Radical cyclisation studies of β-nitroamines from the nitro-Mannich reaction

Accepted Manuscript

Abil Aliev, James C. Anderson, Mérina Corpinot, Emily S.J. Gascoigne

PII:

S0040-4020(18)30711-7

10.1016/j.tet.2018.06.022

TET 29618

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Reference:

To appear in: Tetrahedron

Received Date: 4 May 2018

Revised Date: 7 June 2018

Accepted Date: 8 June 2018

Please cite this article as: Aliev A, Anderson JC, Corpinot Mé, Gascoigne ESJ, Radical cyclisation

studies of β-nitroamines from the nitro-Mannich reaction, Tetrahedron (2018), doi: 10.1016/

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Radical cyclisation studies of β-nitroamines

from the nitro-Mannich reaction

Abil Aliev, James C. Anderson,^*Mérina Corpinot and Emily S. J. Gascoigne

Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK

1

ACCEPTED MANUSCRIPT

Tetrahedron

journal homepage: www.elsevier.com

Radical cyclisation studies of β-nitroamines from the nitro-Mannich reaction

Abil Aliev, James C. Anderson,^*Mérina Corpinot and Emily S. J. Gascoigne

Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK. E-mail:j.c.anderson@ucl.ac.uk

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

A range of novel β-nitroacetamides with an alkenyl- or alkynyl tether were synthesized using the

deprotonative or conjugate addition nitro-Mannich reaction. They were subjected to radical

denitration-cyclisation with a 10 equivalent excess of tributyltin hydride, catalytic AIBN in

refluxing benzene to explore the structural and electronic requirements for efficient cyclisation.

Cyclisations of the β-nitroacetamides were successful in most cases, undergoing 5-exo-trig

cyclisation to give the desired cyclopentyl or indanyl structures. Radical 1,4-translocation of a

phenyl group was observed in several cases. Diastereoselectivity was low, with 2 or 3 of 4

possible diastereoisomers observed in most cases. Further purification by crystallisation allowed

the isolation of some as single diastereoisomers. It was found that higher yields were obtained

by increasing the substitution or reducing the degrees of freedom of the tether between the nitro

group and the radical acceptor.

Available online

Keywords:

Cyclisation

Free radical

Indanes

Cyclopentanes

Nitro-Mannich

.

1. Introduction

2. Results and discussion

The nitro-Mannich (or aza-Henry) reactions is a versatile

method for the synthesis of β-nitroamines.¹The nitro function

has been transformed into many other functional groups such as

carboxylic acids in α-amino acids (via Nef reaction), vicinal

diamines (via nitro reduction) and peptides.^2-4A less common

transformation is reduction of the nitro group to a carbon-centred

radical followed by addition of a hydrogen⁵or formation of a

carbon-carbon bond.⁶The deprotonative^3a,7or conjugate addition⁸

nitro Mannich reactions are useful routes to stereodefined β-

nitroamines that can be used for the synthesis of an array of

amino heterocycles.⁹We were interested to investigate the

synthesis of carbocyclic structures through the radical denitration

of the secondary nitro function in β-nitroamines onto a tethered

alkene or alkyne. The radical denitration cyclisation of a β-

nitroamine has been reported by Kamimura in 2006.¹⁰A β-

nitroformamide underwent cyclisation on treatment with an

2.1. Preliminary results

The radical denitration of β-nitroacetamides and subsequent

replacement of the nitro group with hydrogen, or carbon-carbon

bond formation, required the synthesis of novel β-

nitroacetamides by the nitro-Mannich reaction. In order to probe

the feasibility of radical denitration of these compounds, β-

nitroacetamide 1, previously generated by us via the conjugate

hydride addition nitro-Mannich reaction,^8bwas subjected to

preliminary investigation. Methods described for radical

denitration, including the use of MeSNa,¹¹KOH/ethylene

glycol,¹²1-benzyl-1,4-dihydronicotinamide,^13a,bNaTeH¹⁴and tri-

ⁿbutyltinhydride,^5b,15are mainly limited to the denitration of

tertiary nitro compounds^11,12,14,16or nitro compounds activated by

an adjacent stabilising group (COR, CO₂R, CN, Ar).¹³Ono

showed that ⁿBu₃SnH could be used for the denitration of

unactivated secondary nitro compounds¹⁷under harsh conditions

n

unspecified quantity of Bu₃SnH and AIBN in toluene to afford

n

(toluene, reflux, 5 equiv. Bu₃SnH). A search of the literature

the corresponding pyrrolidine in very good yield (Figure 1). Only

two of a possible four diastereoisomers were observed, with a dr

of 60:40, but with unknown stereochemistry.

n

showed a focus on Bu₃SnH as the method of choice for radical

denitration of secondary nitro compounds, with high variation in

yield depending on structure.¹⁸Furthermore ⁿBu₃SnH has

previously been used in radical denitration reactions of β-

nitroamine derivatives and was thus picked as the reagent for

radical denitration in this work.^{13c,16,18b,d-h}Initial reaction of 1

n

with Bu₃SnH (1.2 equiv.) and AIBN (0.3 equiv.) in toluene at

reflux resulted in trace amounts of a possible denitration product

2 (Scheme 1). As expected, increasing the equivalents of

ⁿBu₃SnH resulted in higher yield, although disappointingly, the

reported denitration conditions for secondary nitro compounds (5

equiv.) resulted in only 17% yield. Pleasingly, a further increase

Figure 1. Radical denitration-cyclisation of a β-nitroformamide

by Kamimura

2

Tetrahedron

n

in the equivalents of Bu₃SnH used (10 eq, 0.7 eq AIBN)

rate of cyclisation might be increased by modification of the β-

nitroacetamide to incorporate electron stabilizing groups on the

terminus of the alkene tether.

ACCEPTED MANUSCRIPT

resulted in the isolation of acetamide 2 in very good (79 %) yield

(Scheme 1). With these results in hand, application to the more

interesting and useful addition of the intermediate radical formed

to alkenes was investigated.

2.2. Synthesis β-nitroacetamide cyclisation precursors.

The first series of cyclisation precursors were derived from

nitro coupling partners containing unsaturated substituents. The

first of these was the styrl-tether derivatives 8. This series was

derived from nitroalkene 9, which was synthesised from 2-

vinylbenzaldehyde²⁰10 by a Henry reaction with nitro methane

in good 85% yield (Scheme 4).^8b,9dA reductive conjugate

addition nitro-Mannich reaction^8b,cwith imines derived from

benzaldehyde or glyoxal gave β-nitroacetamides 8a and 8b in

38% and 63% yield respectively, both with diastereoselectivity

>95:5.

ⁿBu₃SnH (x equiv.)

AIBN (0.3 equiv.)

TFA

PMP

TFA

PMP

N

PhMe, reflux, 30 min

NO₂

2

1

x

yield

1.2

2

5

<1%

4%

17%

79%

10 (0.7 equiv AIBN)

Scheme 1. TFA=CF₃CO, PMP=CH₃OC₆H₅,

PMP

R

N

i) LiHBEt₃;

AIBN=NC(CH₃)₂CN=NC(CH₃)₂CN

NO₂

MeNO₂

CF₃CO₂H, - 78 ^o

C

O

The investigation of the addition reactions of radicals formed

via denitration of β-nitroacetamides was initiated with the

formation of the simplest precursor based on the 5-hexen-1-yl

radical template. Formation of nitroalkene 3 from aldehyde 4 was

achieved by a Henry reaction with nitromethane in good yield

(Scheme 2). Formation of β-nitroacetamide 5 was achieved with

a conjugate addition nitro-Mannich reaction of nitroalkene 3 with

Superhydride (LiHBEt₃), trapping of the nitronate with imine and

TFA protection. Although the nitro-Mannich reaction proceeded

with good diastereoslectivity, the loss of stereochemical integrity

that takes place upon formation of the radical negates any need

for specificity in the nitro-Mannich reaction.

NaOH

85%

ii) TFAA, DIPEA

10

9

TFA

PMP

N

R

8a R=Ph

8b

38%, dr >95:5

R=CO₂Et 63%, dr >95:5

NO₂

Scheme 4.

Late stage functionalisation of the terminal alkene of 8a was

an attractive option to prepare more functionalised substrates and

was achieved through olefin metathesis. We were hoping to

prepare an array of electron rich and electron poor styryl tethers,

but after some optimisation only methyl acrylate and styrene led

to products 11 (Scheme 4).²¹The E-alkenes were formed

exclusively as expected (11a J=16.0 Hz and 11b J=15.7 Hz).

Scheme 2. DIPEA=ⁱPr₂EtN, TFAA=CF₃CO)₂O

Radical denitration-cyclisation was attempted using 5 and 10

n

equivalents of Bu₃SnH. While 5-hexen-1-yl radical cyclisations

are known to be extremely fast, at higher concentrations of

ⁿBu₃SnH the rate of reduction increases. However the use of less

ⁿBu₃SnH resulted in a complex mixture of starting material,

possible cyclopentane diastereoisomers and decomposition

products resulting from elimination of the TFA-NH-PMP group

(Scheme 3), which is known to occur at high temperatures.¹²Use

of the optimized conditions for protodenitration (10 equiv.

ⁿBu₃SnH, 0.7 equiv. AIBN) resulted in the isolation of an

inseperable mixture of the protodenitrated product 6 with the

desired cyclized product 7 in a 2:1 ratio in 60% yield.

Scheme 5.

Conversion of terminal alkene 8a to the corresponding

nitroalkene 11c was achieved using the AgNO₃/TEMPO

methodology described by Maity²²which we had used on

sensitive substrates before (Scheme 6).^9h,i

TFA

PMP

TFA

PMP

TFA

PMP

N

ⁿBu₃SnH (x equiv.)

AIBN (0.7 equiv.)

Ph

+

NO₂

7

PhMe, reflux, 1 h

6

5

x

Scheme 6.

yield

-

5

The synthesis of alkynyl analogues 12a was attempted by

Sonogashira coupling of 13 (Scheme 7). Although successful

(40%) the product could not be separated from residual starting

material or scaled up. The corresponding alkynyl nitro styrene

derivatives 14a²³and 14b²⁴are known and were used in a

reductive conjugate addition nitro-Mannich reaction with PMP

protected benzaldehyde imine. Protection of the product as the

trifluoroacetamide gave the β-nitroacetamides 12a,b in good

yield and diastereoselectivity (Scheme 7).

10 6:7, 2:1, 60%

Scheme 3.

We envisaged that a lower boiling point solvent such as

benzene might reduce the amount of thermal decomposition

products. It was hoped that the addition of substituents on the

tether may increase the rate of cyclisation over that of reduction

by holding the reactive centres in closer proximity.¹⁹Also the

3

ACCEPTED MANUSCRIPT

Scheme 10.

Late stage functionalization of the alkene in 19a was also

attempted by olefin metathesis as for substrate 8a (scheme 5).

Surprisingly under identical conditions and attempted

optimisations, no cross coupling could be detected with methyl

acrylate. Cross coupling with styrene led to product formation

(40%), but the product was inseparable from styrene.

Alternatively stilbene 19b was prepared from another nitro-

Mannich reaction using imine 20b (scheme 10) in 36% yield as

90:10 diastereomeric ratio in favour of the anti-diastereoisomer.

Scheme 7.

Non-planar tethers could potentially be made more prone to

cyclisation by the Thorpe Ingold effect through the incorporation

of geminal substituents. Formation of the gem-dimethyl substrate

15 of the hexenyl tether was found to be viable from

commercially available aldehyde 16 which underwent standard

nitroalkene formation via a Henry reaction to give 17 in 52%

yield. Reductive conjugate addition nitro-Mannich reaction with

PMP protected benzaldehyde imine and protection as the

trifluoroacetamide gave the β-nitroacetamide 15 in 67% yield

essentially as the single anti-diastereoisomer (Scheme 8).^8b

It was envisaged that further electronically different analogues

of 19 could be made from the aldehyde 21 by Wittig reaction.

The generation of acetal protected imine 22 was straightforward

from the known aldehyde.²⁶Reductive conjugate addition nitro-

Mannich reaction of nitrostyrene with 22 gave β-nitroacetamide

23 in 48% yield essentially as the single anti-diastereoisomer.

(Scheme 11). The aldehyde was unmasked in 82% yield using

FeCl₃.²⁷

Scheme 11.

Scheme 8.

Aldehyde 21 degraded upon treatment with the Horner-

Mono-substitution of the hexenyl tether was achieved by

using a copper catalyzed 1,4-conjugate addition nitro-Mannich

reaction previously described by us.^8aOur original protocol used

dialkyl zinc reagents as carbon nucleophiles, but the cuprate

generated from the Grignard of 4-bromobut-1-ene performed

reasonably well to give 18 in 37% yield with a dr 75:25 (Scheme

9). The crude reaction mixture had a dr 50:25:25, which changed

upon trifluoro acetate protection to dr 75:25. From our previous

work we know that the major product from homogeneous

reactions is normally the syn (from conjugate addition), anti

(from nitro-Mannich) -diastereoisomer. We found that the syn,

syn-diastereoisomer is normally resistant to trifluoro acetate

protection and so the minor diastereoisomer was tentatively

assigned as anti, syn-18.^8a

Wadsworth-Emmons

reagent

derived

from

diethylcyanophosphonate, giving TFA-NH-PMP. This suggested

that the anion is basic enough to deprotonate the CHNO₂proton.

The

less

basic

Wittig

reagent

(carboethoxymethylene)triphenylphosphorane (pKa 8.5 (H₂O)²⁸)

gave a mixture of products 19c (R=CO₂Me, 85:10:5) in 31%

yield, but could not be definitively assigned. The mixture would

make the analysis of any radical cyclisations complex, so this

reaction was not optimized further.

Although not providing an electronically different alkene,

aldehyde 21 underwent an interesting BF₃initiated aldol-Grob

fragmentation with 3-pentanone, which had been previously

reported by Kabalka, to give alkene derivative 19d (Scheme

12).²⁹

Scheme 9.

Scheme 12.

An alternative series of cyclisation precursors were derived

from imines containing unsaturated substituents. A styrene

A non planar tether derived from crude imine 24 (from the

known aldehyde) was synthesized by a reductive conjugate

addition reaction with nitrostyrene to give β-nitroacetamide 25 in

46% yield essentially as a single anti-diastereoisomer (Scheme

13).

derivative 19a could be derived from known imine 20a.²⁵

A

reductive conjugate addition reaction with nitrostyrene and 20a

gave β-nitroacetamide 19a in 33% yield essentially as a single

anti-diastereoisomer (Scheme 10).

4

Tetrahedron

imines 20b and 24. A standard nitro-Mannich reaction with nitro

ACCEPTED MANUSCRIPT

toluene gave 28 and 29 (Scheme 15). The isolation of planar

tethered 28 was by recrystallization from a complex mixture of

diastereoisomers in 11% yield. The syn-diastereoselectivity was

assigned from a single crystal X-ray determination. The

corresponding styryl imine 20a led to a complex reaction mixture

from which we could not isolate any clean nitro-Mannich

product. The simpler non-planar imine 24 gave 29 in 55% yield

as the single anti-diastereoisomer.

Scheme 13.

The amino-tethered alkene was prepared from the

corresponding known N-allyl imine 26.³⁰Combination of N-

allylamine and benzaldehyde in the presence of the dehydrating

reagent MgSO₄followed by filtration gave the crude imine which

was coupled directly with the nitronate anion from the conjugate

hydride reduction of nitrostyrene (Scheme 14). After protection

as the trifluoroacetamide the β-nitroacetamide 27 was isolated in

39% yield with a slightly reduced dr 75:25. We were unable to

define the major diastereoisomer from the spectral data.

Scheme 15.

2.3. Results of radical denitration cyclisation.

Using the optimized conditions determined for the

rearrangement of 5 (Scheme 3) the β-nitroacetamide cyclisation

precursors were treated with 10 equiv. Bu₃SnH in refluxing

Scheme 14.

n

The final series of cyclisation precursors were those

possessing an activated nitro substituent that upon radical

denitration would give a more stabilized benzylic radical. We

were able to synthesise two from the corresponding unsaturated

benzene and the product mixtures purified by flash column

chromatography and recrystallization where possible. The

structures were elucidated by

a combination of NMR

experiments and X-ray crystallography (Table).

Table. Radical denitration cyclisation of β-nitroacetamides^a

Complex mixture of inseperable

products

-

β-

Total

isolat

ed

Product(s), isolated yields and

diastereomeric ratio^b,d

nitroacetamide

yield

(%)^b

21^g

58^c

24

59

10

55

TFA

Ph

PMP

27

N

Ph

47

NO₂

18

5

obvious in the crude reaction mixture. The byproduct 31 was

ACCEPTED MANUSCRIPT

identified as a phenyl translocation product primarily as it had

NMR signals consistent with an indane ring, but the attachment

of one of the phenyl groups with respect to 30a, was different.

The tentative assignment of the cis stereochemistry of the two

ring substituents is based on a NOESY correlation between the

two methine substituents and would fit the rearrangement

mechanism (vide infra) A detailed NMR analysis can be found in

the supplementary information. Full NMR assignment of 31

corroborated the assignment of 30a as a mixture of indane

diastereoisomers. Many examples of radical aryl migrations are

known.³¹with similar carbon-carbon bond cleavage adjacent to

an amide.³²In this particular case aryl migration from methyl

radical 44 would be most likely if the substituents were cis as

drawn (Scheme 16). Attack of the methyl radical at the ipso-

position of the aromatic ring would lead to spiro-cyclohexadienyl

radical 45 which then clollapses to give a more stable α-

amidoradical 46, which provides the driving force for the

rearrangement from the primary sp³radical 44.228

TFA

PMP

46

34

N

Ph

NO₂

19a

12

-

Complex mixture of inseperable

products

Scheme 16.

12

13

Submission of β-nitroacetamide 8b to the optimised

denitration-cyclisation conditions resulted in successful

cyclisation to give a complex mixture. A ratio of indane

diastereomers 60:20:20 of 30b was observed from the methyl

peak ratios at δ 1.02 ppm (3H, d, J = 7.0, 60 %), 1.13 ppm (3H,

d, J = 7.0, 20 %) and 1.15 ppm (3H, d, J = 7.0, 20 %), with the

presence of small underlying peaks. These peaks may correspond

to a fourth isomer, or a fragmentation isomer. Analysis by MS

found the molecular ion 436 (M + H⁺) and its ammonia adduct at

+

453 (M + NH₄) as the only peaks, suggesting that the mixture

contained indanes 30b and possibly trace amounts of

fragmentation isomers. The NMR data was similar to 30a.

Although the 1,4-acetyl-translocation of C=O type fragments is

known³³via radical processes, NMR analysis ruled this out.

36

Methyl acrylate derivative 11a underwent radical denitration-

cyclisation to give a chromatographically inseperable mixture of

3 diastereoisomers (40:40:20) in a yield of 59%. The mixture of

isomers were recrystallized from CH₂Cl₂/Hexanes, affording pure

samples of the two main isomers in 31 % and 11 % yield.

Diastereoisomer 32a provided a single crystal X-ray structure

(Figure 2).

^aAIBN (0.1 equiv.), ⁿBu₃SnH (10 equiv.), benzene, reflux.

c

^bIsolated by flash column chromatography. 12% recovered 8a.

e

^dStructure elucidated by NMR see text and ESI. Recrystallised

f

from CH2Cl2/hexanes. Single crystal X-ray obtained. ^g50%

recovered 12a.

The β-nitroacetamides 8a gave two isolable products 30a in

38% yield as an inseperable mixture of diastereoisomers

(40:40:20) and an additional stereochemically pure product 31 in

20% yield, with 12% recovered starting material. The mixture of

diastereoisomers of 30a were evident from doublet peaks for the

methyl group on the indane ring. Signals at δ 1.00 ppm (3H, d, J

= 7.0, CH₃, ~40 %) and δ 1.44 ppm (3H, d, J = 7.0, CH₃, ~ 40 %)

confirmed the presence of at least two major diastereoisomers,

and a third doublet at δ 1.28 ppm (3H, d, J = 7.3, CH₃, ~20 %)

appeared to be a minor diastereoisomer, its presence was more

Figure 2. Single crystal X-ray structure of 32a.

6

Tetrahedron

The structure or 32a’ was assigned by MS and NMR. The

to the gem-dimethyl substituents. Radical denitration-cyclisation

ACCEPTED MANUSCRIPT

3

n

1H coupling constant J_1,2for 32a was 6.8 and for 32a’ 6.7. The

coupling constant for the cis-relationship of the ring substituents

was in agreement with literature values³⁴for similar alkyl-

substituted indanes. Diastereoisomer 32a’ was therefore assigned

as the cis,trans-isomer. The crystal structure of 32a allowed for

the corresponding tentative assignment of values in the range ³J_1,2

~ 7 Hz as cis-relative stereochemistry when obtained for

similarly 1,2-dialkyl-substituted indane molecules. This

supported the assignment of the phenyl translocation product 31

as the cis-isomer. In addition to strong nOe interactions (see

ESI), 31 displayed a ³J_1,2value of ~ 7 Hz, a value in the range of

a cis-substituted indane. The full assignment of 32a and 32a’ also

corroborated the assignment of 30a and 30b as complex mixtures

of indanes.

of 18 followed by hydrogen abstraction from Bu₃SnH gave the

mono-substituted hexenyl tether 38 in 24% yield as an

inseperable mixture of diastereoisomers 40:35:25. The 1,4-

phenyl translocated isomer 39 was also isolated in 3% yield. The

relative stereochemistry of the defined ring substituents was from

a strong NOESY interaction between the corresponding ring

protons (see ESI for data correlation table).

Cyclisation of precursors derived from imines containing

unsaturated substituents 19a,b,d and 25 were investigated.

Radical denitration-cyclisation of 19a gave 2-amidoindane 40a in

46% yield as a near 1:1 mixture of diastereoisomers. The trans-

orientation of the benzyl- and acetamido- substituents was

tentatively assigned based upon the coupling constant between

the corresponding ring protons (J=8.7 and 8.8 Hz) being very

similar to the a trans-coupling constant of a similar 2-

aminoindane reported in the literature³⁵and the detection of only

a minor interaction in the NOESY spectrum. These were in

contrast to the corresponding data for the cis-orientation of

substituents in the cis-indane 32a, the structure of which was

confirmed by single crystal X-ray crystallography. A full data

correlation is presented in the supplementary information.

Cyclisation of the stilbene analogue 19b led to indane 40b in

34% yield as an inseperable 60:40 mixture of diastereoisomers.

Full characterisation of the disatereoisomers was possible ( see

structural elucidation and correlation tables in ESI). Cyclisation

of the (E)-methylstyrene derivative 19d gave a low 12% yield of

an inseperable 70:30 mixture of diastereoisomers 40d. Further

purification gave the major diastereoisomer in 95:5 dr, albeit at a

yield of only 4 %, but which did allow full characterisation to be

made. The relative stereochemistry was tentatively assigned as

trans,trans.. The reason for the lower yield of indane 40d is not

clear, however the reaction was conducted on a small scale and

Reaction of stilbene-derived β-nitroacetamide 11b under the

same conditions resulted in the successful denitration-cyclisation

reaction to afford indanes 32b with an identical crude ratio of

diastereoisomers (40:40:20) as that observed for the methyl

acrylate derivative 11a in 47 % yield. The relative

stereochemistry of the ring substituents of the two major

diastereoisomers were assigned as cis- based upon the ³J_1,2values

of 6.6 and 7.2 Hz. A higher yield of inseperable indane

diastereoisomers for 32a (59%) compared to 32b (47%) can be

attributed an electronically more favourable cyclisation with the

electron withdrawn acrylate cyclisation radical acceptor in 11a

versus the stilbene acceptor in 11b. Unfortunately radical

denitration-cyclisation of the nitrostyryl β-nitroacetamide 11c

under the same conditions led to an unidentifiable complex

mixture with no indication of indane products, most probably due

to competing denitration of the nitro-alkene.

Cyclisation of 12a was successful, affording two main

products 34a and 35a, but in low yield. A single crystal X-ray of

35a confirmed the assigned structure (Figure 3). MS analysis

confirmed that 34a and 35a were isomeric and detailed NMR

experiments comfirmed the assignment of 34a (See ESI).

n

separation from the Bu₃SnH residues was difficult, hence it is

likely that some of the product was lost during partitioning of the

product between hexanes/MeCN. The analogous hexenyl tethered

β-nitroacetamide 25 unfortunately led to a complex mixture of

products including recovered starting material. Only trace

amounts of cyclisation and protodenitration was observed, hence

purification was not undertaken. It would appear that radical

denitration did not readily occur in this molecule, and that

cyclisation was not significantly aided by the presence of the

CHN stereocentre on the hexenyl tether.

Subjection of the amino tethered alkene β-nitroacetamide 27

to radical denitration-cyclisation resulted in the formation of

TFA-protected pyrrolidine 41 in low 12% yield, as a complex

inseparable mixture of all four possible diastereoisomers

(50:30:15:5). Characterisation of the pyrrolidine ring was limited

1

Figure 3. Single crystal X-ray structure of 35a showing 1,4-

due to the complex nature of the H NMR spectrum, however

phenyl translocation.

characterisation by mass spectrometry confirmed the desired

molecular ion at 438 (M + H⁺).

Cyclisation of 12b gave a low 10% yield of 34b and the

geometry of the alkene could not be defined.

Radical denitration-cyclisation of the activated secondary

stilbene tethered β-nitroacetamide 28 gave the expected indane

product 42 in a low 13% yield. Analysis of the NOESY

interactions between protons H₁-H₂(w), H₂-H₃(w) and H₁-H₃

(m) and the J_1,2and J_2,3values (9.4 and ~ 9.0 Hz respectively)

of 42 led to the tentative assignment of the major diastereoisomer

as the trans,trans-configuration. Cyclisation of the more flexible

hexenyl tethered activated secondary β-nitroacetamide 28 gave

the expected cyclopentane 43 isolated in an improved 36% yield,

as an inseparable 50:50 mixture of diastereoisomers.

Radical cyclisation of the gem-dimethyl substituted hexenyl β-

nitroacetamide 15 proceeded in a good 55% combined yield of

products 36 and 37. The major product 36 (46% yield) was the

expected 5-exo-trig product and was isolated as a mixture of

three diastereoisomers 40:30:30. The stereochemical assignment

of these methyl cyclopentane isomers was not possible due to the

3

1

complex nature of the H NMR spectrum. The minor product 37

was the phenyl translocation isomer (see ESI for data correlation

table). The relative stereochemistry of the ring substituents in

either 36 or 37 could not be determined, as the J_1,2values could

3

not be deciphered. The combined yield (55%) is similar to the

phenyl-tethered 8a (58%) and shows a Thorpe Ingold effect due

7

3. Conclusion

2854 (C-H) 1687 (C=O, amide) 1606, 1585, 1510, 1455 (C=C,

1

ACCEPTED MANUSCRIPT

Ar) 1182, 1148 (C-F, CF₃) H NMR (CDCl₃, 600 MHz) δ 2.19

(2H, m, CH₂CHN) 2.68 (2H, m, CH₂Ph) 3.79 (3H, s, OCH₃) 6.03

(1H, t, J = 7.7, CHN) 6.08 (1H, dd, J = 8.8, 2.5, ArH) 6.57 (1H,

dd, J = 8.8, 3.0, ArH) 6.87 (1H, dd, J = 8.6, 3.1, ArH) 7.10 (2H,

apt d, J = 6.8, ArH) 7.17 – 7.18 (3H, m, ArH) 7.21 (1H, apt t, J =

7.4, ArH) 7.26 – 7.31 (5H, m, ArH); ¹³C NMR (CDCl₃, 150

MHz) δ 32.6 (CH₂) 32.8 (CH₂) 55.5 (OCH₃) 59.9 (CHN) 113.5

(PMP-C) 113.5 (PMP-C) 116.7 (q, J = 289.1, CF₃) 126.3 (ArC)

126.8 (q, ArC) 128.5 (ArC) 128.5 (2C, ArC) 128.6 (2C, ArC)

128.7 (2C, ArC) 129.2 (2C, ArC) 131.4 (CH) 132.5 (CH) 137.6

(q, ArC) 141.2 (q, ArC) 157.5 (q, J = 35.0, COCF₃) 160.0 (q,

ArCO); ¹⁹F (CDCl₃, 282 MHz) δ – 67.4 ppm (3F, s, CF₃); m/z

A diverse range of β-nitroacetamides were synthesized to

probe the limitations of the radical denitration-cyclisation of

products derived from the nitro-Mannich reaction. It was found

that cyclisation could be performed on a variety of secondary

nitro groups onto tethered alkenes and alkynes. The formation of

indanes or cyclopentanes was achieved in 12-59% yield in

variable dr. Phenyl translocation as seen in products 31, 35a and

39, normally occurs at high dilution (10-4 M),³²but it would

appear can occur at much higher concentrations (0.34 M). The

stability of the resultant amidomethyl radicals providing the

driving force for the translocations. Phenyl translocation in

products 40a was not observed as there is no driving force for the

1,4-translocation, which would hypothetically only give another

primary radical. Cyclisation of 11b was much more successful

than cyclisation of either alkyne 12a,b which can be attributed to

the slower rate of intramolecular addition of radicals to alkynes

vs alkenes.³⁶The combined yields of 36 and 37 (55%) form gem-

dimethyl substituted hexenyl β-nitroacetamide 15 are comparable

to the yields of 30a and 31 (58%) from styryl tether 8a.

Interestingly the proportion of 1,4-phenyl translocation is lower

for 15, possibly reflecting the greater degrees of freedom in the

hexenyl tether. The low reactivity of 25 could also be attributed

to the flexible hexenyl tether. Radical cyclisation of a

comparatively sterically bulky radical derived from 28 resulted in

a lower yield (13%) than the equivalent unactivated secondary β-

nitroacetamide 19b, which underwent cyclisation in 34 % yield.

However the extra steric bulk at the radical centre led to an

increase in diastereoselectivity (cf 40b dr 60:40 to 42 dr 95:5).

Activation of the secondary nitro group by an adjacent benzene

ring resulted in successful cyclisation of the activated secondary

radical 29 to 43 in 36% yield. This is in contrast to the

unactivated secondary radical 5 (Scheme 3) which afforded a

poor yield of cyclized product 7 (20%). Successful cyclisation

(CI⁺) 414 (91 %, M + H⁺) 220 (100 %, C₉H₇F₃NO₂) 195 (42 %,

+

C₁₅H₁₅

)

HRMS (C₂₄H₂₂F₃NO₂) calcd 414.16809 found

414.167626.

4.3 Synthesis of cyclisation precursors.

(E)-1-nitro-hexa-1,5-diene (3)

A solution of nitromethane (3.40 mL, 61 mmol), triethylamine

(4.20 mmol) and 4-penten-1-al (1.00 g, 12.2 mmol) was stirred

overnight under N₂at rt. The excess nitromethane and base were

removed in vacuo; purification by silica plug gave nitroalcohol

which was used directly in the next step. Purified nitroalcohol

(12.2 mmol) was dissolved in dry CH₂Cl₂(120 mL) under N₂and

cooled to 0 C. MsCl (14.4 mmol) was added dropwise and the

reaction stirred for 5 min before dropwise addition of a solution

of DIPEA (30.0 mmol) in dry DCM (25 mL). The reaction was

o

stirred at 0 C until complete before warming to rt. The reaction

was washed with H₂O (60 mL x 2), 2M HCl (60 mL x 2), dried

(MgSO₄) filtered and conc in vacuo. Purification via flash

column chromatography (5 % Et₂O/hexanes) afforded 64c as a

1

colourless oil (1.02 g, 8.02 mmol, 66 %); H NMR (CDCl₃, 500

MHz) δ 2.27 – 2.41 (4H, m, CH₂) 5.04 – 5.12 (2H, m, CH₂) 5.78

(1H, ddt, J = 17.0, 10.4, 6.5, CH₂CHCH₂CH₂) 6.99 (1H, d, J =

13.4, 1.6, CHNO₂) 7.26 (1H, dt, J = 13.4, 7.2, CHCHNO₂); NMR

data was consistent with published data.³⁸

n

required a 10 equivalent excess of Bu₃SnH and higher yields

were attained by increasing the substitution or reducing the

degrees of freedom of the tether between the nitro group and the

alkene.

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-((1R*,2S*)-2-nitro-1-

phenylhept-6-en-1-yl)acetamide (5)

4. Experimental section

4.1. General

To a solution of nitroalkene 3 (1.02 g, 8.02 mmol) in CH₂Cl₂

(40 mL) at rt under N₂was added dropwise LiHBEt₃(8.4 mL of a

1.0 M solution in THF, 8.4 mmol, 1.05 eq) and the reaction was

stirred for 20 min and a white precipitate was formed. The

See supplementary information.

o

reaction mixture was cooled to –78 C and to this was added a

Crystallographic data (excluding structure factors) for the

structures in this paper have been deposited with the Cambridge

Crystallographic Data Centre as supplementary publication nos.

32a 1843325 and 35a 1843326. Copies of the data can be

obtained, free of charge, on application to CCDC, 12 Union

Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-

mail: deposit@ccdc.cam.ac.Uk)

solution of (E)-N-(4-methoxyphenyl)-1-phenylmethanimine (1.91

g, 9.06 mmol) in CH₂Cl₂(25 mL). The reaction was stirred for 10

min before dropwise addition of trifluoroacetic acid (9.22 mmol,

o

1.15 equiv) and the reaction was stirred at –78 C for 1.5 h or

until complete by TLC. The reaction was warmed for 5 min then

quenched with sat. aq. NaHCO₃solution (15 mL), extracted with

Et₂O (20 mL x 3) washed with brine (30 mL), dried (MgSO₄)

filtered and concentrated in vacuo. Crude β-nitroamine was re-

dissolved in CH₂Cl₂(10 ml) and cooled to –78^oC under N₂. To

this solution was added dropwise DIPEA (20.1 mmol, 2.5 equiv.)

followed by dropwise addition of trifluoroacetic anhydride (20.1

mmol, 2.5 mmol) and the reaction stirred for 18 h to rt. The

reaction was quenched with 2 M HCl (20 mL), extracted with

CH₂Cl₂(20 mL x 3), dried (MgSO₄), filtered and concentrated in

vacuo. to give the crude β-nitroacetamide. Purification by flash

column chromatography (10 % Et₂O/hexanes) afforded 5 as a

mixture of diastereoisomers (>90:10) as a yellow oil (1.97 g, 4.52

mmol, 56 %); IR υ_max(CDCl₃cast) 2936 (C-H) 1697 (C=O) 1608

(Ar, C=C) 1585 (Ar, C=C) 1554 (N-O) 1510 (Ar, C=C) 1254 (C-

4.2. N-(1,3-diphenylpropyl)-2,2,2-trifluoro-N-(4-

methoxyphenyl)acetamide (2)

To a solution of β-nitroacetamide 1^8a(20.0 mg, 44.0 ꢀmol, 1 eq),

in PhMe (1 mL) under N₂at rt were added AIBN (5.0 mg, 30

ꢀmol, 0.7 eq) and Bu₃SnH (0.12 mL, 0.45 mmol, 10 eq), the

reaction mixture degassed and heated to reflux for 15 min under

N₂. The reaction mixture was then cooled to rt, concentrated. in

vacuo and the residue taken up in MeCN/Hexane (50:50, 10 mL).

The MeCN/Hexane layers were partitioned, with extraction of the

Hexane layer with MeCN (5 mL x 2). The combined MeCN

extracts were washed with Hexane (10 mL x 3) and the MeCN

layer was concentrated in vacuo. Purification by flash column

chromatography (0 – 10% Et₂O/Pet. ether) afforded 2 as a

colourless oil (12.7 mg, 79 %); IR υ_max(CDCl₃cast) cm^-12931,

O) 1180 (CF₃, C-F) 1033 (C-N) cm^-1; H NMR (400 MHz,

CDCl₃) δ 1.54 – 1.63 (2H, m, CH₂CH₂CH₂) 2.16 – 2.34 (4H, m,

1

8

Tetrahedron

ACCEPTED MANUSCRIPT

CH₂CH₂CH₂) 3.86 (3H, s, OCH₃) 5.08 (1H, br.d, J = 10.1,

130.4 (PMP-C) 131.7 (PMP-C) 131.8 (q, ArCCHCH₂) 133.3 (q,

CH₂CH₂CHCH_2-cis) 5.12 (1H, dm, J = 17.1, CH₂CH₂CHCH_2-trans

)

ArC) 134.2 (ArCCHCH₂) 137.6 (q, ArC) 158.2 (q, J = 36.0,

COCF₃) 160.5 (q, ArCO); ¹⁹F NMR (CDCl₃, 282 MHz) δ – 67.3

ppm (3F, s, CF₃); m/z (CI⁺) 485 (100 %, M + H⁺) 438 (63 %,

C₂₆H₂₃F₃NO₂) 308 (55 %, C₁₆H₁₃F₃NO₂) 219 (94 %, C₉H₈F₃NO₂);

HRMS (C₂₆H₂₄F₃N₂O₄) calcd. 485.1683, found 485.1682.

5.33 (1H, apt br t, J = 10.0, CHNO₂) 5.78 – 5.88 (1H, ddt, J =

17.1, 10.2, 6.7, CH₂CHCH₂) 6.04 (1H, br m, CHN) 6.29 (1H, br

d, J = 7.2, ArH) 6.68 (1H, dd, J = 8.9, 6.6, PMP-H) 6.90 (1H, dd,

J = 8.7, 2.8, PMP-H) 6.96 (1H, br d, J = 1.9, PMP-H) 7.09 (2H,

d, J = 7.4, ArH) 7.25 -7.36 (3H, dm, ArH); ¹³C NMR (CDCl₃,

125 MHz) δ 24.9 (CH₂CH₂CH₂) 31.0 (CH₂CH₂CH₂) 32.6

(CH₂CH₂CH₂) 55.6 (OCH₃) 59.3 (CHN) 87.8 (CNO₂) 114.0

(ArC) 114.3 (ArC) 116.1 (CH₂CHCH₂R) 116.3 (q, J = 286.9, CF₃

) 128.8 (2C, ArC) 129.1 (q) 129.2 (2C, ArC) 129.7 (ArC) 130.1

(ArC) 132.2 (ArC) 133.4 (q) 137.2 (CH₂CHCH₂CH₂) 158.0 (q, J

= 35.3, COCF₃) 160.5 (q, ArCO); ¹⁹F NMR (CDCl₃, 282 MHz) δ

-67.7 (3F, s, CF₃); m/z (CI⁺) 437 (44 %, M + H⁺) 390 (100 %,

ethyl

(2S*,3S*)-3-nitro-2-(2,2,2-trifluoro-N-(4-

methoxyphenyl)acetamido)-4-(2-vinylphenyl)butanoate (8b)

By an identical procedure to the preparation of 5 using 2-

vinyl-trans-β-nitrostyrene 9 (0.78g, 4.42 mmol) and Ethyl N-(4-

methoxyphenyl)-formimidate (1.04 g, 5.02 mmol). Purification

via flash column chromatography afforded the product 8b as a

o

white solid (1.34 g, 2.79 mmol, 63 %) mp 105 - 106 C; IR ν_max

+

C₂₂H₂₃F₃NO₂) 308 (17 %, C₁₆H₁₃F₃NO₂) 220 (16 %,

C₉H₇F₃NO₂); HRMS (C₂₂H₂₃F₃N₂O₄) calcd. 437.1688, found

437.1682.

(thin film) 2983 (C-H) 1747 (C=O, ester) 1701 (C=O, amide)

1561 (N-O, asymm) 1510 (C=C, Ar) 1300 (N-O, symm) 1157

(C-F, CF₃) cm^-1; H NMR (CDCl₃, 600 MHz) δ 1.30 (3H, t, J =

1

7.1, CH₂CH₃) 3.15 (1H, dd, J = 14.1, 11.7, ArCH₂) 3.51 (1H, dd,

J = 14.1, 3.6, ArCH₂) 3.87 (3H, s, ArOCH₃) 4.30 (2H, q, J = 7.1,

CH₂CH₃) 4.94 (1H, d, J = 8.5, CHN) 5.43 (1H, d, J = 10.9,

ArCHCH_2-cis) 5.61 (1H, ddd, J = 11.7, 8.8, 3.6, CHNO₂) 5.72

(1H, d, J = 17.1, ArCHCH_2-trans) 6.84 (1H, dd, J = 17.1, 11.0,

ArCHCH₂) 6.97 (2H, br s, PMP-H) 7.01 (1H, d, J = 7.6, ArH)

7.22 (1H, t, J = 7.5, ArH) 7.30 (1H, t, J = 7.6, ArH) 7.30 (1H, br

s, PMP-H) 7.53 (2H, m, ArH, PMP-H); ¹³C NMR (CDCl₃, 150

MHz) δ 13.9 (CH₂CH₃) 35.5 (ArCH₂) 55.7 (ArOCH₃) 63.3

(OCH₂CH₃) 67.5 (CHN) 86.9 (CNO₂) 114.7 (PMP-C) 115.3

(PMP-C) 116.0 (q, CF₃) 118.2 (ArCHCH₂) 126.8 (ArC) 128.4

(ArC) 128.6 (ArC) 129.2 (PMP-C) 129.6 (PMP-C) 130.1 (ArC)

131.1 (q, ArCCH₂CHNO₂) 132.3 (q, ArCN) 133.3 (CHCH₂)

137.4 (q, ArCCHCH₂) 158.6 (q, J = 37.1, COCF₃) 160.6 (q,

ArCOCH₃) 166.5 (q, COCH₂CH₃) ; ¹⁹F NMR (CDCl₃, 282 MHz)

δ - 67.9 ppm (3F, s, CF₃); m/z (ESI⁺) 544 (58 %, M + MeCN +

Na⁺) 481 (100 %, M + H⁺) 434 (9 %, C₂₃H₂₃F₃NO₄); HRMS

(C₂₃H₂₄F₃N₂O₆) calcd. 481.1616, found 481.1586.

(E)-2-vinyl-β-nitrostyrene (9)

To a solution of aldehyde 2-vinylbenzaldehyde (9) (2.00 g,

15.1 mmol) and nitromethane (2.05 mL, 36.0 mmol) in methanol

(8 mL) at 0 ^oC was added aq. 1M NaOH (35 mL) dropwise while

maintaining an internal reaction temperature of 10-15 °C. Ice

water (25 mL) was added and the reaction stirred at 0 °C for 15

min. The reaction mixture was then added to 8 M HCl (25 mL) at

0 °C to give a blue colour. The reaction was left to stir overnight

giving a yellow colour. The product was extracted with CH₂Cl₂

(80 mL x 3), washed with brine (80 mL) dried (MgSO₄), filtered

and conc in vacuo to give the crude nitroalkene, which was

purified by recrystallisation (Et₂O/Pet. Ether) to give 10 as a

1

yellow oil (2.22 g, 12.7 mmol, 85 % yield); H NMR (CDCl₃,

600 MHz) δ 5.53 (1H, dd, J = 11.0, 0.7, ArCHCH_2-cis) 5.66 (1H,

dd, J = 17.3, 0.8, ArCHCH_2-trans) 7.02 (1H, dd, J = 17.2, 11.0,

ArCHCH₂) 7.34 (1H, t, J = 7.5, ArH) 7.47 (1H, t, J = 7.4, ArH)

7.50 (1H, d, J = 13.6, CHNO₂) 7.51 (1H, d, J = 7.9, ArH) 7.54

(1H, d, J = 7.9, ArH) 8.36 (1H, d, J = 13.5, CHCHNO₂); ¹³C

NMR (CDCl₃, 150 MHz) δ 120.0 (ArCHCH₂) 127.9 (q, ArC)

127.9 (2C, ArC) 128.4 (ArC) 132.0 (ArC) 133.7 (ArCHCH₂)

137.1 (CHCHNO₂) 138.3 (CHNO₂) 139.7 (q, ArC); m/z (CI⁺)

176 (22 %, M + H⁺) 131 (100 %, C₁₀H₉D⁺); HRMS C₁₀H₁₀NO₂

calcd. 176.0706 found 176.0707. NMR Data was consistent with

published data.²²

methyl

(E)-3-(2-((2S*,3R*)-2-nitro-3-phenyl-3-(2,2,2-

trifluoro-N-(4-methoxyphenyl)acetamido)propyl)phenyl)acrylate

(11a)

To a solution of alkene 8a (209 mg, 0.43 mmol) in degassed

methyl acrylate (4.40 mL, 48.6 mmol) was added Hoveyda-

Grubbs 2^ndgeneration catalyst (29.4 mg, 0.046 mmol) and the

o

reaction was stirred at 75 C o/n. Purification by flash column

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-((1R*,2S*)-2-nitro-1-

phenyl-3-(2-vinylphenyl)propyl)acetamide (8a)

chromatography using EtOAc/Hexanes (10-20 %) followed by a

second column using EtOAc/Hexanes (40 %) afforded 11a as a

colourless oil (170 mg, 0.34 mmol, 82 %); mp 67 - 70 ^oC; IR ν_max

(thin film) 2949, 2838 (C-H) 1695 (C=O, amide & ester) 1633

(C=C) 1555 (N-O, asymm) 1508 (C=C, Ar) 1317 (N-O, symm)

By an identical procedure to the preparation of 5 using

nitrostyrene

methoxyphenyl)-1-phenylmethanimine (1.63 g, 7.72 mmol).

Purification via flash column chromatography (40

9

(1.22 g, 6.98 mmol) and (E)-N-(4-

1

%

1153 (C-F, CF₃) cm^-1; H NMR (CDCl₃, 600 MHz) δ 3.63 (1H,

CH₂Cl₂/Hexanes followed by 20 % Et₂O/Hexanes) afforded 8a as

a white solid (1.27 g, 2.62 mmol, 38 %); mp 90 – 92 C; IR ν_max

dd, J = 14.7, 11.6, ArCH₂) 3.73 (1H, dd, J = 14.6, 3.6, ArCH₂)

3.81 (3H, s, ArOCH₃) 3.86 (3H, s, COOCH₃) 5.57 (1H, br s,

CHNO₂) 6.15 (1H, br s, CHN) 6.36 (1H, br s, ArH) 6.48 (1H, d,

J = 15.7, ArCHCHCO₂CH₃) 6.66 (1H, apt d, J = 7.3, ArH) 6.99

(1H, dd, J = 8.7, 2.5, ArH) 7.07 (2H, d, J = 7.2, ArH) 7.16 – 7.37

(7H, m, ArH) 7.60 (1H, dd, J = 7.6, 2.2, ArH) 8.08 (1H, d, J =

15.7, ArCHCHCO₂CH₃); ¹³C NMR (CDCl₃, 150 MHz) δ 35.5

(ArCH₂) 52.0 (COOCH₃) 55.6 (ArOCH₃) 65.9 (CHN) 89.2

(CNO₂) 114.4 (PMP-C) 114.5 (PMP-C) 116.3 (q, J = 287.3, CF₃)

121.4 (CHCOOCH₃) 127.4 (ArC) 128.1 (ArC) 128.7 (ArC) 128.9

(ArC) 129.5 (ArC) 129.8 (ArC) 130.6 (ArC) 130.8 (2C, PMP-C)

132.1 (q, ArCCHCHCO) 133.0 (q, ArCCH₂) 133.7 (q, ArCN)

133.7 (ArCCN) 140.9 (CHCHCOOCH₃) 158.4 (q, J = 35.4,

COCF₃) 160.5 (ArCOCH₃) 167.0 (q, COOCH₃); ¹⁹F NMR

(CDCl₃, 282 MHz) δ – 67.1 ppm (3F, s, CF₃); m/z (CI⁺) 543 (22

o

(thin film) 1696 (C=O stretch, amide) 1556 (N-O, asymm) 1510

1

(C=C, Ar) 1300 (N-O symm) 1153 (C-F, CF₃) cm^-1; H NMR

(CDCl₃, 600 MHz) δ 3.56 (1H, dd, J = 14.5, 11.2, ArCH₂) 3.67

(1H, dd, J = 11.2, 3.3, ArCH₂) 3.81 (3H, s, OCH₃) 5.50 (1H, dd,

J = 10.9, 1.1, ArCHCH_2-trans) 5.74 (1H, dd, J = 17.4, 1.1,

ArCHCH_2-cis) 5.74 (1H, br s, CHNO₂) 5.95 (1H, br s, CH) 6.52

(1H, br s, CH) 6.74 (1H, br d, J = 8.8, PMP-H) 6.89 (1H, dd, J =

8.8, 2.8, PMP-H) 7.03 (1H, br d, J = 8.1, PMP-H) 7.07 (1H, dd, J

= 17.4, 10.9, ArCHCH₂) 7.15 (3H, br d, J = 7.4, ArH) 7.23 – 7.27

(3H, m, ArH) 7.29 (1H, dd, J = 7.7, 1.1, ArH) 7.32 (1H, d, J =

7.5, ArH) 7.52 (1H, d, J = 7.5, ArH); ¹³C NMR (CDCl₃, 150

MHz) δ 35.6 (ArCH₂) 55.6 (OCH₃) 66.9 (CHN) 88.9 (CHNO₂)

114.0 (PMP-C) 114.7 (PMP-C) 116.3 (q, J = 291.2, CF₃) 118.0

(ArCHCH₂) 127.0 (ArC) 128.4 (ArC) 128.5 (ArC) 128.8 (q,

ArC) 129.0 (2C, ArC) 129.5 (ArC) 129.8 (ArC) 129.9 (ArC)

+

%, M + H⁺) 511 (100 %, C₂₇H₂₂F₃N₂O₅) 220 (60 %,

9

C₉H₇F₃NO₂D⁺); HRMS (C₂₈H₂₆F₃N₂O₆) calcd. 543.1743, found

543.1740.

ArCO); ¹⁹F NMR (CDCl₃, 282 MHz) ) δ_anti– 67.4 ppm (3F, s,

ACCEPTED MANUSCRIPT

CF₃) δ_syn– 67.2 ppm (3F, s, CF₃); m/z (ESI⁺) 552 (23 %, M +

Na⁺) 547 (45 %, M + NH₄) 530 (100%, M + H⁺); HRMS (C-

+

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-((1R*,2S*)-2-nitro-1-

phenyl-3-(2-((E)-styryl)phenyl)propyl)acetamide (11b)

₂₆H₂₃F₃N₃O₆) calcd. 530.1539, found 530.1535.

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-((1R*,2S*)-2-nitro-1-

phenyl-3-(2-((trimethylsilyl)ethynyl)phenyl)propyl)acetamide

(12a)

To a degassed mixture of alkene 8a (876 mg, 1.81 mmol) in

CH₂Cl₂(15 mL) was added Hoveyda-Grubbs 2^ndgeneration

catalyst (56.7 mg, 0.091 mmol) followed by degassed styrene

(2.10 mL, 18.9 mmol) and the reaction was heated to 40 ^oC for 7

h before the addition of a second portion of catalyst (28.6 mg,

0.05 mmol) and degassed styrene (1.00 mL, 9.00 mmol), the

reaction was heated o/n until complete by TLC. The reaction was

concentrated in vacuo. Purification by flash column

chromatography using EtOAc/Hexanes (0-10 %) afforded 11b as

By an identical procedure to the preparation of 5 using

nitroalkene 14a²³(2.28 g, 9.30 mmol) and (E)-N-(4-

methoxyphenyl)-1-phenylmethanimine (2.28 g, 10.0 mmol).

Purification by flash column chromatography (50

%

CH₂Cl₂/Hexanes followed by 5 % EtOAc/Petrol) afforded 12a as

o

a white solid (3.06 g, 5.52 mmol, 58 %); mp 49 – 51 C; IR ν_max

o

a white solid (0.79 g, 1.41 mmol, 78 %); mp 68 - 70 C; IR ν_max

(thin film) 2962 (C-H) 2155 (C-C, alkyne) 1698 (C=O, amide)

1556 (N-O, asymm) 1300 (N-O, symm) 1179, 1153 (C-F, CF₃)

(thin film) 1697 (C=O, amide) 1557 (N-O, asymm) 1510 (C=C,

Ar) 1301 (N-O, symm) 1182 (C-F, CF₃) cm^-1; ¹H NMR (CDCl₃,

600 MHz) δ 3.56 (1H, dd, J = 14.4, 11.5, CH₂) 3.70 (3H, s,

OCH₃) 3.77 (1H, dd, J = 14.4, 3.3, CH₂) 5.65 (1H, br s, CHNO₂)

6.02 (1H, br s, CHN) 6.22 (1H, br s, PMP-H) 6.39 (1H, br s,

PMP-H) 6.62 (1H, br d, J = 7.3, PMP-H) 6.89 (1H, dd, J = 8.5,

1.8, PMP-H) 7.05 (2H, br d, J = 6.5, ArH) 7.12 (1H, d, J = 7.5,

1.2, ArH) 7.13 (1H, d, J = 16.0, PhCHCHAr) 7.19 (2H, t, J = 7.8,

ArH) 7.24 (1H, td, J = 7.5, 1.2, ArH) 7.28 (1H, m, ArH) 7.33

(2H, m, ArH) 7.42 (2H, m, ArH) 7.48 (1H, d, J = 16.0,

ArCHCHPh) 7.64 (1H, d, J = 7.6, ArH) 7.67 (2H, d, J = 7.4,

ArH); ¹³C NMR (CDCl₃, 150 MHz) δ 36.1 (CH₂) 55.6 (OCH₃)

66.3 (CHN) 89.3 (CHNO₂) 113.5 (PMP-C) 114.9 (PMP-C) 116.3

(q, CF₃, J = 290.3) 125.3 (ArCHCHPh) 127.1 (ArC) 127.2 (2C,

ArC) 128.3 (ArC) 128.5 (ArC) 128.6 (2C, ArC) 128.9 (2C, ArC)

129.0 (2C, ArC) 129.4 (2C, ArC) 129.7 (ArC) 130.4 (2C, PMP-

C) 131.7 (q, ArCCHCHPh) 132.2 (q, ArCN) 132.8 (ArCHCHPh)

133.2 (q, ArCCHN) 136.8 (q, ArCCH₂) 137.1 (q,

ArCCHCHArCH₂) 158.3 (q, J = 35.6, COCF₃) 160.3 (ArCOCH₃)

1

cm^-1; H NMR (CDCl₃, 600 MHz) δ 0.32 (9 H, s, OSi(CH₃)₃)

3.72 (1H, dd, J = 14.5, 4.0, ArCH₂) 3.81 (1H, dd, J = 14.8, 10.5,

ArCH₂) 3.81 (3H, s, OCH₃) 5.79 (1H, apt t, J = 8.6, CHNO₂) 6.13

(1H, d, J = 7.3) 6.38 (1H, d, J = 6.2, PMP-H) 6.67 (1H, dd, J =

8.9, 2.7, PMP-H) 6.89 (1H, dd, J = 8.7, 2.8, PMP-H) 7.10 (2H, d,

J = 7.5, ArH) 7.13 (1H, d, J = 8.6, ArH) 7.23 (2H, apt d, J = 7.8,

ArH) 7.26 (2H, apt d, J = 8.8, ArH) 7.29 – 7.33 (2H, m, ArH)

7.54 (1H, d, J = 7.7, ArH); ¹³C NMR (CDCl₃, 150 MHz) δ 0.05

(Si(CH₃)₃) 36.5 (CH₂Ar) 55.6 (ArCOCH₃) 65.8 (CHN) 88.0

(CNO₂) 100.1 (q, CSi(CH₃)₃) 102.9 (CCSi) 114.1 (PMP-C) 114.3

(PMP-C) 116.3 (q, J = 288.3, CF₃) 123.3 (q) 127.8 (ArC) 128.3

(q, PMP-CN) 128.8 (ArC) 128.9 (ArC) 129.3 (ArC) 129.5 (ArC)

129.7 (ArC) 130.6 (ArC) 132.1 (PMP-C) 133.3 (q) 133.8 (ArC)

136.3 (q) 158.1 (q, J = 36.0, CF₃CO) 160.4 (ArCOCH₃); ¹⁹F

NMR (CDCl₃, 282 MHz) δ - 67.1 ppm (3F, s, CF₃); m/z (EI) 554

(10 %, M⁺) 508 (7 %, C₂₉H₂₉F₃NO₂Si) 217 (10 %, C₉H₇F₃NO₂);

HRMS (C₂₉H₂₉F₃N₂O₄Si) calcd. 554.1849, found 554.1827.

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-((1R*,2S*)-2-nitro-1-

phenyl-3-(2-(phenylethynyl)phenyl)propyl)acetamide (12b)

;

¹⁹F NMR (CDCl₃, 282 MHz) δ – 67.2 ppm (3F, s, CF₃); m/z

(CI⁺) 578 (20 %, M + H₂O + H⁺) 560 (7 %, M + H⁺) 514 (14 %,

C₃₂H₂₇F₃NO₂); HRMS (C₃₂H₂₇N₂O₄F₃) calcd. 560.1923, found

560.1919.

By an identical procedure to the preparation of 5 using

nitroalkene 14b²⁴(4.23 g, 17.0 mmol) and (E)-N-(4-

methoxyphenyl)-1-phenylmethanimine (4.06 g, 19.2 mmol).

Purification by trituration in MeOH afforded 102wa as a mixture

of isomers (90:10 anti:syn, 6.17 g, 11.1 mmol, 65 %). Further

recrystallisation (Et₂O/Hexanes followed CH₂Cl₂/Hexanes x 2)

afforded anti-12b as a white solid (3.60 g, 6.44 mmol, 38 %); mp

160 – 162 ^oC; IR ν_max(thin film) 1696 (C=O, amide) 1556 (N-O,

asymm) 1509, 1495 (C=C, Ar) 1300 (N-O, symm) 1180, 1153

(C-F, CF₃) cm^-1; ¹H NMR (CDCl₃, 600 MHz) δ 3.62 (3H, s,

OCH₃) 3.73 (1H, dd, J = 14.1, 11.3, CH₂) 3.91 (1H, dd, J = 14.1,

3.8, CH₂) 5.71 (1H, dt, J = 11.0, 3.8, CHNO₂) 6.07 – 6.17 (2H,

m, PMP-H) 6.44 (1H, d, J = 9.1, CHN) 6.49 (1H, dd, J = 8.8, 2.8,

PMP-H) 7.00 (2H, d, J = 7.6, ArH) 7.17 – 7.23 (3H, m, ArH)

7.25 – 7.29 (2H, m, PMP-H & ArH) 7.30 – 7.33 (2H, m, ArH)

7.40 – 7.44 (ArH) 7.61 – 7.67 (ArH); ¹³C NMR (CDCl₃, 150

MHz) δ 37.0 (CH₂) 55.5 (OCH₃) 64.4 (CHN) 87.7 (q, CC) 88.2

(CHNO₂) 94.1 (CC) 113.2 (PMP-C) 114.5 (PMP-C) 116.3 (q, J =

288.4, CF₃) 122.9 (q, ArCCC) 122.9 (ArCCC) 127.3 (q, ArCN)

128.1 (ArC) 128.7 (2C, ArC) 128.8 (2C, ArC) 128.9 (ArC) 129.4

(ArC) 129.5 (2C, ArC) 129.7 (ArC) 129.9 (ArC) 130.6 (ArC)

132.1 (2C, PMP-C) 132.4 (ArC) 132.9 (ArCCHN) 133.6 (ArC)

135.8 (q, ArCCH₂) 158.3 (q, J = 35.6, COCF₃) 160.2 (q, ArCO);

¹⁹F NMR (CDCl₃, 282 MHz) δ – 67.0 (3F, s, CF₃); m/z (EI) 558

(100 %, M⁺) 190 (84 %, C₁₅H₁₁); HRMS (C₃₂H₂₅F₃N₂O₄) calcd.

558.1766, found 558.1734.

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-((1R*,2S*)-2-nitro-3-

(2-((E)-2-nitrovinyl)phenyl)-1-phenylpropyl)acetamide (11c)

A mixture of alkene 8a (0.30 g, 0.62 mmol), AgNO₂(0.29 g,

1.86 mmol) 4 Å molecular sieves (0.19 g) and TEMPO (0.02 mg,

o

0.12 mmol) in DCE (6 mL) was stirred at 70 C for 1.5 h under

air. On completion, the reaction mixture was filtered through

celite, washed with DCM and concentrated in vacuo. Purification

via flash column chromatography (10-20 % EtOAc/Hexanes)

afforded 11c as a white solid (271 mg, 0.51 mmol, 83 %) as a

o

mixture of isomers (90:10); mp 72 – 74 C; IR ν_max(thin film)

2968, 2841 (C-H) 1695 (C=O, amide) 1556 (N-O, asymm) 1509

1

(C=C, Ar) 1341 (N-O, symm) 1180, 1154 (C-F, CF₃) cm^-1; H

NMR (CDCl₃, 600 MHz) δ_anti3.68 (1H, dd, J = 14.7, 10.9, CH₂)

3.72 (1H, dd, J = 14.7, 4.6, CH₂) 3.83 (3H, s, OCH₃) 5.70 (1H, br

s, CHNO₂) 5.99 (1H, br s, CHN) 6.50 (1H, br s, PMP-H) 6.74

(1H, dd, J = 8.7, 2.4, PMP-H) 6.98 (1H, dd, J = 8.7, 2.7, PMP-H)

7.09 (1H, d, J = 7.6, PMP-H) 7.13 (2H, m, ArH) 7.25 (2H, d, J =

7.5, ArH) 7.30 – 7.42 (4H, m, ArH) 7.55 (1H, d, J = 13.4,

CHNO₂) 7.56 (1H, dd, J = 7.7, 1.1, ArH) 8.37 (1H, d, J = 13.4,

CHCHNO₂) δ_syn3.02 (1H, dd, J = 15.2, 2.9, CH₂) 3.18 (1H, dd, J

= 15.2, 11.6, CH₂) 7.93 (1H, d, J = 13.4, CHCHNO₂); ¹³C NMR

(CDCl₃, 150 MHz) δ_anti35.3 (CH₂) 55.6 (OCH₃) 66.8 (CHN) 89.6

(CHNO₂) 114.2 (PMP-C) 115.0 (PMP-C) 116.3 (q, J = 289.1,

CF₃) 128.0 (ArC) 128.5 (q, ArC) 129.0 (3C, ArC) 129.3 (q, ArC)

129.4 (2C, ArC) 130.0 (CH) 130.2 (CH) 131.4 (PMP-C) 131.7

(br CH) 132.5 (ArC) 133.0 (q, ArC) 135.2 (CHCHNO₂) 135.3 (q,

ArC) 139.4 (CHCHNO₂) 158.5 (q, J = 36.0, COCF₃) 160.6 (q,

(E)-1-nitro-2,2-dimethyl-hexa-1,5-diene (17)

A solution of 2,2-dimethylpent-4-enal (2.00 mL, 14.7 mmol),

triethylamine (1.03 mmol, 0.35 equiv.) and nitromethane (4.00

10

Tetrahedron

ACCEPTED MANUSCRIPT

mL, 74.1 mmol, 5.0 equiv.) was stirred overnight under N₂at

in DCM (5 mL) under N₂at – 78 °C over 7 min. The reaction

rt. The nitromethane and trimethylamine were removed in vacuo;

purification by silica plug gave nitroalcohol which was used

directly in the next step. To a solution of the purified nitroalcohol

(14.7 mmol) in dry DCM (45 mL) under N₂at -78 ^oC was added

TFAA (17.6 mmol, 1.2 equiv.) dropwise and the reaction stirred

for 5 min before the dropwise addition of DIPEA (36.8 mmol,

was stirred at – 78 °C for 0.5 h before addition of a solution of

(E)-N-(4-methoxyphenyl)-1-phenylmethanimine (340 mg, 1.60

mmol) in DCM (2.5 mL) to the reaction mixture at – 78 °C. The

reaction was stirred for 10 min before the addition of TFA (0.13

mL, 1.80 mmol) the reaction was then stirred for a further 1.5 h

o

at – 78 C. The reaction was warmed for 5 min before the

o

2.50 equiv.). The reaction was stirred at - 78 C until complete

addition of sat. aq. NaHCO₃solution (15 mL) giving a yellow

colour. The product was extracted with Et₂O (20 mL x 2),

washed with brine (20 mL), dried (MgSO₄) filtered and

concentrated in vacuo. to give the crude nitroamine. The crude β-

nitroamine was redissolved in dry DCM (10 mL) under N₂and

cooled to – 78 °C. To the solution was added DIPEA (0.44 mL,

2.5 mmol) followed quickly by dropwise addition of TFAA (0.35

mL, 2.5 mmol). The reaction mixture was left to stir overnight

and warm to rt and quenched on addition of 2M HCl (15 mL).

The phases were separated and the aq. layer extracted with DCM

(20 mL x 2), dried (MgSO₄), filtered and conc in vacuo.

Purification by flash column chromatography (5 % EtOAc/PE

followed by 10 % EtOAc/Petrol) afforded 18 as a mixture of

diastereoisomers anti:syn 75:25 as a yellow oil (0.19 g, 0.37

mmol, 37 %); IR υ_max(CDCl₃cast) 2947 (C-H) 1697 (C=O)

1607, 1585 (Ar, C=C) 1552 (N-O) 1510 (Ar, C=C) 1254 (C-O)

reaction (tlc) before warming to rt. The reaction was quenched

with 2M HCl (50 mL) extracted with CH₂Cl₂(50 mL x 3),

washed with sat. NaCl solution (50 mL), dried (MgSO₄) filtered

and conc in vacuo. Purification by flash column chromatography

(2 % EtOAc/Hexanes) afforded 17 as a colourless oil (1.19 g,

7.67 mmol, 52 %); IR ν_max(thin film) 2966 (C-H) 1642 (C=C)

1524 (N-O, asymm) 1348 (N-O, symm) cm^-1; ¹H NMR (CDCl₃,

500 MHz) δ 1.13 (6H, s, C(CH₃)₂) 2.18 (2H, apt dt, J = 7.4, 1.0,

CCH₂) 5.07 (1H, dm, J = 17.0, CH₂CHCH_2-trans) 5.12 (1H, dm, J

= 10.2, CH₂CHCH_2-cis) 5.70 (1H, ddt, J = 17.0, 10.3, 7.4,

CH₂CH) 6.88 (1H, d, J = 13.6, CHCHNO₂) 7.25 (1H, d, J = 13.7,

CHCHNO₂); ¹³C NMR (CDCl₃, 125 MHz) δ 26.1 (2C, CH₃) 35.9

(q, C(CH₃)₂) 46.3 (C(CH₃)₂CH₂) 119.0 (CCH₂CHCH₂) 133.1

(CHCH₂) 138.0 (CHNO₂) 150.9 (CHCHNO₂); m/z (ESI+) 194.1

(6 %, M + K⁺) 178.1 (72 %, M + Na⁺) 156.1 (100 %, M + H⁺);

HRMS C₈H₁₄NO₂calcd. 156.1024 found 156.1030.

1179, 1154 (CF₃, C-F) 1033 (C-N) cm^-1; H NMR (CDCl₃, 400

1

MHz) ¹H NMR major anti δ 1.81 – 2.10 (3H, m, CH₂) 2.30 (1H,

m, CH₂) 3.49 (1H, dt, J = 12.5, 3.4, PhCHC₄H₇) 3.78 (3H, s,

OCH₃) 4.97 (1H, dd, J = 16.9, 1.3, CH₂CH₂CHCH_2-trans) 5.04

(1H, dd, J = 9.7, 0.7, CH₂CH₂CHCH_2-cis) 5.61 (1H, dd, J = 10.8,

4.2, CHNO₂) 5.80 – 5.82 (1H, m, CH₂CH) 6.20 (1H, apt d, J =

8.3, PMP-H) 6.35 (1H, d, J = 10.8, CHN) 6.60 (1H, dd, J = 8.8,

2.9, PMP-H) 6.87 (1H, dd, J = 8.7, 3.0, PMP-H) 7.03 (3H, m,

PMP-H & ArH) 7.45 – 7.19 (8H, m, ArH); ¹H NMR minor syn δ

3.56 (1H, dt, J = 11.6, 3.1, PhCHC₄H₇) 3.81 (3H, s, OCH₃) 5.09

(1H, dd, J = 10.2, 1.2, CH₂CH₂CHCH_2-trans) 6.65 (1H, dd, J = 8.9,

2.9, PMP-H) further signals indistinguishable; ¹³C NMR (CDCl₃,

125 MHz) major anti δ 23.9 (CH₂) 28.3 (CH₂) 44.9 (CHC₄H₇)

55.5 (OCH₃) 62.4 (CHN) 91.7 (CNO₂) 113.8 (PMP-C) 114.1

(PMP-C) 116.5 (CH₂CH) 116.5 (q, CF₃, J = 288.7) 127.5 (ArC)

128.1 (ArC) 128.2 (ArC) 128.4 (ArC) 128.7 (ArC) 128.8 (ArC)

128.9 (ArC) 129.3 (ArC) 129.5 (ArC) 130.5 (ArC) 132.4 (ArC)

133.4 (q, ArC) 134.8 (q, ArC) 137.0 (ArC) 137.3 (CH₂CH) 138.8

(q, ArC) 158.5 (q, J = 35.5, COCF₃) 160.4 (q, ArCO); ¹⁹F

(CDCl₃, 282 MHz) major anti δ -67.5 (3F, s, CF₃); m/z (CI⁺) 513

N-((1R*,2S*)-4,4-dimethyl-2-nitro-1-phenylhept-6-en-1-yl)-

2,2,2-trifluoro-N-(4-methoxyphenyl)acetamide (15)

By an identical procedure to the preparation of 5 using

nitroalkene 17 (0.70 g, 4.51 mmol) and (E)-N-(4-

methoxyphenyl)-1-phenylmethanimine (1.08 g, 5.11 mmol).

Purification by flash column chromatography (50

%

CH₂Cl₂/Hexanes) afforded 15 as a yellow oil (1.41g, 3.04 mmol,

67 %); IR ν_max(thin film) 2964 (C-H) 1701 (C=O, amide) 1556

(N-O asymm) 1510 (C=C, Ar) 1350 (N-O, symm) 1181, 1157

(C-F, CF₃) cm^-1; ¹H NMR (CDCl₃, 600 MHz) δ 0.95 (3H, s, CH₃)

1.07 (3H, s, CH₃) 2.05 – 2.11 (3H, m, CH₂) 2.33 (1H, dd, J =

15.3, 11.2, CH₂CHNO₂) 3.81 (3H, s, OCH₃) 5.11 (1H, dm, J =

17.0, CH₂CHCH_2-trans) 5.16 (1H, dm, J = 10.3, CH₂CHCH_2-cis

)

5.53 – 5.78 (2H, m, CHNO₂& CHN) 5.84 (1H, ddt, J = 17.1,

10.1, 7.4, CH₂CHCH₂) 6.40 (1H, m, PMP-H) 6.71 (1H, dd, J =

8.8, 2.2, PMP-H) 6.86 (1H, dd, J = 8.8, 2.9, PMP-H) 6.93 (1H,

apt d, J = 8.1, PMP-H) 7.12 (2H, d, J = 7.4, ArH) 7.25 (2H, apt t,

J = 7.7, ArH) 7.32 (1H, tm, J = 7.4, ArH); ¹³C NMR (CDCl₃, 150

MHz) δ 25.5 (CH₃) 26.6 (CH₃) 33.4 (C(CH₃)₂) 42.1 (CH₂CHNO₂)

47.9 (CH₂C(CH₃)₂) 55.6 (OCH₃) 66.8 (CHN) 85.0 (CHNO₂)

113.9 (PMP-C) 114.5 (PMP-C) 116.3 (q, J = 289.4, CF₃) 118.8

(CH₂CHCH₂C(CH₃)₂) 128.5 (q, ArCN) 128.8 (2C, ArC) 129.7

(2C, ArC) 129.8 (ArC) 130.3 (PMP-C) 131.9 (PMP-C) 132.9 (q,

ArCCHN) 134.2 (CH₂CHCH₂) 157.9 (q, J = 34.8, COCF₃) 160.4

(q, ArCO); ¹⁹F NMR (CDCl₃, 282 MHz) δ - 67.4 ppm (3F, s,

CF₃); m/z (ESI⁺) m/z 503 (21 %, M + K⁺) 497 (40 %, M +

CH₃OH + H⁺) 465 (100 %, M + H⁺); HRMS (C₂₄H₂₈F₃N₂O₄)

calcd. 465.2001, found 465.2018.

+

(42 %, M + H⁺) 466 (100 %, C₂₈H₂₇F₃NO₂) 308 (52 %,

+

C₁₆H₁₃F₃NO₂) 294 (22 %, C₁₉H₂₀NO₂) 220 (32 %, C₉H₇F₃NO₂)

145 (22 %C₁₁H₁₃⁺) HRMS C₂₈H₂₈F₃N₂O₄calcd. 513.2001 found

513.2006.

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-((1R*,2S*)-2-nitro-3-

phenyl-1-(2-vinylphenyl)propyl)acetamide (19a)

By an identical procedure to the preparation of 5 using trans-

β-nitrostyrene (1.00 g, 6.70 mmol) and imine 20a²⁵(1.80 g, 7.60

mmol). Purification by recrystallisation (MeOH/Hexanes)

afforded nitroacetamide 19a as a white solid (1.08 g, 2.22 mmol,

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-((1R*,3R*)-2-nitro-

1,3-diphenylhept-6-en-1-yl)acetamide (18)

o

33 %); mp 128 – 130 C; IR ν_max(thin film) 1697 (C=O, amide)

1556 (N-O, asymm) 1511 (C=C, Ar) 1325 (N-O, symm) 1182

1

(C-F, CF₃) cm^-1; H NMR (CDCl₃, 600 MHz) δ 3.55 (2H, m,

A flask charged with Mg (39.2 mg, 1.60 mmol) was flame

dried and stirred overnight under N₂to activate the magnesium.

Dry THF (2 mL) and a crystal of I₂were added and the mixture

heated to 70 °C. A portion of 4-bromobutene (0.03 mL, 0.30

mmol) was added to the reaction. After 50 min stirring at reflux,

the rest of the bromide (0.12 mL, 1.20 mmol) in THF (1 mL) was

added over 1 h at 0 °C, then the reaction was stirred at rt for 90

min to complete the generation of the Grignard reagent. The but-

3-enyl magnesium bromide was added to a solution of trans-β-

nitrostyrene (0.15 g, 1.00 mmol) and CuI (17.7 mg, 0.093 mmol)

CH₂CHNO₂) 3.80 (3H, s, OCH₃) 5.45 (1H, d, J = 10.9,

ArCHCH_2-cis) 5.45 (1H, br s, CHNO₂) 5.64 (1H, d, J = 17.2,

ArCHCH_2-trans) 6.07 (1H, br d, J = 6.1, PMP-H) 6.55 (1H, dd, J =

6.3, 2.8, PMP-H) 6.71 (2H, m, PMP-H, CHN) 6.91 (1H, dd, J =

8.7, 3.0, PMP-H) 6.96 (1H, t, J = 7.6, ArH) 7.03 (1H, dd, J =

17.0, 11.0, ArCHCH₂) 7.06 (1H, m, ArH) 7.23 – 7.28 (3H, m,

ArH) 7.32 (1H, apt t, J = 7.2, ArH) 7.37 (2H, apt t, J = 7.5, ArH)

7.49 (1H, d, J = 7.8, ArH); ¹³C NMR (CDCl₃, 150 MHz) δ 38.4

(PhCH₂) 55.6 (OCH₃) 58.5 (CHNPMP) 89.4 (CNO₂) 113.9

11

(PMP-C) 114.4 (PMP-C) 116.4 (q, J = 289.5) 119.2 (ArCHCH₂)

126.9 (q, ArCN) 127.4 (ArC) 127.6 (PMP-C) 127.8 (ArC) 128.0

(ArC) 128.7 (2C, ArC) 129.3 (2C, ArC) 129.8 (ArC) 129.9 (q,

ArCCHN) 130.0 (ArC) 132.6 (PMP-C) 133.7 (ArCHCH₂) 134.7

(q, ArCCH₂) 139.3 (q, ArCCHCH₂) 158.0 (q, J = 35.6, CF₃CO)

160.5 (ArCOCH₃); ¹⁹F NMR (CDCl₃, 282 MHz) δ - 67.0 ppm

(3F, s, CF₃); m/z (ES⁺) 507 (100%, M + Na⁺) 485 (80 %, M +

H⁺) 438 (75 %, C₂₆H₂₃F₃NO₂); HRMS (C₂₆H₂₄F₃N₂O₄) calcd.

485.1668, found 485.1688; Anal. Calcd. For C₂₆H₂₃F₃N₂O₄: C,

64.46; H, 4.79; N, 5.78; found: C, 64.46; H, 4.80; N, 5.76%.

(CHNO₂) 101.2 (CHO₂) 113.6 (PMP-C) 114.1 (PMP-C) 116.5

ACCEPTED MANUSCRIPT

(q, J = 288.5, CF₃) 126.8 (q, ArCN) 127.6 (ArC) 128.0 (ArC)

128.4 (ArC) 128.7 (2C, ArC) 128.8 (ArC) 129.2 (2C, ArC) 129.6

(ArC) 130.0 (PMP-C) 131.1 (q, ArCCHN) 133.2 (PMP-C) 135.0

(q, ArCCH₂) 136.7 (q, ArCCHO₂) 158.1 (q, J = 35.5, COCF₃)

160.3 (ArCOCH₃); ¹⁹F NMR (CDCl₃, 282 MHz) δ – 67.4 ppm

(3F, s, CF₃); m/z (CI⁺) 531 (100 %, M + H⁺) 484 (43 %,

C₂₇H₂₅F₃NO₄) 440 (6 %, C₂₀H₁₉F₃N₂O₆); HRMS (C₂₇H₂₆F₃N₂O₆)

calcd. 531.1738, found 531.1737.

2,2,2-trifluoro-N-((1R*,2S*)-1-(2-formylphenyl)-2-nitro-3-

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-((1R*,2S*)-2-nitro-3-

phenylpropyl)-N-(4-methoxyphenyl)acetamide (21)

phenyl-1-(2-((E)-styryl)phenyl)propyl)acetamide (19b)

A solution of nitroacetamide 23 (1.42 g, 2.69 mmol) and

FeCl₃/SiO₂(0.29 g, 5 % by weight) in acetone (64 mL) and the

reaction was stirred for 30 h. Additional portions of FeCl₃/SiO₂

(2 x 0.14 g) were added after 6 h and 24 h until there was no

further conversion. The reaction mixture was filtered through

celite and concentrated in vacuo. Purification by flash column

chromatography (15 – 25 % EtOAc/Hexanes) followed by

recrystallisation (CHCl₃/Hexanes) afforded 21 as a white solid

A solution of Al₂O₃(1 g per mmol) and p-anisidine (6.22

mmol) in dry DCM (30 mL) was stirred at rt under N₂for 5 min

before the addition of (E)-2-styrylbenzaldehyde³⁸(6.22 mmol)

and the reaction was stirred until complete (tlc). The reaction

mixture was filtered through celite and concentrated in vacuo to

give the crude imine 20b as an oil which was used directly

without further purification (97 % conversion).

o

(1.08 g, 2.22 g, 82 %); mp 90 - 92 C; IR ν_max(thin film) 2836

By an identical procedure to the preparation of 5 using trans-

β-nitrostyrene (0.83 g, 5.55 mmol) and imine 20b (1.95 g, 6.22

mmol). Purification by flash column chromatography (40 %

CH₂Cl₂/Hexanes) afforded 19b as a mixture of diastereomers

(95:5) as a white solid (1.11 mg, 2.00 mmol, 36 %); mp 65 - 67

^oC; IR ν_max(thin film) 1695 (C=O, amide) 1556 (N-O, asymm)

(C-H) 1692 (C=O, amide, aldehyde overlapped) 1604, 1508,

1454 (C=C, Ar) 1553 (N-O, asymm) 1300 (N-O, symm) 1150

(C-F, CF₃) cm^-1; ¹H NMR (CDCl₃, 600 MHz) δ 3.55 (1H, dd, J =

14.6, 10.4, CH₂) 3.59 (1H, dd, J = 14.5, 4.0, CH₂) 3.81 (3H, s,

OCH₃) 5.81 (1H, td, J = 10.4, 3.5, CHNO₂) 6.48 (1H, br d, J =

7.8, PMP-H) 6.71 (1H, dd, J = 8.9, 2.8, PMP-H) 6.86 (1H, dd, J

= 8.7, 2.8, PMP-H) 6.90 (1H, apt d, J = 8.5, PMP-H) 7.17 (1H, d,

J = 10.8, CHN) 7.26 (2H, d, J = 7.5, ArH) 7.29 – 7.39 (4H, m,

ArH) 7.42 (1H, td, J = 7.7, 1.2, ArH) 7.52 (1H, td, J = 7.5, 1.0,

ArH) 7.84 (1H, dd, J = 7.7, 1.3, ArH) 10.12 (1H, s, CHO); ¹³C

NMR (CDCl₃, 150 MHz) δ 38.5 (CH₂) 55.6 (OCH₃) 58.7 (CHN)

90.2 (CHNO₂) 114.0 (PMP-C) 114.9 (PMP-C) 116.2 (q, J =

289.0, CF₃) 128.1 (2C, ArC) 128.1 (q, ArCN) 128.8 (2C, ArC)

129.2 (ArC) 129.7 (ArC) 130.1 (PMP-C) 130.2 (ArC) 131.8

(PMP-C) 133.1 (ArC) 133.9 (ArC) 134.1 (q, ArC) 134.6 (q, ArC)

134.7 (q, ArC) 158.1 (q, J = 36.0, COCF₃) 160.6 (ArCOCH₃)

191.3 (CHO); ¹⁹F NMR (CDCl₃, 282 MHz) δ – 67.2 ppm (3F, s,

1510 (C=C, Ar) 1301 (N-O, symm) 1181 (C-F, CF₃) cm^-1; H

1

NMR (CDCl₃, 600 MHz) δ 3.58 (1H, dd, J = 14.6, 10.6, CH₂)

3.61 (1H, dd, 14.6, 4.0, CH₂) 3.77 (3H, s, OCH₃) 5.53 (1H, br s,

CHNO₂) 6.18 (1H, br s, PMP-H) 6.58 (1H, dd, J = 8.8, 2.6, PMP-

H) 6.81 (2H, br s, CH) 6.92 (1H, dd, J = 8.7, 2.8, PMP-H) 6.95 –

7.02 (2H, m, CH) 7.09 (1H, br d, J = 8.0, CH) 7.27 (2H, d, J =

7.2, CH) 7.30 – 7.35 (3H, m, CH) 7.36 – 7.44 (5H, m, CH) 7.57

(2H, d, J = 7.2, ArH) 7.65 (1H, d, J = 7.6, ArH); ¹³C NMR

(CDCl₃, 150 MHz) δ 38.4 (CH₂) 55.5 (OCH₃) 58.9 (CHN) 89.3

(CHNO₂) 113.9 (PMP-C) 114.4 (PMP-C) 116.3 (q, J = 288.1,

CF₃) 124.4 (CH) 127.0 (CH) 127.0 (CH) 127.4 (CH) 128.0 (CH)

128.1 (CH) 128.3 (CH) 128.7 (4C, CH) 128.7 (CH) 128.9 (CH)

129.0 (CH) 129.3 (CH) 129.8 (CH) 130.0 (CH) 130.1 (q, C)

132.4 (q, C) 133.5 (CH) 134.7 (q, C) 136.9 (q, C) 138.6 (q, C)

158.0 (q, J = 35.9, COCF₃) 160.5 (q, ArCO); ¹⁹F NMR (CDCl₃,

282 MHz) δ – 67.1 ppm (3F, s, CF₃); m/z (ESI⁺) 583 (100 %, M

+ Na⁺); HRMS (C₃₂H₂₇F₃N₂O₄Na) calcd. 583.1821, found

583.1823.

+

CF₃); m/z (ESI⁺) 504.2 (15 %, M + NH₄) 487.2 (100 %, M + H⁺)

440.2 (7 %, C₂₅H₂₁F₃NO₃); HRMS (C₂₅H₂₂F₃N₂O₅) calcd.

487.1481, found 487.1472.

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-((1R*,2S*)-2-nitro-3-

phenyl-1-(2-((E)-prop-1-en-1-yl)phenyl)propyl)acetamide (19d)

To a solution of aldehyde 21 (111 mg, 0.23 mmol) and 3-

pentanone (22 ꢀL, 0.21 mmol) in hexane (1 mL) was added

BF₃.OEt₂(0.015 mL, 0.15 mmol) and the solution was refluxed

for 90 mins and quenched with water (2 mL), extracted with Et₂O

(5 mL x 3), dried and concentrated in vacuo. Purification by flash

column chromatography (15 % EtOAc/hexanes) afforded 19d as

a colourless yellow oil (63.5 mg, 0.13 mmol, 61 % yield); IR ν_max

(thin film) 2914, 2847 (C-H) 1694 (C=O, amide) 1554 (N-O,

asymm) 1509 (C=C, Ar) 1298 (N-O, symm) 1178 (C-F, CF₃) cm^-

N-((1R*,2S*)-1-(2-(1,3-dioxolan-2-yl)phenyl)-2-nitro-3-

phenylpropyl)-2,2,2-trifluoro-N-(4-methoxyphenyl)acetamide

(23)

Imine 22 was formed in an identical method to 20b above

using 2-(1,3-dioxolan-2-yl)benzaldehyde.²⁶

By an identical procedure to the preparation of 5 using trans-

β-nitrostyrene (0.30 g, 2.00 mmol) and imine 22 (2.26 mmol).

Purification by flash column chromatography (40 - 60 %

CH₂Cl₂/Hexanes) afforded 23 as a white solid (0.51 g, 0.96

1

¹; H NMR (CDCl₃, 600 MHz) δ 1.92 (3H, dd, J = 6.6, 1.5,

CHCHCH₃) 3.54 – 3.58 (2H, m, CH₂) 3.79 (3H, s, OCH₃) 5.45

(1H, m, CHNO₂) 6.07 (2H, m, CHCHCH₃& PMP-H) 6.55 (1H,

dd, J = 8.9, 2.8, PMP-H) 6.67 – 6.77 (3H, m, CHN, CHCHCH₃&

ArH) 6.91 (1H, dd, J = 8.7, 2.6, PMP-H) 6.92 (1H, m, ArH) 7.06

(1H, apt d, J = 8.4, PMP-H) 7.23 (1H, td, J = 7.6, 0.5, ArH) 7.25

– 7.27 (2H, m, ArH) 7.30 – 7.39 (3H, m, ArH) 7.40 (1H, d, J =

7.5, ArH); ¹³C NMR (CDCl₃, 150 MHz) δ 18.8 (CHCH₃) 38.4

(CH₂) 55.6 (OCH₃) 58.8 (CHN) 89.4 (CHNO₂) 113.8 (PMP-C)

114.3 (PMP-C) 116.4 (q, J = 287.9, CF₃) 126.7 (ArC) 127.0 (q,

ArCN) 127.5 (ArC) 127.6 (CH) 127.8 (ArC) 128.0 (ArC) 128.7

(2C, ArC) 129.2 (2C, ArC) 129.6 (q, ArCCHN) 129.6 (CH)

130.0 (PMP-C) 131.1 (CHCHCH₃) 132.4 (PMP-C) 134.8 (q,

o

mmol, 48 %); mp 109 - 110 C; IR ν_max(thin film) 2890 (C-H)

1696 (C=O, amide) 1554 (N-O asymm) 1509 (C=C, Ar) 1299

(N-O, symm) 1180 (C-F, CF₃) cm^-1; ¹H NMR (CDCl₃, 600 MHz)

δ 3.55 – 3.60 (2H, m, CH₂) 3.78 (3H, s, OCH₃) 4.01 – 4.23 (4H,

m, OCH₂CH₂O) 5.37 (1H, ddd, J = 10.9, 9.5, 5.0, CHNO₂) 5.99

(1H, s, CHO₂) 6.16 (1H, dd, J = 8.8, 2.1, PMP-H) 6.47 (1H, dd, J

= 8.8, 2.9, PMP-H) 6.61 (1H, d, J = 7.9, ArH) 6.93 (1H, dd, J =

8.7, 3.0, PMP-H) 6.99 – 7.03 (2H, m, CHN & ArH) 7.14 (1H, dd,

J = 8.7, 2.6, PMP-H) 7.23 – 7.40 (6H, m, ArH) 7.69 (1H, dd, J =

7.8, 1.2, ArH); ¹³C NMR (CDCl₃, 150 MHz) δ 38.4 (ArCH₂) 55.5

(OCH₃) 56.7 (CHN) 65.3 (OCH₂CH₂O) 65.4 (OCH₂CH₂O) 89.5

12

Tetrahedron

ArCCH₂) 139.6 (q, ArCCHCHCH₃) 157.9 (q, J = 35.6,

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-((1R*,2R*)-2-nitro-2-

ACCEPTED MANUSCRIPT

COCF₃) 160.4 (q, ArCO); ¹⁹F NMR (CDCl₃, 282 MHz) δ - 67.2

phenyl-1-(2-((E)-styryl)phenyl)ethyl)acetamide (28)

ppm (3F, s, CF₃); m/z (CI⁺) 516 (76 %, M + NH₄) 499 (100 %,

+

To a solution of α-nitrotoluene (0.54 mL g, 4.50 mmol) in

M + H⁺) 452 (100 %, C₂₇H₂₅F₃NO₂) 348 (20 %, C₁₉H₁₇F₃NO₂)

+

o

n

THF (20 mL) at – 78 C under N₂was added dropwise BuLi

(4.95 mL of a 1.0 M solution in hexanes, 4.95 mmol, 1.10 eq,).

The reaction mixture was stirred for 15 min before addition of a

solution of imine 20b (1.60 g, 5.10 mmol) in THF (12 mL). The

reaction was stirred for 10 min before dropwise addition of

trifluoroacetic acid (5.13 mmol, 1.14 equiv) and the reaction was

+

280 (18 %, C₁₈H₁₈NO₂); HRMS (C₂₇H₂₆F₃N₂O₄) calcd.

499.1839, found 499.1839.

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-((2S*,3R*)-2-nitro-1-

phenylhept-6-en-3-yl)acetamide (25)

Imine 24 was formed in an identical method to 20b (in

preparation of 19b) using pent-4-enal.

o

stirred at – 78 C for 1.5 h or until complete by TLC. The

reaction was warmed for 5 min then quenched with sat. aq.

NaHCO₃solution (50 mL), extracted with Et₂O (50 mL x 3)

washed with brine (50 mL), dried (MgSO₄) filtered and

concentrated in vacuo. Crude β-nitroamine was re-dissolved in

CH₂Cl₂(50 ml) and cooled to – 78^oC under N₂. To this solution

was added dropwise DIPEA (11.3 mmol, 2.5 equiv.) followed by

dropwise addition of trifluoroacetic anhydride (11.3 mmol, 2.5

equiv.) and the reaction stirred for 18 h to rt. The reaction was

quenched with 2 M HCl (80 mL), extracted with CH₂Cl₂(50 mL

x 3), dried (MgSO₄), filtered and concentrated in vacuo. to give

the crude β-nitroacetamide. Purification by flash column

chromatography (40 % CH₂Cl₂/Hexanes followed by 10 – 20 %

Et₂O/Hexanes) gave 28 as white crystals (276 mg, 0.51 mmol, 11

%); mp 153 - 155 ^oC; IR ν_max(thin film) 1698 (C=O, amide) 1558

(N-O, asymm) 1511 (C=C, Ar) 1357 (N-O, symm) 1181 (C-F,

By an identical procedure to the preparation of 5 using trans-

β-nitrostyrene (0.53 g, 3.60 mmol) and imine 24 (0.77 g, 4.07

mmol). Purification by flash column chromatography (40 %

CH₂Cl₂/Hexanes) and recrystallisation (Et₂O/Hexanes) afforded

102ac as colourless crystals (0.72 g, 1.65 mmol, 46 %); mp 86 -

o

88 C; IR ν_max(thin film) 2935 (C-H) 1697 (C=O, amide) 1554

(N-O asymm) 1509 (C=C, Ar) 1298 (N-O symm) 1151 (C-F,

CF₃) cm^-1; ¹H NMR (CDCl₃, 600 MHz) δ 1.56 (1H, m, CHNCH₂)

1.80 (1H, apt br d, J = 8.3, CHNCH₂) 2.16 (1H, m, CH₂CH₂CH)

2.26 (1H, m, CH₂CH₂CH) 3.34 (1H, dd, J = 14.8, 3.8, PhCH₂)

3.38 (1H, dd, J = 14.8, 10.6, PhCH₂) 3.88 (3H,s, OCH₃) 4.91

(1H, m, CHNO₂) 5.00 (1H, m, CHN) 5.03 – 5.06 (2H, m,

CH₂CH₂CHCH₂) 5.74 (1H, ddt, J = 16.0, 11.4, 6.3, CH₂CHCH₂)

7.00 (2H, m, PMP-H) 7.15 (2H, m, ArH) 7.20 (2H, d, J = 8.5,

1

CF₃) cm^-1; H NMR (CDCl₃, 600 MHz) δ 3.80 (3H, s, OCH₃)

PMP-H) 7.27 – 7.30 (1H, m, ArH) 7.30 – 7.34 (2H, m, ArH); ¹³

NMR (CDCl₃, 150 MHz) 27.5 (CHNCH₂) 30.3

C

6.44 (2H, br s, CHNO₂& PMP-H) 6.59 (1H, br s, CH) 6.68 (1H,

dd, J = 8.8, 2.8, PMP-H) 6.79 (1H, d, J = 15.3, ArCHCH) 6.89

(1H, apt t, J = 6.4, CH) 6.95 (1H, dd, J = 8.8, 2.7, PMP-H) 7.15 –

7.24 (5H, m, CH) 7.28 – 7.34 (2H, m, CH) 7.37 (2H, d, J = 7.3,

CH) 7.42 (2H, t, J = 7.7, CH) 7.47 – 7.58 (4H, m, CH); ¹³C NMR

(CDCl₃, 150 MHz) δ 55.6 (OCH₃) 59.5 (CHN) 91.3 (CHNO₂)

113.9 (PMP-C) 114.4 (PMP-C) 116.2 (q, J = 288.3, CF₃) 124.9

(CH) 126.9 (2C, CH) 127.1 (2C, PMP-C) 128.3 (2C, CH) 128.8

(2C, CH) 128.9 (2C, CH) 129.0 (CH) 129.3 (CH) 129.7 (CH)

130.1 (q, CH) 130.3 (CH) 131.1 (q, CH) 131.3 (CH) 132.7 (q,

CH) 133.6 (CH) 136.9 (q, CH) 138.6 (q, CH) 157.6 (q, J = 35.6,

COCF₃) 160.5 (q, ArCO) ; ¹⁹F NMR (CDCl₃, 282 MHz) δ - 67.2

ppm (3F, s, CF₃); m/z (ESI⁺) 579 (22 %, M + CH₃OH + H⁺) 569

δ

(CH₂CH₂CHCH₂) 37.8 (PhCH₂) 55.7 (OCH₃) 60.3 (CHN) 91.4

(CNO₂) 114.7 (PMP-C) 114.9 (PMP-C) 116.3 (q, J = 288.6, CF₃)

116.7 (CH₂CH₂CHCH₂) 127.4 (q, ArCN) 127.9 (ArC) 128.6 (2C,

ArC) 129.2 (2C, ArC) 130.4 (PMP-C) 131.0 (PMP-C) 134.6 (q,

ArCCH₂) 135.9 (CHCH₂) 158.8 (q, J = 35.7, COCF₃) 160.7 (q,

ArCO); ¹⁹F NMR (CDCl₃, 282 MHz) δ – 67.0 ppm (3F, s, CF₃);

+

m/z (ESI⁺) 453 (96 %, M + NH₄) 437 (100 %, M + H⁺); HRMS

(C₂₂H₂₄F₃N₂O₄) calcd. 437.1688, found 437.1678.

N-allyl-2,2,2-trifluoro-N-((1R*,2S*)-2-nitro-1,3-

diphenylpropyl)acetamide (27)

By an identical procedure to the preparation of 5 using trans-

β-nitrostyrene (1.50 g, 10.0 mmol) and imine 26³⁰(2.91 g, 20.0

mmol). Purification via flash column chromatography (40 %

CH₂Cl₂/Hexanes followed by 20 % Et₂O/Hexanes) afforded 27 as

a mixture of diastereomers (75:25) as a yellow oil (1.53 g, 3.90

+

(21 %, M + Na⁺) 564 (100 %, M + NH₄) 547 (38 %, M + H⁺);

HRMS (C₃₁H₂₆F₃N₂O₄) calcd. 547.1845, found 547.1870.

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-((1S*,2R*)-1-nitro-1-

phenylhex-5-en-2-yl)acetamide (29)

o

mmol, 39 %); mp_anti90 - 91 C; IR major anti ν_max(thin film)

By an identical procedure to the preparation of 28 using α-

nitrotoluene (0.92 g, 6.73 mmol) and imine 24 (1.44 g, 7.62

mmol). Purification by flash column chromatography (40 %

CH₂Cl₂/Hexanes) and recrystallisation from Et₂O/Hexanes

afforded 29 as white crystals (1.56 g, 3.69 mmol, 55 %); mp 93 -

3029 (C-H) 1691 (C=O, amide) 1555 (N-O, asymm) 1454 (C=C,

1

Ar) 1146 (C-F, CF₃) cm^-1; H NMR (CDCl₃, 600 MHz) major

anti δ 3.16 (2H, m, CH₂Ph) 3.86 (1H, dd, J = 16.3, 7.2, CH₂N)

4.14 (1H, dd, J = 16.3, 5.8, CH₂N) 5.22 (1H, d, J = 10.6, CHN)

5.51 (2H, m, CH₂CHCH₂N) 5.88 (1H, ddt, J = 17.0, 10.2, 6.7,

CHCH₂N) 6.07 (1H, ddd, J = 10.7, 9.6, 5.0, CHNO₂) 7.17 (2H,

o

94 C; IR ν_max(thin film) 2936, 2838 (C-H) 1693 (C=O, amide)

1

1606, 1508, 1456 (C=C, Ar) 1552 (N-O, asymm) 1357 (N-O,

symm) 1150 (C-F, CF₃) cm^-1; ¹H NMR (CDCl₃, 600 MHz, 60 ^oC)

δ 1.70 – 1.80 (1H, m, CHNCH₂) 2.09 – 2.40 (3H, m, CHNCH₂&

CHNCH₂CH₂) 3.79 (3H, s, OCH₃) 5.08 (1H, dm, J = 10.2,

CHCH_2-cis) 5.11 (1H, dm, J = 17.2, CHCH_2-trans) 5.31 (1H, br s,

CHN) 5.72 (1H, br s, CHNO₂) 5.84 (1H, ddt, J = 17.0, 10.3, 6.4,

CH₂CHCH₂) 6.36 (1H, br s, PMP-H) 6.61 (1H, br s, PMP-H)

6.75 (2H, br m, PMP-H) 7.39 – 7.55 (5H, m, ArH); ¹³C NMR

(CDCl₃, 150 MHz, 60 ^oC) δ 28.8 (CHNCH₂) 30.3 (CHNCH₂CH₂)

55.4 (OCH₃) 92.5 (CHNO₂) 114.2 (2C, PMP-C) 115.7 (q, J =

288.5, CF₃) 116.2 (CH₂CH₂CHCH₂) 128.7 (2C, ArC) 129.1 (2C,

ArC) 130.1 (q, ArC) 130.7 (ArC) 131.8 (q, ArC) 136.0

(CH₂CHCH₂) 158.1 (q, J = 36.2, COCF₃) 160.3 (ArCO) further

signals indistinguishable; ¹⁹F NMR (CDCl₃, 282 MHz) δ - 67.4

ppm (3F, s, CF₃); m/z (ESI⁺) 867 (6 %, 2M + Na⁺) 445 (23 %, M

m, ArH) 7.26 – 7.38 (6H, m, ArH) 7.46 (2H, m, ArH); H NMR

(CDCl₃, 600 MHz) minor syn δ 2.85 (1H, dd, J = 14.7, 3.0,

CH₂Ph) 3.01 (1H, dd, J = 14.8, 11.1, CH₂Ph) 3.93 – 4.04 (2H, m,

CH₂N) 4.96 (1H, d, J = 11.0, CHN) 5.33 (2H, m, CH₂CHCH₂N)

5.65 (1H, ddt, J = 17.0, 10.0, 6.4, CHCH₂N) 6.26 (1H, td, J =

11.0, 3.0, CHNO₂) 7.03 (2H, m, ArH) further signals

indistinguishable;¹³C NMR (CDCl₃, 150 MHz) major anti δ 38.0

(ArCH₂) 50.9 (CH₂N) 64.8 (CHN) 91.0 (CHNO₂) 116.4 (q, J =

288.1, CF₃) 122.2 (CH₂CHCH₂N) 127.9 (ArC) 128.8 (2C, ArC)

129.1 (2C, ArC) 129.1 (2C, ArC) 129.4 (ArC) 129.9 (ArC) 132.0

(ArC) 134.0 (q, ArC) 134.6 (q, ArC) 157.8 (q, J = 36.4, COCF₃);

¹⁹F NMR (CDCl₃, 282 MHz) major anti δ - 68.9 ppm (3F, s,

+

CF₃); m/z (CI⁺) 410 (100 %, M + NH₄); HRMS (C₂₀H₁₉F₃O₃N₂+

+

NH₄) calcd. 410.1686, found 410.1685.

13

+ Na⁺) 423 (M + H⁺) 376 (100 %, C₂₁H₂₁F₃NO₂); HRMS

yl)acetate

(32a)

and

methyl

2-((1R*,2R*)-2-((S*)-

ACCEPTED MANUSCRIPT

(C₂₁H₂₂F₃N₂O₄) calcd. 423.1532, found 423.1522.

4.4 Radical denitration cyclisation.

General procedure.

phenyl(2,2,2-trifluoro-N-(4-methoxyphenyl)acetamido)methyl)-

2,3-dihydro-1H-inden-1-yl)acetate (32a’)

Prepared by the general procedure using β-nitroacetamide 11a

(0.50 g, 0.92 mmol). Purification by flash column

chromatography (10 % Et₂O/Hexanes) afforded 32 as a mixture

of diastereoisomers (40:40:20) as a colourless oil (267 mg, 0.54

mmol, 59 %). Recrystallisation (CH₂Cl₂/hexanes) afforded 32a as

a white solid (140 mg, 0.28 mmol, 31 %) and 32a’ as a white

solid (49.8 mg, 0.10 mmol, 11 %). Data for 32a; mp 152 – 153

^oC; IR νmax (thin film) 2954 (C-H) 1735 (C=O, ester) 1688

To a solution of β-nitroacetamide (1 mmol) in benzene (48

mL) under N₂at rt were added AIBN (0.3 mmol) and Bu₃SnH

(10 mmol) and the reaction mixture was degassed. The reaction

mixture was heated to reflux for 6 hours or until no change was

observed by TLC. The reaction mixture was cooled to rt,

concentrated in vacuo and taken up in MeCN/Hexane (50:50, 20

mL). The layers were seperated, the Hexane layer extracted with

MeCN (10 mL x 2). The combined MeCN extracts were washed

with Hexane (20 mL x 3) and the MeCN layer was concentrated

in vacuo. The crude product was purified by flash column

chromatography (0 – 10 % Et₂O). In some cases recrystallization

afforded single separation of diastereoisomers.

1

(C=O, amide) 1511 (C=C, Ar) 1184, 1154 (C-F, CF₃) cm^-1; H

NMR (CDCl₃, 600 MHz) δ 2.41 (1H, dd, J = 15.2,

10.9,CH₂CO₂CH₃) 2.54 (2H, d, J = 9.5, ArCH₂CHCHN) 2.96

(1H, dd, J = 15.2, 4.0, CH₂CO₂CH₃) 3.07 (1H, m, CHCHN) 3.70

(3H, s, COOCH₃) 3.80 (3H, s, ArOCH₃) 3.94 (1H, ddd, J = 10.9,

6.8, 4.0, ArCHCH₂COOCH₃) 6.07 (1H, dd, J = 9.0, 1.9, PMP-H)

6.15 (1H, d, J = 12.1, CHN) 6.61 (1H, dd, J = 8.8, 3.0, PMP-H)

6.92 (1H, dd, J = 8.8, 3.0, PMP-H) 7.04 (1H, m, ArH) 7.12 – 7.16

(4H, m, ArH) 7.25 (1H, d, J = 5.5, ArH) 7.29 – 7.37 (3H, m,

ArH) 7.49 (1H, dd, J = 8.8., 2.1, PMP-H); ¹³C NMR (CDCl₃, 150

MHz) δ 35.2 (CH₂CO) 35.7 (ArCH₂) 42.4 (ArCHCH₂CO) 43.6

(CHCHN) 51.8 (COOCH₃) 55.5 (ArOCH₃) 60.3 (CHN) 113.4

(PMP-C) 113.7 (PMP-C) 116.6 (q, J = 288.4, CF₃) 124.6 (ArC)

124.7 (ArC) 126.2 (q, ArCN) 126.8 (ArC) 127.4 (ArC) 128.5

(2C, ArC) 128.8 (ArC) 129.8 (2C, ArC) 131.2 (PMP-C) 133.2

(PMP-C) 137.3 (q, ArCCHN) 141.2 (q, ArCCH₂) 146.1 (q,

ArCCHCH₂CO) 158.0 (q, J = 35.2, COCF₃) 160.2 (q, ArCOCH₃)

173.1 (CO₂CH₃); ¹⁹F NMR (CDCl₃, 282 MHz) δ – 66.9 (3F, s,

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-((1-methyl-2,3-

dihydro-1H-inden-2-yl)(phenyl)methyl)acetamide (30a) and N-

(((1R*,2R*)-1-benzyl-2,3-dihydro-1H-inden-2-yl)methyl)-2,2,2-

trifluoro-N-(4-methoxyphenyl)acetamide (31).

Prepared by the general procedure using β-nitroacetamide 8a

(51.5 mg, 0.11 mmol). Purification using flash column

chromatography (0 – 10 % Et₂O/Hexanes) gave 30a as a mixture

of diastereoisomers (40:40:20) as a colourless oil (16.7 mg, 0.038

mmol, 38 %) and 31 as a colourless oil (8.6 mg, 0.020 mmol, 20

%); Data for 30a IR ν_max(thin film) 3019, 2931, 2836 (C-H) 1685

(C=O, amide) 1604, 1582, 1509 (C=C, Ar) 1180, 1146 (C-F,

CF₃) cm^-1; ¹H and ¹³C NMR data display a complex mixture; m/z

(ESI⁺) 462 (100 %, M + H⁺); HRMS (C₂₆H₂₄F₃NO₂Na) calcd.

462.1639, found 462.1657. Data for 31 IR ν_max(thin film) 2923

(C-H) 1694 (C=O, amide) 1511 (C=C, Ar) 1152 (C-F, CF₃) cm^-1;

¹H NMR (CDCl₃, 600 MHz) δ 2.62 (1H, dd, J = 13.3, 10.3,

CH₂Ph) 2.72 (1H, m, CHCH₂N) 2.90 (1H, dd, 13.4, 6.0, CH₂Ph)

2.93 (2H, d, J = 8.1, CH₂CHCH₂N) 3.36 (1H, dt, J = 10.2, 6.5,

CHCHCH₂N) 3.74 (1H, dd, J = 13.3, 5.3, CH₂N) 3.84 (3H, s,

OCH₃) 4.31 (1H, dd, J = 13.3, 9.8, CH₂N) 6.42 (1H, d, J = 7.5,

ArH) 6.87 – 6.92 (2H, m, PMP-H) 6.94 (1H, td, J = 7.5, 1.0,

ArH) 6.96 – 7.00 (2H, m, ArH) 7.13 (1H, td, J = 7.5, 0.9, ArH)

7.14 – 7.25 (6H, m PMP-H & ArH); ¹³C NMR (CDCl₃, 150

MHz) δ 35.2 (CH₂CHCH₂N) 35.4 (CH₂Ph) 41.5 (CHCH₂N) 48.0

(CHCH₂Ph) 52.0 (CH₂N) 55.6 (OCH₃) 115.0 (2C, br, PMP-C)

116.6 (q, J = 284.9, CF₃) 124.7 (ArC) 125.0 (ArC) 125.8 (ArC)

126.2 (ArC) 126.9 (ArC) 128.3 (2C, ArC) 129.4 (2C, ArC) 130.0

(2C, br, PMP-C) 131.2 (q, ArCN) 139.8 (q, ArCCH₂) 141.8 (q,

ArCCH₂) 145.6 (q, ArCCHCH₂Ph) 157.5 (q, J = 34.9, COCF₃)

159.9 (q, ArCO); ¹⁹F NMR (CDCl₃, 282 MHz) δ – 66.9 ppm (3F,

s, CF₃); m/z (ESI⁺) 440 (100 %, M + H⁺); HRMS (C₂₆H₂₅F₃NO₂)

calcd. 440.1837, found 440.1821. See supplementary information

for details of structural elucidation and data correlation table.

+

CF₃); m/z (CI+) 466 (12 %, C₂₇H₂₃F₃NO₃) 279 (100 %,

C₁₉H₁₉O₂); HRMS (C₂₉H₂₆F₃NO₄) calcd. 498.18922, found

498.189495; Anal. Calcd. For C₂₈H₂₆F₃NO₄: C, 67.60; H, 5.27;

N, 2.82; found: C, 67.68; H, 5.29; N, 2.79%. X-ray

Crystallography data in supplementary information. Data for

+

o

32a’; mp 157 – 158 C; IR ν_max(thin film) 2951 (C-H) 1735

(C=O, ester) 1687 (C=O, amide) 1510 (C=C, Ar) 1183, 1168 (C-

F, CF₃) cm ^-1; H NMR (CDCl₃, 600 MHz) δ 2.31 (1H, dd, J =

1

14.7, 3.9, CH₂CO₂Me) 2.38 (1H, dd, J = 14.5, 11.5, CH₂CO₂Me)

3.18 – 3.23 (2H, m, CHCHN & CH₂Ar) 3.30 (1H, apt dd, J =

15.1, 12.6, CH₂Ar) 3.40 (1H, ddd, J = 11.2, 6.7, 4.5,

CHCH₂CO₂CH₃) 3.48 (3H, s, OCH₃) 3.76 (3H, s, OCH₃) 5.84

(1H, br s, PMP-H) 6.30 (1H, br d, J = 6.9, CHN) 6.48 (1H, br d, J

= 5.0, PMP-H) 6.83 (1H, dd, J = 8.8, 2.9, PMP-H) 6.99 – 7.15

(4H, m, ArH) 7.21 – 7.34 (6H, m, ArH); ¹³C NMR (CDCl₃, 150

MHz) δ 34.5 (CH₂CO₂CH₃) 35.1 (ArCH₂) 42.5 (CHCH₂CO₂CH₃)

43.5 (CHCHN) 51.5 (CO₂CH₃) 55.5 (ArOCH₃) 61.3 (CHN)

113.5 (2C, PMP-C) 116.8 (q, J = 289.0, CF₃) 124.9 (ArC) 124.9

(2C, ArC)126.5 (ArC) 126.7 (ArC) 127.5 (PMP-C) 128.8 (ArC)

129.1 (2C, ArC) 129.6 (q) 130.6 (ArC) 133.1 (PMP-C) 135.9 (q)

141.5 (q) 145.9 (q) 157.5 (q, J = 35.4, COCF₃) 160.0 (q,

ArCOCH₃) 172.4 (q, CO₂CH₃); ¹⁹F NMR (CDCl₃, 282 MHz) δ –

66.9 (3F, s, CF₃); m/z (EI) 497 (100 %, M⁺) 466 (25 %,

+

ethyl

2-(1-methyl-2,3-dihydro-1H-inden-2-yl)-2-(2,2,2-

C₂₇H₂₃F₃NO₃) 428 (8 %, C₂₇H₂₆NO₄) 400 (7 %, C₂₆H₂₆NO₃)

+

trifluoro-N-(4-methoxyphenyl)acetamido)acetate (30b)

279 (10 %, C₁₉H₁₉O₂); HRMS (C₂₈H₂₆F₃NO₄) calcd. 497.18139,

found 497.181034.

Prepared by the general procedure using β-nitroacetamide 8b

(0.30 g, 0.63 mmol). Purification via flash column

chromatography (0 – 10 % Et₂O/Hexanes) afforded 30b as a

mixture of diastereoisomers (60:20:20) as a colourless oil (66.9

mg, 0.15 mmol, 24 %); IR ν_max(thin film) 2957, 2933, 2839 (C-

H) 1739 (C=O, ester) 1694 (C=O, amide) 1509 (C=C, Ar) 1149

(C-F, CF₃) cm^-1; ¹H and ¹³C NMR data display a complex

N-(((1R*,2R*)-1-benzyl-2,3-dihydro-1H-inden-2-

yl)(phenyl)methyl)-2,2,2-trifluoro-N-(4-

methoxyphenyl)acetamide (33b)

Prepared by the general procedure using β-nitroacetamide

11b (450 mg, 0.80 mmol). Purification by flash column

chromatography (0 - 8 % Et₂O/Hexanes) a mixture of

diastereoisomers (40:40:20) as a colourless oil (172 mg, 0.33

mmol, 47 %). Recrystallisation (CH₂Cl₂/Hexanes) afforded 32b

as a single diastereomer as a white solid (11.0 mg, 0.021 mmol, 3

+

mixture; m/z (CI⁺) 453 (100 %, M + NH₄) 436 (6 %, M + H⁺);

HRMS (C₂₃H₂₅F₃NO₄) calcd. 436.1730, found 436.17298.

methyl

2-((1R*,2R*)-2-((R*)-phenyl(2,2,2-trifluoro-N-(4-

methoxyphenyl)acetamido)methyl)-2,3-dihydro-1H-inden-1-

14

Tetrahedron

ACCEPTED MANUSCR

o

%); mp 162 – 164 C; IR ν_max(thin film) 2934 (C-H) 1684

291 (6 %, C₂H₂Si⁺); HRMS (C₂₉H₃₁F₃NO₂Si) calcd. 510.2071,

0 3

IPT

(C=O, amide) 1584, 1510, 1454 (C=C, Ar) 1181, 1148 (C-F,

found 510.2070. Anal. Calcd. For C₂₉H₃₀F₃NO₂Si: C, 68.35; H,

5.93; N, 2.75; found: C, 68.39; H, 5.91; N, 2.69 %. See

supplementary information for data correlation table and X-ray

crystallography data.

CF₃) cm^-1; H NMR (CDCl₃, 600 MHz) δ 2.39 (1H, apt t, J =

1

12.3, PhCH₂CH) 2.77 (1H, dd, J = 12.6, 3.4, PhCH₂CH) 3.03

(1H, ddd, J = 11.2, 6.6, 3.4, BnCHAr) 3.17 – 3.25 (2H, m,

CHCHN & ArCH₂CHCHN) 3.38 (1H, m, ArCH₂CHCHN) 3.77

(3H, s, OCH₃) 5.95 (1H, br s, PMP-H) 6.10 (1H, d, J = 7.5, ArH)

6.46 – 6.59 (4H, m, CHN, ArH, 2 x PMP-H) 6.84 (1H, dd, J =

8.8, 3.0, PMP-H) 6.87 (1H, t, J = 7.5, ArH) 7.06 – 7.12 (4H, m,

ArH) 7.16 (2H, dt, J = 7.5, 0.7, ArH) 7.25 – 7.28 (1H, m, ArH)

7.30 – 7.36 (3H, m, ArH) 7.39 (1H, tm, J = 7.3, ArH); ¹³C NMR

(CDCl₃, 150 MHz) δ 35.2 (ArCH₂) 35.2 (ArCH₂) 44.2 (CHCHN)

48.7 (CHCHCHN) 55.5 (OCH₃) 61.6 (CHN) 113.4 (2C, PMP-C)

116.8 (q, J = 288.8, CF₃) 124.6 (ArC) 125.5 (2C, ArC) 125.5

(ArC) 126.0 (ArC) 126.9 (PMP-C) 128.0 (2C, ArC) 128.7 (2C,

ArC) 128.9 (ArC) 129.6 (3C, ArC) 129.8 (q, ArCN) 130.8 (ArC)

133.2 (PMP-C) 136.5 (q, ArCCHN) 139.9 (q, ArCCH₂) 141.6 (q,

ArCCH₂CHCHN) 146.0 (q, ArCCH) 157.5 (q, J = 35.4, COCF₃)

160.0 (ArCOCH₃); ¹⁹F NMR (CDCl₃, 282 MHz) δ – 66.8 (3F, s,

CF₃); m/z (ESI⁺) 538 (100 %, M + Na⁺) 516 (100 %, M + H⁺);

HRMS (C₃₂H₂₉F₃NO₂) calcd. 516.2150, found 516.2166.

N-((1-benzylidene-2,3-dihydro-1H-inden-2-

yl)(phenyl)methyl)-2,2,2-trifluoro-N-(4-

methoxyphenyl)acetamide (34b)

Prepared by the general procedure using β-nitroacetamide

12b (422 mg, 0.75 mmol). Purification by flash column

chromatography (0 - 10 % Et₂O/Hexanes gave 34b followed by

recrystallisation (Et₂O/hexanes) as a white solid (40.3 mg, 0.078

mmol, 10 % yield); mp 100 – 102 ^oC; IR ν_max(thin film) 2956 (C-

H) 1692 (C=O, amide) 1509 (C=C, Ar) 1185, 1150 (C-F, CF₃)

cm^-1; ¹H NMR (CDCl₃, 600 MHz) δ 2.85 (1H, m, CHCHN) 2.91

(1H, dd, J = 16.0, 7.5, CH₂) 3.16 (1H, dd, J = 15.8, 8.0, CH₂)

3.80 (3H, s, OCH₃) 6.23 – 6.27 (2H, m, CHN & CH) 6.79 (1H,

dd, J = 9.0, 2.7, PMP-H) 6.85 – 6.88 (2H, m, CH) 6.94 (1H, dd, J

= 8.9, 2.7, PMP-H) 7.10 – 7.14 (2H, m, ArH) 7.21 (1H, m, ArH)

7.25 (1H, d, J = 7.4, ArH) 7.28 – 7.58 (10H, m, ArH); ¹³C NMR

(CDCl₃, 150 MHz) δ 36.8 (CH₂) 39.9 (CHCHN) 55.6 (OCH₃)

64.4 (CHN) 113.6 (PMP-C) 114.5 (PMP-C) 124.4 (CCH) 130.7

(q) 131.8 (q) 138.1 (q) 138.4 (q) 139.0 (q) 139.8 (q) 146.0 (q)

158.9 (q, J = 35.2, COCF₃) 160.1 (q, ArCO) further signals

indistinguishable; m/z (ESI) 514 (100 %, M + H⁺) 295 (33 %,

C₂₃H₁₉⁺); HRMS (C₃₂H₂₇F₃NO₂) calcd. 514.1994, found

514.1999.

(Z)-2,2,2-trifluoro-N-(4-methoxyphenyl)-N-(phenyl(1-

((trimethylsilyl)methylene)-2,3-dihydro-1H-inden-2-

yl)methyl)acetamide

methoxyphenyl)-N-((1-(phenyl(trimethylsilyl)methylene)-2,3-

dihydro-1H-inden-2-yl)methyl)acetamide (35a)

(34a)

and

(Z)-2,2,2-trifluoro-N-(4-

Prepared by the general procedure using β-nitroacetamide 12a

(556 mg, 1.00 mmol). Purification by flash column

chromatography (0 - 10 % Et₂O/Hexanes afforded 34a as a

yellow oil (74.0 mg, 0.15 mmol, 15 % yield) and 35a as a white

solid (30.0 mg, 0.59 mmol, 6 % yield). Data for 34a; IR ν_max(thin

film) 2952 (C-H) 1690 (C=O, amide) 1606, 1583, 1509 (C=C,

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-(phenyl(2,4,4-

trimethylcyclopentyl)methyl)acetamide (36) and N-((1-benzyl-

2,3-dihydro-1H-inden-2-yl)methyl)-2,2,2-trifluoro-N-(4-

methoxyphenyl)acetamide (37)

Ar) 1179, 1148 (C-F, CF₃) cm^-1; H NMR (CDCl₃, 600 MHz) δ

1

Prepared by the general procedure using β-nitroacetamide 15

(257 mg, 0.55 mmol). Purification by flash column

chromatography (10 % Et₂O/Hexanes) afforded 36 as a mixture

of diastereoisomers (40:30:30) as a white solid (52.6 mg, 0.13

mmol, 46 %) and 37 as a white solid (19.6 mg, 0.047 mmol, 9

%). Data for 36; IR ν_max(thin film) 3031, 2450, 2862 (C-H) 1685

(C=O, amide) 1606, 1582, 1509 (C=C, Ar) 1179, 1146 (C-F,

CF₃) cm^-1; ¹H and ¹³C NMR data display a complex mixture; m/z

(ESI⁺) 839 (23 %, 2M + H⁺) 461 (9 %, M + MeCN + H⁺) 420

(100 %, M + H⁺); HRMS (C₂₄H₂₉F₃NO₂) calcd. 420.2150, found

420.2153. Data for 37; mp 109 – 111 ^oC; IR ν_max(thin film) 2951

2933 2865 (C-H) 1697 (C=O, amide) 1512 (C=C, Ar) 1202, 1151

(C-F, CF₃) cm^-1; ¹H NMR (CDCl₃, 600 MHz) δ 0.92 (3H, s, CH₃)

1.11 (3H, s, CH₃) 1.34 (1H, dd, J = 13.0, 8.5, CH₂C(CH₃)₂) 1.40

(1H, dd, J = 13.0, 6.6, CH₂C(CH₃)₂) 1.50 (1H, dd, J = 13.0, 7.8,

CH₂CHCH₂N) 1.58 (1H, dd, J = 13.0, 7.3, CH₂CHCH₂N) 2.27

(1H, m, CHCH₂N) 2.38 (1H, m, CHCH₂Ph) 2.43 (1H, dd, J =

12.8, 10.7, CH₂Ph) 2.70 (1H, dd, J = 12.8, 4.7, CH₂Ph) 3.49 (1H,

dd, J = 13.1, 4.9, CH₂N) 3.85 (3H, s, OCH₃) 4.25 (1H, dd, J =

13.0, 11.0, CH₂N) 6.91 (2H, apt d, J = 8.7, PMP-H) 7.08 (2H, apt

d, J = 7.8, ArH) 7.11 (2H, d, J = 8.6, PMP-H) 7.16 (1H, tm, J =

7.4, ArH) 7.22 – 7.25 (2H, m, ArH); ¹³C NMR (CDCl₃, 150

MHz) δ 30.6 (C(CH₃)₂) 31.4 (C(CH₃)₂) 36.5 (CH₂Ph) 37.4 (q,

C(CH₃)₂) 38.8 (CHCH₂N) 42.4 (CHCH₂Ph) 44.7 (CH₂CHCH₂N)

46.3 (CH₂CHCH₂Ph) 52.4 (CH₂N) 55.6 (OCH₃) 114.0 (PMP-C)

114.7 (PMP-C) 116.7 (q, J = 288.8, CF₃) 125.9 (ArC) 128.4 (2C,

ArC) 128.8 (2C, ArC) 129.4 (br, PMP-C) 130.0 (br, PMP-C)

131.2 (ArCN) 141.4 (q, ArCCH₂) 157.5 (q, J = 34.8, COCF₃)

159.8 (q, ArCOCH₃); ¹⁹F NMR (CDCl₃, 282 MHz) δ – 66.9 ppm

(3F, s, CF₃); m/z (ESI⁺) 839 (27 %, 2M + H⁺) 420 (100 %, M +

H⁺) ; HRMS (C₂₄H₂₉F₃NO₂) calcd. 420.2150, found 420.2152.

See supplementary information for data correlation table.

0.29 (9H, s, Si(CH₃)₃) 2.27 (1H, apt d, J = 16.7, CH₂) 3.04 (1H,

dd, J = 16.6, 7.5, CH₂) 3.78 (3H, s, OCH₃) 4.21 (1H, br dd, J =

10.8, 7.6, CHCHN) 4.55 (1H, br d, J = 10.8, CHN) 5.99 (1H, s,

CHSi) 6.67 (1H, dd, J = 8.9, 3.0, PMP-H) 6.71 – 6.74 (1H, m,

PMP-H) 6.80 (1H, dd, J = 8.7, 2.7, PMP-H) 7.07 (1H, m, PMP-

H) 7.11 (1H, d, J = 7.7, ArH) 7.18 – 7.31 (7H, m, ArH) 7.67 (1H,

d, J = 7.5, ArH); ¹³C NMR (CDCl₃, 150 MHz) δ 0.05 (Si(CH₃)₃)

35.5 (CH₂) 48.0 (CHCHN) 55.5 (OCH₃) 71.1 (CHN) 113.5

(PMP-C) 114.3 (PMP-C) 124.6 (ArC) 124.8 (ArC) 125.7 (ArC)

126.6 (ArC) 128.3 (2C, ArC) 128.5 (2C, ArC) 128.7 (ArC) 130.1

(PMP-C) 130.4 (q, ArCN) 131.2 (PMP-C) 137.3 (q, ArC) 140.4

(q, ArC) 145.7 (q, ArCCH₂) 156.9 (q, J = 35.5, COCF₃) 159.3 (q,

CCHSi) 159.6 (ArCO) further signals indistinguishable; ¹⁹F

NMR (CDCl₃, 282 MHz) δ – 67.5 ppm (3F, s, CF₃); m/z (EI) 509

+

(< 5 %, M⁺) 308 (100 %, C₁₆H₁₃F₃NO₂) 202 (37 %, C₁₃H₁₇Si⁺).

See supplementary information for data correlation table. Data

o

for 35a; mp 144 – 146 C; IR ν_max(thin film) 3056, 2956, 2092,

2840 (C-H) 1696 (C=O, amide) 1511 (C=C, Ar) 1201, 1153 (C-

F, CF₃) cm^-1; ¹H NMR (CDCl₃, 600 MHz) δ 0.07 (9H, s,

Si(CH₃)₃) 2.72 (1H, apt d, J = 15.4, ArCH₂) 2.90 (1H, dd, J =

13.3, 3.3, CH₂N) 2.93 – 3.03 (2H, m, CHCH₂N & ArCH₂) 3.85

(3H, s, OCH₃) 4.01 (1H, dd, J = 13.1, 11.5, CH₂N) 6.60 – 7.17

(9H, br m, ArH & PMP-H) 7.24 (1H, apt t, J = 7.4, ArH) 7.28

(1H, dd, J = 7.2, 1.0, ArH) 7.32 (1H, d, J = 7.3, ArH) 7.66 (1H,

d, J = 7.5, ArH); ¹³C NMR (CDCl₃, 150 MHz) δ 0.5 (Si(CH₃)₃)

33.5 (ArCH₂) 42.1 (CHCH₂N) 52.3 (CH₂N) 55.6 (OCH₃) 116.5

(q, J = 288.9, CF₃) 125.2 (ArC) 125.5 (1C, ArC) 126.0 (1C, ArC)

126.3 (1C, ArC) 127.4 (br, ArC) 128.8 (ArC) 130.0 (q, ArCN)

139.4 (q, CSiMe₃) 139.8 (q, ArCCH₂) 145.2 (ArCCSiMe₃) 146.6

(ArCCCSiMe₃) 153.5 (CCSiMe₃) 157.6 (q, J = 35.4, COCF₃)

159.3 (q, ArCO); ¹⁹F NMR (CDCl₃, 282 MHz) δ – 67.0 ppm (3F,

+

s, CF₃); m/z (CI⁺) 527 (46 %, M + NH₄) 510 (100 %, M + H⁺)

15

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-((2-methyl-5-

439.17591, found 439.176345. See supplementary

information for data correlation table.

ACCEPTED MANUSCRIPT

phenylcyclopentyl)(phenyl)methyl)acetamide (38) and N-

(((1S*,5R*)-2-benzyl-5-phenylcyclopentyl)methyl)-2,2,2-

trifluoro-N-(4-methoxyphenyl)acetamide (39)

N-(2,3-dibenzyl-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoro-N-

(4-methoxyphenyl)acetamide (40b)

Prepared by the general procedure using β-nitroacetamide 18

(87.0 mg, 0.17 mmol). Purification by flash column

chromatography (10 % Et₂O/Hexanes) afforded 38 as a mixture

of diastereoisomers (40:35:25) as white solid (19.0 mg, 0.041

mmol, 24 %) and 39 as a white solid (2.5 mg, 0.003 mmol, 3 %).

Data for 38; IR ν_max(thin film) 2960, 2932 (C-H) 1689 (C=O,

amide) 1511, 1445 (C=C, Ar) 1204, 1184 (C-F, CF₃) cm^-1; ¹H and

¹³C NMR data display a complex mixture; m/z (EI) 935 (8 %,

2M⁺) 468 (100 %, M⁺); HRMS (C₂₈H₂₈F₃NO₂) calcd. 468.2152,

found 468.2150. Data for 39; IR ν_max(thin film) 3027, 2954, 2935

(C-H) 1692 (C=O, amide) 1602, 1511, 1445 (C=C, Ar) 1202,

Prepared by the general procedure using β-nitroacetamide

19b (558 mg, 1.00 mmol). Purification by flash column

chromatography (10 % Et₂O/Hexanes) afforded 40b as two

diastereomers (60:40) as a colourless oil (174 mg, 0.34 mmol, 34

%); IR ν_max(thin film) 3063, 3026, 2934 (C-H) 1689 (C=O,

1

amide) 1584, 1511 (C=C, Ar) 1186, 1170 (C-F, CF₃) cm^-1; H

NMR (CDCl₃, 600 MHz) major trans, trans δ 2.21 (1H, dtd, J =

9.6, 7.1, 4.8 CHNCH) 2.24 (1H, dd,

J = 13.4, 8.2,

CHNCHCHCH₂) 2.51 (1H, dd, J = 13.3, 4.6, CHNCHCH₂) 2.70

(1H, dd, J = 13.4, 9.6, CHNCHCH₂) 2.79 (1H, dd, J = 13.6, 6.3,

CHNCHCHCH₂) 3.13 – 3.18 (1H, m, CHNCHCH) 3.78 (3H, s,

OCH₃) 6.17 (1H, d, J = 7.8, PMP-H) 6.31 (1H, d, J = 7.1, CHN)

6.42 (1H, dd, J = 8.7, 2.6, PMP-H) 6.54 (1H, dd, J = 8.9, 3.0,

PMP-H) 6.75 (1H, dd, J = 8.8, 3.0, PMP-H) 6.91 (2H, m, ArH)

7.05 (3H, apt d, J = 7.0, ArH) 7.15 – 7.35 (8H, m, ArH) 7.37

(1H, d, J = 7.4, ArH) minor trans, cis δ 2.44 (1H, dd, J = 13.4,

8.2, CHNCHCHCH₂) 2.69 (1H, m, CHNCH) 3.05 (2H, m,

CHNCHCH₂) 3.10 (1H, ddd, J = 10.8, 7.5, 5.0, CHNCHCH) 3.13

– 3.18 (1H, m, CHNCHCHCH₂) 3.78 (3H, s, OCH₃) 6.24 (1H, d,

J = 7.3, ArH) 6.28 (1H, d, J = 9.2, CHN) 6.63 (1H, dd, J = 8.9,

2.9, PMP-H) 6.69 (1H, dd, J = 8.9, 2.5, PMP-H) 6.78 (2H, m,

ArH) 6.86 (1H, dd, J = 8.8, 2.9, PMP-H) 6.95 (1H, m, PMP-H)

7.00 (1H, apt t, J = 7.4, ArH) 7.15 – 7.35 (9H, m, ArH) 7.40 (1H,

d, J = 7.6, ArH); ¹³C NMR (CDCl₃, 150 MHz) major trans, trans

δ 41.0 (CH₂CHCHN) 41.2 (CH₂CHCHCHN) 47.5 (CHCHN)

49.8 (CHCHCHN) 55.5 (OCH₃) 67.3 (CHN) 113.5 (PMP-C)

113.7 (PMP-C) 116.6 (q, J = 288.7, CF₃) 124.5 – 129.4 (14C,

ArC, indistinguishable) 128.0 (q, ArCN) 130.3 (PMP-C) 132.3

1

1152 (C-F, CF₃) cm^-1; H NMR (CDCl₃, 600 MHz) δ 1.54 (1H,

m, CH₂CH₂CHPh) 1.61 (1H, m, CH₂CHPh) 1.74 (1H, m,

CH₂CH₂CHPh) 2.25 -2.33 (2H, m, 1H, m, CH₂CHPh &

CHCH₂N) 2.40 – 2.47 (2H, m, CH₂Ph & CHCH₂Ph) 2.77 (1H, m,

CH₂Ph) 3.13 (1H, dt, J = 9.0, 8.2, CHPh) 3.62 (1H, dd, J = 13.5,

6.0, CH₂N) 3.79 (3H, s, OCH₃) 4.28 (1H, dd, J = 13.4, 9.1,

CH₂N) 6.84 – 7.55 (14 H, m, ArH & PMP-H); ¹³C NMR (CDCl₃,

150 MHz) δ 30.8 (CH₂) 34.7 (CH₂CHPh) 35.6 (CH₂Ph) 43.9

(CHCH₂Ph) 47.6 (CHCH₂N) 49.0 (CHPh) 52.6 (CH₂N) 55.5

(OCH₃) 126.0 (ArC) 126.4 (ArC) 127.5 (ArC) 128.5 (ArC) 128.7

(ArC) 128.9 (ArC) 131.0 (q, ArCN) 141.2 (q, ArC) 146.5 (q,

ArC) 157.6 (q, J = 34.4, CF₃) 159.5 (ArCO) further signals

indistinguishable; ¹⁹F NMR (CDCl₃, 282 MHz) δ – 67.0 ppm (3F,

s, CF₃); m/z (ES⁺) 935 (16 %, 2M + H⁺) 468 (100 %, M + H⁺);

HRMS (C₂₈H₂₉F₃NO₂) calcd. 468.2150, found 468.2154. See

supplementary information for data correlation table.

N-(2-benzyl-3-methyl-2,3-dihydro-1H-inden-1-yl)-2,2,2-

trifluoro-N-(4-methoxyphenyl)acetamide (40a)

(PMP-C) 139.3

(q, ArCCH₂CHCHCHN) 139.6 (q,

ArCCH₂CHCHN) 140.2 (ArCCHN) 145.6 (q, ArCCHCHCHN)

157.6 (q, J = 34.8, COCF₃) 159.8 (q, ArCO) minor trans, cis δ

34.1 (CH₂CHCHN) 36.5 (CH₂CHCHCHN) 46.0 (CHCHN) 46.2

(CHCHCHN) 55.5 (OCH₃) 66.0 (CHN) 113.9 (PMP-C) 114.0

(PMP-C) 116.7 (q, J = 289.4, CF₃) 124.5 – 129.4 (14C, ArC,

indistinguishable) 127.8 (q, ArCN) 130.8 (PMP-C) 131.6 (PMP-

C) 139.5 (q, ArCCH₂CHCHN) 139.6 (q, ArCCHN) 139.8 (q,

ArCCH₂CHCHCHN) 145.7 (q, ArCCHCHCHN) 158.6 (q, J =

34.7, COCF₃) 160.1 (q, ArCO); ¹⁹F NMR (CDCl₃, 282 MHz)

major trans, trans δ – 67.0 ppm (3F, s, CF₃) minor trans, cis δ –

Prepared by the general procedure using β-nitroacetamide 19a

(0.48 g, 0.99 mmol). Purification by flash column

chromatography (10 % Et₂O/Hexanes) afforded 437 as an

inseparable mixture of diastereomers (55:45) as a colourless oil

(200 mg, 0.46 mmol, 46 %); IR ν_max(thin film) 1686 (C=O,

1

amide) 1510 (C=C, Ar) 1186, 1153 (C-F, CF₃) cm^-1; H NMR

(CDCl₃, 600 MHz) major trans, trans δ 0.97 (3H, d, J = 7.0,

CHCH₃) 1.99 (1H, tdd, J = 8.7, 7.6, 6.1, CHCHN) 2.85 (1H, m,

CHCH₃) 2.95 (1H, dd, J = 13.7, 6.0, CH₂Ph) 3.03 (1H, dd, J =

13.7, 7.5, CH₂Ph) 3.76 (3H, s, OCH₃) 6.28 (1H, d, J = 8.8, CHN)

6.37 (1H, apt d, J = 8.6, PMP-H) 6.59 (1H, dd, J = 8.9, 2.9, PMP-

H) 6.61 – 6.65 (1H, m, PMP-H) 6.76 (1H, dd, J = 8.8, 2.9, PMP-

H) 7.09 – 7.13 (2H, m, ArH) 7.23 -7.39 (7H, m, ArH); minor

trans, cis δ 1.12 (3H, d, J = 7.3, CH₃) 2.60 (1H, tdd, J = 9.2, 7.9,

6.7, CHCHN) 2.90 (1H, dd, J = 14.5, 9.2, CH₂Ph) 2.96 – 3.04

(2H, m, CH₂Ph & CHCHCHN) 3.77 (3H, s, OCH₃) 6.24 (1H, d, J

= 9.2, CHN) 6.61 – 6.65 (1H, m, PMP-H) 6.70 (1H, dm, J = 8.7,

PMP-H) 6.83 (2H, m, PMP-H) 7.18 (2H, apt d, J = 7.5, ArH)

7.23 – 7.39 (7H, m, ArH); ¹³C NMR (CDCl₃, 150 MHz) major

trans, trans δ 18.8 (CH₃CH) 39.2 (CH₂) 42.6 (CH₃CH) 51.4

(CHCHN) 55.4 (OCH₃) 67.0 (CHN) 113.6 – 132.1 (ArC & PMP-

C) 116.6 (q, J = 288.3, CF₃) 127.9 (q, ArCN) 139.6 (q, ArCCHN)

139.6 (q, ArCCH₂) 146.7 (q, ArCCHCH₃) 158.2 (q, J = 35.1,

CF₃CO) 159.8 (q, ArCO); minor trans, cis δ 17.3 (CH₃CH) 34.4

(CH₂) 39.3 (CH₃CH) 45.3 (CHCHN) 55.5 (OCH₃) 66.3 (CHN)

113.6 – 132.1 (ArC & PMP-C) 116.6 (q, J = 289.2, CF₃) 127.8

(q, ArCN) 139.1 (q, ArC) 140.0 (q, ArC) 148.7 (q, ArCCHCH₃)

158.5 (q, J = 34.6, CF₃CO) 160.0 (q, ArCO) ; ¹⁹F NMR (CDCl₃,

282 MHz) major trans, trans δ – 66.9 ppm (3F, s, CF₃); minor

trans, cis δ – 66.8 ppm (3F, s, CF₃); m/z (EI) 439 (6 %, M⁺) 221

+

66.8 ppm (3F, s, CF₃); m/z (ESI⁺) 533 (37 %, M + NH₄) 516

(48 %, M + H⁺); HRMS (C₃₂H₂₉F₃NO₂) calcd. 516.2150, found

516.2152. See supplementary information for data correlation

table.

N-((1S*,2R*,3R*)-2-benzyl-3-ethyl-2,3-dihydro-1H-inden-1-

yl)-2,2,2-trifluoro-N-(4-methoxyphenyl)acetamide (40d)

Prepared by general procedure I using β-nitroacetamide 19d

(134 mg, 0.27 mmol). Purification via flash column

chromatography (0 – 10 % Et₂O/hexanes) afforded 40d as a

mixture of diastereoisomers (70:30) as a colourless oil (14.7 mg,

0.032 mmol, 12 %); IR ν_max(thin film) 2958, 2928, 2857 (C-H)

1688 (C=O, amide) 1510, 1454 (C=C, Ar) 1187, 1150 (C-F, CF₃)

cm^-1; ¹H NMR (CDCl₃, 600 MHz) δ_trans,trans0.44 (3H, s, CH₂CH₃)

1.29 (1H, m, CH₂CH₃) 1.41 (1H, m, CH₂CH₃) 2.22 (1H, apt

quint, J = 7.3, CHCHN) 2.86 (1H, m, CHEt) 2.93 (2H, d, J = 7.1,

CH₂Ph) 3.73 (3H, s, OCH₃) 6.25 (1H, dd, J = 8.7, 1.1, PMP-H)

6.30 (1H, d, J = 7.6, CHN) 6.48 (1H, dd, J = 8.8, 2.6, PMP-H)

6.53 (1H, dd, J = 8.8, 2.9, PMP-H) 6.72 (1H, dd, J = 8.8, 2.9,

PMP-H) 7.09 (1H, m, ArH) 7.24 – 7.30 (5H, m, ArH) 7.32 – 7.37

(3H, m, ArH); ¹³C NMR (CDCl₃, 150 MHz) δ

9.76

+

(100 %, C₁₇H₁₇⁺) 91 (98 %, C₇H₇); HRMS (C₂₆H₂₄F₃NO₂) calcd.

trans,trans

(CH₂CH₃) 25.1 (CH₂CH₃) 40.8 (PhCH₂) 46.4 (CHCHN) 49.0

16

Tetrahedron

ACCEPTED MANUSCRIPT

(CHEt) 55.5 (OCH₃) 67.3 (CHN) 113.5 (PMP-C) 113.7

We thank the Engineering and Physical Sciences Research

(PMP-C) 116.6 (q, J = 288.2, CF₃) 124.2 (ArC) 124.5 (ArC)

126.7 (ArC) 127.2 (ArC) 127.9 (q, ArCN) 128.5 (ArC) 128.6

(2C, ArC) 129.4 (2C, ArC) 130.5 (PMP-C) 132.2 (PMP-C) 139.9

(q, ArCCH₂) 140.3 (q, ArCCHN) 145.5 (q, ArCCHEt) 157.8 (q, J

= 34.9, COCF₃) 159.8 (ArCOCH₃); ¹⁹F NMR (CDCl₃, 282 MHz)

δ - 67.0 ppm (3F, s, CF₃); m/z (ESI⁺) 929 (47 %, 2M + H + Na⁺)

476 (100 %, M + H⁺) 235 (30 %, C₁₈H₁₉⁺); HRMS

(C₂₇H₂₆NO₂F₃Na) calcd. 476.1808, found 476.1808.

Council (DTA) and University College London for funding, Dr.

V.J. Gray and Dr K. Karu for mass spectra, Mrs. J. Maxwell

(UCL) for microanalytical data and Ms M. Corpinot for

assistance with X-ray crystallography.

1. (a) Noble, A.; Anderson, J. C. Chem. Rev., 2013, 113, 2887. (b)

Marqués-López, E.; Merino, P.; Tejero, T.; Herrera, R. P. Eur. J.

Org. Chem. 2009, 2401.

2. For α-aminocarbonyl compounds, see: (a) Ballini, R.; Petrini, M.

Tetrahedron 2004, 60, 1017. (b) Palomo, C.; Oiarbibe, M.;

Halder, R.; Laso, A.; López, R. Angew. Chem. Int. Ed. 2006, 45,

117.

1-(3-benzyl-4-methyl-2-phenylpyrrolidin-1-yl)-2,2,2-

trifluoroethan-1-one (41)

3. For the synthesis of 1,2-diamines, see: (a) Adams, H.; Anderson,

J. C.; Peace, S.; Pennell, A. M. K. J. Org. Chem. 1998, 63, 9932.

(b) Bernardi, L.; Bonini, B. F.; Capitò, E.; Dessole, G.; Comes-

Franchini, M.; Fochi, M.; Ricci, A. J. Org. Chem. 2004, 69, 8168.

(c) Sturgess, A. M.; Yarberry, D. J. Tetrahedron Lett. 1993, 34,

4743.

4. For peptide synthesis, see: Shen, B.; Makley, D. M.; Johnston, J.

N. Nature 2010, 465, 1027

5. (a) Ono, N.; Miyake, H.; Tamura, R.; Kaji, A. Tetrahedron Lett.

1981, 22, 1705. (b) Tanner, D. D. ; Blackburn, B. B. ; Diaz, G. E.

J. Am. Chem. Soc. 1981, 103, 1557.

Prepared by the general procedure using nitro compound 27

(150 mg, 0.38 mmol). Purification by flash column

chromatography (10 % Et₂O/Hexanes) afforded 41 as a mixture

of diastereoisomers (50:30:15:5) as a colourless oil (16.3 mg,

0.05 mmol, 12 %); IR ν_max(thin film) 3059, 3026, 2918, 2847 (C-

H) 1686 (C=O, amide) 1601, 1493, 1451 (C=C, Ar) 1196, 1135

(C-F, CF₃); ¹H and ¹³C NMR data display a complex mixture; m/z

(ESI) 717 (100 %, 2M + Na⁺) 370 (63 %, M + Na⁺) 348 (100 %,

M + H⁺); HRMS (C₂₀H₂₁F₃NO) calcd. 348.1570, found 348.1575.

6. (a) DuPuis, J. ; Giese, B. ; Hartung, J. ; Leising, M. J. Am. Chem.

Soc. 1985, 107, 4332. (b) Yankar, Y. D. ; Bawa, A. ; Kumaravel,

G. Tetrahedron 1991, 47, 2027. (c) Yankar, Y. D. ;hauduri, N. C.

Synth. Commun. 1991, 21, 885. (d) Crich, D. ; Shirai, M. ;

Rumthao, S. Org. Lett. 2003, 5, 3767. (e) Luzzio, F. A. ; Ott, J.

P. ; Duveau, D. Y. J. Org. Chem. 2006, 71, 5027.

7. (a) Anderson, J. C.; Peace, S.; Pih, S. Synlett 2000, 850. (b)

Anderson, J. C.; Howell, G. P. J. Org. Chem. 2005, 70, 549. (c)

Anderson, J. C.; Howell, G. P.; Lawrence, R. M.; Wilson, C. J.

Org. Chem. 2005, 70, 5665. (d) Anderson, J. C.; Chapman, H. A.

Synthesis 2006, 3309.

8. (a) Anderson, J. C.; Stepney, G. J.; Mills, M. R.; Horsfall, L. R.;

Blake, A. J.; Lewis, W. J. Org. Chem. 2011, 76, 1961. (b)

Anderson, J. C.; Blake, A. J.; Koovits, P. J.; Stepney, G. J. J. Org.

Chem. 2012, 77, 4711. (c) Anderson, J. C.; Koovits, P. J. Chem.

Sci. 2013, 4, 2897. (d) Anderson, J. C.; Kalogirou, A. S; Tizzard,

G. J. Tetrahedron 2014, 17, 9337.

9. (a) Anderson, J. C.; Chapman, H. A. Org. Biomol. Chem. 2007, 5,

2413. (b) Anderson, J. C.; Horsfall, L. R.; Kalogirou, A. S.; Mills,

M. R.; Stepney, G. J.; Tizzard, G.J. J. Org. Chem. 2012, 77, 6186.

(d) Anderson, J. C.; Noble, A.; Tocher, D. A. J. Org. Chem. 2012,

77, 6703. (e) Anderson, J. C.; Noble, A.; Ribelles Torres, P.

Tetrahedron Lett. 2012, 53, 5707. (f) Anderson, J. C.; Kalogirou,

A. S.; Porter, M. J.; Tizzard, G. J. Beil. J. Org. Chem. 2013, 9,

1737. (g) Anderson, J. C.; Campbell, I. B.; Campos, S.; Shannon,

J.; Tocher, D. A. Org. Biomol. Chem. 2015, 13, 170. (h)

Anderson, J. C.; Barham, J. P.; Rundell, C. D. Org. Lett. 2015, 17,

4090. (i) Anderson, J. C.; Rundell, C. D. Synlett 2016, 27, 41. (j)

Anderson, J. C.; Campbell, I. B.; Campos, S.; Reid, I. H.; Rundell,

C. D.; Shannon, J.; Tizzard, G. J. Org. Biomol. Chem. 2016, 14,

8270.

N-((1R*,2R*,3S*)-3-benzyl-2-phenyl-2,3-dihydro-1H-inden-1-

yl)-2,2,2-trifluoro-N-(4-methoxyphenyl)acetamide (42)

Prepared by the general procedure using nitro compound 28

(253 mg, 0.46 mmol). Purification by flash column

chromatography (10 % Et₂O/Hexanes) afforded 42 as a mixture

of diastereoisomers (95:5) as a colourless oil (30.0 mg, 0.06

mmol, 13 %); IR ν_max(thin film) 2920, 2836 (C-H) 1689 (C=O,

amide) 1603, 1509, 1453 (C=C, Ar) 1147, 1109 (C-F, CF₃) cm^-1;

¹H NMR (CDCl₃, 600 MHz) δ 2.67 (1H, dd, J = 14.5, 7.9,

CH₂Ar) 2.85 (1H, dd, J = 14.5, 5.0, CH₂Ar) 3.02 (1H, t, J = 9.2,

CHCH₂Ar) 3.53 (1H, m, CHCHN) 3.81 (3H, s, OCH₃) 6.48 (1H,

d, J = 9.4, CHN) 6.61 (1H, dd, J = 8.8, 2.6, PMP-H) 6.65 (1H,

apt d, J = 8.9, PMP-H) 6.84 (1H, dd, J = 8.7, 2.6, PMP-H) 6.90 –

6.94 (3H, m, ArH) 7.01 (1H, d, J = 7.6, ArH) 7.09 – 7.18 (5H, m,

PMP-H & ArH) 7.24 – 7.28 (2H, m, ArH) 7.30 – 7.35 (3H, m,

ArH) 7.38 (1H, d, J = 7.6, ArH); ¹³C NMR (CDCl₃, 150 MHz) δ

38.5 (CH₂Ar) 51.9 (CHCHN) 53.7 (CHCH₂Ar) 55.5 (OCH₃) 68.8

(CHN) 113.7 (PMP-C) 114.1 (PMP-C) 116.6 (q, J = 288.5, CF₃)

124.0 (ArC) 124.6 (ArC) 126.1 (ArC) 127.2 (ArC) 127.6 (2C,

ArC) 128.0 (q, ArCN) 128.3 (2C, ArC) 128.5 (2C, ArC) 128.5

(ArC) 128.9 (ArC) 129.3 (2C, ArC) 130.6 (PMP-C) 132.2 (PMP-

C) 139.3 (q, ArCCH₂) 139.7 (q, ArCCHN) 140.8 (q,

ArCCHCHN) 144.5 (q, ArCCHCHCHN) 158.2 (q, J = 35.2,

COCF₃) 160.0 (ArCO) ; ¹⁹F NMR (CDCl₃, 282 MHz) δ – 67.0

ppm (3F, s, CF₃); m/z (EI) 501.2 (2 %, M⁺) 283.2 (59 %,

C₂₂H₁₉⁺); HRMS (C₃₁H₂₆F₃NO₂) calcd. 501.19102, found

501.190981.

10. Kamimura, A.; Kadowaki, A.; Nagata, Y.; Uno, H. Tetrahedron

Lett. 2006, 47, 2471.

11. (a) Kornblum, N.; Carlson, S. C.; Smith, R. G. J. Am. Chem. Soc

1979, 101, 647. (b) Kornblum, N.; Carlson, S. C.; Smith, R. G. J.

Am. Chem. Soc 1978, 100, 289.

2,2,2-trifluoro-N-(4-methoxyphenyl)-N-(3-methyl-2-

phenylcyclopentyl)acetamide (43)

12.

L

̵

ytko-Krasuska, A.; Piotrowska, H.; Urbański, T. Tetrahedron

Lett. 1979, 20, 1243.

Prepared by the general procedure using β-nitroacetamide 29

(0.42 g, 1.00 mmol). Purification by flash column

chromatography (10 % Et₂O/Hexanes) afforded 43 as a mixture

of inseparable diastereomers (50:50) as a colourless oil (134 mg,

0.36 mmol, 36 %); IR ν_max(thin film) 2954, 2914 (C-H) 1684

(C=O, amide) 1509, 1453 (C=C, Ar) 1187, 1149 (C-F, CF₃) cm^-1;

¹H and ¹³C NMR data display a complex mixture; m/z (CI⁺) 772

13. (a) Ono, N.; Tamura, R.; Kaji, A. J. Am. Chem. Soc 1980, 102,

2851; (b) Ono, N.; Tamura, R.; Kaji, A. J. Am. Chem. Soc 1983,

105, 4017. (c) Shen, B.; Johnston, J. N. Org. Lett. 2008, 10, 4397.

14. Suzuki, H.; Takaoka, K.; Osuka, A. Bull. Chem. Soc. Jpn. 1985,

58, 1067.

15. Ono, N. ; Miyake, H. ; Kamimura. A. ; Hamamoto, I. ; Tamura,

R. ; Kaji, A. Tetrahedron 1985, 41, 4013.

16. (a) Yoshikawa, M.; Cha, B. C.; Okaichi, Y.; Takinami, Y.;

Yokokawa, Y.; Kitagawa, I. Chem. Pharm. Bull. 1988, 36, 4236;

(b) Kitagawa, I.; Cha, B. C.; Nakae, T.; Okaichi, Y.; Takinami, Y.;

Yoshikawa, M. Chem. Pharm. Bull. 1989, 37, 542; (c) Yoshikawa,

M.; Murakami, N.; Inoue, Y.; Kuroda, Y.; Kitagawa, I. Chem.

Pharm. Bull. 1993, 41, 1197; (d) Julina, R.; Müller, I.; Vasella, A.;

Wyler, R. Carbohydr. Res. 1987, 164, 415; (e) Yoshikawa, M.;

Okaichi, Y.; Cheon Cha, B.; Kitagawa, I. Tetrahedron 1990, 46,

7459. (f) Giese, B.; Dupuis, J. Tetrahedron Lett. 1984, 25, 1349.

+

(100 %, 2M + CH₅) 755 (99 %, 2M + H⁺) 395 (100 %, M +

+

CH₅) 378 (90 %, M + H⁺); HRMS (C₂₁H₂₂F₃NO₂) calcd.

378.16754, found 378.167530

Acknowledgments

17

(g) Petrini, M.; Torregiani, E. Tetrahedron Lett. 2006, 47, 3501-

ACCEPTED MANUSCRIPT

3503; (h) Han, B.; Liu, Q.-P.; Li, R.; Tian, X.; Xiong, X.-F.;

Deng, J.-G.; Chen, Y.-C. Chem. Eur. J. 2008, 14, 8094. (i) Davis,

T. A.; Danneman, M. W.; Johnston, J. N. Chem. Commun. 2012,

48, 5578.

17. Ono, N.; Miyake, H.; Kaji, A. J. Org. Chem. 1984, 49, 4997.

18. (a) Ono, N.; Kaji, A. Synthesis 1986, 693; (b) Rosini, G.; Ballini,

R. Synthesis 1988, 833. (c) Tormo, J.; Hays, D. S.; Fu, G. C. J.

Org. Chem. 1998, 63, 5296. (d) Barber, D. M.; Sanganee, H. J.;

Dixon, D. J. Org. Lett. 2012, 14, 5290-5293; (e) Duris, A.; Barber,

D. M.; Sanganee, H. J.; Dixon, D. J. Chem. Commun. 2013, 49,

2777-2779; (f) Hynes, P. S.; Stupple, P. A.; Dixon, D. J. Org. Lett.

2008, 10, 1389-1391; (g) Jakubec, P.; Cockfield, D. M.; Dixon, D.

J. J. Am. Chem. Soc 2009, 131, 16632-16633; (h) Kyle, A. F.;

Jakubec, P.; Cockfield, D. M.; Cleator, E.; Skidmore, J.; Dixon, D.

J. Chem. Commun. 2011, 47.

19. Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735.

20. Šagud, I.; Božić, S.; Marinić, Ž.; Šindler-Kulyk, M. Beilstein. J.

Org. Chem. 2014, 10, 2222.

21. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.

Am. Chem. Soc 2003, 125, 11360.

22. Maity, S.; Manna, S.; Rana, S.; Naveen, T.; Mallick, A.; Maiti, D.

J. Am. Chem. Soc 2013, 135, 3355.

23. Arigela, R. K.; Samala, S.; Mahar, R.; Shukla, S. K.; Kundu, B. J.

Org. Chem. 2013, 78, 10476.

24. Loh, C. C. J. B., J.; Raabe, G.; Enders, D.; Chem. Eur. J. 2011, 17,

13409.

25. Taniyama, D.; Hasegawa, M.; Tomioka, K. Tetrahedron:

Asymmetry 1999, 10, 221.

26. Che, C.; Li, S.; Yu, Z.; Li, F.; Xin, S.; Zhou, L.; Lin, S.; Yang, Z.

ACS Combinatorial Science 2013, 15, 202.

27. Lin, S.; Song, C.-X.; Cai, G.-X.; Wang, W.-H.; Shi, Z.-J. J. Am.

Chem. Soc 2008, 130, 12901.

28. Zhang, X. M.; Bordwell, F. G. J. Am. Chem. Soc 1994, 116, 968.

29. Kabalka, G. W.; Li, N.-S.; Tejedor, D.; Malladi, R. R.; Trotman,

S. J. Org. Chem. 1999, 64, 3157.

30. D'Hooghe, M.; Waterinckx, A.; De Kimpe, N. J. Org. Chem.

2005, 70, 227.

31. Chen, Z.-M.; Zhang, X.-M.; Tu, Y.-Q. Chem. Soc. Rev. 2015, 44,

5220.

32. Ishibashi, H. N., N.; Ito, K.; Kitayama, S.; Ikeda, M.; Heterocycles

1990, 31, 1781.

33. Beckwith, A. L. J.; O'Shea, D. M.; Westwood, S. W. J. Am. Chem.

Soc 1988, 110, 2565.

34. (a) Kinoshita, H.; Ingham, O. J.; Ong, W. W.; Beeler, A. B.;

Porco, J. A. J. Am. Chem. Soc 2010, 132, 6412. (b) Blum, R.;

Giovannini, E.; Hengartner, U.; Vallat, G. Helv. Chim. Acta 2002,

85, 1827.

35. (a) Kinoshita, H.; Ingham, O. J.; Ong, W. W.; Beeler, A. B.;

Porco, J. A. J. Am. Chem. Soc 2010, 132, 6412; (b) Shi, Y.; Yang,

B.; Cai, S.; Gao, S. Angew. Chem. Int. Ed. 2014, 53, 9539; (c)

Ebe, Y.; Hatano, M.; Nishimura, T. Adv. Synth. Catal. 2015, 357,

1425.

36. (a) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111, 6513; (b)

Alabugin, I. V.; Gilmore, K.; Manoharan, M. J. Am. Chem. Soc

2011, 133, 12608.

37. Luo, G. D. G., M.; Macor, J. E.; Chen, L.; Bristol-Myers Squibb

Company; WO2012/154354 A1.

38. Xu, H.-J.; Zhao, Y.-Q.; Zhou, X.-F. J. Org. Chem. 2011, 76, 8036.

Article Doi

Radical cyclisation studies of β-nitroamines from the nitro-Mannich reaction

DOI: 10.1016/j.tet.2018.06.022

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