4-(1-Haloalkyl)-3-nitrotetrahydrofurans as versatile scaffolds for the synthesis of diversely functionalized tetrahydrofurans

Article abstract of DOI:10.1016/j.tet.2011.11.023

4-(1-Haloalkyl)-3-nitrotetrahydrofurans, which are accessible by tandem oxidative oxa-Michael addition/radical cyclization/ligand transfer reactions, can be processed to diversely substituted tetrahydrofuran derivatives. Selective epimerization at the nit

Full text of DOI:10.1016/j.tet.2011.11.023

Tetrahedron 68 (2012) 447e463
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4-(1-Haloalkyl)-3-nitrotetrahydrofurans as versatile scaffolds for the synthesis of
diversely functionalized tetrahydrofurans
,
b
c
Ullrich Jahn a , Dmytro Rudakov , Peter G. Jones
*
a Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo namesti 2, 16610 Prague, Czech Republic
Institut fur Organische Chemie, Technische Universitat Braunschweig, Hagenring 30, 38106 Braunschweig, Germany
Institut fur Anorganische und Analytische Chemie, Technische Universitat Braunschweig, Hagenring 30, 38106 Braunschweig, Germany
b
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€
c
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a r t i c l e i n f o
a b s t r a c t
Article history:
4-(1-Haloalkyl)-3-nitrotetrahydrofurans, which are accessible by tandem oxidative oxa-Michael addi-
tion/radical cyclization/ligand transfer reactions, can be processed to diversely substituted tetrahydro-
furan derivatives. Selective epimerization at the nitro function provides tetrahydrofuran diastereomers,
which cannot be prepared by the tandem process. Intramolecular alkylations furnish interesting
bridgehead nitro oxabicyclo[3.1.0]hexane derivatives in high yields. Intermolecular substitution reactions
of the halide functions succeed only with nucleophiles, which are not basic enough to trigger intra-
molecular alkylations. The aryl substituent in 2-aryl-3-nitrotetrahydrofurans can be selectively oxida-
tively transformed to carboxylic acid derivatives using catalytic Ru(III) and NaIO4 without affecting the
nitro group. Reduction and hydrogenation reactions provide differently substituted 3-
aminotetrahydrofuran derivatives depending on the conditions with moderate to good chemoselectivity.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 9 September 2011
Received in revised form 19 October 2011
Accepted 7 November 2011
Available online 15 November 2011
Keywords:
3-oxabicyclo[3.1.0]hexanes
Oxidation
Hydrogenation
Aminotetrahydrofurans
2
R
3
1. Introduction
R
2
2
Highly functionalized saturated heterocycles represent impor-
tant targets in many applications, such as drug design, agricultural
chemistry, and functional materials. An attractive strategy for gen-
erating such scaffolds is the design of generallyapplicable domino or
tandem processes, which allow the time- and resource-efficient
preparation of such platforms from very simple precursors.1 Cen-
tral to the success of this strategy is that the products can be easily
processed further to diversely functionalized structures.
R
LiO R
O N
3
3
O N
R
R
2
CuX
2
LiO
1
-CuX
+
1
1
NO
R
R
O
B
2
O
A
1
Recently, we reported a new general approach for the synthesis
of halogenated nitrotetrahydrofurans based on a tandem reaction
consisting of anionic conjugate addition of alkoxides 1 to nitro-
R
2
X
R
2
O N
3
2
R
alkenes 2, SET oxidation of the resulting nitronate A to
a-nitro
radical B, radical 5-exo cyclization to radical C and final ligand
transfer to tetrahydrofuran diastereomers 3 and 4 mediated by
cupric halides (Scheme 1).2
Nitrotetrahydrofurans 3 and 4 can be envisioned as versatile
precursors to access functionalized ring systems via substitution
and redox reactions (Fig. 1). The nitro group serves as a convenient
hydrogen or amine surrogate and the developed method may thus
serve as a strategy to approach natural products, such as tetrahy-
drofuran lignans D,3 amino glycosides E,4 or aminotetrahydrofuran
1
2
R
O
3
R
3
CuX
O N
R
2
2
+
2
X
-CuX
R
1
O N
2
3
R
O
C
R
1
R
O
4
* Corresponding author. Tel.: þ420 220 183 219; fax: þ420 220 183 578; e-mail
Scheme 1. Oxidative tandem anionic-radical reactions of allylic alkoxides and nitro-
alkenes to tetrahydrofurans 3 and 4.
address: jahn@uochb.cas.cz (U. Jahn).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.023

448
U. Jahn et al. / Tetrahedron 68 (2012) 447e463
2
2
3
2
3
Cl
R
R
R
R
R
HO
O N
O N
O N
3
2
2
2
R
O
H
H
O
m
OR
(HO)
n
1
1
1
R
R
R
O
O
II
O
AcHN
E Amino glycosides
(OR)
(RO)
m
n
I
III
D Tetrahydrofuran lignans
(All diastereomers known
as natural products)
Base
Cl
Base
Alkylation
Epimerization
2
2
Y
R
R
NMe
N
2
O N
O N
2
3
3
2
R
R
N
N
Y
1
1
R
R
Substitution
O
N
O
3,4-cis-3
O
IV
2
2
R
R
HO
3,4-trans-4
1
R
HN
OH
O
O
H
Reduction
X
X
H N
2
Oxidation
G Bicyclo[3.1.0]hexane
2
2
Cl
R
R
3
Scaffold X = O, NR
BocHN
O N
3
3
2
R
R
1
R
HO C
2
O
O
V
MeO
X = Cl VI
X = H VII
X = OH VIII
F Puromycin
Fig. 1. Biologically interesting (amino)tetrahydrofuran and related structural motifs.
antibiotics, such as puromycin F.5 They also represent interesting
scaffolds G for medicinal chemistry and drug design, mimicking
nucleosides6 or acting as HCV protease inhibitors.7
Fig. 2. Transformations of 4-(1-haloalkyl)-3-nitrotetrahydrofurans 3 and 4.
undesired reaction can, however, be applied deliberately to syn-
thesize nitrotetrahydrofuran diastereomers that are not accessible
directly because of unfavorable transition state geometries.2a Thus,
when 3a or 3b were subjected to their corresponding lithium
allyloxides, a clean inversion at C-3 to nitrotetrahydrofurans 5a and
5b was observed (Scheme 2).
In contrast to known nitrotetrahydrofurans,8 the structural
features of compounds 3 and 4 represent a special challenge for
selective functionalization reactions, since the reactivity patterns of
the individual functional groups are strongly coupled. Thus, the
selectivity and order of steps has to be explored before target-
oriented work can start. We present here a reactivity study of
nitrotetrahydrofurans 3 and 4 (Fig. 2). Results on basic epimeriza-
tion reactions at C-3 to tetrahydrofurans I, intramolecular alkyl-
ations at C-3 affording oxabicyclo[3.1.0]hexanes II or III and
nucleophilic substitutions of the halide functions providing tetra-
hydrofurans IV are presented. It is shown that substituted tetra-
R
R
1.0 equiv.
Cl
Cl
R
R
O N
2
O N
2
OLi
R
R
+ 3a,b
THF, 0 °C,
25 min
hydrofurans
3
and
4
can be converted oxidatively to
Ph
Ph
O
O
tetrahydrofuran-2-carboxylic acids V. The reduction to 3-
aminotetrahydrofurans of type VIeVIII was studied.
88%
12%
26%
3a R = Me
5a
5b
66%
3b R = H
The access to new compound classes IeVIII represents an at-
tractive and straightforward strategy since they can be prepared in
only two steps from simple precursors by the tandem addition/
cyclization process via 3 and 4 (Scheme 1).2 These classes will find
interest, since structurally similar derivatives are applied as HCV
protease inhibitors,7 constrained amino acids,9 and modified nu-
cleosides.6 Compounds VeVIII represent interesting building
Single diastereomers
Scheme 2. Epimerization of 3a,b induced by lithium alkoxides.
Other epimerization conditions, such as subjecting 3a to sodium
acetate in acetic acid, were less efficient. Amine bases also triggered
epimerization, but were generally much better promoters of al-
kylations (vide infra). In contrast, the corresponding trans,trans-4-
(1-chloroalkyl)-3-nitro-2-phenyltetrahydrofuran diastereomers 4
do not epimerize even after long reaction times and increased
temperatures to the corresponding cis,cis-isomers.
blocks for new non-natural tetrahydrofuran-based
b-amino acid
derivatives,10 which may become building blocks for new fol-
damers and related structures.11
2. Results and discussion
2.2. Intramolecular alkylations
2.1. Epimerization reactions of nitrotetrahydrofurans
Under the conditions of their preparation 4-(1-chloroalkyl)-3-
When nitrotetrahydrofurans 3 and 4 were treated with tertiary
amines, the reaction outcome was dependent on their amounts
(Scheme 3, Table 1). On treatment with catalytic amounts of DBU in
dichloromethane, 3a was recovered almost quantitatively without
nitrotetrahydrofurans
3
were prone to epimerization.2a This

U. Jahn et al. / Tetrahedron 68 (2012) 447e463
449
noticeable epimerization, but trace amounts of cyclopropane de-
rivative 6a were detected (entry 1). With 1 equiv of DBU, the major
reaction product was the bicyclic cyclopropane derivative 6a iso-
lated in 66% yield (entry 2). It was accompanied by 33% of 5a.
Quantitative conversion to oxabicyclo[3.1.0]hexane derivatives 6 or
7 was achieved in the presence of 2 equiv of DBU in refluxing
dichloromethane.12 The yields were good to excellent and reaction
times were quite short for all substrates (entries 3e5, 8e11). The
reaction conditions are compatible with epimerization-sensitive
functionalities, such as in 6d or 6e (entries 6,7). For carboxylic
acid derivative 3d, it proved more convenient to treat it with
a saturated sodium bicarbonate solution at room temperature for
10 min and to isolate 6d after neutralization with hydrochloric acid
(entry 6). The weaker base triethylamine can also be used in the
cyclopropanation of 5b, however, the reaction times increased
considerably (entry 12).
The configuration of bicycles 6 and 7 was determined by NOE or
NOESY experiments. The structure of 6a was unambiguously
established by X-ray crystallography (Fig. 3).13 The nitro and phenyl
groups are oriented cis to each other on the convex face of the bi-
cycle. The tetrahydrofuran ring adopts a flattened envelope con-
ꢀ
formation with the oxygen atom lying 0.28 A out of the plane of the
other four atoms.
2
3
R
R
O N
2
Cl
H
2
3
1
R
R
R
O
3
Base
O N
2
H
CH Cl ,
2
2
2
3
temp.
R
R
1
R
O
6
O N
2
Cl
H
1
R
O
5
2
3
2
3
R
Fig. 3. X-ray crystal structure of 6a. Relative configurations are R*,S*,R* at C1, C2, and
C3, respectively.
R
R
R
O N
O N
2
2
Cl
H
Base
H
From all reactions, starting from single diastereomers 3 or 4,
single diastereomers of bicycles 6 and 7 were isolated. Since the
substitution leading to 6 and 7 certainly occurs thus according to
a SN2 mechanism, inversion of configuration at the exocyclic ster-
eocenter can be assumed and the configuration on this basis safely
derived. Therefore, the intramolecular cyclopropanation is a very
useful tool in assigning the exocyclic stereocenter in 4-(1-
chloroalkyl)-3-nitrotetrahydrofurans 3c, 3f, 3g and also of 4c and
4g. The stereoconvergent formation of 6 from 3 and 5 is also a safe
way to detect epimerized products.2a
CH Cl ,
2
2
1
1
temp.
R
R
O
4
O
7
Scheme 3. Synthesis of oxabicyclo[3.1.0]hexane derivatives
chloroalkyl)-3-nitrotetrahydrofuran diastereomers 3, 4, and 5.
6
and
7
from 4-(1-
Table 1
Base-mediated intramolecular alkylations of 3, 4, and 5a
Even the bicyclic derivative 4h underwent the cyclopropanation
reaction cleanly in almost quantitative yield (Scheme 4). Because of
the structural constraints of the bicyclic substrate, the reaction
times for the synthesis of 7h were much longer.
Entry 3,4,5
R1
R2 R3 Base (equiv) T (ꢀC) 6,7 (%, dr)b
1
2
3
4
5
6
7
8
9
3a
3a
3a
3b
Ph
Ph
Ph
Ph
Ph
Me Me DBU (0.05)
Me Me DBU (1.0)
Me Me DBU (2.0)
25
25
40
40
40
6a (traces)
6a (66)c
6a (97)
6b (80)
6c/7c (70, 1.6:1)
6d (94)
6e (98)
6f (97)
6g 6g/7g (90, 2.2:1)
7g
7a (96)
Tricycle 7h is sensitive to air and converted slowly to hydro-
peroxide 7hOOH on standing at room temperature in air. On pro-
longed exposure 4% of crystalline peroxide 8 was isolated by
chromatography. Its structure was established by X-ray crystal-
lography (Fig. 4), although the quality of the structure is not high
(diffraction was weak and there was disorder of atom C6). Sur-
prisingly, the peroxide displays a (2R)- and (20S)-configuration at
the tricyclic units in the molecule. The tetrahydrofuran rings adopt
distorted envelope conformations. The trans-arrangement of the
phenyl and nitro groups is retained in 8. The benzylic hydrogen in
the tricyclic derivative 7h appears to be easily abstracted by mo-
lecular oxygen. Only the heterochiral peroxyl radical seems able to
couple with the benzylic radical from the more accessible convex
face. This structure confirms the stereochemical assignment of its
precursor 7h.
H
Ph
H
H
DBU (2.0)
DBU (2.0)
3c/4c (3:1)
3d
CO2H Me H NaHCO3 (3.1)d 25
3e/5e (1:2.4)
CO2Me Me H DBU (3.0)
Ph Me H DBU (2.0)
Me DBU (2.0)
40
40
40
3f
3g/4g (2.4:1) 3g Ph
4g Ph
H
Me H
Me Me DBU (2.0)
10
11
4a
5b
Ph
Ph
Ph
40
40
55
H
H
H
H
DBU (2.0)
NEt3 (7.0)
6b (80)
6b (95)
12e 5b
a
Substrate (0.37 mmol) in dichloromethane at the given temp. Reaction times
varied from 15 to 60 min.
b
Isolated yields.
c
In addition, 33% of 5a was isolated.
The reaction was carried out by dissolving acid 3d in saturated NaHCO3 solution.
d
The characterization was performed after conversion into methyl ester 6e.
e
Reaction in acetonitrile/H2O 3:1 at 55 ꢀC for 5 h.

450
U. Jahn et al. / Tetrahedron 68 (2012) 447e463
reaction did not go to completion even after 8 days and 8e16% of
Cl
H
O N
O N
2
2
H
H
H
epimerized 5b was recovered. The corresponding bromides 9b and
10b proved to be more reactive, since no halide exchange by iodide
was necessary to promote the substitution reaction. After four days
of reflux in acetonitrile 72% and 70% of 11b and 12b, respectively,
were formed. The results with 11b and 12b demonstrate that epi-
merization is bidirectional; however, 12b and/or 10b seem to be the
thermodynamically favored diastereomers.
2 equiv. DBU
Ph
Ph
CH Cl , 40 °C,
2
2
O
O
24 h
H
4h
7h 95%
When the more basic dibenzylamine was reacted with 9b, only
traces of 4-(aminomethyl)tetrahydrofurans were detected, but bi-
cyclic cyclopropane 6b was formed in 62% yield. This divergent
reactivity of 3b, 9b or 10b toward secondary amines can be ratio-
nalized by taking into account that weakly basic methylaniline acts
primarily as a nucleophile. Although it seems to be basic enough to
H
H
O N
2
H
O N
2
H
H
air
air
Ph
O
O
H
O
Ph
deprotonate the a-position to the nitro function in 3b, 9b, and 10b,
H
O
Ph
O
HOO
the equilibrium lies on the left. This explains the occurrence of
epimerization, the formation of 11b and 12b and the failure to
detect 6b in these reactions. Irreversible deprotonation of the hy-
drogen at C-3 is in contrast the preferred pathway for more basic
aliphatic secondary and tertiary amines, resulting in cyclo-
propanation to 6 and 7.
7hOOH 5%
O N
H
H
2
8 4%
Since reactions with most amines did not successfully in-
corporate nitrogen in the exocyclic position, substitution of the
halogenide function by sodium azide as an ammonia equivalent
was investigated (Scheme 6). When 3b was subjected to excess
sodium azide in DMF at room temperature for 30 min, no trace of
azidomethyltetrahydrofurans 13b/14b was observed, but a clean
epimerization to 5b occurred in 73% yield, indicating that the azide
acted primarily as a base to the hydrogen atom at the nitro function.
Oxabicyclo[3.1.0]hexane derivative 6b was formed in 6% yield and
15% of 3b were recovered. Heating the reaction mixture to 60 ꢀC for
4 h shifted the product spectrum. Bicyclic 6b (52% yield) and also
azides 13b and 14b (37% yield as a 1:4 mixture) proved to be the
Scheme 4. Formation of tricyclic cyclopropane 7h from oxabicyclo[4.3.0]nonane 4h
and its autoxidation to 8.
2.3. Substitution reactions by nitrogen nucleophiles
The susceptibility of the halogenide function toward in-
termolecular substitution was examined briefly. When 3b was
treated with 2.5 equiv of N-methylaniline in refluxing acetonitrile
in the presence of substoichiometric amounts of sodium iodide,
a slow reaction occurred (Scheme 5) and a mixture of 4-(amino-
methyl)tetrahydrofurans 11b and 12b was obtained in 56% yield.
Thus, during the reaction extensive epimerization occurred. The
Fig. 4. X-ray crystal structure of the bis-tricyclic peroxide 8. Only one of two independent molecules is shown. The ellipsoids correspond to 30% probability levels. The relative
configurations are R*,R*,R*,R*,S* at C1, C2, C3, C4, and C8, respectively, and are reversed in the other half of the molecule.

U. Jahn et al. / Tetrahedron 68 (2012) 447e463
451
azide under similar reaction conditions, resulting in 37% of azide
14b. The major product again proved to be 6b, which was isolated
in 62% yield.
X
Br
O N
2
O N
2
4-(Azidomethyl)tetrahydrofuran 14b may in principle form ei-
ther by direct substitution of the chloride or by nucleophilic ring
opening of the nitrocyclopropane 6b by the azide ion. A control
experiment, in which 6b was treated with sodium azide under
otherwise identical reaction conditions, ruled out the latter possi-
bility. Azide 14b was formed in only 5% yield after a very long re-
action time of four days, but 70% of 5b was recovered. Additionally,
22% of (a-allyloxy)phenylacetonitrile 15 was produced, which was
not detected in the other experiments. Its formation cannot be
explained satisfactorily at present.
To summarize this part, cyclopropanation under basic condi-
tions is a very efficient reaction. Intermolecular substitutions at the
halogen function of 3b are strongly dependent on the basicity of the
reagent. Only weakly basic nucleophiles, such as N-methylaniline
substituted the halogenide. With more basic nucleophiles cyclo-
propanation and epimerization prevailed.
Ph
Ph
O
O
10b
3b X = Cl
9b X = Br
(10b/9b 19:1)
For 3b: 2.5 equiv. PhNHMe,
0.67 equiv. NaI, CH CN,
3
reflux, 8 days
For 9b/10b:
2.5 equiv. PhNHMe,
CH CN, reflux,
3
4 days
Ph
Ph
Me N
O N
Me N
O N
2.4. Oxidative degradation of the aryl ring in
tetrahydrofurans 3, 4, 5
2
2
+
Aryl rings represent a convenient protected form of a carboxyl-
ate group.14 It is however important to keep in mind that nitro
compounds are amenable to Nef reactions under oxidative condi-
tions.15 Therefore, the oxidative degradation of the aryl ring in se-
lected derivatives was investigated using ruthenium catalysis
(Scheme 7, Table 2). The transformation was performed using
10 mol % of ruthenium trichloride and sodium periodate (Method
A) or periodic acid (Method B) as the stoichiometric oxidants at
room temperature. The arene units in diastereomeric 3, 4, and 5
were in all cases cleanly oxidatively cleaved to the carboxylic acid
function (entries 1e5). Potential oxidations at the 5-position or
Nef-type oxidations at the nitro group were not observed. The
Ph
Ph
O
11b
11b
11b
O
12b
12b
12b
From 3b:
From 9b:
56% 1:5.6
72% 1:1
From 10b:
70% 1:8.3
Scheme 5. Substitution of the halide in 3b, 9b or 10b by N-methylaniline.
major products. To decrease the basicity of the reaction medium,
chlorotrimethylsilane was added to the reaction mixture. The re-
action with the in situ formed trimethylsilyl azide led to a similar
product distribution of 6b, 13b, and 14b as with NaN3 alone. The
configuration of 14b was determined by reacting 5b with sodium
Cl
N
3
N
3
Cl
3 equiv. NaN , DMF,
3
O N
2
O N
2
O N
2
O N
2
O N
2
H
conditions
+
+
+
Ph
Ph
Ph
Ph
Ph
O
3b
O
O
14b
O
6b
O
5b
Conditions
25 °C, 0.5 h
60 °C, 4 h
13b
0%
7%
5%
0%
30%
33%
6%
52%
40%
73%
0%
0%
1.5 equiv. Me SiCl, 25 °C, 24 h,
3
then 60 °C, 2 h
Cl
N
3
O N
O N
O N
2
3 equiv. NaN , DMF,
2
2
3
H
H
+
+
60 °C, 7 h
Ph
Ph
14b
Ph
O
5b
O
37%
O
6b 62%
N
3
O N
N
O N
2
O N
3 equiv. NaN , DMF,
2
2
3
H
60 °C, 4 days
+
Ph
14b 5%
Ph
15 22%
Ph
Ph
O
O
O
6b
O
6b 70%
Scheme 6. Reaction of 3b, 5b, and 6b with sodium azide.

452
U. Jahn et al. / Tetrahedron 68 (2012) 447e463
reaction times were, however, rather long. Using NaIO4 as the
stoichiometric oxidant, it took a week to complete the reactions,
whereas they were finished after two days when periodic acid was
employed. An increase of the reaction temperature had no effect.
compounds 3, 4, and 5 may be reduced. All three reduction modes
to access the different products selectively are addressed.
(a) Metal-based reduction: nickel boride, generated in situ from
3 equiv of NaBH4 and 1 equiv of NiCl2$6H2O, was used initially as
the mediator (Scheme 8).16 A 1:1 mixture of compounds 3a and 4a
was reduced smoothly (Table 3, entry 1). Products 22a and 23a
were obtained after treatment of the crude amines with Boc an-
hydride in 75% yield as a separable 1:1 diastereomeric mixture. In
addition, considerably more polar alcohol 24a was isolated as
a single diastereomer in 15% yield.
Using diastereomerically pure 3b under similar conditions
provided in contrast alcohol 24b as the major product in 60% yield
(entry 2). Some chlorine-containing derivative 25b and minor
amounts of fully reduced 22b were also formed as single
diastereomers. When a diastereomeric mixture of 3b and 5b was
subjected to nickel boride, alcohol 24b was isolated again as a sin-
gle isomer in 52% yield, while fully reduced 26b and 22b were
isolated as a diastereomeric mixture (entry 3). No trace of an al-
cohol resulting from 5b was formed. A 1:3:8 diastereomeric mix-
ture of 1-(chloroethyl)tetrahydrofurans 3g, 4g, and 5f gave
a mixture of fully reduced diastereomers 23g and 26f in 57% yield
(entry 4). Moreover, 24% of chloro aminotetrahydrofuran 27f, but
no product corresponding to alcohols 24 was isolated.
1
1
R
R
2
2
R
R
O N
2
Cl
O N
2
Cl
Method A or B
3
Ar
R O C
O
3a,b,f,i
O
2
3
Me SiCHN ,
3d, 16, 17 (R =H)
3
2
4a
MeOH, THF,
25°C
3
3e, 18, 19 (R =Me)
Ar = Ph,
4-MeO-C H -
6
4
Cl
Cl
1
1
2
R
R
R
R
O N
2
O N
2
2
Method A or B
1
2
When a mixture of 3a and 4a was treated with Zn dust in the
presence of 10% HCl at 35 ꢀC, the chloro oxime 28a was obtained as
the only significant product in 37% yield (Scheme 9). Attempts to
employ Zn/acetic acid or lithium aluminum hydride for reduction
of the nitro group were not successful.
(b) Catalytic hydrogenation: several catalytic systems are
known.17 When diastereomerically pure 4a was hydrogenated us-
ing palladium on charcoal as the catalyst under 20 bar hydrogen,
followed by protection with Boc anhydride, the fully reduced tet-
rahydrofuran 23a was obtained as the major product in 60% yield
(Scheme 10). Minor side products isolated were the chlorinated
aminotetrahydrofuran 29a and, surprisingly, the acyclic amino
R = R = H
3
Ar
R O C
2
O
O
3
5b
20 (R =H)
Me SiCHN ,
MeOH, THF,
25°C
3
2
3
21 (R =Me)
Method A:
10 mol% RuCl , NaIO ,
25 °C, H O, CH CN, CCl
Method B:
10 mol% RuCl , H IO ,
25 °C, CH CN, CCl
3 4
3
4
3
5
6
2
3
4
Scheme 7. Oxidative preparation of tetrahydrofuran-2-carboxylates.
ether 30a. When
a 1.5:1 diastereomeric mixture of nitro-
Table 2
Oxidative transformation of 2-aryltetrahydrofurans 3e5 to acids 3d, 16, 17, 20 and esters 3e, 18, 19, 21
Entry
Substrate (dr)
Ar
R1
R2
Method
3d,16,17,20 (%, dr)
3e,18,19,21 (%)
1
2
3
4
5
3a/4a (1.2:1)
3a/4a (11:1)
3b/5b (1:6)
3i/5i (1:1)
3f (1:0)
Ph
Ph
Ph
Me
Me
H
H
Me
Me
Me
H
H
H
A
B
B
B
A
16a/17a (61, 1.2:1)
(N.D.b)
18a/19a (95, 1.4:1)a
18a/21a (60, 2:1)c
18b/21b (99, 1:2)
18b/21b (34, 1:1.5)
3e/5e (95, 1:2.4)c
16b/20b (57, 1:3)
4-MeOC6H4
Ph
N.D.b
3d (77, 1:0)
a
Quick column purification.
N.D.¼Not determined.
b
c
Long column, epimerization does not occur during the reaction, as determined by 1H NMR of the crude mixture.
The carboxylic acids 3d, 16, 17, and 20 were isolated as crude
tetrahydrofurans 3a and 4a was subjected to similar conditions, 4a
gave 23a exclusively, while diastereomer 3a provided the oxygen-
ated aminotetrahydrofuran 24a and the fully reduced amino-
tetrahydrofuran 22a. Since the overall yield was no better than the
reduction of 3a, 4a with nickel boride, this reaction was not further
optimized. Transfer hydrogenation using NH4O2CH in the presence
of PdeC as the catalyst was not successful, since a complex mixture
of unidentified products was formed.
When the hydrogenation was performed with Raney nickel as
the catalyst, the product spectrum was strongly dependent on the
substrate and the conditions applied (Scheme 11, Table 4). Fully
reduced tetrahydrofurans 22a and 23a were obtained as the major
products on hydrogenation of a 6:1 mixture of 3a and 4a in mod-
erate yield using 5 bar pressure. A small amount of alcohol 24a and
amino ether 30a, but no chlorine-containing products 25a, were
additionally isolated (entry 1). Varying the conditions had only
limited influence on the product distribution (entries 2e5). The
product ratio is only slightly dependent on hydrogen pressure
materials and converted immediately to the corresponding methyl
esters 3e, 18, 19, and 21 by treatment with trimethylsilyldiazo-
methane in THF/methanol solution. An exceptional case was tet-
rahydrofuran 3i, bearing the more electron-rich anisyl group (entry
4). Methyl esters 18b and 21b were isolated in a moderate yield of
only 34% applying periodic acid, while almost no conversion was
observed with NaIO4. It must be noted that epimerization was
observed in methyl esters 18a,b, and 3e. This occurred on purifi-
cation of crude esters 18 or 3e by column chromatography, but not
during esterification of the crude acids (entries 2e5). Thus purifi-
cation must be performed as quickly as possible (entries 1 vs 2).
2.5. Reduction of the nitro group and/or the halogenide
functions
The reduction of 3, 4 or 5 presented a challenge since the nitro
group as well as the halogen function and the benzylic ether unit in

U. Jahn et al. / Tetrahedron 68 (2012) 447e463
453
1
1
1
2
2
2
Boc R
R
1
Boc R
HN
R
Boc HO
HN
R
R
R
O N
2
HN
H
2
Cl
Cl
R
H
H
H
H
Ph
25a,b
Ph
Ph
O
22a,b
Ph
24a,b
O
O
3a,b
O
1
1
2
2
10 equiv. NaBH ,
R
Boc R
HN
4
R
R
1 equiv. NiCl , EtOH,
O N
2
2
Cl
H
then Boc O, NEt .
2
3
H
H
Ph
Ph
O
4a,g
O
23a,g
1
1
1
2
2
2
R
Boc R
HN
Boc R
HN
R
R
R
O N
2
Cl
H
Cl
H
H
H
Ph
Ph
26b,f
Ph
27f
O
5b,f
O
O
Scheme 8. Reduction of the nitro group in nitrotetrahydrofurans by nickel boride.
Table 3
Reduction of nitrotetrahydrofurans 3,4,5 with nickel boride in ethanola
Entry
3/4/5 (dr)
R1
R2
Temp (ꢀC)
Time (min)
22, 23, 26 (%, dr)
24 (%)
25, 27 (%)
1
2
3
4
3a, 4a (1:1)
3b
Me
H
H
Me
H
H
0e37a
0e40b
0e40c
0e40e
420b
130c
390d
290
22a, 23a (75, 1:1)
22b (3)
22b, 26b (30, 1:1.4)
23g, 26f (57, 1:1.4)
15
60
52
d
d
25b (8)
d
3b, 5b (5:1)
3g, 4g,5f (1:3:8)f
Me H
H Me
27f (24)
a
Substrate 0.7 mmol.
b
c
d
e
f
0
0
0
0
ꢀC, 0.5 h, 25 ꢀC, 4 h, then 37 ꢀC, 2.5 h.
ꢀC, 1 h, then 40 ꢀC, 70 min.
ꢀC, 1.0 h, then 40 ꢀC, 5.5 h.
ꢀC, 50 min, 40 ꢀC, 240 min.
Starting material was a 1:3:8 mixture of 3g, 4g, and 5f. Products derived from 3g were not isolated.
HO Cl
Zn dust, 10% HCl,
slow at pressures lower than 5 bar. At 5 bar hydrogen pressure in
a preheated autoclave at 37 ꢀC, chlorinated aminotetrahydrofuran
25b was the major product isolated in satisfactory 60% yield (entry
6). In addition, fully reduced aminotetrahydrofuran 22b was
formed in 36% yield. Reducing the reaction time further or applying
lower temperatures did not have beneficial effects. With increasing
reaction times of up to 8 h, the amount of 22b increased at the
expense of 25b (entries 7e9). The chlorine function was removed
essentially completely after 14 h, but at reaction times longer than
O N
N
2
EtOH, 35 °C
Cl
Ph
Ph
O
O
28a 37%
3a,4a (d.r. 1.8:1)
Scheme 9. Reduction of 3a and 4a by zinc and HCl.
8 h benzylic cleavage of the tetrahydrofuran ring leading to
g-
(entries 1e3). With increasing temperature the yield of 22a drop-
ped at the expense of both 24a and 30a (entries 1e3 vs 4,5). Ex-
tended reaction times led to an overall decrease of the yield (entries
4,5). The best yield of 22a (50%) was obtained applying 20 bar
hydrogen pressure for 14 h at room temperature (entry 3).
The formation of 30a was surprising, since pure cyclized 3a was
amino alcohol 31b started to compete (entry 10). It was also pos-
sible to operate the hydrogenation with similar yields and ratios of
25b and 22b at 20 bar hydrogen pressure and 60 ꢀC over much
shortened reaction times (entries 12 and 13). After an extended
reaction time of 17 h at 20 bar hydrogen pressure and a tempera-
ture of 60 ꢀC,
g-amino alcohol 31b was obtained in 70% yield as the
the starting material. Possible precursors may be
or the -amino prenyl ether analog 33a. To gain some insight,
nitro ether 32a was hydrogenated under identical conditions
(Scheme 12). An almost equimolar mixture of 30a and -amino
b-nitro ether 32a
major product of the hydrogenation reaction (entry 14).
b
b-
The reactivity of tetrahydrofuran-2-carboxylates 18a and 19a
was also investigated briefly. Carboxylate 18a was hydrogenated at
60 ꢀC at 20 bar hydrogen to fully reduced tetrahydrofuran-derived
b
prenyl ether 33a was obtained in good yield, suggesting that 30a
results from hydrogenation of a prenyl ether precursor (vide infra).
Compound 3b behaved differently from 3a under Raney nickel-
catalyzed hydrogenation conditions. The hydrogenation was very
b
-amino ester 22j in 64% yield (entry 15). In addition 31% of frag-
mentation product 30j was isolated. Nitrotetrahydrofuran ester 19a
gave a partially separable mixture of chlorinated and fully reduced
tetrahydrofuran esters 29j and 23j at lower temperature and

454
U. Jahn et al. / Tetrahedron 68 (2012) 447e463
method is suitable for the chemoselective reductive removal of the
H
Cl
nitro group in the presence of the chloride function affording
BocHN
Ph
BocHN
+
BocHN
+
nitrogen-free chloro tetrahydrofuran derivatives.3
The relative configuration of all products was assigned based on
that of the starting materials and on NOE or NOESY measurements.
Ph
29a 5%
Ph
O
O
O
The
relative
configuration
of
4-(1-chloroethyl)-3-nitro-
23a 60 %
30a 3%
tetrahydrofurans 27f was unequivocally established by X-ray
crystallography (Fig. 5). The 2,3-cis-3,4-trans-configuration is
clearly seen. The tetrahydrofuran ring has an envelope conforma-
ꢀ
Pd-C/20 bar H , EtOH
2
tion, in which C4 lays 0.60 A out of the plane of the other four
3a:4a 0:1
20 °C, 68 h,
atoms. The molecules are linked to form chains parallel to the b axis
by classical hydrogen bonds NeH/O1.
then Boc O, NEt , 20 °C
2
3
Compound 22j also crystallized and its structure was de-
termined by X-ray crystallography (Fig. 6). The 2,3-trans-3,4-cis-
arrangement of the substituents is confirmed. The methoxy-
carbonyl group and isopropyl groups occupy pseudo-equatorial
positions in the molecule, while the NHBoc group is oriented
Cl
O N
2
Ph
axially. No intramolecular hydrogen bonding is seen in the
b-
O
3a,4a
amino ester unit (in fact the molecules are linked to form
inversion-symmetric pairs by the interaction NeH/O4). The
tetrahydrofuran ring adopts an envelope conformation C3 lying
Pd-C/20 bar H , EtOH
2
20 °C, 17 h,
3a:4a 1.5:1
ꢀ
then Boc O, NEt , 20 °C
0.58 A out of the plane of the other four atoms. The relative con-
2
3
figuration of 24b was also unambiguously assigned by X-ray
crystallography; the structure is, however, not publishable be-
cause of extensive disorder.
H
H
HO
BocHN
Ph
BocHN
BocHN
Ph
The outcome of the reductions reveals the following trends.
Both the chlorine and the nitro functions are reduced competitively
(Scheme 13). With all tested reduction systems, epimerization does
not occur at any stage of the reduction process. The rate of chloride
hydrogenation is dependent on the substitution degree at this
carbon atom. In tertiary chlorides 3a or 4a, reduction of the chloride
is fast and proceeds preferentially via intermediates 34 and 35 to
fully reduced compounds 22a or 23a. The primary chloride in 3b is
reduced significantly more slowly than the tertiary chloride func-
tion in 3a. The reduction of the nitro group occurs first via the
corresponding nitroso compound 36 and to a hydroxylamine (not
shown), which cyclizes to bicyclic intermediate 37. Compound 37
may alternatively form via tautomerization of the nitroso com-
pound 36 to oxime 28. This can cyclize. The C]N double bond of
+
+
Ph
22a 13%
O
O
O
23a 15%
24a 33%
Scheme 10. Catalytic hydrogenation of tetrahydrofurans 3a and 4a with Pd/C as the
catalyst (substrate 0.36 mmol, 10 mg Pd/C).
pressure (entry 16). A cleavage product comparable to 30j was
formed in 15% yield.
Although the method was not applied here, it should be men-
tioned that the nitro group can be completely removed reductively
under radical conditions using tributyltin hydride.3,8f,18 This
H
HO
BocHN
BocHN
BocHN
Raney-Ni, H , EtOH
2
+
+
then Boc O, NEt , 25 °C
2
3
1
1
1
R
22a,j/23a,j
R
R
O
O
24a,j
O
30a,j
3a, 4a, 18a, 19a
1
2
3
22-24a,30a: R = Ph, R = R = Me
1
2
3
22-24j,30j: R = CO Me, R = R = Me
2
2
Cl
R
O N
2
3
R
For conditions, see Table 4
1
R
O
3a,b,4a,18a,19a
H
X
BocHN
Ph
BocHN
Ph
BocHN
CH
3
Raney-Ni, H , EtOH
2
3b
+
+
then Boc O, NEt , 25 °C
2
3
Ph
O
O
HO
22b
24b X = OH
31b
25b X = Cl
Scheme 11. Catalytic hydrogenation of 4-(1-chloroalkyl)-3-nitrotetrahydrofurans 3a,b, 4a, 18a, and 19a.

U. Jahn et al. / Tetrahedron 68 (2012) 447e463
455
Table 4
Raney nickel-catalyzed hydrogenation of tetrahydrofurans 3a,b, 4a, 18a, and 19aa
Entry
Substrate
p (bar)
T (ꢀC)
Time (h)
22,23 (%, (dr))
24 (%)
25 (%)
30a,j (%)
31b (%)
1
2
3a/4a (6:1)
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
3b
18a
19a
5
5
20
20
20
5
5
5
5
5
20
20
20
20
20
10
35
25
25
60
60
37
37
37
4
8
14
4
18
0.5
1
3
8
14
4
1
45 (6:1)
42
50
33
22
36
33
54
64
68
45
66
59
9
9
15
22
21
2
d
d
d
d
d
60
40
36
16
1
26
12
3
4
d
16
20
18
30
15
d
d
d
3
d
4b
5
d
d
6b
7
d
2
d
d
8
9
d
d
d
9
d
d
20e37c
37
d
4
10
11
12
13
14b
15
16
d
18
Traces
6.5
28
70
d
25e40d
60
d
2
d
60
60
60
37
2
17
4
d
d
d
d
d
5
d
22j 64
23j 36
30j 31
30j 15
4
29j 30
d
a
Substrate 0.29 mmol.
b
c
Reaction was run in duplicate and gave almost identical results.
25e37 ꢀC, 15 min, 37 ꢀC, 7.5 h.
d
25e40 ꢀC, 45 min, 40 ꢀC, 3 h.
resulting isoxazoline will probably be hydrogenated further from
the convex face, thus also providing 37 under the reduction con-
ditions. This explains why only 3,4-cis-substituted alcohols are
formed. Reductive NeO bond cleavage finally furnishes 24b. The
formation of alcohols 24 is thus an interesting indicator for the
rates of chloride and nitro group reduction. The latter reaction
course is also supported by the reduction of 3a with the weaker
reductant zinc/HCl, whereby the nitro group is reduced quickly but
the reaction stops at the stage of the chloro oxime 28a.
The formation of amino ethers 30 during hydrogenation can be
rationalized by a Grob-type fragmentation of either chloro amine
25 or cyclic amino alcohol 24 to an acyclic alkenyl iminium ion,
which is further reduced to 30.
Raney-Ni,
20 bar H ,
2
EtOH,
BocHN
+
O N
2
25 °C, 24 h,
30a
then Boc O,
2
40%
Ph
O
Ph
NEt , 25 °C
O
32a
3
33a 35%
Scheme 12. Raney nickel-catalyzed hydrogenation of 32a.
Fig. 5. X-ray crystal structure of 4-(1-chloroethyl)-3-nitrotetrahydrofuran 27f. Relative configurations are S*,S*,S*,R* at C2, C3, C4, C6, respectively.

456
U. Jahn et al. / Tetrahedron 68 (2012) 447e463
Fig. 6. X-ray crystal structure of 3-aminotetrahydrofuran-2-carboxylate 22j. Relative configurations are R*,R*,S* at C2, C3, and C4, respectively.
basicity to prevent competitive irreversible deprotonation of the
very acidic a-position to the nitro group. The aryl units of 2-aryl-3-
2
2
H
H
R
R
nitrotetrahydrofurans are cleanly degraded to carboxylic functions.
Nef-type oxidative reactions do not compete significantly under the
reaction conditions. Reduction reactions of the nitro and chloro
groups were strongly dependent on the reactivity of the chloride
function, the relative stereochemistry of the substrates and the
applied catalysts. Depending on the conditions, amino hydroxy-,
amino chloro- or amino alkyltetrahydrofurans can be synthesized
with reasonable selectivity. Hydrogenative ring opening of tetra-
hydrofurans may offer interesting perspectives to synthesize amino
alcohols with defined stereochemistry. All products can be envis-
O N
BocHN
2
2
n
H
R
R
3,4
1
1
R
R
O
O
H
34 n=1, 35 n = 2
22,23
2
2
Cl
R
R
ON
aged as valuable platforms for the synthesis of new b-amino acid
derivatives, amino alcohol ligands or bicyclic amines. Research
along these lines is underway in these labs.
2
H
H
R
O
1
HN
H
2
R
O
36
R
H
1
4. Experimental section
4.1. General
R
O
37
OH
N
2
Cl
R
All reactions were conducted in flame dried glassware under ni-
trogen atmosphere. THF, DME, CH2Cl2, Et2O, and EtOH were dried
following standard methods under nitrogen atmosphere. TLC plates
POLYGRAMSILG/UV254 (MachereyeNagel)wereusedformonitoring
reactions. Flash column chromatographic separations were per-
formed on silica gel 60 (Fluka, 230e400 mesh). IR spectra were taken
on a Bruker Tensor 27 spectrometer (Dura Sample Diamant-ATR, 1
Reflexion). UV spectra were recorded on a Varian Cary 100 spec-
trometer. 1H and 13C NMR spectra were recorded, unless otherwise
noted, in CDCl3 on Bruker DRX 400, AV 300 or AC 200 spectrometers
at 400, 300 or 200, and 100, 75 or 50 MHz, respectively. Connectivity
was determined by 1He1H COSY experiments. Relative configura-
tions were determined by NOE or NOESY experiments. 13C NMR as-
signments were obtained from DEPT and C,H-correlation
experiments. EI-mass spectra were recorded on Finnigan MAT 95
spectrometers at 70 eV. ESI-mass spectra were obtained on a Fin-
2
R
2
HO
R
BocHN
2
R
1
R
O
28
1
R
O
24
Scheme 13. Course of the reduction of tetrahydrofurans 3 and 4.
3. Conclusion
The reactivity profile of several 3-nitrotetrahydrofurans 3, 4, and
5 was investigated. The compounds undergo very efficient intra-
molecular alkylations to bicyclic cyclopropanes. Intermolecular
substitution reactions of the halogenide functions are slow. The
range of nucleophiles is limited to such derivatives having low
nigan MAT 95XLT, sample concentration approx. 50 mg/mL in MeOH,

U. Jahn et al. / Tetrahedron 68 (2012) 447e463
457
spray voltage pos. mode: 1.3e1.8 kV, spray voltage neg. mode:
1.1e2.3 kV, HRMS resolution: 10,000 (10% valley definition). Com-
bustion analyses were performed at the Microanalytical Laboratories
of the Technical University of Braunschweig. The preparation of
compounds 3a, 3b, 3f, 3g, 4a, 4h, 9b, and 32a is described in Ref. 2.
1H), 5.16 (s, 1H), 7.26e7.32 (m, 5H); 13C NMR (100 MHz)
20.7 (q), 30.4 (s), 35.5 (d), 67.5 (t), 80.0 (d), 83.2 (s), 127.1 (d), 128.7
(d), 128.8 (d), 138.4 (s).
d
13.4 (q),
4.3.1.2. 6,6-Dimethyl-1(R*)-nitro-2(R*)-phenyl-3-oxabicyclo
[3.1.0]hexane (7a). Colorless oil, yield 83 mg (96%). Rf¼0.45, hex-
4.2. Typical procedure for epimerization of 3a or 3b
ane/EtOAc 10:1; 1H NMR (400 MHz)
d 1.09 (s, 3H), 1.41 (s, 3H), 2.54
(d, J¼4.2 Hz, 1H), 3.96 (d, J¼9.4 Hz, 1H), 4.30 (dd, J¼9.4, 4.2 Hz, 1H),
To the corresponding allylic alcohol (0.33 mmol) in 3 mL anhy-
drous THF was added n-BuLi (0.21 mL, 0.33 mmol, 1.6 M solution in
hexane) viasyringeatꢁ78ꢀC. Themixturewasstirredfor15min and
warmed to 0 ꢀC. Nitrotetrahydrofuran 3a or 3b (0.33 mmol) was
added and the mixture was stirred for 25 min. The reaction mixture
was quenched with two drops of a saturated NH4Cl solution, diluted
with Et2O, filtered through a pad of silica gel and concentrated under
reduced pressure. The mixture of 3 and 5 was purified by column
chromatography (hexane/EtOAc, gradient 10:1 to 5:1).
5.72 (s, 1H), 7.27e7.34 (m, 3H), 7.42e7.44 (m, 2H); 13C NMR
(100 MHz) d 17.0 (q), 21.7 (q), 34.1 (s), 39.1 (d), 66.9 (t), 80.5 (s), 81.3
(d), 127.2 (d), 127.8 (d), 128.0 (d), 136.8 (s).
4.3.2. 1(R*)-Nitro-2(R*)-phenyl-3-oxabicyclo[3.1.0]hexane
(6b). Colorless oil, yield 61 mg (80%). Rf¼0.26, hexane/EtOAc 5:1; IR
(neat) 3066, 3034, 2947, 2883, 1524, 1377, 1330, 1196, 1050, 1004,
894, 759, 700 cmꢁ1; MS (EI) m/z 205 (Mþ, 13), 188 (23),157 (12),128
(11), 115 (17), 105 (100), 91 (13), 77 (35), 51 (14); Anal. Calcd for
C11H11NO3 (205.21): C 64.38 H 5.40 N 6.32. Found: C 64.31 H 5.50 N
4.2.1. 4(R*)-(1-Chloro-1-methylethyl)-3(R*)-nitro-2(R*)-phenyl-
tetrahydrofuran (5a). Colorless oil, yield 81 mg (88%). Rf¼0.41,
hexane/EtOAc 10:1; MS (CI) m/z 306/304 ([MþNH3þNH4]þ, 3/10),
289/287 ([MþNH4]þ, 24/100), 273/271 (5/10), 256/254 (8/20), 237
(23), 220 (23), 202 (19), 145 (7); Anal. Calcd for C13H16ClNO3
(269.72): C 57.89 H 5.98 N 5.19. Found: C 58.19 H 6.12 N 4.93. 1H
6.68. 1H NMR (400 MHz)
d
1.65 (t, J¼5.6 Hz, 1H), 2.00 (dd, J¼9.2,
5.6 Hz, 1H), 3.00 (ddd, J¼9.2, 5.6, 2.9 Hz, 1H), 3.70 (d, J¼9.2 Hz, 1H),
4.16 (dd, J¼9.2, 2.9 Hz, 1H), 5.23 (s, 1H), 7.25e7.28 (m, 2H),
7.31e7.34 (m, 3H); 13C NMR (100 MHz)
d 21.4 (t), 28.0 (d), 66.1 (t),
71.4 (s), 79.2 (d), 127.1 (d), 129.0 (d, 3C), 137.2 (s).
NMR (400 MHz)
d
1.57 (s, 3H), 1.63 (s, 3H), 3.39 (dt, J¼8.8, 4.1 Hz,
4.3.3. 1-Nitro-2,6-diphenyl-3-oxabicyclo[3.1.0]hexanes (6c,7c). The
following analyses were performed before further separation. IR
(neat) 3059, 3036, 2944, 2887, 1521, 1495, 1370, 1078, 1026, 1005,
891, 806, 763, 728, 697 cmꢁ1; MS (EI) m/z 281 (Mþ, 4), 203 (10), 202
(10), 145 (85), 128 (30), 127 (22), 117 (35), 115 (45), 106 (50), 105
(100), 95 (20), 91 (35), 83 (11), 81 (25), 77 (75), 71 (15), 69 (20), 67
(23), 57 (27); Anal. Calcd for C17H15NO3 (281.31): C 72.58 H 5.37 N
4.98. Found: C 72.28 H 5.31 N 4.92.
1H), 3.94 (t, J¼8.8 Hz, 1H), 4.52 (t, J¼8.8 Hz, 1H), 5.11 (d, J¼6.7 Hz,
1H), 5.36 (dd, J¼6.7, 4.1 Hz, 1H), 7.27e7.31 (m, 5H); 13C NMR
(100 MHz) d 31.0 (q), 32.4 (q), 57.1 (d), 68.6 (s), 69.2 (t), 84.7 (d), 93.2
(d), 126.1 (d), 128.4 (d), 128.9 (d), 133.9 (s).
4.2.2. 4(R*)-(Chloromethyl)-3(R*)-nitro-2(R*)-phenyltetrahydrofuran
(5b). Colorless solid, yield 53 mg (66%). Mp 65 ꢀC; Rf¼0.29, hexane/
EtOAc 5:1; MS (EI) m/z 243/241 (Mþ, 1/3), 196/194 (5/14), 145 (100),
105 (50), 91 (19), 86 (13), 77 (28); Anal. Calcd for C11H12ClNO3
(241.67): C 54.67 H 5.00 N 5.80. Found: C 54.84 H 4.91 N 5.65. 1H
4.3.3.1. 1(R*)-Nitro-2(R*),6(R*)-diphenyl-3-oxabicyclo[3.1.0]hex-
ane (6c). Colorless solid as a partly separable mixture with 7c, yield
45 mg (43%). Mp 138 ꢀC; Rf¼0.33, hexane/EtOAc 10:1; 1H NMR
NMR (400 MHz)
d
3.57e3.65 (m, 1H), 3.65 (dd, J¼11.3, 6.2 Hz, 1H),
3.76 (dd, J¼11.3, 5.1 Hz, 1H), 3.83 (dd, J¼9.1, 7.2 Hz, 1H), 4.62 (dd,
(300 MHz)
d
3.14 (d, J¼6.1 Hz, 1H), 3.43 (dd, J¼6.1, 3.1 Hz, 1H), 4.00
J¼9.1, 8.0 Hz, 1H), 5.21 (d, J¼6.3 Hz, 1H), 5.28 (dd, J¼6.3, 3.1 Hz, 1H),
(d, J¼9.1 Hz, 1H), 4.45 (dd, J¼9.1, 3.1 Hz, 1H), 5.47 (s, 1H), 7.29e7.38
7.29e7.37 (m, 5H); 13C NMR (100 MHz)
d
43.4 (t), 46.7 (d), 70.6 (t),
(m, 10H); 13C NMR (75 MHz)
d
29.7 (d), 36.0 (d), 67.5 (t), 79.3 (s),
84.3 (d), 93.2 (d), 126.3 (d), 128.8 (d), 129.3 (d), 134.2 (s).
81.0 (d), 127.3 (d), 128.3 (d), 128.6 (d), 128.7 (d), 129.0 (d), 129.2 (d),
131.4 (s), 137.2 (s).
4.3. Oxabicyclo[3.1.0]hexanes 6 or 7 from 3, 4 or 5 using DBU
(general procedure)
4.3.3.2. 1(S*)-Nitro-2(R*),6(S*)-diphenyl-3-oxabicyclo[3.1.0]hex-
ane (7c). Colorless oil, yield 28 mg (27%). Rf¼0.27, hexane/EtOAc
DBU (113 mg, 0.74 mmol) was added to a solution of compounds
3, 4 or 5 (0.37 mmol) in 5 mL dry CH2Cl2 at 20 ꢀC. The reaction
mixture was warmed to 40 ꢀC until complete according to TLC. The
reaction mixture was acidified with 1 mL of 2 N HCl, 3 mL water
was added and the aqueous layer was extracted three times with
CH2Cl2. The organic solution was dried over Na2SO4 and concen-
trated in vacuum. The crude oils were purified by column chro-
matography (hexane/EtOAc, gradient 10:1 to 5:1).
10:1; 1H NMR (400 MHz, C6D6)
d
2.37 (dd, J¼7.1, 3.1 Hz, 1H), 2.71 (d,
J¼7.1 Hz, 1H), 3.21 (d, J¼8.8 Hz, 1H), 3.26 (dd, J¼8.8, 3.1 Hz, 1H), 5.17
(s, 1H), 7.44e7.46 (m, 10H); 1H NMR (400 MHz, CDCl3)
d
3.28 (d,
J¼7.4 Hz, 1H), 3.29 (dd, J¼7.4, 2.6 Hz, 1H), 4.17 (d, J¼9.1 Hz, 1H), 4.31
(dd, J¼9.0, 2.5 Hz, 1H), 5.69 (s, 1H), 7.14e7.16 (m, 2H), 7.25e7.47 (m,
6H), 7.63e7.66 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 34.3 (d), 35.4
(d), 68.3 (t), 78.2 (s), 79.4 (d), 127.3 (d), 128.0 (d), 128.46 (d), 128.48
(d), 128.7 (d) 129.0 (d), 131.3 (s), 136.5 (s).
4.3.1. 6,6-Dimethyl-1-nitro-2-phenyl-3-oxabicyclo[3.1.0]hexanes
(6a,7a). The following analyses were performed on the dia-
stereomeric mixture before further separation. IR (neat) 3087, 3034,
2922, 2884, 1648, 1517, 1462, 1377, 1359, 1346, 1105, 1067, 1050, 1013,
891, 795, 763, 700 cmꢁ1; MS (EI) m/z 233 (Mþ, 2), 186 (4), 145 (100),
141 (10), 129 (15), 127 (14), 117 (38), 115 (95), 105 (40), 91 (23), 81
(10), 79 (21), 77 (30), 53 (11), 51 (14); Anal. Calcd for C13H15NO3
(233.26): C 66.94 H 6.48 N 6.00. Found: C 66.97 H 6.48 N 6.04.
4.3.4. Methyl 6(R*)-methyl-1(R*)-nitro-3-oxabicyclo[3.1.0]hexane-
2(S*)-carboxylate (6e). Colorless solid, yield 73 mg (98%). Mp 87 ꢀC;
Rf¼0.25, hexane/EtOAc 10:1; IR (neat) 3061, 3011, 2968, 2901, 1730,
1523, 1446, 1357, 1240, 1212, 1182, 1089, 1066, 1039, 1008, 981, 907,
881, 803, 786, 731 cmꢁ1; MS (EI) m/z 142 (100), 95 (18), 67 (30); Anal.
Calcd for C8H11NO5 (201.18): C 47.76 H 5.51 N 6.96. Found: C 47.86 H
5.38 N 6.90. 1H NMR (400 MHz)
d
1.38 (d, J¼6.4 Hz, 3H), 1.82 (quint,
J¼6.4Hz,1H),2.64(dd,J¼6.4,3.1Hz,1H),3.78(s,3H), 3.84(d, J¼8.6Hz,
1H), 4.30(dd, J¼8.6, 3.1 Hz,1H), 4.70 (s,1H); 13C NMR (100 MHz)
d 10.0
4.3.1.1. 6,6-Dimethyl-1(S*)-nitro-2(R*)-phenyl-3-oxabicyclo[3.1.0]
(q), 27.2 (d), 33.9 (d), 52.6 (q), 69.4 (t), 76.8 (d), 77.2 (s), 168.8 (s).
hexane (6a). Colorless solid, yield 84 mg (97%). Mp 102 ꢀC; Rf¼0.40,
hexane/EtOAc 10:1; 1H NMR (400 MHz)
d
1.23 (s, 3H), 1.35 (s, 3H),
4.3.5. 6-Methyl-1-nitro-2-phenyl-3-oxabicyclo[3.1.0]hexanes
2.63 (d, J¼4.0 Hz, 1H), 3.86 (d, J¼9.3 Hz, 1H), 4.47 (dd, J¼9.3, 4.0 Hz,
(6f,6g,7g). The following analyses were performed before further

458
U. Jahn et al. / Tetrahedron 68 (2012) 447e463
separation. IR (neat) 3062, 3033, 3009, 2942, 2885, 1521, 1496,
1456, 1362, 1336, 1203, 1107, 1061, 1018, 995, 925, 895, 786, 743,
699 cmꢁ1; MS (EI) m/z 219 (Mþ, 38), 202 (50), 128 (14), 115 (15), 105
(100), 91 (10), 77 (30), 55 (17), 51 (13); Anal. Calcd for C12H13NO3
(219.24): C 65.74 H 5.98 N 6.39. Found: C 65.85 H 6.19 N 6.53.
stirred for 10 min. The mixture was extracted with 3 mL diethyl
ether and phases were separated. To the water phase was added
concd HCl (0.1 mL, 1.2 mmol) and it was stirred for 10 min. The
mixture was extracted three times with 10 mL diethyl ether. Con-
centration of the combined organic layers in vacuum and drying
yielded 6d. Colorless solid, yield 30 mg (72%). 1H NMR (200 MHz)
4.3.5.1. 6(R*)-Methyl-1(R*)-nitro-2(R*)-phenyl-3-oxabicyclo
[3.1.0]hexane (6f). Colorless solid, yield 79 mg (97%). Mp 51 ꢀC;
Rf¼0.30, hexane/EtOAc 10:1; IR (neat) 3065, 3034, 2970, 2939,
2882, 1522, 1456, 1371, 1279, 1207, 1089, 1056, 1031, 1008, 992, 898,
885, 759, 699 cmꢁ1; MS (EI) m/z 219 (Mþ, 24), 128 (24), 117 (10), 115
(30), 107 (10), 105 (100), 91 (22), 79 (11), 77 (35), 69 (14), 67 (14), 55
d
1.38 (d, J¼6.4 Hz, 3H), 1.82 (quint, J¼6.4 Hz, 1H), 2.63 (dd, J¼6.4,
3.1 Hz,1H), 3.86 (d, J¼8.7 Hz,1H), 4.30 (dd, J¼8.7, 3.1 Hz,1H), 4.71 (s,
1H), 10.55 (br s, 1H); 13C NMR (50 MHz)
69.6 (t), 76.0 (s), 77.0 (d), 173.8 (s).
d 9.9 (q), 27.3 (d), 34.0 (d),
4.5. 4-((N-Methyl-N-phenylamino)methyl)-3-nitro-2-
phenyltetrahydrofurans 11b, 12b (general procedure)
(17), 51 (19); 1H NMR (400 MHz)
d
1.32 (d, J¼6.2 Hz, 3H),1.89 (quint,
J¼6.2 Hz, 1H), 2.70 (dd, J¼6.2, 3.0 Hz, 1H), 3.81 (d, J¼9.0 Hz, 1H),
4.26 (dd, J¼9.0, 3.0 Hz,1H), 5.25 (s, 1H), 7.29e7.39 (m, 5H); 13C NMR
To a solution of 3b, 9b or 10b (0.3 mmol) in 2 mL dry CH3CN was
added a solution of N-methylaniline (80 mg, 0.75 mmol) in 1 mL
dry CH3CN and NaI (30 mg, 0.2 mmol) at 20 ꢀC. The reaction mix-
ture was heated to reflux until the starting material was consumed
as indicated by TLC. The reaction mixture was concentrated in
vacuum, diluted with 10 mL diethyl ether and filtered. The ethereal
solution was concentrated and the residual oil was purified by
column chromatography (hexane/EtOAc, gradient 10:1 to 5:1). The
same substitution of 9b and 10b was performed in the absence of
NaI. The following analyses were performed on the diastereomeric
mixture before further separation. IR (neat) 2955, 2923, 2854, 1599,
(100 MHz)
d 10.5 (q), 26.4 (d), 32.6 (d), 67.2 (t), 78.2 (s), 80.6 (d),
127.2 (d), 128.96 (d), 129.02 (d), 137.6 (s).
4.3.5.2. 6(S*)-Methyl-1(R*)-nitro-2(R*)-phenyl-3-oxabicyclo
[3.1.0]hexane (6g). Colorless oil, yield 50 mg (62%). Rf¼0.24, hex-
ane/EtOAc 5:1; MS (EI) m/z 219 (Mþ,13), 202 (65),157 (10),128 (27),
117 (10),115 (30),105 (100), 91 (23), 77 (31), 67 (11), 65 (12), 55 (17),
51 (16); 1H NMR (300 MHz)
d
1.39 (d, J¼6.5 Hz, 3H), 2.32 (dq, J¼9.7,
6.5 Hz, 1H), 3.10 (dd, J¼9.7, 3.6 Hz, 1H), 3.87 (dd, J¼9.5, 0.4 Hz, 1H),
4.44 (dd, J¼9.5, 3.6 Hz, 1H), 5.22 (s, 1H), 7.30e7.40 (m, 5H); 13C NMR
(75 MHz)
d
6.2 (q), 29.3 (d), 31.4 (d), 65.3 (t), 75.8 (s), 78.1 (d), 127.0
1552, 1503, 1464, 1377, 1345, 1100, 1072, 992, 967, 744, 693 cmꢁ1
;
(d), 128.8 (d), 128.9 (d), 138.3 (s).
MS (EI) m/z 312 (Mþ, 7), 266 (25), 248 (16), 159 (21), 145 (81), 120
(100), 117 (11), 115 (14), 105 (55), 91 (24), 77 (48), 51 (21); Anal.
Calcd for C18H20N2O3 (312.36): C 69.21 H 6.45 N 8.97. Found: C
69.21 H 6.42 N 8.92.
4.3.5.3. 6(S*)-Methyl-1(S*)-nitro-2(R*)-phenyl-3-oxabicyclo
[3.1.0]hexane (7g). Colorless solid, yield 23 mg (28%). Mp 70 ꢀC;
Rf¼0.26, hexane/EtOAc 5:1; 1H NMR (400 MHz)
1.44 (d, J¼6.5 Hz,
d
3H), 2.03 (quint, J¼6.5 Hz, 1H), 2.58 (dd, J¼6.5, 3.2 Hz, 1H), 4.00 (d,
J¼9.0 Hz, 1H), 4.13 (dd, J¼9.0, 3.2 Hz, 1H), 5.59 (s, 1H), 7.34e7.42 (m,
4.5.1. 4(R*)-((N-Methyl-N-phenylamino)methyl)-3(S*)-nitro-2(R*)-
phenyltetrahydrofuran (11b). Colorless oil, yield starting from 3b
8 mg (8%); yield starting from 9b 34 mg (36%). Rf¼0.33, hexane/
3H), 7.50e7.53 (m, 2H); 13C NMR (100 MHz)
d 10.4 (q), 26.2 (d), 37.6
(d), 68.3 (t), 77.2 (s), 79.5 (d), 127.3 (d), 128.4 (d), 128.5 (d), 136.5 (s).
EtOAc 5:1; 1H NMR (400 MHz)
d 2.96 (s, 3H), 3.04 (m, 1H), 3.37 (dd,
J¼15.0, 8.5 Hz, 1H), 3.59 (dd, J¼15.0, 5.6 Hz, 1H), 4.18 (dd, J¼10.5,
8.5 Hz, 1H), 4.36 (dd, J¼8.5, 7.5 Hz, 1H), 5.00 (dd, J¼7.5, 3.0 Hz, 1H),
5.53 (d, J¼3.0 Hz, 1H), 6.61e6.83 (m, 3H), 7.16e7.44 (m, 7H); 13C
4.3.6. (2R*,2aS*,2bR*,5aS*,5bS*)-2a-Nitro-2-phenyloctahydro-1-
oxacyclopropa[cd]indene (7h). Colorless oil, yield 86 mg (95%).
Rf¼0.36, hexane/EtOAc 10:1; IR (neat) 3034, 2927, 1522, 1495, 1451,
1349, 1260, 1090, 1042, 1027, 934, 800, 776, 732, 696 cmꢁ1; MS (EI)
m/z 245 (Mþ, 1), 228 (100), 198 (16), 170 (17), 157 (28), 141 (34), 128
(34), 115 (67), 105 (99), 91 (57), 81 (35), 79 (32), 77 (97), 67 (13), 65
(22), 63 (11), 53 (13), 51 (34); HRMS (EI) calcd for C14H15NO3
NMR (100 MHz)
d 39.5 (q), 42.1 (d), 49.5 (t), 71.9 (t), 85.0 (d), 94.2
(d), 112.9 (d), 117.6 (d), 125.3 (d), 128.6 (d), 128.9 (d), 129.42 (d),
139.0 (s), 148.5 (s).
4.5.2. 4(R*)-((N-Methyl-N-phenylamino)methyl)-3(R*)-nitro-2(R*)-
phenyltetrahydrofuran (12b). Colorless solid, yield starting from 3b
46 mg (48%); yield starting from 9b 34 mg (36%). Mp 87 ꢀC; Rf¼0.18,
245.1052, found 245.1053; 1H NMR (400 MHz)
d 1.25 (m, 1H), 1.36
(m, 1H), 1.41 (m, 1H), 1.62 (m, 1H), 1.70 (m, 1H), 1.82 (m, 1H), 2.87
(dd, J¼9.9, 4.6 Hz, 1H), 2.95 (dt, J¼9.1, 4.6 Hz, 1H), 4.75 (m, 1H), 6.09
(s, 1H), 7.31e7.38 (m, 3H), 7.41e7.45 (m, 2H); 13C NMR (100 MHz)
hexane/EtOAc 5:1; 1H NMR (400 MHz)
d 2.91 (s, 3H), 3.35 (dd,
J¼17.4, 10.7 Hz, 1H), 3.50 (m, 2H), 3.74 (dd, J¼8.9, 5.8 Hz, 1H), 4.56
(dd, J¼8.9, 7.1 Hz, 1H), 5.09 (dd, J¼6.4, 2.9 Hz, 1H), 5.25 (d, J¼6.4 Hz,
1H), 6.72e6.79 (m, 3H), 7.20e7.30 (m, 7H); 13C NMR (100 MHz)
d
15.7 (t), 16.4 (t), 25.2 (t), 29.7 (d), 34.6 (d), 73.4 (d), 74.1 (s), 79.1
(d), 126.9 (d), 127.9 (d) 128.3 (d), 137.0 (s).
d
39.2 (q), 44.4 (d), 53.8 (t), 71.4 (t), 83.1 (d), 92.9 (d), 113.4 (d), 118.2
4.3.7. (2R*,2aR*,2bS*,5aR*,5bR*,20S*,2a0S*,2b0R*,5a0S*,5b0R*)-2,20-Di-
oxybis(2a-nitro-2-phenyloctahydro-1-oxacyclopropa[cd]indene)
(8). Colorless solid, yield 8 mg (4%). Mp 135 ꢀC; Rf¼0.30, hexane/
EtOAc 10:1; IR (neat) 3064, 2950, 1529, 1451, 1359, 1233, 1095, 1016,
974, 938, 910, 789, 762, 695 cmꢁ1; MS (EI) m/z 244 (100), 202 (35),
198 (8), 141 (10), 128 (14), 115 (20); HRMS (EI) calcd for C14H14NO3
(MþꢁO2eC14H14NO3) 244.0974, found 244.0968; 1H NMR
(d), 126.0 (d), 128.4 (d), 128.8 (d), 129.44 (d), 134.4 (s), 149.3 (s).
4.6. 4-(Azidomethyl)-3-nitro-2-phenyltetrahydrofurans 13, 14
(general procedure)
To a solution of 3b or 5b (115 mg, 0.46 mmol) in 2 mL dry DMF
was added NaN3 (90 mg, 1.38 mmol) at 20 ꢀC. The reaction mixture
was warmed to 60 ꢀC with stirring until complete according to TLC.
The reaction mixture was concentrated in vacuum, diluted with
10 mL diethyl ether and filtered. The ethereal solution was con-
centrated and the residual oil was purified by column chromatog-
raphy (hexane/EtOAc, gradient 10:1 to 5:1). The following analyses
were performed on the diastereomeric mixture of 13b and 14b
before further separation. IR (neat) 3067, 3034, 2980, 2929, 2871,
2100, 1547, 1453, 1359, 1333, 1276, 1097, 1069, 1029, 983, 747,
698 cmꢁ1; MS (CI) m/z 266 ([MþNHþ4 ], 100), 240 (12), 233 (10), 223
(200 MHz)
d 1.19e1.44 (m, 4H), 1.59 (m, 1H), 1.80 (m, 1H), 2.58 (dt,
J¼9.2, 4.7 Hz, 1H), 3.05 (dd, J¼9.6, 4.7 Hz, 1H), 4.75 (m, 1H),
7.36e7.43 (m, 3H), 7.57e7.62 (m, 2H).
4.4. 6(R*)-Methyl-1(R*)-nitro-3-oxabicyclo[3.1.0]hexane-
2(S*)-carboxylic acid (6d) from 3d using NaHCO3
Crude 3d (54 mg, 0.22 mmol) was dissolved in a saturated
aqueous solution of NaHCO3 (0.6 mL, 0.69 mmol) at 20 ꢀC and

U. Jahn et al. / Tetrahedron 68 (2012) 447e463
459
(14), 221 (16), 219 (16), 207 (13), 202 (25), 196 (44), 193 (18), 191
(11), 178 (30), 176 (55), 174 (25), 164 (100), 162 (25), 147 (12), 145
(19), 61 (18); Anal. Calcd for C11H12N4O3 (248.24): C 53.22 H 4.87 N
22.57. Found: C 53.12 H 4.89 N 22.59.
performed on the diastereomeric mixture of 18a and 19a before
further separation. IR (neat) 3047, 2969, 2893, 1744, 1732, 1553,
1440, 1375, 1223, 1132, 1102, 1083, 1032, 939, 923, 785 cmꢁ1; MS
(EI) m/z 194/192 (25/75), 169 (12), 151 (15), 148/146 (14/42), 145
(20), 141 (13), 127 (100), 109 (55), 97 (38), 95 (18), 83 (15), 81 (55),
79 (35), 77 (40); HRMS (EI) calcd for C7H11 35ClNO3 (MþꢁCH3O(O)C)
192.0427, found 192.0424.
4.6.1. 4(R*)-(Azidomethyl)-3(S*)-nitro-2(R*)-phenyltetrahydrofuran
(13b). Colorless oil, for yields see Scheme 6. Rf¼0.26, hexane/EtOAc
5:1;1HNMR (200 MHz)
d
2.92(dq, J¼10.3, 7.6 Hz,1H), 3.47 (dd, J¼12.5,
7.6 Hz, 1H), 3.56 (dd, J¼12.5, 7.6 Hz, 1H), 4.05 (dd, J¼10.3, 8.6 Hz, 1H),
4.44 (dd, J¼8.6, 7.6 Hz, 1H), 5.02 (dd, J¼7.6, 3.2 Hz, 1H), 5.54 (d,
4.8.2.1. Methyl 4(R*)-(1-chloro-1-methylethyl)-3(S*)-nitrotetra-
hydrofuran-2(S*)-carboxylate (18a). Colorless solid, yield according
to method A 79 mg (58%, 18a/19a 1.4:1); yield according to method
B 55 mg (40%). Mp 109 ꢀC; Rf¼0.30, hexane/EtOAc 2:1; 1H NMR
J¼3.2 Hz,1H), 7.26e7.38 (m, 5H); 13C NMR (100 MHz)
d 34.8 (d), 48.0
(t), 70.9 (t), 86.0 (d), 93.0 (d), 125.3 (d), 128.9 (d), 129.6 (d), 137.5 (s).
(400 MHz)
d
1.67 (s, 3H), 1.701 (s, 3H), 2.95 (ddd, J¼11.4, 8.0, 6.2 Hz,
4.6.2. 4(R*)-(Azidomethyl)-3(R*)-nitro-2(R*)-phenyltetrahydrofuran
1H), 3.82 (s, 3H), 4.35 (dd, J¼11.4, 8.0 Hz, 1H), 4.44 (t, J¼8.0 Hz, 1H),
(14b). Colorless oil, for yields see Scheme 6. Rf¼0.15, hexane/EtOAc
5.02 (d, J¼1.0 Hz, 1H), 5.28 (dd, J¼6.2, 1.0 Hz, 1H); 13C NMR
5:1; 1H NMR (200 MHz)
d
3.31 (m, 1H), 3.51 (dd, J¼12.4, 6.3 Hz, 1H),
(100 MHz) d 30.5 (q), 32.4 (q), 53.1 (q), 56.0 (d), 65.0 (s), 69.5 (t),
3.65 (dd, J¼12.4, 5.6 Hz, 1H), 3.73 (dd, J¼8.9, 7.1 Hz, 1H), 4.58 (dd,
J¼8.9, 8.1 Hz, 1H), 5.15 (dd, J¼6.3, 2.7 Hz, 1H), 5.19 (d, J¼6.3 Hz, 1H),
81.4 (d), 87.4 (d), 169.4 (s).
7.30e7.34 (m, 5H); 13C NMR (50 MHz)
d
44.3 (d), 51.0 (t), 70.1 (t),
4.8.2.2. Methyl 4(S*)-(1-chloro-1-methylethyl)-3(S*)-nitrotetra-
83.7 (d), 92.6 (d), 126.0 (d), 128.4 (d), 128.9 (d), 134.0 (s).
hydrofuran-2(S*)-carboxylate (19a). Colorless oil. Rf¼0.35, hexane/
EtOAc 2:1; 1H NMR (400 MHz)
d 1.55 (s, 3H), 1.695 (s, 3H), 3.26 (dt,
4.7. Oxidative degradation of the phenyl ring using NaIO4/
RuCl3 (method A)
J¼8.7, 4.8 Hz, 1H), 3.83 (s, 3H), 4.11 (dt, J¼8.7, 0.6 Hz, 1H), 4.37 (t,
J¼8.7 Hz, 1H), 5.10 (d, J¼3.0 Hz, 1H), 5.33 (dd, J¼4.8, 3.0 Hz, 1H); 13C
NMR (100 MHz)
d 31.1 (q), 32.1 (q), 53.0 (q), 57.2 (d), 68.4 (s), 70.6
To a mixture of 3, 4, or 5 (0.54 mmol) in 4 mL CH3CN, 4 mL CCl4,
and 6 mL H2O were added subsequently with vigorous stirring NaIO4
(797 mg, 3.72 mmol) and RuCl3$1H2O (9 mg, 0.04 mmol) at 20 ꢀC.
The white-yellow reaction mixture was stirred at room temperature
until the starting material was consumed. When the reaction mix-
ture changed its color to gray-brown and the starting material was
not completely consumed, additional NaIO4 (797 mg, 3.72 mmol)
and 4 mL H2O was added. The reaction mixture was extracted three
times with 20 mL CH2Cl2 and then three times with 20 mL EtOAc. The
organic extracts were combined, dried over Na2SO4, and concen-
trated in vacuum. The crude acids 3d, 16, 17, or 20 were analyzed by
NMR and then immediately converted to the corresponding methyl
esters 3e,18,19, or 21 by dissolving them in 4 mL anhydrous THF and
0.2 mL dry MeOH and adding trimethylsilyldiazomethane (0.243 mL,
0.486 mmol, 2 M solution in Et2O). The reaction mixture was stirred
for 2 h at room temperature, concentrated in vacuum and purified by
column chromatography (hexane/EtOAc, gradient 10:1 to 2:1).
(t), 81.6 (d), 90.5 (d), 168.8 (s).
4.8.2.3. Methyl 4(R*)-(1-chloro-1-methylethyl)-3(R*)-nitrotetra-
hydrofuran-2(S*)-carboxylate (21a). Colorless oil, yield according to
method B 28 mg (20%). Rf¼0.44, hexane/EtOAc 2:1; 1H NMR
(400MHz)
d
1.57(s, 3H),1.75(s, 3H), 3.08(dt,J¼8.2,4.2Hz,1H),3.80(s,
3H), 3.96(dd,J¼9.1, 8.2Hz,1H), 4.50(t, J¼8.7 Hz,1H), 4.65(d, J¼6.3 Hz,
1H), 5.40 (dd, J¼6.3, 4.2 Hz, 1H); 13C NMR (100 MHz)
d 31.0 (q), 32.2
(q), 52.9 (q), 57.6 (d), 69.0 (s), 69.7 (t), 80.2 (d), 89.0 (d), 166.8 (s).
4.8.3. Methyl 4-(chloromethyl)-3-nitrotetrahydrofuran-2-carboxylates
(18b,21b). The following analyses were performed on the dia-
stereomeric mixture before further separation. IR (neat) 3011, 2958,
2898, 1757, 1740, 1554, 1440, 1363, 1289, 1263, 1215, 1182, 1118, 1066,
1022, 929, 850, 736 cmꢁ1; MS (EI) m/z 178/176 (1/3),166/164 (15/45),
127 (18), 120/118 (17/55), 119/117 (5/12), 69 (100), 59 (35), 53 (14);
HRMS (EI) calcd for C5H375ClNO3 (MþꢁCH3OOC) 164.0114, found
164.0112.
4.8. Oxidative degradation of the phenyl ring using H5IO6/
RuCl3 (method B)
4.8.3.1. Methyl 4(R*)-(chloromethyl)-3(S*)-nitrotetrahydrofuran-
2(S*)-carboxylate (18b). Colorless oil, yield 42 mg (56%, 18b/21b
A mixture of 3, 4, or 5 (0.33 mmol) in 3 mL CCl4 and RuCl3$1H2O
(7.6 mg, 0.033 mmol) in 1 mL CH3CN was added to a stirred solution
of H5IO6 (753 mg, 3.3 mmol) in 10 mL CH3CN at 20 ꢀC. The reaction
mixture was stirred at room temperature until the reaction was
complete according to TLC, and concentrated in vacuum. The resi-
due was mixed with a small amount of water and extracted three
times with Et2O. The combined extracts were dried over Na2SO4
and concentrated in vacuum. The crude products 3d, 16, 17, or 20
were transformed to the methyl esters 3e, 18, 19, or 21 by the
procedure described above.
1:2). Rf¼0.44, hexane/EtOAc 2:1; 1H NMR (400 MHz)
d 3.14 (m, 1H),
3.48 (dd, J¼11.4, 8.3 Hz, 1H), 3.62 (dd, J¼11.4, 7.1 Hz, 1H), 3.83 (s,
3H), 4.03 (t, J¼8.8 Hz, 1H), 4.40 (dd, J¼8.8, 7.5 Hz, 1H), 5.08 (d,
J¼2.5 Hz,1H), 5.35 (dd, J¼7.2, 2.5 Hz,1H); 13C NMR (100 MHz)
d 39.2
(t), 45.9 (d), 53.2 (q), 71.6 (t), 80.9 (d), 88.8 (d), 168.9 (s).
4.8.3.2. Methyl 4(R*)-(chloromethyl)-3(R*)-nitrotetrahydrofuran-
2(S*)-carboxylate (21b). Colorless oil. Rf¼0.40, hexane/EtOAc 2:1;
1H NMR (400 MHz)
d
3.40 (m, 1H), 3.66 (dd, J¼11.9, 5.8 Hz, 1H), 3.79
(s, 3H), 3.82 (dd, J¼11.9, 5.4 Hz, 1H), 3.89 (dd, J¼9.2, 6.2 Hz,1H), 4.51
(dd, J¼9.2, 7.8 Hz, 1H), 4.77 (d, J¼6.6 Hz, 1H), 5.32 (dd, J¼6.6, 4.3 Hz,
4.8.1. 4(R*)-(1(S*)-Chloroethyl)-3(S*)-nitrotetrahydrofuran-2(S*)-
1H); 13C NMR (100 MHz)
(d), 88.3 (d), 167.2 (s).
d 43.1 (t), 46.9 (d), 52.9 (q), 70.5 (t), 79.2
carboxylic acid (3d). Colorless oil, yield 93 mg (77%). Rf¼0.20,
hexane/EtOAc 2:1; 1H NMR (200 MHz)
d
1.60 (d, J¼6.5 Hz, 3H), 2.87
(m, 1H), 3.85 (dq, J¼10.4, 6.5 Hz, 1H), 4.12 (dd, J¼10.9, 8.8 Hz, 1H),
4.8.4. Methyl 4(R*)-(1(S*)-chloroethyl)-3(S*)-nitrotetrahydrofuran-
2(S*)-carboxylate (3e). Colorless oil as a partially separable mixture
with 5e, yield 94 mg (73%, 3e/5e 1:2.4). Rf¼0.20, hexane/EtOAc
10:1; IR (neat) 2960, 2939, 2902, 1714, 1551, 1454, 1368, 1268, 1221,
1130, 1097, 1034, 935, 908, 802 cmꢁ1; MS (EI) m/z 178/176 (9/27),
132 (30), 127 (10), 95 (11), 69 (100), 59 (20), 55 (10); 1H NMR
4.47 (dd, J¼8.8, 7.9 Hz, 1H), 5.06 (d, J¼1.5 Hz, 1H), 5.23 (dd, J¼6.6,
1.5 Hz, 1H), 9.50 (br s, 1H); 13C NMR (50 MHz)
53.1 (d), 72.9 (t), 81.7 (d), 88.5 (d), 172.1 (s).
d 24.6 (q), 51.9 (d),
4.8.2. Methyl 4-(1-chloro-1-methylethyl)-3-nitrotetrahydrofuran-2-
carboxylates (18a,19a,(21a)). The following analyses were
(400 MHz)
d
1.66 (d, J¼6.4 Hz, 3H), 2.96 (m, 1H), 3.84 (s, 3H), 3.92

460
U. Jahn et al. / Tetrahedron 68 (2012) 447e463
(m, 1H), 4.17 (dd, J¼10.8, 8.6 Hz, 1H), 4.51 (t, J¼8.6 Hz, 1H), 5.05 (d,
4.9.2. 3(S*)-(N-tert-Butoxycarbonylamino)-4(R*)-(1-hydroxy-1-
methylethyl)-2(R*)-phenyltetrahydrofuran (24a). Colorless solid, for
yields and ratios, see Tables 3 and 4 and Scheme 10. Mp 157 ꢀC;
Rf¼0.23, hexane/EtOAc 2:1; UV (CH2Cl2, 6.0ꢂ10ꢁ5 M): lmax 258,
227 nm; IR (neat) 3435, 3330, 2974, 2933, 2887, 1679, 1450, 1385,
1364, 1345, 1328, 1127, 1091, 1064, 988, 928, 815, 779, 737,
715 cmꢁ1; MS (ESI) m/z 344 ([MþNaþ], 100); MS (EI) m/z 321 (Mþ,
1), 264 (6), 190 (13), 186 (20), 176 (10), 146 (76), 144 (21), 141 (13),
120 (50), 118 (15), 116 (13), 107 (43), 105 (25), 101 (26), 97 (42), 91
(22), 82 (100), 79 (18), 77 (26), 70 (34); Anal. Calcd for C18H27NO4
(321.41): C 67.26 H 8.47 N 4.36. Found: C 67.03 H 8.28 N 4.32; 1H
J¼1.6 Hz, 1H), 5.23 (dd, J¼6.5, 1.6 Hz, 1H); 13C NMR (100 MHz)
d 24.6
(q), 51.98 (d), 53.2 (q), 53.3 (d), 72.8 (t), 82.1 (d), 88.6 (d), 169.0 (s).
4.8.5. Methyl 4(R*)-(1(S*)-chloroethyl)-3(R*)-nitrotetrahydrofuran-
2(S*)-carboxylate (5e). Colorless oil as a partially separable mixture
with 3e, yield 94mg (73%, 3e/5e1:2.4). Rf¼0.17, hexane/EtOAc 10:1;IR
(neat) 2960, 2939, 2902,1714,1551,1454,1368,1268,1221,1130,1097,
1034, 935, 908, 802 cmꢁ1; MS (EI) m/z 178/176 (9/27), 132 (30), 127
(10), 95 (11), 69 (100), 59 (20), 55 (10); 1H NMR (400 MHz)
d 1.56 (d,
J¼6.8 Hz, 3H), 3.27 (tt, J¼8.1, 4.8 Hz, 1H), 3.79 (s, 3H), 3.98 (dd, J¼9.1,
7.7 Hz, 1H), 4.44 (dq, J¼6.8, 4.8 Hz, 1H), 4.48 (t, J¼8.8 Hz, 1H), 4.71 (d,
NMR (400 MHz)
d 1.22 (s, 3H), 1.31 (s, 3H), 1.49 (s, 9H), 1.94 (br s,
J¼6.6 Hz, 1H), 5.27 (dd, J¼6.6, 4.8 Hz, 1H); 13C NMR (100 MHz)
d
23.4
1H), 2.19 (m, 1H), 4.08 (m, 1H), 4.27 (m, 2H), 5.22 (br s, 1H), 6.62 (br
(q), 52.04 (d), 52.9 (q), 56.8 (d), 68.7 (t), 79.3 (d), 88.8 (d), 167.2 (s).
s, 1H), 7.24 (m, 1H), 7.34 (m, 2H), 7.48 (m, 2H); 13C NMR (100 MHz)
d
28.8 (q), 29.6 (q), 31.7 (q), 47.8 (d), 60.8 (d), 68.1 (t), 71.0 (s), 79.7
4.9. Reduction of tetrahydrofurans 3a,b,g, 4a,g, and 5b,f by
NiCl2/NaBH4 (general procedure)
(s), 85.3 (d), 125.4 (d), 127.3 (d), 128.5 (d), 142.0 (s), 156.5 (s).
4.9.3. 3(S*)-(N-tert-Butoxycarbonylamino)-4(R*)-methyl-2(R*)-phe-
nyltetrahydrofuran (22b). Colorless solid, for yields and ratios, see
Tables 3 and 4. Mp 102 ꢀC; Rf¼0.30, hexane/EtOAc 5:1; IR (neat)
3370, 3066, 3032, 2980, 2965, 2941, 2874, 1680, 1517, 1454, 1389,
1366, 1278, 1248, 1167, 1090, 1055, 1008, 980, 929, 871, 755, 740,
698 cmꢁ1; MS (EI) m/z 220 (29),160 (64),146 (16),115 (25),107 (12),
91 (11), 77 (10), 70 (40), 57 (100); Anal. Calcd for C16H23NO3
(277.36): C 69.29 H 8.36 N 5.05. Found: C 69.07 H 8.51 N 5.37. 1H
(a) Preparation of the Ni2B catalyst: to a solution of NiCl2$6H2O
(166 mg, 0.7 mmol) in 6 mL dry EtOH was added NaBH4 (83 mg,
2.2 mmol) at 0 ꢀC and the mixture was stirred for 30 min. (b) Re-
duction of the NO2 group: To a mixture of 3, 4 or 5 (0.7 mmol),
NaBH4 (265 mg, 7.0 mmol) and 13 mL dry EtOH was added the
freshly prepared Ni2B catalyst suspension at the given starting
temperature (see Table 3). The mixture was stirred for the indicated
time at 0 ꢀC and subsequently warmed to 40 ꢀC with stirring for the
given time. After completion of the reaction, the mixture was
cooled to room temperature and Et3N (0.142 mL, 1.4 mmol) fol-
lowed by Boc2O (327 mg, 1.5 mmol) was added. The reaction
mixture was stirred overnight, filtered, and concentrated in vac-
uum. The residual oil was purified by column chromatography
(hexane/EtOAc, gradient 10:1 to 2:1).
NMR (300 MHz)
d
1.00 (d, J¼6.9 Hz, 3H), 1.46 (s, 9H), 2.49 (m, 1H),
3.58 (t, J¼8.7 Hz, 1H), 4.14 (m, 1H), 4.29 (dd, J¼8.7, 7.7 Hz, 1H), 4.75
(br s, 1H), 4.77 (br d, J¼3.9 Hz, 1H), 7.23e7.39 (m, 5H); 13C NMR
(75 MHz) d 11.1 (q), 28.3 (q), 34.8 (d), 61.0 (d), 73.9 (t), 77.2 (s), 85.8
(d), 125.4 (d), 127.5 (d), 128.4 (d), 141.0 (s), 155.5 (s).
4.9.4. 3(S*)-(N-tert-Butoxycarbonylamino)-4(S*)-(hydroxymethyl)-
2(R*)-phenyltetrahydrofuran (24b). Colorless solid, for yields and
ratios, see Tables 3 and 4. Mp 130 ꢀC; Rf¼0.26, hexane/EtOAc 2:1; IR
(neat) 3483, 3418, 3376, 3067, 3035, 2980, 2933, 2904, 2868, 1681,
1516, 1389, 1254, 1165, 1094, 1046, 1014, 981, 951, 873, 755, 740,
698 cmꢁ1; MS (ESI) m/z 316 ([MþNaþ], 100); MS (EI) m/z 236 (7),
220 (5), 176 (30), 145 (35), 131 (15), 107 (13), 91 (12), 86 (15), 77
(20), 68 (25), 59 (14), 57 (90), 56 (100); Anal. Calcd for C16H23NO4
(293.36): C 65.51 H 7.90 N 4.77. Found: C 65.63 H 7.93 N 4.81. 1H
4.9.1. 3-(N-tert-Butoxycarbonylamino)-4-isopropyl-2-phenyl-
tetrahydrofurans (22a,23a). The combustion analysis was performed
on the diastereomeric mixture before further separation. Anal. Calcd
for C18H27NO4 (305.41): C 70.79 H 8.91 N 4.59. Found: C 70.62 H 8.92
N 4.68.
4.9.1.1. 3(S*)-(N-tert-Butoxycarbonylamino)-4(R*)-isopropyl-
2(R*)-phenyltetrahydrofuran (22a). Colorless solid, for yields and
ratios, see Tables 3 and 4 and Scheme 10. Mp 124 ꢀC; Rf¼0.55,
hexane/EtOAc 5:1; IR (neat) 3334, 3271, 3146, 3064, 2961, 2926,
2872,1702,1533,1449, 1388, 1365, 1348, 1164, 1085, 1059, 1027, 991,
971, 928, 776, 734, 699, 681 cmꢁ1; MS (EI) m/z 305 (Mþ, 4), 290 (25),
249 (11), 248 (64), 188 (5), 99 (14), 56 (100); 1H NMR (400 MHz)
NMR (400 MHz, DMSO-d6) d 1.38 (s, 9H), 2.44 (m, 1H), 3.43 (m, 1H),
3.52 (m, 1H), 3.86 (m, 2H), 4.16 (dd, J¼8.5, 7.5 Hz, 1H), 4.55 (t,
J¼5.0 Hz,1H), 4.60 (d, J¼6.4 Hz,1H), 7.12 (d, J¼8.5 Hz,1H), 7.24e7.29
(m,1H), 7.31e7.36 (m, 4H); 13C NMR (100 MHz, DMSO-d6)
d 28.1 (q),
42.6 (d), 58.7 (t), 59.8 (d), 70.3 (t), 78.0 (s), 83.2 (d), 125.5 (d), 127.3
(d), 128.1 (d), 141.6 (s), 155.4 (s).
d
0.87 (d, J¼6.6 Hz, 3H), 0.89 (d, J¼6.6 Hz, 3H), 1.49 (s, 9H), 1.61 (m,
1H),1.92 (m,1H), 3.68 (dd, J¼11.1, 8.6 Hz,1H), 4.19 (dd, J¼8.6, 6.0 Hz,
1H), 4.31 (t, J¼8.6 Hz, 1H), 4.88 (br d, J¼8.6 Hz, 1H), 5.07 (br s, 1H),
4.9.5. 3(S*)-(N-tert-Butoxycarbonylamino)-4(R*)-(chloromethyl)-
2(R*)-phenyltetrahydrofuran (25b). Colorless solid, for yields and
ratios, see Tables 3 and 4. Mp 124 ꢀC; Rf¼0.50, hexane/EtOAc 5:1; IR
(neat) 3360, 3037, 2978, 2935, 2880, 1672, 1517, 1454, 1370, 1352,
1274, 1250, 1157, 1054, 1013, 968, 900, 756 cmꢁ1; MS (EI) m/z 256/
254 (3/8), 158 (11), 145 (13), 107 (14), 105 (30), 91 (17), 77 (25), 70
(100), 68 (30), 57 (48); Anal. Calcd for C16H22ClNO3 (311.80): C 61.63
H 7.11 N 4.49. Found: C 61.65 H 6.98 N 4.22. 1H NMR (300 MHz)
7.23e7.52 (m, 5H); 13C NMR (100 MHz)
d 21.5 (q), 21.8 (q), 26.8 (d),
28.4 (q), 47.1 (d), 59.5 (d), 71.7 (t), 79.7 (s), 88.1 (d), 125.0 (d), 127.1
(d), 128.275 (d), 141.6 (s), 155.5 (s).
4.9.1.2. 3(S*)-(N-tert-Butoxycarbonylamino)-4(S*)-isopropyl-
2(R*)-phenyltetrahydrofuran (23a). Colorless solid, for yields and
ratios, see Tables 3 and 4 and Scheme 10. Mp 102 ꢀC; Rf¼0.30,
hexane/EtOAc 5:1; IR (neat) 3361, 3033, 3008, 2959, 2934, 2874,
1684, 1525, 1456, 1368, 1291, 1236, 1167, 1091, 1042, 1021, 975, 872,
862, 759, 699 cmꢁ1; MS (EI) m/z 248 (7), 188 (33), 174 (14), 145 (42),
107 (30), 105 (15), 99 (11), 97 (18), 91 (13), 82 (14), 79 (14), 77 (16),
d
1.44 (s, 9H), 2.84 (m, 1H), 3.54 (dd, J¼11.0, 8.6 Hz, 1H), 3.71 (dd,
J¼11.0, 5.1 Hz, 1H), 3.91 (t, J¼8.8 Hz, 1H), 4.30 (m, 1H), 4.40 (dd,
J¼8.8, 8.2 Hz, 1H), 4.79 (d, J¼3.9 Hz, 1H), 4.85 (br d, J¼7.9 Hz, 1H),
7.26e7.39 (m, 5H); 13C NMR (75 MHz)
d 28.3 (q), 42.6 (t), 42.9 (d),
59.8 (d), 70.8 (t), 77.2 (s), 85.8 (d), 125.4 (d), 127.9 (d), 128.6 (d),
139.8 (s), 155.3 (s).
59 (20), 56 (100); 1H NMR (400 MHz)
d
0.89 (d, J¼6.3 Hz, 3H), 0.96
(d, J¼6.7 Hz, 3H),1.40 (s, 9H),1.72 (m,1H),1.96 (m,1H), 3.85 (m,1H),
3.93 (m, 1H), 4.13 (t, J¼8.7 Hz, 1H), 4.61 (br d, J¼5.9 Hz, 1H), 4.72 (br
4.9.6. 3(R*)-(N-tert-Butoxycarbonylamino)-4(R*)-methyl-2(R*)-phe-
nyltetrahydrofuran (26b). Colorless solid, as an inseparable mixture
with 22b, yield 58 mg (30%, 26b/22b 1.4:1). Rf¼0.30, hexane/EtOAc
d, J¼7.9 Hz, 1H), 7.24e7.46 (m, 5H); 13C NMR (100 MHz)
d 20.3 (q),
20.7 (q), 28.5 (q), 30.1 (d), 52.9 (d), 62.9 (d), 70.5 (t), 79.4 (s), 85.6
(d), 125.1 (d), 128.1 (d), 128.283 (d), 140.0 (s), 154.9 (s).
5:1; 1H NMR (200 MHz)
d
1.14 (d, J¼6.8 Hz, 3H), 1.31 (s, 9H), 2.17 (m,

U. Jahn et al. / Tetrahedron 68 (2012) 447e463
461
1H), 3.52 (t, J¼8.5 Hz, 1H), 4.07 (m, 2H), 4.29 (t, J¼8.5 Hz, 1H), 5.11
evaporation was purified by column chromatography (hexane/
EtOAc, gradient 10:1 to 2:1). Colorless solid, yield 49 mg (37%). Mp
80 ꢀC; Rf¼0.40, hexane/EtOAc 10:1; IR (neat) 3270, 3065, 3034,
2982, 2931, 2881, 1724, 1452, 1372, 1271, 1208, 1183, 1111, 1066,
1049, 999, 951, 931, 902, 757, 696 cmꢁ1; MS (EI) m/z 255/253 (Mþ,
3/8), 238/236 (9/30), 107 (90), 105 (100), 94 (10), 82 (14), 79 (28), 77
(58), 67 (14), 51 (28); HRMS (EI) calcd for C13H16 35ClNO2 253.0869,
(br d, J¼6.0 Hz, 1H), 7.21e7.37 (m, 5H); 13C NMR (50 MHz)
d 15.4 (q),
28.2 (q), 39.4 (d), 60.5 (d), 73.4 (t), 77.0 (s), 81.0 (d), 126.4 (d, 3C),
128.3 (d), 141.5 (s), 156.0 (s).
4.9.7. 3-(N-tert-Butoxycarbonylamino)-4-ethyl-2-phenyltetrahydro-
furans (23g,26f). The combustion analysis was performed on the
diastereomeric mixture before further separation. Anal. Calcd for
C17H25NO3 (291.39): C 70.07 H 8.65 N 4.81. Found: C 69.58 H 8.92 N
4.81.
found 253.0871; 1H NMR (400 MHz)
d 1.72 (s, 3H), 1.82 (s, 3H), 3.40
(m,1H), 4.21 (dd, J¼9.5, 6.5 Hz,1H), 4.30 (ddd, J¼9.5, 7.7, 0.4 Hz,1H),
5.71 (d, J¼0.8 Hz, 1H), 7.11 (br s, 1H), 7.30e7.37 (m, 5H); 13C NMR
(100 MHz)
d 28.2 (q), 32.7 (q), 54.0 (d), 69.6 (t), 70.5 (s), 80.1 (d),
4.9.7.1. 3(S*)-(N-tert-Butoxycarbonylamino)-4(S*)-ethyl-2(R*)-
phenyltetrahydrofuran (23g). Colorless solid, yield 49 mg (24%). Mp
107 ꢀC; Rf¼0.35, hexane/EtOAc 5:1; IR (neat) 3325, 3059, 3032,
2962, 2933, 2877, 2858, 1699, 1689, 1532, 1458, 1365, 1269, 1248,
1166, 1048, 1021, 901, 860, 739, 718, 701 cmꢁ1; MS (EI) m/z 234 (11),
218 (5), 174 (45), 160 (18), 145 (30), 129 (27), 107 (17), 105 (13), 91
(14), 84 (37), 77 (17), 70 (12), 57 (100), 56 (90); 1H NMR (400 MHz):
127.5 (d), 128.3 (d), 128.5 (d), 137.6 (s), 162.4 (s).
4.11. Hydrogenation of tetrahydrofurans 3a and 4a by
palladium on charcoal
The palladium catalyst (10 mg, 10% Pd on activated charcoal)
was placed into an autoclave and a solution of 3a or 4a (100 mg,
0.36 mmol) in 7 mL EtOH was added. The autoclave was flushed
three times with hydrogen and charged with H2 to 20 bar at 20 ꢀC
for the given time (see Scheme 10). Subsequently, Et3N (0.10 mL,
0.72 mmol) and Boc2O (168 mg, 0.77 mmol) were added. The re-
action mixture was stirred overnight, filtered, concentrated in
vacuum, and the crude products were purified by flash chroma-
tography (hexane/EtOAc, gradient 10:1 to 2:1).
d
¼0.92 (t, J¼7.4 Hz, 3H), 1.41 (s, 9H), 1.61 (m, 2H), 2.12 (m, 1H), 3.57
(m, 1H), 3.80 (dd, J¼8.7, 7.5 Hz, 1H), 4.19 (dd, J¼8.7, 8.0 Hz, 1H), 4.59
(m, 1H), 4.66 (m, 1H), 7.25e7.40 (m, 5H); 13C NMR (100 MHz)
12.3
d
(q), 24.9 (t), 28.3 (q), 48.3 (d), 63.6 (d), 72.3 (t), 79.6 (s), 85.3 (d),
125.8 (d), 127.6 (d), 128.4 (d), 140.3 (s), 155.1 (s).
4.9.7.2. 3(R*)-(N-tert-Butoxycarbonylamino)-4(R*)-ethyl-2(R*)-
phenyltetrahydrofuran (26f). Colorless solid, yield 67 mg (33%). Mp
89 ꢀC; Rf¼0.40, hexane/EtOAc 5:1; IR (neat) 3352, 3067, 3033, 3013,
2955, 2932, 2875, 1685, 1532, 1455, 1391, 1299, 1240, 1167, 1040,
1017, 979, 756, 694 cmꢁ1; MS (ESI) m/z 314 ([MþNaþ], 100); MS (EI)
m/z 234 (11), 218 (5), 174 (40), 161 (18), 145 (28), 129 (17), 107 (14),
105 (12), 91 (13), 84 (31), 77 (13), 70 (12), 57 (85), 56 (100); HRMS
4.11.1. N-tert-Butoxycarbonyl-2-(3-methylbutoxy)-2-
phenylethylamine (30a). Colorless oil, for yields and ratios, see
Scheme 10 and Table 4. Rf¼0.56, hexane/EtOAc 5:1; IR (neat) 3454,
3357, 3064, 3031, 2958, 2930, 2871, 1710, 1497, 1453, 1390, 1366,
1270, 1249, 1167, 1098, 1069, 981, 863, 755, 701 cmꢁ1; MS (EI) m/z
307 (Mþ, 30),177 (80),107 (100), 79 (15), 77 (13), 71 (53), 57 (18), 55
(10), 43 (63); Anal. Calcd for C18H29NO3 (307.43): C 70.32 H 9.51 N
t
(EI) calcd for C13H16NO3 ([Mꢁ Bu]þ) 234.1130, found: 234.1129; 1H
NMR (400 MHz)
d
0.95 (t, J¼7.5 Hz, 3H), 1.29 (s, 9H), 1.45 (m, 1H),
1.69 (m, 1H), 2.08 (m, 1H), 3.57 (t, J¼8.7 Hz, 1H), 4.15 (m, 2H), 4.31
(dd, J¼8.7, 7.6 Hz, 1H), 5.05 (br d, J¼4.9 Hz, 1H), 7.24e7.27 (m, 3H),
4.56. Found: C 70.27 H 9.68 N 4.48. 1H NMR (400 MHz)
d 0.85 (d,
J¼6.6 Hz, 3H), 0.88 (d, J¼6.6 Hz, 3H), 1.44 (s, 9H), 1.47 (m, 2H), 1.69
(non, J¼6.6 Hz, 1H), 3.15 (dd, J¼13.3, 4.5 Hz, 1H), 3.30 (dt, J¼9.3,
6.6 Hz, 1H), 3.40 (dt, J¼9.3, 6.6 Hz, 1H), 3.48 (m, 1H), 4.33 (dd, J¼4.5,
3.0 Hz, 1H), 4.93 (br s, 1H), 7.26e7.37 (m, 5H); 13C NMR (100 MHz)
7.31e7.35 (m, 2H); 13C NMR (100 MHz)
d 12.4 (q), 24.5 (t), 28.2 (q),
47.0 (d), 59.2 (d), 72.1 (t), 79.3 (s), 81.5 (d), 126.2 (d), 127.2 (d), 128.1
(d), 138.5 (s), 155.4 (s).
d
22.5 (q), 22.7 (q), 25.0 (d), 28.4 (q), 38.7 (t), 47.1 (t), 67.5 (t), 81.0
4.9.8. 3(R*)-(N-tert-Butoxycarbonylamino)-4(R*)-(1(S*)-chloro-
ethyl)-2(R*)-phenyltetrahydrofuran (27f). Colorless solid, yield
55 mg (24%). Mp 122 ꢀC; Rf¼0.45, hexane/EtOAc 5:1; IR (neat) 3322,
2978, 2935, 2901, 1703, 1536, 1457, 1366, 1338, 1290, 1251, 1166,
1132, 1045, 1022, 907, 723 cmꢁ1; MS (EI) m/z 270/268 (4/13), 254/
252 (2/6), 210/208 (6/18), 194 (10), 172 (35), 145 (40), 128 (17), 118
(27), 107 (14), 105 (16), 91 (11), 84 (63), 77 (18), 57 (100), 55 (13);
Anal. Calcd for C17H24ClNO3 (325.83): C 62.67 H 7.42 N 4.30. Found:
(d), 85.2 (s), 126.6 (d), 127.8 (d), 128.5 (d), 140.0 (s), 155.9 (s).
4.12. Hydrogenation of tetrahydrofurans 3a,b, 4a, and 18a, 19a
by Raney nickel (general procedure)
(a) Preparation of Raney nickel catalyst: Raney nickel alloy
(230 mg) was treated with 360 mg NaOH dissolved in 3.5 mL H2O at
80 ꢀC under N2 atmosphere for 30 min. The solvent was decanted
and the solid washed to neutral pH with water and subsequently
several times with dry EtOH without letting the catalyst become dry.
(b) Reduction: freshlypreparedwetRaney nickelcatalyst was placed
into an autoclave and a solution of 3, 4, 18a or 19a (0.29 mmol) in
5 mL EtOH was added. The autoclave was flushed three times with
hydrogen and charged with H2 to working pressure at the desired
reaction temperature for the given time (see Table 4). The reaction
mixture was cooled to room temperature and Et3N (0.08 mL,
0.58 mmol) and Boc2O (135 mg, 0.62 mmol) were added sub-
sequently. The reaction mixture was stirred overnight, filtered,
concentrated in vacuum and the crude products were purified by
flash chromatography (hexane/EtOAc, gradient 10:1 to 2:1).
C 62.77 H 7.69 N 4.20. 1H NMR (300 MHz, C6D6)
d
1.25 (d, J¼6.2 Hz,
3H), 1.26 (s, 9H), 1.92 (dq, J¼8.7, 6.2 Hz, 1H), 3.55 (t, J¼8.7 Hz, 1H),
3.74 (dq, J¼8.7, 6.2 Hz, 1H), 3.99 (d, J¼9.4 Hz, 1H), 4.12 (t, J¼8.7 Hz,
1H), 4.27 (dt, J¼9.4, 6.2 Hz, 1H), 4.79 (d, J¼6.2 Hz, 1H), 7.04e7.09 (m,
1H), 7.13e7.19 (m, 2H), 7.27e7.29 (m, 2H); 13C NMR (75 MHz, C6D6)
d
23.8 (q), 27.9 (q), 55.0 (d), 57.5 (d), 58.9 (d), 69.5 (t), 78.6 (s), 82.8
(d), 126.5 (d), 127.3 (d), 128.0 (d), 137.7 (s), 154.7 (s).
4.10. Reduction of 3a to 4(R*)-(1-chloro-1-methylethyl)-2(R*)-
phenyldihydrofuran-3-one oxime (28a)
To a stirred solution of 3a (141 mg, 0.52 mmol) in 7 mL EtOH was
added 1.3 mL 10% HCl and zinc dust (120 mg, 1.82 mmol) at 30 ꢀC.
The mixture was stirred at the same temperature for 24 h. Another
1.3 mL 10% HCl and Zn dust (120 mg, 1.82 mmol) were added and
stirring was continued for three days at 30 ꢀC. The reaction mixture
was diluted with 10 mL EtOAc, filtered, concentrated, diluted with
10 mL EtOAc, and washed with a saturated solution of NaHCO3 and
brine. The organic layer was dried over Na2SO4 and the residue after
4.12.1. 3(R*)-(N-tert-Butoxycarbonylamino)-2(R*)-methyl-4-
phenylbutanol (31b). Colorless solid, for yields and ratios, see Table
4. Mp 89 ꢀC; Rf¼0.25, hexane/EtOAc 2:1; IR (neat) 3447, 3363, 3065,
3031, 2984, 2930, 2884, 1679, 1520, 1445, 1390, 1313, 1275, 1251,
1170, 1041, 1008, 777, 754, 700 cmꢁ1; MS (ESI) m/z 302 ([MþNaþ],
100); MS (EI) m/z 206 (8), 188 (35), 132 (70), 120 (15), 102 (13), 91

462
U. Jahn et al. / Tetrahedron 68 (2012) 447e463
(26), 88 (73), 57 (100), 44 (18); Anal. Calcd for C16H25NO3 (279.37):
C 68.79 H 9.02 N 5.01. Found: C 68.69 H 8.98 N 4.98. 1H NMR
70.79 H 8.91 N 4.59. Found: C 70.72 H 9.17 N 4.62. 1H NMR
(200 MHz)
d
1.44 (s, 9H), 1.56 (s, 3H), 1.75 (s, 3H), 3.20 (dd, J¼8.7,
(400 MHz)
d
1.14 (d, J¼6.9 Hz, 3H), 1.36 (s, 9H), 1.55 (m, 1H), 1.78 (br
4.4 Hz, 1H), 3.39 (m, 1H), 3.80 (dd, J¼11.3, 7.6 Hz, 1H), 3.91 (dd,
J¼11.3, 6.9 Hz,1H), 4.40 (dd, J¼8.7, 4.0 Hz,1H), 4.96 (m,1H), 5.36 (m,
s,1H), 2.71 (dd, J¼14.2, 8.1 Hz,1H), 2.99 (dd, J¼14.2, 5.1 Hz,1H), 3.47
(m, 1H), 3.77e3.87 (m, 2H), 4.68 (br d, J¼9.1 Hz, 1H), 7.19e7.32 (m,
1H), 7.26e7.37 (m, 5H); 13C NMR (50 MHz)
d 18.0 (q), 25.8 (q), 28.4
5H); 13C NMR (100 MHz)
d
15.4 (q), 28.6 (q), 38.7 (t), 39.2 (d), 53.6
(q), 47.0 (t), 65.3 (t), 79.2 (s), 80.1 (d), 120.8 (d), 126.7 (d), 127.9 (d),
128.5 (d), 137.5 (s), 139.8 (s), 155.7 (s).
(d), 64.9 (t), 79.9 (s), 126.7 (d),128.8 (d), 129.5 (d),138.4 (s), 157.1 (s).
4.12.2. Methyl 3-(tert-butoxycarbonylamino)-4-isopropyltetra-
hydrofuran-2-carboxylates (22j,23j). The following analyses were
performed on the diastereomeric mixture before further separa-
tion. IR (neat) 3260, 3135, 3004, 2967, 2936, 2876, 1756, 1694, 1478,
1451, 1434, 1389, 1364, 1200, 1160, 1093, 1067, 995, 931, 917, 781,
716, 698 cmꢁ1; MS (EI) m/z 172 (18), 154 (16), 142 (19), 99 (45), 69
(13), 59 (22), 57 (100), 56 (95); Anal. Calcd for C14H25NO5 (287.35):
C 58.52 H 8.77 N 4.87. Found: C 58.47 H 8.81 N 4.88.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (Ja896/2-1)
and the Institute of Organic Chemistry and Biochemistry of the
Academy of Sciences (Z4 055 0506) for generous funding of this
work. D.R. thanks the Otto-Benecke-Stiftung and the Degussa
Stiftung for support by Ph.D. fellowships. We thank Mr. A. Weinkauf
for registering the X-ray data of 22j.
4.12.2.1. Methyl 3(S*)-(tert-butoxycarbonylamino)-4(R*)-isoprop-
yltetrahydrofuran-2(S*)-carboxylate (22j). Colorless solid, yield
53 mg (64%). Mp 110 ꢀC; Rf¼0.40, hexane/EtOAc 5:1; 1H NMR
Supplementary data
Experimental procedures, analytical characterization, and con-
figuration assignment of all new compounds. Copies of 1H and 13
C
(400 MHz)
d
0.89 (d, J¼6.6 Hz, 3H), 0.97 (d, J¼6.6 Hz, 3H), 1.46 (s,
9H), 1.59 (m, 1H), 2.05 (m, 1H), 3.61 (br t, J¼8.4 Hz, 1H), 3.77 (s, 3H),
4.28 (br t, J¼8.4 Hz, 1H), 4.42 (m, 1H), 4.44 (s, 1H), 4.76 (br d,
NMR spectra. Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tet.2011.11.023.
J¼8.2 Hz, 1H); 13C NMR (100 MHz)
d 21.56 (q), 21.62 (q), 26.9 (d),
28.3 (q), 48.5 (d), 52.3 (q), 55.9 (d), 72.0 (t), 80.0 (s), 84.3 (d), 155.1
(s), 171.7 (s).
References and notes
1. Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, 2006.
2. (a) Jahn, U.; Rudakov, D.; Jones, P. G. Tetrahedron 2012, 68 accepted for publi-
cation; (b) Jahn, U.; Rudakov, D. Synlett 2004, 1207e1210.
4.12.2.2. Methyl 3(S*)-(tert-butoxycarbonylamino)-4(S*)-isoprop-
yltetrahydrofuran-2(S*)-carboxylate (23j). Colorless solid, yield
30 mg (36%). Mp 91 ꢀC; Rf¼0.37, hexane/EtOAc 5:1; 1H NMR
3. Initial results: Jahn, U.; Rudakov, D. Org. Lett. 2006, 8, 4481e4484.
4. Recent review: Schmidt, R. R.; Vankar, Y. D. Acc. Chem. Res. 2008, 41, 1059e1073.
5. Review: Rosemeyer, H. Chem. Biodiversity 2004, 1, 361e401.
(500 MHz)
d
0.88 (d, J¼6.7 Hz, 3H), 0.98 (d, J¼6.7 Hz, 3H), 1.44 (s,
9H),1.70 (dsept, J¼8.8, 6.7 Hz,1H),1.83 (m, 1H), 3.76 (s, 3H), 3.80 (br
t, J¼9.0 Hz, 1H), 4.11 (dd, J¼9.0, 8.0 Hz, 1H), 4.17 (m, 2H), 4.69 (br s,
€
6. Reviews: (a) Handbook of Nucleoside Synthesis; Vorbruggen, H., Ruh-Pohlenz, C.,
€
Eds.; Wiley: New York, NY, 2001; (b) Vorbruggen, H.; Ruh-Pohlenz, C. In Organic
1H); 13C NMR (126 MHz)
d
20.6 (q), 21.0 (q), 28.3 (q), 29.8 (d), 52.3
Reactions; Paquette, L. A., Ed.; John Wiley: New York, NY, 2000; Vol. 55,
pp 1e630.
7. Reviews: Njoroge, F. G.; Chen, K. X.; Shih, N.-Y.; Piwinski, J. J. Acc. Chem. Res.
2008, 41, 50e59.
(q), 52.8 (d), 58.6 (d), 71.2 (t), 79.9 (s), 82.6 (d), 154.6 (s), 171.8 (s).
4.12.3. Methyl 3(S*)-(tert-butoxycarbonylamino)-4(S*)-(1-chloro-1-
8. For the synthesis of polycyclic nitro tetrahydrofurans: by DielseAlder reactions.
ꢁ
ꢁ
(a) Araujo, N.; Gil, M. V.; Roman, E.; Serrano, J. A. Tetrahedron: Asymmetry 2009,
20, 1999e2006 and cited ref; (b) Bwire, R. N.; Majinda, R. R.; Masesane, I. B.;
Steel, P. G. Pure Appl. Chem. 2009, 81, 105e112 and cited ref; (c) Masesane, I. B.;
Batsanov, A. S.; Howard, J. A. K.; Mondal, R.; Steel, P. G. Beilstein J. Org. Chem.
2006, 2; (d) Mahmood, S. Y.; Lallemand, M.-C.; Sader-Bakaouni, L.; Charton, O.;
methylethyl)-tetrahydrofuran-2(S*)-carboxylate
solid as a mixture with 23j, yield 28 mg (30%). Rf¼0.33, hexane/
EtOAc 5:1; 1H NMR (500 MHz)
1.44 (s, 9H),1.55 (s, 3H),1.63 (s, 3H),
(29j). Colorless
d
2.53 (m,1H), 3.77 (s, 3H), 4.05 (dd, J¼9.3, 8.2 Hz,1H), 4.19 (t, J¼9.3 Hz,
ꢁ
ꢁ
Verite, P.; Dufat, H.; Tillequin, F. Tetrahedron 2004, 60, 5105e5110 and cited ref;
(e) Klenz, O.; Evers, R.; Miethchen, R.; Michalik, M. J. Fluorine Chem. 1997, 81,
205e210; (f) Hossain, N.; Plavec, J.; Thibaudeau, C.; Chattopadhyaya, J. Tetra-
hedron 1993, 49, 9079e9088 and cited ref; (g) Grieco, P. A.; Lis, R.; Zelle, R. E.;
Finn, J. J. Am. Chem. Soc. 1986, 108, 5908e5919 and cited ref; (h) Just, G.; Liak, T.
J.; Lim, M.-I.; Potvin, P.; Tsantrizos, Y. S. Can. J. Chem. 1980, 58, 2024e2033 By
[3þ2] cycloadditions: (i) Nair, V.; Mathai, S.; Varma, R. L. J. Org. Chem. 2004, 69,
1413e1414; (j) Hassner, A.; Friedman, O.; Dehaen, W. Liebigs Ann./Recl. 1997,
587e594.
1H), 4.30 (br d, J¼5.5 Hz, 1H), 4.36 (m, 1H), 4.88 (br d, J¼8.4 Hz, 1H);
13C NMR (126 MHz)
d 28.3 (q), 30.2 (q), 31.5 (q), 52.4 (q), 57.4 (d) 58.0
(d), 66.9 (s), 70.2 (t), 79.9 (s), 82.7 (d), 154.6 (s), 170.9 (s).
4.12.4. Methyl 3-(N-tert-butoxycarbonylamino)-2-(3-methylbutoxy)
propionate (30j). Colorless oil, yield 26 mg (31%) from 18a and
13 mg (15%) from 19a. Rf¼0.44, hexane/EtOAc 5:1; IR (neat) 3374,
2956, 2933, 2872, 1746, 1715, 1509, 1458, 1391, 1366, 1248, 1203,
1162, 1126, 982, 863 cmꢁ1; MS (ESI) m/z 312 ([MþNaþ], 100); MS
(EI) m/z 231 (18), 171 (10), 160 (16), 91 (12), 71 (23), 69 (29), 59 (25),
57 (48), 55 (22), 44 (100); Anal. Calcd for C14H27NO5 (289.37): C
58.11 H 9.40 N 4.84. Found: C 58.59 H 9.39 N 4.93. 1H NMR
ꢁ~
9. (a) Cativiela, C.; Ordonez, M. Tetrahedron: Asymmetry 2009, 20, 1e63; (b) Ha-
nessian, S.; Auzzas, L. Acc. Chem. Res. 2008, 41, 1241e1251; (c) Brackmann, F.; de
Meijere, A. Chem. Rev. 2007, 107, 4538e4583; (d) Krow, G. R.; Cannon, K. C. Org.
Prep. Proced. Int. 2000, 32, 103e122.
10. Recent reviews on tetrahydrofuran-containing, but usually sugar-based amino
acids: (a) Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. Rev. 2002, 102,
491e514; (b) Risseeuw, M. D. P.; Overhand, M.; Fleet, G. W. J.; Simone, M. I.
Tetrahedron: Asymmetry 2007, 18, 2001e2010.
11. Reviews: (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173e180; (b) Hill, D. J.; Mio,
M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev. 2001, 101, 3893e4011; (c)
Licini, G.; Prins, L. J.; Scrimin, P. Eur. J. Org. Chem. 2005, 969e977; (d) Foldamers.
Structure, Properties and Applications; Hecht, S., Huc, I., Eds.; Wiley-VCH:
Weinheim, 2007; (e) Horne, W. S.; Gellman, S. H. Acc. Chem. Res. 2008, 41,
1399e1408.
12. For other syntheses of nitrocyclopropanes: reviews: (a) Averina, E. B.; Yashin,
N. V.; Kuznetsova, T. S.; Zefirov, N. S. Russ. Chem. Rev. 2009, 78, 887e902; (b)
Ballini, R.; Palmieri, A.; Fiorini, D. ARKIVOC 2007, 172e194 Pt. 7. For an oxidative
direct approach, see: (c) Kamimura, A.; Kadowaki, A.; Yoshida, T.; Takeuchi, R.;
Uno, H. Chem.dEur. J. 2009, 15, 10330e10334.
13. Full crystallographic details were deposited at the Cambridge Crystallographic
Data Centre under the numbers CCDC-848779 (6a), CCDC-848780 (8), CCDC-
848781 (22j), CCDC-848782 (27f). This material may be obtained free of
charge from http://www.ccdc.cam.ac.uk/products/csd/request.
(400 MHz)
d
0.90 (d, J¼6.7 Hz, 3H), 0.91 (d, J¼6.7 Hz, 3H), 1.44 (s,
9H), 1.46e1.53 (m, 2H), 1.72 (non, J¼6.7 Hz, 1H), 3.37 (m, 1H), 3.40
(dt, J¼9.2, 6.8 Hz, 1H), 3.53 (m, 1H), 3.68 (m, 1H), 3.75 (s, 3H), 3.96
(br dd, J¼5.6, 4.4 Hz, 1H), 4.91 (m, 1H); 13C NMR (100 MHz)
¼22.5
d
(q), 24.9 (d), 28.3 (q), 38.3 (t), 42.6 (t), 52.0 (q), 69.5 (t), 77.8 (d), 79.7
(s), 155.8 (s), 171.5 (s).
4.12.5. N-tert-Butoxycarbonyl-2-(3-methyl-2-butenyloxy)-2-phenyl-
ethylamine (33a). Colorless oil, yield 16 mg (35%). Rf¼0.47, hexane/
EtOAc 5:1; IR (neat) 3557, 3063, 3029, 2975, 2931, 2871, 1700, 1500,
1454, 1391, 1366, 1250, 1168, 1097, 1067, 1027, 863, 755, 701 cmꢁ1
;
GCeMS (EI) m/z 231 (78), 108 (10), 107 (100), 105 (10), 79 (18), 77
(12), 71 (63), 59 (14), 57 (36); Anal. Calcd for C18H27NO3 (305.41): C
14. Review: Mander, L. N.; Williams, C. M. Tetrahedron 2003, 59, 1105e1136.

U. Jahn et al. / Tetrahedron 68 (2012) 447e463
463
15. Recent review: Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017e1047.
16. Overview: Caggiano, T. J. In Handbook of Reagents for Organic Synthesis. Oxi-
dizing and Reducing Agents; Burke, S. D., Danheiser, R. L., Eds.; Wiley: Chichester,
UK, 1999; pp 246e250.
17. Recent reviews: (a) Blaser, H.-U.; Steiner, H.; Studer, M. ChemCatChem 2009,
1, 210e221; (b) Ballini, R.; Petrini, M. ARKIVOC 2009, 195e223 Pt. 9; (c) King,
A. O.; Larsen, R. D.; Negishi, E.-I. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-I., Ed.; Wiley: Hoboken, 2002; Vol. 2,
pp 2719e2752; (d) Figueras, F.; Coq, B. J. Mol. Catal. A: Chem. 2001, 173,
223e230.
18. Selected references: (a) Tormo, J.; Hays, D. S.; Fu, G. C. J. Org. Chem. 1998, 63,
5296e5297; (b) Voituriez, A.; Moulinas, J.; Kouklovsky, C.; Langlois, Y. Synthesis
2003, 1419e1426; (c) Crossley, M. J.; Fung, Y. M.; Kyriakopoulos, E.; Potter, J. J. J.
Chem. Soc., Perkin Trans. 11998, 1123e1130; (d) Witczak, Z. J.; Chhabra, R.; Choj-
nacki, J. Tetrahedron Lett.1997, 38, 2215e2218; (e) Barco, A.; Benetti, S.; De Risi, C.;
Pollini, G. P.; Romagnoli, R.; Zanirato, V. Tetrahedron Lett. 1996, 37, 7599e7602.