Oxidative tandem alkoxide conjugate addition to nitroalkenes/radical 5-exo cyclizations - A versatile synthesis of functionalized 3-nitrotetrahydrofurans

Tetrahedron 68 (2012) 1521e1539

Contents lists available at SciVerse ScienceDirect

Tetrahedron

journal homepage: w ww.elsevier.com/locate/tet

Oxidative tandem alkoxide conjugate addition to nitroalkenes/radical 5-exo

cyclizationsda versatile synthesis of functionalized 3-nitrotetrahydrofurans

,

b

c

Ullrich Jahn ^a, Dmytro Rudakov , Peter G. Jones

*

^aInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 16610 Prague 6, 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

€

c

€

a r t i c l e i n f o

a b s t r a c t

Article history:

Structurally diverse functionalized 4-(1-haloalkyl)-3-nitrotetrahydrofurans were conveniently obtained

in moderate to good yield and moderate to very good diastereoselectivity by an oxidative tandem process

consisting of conjugate addition reaction of lithium allyloxides to nitroalkenes followed by SET oxidation

of the resulting nitronates. This triggers a radical cyclization; ligand transfer from the oxidant provides

the products. The inﬂuence of the counter ion of the initial alkoxide and intermediate nitronate, the

solvent and additives on the outcome of the tandem process was investigated. Optimal conditions for the

tandem reactions consist of using butyllithium as the base for deprotonation in DME as the solvent.

Cupric halides proved to be the SET oxidants of choice in the tandem reactions. A stereochemical model

for the radical cyclization and ligand transfer steps is proposed.

Received 5 September 2011

Received in revised form 16 November 2011

Accepted 6 December 2011

Available online 9 December 2011

Keywords:

Electron transfer

Oxidation

Radicals

Tandem reaction

Tetrahydrofurans

1. Introduction

quantitative and fast compared to all other reaction steps. Thus, the

development of such sequences is more complex and represents

Tandem, cascade or domino reactions enjoy a high popularity in

organic chemistry since they allow the time and resource-efﬁcient

assembly of molecules in a one-pot operation.¹Several bonds are

formed (and sometimes also cleaved) in the course of the sequence.

A signiﬁcant advantage is offered by the use of very simple pre-

cursors as starting materials, from which a considerable increase of

the complexity of a carbon framework is achieved throughout the

sequence. Most tandem reactions are developed on the basis of

a carefully chosen intermediate type or a pericyclic process. So far,

most of the known strategies consist of a deﬁned order of reaction

steps based on only one intermediate type (organometallic species²

or radicals³or carbocations⁴or carbenes⁵). This deﬁnes the scope

but also the limitations of the tandem process, since species-typical

reactivity patterns have to be obeyed.

These inherent limitations may be overcome by switching the

redox state in a domino process, since the reactivities of in-

termediates of different oxidation state are often complementary to

each other. This can be achieved by incorporation of single electron

transfer (SET) steps in tandem reactions. However, such reaction

sequences will only succeed if the electron transfer steps are

a formidable challenge, since multiple intermediate types and the

SET steps must be controlled. Most of the work on the realization of

such ‘multiple intermediate’ sequences have so far been developed

in the reductive direction mediated by reagents, such as samarium

diiodide⁶or titanocene chloride.⁷In the area of oxidatively induced

tandem processes, radical-(cationic) reactions of neutral (di)car-

8

bonyl compounds induced by Mn(OAc)₃or ceric ammonium ni-

trate (CAN)⁹or electrochemically induced sequences of electron-

rich alkenes¹⁰are notable.

Our interest concentrates on the development of oxidative

tandem methodology combining the advantages of organometallic,

radical, and carbocationic intermediates. Recently, we introduced

oxidative radical cyclizations using enolates as precursors to avoid

toxic tin hydrides as a radical source.¹¹Based on that, efﬁcient

tandem anionic-radical processes for the rapid assembly of hetero-

and carbocyclic compounds¹²were developed. In this context we

became interested in coupling oxa-Michael additions¹³as the an-

ionic reaction step with radical cyclizations for the synthesis of

tetrahydrofuran derivatives,¹⁴which are structural elements in

a large number of biologically active molecules, such as lignans,

acetogenins, macrolides, and terpenoids. Here, we provide a full

account on the realization of such sequences¹⁵applying allylic

alkoxides and nitroalkenes.¹⁶This approach affords highly func-

tionalized tetrahydrofurans and has potential in natural product

* Corresponding author. Tel.: þ420 220 183 219; fax: þ420 220 183 578; e-mail

address: jahn@uochb.cas.cz (U. Jahn).

doi:10.1016/j.tet.2011.12.010

1522

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

synthesis.¹⁷Moreover, this anionic-radical tandem strategy is

unique, since purely anionic addition/cyclizations do not work for

alkene units in the allylic alcohol part (vide infra), and comple-

mentary to the behavior of propargylic nitro ethers, which can be

cyclized anionically.¹⁸Alternative radical processes consisting of

intermolecular alkoxyl radical addition and subsequent cyclization

Table 1

Optimization of the conjugate addition of allylic alcohols 1A and 1B to nitrostyrene

2a

Entry

1

Base^a

Solvent Additives (equiv) 3^b(%) Other products^b

1

2

3

4

5

6

A

B

n-BuLi^c

NaH^e

THF

DME

THF

d

74

97

87

97

94^h

48

83

62

37

46

2a (25%)^d

d

steps are generally not efﬁcient,¹⁹whereas a few individual

a-nitro

NaHMDS^fTHF

KHMDS^gTHF

MeMgClⁱTHF

d

radical cyclizations²⁰and additions²¹are known.

d

2a (48%)^d

2a (9%)^d

2a (30%),^d1B (53%)^d

1B (73%)^d

4Ba (24%)

7^j

8^j

9^j

10^j

n-BuLi^c

NaH^e

THF

d

2. Results

LiCl (10)^k

HMPA (6)^l,

d

m

Initial experiments focused on the synthesis of b-nitro ethers

3Aa,3Ba by conjugate addition²²of allylic alkoxides 1A,B to nitro-

alkene 2a under reliable conditions in optimal yields using the least

excess of one component to establish the envisaged tandem pro-

cess most efﬁciently (Scheme 1, Table 1).²³Best yields of 3Aa and

complete conversion were achieved by deprotonation of 1.5 equiv

of 1A with an equimolar amount of strong alkali metal base in THF

or DME at ꢀ78 ^ꢁC for 15e30 min, followed by addition of 1.0 equiv

of 2a at ꢀ78 ^ꢁC (entries 1e5). In contrast, the magnesium alkoxide

of 1A provided 3Aa only in low yield (entry 6), while amine bases,

such as DBU initiated polymerization of 2a. Cinnamic alkoxide 1B

reacted much more slowly than 1A, but also gave complete con-

version to 3Ba in good yield at ꢀ45 ^ꢁC (entry 7). Attempts to in-

crease the reactivity of the alkoxide of 1B by adding aggregate-

modifying additives, such as anhydrous LiCl prior to deprotona-

tion, or HMPA²⁴thereafter, gave inferior results. While LiCl retarded

the reaction rate but did not alter the product formation (entry 8),

HMPA triggered the competitive undesired consumption of 2a,

most probably by Michael addition-initiated polymerization of

3Ba^ꢀwith 2a (entry 9). Since nitronates 3^ꢀmay be susceptible to

retro-Michael reactions promoted by these additives thus dimin-

ishing the yield, both additives were also introduced into the re-

action mixture after complete formation of 3Ba^ꢀ. Here, the isolated

yield of 3Ba (85% and 78%, respectively) did not decrease, thus

ruling out signiﬁcant reversibility of the conjugate addition under

the reaction conditions (vide infra). When sodium hydride was

a

Compound 1 (1.0 equiv) at ꢀ78 ^ꢁC, ratio 1:2a 1.5 mmol:1 mmol unless other-

wise stated.

b

c

d

e

f

Isolated yields.

Hexanes (1.6 M).

Recovered s.m., isolated.

Suspension (80%) in mineral oil, ratio NaH/1A/2a 2:1.5:1.

THF (2.0 M), ratio NaHMDS/1A/2a 1.4:1.4:1.

Toluene (0.5 M), ratio KHMDS/1A/2a 1:1:1.

Determined by ¹H NMR.

g

h

i

THF (3.0 M), ratio MeMgCl/1A/2a 1.8:1.5:1, reaction time two days at room

temperature.

j

Reaction temperature ꢀ45 ^ꢁC.

k

l

Added before deprotonation of 1B.

No 2a detected.

m

Added after deprotonation of 1B.

used as the base, a further Michael addition of 3Ba^ꢀto 2a competed

signiﬁcantly to afford 4Ba as a single diastereomer of unassigned

relative conﬁguration in 24% yield (entry 10). It should be noted

here that the reaction mixture must be quenched with glacial acetic

acid for optimal yields of 3.

With optimized conditions for the conjugate addition of alk-

oxides to nitroalkenes in hand, the substrate scope of the oxa-

Michael addition with respect to various nitroalkenes 2aee and

achiral allylic alcohols 1AeG was determined (Scheme 2, Table 2).

In general, lithium alkoxides derived from substituted allylic

alcohols 1CeF underwent the conjugate addition to nitrostyrene 2a

Base,

efﬁciently to give b-nitro ethers 3Cae3Fa in good to excellent yields

R

additives,

–78 °C,

(entries 1e2, 4e5). Sodium alkoxides proved again much less ef-

ﬁcient in the conjugate addition (entry 3). Even the sterically most

congested allylic alcohol 1G afforded nitro ether 3Ga in DME after

longer reaction time at ꢀ40 to 0 ^ꢁC in a reasonable crude yield of

67%. Extensive decomposition was, however, observed on ﬂash

chromatography, so that only 24% of pure 3Ga was isolated (entry

6). Other nitroalkenes, such as 2bed were also applicable in the

oxa-Michael addition giving the adducts 3Abe3Dd in good yields

(entries 7e13). Generally, the addition proceeded with similar

yields in DME and THF. A difference was, however, found in the

15-30 min

(see Table 1)

HO

O

1A

M

–

1A R = H

M = Li, Na, K, Mg

–

1B

1B R = Ph

A: –78 °C

B: –78 - –45 °C

NO

2a

2

Ph

cyclization step (vide infra). The addition of 1D to b-disubstituted

M

2e did not go to completion and the addition product 3De was

isolated in moderate yield (entry 14). Additionally, some un-

identiﬁed and polymeric material formed after longer reaction

O R

R

O

N

AcOH O N

2

times.

b-Methylnitrostyrene gave only undeﬁned polymeric ma-

terial in the addition with 1D using a number of bases.²⁵

Ph

O

3Aa

–

3Aa

3Ba

Base, THF or DME, –78 °C

1

R

6

M = Na

2a

2

R

2

3

R

O N

R

then

2a-e

2

R

NO

3

NO

2

R

2

5

4

6

R

O

Ph

4

O N

5

then AcOH

2

R

O

3Ab-3Ga

HO

1A-G

Ph Ph

4Ba

Scheme 1. Optimization of conjugate addition of 1A,B to 2a.

Scheme 2. Conjugate addition of alkoxides 1AeG to nitroalkenes 2aee.

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

1523

Table 2

Scope of conjugate additions of allylic alkoxides 1AeG to nitroalkenes 2aee^a

Li

O R

R¹

R²

R³

R⁴

2

R⁵

R⁶Solvent 3 (%)

1.) n-BuLi,

solvent

O

Entry

1

N

R

1^b

C

Me

Me Me

H

Me Me

H

Ph

Me

H

Me

H

Me

H

a

b

c

d

e

Ph

H

DME

THF

DME

THF

3Ca (93)

3Da (97)

3Da (20)

3Ea (67)

3Fa (70)^e

3Ga (24)^f

3Ab (95)

3Ac (63)

3Bc (55)

3Cc (75)

3Dc (75)

3Bd (95)

3Dd (73)^g

3De (52)

1A

or

2^b

D

E^d

F

G

A

B

C

D

B

D

2.) 2a, –78 °C

PF

Fe

6

3^c

4^b

H

1D

Ph

O

5

5^b

–

3Aa R = H

6^b

–

3Da R = Me

7^b

H

4-MeOC₆H₄

Et

i-Pr

e(CH₂)₅e

8^b

THF

oxidant/

9^b

DME

THF

DME

TMP=

10^b

11^b

12^b

13^b

14^b

trapping

reagent

(see Table 3)

N

O

Me Me

Ph

Me Me

6

H

a

Substrate 1 (1.5 mmol), 2 (1 mmol), isolated yields.

n-BuLi (1.6 M in hexanes) as the base.

NaH as the base. Additionally, 33% of 4Da (cf. Scheme 1) was isolated as a 2:1

X

R

b

c

O

R

N

O N

2

O N

R

2

R

diastereomeric mixture.

H

d

X

Reaction time 3 h at ꢀ50 ^ꢁC.

e

Compound 2a (11%) recovered.

Isolated yield after chromatography. The crude yield of 3Ga was 67% as de-

Ph

f

Ph

O

12Da

O

termined by ¹H NMR. This compound is apparently very sensitive to acidic condi-

3Aa,Da X = H

10Aa,Da X = Cl

tions; 6% of 2a recovered.

7Aa,Da X = OTMP 11Aa,Da X = Br

8Aa,Da X = Cl

g

An experiment in THF gave exactly the same result.

9Aa,Da X = Br

O N

2

The conjugate addition of propargylic alcohols 1H and 1I to

nitrostyrene 2a furnished nitro ethers 3Ha and 3Ia in good yields

(Scheme 3).

Fe

Ph

O

13Da

O

14Da

R

n-BuLi, THF, –78 °C

NO

R

Scheme 4. Screening of SET oxidants in tandem alkoxide conjugate addition/radical 5-

exo cyclization/termination reactions of 1A,D to 2a (Stereochemistry of 10,11 omitted

for clarity, vide infra).

2

O N

2

then

2a

Ph

then AcOH

Table 3

Addition/SET/cyclization of 1A,D and 2a using different oxidants^a

Ph

HO

O

Entry

1

Oxidant (equiv)/ T^c(^ꢁC) Solvent^d3, 7,

10, 11,

14 (%)

12 13

(%) (%)

1H R = H

3Ha 66%

termination^b

8, 9 (%)

1I R = Ph

3Ia 95%

1

2

3

4

A

D

A

5 (1.2)/6

5 (1.6)/6

5 (1.6)

CuCl₂(1.0)/6

CuCl₂(3.5)

CuCl₂(3.0)

CuBr₂(3.0)

Cu(OTf)₂(2.0)

0

DME

THF

7Aa (88)^e

d

Scheme 3. Conjugate additions of propargylic alkoxides 1H and 1I to nitrostyrene 2a.

7Da (93)^e

3Da (18) 14Da (9)

7Da (87)^f

3Aa (10) 10Aa (69)

3Aa (3)

10Aa (78)ⁱ

9Aa (35)^k11Aa (49)^l

3Aa (73)

55 14

0

d

5^g

6^h

7^j

8^m

ꢀ60

Based on the optimized conditions for the alkoxide conjugate

addition, the oxidative tandem alkoxide conjugate addition/radical

5-exo cyclization sequences were studied in detail. Application of

ferrocenium hexaﬂuorophosphate 5, known to be one of the best

and most general SET oxidants for carbanions, enolates, and radi-

cals,^11,12and TEMPO 6 in the tandem addition/cyclization reaction

of 1A or 1D and 2a resulted exclusively in the acyclic TEMPO-

trapping products 7Aa and 7Da in high yields (Scheme 4, Table 3,

entries 1, 2).²⁶These experiments indicated that the nitronates 3^ꢀ

0

THF

d

a

Substrate 1 (1.5 mmol), 2a (1 mmol).

TEMPO 6 (1.0 equiv) used.

Oxidation temperature.

Concentration 0.1 M with respect to 2a.

1.1:1 anti/syn-mixture, diastereomers not assigned.

1:1 anti/syn-diastereomeric mixture, diastereomers not assigned.

b

c

d

e

f

g

Compound 2a (7%) was recovered, 10Aa is a 2.1:1 2,3-trans-3,4-cis/2,3-cis-3,4-

were oxidized to

slow compared to coupling by TEMPO 6. To check the general cy-

clization ability of -nitro radicals under these conditions, the ox-

a-nitro radicals, but that the cyclization step was

trans-diastereomeric mixture.

h

Compound 2a (11%) was recovered.

Isolated as a 1.6:1 2,3-trans-3,4-cis/2,3-cis-3,4-trans-diastereomeric mixture,

i

a

traces of 16Aa detected (vide infra).

idative sequence was repeated with 1D, 2a, and 5 in the absence of

6, since it was known that the cyclized radical will stabilize by

a second SET oxidation to a carbocation.¹¹The addition/cyclization

sequence indeed gave cyclic products 12Dae14Da in reasonable

combined yield together with small amounts of 3Da (entry 3).

The structure and conﬁguration of compound 13Da was de-

termined by X-ray crystallography (Fig. 1).²⁷The all-trans orienta-

tion of the substituents in pseudo-equatorial positions is

established, with relative conﬁguration R*,S*,S* at C2, C3, C4, re-

spectively; the compound crystallizes with two similar molecules

j

Compound 2a (12%) was recovered.

2:1 anti/syn-mixture, diastereomers not assigned.

k

l

Isolated as

a

2.8:1 2,3-trans-3,4-cis/2,3-cis-3,4-trans-diastereomeric mixture

(vide infra).

m

Reaction time 1 h, 26% of 2a recovered.

distorted envelope conformations, whereby the oxygen atoms lie

ꢀ

0.56/0.55 A out of the plane of the other four atoms.

The application of anhydrous CuCl₂as the oxidant in the pres-

ence of 6 provided 7Da in high yield (entry 4). Initiation of the

cyclization of 3Aa^ꢀ, resulting from anionic conjugate addition of 1A

to 2a at ꢀ78 ^ꢁC in dry DME using CuCl₂in the absence of 6 at

ꢀ60 ^ꢁC, provided a 69% yield of tetrahydrofuran 10Aa as a 2.1:1

ꢀ

in the asymmetric unit (rms deviation 0.15 A). The ferrocene unit is

located underneath the tetrahydrofuran ring, while the exocyclic

methyl groups point outward. The tetrahydrofuran rings adopt

1524

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

Table 4

Addition/cyclization sequences of 1A and 2a using various bases^a

Entry Base

Oxidant

(equiv)

Solvent^b3Aa 10Aa

16Aa 2a

(%)

(%) (dr)^c

(%)^d

1

2

3

4

5

6

7

8

9

10

n-BuLi

LDA

LiHMDS

NaHMDS CuCl₂(2.5)

CuCl₂(3.0)

CuCl₂(2.5)

CuCl₂(3.0)

CuCl₂(2.5)

DME

THF

3

7

60

3

47

11

21

19

75

36

78 (1.6:1) Trace 11

65 (4.1:1) Trace

7

20

4

10

12

11

16

24

32

16

4

39 (8:1)

d

15

46^e

12

40^e

21

d

NaH

CuCl₂(2.5)

Cu(OTf)₂(2.5) THF

CuCl₂(2.5)

Traces

d

KHMDS

KO^tBu

d

THF

d

MeMgCl

2

d

a

Substrate 1A (1.5 mmol), 2a (1 mmol).

Concentration 0.1 M with respect to 2a.

2,3-trans-3,4-cis/2,3-cis-3,4-trans-diastereomeric ratio in parentheses (vide

b

c

Fig. 1. X-ray crystallographic view of ferrocene adduct 13Da.

infra).

d

Compound 2a was recovered.

Compound 15Aa is the major product in the crude reaction mixture, but con-

diastereomeric mixture (entry 5). The yield of 10Aa improved to

78% when CuCl₂was added at 0 ^ꢁC (entry 6). Cupric bromide proved

also effective as a SET oxidant/ligand transfer reagent, providing

e

version to 16Aa occurs during chromatography.

11Aa; however, a signiﬁcant amount of b-bromo-b-nitro ether 9Aa

elimination of TMSOH to form the stable bicyclic isoxazoline 16Aa

in moderate yields (entries 4e5, 7e8).³⁰

was also formed (entry 7). In contrast, Cu(OTf)₂did not oxidize

3Aa^ꢀbut promoted a slow retro-Michael reaction of 3Aa^ꢀto 2a

(entry 8). Other common SET oxidants, such as copper(II) dicar-

boxylates,²⁸FeCl₃,²⁹Fe(acac)₃,²⁹or Mn(OAc)₃⁸were not effective in

the tandem reactions.

The outcome of the Cu(II)-promoted addition/cyclization se-

quence depended strongly on the applied base/counterion of

nitronates 3^ꢀ(Scheme 5, Table 4). Compared to standard n-BuLi

(entries 1, 2), LDA gave only a low yield of cyclization product 10Aa

(entry 3). When LiHMDS was used as the base, bicyclic 16Aa was

surprisingly isolated as an additional product besides 3Aa and 10Aa

(entry 4); it became the major product in unoptimized yield, when

NaHMDS or KHMDS were used as the base (entries 5, 7, 8). It was

found that the crude material of the cyclization reactions after

workup did not contain 16Aa but unstable bicyclic 15Aa. This

compound was characterized by NMR, but it undergoes rapid

NaH, KO^tBu or MeMgCl proved to be unsuitable bases in the

sequences, since nitronates 3Aa^ꢀwere oxidized much more slowly

(entries 6, 10) or not at all (entry 9) by CuCl₂. Thus, the conditions of

nitronate generation and the presence of an amine or HMDS in-

ﬂuence the course of the tandem reactions signiﬁcantly.³¹In all

experiments involving Cu(II) salts, a certain amount of nitrostyrene

2a was recovered, which was not present prior to addition of the

copper salts as indicated by TLC (entries 1e9).

The applicability of other solvents was investigated brieﬂy.

Acetonitrile can be used in the sequences (50% yield of 10Da);

however, it underwent apparently slow anionic polymerization

under the reaction conditions, thus making workup impractical. In

toluene, the oxidative cyclization was very slow (16% yield of 10Da)

because of the insufﬁcient solubility of CuCl₂and a passivation ef-

fect of the surface by insoluble reduced CuCl.

With optimal conditions in hand the scope of tandem alkoxide

conjugate addition/SET-oxidation/radical 5-exo cyclization/ligand

transfer reactions mediated by CuCl₂was determined for

substrates 1AeG and 2aee. 2-Substituted 4-(1-haloalkyl)-3-

nitrotetrahydrofurans 17e21 were isolated in moderate to good

yields and diastereoselectivities (Scheme 6, Table 5). It was notable

that the tandem reactions led to higher yields in DME than in THF

(entries 1, 7, 24 vs 3, 8, 25). The optimum temperature for the ox-

idative step of the reaction sequences was 0 ^ꢁC. The oxidation

proceeded, however, with unhindered substrates in comparable

yield even at ꢀ60 ^ꢁC (entries 2, 9), but the improvement of the

diastereoselectivity was marginal (entries 1, 8 vs 2, 9). In some

cases, even a considerable variation of the diastereoselectivity was

found (entries 1, 2 vs 3, vide infra). The yields of oxidative cycli-

zations did not decrease when the tandem reactions were per-

formed at slightly elevated temperature (entries 6,12,15). However,

in some cases the diastereoselectivity of the cyclization and of li-

gand transfer worsened considerably (entry 5 vs 6). Normally an-

hydrous CuCl₂was used in the tandem reactions; however, cupric

chloride dihydrate also served as an efﬁcient oxidant with only

a slight decrease of the yield (entry 10).

M

O

N

Base, THF,

2a, –78 °C

1A

Ph

O

–

3Aa

(see Table 4)

oxidant, 0 °C

Cl

O

Me SiO

3

N

O N

2

+

3Aa

H

Ph

O

10Aa

O

15Aa

chromatography

H

O

N

In case of substrate 1E, the cyclization rate was retarded due to

the substituents at the 2-position of the allylic alkoxide. An increase

of the temperature improved the yield of 17Ea (entry 11 vs 12), but

chlorine transfer to the acyclic radical leading to the formation of

8Ea could not be suppressed. A further temperature increase to

50 ^ꢁC led to no further improvement (entry 13). This reaction was

the only instance in which small amounts of 6-endo cyclization

product 22Ea formed as a single diastereomer. When the allylic

Ph

16Aa

Scheme 5. Screening of bases for tandem alkoxide conjugate additions of 1A to 2a/

radical 5-exo cyclization/ligand transfer reactions (Stereochemistry of 10Aa omitted for

clarity).

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

1525

2

1

2

R

3

R

3

R

3

R

3

1

2

1

n-BuLi,

R

O N R

2

O N R

2

O N R

2

O N R

2

solvent

CuCl ,

2

Cl

+

then 2a-e

0 °C

6

4

6

4

6

4

6

4

–

3Aa -3Ga

–

R

1A-G

4

5

–78 °C

O

17

O

18

O

19

O

20

1

2

3

4

5

6

1

R

H

R

H

R

H

R

H

2 R

a Ph

R

Side products:

A

B

C

D

E

F

H

b 4-MeOC H

1

Ph

Me

1

6

4

R

c

2

Et

3

O N H

Cl O N

2

O N

2

R

4

2

Cl

R

O N

2

Me Me H

d i-Pr

e

Cl

4

R

6

H

Me H

Me

-(CH ) -

R

2 5

4

5

Ph

R

O

Ph

O

22Ea

O

8

R

H

1

14Da, 14Ga

21Aa,Ab R = H

G

Me Me H Me

1

21Ca R = Me

Scheme 6. Scope of the tandem alkoxide conjugate addition/radical 5-exo cyclization/ligand transfer reactions.

Table 5

Tandem alkoxide conjugate addition/radical 5-exo cyclization/ligand transfer reactions promoted by CuCl₂

a

Entry

1

2

Solvent

Yield^b

17e21

Diastereomeric ratio

Other products

Yield (%)

17þ18 (17/18)^c

1.6 (d)

2.1 (d)

40 (d)

2.1 (5:1)

5.6 (4.6:1)

6.5 (2.8:1)

1.3 (d)

1.5 (d)

1.6 (d)

1.4 (d)

1 (d)

7.5 (d)

1 (d)

9.4 (d)

10 (d)

2 (d)

2.75 (d)

13 (d)

5.9 (d)

3.7 (3.4:1)

1.6 (2.5:1)

4.3 (6.7:1)

1.7 (d)

1.8 (d)

1.5 (d)

2.5 (d)

19þ20 (19/20)^c

21

1^d

A

B

C

D

E

F

a

b

c

DME

THF

DME

THF

78

69

65

0 (d)

1 (d)

1 (4:1)

1 (5:1)

1.4 (1.7:1)

1 (d)

0 (d)

1 (d)

0 (d)

1 (d)

Traces

1 (d)

0 (d)

1 (2:1)

1 (2.6:1)

1 (1.9:1)

1 (d)

1

8

0

3Aa (2), 2a (11)

3Aa (10), 2a (7)

3Aa (7), 2a (7)

3Ba (3), 2a (33)

3Ca (3), 2a (13)

2a (12)

2^e,f

3

4

47 (70)

65 (74)

68 (77)

73

64 (72)

41

58 (72)

16 (24)

37 (60)

37 (50)

42 (52)

45 (59)

24

52 (76)

46 (76)

61

70

55

58

50

44

38

34 (40)

5^d

Trace

1

0

1

9

1

0

6^g,h

7

3Da (20), 14Da (1)

3Da (7), 14Da (2), 2a (12)

3Da (26), 2a (9)

3Da (6), 14Da (4), 2a (20)

8^d

9^e

THF

10^g,i

11^f

12^f,h

13^g,k

14^d

15^d,h

16^m

17

DME

THF

DME

THF

3Ea (12), 8Ea (20),^j22Ea (6), 2a (34)

8Ea (17)^j, 22Ea (4), 2a (39)

8Ea (26)^l, 22Ea (6), 2a (25)

3Fa (1), 2a (20)

2a (24)

F

G

A

B

C

D

2a (8), 14Ga (8)ⁿ

3Ab (15), 2b (32)

3Ab (8), 2b (40)

3Ac (4)

18^f

19^d

20

c

d

c

d

21

3Bd (9)

d

22^d

23^d

24

0

c

d

e

3Dd (15)

3Dd (11)

2e (15)

25

26^d

DME

0

a

Standard conditions: 1.5 mmol 1 and BuLi, 1 mmol 2, 2.5 mmol anhydrous CuCl₂, 0 ^ꢁC.

Isolated yield, numbers in parentheses indicate yield based on recovered 2.

The sum indicates the relative amount of ring diastereomers; the ratio in parentheses indicates the diastereomeric ratio at the exocyclic stereocenter with respect to

b

c

a deﬁned ring stereoisomer.

d

CuCl₂(3.0 equiv) was used.

e

Oxidation at ꢀ60 ^ꢁC.

f

CuCl₂(3.5 equiv) was used.

g

CuCl₂(4.0 equiv) was used.

h

Oxidation temperature þ30 ^ꢁC.

i

CuCl₂$2H₂O was used.

j

Compound 8Ea consists of a 2.4:1 anti/syn-mixture of unassigned diastereomers.

k

Oxidation temperature þ50 ^ꢁC, 4.0 equiv CuCl₂was added in one portion.

l

Compound 8Ea consists of a 1.8:1 anti/syn-mixture of unassigned diastereomers.

m

oxa-Michael addition for 1 h at ꢀ50 ^ꢁC, then 3 h at 20 ^ꢁC until completed, then 3.0 equiv CuCl₂at 0 ^ꢁC.

n

Diastereomeric ratio at 4-position 1:1.

alcohol was disubstituted in 1-position, as in 1F and 1G, the yield of

cyclized products was moderate (entries 14e16). At least for 1G the

lower yield may be ascribed to a competitive action of CuCl₂as

a Lewis acid, promoting the decomposition of 3Ga (vide supra).

With nitroalkenes disubstituted in b-position, the yield of cycliza-

tion products 17De and 19De decreased, probably associated with

slower Michael addition steps (entry 26).

trans-selectivity. The cyclization diastereoselectivity was generally

good for 1E and 1F (entries 11e15). The tandem reactions involving

crotyl alcohol 1C also gave a reasonable diastereoselectivity (entries

5, 6, 22). On the other hand, tandem processes involving alkene

units with sterically more demanding substituents at the alkene

terminus, such as 1B, 1D, and 1G, cyclized generally only with low

diastereoselectivity. It is notable that chlorine transfer occurred

with surprisingly good diastereoselectivities if the cyclic radical

was prochiral (entries 4, 5, 22). The substitution pattern of 2 was

All substrate combinations except those involving 1A un-

derwent the addition/cyclization sequences with exclusive 2,3-

1526

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

only of minor importance for the diastereoselectivity, although

especially for 2a and 2b epimerization has to be taken into account.

The tandem reactions involving 1A and nitrostyrenes 2a,b de-

serve a comment (entries 1e3, 17e19). As mentioned above, ex-

clusive 2,3-trans-selectivity was observed for most substrates in the

tandem process leading to 17e20. In the original communication,¹⁵

the relative conﬁguration of the minor cyclization product was

assigned therefore to be 19Aa by analogy.¹²Further experiments

and the reaction behavior of ‘19AaeAc’ subsequently cast serious

doubts on the correctness of this assignment; it was shown that the

correct structure of the minor cyclization diastereomer in addition/

cyclization sequences of 1A with 2aec is in fact 21AaeAc (entries

1e3, 17e19). Authentic 19Aa was detected in trace amounts on

large-scale preparations of 17Aa.

The correction of stereochemical assignment stems from a cru-

cial experiment, which was initially conceived as a simple test of

the performance of the tandem reactions versus a stepwise pro-

cedure (Scheme 7). This experiment indeed showed that the tan-

dem process is more efﬁcient than a stepwise procedure with

isolation of 3Aa. More signiﬁcantly, however, the oxidative cycli-

zation of 3Aa^ꢀ, generated by deprotonation with exactly 1 equiv of

n-BuLi, provided 17Aa as a single diastereomer, in stark contrast to

the 2:1 diastereomeric mixture in the tandem process (Table 5,

entries 1, 2), but more closely related to the result in THF (entry 3).

This indicated that epimerization rather than simple cyclization

diastereoselectivity was responsible for the formation of the minor

diastereomer. Two experiments revealed the factors responsible for

the facile epimerization. First, when diastereomerically pure 17Aa

was subjected to 1 equiv of the lithium alkoxide of 1A at 0 ^ꢁC for

25 min, a facile epimerization to a separable 1:2 mixture of 17Aa/

21Aa was observed. Secondly, 17Aa was subjected to silica gel in the

chromatography solvent system hexane/CH₂Cl₂(2:1) and the

mixture was stirred at room temperature for 15 h. Epimerization

leading to a separable 1:2 mixture of 17Aa/21Aa was also found

under acidic conditions. These results rule out 19Aa, but prove 21Aa

to be the minor diastereomer in the tandem process. The conﬁgu-

ration of 21Aa was assigned by NOE difference experiments (See

the Supplementary data) and an intramolecular alkylation re-

action.³²Thus, the tandem reaction of 1A and 2a was highly dia-

stereoselective to give 17Aa, but the diastereoselectivity was

compromised by the basic reaction conditions and the acidity

during ﬂash chromatography.

Copper bromide as the oxidant gave similar results in the tan-

dem reactions (Scheme 8, Table 6). The yields of cyclized products

23e25 were slightly lower than those of the corresponding chlo-

rides (vide supra), and signiﬁcant amounts of acyclic b-bromo-b-

nitro ethers 9 were formed in these sequences. Based on the

knowledge gained in the epimerization experiments (vide supra),

a tandem reaction of 1A and 2a with minimal workup and puriﬁ-

cation times led to a slight increase of the yield, but a signiﬁcant

improvement of the diastereomeric ratio of bromomethyltetrahy-

drofurans 23Aa and 25Aa (entry 2).

2

R

1

R

O N

2

Br

+

n-BuLi,

solvent, then

2a, –78 °C

Ph

O

23Aa,23Da

O

24Aa,24Da

1A,D

CuBr , 0 °C

2

1

R

1

R

2

O N

R

2

Br

+

Br

Ph

25Aa,25Da

O

9Aa,9Da

Scheme 8. Use of CuBr₂as oxidant and ligand transfer reagent in the tandem

reactions.

Table 6

a

Bromotetrahydrofurans from addition/cyclization sequences using CuBr₂

Entry

1

Solvent

23þ24þ25 (%)^b

52

62

69

42

23/24/25

9 % (dr^c)

1^d

2^e

3^f

A

D

DME

THF

1:0:1.4

11:0:1

2:1:0

18 (2:1)

9 (1.7:1)

15 (1.5:1)

24 (3:1)

4^g

1.2:1:0

a

Substrate 1A (1.5 mmol), 2a (1 mmol).

Isolated yield.

anti/syn-mixture of unassigned diastereomers.

Anhydrous CuBr₂(2.0 equiv).

b

c

d

e

CuBr₂(2.5 equiv). Fast workup and ﬂash chromatography to avoid

epimerization.

f

CuBr₂(2.8 equiv).

CuBr₂(3.0 equiv).

g

The relative ring conﬁgurations of almost all diastereomers

17e21 were assigned by NOE and NOESY experiments (See the

Supplementary data). The conﬁguration at the exocyclic stereocenter

in compounds 17e20Ba and 17e20Ca was unambiguously assigned

by intramolecular alkylation reactions with inversion and other

follow-up reactions.³²The conﬁguration at the exocyclic stereocenter

of 17e20Bc, 17e20Bd, and 17e20Cc was assigned by comparison of

the NMR spectra with those of 17e20Ba and 17e20Ca. The following

spectral properties of the diastereomeric tetrahydrofurans are

also diagnostic. The ring protons of diastereomers 17 and 18 are

similar to each other, as are those of 19 and 20. Diastereomers 17 and

18 display generally an H4 resonance upﬁeld-shifted by 0.3e0.5 ppm

relative to diastereomers 19 and 20. Moreover the coupling constant

between H2 and H3 amounts to 1.3e3.0 Hz for 17 and 18, while

this value is 5e7 Hz for 19 and 20. The ¹³C NMR resonances of the

chlorine-bearing carbon atoms are also diagnostic. The resonances of

17 and 18 are again similar to each other, as are those of 19 and 20.

Those of 17 and 18 are, however, 3e6 ppm upﬁeld-shifted compared

to 19 and 20. The bromine derivatives 23 and 24 display similar

properties.

Cl

1.0 equiv. n-BuLi,

O N

2

DME, –78 °C,

+ 2a

2.5 equiv. CuCl ,

2

Ph

0 °C

Ph

O

3Aa

O

4%

17Aa 81% single

(15% recovered)

1.0 equiv.

diastereomer

SiO ,

2

LiO

DME or THF

0 °C, 25 min

hexane/

CH Cl

2

2:1, r.t.

Cl

O N

2

17Aa +

Ph

O

21Aa

26%

66%

The applicability of propargylic alkoxides in the sequences was

also checked (Scheme 9). Propargyl alcohol 1H underwent the

Scheme 7. Oxidative radical cyclization of 3Aa and epimerization of 17Aa.

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

1527

oxidative cyclization in DME giving 26h in 28% yield as a 2.8:1 E/

3. Discussion

Z-mixture. 3-Phenylpropargylalcohol 1I furnished 4-(chloro-

benzylidene)-3-nitro-2-phenyltetrahydrofuran 26i in 25% yield as

a 1:1.5 E/Z-diastereomeric mixture in THF at 0 ^ꢁC. In DME, the yield

increased to 36% and a higher E/Z-ratio of 1:5 was observed. The

relative conﬁguration and the double bond geometry of com-

pounds 26 was determined by NOESY experiments (See the

Supplementary data). From all three experiments surprisingly large

amounts of 2a were recovered although the conjugate addition

reactions of 1H and 1I to 2a were complete.

The reaction course of the addition/cyclization sequences with

cupric halides (X¼Cl, Br) as SET oxidants is best rationalized as

follows (Scheme 11). After deprotonation of the allylic alcohol 1 by

the chosen base, the derived alkoxide undergoes a conjugate ad-

dition to the nitroalkene 2; the rate of this step is dependent on the

nucleophilicity of the allylic alkoxide. Qualitatively, lithium prenyl

oxide 1D added faster than crotyl oxide 1C, allyloxide 1A and cin-

namyl oxide 1B. The rate of alkoxide addition is also dependent on

steric features of 1 and 2. The addition reaction rate decreased as

R

the degree of substitution at the b-position of the nitroalkene and

Cl

n-BuLi, solvent,

the 1-position of the alkoxide increases. With tertiary alkoxides,

such as 1G even fragmentations of the nitronates 3Ga^ꢀbecame

competitive. It is mandatory to use strong bases, such as alkyl-

lithium or alkali metal bis(trimethylsilyl)amides, promoting irre-

versible deprotonation of 1 to the alkoxide, because equilibrium

deprotonation triggers polymerization of the nitroalkenes 2. The

O N

R

2

2a, –78 °C,

5 equiv. CuCl , 0 °C

2

+ 2a + 3Ha,Ia

Ph

OH

O

(E,Z)-26

1H R = H

1I R = Ph

26h DME 28% E/Z = 2.8:1 43% 2%

26i THF 25% E/Z = 1:1.5 41% 8%

26i DME 36% E/Z = 1:5 61% 2%

alkali b

-alkoxy nitronates 3^ꢀresulting from addition of 1 are rela-

tively stable under the reaction conditions. The conjugate addition

reaction is apparently not reversible. Incomplete additions and

retro-oxa-Michael additions were, however, observed when more

strongly Lewis acidic magnesium alkoxides were used or when

external Lewis acids, such as Cu(OTf)₂were present in the reaction

mixture.

Scheme 9. Tandem conjugate addition/radical 5-exo cyclization/ligand transfer re-

actions using propargylic alcohols.

To broaden the scope of the tandem reaction further, other ox-

idation/termination modes, namely using molecular oxygen, were

explored for the addition/cyclization sequences (Scheme 10). The

conjugate addition of allylic alkoxide 1D to 2a was performed as

described above under nitrogen atmosphere. When the addition

step was complete as judged by TLC, dry oxygen was bubbled

through the reaction mixture³³and CuCl₂was added. The reaction

outcome was dependent on the temperature. When CuCl₂was

added at 0 ^ꢁC in THF or DME solution, the major cyclized product

proved to be a diastereomeric mixture of the cyclized alcohols 27

and 28. In addition, minor amounts of the cyclized ligand transfer

products 17Da and 19Da were formed. Nitro ether 3Da and also 2a

were recovered in notable amounts, especially in THF. When the

reaction temperature was lowered to ꢀ30 ^ꢁC, the yield of 27 and 28

remained the same, but a decrease in the yield of 17Da and 19Da to

5% was found. In addition, 3Da, 2a, and a small amount of 14Da

were also isolated. Thus, the use of molecular oxygen to terminate

the reaction sequence is limited by the insufﬁcient chemo-

selectivity of trapping of the cyclized radical.

The counter ion in 3^ꢀand the choice of the SET oxidant affect the

further course of the tandem reactions. The lithium cation proved

to be the counter ion of choice for the SET oxidations of 3^ꢀ(Scheme

11, Path I). Of the oxidants tried, only cupric halides and ferroce-

nium hexaﬂuorophosphate 5 oxidized nitronates 3^ꢀefﬁciently to

a

-nitro radicals 29. The SET oxidation should proceed with cupric

halides as inner-sphere oxidants via initial transmetalation of 3^ꢀto

3^ꢀCu. It was, however, important that basic amines, such as the co-

formed diisopropylamine from LDA, were not present in the re-

action mixture, since they retarded SET oxidation considerably,

probably by coordination to the Cu(II) ion.

The reaction course switched completely when sodium or

potassium nitronates 3^ꢀwere employed (Path II). Their CuCl₂-in-

duced tandem reactions did not afford ligand transfer-derived

products 17e20 but bicyclic isoxazoline 16, especially when

hexamethyldisilazides were used as bases. Since sodium and

potassium nitronates are expected to be oxidized with more

difﬁculty,³¹these tandem reactions are in fact not anionic/radical

O N

2

OH

Cl

OH

Cl

+ 3Da + 2a

+

Ph

O

n-BuLi, solvent

2a, –78 °C

27

28

1D

then CuCl , O ,

2

temp.

O N

2

O N

2

O N

2

+

Ph

14Da

O

17Da

19Da

Solvent temp.

27/28 (d.r.)

29% 1.6:1

33% 1.5:1

(d.r.) 3Da 2a 14Da

17Da/19Da

12%

THF

0 °C

1:1

3:1

40% 18%

6% 10%

-

DME

THF –30 °C

4%

28%

1:1

30% 18% 2%

5%

Scheme 10. Tandem alkoxide conjugate addition/radical 5-exo cyclization/oxygenation reactions in the presence of molecular oxygen.

1528

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

Path III

XCu

R¹

Protonation

M

3Aa-3Ga

O R¹

R

NO₂

R²

O

Path V

3

R³

+

N

R²CuX₂

N

R²

R⁴

Base

R

Retro-oxa-

R⁴

R⁶

Michael reaction

Path IV

R⁴

R⁶

R⁵

R⁴

M = Li

-LiX

2a,b

β-Fragmentation

R⁵

2a-e

Hydrogen

HO

1A-G

R⁴

R⁵

O

abstraction

3^–M = Li, Na, K

3^–Cu

M = Na, K

R¹-R⁴= H

R⁵= Ph

Path I

R¹

SET oxidation

3

O₂N

R²

R

Path II

R⁴

R⁶

[3+2] cycloaddition

Path VI

SET reduction

CuCl₂

R⁴

R⁵

O

29

O

R¹

X

R¹

TEMPO 6

CuCl₂

N

O₂N R³

R⁶

R⁵

R²

R⁴

O₂N R³

R⁶

R²

R⁴

5-exo

CuX₂

H

CuBr₂

Ph

O

16

R¹

O

R⁵

O

30

3

O₂N

X

R²

17-20,23-24

R

R⁴

R⁶

R⁴

R⁵

O

TMP =

N

7Aa, 7Da X = OTMP

8 X = Cl

9 X = Br

Scheme 11. Mechanistic rationalization of product formation in the tandem reactions.

reactions. It is more likely that 16 forms by a tandem alkoxide

conjugate addition/[3þ2] cycloaddition process,³⁰which proceeds

by O-silylation of nitronate 3^ꢀby co-formed HMDS and subsequent

promotion of the cycloaddition by Cu(II) salts acting merely as

a Lewis acid rather than as a SET oxidant (Table 4). The mechanism

and the potential of these reactions are interesting in its own right

and will be investigated in due course. It should be noted here that

the much stronger SET oxidant ceric ammonium nitrate (CAN) was

applied for similar cyclizations of a number of sodium nitronates,

thus being complementary to the present tandem reactions.^16a,b

(Table 5, entries 11e13; Scheme 9). Since it can be safely assumed

that all nitronates 3^ꢀundergo SET oxidation by CuCl₂with very

similar rates, the re-formation of 2a,b can most probably be traced

to two competing processes: First, Cu(II) salts promote a retro-oxa-

Michael reaction by acting as Lewis acids prior to oxidation. This

explains why 2a,b form in all reactions, even when no oxidation

proceeds (Path V). The especially large amounts of recovered 2a,b

during slow cyclizations indicate that back electron transfer from

Cu(I) to radical 29 returning 3^ꢀCu may compete to a certain extent

with radical 5-exo cyclization to 30 (Path VI).³⁴An alternative direct

The fate of

a

-nitro radicals 29 generated by SET oxidation is

b-fragmentation of b-allyloxy-a-nitro radicals 29 to 2a,b and an

determined by the efﬁciency of the radical traps present. With

TEMPO 6, radicals 29 are trapped completely to 7. The cyclizations

of 29 to 30 must thus be considerably slower compared to cycli-

zations of related

CuCl₂ﬁtted in contrast much better to the slower cyclization of 29.

When CuCl₂and 6 competed for 29, TEMPO adduct 7 was formed as

allyloxyl radical seems to be less likely. This is also supported by the

especially large amounts of re-formed 2a in the tandem processes

involving propargylic alkoxides 1H,I, which can be traced to a po-

tential reversibility of the radical cyclization process, thus extend-

ing the lifetime of 29.

a

-carbonyl radicals.^11,12Ligand transfer from

Once cyclized, radicals 30 usually underwent efﬁcient ligand

transfer from the cupric halides to afford the cyclic products 17e20

or 23e25. These reactions are known to be very fast with rate

the exclusive product. Thus ligand transfer of CuCl₂to

a-nitro

radicals is slow and enables the efﬁcient radical 5-exo cyclization of

unhindered 29 to 30 at 0 ^ꢁC. However, when the substitution pat-

tern of 29 leads to a retardation of the 5-exo cyclization, as in that of

radical 29Ea derived from methallylic alcohol 1E, ligand transfer

from CuCl₂to 29 competed to some extent, giving chloro nitro

ethers 8Ea. Ligand transfer from CuBr₂to 29 proved to be faster

than that from CuCl₂, since acyclic bromo nitro ethers 9 formed

always.

constants in the range of 1e5ꢂ10⁸M^ꢀ1s^{ꢀ1 35}

.

Chlorine transfer

competed even with coupling of 30 with oxygen to a certain extent,

which occurs with rate constants of z10⁹M^ꢀ1s^ꢀ1(Scheme 10).³⁶

When the cyclized radical 30 is further oxidizable by outer-

sphere SET oxidant 5 in the absence of radical traps carbocation-

derived products 12Dae14Da form (cf. Scheme 4). However, the

selectivity of these tandem reactions must be further improved.

The stereoselectivity of the sequences was most strongly inﬂu-

enced by the substitution pattern of the alkene unit. The observed

diastereomeric ratios can be explained best by a BeckwitheHouk

transition state for the radical cyclizations (Scheme 12).³⁷With all

substitution patterns of the alkene function, chair transition state A,

giving products 17/18 with exclusive 2,3-trans-diastereoselectivity

and a 3,4-cis-stereochemistry, was preferred over boat transition

state B, which leads to minor diastereomers 19/20 with a 3,4-trans-

relationship. For prochiral cyclized radicals CeF (R¹sR²), ligand

transfer from CuCl₂is preferred via more strain-free conformations

C and E, respectively, while rotamers D and F display unfavorable

strain of substituents R¹and R⁴. The ligand transfer to C occurs

preferentially from the less hindered front face, affording 17 as the

The small amounts of b-nitro ethers 3 formed in the majority of

the reactions result either from incomplete oxidation of 3^ꢀand

subsequent protonation (Path III) or from hydrogen abstraction of

29 from the ethereal solvents (Path IV). Since no deuterium in-

corporation into 3 was observed after the reaction mixtures were

quenched with D₂O, the latter pathway is supported. The very

general recovery of signiﬁcant amounts of nitrostyrenes 2a,b (but

not 2c,d) was unexpected, since the anionic conjugate additions

always went to completion as indicated by TLC and isolation of an

aliquot of 3. The re-isolated amounts of 2a were especially high in

tandem reactions, where the oxidation does not occur, such as in

experiments using Cu(OTf)₂(Table 3, entry 8; Table 4, entry 8), and

also in such tandem reactions where the cyclization rate is retarded

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

1529

1

CuCl

LiO R

3

CuCl

2

O

R

2

N

R

4

R

4

R

NO

4

2

R

4

5

R

5

R

NO

3

O

3Aa -3Ga

R

5

2

R

–

O

4

1

R

3

1

R

2

A

R

B

Cl

5

Cu

Cl

Cu

4

Cl

R

Cl

NO

2

1

2

4

5

Cu

R

3

R

Cl

R

NO

Cl

NO

5

2

R

O

>

O

4

>

4

H

1

H

O

R

4

1

4

2

R

1

2

3

R

2

R

Cl

Cu

Cl

C

D

E

F

Cl

Cu

Cl

17

18

19

20

Scheme 12. Diastereoselectivity of the oxidative radical 5-exo cyclizations and ligand transfer of 3Aa^ꢀe3Ga^ꢀ

.

major diastereomer of the sequences. Similarly, ligand transfer to E

affording 19 is preferred in the minor diastereomeric series, though

face selectivity is somewhat less pronounced.

be predicted on the basis of the present study. Investigations along

these lines are underway.

Especially high cyclization diastereoselectivities are observed for

R¹eR³¼H and also for R¹eR²¼H and R³¼Me. However, because of

the highly acidic nature of the nitro function, the least-substituted

compounds 17AaeAc subsequently epimerized to 21AaeAc

displaying a 2,3-cis-stereochemistry under the reaction conditions,

thus compromising the good overall diastereoselectivity. To achieve

optimal results, reaction and especially workup and chromatogra-

phy puriﬁcation times should be kept as short as possible. In some

cases, it may be better to perform the addition and cyclization

steps separately as indicated in Scheme 7, since epimerization is

prevented through the less basic conditions starting from nitro

ethers 3Aa and an equimolar amount of base to generate 3Aa^ꢀ. The

lowest cyclization diastereoselectivities were observed for prenol-

derived radicals. Here, A^1,3-strain levels the energy differences of

both transition states A and B.

5. Experimental section

5.1. General

All reactions were conducted in ﬂame-dried glassware under

nitrogen atmosphere. THF, DME, CH₂Cl₂, Et₂O, MeCN, toluene, CuCl₂,

CuBr₂, and 5 were dried following standard methods under nitrogen

atmosphere. TLC plates POLYGRAM SIL G/UV₂₅₄(MachereyeNagel)

were used for monitoring reactions. Flash column chromatographic

separations were performed 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 spectrometer. ¹H and ¹³C NMR spectra were recor-

ded, unless otherwise noted, in CDCl₃on 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 experi-

ments. Relative conﬁgurations were determined by NOE or NOESY

experiments. ¹³C NMR assignments were obtained from DEPT and

HSQC experiments. EI-mass spectra were recorded on Finnigan

MAT 95 spectrometers at 70 eV. ESI-mass spectra were obtained on

4. Conclusions

The presented anionic-radical tandem reactions consisting of

conjugate addition of alkoxides to nitroalkenes and radical 5-exo

cyclizations connected by SET oxidation of the intermediate nitro-

nates by CuCl₂or CuBr₂are a convenient strategy for obtaining

functionalized tetrahydrofurans in a single step from very simple

precursors. Several parameters that inﬂuence the outcome of the

reaction sequences, such as the counter ion in the allylic alkoxide

and the nitronates, applicable SET oxidants, solvents or the reaction

temperature were investigated. Under optimized conditions, the

substrate scope of allylic alcohols 1 and nitroalkenes 2 is broad.

Propargylic alcohols are, however, less useful. Anhydrous CuCl₂

proved to be the SET oxidant of choice. However, CuBr₂, and with

some restrictions ferrocenium hexaﬂuorophosphate, can also be

applied in the reaction sequences. The tandem reactions display

interesting stereochemical features. The diastereoselectivity of the

radical 5-exo cyclizations and also the ligand transfer were mod-

erate to excellent. Thus a good potential of the tandem process for

application in target-oriented synthesis can be expected. Future

work is certainly necessary to improve the diastereoselectivity of

the cyclizations by minimizing epimerization. Methods to conduct

the anionic addition step asymmetrically have to be devised, since

the diastereoselectivity of the subsequent radical cyclizations can

a Finnigan MAT 95XLT, sample concentration approx. 50 mg/mL in

MeOH, spray voltage pos. mode: 1.3e1.8 kV, spray voltage neg.

mode: 1.1e2.3 kV, HRMS resolution: 10,000 (10% valley deﬁnition).

Combustion analyses were performed at the Microanalytical Labo-

ratories of the Technical University of Braunschweig. Allylic alcohol

1G and nitroalkenes 2cee were synthesized according to literature

procedures.³⁸

5.2.

b-(Allyloxy) nitroalkanes 3 (general procedure)

At ꢀ78 ^ꢁC under N₂, n-BuLi (0.937 mL, 1.5 mmol, 1.6 M solution

in hexane) was added via syringe to a stirred solution of allylic

alcohol 1 (1.5 mmol) in 10 mL dry DME or THF. After 15 min, a so-

lution of nitroalkene 2 (1.0 mmol) in 1 mL dry DME or THF was

added. The reaction mixture was warmed to 0 ^ꢁC after 10 min and

maintained at this temperature until complete by TLC. The reaction

mixture was quenched with acetic acid (0.086 mL, 1.5 mmol), di-

luted with 30 mL diethyl ether, ﬁltered through a pad of silica gel,

and concentrated in vacuum. The crude oily products were puriﬁed

by ﬂash column chromatography (hexane/EtOAc 10:1).

b-Nitro

1530

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

ethers 3Aa,^23c,h3Ba,^23h3Ca,^23b3Ea,^23b3Ab,^23c3Ac,^23cand 3Ha³⁹

are known compounds and their analytical data are in agreement

with the published values.

NMR (50 MHz) d 9.2 (q), 17.7 (q), 25.0 (t), 71.0 (t), 76.9 (d), 78.6 (t),

127.0 (d), 130.2 (d).

5.2.6. 1-Nitro-2-(prenyloxy)butane (3Dc). Colorless oil, yield

140 mg (75%). R_f¼0.34, hexane/EtOAc 10:1; IR (neat) 2972, 2934,

2881, 1552, 1449, 1382, 1123, 1084, 1049, 981 cm^ꢀ1; GCeMS (EI) m/z

172 (3), 102 (18), 85 (100), 83 (22), 71 (52), 69 (80), 67 (15), 57 (14),

55 (60), 53 (12); Anal. Calcd for C₉H₁₇NO₃(187.24): C 57.73 H 9.15 N

7.48. Found: C 57.10 H 9.40 N 7.42. Despite many attempts, a better

5.2.1. 2-Nitro-1-phenyl-1-(prenyloxy)ethane (3Da). Colorless oil,

yield 228 mg (97%). R_f¼0.56, hexane/EtOAc 10:1; IR (neat) 3064,

3032, 2974, 2915, 2879,1553,1452,1378,1086,1065, 1014 cm^ꢀ1; MS

(EI) m/z 150 (4),104 (100),103 (12), 85 (30), 77 (15), 69 (45), 57 (21);

Anal. Calcd for C₁₃H₁₇NO₃(235.28): C 66.36 H 7.28 N 5.95. Found: C

66.31 H 7.47 N 6.20. ¹H NMR (400 MHz)

d

1.53 (s, 3H), 1.73 (d,

matching analysis was not obtained. ¹H NMR (400 MHz)

d 0.93 (t,

J¼0.4 Hz, 3H), 3.85 (dd, J¼11.4, 7.5 Hz, 1H), 3.93 (dd, J¼11.4, 6.6 Hz,

1H), 4.38 (dd, J¼12.7, 3.5 Hz, 1H), 4.62 (dd, J¼12.7, 10.0 Hz, 1H), 5.10

(dd, J¼10.0, 3.5 Hz, 1H), 5.29 (m, 1H), 7.36e7.41 (m, 5H); ¹³C NMR

J¼7.5 Hz, 3H), 1.59 (m, 2H), 1.62 (s, 3H), 1.70 (s, 3H), 3.93e4.03 (m,

3H), 4.35 (dd, J¼12.3, 4.2 Hz, 1H), 4.41 (dd, J¼12.3, 8.0 Hz, 1H), 5.26

(m,1H); ¹³C NMR (100 MHz)

d 9.5 (q), 18.2 (q), 25.2 (t), 26.0 (q), 66.8

(t), 77.0 (d), 79.0 (t), 120.7 (d), 138.2 (s).

(100 MHz)

d

17.9 (q), 25.7 (q), 65.5 (t), 77.2 (d), 80.5 (t), 119.9 (d),

126.8 (d), 129.0 (d, 3C), 136.7 (s), 138.5 (s).

5.2.7. 2-(Cinnamyloxy)-3-methyl-1-nitrobutane

(3Bd). Colorless

5.2.2. 1-(2-Methyl-3-buten-2-yloxy)-2-nitro-1-phenylethane

(3Fa). Puriﬁed by ﬂash chromatography hexane/Et₂O 5:1. Colorless

oil, yield 165 mg (70%). R_f¼0.62, hexane/Et₂O 5:1; IR (neat) 3088,

3065, 3031, 2980, 2931, 1552, 1454, 1416, 1379, 1224, 1145, 1086,

1064, 964, 926 cm^ꢀ1; MS (EI) m/z 220 (10), 150 (30), 107 (18), 104

(100), 78 (11), 77 (16), 71 (28), 69 (76); Anal. Calcd for C₁₃H₁₇NO₃

(235.28): C 66.36 H 7.28 N 5.95. Found: C 66.44 H 7.37 N 6.15. ¹H

oil, yield 236 mg (95%). R_f¼0.35, hexane/EtOAc 10:1; IR (neat) 3028,

2963, 2933, 2875, 1553, 1466, 1451, 1383, 1074, 967 cm^ꢀ1; MS (EI)

m/z 249 (M^þ, 3), 189 (5), 133 (56), 132 (12), 131 (25), 117 (89), 116

(21), 115 (70), 105 (100), 103 (14), 92 (24), 91 (35), 79 (12), 78 (13),

77 (24), 69 (58), 57 (17), 51 (18); HRMS (EI) calcd for C₁₄H₁₉NO₃

249.1365, found 249.1362; Anal. Calcd for C₁₄H₁₉NO₃(249.31): C

67.45 H 7.68 N 5.62. Found: C 67.95 H 7.73 N 5.25. ¹H NMR

NMR (200 MHz)

d

1.10 (s, 3H), 1.24 (s, 3H), 4.30 (dd, J¼11.9, 3.8 Hz,

(200 MHz)

d

0.98 (d, J¼6.9 Hz, 3H), 0.99 (d, J¼6.9 Hz, 3H), 1.98

1H), 4.52 (dd, J¼11.9, 9.7 Hz, 1H), 5.07 (dd, J¼10.6, 1.1 Hz, 1H), 5.10

(dsept, J¼6.9, 5.1 Hz, 1H), 3.98 (ddd, J¼8.1, 5.1, 4.1 Hz, 1H), 4.21 (dt,

J¼6.1, 1.1 Hz, 2H), 4.44 (dd, J¼12.4, 4.1 Hz, 1H), 4.47 (dd, J¼12.4,

8.1 Hz, 1H), 6.20 (dt, J¼15.9, 6.1 Hz, 1H), 6.58 (dt, J¼15.9, 1.1 Hz, 1H),

(dd, J¼17.7, 1.1 Hz, 1H), 5.16 (dd, J¼9.7, 3.8 Hz, 1H), 5.67 (dd, J¼17.7,

10.6 Hz, 1H), 7.29e7.40 (m, 5H); ¹³C NMR (50 MHz)

d 25.8 (q), 26.8

(q), 72.7 (d), 77.4 (s), 81.8 (t), 114.6 (t), 126.4 (d), 128.3 (d), 128.7 (d),

140.0 (s), 142.9 (d).

7.23e7.41 (m, 5H); ¹³C NMR (50 MHz)

d 17.8 (q), 17.9 (q), 30.3 (d),

71.7 (t), 77.3 (t), 80.8 (d), 125.4 (d), 126.5 (d), 127.8 (d), 128.5 (d),

132.8 (d), 136.5 (s).

5.2.3. 1-(2,4-Dimethyl-3-penten-2-yloxy)-2-nitro-1-phenylethane

(3Ga). The crude yield as determined by NMR amounted to 67%.

After column chromatography only 64 mg (24%) of 3Ga was iso-

lated as a colorless oil. The compound is very acid sensitive. An

optimization was not performed. Despite many attempts, neither

a satisfactory combustion analysis nor reasonable mass spectral

data were obtained. R_f¼0.35, hexane/EtOAc 10:1; ¹H NMR

5.2.8. 3-Methyl-1-nitro-2-(prenyloxy)butane (3Dd). Puriﬁed by

ﬂash column chromatography hexane/Et₂O 5:1. Colorless oil, yield

147 mg (73%). R_f¼0.62, hexane/Et₂O 5:1; IR (neat) 2967, 2934, 2915,

2878, 1553, 1468, 1449, 1423, 1382, 1224, 1076, 1052, 998 cm^ꢀ1; MS

(EI) m/z 200 ([MeH]^þ, 2), 85 (46), 69 (100), 57 (24), 55 (25), 53 (22);

Anal. Calcd for C₁₀H₁₉NO₃(201.26): C 59.68 H 9.52 N 6.96. Found: C

(200 MHz)

d

1.16 (s, 3H), 1.28 (s, 3H), 1.61 (d, J¼1.3 Hz, 3H), 1.63 (d,

59.79 H 9.80 N 6.88. ¹H NMR (400 MHz)

d

0.96 (d, J¼6.9 Hz, 3H),

J¼1.3 Hz, 3H), 4.33 (dd, J¼11.8, 4.3 Hz, 1H), 4.59 (dd, J¼11.8, 9.0 Hz,

0.98 (d, J¼6.9 Hz, 3H), 1.65 (d, J¼1.1 Hz, 3H), 1.74 (d, J¼1.1 Hz, 3H),

1.95 (dsept, J¼6.9, 5.3 Hz, 1H), 3.88 (ddd, J¼8.1, 5.3, 4.1 Hz, 1H), 4.00

(dd, J¼11.6, 7.5 Hz,1H), 4.05 (dd, J¼11.6, 7.5 Hz,1H), 4.40 (dd, J¼12.4,

4.1 Hz, 1H), 4.45 (dd, J¼12.4, 8.1 Hz, 1H), 5.29 (tquint, J¼7.5, 1.1 Hz,

1H), 5.09 (quint, J¼1.3 Hz, 1H), 5.21 (dd, J¼9.0, 4.3 Hz, 1H),

7.27e7.39 (m, 5H); ¹³C NMR (50 MHz)

d 19.1 (q), 27.4 (q), 28.7 (q),

28.9 (q), 72.9 (d), 77.4 (s), 81.8 (t), 126.6 (d), 128.2 (d), 128.6 (d),

129.1 (d), 136.4 (s), 140.4 (s).

1H); ¹³C NMR (100 MHz)

d 17.5 (q), 17.6 (q), 17.7 (q), 25.4 (q), 30.0

(d), 67.2 (t), 77.0 (t), 80.3 (d), 120.0 (d), 137.6 (s).

5.2.4. 2-(Cinnamyloxy)-1-nitrobutane (3Bc). Colorless oil, yield

130 mg (55%). R_f¼0.21, hexane/EtOAc 10:1; IR (neat) 3028, 2970,

5.2.9. 1-(3-Methylbut-2-enyloxy)-1-(nitromethyl)cyclohexane

(3De). Colorless oil, yield 118 mg (52%). R_f¼0.44, hexane/EtOAc

10:1; IR (neat) 2934, 2860, 1547, 1449, 1379, 1050, 1028 cm^ꢀ1; MS

(ESI) m/z 250 (MþNa^þ, 100); Anal. Calcd for C₁₂H₂₁NO₃(227.30): C

63.41 H 9.31 N 6.16. Found: C 63.64 H 9.51 N 6.04. ¹H NMR

2936, 2880,1550,1461,1451,1421,1383,1142,1075,1050, 966 cm^ꢀ1

;

MS (EI) m/z 235 (M^þ, 4), 133 (69), 131 (45), 118 (11), 117 (100), 115

(92), 105 (82), 104 (61), 103 (24), 91 (50), 89 (11), 79 (22), 77 (38), 65

(12), 63 (11), 55 (70), 51 (25); Anal. Calcd for C₁₃H₁₇NO₃(235.28): C

66.36 H 7.28 N 5.95. Found: C 66.38 H 7.49 N 5.96. ¹H NMR

(400 MHz)

3H), 1.75 (d, J¼1.0 Hz, 3H), 1.89 (m, 2H), 3.98 (d, J¼6.9 Hz, 2H), 4.50

(s, 2H), 5.33 (m, 1H); ¹³C NMR (100 MHz)

18.0 (q), 21.5 (t, 2C), 25.3

d

1.24e1.34 (m, 1H), 1.43e1.68 (m, 7H), 1.70 (d, J¼0.9 Hz,

(200 MHz)

d

0.92 (t, J¼7.4 Hz, 3H), 1.59 (m, 2H), 4.03 (ddt, J¼8.1, 6.0,

4.1 Hz, 1H), 4.13 (dd, J¼6.1, 1.5 Hz, 2H), 4.32 (dd, J¼12.4, 4.1 Hz, 1H),

d

4.43 (dd, J¼12.4, 8.1 Hz, 1H), 6.16 (dt, J¼15.9, 6.1 Hz, 1H), 6.53 (dt,

(t), 25.9 (q), 32.9 (t, 2C), 58.1 (t), 74.9 (s), 80.4 (t), 120.7 (d), 136.7 (s).

J¼15.9, 1.5 Hz, 1H), 7.18e7.36 (m, 5H); ¹³C NMR (50 MHz)

d 9.2 (q),

24.9 (t), 70.8 (t), 77.0 (d), 78.6 (t), 125.3 (d),126.5 (d), 127.8 (d),128.5

(d), 132.9 (d), 136.5 (s).

5.2.10. 2-Nitro-1-phenyl-1-(3-phenylpropargyloxy)ethane

(3Ia). Puriﬁed by ﬂash column chromatography hexane/Et₂O 5:1.

Colorless oil, yield 267 mg (95%). R_f¼0.40, hexane/Et₂O 5:1; IR

(neat) 3062, 3033, 2905, 2856, 2240, 1553, 1490, 1417, 1379, 1260,

1085, 1066, 1027, 917 cm^ꢀ1; MS (EI) m/z 281 (M^þ, 1), 220 (10), 149

(14), 132 (28), 131 (46), 115 (100), 104 (57), 102 (26), 91 (20), 89 (19),

78 (20), 77 (46), 66 (12), 63 (14), 51 (32), 50 (14). Anal. Calcd for

C₁₇H₁₅NO₃(281.31): C 72.58 H 5.37 N 4.98. Found: C 72.39 H 5.34 N

5.2.5. 2-(Crotyloxy)-1-nitrobutane (3Cc). Colorless oil, yield 130 mg

(75%). R_f¼0.35, hexane/EtOAc 10:1; IR (neat) 2970, 2938, 2881,

2861, 1552, 1383, 1087, 1043, 967 cm^ꢀ1; GCeMS (EI) m/z 113 (3), 102

(32), 72 (65), 71 (98), 57 (80), 55 (100), 53 (25); Anal. Calcd for

C₈H₁₅NO₃(173.21): C 55.47 H 8.73 N 8.09. Found: C 55.26 H 8.94 N

7.87. ¹H NMR (200 MHz)

d

0.92 (t, J¼7.4 Hz, 3H), 1.60 (m, 2H), 1.66

4.99. ¹H NMR (200 MHz)

d

4.18 (d, J¼15.9 Hz,1H), 4.41 (d, J¼15.9 Hz,

(dd, J¼6.1, 1.2 Hz, 3H), 3.90e4.04 (m, 3H), 4.35 (dd, J¼12.3, 4.2 Hz,

1H), 4.45 (dd, J¼12.8, 3.5 Hz, 1H), 4.72 (dd, J¼12.8, 9.9 Hz, 1H), 5.43

1H), 4.41 (dd, J¼12.3, 7.9 Hz, 1H), 5.47 (m, 1H), 5.66 (m, 1H); ¹³C

(dd, J¼9.9, 3.5 Hz, 1H), 7.27e7.36 (m, 3H), 7.37e7.46 (m, 7H); ¹³C

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

1531

NMR (50 MHz)

d

57.1 (t), 76.9 (d), 80.1 (t), 83.7 (s), 87.2 (s), 122.3 (s),

R_f¼0.64, hexane/EtOAc 10:1; IR (neat) 3008, 2975, 2934, 2875,1561,

1454, 1379, 1366, 1124, 1087, 1065, 991, 980 cm^ꢀ1; MS (EI) m/z 390

(M^þ, 1), 375 (4), 186 (13), 156 (20), 143 (13), 140 (19), 126 (11), 107

(30), 105 (73), 91 (14), 83 (17), 79 (13), 77 (30), 69 (100), 58 (30), 55

(38); Anal. Calcd for C₂₂H₃₄N₂O₄(390.52): C 67.66 H 8.78 N 7.17.

Found: C 67.69 H 8.80 N 7.08. Diastereomer 1: ¹H NMR (400 MHz)

127.1 (d), 128.3 (d), 128.5 (d), 129.1 (d), 129.3 (d), 131.7 (d), 135.5 (s).

5.3. 1-(2-Allyloxy-1-nitro-2-phenylethoxy)-2,2,6,6-

tetramethylpiperidine (7Aa)

n-BuLi (0.938 mL, 1.5 mmol, 1.6 M in hexane) was added via

syringe to a stirred solution of 1A (0.102 mL, 1.5 mmol) in 10 mL dry

DME at ꢀ78 ^ꢁC. After 15 min, a solution of 2a (149 mg, 1.0 mmol) in

1 mL dry DME was added. The reaction mixture was warmed slowly

to ꢀ30 ^ꢁC and maintained at this temperature until complete, as

indicated by TLC. A thoroughly homogenized mixture of dry 5

(258 mg, 0.78 mmol) and 6 (156 mg, 1.0 mmol) was added in por-

tions with vigorous stirring as fast as it was consumed, as indicated

by discoloration of the mixture. After consumption more dry 5

(125 mg, 0.38 mmol) was added at the same temperature in 5

portions until the reaction mixture became green-blue and in-

homogeneous. After 30 min, the reaction was quenched with AcOH

(0.2 mL, 3.2 mmol) and 4 drops of water. The inhomogeneous

green-blue mixture was diluted with 20 mL diethyl ether and ﬁl-

tered through a pad of silica gel. The solution was evaporated in

vacuum and the crude product was puriﬁed by ﬂash chromatog-

raphy (hexane/EtOAc, gradient 80:1 to 10:1). Orange oil, yield

320 mg (88%) as an inseparable 1.1:1 mixture of unassigned anti/

syn-diastereomers. R_f¼0.61, hexane/EtOAc 10:1; IR (neat) 3067,

3009, 2976, 2935, 2874, 1561, 1455, 1366, 1129, 1092, 1066, 991,

927 cm^ꢀ1; MS (EI) m/z 362 (M^þ, 9), 347 (25), 156 (56), 147 (68), 140

(100), 124 (25), 123 (20), 107 (11), 105 (55), 98 (12), 91 (39), 83 (73),

77 (21), 69 (58), 58 (93), 56 (50), 55 (79); Anal. Calcd for C₂₀H₃₀N₂O₄

(362.46): C 66.27 H 8.34 N 7.73. Found: C 66.30 H 8.38 N 7.66.

d 0.90 (s, 3H), 1.15 (s, 3H), 1.19e1.55 (m, 6H), 1.27 (s, 3H), 1.44 (s, 3H),

1.54 (s, 3H), 1.73 (s, 3H), 3.92 (dd, J¼11.3, 6.6 Hz, 1H), 3.99 (dd,

J¼11.3, 6.6 Hz, 1H), 4.69 (d, J¼7.9 Hz, 1H), 5.31 (t, J¼6.6 Hz, 1H), 5.89

(dd, J¼7.9, 0.4 Hz,1H), 7.25e7.33 (m, 5H); ¹³C NMR (100 MHz)

d 16.7

(t), 17.9 (q), 19.9 (q), 20.3 (q), 25.6 (q), 31.6 (q), 32.4 (q), 40.5 (t), 40.6

(t), 59.8 (s), 62.0 (s), 66.0 (t), 79.7 (d), 117.2 (d), 120.3 (d), 127.9 (d),

128.3 (d), 128.8 (d), 135.1 (s), 137.3 (s). Diastereomer 2: ¹H NMR

(400 MHz)

d 0.51 (s, 3H), 0.59 (s, 3H), 0.96 (s, 3H), 1.08 (s, 3H),

1.19e156 (m, 6H), 1.49 (s, 3H), 1.71 (s, 3H), 3.79 (dd, J¼11.2, 6.9 Hz,

1H), 3.91 (dd, J¼11.2, 6.9 Hz, 1H), 4.75 (d, J¼8.6 Hz, 1H), 5.23 (t,

J¼6.9 Hz, 1H), 5.70 (d, J¼8.6 Hz, 1H), 7.34e7.41 (m, 3H), 7.47e7.49

(m, 2H); ¹³C NMR (100 MHz)

d 16.5 (t), 17.7 (q), 19.6 (q), 20.3 (q),

25.6 (q), 31.2 (q), 32.1 (q), 40.4 (t), 40.5 (t), 60.0 (s), 61.5 (s), 65.7 (t),

78.7 (d), 116.2 (d), 119.5 (d), 128.3 (d, 3C), 128.4 (d, 2C), 136.0 (s),

138.7 (s).

5.5. Tandem addition/cyclization mediated by 5 in the

absence of TEMPO 6

n-BuLi (0.938 mL, 1.5 mmol, 1.6 M in hexane) was added via

syringe to a stirred solution of 1D (0.152 mL, 1.5 mmol) in 10 mL dry

DME at ꢀ78 ^ꢁC. After 15 min, a solution of 2a (149 mg, 1.0 mmol) in

1 mL dry DME was added. The reaction mixture was warmed slowly

to ꢀ60 ^ꢁC and maintained at this temperature until complete as

indicated by TLC. Dry 5 (662 mg, 2.0 mmol) was added in portions

with vigorous stirring as fast as it was consumed as indicated by

discoloration of the mixture. After 30 min, the reaction was

quenched with 12 drops of saturated NH₄Cl solution. The in-

homogeneous green-blue mixture was diluted with 20 mL diethyl

ether and ﬁltered through a pad of silica gel. The solution was

evaporated in vacuum and the crude product was puriﬁed by ﬂash

chromatography (hexane/EtOAc, gradient 80:1 to 2:1).

Diastereomer 1: ¹H NMR (400 MHz)

d 0.86 (s, 3H), 1.12 (s, 3H),

1.17e1.55 (m, 6H), 1.24 (s, 3H), 1.42 (s, 3H), 3.94 (m, 2H), 4.69

(d, J¼8.1 Hz, 1H), 5.11 (m, 1H), 5.20 (m, 1H), 5.83 (m, 1H), 5.88

(d, J¼8.1 Hz, 1H), 7.24e7.32 (m, 5H); ¹³C NMR (100 MHz)

d 16.5 (t),

19.8 (q), 20.1 (q), 31.3 (q), 32.3 (q), 40.3 (t), 40.4 (t), 59.6 (s), 61.9 (s),

70.3 (t), 80.0 (d), 116.9 (d), 117.0 (t), 127.7 (d), 128.2 (d), 128.84 (d),

133.5 (d), 134.5 (s). Diastereomer 2: ¹H NMR (400 MHz)

d 0.48

(s, 3H), 0.56 (s, 3H), 0.92 (s, 3H), 1.04 (s, 3H), 1.17e1.45 (m, 6H), 3.74

(m, 1H), 3.94 (m, 1H), 4.74 (d, J¼8.6 Hz, 1H), 5.17 (m, 2H), 5.67

(d, J¼8.6 Hz, 1H), 5.73 (m, 1H), 7.33e7.38 (m, 3H), 7.43e7.45

5.5.1. 3,3-Dimethyl-6(R*)-phenyl-3a(R*),4-dihydro-3H,6H-furo[3,4-

c]isoxazole-1-oxide (12Da). Solid, which quickly degrades at room

temperature and in the presence of traces of acid. Yield 128 mg

(55%). Mp 68 ^ꢁC; R_f¼0.32, hexane/EtOAc 3:1; IR (neat) 3032, 2979,

2942, 2881, 1672, 1456, 1373, 1288, 1249, 1224, 1169, 1143, 1007,

963 cm^ꢀ1; MS (EI) m/z 233 (M^þ, 1), 145 (100), 127 (15), 117 (35), 115

(99), 105 (83), 91 (13), 89 (10), 88 (10), 77 (38), 69 (22), 58 (10), 55

(13); MS (ESI) m/z 256 (MþNa^þ, 100); HRMS (ESI) C₁₃H₁₅NO₃calcd

for [MþNa^þ] 256.0950, found 256.0947; Anal. Calcd for C₁₃H₁₅NO₃

(233.26): C 66.94 H 6.48 N 6.00. Found: C 66.90 H 6.28 N 5.80. ¹H

(m, 2H); ¹³C NMR (100 MHz)

d 16.4 (t), 19.4 (q), 20.1 (q), 31.0 (q),

32.0 (q), 40.3 (t, 2C), 59.8 (s), 61.3 (s), 70.1 (t), 78.7 (d), 115.9 (d),

117.6 (t), 128.1 (d), 128.2 (d), 128.82 (d), 133.1 (d), 135.5 (s).

5.4. 2,2,6,6-Tetramethyl-1-[1-nitro-2-phenyl-2-(prenyloxy)

ethoxy]piperidine (7Da)

n-BuLi (0.938 mL, 1.5 mmol, 1.6 M in hexane) was added via

syringe to a stirred solution of 1D (0.152 mL, 1.5 mmol) in 10 mL dry

DME at ꢀ78 ^ꢁC. After 15 min, a solution of 2a (149 mg, 1.0 mmol) in

1 mL dry DME was added. The reaction mixture was slowly warmed

to 0 ^ꢁC and maintained at this temperature until complete as in-

dicated by TLC. A thoroughly homogenized 1:1 mixture of anhy-

drous CuCl₂(135 mg, 1.0 mmol) and 6 (156 mg, 1.0 mmol) was

quickly added in portions with vigorous stirring. After it was con-

sumed, as detected by a lightening of the initially coffee-brown

mixture, additional anhydrous CuCl₂(135 mg, 1.0 mmol) was

added. After 30 min, the reaction was quenched with 12 drops of

saturated NH₄Cl solution. The inhomogeneous mixture was diluted

with 80 mL diethyl ether and washed with 100 mL saturated NH₄Cl

solution. After separation the aqueous layer was extracted four

times with diethyl ether. The organic layers were combined and

dried with Na₂SO₄. The organic layer was evaporated in vacuum

and the crude product was puriﬁed by ﬂash chromatography

(hexane/EtOAc 10:1). Orange oil, yield 340 mg (87%) as an in-

separable 1.1:1 mixture of unassigned anti/syn-diastereomers.

NMR (400 MHz, C₆D₆)

d

0.93 (s, 3H), 0.95 (s, 3H), 3.24 (dt, J¼8.3,

2.0 Hz, 1H), 3.38 (t, J¼8.3 Hz, 1H), 3.47 (dd, J¼8.3, 2.0 Hz, 1H), 5.61

(d, J¼2.0 Hz,1H), 7.07e7.11 (m,1H), 7.14e7.19 (m, 2H), 7.48e7.50 (m,

2H); ¹³C NMR (100 MHz, C₆D₆)

d 22.3 (q), 26.6 (q), 56.8 (d), 65.6 (t),

75.3 (d), 84.4 (s), 126.2 (d), 128.3 (d), 128.7 (d), 138.0 (s), 216.1 (s).

5.5.2. 4(S*)-(1-Ferrocenyl-1-methylethyl)-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (13Da). Orange solid, yield 58 mg (14%) as a single

diastereomer. Mp 85 ^ꢁC; R_f¼0.45, hexane/EtOAc 10:1; IR (neat)

3101, 3083, 3060, 2985, 2962, 2936, 2869, 1542, 1469, 1453, 1370,

1323, 1292, 1095, 1075, 1029, 990, 766 cm^ꢀ1

; UV (CHCl₃,

1.56ꢂ10^ꢀ4M) l_max240, 439 nm; MS (EI) m/z 419 (M^þ, 99), 372 (10),

227 (100), 212 (17), 199 (17), 186 (33), 121 (40), 77 (11), 55 (25);

Anal. Calcd for C₂₃H₂₅FeNO₃(419.29): C 65.88 H 6.01 N 3.34. Found:

C 66.01 H 6.16 N 3.49. ¹H NMR (400 MHz)

d 1.28 (s, 6H), 3.00 (m,

1H), 3.98 (m, 2H), 4.01 (m, 1H), 4.03 (d, J¼2.7 Hz, 1H), 4.09 (m, 2H),

4.11 (s, 5H), 4.64 (t, J¼6.9 Hz, 1H), 4.94 (d, J¼6.9 Hz, 1H), 7.06e7.09

1532

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

(m, 2H), 7.25e7.26 (m, 3H); ¹³C NMR (100 MHz)

35.3 (s), 57.5 (d), 66.1 (d), 66.3 (d), 67.7 (d, 2C), 68.5 (d, 5C), 69.6 (t),

85.9 (d), 93.8 (d), 96.2 (s), 125.7 (d, 2C), 128.6 (d, 3C), 137.6 (s).

d

26.1 (q), 26.2 (q),

5.7.1. 4-(Chloromethyl)-3-nitro-2-phenyltetrahydrofurans

(17Aa,

19Aa, 21Aa). Puriﬁed by ﬂash chromatography hexane/EtOAc,

gradient 10:1 to 5:1. For yields and ratios, see Table 5 and Scheme 7.

The following analyses were performed on the diastereomeric

mixture before further separation. MS (EI) m/z 243/241 (M^þ, 1/3),

197/195 (3/8), 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.

5.6. Tandem addition/cyclization mediated by cupric chloride

in the presence of NaHMDS

At ꢀ78 ^ꢁC under N₂, NaHMDS (0.70 mL, 1.4 mmol, 2.0 M solution

in THF) was added via syringe to a stirred solution of 1A (0.102 mL,

1.4 mmol) in 10 mL dry THF. After 40 min, at ꢀ70 ^ꢁC a solution of 2a

(149 mg, 1.0 mmol) in 1 mL dry THF was added via syringe. The

reaction mixture was warmed to ꢀ50 ^ꢁC and maintained at this

temperature until completion (TLC monitoring). The reaction

mixture was warmed to 0 ^ꢁC and anhydrous CuCl₂(336 mg,

2.5 mmol) was added at the same temperature in one portion with

vigorous stirring. After 30 min, the reaction was quenched with

0.5 mL of a saturated NH₄Cl solution and stirred for 30 min at 20 ^ꢁC.

The inhomogeneous mixture was diluted with 15 mL diethyl ether

and ﬁltered through a pad of silica gel. The solution was evaporated

in vacuum and the crude product was puriﬁed by ﬂash column

chromatography (hexane/Et₂O, gradient 5:1 to 1:1).

5.7.1.1. 4(R*)-(Chloromethyl)-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (17Aa). Colorless oil. R_f¼0.50, hexane/EtOAc 5:1;

¹H NMR (400 MHz)

d

¼3.04 (dquint, J¼10.3, 7.6 Hz, 1H), 3.50 (dd,

J¼11.3, 7.6 Hz, 1H), 3.60 (dd, J¼11.3, 7.6 Hz, 1H), 4.05 (dd, J¼10.3,

8.6 Hz, 1H), 4.44 (dd, J¼8.6, 7.6 Hz, 1H), 5.01 (dd, J¼7.6, 3.1 Hz, 1H),

5.49 (d, J¼3.1 Hz, 1H), 7.27e7.37 (m, 5H); ¹³C NMR (100 MHz)

d 39.3

(t), 45.7 (d), 71.3 (t), 85.0 (d), 93.2 (d), 125.2 (d), 128.7 (d), 128.9 (d),

138.5 (s).

5.7.1.2. 4(S*)-(Chloromethyl)-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (19Aa). Colorless oil formed in trace amounts in

large scale setups. R_f¼0.45, hexane/EtOAc 5:1; ¹H NMR (300 MHz)

d

3.40 (m, 1H), 3.59 (dd, J¼11.3, 7.1 Hz, 1H), 3.69 (dd, J¼11.3, 6.9 Hz,

5.6.1. 6(R*)-Phenyl-1-trimethylsilyloxy-3a(R*),6a(S*)-tetrahydrofuro

[3,4-c]isoxazole (15Aa).⁴⁰Puriﬁed by ﬂash chromatography hex-

ane/Et₂O, gradient 5:1 to 1:1. Colorless oil. R_f¼0.38, hexane/Et₂O

1H), 4.15 (dd, J¼9.5, 3.7 Hz, 1H), 4.33 (dd, J¼9.5, 3.7 Hz, 1H), 4.82

(dd, J¼6.2, 4.4 Hz, 1H), 5.27 (d, J¼6.2 Hz, 1H), 7.35e7.41 (m, 5H); ¹³C

NMR (75 MHz)

d 43.9 (t), 48.1 (d), 70.8 (t), 85.0 (d), 93.5 (d), 125.7

1:1; ¹H NMR (200 MHz)

d

0.00 (s, 9H), 3.28 (m, 1H), 3.53 (dd, J¼9.1,

(d), 128.907 (d), 128.949 (d), 137.5 (s).

7.1 Hz, 1H), 3.74 (bd, J¼7.1 Hz, 1H), 3.87 (dd, J¼8.4, 6.8 Hz, 1H), 4.25

(dd, J¼8.4, 6.6 Hz, 1H), 4.26 (t, J¼8.4 Hz, 1H), 4.39 (d, J¼6.8 Hz, 1H),

5.7.1.3. 4(R*)-(Chloromethyl)-3(R*)-nitro-2(R*)-phenyl-

tetrahydrofuran (21Aa). Colorless solid. Mp 65 ^ꢁC; R_f¼0.44, hexane/

EtOAc 5:1; IR (KBr) 3070, 3049, 3033, 3016, 2978, 2958, 2896, 2868,

1549, 1510, 1453, 1381, 1366, 1339, 1305, 1278, 1097, 1072, 1062, 980,

7.12e7.29 (m, 5H); ¹³C NMR (50 MHz)

d e0.6 (q), 46.0 (d), 71.5 (t),

73.8 (t), 83.8 (d), 87.7 (d), 125.6 (d), 127.6 (d), 128.4 (d), 140.3 (s).

5.6.2. 6(R*)-Phenyl-3a(R*),4-dihydro-3H,6H-furo[3,4-c]isoxazole

(16Aa).^23a,b,h,40Puriﬁed by ﬂash chromatography hexane/Et₂O,

gradient 5:1 to 1:1. Colorless solid. For yields and ratios, see Table 4.

Mp 77 ^ꢁC; R_f¼0.29, hexane/Et₂O 1:1; IR (neat) 3068, 3036, 3009,

2945, 2917, 2873, 2857, 1501, 1457, 1451, 1358,1200, 1097, 1008, 975,

947 cm^ꢀ1; MS (EI) m/z 189 (M^þ, 36), 188 (65), 112 (16), 105 (100), 77

(56), 57 (17), 54 (18), 51 (23); Anal. Calcd for C₁₁H₁₁NO₂(189.21): C

69.83 H 5.86 N 7.40. Found: C 69.67 H 5.85 N 7.39. ¹H NMR

852, 814 cm^ꢀ1; ¹H NMR (400 MHz)

d

3.61 (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, J¼9.1, 8.0 Hz, 1H), 5.21 (d, J¼6.3 Hz, 1H), 5.28 (dd, J¼6.3,

3.1 Hz, 1H), 7.29e7.37 (m, 5H); ¹³C NMR (100 MHz)

d 43.4 (t), 46.7

(d), 70.6 (t), 84.3 (d), 93.2 (d),126.3 (d),128.8 (d),129.3 (d),134.2 (s).

5.7.2. 4-(Chlorobenzyl)-3-nitro-2-phenyltetrahydrofurans

(17Bae20Ba). Puriﬁed by ﬂash chromatography hexane/Et₂O

5:1. Yield 150 mg (47%) as an 8.8:1.8:4:1 mixture of 17Ba/18Ba/

19Ba/20Ba. The following analyses were performed on the

diastereomeric mixture before further separation. IR (neat) 3064,

3022, 3004, 2968, 2941, 2905, 1553, 1480, 1365, 1335, 1230, 1115,

1061, 1028, 943, 928, 711, 695 cm^ꢀ1; MS (CI) m/z 335/337

([MþNH₄]^þ, 32/100), 300 (21), 299 (55), 285 (51), 283 (41), 254

(37), 252 (20), 250 (35), 237 (10), 179 (10), 162 (28), 106 (10); Anal.

Calcd for C₁₇H₁₆ClNO₃(317.77): C 64.26 H 5.08 N 4.41. Found: C

64.25 H 4.96 N 4.19.

(400 MHz)

1H), 4.24 (m, 1H), 4.44 (dt, J¼8.3, 0.7 Hz, 1H), 4.59 (dd, J¼9.4, 8.2 Hz,

1H), 5.61 (s, 1H), 7.31e7.44 (m, 5H); ¹³C NMR (100 MHz)

54.8 (d),

d

3.82 (dd, J¼9.5, 8.3 Hz, 1H), 4.07 (dd, J¼12.3, 8.2 Hz,

d

70.3 (t), 73.3 (d), 74.0 (t), 126.0 (d), 128.8 (d), 129.0 (d), 137.7 (s),

170.6 (s).

5.7. General procedure for the conjugate addition/radical 5-

exo cyclization reactions in the presence of cupric chloride or

cupric bromide

At ꢀ78 ^ꢁC under N₂, n-BuLi (0.938 mL, 1.5 mmol, 1.6 M solution

in hexane) was added via syringe to a stirred solution of allylic

alcohols 1 (1.5 mmol) in 10 mL dry DME or THF. After 15 min,

a solution of nitroalkenes 2 (1.0 mmol) in 1 mL dry DME or THF was

added. The reaction mixture was warmed to 0 ^ꢁC after 10 min and

maintained at this temperature until completion (TLC monitoring).

Anhydrous CuCl₂(336 mg, 2.5 mmol) or CuBr₂(558 mg, 2.5 mmol)

was added at the same temperature in one portion with vigorous

stirring. After 30 min, the reaction was quenched with two drops of

saturated NH₄Cl solution. The inhomogeneous green-brown mix-

ture was diluted with 30 mL diethyl ether or dichloromethane and

ﬁltered through a pad of silica gel. The solution was evaporated in

vacuum and the crude product was puriﬁed by ﬂash column

chromatography (hexane/EtOAc, gradient 10:1 to 2:1). Dichloro-

methane was the preferred solvent for ﬁltration of larger scale re-

actions or those involving a larger excess CuCl₂, since it retained

copper species better on silica.

5.7.2.1. 4(R*)-((R*)-Chlorobenzyl)-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (17Ba). Colorless solid, for yields and ratios, see

Table 5. Its relative conﬁguration is supported by a X-ray crystal

structure analysis, from which the conﬁguration can be derived

unambiguously. The structure is, however, not publishable due to

extensive disorder. For the assignment of the conﬁguration, see

Ref. 32 and the Supplementary material. Mp 117 ^ꢁC; R_f¼0.50, hex-

ane/Et₂O 5:1; ¹H NMR (400 MHz)

d

3.44 (tt, J¼10.9, 7.5 Hz, 1H), 4.55

(dd, J¼10.9, 8.5 Hz, 1H), 4.56 (dd, J¼7.5, 2.5 Hz, 1H), 4.81 (dd, J¼8.5,

7.5 Hz, 1H), 5.14 (d, J¼10.9 Hz, 1H), 5.49 (d, J¼2.5 Hz, 1H), 7.30e7.45

(m, 10H); ¹³C NMR (100 MHz)

d 51.3 (d), 59.5 (d), 73.0 (t), 87.3 (d),

93.5 (d),125.3 (d),127.4 (d),129.0 (d),129.24 (d),129.5 (d),129.8 (d),

138.6 (s), 139.0 (s).

5.7.2.2. 4(R*)-((S*)-Chlorobenzyl)-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (18Ba). Colorless oil as an inseparable mixture

with 17Ba and 19Ba. For the assignment of the conﬁguration, see

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

1533

the Supplementary data. R_f¼0.50, hexane/Et₂O 5:1; ¹H NMR

4.334 (dd, J¼9.4, 8.1 Hz, 1H), 4.84 (dd, J¼7.0, 6.5 Hz, 1H), 5.26 (d,

(400 MHz)

d

3.33 (m, 1H), 3.77 (m, 1H), 4.03 (dd, J¼11.2, 8.6 Hz, 1H),

J¼7.0 Hz,1H), 7.33e7.42 (m, 5H); ¹³C NMR (100 MHz)

d 23.1 (q), 53.3

4.99 (d, J¼11.2 Hz, 1H), 5.28 (dd, J¼6.5, 2.2 Hz, 1H), 5.50 (d, J¼2.2 Hz,

(d), 57.0 (d), 69.5 (t), 84.8 (d), 93.3 (d), 125.82 (d), 128.9 (d), 129.0

(d), 137.24 (s).

1H), 7.26e7.40 (m, 10H); ¹³C NMR (50 MHz)

d

52.6 (d), 58.2 (d), 70.7

(t), 86.3 (d), 94.0 (d), 125.1 (d),126.87 (d), 126.91 (d),128.9 (d),129.0

(d), 129.5 (d), 137.1 (s), 138.8 (s).

5.7.3.4. 4(S*)-(1(S*)-Chloroethyl)-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (20Ca). Colorless oil as a partially separable mix-

ture with 17Cae19Ca. For the assignment of the conﬁguration, see

the Supplementary data. R_f¼0.44, hexane/EtOAc 5:1; ¹H NMR

5.7.2.3. 4(S*)-((S*)-Chlorobenzyl)-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (19Ba). Colorless oil as

a partially separable

mixture with 17Ba and 18Ba. For the assignment of the conﬁgu-

ration, see Ref. 32 and the Supplementary data. R_f¼0.50, hexane/

(400 MHz)

d

1.57 (d, J¼6.7 Hz, 3H), 3.40 (dddd, J¼7.9, 6.7, 5.1, 4.5 Hz,

1H), 4.10 (quint, J¼6.7 Hz,1H), 4.13 (dd, J¼9.6, 4.5 Hz,1H), 4.333 (dd,

J¼9.6, 7.9 Hz, 1H), 5.01 (dd, J¼6.6, 5.1 Hz, 1H), 5.19 (d, J¼6.6 Hz, 1H),

Et₂O 5:1; ¹H NMR (400 MHz)

d

3.79 (ddt, J¼9.6, 7.0, 4.1 Hz, 1H),

4.39 (dd, J¼9.5, 7.0 Hz, 1H), 4.50 (dd, J¼9.5, 4.1 Hz, 1H), 4.51 (m,

1H), 4.85 (d, J¼9.6 Hz, 1H), 5.25 (d, J¼5.8 Hz, 1H), 7.21e7.39 (m,

7.34e7.43 (m, 5H); ¹³C NMR (100 MHz)

d 23.4 (q), 53.6 (d), 57.2 (d),

70.5 (t), 85.6 (d), 93.7 (d), 125.80 (d), 128.9 (d), 129.0 (d), 137.16 (s).

10H); ¹³C NMR (100 MHz)

d 53.8 (d), 62.7 (d), 71.0 (t), 85.2 (d),

93.7 (d), 125.59 (d), 127.3 (d), 128.89 (d), 128.94 (d), 129.2 (d),

129.4 (d), 137.5 (s), 137.9 (s).

5.7.3.5. 4(R*)-(1(S*)-Chloroethyl)-3(R*)-nitro-2(R*)-phenyl-

tetrahydrofuran (21Ca). Colorless liquid as a partially separable

mixture with 17Ca, 18Ca, and 20Ca. It forms from 17Ca during

column chromatography. For the assignment of the conﬁguration,

see Ref. 32 and the Supplementary data. R_f¼0.50, hexane/EtOAc

5.7.2.4. 4(S*)-((R*)-Chlorobenzyl)-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (20Ba). Colorless oil. For the assignment of the

conﬁguration, see the Supplementary data. R_f¼0.35, hexane/Et₂O

5:1; ¹H NMR (400 MHz)

d

1.54 (d, J¼6.8 Hz, 3H), 3.50 (ddt, J¼8.7, 5.1,

5:1; ¹H NMR (400 MHz)

d

3.81 (m, 1H), 3.82 (dd, J¼10.3, 3.3 Hz, 1H),

3.9 Hz,1H), 3.94 (t, J¼8.7 Hz,1H), 4.33 (dq, J¼6.8, 5.1 Hz,1H), 4.54 (t,

J¼8.7 Hz, 1H), 5.16 (d, J¼6.6 Hz, 1H), 5.22 (dd, J¼6.6, 3.9 Hz, 1H),

4.09 (dd, J¼10.3, 7.5 Hz, 1H), 4.76 (d, J¼10.7 Hz, 1H), 5.13 (dd, J¼6.0,

3.7 Hz, 1H), 5.20 (d, J¼6.0 Hz, 1H), 7.36e7.45 (m, 10H); ¹³C NMR

7.25e7.39 (m, 5H); ¹³C NMR (100 MHz)

68.5 (t), 84.3 (d), 93.5 (d), 126.1 (d), 128.4 (d), 128.9 (d), 133.9 (s).

d

¼23.6 (q), 51.7 (d), 56.9 (d),

(100 MHz)

d

54.2 (d), 63.1 (d), 70.5 (t), 86.0 (d), 94.9 (d), 125.7 (d),

127.4 (d), 129.0 (d, 3C), 129.2 (d), 129.37 (d), 137.2 (s), 138.5 (s).

5.7.4. 4-(1-Chloro-1-methylethyl)-3-nitro-2-phenyltetrahydrofurans

(17Da, 19Da). Puriﬁed by ﬂash chromatography hexane/EtOAc,

gradient 10:1 to 5:1. For yields and ratios, see Table 5. The following

analyses were performed on the diastereomeric mixture before

further separation. 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.

5.7.3. 4-(1-Chloroethyl)-3-nitro-2-phenyltetrahydrofurans

(17Cae21Ca). Puriﬁed by ﬂash chromatography hexane/EtOAc,

gradient 10:1 to 5:1. For yields and ratios, see Table 5. The following

analyses were performed on the diastereomeric mixture before

further separation. MS (CI) m/z 292/290 ([MþNH₃þNH₄]^þ, 4/13),

275/273 ([MþNH₄]^þ, 30/100), 239 (43), 238 (30), 226 (23), 222 (70),

209 (20), 206 (30), 191 (14), 188 (35); Anal. Calcd for C₁₂H₁₄ClNO₃

(255.70): C 56.37 H 5.52 N 5.48. Found: C 56.64 H 5.43 N 5.29.

5.7.4.1. 4(R*)-(1-Chloro-1-methylethyl)-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (17Da). Colorless solid. Mp 110 ^ꢁC; R_f¼0.47, hex-

ane/EtOAc 10:1; IR (KBr) 3089, 3064, 3031, 3019, 2995, 2979, 2905,

5.7.3.1. 4(R*)-(1(S*)-Chloroethyl)-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (17Ca). Colorless solid as a partially separable

mixture with 18Cae20Ca. For the assignment of the conﬁguration,

see Ref. 32 and the Supplementary data. Mp 78 ^ꢁC; R_f¼0.58, hexane/

EtOAc 5:1; IR (KBr) 3064, 3035, 3024, 2992, 2925, 2896, 1551, 1478,

1449,1391,1365,1341,1317,1285,1244, 1160, 1094, 1074,1063, 1027,

1548, 1378, 1137, 1103, 1073, 724, 699 cm^ꢀ^{1 1}H NMR (400 MHz)

;

d

1.60 (s, 3H), 1.62 (s, 3H), 2.85 (ddd, J¼11.2, 8.0, 6.2 Hz, 1H), 4.45

(dd, J¼11.2, 8.0 Hz, 1H), 4.49 (t, J¼8.0 Hz, 1H), 4.97 (dd, J¼6.2, 1.3 Hz,

1H), 5.58 (br s, 1H), 7.27e7.39 (m, 5H); ¹³C NMR (100 MHz)

30.3

d

935, 788, 737, 704 cm^ꢀ1

;

¹H NMR (400 MHz)

d

1.56 (d, J¼6.5 Hz,

(q), 32.2 (q), 55.3 (d), 65.7 (s), 69.1 (t), 85.1 (d), 92.2 (d), 125.1 (d),

128.5 (d), 128.91 (d), 139.4 (s).

3H), 2.88 (tt, J¼10.8, 7.3 Hz, 1H), 4.04 (dq, J¼10.8, 6.5 Hz, 1H), 4.29

(dd, J¼10.8, 8.8 Hz, 1H), 4.59 (dd, J¼8.8, 7.3 Hz, 1H), 4.94 (dd, J¼7.3,

2.1 Hz, 1H), 5.57 (d, J¼2.1 Hz, 1H), 7.31e7.45 (m, 5H); ¹³C NMR

5.7.4.2. 4(S*)-(1-Chloro-1-methylethyl)-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (19Da). Colorless oil as a partially separable mix-

ture with 17Da. R_f¼0.47, hexane/EtOAc 10:1; ¹H NMR (200 MHz)

(100 MHz)

d 24.59 (q), 51.7 (d), 53.7 (d), 72.6 (t), 86.2 (d), 93.4 (d),

125.1 (d), 128.7 (d), 129.0 (d), 138.9 (s).

d

1.57 (s, 3H), 1.59 (s, 3H), 3.43 (ddd, J¼8.2, 6.1, 5.3 Hz, 1H), 4.27 (dd,

5.7.3.2. 4(R*)-(1(R*)-Chloroethyl)-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (18Ca). Colorless oil as a partially separable mix-

ture with 17Ca, 19Ca, and 20Ca. For the assignment of the

conﬁguration, see Ref. 32 and the Supplementary data. R_f¼0.50,

J¼9.3, 5.3 Hz, 1H), 4.34 (dd, J¼9.3, 8.2 Hz, 1H), 4.97 (dd, J¼7.1, 6.1 Hz,

1H), 5.16 (d, J¼7.1 Hz, 1H), 7.32e7.38 (m, 5H); ¹³C NMR (50 MHz)

d

30.81 (q), 30.84 (q), 57.7 (d), 69.3 (s), 69.8 (t), 86.0 (d), 93.9 (d),

125.8 (d), 128.87 (d), 129.0 (d), 137.1 (s).

hexane/EtOAc 5:1; ¹H NMR (400 MHz)

d

1.5416 (d, J¼6.6 Hz, 3H),

2.87 (ddt, J¼10.9, 8.2, 6.5 Hz, 1H), 4.148 (dq, J¼10.9, 6.6 Hz, 1H), 4.15

(dd, J¼10.9, 8.2 Hz, 1H), 4.35 (t, J¼8.2 Hz, 1H), 5.16 (dd, J¼6.5, 2.0 Hz,

1H), 5.47 (d, J¼2.0 Hz, 1H), 7.33e7.43 (m, 5H); ¹³C NMR (100 MHz)

5.7.5. 4-(Chloromethyl)-4-methyl-3-nitro-2-phenyltetrahydrofurans

(17Ea,19Ea). Puriﬁed by ﬂash chromatography hexane/Et₂O 20:1,

then hexane/EtOAc 10:1. For yields and ratios, see Table 5. The

following analyses were performed on the diastereomeric mixture

before further separation. IR (neat) 3065, 3033, 2980, 2877, 1547,

1455, 1366, 1085, 1064, 947, 741, 697 cm^ꢀ1; MS (EI) m/z 210/208 (2/

5), 159 (100), 105 (10), 91 (10), 77 (11); Anal. Calcd for C₁₂H₁₄ClNO₃

(255.70): C 56.37 H 5.52 N 5.48. Found: C 56.76 H 5.58 N 5.21.

d

24.6 (q), 52.5 (d), 52.9 (d), 70.4 (t), 85.9 (d), 94.2 (d), 125.0 (d),

128.6 (d), 128.9 (d), 138.8 (s).

5.7.3.3. 4(S*)-(1(R*)-Chloroethyl)-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (19Ca). Colorless oil as partially separable mixture

with 17Ca, 18Ca, and 20Ca. For the assignment of the conﬁguration,

see Ref. 32 and the Supplementary data. R_f¼0.44, hexane/EtOAc

5.7.5.1. 4(R*)-(Chloromethyl)-4-methyl-3(S*)-nitro-2(R*)-phenyl-

5:1; ¹H NMR (400 MHz)

6.5 Hz, 1H), 4.25 (quint, J¼6.5 Hz, 1H), 4.27 (dd, J¼9.4, 6.5 Hz, 1H),

d

¼1.5424 (d, J¼6.5 Hz, 3H), 3.35 (dq, J¼8.1,

tetrahydrofuran (17Ea). Colorless oil. R_f¼0.32, hexane/Et₂O 20:1;

¹H NMR (400 MHz)

d

1.43 (s, 3H), 3.56 (d, J¼11.2 Hz, 1H), 3.64 (d,

1534

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

J¼11.2 Hz, 1H), 3.94 (d, J¼9.1 Hz, 1H), 4.22 (d, J¼9.1 Hz, 1H), 4.71 (d,

J¼6.2 Hz, 1H), 5.55 (d, J¼6.2 Hz, 1H), 7.31e7.41 (m, 5H); ¹³C NMR

5H); ¹³C NMR (100 MHz)

d 21.6 (q), 29.7 (q), 39.5 (t), 55.0 (d), 82.5

(d), 83.9 (s), 95.2 (d), 125.91 (d), 129.1 (d), 129.2 (d), 138.9 (s).

(100 MHz)

d 22.7 (q), 46.7 (t), 49.7 (s), 76.9 (t), 83.9 (d), 99.0 (d),

5.7.8.2. 3(S*)-(Chloromethyl)-2,2-dimethyl-4(S*)-nitro-5(R*)-

phenyltetrahydrofuran (19Fa). Colorless oil as a partially separable

mixture with 17Fa. R_f¼0.29, hexane/EtOAc 10:1; ¹H NMR

125.3 (d), 128.7 (d), 128.9 (d), 138.5 (s).

5.7.5.2. 4(S*)-(Chloromethyl)-4-methyl-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (19Ea). Colorless oil as a partially separable mix-

ture with 2a, 3Ea, and 17Ea. R_f¼0.28, hexane/Et₂O 20:1; ¹H NMR

(400 MHz)

d

1.39 (s, 3H), 1.58 (s, 3H), 3.25 (dt, J¼8.0, 6.9 Hz, 1H),

3.63 (dd, J¼11.5, 8.0 Hz, 1H), 3.73 (dd, J¼11.5, 6.9 Hz, 1H), 4.76 (t,

J¼8.0 Hz, 1H), 5.34 (d, J¼8.0 Hz, 1H), 7.32e7.38 (m, 5H); ¹³C NMR

(400 MHz)

d

1.25 (s, 3H), 3.59 (d, J¼11.3 Hz, 1H), 3.68 (d, J¼11.3 Hz,

(100 MHz)

d 24.3 (q), 29.0 (q), 42.2 (t), 55.5 (d), 81.0 (d), 82.7 (s),

1H), 3.93 (d, J¼9.4 Hz, 1H), 4.23 (d, J¼9.4 Hz, 1H), 4.85 (d, J¼6.9 Hz,

95.0 (d), 125.85 (d), 128.9 (d), 129.0 (d), 137.7 (s).

1H), 5.59 (d, J¼6.9 Hz, 1H), 7.31e7.46 (m, 5H); ¹³C NMR (100 MHz)

d

17.0 (q), 50.0 (s), 50.1 (t), 76.1 (t), 82.9 (d), 95.8 (d), 125.6 (d), 128.8

5.7.9. 3-(1-Chloro-1-methylethyl)-2,2-dimethyl-4-nitro-5-

phenyltetrahydrofurans (17Ga, 19Ga). Puriﬁed by ﬂash chromatog-

raphy hexane/Et₂O 5:1. Yield 72 mg (24%) as a 2:1 mixture of

17Ga and 19Ga. The following analyses were performed on the

diastereomeric mixture before further separation. IR (neat) 3066,

(d), 129.0 (d), 137.9 (s).

5.7.6. 5(S*)-Chloro-5(S*)-methyl-3(S*)-nitro-2(R*)-phenyl-

tetrahydropyran (22Ea). Puriﬁed by ﬂash chromatography hexane/

Et₂O 20:1, then hexane/EtOAc 10:1. Colorless oil, for yields and ra-

tios, see Table 5. R_f¼0.30, hexane/EtOAc 10:1; IR (neat) 3067, 3037,

2975, 2930, 2883, 2848, 1547, 1375, 1271, 1098, 1084, 1019, 759,

699 cm^ꢀ1; MS (EI) m/z 257/255 (M^þ, 0.2/0.5), 210/208 (15/55), 173

(50), 132 (17), 115 (12), 107 (35), 105 (100), 91 (35), 79 (14), 77 (30),

51 (13); Anal. Calcd for C₁₂H₁₄ClNO₃(255.70): C 56.37 H 5.52 N 5.48.

2982, 2938, 2905,1552,1454,1388,1367,1093,1063, 760, 699 cm^ꢀ1

;

MS (EI) m/z 252/250 (1/3),173 (100),157 (32),142 (15),129 (20),128

(10), 115 (15), 105 (24), 91 (14), 77 (20); Anal. Calcd for C₁₅H₂₀ClNO₃

(297.78): C 60.50 H 6.77 N 4.70. Found: C 60.56 H 6.69 N 4.76.

5.7.9.1. 3(R*)-(1-Chloro-1-methylethyl)-2,2-dimethyl-4(S*)-nitro-

5(R*)-phenyltetrahydrofuran (17Ga). Colorless oil as a partially

separable mixture with 19Ga. R_f¼0.50, hexane/Et₂O 5:1; ¹H NMR

Found: C 57.00 H 5.65 N 5.24. ¹H NMR (400 MHz)

d 1.62 (s, 3H), 2.43

(dd, J¼13.5, 11.8 Hz, 1H), 2.71 (ddd, J¼13.5, 4.2, 2.6 Hz, 1H), 3.66 (d,

J¼12.6 Hz, 1H), 4.00 (dd, J¼12.6, 2.6 Hz, 1H), 4.59 (d, J¼9.8 Hz, 1H),

5.02 (ddd, J¼11.8, 9.8, 4.2 Hz, 1H), 7.29e7.36 (m, 5H); ¹³C NMR

(400 MHz)

d 1.65 (s, 3H), 1.73 (s, 3H), 1.74 (s, 3H), 1.81 (s, 3H), 2.66

(d, J¼8.7 Hz, 1H), 5.22 (dd, J¼8.7, 4.0 Hz, 1H), 5.63 (d, J¼4.0 Hz, 1H),

7.32e7.38 (m, 5H); ¹³C NMR (100 MHz)

d

23.8 (q), 32.5 (q), 33.17 (q),

(100 MHz)

d 28.0 (q), 43.7 (t), 65.5 (s), 77.2 (t), 81.1 (d), 85.2 (d),

127.0 (d), 128.8 (d), 129.4 (d), 135.9 (s).

33.22 (q), 64.3 (d), 66.2 (s), 81.4 (d), 85.1 (s), 95.8 (d),125.3 (d),128.5

(d), 128.9 (d), 139.9 (s).

5.7.7. 2-Chloro-1-(methallyloxy)-2-nitro-1-phenylethane

(8Ea). Puriﬁed by ﬂash chromatography hexane/Et₂O 20:1, then

hexane/EtOAc 10:1. Pale yellow oil as a partially separable anti/syn-

mixture of unassigned diastereomers. For yields and ratios, see

Table 5. R_f¼0.44 and 0.35, hexane/Et₂O 20:1; IR (neat) 3068, 3035,

2978, 2935, 2914, 2873, 1570, 1555, 1454, 1353, 1087, 1071, 764,

699 cm^ꢀ1; MS (EI) m/z 257/255 (M^þ, 1/3), 210/208 (25/75), 173 (35),

138/140 (23/66), 135 (13), 132 (22), 128 (12), 115 (14), 107 (63), 105

(100), 103 (19), 91 (50), 79 (18), 77 (35), 55 (17), 51 (11); Anal. Calcd

for C₁₂H₁₄ClNO₃(255.70): C 56.37 H 5.52 N 5.48. Found: C 56.56 H

5.7.9.2. 3(S*)-(1-Chloro-1-methylethyl)-2,2-dimethyl-4(S*)-nitro-

5(R*)-phenyltetrahydrofuran (19Ga). Colorless oil as a partially

separable mixture with 17Ga. R_f¼0.40, hexane/Et₂O 5:1; ¹H NMR

(300 MHz)

d 1.60 (s, 3H), 1.61 (s, 3H), 1.63 (s, 3H), 1.72 (s, 3H), 3.24

(d, J¼7.7 Hz, 1H), 5.16 (t, J¼7.7 Hz, 1H), 5.20 (d, J¼7.7 Hz, 1H),

7.35e7.38 (m, 5H); ¹³C NMR (75 MHz)

d

26.0 (q), 31.1 (q), 31.6 (q),

33.0 (q), 64.1 (d), 68.6 (s), 81.2 (d), 84.3 (s), 95.5 (d), 125.9 (d), 128.8

(d), 128.9 (d), 138.0 (s).

5.74 N 5.37. Diastereomer 1: ¹H NMR (400 MHz)

d 1.63 (s, 3H), 3.66

5.7.10. 4-(Chloromethyl)-2-(4-methoxyphenyl)-3-nitro-

tetrahydrofurans (17Ab, 19Ab, 21Ab). Puriﬁed by ﬂash chromatog-

raphy hexane/Et₂O, gradient 5:1 to 2:1. For yields and ratios,

see Table 5. The following analyses were performed on the

diastereomeric mixture before further separation. IR (neat) 3011,

2960, 2935, 2866, 2839,1612,1552,1510,1467,1377,1308,1249,1221,

1172,1080,1028, 983, 852, 814 cm^ꢀ1; MS (EI) m/z 273/271 (M^þ, 3/10),

175 (100), 135 (40), 121 (10), 77 (18); Anal. Calcd for C₁₂H₁₄ClNO₄

(271.70): C 53.05 H 5.19 N 5.16. Found: C 53.20 H 5.18 N 5.02.

(d, J¼12.2 Hz,1H), 3.89 (d, J¼12.2 Hz,1H), 4.81 (m, 1H), 4.85 (m,1H),

5.06 (d, J¼4.9 Hz, 1H), 5.83 (d, J¼4.9 Hz, 1H), 7.29e7.33 (m, 5H); ¹³C

NMR (100 MHz) d 19.3 (q), 73.4 (t), 80.6 (d), 94.5 (d), 114.2 (t), 127.6

(d), 128.98 (d), 129.6 (d), 134.1 (s), 140.51 (s). Diastereomer 2: ¹H

NMR (400 MHz)

1.55 (s, 3H), 3.60 (d, J¼12.0 Hz, 1H), 3.76 (d,

d

J¼12.0 Hz, 1H), 4.74 (m, 1H), 4.77 (d, J¼9.0 Hz, 1H), 4.81 (m, 1H),

5.73 (d, J¼9.0 Hz, 1H), 7.32e7.35 (m, 5H); ¹³C NMR (100 MHz)

d 19.2

(q), 73.6 (t), 81.8 (d), 91.5 (d), 114.0 (t), 128.3 (d), 128.8 (d), 129.7 (d),

133.7 (s), 140.47 (s).

5.7.10.1. 4(R*)-(Chloromethyl)-2(R*)-(4-methoxyphenyl)-3(S*)-

nitrotetrahydrofuran (17Ab). Colorless oil. R_f¼0.35, hexane/Et₂O

5.7.8. 3-(Chloromethyl)-2,2-dimethyl-4-nitro-5-phenyl-

tetrahydrofurans (17Fa, 19Fa). Puriﬁed by ﬂash chromatography

hexane/EtOAc, gradient 10:1 to 5:1. For yields and ratios, see Table

5. The following analyses were performed on the diastereomeric

mixture before further separation. IR (neat) 3066, 3033, 2977, 2938,

2:1; ¹H NMR (300 MHz)

d

3.10 (dquint, J¼10.3, 7.7 Hz, 1H), 3.55 (dd,

J¼11.3, 7.7 Hz, 1H), 3.66 (dd, J¼11.3, 7.7 Hz, 1H), 3.811 (s, 3H), 4.07

(dd, J¼10.3, 8.7 Hz, 1H), 4.48 (dd, J¼8.7, 7.7 Hz, 1H), 5.02 (dd, J¼7.7,

3.4 Hz, 1H), 5.47 (d, J¼3.4 Hz, 1H), 6.89e6.94 (m, 2H), 7.22e7.27 (m,

2H); ¹³C NMR (75 MHz)

d 39.4 (t), 45.9 (d), 55.4 (q), 71.3 (t), 85.0 (d),

2909, 1550, 1451, 1370, 1316, 1088, 1060, 1027, 919, 732, 697 cm^ꢀ1

;

93.3 (d), 114.3 (d), 126.7 (d), 130.4 (s), 159.9 (s).

MS (EI) m/z 224/222 (4/10),173 (100),129 (28),128 (15),105 (18), 91

(10), 77 (18); Anal. Calcd for C₁₃H₁₆ClNO₃(269.72): C 57.89 H 5.98 N

5.19. Found: C 58.31 H 6.31 N 5.54.

5.7.10.2. 4(S*)-(Chloromethyl)-2(R*)-(4-methoxyphenyl)-3(S*)-

nitrotetrahydrofuran (19Ab). Colorless oil. R_f¼0.32, hexane/Et₂O

2:1; ¹H NMR (300 MHz)

d

3.10 (m, 1H), 3.57 (dd, J¼11.3, 7.1 Hz, 1H),

5.7.8.1. 3(R*)-(Chloromethyl)-2,2-dimethyl-4(S*)-nitro-5(R*)-

3.71 (dd, J¼11.3, 6.8 Hz, 1H), 3.814 (s, 3H), 4.13 (dd, J¼9.5, 3.7 Hz,

1H), 4.31 (dd, J¼9.5, 7.2 Hz, 1H), 4.79 (dd, J¼6.4, 4.5 Hz, 1H), 5.18 (d,

J¼6.4 Hz, 1H), 6.89e6.94 (m, 2H), 7.27e7.31 (m, 2H); ¹³C NMR

phenyltetrahydrofuran (17Fa). Colorless oil. R_f¼0.44, hexane/EtOAc

10:1; ¹H NMR (400 MHz)

8.9, 6.9 Hz, 1H), 3.55 (dd, J¼11.5, 6.9 Hz, 1H), 3.73 (dd, J¼11.5, 8.9 Hz,

1H), 5.11 (dd, J¼9.8, 5.8 Hz, 1H), 5.47 (d, J¼5.8 Hz,1H), 7.32e7.41 (m,

d

1.47 (s, 3H),1.55 (s, 3H), 2.83 (ddd, J¼9.8,

(75 MHz)

d 44.1 (t), 48.0 (d), 55.3 (q), 70.6 (t), 77.2 (d), 93.5 (d),114.3

(d), 126.7 (d), 130.4 (s), 159.9 (s).

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

1535

5.7.10.3. 4(R*)-(Chloromethyl)-2(R*)-(4-methoxyphenyl)-3(R*)-

¹H NMR (400 MHz)

d

0.98 (t, J¼7.4 Hz, 3H), 1.65e1.79 (m, 2H), 3.70

nitrotetrahydrofuran (21Ab). Colorless solid. Mp 89 ^ꢁC; R_f¼0.29,

(ddt, J¼9.6, 6.9, 4.3 Hz, 1H), 4.07 (m, 1H), 4.18 (dd, J¼9.6, 6.9 Hz, 1H),

hexane/Et₂O 2:1; ¹H NMR (300 MHz)

d 3.57e3.65 (m, 2H),

4.25 (dd, J¼6.3, 4.3 Hz, 1H), 4.27 (dd, J¼9.6, 4.3 Hz, 1H), 4.86 (d,

3.69e3.81 (m, 2H), 3.77 (s, 3H), 4.58 (m, 1H), 5.15 (d, J¼6.4 Hz, 1H),

J¼9.6 Hz, 1H), 7.33e7.39 (m, 5H); ¹³C NMR (100 MHz)

d 9.53 (q),

5.21 (dd, J¼6.4, 3.1 Hz, 1H), 6.83e6.88 (m, 2H), 7.21e7.26 (m, 2H);

26.5 (t), 53.5 (d), 62.9 (d), 70.2 (t), 85.6 (d), 91.2 (d), 127.3 (d), 129.26

(d), 129.39 (d), 139.0 (s).

¹³C NMR (75 MHz)

d 43.1 (t), 46.3 (d), 55.2 (q), 70.2 (t), 83.8 (d), 92.9

(d), 113.9 (d), 125.8 (s), 127.3 (d), 160.0 (s).

5.7.12.4. 4(S*)-((R*)-Chlorobenzyl)-2(R*)-ethyl-3(S*)-nitro-

tetrahydrofuran (20Bc). Colorless oil as an inseparable mixture

with 17Bc and 18Bc. R_f¼0.38, hexane/EtOAc 10:1; ¹H NMR

5.7.11. 4-(Chloromethyl)-2-ethyl-3-nitrotetrahydrofurans

(17Ac,

21Ac). Puriﬁed by ﬂash chromatography hexane/Et₂O 5:1. Yield

118 mg (61%) as a 5.9:1 mixture of 17Ac and 21Ac. The following

analyses were performed on the diastereomeric mixture before

further separation. IR (neat) 2969, 2938, 2880, 1548, 1463, 1361,

1113, 1086, 1052, 936, 732 cm^ꢀ1; MS (CI) m/z 213/211 ([MþNH₄]^þ,

11/38), 197 (30), 195 (28), 177 (21), 166/164 (4/16), 161 (100), 144

(30), 128 (10), 126 (50); Anal. Calcd for C₇H₁₂ClNO₃(193.63): C

43.42 H 6.25 N 7.23. Found: C 43.83 H 6.36 N 6.97.

(400 MHz)

d

1.05 (t, J¼7.4 Hz, 3H), 1.82e1.94 (m, 2H), 3.60 (dd,

J¼9.8, 3.5 Hz, 1H), 3.68 (ddt, J¼10.8, 7.0, 3.5 Hz, 1H), 3.89 (dd, J¼9.8,

7.0 Hz, 1H), 4.05 (m, 1H), 4.74 (d, J¼10.8 Hz, 1H), 4.87 (dd, J¼6.3,

3.5 Hz,1H), 7.35e7.41 (m, 5H); ¹³C NMR (100 MHz)

d 9.6 (q), 26.8 (t),

54.0 (d), 63.4 (d), 70.0 (t), 86.2 (d), 92.6 (d), 127.4 (d), 129.1 (d),

129.29 (d), 138.1 (s).

5.7.13. 4-(Chlorobenzyl)-2-isopropyl-3-nitrotetrahydrofurans

(17Bde20Bd). Puriﬁed by ﬂash chromatography hexane/Et₂O 10:1.

Yield 156 mg (55%) as a 4.1:1.6:2.6:1 mixture of 17Bd/18Bd/19Bd/

20Bd. The following analyses were performed on the di-

astereomeric mixture before further separation. IR (neat) 3034,

2964, 2936, 2877, 1551, 1469, 1456, 1370, 1353, 1254, 1089, 1062,

953, 797, 765, 699 cm^ꢀ1; MS (EI) m/z 157 (8), 129 (18), 128 (10), 125

(20), 115 (13), 111 (100), 105 (68), 91 (30), 71 (12), 69 (70); Anal.

Calcd for C₁₄H₁₈ClNO₃(283.75): C 59.26 H 6.39 N 4.94. Found: C

59.26 H 6.39 N 4.71.

5.7.11.1. 4(R*)-(Chloromethyl)-2(R*)-ethyl-3(S*)-nitro-

tetrahydrofuran (17Ac). Colorless oil. R_f¼0.35, hexane/Et₂O 5:1; ¹H

NMR (400 MHz)

d

0.96 (t, J¼7.5 Hz, 3H), 1.64 (m, 2H), 2.95 (dquint,

J¼10.4, 7.7 Hz, 1H), 3.48 (dd, J¼11.3, 7.7 Hz, 1H), 3.59 (dd, J¼11.3,

7.7 Hz, 1H), 3.85 (dd, J¼10.4, 8.7 Hz, 1H), 4.18 (dd, J¼8.7, 7.7 Hz, 1H),

4.32 (dt, J¼6.6, 3.6 Hz, 1H), 4.85 (dd, J¼7.7, 3.6 Hz, 1H); ¹³C NMR

(100MHz)d 9.4 (q), 27.4(t), 39.3 (t), 46.5(d), 70.5(t),85.4(d), 90.7 (d).

5.7.11.2. 4(R*)-(Chloromethyl)-2(R*)-ethyl-3(R*)-nitro-

tetrahydrofuran (21Ac). Colorless oil as a partially separable mix-

5.7.13.1. 4(R*)-((R*)-Chlorobenzyl)-2(R*)-isopropyl-3(S*)-nitro-

tetrahydrofuran (17Bd). Colorless oil as an inseparable mixture

with 18Bde20Bd. R_f¼0.39, hexane/Et₂O 10:1; ¹H NMR (400 MHz)

ture with 17Ac. R_f¼0.27, hexane/Et₂O 5:1; ¹H NMR (400 MHz)

d 1.01

(t, J¼7.4 Hz, 3H), 1.51 (m, 2H), 3.44 (m, 1H), 3.53 (dd, J¼11.4, 6.8 Hz,

1H), 3.58 (dd, J¼9.1, 7.1 Hz, 1H), 3.67 (dd, J¼11.4, 5.5 Hz, 1H), 3.92

(dt, J¼7.7, 5.8 Hz, 1H), 4.36 (dd, J¼9.1, 8.2 Hz, 1H), 5.01 (dd, J¼5.8,

d

0.88 (d, J¼6.8 Hz, 3H), 0.95 (d, J¼6.8 Hz, 3H), 1.81 (oct, J¼6.8 Hz,

1H), 3.22 (tt, J¼11.1, 7.3 Hz,1H), 4.05 (dd, J¼6.8, 3.4 Hz,1H), 4.25 (dd,

J¼11.0, 8.7 Hz, 1H), 4.37 (dd, J¼7.3, 3.4 Hz, 1H), 4.49 (dd, J¼8.7,

7.3 Hz, 1H), 5.00 (d, J¼11.0 Hz, 1H), 7.31e7.35 (m, 2H), 7.36e7.40 (m,

2.9 Hz, 1H); ¹³C NMR (100 MHz)

69.8 (t), 83.3 (d), 91.3 (d).

d 10.6 (q), 22.7 (t), 43.3 (t), 46.6 (d),

3H); ¹³C NMR (100 MHz)

d 17.8 (q), 17.96 (q), 32.31 (d), 52.4 (d), 59.0

5.7.12. 4-(Chlorobenzyl)-2-ethyl-3-nitrotetrahydrofurans

(17Bce20Bc). Puriﬁed by ﬂash chromatography hexane/EtOAc,

gradient 10:1 to 5:1. Yield 189 mg (70%) as a 8.6:2.5:2:1 mixture of

17Bc/18Bc/19Bc/20Bc. The following analyses were performed on

the diastereomeric mixture before further separation. IR (neat)

3066, 3034, 2970, 2938, 2880, 1550, 1457, 1357, 1253, 1118, 1092,

1056, 938, 701 cm^ꢀ1; MS (CI) m/z 306/304 ([MþNH₃þNH₄]^þ, 3/9),

289/287 ([MþNH₄]^þ, 18/60), 253 (65), 251 (45), 234 (100), 222 (28),

220 (26), 139 (10); Anal. Calcd for C₁₃H₁₆ClNO₃(269.72): C 57.89 H

5.98 N 5.19. Found: C 57.87 H 6.06 N 5.12.

(d), 72.1 (t), 89.3 (d), 91.5 (d), 127.1 (d), 129.2 (d), 129.5 (d), 138.4 (s).

5.7.13.2. 4(R*)-((S*)-Chlorobenzyl)-2(R*)-isopropyl-3(S*)-nitro-

tetrahydrofuran (18Bd). Colorless oil as an inseparable mixture

with 17Bd, 19Bd, and 20Bd. R_f¼0.41, hexane/Et₂O 10:1; ¹H NMR

(400 MHz)

d

0.94 (d, J¼6.8 Hz, 3H), 1.00 (d, J¼6.8 Hz, 3H), 1.89 (m,

1H), 3.12e3.26 (m, 1H), 3.47 (dd, J¼8.6, 7.3 Hz, 1H), 3.82 (dd, J¼11.4,

8.6 Hz, 1H), 4.09 (dd, J¼7.0, 3.3 Hz, 1H), 4.93 (d, J¼11.3 Hz, 1H), 5.13

(dd, J¼7.1, 3.3 Hz, 1H), 7.36e7.40 (m, 5H); ¹³C NMR (100 MHz)

d

17.91 (q), 17.95 (q), 32.35 (d), 54.3 (d), 58.2 (d), 70.1 (t), 90.0 (d),

90.9 (d), 126.8 (d), 129.1 (d), 129.3 (d), 139.0 (s).

5.7.12.1. 4(R*)-((R*)-Chlorobenzyl)-2(R*)-ethyl-3(S*)-nitro-

tetrahydrofuran (17Bc). Colorless oil. R_f¼0.44, hexane/EtOAc 10:1;

5.7.13.3. 4(S*)-((S*)-Chlorobenzyl)-2(R*)-isopropyl-3(S*)-nitro-

tetrahydrofuran (19Bd). Colorless oil as an inseparable mixture

¹H NMR (400 MHz)

d

0.93 (t, J¼7.5 Hz, 3H), 1.58 (m, 1H), 1.68 (m,

with 18Bd. R_f¼0.39, hexane/Et₂O 10:1; ¹H NMR (400 MHz)

d 0.95

1H), 3.30 (tt, J¼11.1, 7.3 Hz,1H), 4.25 (m, 1H), 4.26 (dd, J¼11.1, 8.7 Hz,

1H), 4.32 (dd, J¼7.3, 3.2 Hz, 1H), 4.49 (dd, J¼8.7, 7.3 Hz, 1H), 5.03 (d,

(d, J¼6.5 Hz, 3H), 0.97 (d, J¼6.5 Hz, 3H), 1.90 (oct, J¼6.5 Hz,1H), 3.62

(tdd, J¼9.9, 6.6, 3.9 Hz, 1H), 3.94 (t, J¼6.5 Hz, 1H), 4.18 (dd, J¼9.6,

6.6 Hz, 1H), 4.28 (dd, J¼9.6, 3.9 Hz, 1H), 4.32 (dd, J¼6.5, 3.9 Hz, 1H),

4.82 (d, J¼9.9 Hz, 1H), 7.31e7.35 (m, 2H), 7.36e7.40 (m, 3H); ¹³C

J¼11.1 Hz, 1H), 7.31e7.40 (m, 5H); ¹³C NMR (100 MHz)

d 9.4 (q), 28.0

(t), 51.9 (d), 59.1 (d), 72.1 (t), 87.5 (d), 90.7 (d), 127.1 (d), 129.2 (d),

129.5 (d), 138.4 (s).

NMR (100 MHz) d 17.8 (q), 18.25 (q), 31.3 (d), 54.3 (d), 62.5 (d), 70.3

5.7.12.2. 4(R*)-((S*)-Chlorobenzyl)-2(R*)-ethyl-3(S*)-nitro-

tetrahydrofuran (18Bc). Colorless oil as an inseparable mixture with

17Bc and 20Bc. R_f¼0.38, hexane/EtOAc 10:1; ¹H NMR (400 MHz)

(t), 89.5 (d), 89.7 (d), 127.3 (d), 129.3 (d), 129.41 (d), 138.1 (s).

5.7.13.4. 4(S*)-((R*)-Chlorobenzyl)-2(R*)-isopropyl-3(S*)-nitro-

tetrahydrofuran (20Bd). Colorless oil as an inseparable mixture

with 17Bde19Bd. R_f¼0.39, hexane/Et₂O 10:1; ¹H NMR (400 MHz)

d

1.02 (t, J¼7.4 Hz, 3H),1.64e1.80 (m, 2H), 3.26 (tt, J¼11.3, 7.2 Hz,1H),

3.49 (dd, J¼8.7, 7.2 Hz,1H), 3.81 (dd, J¼11.3, 8.7 Hz,1H), 4.30 (m,1H),

4.94 (d, J¼11.3 Hz, 1H), 5.08 (dd, J¼7.2, 2.9 Hz, 1H), 7.35e7.40 (m,

d

1.04 (d, J¼6.5 Hz, 3H), 1.05 (d, J¼6.5 Hz, 3H), 2.01 (oct, J¼6.5 Hz,

5H); ¹³C NMR (100 MHz)

d 9.54 (q), 28.1 (t), 53.7 (d), 58.2 (d), 70.1 (t),

1H), 3.53e3.60 (m, 2H), 3.89 (dd, J¼10.0, 6.8 Hz, 1H), 3.93 (t,

J¼6.5 Hz, 1H), 4.70 (d, J¼11.1 Hz, 1H), 5.00 (dd, J¼6.5, 3.3 Hz, 1H),

86.9 (d), 91.4 (d), 126.9 (d), 129.1 (d), 129.387 (d), 139.0 (s).

7.35e7.40 (m, 5H); ¹³C NMR (100 MHz)

d 17.9 (q), 18.27 (q), 31.5 (d),

54.9 (d), 63.0 (d), 69.9 (t), 90.0 (d), 91.5 (d), 127.5 (d), 129.1 (d),

129.37 (d), 138.7 (s).

5.7.12.3. 4(S*)-((S*)-Chlorobenzyl)-2(R*)-ethyl-3(S*)-nitro-

tetrahydrofuran (19Bc). Colorless oil. R_f¼0.45, hexane/EtOAc 10:1;

1536

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

5.7.14. 4-(1-Chloroethyl)-2-ethyl-3-nitrotetrahydrofurans

(17Cce20Cc). Puriﬁed by ﬂash chromatography hexane/EtOAc,

gradient 10:1 to 5:1. Yield 121 mg (58%) as a 11:1.6:1.9:1 mixture

of 17Cc/18Cc/19Cc/20Cc. The following analyses were performed

on the diastereomeric mixture before further separation. IR (neat)

2971, 2936, 2880, 1549, 1460, 1384, 1357, 1283, 1243, 1087, 1071,

1052, 939, 907, 781, 683 cm^ꢀ1; MS (CI) m/z 227/225 ([MþNH₄]^þ,

2/7), 213/211 (5/15), 191 (23), 178 (37), 175 (100), 160 (33), 158

(90), 142 (13), 140 (45), 114 (11), 69 (12); Anal. Calcd for

C₈H₁₄ClNO₃(207.65): C 46.27 H 6.80 N 6.75. Found: C 46.25 H 6.86

N 6.34.

5.7.15.2. 4(S*)-(1-Chloro-1-methylethyl)-2(R*)-ethyl-3(S*)-nitro-

tetrahydrofuran (19Dc). Colorless oil. This compound could not be

puriﬁed to homogeneity. R_f¼0.35, hexane/EtOAc 10:1; ¹H NMR

(400 MHz)

d

0.98 (t, J¼7.4 Hz, 3H), 1.51 (s, 3H), 1.56 (s, 3H), 1.73 (m,

2H), 3.29 (dt, J¼8.4, 5.9 Hz, 1H), 3.97 (dd, J¼9.4, 5.9 Hz, 1H), 4.05 (m,

1H), 4.13 (m,1H), 4.73 (t, J¼5.9 Hz,1H); ¹³C NMR (100 MHz)

d 9.5 (q),

25.8 (t), 30.8 (q), 31.2 (q), 57.4 (d), 68.9 (t), 69.3 (s), 85.9 (d), 91.4 (d).

5.7.16. 4-(1-Chloro-1-methylethyl)-2-isopropyl-3-nitro-

tetrahydrofurans (17Dd, 19Dd). Puriﬁed by ﬂash chromatography

hexane/Et₂O 5:1. For yields and ratios, see Table 5. The following

analyses were performed on the diastereomeric mixture before

further separation. IR (neat) 3039, 2985, 2959, 2901, 1551, 1467,

1377, 1223, 1131, 1103, 1053, 1024, 901, 781 cm^ꢀ1; MS (EI) m/z 194/

192 (1/3), 148/146 (3/8), 111 (100), 71 (14), 69 (62), 68 (18), 55 (10);

Anal. Calcd for C₁₀H₁₈ClNO₃(235.71): C 50.96 H 7.70 N 5.94. Found:

C 51.05 H 7.70 N 6.11.

5.7.14.1. 4(R*)-(1(S*)-Chloroethyl)-2(R*)-ethyl-3(S*)-nitro-

tetrahydrofuran (17Cc). Colorless oil as a partially separable mix-

ture with 18Cce20Cc. R_f¼0.34, hexane/EtOAc 10:1; ¹H NMR

(400 MHz)

d

1.00 (t, J¼7.5 Hz, 3H), 1.60 (d, J¼6.5 Hz, 3H), 1.62e1.71

(m, 2H), 2.77 (tt, J¼10.8, 7.3 Hz, 1H), 4.01 (dq, J¼10.8, 6.5 Hz, 1H),

4.08 (dd, J¼10.8, 8.8 Hz, 1H), 4.32 (dd, J¼8.8, 7.3 Hz, 1H), 4.37 (m,

1H), 4.77 (dd, J¼7.3, 2.8 Hz, 1H); ¹³C NMR (100 MHz)

d 9.6 (q), 24.7

5.7.16.1. 4(R*)-(1-Chloro-1-methylethyl)-2(R*)-isopropyl-3(S*)-

nitrotetrahydrofuran (17Dd). Colorless solid. Mp 57 ^ꢁC; R_f¼0.53,

(q), 28.00 (t), 52.9 (d), 53.6 (d), 71.9 (t), 86.8 (d), 90.9 (d).

hexane/Et₂O 5:1; ¹H NMR (400 MHz)

d

0.94 (d, J¼7.0 Hz, 3H), 0.99

(d, J¼7.0 Hz, 3H), 1.64 (s, 3H), 1.68 (s, 3H), 1.77 (oct, J¼7.0 Hz, 1H),

2.75 (dt, J¼11.4, 7.1 Hz, 1H), 4.214 (dd, J¼8.4, 7.1 Hz, 1H), 4.216 (dd,

J¼7.0, 2.2 Hz, 1H), 4.26 (dd, J¼11.4, 8.4 Hz, 1H), 4.91 (dd, J¼7.1,

5.7.14.2. 4(R*)-(1(R*)-Chloroethyl)-2(R*)-ethyl-3(S*)-nitro-

tetrahydrofuran (18Cc). Colorless oil as a partially separable mix-

ture with 17Cc, 19Cc, and 20Cc. R_f¼0.44, hexane/EtOAc 10:1; ¹H

2.2 Hz, 1H); ¹³C NMR (100 MHz)

d 17.8 (q), 18.0 (q), 30.4 (q), 31.4 (q),

NMR (400 MHz)

d

0.96 (m, 3H), 1.49 (d, J¼6.4 Hz, 3H), 1.59e1.69 (m,

32.1 (d), 57.3 (d), 65.7 (s), 68.0 (t), 88.1 (d), 89.6 (d).

2H), 2.76 (m, 1H), 3.89 (dd, J¼11.2, 8.3 Hz, 1H), 4.04 (m, 1H), 4.05 (t,

J¼8.0 Hz, 1H), 4.23 (dt, J¼6.8, 2.8 Hz, 1H), 4.92 (dd, J¼7.0, 2.8 Hz,

5.7.16.2. 4(S*)-(1-Chloro-1-methylethyl)-2(R*)-isopropyl-3(S*)-

nitrotetrahydrofuran (19Dd). Colorless oil as a partially separable

mixture with 17Dd. R_f¼0.62, hexane/Et₂O 5:1; ¹H NMR (400 MHz)

1H); ¹³C NMR (100 MHz)

d 9.5 (q), 24.5 (q), 27.98 (t), 52.6 (d), 54.0

(d), 69.7 (t), 86.5 (d), 91.5 (d).

d

1.00 (d, J¼7.0 Hz, 3H),1.01 (d, J¼7.0 Hz, 3H),1.56 (s, 3H),1.60 (s, 3H),

5.7.14.3. 4(S*)-(1(R*)-Chloroethyl)-2(R*)-ethyl-3(S*)-nitro-

tetrahydrofuran (19Cc). Colorless oil as a partially separable mix-

ture with 17Cc, 18Cc, and 20Cc. R_f¼0.34, hexane/EtOAc 10:1; ¹H

1.97 (oct, J¼7.0 Hz, 1H), 3.27 (dt, J¼8.4, 6.1 Hz, 1H), 3.92 (dd, J¼7.0,

6.1 Hz, 1H), 3.99 (dd, J¼9.2, 6.1 Hz, 1H), 4.17 (dd, J¼9.2, 8.4 Hz, 1H),

4.90 (t, J¼6.1 Hz, 1H); ¹³C NMR (100 MHz)

d 18.0 (q), 18.3 (q), 30.8

NMR (400 MHz)

d

0.964 (m, 3H), 1.52 (d, J¼6.7 Hz, 3H), 1.70e1.80

(q), 31.0 (q), 31.2 (d), 58.3 (d), 69.0 (t), 69.3 (s), 90.0 (d), 90.2 (d).

(m, 2H), 3.22 (m, 1H), 3.94 (m, 1H), 4.03 (m, 1H), 4.04 (m, 1H), 4.11

(m, 1H), 4.71e4.75 (m, 1H); ¹³C NMR (100 MHz)

d

9.5 (q), 23.4 (q),

5.7.17. 3-(1-Chloro-1-methylethyl)-4-nitro-1-oxaspiro[4.5]decanes

(17De, 19De). Puriﬁed by ﬂash chromatography hexane/EtOAc,

gradient 10:1 to 5:1. Yield 89 mg (34%) as a 2.5:1 mixture of

17De and 19De. The following analyses were performed on the

diastereomeric mixture before further separation. IR (neat) 2992,

2970, 2933, 2897, 2857, 1551, 1360, 1131, 1045, 829, 776 cm^ꢀ1; UV

(CHCl₃, 0.111ꢂ10^ꢀ3M) l_max239, 232 nm; MS (EI) m/z 217/215 (10/

36), 179 (35), 177 (10), 161 (34), 149 (45), 145 (11), 139 (17), 137 (20),

123 (19), 121 (20), 109 (21), 107 (23), 105 (14), 103 (15), 99 (25), 97

(75), 95 (77), 93 (38), 91 (20), 85 (10), 83 (35), 81 (70), 79 (39), 77

(30), 69 (100), 67 (45), 57 (12), 55 (55), 53 (18); MS (ESI) 286/284

([MþNa^þ], 35/100); HRMS (ESI) calcd for C₁₂H₂₀³⁵ClNNaO₃

284.1029, found 284.1026; Anal. Calcd for C₁₂H₂₀ClNO₃(261.74): C

55.06 H 7.70 N 5.35. Found: C 55.45 H 7.79 N 5.37.

26.2 (t), 51.9 (d), 57.0 (d), 68.1 (t), 83.6 (d), 92.0 (d).

5.7.14.4. 4(S*)-(1(S*)-Chloroethyl)-2(R*)-ethyl-3(S*)-nitro-

tetrahydrofuran (20Cc). Colorless oil as a partially separable mix-

ture with 17Cce19Cc. R_f¼0.34, hexane/EtOAc 10:1; ¹H NMR

(400 MHz)

d

0.96 (m, 3H), 1.49 (d, J¼6.4 Hz, 3H), 1.70e1.80 (m,

2H), 3.36 (m, 1H), 3.73 (t, J¼8.6 Hz, 1H), 3.90 (m, 1H), 4.28 (m, 1H),

4.30 (m, 1H), 4.98 (dd, J¼6.1, 3.6 Hz, 1H); ¹³C NMR (100 MHz)

d

10.5 (q), 23.5 (q), 26.0 (t), 53.4 (d), 57.2 (d), 68.6 (t), 85.6 (d),

91.3 (d).

5.7.15. 4-(1-Chloro-1-methylethyl)-2-ethyl-3-nitrotetrahydrofurans

(17Dc, 19Dc). Puriﬁed by ﬂash chromatography hexane/EtOAc,

gradient 10:1 to 5:1. Yield 121 mg (50%) as a 1.7:1 mixture of

17Dc and 19Dc. The following analyses were performed on the

diastereomeric mixture before further separation. IR (neat) 2972,

2935, 2897, 1552, 1461, 1375, 1365, 1219, 1131, 1101, 1057, 1030, 887,

779 cm^ꢀ1; MS (CI) m/z 239 ([MþNH₄]^þ, 1), 203 (13), 189 (8), 156

(19), 139 (100), 137 (45); Anal. Calcd for C₉H₁₆ClNO₃(221.68): C

48.76 H 7.27 N 6.32. Found: C 48.81 H 7.27 N 6.09.

5.7.17.1. 3(R*)-(1-Chloro-1-methylethyl)-4(S*)-nitro-1-oxaspiro

[4.5]decane (17De). Colorless solid. Mp 91 ^ꢁC; R_f¼0.44, hexane/

EtOAc 10:1; ¹H NMR (400 MHz)

d 1.34e1.80 (m, 10H), 1.61 (s, 3H),

1.65 (s, 3H), 3.28 (ddd, J¼11.3, 8.4, 5.4 Hz, 1H), 4.19 (t, J¼8.4 Hz, 1H),

4.38 (dd, J¼11.3, 8.4 Hz, 1H), 4.95 (d, J¼5.4 Hz, 1H); ¹³C NMR

(100 MHz) d 22.9 (t), 23.0 (t), 25.2 (t), 30.9 (q), 31.4 (q), 32.3 (t), 37.8

(t), 56.0 (d), 66.9 (s), 67.3 (t), 85.5 (s), 92.6 (d).

5.7.15.1. 4(R*)-(1-Chloro-1-methylethyl)-2(R*)-ethyl-3(S*)-nitro-

tetrahydrofuran (17Dc). Colorless solid. Mp 53 ^ꢁC; R_f¼0.30, hexane/

5.7.17.2. 3(S*)-(1-Chloro-1-methylethyl)-4(S*)-nitro-1-oxaspiro

EtOAc 10:1; ¹H NMR (400 MHz)

d

0.95 (t, J¼7.2 Hz, 3H), 1.49 (sext,

[4.5]decane (19De). Colorless oil. R_f¼0.62, hexane/EtOAc 10:1; ¹H

J¼7.2 Hz, 1H), 1.59 (m, 1H), 1.61 (s, 3H), 1.64 (s, 3H), 2.80 (dt, J¼11.2,

6.9 Hz, 1H), 4.20 (dd, J¼8.3, 6.9 Hz, 1H), 4.24 (dd, J¼11.2, 8.3 Hz, 1H),

4.39 (dt, J¼7.2, 1.5 Hz, 1H), 4.81 (dd, J¼6.9, 1.5 Hz, 1H); ¹³C NMR

NMR (400 MHz)

d 1.18e1.35 (m, 2H), 1.54 (s, 3H), 1.56 (s, 3H),

1.57e1.77 (m, 7H), 1.90e1.99 (m, 1H), 3.46 (dt, J¼8.6, 6.9 Hz, 1H),

3.85 (dd, J¼9.1, 8.6 Hz, 1H), 4.18 (t, J¼8.6 Hz, 1H), 4.82 (d, J¼6.9 Hz,

1H); ¹³C NMR (100 MHz)

d 21.8 (t), 22.1 (t), 25.0 (t), 30.6 (t), 34.5 (t),

(100 MHz)

d 9.8 (q), 28.5 (t), 30.6 (q), 31.8 (q), 56.8 (d), 65.9 (s), 68.3

(t), 85.7 (d), 89.7 (d).

31.3 (q), 31.7 (q), 56.2 (d), 66.1 (s), 69.0 (t), 84.6 (s), 96.1 (d).

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

1537

5.8. SET-oxidation/radical 5-exo cyclization of 3Aa

d

70.5 (t), 80.9 (d), 83.9 (d), 118.6 (t), 127.6 (d), 129.0 (d), 129.7 (d),

133.1 (d), 134.5 (s). Diastereomer 2: ¹H NMR (400 MHz)

d

3.79 (ddt,

At ꢀ78 ^ꢁC under N₂, n-BuLi (0.246 mL, 0.394 mmol, 1.6 M so-

lution in hexane) was added via syringe to a stirred solution of 3Aa

(68 mg, 0.328 mmol) in 4 mL dry DME or THF. After 15 min the

reaction mixture was warmed to 0 ^ꢁC and anhydrous CuCl₂(119 mg,

0.89 mmol) was added at the same temperature in one portion with

vigorous stirring. After 30 min, the reaction was quenched with one

drop of saturated NH₄Cl solution. The inhomogeneous mixture was

diluted with 10 mL diethyl ether and ﬁltered through a pad of silica

gel. The solution was evaporated in vacuum and the crude product

was puriﬁed by ﬂash column chromatography (hexane/EtOAc,

gradient 10:1 to 2:1). Yield 81% as a single diastereomer.

J¼12.6, 6.5, 1.3 Hz, 1H), 3.96 (ddt, J¼12.6, 5.1, 1.5 Hz, 1H), 4.96 (d,

J¼9.5 Hz, 1H), 5.17 (dq, J¼14.2, 1.5 Hz, 1H), 5.18 (dq, J¼10.8, 1.3 Hz,

1H), 5.75 (dddd, J¼14.2, 10.8, 6.5, 5.1 Hz, 1H), 5.88 (d, J¼9.5 Hz, 1H),

7.40e7.42 (m, 5H); ¹³C NMR (100 MHz)

d 70.7 (t), 80.1 (d), 82.0 (d),

118.4 (t), 128.4 (d), 128.8 (d), 129.8 (d), 133.0 (d), 134.0 (s).

5.11. 4-(1-Bromo-1-methylethyl)-3-nitro-2-

phenyltetrahydrofurans (23Da, 24Da)

Puriﬁed by ﬂash chromatography hexane/Et₂O 5:1. For yields

and ratios, see Table 6. The following analyses were performed on

the diastereomeric mixture before further separation. IR (neat)

3064, 3031, 2992, 2975, 2902, 1545, 1487, 1376, 1299, 1218, 1129,

1101, 1071, 1057, 934, 732, 698 cm^ꢀ1; MS (EI) m/z 315/313 (M^þ, 1/1),

268/266 (4/4), 187 (8), 186 (10), 146 (62), 145 (100), 128 (30), 117

(50), 115 (26), 107 (18), 105 (64), 91 (35), 79 (16), 77 (39), 69 (15), 51

(10); Anal. Calcd for C₁₃H₁₆BrNO₃(314.18): C 49.70 H 5.13 N 4.46.

Found: C 49.85 H 5.11 N 4.32.

5.9. Epimerization of 17Aa by lithium allyloxide

To 1A (19.2 mg, 0.33 mmol) in 3 mL anhydrous THF was added n-

BuLi (0.21 mL, 0.33 mmol, 1.6 M solution in hexane) via syringe at

ꢀ78 ^ꢁC. The mixture was stirred for 15 min and warmed to 0 ^ꢁC.

Diastereomerically pure 17Aa (76 mg, 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 resulting oil (70 mg) consisted of

a 1:2.5 mixture of 17Aa/21Aa.

5.11.1. 4(R*)-(1-Bromo-1-methylethyl)-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (23Da). Colorless solid. Mp 103 ^ꢁC; R_f¼0.41, hex-

ane/Et₂O 5:1; ¹H NMR (400 MHz)

d 1.80 (s, 3H), 1.87 (s, 3H), 2.99

(ddd, J¼11.5, 7.7, 6.1 Hz, 1H), 4.50 (dd, J¼11.5, 8.3 Hz, 1H), 4.58 (dd,

J¼8.3, 7.7 Hz, 1H), 5.02 (dd, J¼6.1, 1.3 Hz, 1H), 5.63 (s, 1H), 7.30e7.44

5.10. 4-(Bromomethyl)-3-nitro-2-phenyltetrahydrofurans

(23Aa, 25Aa)

(m, 5H); ¹³C NMR (100 MHz)

d¼31.6 (q), 33.4 (q), 56.3 (d), 59.8 (s),

69.8 (t), 85.3 (d), 92.4 (d), 125.1 (d), 128.6 (d), 129.0 (d), 139.3 (s).

Puriﬁed by ﬂash chromatography hexane/EtOAc, gradient 10:1

to 5:1. For yields and ratios, see Table 6. The following analyses were

performed on the diastereomeric mixture before further separation.

IR (neat) 3064, 3031, 2969, 2948, 2885, 1547, 1451, 1361, 1295, 1229,

1114, 1089, 1067, 933, 737, 698 cm^ꢀ1; MS (EI) m/z 240/238 (4/5), 145

(100),117 (15),105 (18), 91 (12), 77 (19); Anal. Calcd for C₁₁H₁₂BrNO₃

(286.12): C 46.18 H 4.23 N 4.90. Found: C 46.36 H 4.12 N 4.80.

5.11.2. 4(S*)-(1-Bromo-1-methylethyl)-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (24Da). Colorless oil. R_f¼0.35, hexane/Et₂O 5:1; ¹H

NMR (300 MHz)

d

1.75 (s, 3H), 1.77 (s, 3H), 3.37 (ddd, J¼8.5, 6.2,

5.0 Hz, 1H), 4.28 (dd, J¼9.5, 5.0 Hz, 1H), 4.36 (dd, J¼9.5, 8.5 Hz, 1H),

4.97 (dd, J¼7.2, 6.2 Hz, 1H), 5.17 (d, J¼7.2 Hz, 1H), 7.36e7.41 (m, 5H);

¹³C NMR (75 MHz)

d 32.3 (q), 32.6 (q), 58.4 (d), 65.3 (s), 70.8 (t), 86.1

(d), 94.8 (d), 125.9 (d), 128.9 (d), 129.1 (d), 137.0 (s).

5.10.1. 4(R*)-(Bromomethyl)-3(S*)-nitro-2(R*)-phenyl-

5.11.3. 2-Bromo-2-nitro-1-phenyl-1-(prenyloxy)ethane (9Da). Puri-

ﬁed by ﬂash chromatography hexane/Et₂O 5:1. Pale yellow oil. For

yields and ratios, see Table 6. R_f¼0.53, hexane/Et₂O 5:1; IR (neat)

3065, 3032, 2975, 2913, 2878,1565,1453,1352,1203,1059,1026, 981,

944, 905, 764, 713, 697 cm^ꢀ1; GCeMS (EI) m/z 183/181 (55/57), 150

(55),117 (15),107 (22),105 (24),103 (25), 91 (13), 85 (90), 77 (60), 69

(100), 57 (30), 53 (12), 51 (20); Anal. Calcd for C₁₃H₁₆BrNO₃(314.18):

C 49.70 H 5.13 N 4.46. Found: C 49.79 H 5.25 N 4.34. Diastereomer 1:

tetrahydrofuran (23Aa). Colorless oil. R_f¼0.50, hexane/EtOAc 5:1;

¹H NMR (400 MHz)

d

3.12 (m, 1H), 3.33 (dd, J¼10.5, 8.5 Hz, 1H), 3.45

(dd, J¼10.5, 7.2 Hz, 1H), 4.07 (dd, J¼10.4, 8.7 Hz, 1H), 4.51 (dd, J¼8.7,

7.5 Hz, 1H), 5.03 (dd, J¼7.3, 3.1 Hz, 1H), 5.55 (d, J¼3.1 Hz, 1H),

7.30e7.41 (m, 5H); ¹³C NMR (100 MHz)

d 25.6 (t), 45.7 (d), 72.1 (t),

85.1 (d), 93.8 (d), 125.2 (d), 128.7 (d), 128.9 (d), 138.5 (s).

5.10.2. 4(R*)-(Bromomethyl)-3(R*)-nitro-2(R*)-phenyl-

¹HNMR (400 MHz)

d

1.54(d, J¼0.8Hz, 3H),1.75(d, J¼0.4 Hz, 3H), 3.92

tetrahydrofuran (25Aa). Colorless oil. R_f¼0.62, hexane/EtOAc 10:1;

¹H NMR (400 MHz)

d 3.50 (dd, 10.6, 6.4 Hz, 1H), 3.60 (dd, 10.6,

(dd, J¼11.6, 8.2 Hz,1H), 4.02 (dd, J¼11.6, 6.5 Hz,1H), 4.98 (d, J¼6.5 Hz,

1H), 5.31 (m,1H), 5.99 (d, J¼6.5 Hz,1H), 7.35e7.42 (m, 5H); ¹³C NMR

5.6 Hz, 1H), 3.65 (m, 1H), 3.80 (dd, J¼9.1, 7.2 Hz, 1H), 4.63 (dd, J¼9.1,

7.8 Hz, 1H), 5.23 (m, 2H), 7.30e7.37 (m, 5H); ¹³C NMR (100 MHz)

(100 MHz)

d 18.0 (q), 25.8 (q), 65.9 (t), 80.6 (d), 84.0 (d), 119.4 (d),

127.6 (d),128.9 (d),129.60 (d),134.8 (s),139.4 (s). Diastereomer 2: ¹H

NMR (400 MHz)

d

31.1 (t), 46.2 (d), 71.4 (t), 83.9 (d), 93.9 (d), 126.0 (d), 128.5 (d),

d

1.49 (d, J¼0.7 Hz, 3H),1.72 (s, 3H), 3.83 (dd, J¼11.5,

129.0 (d), 133.8 (s).

7.7 Hz, 1H), 3.90 (ddd, J¼11.5, 6.6, 0.7 Hz, 1H), 4.92 (d, J¼9.6 Hz, 1H),

5.20 (m, 1H), 5.85 (d, J¼9.6 Hz, 1H), 7.40e7.42 (m, 5H); ¹³C NMR

5.10.3. 1-Allyloxy-2-bromo-2-nitro-1-phenylethane (9Aa). Puriﬁed

by ﬂash chromatography hexane/EtOAc, gradient 10:1 to 5:1. Pale

yellow unstable oil. For yields and ratios, see Table 6. R_f¼0.59, hex-

ane/EtOAc 5:1; IR (neat) 3068, 3032, 3017, 2909, 2869, 1564, 1454,

1351, 1061, 987, 929 cm^ꢀ1; GCeMS (EI) m/z 183/181 (25/27), 147

(100),119 (12),105 (61),103 (20), 91 (53), 77 (32), 51 (11); Anal. Calcd

for C₁₁H₁₂BrNO₃(286.12): C 46.18 H 4.23 N 4.90. Found: C 46.78 H

4.22 N 4.65. Despite many attempts, a better matching combustion

analysis was not obtained for this unstable compound. Diastereomer

(100 MHz)

d 17.9 (q), 25.7 (q), 66.2 (t), 80.2 (d), 81.7 (d), 119.3 (d),

128.4 (d), 128.8 (d), 129.65 (d), 134.5 (s), 139.3 (s).

5.12. (E)- and (Z)-4-(Chloromethylene)-3(S*)-nitro-2(R*)-

phenyltetrahydrofuran (26h)

Puriﬁed by ﬂash chromatography hexane/Et₂O 5:1. The double

bond geometry was determined by a NOESY experiment, see the

Supplementary data. Colorless oil as a partly separable 2.8:1 E/Z-

mixture, yield 67 mg (28%). R_f(Z)¼0.60, hexane/Et₂O 5:1; R_f(E)¼0.50,

hexane/Et₂O 5:1; IR (neat) 3075, 3034, 2860, 1671, 1552, 1455, 1364,

1335, 1310, 1085, 1061, 1026, 921, 827, 750, 696 cm^ꢀ1; UV (CHCl₃,

1: ¹H NMR (400 MHz)

d

3.88 (ddt, J¼12.7, 6.5, 1.3 Hz, 1H), 4.09 (ddt,

J¼12.7, 5.1,1.5 Hz,1H), 5.03 (d, J¼6.4 Hz,1H), 5.23 (dq, J¼10.4,1.5 Hz,

1H), 5.26 (dq, J¼17.1, 1.3 Hz, 1H), 5.87 (dddd, J¼17.1, 10.4, 6.5, 5.1 Hz,

1H), 6.01 (d, J¼6.4 Hz, 1H), 7.35e7.45 (m, 5H); ¹³C NMR (100 MHz)

1538

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

0.42ꢂ10^ꢀ3M) l_max240 nm; MS (EI) m/z 241/239 (M^þ, 1), 194/192

(35/95), 157 (58), 133 (12), 129 (100), 128 (60), 127 (30), 105 (20), 91

(20), 77 (50), 63 (14), 51 (50); Anal. Calcd for C₁₁H₁₀ClNO₃(239.65):

C 55.13 H 4.21 N 5.84. Found: C 55.02 H 4.23 N 5.83. (E)-Isomer: ¹H

(400 MHz)

6.2 Hz, 1H), 4.43 (d, J¼9.8 Hz, 2H), 5.00 (dd, J¼6.2, 1.3 Hz, 1H), 5.59

(s, 1H), 7.26e7.41 (m, 5H); ¹³C NMR (100 MHz)

28.7 (q), 30.2 (q),

53.3 (d), 68.5 (t), 69.15 (s), 84.9 (d), 92.1 (d), 125.1 (d), 128.3 (d),

128.78 (d), 139.7 (s).

d

1.27 (s, 3H), 1.38 (s, 3H), 1.68 (br s, 1H), 2.58 (dt, J¼9.8,

d

NMR (400 MHz)

d

4.73 (m, 2H), 5.41 (d, J¼4.5 Hz, 1H), 5.52 (ddt,

J¼4.5, 1.2, 0.4 Hz, 1H), 6.47 (q, J¼1.9 Hz, 1H), 7.34e7.44 (m, 5H); ¹³C

NMR (100 MHz)

d

70.5 (t), 85.7 (d), 91.5 (d), 119.0 (d), 125.6 (d),

5.14.2. 4(S*)-(1-Hydroxy-1-methylethyl)-3(S*)-nitro-2(R*)-phenyl-

128.98 (d), 129.00 (d), 135.9 (s), 137.4 (s). (Z)-Isomer: ¹H NMR

(200 MHz)

4.79 (dd, J¼2.7, 1.6 Hz, 1H), 4.83 (d, J¼2.7 Hz, 1H), 5.34

(m, 1H), 5.68 (d, J¼4.0 Hz, 1H), 6.54 (dt, J¼2.6, 1.5 Hz, 1H), 7.31e7.43

(m, 5H); ¹³C NMR (50 MHz)

71.6 (t), 84.8 (d), 91.4 (d), 118.9 (d),

tetrahydrofuran (28). Colorless oil. ¹H NMR (200 MHz)

d 1.22 (s,

d

3H), 1.24 (s, 3H), 1.90 (br s, 1H), 3.12 (dt, J¼8.3, 5.6 Hz, 1H), 4.17 (dd,

J¼9.4, 5.6 Hz, 1H), 4.26 (dd, J¼9.4, 8.3 Hz, 1H), 4.96 (dd, J¼7.0,

5.6 Hz, 1H), 5.16 (d, J¼7.0 Hz, 1H), 7.28e7.40 (m, 5H); ¹³C NMR

d

125.5 (d), 129.0 (d, 3C), 135.8 (s), 137.0 (s).

(50 MHz) d 27.5 (q), 28.3 (q), 56.3 (d), 69.24 (t), 70.7 (s), 85.7 (d),

93.1 (d), 125.8 (d), 128.82 (d, 3C), 137.6 (s).

5.13. (E)- and (Z)-4-(Chlorobenzylidene)-3(S*)-nitro-2(R*)-

phenyltetrahydrofuran (26i)

Acknowledgements

Puriﬁed by ﬂash chromatography hexane/Et₂O 5:1. The double

bond geometry was determined by a NOESY experiment, see the

Supplementary data. Colorless oils, as a partly separable E/Z-mix-

ture, for yields and ratios, see Scheme 9. R_f(Z)¼0.52, hexane/Et₂O

5:1; R_f(E)¼0.44, hexane/Et₂O 5:1; IR (neat) 3063, 3032, 2909, 2863,

1672, 1551, 1446, 1358, 1220, 1086, 1063, 1027, 928, 895, 731,

694 cm^ꢀ1; UV (CHCl₃, 0.785ꢂ10^ꢀ4M) l_max245 nm; MS (ESI) m/z

338 ([MþNa]^þ, 100); Anal. Calcd for C₁₇H₁₄ClNO₃(315.75): C 64.67

H 4.47 N 4.44. Found: C 64.65 H 4.55 N 4.57. (Z)-Isomer: MS (EI) m/z

271/269 (9/30), 233 (12), 205 (35), 129 (25), 105 (100), 91 (20), 77

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. D.R.

thanks the Otto-Benecke-Stiftung and the Degussa Stiftung for

support by Ph.D fellowships. We thank Mr. A. Weinkauf for regis-

tering the X-ray data.

Supplementary data

(70), 51 (25), 50 (13); ¹H NMR (400 MHz)

d

4.96 (dd, J¼14.3, 1.0 Hz,

Experimental procedures, analytical characterization and con-

ﬁguration assignment of all new compounds. Copies of ¹H and ¹³

C

1H), 4.99 (dt, J¼14.3, 0.6 Hz, 1H), 5.30 (ddd, J¼2.5, 1.0, 0.6 Hz, 1H),

5.58 (d, J¼2.5 Hz, 1H), 7.20e7.45 (m, 10H); ¹³C NMR (100 MHz)

NMR spectra. Supplementary data related to this article can be

found online at doi:10.1016/j.tet.2011.12.010.

d

71.9 (t), 86.9 (d), 92.3 (d), 125.3 (d), 127.6 (d), 128.8 (d), 128.89 (d),

129.0 (d), 130.0 (d), 131.1 (s), 134.2 (s), 136.2 (s), 137.5 (s). (E)-Isomer:

MS (EI) m/z 271/269 (6/20), 205 (23), 202 (12), 129 (13), 105 (100),

References and notes

91 (10), 77 (30), 69 (15), 51 (10); ¹H NMR (400 MHz)

d 4.66 (dd,

J¼13.0, 0.6 Hz, 1H), 4.97 (dd, J¼13.0, 1.6 Hz, 1H), 5.41 (d, J¼4.7 Hz,

1. (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis;

Wiley-VCH: Weinheim, 2006; (b) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G.

Angew. Chem., Int. Ed. 2006, 45, 7134e7186; (c) Tietze, L. F. Chem. Rev. 1996, 96,

115e136.

1H), 5.70 (dd, J¼4.7, 1.6 Hz, 1H), 7.37e7.42 (m, 5H), 7.42e7.44 (m,

5H); ¹³C NMR (100 MHz)

d 71.0 (t), 85.5 (d), 94.3 (d), 125.7 (d), 127.8

(d), 128.6 (d), 128.95 (d, 3C), 130.1 (d), 131.5 (s), 133.5 (s), 136.0 (s),

137.6 (s).

2. Selected Reviews: (a) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1e21; (b)

Balme, G.; Bouyssi, D.; Monteiro, N. Top. Organomet. Chem. 2006, 19, 115e148;

(c) Dragutan, V.; Dragutan, I. J. Organomet. Chem. 2006, 691, 5129e5147; (d) de

Meijere, A.; von Zezschwitz, P.; Brase, S. Acc. Chem. Res. 2005, 38, 413e422; (e)

Ajamian, A.; Gleason, J. L. Angew. Chem., Int. Ed. 2004, 43, 3754e3760; (f) Garcia,

€

5.14. 4-(1-Hydroxy-1-methylethyl)-3(S*)-nitro-2(R*)-

phenyltetrahydrofurans 27 and 28

G. V.; Nudelman, N. S. Org. Prep. Proced. Int. 2003, 35, 445e500; (g) de Meijere,

€

A.; von Zezschwitz, P.; Nuske, H.; Stulgies, B. J. Organomet. Chem. 2002, 653,

129e140; (h) Rodriguez, J. Synlett 1999, 505e518; (i) Guo, H.-C.; Ma, J.-A. An-

gew. Chem., Int. Ed. 2006, 45, 354e366; (j) Poli, G.; Giambastiani, G.; Heumann,

A. Tetrahedron 2000, 56, 5959e5989; (k) Ikeda, S.-I. Acc. Chem. Res. 2000, 33,

At ꢀ78 ^ꢁC under N₂, n-BuLi (0.937 mL, 1.5 mmol, 1.6 M in hex-

ane) was added via syringe to a stirred solution of 1D (129 mg,

1.5 mmol) in 10 mL dry DME or THF. After 15 min, a solution of 2a

(149 mg, 1.0 mmol) in 1 mL dry DME or THF was added. The re-

action mixture was warmed to 0 ^ꢁC after 10 min and maintained at

this temperature until completion (TLC monitoring). A strong

stream of dry O₂was bubbled through the solution and anhydrous

CuCl₂(268.9 mg, 2.0 mmol) was added simultaneously in small

portions with vigorous stirring. After 30 min, the reaction was

quenched with two drops of saturated NH₄Cl solution. The in-

homogeneous green-brown mixture was diluted with 30 mL Et₂O

and ﬁltered through a pad of silica gel. The solution was concen-

trated under reduced pressure and the crude product was puriﬁed

by ﬂash column chromatography (hexane/EtOAc, gradient 10:1 to

2:1). For yields and ratios, see Scheme 10. The following analyses

were performed on the diastereomeric mixture before further

separation. R_f¼0.15, hexane/EtOAc 10:1; IR (neat) 3434, 2999, 2972,

2933, 2910, 2881, 1549, 1476, 1381, 1335, 1182, 1101, 1063, 1045,

930 cm^ꢀ1; MS (CI) m/z 269 ([MþNH₄]^þ,100), 222 (45), 205 (39),189

(16), 162 (85), 160 (10); Anal. Calcd for C₁₃H₁₇NO₄(251.28): C 62.14

H 6.82 N 5.57. Found: C 61.99 H 6.94 N 5.59.

511e519.

ˇ

3. General reviews: (a) Albert, M.; Fensterbank, L.; Lacote, E.; Malacria, M. Top.

Curr. Chem. 2006, 264, 1e62; (b) Radicals in Organic Synthesis; Renaud, P., Sibi,

M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1þ2; (c) Giese, B.; Kopping, B.;

€

Gobel, T.; Dickhaut, J.; Thoma, G.; Kulicke, K. J.; Trach, F. Org. React. 1996, 48,

301e856.

4. Selected reviews: (a) Brunoldi, E.; Luparia, M.; Porta, A.; Zanoni, G.; Vidari, G.

Curr. Org. Chem. 2006, 10, 2259e2282; (b) Padwa, A. Pure Appl. Chem. 2003, 75,

47e62.

5. Selected reviews: (a) Padwa, A. Helv. Chim. Acta 2005, 88, 1357e1374; (b)

Mehta, G.; Muthusamy, S. Tetrahedron 2002, 58, 9477e9504.

6. Reviews: (a) Procter, D. J.; Flowers, R. A., II; Skrydstrup, T. Organic Synthesis

Using Samarium Diiodide; RSC: Cambridge, 2009; (b) Edmonds, D. J.; Johnston,

D.; Procter, D. J. Chem. Rev. 2004, 104, 3371e3404; (c) Molander, G. A.; Harris, C.

R. Tetrahedron 1998, 54, 3321e3354.

7. Reviews: (a) Cuerva, J. M.; Justicia, J.; Oller-Lopez, J. L.; Oltra, J. E. Top. Curr. Chem.

ꢁ

2006, 264, 63e91; (b) Barrero, A. F.; Quílez del Moral, J. F.; Sanchez, E. M.;

Arteaga, J. F. Eur. J. Org. Chem. 2006, 1627e1641.

8. Recent reviews: (a) Snider, B. B. Tetrahedron 2009, 65, 10738e10744; (b) Demir,

A. S.; Emrullahoglu, M. Curr. Org. Synth. 2007, 4, 321e350; (c) Linker, T. J. Or-

ganomet. Chem. 2002, 661, 159e167; (d) Melikyan, G. G. Org. React. 1997, 49,

427e675.

9. Reviews: (a) Nair, V.; Deepthi, A. Tetrahedron 2009, 65, 10745e10755; (b) Nair,

V.; Balagopal, L.; Rajan, R.; Mathew, J. Acc. Chem. Res. 2004, 37, 21e30; (c) Nair,

V.; Panicker, S. B.; Nair, L. G.; George, T. G.; Augustine, A. Synlett 2003, 156e165;

(d) Nair, V.; Mathew, J.; Prabhakaran, J. Chem. Soc. Rev. 1997, 26, 127e132.

10. Reviews: (a) Moeller, K. D. Synlett 2009, 1208e1218; (b) Moeller, K. D. Tetra-

hedron 2000, 56, 9527e9554; (c) Moeller, K. D. Top. Curr. Chem. 1997, 185,

49e86.

5.14.1. 4(R*)-(1-Hydroxy-1-methylethyl)-3(S*)-nitro-2(R*)-phenyl-

tetrahydrofuran (27). Colorless solid. Mp 113 ^ꢁC; ¹H NMR

U. Jahn et al. / Tetrahedron 68 (2012) 1521e1539

1539

11. (a) Jahn, U.; Hartmann, P.; Dix, I.; Jones, P. G. Eur. J. Org. Chem. 2001, 3333e3355;

(b) Jahn, U.; Hartmann, P.; Dix, I.; Jones, P. G. Eur. J. Org. Chem. 2002, 718e735;

(c) Jahn, U.; Hartmann, P.; Kaasalainen, E. Org. Lett. 2004, 6, 257e260; (d) Jahn,

U.; Kafka, F.; Pohl, R.; Jones, P. G. Tetrahedron 2009, 65, 10917e10929; (e) Jahn,

U.; Dinca, E. Chem.dEur. J. 2009, 15, 58e62; (f) Jahn, U.; Dinca, E. J. Org. Chem.

2010, 75, 4480e4491.

24. Review: (a) Seebach, D.; Beck, A. K.; Studer, A. Modern Synthetic Methods; VCH:

Weinheim, 1995; Vol. 7, pp. 3e178; For a recent account on the reactivity of LiCl

in conjugate additions, see: (b) Ma, Y.; Hoepker, A. C.; Gupta, L.; Faggin, M. F.;

Collum, D. B. J. Am. Chem. Soc. 2010, 132, 15610e15623.

25. Isomerization of this nitrostyrene to the allylic isomer is apparently signiﬁ-

cantly faster than conjugate addition. For isomerizations, see: (a) Sun, X.;

Sengupta, S.; Petersen, J. L.; Wang, H.; Lewis, J. P.; Shi, X. Org. Lett. 2007, 9,

4495e4498; (b) Tamura, R.; Hegedus, L. S. J. Am. Chem. Soc. 1982, 104,

3727e3729; (c) Tamura, R.; Hayashi, K.; Kakihana, M.; Tsuji, M.; Oda, D. Tet-

rahedron Lett. 1985, 26, 851e854; (d) Tamura, R.; Hayashi, K.; Kakihana, M.;

Tsuji, M.; Oda, D. Chem. Lett. 1985, 229e232; (e) Ferrand, J. C.; Schneider, R.;

€

12. (a) Jahn, U.; Muller, M.; Aussieker, S. J. Am. Chem. Soc. 2000, 122, 5212e5213; (b)

Jahn, U. Chem. Commun. 2001, 1600e1601.

13. For a recent review, see: Nising, C. F.; Brase, S. Chem. Soc. Rev. 2008, 37,

€

1218e1228.

14. For other tandem addition/cyclization approaches to tetrahydrofurans, see: (a)

Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261e290; (b) Ref. 2b. (c) Balme, G.;

Bossharth, E.; Monteiro, N. Eur. J. Org. Chem. 2003, 4101e4111; (d) Balme, G.;

Bouyssi, D.; Lomberget, T.; Monteiro, N. Synthesis 2003, 2115e2134; (e) Ma-

jumdar, K. C.; Basu, P. K.; Chattopadhyay, S. K. Tetrahedron 2007, 63, 793e826

and earlier reviews in this series.

ꢁ

Gerardin, P.; Loubinoux, B. Synth. Commun. 1996, 26, 4329e4336.

26. A blank experiment proved that TEMPO did not react with nitronates 3^ꢀ.

27. Full crystallographic details for structure 13Da were deposited at the Cam-

bridge Crystallographic Data Centre under the number CCDC-849156. This

material may be obtained free of charge from http://www.ccdc.cam.ac.uk/

products/csd/request.

15. Preliminary communication: Jahn, U.; Rudakov, D. Synlett 2004, 1207e1210.

ꢂ

16. For other studies, see: (a) Durand, A.-C.; Dumez, E.; Rodriguez, J.; Dulcere, J.-P.

28. For the use of copper dicarboxylates in oxidative radical cyclizations, see: (a)

ꢂ

Chem. Commun. 1999, 2437e2438; (b) Durand, A.-C.; Rodriguez, J.; Dulcere, J.-P.

Chemler, S. R. Org. Biomol. Chem. 2009, 7, 3009e3019 and cited ref; (b) Jia, Y.-X.;

€

Synlett 2000, 731e733; (c) Kamimura, A.; Kadowaki, A.; Yoshida, T.; Takeuchi,

Kundig, E. P. Angew. Chem., Int. Ed. 2009, 48, 1636e1639; (c) Perry, A.; Taylor, R.

R.; Uno, H. Chem.dEur. J. 2009, 15, 10330e10334; (d) Goddard, J.-P.; Gomez, C.;

Brebion, F.; Beauviere, S.; Fensterbank, L.; Malacria, M. Chem. Commun. 2007,

2929e2931.

J. K. Chem. Commun. 2009, 3249e3251; (d) Pugh, D. S.; Klein, J. E. M. N.; Perry,

A.; Taylor, R. J. K. Synlett 2010, 934e938; (e) Klein, J. E. M. N.; Perry, A.; Pugh, D.

S.; Taylor, R. J. K. Org. Lett. 2010, 12, 3446e3449 All these cyclizations require

harsh conditions to proceed.

ꢂ

17. For an initial application, see: Jahn, U.; Rudakov, D. Org. Lett. 2006, 8,

4481e4484.

29. For the application of iron

b-diketonates in intramolecular radical coupling

18. (a) Dumez, E.; Durand, A.-C.; Guillaume, M.; Roger, P.-Y.; Faure, R.; Pons, J.-M.;

reactions, see: (a) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008,

130, 11546e11560; (b) Richter, J. M.; Ishihara, Y.; Masuda, T.; Whiteﬁeld, B. W.;

Llamas, T.; Pohjakallio, A.; Baran, P. S. J. Am. Chem. Soc. 2008, 130,

17938e17954.

ꢂ

Herbette, G.; Dulcere, J.-P.; Bonne, D.; Rodriguez, J. Chem.dEur. J. 2009, 15,

12470e12488; (b) Review: Yamazaki, S. Chem.dEur. J. 2008, 14, 6026e6036.

19. Some oxyl radicals add to alkynes: Wille, U.; Jargstorff, C. J. Chem. Soc., Perkin

Trans. 1 2002, 1036e1041 and cited ref.

20. (a) Snider, B. B.; Che, Q. Tetrahedron 2002, 58, 7821e7827; (b) Arai, N.; Nar-

asaka, K. Bull. Chem. Soc. Jpn. 1997, 70, 2525e2534 and cited ref; (c) Bowman,

W. R.; Brown, D. S.; Burns, C. A.; Crosby, D. J. Chem. Soc., Perkin Trans. 1 1994,

2083e2090; (d) Bowman, W. R.; Brown, D. S.; Burns, C. A.; Crosby, D. J. Chem.

Soc., Perkin Trans. 1 1993, 2099e2105; (e) Hobbs-Mallyon, D.; Whiting, D. A. J.

Chem. Soc., Chem. Commun. 1991, 899e900; (f) Kende, A. S.; Koch, K. Tetrahedron

30. Precedence for the formation of 16Aa from silyl nitronates: Namboothiri, I. N.

N.; Hassner, A. Top. Curr. Chem. 2001, 216, 1e49.

31. For the inﬂuence of amines on the course of oxidative reactions, see: Jahn, U.;

Hartmann, P. J. Chem. Soc., Perkin Trans. 1 2001, 2277e2282.

32. Tetrahydrofurans 17e20 undergo stereospeciﬁc intramolecular alkylation re-

actions mediated by DBU, which provide 2-oxabicyclo[3.1.0]hexanes. From

their relative conﬁguration the conﬁguration at the exocyclic centers in 17e20

as well as that of the nitro center of 17e20 can be established, see: Jahn, U.;

Rudakov, D.; Jones, P. G. Tetrahedron 2012, 68, 447e463.

Lett. 1986, 27, 6051e6054 For a recent b-nitro radical cyclization mediated by

iron compounds see: (g) Taniguchi, T.; Ishibashi, H. Org. Lett. 2010, 12, 124e126.

21. Wilson, J. E.; Casarez, A. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131,

11332e11334.

33. A blank experiment showed that oxygen itself does not react with the nitronate

3Da^ꢀduring 1.5 h.

22. For reviews on conjugate additions to nitroalkenes, see: (a) Berner, O. M.; Te-

deschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877e1894; (b) Thirumalaikumar,

M. Org. Prep. Proced. Int. 2011, 43, 67e129.

34. We thank a referee for this suggestion.

35. Kochi, J. K. In Free Radicals; Kochi, J. K., Ed.; Wiley: New York, NY, 1973; Vol. 1,

pp 591e683.

23. Usually 3e6 equiv of alcohol and several bases were used in prior syntheses of

3: using KO^tBu: (a) Cheng, Q.; Oritani, T.; Horiguchi, T.; Shi, Q. Eur. J. Org. Chem.

1999, 2689e2693; (b) Hassner, A.; Friedman, O.; Dehaen, W. Liebigs Ann./Recl.

1997, 587e594; (c) Hassner, A.; Dehaen, W. Chem. Ber. 1991, 124, 1181e1186

Using BuLi: (d) Kim, H. R.; Kim, K. M.; Kim, J. N.; Ryu, E. K. Synth. Commun. 1994,

24, 1107e1116; (e) Kim, H. R.; Kim, H. J.; Duffy, J. L.; Olmstead, M. M.; Ruhlandt-

Senge, K.; Kurth, M. J. Tetrahedron Lett. 1991, 32, 4259e4262 Using KH or NaH:

(f) Duffy, J. L.; Kurth, J. A.; Kurth, M. J. Tetrahedron Lett. 1993, 34, 1259e1260; (g)

Beebe, X.; Chiappari, C. L.; Kurth, M. J.; Schore, N. E. J. Org. Chem. 1993, 58,

7320e7321; (h) Huang, KS.-L.; Lee, E. H.; Olmstead, M. M.; Kurth, M. J. J. Org.

Chem. 2000, 65, 499e503.

36. Maillard, B.; Ingold, K. U.; Scaiano, J. C. J. Am. Chem. Soc. 1983, 105, 5095e5099.

37. (a) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925e3941; (b)

Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959e974.

38. 1G: Kelkar, S. V.; Arbale, A. A.; Joshi, G. S.; Kulkarni, G. H. Synth. Commun. 1990,

20, 839e847 2c, 2d: Stevens, T. E.; Emmons, W. D. J. Am. Chem. Soc. 1957, 79,

6008e6014 2e: Lin, W.-W.; Jang, Y.-J.; Wang, Y.; Liu, J.-T.; Hu, S.-R.; Wang, L.-Y.;

Yao, C.-F. J. Org. Chem. 2001, 66, 1984e1991.

39. Kao, K.-H.; Yang, C.-S.; Liu, J.-T.; Lin, W.-W.; Fang, H.-Y.; Yao, C.-F.; Chen, K.

Tetrahedron 1998, 54, 13997e14014.

40. Yan, M.-C.; Liu, J.-Y.; Lin, W.-W.; Kao, K.-H.; Liu, J.-T.; Jang, J.-J.; Yao, C.-F. Tet-

rahedron 1999, 55, 12493e12514.

Article Doi

Oxidative tandem alkoxide conjugate addition to nitroalkenes/radical 5-exo cyclizations - A versatile synthesis of functionalized 3-nitrotetrahydrofurans

DOI: 10.1016/j.tet.2011.12.010

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.tet.2011.12.010

Full text of DOI:10.1016/j.tet.2011.12.010

Products guided by the article

R&D Labs maybe for 1356714-98-1

Relevant to this article

Hot Product