Asymmetric conjugate addition of azide to α,β-unsaturated nitro compounds catalyzed by cinchona alkaloids

Article abstract of DOI:10.1016/j.tet.2007.02.047

The cinchona alkaloid catalyzed asymmetric addition of azide to α,β-unsaturated nitro compounds giving optically active β-azido nitro compounds in high yields and with low enantioselectivity is presented. Subsequent modifications allow for the formation of chiral 1,2-diamines.

Full text of DOI:10.1016/j.tet.2007.02.047

Tetrahedron 63 (2007) 5849–5854
Asymmetric conjugate addition of azide to a,b-unsaturated
nitro compounds catalyzed by cinchona alkaloids
*
Martin Nielsen, Wei Zhuang and Karl Anker Jørgensen
Danish National Research Foundation: Center for Catalysis, Department of Chemistry, Aarhus University,
DK-8000 Aarhus C, Denmark
Received 22 January 2007; revised 10 February 2007; accepted 12 February 2007
Available online 15 February 2007
Abstract—The cinchona alkaloid catalyzed asymmetric addition of azide to a,b-unsaturated nitro compounds giving optically active b-azido
nitro compounds in high yields and with low enantioselectivity is presented. Subsequent modifications allow for the formation of chiral
1,2-diamines.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
A drawback of these approaches is that racemic adducts are
obtained, so that a chiral auxiliary is needed as the source
for stereoselectivity in order to obtain optically active vicinal
diamines. In order to catalytically promote the formation of
chiral 1,2-diamino moiety, we envisioned that the most obvi-
ous route would be the direct addition of the nitrogen source
Vicinal diamines1 are abundant in nature and are used as im-
portant building blocks for the syntheses of a variety of useful
compounds having biological activity,1b,2 as organocata-
lysts,3 and as ligands for metal complexes.1b,4 Terminal
vicinal diamines are utilized as starting compounds for the
synthesis of a-amino amides, obtainable from the oxidation
of vicinal diamines5 and for the synthesis of bleomycin deriv-
atives,6 a family of glycopeptide antibiotics that show anti-
tumor activity.
to a,b-unsaturated nitrogen-based electrophiles. Recently,
MacMillan et al.14 and Cordova et al. independently re-
15
ꢀ
ported highly enantioselective additions of an N-protected
hydroxylamine to a,b-unsaturated aldehydes using second-
ary amines as chiral catalysts. For the nucleophilic addition
of a nitrogen source to a,b-unsaturated electrophiles, hydr-
azoic acid has also proven effective as the nucleophile using
organometallic and tertiary amines as catalysts. The enantio-
selective addition of azide to a,b-unsaturated electrophiles is
a simple and easy approach to form optically active b-azido
compounds.16 Using nitrogen-based electrophiles may then
lead to b-azido nitro compounds, which subsequently can
be reduced to the attractive 1,2-diamines. Jacobsen and
Myers17 have reported the addition of hydrazoic acid to
a,b-unsaturated imides with moderate to excellent enantio-
selectivity using a (salen)Al(III) complex as the catalyst,
while the group of Miller presented the tertiary-amine
promoted racemic addition of azide to cyclic a,b-unsaturated
ketones and to an oxazolidinone.18 The same group later
developed an enantioselective variant using peptide-based
catalysts.19,20
There are several approaches for the synthesis of the termi-
nal 1,2-diamino scaffold. In 1913, Frankland and Smith7
used a dihalide source as the electrophile for the reaction
with two nucleophilic primary amines to form the desired
product, while Dittmer et al.8 formed vicinal diamines by
an acid promoted hydrolysis of imidazolidin-2-ones. More
recently, Mukaiyama et al.9 have reported the formation of
vicinal amines in a one-pot preparation by the addition of
O-ethylhydroxylamine to vinylic nitro compounds and sub-
sequent reduction. O’Neil et al.10 showed that the addition of
hydroxylamines to vinylic nitro compounds proceeded in
excellent yield, and Enders and Wiedemann11 have suc-
ceeded in the stereoselective addition of a nitrogen nucleo-
phile having a C2-symmetric N-aminopyrrolidine as chiral
auxiliary. Optically active vicinal diamines have also been
obtained using the chiral auxiliary approach as developed
by Lucet et al.12 Furthermore, the 1,2-diamino moiety can
also be formed by the reduction of a-amino amides.13
For the electrophilic partner in these reactions, the majority
of reactions have been performed for substrates having car-
bonyl functionalities as the electrophilic substituent, and ni-
tro alkenes have only received very little attention.21 In this
paper, we wish to present the unprecedented stereoselective
addition of azide to a,b-unsaturated nitro compounds
* Corresponding author. E-mail: kaj@chem.au.dk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.047

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M. Nielsen et al. / Tetrahedron 63 (2007) 5849–5854
catalyzed by a dimeric cinchona alkaloid. Based on a very
easy reaction procedure, the b-azido nitro products are
formed in high yields with moderate enantioselectivity. It
will also be shown that the subsequent reduction produces
the desired 1,2-diamino adduct (Scheme 1). Moreover, to
the best of our knowledge, using cinchona alkaloids as the
catalyst for the nucleophilic addition of azides to vinylic
electrophiles has not been reported until now.
carbonyl compounds. These facts, together with the well-
known ability of cinchona alkaloids to facilitate nucleophilic
addition to nitro alkenes,22 were the inspiration to add
TMSN3 1 (10 equiv) to 1-nitro-hept-1-ene 2a in the presence
of catalytic amounts of Et3N (Eq. 1). To our delight a quan-
titative yield of 2-azido-1-nitro-heptane 3a was obtained
after a simple purification process.
HOAc (10 eq)
N3
Et3N (20 mol%)
Cinchona
alkaloid
N3
NO2
NO2
TMSN3 +
rt
16 h
NO2
NO2
TMSN3
+
R
R
1
2a
3a
(10 equiv)
NH2
Pd/C, H2
NH2
ð1Þ
R
Scheme 1.
Miller et al. have proposed that mixing TMSN3 and AcOH
leads to hydrazoic acid and trimethylsilyl acetate during a
disproportionation reaction18 and in the present case it was
observed that TMSOAc was formed as a by-product in the
reaction. It was also found that in the absence of a base,
the conversion was comparably very slow. Intrigued by the
initial result, different commercially available cinchona
alkaloids and other cinchona alkaloid derivatives were
screened as chiral substitutes for Et3N. The most promising
catalysts are shown in relation to the screening results
presented in Table 1.
2. Results and discussion
It is well known that azide salts and hydrazoic acid are toxic
and it is of great interest to avoid them. Miller et al. have
shown that mixing the TMS-protected azide with a carboxy-
lic acid in the presence of a tertiary amine will form the
hydrazoic acid in situ.18 The same authors also showed
that a catalytic amount of a tertiary amine could promote
the addition of the in situ formed azide to a,b-unsaturated
Table 1. Screening of catalysts for the b-azidation of 1-nitro-hept-1-ene 2a
Et
Et
Et
Et
N
N
N
N
N
N
O
O
O
O
N
N
OMe
OMe MeO
MeO
N
N
N
N
(DHQD)2PYR 4a
(DHQD)2PHAL 4b
Et
Et
N
N
O
O
OMe
MeO
O
O
N
N
(DHQD)2AQN 4c
Entry
Catalyst
Equiv AcOH (h)
Conversion (%)
eea (%)
1
2
3
4
5
6
7
8
—
10
10
10
10
10
10
5
10
10
10
10
10
25
100
>95
100
100
100
18
100
100
100
100
14
—
—
ꢀ15
+15
ꢀ4
0
Et3N
Quinine
Quinidine
Cinchonine
Cinchonidine
9-O-Benzylcupreine
(DHQD)2PYR 4a
(DHQD)2PHAL 4b
(DHQD)2AQN 4c
(DHQ)2PYR
0
ꢀ33
ꢀ3
+5
+5
n.d.
9
10
11
12
N-Benzylcinchonidinium chloride
Entries 1 and 2 are conducted at rt for 16 h. Entries 3–12 are conducted at ꢀ78 ꢁC. All reactions, except entry 7, are with 10 equiv AcOH. Entry 7 is with 5 equiv
AcOH. All reactions are in Et2O and with 0.2 equiv catalyst.
Determined by GC.
a

M. Nielsen et al. / Tetrahedron 63 (2007) 5849–5854
5851
The results in Table 1, entries 1–3, clearly show the rate de-
pendence of the reaction on the presence of a base indicat-
ing that the rate-determining step is the addition of azide to
the vinylic nitro compound (vide infra).23 The application of
the cinchona alkaloids, quinine and quinidine gave low
yield and opposite enantioselectivity (entries 3 and 4). It
was found that the cinchonines gave close to racemic prod-
ucts (entries 5 and 6), while the 9-O-benzylcupreine was
catalytically inactive (entry 7). These results indicated that
the monomeric alkaloids seem not to be the optimal choice
for good stereoselectivity. The application of the dimeric
cinchona alkaloids having the PYR-linker 4a showed
more promising results giving a moderate enantiomeric
excess of 33% (entries 8–10), while both the PHAL- and
AQN-linker, 4a and 4b, respectively, catalyzed additions
with almost no face-selectivity. Similar results were ob-
tained for a quinine dimer, (DHQ)2PYR (entry 11). As a
part of the screening process, a single phase-transfer cata-
lyst (PTC), N-benzylcinchonidinium chloride, was also
tested; however, as shown in entry 12, very low conversion
was obtained using the PTC catalyst.
for the non-acidic and non-basic solvents, the Hildebrand
solubility parameter24 could explain the selectivity in the
reaction.
It was also found that the acid added had a great influence on
the reaction course not only on the enantiomeric excess but
also on the face-selectivity. A summary of the screening of
organic and inorganic proton donors, as well as other organic
compounds, for the reaction of TMSN3 1 with 1-nitro-hept-
1-ene 2a using (DHQD)2PYR 4a as the catalyst is presented
in Table 3.
The results in Table 3 show a very interesting role of the ad-
ditives; the addition of a proton donor not only increases the
enantiomeric excess but also inverts the enantioselectivity
(compare e.g., entry 1 with entry 2). Thus, it must be ex-
pected that the additive is part of the stereoselective step in
the catalytic cycle. An enantioselectivity of 57% ee was ob-
served for AcOH and 50% ee for benzoic acid, showing that
the aliphatic carboxylic acid has a greater influence on the
enantioselective step, compared to the aromatic carboxylic
acid (entries 2 and 3). For the aromatic carboxylic acids,
the substitution pattern influences the enantioselectivity.
The highest enantioselectivity (62% ee) was obtained for
2,4,6-trimethoxy benzoic acid (entries 4–6). Compared to
benzoic acid, only a slight improvement in enantioselectivity
is noticed when enlarging the aromatic system to a naphthoic
group (entries 3 and 7). The results in entries 8–12 showed
that a carboxylic acid was not necessary as long as a proton
donor is available. Surprisingly, using the insoluble KHSO4
resulted in an enantioselectivity even higher than that for
benzoic acid (entry 8). It is notable that a much weaker pro-
ton donor also affects the enantioselectivity as phenol results
in inversion of the face-selectivity, however, low enantio-
meric excess was observed (entry 9). Substituting the aro-
matic scaffold in phenol with two tert-butyl groups at the
meta-positions greatly improved the enantioselectivity to
60% ee (entry 10) from 17% ee in the case of phenol.
Even nitrogen-based proton donors were able to affect the
enantioselectivity, though only low enantioselectivities are
observed (entries 11 and 12). Surprisingly, using aldehydes
as additives keep the same face-selectivity as when using
no additive, but with better enantioselectivity compared to
the absence of an additive (entry 1 vs entries 13 and 14).
Next the optimizing of equivalents of TMSN3 and AcOH was
studied. It was found that there was almost no difference in
conversion or enantioselectivity when lowering the equiva-
lents of both compounds to 5. However, lowering the amount
of TMSN3 to 1.5 equiv, while still having 5 equiv of AcOH
reduced the conversion and gave a racemic product. Thus,
having excess of acid, compared to TMSN3, interfered with
the catalytic cycle in a negative manner. This was further es-
tablished by the fact that when lowering the amount of AcOH
to 2 equiv, full conversion with an enantioselectivity of about
30% ee was observed. The reaction with 5 equiv of TMSN3
and 1.5 equiv of AcOH reduced the conversion to 88%, with-
out altering the enantioselectivity. It was concluded that
5 equiv of TMSN3 and AcOH are necessary for full conver-
sion and good enantioselectivity.
Table 2 shows the results of the solvent screening for the
addition of TMSN3 1 to 1-nitro-hept-1-ene 2a using
(DHQD)2PYR 4a as the catalyst.
It appears from results in Table 2, entries 1–5, that lower
enantioselectivities (23–36% ee) were obtained in polar
solvents, compared to CH2Cl2 and toluene where 46 and
57% ee were obtained (entry 6 and 7), while n-hexane, on
the contrary, gave the second lowest stereoselectivity of
only 28% ee (entry 8). In an attempt to account for the sol-
vent influence on the enantioselectivity, it was found that,
Table 3. Influence of proton donors on the conversion and enantioselectivity
Entry
Additive (5 equiv)
Conversion (%)
ee (%)
1
2
3
4
5
6
7
8
—
AcOH
PhCO2H
2,4,6-Trihydroxy benzoic acid
3,4,5-Trihydroxy benzoic acid
2,4,6-Trimethoxy benzoic acid
1-Naphthoic acid
KHSO4
n.d.
100
100
100
100
100
100
100
90
100
n.d.
n.d.
n.d.
60
+17
ꢀ57
ꢀ50
ꢀ55
ꢀ6
Table 2. Solvent screening for the TMSN3 1 to 1-nitro-hept-1-ene 2a
catalyzed by (DHQD)2PYR
Entry
Solvent
Conversion (%)
ee (%)
ꢀ62
ꢀ55
ꢀ52
ꢀ17
ꢀ60
ꢀ27
ꢀ33
+20
+28
1
2
3
4
5
6
7
8
Et2O
100
100
100
100
100
100
100
100
34
30
36
30
23
46
57
28
EtOAc
Acetone
THF
MeOH
CH2Cl2
Toluene
n-Hexane
9
Phenol
10
11
12
13
14
3,5-Di-tert-butyl phenol
Aniline
Benzamide
Acetaldehyde
Benzaldehyde
All reactions are conducted for 16 h at ꢀ78 ꢁC in toluene with 5 equiv
All reactions are performed in toluene at ꢀ78 ꢁC for 16 h using 5 equiv
of 1.
AcOH.

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M. Nielsen et al. / Tetrahedron 63 (2007) 5849–5854
Table 4. Organocatalytic azide addition to different nitro alkenes
seen for 1-nitrohept-1-ene 2a and 3,3-dimethyl-1-nitrobut-
1-ene 2b (entries 1 and 2). Unfortunately, having a phenyl
group substituted remote from the reaction center results
in a drastic lowering of the enantioselectivity when com-
pared to the normal chain (entries 1 and 3). The result in
entry 4 shows that an ester group is tolerated resulting in high
yield and a moderate enantioselectivity of 35% ee. Having
a cyclic aliphatic moiety substituted results in a high yield
and a moderate enantioselectivity of 27% ee (entry 5). Un-
fortunately, addition of azide to 1-nitrocyclohex-1-ene 2f
results in a completely racemic product, though practically
only one diastereomer is observed (entry 6).
Entry Substrate
(R)
Catalyst Acid
Yield eea
(%)
(%)
1
2
n-Pentyl—2a
4a
4c
4c
2,4,6-Trimethoxy 85
benzoic acid
2,4,6-Trimethoxy 70
benzoic acid
62
t-Bu—2b
44
3
4
5
PhCH2CH2—2c
(CH2)4CO2Me—2d 4a
Cyclohexyl—2e 4c
AcOH
AcOH
84
94
24b
35
2,4,6-Trimethoxy 96
benzoic acid
27
6
1-Cyclohexenyl—2f 4a
2,4,6-Trimethoxy 40
benzoic acid
0c
All reactions are performed in toluene at ꢀ78 ꢁC for 16 h.
a
A very easy approach was used in order to obtain the 1,2-di-
amino scaffold from the formed 2-azido-1-nitro compounds.
A simple hydrogenation procedure allowed for the reduction
of the azide and nitro functional groups leading to the free
amines. After reduction of 3a subsequent amidation forms
product 5a in 31% overall yield under non-optimized reac-
tion conditions.
Determined by GC.
Determined by HPLC.
dr>99:1.
b
c
These results show that it is possible to control which enan-
tiomer is in excess by changing the achiral additive while
keeping the same catalyst.
With the reaction conditions developed, different vinylic
nitro compounds were reacted in the presence of AcOH
and 2,4,6-trimethoxy benzoic acid as additive (Eq. 2), as
the former for some substrates turned out to give better
results. Furthermore, different linkers for the dimeric dihy-
droquinidine catalyst proved to be optimal in some cases.
The results are presented in Table 4.
Pd/C
N3
NH2
H
2 (10 bar)
NO2
NH2
n-pentyl
n-pentyl
3a
Cl
O
Et3N
Cl
HN
H
N
4-chlorobenzoyl
chloride
n-pentyl
Acid (5 eq)
Cat (20 mol%)
N3
O
NO2
NO2
TMSN3
5a
+
R
R
Toluene
-78 °C
16 h
ð2Þ
overall yield: 31%
1
2
3
(5 equiv)
The suggested catalytic cycle is presented in Figure 1.
The results in Table 4 show that several nitro alkenes are
tolerated in this reaction. Both normal and branched chains
result in good yields and moderate enantiomeric excess as
Due to the significant effect of acid (shown as AcOH in
Fig. 1) on the stereoselectivity, it is proposed that the acid
is a part of the catalytic cycle and probably present during
4a
HOAc
N3
NO2
NO2
R
R
4aH
OAc
4aH
OAc
H
4aH
OAc
NO2
N3
O
N
R
R
O
4aH
OAc
H
N3
NO2
R
HN3
TMSOAc
TMSN3
HOAc
Figure 1. Proposed catalytic cycle.

M. Nielsen et al. / Tetrahedron 63 (2007) 5849–5854
5853
the enantioselective azide addition to the nitro alkene. Thus,
one of the two basic sites present in the dimeric alkaloid is
probably coordinated to the acid. This partially charged
moiety then coordinates to the nitro group. The second basic
site in the catalyst then coordinates to the in situ generated
hydrazoic acid, which then undergoes the nucleophilic
attack on the activated a,b-unsaturated nitro compound.
Finally, a protonation of the anionic intermediate forms
the product and leaving the protonated catalyst ready for
a new catalytic cycle. This proposal may also explain why
large excess of acid relative to TMSN3 diminishes the stereo-
selectivity. When too much acid is used, both the basic sites
might be protonated leaving no coordination site left for
hydrazoic acid.
3.2.2. 2-Azido-3,3-dimethyl-1-nitro-butane (3b). 1H
NMR: d 4.51 (dd, 1H, J¼13.6, 2.4 Hz), 4.29 (dd, 1H,
J¼13.6, 10.8 Hz), 3.90 (dd, 1H, J¼11.2, 2.4 Hz), 1.02 (s,
9H). 13C NMR: d 75.7, 69.3, 35.5, 26.2 (2C). The ee was
determined by GC on a Chrompak CP-Chirasil Dex CB-
column. Temperature program from 70 to 140 ꢁC at a rate
of 10 ꢁC/min, isotherm for 3 min. tR (min): 8.17 (major enan-
tiomer), 8.36 (minor enantiomer). [a]2D5 ꢀ2.4 (c 1.3, CHCl3).
3.2.3. (3-Azido-4-nitro-butyl)-benzene (3c). 1H NMR:
d 7.25 (td, 2H, J¼7.6, 1.2 Hz), 7.17 (td, 1H, J¼7.6,
1.2 Hz), 7.13 (d, 2H, J¼8.0 Hz), 4.30 (d, 2H, J¼6.8 Hz),
4.02 (m, 1H), 2.80 (m, 1H), 2.68 (m, 1H), 1.81 (m, 2H).
13C NMR: d 139.5, 128.8 (2C), 128.3, 128.2, 126.6, 77.6,
58.6, 33.4, 31.7. The ee was determined by HPLC on Daicel
Chiralpak AD column with hexane/i-PrOH (99:1) as the
eluent: tR (min): 15.1 (major enantiomer), 16.7 (minor enan-
tiomer). [a]2D5 ꢀ3.8 (c 2.2, CHCl3).
In summary, we have presented the formation of optically
active b-azido-a-nitro compounds through a stereoselective
addition of azide to vinylic nitro compounds catalyzed by
dimeric quinidines. The addition of additive proved to have
tremendous effect on the facial selectivity. Reduction of the
azido nitro moiety forms the attractive 1,2-diamino scaffold.
3.2.4. 6-Azido-7-nitro-heptanoic acid methyl ester (3d).
1H NMR: d 4.38 (m, 2H), 4.13 (m, 1H), 3.68 (s, 3H), 2.35
(m, 2H), 1.72–1.43 (m, 6H). 13C NMR: d 173.6, 77.6,
59.2, 51.6, 33.5, 31.5, 25.1, 24.3. The ee was determined by
GC on an Astec G-TA column. Temperature program from
70 to 160 ꢁC at a rate of 10 ꢁC/min, isotherm for 15 min,
then to 180 ꢁC at a rate of 10 ꢁC/min, isotherm for 8 min.
tR (min): 29.6 (minor enantiomer), 30.0 (major enantiomer).
[a]2D5 ꢀ5.2 (c 1.1, CHCl3).
3.2.5. (1-Azido-2-nitro-ethyl)-cyclohexane (3e). 1H NMR:
d 4.46 (ddd, 1H, J¼13.6, 4.0, 0.8 Hz), 4.34 (ddd, 1H, J¼
13.2, 9.6, 0.8 Hz), 3.99 (m, 1H), 1.83–1.53 (m, 6H), 1.31–
1.09 (m, 5H). 13C NMR: d 77.3, 64.7, 40.7, 29.5, 28.4,
25.8, 25.8, 25.6. The ee was determined by GC on an Astec
G-TA column. Temperature program from 70 to 165 ꢁC at
a rate of 5 ꢁC/min, isotherm for 10 min. tR (min): 24.7
(major enantiomer), 25.0 (minor enantiomer). [a]2D5 +9.2
(c 2.3, CHCl3).
3. Experimental section
3.1. General
1
The H NMR and 13C NMR spectra were recorded at 400
and 100 MHz, respectively. The chemical shifts are reported
in parts per million relative to CHCl3 (d¼7.26) for 1H NMR
and relative to the central CDCl3 resonance (d¼77.0) for 13
C
NMR. Flash chromatography (FC) was carried out using
Iatrobeads 6RS-8060 (Spherical silica gel). Optical rotation
was measured on a Perkin–Elmer 241 polarimeter. Tri-
methylsilyl azide 1, 1-nitrocyclohex-1-ene 2g, catalysts
4a–d, and acids 5a–b are commercially available and used
as received. Substrates 2a–f were synthesized according to
the literature procedures.25 All solvents were of p.a. quality
and used without further purification.
1
3.2.6. 1-Azido-2-nitro-cyclohexane (3f). H NMR: d 4.52
3.2. General procedure for the addition of azide to
vinylic nitro compounds forming 3
(br, 1H), 4.29 (m, 1H), 2.20–2.01 (m, 4H), 1.93–1.88 (m,
1H), 1.72–1.62 (m, 1H), 1.59–1.54 (m, 1H), 1.35–1.25 (m,
1H). 13C NMR: d 84.0, 59.2, 29.2, 24.1, 23.3, 19.2. The ee
was determined by GC on an Astec G-TA column. Temper-
ature program from 70 to 160 ꢁC at a rate of 5 ꢁC/min,
isotherm for 8 min. tR minor diastereoisomer (min): 21.6
(major enantiomer), 21.8 (minor enantiomer); tR major dia-
stereoisomer (min): 22.1 (major enantiomer), 23.2 (minor
enantiomer). [a]2D5 0 (c 1.0, CHCl3).
TMSN3 1 (164 mL, 1.25 mmol) and the acid 5 (1.25 mmol)
were mixed in 2 mL toluene in a Schlenk tube and stirred
for 20 min at rt. Then the mixture was cooled to ꢀ78 ꢁC
and the catalyst 4 (0.05 mmol) was added. Immediately after
that the vinylic nitro compound 2 (0.25 mmol) was added.
The mixture was stirred at ꢀ78 ꢁC for 16–30 h and the reac-
tion mixture was plugged using Et2O in pentane as eluent.
If the TMS-protected additive was present, the resulting
mixture was then stirred in MeOH at 50 ꢁC for 5 h.26 After
evaporation of MeOH, the pure product was obtained after
column chromatography.
3.3. General procedure for the reduction of 2-azido-1-
nitro compounds and subsequent amidation forming 5
The 2-azido-1-nitro compound 3 (0.350 mmol) is dissolved
in Et2O. Then 140 mg of Pd/C is added. After 30 min in
10 barH2 the mixture is filtered and mixed with 4 equiv
Et3N and 3 equiv 4-chlorobenzoyl chloride in dichloro-
methane at 0 ꢁC.27 After 3 h the mixture is columned using
Et2O in CH2Cl2 providing pure product 5.
3.2.1. 2-Azido-1-nitro-heptane (3a). 1H NMR: d 4.37 (dd,
1H, J¼22.8, 13.6 Hz), 4.36 (dd, 1H, J¼22.0, 13.2 Hz),
4.12 (m, 1H), 1.62–1.31 (m, 10H), 0.90 (m, 3H). 13C
NMR; d 77.7, 59.4, 31.7, 21.2, 25.2, 22.3, 13.9. The ee
was determined by GC on an Astec G-TA column. Temper-
ature program from 70 to 130 ꢁC at a rate of 10 ꢁC/min,
isotherm for 23 min. tR (min): 24.1 (minor enantiomer),
26.4 (major enantiomer). [a]2D5 ꢀ8.7 (c 2.0, CHCl3).
3.3.1. N,N0-(Heptane-1,2-diyl)bis(4-chlorobenzamide)
(5a). The title compound was prepared according to the gen-
eral procedure described above. H NMR: d 7.71 (t, 4H,
1

5854
M. Nielsen et al. / Tetrahedron 63 (2007) 5849–5854
10. O’Neil, A.; Cleator, E.; Southern, J. M.; Bickley, J. F.;
Tapolczay, D. J. Tetrahedron Lett. 2001, 42, 8251.
11. Enders, D.; Wiedemann, J. Synthesis 1996, 1443.
12. Lucet, D.; Toupet, L.; Le Gall, T.; Mioskowski, C. J. Org.
Chem. 1997, 62, 2682.
13. Schnell, S.; Karrer, P. Helv. Chim. Acta 1955, 38, 2036.
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J¼7.8 Hz), 7.42–7.34 (m, 5H), 6.86 (d, 1H, J¼8 Hz), 4.29–
4.24 (m, 1H), 3.74–3.66 (m, 1H), 3.50–3.41 (m, 1H), 1.63–
1.57 (m, 4H), 1.43–1.19 (m, 6H), 0.86 (t, 3H, J¼7). 13C
NMR: d 167.6 (2C), 137.9 (2C), 132.3 (2C), 128.8 (2C),
128.8 (2C), 128.4 (2C), 128.4 (2C), 51.2, 45.5, 32.8, 31.6,
25.8, 22.5, 14.0. HRMS calcd C21H24Cl2N2NaO+2:
429.1107, found: 429.1100.
ꢀ
15. Ibrahem, I.; Rios, R.; Vesely, J.; Zhao, G.; Cordova, A. Chem.
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