Novel nitrogen containing chelating ligands from aziridines -Preparation, coordination studies, and catalytic application in the cyclopropanation of styrene

Article abstract of DOI:10.1139/v05-113

Novel ligands have been synthesized by the reaction of readily available aziridines with appropriate nitrogen based nucleophiles under mild conditions. Complexes of different stoichiometry can be readily obtained upon reaction between these ligands and the corresponding copper salts. The enantiomerically pure form of one of the ligands was obtained and applied in the styrene cyclopropanation reaction, where the copper catalyst revealed unexpectedly high diastereoselectivity in comparison with the known systems.

Full text of DOI:10.1139/v05-113

1025
Novel nitrogen containing chelating ligands from
aziridines — Preparation, coordination studies,
and catalytic application in the cyclopropanation
of styrene1
Larissa B. Krasnova and Andrei K. Yudin
Abstract: Novel ligands have been synthesized by the reaction of readily available aziridines with appropriate nitrogen
based nucleophiles under mild conditions. Complexes of different stoichiometry can be readily obtained upon reaction
between these ligands and the corresponding copper salts. The enantiomerically pure form of one of the ligands was
obtained and applied in the styrene cyclopropanation reaction, where the copper catalyst revealed unexpectedly high
diastereoselectivity in comparison with the known systems.
Key words: ligands, aziridines, cyclopropanation, copper catalysts, metal complexes.
Résumé : On a effectué la synthèse de nouveaux ligands en procédant à la réaction, dans des conditions douces,
d’aziridines facilement disponibles avec des nucléophiles appropriés à base d’azote. On peut facilement obtenir des
complexes de stoechiométries différentes par réaction de ces ligands avec les sels de cuivre correspondants. On a pu
obtenir la forme énantiomériquement pure d’un de ces ligands et on l’a appliquée à la réaction de cyclopropanation du
styrène pour laquelle le catalyseur de cuivre conduit à une diastéréosélectivité aussi haute qu’inattendue par comparai-
son avec les systèmes connus.
Mots clés : ligands, aziridines, cyclopropanation, catalyseurs de cuivre, complexes métalliques.
[Traduit par la Rédaction] Krasnova and Yudin 1032
Introduction
groups. The present manuscript details our explorations in
this area.
Cheleating ligands based on a rigid cyclohexyl backbone
have been widely used in asymmetric catalysis (1). Among
them is Trost’s ligand for asymmetric palladium catalyzed
allylic substitution (2), alkylation of β-ketoesters (3), and ad-
dition of alcohols to vinyl epoxides (4). The salen-type lig-
ands, which have been extensively studied by Jacobsen,
were successfully applied in the epoxidation of olefins (5),
asymmetric sulfoxidation (6), hetero-Diels–Alder reaction
(7), ene reaction (8), asymmetric ring opening of epoxides
(9), and cyclopropanation (10). Recently, a new type of P,N-
ligands containing a cyclohexyl backbone was developed in
our lab and applied in the Suzuki coupling with sterically
hindered substrates (11). The relative facility of the aziridine
ring opening coupled with complete trans selectivity should
also make cyclohexyl aziridine a convenient precursor to-
wards cyclohexyl-backbone-containing ligands with an anti
relationship between the two nitrogen containing functional
Results and discussion
Our recent interest in aziridine chemistry prompted us
to explore simple aziridine building blocks as precursors
to new nitrogen containing ligands. The 7-azabicyclo-
[4.1.0]heptane was synthesized from cyclohexyl oxide using
the Staudinger reaction (Scheme 1) (12). The resulting
aziridine was opened with hydrazine hydrate. The product of
the reaction was characterized by NMR and was submitted
to the next step without purification. The reaction with 2,4-
pentanedione led to the formation of racemic pyrazole 1.
The reaction between 7-azabicyclo[4.1.0]heptane and 5-
phenyltetrazole occurred under mild conditions at pH 5
(Scheme 1) giving tetrazole 2 (13).
Several chiral acids were screened to resolve the ligand 2
in enantiomerically pure form. The best results were
Received 29 April 2005. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 7 September 2005.
Dedicated to Professor Howard Alper in recognition of his contributions to chemistry.
L.B. Krasnova and A.K. Yudin.2 Davenport Building, Department of Chemistry, University of Toronto, 80 St. George Street,
Toronto, ON M5S 3H6, Canada.
1This article is part of a Special Issue dedicated to Professor Howard Alper.
2Corresponding author (e-mail: ayudin@chem.utoronto.ca).
Can. J. Chem. 83: 1025–1032 (2005)
doi: 10.1139/V05-113
© 2005 NRC Canada

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Can. J. Chem. Vol. 83, 2005
Scheme 1.
NaN3,
acetone/H2O,
reflux, 17 h,
96%
OH
N3
Ph3P, THF,
reflux, 16 h,
70%
O
NH
O
O
NH
NH
2
2
NH NH *H O
2
2
2
NH
H O
2
r.t., 24 h
EtOH,
2 to 3 h reflux
N
NHNH
N
2
1
Characterized
by NMR
Yield 64% - 70%
N
N
HN
COOH
Ph
N
NH2
N
NH2
1.
Ph
EtOH
OH
N
N
H2O (pH 5) / ether
Bu4NBF4 (10 mol%)
r.t., overnight
N
N
Ph
Ph
2. KOH(30%)/
EtOAc-extraction
N
N
N
2
Yield 70%
Scheme 3.
Scheme 2.
Ar
Ar
NH2
N
NH2
N
ArCHO
ArCHO
N
N
N
EtOH
reflux, 2h
N
N
N
N
N
EtOH
reflux, 2 h
N
N
Ph
Ph
1
3
N
N
2
4
t-Bu
t-Bu
Ar =
Ar =
HO
HO
F
t-Bu
N
N
3b
t-Bu
3a
3c
65%
3d
HO
Yield
77%
89%
70%
4a
4b
4c
Yield
Scheme 4.
NH2
95%
97%
93%
achieved with (S)-(–)-mandelic acid and (S)-(+)-camphor-
sulfonic acid. The enantiomeric purity was measured by 19F
NMR of the Mosher amide with (R)-(–)-MTPA.3 The abso-
lute stereochemistry of the amine was determined from the
X-ray analysis of the diastereomeric salt obtained with (S)-
(+)-mandelic acid. The amine 1 was resolved with D- or L-
dibenzoyltartaric acid, however, we were not able to prove
the absolute stereochemistry of enaniomerically pure 1.
The corresponding imines of ligand precursor 1 were syn-
thesized in good yields (Scheme 2). Different aromatic alde-
hydes were also used under similar reaction conditions to
give the corresponding imines from aminotetrazole 2
(Scheme 3). The imines were synthesized in high yields.
The amine 2 was found to be more stable than 1 and its de-
rivatives and can be stored at room temperature without de-
Br
N
Br
K2CO3, toluene
reflux, 24 h
N
N
N
N
N
N
Ph
Ph
N
N
5
Yield 63%
composition. In addition, tertiary amine 5 can be easily syn-
thesized from 2 according to Scheme 4.
3 The stereochemistry of the enantiomer obtained from the diastereomeric salt with (S)-(+)-10-camphorsulfonic acid was assigned to be oppo-
site, since both enantiomers have different 19F NMR signals in the Mosher amide with (R)-(+)-α-methoxy-α-(trifluoromethyl)phenyl acetic
acid.
© 2005 NRC Canada

Krasnova and Yudin
1027
1
1
Fig. 1. H NMR studies of Cu(I) coordination to ligand 3d.
Fig. 2. H NMR studies of Cu(I) coordination to ligand 4b.
3d
Shift of pyrazole and imine protons
indicate coordination of Cu(I) to both
pyrazole and imine functionalities.
para
N
N
F
N
Free ligand
Free ligand
Coordination to Cu(I)
Coordination to Cu(I)
1
We used H NMR to evaluate the coordination ability of
preserves the C2 symmetry present in the starting material.
On the other hand, mixing Cu(I) and ligand 5 showed coor-
dination to the tertiary amine, whereas coordination to the
the newly synthesized ligands to transition metals. This al-
lowed us to screen several complexes of different ligands
with CuOTf·0.5C6H6. Coordination of the metal to the
heterocycle moiety is known to induce a downfield shift of
the aromatic proton signals (14). For example, ligand 3d
(Fig. 1) shows coordination to Cu(I) through the pyrazole
and imine nitrogens. The imine proton shifts from 8.0 to
8.22 ppm, whereas the pyrazole proton shifts from 5.48 to
5.82 ppm. In addition, nonequivalent methyl protons of the
pyrazole ring were observed in the spectrum of the Cu(I)/3d
mixture. The other two examples did not reveal any copper
coordination to the heterocycle moiety. Thus, comparison of
1
tetrazole was not detected by H NMR at all (Fig. 4).
No catalytic activity was observed when ligands 3a–3c
and 4a were applied in asymmetric cyclopropanation accord-
ing to the literature conditions (15). In light of these negative
results, we were encouraged to obtain interesting data in the
cyclopropanation using 4b as the catalyst precursor
(Scheme 5). The diastereoselectivity of the copper catalyzed
cyclopropanation is known to mostly depend on the nature
of the diazo compound ester group. The sterically bulky
menthyl group usually gives the best trans:cis ratio. How-
ever, in the case of ligand 4b, a 93:7 trans:cis ratio (deter-
1
the H NMR of ligand 4b with and without Cu(I) (Fig. 2)
1
shows the downfield shift of the pyridine para proton (7.7–
8.1 ppm) and corresponds to the copper coordination to the
imine. This fact was also confirmed by the X-ray analysis of
complex 6 (Fig. 3). No coordination between the tetrazole
group and Cu(I) was observed. Importantly, the complex
mined by H NMR) of the regioisomers was obtained even
with a group as small as methyl. Unfortunately, the
enantioselectivity was very low (<5%). In comparison, the
background reaction without the ligand proceeds with a
57:43 trans:cis ratio. Under the same conditions, ligand 4c
© 2005 NRC Canada

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Can. J. Chem. Vol. 83, 2005
Fig. 3. X-ray structure of (S)-(S)-[2,6-di-trans-(5-phenyltetrazol-2-yl)cyclohexyl]pyridin-2-yl methylene-amine / Cu(I) complex (6).
Ph
N
N
N
N
N
N
N
Ph
N
N
N
N
Cu
N
Cu
N
N
N
N
Ph
N
N
N
N
N
N
Ph
1
gave lower diastereoselectivity (trans:cis ratio, 73:27). These
results demonstrate that ligand 4b gives the highest reported
diastereoselectivity in cyclopropanation among the ligands
synthesized to date. Unexpectedly, ruthenium, which is
known to show better results with the pybox system com-
pared to copper, showed no diastereoselectivity in the case
of ligand 4b. In comparison, diastereoselectivity as well as
enantioselectivity for the cyclopropanation of styrene cata-
lyzed by Cu(I) with a pybox-type ligand was found to be
low (16).
Fig. 4. H NMR studies of Cu(I) coordination to ligand 5.
Free ligand
In summary, new N,N-ligands have been synthesized by
the reaction of readily available cyclohexane based
aziridines with appropriate nitrogen based nucleophiles un-
der mild conditions. It was shown that Cu(I) coordinates to
these ligands and, depending on modifications of the amino
group, complexes of different stoichiometry can be obtained.
The enantiomerically pure forms of one of the ligands were
obtained and applied in the cyclopropanation reaction, where
the copper catalyst revealed unexpectedly high diastereo-
selectivity in comparison with the ruthenium catalyst. The
observed diastereoslectivity is superior to the known copper
catalyzed cyclopropanation systems. The mechanistic basis
for this observation is currently under scrutiny, along with
attempts to find enantioselective systems in this new struc-
tural class.
Coordination to Cu(I)
Experimental section
Dichloromethane, ether, acetonitrile, toluene, and hexanes
were purchased from Aldrich as “anhydrous”. Tetrahydro-
furan (THF) was dried over sodium benzophenone ketyl.
Moisture-sensitive reactions were carried out using standard
1
syringe–septum techniques under a nitrogen atmosphere. H
and 13C NMR spectra were recorded on 300 or 400 MHz
1
spectrometers. H NMR spectra were referenced to residual
CHCl3 (δ 7.27 ppm), CH2Cl2 (δ 5.32 ppm), DMSO (δ 2.50 ppm),
CH3CN (δ 1.94 ppm), and benzene (δ 7.16 ppm); 13C NMR
spectra were referenced to CDCl3 (δ 77.0 ppm), CD2Cl2
(δ 54.0 ppm), DMSO-d6 (δ 99.5 ppm), CD3CN (δ
118.7 ppm), and benzene-d6 (δ 128.4 ppm).
© 2005 NRC Canada

Krasnova and Yudin
1029
Scheme 5.
COOMe
N2CHCOOMe 1 equiv.
Metal 2 mol%
1.20b 2.5 mol%
CH2Cl2
7
5 equiv.
Ph
Metal source
[RuCl2C6H6]2
Yield (%)
trans:cis
N
N
N
66
71:29
N
N
N
N
CuOTf 1/2C H
·
6
86
93:7
6
N
N
N
Ph
4b
N
(DMSO-d6) δ: 1.14 (m, 4H), 1.60 (s, 2H), 1.73 (m, 1H), 1.83
(m, 2H), 2.29 (dt, J = 4.2, 10.5 Hz, 1H), 2.65 (dt, J = 4.2,
10.5 Hz, 1H), 3.56 (m, 1H). 13C NMR (DMSO-d6) δ: 24.5,
29.1, 31.6, 53.4, 63.2, 67.5.
7-Azabicyclo[4.1.0]heptane (12)
A mixture of cyclohexene oxide (31 mL, 306 mmol) and
NaN3 (50.4 g, 775 mmol) in H2O–acetone (1:1, 320 mL)
mixture was heated to reflux for 17 h (temperature of the oil
bath was 75 °C). Acetone was removed under reduced pres-
sure and the residue extracted with Et2O (3 × 160 mL). The
combined extracts were washed with H2O (2 × 40 mL) and
dried over MgSO4. After filtration, removal of the solvent
yielded the azido alcohol (~93%–96% yield) as a practically
pure yellow oil, which was concentrated and used in the next
The crude trans-2-hydrazinocyclohexylamine was sus-
pended in 20 mL of ethanol and at 0 °C, 1 mL (12 mmol) of
2,4-pentadione was added dropwise and the reaction was
stirred for another 30 min and then concentrated. The resi-
due was washed with 5 mL of 30% KOH, and the water
layer was extracted with EtOAc (3 × 25 mL), which was
washed with brine, dried over Na2SO4, concentrated, and
dried under the high vacuum. The product can be further
purified by Kugelrohr distillation. trans-2-(3,5-Dimethylpy-
razol-1-yl)cyclohexylamine (1.25 g, 65% yield) was obtained
1
step without further purification. H NMR (benzene-d6) δ:
0.72–1.12 (m, 4H), 1.20–1.34 (m, 2H), 1.59 (m, 1H), 1.74
(m, 1H), 2.23 (s, 1H), 2.79 (m, 1H), 3.10 (m, 1H). 13C NMR
(benzene-d6) δ: 24.7, 25.0, 30.7, 34.2, 67.7, 74.3.
1
as a beige solid; mp 120 °C / 1 mmHg. H NMR (CDCl3) δ:
Triphenylphosphine (77.2 g, 294 mmol) was added within
30 min to a solution of azidocyclohexanol (41.7 g,
294 mmol) in THF (250 mL) while N2 evolved from the re-
action mixture. The reaction mixture was then refluxed for
16 to 17 h. Pentane (~1 L) was added to precipitate Ph3P=O,
and the white precipitate was filtered off and the solvent was
removed on a rotary evaporator (water bath 30–45 °C). The
1.25–1.46 (m, 4H), 1.60–2.05 (m, 6H), 2.23 (s, 3H), 2.25 (s,
3H), 3.40 (dt, J = 5.2, 10.8 Hz, 1H), 3.59 (dt, J = 5.2,
10.8 Hz, 1H), 5.77 (s, 1H). 13C NMR (CDCl3) δ: 11.3, 13.8,
24.8, 25.6, 32.2, 34.6, 53.8, 64.5, 104.6, 139.5, 147.8.
trans-2-(5-Phenyltetrazol-2-yl)cyclohexylamine (2)
THF was distilled off at 25 mmHg (1 mmHg
=
Aziridine (1.75 mL, 17 mmol) was added to the reaction
mixture containing Bu4NBF4 (570 mg, 1.7 mmol) and 2.5 g
(17 mmol) of tetrazole in 34 mL of buffered H2O (AcONa–
AcOH, pH 5) / ether mixture (1:1). The reaction was stirred
for 5 to 6 h. Completion of the reaction was confirmed by
TLC (hexane–EtOAc, 8:2). The reaction was quenched with
5% NaOH and extracted with EtOAc. Combined organic
extracts were washed with brine, dried over MgSO4, and
concentrated. The product was purified by flash chromatog-
raphy on silica gel (hexane–EtOAc, 6:4 with 3 vol% of
Et3N). trans-2-(5-Phenyltetrazol-2-yl)cyclohexylamine (2.96 g,
133.322 4 Pa), and the residue was again distilled at 45 °C
(oil bath temperature) under vacuum (1 mmHg), collecting
aziridine in the receiving flask, which was placed in a dry
ice – acetone bath. 7-Azabicyclo[4.1.0]heptane (20 g, 70%
yield) was obtained as a colorless oil, which solidified upon
cooling at –5 °C. Storage: over KOH; bp 50 °C / 1 mmHg.
1H NMR (CDCl3) δ: 1.19–1.37 (m, 6H), 1.81 (m, 6H), 2.17
(m, 2H). 13C NMR (CDCl3) δ: 20.0, 24.5, 29.3.
trans-2-(3,5-Dimethyl-pyrazole-1-yl)cyclohexylamine (1)
NH2NH2·H2O (490 µL, 10 mmol) was added to the
1 mol% solution of NH4Cl in 2 mL of H2O and 1 mL
(10 mmol) of aziridine. The reaction was stirred at room
temperature for several hours (24 h) and turned from a white
suspension to the colorless solution. Upon completion, the
reaction mixture was treated with 25–50 mL of benzene,
concentrated, and dried under high vacuum. trans-2-Hydra-
zinocyclohexylamine was obtained as a colorless oil and was
1
70% yield) was obtained as a white solid; mp 70–72 °C. H
NMR (CDCl3) δ: 1.35–1.54 (m, 4H), 1.85–2.24 (m, 4H),
3.37 (dt, J = 4.5, 11.1 Hz, 1H), 4.47 (m, 1H), 7.43–8.15 (m,
5H). 13C NMR (CDCl3) δ: 25.0, 25.3, 32.5, 35.0, 54.1, 71.5,
126.8, 127.6, 128.9, 130.2, 164.8.
Resolution of trans-2-(3,5-dimethylpyrazol-1-yl)cyclo-
hexylamine (1) with D-(+)-dibenzoyl tartaric acid
D-(+)-Dibenzoyltartaric acid (1.5 equiv.) was added to the
1
used without further purification in the next step. H NMR
© 2005 NRC Canada

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Can. J. Chem. Vol. 83, 2005
solution of amine in a minimum amount of CH2Cl2–MeOH
(9:1). The reaction was heated to dissolve the acid and then
cooled to room temperature. The precipitate was filtered off
7.57 (m, 2H), 8.08 (m, 3H). 13C NMR (DMSO-d6) δ: 19.6,
20.2, 22.9, 23.6, 24.1, 26.4, 29.5, 31.5, 42.2 (d, J =
44.4 Hz), 46.7, 47.1, 52.4, 58.2, 64.3, 126.5, 127.1, 129.3,
130.7, 164.4, 216.4.
1
and recrystallized from CH2Cl2–MeOH. H NMR (DMSO-
d6) δ: 1.29–1.80 (m, 8H), 2.10 (s, 3H), 2.18 (s, 3H), 2.59 (s,
4H), 3.58 (dt, J = 4.5, 10.2 Hz, 1H), 4.97 (dt, J = 4.5,
10.2 Hz, 1H), 5.73 (s, 1H), 7.49–8.00 (m, 10H).
The precipitate was hydrolyzed with KOH, and extracted
with EtOAc, dried over Na2SO4, and concentrated to give
184 g (48% yield) of one of the enantiomers of trans-2-(3,5-
dimethylpyrazol-1-yl)cyclohexylamine obtained as a white
solid, with 99.9% ee determined from the 19F NMR of the
Mosher amide (–69.55 ppm signal).
General procedure for Mosher amide synthesis (17)
Oxalyl chloride (5 µL, 0.057 mmol) was added to a stock
solution of (R)-(+)-MTPA (2.8 mg, 0.012 mmol) in DMF
(0.95 µL, 0.012 mmol) / hexane (0.5 mL) at room tempera-
ture. A white precipitate formed immediately with evolution
of gas. After 1 h, the mixture was filtered and concentrated
in vacuo. A solution of amine (0.01 mmol), Et3N (4 µL,
0.03 mmol), and DMAP (small crystals, ~1 mg) in CDCl3
1
(100 µL) was added to the residue. After 1 h, H NMR and
19F NMR of the mixture revealed the conversion into the
diastereomeric Mosher amide. N-[trans-2-(3,5-Dimethylpy-
razol-1-yl)-cyclohexyl]-3,3,3-trifluoro-2-methoxy-2-phenyl-
propionamide: 19F NMR (CDCl3, ppm) δ: –65.5 or –69.5.
3,3,3-Trifluoro-2-methoxy-2-phenyl-N-[trans-2-(5-phenyltetrazol-
2-yl)cyclohexyl]propionamide: 19F NMR (CDCl3, ppm) δ:
–69.8 or –70.1.
General procedure for the resolution of trans-2-(5-
phenyltetrazol-2-yl)cyclohexylamine (2)
Racemic trans-2-(5-phenyltetrazol-2-yl)cyclohexylamine
(4.23 g, 17.4 mmol) was dissolved in 50 mL of 95% EtOH
and reacted with 0.7 equiv. (12.2 mmol) of resolving acid. In
the case of mandelic acid, the precipitate was dissolved in an
additional 200 mL of ethanol. The hot, clear solution was
then cooled down to room temperature and a crystalline pre-
cipitate was filtered off and recrystallized from ethanol. The
precipitate was hydrolyzed with KOH and the water layer
was extracted with EtOAc (3 × 50 mL), dried over Na2SO4,
and concentrated.
General procedure for imine synthesis (18)
A solution of the amine (1 or 2 equiv. in case 4b) and the
appropriate aromatic aldehyde (1–1.2 equiv.) in EtOH
(0.1 mol/L reaction mixture) was refluxed for 2 to 3 h. The
solvent was removed and pentane was added to the resulting
oil. If the imine does not crystallize after 24 h at –25 °C, it
can be purified by column chromatography on silica gel
(eluent: hexane–EtOAc, 6:4 with 5 vol% of Et3N) followed
by crystallization from pentane or hexane.
(R)-(R)-trans-2-(5-Phenyltetrazol-2-yl)cyclohexylamine (2)
(R)-(R)-trans-2-(5-phenyltetrazol-2-yl)cyclohexylamine
(490 mg, 70% yield) was obtained through the formation of
a diastereomeric salt with (S)-(+)-mandelic acid, followed by
hydrolysis. (R)-(R)-trans-2-(5-Phenyltetrazol-2-yl)cyclohexyl-
amine was isolated as a white solid with 99.9% ee, deter-
mined from the 19F NMR of the Mosher amide (–69.82 ppm).
Absolute stereochemistry of the amine was determined from
the X-ray analysis (see Supplementary notes)4 of the
diastereomeric salt with (S)-(+)-mandelic acid. A sample for
X-ray analysis was obtained after recrystallization from eth-
2,4-Di-(tert-butyl-6-{[trans-2-(3,5-dimethylpyrazol-1-
yl)cyclohexylimino]methyl}phenol (3a)
2,4-Di-(tert-butyl-6-{[trans-2-(3,5-dimethylpyrazol-1-
yl)cyclohexylimino]methyl}phenol (36.5 mg, 77% yield)
was obtained as a yellow solid after recrystallization from
1
1
pentane. H NMR (CDCl3) δ: 1.26 (s, 9H), 1.41 (s, 9H),
anol; mp 204–205.5 °C. H NMR (DMSO-d6) δ: 1.42 (m,
1.46–2.24 (m, 8H), 2.09 (s, 3H), 2.19 (s, 3H), 3.67 (dt, J =
4.5, 10.8 Hz, 1H), 3.97 (m, 1H), 5.53 (s, 1H), 6.80 (d, J =
2.7 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.76 (s, 1H). 13C
NMR (CDCl3) δ: 11.3, 14.1, 24.5, 25.8, 29.8, 31.7, 31.8,
34.4, 35.3, 61.2, 72.1, 100.1, 104.4, 117.9, 126.0, 126.7,
136.3, 139.7, 147.3, 157.8, 163.0, 166.0.
2H), 1.68–2.20 (m, 5H), 3.39 (m, 1H), 4.70 (s, 1H), 4.81 (dt,
J = 4.2, 11.7 Hz, 1H), 5.20 (br s, 1H), 7.18–8.08 (m, 10H).
13C NMR (DMSO-d6) δ: 23.7, 24.0, 31.9 (d, J = 78.9 Hz),
52.9, 67.0, 72.8, 126.0, 126.1, 126.4, 126.9, 127.3, 128.9,
130.1, 141.8, 163.5, 173.9.
(S)-(S)-trans-2-(5-Phenyltetrazol-2-yl)cyclohexylamine (2)
(S)-(S)-trans-2-(5-Phenyltetrazol-2-yl)cyclohexylamine
(455 mg, 65% yield) was obtained through the formation of
a diastereomeric salt with (S)-(+)-10-camphorsulfonic acid,
followed by hydrolysis. (S)-(S)-trans-2-(5-Phenyltetrazol-2-
yl)cyclohexylamine was isolated as a white solid with
99.9% ee, determined from the 19F NMR of the Mosher am-
2-{[trans-2-(3,5-Dimethylpyrazol-1-yl)cyclohexylimino]-
methyl}phenol (3b)
2-{[trans-2-(3,5-Dimethylpyrazol-1-yl)cyclohexylimino]-
methyl}phenol (2.65 g, 89% yield) was obtained as an or-
1
ange solid. H NMR (CDCl3) δ: 1.40–2.00 (m, 8H), 2.07 (s,
3H), 2.20 (s, 3H), 3.95 (dt, J = 4.2, 9.9 Hz, 1H), 3.70 (m,
1H), 5.56 (s, 1H), 6.79–7.26 (m, 4H), 7.71 (s, 1H). 13C
NMR (CDCl3) δ: 11.1, 13.8, 24.2, 25.5, 31.4, 33.8, 60.9,
72.1, 104.4, 117.0, 118.7, 118.9, 131.6, 132.3, 140.0, 147.7,
161.1, 165.4.
1
ide (–70.07 ppm); mp 194 °C. H NMR (DMSO-d6) δ: 0.73
(s, 3H), 1.03 (s, 3H), 1.26 (m, 1H), 1.40–2.30 (m, 9H), 2.38
(d, J = 15 Hz, 1H), 2.66 (m, 1H), 2.88 (d, J = 15 Hz, 1H),
3.38 (s, 3H), 3.69 (m, 1H), 5.04 (dt, J = 3.9, 11.4 Hz, 1H),
4 Supplementary data for this article are available on the Web site or may be purchased from the Depository of Unpublished Data, Document
Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0S2, Canada. DUD 4003. For more information on obtaining mate-
rial refer to http://cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml. CCDC 271471 contains the crystallographic data for this manuscript. These
data can be obtained, free of charge, via 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 336033; or deposit@ccdc.cam.ac.uk).
© 2005 NRC Canada

Krasnova and Yudin
1031
0.411 mmol) 1,4-dibromobutane (54 µL, 0.452 mmol,
1.1 equiv.), and 68 mg (0.822 mmol, 2 equiv.) of NaHCO3
in toluene (1 to 2 mL) were refluxed under N2 with good
stirring and Dean–Stark removal of water for 19–24 h (con-
trolled by TLC). The reaction mixture was concentrated and
purified by column chromatography (hexane with 5 vol% of
Et3N, then hexane–EtOAc, 6:4 with 5 vol% of Et3N).
5-Phenyl-2-(trans-2-pyridin-1-ylcyclohexyl)-2H-tetrazole
Benzylidene[trans-2-(3,5-dimethylpyrazol-1-yl)cyclo-
hexyl]amide (3c)
Benzylidene[2-(3,5-dimethylpyrazol-1-yl)cyclohexyl]am-
ide (1.69 g, 75% yield) was obtained as a yellow solid (puri-
fied by column chromatography and then recrystallized from
pentane); mp 89 °C. 1H NMR (CDCl3) δ: 1.10–2.25 (m, 8H),
2.11 (s, 3H), 2.18 (s, 3H), 3.61 (dt, J = 4.5, 10.5 Hz, 1H),
4.02 (m, 1H), 5.50 (s, 1H), 7.32–7.50 (m, 5H), 7.64 (s, 1H).
13C NMR (CDCl3) δ: 11.5, 14.1, 24.5, 25.8, 31.4, 33.9, 60.9,
74.1, 103.9, 127.9, 128.4, 130.4, 136.4, 139.8, 147.0,
161.00.
1
(230 mg, 77% yield) was obtained as a brown solid. H
NMR (CD2Cl2) δ: 1.30–2.10 (m, 6H), 1.92 (br s, 2H), 2.18
(br s, 2H), 2.39 (br s, 2H), 2.69 (br s, 2H), 3.36 (br s, 1H),
4.85 (br s, 1H), 7.40–8.20 (m, 5H). 13C NMR (CD2Cl2) δ:
23.9, 24.8, 25.1, 25.3, 31.1, 31.8, 32.9, 47.7, 62.2, 66.1,
127.0, 128.2, 129.0, 130.1, 164.4.
[trans-2-(3,5-Dimethylpyrazol-1-yl)cyclohexyl]-(2-fluoro-
benzylidene)amine (3d)
[2-(3.5-Dimethylpyrazol-1-yl)cyclohexyl]-(2-fluoroben-
zylidene)amine (21 mg, 70% yield) was obtained as a beige
solid; mp 74 °C. H NMR (CDCl3) δ: 1.40–2.40 (m, 8H),
2.16 (s, 3H), 2.21 (s, 3H), 3.70 (dt, J = 4.2, 10.5 Hz, 1H),
4.07 (m, 1H), 5.56 (s, 1H), 6.98–7.82 (m, 4H), 8.05 (s, 1H).
13C NMR (CDCl3) δ: 11.3, 13.8, 24.2, 25.6, 31.2, 33.7, 60.8,
74.4, 104.0, 115.9 (d, J = 84.3 Hz), 124.0, 124.3, 127.5,
132.1 (d, J = 34 Hz), 139.9, 147.5, 154.8, 164.0. 19F NMR
(CDCl3) δ: –122.1 (dq, J = 5.7, 7.5 Hz).
1
General procedure for H NMR studies
1
The ligand (0.02 mmol) in CD2Cl2 was mixed at room
temperature with 0.02 mmol of CuOTf·0.5C6H6, stirred at
room temperature for 1 h, and filtered. In the case of 4b,
upon mixing in an 1:1 ratio (CuI/L), part of the metal com-
plex did not dissolve. A sample of 1:2 ratio (CuI/L) was pre-
1
pared, which showed the same H NMR spectra as the first
sample.
CuI coordination to 3d
(S)-(S)-2,4-Di-tert-butyl-6-{[trans-2-(5-phenyltetrazol-2-
yl)cyclohexylimino]methyl}phenol (4a)
1H NMR (CD2Cl2) δ: 1.44–1.61 (m, 2H), 1.85–2.60 (m,
6H), 2.12 (s, 3H), 2.34 (s, 3H), 3.90 (br s, 1H), 4.45 (br s,
1H), 5.87 (s, 1H), 7.03–7.79 (m, 4H), 8.25 (s, 1H). 19F NMR
(CD2Cl2) δ: –122.1 (dq, J = 5.7, 7.5 Hz).
(S)-(S)-2,4-Di-tert-butyl-6-{[trans-2-(5-phenyltetrazol-2-
yl)cyclohexylimino]methyl}phenol (210 mg, 95% yield) was
obtained as a yellow solid after recrystallization from
1
pentane. H NMR (CDCl3) δ: 1.18 (s, 9H), 1.28 (s, 9H),
CuI coordination to 4b
The NMR sample gave red crystals of complex 1.23 after
storage at room temperature for several days in an inert at-
mosphere upon slow addition of hexane. These sample crys-
1.48–2.34 (m, 8H), 3.91 (dt, J = 4.8, 10.8 Hz, 1H), 5.01 (m,
1H), 6.87 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H),
7.7.43–8.01 (m, 5H), 8.15 (s, 1H). 13C NMR (CDCl3) δ:
24.1, 24.8, 29.5, 29.6, 31.5, 31.6, 31.1, 34.2, 35.2, 68.0,
71.1, 117.7, 126.3, 127.1, 127.5, 129.0, 130.3, 136.8, 140.3,
158.0, 164.8, 166.9.
1
tals were further characterized by X-ray analysis. H NMR
(CD2Cl2) δ: 1.26–2.23 (m, 8H), 3.95 (br s, 1H), 5.11 (br s,
1H), 7.52 (br s, 3H), 7.85 (m, 1H), 8.01 (t, J = 8 Hz, 0.5H),
8.10 (m, 2H).
(S)-(S)-[2,6-Di-trans-(5-phenyltetrazol-2-yl)cyclohexyl]py-
ridin-2-yl methyleneamine (4b)
CuI coordination to 5
(S)-(S)-[2,6-Di-trans-(5-phenyltetrazol-2-yl)cyclohexyl]py-
ridin-2-yl methyleneamine (142 mg, 97% yield) was ob-
tained as a beige solid after recrystallization from pentane.
1H NMR (CDCl3) δ: 1.50–2.30 (m, 8H), 3.92 (dt, J = 5.1,
9.9 Hz, 1H), 5.07 (m, 1H), 7.40 (m, 3H), 7.55 (t, J = 7.8 Hz,
0.5H), 7.77 (d, J = 7.8 Hz, 1H), 8.02 (m, 2H). 13C NMR
(CDCl3) δ: 24.1, 25.1, 32.0, 33.7, 67.9, 72.2, 122.5, 126.8,
127.7, 128.7, 130.0, 136.8, 153.5, 162.2, 164.6.
1H NMR (CD2Cl2) δ: 1.50 (m, 2H), 1.86–2.20 (m, 8H),
2.39 (m, 2H), 2.78 (br s, 1H), 3.04 (br s, 1H), 3.77 (m, 1H),
4.00 (m, 1H), 5.39 (m, J = 4.4, 10.8 Hz, 1H), 7.50 (m, 3H),
8.17 (d, J = 7.2 Hz, 2H), 9.09 (br s, 1H).
General procedure for cyclopropanation
A flame-dried Schlenk flask was charged with metal pre-
cursor (2 mol%, 0.007 mol/L stock solution in CH2Cl2),
ligand (4 mol%, 0.1 mol/L stock solution in CH2Cl2), and
styrene (5 equiv.) and the reaction was stirred under an inert
atmosphere at room temperature in approximately 1 mL of
CH2Cl2. A solution of 1 mL (1 equiv., 1 mmol) of
N2CHCOOMe in dichloromethane (1 mL) was added gradu-
ally over 8–10 h via a syringe pump and the reaction
mixture was stirred for another 10–12 h. The reaction was
concentrated and the product was purified by column chro-
matography (hexane, then hexane–EtOAc (8:2)).
(S)-(S)-[trans-2-(5-Phenyltetrazol-2-yl)cycloexyl]pyridin-
2-yl methyleneamine (4c)
(S)-(S)-[trans-2-(5-Phenyltetrazol-2-yl)cyclohexyl]pyridin-
2-yl methyleneamine (123 mg, 93% yield) was obtained as a
1
pale brown solid. H NMR (CDCl3) δ: 1.50–2.30 (m, 8H),
4.00 (dt, J = 4.8, 10.2 Hz, 1H), 5.12 (m, 1H), 7.17–8.50 (m,
7H), 8.15 (s, 1H). 13C NMR (CDCl3) δ: 24.1, 25.0, 32.0,
33.6, 67.8, 72.1, 121.5, 124.8, 126.7, 127.5, 128.7, 130.0,
136.4, 149.1, 153.8, 162.4, 164.5.
5-Phenyl-2-((R)-(R)-trans-2-pyridin-1-ylcyclohexyl)-2H-
tetrazole (5)
trans-2-(3,5-Dimethylpyrazol-1-yl)cyclohexylamine (100 mg,
2-Phenylcyclopropanecarboxylic acid methyl ester (7)
2-Phenylcyclopropanecarboxylic acid methyl ester was
obtained as a colorless oil. Yield with [RuCl2C6H6]2 was
© 2005 NRC Canada

1032
Can. J. Chem. Vol. 83, 2005
5. M. Palucki, P.J. Pospisil, W. Zhang, and E.N. Jacobsen. J. Am.
Chem. Soc. 116, 9333 (1994).
6. M. Palucki, P. Hanson, and E.N. Jacobsen. Tetrahedron Lett.
33, 7111 (1992).
7. S.E. Schaus, J. Brånalt, and E.N. Jacobsen. J. Org. Chem. 63,
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found to be 66% with a trans:cis ratio of 71:29 determined
1
from H NMR. Yield with CuOTf·0.5C6H6 was found to be
86% with a trans:cis ratio of 93:7 determined from 1H NMR.
a: 1H NMR (CDCl3) δ: 1.32 (m, 1H), 1.60 (m, 1H), 1.90 (m,
1
1H), 2.43 (m, 1H), 3.72 (s, 3H), 7.09–7.31 (m, 5H). b: H
NMR (CDCl3) δ: 0.88 (m, 1H), 1.70 (m, 1H), 2.10 (m, 1H),
2.57 (m, 1H), 3.45 (s, 3H), 7.09–7.31 (m, 5H)
8. R.T. Ruck and E.N. Jacobsen. J. Am. Chem. Soc. 124, 2882
(2002).
9. L.E. Martinez, J.L. Leighton, D.H. Carsten, and E.N.
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Rev. 100, 2159 (2000).
11. A. Caiazzo, S. Dalili, and A.K. Yudin. Org. Lett. 4, 2597
(2002).
Acknowledgments
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC), Foundation for Innovation,
ORDCF, Affinium Pharmaceuticals, Amgen, and the Univer-
sity of Toronto for financial support.
12. J. Christoffers, Y. Schulze, and J. Pickardt. Tetrahedron, 57,
1765 (2001).
13. H.C. Kolb, M.G. Finn, and K.B. Sharpless. Angew. Chem. Int.
Ed. 40, 2004 (2001).
14. (a) H. Günther. NMR spectroscopy. John Wiley and Sons,
Ltd., Toronto, Ontario. 1980; (b) For a specific example, see:
F. Tuna, J. Hamblin, A. Jackson, G. Clarkson, N.W. Alcock,
and M.J. Hannon. Dalton Trans. 11, 2141 (2003).
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© 2005 NRC Canada