Copper-catalyzed tethered aziridination of unsaturated N-tosyloxy carbamates

Article abstract of DOI:10.1021/jo0705014

(Chemical Equation Presented) Aziridines were formed by copper-catalyzed intramolecular nitrene addition to alkenes. The carbamate group was used as the tether between the alkene and the nitrene. Subsequent nucleophilic attack of the aziridine was accomplished using RSH, R₂NH, N₃ ^-, or ROH as the nucleophile. This addition was found to be regio- and stereoselective. This methodology has been used to demonstrate its utility in the regio-and stereoselective synthesis of a 1,2-diamino-3- hydroxycyclohexane. This substitution pattern is found in natural products such as Tamiflu.

Full text of DOI:10.1021/jo0705014

Copper-Catalyzed Tethered Aziridination of Unsaturated
N-Tosyloxy Carbamates
Renmao Liu, Steven R. Herron, and Steven A. Fleming*
Department of Chemistry, Brigham Young UniVersity, ProVo, Utah 84602
steVe_fleming@byu.edu
ReceiVed March 9, 2007
Aziridines were formed by copper-catalyzed intramolecular nitrene addition to alkenes. The carbamate
group was used as the tether between the alkene and the nitrene. Subsequent nucleophilic attack of the
-
aziridine was accomplished using RSH, R2NH, N3 , or ROH as the nucleophile. This addition was found
to be regio- and stereoselective. This methodology has been used to demonstrate its utility in the regio-
and stereoselective synthesis of a 1,2-diamino-3-hydroxycyclohexane. This substitution pattern is found
in natural products such as Tamiflu.
Introduction
stoichiometric amount of iodobenzene. Recently, Lebel et al.
have reported a highly efficient method using rhodium catalysis
for nitrenes which undergo C-H insertion to give amines or
alkene addition to give aziridines.4 They used N-tosyloxy
derivatives of carbamates as nitrene sources, thus avoiding
addition of hypervalent iodine reagents which generate iodo-
benzene. More recently, Donohoe et al. successfully employed
these carbamates as reoxidants for the aminohydroxylation
reaction under conditions more convenient and mild than
traditional methods.5 Our interest is to investigate copper
complexes as catalysts in this new aziridination reaction since
copper complexes are readily available and have shown high
efficiency in previous aziridination applications. We describe
here the copper-catalyzed version of this process and, in
particular, report the regio- and stereoselective nucleophilic
opening of these bicyclic fused aziridines.
Remarkable advances have been made in methods for
aziridination using transition-metal-catalyzed nitrene addition
to olefins during the past decade.1-3 One efficient process makes
use of N-arene sulfonyl iminoiodinanes as the nitrene source.3a
Other alternative nitrogen sources include carbamate esters,3b,c
sulfamate esters,3d,e and sulfonamides2e,3g in combination with
hypervalent iodine reagents. However, one of the major
drawbacks of these particular routes is the formation of a
(1) Reviews: (a) Espino, C. G.; Du Bois J. In Modern Rhodium-
Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim,
Germany, 2005: Chapter 17, pp 379-416. (b) Hafen, J. A. Curr. Org.
Chem. 2005, 9, 657. (c) Watson, I. D. G.; Yu, L.; Yudin, A. K. Acc. Chem.
Res. 2006, 39, 194. (d) Mueller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905.
(2) For representative references, see: (a) Evans, D. A.; Faul, M. M.;
Bilodeau, M. T. J. Am. Chem. Soc. 1994, 116, 2742. (b) Du Bois, J.; Hong,
J.; Carreira, E. M.; Day, M. W. J. Am. Chem. Soc. 1996, 118, 915. (c) Au,
S.-M.; Huang, J.-S.; Yu, W.-Y.; Fung, W.-H.; Che, C.-M. J. Am. Chem.
Soc. 1999, 121, 9120. (d) Brandt, P.; So¨dergren, M. J.; Andersson, P. G.;
Norrby, P.-O. J. Am. Chem. Soc. 2000, 122, 8013. (e) Dauban, P.; Sanie`re,
L.; Tarrade, A.; Dodd, R. H. J. Am. Chem. Soc. 2001, 123, 7707. (f) Cui,
Y.; He, C. J. Am. Chem. Soc. 2003, 125, 16202. (g) Man, W.-L.; Lam, W.
W. Y.; Yiu, S.-M.; Lau, T.-C.; Peng, S.-M. J. Am. Chem. Soc. 2004, 126,
15336. (h) Catino, A. J.; Nichols, J. M.; Forslund, R. E.; Doyle, M. P. Org.
Lett. 2005, 7, 2787. (i) Li, Z.; Ding, X.; He, C. J. Org. Chem. 2006, 71,
5876.
Results and Discussion
The starting N-sulfonyloxy carbamates were prepared from
the corresponding alcohols in a good yield using a known two-
pot procedure, as shown in Scheme 1 (CDI ) 1,1′-carbonyl
diimidazole).
(3) (a) Li, Z.; Quan, R. W.; Jacobsen, E. N. J. Am. Chem. Soc. 1995,
117, 5889. (b) Levites-Agababa, E.; Menhaji, E.; Perlson, L. N.; Rojas, C.
M. Org. Lett. 2002, 4, 863. (c) Padwa, A.; Stengel, T. Org. Lett. 2002, 4,
2137. (d) Guthikonda, K.; Du Bois, J. J. Am. Chem. Soc. 2002, 124, 13672.
(e) Duran, F.; Leman, L.; Ghini, A.; Burton, G.; Dauban, P.; Dodd, R. H.
Org. Lett. 2002, 4, 2481. (f) Liang, J.-L.; Yuan, S.-X.; Chan, P. W. H.;
Che, C.-M. Org. Lett. 2002, 4, 4507.
(4) (a) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127,
14198. (b) Lebel, H.; Leogane, O.; Huard, K.; Lectard, S. Pure Appl. Chem.
2006, 78, 363.
(5) Donohoe, T. J.; Chughtai, M. J.; Klauber, D. J.; Griffin, D.; Campbell,
A. D. J. Am. Chem. Soc. 2006, 128, 2514.
10.1021/jo0705014 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/27/2007
J. Org. Chem. 2007, 72, 5587-5591
5587

Liu et al.
SCHEME 1. Synthesis of N-Tosyloxy Carbamates
Typical experimental conditions for intramolecular aziridi-
nation employed 5-10 mol % of a copper salt and an excess
of K2CO3 (usually 7 equiv) in acetonitrile (0.05 M) with stirring
at room temperature for 16 h. Moderate to good yields were
obtained (see Table 1). Different copper complexes, including
Cu(CH3CN)4PF6, (CF3SO3Cu)2•C6H6, (CF3SO3)2Cu, and CuBr,
were studied using compound 1a. Although each of these
complexes led to aziridine formation, (CF3SO3Cu)2•C6H6 pro-
vided the highest efficiency for the reaction. So (CF3SO3-
Cu)2•C6H6 was chosen as our standard catalyst for this study.
Use of potassium bases proved to be critical to the experiment.
For example, K2CO3 was the most convenient base, although
other potassium bases, such as KOH, were equally efficient.
Bases such as Na2CO3, Cs2CO3, and Ag2CO3 gave only low
conversion. Acetonitrile was used as the standard solvent, but
similar yields were obtained in acetone. Under the standard
conditions described above, the two monosubstituted allylic
carbamates (1a and 1b) gave modest isolated yields of the trans
product. The reaction is not stereospecific.6 The trans-alkene
(1a) gives predominantly trans-aziridine (2a), but the cis isomer
results in a 1.5:1 ratio of trans:cis aziridine diastereomers.
Calculations on the aziridine products (2a and 2b) at the ab
initio level show that they differ in energy by only 1.5 kcal/
mol.
This reflects the preference for the trans isomer at room
temperature from either starting material and supports the radical
nature of the copper-catalyzed reaction.2a,3a The dimethyl- and
phenyl-substituted carbamates (1c and 1d) gave excellent yields
(>90%). The yields of the latter two substrates were based on
the NMR spectrum of the crude products. Attempts to further
purify these products by chromatography on silica gel failed
because of significant decomposition of the strained bicyclic
compound. The high efficiency for the latter two substrates can
be attributed to the electron-rich double bonds which make them
TABLE 1. Intramolecular Aziridination of Various Alkenes
5588 J. Org. Chem., Vol. 72, No. 15, 2007

Cu-Catalyzed Aziridination of N-Tosyloxy Carbamates
SCHEME 2. Aziridination and Subsequent Ring Opening of Cinnamyl Moiety
SCHEME 3. Ring Opening of Bicyclic Aziridines
a better match for the electron-deficient nitrenes generated from
the carbamates. The reaction also worked well for homoallylic
carbamates (1e). A side reaction of detosylation produced a
measurable amount of carbamates (15-30%), which decreased
the efficiency of aziridination and resulted in the relative low
yield for 1a, 1b, and 1e. For 1e, a small amount (<8%) of C-H
insertion was also observed. For all of the trans substrates, the
aziridination reaction is stereoselective, as the stereochemistry
of the major product is also trans.
Studies were also carried out to probe the electrophilic
reactivity of these heterocyclic aziridines, particularly with
respect to the regio- and stereoselectivity of ring opening.3b,7
In our first analysis, crude aziridine 2d was reacted without
purification with different types of nucleophiles (N-methyl
benzylamine, thiophenol, methane, sodium azide, and TMSI).
This approach afforded the oxazolidinones 3-7 in moderate
overall yields for the two steps. Only one diastereomer generated
by nucleophilic attack at the less substituted aziridine carbon
was obtained for each substrate (Scheme 2). The structures were
confirmed by the X-ray crystallography of 5 and analysis of
aziridine carbon in light of the report by Duran et al.3e.9 that
the sulfamate-fused aziridine undergoes ring opening at a
bridgehead carbon. Their work, however, dealt with the [4.1.0]
bicyclic sulfamate system rather than the bicyclo[3.1.0]carba-
mate structures that is the target of this report. In this work,
even the [4.1.0]carbamate undergoes ring opening at the non-
bridgehead carbon (see Scheme 3). Our ab initio calculations
of the aziridines of the carbamate and the sulfamate show that
the LUMO density correctly predicts the aziridine opening to
give the larger ring for the sulfamate and the smaller ring in
the carbamate system. The reason for this selectivity is not
apparent.
1
the 2D H NMR.8
The X-ray structure established that the ring opening occurs
with high stereoselectivity to afford 3-7 with inversion of con-
figuration at the reaction site. We then tested the other crude
aziridines 2a, 2c, and 2e, and similar results were obtained
(Scheme 3), except for the thiophenol addition to aziridine 2a,
which also gave a minor amount (ca. 10%) of the presumed
diastereomeric ring-opened product. The X-ray structure of 9
further confirmed that the ring-opening process was regiose-
lective for this particular reaction. We were surprised that the
nucleophilic attack occurred selectively at the nonbridgehead
We chose to apply this aziridination and ring-opening
methodology to cyclic substrates such as 1f (Scheme 4). In our
first attempt, an unexpected non-aziridine product was obtained.
(6) We appreciate the comments from the reviewer concerning this non-
stereospecific addition. For a similar observation, see: Han, H.; Bae, I.;
Yoo, E. J.; Lee, J.; Do, Y.; Chang, S. Org. Lett. 2004, 6, 4109.
(7) (a) Padwa, A.; Flick, A. C.; Leverett, C. A.; Stengel, T. J. Org. Chem.
2004, 69, 6377. (b) Bergmeier, S. C.; Stanchina, D. M. J. Org. Chem. 1997,
62, 4449. (c) Hayes, C. J.; Beavis, P. W.; Humphries, L. A. Chem. Commun.
2006, 4501. (d) Hu, X. E. Tetrahedron 2004, 60, 2071.
(8) See the Supporting Information.
(9) Guthikonda, K.; When, P. M.; Caliando, B. J.; Du Bois, J.
Tetrahedron 2007, 62, 11331.
J. Org. Chem, Vol. 72, No. 15, 2007 5589

Liu et al.
SCHEME 4. Intramolecular Aziridination of Cyclohexene
After further study, the product 11 was isolated and we surmised
that it results from in situ ring opening of the strained aziridine
by the weakly nucleophilic tosylate group, which is formed
during the reaction. A second minor product which results from
hydrolysis of the starting carbamate was also isolated, as shown
in Scheme 4. When we shortened the reaction time, we did
observe a minor amount of the desired aziridine. Its presence
unit. The stereochemical assignment for the three consecutive
stereocenters of compound 13 is supported by the NMR data.
The coupling constants for the H3a doublet of doublets (see
Scheme 4) are 8.06 Hz with H4 and 6.05 Hz with H7a as verified
by 2D NMR. These values are consistent with an axial-
equatorial relationship for H3a-H7a and an axial-axial relation-
ship for H3a-H4, which is expected for a trans relationship
between the nitrogen groups on the cyclohexane ring and a cis
relationship for the carbamate group. Inversion of the oxygen
substituent would give the 1,2-diamino-3-hydroxy combination
that occurs on Tamiflu (oseltamivir phosphate), which is
receiving intense scrutiny as an oral drug for avian flu.12
In conclusion, copper-catalyzed intramolecular aziridination
of unsaturated carbamates has been described as a complement
to the previous rhodium-catalyzed version. Different nucleo-
philes can be introduced both regioselectively and stereoselec-
tively on these heterocycles. The unique regioselectivity for this
process has been established by X-ray of two ring-opened
products. Improvement of the reaction efficiency and application
of this strategy to the total synthesis of natural products is under
further investigation.
1
was confirmed by H NMR analyses of the crude reaction
mixture. In an attempt to improve the aziridination process in
this system, we explored the use of other copper catalysts.
Recently a N-heterocyclic carbene copper chloride complex has
been successfully used for the aziridination reaction during the
total synthesis of agelastatin A.10,11 Considering its efficiency
for the addition to the electron-deficient cyclopentene in the
synthesis of agelastatin A, we chose to employ this catalyst with
substrate 1f. We were pleased to find that the desired aziridine
1
was the major product in this run as determined by H NMR
analysis of the crude product. Unfortunately, further attempts
to purify the strained tricyclic compound by silica gel chroma-
tography led to significant decomposition. Thus, we opted to
trap the crude aziridine by nucleophilic ring opening using
TMSN3 as an in situ nucleophile (Scheme 4). This strategy
provides a potential way to assemble the stereochemistry of three
adjacent functional groups, such as the 1,2-diamino-3-hydroxy
Experimental Section
General Procedure A: Synthesis of Allylic N-Hydroxy
Carbamates.4a,5 1,1′-Carbonyldiimidazole (1.5 equiv) was added
to a solution of alcohol (1.0 equiv) in acetonitrile (5 mL/mmol of
(10) Trost, B. M.; Dong, G. J. Am. Chem. Soc. 2006, 128, 6054.
(11) For other recent examples using N-heterocyclic carbene copper
complexes, see: (a) Jurkauskas, V.; Sadighi, J. P.; Buchwald, S. L. Org.
Lett. 2003, 5, 2417. (b) Fructos, M. R.; Belderrain, T. R.; Nicasio, M. C.;
Nolan, S. P.; Kaur, H.; Diaz-Requejo, M. M.; Pe´rez, P. J. J. Am. Chem.
Soc. 2004, 126, 10846. (c) Mankad, N. P.; Gray, T. G.; Laitar, D. S.; Sadigih,
J. P. Organometallics 2004, 23, 1191.
(12) (a) Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006,
128, 6310. (b) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2006, 128, 6312.
5590 J. Org. Chem., Vol. 72, No. 15, 2007

Cu-Catalyzed Aziridination of N-Tosyloxy Carbamates
substrate) and stirred, under argon, at room temperature until TLC
indicated complete consumption of the alcohol (typically after 2
h). Imidazole (4.0 equiv) and hydroxylamine hydrochloride (5.0
equiv) were added, and stirring continued until TLC showed
complete consumption of the initial alcohol adduct. After removal
of the reaction solvent, the residue was partitioned between ethyl
acetate and 1 M HCl followed by extraction of the aqueous phase
with ethyl acetate. The organic phase was washed with brine, dried
(Na2SO4), filtered, and concentrated in vacuo to afford the crude
product, which was purified by flash column chromatography using
40% ethyl acetate-hexane.
purified by flash chromatography on silica gel using 30% ethyl
acetate-hexane as eluent to give the desired compound as a yellow
oil.
Using in situ Azide on Bicyclo[4.1.0]aziridine. To a solution
of 0.3 mmol aziridine 2e in THF were added azidotrimethylsilane
(1.1 equiv) and TBAF (1.0 equiv) at 0 °C under nitrogen. The
reaction mixture was warmed to room temperature, stirred for 36
h, and filtered through silica gel. The filter pad was washed with
EtOAc, and the filtrate and washing were evaporated under reduced
pressure to afford the crude product, which was purified by flash
chromatography using 30% ethyl acetate-hexane on silica gel to
give the desired compound as a colorless oil (yield of 60%). Starting
material was also recovered (ca. 30%).
Using in situ Azide on Tricyclic Aziridine. To a solution of
0.5 mmol crude product after aziridination of N-tosyloxy carbamate
1f in THF were added azidotrimethylsilane (1.1 equiv) and TBAF
(0.1 equiv) at 0 °C under nitrogen. The reaction mixture was
warmed to room temperature, stirred for 4 h, and filtered through
silica gel. The filter pad was washed with EtOAc, and the filtrate
and washing were evaporated under reduced pressure to afford the
crude product, which was purified by flash chromatography on silica
gel using 30% ethyl acetate-hexane to give the desired compound
as a white amorphous solid (40%).
Using Methanol. The phenyl-substituted bicyclo[3.1.0]aziridine
2c (1.0 mmol) was dissolved in methanol (5 mL) and stirred for
48 h at 25 °C under nitrogen. The reaction mixture was concentrated
under reduced pressure, and the residue was purified by flash
chromatography 30% ethyl acetate-hexane as eluent on silica gel
to give the desired compound.
Using Sodium Iodide. To a solution of phenyl-substituted
bicyclo[3.1.0]aziridine 2c in THF were added iodotrimethylsilane
(1.1 equiv) and TBAF (0.1 equiv) at 0 °C under nitrogen. The
reaction mixture was warmed to room temperature, stirred for 4 h,
and filtered through silica gel. The filter pad was washed with
EtOAc, and the filtrate and washing were evaporated under reduced
pressure to afford the crude product, which was purified by flash
chromatography using 30% ethyl acetate-hexane on silica gel to
give the desired compound.
General Procedure B: Synthesis of N-Tosyloxy Carbamates.4a,5
To a solution of N-hydroxy carbamate (6 mmol) in Et2O at 0 °C
was added p-toluenesulfonyl chloride (1.26 g, 6.60 mmol). Tri-
ethylamine (0.85 mL, 6.1 mmol) was then added slowly, and the
resulting white suspension was stirred for 12 h at room temperature.
The mixture was washed with water (20 mL) and brine (20 mL),
then dried over Na2SO4. The solvent was removed under reduced
pressure, and the tosyloxy carbamate was purified by flash
chromatography using 25% ethyl acetate-hexane as the eluent.
General Procedure C: Aziridination of N-Tosyloxy Carba-
mates.4a The N-tosyloxy carbamate (1.00 mmol), K2CO3 (0.967 g,
7.00 mmol), and (CF3SO3Cu)2‚C6H6 (25.2 mg, 0.050 mmol) were
dissolved in acetonitrile (20 mL) at 25 °C. The mixture was stirred
vigorously for 16 h. Dichloromethane (30 mL) was added, and the
solution was filtered. The filtrate was concentrated, and the residue
was purified by flash chromatography on silica gel using 30%
EtOAc-hexane as the eluent or the aziridine was directly used for
the next ring-opening step.
General Procedure for the Nucleophilic Ring Opening of
Aziridines: Using N-Methyl Benzylamine. To a solution of
aziridine 2c in THF were added N-methyl benzylamine (1.2 equiv)
and triethylamine (0.2 equiv) at 25 °C under nitrogen. The reaction
mixture was stirred for 5 h and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel to
give the desired compound. Then the compound was recrystallized
from a mixture of hexane and EtOAc.
Using Thiophenol on Bicyclo[3.1.0]aziridines. To a solution
of aziridine 2c in CHCl3 was added thiophenol (1.5 equiv) at
25 °C under nitrogen. The reaction mixture was stirred for 48 h
and concentrated under reduced pressure. The residue was purified
by flash chromatography with 25% ethyl acetate-hexane on silica
gel to give the desired compound.
Using Sodium Azide. To a solution of aziridine 2c in DMF was
added NaN3 (3 equiv) under nitrogen. The reaction mixture was
stirred for 24 h at 80 °C, cooled to room temperature, and poured
into water and brine. The mixture was extracted with Et2O. The
combined organic extracts were washed with water, dried over Na2-
SO4, and concentrated under reduced pressure. The residue was
Supporting Information Available: The general experimental
procedures for this work and the spectral data for 1a-f, 2a-e, and
3-13 are provided as supplemental information. Crystallographic
data for compounds 5 and 9 and their ORTEP drawings are also
provided. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO0705014
J. Org. Chem, Vol. 72, No. 15, 2007 5591