method 3. Potassium halide
(KBr or KI, 1.5 equiv) and 18-crown-6 (2.0 equiv) were stirred in dry
CH2Cl2 (1 mL) at 0 °C until fully dissolved (approximately 20−30
min). α-Aryliodonium diazoacetate triflate 1A or phosphonate 2A
(0.1−0.2 mmol, 1.0 equiv) was added and the mixture stirred at 0 °C
Characterization of trans-Cyclopropanes 1D−1F and 2D−
2F, trans-α-Bromo-β-lactam 3D, and Byproducts 3E and 3F.
Halocyclopropyl esters 1D−1F9d and halocyclopropanephosphonates
2D−2F9a have been fully characterized before; thus, only H NMR
1
data are given. 1H NMR data of trans-α-bromo-β-lactam 3D
correspond to the reported data in the literature.28
trans-Ethyl 1-Iodo-2-phenylcyclopropanecarboxylate (1D).
1
Yield: 54.5 mg (0.17 mmol, 66%, with method 2). H NMR (200
MHz, CDCl3, 23 °C): δ = 7.38−7.29 (m, 3H, ArH), 7.23−7.15 (m,
2H, ArH), 4.23 (q, J = 7.1 Hz, 2H, CH2), 2.64−2.50 (m, 1H, CH),
2.29 (dd, J = 9.9 Hz, 5.8 Hz, 1H, CH2), 1.74 (dd, J = 8.2 Hz, 5.8 Hz,
1H, CH2), 1.32 (t, J = 7.1 Hz, 3H, CH3).
trans-Ethyl 1-Bromo-2-phenylcyclopropanecarboxylate
1
(1E). Yield: 40.3 mg (0.15 mmol, 77%, with method 3). H NMR
(200 MHz, CDCl3, 23 °C): δ = 7.39−7.30 (m, 3H, ArH), 7.29−7.21
(m, 2H, ArH), 4.28 (q, J = 7.1 Hz, 2H, CH2), 3.03−2.89 (m, 1H, CH),
2.22 (dd, J = 10.1 Hz, 6.0 Hz, 1H, CH2), 1.81 (dd, J = 8.5 Hz, 6.0 Hz,
1H, CH2), 1.35 (t, J = 7.1 Hz, 3H, CH3).
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trans-Ethyl 1-Chloro-2-phenylcyclopropanecarboxylate
determination, Dirk Petersen and Frode Rise (UiO) for
NMR assistance, and Osamu Sekiguchi for MS service.
1
(1F). Yield: 21.8 mg (0.097 mmol, 50%, with method 1). H NMR
(200 MHz, CDCl3, 23 °C): δ = 7.42−7.33 (m, 3H, ArH), 7.33−7.25
(m, 2H, ArH), 4.33 (q, J = 7.1 Hz, 2H, CH2), 3.21−3.05 (m, 1H, CH),
2.20 (dd, J = 10.1 Hz, 6.0 Hz, 1H, CH2), 1.80 (dd, J = 8.5 Hz, 6.0 Hz,
1H, CH2), 1.39 (t, J = 7.1 Hz, 3H, CH3).
REFERENCES
■
(1) For selected examples of catalyst-free reactions with diazo
compounds, see the following papers. Cycloadditions: (a) McGrath,
N. A.; Raines, R. T. Chem. Sci. 2012, 3 (11), 3237−3240. (b) Sha, Q.;
Wei, Y. Synthesis 2013, 45, 413−420. (c) Ovalles, S. R.; Hansen, J. H.;
Davies, H. M. L. Org. Lett. 2011, 13 (16), 4284−4287.
(d) Muruganantham, R.; Mobin, S. M.; Namboothiri, I. N. N. Org.
Lett. 2007, 9 (6), 1125−1128. For a review on Wolff rearrangements,
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For the original publication on the Arndt−Eistert homologation, see:
(f) Arndt, F.; Eistert, B. Ber. Dtsch. Chem. Ges. 1935, 68 (1), 200−208.
Seyferth−Gilbert reaction: (g) Seyferth, D.; Marmor, R. S.; Hilbert, P.
J. Org. Chem. 1971, 36 (10), 1379−86.
trans-Diethyl 1-Iodo-2-phenylcyclopropanephosphonate
(2D). Yield: 42.3 mg (0.11 mmol, 70%, with method 2). Rf = 0.14
1
(50% EtOAc/n-hexane). H NMR (200 MHz, CDCl3, 23 °C): δ =
7.38−7.29 (m, 3H, ArH), 7.23−7.08 (m, 2H, ArH), 4.32−4.14 (m,
4H, CH2), 2.48 (ddd, J = 13.8 Hz, 10.2 Hz, 7.6 Hz; 1H, CH), 2.22−
2.06 (m, 1H, CH2), 1.61 (ddd, J = 10.2 Hz, 7.6 Hz, 6.2 Hz, 2H, CH2),
1.47−1.33 (m, 6H, CH3).
trans-Diethyl 1-Bromo-2-phenylcyclopropanephosphonate
(2E). Yield: 38.2 mg (0.11 mmol, 71%, with method 1). Rf = 0.18 (50%
1
EtOAc/n-hexane). H NMR (200 MHz, CDCl3, 23 °C): δ = 7.38−
7.28 (m, 3H, ArH), 7.25−7.17 (m, 2H, ArH), 4.34−4.18 (m, 4H,
CH2), 2.87 (ddd, J = 12.8 Hz, 10.0 Hz, 8.2 Hz, 1H, CH), 2.05 (ddd, J
= 13.7 Hz, 10.0 Hz, 6.5 Hz, 1H, CH2), 1.68 (td, J = 8.2 Hz, 6.5 Hz,
1H, CH2), 1.40 (td, J = 6.7 Hz, 1.9 Hz, 6H, CH3).
(2) For selected examples of different transition-metal-catalyzed
carbenoid transformations, see the following papers. (a) Zhu, S.-F.;
Zhou, Q.-L. Acc. Chem. Res. 2012, 45 (8), 1365−1377. Rhodium:
(b) Hansen, J.; Davies, H. M. L. Coord. Chem. Rev. 2008, 252 (5−7),
545−555. (c) Doyle, M. P. J. Org. Chem. 2006, 71 (25), 9253−9260.
(d) Timmons, D.; Doyle, M. Chiral Dirhodium(II) Catalysts and
Their Applications. In Multiple Bonds between Metal Atoms; Cotton, F.
A., Murillo, C. A., Walton, R. A., Eds.; Springer: New York, 2005; pp
591−632. Copper: (e) Zhao, X.; Zhang, Y.; Wang, J. Chem. Commun.
2012, 48 (82), 10162−10173. Palladium: (f) Zhang, Y.; Wang, J. Eur.
J. Org. Chem. 2011, 6, 1015−1026. Silver: (g) Li, Z.; He, C. Eur. J. Org.
Chem. 2006, 2006 (19), 4313−4322. Ruthenium: (h) Maas, G. Chem.
Soc. Rev. 2004, 33 (3), 183−190. Iron: (i) Morandi, B.; Carreira, E. M.
Science 2012, 335 (6075), 1471−1474.
trans-Diethyl 1-Chloro-2-phenylcyclopropanephosphonate
(2F). Yield: 19.2 mg (0.066 mmol, 63%, with method 1). Rf = 0.2
1
(50% EtOAc/n-hexane). H NMR (200 MHz, CDCl3, 23 °C): δ =
7.45−7.32 (m, 3H, ArH), 7.32−7.19 (m, 2H, ArH), 4.39−4.20 (m,
4H, CH2), 3.14−2.92 (m, 1H, CH), 2.03 (ddd, J = 13.0 Hz, 10.1 Hz,
6.1 Hz, 1H, CH2), 1.67 (dd, J = 14.4 Hz, 7.7 Hz, 1H, CH2), 1.44 (d, J
= 7.1 Hz, 6H, CH3).
trans-7-Bromo-1-azabicyclo[4.2.0]octan-8-one (3D). Yield:
1
13.4 mg (0.067 mmol, 51%, with method 3). H NMR (400 MHz,
CDCl3, 23 °C): δ = 4.42 (d, J = 1.3 Hz, 1H, CH), 3.87 (dd, J = 13.3
Hz, 4.5 Hz, 1H, CH2), 3.55 (dd, J = 10.8 Hz, 4.4 Hz, 1H, CH), 2.84−
2.75 (m, 1H, CH2), 2.21−2.12 (m, 1H, CH2), 1.96−1.89 (m, 1H,
CH2), 1.74−1.66 (m, 1H, CH2), 1.46−1.38 (m, 2H, CH2), 1.31−1.19
(m, 2H, CH2). 13C NMR (100 MHz, CDCl3, 23 °C): δ = 161.8 (CO),
59.3 (CH), 48.5 (CH), 39.8 (CH2), 29.6 (CH2), 24.6 (CH2), 22.1
(CH2). MS (EI): m/z (rel intens) 203/205 (3/3) [M+], 134 (12), 132
(12), 124 (100), 81 (13), 41 (16). HRMS (EI): m/z calcd for
C7H10BrNO: 202.9946, found 202.9944 (1.0 ppm).
(3) For a review of reactions of diazocarbonyl compounds, see:
Zhang, Z.; Wang, J. Tetrahedron 2008, 64 (28), 6577−6605.
(4) For a review of cyclopropanations, see: Pellissier, H. Tetrahedron
2008, 64 (30−31), 7041−7095.
(5) For reviews, see: (a) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou,
L. Chem. Rev. 2010, 110 (2), 704−724. (b) Davies, H.; Dick, A. Top.
Curr. Chem. 2010, 292, 303−345. (c) Davies, H. M. L.; Manning, J. R.
Nature 2008, 451 (7177), 417−424. (d) Diaz-Requejo, M. M.;
Belderrain, T. R.; Nicasio, M. C.; Perez, P. J. Dalton Trans. 2006, 47,
5559−5566. (e) Davies, H. M. L. Angew. Chem., Int. Ed. 2006, 45 (39),
6422−6425.
1
2,2-Dibromo-1-(piperidin-1-yl)ethanone (3E). H NMR (400
MHz, CDCl3, 23 °C): δ = 6.14 (s, 1H, CH), 3.68−3.55 (m, 4H, CH2),
1.69 (s, 4H, CH2), 1.61 (s, 2H, CH2). 13C NMR (100 MHz, CDCl3,
23 °C): δ = 48.4 (CH2), 44.7 (CH2), 35.7 (CH), 25.9 (CH2), 25.6
(CH2), 24.3 (CH2). MS (EI): m/z (rel intens) 283/285/287 (2/5/2)
[M+], 204/206 (36/36), 112 (100), 84 (12), 69 (41), 55 (11), 41
(23).
(6) For a review, see: Padwa, A. Helv. Chim. Acta 2005, 88 (6),
1357−1374.
(7) For reviews of the synthesis of diazo compounds, see: (a) Maas,
G. Angew. Chem., Int. Ed. 2009, 48 (44), 8186−8195. (b) Heydt, H.
Sci. Synth. 2004, 27, 843−935.
2,2,2-Tribromo-1-(piperidin-1-yl)ethanone (3F). 1H NMR
(400 MHz, CDCl3, 23 °C): δ = 3.79 (s, 4H, CH2), 1.69 (s, 6H,
CH2). 13C NMR (100 MHz, CDCl3, 23 °C): δ = 158.9 (CO), 37.0
(C), 31.1 (CH2), 25.7 (CH2), 24.1 (CH2). MS (EI): m/z (rel intens)
361/363/365/367 (1/2/2/1) [M+], 282/284/286 (3/6/3), 112
(100), 84 (7), 69 (38), 55 (12), 41 (29).
(8) For a review of electrophilic functionalizations of diazo
compounds, see: Zhang, Y.; Wang, J. Chem. Commun. 2009, 36,
5350−5361.
(9) Electrophilic halogenations of diazophosphonates: (a) Schnaars,
C.; Hansen, T. Org. Lett. 2012, 14 (11), 2794−2797. Electrophilic
halogenations of diazoesters: (b) Bonge, H. T.; Hansen, T. Pure Appl.
Chem. 2011, 83 (3), 565−575. (c) Bonge, H. T.; Hansen, T. Synthesis
2009, 2009, 91−96. (d) Bonge, H. T.; Pintea, B.; Hansen, T. Org.
Biomol. Chem. 2008, 6 (20), 3670−3672. Electrophilic halogenations
of diazoacetamides: (e) Kaupang, Å. Master thesis, University of Oslo,
Norway, 2010; https://www.duo.uio.no/handle/123456789/12702;
manuscript accepted for publication in Beilstein J. Org. Chem.
(10) Weiss, R.; Seubert, J.; Hampel, F. Angew. Chem., Int. Ed. 1994,
33 (19), 1952−1953.
ASSOCIATED CONTENT
* Supporting Information
NMR spectra for all relevant compounds, kinetic plots, and
computational and crystallographic (CIF) data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: tore.bonge-hansen@kjemi.uio.no.
Notes
■
(11) Nucleophilic halogenations starting from α-aryliodonio
diazoacetate triflate 1A was first proposed by Heydt; see ref 7b.
(12) Crystal structures have been deposited on the Cambridge
Crystallographic Data Base: 1B, CCDC 914760; 1C, CCDC 914758.
The authors declare no competing financial interest.
1
(13) The generation of iodobenzene was followed over time via H
ACKNOWLEDGMENTS
NMR. See the Supporting Information for 1H NMR spectra and
kinetic plots.
■
Financial support from the Norwegian Research Council (NFR,
KOSK II) is greatly acknowledged. We thank Vitthal N. Yadav
(University of Oslo, UiO) for X-ray crystal structure
(14) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem.
Soc. 2004, 126 (47), 15378−15379.
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(15) Compound 1A is partially soluble in H2O, and 1A and the
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given in the Supporting Information.
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1
(24) Iodobenzene is released in CDCl3 at room temperature. H
NMR experiments have shown approximately 50% decomposition of
2A in CDCl3 after 24 h.
(25) 1H NMR experiments of 3A in CDCl3 showed quantitative loss
of iodobenzene and decolorization after 75 min at room temperature,
whereas 1A and 2A were stable for several hours.
(26) The overbrominated byproducts 3E and 3F could formally
result from insertion of the carbene of the brominated 3A-Br or
nonbrominated diazopiperidinylamide 3A into elemental bromine,
which may have been formed in small amounts during the reaction.
Attempts to suppress formation of elemental bromine, however, did
not change the ratio of product to byproducts.
(27) The amount of iodobenzene over time was monitored as an
indicator for the conversion. All NMR spectra for the conversion
measurements over time can be found in the Supporting Information.
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