Catalytic and enantioselective aza-ene and hetero-Diels-Alder reactions of alkenes and dienes with azodicarboxylates

Article abstract of DOI:10.1039/b503744a

Lewis acids such as Cu(OTf)₂, Zn(OTf)₂, Yb(OTf) ₃ and Nd(OTf)₃ catalyze the aza-ene reaction of alkenes with azodicarboxylates, giving the allylic animation adducts. The use of bis(2,2,2-trichloroethyl)azodicarb

Full text of DOI:10.1039/b503744a

View Article Online / Journal Homepage / Table of Contents for this issue
A R T I C L E
Catalytic and enantioselective aza-ene and hetero-Diels–Alder
reactions of alkenes and dienes with azodicarboxylates
Pompiliu S. Aburel, Wei Zhuang, Rita G. Hazell and Karl Anker Jørgensen*
Danish National Research Foundation: Center for Catalysis, Department of Chemistry, Aarhus
University, DK-8000, Aarhus C, Denmark. E-mail: kaj@chem.au.dk; Fax: 45 8619 6199;
Tel: 45 8942 3910
Received 14th March 2005, Accepted 5th May 2005
First published as an Advance Article on the web 19th May 2005
Lewis acids such as Cu(OTf)2, Zn(OTf)2, Yb(OTf)3 and Nd(OTf)3 catalyze the aza-ene reaction of alkenes with
azodicarboxylates, giving the allylic amination adducts. The use of bis(2,2,2-trichloroethyl)azodicarboxylate as the
amination reagent and Cu(OTf)2 and Yb(OTf)3 as the catalysts gave the aza-ene reaction of different alkenes, leading
to the corresponding allyl amines in high yields. Chiral copper complexes prepared from Cu(OTf)2 and chiral
bisoxazoline ligands were found to catalyze the enantioselective aza-ene reaction of azodicarboxylates with alkenes
and the hetero-Diels–Alder reaction with cyclopentadiene, giving the corresponding aza-ene- and hetero-Diels–Alder
adducts, respectively, in good yields and moderate enantioselectivities.
Introduction
The ene reaction provides a powerful method for C–C bond for-
mation with concomitant activation of an allylic C–H bond. The
ene reaction converts alkenes into more functionalized allylic
compounds; e.g. the use of aldehydes as enophiles leads to
homoallylic alcohols (carbonyl-ene reaction)1 and aldimines af-
ford homoallylic amines (imine-ene reaction).1a,2 Allylic amines
Scheme 1 Catalytic aza-ene- (eqn. 1) and hetero-Diels–Alder (eqn. 2)
are important functional groups in organic chemistry3 and few
reaction of azadicarboxylates.
options are offered to synthetic chemists for their preparation
from alkenes.2b The existing methods mainly involve e.g. sulfur4,5
The enantioselectivity during Diels–Alder reactions is often
effected by chiral ligand-bearing metal complexes. Catalysts pro-
or selenium diimido compounds,6 N-sulfinylben-zenesulfona-
mide,3 N-phenyl-1,2,4-triazoline,7a N-methyl- and N-phenyl-
ducing the cycloadducts in high enantioselectivities include C2-
1,2,4-triazoline-3,5-diones7b,c or acylnitroso compounds8 as am-
inating species for alkenes.
symmetric bisoxazoline-metal complexes,12 which have proven
to be successful when N-enoylimides and a-hydroxyenones are
employed as dienophiles.13
An interesting alternative for the synthesis of allylic amines,
which would also be complementary to the previous methods,
is the use of azo compounds as aminating agents. Thus,
the amination of an alkene could take place via an aza-ene
reaction to afford the aminated product with transposition of
the double bond using e.g. diethyl azodicarboxylate (DEAD)9
and bis(2,2,2,-trichloroethyl)azodicarboxylate (BTCEAD)10 as
the nitrogen source.
Results and discussion
The allylic amination of cyclopentene 1a by DEAD 2a and
BTCEAD 2b catalyzed by Lewis acids (eqn. 3) are presented
in Table 1.
It is well known that Lewis acids can catalyze carbonyl-ene
and imine-ene reactions.1a,c In contrast, Lewis-acid catalysis of
the analog aza-ene reactions has received little attention. Initial
attempts to mediate the ene-reaction of 1-pentene with DEAD
using Et2AlCl or Me2AlCl, in toluene, at −78 ◦C led to a
transfer of the alkyl group from the Lewis acid to the azo
compound.9a The use of BF3·Et2O, Et2BBr and ZnBr2 showed
no reaction at rt, while Ti(OiPr)4 resulted in reduction of the
azo compound to the corresponding hydrazine. Finally, it was
discovered that a stoichiometric amount of SnCl4 successfully
mediated the d◦esired aza-ene reaction of various alkenes with
DEAD at −60 C.9a
(3)
Cyclopentene 1a reacted with DEAD 2a in the presence
of Yb(OTf)3 (10 mol%) and Cu(OTf)2 (20 mol%) to give the
aminated product 3a in 10 and 33% yield, respectively, after
long reaction times (entries 1, 2). The use of Sn(OTf)2 as the
catalyst afforded no reaction even when 1.0 eq. was used. The
more reactive azodicarboxylate, BTCEAD 2b, afforded the aza-
ene reaction in up to 95% yield (entries 4–11) when Lewis acids
such as Yb(OTf)3, Cu(OTf)2, Nd(OTf)3 and Zn(OTf)2 were used.
Apart from the aza-ene reaction catalyzed by Cu(OTf)2 (entries
6, 7), catalyst loading did not affect yields and reaction times
significantly. A screening of solvents revealed that CH2Cl2 was
the best for the aza-ene reaction.
To the best of our knowledge, no catalytic aza-ene reaction
has been reported. In this paper we disclose the development
of the Lewis-acid catalyzed reactions of azodicarboxylates with
different alkenes (eqn. 1, Scheme 1). Furthermore, we will also
present that this Lewis-acid catalyzed approach can be used
for the hetero-Diels–Alder reaction of conjugated dienes with
azodicarboxylates (eqn. 2, Scheme 1).
With a series of catalytically active Lewis acids for the aza-
ene reaction, various acyclic and cyclic alkenes were treated with
BTCEAD 2b to determine the scope of reaction (eqn. 4). The
Lewis acids Cu(OTf)2 (20 mol%) and Yb(OTf)3 (10 mol%) were
The field of asymmetric catalysis has produced remarkable
results in the area of Diels–Alder and hetero-Diels–Alder reac-
tions, where a high degree of development has been achieved.11
2 3 4 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 4 4 – 2 3 4 9
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

View Article Online
Table 1 Lewis-acid catalyzed aza-ene reaction of cyclopentene 1a with azodicarboxylates 2a, b
Entry
Azodicarboxylate
Lewis acid
Catalyst (%)
Time/h
Yielda (%)
1
2
3
4
5
6
7
8
9
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
Yb(OTf)3
Cu (OTf)2
Sn(OTf)2
Yb(OTf)3
Yb(OTf)3
Cu(OTf)2
Cu(OTf)2
Nd(OTf)2
Nd(OTf)2
Zn(OTf)2
Zn(OTf)2
10
20
100
10
20
10
20
10
20
10
20
144
98
20
60
48
44
22
45
45
48
48
3a–10
3a–33
3a–nr
3b–95
3b–92
3b–55
3b–76
3b–93
3b–95
3b–92
3b–90
10
11
a Isolated yield.
Table 2 Aza-ene reactions of alkenes with BTCEBAD 2b catalyzed by Cu(OTf)2 and Yb(OTf)2
Entry
1
Alkene
Lewis acid
Catalyst load (%)
Time/h
Product
Yielda(%)
Cu(OTf)2
Yb(OTf)3
20
10
22
60
76
95
2
3
Cu(OTf)2
Yb(OTf)3
20
10
72
72
44
43
Cu(OTf)2
Yb(OTf)3
20
10
1
2
98b
99
4
Cu(OTf)2
20
1
96
Yb(OTf)3
10
144
41c
5
6
Cu(OTf)2
Yb(OTf)3
20
10
25
20
85
92
Cu(OTf)2
Yb(OTf)3
20
10
20
20
98
93
a Isolated yield. b See reference 10. c Total yield. The isomers mixture could not be separated by FC. d Isomers ratio determinated by 1H NMR.
chosen as standard catalysts and the results are presented in
Table 2.
acid catalyzed aza-ene reaction. Formation of the (E)-alkene was
favored for both Lewis acids tested. Both (E)-hex-3-ene 1e and
1-pentene 1f gave the aminated products 3g and 3h, respectively,
in high yields, using Cu(OTf)2 and Yb(OTf)3 as the catalysts
(entries 5, 6).
By the use of literature methods the corresponding amines
could be obtained in good yield from the aza-ene reaction
products using Zn, HOAc–acetone10,14 or Li–NH3.9a,15
(4)
Based on the results of the Lewis-acid catalyzed aza-ene
reactions, we next focused on trying to develop this reaction to be
enantioselective using Lewis acids coordinated to a chiral ligand.
So far, there have been no reports of catalytic enantioselective
aza-ene reaction of alkenes with azodicarboxylates. Only a
related procedure using chiral azo-enophile mediated by SnCl4
has been disclosed by Brimble and Lee.16
The first attempt of an enantioselective aza-ene reaction
of BTCAD 2b with cyclopentene 1a catalyzed by chiral
bisoxazoline(BOX)–Cu(II) complexes12,17 gave a racemic prod-
uct, probably due to mono-coordination between Cu(II) and
one of the oxygen atoms in the azodicarboxylate. The aminated
product 3b was isolated as a racemate in 90% yield, in contrast
to the 76% yield when the reaction was catalyzed by Cu(OTf)2
alone. It was envisaged that an additional coordinative site in the
azodicarboxylate could lead to a more stable catalyst–substrate
Cyclohexene 1b was less reactive than cyclopentene 1a and
after 72 h, 43–44% yield of product 3c was isolated for both
catalysts. In order to assess the regioselectivity of the reaction,
alkenes with more than one allylic site were investigated. When
ethylidenecyclohexane 1c was used as the substrate, the reaction
was complete in 1 or 2 h (entry 3) and the internal alkene 3d
was isolated as the main product in excellent yield.10 With 2,4,4-
trimethyl-pent-2-ene 1d as the substrate (entry 4) the reaction
course is dependent on the Lewis acid; Cu(OTf)2 gave only
adduct 3e in very high yield (96%) after 1 h, while the reaction
catalyzed by Yb(OTf)3 gave a mixture of adducts 3e and 3f
(ratio 4 : 1) in only 41% total yield after 144 h. The reason for
this pronounced difference in reaction course using Cu(OTf)2
and Yb(OTf)3 is not known at present. Acyclic alkenes with
internal and terminal double bonds also undergo the Lewis-
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 4 4 – 2 3 4 9
2 3 4 5

View Article Online
Table 3 Catalytic enantioselective aza-ene reaction of cyclopentene 1a with TOCDF 2c catalyzed by chiral BOX–Cu(OTf)2 (20 mol%) complexes
Entry
Catalyst
Temp/◦C
Time/h
Yielda (%) 6a – 7a
Eeb (%) 6a – 7a
1
2
3
4
5
Cu(OTf)2
Yb(OTf)3
Cu(OTf)2 (R)–Ph–BOX
Cu(OTf)2 (R)–Ph–BOX
Cu(OTf)2 (S)-t-Bu–BOX
Rt
Rt
Rt
20
20
16
48
16
5 – 47
36 – 9
60 –
45 –
35 – 34
—
—
40 – nd
40 – nd
Rac – nd
c
−24
Rt
a Isolated yield. b Determined by chiral stationary HPLC. c 10 mol%
complex and thereby improve the enantioselectivity. It was also
postulated that coordination to the chiral BOX–Cu(II) complex 4
would lead to an intermediates such as 5, which might participate
in the enantioselective aza-ene reaction. Adducts of this type
are involved in the enantioselective enol-amination18 in direct
analogy to the previously reported Diels–Alder reactions.17d
Some representative screening results of the enantioselective
aza-ene reaction of cyclopentene 1a with 2,2,2-trichloroethyl-
{[(2-oxo-1,3-oxazolidin-3-yl)carbonyl]diazenyl} formate (TOCDF)
2c catalyzed by (R)–R–BOX–Cu(OTf)2 (20 mol%) (eqn. 5) are
presented in Table 3.
Fig. 1 X-Ray structure of 6a.
(6)
(5)
To further explore the scope of the reaction, a few other
alkenes were reacted with TOCDF 2c in the presence of (R)–Ph–
BOX–Cu(OTf)2 (20 mol%) (eqn. 6). The results are presented in
Table 4. Ethylidenecyclohexane 1c (entry 2) reacts with 2c to
give 7b as the major product in high yields (94%) and 60% ee.
(E)-hex-3-ene 1e (entry 3) gave adduct 6c as the minor product
in 15% yield and 7% ee, in contrast to adduct 7c, which were
formed in 50% yield and 33% ee.
The reaction of cyclopentene 1a with TOCDF 2c catalyzed
by Cu(OTf)2 (20 mol%) gave a mixture of the allylic aminated
product 6a as a minor product and 7a as a major product,
which could be separated by flash chromatography. In contrast,
the same reaction catalyzed by Yb(OTf)3 (10 mol%) gave the
opposite result; 6a was formed as the major product and 7a
as the minor product (Table 3, entries 1, 2). Due to the fact
that Cu(OTf)2 gave a slightly better yield and our experience
with chiral copper complexes in asymmetric catalysis,19 we
decided to investigate some chiral BOX ligands for the aza-ene
reaction.
The (R)–Ph–BOX–Cu(OTf)2 (20 mol%) complex catalyzed
the aza-ene reaction of cyclopentene 1a with TOCDF 2c, giving
6a only (Table 3, entry 3). The switch in product obtained using
the chiral catalyst, compared to the use of Cu(OTf)2 only, should
be noted (entry 3 vs. 1). Product 6a was obtained in 60% yield
and 40% ee and the structure was confirmed by X-ray analysis
outlined in Fig. 1. Performing the same reaction at a lower
temperature (−24 ◦C) did not improve the enantioselectivity
(entry 4). Changing the chiral bisoxazoline ligand to (S)-t–Bu–
BOX (entry 5) resulted in moderate yield of the aza-ene adducts,
with a 1 : 1 ratio of the regioisomers 6a : 7a and product 6a was
formed as a racemate (entry 5).
Table 4 Catalytic enantioselective aza-ene reactions of the alkenes 1a,
c and e with TOCDF 2c catalyzed by (R)–Ph–BOX–Cu(OTf)2 (20 mol%)
at rt in CH2Cl2
Entry
1
Alkene
Time/h
17
Yielda (%)
Eeb (%) 6 – 7
6a 60 –
40 – nd
2
3
19
20
– 7b 94
Nd – 60
7 – 33
6c 15 – 7c 50
a Isolated yield. b Determined by chiral stationary HPLC.
2 3 4 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 4 4 – 2 3 4 9

View Article Online
Table 5 Catalytic enantioselective hetero-Diels–Alder reaction of cyclopentadiene 9 with azodicarboxylates 2c, d catalyzed by (R)–Ph–BOX–
Cu(OTf)2
Entry
Azodicarboxylate
Catalyst load (%)
Temp/◦C
Time/min
Yielda (%)
Eeb (%)
1
2
3
4
2c
2c
2d
2d
10
10
5
Rt
10
30
10
60
8a – 90
8a – 92
8b – 71
8b – 73
22
22
20
20
−20
Rt
10
−20
a Isolated yield. b Determined by chiral stationary HPLC.
Azodicarboxylates in Lewis-acid catalyzed enantioselective
hetero-Diels–Alder reactions
NMR spectra were run at 60 ◦C due to line broading. Coupling
constants in 1H NMR are in Hz. Solvents were dried according
to standard procedures. Flash chromatography (FC) was carried
out using Merck silica gel 60 (230–400 mesh). Optical rotations
were measured on Perkin-Elmer 241 polarimeter and CHCl3 was
used as solvent. The enantiomeric excess (ee) of the products
was determined by HPLC using Daicel Chiralpack AD with i-
PrOH–hexane as eluent or Chiralcel OD–R with MeCN–MeOH
as eluent.
Polysubstituted cyclopentanes are key intermediates in the
preparation of various natural or synthetic biologically active
compounds, including glycosidase inhibitors,20 antiviral and
antitumor carbonucleoside21 or kinase inhibitors.22 Recently, it
has been described that polysubstituted cyclopentene can be
obtained by desymetrization and ring opening23 of hydrazine 8.
Materials
Diethyl azodicarboxylate, (E)-hex-3-ene 1-pentene, were pur-
chased from Lancaster and used as received. Bis(2,2,2,-
trichloroethyl) azodicarboxylate, 2,4,4-trimethyl-2-pentene were
purchased from Fluka and used as received. Cyclopentene,
cyclohexene, ethylidenecyclohexan, (R)–(+)-2,2ꢀ-isopropyli-
denebis(4-phenyl-2-oxazoline), 2,2ꢀ-isopropylidenebis[(4R)-4-
tert-butyl-2-oxazoline], Yb(OTf)3, Cu(OTf)2, Sn(OTf)2, Nd(OTf)3
and Zn(OTf)2, were purchased from Aldrich and used as
received. 2,2,2-Trichloroethyl{[(2-oxo-1,3-oxazolidin-3yl)carbo-
nyl]diazenyl} formate and phenylmethyl{[(2-oxo-1,3-oxazolidin-
3yl)carbonyl]diazenyl} formate were prepared following a
literature procedure.18
We wish to present that the catalytic and enantioselective
aza-aene reaction presented above can be extended to the
hetero-Diels–Alder reaction of cyclopentadiene 9 (eqn. 7). Some
representative results for the reaction of 9 with TOCDF 2c and
phenymethyl{[(2-oxo-1,3-oxazolidin-3-yl)carbonyl]diazenyl}
formate 2d in the presence of (R)–Ph–BOX–Cu(OTf)2 are
presented in Table 5.
(7)
General procedure for catalytic aza-ene reactions of alkenes with
BTCEAD
Cyclopentadiene 9 reacted with TOCDF 2c catalyzed by (R)–
Ph–BOX–Cu(OTf)2 (10 mol%) to give the hetero-Diels–Alder
adduct 8a in high yield (up to 92%) with 22% ee. The reaction
proceeded in CH2Cl2 at different temperatures (rt, −20 ◦C,
entries 1, 2) with no improvement of enantioselectivity. Using
benzyl azodycarboxylate derivative 2d, adduct 8b was obtained
in a good yield and 20% ee (entries 3, 4). Unfortunately, changing
the chiral ligand to more steric hindered ligand did not improved
the enantioselectivity.
To a glass tube with a magnetic stirring bar and 2 mL of CH2Cl2
was added BTCEAD 2b (190 mg, 0.5 mmol) cyclopentene 1a
(68.3 mg, 1 mmol) and catalyst (0.05–0.1 mmol) and stirred at
rt. The yellow solution turned colorless after the time indicated
in the tables. The crude mixture was then purified by FC (hexane :
EtOAc 4 : 1) to give the aza-ene adduct.
Diethyl 1-(2-cyclopenten-1-yl)-1,2-hydrazinedicarboxylate 3a.24
1-(2-Cyclopentene-1-yl)-1,2-hydrazinedicarboxylic acid bis(2,2,2-
trichloroethyl) ester 3b. Colorless oil. 1H NMR (CD3CN
353 K);3 13C NMR (CDCl3, 333 K) d 27.5, 31.6, 65.8, 75.4, 76.0,
95.1, 95.2, 128.0, 137.0, 154.0, 154.7; HRMS C11H12Cl6N2O4
[M + Na]+ calcd 468.8826, found 468.8834.
1-(2-Cyclohexene-1-yl)-1,2-hydrazinedicarboxylic acid bis(2,2,2-
trichloroethyl) ester 3c. Colorless solid. Mp = 118–120 ◦C.
1H NMR (CD3CN 353 K);3 13C NMR (CDCl3, 333 K) d 20.7,
24.4, 26.8, 55.8, 75.3, 75.8, 95.0, 95.1, 125.5, 132.6, 154.1,
154.6; HRMS C12H14Cl6N2O4 [M + Na]+ calcd 482.8982, found
482.8994.
Conclusion
In summary, bis(2,2,2,-trichloroethyl)azodicarboxylate is an
efficient amination reagent for the aza-ene reaction with alkenes
catalyzed by Cu(OTf)2, Zn(OTf)2, Yb(OTf)3 and Nd(OTf)3.
The scope of the Lewis-acid catalyzed aza-ene reaction is
demonstrated for different alkenes with formation of the allylic
amines in up to 99% yield. The reactions can also be catalyzed
by chiral Ph–BOX–Cu(OTf)2 and proceed with good yield
and moderate enantiomeric excess. Furthermore, chiral Ph–
BOX–Cu(OTf)2 can catalyze the hetero-Diels–Alder reaction of
cyclopentadiene with azodicarboxylate derivatives giving high
yields and low enantioselectivities.
1-[1-(1-Cyclohexen-1-yl)ethyl]-1,2-hydrazinedicarboxylic acid
bis(2,2,2-trichloroethyl) ester 3d. Colorless foam. 1H NMR
(CD3CN 353 K);10 13C NMR (CDCl3, 333 K) d 15.1, 22.1,
22.6, 25.1, 26.7, 58.9, 75.1, 75.7, 95.1, 124.6, 135.4, 154.1,
154.3; HRMS C14H18Cl6N2O4 [M + Na]+ calcd 510.9295, found
510.9284.
Experimental
General methods
1
The H and 13C NMR spectra were recorded at 400 MHz and
1(4,4-Dimethyl-2-methyl-penten-1-yl)-1,2-hydrazinedicarb-
oxylic acid bis(2,2,2-trichloroethyl)ester 3e. Colorless solid.
Mp = 118–121 ◦C. 1H NMR (CDCl3 333 K) d 0.91 (s, 9H), 1.93
(s, 3H), 4.17 (s, 2H), 4.75 (d, J = 8 Hz, 2H), 4.93 (s, 1H), 5.01
100 MHz, respectively. The chemical shifts are reported in ppm
1
downfield to CDCl3 (d = 7.25) for H NMR and relative to
the central CDCl3 resonance (d = 77.0) for 13C NMR. The
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 4 4 – 2 3 4 9
2 3 4 7

View Article Online
(s, 1H), 7.03 (br, 1H); 13C NMR (CDCl3 333 K) d 29.8, 31.5,
47.1, 56.7, 75.2, 75.9, 94.9, 116.6, 140.9, 153.7, 154.4; HRMS
C14H20Cl6N2O4 [M + Na]+ calcd 512.9452, found 512.9803
1-(4,4-Dimethyl-2-methylene-penten-1-yl)-1,2-hydrazinedi-
carboxylic acid bis(2,2,2-trichloroethyl) ester 3e and 1-(1-tert-
butyl-2-methyl-allyl)-1,2-hydrazine dicarboxylic acid bis(2,2,2-
trichloroethyl) ester 3f. Colorless solid. 1H NMR (CDCl3
333 K) d 0.94 and 1.02 (s, 3f and s, 3e, 9H), 1.88 and 1.93 (2s, 3e
and 3f, 3H), 4.20 and 4.52 (br, 3e and br s, 3f, 2H), 4.77 and 4.79
(2s, 3e and 3f, 4H), 4.96 (s, 3e, 1H), 5.03 (s, 3e, 1H), 5.12 (br, 3f,
1H), 5.17 (br, 3f 1H), 6.60 (br, 3e, 1H), 6.87 (br, 3f, 1H); HRMS
C14H20Cl6N2O4 [M + Na]+ calcd 512.9452, found 512.9451.
(E)-1-(2-Hexen-4-yl)-1,2-hydrazinedicarboxylic acid bis(2,2,2-
trichloroethyl) ester 3g. Colorless oil. 1H NMR (CDCl3 333 K)
d 0.93 (t, J = 7.6 Hz, 3H), 1.53–1.62 (m, 1H), 1.67 (d, J = 6 Hz,
3H), 1.70–1.78 (m, 1H), 4.46–4.52 (m, 1H), 4.76–4.79 (m, 4H),
5.44 (dd, J = 15.2, 7.2 Hz, 1H), 5.70 (dq, J = 15.6, 6.8 Hz,
1H), 6.62 (br, 1H); 13C NMR (CDCl3, 333 K) d 10.8, 17.7, 24.9,
63.1, 75.3, 75.8, 94.9, 95.1, 128.0, 129.7, 154.1, 154.6; HRMS
C12H16Cl6N2O4 [M + Na]+ calcd 484.9139, found 484.9102.
(E)-1-(2-Penten-1-yl)-1,2-hydrazinedicarboxylic acid bis(2,2,2-
trichloroethyl) ester 3h. Colorless oil. 1H NMR (CDCl3 333 K)
d (t, J = 7.6 Hz, 3H), 2.04 (quintet, J = 7.6 Hz, 2H), 4.13
(d, J = 6 Hz, 2H), 4.74 (s, 4H), 5.44–5.51 (m, 1H), 5.69–5.76
(m, 1H), 7.03 (br, 1H); 13C NMR (CDCl3, 333 K) d 13.2, 25.2,
52.7, 75.2, 75.8, 94.9, 95.0, 121.8, 138.4, 153.9, 154.0; HRMS
C11H14Cl6N2O4 [M + Na]+ calcd 470.8982, found 470.8979.
J = 6.8 Hz, 3H), 1.50–1.64 (m, 4H), 1.88–2.09 (m, 4H), 4.02 (t,
J = 8.4 Hz, 2H), 4.43 (t, J = 8.8 Hz 2H), 4.69–4.79 (m, 3H),
5.64–5.66 (m, 1H), 9.14 (s, 1H); 13C NMR (CDCl3, 333 K) d
15.1, 22.1, 22.6, 25.1, 26.7, 42.4, 58.9, 62.9, 75.6, 95.1, 124.7,
135.5, 151.5, 153.7, 155.2; HRMS C15H20Cl3N3O5 [M + Na]+
calcd 450.0366, found 450.0365.
Nꢀ -(1-Ethyl-but-2-enyl)-Nꢀ -(2-oxo-oxazolidine-3-carbonyl)-
hydrazinecarboxylic acid 2,2,2-trichloro-ethyl ester 6c.
Colorless oil. The enantiomers were separated by HPLC
using a Chiralpak AD chiral stationary phase in hexane–i-
PrOH 80 : 20 (smajor = 6.07 min, sminor = 6.90 min). [a]Drt
=
−2.1 (c = 1.0, CHCl3, 7% ee); 1H NMR (CDCl3 333 K) d 0.94
(t, J = 6.4 Hz, 3H), 1.47–1.77 (m, 5H), 4.11–4.84 (m, 7H),
5.43–5.49 (m, 1H), 5.69–5.78 (m, 1H), 7.76 (br s, 1H); HRMS
C13H18Cl3N3O5 [M + Na]+ calcd 424.0210, found 424.0221.
N-(1-Ethyl-but-2-enyl)-Nꢀ -(2-oxo-oxazolidine-3-carbonyl)-
hydrazinecarboxylic acid 2,2,2-trichloro-ethyl ester 7c.
Colorless oil. The enantiomers were separated by HPLC
using a Chiralpak AD chiral stationary phase in hexane–i-
PrOH 80 : 20 (sminor = 7.93 min, smajor = 9.20 min). [a]rDt = +2.1
1
(c = 1.0, CHCl3, 33% ee); H NMR (CDCl3 333 K) d 0.96 (t,
J = 7.6 Hz, 3H), 1.53–1.77 (m, 5H), 4.04 (t, J = 8.4 Hz, 2H),
4.42–4.53 (m, 3H), 4.74 (br, 2H), 5.44 (dd, J = 15.6, 7.6 Hz,
1H), 5.67–5.73 (m, 1H), 9.22 (s, 1H); 13C NMR (CDCl3, 333 K)
d 10.7, 17.6, 25.0, 42.5, 62.1, 63.0, 75.7, 95.2, 128.1, 129.6,
151.8, 153.7, 155.3; HRMS C13H18Cl3N3O5 [M + Na]+ calcd
424.0210, found 424.0209.
General procedure for catalytic enantioselective aza-ene
reactions
General procedure for catalytic enantioselective
hetero-Diels–Alder reactions
In an oven dried Schlenk tube equipped with a magnetic
stirrer bar, Cu(OTf)2 (36.2 mg, 0.1 mmol) and (R)-(+)-2,2-
isopropylidene-bis(4-phenyl-2-oxazoline) (36.8 mg, 0.11 mmol)
were added. The mixture was stirred under a vacuum
for 2 h and filled with N2. Dry CH2Cl2 (1 mL) was added
and the solution stirred for 1 h. 160 mg (0.5 mmol) of 2,2,2-
trichloroethyl{[(2-oxo-1,3-oxazolidin-3-yl)carbonyl]diazenyl}-
formate 2c was added, followed by the addition of the alkene
(1 mmol) and stirred at rt. After the time indicated in the table
the product was isolated by FC (CH2Cl2 : EtOAc 4 : 1).
In a oven dried Schlenk tube equipped with a magnetic
stirrer bar, Cu(OTf)2 (18,1 mg, 0.05 mmol) and (R)-(+)-2,2-
isopropilidene-bis(4phenyl-2-oxazoline) (18.4 mg, 0.055 mmol)
were added. The mixture was stirred under a vacuum for
2 h and filled with N2. Dry CH2Cl2 (1 mL) was added and
the solution stirred for 1 h. 160 mg (0.5 mmol) of 2,2,2-
trichloroethyl{[(2-oxo-1,3-oxazolidin-3-yl)carbonyl]diazenyl}-
formate 2c was added, followed by the addition of
cyclopentadiene 9 (33 mg, 0.5 mmol) and stirring at rt.
After the time indicated in the table the product was isolated by
FC (CH2Cl2 : EtOAc 4 : 1).
Nꢀ-Cyclopent-2-enyl-Nꢀ-(2-oxo-oxazolidine-3-carbonyl)-hydra-
zinecarboxylic acid 2,2,2-trichloro-ethyl ester 6a. Colorless
solid. Mp = 88–90 ◦C. The enantiomers were separated
by HPLC using a Chiralpak AD chiral stationary phase in
hexane–i-PrOH 80 : 20 (smajor = 10.13 min, sminor = 9.04 min).
[a]rDt = −16.3 (c = 1.0, CHCl3, 40% ee); 1H NMR (CDCl3 333 K)
d 2.17–2.42 (m, 4H), 4.01–4.89 (m, 6H), 5.39 (br s, 1H), 5.67
(br s, 1H), 6.01 (br s, 1H), 7.74 (br s, 1H); 13C NMR (CDCl3
333 K) d 27.1, 31.4, 44.1, 63.1, 65.6, 74.9, 94.0, 127.8, 136.6,
150.0, 153.5, 153.9; HRMS C12H14Cl3N3O5 [M + Na]+ calcd
407.9879, found 407.9907.
3-(2-Oxo-oxazolidine-3-carbonyl)-2,3-diaza-bicyclo-[2.2.1]-
hept-5-ene-2-carboxylic acid 2,2,2-trichloro-ethyl ester 8a.
Colorless solid. Mp = 159–160 ◦C. The enantiomers were
separated by HPLC using a Daicel Chiralcel OD–R chiral
stationary phase in MeOH–MeCN 90 : 10, 22% ee (smajor
=
8.86 min, sminor = 11.11 min). [a]rDt = −10.9 (c = 1.0, CHCl3);
1H NMR (CDCl3 333 K) d 1.82 (d, J = 8.8 Hz, 1H), 1.97 (d,
J = 8.8 Hz, 1H), 3.92–3.98 (m, 1H), 4.12 (q, J = 9.2 Hz, 1H),
4.35–4.46 (m, 2H), 4.68 (d, J = 12 Hz, 1H), 4.79 (d, J = 12 Hz,
1H), 5.20 (br, 2H), 6.57–6.62 (m, 2H); 13C NMR (CDCl3, 333 K)
d 44.1, 47.5, 62.4, 64.9, 69.1, 75.5, 95.0, 135.7, 137.1, 152.5,
153.5, 155.1; HRMS C12H12Cl3N3O5 [M + K]+ calcd 405.9530,
found 405.9594.
N-Cyclopent-2-enyl-N’-(2-oxo-oxazolidine-3-carbonyl)-hydra-
zinecarboxylic acid 2,2,2-trichloro-ethyl ester 7a. Colorless
1
solid. H NMR (CDCl3 333 K) d 1.91 (br s, 1H), 2.22–2.31
(m, 2H), 2.39–2.49 (m, 1H), 4.02 (t, J = 8.4 Hz, 2H), 4.44 (t,
J = 8.6 Hz, 2H), 4.74 (s, 2H), 5.37–5.40 (m, 1H), 5.68–5.70 (m,
1H), 5.99–6.02 (m, 1H), 9.21 (s, 1H); 13C NMR (CDCl3, 333 K)
d 27.5, 31.4, 42.5, 63.0, 65.7, 75.8, 95.2, 128.1, 136.5, 151.9,
155.2; HRMS C12H14Cl3N3O5 [M + Na]+ calcd 407.9879, found
407.9886.
3-(2-Oxo-oxazolidine-3-carbonyl)-2,3-diaza-bicyclo-[2.2.1]-
hept-5-ene-2-carboxylic acid benzyl ester 8b. Colorless foam.
The enantiomers were separated by HPLC using a Daicel
Chiralcel OD–R chiral stationary phase in MeOH–MeCN
90 : 10, 20% ee (sminor = 15.94 min, smajor = 17.51 min). [a]Drt
=
−6.9 (c = 1.0, CHCl3); 1H NMR (CDCl3 333 K) d 1.70 (d, J =
8.8 Hz, 1H), 1.85 (d, J = 8.8 Hz, 1H), 3.82–3.88 (m, 1H), 4.05
(q, J = 9.2 Hz, 1H), 4.24–4.36 (m, 2H), 5.06–5.21 (m, 4H),
6.43–6.47 (m, 2H), 7.23 (br, 5H); 13C NMR (CDCl3, 333 K)
d 43.9, 47.3, 62.3, 64.5, 67.7, 68.7, 127.5, 127.9, 128.3, 135.3,
136.9, 152.6, 153.4, 157.1; HRMS C17H17N3O5 [M + K]+ calcd
366.0879, found 366.0879.
N-(1-Cyclohex-1-enyl-ethyl)-N’-(2-oxo-oxazolidine-3-carbonyl)-
hydrazinecarboxylic acid 2,2,2-trichloro-ethyl ester 7b.
Colorless oil. The enantiomers were separated by HPLC
using a Chiralpak AD chiral stationary phase in hexane–i-
PrOH 80 : 20 (sminor = 8.09 min, smajor = 9.59 min). [a]rDt = −19.2
1
(c = 1.0, CHCl3, 60% ee); H NMR (CDCl3 333 K) d 1.30 (d,
2 3 4 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 4 4 – 2 3 4 9

View Article Online
X-Ray structure analysis of Nꢀ-cyclopent-2-enyl-Nꢀ-(2-oxo-
oxazolidine-3-carbonyl)-hydrazinecarboxylic acid
2,2,2-trichloro-ethyl ester 6a
Thieme, Stuttgart, 1996, vol. E21/5, p. 2735; (b) F. Fringueli and
A. Taticchi, The Diels–Alder Reaction. Selected Practical Methods,
John Wiley, New York, 2002; (c) S. Kobayashi and K. A. Jørgensen,
Cycloaddition Reactions in Organic Synthesis, Wiley-VCH, Wein-
heim, 2002; (d) K. C. Nicolau, S.A. Snyder, T. Montagnon and G.
Vassilikogiannakis, Angew. Chem., Int. Ed., 2002, 41, 1668; (e) E. N.
Jacobsen, A. Pfatz and H. Yamamoto, Comprehensive Asymmetric
Catalysis, Springer, Berlin, 1999, vol. III, p. 1177; (f) E. J. Corey,
Angew. Chem., Int. Ed., 2002, 41, 1650; (g) K. A. Jørgensen, Angew.
Chem., Int. Ed., 2000, 39, 3559.
Crystals of 6a are orthorhombic, Pbca, with unit cell at 100
˚
˚
˚
K: a = 11.4775(5) A, b = 11.1987(5) A, c = 24.918(1) A,
3
V = 3202.8(2) A , Z = 8, qcalcd = 1.604, l = 0.600 cm−1
˚
˚
(MoKa radiation, k = 0.71073 A), F(000) = 1584, T = 100 K.
49 125 reflections collected on a SMART diffractometer, 4589
independent, 3282 significant (I > 3r(I)). Structure solved by
means of the SIR97 program system.25 205 parameters were
refined, final R = 0.048, Rw = 0.054. The cyclopentene ring
is disordered (rotated 180◦ around the N–C bond) and the
outer carbon atoms are split into two each with occupancies
constrained to add up to 1.0.†
12 (a) For reviews about chiral bisoxazoline-copper(II) complexes
see: A. K. Ghosh, P. Mathivanen and J. Cappiello, Tetrahedron:
Asymmetry, 1998, 9, 1; (b) K. A. Jørgensen, M. Johannsen, S. Yao, H.
Audrain and J. Thorhauge, Acc. Chem. Res., 1999, 32, 605; (c) D. A.
Evans and J. S. Johnson, Acc. Chem. Res., 2000, 33, 325.
13 C. Palomo, M. Oiarbide, J. M. Garcia, A. Gonzalez and E. Arceo,
J. Am. Chem. Soc., 2003, 125, 13942 and references therein.
14 Y. Leblanc and B. J. Fitzsimmonsi, Tetrahedron Lett., 1989, 30, 2889.
15 S. E. Denmark, O. Nicaise and J. P. Edwards, J. Org. Chem., 1990,
55, 6219.
Acknowledgements
16 M. A. Brimble and C. K. Y. Lee, Tetrahedron: Asymmetry, 1998, 9,
This work has been made possible by a grant of the Danish
National Research Foundation.
873.
17 (a) D. A. Evans, J. A. Kozlowsky, C. S. Burgey and B. Connell, J. Am.
Chem. Soc., 1999, 121, 669 and references therein; (b) D. A. Evans
and J. S. Johnson, J. Am. Chem. Soc., 1998, 120, 4895; (c) D. A.
Evans, E. J. Olhava, J. S. Johnson and J. M. Janey, Angew. Chem.,
Int. Ed., 1998, 37, 3372; (d) D. A. Evans, S. J. Miller and T. C. Lectka,
Tetrahedron Lett., 1993, 34, 7027.
18 D. A. Evans and D. S. Johnson, Org. Lett., 1999, 1, 595.
19 For some recent papers see for example: (a) M. Marigo, K. Juhl
and K. A. Jørgensen, Angew. Chem., Int. Ed., 2003, 42, 1367;
(b) M. Marigo, A. Kjærsgaard, K. Juhl, N. Gathergood and K. A.
Jørgensen, Chem. Eur. J., 2003, 9, 2359; (c) K. R. Knudsen, S.
Bachmann and K. A. Jørgensen, Chem. Commun., 2003, 2602;
(d) K. R. Knudsen, T. Risgaard, N. Nishiwaki, K. V. Gothelf
and K. A. Jørgensen, J. Am. Chem. Soc., 2001, 123, 5843; (e) N.
Nishiwaki, K. R. Knudsen, K. V. Gothelf and K. A. Jørgensen,
Angew. Chem., Int. Ed., 2001, 40, 2992; (f) K. Juhl, N. Gathergood
and K. A. Jørgensen, Angew. Chem., Int. Ed., 2001, 40, 2995; (g) A.
Kjærsgaard and K. A. Jørgensen, Org. Biomol. Chem., 2005, 3, 804;
(h) L. Bernardi and K. A. Jørgensen, Chem. Commun., 2005, 1324;
(i) L. Bernardi, W. Zhuang and K. A. Jørgensen, J. Am. Chem. Soc.,
2005, 127, 5772.
References
1 (a) N. A. Caplan, F. E. Hancock, P. C. Bulman Page and G. J.
Hutchings, Angew. Chem., Int. Ed., 2004, 43, 1685; (b) B. B. Snider,
The Prins and Carbonyl-Ene Reaction, in Comprehensive Organic
Synthesis, ed. B. M. Trost, Pergamon, Oxford, 1991, vol. 2, p. 527;
(c) K. Mikami and M. Shimizu, Chem. Rev., 1992, 92, 1021.
2 See for example: (a) R. M. Borzilleri and S. M. Weinreb, Synthesis,
1995, 347; (b) M. Johannsen and K. A. Jørgensen, Chem. Rev., 1998,
98, 1689.
3 See for example: G. Deleris, J. Dunogues and A. Gadras, Terahedron,
1988, 44, 4243 and references therein.
4 (a) T. J. Katz and S. Shi, J. Org. Chem., 1994, 59, 8297; (b) G. Kresze
and H. Mu¨nsterer, J. Org. Chem., 1983, 48, 3561; (c) S. P. Singer and
K. B. Sharpless, J. Org. Chem., 1978, 43, 1448.
5 (a) K. B. Sharpless, T. Hori, L. K. Truesdale and C. L. Dietrich,
J. Am. Chem. Soc., 1976, 98, 269; (b) K. B. Sharpless and T. Hori,
J. Org. Chem., 1976, 41, 176.
6 (a) M. Bruncko, T.-A. Khuong and K. B. Sharpless, Angew. Chem.,
Int. Ed. Engl., 1996, 35, 454; (b) N. Kurose, T. Takahashi and T.
Koizumi, T., J. Org. Chem., 1996, 61, 2932; (c) S. Tsushima, Y.
Yamada, T. Onami, K. Oshima, M. O. Chaney, N. D. Jones and
J. K. Swartzendruber, Bull. Chem. Soc. Jpn., 1989, 62, 1167.
7 (a) T. R. Hoye, K. J. Bottoroff, A. J. Caruso and J. F. Dellaria, J. Org.
Chem., 1980, 45, 4287; (b) W. Adam, A. Pastor and T. Wirth, Org.
Lett., 2000, 2, 1295; (c) C. B. Lee and D. R. Taylor, J. Chem. Soc.,
Perkin Trans. 1, 1977, 1463.
8 G. E. Keck, R. R. Webb and J. B. Yates, Tetraherdon, 1981, 37, 4007.
9 (a) M. A. Brimble and C. H. Heathcock, J. Org. Chem., 1993, 58,
5261; (b) M. B. Jacobsen, G. M. Arvanitis, C. A. Eliasen and R.
Mitelman, J. Org. Chem., 1985, 50, 194; (c) W. Thaler and B. Franzus,
J. Org. Chem., 1964, 29, 2226;(d) B. Franzus and J. H. Surridge, J. Org.
Chem., 1962, 27, 1951; (e) B. T. Gillis and P. E. Beck, J. Org. Chem.,
1962, 27, 1947.
20 (a) V. H. Lillelund, H. H. Jensen, X. Liang and M. Bols, Chem. Rev.,
2002, 102, 515; (b) A. Berecibar, C. Grandjean and A. Siriwardena,
Chem. Rev., 1999, 99, 779; (c) S. Ogawa and T. Morikawa, Bioorg.
Med. Chem. Lett., 2000, 10, 1047.
21 M. T. Crimmins, Tetrahedron, 1998, 54, 9229.
22 M. J. Jarvis, H. Yu, S. McGaraughty, C. T. Wismer, J. Mikusa, C.
Zhu, K. Chu, K. Kohlhass, M. Cowart, C.-H. Lee, A. O. Stewart,
B. F. Cox, J. Polakowski and E. A. Kowaluk, Pain, 2000, 96, 107.
23 (a) A. P. Luna, M. Cesario, M. Bonin, L. Micouin and H.-P. Husson,
Org. Lett., 2003, 5, 4771; (b) A. P. Luna, M.-A. Ceschi, M. Bonin, L.
Micouin and H.-P. Husson, J. Org. Chem., 2002, 67, 3522.
24 (a) M. A. Brimble and C. H. Heathcock, J. Org. Chem., 1993, 58,
5261; (b) M. B. Jacobsen, G. M. Arvanitis, C. A. Eliasen and R.
Mitelman, J. Org. Chem., 1985, 50, 194; (c) W. Thaler and B. Franzus,
J. Org. Chem., 1964, 29, 2226;(d) B. Franzus and J. H. Surridge, J. Org.
Chem., 1962, 27, 1951; (e) B. T. Gillis and P. E. Beck, J. Org. Chem.,
1962, 27, 1947.
10 Y. Leblanc, R. Zamboni and M. A. Bernstein, J. Org. Chem., 1991,
56, 1971.
11 For reviews of the Diels–Alder reaction see for example: (a) J. Jurczak,
T. Bauer and C. Chapuis, Stereoselective Synthesis (Houben-Weyl),
ed. G. Helmchen, R. W. Hoffmann, J. Mulzer and E. Schumann,
25 A. Altomare, G. Cascarano, C. Giacocazzo, A. Guagliardi, A. G. G.
Moliterni, M. C. Burla, G. Polidori, M. Camalli and R. Spagna,
SIR(97), 1997, University of Bari, Italy.
† CCDC reference numbers 268562. See http://www.rsc.org/suppdata/
ob/b5/b503744a/ for crystallographic data in CIF or other electronic
format.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 4 4 – 2 3 4 9
2 3 4 9