Chemo- and diastereoselective cyclopropanation of allylic amines and carbamates

Tetrahedron 66 (2010) 8420e8440

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Tetrahedron

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Chemo- and diastereoselective cyclopropanation of allylic amines and carbamates

*

Kristína Csatayová, Stephen G. Davies , James A. Lee, Kenneth B. Ling, Paul M. Roberts,

Angela J. Russell, James E. Thomson

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansﬁeld Road, Oxford OX1 3TA, UK

a r t i c l e i n f o

a b s t r a c t

Article history:

A highly chemo- and diastereoselective protocol for the cyclopropanation of tertiary allylic amines with

Shi’s carbenoid [CF₃CO₂ZnCH₂I] is described. The high levels of diastereoselectivity observed in these

reactions may be attributed to chelation of the nitrogen atom to the zinc reagent, which then transfers

a methylene unit to the syn-face of the oleﬁn. Furthermore, a stereodivergent protocol for the cyclo-

propanation of a range of allylic carbamates has been developed, which provides access to both di-

astereoisomers of the corresponding cyclopropanes with very high levels of diastereoselectivity:

cyclopropanation with the WittigeFurukawa reagent [Zn(CH₂I)₂] proceeds under chelation control to

give the corresponding syn-product, whilst reaction with Shi’s carbenoid proceeds under steric control to

give the corresponding anti-cyclopropane, in >95:5 dr in both cases.

Received 14 July 2010

Accepted 23 August 2010

Available online 27 August 2010

Keywords:

Cyclopropanation

Allylic amines

Allylic carbamates

SimmonseSmith

Shi’s carbenoid

1. Introduction

Although a wide range of methods have been developed to fa-

cilitate the stereoselective synthesis of cyclopropanes the area has

The cyclopropane motif is found in a wide range of natural

products.¹These range from very simple structures such 1-ami-

nocyclopropanecarboxylic acid 1, a biosynthetic precursor of the

plant hormone ethylene,²to polycyclopropanated structures, such

as the cholesteryl ester transfer protein inhibitor U-106305 2, iso-

lated from the fermentation broth of Streptomyces sp. UC 11136

(Fig. 1).³In addition to being present in structures of wide-ranging

complexity, the cyclopropane motif is also found in secondary

metabolites from a variety of biosynthetic pathways. These include

polyacetates, fatty acids, amino acids, polyether antibiotics, terpe-

noids, steroids and alkaloids.⁴

been broadly dominated by three principal methods: (i) transition-

metal catalysed decomposition of diazo compounds followed by

addition to an oleﬁn;^5e7(ii) Michael-initiated ring closure (MIRC)^8,9

and (iii) the cyclopropanation of oleﬁns with halomethyl metal

reagents.^10,11The SimmonseSmith cyclopropanation reaction has

been one of the most widely used methods to promote the ste-

reospeciﬁc conversion of an oleﬁn into a cyclopropane for over 50

years,¹²and new classes of highly reactive zinc carbenoids have

been developed, in particular over the past decade.¹³As such, the

efﬁcient cyclopropanation of isolated and electron poor double

bonds is now possible, and the substrate scope of the reaction is

therefore immensely broad.^10bDiastereoselective cyclopropanation

employing a zinc carbenoid, relying upon delivery of the incoming

methylene group by the binding of an allylic hydroxyl group to the

NH₂

zinc atom, has long been exploited. Other groups including

a,b-

CO₂H

unsaturated acetals,¹⁴amides¹⁵and boronates¹⁶have also been

shown to enable diastereoselective reaction. Although allylic

amines have the same potential for directing cyclopropanation, the

competing formation of a zinc-complexed ammonium ylide often

thwarts cyclopropanation.¹⁷The diastereoselective Simmonse

Smith cyclopropanation of allylic amines¹⁸using N-protecting

groups bearing free hydroxyl moieties to promote cyclo-

propanation has recently been reported: Aggarwal et al.¹⁹

demonstrated that treatment of 3 [derived from (1R,2R)-pseu-

doephredrine] with Zn(CH₂I)₂gave the corresponding cyclopropane 4

in 95% yield and >99:1 dr whilst Katigiri et al.²⁰reported that cyclo-

propanation of 6 [derived from (S)-1,2-epoxy-3,3,3-triﬂuoropropane]

AAC 1

H

Me

N

O

U-106305 2

Fig. 1. Natural products containing the cyclopropane motif.

* Corresponding author. E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).

doi:10.1016/j.tet.2010.08.055

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

8421

can be achieved to give 7 in 86% yield and >99:1 dr. One disad-

NBn₂

(i) or (ii)

or (iii)

vantage of these approaches, however, is the relatively harsh re-

action conditions required for removal of the N-substituent (via

quarternization with MeI followed by treatment with base), which

therefore inherently limits this methodology to the preparation of

the corresponding N,N-dimethyl protected derivatives such as 5

(Scheme 1).

8

syn-9, >99:1 dr^a

(i). 11%; (ii). 33%; (iii). 92%

Me

I

Me

NBn₂

I

OH

Me

N

Me

N

(i)

Ph

Me

3

4, 95%

10

11

>99:1 dr

(iii)

Scheme 2. Reagents and conditions: (i) Et₂Zn, CH₂I₂, CH₂Cl₂, rt, 1 h; (ii) Et₂Zn, ICH₂Cl,

CH₂Cl₂, rt, 1 h; (iii) Et₂Zn, CH₂I₂, TFA, CH₂Cl₂, rt, 1 h. [^acrude and puriﬁed].

Me₂N

Ph

5, >99:1 dr

93% from 4

81% from 7

(iv)

OH

Me

N

Me

N

(ii)

Ph

F₃C

6

7, 86%

>99:1 dr

Scheme 1. Reagents and conditions: (i) Zn(CH₂I)₂, CH₂Cl₂, 0 ^ꢀC, 2 days; (ii) Zn(CH₂I)₂,

CH₂Cl₂, ꢁ5 ^ꢀC, 1 h; (iii) MeI, 6 days then NaH, THF, reﬂux, 3.5 h; (iv) MeI, EtOH, reﬂux,

16 h then KO^tBu, 18-crown-6, THF, rt, 24 h.

As part of an ongoing research programe directed towards the

chemo- and stereoselective functionalisation of allylic amines at the

oleﬁn,^21e23we became interested in the potential of allylic amines

as substrates for the SimmonseSmith reaction. In this manuscript

we report our full investigations into the cyclopropanation of allylic

amines and their derivatives; part of this work has been commu-

nicated previously.²¹

Fig. 2. Chem 3D representation of the single crystal X-ray structure of 9$HBF₄(some H

atoms have been omitted for clarity).

2. Results and discussion

2.1. Cyclopropanation of 3-(N,N-dibenzylamino)cyclohexene:

model studies

controlled mechanism. 4,4-Diphenylcyclohex-1-ene 12 and N,N-

dibenzylcyclohexylamine 13 were chosen as mimics for the oleﬁn

and tertiary amino functionalities within allylic amine 8, re-

spectively;³¹cyclohexene was deemed to be unsuitable for this

purpose as its volatility (bp 83 ^ꢀC), or indeed the volatility of the

corresponding cyclopropane, would mean that accurate de-

termination of the product distributions from any competition ex-

periments would be extremely problematic. It was hoped that the

gem-diphenyl group within 12 would signiﬁcantly reduce this vol-

atility, whilst being remote enough so as to not suppress the cyclo-

propanation reaction. Reaction of either 8 or 12 with 2.0 equiv of

Shi’s carbenoid [CF₃CO₂ZnCH₂I] for 30 min resulted in essentially

complete conversion (>98%) to give cyclopropanes syn-9 (>99:1 dr)

and 14, respectively. The same reactions were then conducted in the

presence 1.0 equiv of 13 (as an external tertiary amine) in each case.

Reaction of 8 under these conditions resulted in >98% conversion to

syn-9 (>99:1 dr), whereas in the case of 12 cyclopropane 14 was

produced in only 8% conversion. The observation that the rate of

non-directed cyclopropanation of 12 is reduced by the presence of

a tertiary amine is consistent with co-ordination of the nitrogen

atom to zinc, stabilizing the carbenoid and reducing its reactivity.³²

In addition, the observation that the cyclopropanation of allylic

amine 8 is not hindered by the presence of a tertiary amine suggests

that chelation controlled cyclopropanation is taking place in this

case. Furthermore, when an equimolar mixture of allylic amine 8 and

oleﬁn 12 was treated with 2.0 equiv of Shi’s carbenoid for 30 min

syn-9 (>99:1 dr) was produced in >98% conversion, whereas only 9%

Initial studies focussed on cyclopropanation of our model

substrate 3-(N,N-dibenzylamino)cyclohexene 8.²⁴Attempted

cyclopropanation of 8 with the WittigeFurukawa reagent [Zn(CH₂I)₂]²⁵

or Denmark’s reagent [Zn(CH₂Cl)₂]²⁶proceeded with almost

complete consumption of starting material,²⁷giving a low mass

return of cyclopropane syn-9 (>99:1 dr) as the only product in 11

and 33% isolated yield, respectively. Although no other products

were isolated from these reactions, comparison of the ¹H NMR

spectra of the crude reaction mixtures with those of authentic

samples of N-methyl ammonium species 10 (prepared in quanti-

tative conversion via treatment of 8 with MeI in MeCN at 40 ^ꢀC for

2 days) and 11 (prepared via treatment of 9 with Zn(CH₂I)₂)²⁸

revealed that N-methylation was the major deleterious side-

reaction in this system and accounts for the poor mass return.

Cyclopropanation of 8 with the more reactive Shi’s carbenoid

[CF₃CO₂ZnCH₂I],^13ahowever, proceeded with full conversion to

give syn-9 in 92% isolated yield and >99:1 dr (Scheme 2).^29,30The

relative syn-conﬁguration within 9 was proven unambiguously by

single crystal X-ray analysis of the corresponding tetraﬂuoroborate

salt 9$HBF₄(Fig. 2). This stereochemical outcome is presumably

a result of initial binding of the zinc carbenoid by the nitrogen

atom, followed by rapid intramolecular cyclopropanation.

A series of competition experiments was designed to probe fur-

ther the hypothesis that the high syn-diastereoselectivity observed

during the cyclopropanation of 8 was a result of a chelation

8422

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

conversion to 14 was observed. An interesting observation is that in

the case of cyclopropanation of 12 in the presence of amine 13,

1.0 equiv of amine is able to inhibit 2.0 equiv of carbenoid. This

suggests that the carbenoid is likely to be present as a dimer. In

support of this, the reaction was repeated with 4.0 equiv of carbe-

noid, which resulted in >98% conversion to 14 after 30 min; this

result is consistent with the amine sequestering 2.0 equiv of the

carbenoid, leaving the other 2.0 equiv to effect cyclopropanation of

12 (Scheme 3).

16e18³⁴was next investigated. Thus, treatment of the ﬁve-mem-

bered ring substrate 16 with Shi’s carbenoid afforded syn-19 in 84%

yield and >99:1 dr. The relative syn-conﬁguration within 19 was

assigned by analogy to the stereochemical outome observed upon

cyclopropanation of the six-membered ring substrate 8 (giving

syn-9), and this assignment was further supported by ¹H NMR

NOE analysis. This stereochemical outcome is consistent with our

observations concerning the ammonium directed oxidation of

ﬁve-membered ring substrate 16^22cand may be rationalised by co-

ordination of the nitrogen atom to the zinc reagent followed by

intramolecular delivery of the methylene unit to the syn-face,

although minimisation of torsional strain in the transition state may

also contribute.³⁵Reaction of the 7- and 8-membered ring substrates

17 and 18 with CF₃CO₂ZnCH₂I gave anti-20 and anti-21 in 90 and 96%

yield, respectively, and in >99:1 dr in each case (Scheme 4). The

relative anti-conﬁgurations within 20 and 21 were proven

unambiguously by single crystal X-ray analyses (Figs. 4 and 5). These

results are consistent with the high levels of anti-diastereoselectivity

observed in our studies concerning the epoxidations of 17 and 18

by m-CPBA in the presence of Cl₃CCO₂H.^22cThe high degree of

anti-diastereoselectivity in the cyclopropanation of 18 parallels the

cyclopropanation of cis-cyclooct-2-en-1-ol,^36,37which has also been

reported as proceeding with complete anti-diastereoselectivity; the

accepted explanation for anti-cyclopropanation in this case is that, in

the preferred low-energy chair-boat conformation³⁸of the cyclo-

octene ring, addition reactions can only occur on the sterically more

accessible face of the oleﬁn, which is not blocked by the rest of

the ring. Indeed, in the solid-state both allylic amine 18³⁹and anti-

cyclopropane 21 display chair-boat conformations, with the N,N-

dibenzylamino group occupying a pseudobowsprit position. The

high level of anti-diastereoselectivity observed in the

NBn₂

(i)

+

Ph

12

13

8

14

9

12

13

8

CF₃CO₂ZnCH₂I

(equiv)

Coversion

to 14 (%)

Coversion

a

to 9 (%)

(equiv)

(equiv) (equiv)

0

1

0

1

0

1

0

1

0

1

0

2

4

--

>98

8

>98

--

>98

--

9

>98

Scheme 3. Reagents and conditions: (i) Et₂Zn, CH₂I₂, TFA, CH₂Cl₂, 0 ^ꢀC to rt, 30 min.

[^a>99:1 dr].

L₂Zn

I

NBn ₂

NBn₂

O₂CCF₃

Zn

Et₂Zn, CH₂I₂

TFA, CH₂Cl₂

rt, 1 h

NBn₂

8

syn-9

>99:1 dr

15

Fig. 3. Proposed transition state model 15 for the directed cyclopropanation of allylic

amine 8 with Shi’s carbenoid. [L¼ligand].

NBn₂

(i)

These data are consistent with the cyclopropanation of allylic

amine 8 proceeding via transition state model 15 where a dimeric

zinc species derived from Shi’s carbenoid [CF₃CO₂ZnCH₂I] is

chelated to the nitrogen atom such that the carbenoid may be de-

livered to the syn-face of the double bond, producing syn-9 with

very high diastereoselectivity (Fig. 3).³³

16

-19, 84%, >99:1 dr^a

syn

NBn₂

NB n₂

(i)

anti-20, 90%, >99:1 dr^a

17

NBn₂

2.2. Cyclopropanation of 5-, 7- and 8-membered ring allylic

amines

(i)

Having shown that the cyclopropanation of our model substrate 8

proceeds with excellent diastereoselectivity when Shi’s carbenoid

[CF₃CO₂ZnCH₂I] is employed, the scope of the reaction with respect

to the corresponding 5-, 7- and 8-membered ring allylic amines

-21, 96%, >99:1 dr^a

18

anti

Scheme 4. Reagents and conditions: (i) Et₂Zn, CH₂I₂, TFA, CH₂Cl₂, rt, 1 h. [^acrude and

puriﬁed].

Fig. 4. Chem 3D representations of the single crystal X-ray structures of allylic amine 17 and anti-cyclopropane 20 (some H atoms have been omitted for clarity).

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

8423

Fig. 5. Chem 3D representations of the single crystal X-ray structures of allylic amine 18 and anti-cyclopropane 21 (some H atoms have been omitted for clarity).

cyclopropanation of 17, however, is in contrast to the poorly dia-

stereoselective cyclopropanation of cyclohept-2-en-1-ol with either

the SimmonseSmith⁴⁰(Zn/Cu, CH₂I₂) or Molander⁴¹(Sm/Hg, CH₂I₂)

reagents; in these cases the low diastereoselectivities suggest that

the seven-membered ring is conformationally ill-deﬁned, consistent

with the known conformational lability of cycloheptene itself.⁴²The

sterically-demanding N,N-dibenzylamino group may therefore be

enforcing a more well-deﬁned ground state conformation, which is

reﬂected in the transition state for the cyclopropanation of 17 and the

stereochemical outcome may therefore be simply ascribed to re-

action on the least hindered face. In the solid-state structures of both

allylic amine 17⁴³and anti-cyclopropane 20 the seven-membered

ring adopts a chair-type conformation, and it has been shown that

both cycloheptene⁴²and cycloheptene oxide⁴⁴favour this confor-

mation in solution. Therefore, chelation of the nitrogen atom to zinc

resulting in chelation controlled cyclopropanation of neither 17 nor

18 need be invoked to explain the high diastereofacial selectivity, but

may still be involved in stabilizing the transition state, especially

when the relatively close proximity of the N,N-dibenzylamino group

to the anti-face of the oleﬁn is considered (Figs. 4 and 5).

high yield, although the reaction of (E)-29 (which experiences far

less 1,3-allylic strain than 24e28) with Shi’s carbenoid proceeded to

give 92% conversion to37 in 89:11 dr, whichwas isolatedin 60% yield

(Scheme 6).⁴⁶The relative conﬁgurations within 33 and 36

were unambiguously established by single crystal X-ray analyses

(Figs. 6 and 7), and the relative conﬁgurations within the remaining

cyclopropanes 32, 34, 35 and 37 were assigned by analogy.

NBn₂R²

(i)

R¹

R³

R¹

R³

R⁴

24-29

32-37

Allylic amine

Product Yield % dr^a

R¹R²R³R⁴

24

25

26

27

28

29

32

33

34

35

36_b

37

66

88

71

37

79

60

>99:1

89:11

Ph Me

Ph Me Me

Ph Me

H

Me

Ph Me Me Me

ⁱPr Me Me

Ph Me

H

Scheme 6. Reagents and conditions: (i) Et₂Zn, CH₂I₂, TFA, CH₂Cl₂, rt, 1 h. [^acrude and

puriﬁed; ^b92% conversion].

2.3. Cyclopropanation of acyclic allylic amines

The effects of 1,2- and 1,3-allylic strain within the diaster-

eoselective cyclopropanation reaction manifold were assessed by

reaction of a range of acyclic N,N-dibenzyl substituted allylic

amines 24e31 with Shi’s carbenoid. The synthesis of the requi-

site substrates 24e31 employed the addition of a range of

Grignard reagents to a-benzotriazolyl substituted amines 22 and

23⁴⁵to give allylic amines 24e31 in moderate to good yield and,

where applicable, in sufﬁciently high diastereoisomeric purity

(Scheme 5).

N

NBn₂R²

N

(i)

N

R¹

R³

R⁴

R¹

NBn₂

22 R¹= Ph

24-31

23 R¹= ⁱPr

1

2

3

R

4

dr (E):(Z)

Product

R

Yield %

Fig. 6. Chem 3D representation of the single crystal X-ray structure of 33 (some H

atoms have been omitted for clarity).

24

25

26

27

28

29

30

31

Ph Me

Ph Me Me

Ph Me

H

75

93

87

40

88

38

92

9:91

--

H

Me

4:96

--

Ph Me Me Me

i

--

Pr Me Me

H

Treatment of allylic amines 30 and 31 (which contain

a terminal oleﬁn) with the deuterium labelled analogue of

Shi’s carbenoid [CF₃CO₂ZnCD₂I] gave cyclopropanes 39 and 41

in 72 and 94% yield, and 70:30 and 58:42 dr, respectively;

comparable yields of the unlabelled cyclopropanes 38 and 40

were obtained upon reaction of 30 and 31 with CF₃CO₂ZnCH₂I

(Scheme 7).⁴⁷

Ph

H

Me

H

>99:1

--

H

Me quant

Scheme 5. Reagents and conditions: (i) RMgX, PhMe, 50 ^ꢀC, 2 h.

Treatment of substrates 24e28 with Shi’s carbenoid gave cyclo-

propanes 32e36 as single diastereoisomers (>99:1 dr) in typically

8424

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

Ts

Boc

O

OH

N

(i)

(iii)

45

46, 97%

48, quant

(ii)

(iv)

NPhth

NHBoc

47, 50%

49, 47%

Scheme 8. Reagents and conditions: (i) NaBH₄, CeCl₃$7H₂O, MeOH; (ii) phthalamide,

PPh₃, DEAD, THF; (iii) TsNHBoc, PPh₃, DEAD, THF, rt, 24 h; (iv) sodium naphthalide,

THF, rt, 3 h. [NPhth¼phthalimido].

Fig. 7. Chem 3D representation of the single crystal X-ray structure of 36 (some H

atoms have been omitted for clarity).

Reaction of 47 with Zn(CH₂I)₂proceeded to 27% conversion (after

3 h), giving an 18:82 mixture of syn-50/anti-51,⁴⁸whereas reaction

of 47 with CF₃CO₂ZnCH₂I under identical conditions gave 62%

conversion to a 17:83 mixture of syn-50/anti-51, from which syn-50

and anti-51 were isolated as single diastereoisomers (>99:1 dr) in 8

and 33% yield, respectively. The relative conﬁguration within anti-

51 was initially established via independent chemical synthesis

from cyclohex-2-enol 46:⁴⁹cyclopropanation of allylic alcohol 46

with Denmark’s reagent [Zn(CH₂Cl)₂] gave syn-52 in 56% yield and

>99:1 dr. Installation of the phthalimido group and inversion of

conﬁguration was then achieved by Mitsunobu reaction of syn-52

with phthalimide to give anti-51 in 67% yield and >99:1 dr

(Scheme 9). Subsequent single crystal X-ray analysis of syn-50

allowed its relative conﬁguration (and therefore also the relative

conﬁguration within anti-51) to be unambiguously assigned.⁵⁰Al-

though the diastereoselectivity of cyclopropanation appears to be

predominantly a result of steric control, competing chelation by one

of the carbonyl groups may give rise to the minor product syn-50.

NBn₂

R

(i) or (ii)

Ph

CX₂

R⁴

30-31

38-41

4

a

Allylic amine

R

Product X

Yield % dr

30

31

H

38

39

40

41

H

D

H

D

73

--

H

72^b70:30

Me

94

--

58:42

Scheme 7. Reagents and conditions: (i) Et₂Zn, CH₂I₂, TFA, CH₂Cl₂, rt, 1 h; (ii) Et₂Zn,

CD₂I₂, TFA, CH₂Cl₂, rt, 3 h. [^acrude and puriﬁed; ^b86% conversion].

1,3-Allylic strain is minimised within the solid-state conforma-

tions of 33 and 36, and it may also be reasoned that the corre-

sponding allylic amines adopt a similar conformation in solution.

The stereochemical outcome (and high levels of diaster-

eoselectivity) observed in the cyclopropanation of acyclic allylic

amines 24e28 is consistent with transition state model 43 in which

1,3-allylic strain is minimised and cyclopropanation occurs under

chelation control (Fig. 8). The lower diastereoselectivity observed

upon cyclopropanation of 29 (89:11 dr), 30 (70:30 dr) and 31 (58:42

dr) reﬂects their increased conformational freedom due to a de-

crease in 1,3-allylic strain.

NPhth

(i). 27% conv

18:82 (50:51)

+

(ii). 62% conv

a

syn-50

anti-51

17:83 (50:51)

47

(ii). 8%

(ii). 33%, (iv). 67%

(iv)

OH

A_1,3strain minimised

OH

L₂Zn

I

O₂CCF₃

Zn

(iii)

Et₂Zn, CH₂I₂

TFA, CH₂Cl₂

rt, 1 h

NBn₂R'

NBn

H

R''

R'

2

syn-52, 56%^a

46

R

R''

R

R''

H

R

Scheme 9. Reagents and conditions: (i) Et₂Zn, CH₂I₂, CH₂Cl₂, rt, 3 h; (ii) Et₂Zn, CH₂I₂,

TFA, CH₂Cl₂, rt, 3 h; (iii) Et₂Zn, ICH₂Cl, CH₂Cl₂, rt, 1 h; (iv) phthalimide, PPh₃, DEAD,

THF, rt, 24 h. [^aIsolated in >99:1 dr; NPhth¼phthalimido].

42

43

44, >99:1 dr

Fig. 8. Proposed transition state model for the directed cyclopropanation of acyclic

allylic amines 24e28 with Shi’s carbenoid.

Cyclopropanation of allylic carbamate 49 was next investigated.

Treatment of 49 with the WittigeFurukawa reagent [Zn(CH₂I)₂]

was found to give syn-cyclopropane 53 in >99:1 dr⁵¹and 67%

isolated yield, whereas treatment of 49 with Shi’s carbenoid

[CF₃CO₂ZnCH₂I] gave the corresponding anti-cyclopropane 54 in

70% yield and >99:1 dr (Scheme 10). The relative conﬁgurations

2.4. Cyclopropanation of allylic imides, carbamates, amides

and sulfonamides

The N-protecting groups were next varied, in order to probe

the possibility of preparing the corresponding anti-cyclopropanes.

Representative substrates 47 and 49 were chosen for initial

screening. Thus, cyclohexenone 45 was reduced under Luche

conditions to give allylic alcohol 46 in 97% yield. Subsequent

Mitsunobu reaction with either phthalimide or N-(tert-butoxy-

carbonyl)-p-toluenesulfonamide gave 47 and 48 in 50% and

quantitative yield, respectively. Finally, 48 was treated with so-

dium naphthalide to afford tert-butyl carbamate 49 in 47% yield

(Scheme 8).

NHBoc

(i)

(ii)

syn-53, 67%

49

anti-54, 70%

>99:1 dr^a

Scheme 10. Reagents and conditions: (i) Et₂Zn, CH₂I₂, CH₂Cl₂, rt, 3 h; (ii) Et₂Zn, CH₂I₂,

TFA, CH₂Cl₂, rt, 3 h. [^acrude and puriﬁed].

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

8425

O

within syn-53 and anti-54 were established via chemical correla-

tion (vide infra).

HN

R

HN

R

HN

R

The complementary diastereoselectivities of this reaction are

postulated to be a result of initial formation of an intermediate zinc

complex by deprotonation of the NH proton of the carbamate. In

the case of Zn(CH₂I)₂the co-ordinated zinc carbenoid 55 is able to

effect intramolecular cyclopropanation of the double bond to give

syn-53, whereas with CF₃CO₂ZnCH₂I a second equivalent of the zinc

reagent is required to undergo intermolecular cyclopropanation of

the double bond by approach to the least hindered face of 56, giving

the corresponding anti-cyclopropane 54 (Fig. 9).⁵²

(i)

(ii)

-63-66

syn

59-62

-67-70

anti

a

R

Yield % dr

R

R Yield % dr

63 OMe

64 OPh

65 OBn

99 >99:1

84 >99:1

59 OMe

60 OPh

61 OBn

62 Ph

67 OMe

68 OPh

69

83^b98:2

75^c95:5

OBn

98:2

89

66 Ph quant >99:1

70 Ph

80^d>99:1

Scheme 12. Reagents and conditions: (i) Et₂Zn, CH₂I₂, CH₂Cl₂, rt, 1 h; (ii) Et₂Zn, CH₂I₂,

TFA, CH₂Cl₂, rt, 1 h. [^acrude and puriﬁed; ^b88% conversion; ^c80% conversion; ^d92%

conversion].

O^tBu

NHBoc

Wittig

Furukawa

reagent

I

Zn O

N

70 were assigned by analogy to those of the N-Boc and N-Cbz pro-

tected analogues 53, 54, 65 and 69.

49

55

syn-53

O

Surprisingly, cyclopropanation of N-tosyl protected 71 with ei-

ther the WittigeFurukawa reagent [Zn(CH₂I)₂] or Shi’s carbenoid

[CF₃CO₂ZnCH₂I] gave the same product syn-72 in 60 and 53% yield,

respectively, and in >99:1 dr in each case (Scheme 13). The relative

syn-conﬁguration within 72 was initially established by ¹H NMR

NOE studies and was then unambiguously established by single

crystal X-ray analysis (Fig. 10).

Zn

O

O^tBu

CF₃

F₃C

O

NHBoc

N

Shi's

reagent

O

I

Zn

O

49

56

anti-54

Fig. 9. Proposed mechanistic rationale for the stereodivergent cyclopropanation of

allylic carbamate 49 with either Zn(CH₂I)₂or CF₃CO₂ZnCH₂I.

NHTs

(i) or (ii)

Consistent with this hypothesis, treatment of allylic carbamate

49 with 1.0 equiv of Zn(CH₂I)₂gave 37% conversion to syn-53

after 1 h, whereas analogous treatment of 49 with 1.0 equiv of

CF₃CO₂ZnCH₂I gave no observable cyclopropanation products.

Moreover, treatment of the corresponding N-methyl-N-Boc pro-

tected substrate 57²³with 2.0 equiv of Zn(CH₂I)₂gave no reaction.

When 2.0 equiv of CF₃CO₂ZnCH₂I was employed, however, anti-58

was isolated in 46% yield and >99:1 dr. In order to corroborate this

stereochemical assignment, an authentic sample of anti-58 was

prepared via N-methylation of anti-54 (Scheme 11).

-72

71

syn

(i). 60%, >99:1 dr^a

(ii). 53%, >99:1 dr^a

Scheme 13. Reagents and conditions: (i) Et₂Zn, CH₂I₂, CH₂Cl₂, rt, 1 h; (ii) Et₂Zn, CH₂I₂,

TFA, CH₂Cl₂, rt, 12 h. [^acrude and puriﬁed].

NMeBoc

(i) or (ii)

NMeBoc

NHBoc

(iii)

anti-58, (i). 0%

anti-54

>99:1 dr

57

(ii). 46%, >99:1 dr^a

Scheme 11. Reagents and conditions: (i) Et₂Zn, CH₂I₂, CH₂Cl₂, rt, 1 h; (ii) Et₂Zn, CH₂I₂,

TFA, CH₂Cl₂, rt, 1 h; (iii) NaH, MeI, THF, 0 ^ꢀC, 16 h. [^acrude and puriﬁed].

A range of other carbamates 59e61⁵³were next subjected to the

optimised cyclopropanation conditions. In each case, treatment of

carbamates 59e61 with the WittigeFurukawa reagent [Zn(CH₂I)₂]

gave the corresponding syn-cyclopropanes 63e65 in >99:1

dr, whereas similar treatment of 59e61 with Shi’s carbenoid

[CF₃CO₂ZnCH₂I] gave the corresponding anti-cyclopropanes 67e69

in ꢂ95:5 dr. Furthermore, this stereodivergent protocol also proved

to be applicable to the cyclopropanation of allylic amides: treatment

of benzamide 62 with the WittigeFurukawa reagent gave syn-66 in

quantitative yield and >99:1 dr and treatment of 62 with Shi’s car-

benoid gave anti-70 in 80% yield and >99:1 dr (Scheme 12). The

relative conﬁgurations within syn-65 and anti-69 were initially

assigned by ¹H NMR NOE analyses. In particular, anti-69 exhibited

a strong enhancement between C(2)H and C(7)H_A. Crucially, this

enhancement was absent for syn-65, which instead showed a strong

enhancement between NH and C(7)H_A. Subsequent chemical corre-

lation studies unambiguously conﬁrmed the assigned relative con-

ﬁgurations within syn-65 and anti-69; the relative conﬁgurations

within the remaining cyclopropanated products 63, 64, 66, 67, 68 and

Fig. 10. Chem 3D representation of the single crystal X-ray structure of syn-72 (some H

atoms have been omitted for clarity).

2.5. N-Deprotections

In order to conﬁrm the assigned relative conﬁgurations within

these cyclopropanated products and to demonstrate the utility of

this protocol in synthesis, deprotection of the N,N-dibenzyl, phtha-

limido, N-Cbz and N-Boc protected substrates was undertaken. It was

found that under 1 atm of hydrogen, in the presence of Pd/C,

selective mono-debenzylation of syn-9 could be achieved allowing

isolation of syn-73 in 65% yield. Under more forcing conditions

(5 atm) hydrogenolysis of syn-9, followed by treatment with TFA,

gave syn-74 in quantitative yield; in each case, no products arising

8426

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

from cleavage of the cyclopropane ring were observed. Deprotection

of the phthalimido groups within syn-50 and anti-51 was achieved

upon treatment with hydrazine, giving syn-74 and anti-75 (after

treatment with TFA) in quantitative yield and >99:1 dr in each case.

Deprotection of the N-Cbz protected substrates syn-65 and anti-69

via hydrogenolysis also gave syn-74 and anti-75 (following treatment

with TFA), both in quantitative yield and >99:1 dr; again no products

arising from cleavage of the cyclopropane ring were observed in

either case. Cleavage of the N-Boc protecting groups within syn-53

and anti-54 was achieved upon treatment with TFA giving syn-74

and anti-75 directly, in quantitative yield and >99:1 dr in each case

(Scheme 14). These studies therefore allowed for the relative con-

ﬁgurations within 53, 54, 65 and 69 to be unambiguously assigned.

carbamate functionality within 78. Reaction of 1-phenylcyclohexene

76 with1.0 equivofZn(CH₂I)₂for60 minresultedin13%conversionto

cyclopropane 79, whilst reaction with 2.0 equiv of Zn(CH₂I)₂resulted

in 20% conversion to 79. Under identical conditions reaction of 76 in

the presence of 1.0 equiv of carbamate 77 resulted in 24% conversion

to 79 when 1.0 equiv of Zn(CH₂I)₂was used and 44% conversion to 79

with 2.0 equiv of Zn(CH₂I)₂. The increased reactivity of 76 in the

presence of carbamate 77 can be rationalized by the formation of

intermediate iodomethylzinc amide 81 which, due to the electron

withdrawingnatureofthecarbamatefunctionality, ispostulatedtobe

a more reactive carbenoid than Zn(CH₂I)₂, consistent with the ob-

servations of Shi et al.^13cIt should be noted, however, that the ob-

served rate of intermolecular cyclopropanation mediated by

iodomethylzinc amide 81 is still signiﬁcantly slower than that ob-

served for the cyclopropanation of allylic carbamate 78,⁵⁷consistent

with intramolecular cyclopropanation in the latter case. In support of

this hypothesis, cyclopropanation of 1-phenylcyclohexene 76 in the

presence of 1.0 equiv of allylic carbamate 78 was next investigated.

Reaction with 1.0 equiv of Zn(CH₂I)₂resulted in 17% conversion of 76

to 79 and 96% conversion of 78 to 80,⁵⁸whereas reaction with

2.0 equiv of Zn(CH₂I)₂resultedin59%conversionof 76 to 79and >98%

conversion of 78 to 80 (Scheme 15). Moreover, further kinetic stud-

ies⁵⁹revealed that cyclopropanation of 78 with 2.0 equiv of Zn(CH₂I)₂

was found to reach completion after only 25 min, whereas treatment

of 76 with 2.0 equiv of Zn(CH₂I)₂for 25 min only produced 79 in 27%

conversion. These results strongly suggest that 78 reacts via an

intramolecular cyclopropanation step, since the reaction rate is sig-

niﬁcantly higher than that observed for intermolecular cyclo-

propanation in the presence of an external carbamate (the ratio of

79/80 is w1:8 respectively after 10 min).

R

R'

NHBn

NH₂·TFA

N

(ii), (iii),

(i)

(iv) or (v)

R = R' = Bn

a

syn-73

syn-74

(i). 65%

(ii). quant from 9

(iii). quant from 50

(iv). quant from 65

(v). quant from 53

syn-9, R = R' = Bn

syn-50, R, R' = Phth

-65, R = H, R' = Cbz

syn

syn-53, R = H, R' = Boc

R

R'

NH₂·TFA

(iii), (iv)

or (iv)

N

a

anti-75

anti-51, R, R' = Phth

anti-69, R = H, R' = Cbz

anti-54, R = H, R' = Boc

(iii). quant from 51

(iv). quant from 69

(v). quant from 54

Scheme 14. Reagents and conditions: (i) H₂(1 atm), Pd/C (50 wt %), MeOH/H₂O/AcOH

(40:4:1), rt, 16 h; (ii) H₂(5 atm), Pd/C (50% w/w), MeOH/H₂O/AcOH (40:4:1), rt, 12 h;

(iii) NH₂NH₂, MeOH, reﬂux, 12 h; (iv) H₂(1 atm), MeOH/EtOAc (4:1), rt, 1 h; (v) TFA,

CH₂Cl₂, rt, 1 h. [^aIsolated in >99:1 dr; NPhth¼phthalimido].

The same series of experiments were next performed with

CF₃CO₂ZnCH₂I, in order to probe the proposed intermolecular na-

ture of the anti selective cyclopropanation reaction manifold. Re-

action of 1-phenylcyclohexene 76 with 1.0 equiv of CF₃CO₂ZnCH₂I

resulted in 53% conversion to 79, whilst cyclopropanation of 76

with 2.0 equiv of CF₃CO₂ZnCH₂I proceeded to give 79 in 95% con-

version. In the presence of 1.0 equiv of carbamate 77, reaction of 76

with 1.0 equiv of CF₃CO₂ZnCH₂I gave 79 in only 4% conversion,

consistent with 1.0 equiv of CF₃CO₂ZnCH₂I being consumed by

deprotonation of carbamate 77 to form intermediate 83, whereas

reaction with 2.0 equiv of CF₃CO₂ZnCH₂I proceeded to give 79 in

72% conversion. As expected, reaction of 76 in the presence of allylic

carbamate 78 and only 1.0 equiv of CF₃CO₂ZnCH₂I resulted in ex-

tremely low conversion to either 79 or 82. Reaction of 76 and 78

with 2.0 equiv of CF₃CO₂ZnCH₂I resulted in 53% conversion of 78 to

82 and 61% conversion of 76 to 79. Importantly, the carbenoid ap-

pears to show no strong preference for cyclopropanation of sub-

strate 78 over 1-phenylcyclohexene 76, consistent with an

intermolecular rather than intramolecular cyclopropanation

mechanism in each case (Scheme 16). These experiments support

2.6. Cyclopropanation of allylic carbamates: mechanistic

investigations

Having proposed that syn-cyclopropanation of the allylic carba-

mates occurs via intramolecular cyclopropanation, whereas anti-

cyclopropanation occurs via intermolecular cyclopropanation, we

wished to design a series of competition experiments to verify this

hypothesis. We have recently reported the application of this ster-

eodivergent cyclopropanationprotocol in the syntheses of trans-SCH-

A

⁵⁴and its epimercis-SCH-A^11bviathecyclopropanationofaC(3)-aryl

substituted allylic carbamate^21bin which C(3)-phenyl substituted

allylic carbamate 78 was employed as a model system for reaction

optimisation. Commercially available 1-phenylcyclohexene 76 (bp

251e253 ^ꢀC) was selected as a suitable mimic for the oleﬁn func-

tionality within C(3)-phenyl substituted allylic carbamate 78.⁵⁵In

addition, it was proposed that 77⁵⁶could be used as a mimic for the

NHCbz

(i)

+

Ph

I

Zn

Cbz

76

77

78

79

80

N

77

78

Zn(CH₂I)₂

(equiv)

Conversion Conversion

to 80 (%)^a

(equiv) (equiv) (equiv)

to 79 (%)

1

0

1

0

1

2

1

2

1

2

13

20

24

44

17

59

0

81

0

96

>98

Scheme 15. Reagents and conditions: (i) ZnEt₂, CH₂I₂, CH₂Cl₂, rt, 60 min. [^a>99:1 dr].

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

8427

Cbz

HN

(i)

+

Ph

Zn

Cbz

76

77

78

79

82

N

F₃CCO₂

77

78

F₃CCO₂ZnCH₂I

(equiv)

Conversion Conversion

to 82 (%)^a

(equiv) (equiv) (equiv)

to 79 (%)

1

0

1

0

1

2

1

2

1

2

53

95

4

0

83

0

72

4

0

3

61

53

Scheme 16. Reagents and conditions; (i) ZnEt₂, CH₂I₂, TFA, CH₂Cl₂, rt, 60 min. [^a>99:1 dr].

the proposed rationale that syn-cyclopropanation arises through

chelation control whilst anti-cyclopropanation arises from a steri-

cally directed intermolecular reaction.

resolution mass spectra were recorded on either a VG MassLab

20e250 or a Micromass Platform 1 spectrometer. Accurate mass

measurements were run on either a Bruker MicroTOF internally

calibrated with polyalanine, or a Micromass GCT instrument ﬁtted

with a Scientiﬁc Glass Instruments BPX5 column (15 mꢃ0.25 mm)

using amyl acetate as a lock mass.

3. Conclusion

In conclusion, a highly chemo- and diastereoselective protocol

for the cyclopropanation of a range of cyclic and acyclic tertiary

allylic amines employing Shi’s carbenoid [CF₃CO₂ZnCH₂I] has been

developed. The high levels of diastereoselectivity observed in these

systems may be rationalised by chelation of the nitrogen atom to

the carbenoid, which is then delivered to the syn-face of the oleﬁn.

In addition, the reaction of a range of cyclic allylic amides and

carbamates with either the WittigeFurukawa reagent [Zn(CH₂I)₂]

or Shi’s carbenoid provides access to both syn- and anti-di-

astereoisomers of the corresponding cyclopropanes, respectively,

in high dr. This stereodivergent protocol is consistent with co-or-

dination of the zinc carbenoid to the nitrogen atom followed by

either (i) intramolecular syn-cyclopropanation in the case of Zn

(CH₂I)₂or (ii) intermolecular anti-cyclopropanation by a second

equivalent of the zinc reagent in the case of CF₃CO₂ZnCH₂I.

4.2. General experimental procedures

4.2.1. General procedure 1: cyclopropanation with the Wit-

tigeFurukawa reagent [Zn(CH₂I)₂]. CH₂I₂(4.0 equiv) was added

dropwise to a stirred solution of ZnEt₂(1.0 M in hexanes, 2.0 equiv)

in CH₂Cl₂(0.5 M w.r.t. substrate) at ꢁ78 ^ꢀC. The resultant mixture

was vigorously stirred at 0 ^ꢀC for 15 min resulting in the formation

of a white precipitate. The requisite substrate (1.0 equiv) was then

added to the reaction mixture, either neat or as a solution in CH₂Cl₂.

The reaction mixture was stirred at rt for the speciﬁed time then

satd aq Na₂EDTA (w1 mL/mmol) was added. The resultant mixture

was vigorously stirred for 5 min then diluted with CH₂Cl₂(w10 mL/

mmol) and satd aq NaHCO₃(w10 mL/mmol). The aqueous layer

was extracted with three portions of CH₂Cl₂and the combined

organic extracts were dried and concentrated in vacuo.

4. Experimental

Safety note: The preparation of Zn(CH₂I)₂on a large-scale

(>8 mmol) has been reported to be potentially explosive.⁶¹The

modiﬁed procedure described above appears to signiﬁcantly re-

duce the chance of explosion, and has been performed numerous

times on large-scale (>20 mmol) without incident. The principal

difference is the careful addition of CH₂I₂to ZnEt₂at ꢁ78 ^ꢀC, which

allows the gradual exothermic formation of Zn(CH₂I)₂.

4.1. General experimental

All reactions involving organometallic or other moisture-sen-

sitive reagents were carried out under a nitrogen or argon at-

mosphere using standard vacuum line techniques and glassware

that was ﬂame dried and cooled under nitrogen before use. Sol-

vents were dried according to the procedure outlined by Grubbs

et al.⁶⁰Water was puriﬁed by an Elix^ÒUV-10 system. All other

reagents were used as supplied (analytical or HPLC grade) with-

out prior puriﬁcation. Organic layers were dried over MgSO₄. Thin

layer chromatography was performed on aluminium plates coated

with 60 F₂₅₄silica. Plates were visualised using UV light (254 nm),

iodine, 1% aq KMnO₄, or 10% ethanolic phosphomolybdic acid.

Flash column chromatography was performed on Kieselgel 60

silica.

Melting points were recorded on a Gallenkamp Hot Stage ap-

paratus and are uncorrected. Optical rotations were recorded on

a PerkineElmer 241 polarimeter with a water-jacketed 10 cm cell.

Speciﬁc rotations are reported in 10^ꢁ1deg cm²g^ꢁ1and concen-

trations in g/100 mL. IR spectra were recorded on a Bruker Tensor

27 FT-IR spectrometer as either a thin ﬁlm on NaCl plates (ﬁlm) or

a KBr disc (KBr), as stated. Selected characteristic peaks are

reported in cm^ꢁ1. NMR spectra were recorded on Bruker Avance

spectrometers in the deuterated solvent stated. Spectra were

recorded at rt unless otherwise stated. The ﬁeld was locked by

external referencing to the relevant deuteron resonance. Low-

4.2.2. General procedure 2: cyclopropanation with Shi’s carbenoid

[CF₃CO₂ZnCH₂I]. CH₂I₂(4.0 equiv) was added dropwise to a stir-

red solution of ZnEt₂(1.0 M in hexanes, 2.0 equiv) in CH₂Cl₂

(0.5 M) at ꢁ78 ^ꢀC and the resultant mixture was allowed to stir at

0 ^ꢀC for 15 min resulting in the formation of a white precipitate.

TFA (2.0 equiv) was then added to the mixture resulting in the

rapid formation of a homogeneous colourless solution which was

allowed to stir at 0 ^ꢀC for 15 min. The requisite substrate

(1.0 equiv) was added to the mixture, either neat or as a solution

in CH₂Cl₂. The resultant mixture was stirred at rt for the speciﬁed

time then satd aq Na₂EDTA (w1 mL/mmol) was added. The re-

sultant mixture was vigorously stirred for 5 min then diluted

with CH₂Cl₂(w10 mL/mmol) and satd aq NaHCO₃(w10 mL/

mmol). The aqueous layer was extracted with three portions of

CH₂Cl₂and the combined organic extracts were dried and con-

centrated in vacuo.

4.2.3. General procedure 3: synthesis of acyclic allylic amines. Method

A: The requisite Grignard reagent (1.5 equiv) was added via syringe

to a stirred solution of the requisite a-benzotriazole (1.0 equiv) in

8428

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

PhMe (0.4 M) at rt. The resultant suspension was stirred at 50 ^ꢀC for

2 h then allowed to cool to rt before satd aq NH₄Cl was carefully

added. The resultant mixture was diluted with Et₂O and the

aqueous layer was extracted with three portions of Et₂O. The

combined organic extracts were washed sequentially with 1.0 M aq

NaOH and brine, then dried and concentrated in vacuo.

Method B: The requisite vinyl bromide (1.5 equiv) was added

dropwise to a stirred suspension of Mg turnings (1.5 equiv) and I₂

(cat) in THF (0.5 M) at rt. The resultant suspension was gently

heated to initiate Grignard formation at which point the solution

turned colourless. The reaction mixture was heated at reﬂux for

2 h (or until all the Mg had been consumed), then allowed to cool

mm^ꢁ1, colourless plate, crystal dimensions¼0.1ꢃ0.1ꢃ0.1 mm. A to-

tal of 4489 unique reﬂections were measured for 5<q<27 and 2693

reﬂections were used in the reﬁnement. The ﬁnal parameters were

(I)]. Crystallographic data (ex-

wR₂¼0.146 and R₁¼0.057 [I>3.0

s

cluding structure factors) have been deposited with the Cambridge

Crystallographic Data Centre as supplementary publication number

CCDC 783809. Copies of the data can be obtained, free of charge, on

application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:

þ44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].

4.4. 4,4-Diphenyl-2-cyclohexenone tosylhydrazone 85

Ts

to rt before being transferred to a stirred solution of

a-benzo-

NH

N

triazole (1.0 equiv) in PhMe (0.25 M) at rt. The resultant suspen-

sion was stirred at 50 ^ꢀC for 2 h then allowed to cool to rt before

satd aq NH₄Cl was carefully added. The reaction mixture was then

diluted with Et₂O and the aqueous layer was extracted with three

portions of Et₂O. The combined organic extracts were washed

sequentially with 1.0 M aq NaOH and brine, then dried and con-

centrated in vacuo.

Ph Ph

A solution of tosylhydrazide (825 mg, 4.43 mmol) in PhMe

(5 mL) was added to a stirred solution of 4,4-diphenyl-2-cyclo-

hexen-1-one 84 (1.00 g, 4.03 mmol) in MeOH (10 mL) and the re-

sultant mixture was stirred at rt for 16 h. The reaction mixture was

then concentrated in vacuo and the residue was dissolved in EtOAc

(25 mL). The resultant solution was washed with H₂O (3ꢃ10 mL)

then dried and concentrated in vacuo to give 85 as a pale yellow

solid (1.62 g, 96%);⁶³mp 165 ^ꢀC (dec) (lit.⁶³mp 191e192 ^ꢀC); d_H

(400 MHz, CDCl₃) 2.23 (2H, t, J 6.3, C(5)H₂), 2.41e2.46 (2H, m, C(6)

H₂) overlapping 2.44 (3H, s, CH₃), 6.37 (1H, d, J 10.2, C(2)H), 6.60

(1H, d, J 10.2, C(3)H), 7.15e7.38 (12H, m, Ar), 7.66 (1H, br s, NH), 7.85

(2H, d, J 8.3, Ar).

4.2.4. General procedure 4: synthesis of allylic carbamates and

amides. The requisite alcohol (1.0 equiv), either neat or as a so-

lution in either THF or 1,4-dioxane, was added to a stirred solu-

tion of Bi(OTf)₃(0.05 equiv), KPF₆(0.05 equiv), MgSO₄(w150 mg/

mmol) and the requisite amide or carbamate (1.5 equiv) in THF or

1,4-dioxane (0.1e0.2 M) at rt. The resultant mixture was allowed

to stir at rt for the speciﬁed time, then ﬁltered through a pad of

Celite (eluent Et₂O or EtOAc). The ﬁltrate was then concentrated

in vacuo.

4.3. (1RS,2SR,3RS)-N,N-Dibenzylbicyclo[4.1.0]heptan-2-amine 9

NBn₂

4.5. 4,4-Diphenylcyclohex-1-ene 12

Ph

Following General procedure 2, 8²⁴(277 mg, 1.00 mmol), ZnEt₂

(2.0 mL, 2.0 mmol), CH₂I₂(0.32 mL, 4.0 mmol) and TFA (0.15 mL,

2.0 mmol) were reacted in CH₂Cl₂(2.0 mL) for 1 h to give, after

puriﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢀC

petrol/Et₂O, 20:1), 9 as a colourless oil (268 mg, 92%, >99:1 dr);

n_max(ﬁlm) 2930 (CeH), 1494, 1453; d_H(400 MHz, CDCl₃) 0.26e0.30

(1H, m, C(7)H_A), 0.62e0.68 (1H, m, C(7)H_B), 0.75e0.84 (1H, m, C(6)

H), 0.97e1.08 (3H, m, C(1)H, C(4)H_A, C(3)H_A), 1.16e1.25 (1H, m, C(5)

H_A), 1.36e1.42 (1H, m, C(4)H_B), 1.45e1.53 (1H, m, C(3)H_B), 1.73e1.80

(1H, m, C(5)H_B), 3.00e3.09 (1H, m, C(2)H), 3.64 (2H, d, J 14.1, N

(CH_APh)₂), 3.69 (2H, d, J 14.1, N(CH_BPh)₂), 7.09e7.13 (2H, m, Ph),

7.18e7.22 (4H, m, Ph), 7.31e7.33 (4H, m, Ph); d_C(100 MHz, CDCl₃)

8.7 (C(6)), 11.2 (C(7)), 12.7 (C(1)), 22.5 (C(3)), 23.8 (C(4), C(5)), 54.4

(C(2), N(CH₂Ph)₂), 126.6, 128.2, 128.6 (o,m,p-Ph), 141.4 (i-Ph); m/z

(ESI^þ) 292 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₁H₂₆N^þ([MþH]^þ) re-

quires 292.2065, found 292.2065.

Catechol borane (0.23 mL, 2.2 mmol) was added to a stirred

solution of 85 (833 mg, 2.0 mmol) in CHCl₃(5 mL) at 0 ^ꢀC and the

resultant mixture was stirred at rt for 2 h. NaOAc$3H₂O (816 mg,

6.0 mmol) was then added and the reaction mixture was heated at

60 ^ꢀC for 1 h before being allowed to cool to rt. H₂O (5 mL) was

added and the resultant mixture was extracted with CH₂Cl₂

(3ꢃ10 mL). The combined organic extracts were dried and con-

centrated in vacuo. Puriﬁcation by ﬂash column chromatography

(eluent 30e40 ^ꢀC petrol/EtOAc, 1:0 to 20:1 gradient elution) gave

12 as a white solid (351 mg, 75%);⁶³mp 59e60 ^ꢀC (lit.⁶³mp

62e63 ^ꢀC); d_H(400 MHz, CDCl₃) 1.77e1.83 (2H, m, C(5)H₂), 2.38

(2H, t, J 6.1, C(6)H₂), 2.61e2.64 (2H, m, C(3)H₂), 5.64e5.70 (1H, m, C

(1)H), 5.85e5.90 (1H, m, C(2)H), 7.15e7.29 (10H, m, Ph).

4.6. (RS)-N,N-Dibenzylcyclohexanamine 13

4.3.1. X-ray crystal structure determination for 9$HBF₄. Data were

NBn₂

collected using an EnrafeNonius

k-CCD diffractometer with

graphite monochromated Mo K radiation using standard pro-

a

cedures at 150 K. The structure was solved by direct methods

(SIR92); all non-hydrogen atoms were reﬁned with anisotropic

thermal parameters. Hydrogen atoms were added at idealised po-

sitions. The structure was reﬁned using CRYSTALS.⁶²

A mixture of cyclohexylamine 86 (0.44 mL, 4.0 mmol) and BnBr

(0.96 mL, 8.0 mmol) in 0.5 M aq NaOH (17.6 mL, 8.8 mmol) was

heated at 80 ^ꢀC (microwave) for 30 min. The reaction mixture was

then allowed to cool to rt and extracted with EtOAc (3ꢃ15 mL).

X-ray crystal structure data for 9$HBF₄[C₂₁H₂₆BF₄N]: M¼379.25,

monoclinic, space group P 2₁/c, a¼9.3534(2) Å, b¼15.3985(3) Å,

c¼13.8619(4) Å,

b

¼100.7273(9)^ꢀ, V¼1961.62(8) Å³, Z¼4,

m¼0.100

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

8429

The combined organic extracts were then dried and concentrated

in vacuo. Puriﬁcation by ﬂash column chromatography (30e40 ^ꢀC

petrol/EtOAc, 1:0 to 5:1 gradient elution) gave 13 as a white solid

(940 mg, 84%);⁶⁴mp 61e62 ^ꢀC (lit.⁶⁴mp 62 ^ꢀC); d_H(400 MHz,

CDCl₃) 1.13e1.44 (6H, m, 6ꢃCH₂), 1.81e1.89 (2H, m, 2ꢃCH₂),

1.95e2.01 (2H, m, 2ꢃCH₂), 2.56 (1H, tt, J 11.6, 3.4, CHNBn₂), 3.72

(4H, s, N(CH₂Ph)₂), 7.25e7.28 (2H, m, Ph), 7.34e7.49 (8H, m, Ph).

30e40^ꢀC petrol/EtOAc, 1:0 to 99:1 gradient elution), 20 as

a white crystalline solid (940 mg, 90%, >99:1 dr); mp 43e45 ^ꢀC;

n_max(KBr) 3025, 2920, 2850 (CeH), 1495, 1455, 1125, 1030, 975,

740, 700, 665; d_H(400 MHz, CDCl₃) 0.08 (1H, q, J 4.7, C(8)H_A),

0.48e0.57 (1H, m, C(6)H_A), 0.72e0.78 (1H, m, C(7)H), 0.90 (1H,

app td, J 8.0, 4.3, C(8)H_B), 0.97e1.13 (2H, m, C(1)H and C(4)H_A),

1.20e1.29 (1H, m, C(5)H_A), 1.65e1.76 (2H, m, C(3)H_A, C(5)H_B),

1.87e1.92 (1H, m, C(4)H_B), 1.98e2.03 (1H, m, C(3)H_B), 2.08e2.14

(1H, m, C(6)H_A), 2.22 (1H, t, J 9.8, C(2)H), 3.75 (4H, s, N(CH₂Ph)₂),

7.21e7.25 (2H, m, Ph), 7.32 (4H, app t, J 7.4, Ph), 7.45 (4H, app d, J

7.4, Ph); d_C(100 MHz, CDCl₃) 12.8 (C(7)), 15.6, 15.6 (C(1), C(8)),

28.9 (C(5)), 30.1 (C(4)), 31.1 (C(6)), 35.5 (C(3)), 54.2 (N(CH₂Ph)₂),

61.4 (C(2)), 128.1, 128.5, 128.5 (o,m,p-Ph), 141.1 (i-Ph); m/z (CI^þ)

306 ([MþH]^þ, 100%); HRMS (CI^þ) C₂₂H₂₈N^þ([MþH]^þ) requires

306.2222, found 306.2233.

4.7. (RS,RS)-3,3-Diphenylbicyclo[4.1.0]heptane 14

Ph

Following General procedure 2, 12 (28 mg, 0.10 mmol), ZnEt₂

(0.2 mL, 0.2 mmol), CH₂I₂(30 mL, 0.4 mmol) and TFA (15 mL,

4.9.1. X-ray crystal structure determination for 20. Data were col-

0.2 mmol) were reacted in CH₂Cl₂(0.2 mL) for 1 h to give, after

puriﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢀC

petrol/Et₂O, 20:1), 14 as a colourless oil (30 mg, quant); n_max(ﬁlm)

3055, 2995, 2935, 2860 (CeH), 1600, 1495, 1465, 1110, 1020, 765,

740, 700; d_H(400 MHz, CDCl₃) 0.12e0.16 (1H, m, C(7)H_A), 0.66 (1H,

app t, J 8.8, 4.5, C(7)H_B), 0.82 (1H, app tt, J 9.3, 5.0, C(6)H), 1.19e1.23

(1H, m, C(1)H), 1.44 (1H, app tt, J 13.5, 5.3, C(5)H_A), 1.65 (1H, app dd,

J 15.0, 2.6, C(2)H_A),1.81e1.86 (1H, m, C(5)H_B),1.96 (1H, app td, J 13.2,

4.5, C(4)H_A), 2.13 (1H, app ddt, J 13.1, 5.0, 2.6, C(4)H_B), 2.95 (1H, app

ddd, J 15.0, 9.2, 2.8, C(2)H_B), 7.13e7.37 (10H, m, Ph); d_C(100 MHz,

CDCl₃) 9.4, 9.6 (C(1) and C(6)), 10.7 (C(7)), 19.8 (C(5)), 30.2 (C(4)),

38.1 (C(2)), 45.0 (C(3)), 125.4, 125.5, 126.6, 127.9, 128.0, 128.6 (o,m,p-

Ph), 146.9, 152.0 (i-Ph); m/z (FI^þ) 248 ([M]^þ, 100%); HRMS (FI^þ)

lected using an EnrafeNonius

graphite monochromated Mo K

cedures at 150 K. The structure was solved by direct methods

(SIR92); all non-hydrogen atoms were reﬁned with anisotropic

thermal parameters. Hydrogen atoms were added at idealised

positions. The structure was reﬁned using CRYSTALS.⁶²

k

-CCD diffractometer with

a

radiation using standard pro-

X-ray crystal structure data for 20 [C₂₂H₂₇N]: M¼305.46,

monoclinic, space group C 2/c, a¼25.5945(4) Å, b¼9.9031(2)

Å, c¼14.6450(2) Å,

b

¼104.7501(8)^ꢀ, V¼3589.67(10) Å³, Z¼8,

m

¼0.065 mm^ꢁ1

,

colourless plate, crystal dimensions¼0.05

ꢃ0.05ꢃ0.1 mm. A total of 4068 unique reﬂections were measured

for 5<

q

<27 and 4068 reﬂections were used in the reﬁnement. The

(I)].

ﬁnal parameters were wR₂¼0.116 and R₁¼0.070 [I>ꢁ3.0

s

þ

C₁₉H₂₀([M]^þ) requires 248.1572, found 248.1565.

Crystallographic data (excluding structure factors) has been de-

posited with the Cambridge Crystallographic Data Centre as

supplementary publication number CCDC 783810. Copies of the

data can be obtained, free of charge, on application to CCDC, 12

Union Road, Cambridge CB2 1EZ, UK [fax: þ44 1223 336033 or

e-mail: deposit@ccdc.cam.ac.uk].

4.8. (1RS,2SR,3RS)-N,N-Dibenzylbicyclo[3.1.0]hexan-2-amine 19

NBn₂

4.10. (1RS,2RS,8SR)-N,N-Dibenzylbicyclo[6.1.0]octan-2-

amine 21

Following General procedure 2, 16³⁴(263 mg, 1.00 mmol),

ZnEt₂(2.0 mL, 2.0 mmol), CH₂I₂(0.32 mL, 4.0 mmol) and TFA

(0.15 mL, 2.0 mmol) were reacted in CH₂Cl₂(2.0 mL) for 1 h to

give, after puriﬁcation by ﬂash column chromatography (eluent

30e40 ^ꢀC petrol/Et₂O, 9:1), 19 as a yellow oil (233 mg, 84%, >99:1

dr); n_max(ﬁlm) 3027, 2928, 2864, 2799 (CeH), 1493, 1453; d_H

(400 MHz, CDCl₃) 0.31e0.36 (1H, m, C(6)H_A), 0.56 (1H, app q, J 4.0,

C(6)H_B), 1.18e1.24 (2H, m, C(5)H, C(3)H_A), 1.28e1.32 (1H, m, C(1)

H), 1.61e1.66 (1H, m, C(3)H_B), 1.69e1.74 (2H, m, C(4)H₂), 3.41e3.46

(1H, m, C(2)H), 3.71e3.78 (4H, m, N(CH₂Ph)₂), 7.22e7.27 (2H, m,

Ph), 7.33 (4H, app t, J 7.4, Ph), 7.42 (4H, d, J 7.4, Ph); d_C(100 MHz,

CDCl₃) 5.1 (C(6)), 15.1 (C(5)), 17.8 (C(1)), 23.0 (C(3)), 25.5 (C(4)),

55.9 (N(CH₂Ph)₂), 63.3 (C(2)), 126.5, 128.0, 128.8 (o,m,p-Ph), 140.7

(i-Ph); m/z (ESI^þ) 278 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₀H₂₄N^þ

([MþH]^þ) requires 278.1903, found 278.1901.

NBn₂

Following General procedure 2, 18³⁴(916 mg, 3.0 mmol),

ZnEt₂(6.0 mL, 6.0 mmol), CH₂I₂(0.97 mL, 12.0 mmol) and TFA

(0.45 mL, 6.0 mmol) in CH₂Cl₂(6 mL) were reacted for 1 h to

give, after puriﬁcation by ﬂash column chromatography (eluent

30e40 ^ꢀC petrol/EtOAc, 1:0 to 9:1 gradient elution), 21 as

a white crystalline solid (920 mg, 96%, >99:1 dr); mp 80e82 ^ꢀC;

n_max(KBr) 3060, 2925, 2850 (CeH), 1490, 1455, 1125, 1025, 905,

745, 700, 665; d_H(400 MHz, CDCl₃) 0.03e0.06 (1H, m, C(9)H_A),

0.36e0.46 (1H, m, C(7)H_A), 0.69e0.84 (3H, m, C(1)H, C(8)H

and C(9)H_B), 0.97e1.05 (1H, m, C(5)H_A), 1.23e1.33 (1H, m, C(6)

H_A), 1.42e1.69 (5H, m, C(3)H_A, C(4)H₂, C(5)H_Band C(6)H_B),

1.77e1.82 (1H, m, C(3)H_B), 1.87e1.95 (1H, m, C(7)H_B), 2.24 (1H,

app dt, J 10.4, 3.3, C(2)H), 3.63 (2H, d, J 13.8, N(CH_APh)₂), 3.84

(2H, d, J 13.8, N(CH_BPh)₂), 7.22e7.25 (2H, m, Ph), 7.32 (4H, app t,

J 7.4, Ph), 7.44 (4H, app d, J 7.4, Ph); d_C(100 MHz, CDCl₃) 9.9 (C

(9)), 15.3, 17.5 (C(1), C(8)), 25.4 (C(4)), 27.0 (C(5)), 28.6 (C(7)),

29.9 (C(6)), 30.7 (C(3)), 54.2 (N(CH₂Ph)₂), 55.8 (C(2)), 126.6,

128.1, 128.7 (o,m,p-Ph), 141.3 (i-Ph); m/z (ESI^þ) 320 ([MþH]^þ,

4.9. (1RS,2RS,7SR)-N,N-Dibenzylbicyclo[5.1.0]octan-2-amine 20

NBn₂

Following General procedure 2, 17³⁴(1.00 g, 3.43 mmol), ZnEt₂

(6.86 mL, 6.86 mmol), CH₂I₂(1.10 mL, 13.7 mmol) and TFA

(0.51 mL, 6.86 mmol) in CH₂Cl₂(7 mL) were reacted for 1 h to

give, after puriﬁcation by ﬂash column chromatography (eluent

8430

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

100%); HRMS (CI^þ) C₂₃H₃₀N^þ([MþH]^þ) requires 320.2378,

4.13. (RS,Z)-N,N-Dibenzyl-1-phenylbut-2-ene-1-amine 24

found 320.2375.

NBn₂Me

Ph

4.10.1. X-ray crystal structure determination for 21. Data were col-

lected using an EnrafeNonius

k-CCD diffractometer with graphite

monochromated Mo K radiation using standard procedures at

a

150 K. The structure was solved by direct methods (SIR92); all non-

hydrogen atoms were reﬁned with anisotropic thermal parameters.

Hydrogen atoms were added at idealised positions. The structure

was reﬁned using CRYSTALS.⁶²

Following General procedure 3, 22 (2.02 g, 5.00 mmol), (Z)-1-

bromoprop-1-ene (0.64 mL, 7.5 mmol) and Mg (182 mg,

7.5 mmol) were reacted to give, after puriﬁcation by ﬂash column

chromatography (eluent 30e40 ^ꢀC petrol/Et₂O, 99:1), 24 as

a white solid (1.23 g, 75%, 91:9 dr);⁶⁷mp 53e55 ^ꢀC; n_max(ﬁlm)

3027 (CeH), 1493, 1453; d_H(400 MHz, CDCl₃) 1.51 (3H, d, J 5.8, C

(4)H₃), 3.53 (2H, d, J 14.8, N(CH_APh)₂), 3.78 (2H, d, J 14.8, N

(CH_BPh)₂), 4.67 (1H, d, J 9.8, C(1)H), 5.84 (1H, app t, J 10.2, C(2)H),

5.99 (1H, m, C(3)H), 7.25e7.46 (13H, m, Ph), 7.61 (2H, app d, J 7.6,

Ph); d_C(100 MHz, CDCl₃) 13.5 (C(4)), 53.8 (N(CH₂Ph)₂), 58.4 (C

(1)), 126.8 (C(3)), 128.2 (C(2)), 126.8, 126.9, 128.1, 128.2, 128.7,

128.9 (o,m,p-Ph), 140.2, 140.4 (i-Ph); m/z (ESI^þ) 328 ([MþH]^þ,

100%); HRMS (ESI^þ) C₂₄H₂₆N^þ([MþH]^þ) requires 328.2060,

found 328.2059.

X-ray crystal structure data for 21 [C₂₃H₂₉N]: M¼319.49, mono-

clinic, space group P 2₁/c, a¼12.1237(3) Å, b¼10.8303(2) Å, c¼14.6175

(3) Å,

b

¼95.1731(11)^ꢀ, V¼1911.51(7) Å³, Z¼4,

m

¼0.063 mm^ꢁ1, col-

ourless plate, crystal dimensions¼0.1ꢃ0.1ꢃ0.2 mm. A total of 4334

unique reﬂections were measured for 5<

were used in the reﬁnement. The ﬁnal parameters were wR₂¼0.179

(I)]. Crystallographic data (excluding structure

q<27 and 3204 reﬂections

and R₁¼0.079 [I>3.0

s

factors) has been deposited with the Cambridge Crystallographic

Data Centre as supplementary publication number CCDC 783811.

Copies of the data can be obtained, free of charge, on application to

CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: þ44 1223 336033

or e-mail: deposit@ccdc.cam.ac.uk].

4.14. (RS)-N,N-Dibenzyl-3-methyl-1-phenylbut-2-en-1-

amine 25

4.11. (RS)-1-[

a

-(Dibenzylamino)benzyl]benzotriazole 22

N

NBn₂Me

Ph

Me

Ph

NBn₂

Following General procedure 3, 22 (2.02 g, 5.00 mmol) and 2-

methyl-1-propenylmagnesium bromide (0.5 M in THF, 15.0 mL,

7.5 mmol) were reacted to give, after puriﬁcation by ﬂash column

chromatography (eluent 30e40 ^ꢀC petrol/Et₂O, 99:1), 25 as a pale

yellow oil (1.59 g, 93%); n_max(ﬁlm) 3027 (CeH), 1493, 1453; d_H

(400 MHz, CDCl₃) 1.54 (3H, s, C(3)Me_A), 1.94 (3H, s, C(3)Me_B), 3.57

(2H, d, J 13.8, N(CH_APh)₂), 3.77 (2H, d, J 13.8, N(CH_BPh)₂), 4.58 (1H, d,

J 9.8, C(1)H), 5.60 (1H, d, J 9.8, C(2)H), 7.25e7.28 (3H, m, Ph),

7.34e7.41 (6H, m, Ph), 7.47 (4H, d, J 7.6, Ph), 7.61 (2H, app d, J 7.3, Ph);

d_C(100 MHz, CDCl₃) 18.5 (C(3)Me_A), 26.2 (C(3)Me_B), 53.9 (N

(CH₂Ph)₂), 60.1 (C(1)), 121.5 (C(3)), 126.7, 126.7, 128.1, 128.2, 128.7,

128.7 (o,m,p-Ph), 136.7 (C(2)), 140.4, 143.1 (i-Ph); m/z (ESI^þ) 342

([MþH]^þ, 100%); HRMS (ESI^þ) C₂₅H₂₈N^þ([MþH]^þ) requires

342.2216, found 342.2217.

A solution of benzaldehyde (10.1 mL, 100 mmol), dibenzylamine

(19.2 mL, 100 mmol) and benzotriazole (11.9 g, 100 mmol) in

MeOH/Et₂O (1:1, 100 mL) was stirred at rt for 30 min, then the re-

sultant homogeneous solution was stored at 0 ^ꢀC for 16 h resulting

in the precipitation of a white solid. The mixture was then ﬁltered

and the solid residue was triturated with cold Et₂O to give 22 (e3:1

mixture of regioisomers) as a white solid (35.3 g, 87%).

Data for mixture: mp 144e146 ^ꢀC (lit.⁶⁵mp 153^ꢀC).

Data for major isomer: d_H(400 MHz, CDCl₃) 3.51 (2H, d, J 14.2, N

(CH_APh)₂), 4.26 (2H, d, J 14.2, N(CH_BPh)₂), 6.85 (1H, s, PhCH),

7.25e7.45 (18H, m, Ar), 8.19 (1H, d, J 8.2, Ar).

4.12. (RS)-N-(1-Benzotriazol-1-yl-2-methylpropyl)

dibenzylamine 23

4.15. (RS,Z)-N,N-Dibenzyl-2-methyl-1-phenylbut-2-en-1-

amine 26

N

NBn₂Me

ⁱPr

NBn₂

Ph

Me

A solution of isobutyraldehyde (9.13 mL, 100 mmol), dibenzyl-

amine (19.2 mL, 100 mmol) and benzotriazole (11.9 g, 100 mmol) in

MeOH/Et₂O (1:1, 100 mL) was stirred at rt for 30 min, then the re-

sultant homogeneous solution was stored at 0 ^ꢀC for 16 h resulting

in the precipitation of a white solid. The mixture was then ﬁltered

and the solid residue was triturated with cold Et₂O to give 23 (e2:1

mixture of regioisomers) as a white solid (29.8 g, 81%).

Data for major isomer: d_H(400 MHz, CDCl₃) 0.48 (3H, d, J 6.5,

CHMe_A), 1.39 (3H, d, J 6.5, CHMe_B), 3.01e3.14 (1H, m, CHMe₂),

3.21e3.30 (4H, m, N(CH₂Ph)₂), 5.09 (1H, d, J 10.6, CHCHMe₂),

7.06e7.09 (1H, m, Ar), 7.27e7.50 (11H, m, Ar), 7.97e8.00 (1H, m, Ar),

8.11e8.13 (1H, m, Ar).

Following General procedure 3, 22 (1.01 g, 2.50 mmol), (Z)-2-

bromobut-2-ene (0.38 mL, 3.75 mmol) and Mg (91 mg, 3.75 mmol)

were reacted to give, after puriﬁcation by ﬂash column chroma-

tography (eluent 30e40 ^ꢀC petrol/Et₂O, 99:1), 26 as a colourless oil

(740 mg, 87%, 96:4 dr); n_max(ﬁlm) 3027, 2925 (CeH), 1493, 1453; d_H

(400 MHz, CDCl₃), 1.87 (3H, d, J 6.8, C(4)H₃), 1.97 (3H, s, C(2)Me),

3.86 (2H, d, J 14.6, N(CH_APh)₂), 4.03 (2H, d, J 14.6, N(CH_BPh)₂), 5.05

(1H, s, C(1)H), 5.61 (1H, q, J 6.8, C(3)H), 7.43e7.46 (3H, m, Ph),

7.51e7.60 (10H, m, Ph), 7.78 (2H, d, J 7.6, Ph); d_C(100 MHz, CDCl₃)

14.0 (C(4)),19.6 (C(2)Me), 52.8 (N(CH₂Ph)₂), 63.9 (C(1)), 124.2 (C(3)),

126.9, 126.9, 128.3, 128.3, 128.5, 129.5 (o,m,p-Ph), 136.6 (C(2)), 138.8,

142.1 (i-Ph); m/z (ESI^þ) 342 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₅H₂₈N^þ

([MþH]^þ) requires 342.2216, found 342.2217.

Data for mixture: mp 96e98 ^ꢀC (lit.⁶⁶mp 83e85^ꢀC).

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

8431

4.16. (RS)-N,N-Dibenzyl-2,3-dimethyl-1-phenylbut-2-en-1-

amine 27

CDCl₃) 1.97 (3H, d, J 7.1, C(4)H₃), 3.65 (2H, d, J 13.7, N(CH_APh)₂), 3.81

(2H, d, J 13.7, N(CH_BPh)₂), 4.37 (1H, d, J 8.6, C(1)H), 5.70e5.79 (1H, m,

C(3)H), 5.84e5.90 (1H, m, C(2)H), 7.34 (3H, app q, J 7.0, Ph),

7.42e7.47 (6H, m, Ph), 7.55 (4H, d, J 7.1, Ph), 7.66 (2H, d, J 7.8, Ph); d_C

(100 MHz, CDCl₃) 18.2 (C(4)), 53.9 (N(CH₂Ph)₂), 64.7 (C(1)), 126.8,

126.9, 128.2, 128.2, 128.3, 128.8 (o,m,p-Ph), 129.0 (C(2)), 130.5 (C(3)),

140.4, 142.6 (i-Ph); m/z (ESI^þ) 328 ([MþH]^þ, 100%); HRMS (ESI^þ)

C₂₄H₂₆N^þ([MþH]^þ) requires 328.2060, found 328.2056.

NBn₂Me

Ph

Me

Following General procedure 3, 22 (2.02 g, 5.00 mmol), 2-

bromo-3-methylbut-2-ene (0.87 mL, 7.5 mmol) and Mg (182 mg,

7.5 mmol) were reacted to give, after puriﬁcation by ﬂash column

chromatography (eluent 30e40 ^ꢀC petrol), 27 as a yellow oil

(713 mg, 40%); n_max(ﬁlm) 3027, 2923 (CeH), 1493, 1453; d_H

(400 MHz, CDCl₃) 1.87 (3H, s, C(3)Me_A), 1.89 (3H, s, C(2)Me), 2.03

(3H, s, C(3)Me_B), 3.89 (2H, d, J 14.4, N(CH_APh)₂), 4.00 (2H, d, J 14.4, N

(CH_BPh)₂), 5.12 (1H, s, C(1)H), 7.45e7.49 (4H, m, Ph), 7.54e7.61 (9H,

m, Ph), 7.81 (2H, app d, J 7.6, Ph); d_C(400 MHz, CDCl₃) 14.0 (C(2)Me),

21.1 (C(3)Me_A), 21.7 (C(3)Me_B), 53.2 (N(CH₂Ph)₂), 66.1 (C(1)), 126.7,

126.9, 128.3, 128.3, 128.4, 129.5 (o,m,p-Ph), 128.8 (C(3)), 129.0 (C(2)),

139.1, 143.0 (i-Ph); m/z (ESI^þ) 356 ([MþH]^þ, 100%); HRMS (ESI^þ)

C₂₆H₃₀N^þ([MþH]^þ) requires 356.2373, found 356.2377.

4.19. (RS)-N,N-Dibenzyl-1-phenyl-prop-2-en-1-amine 30

NBn₂

Ph

Following General procedure 3, 22 (2.02 g, 5.00 mmol) and

vinylmagnesium chloride (1.6 M in THF, 4.69 mL, 7.5 mmol) were

reacted to give, after puriﬁcation by ﬂash column chromatography

(eluent 30e40 ^ꢀC petrol/Et₂O, 99:1), 30 as a yellow oil (1.45 g, 92%);

n_max(ﬁlm) 3027 (CeH),1493,1453; d_H(400 MHz, CDCl₃) 3.56 (2H, d,

J 13.8, N(CH_APh)₂), 3.70 (2H, d, J 13.8, N(CH_BPh)₂), 4.30 (1H, d, J 8.6, C

(1)H), 5.24 (1H, dd, J 17.2, 1.0, C(3)H_A), 5.48 (1H, dd, J 10.1, 1.0, C(3)

H_B), 6.09e6.18 (1H, m, C(2)H), 7.23e7.29 (3H, m, Ph), 7.32e7.39 (6H,

m, Ph), 7.44 (4H, d, J 7.3, Ph), 7.53 (2H, d, J 7.6, Ph); d_C(100 MHz,

CDCl₃) 53.7 (N(CH₂Ph)₂), 65.2 (C(1)), 119.4 (C(3)), 126.8, 127.0, 128.1,

128.2, 128.3, 128.7 (o,m,p-Ph), 135.3 (C(2)), 140.0, 141.4 (i-Ph); m/z

(ESI^þ) 314 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₃H₂₄N^þ([MþH]^þ) re-

quires 314.1903, found 314.1899.

4.17. (RS)-N,N-Dibenzyl-2,5-dimethylhex-4-en-3-amine 28

NBn₂Me

ⁱPr

Me

Following General procedure 3, 23 (1.85 g, 5.00 mmol) and 2-

methyl-1-propenylmagnesium bromide (0.5 M in THF, 15.0 mL,

7.5 mmol) in PhMe (25 mL) were reacted to give, after puriﬁcation

by ﬂash column chromatography (eluent 30e40 ^ꢀC petrol), 28 as

a white solid (1.35 g, 88%); mp 42e44 ^ꢀC; n_max(KBr) 3025, 2955,

2920 (CeH), 1495, 1455, 1100, 1070, 1030, 975, 740, 700; d_H

(400 MHz, CDCl₃) 0.85 (3H, d, J 6.6, C(2)Me_A), 1.27 (3H, d, J 6.6, C(2)

Me_B), 1.56 (3H, s, C(5)Me_A), 1.88e1.93 (1H, m, C(2)H), 1.96 (3H, s, C

(5)Me_B), 2.93 (1H, app t, J 10.4, C(3)H), 3.42 (2H, d, J 14.2, N

(CH_APh)₂), 3.95 (2H, d, J 14.2, N(CH_BPh)₂), 5.29 (1H, d, J 10.6, C(4)H),

7.30e7.33 (2H, m, Ph), 7.41 (4H, app t, J 7.5, Ph), 7.55 (4H, app d, J 7.5,

Ph); d_C(100 MHz, CDCl₃) 19.0 (C(5)Me_A), 20.7 (C(2)Me₂), 26.2 (C(5)

Me_B), 30.4 (C(2)), 53.9 (N(CH₂Ph)₂), 62.9 (C(3)), 122.4 (C(4)), 126.6,

128.2, 128.7 (o,m,p-Ph), 136.0 (C(5)), 141.1 (i-Ph); m/z (CI^þ) 264

([MꢁC₃H₇]^þ, 100%), 308 ([MþH]^þ, 10%); HRMS (CI^þ) C₂₂H₃₀N^þ

([MþH]^þ) requires 308.2378, found 308.2364.

4.20. (RS)-N,N-Dibenzyl-2-methyl-1-phenylprop-2-en-1-

amine 31

NBn₂

Ph

Me

Following General procedure 3, 22 (809 mg, 2.00 mmol) and iso-

propenylmagnesium bromide (0.5 M inTHF, 6.0 mL, 3.0 mmol) were

reacted to give, after puriﬁcation by ﬂash column chromatography

(eluent 30e40 ^ꢀC petrol/Et₂O, 99:1), 31 as a yellow oil (655 mg,

quant); n_max(ﬁlm) 3027 (CeH),1493,1453; d_H(400 MHz, CDCl₃) 1.79

(3H, s, C(2)Me), 3.50 (2H, d, J 14.4, N(CH_APh)₂), 3.81 (2H, d, J 14.4, N

(CH_BPh)₂), 4.30 (1H, s, C(1)H), 5.02 (1H, app br s, C(3)H_A), 5.16 (1H,

app br s, C(3)H_B), 7.25e7.28 (2H, m, Ph), 7.33e7.41 (13H, m, Ph); d_C

(100 MHz, CDCl₃) 20.2 (C(2)Me), 53.4 (N(CH₂Ph)₂), 70.1 (C(1)), 114.3

(C(3)), 126.8, 127.0, 128.0, 128.2, 128.8, 129.4 (o,m,p-Ph), 138.9, 139.3

(i-Ph), 145.6 (C(2)); m/z (ESI^þ) 328 ([MþH]^þ, 100%); HRMS (ESI^þ)

C₂₄H₂₆N^þ([MþH]^þ) requires 328.2060, found 328.2061.

4.18. (RS,E)-N,N-Dibenzyl-1-phenylbut-2-ene-1-amine 29

NBn₂

Ph

Me

4.21. (1RS,1⁰SR,2⁰RS)-N,N-Dibenzyl-1-(2⁰-methylcyclopropyl)-

1-phenylmethanamine 32

^tBuLi (1.7 M in pentane, 8.82 mL, 15.0 mmol) was added to

a stirred solution of (E)-1-bromoprop-1-ene (0.64 mL, 7.5 mmol) in

Et₂O (30 mL) at ꢁ78 ^ꢀC and the resultant mixture was stirred for 1 h

at ꢁ78 ^ꢀC. Solid MgBr₂$OEt₂(1.55 g, 6.00 mmol) was then added

and the reaction mixture was allowed to warm to 0 ^ꢀC over 30 min,

and was then added to a solution of 22 (2.02 g, 5.0 mmol) in PhMe

(30 mL) at 0 ^ꢀC via cannula. The resultant mixture was stirred at 0 ^ꢀC

for 2 h then satd aq NH₄Cl (20 mL) was added. The aqueous layer

was extracted with Et₂O (3ꢃ20 mL) and the combined organic ex-

tracts were washed with 1.0 M aq NaOH (30 mL) and brine (30 mL),

then dried and concentrated in vacuo. Puriﬁcation by ﬂash column

chromatography (eluent 30e40 ^ꢀC petrol/Et₂O, 99:1) gave 29 as

a white solid (621 mg, 38%, >99:1 dr); mp 60e61 ^ꢀC; n_max(KBr)

3025 (CeH), 1495, 1450, 1030, 975, 745, 700, 665; d_H(400 MHz,

NBn₂Me

Ph

Following General procedure 2, 24 (327 mg, 1.0 mmol), ZnEt₂

(2.0 mL, 2.0 mmol), CH₂I₂(0.32 mL, 4.0 mmol) and TFA (0.15 mL,

2.0 mmol) in CH₂Cl₂(2.0 mL) were reacted for 1 h to give, after pu-

riﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢀC petrol),

32 as a white solid (226 mg, 66%, >99:1 dr); mp 48e50 ^ꢀC; n_max(KBr)

3027, 2919, 2833, 2805 (CeH), 1493, 1453; d_H(400 MHz, CDCl₃) 0.35

(1H, app q, J 5.0, C(3⁰)H_A), 0.77 (3H, d, J 6.3, C(2⁰)Me), 0.96e1.02 (1H,

m, C(2⁰)H),1.09e1.17 (1H, m, C(3⁰)H_B),1.38e1.47 (1H, m, C(1⁰)H), 3.46

8432

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

(1H, d, J 10.6, C(1)H), 3.66 (2H, d, J 13.6, N(CH_APh)₂), 3.93 (2H, d, J 13.6,

N(CH_BPh)₂), 7.28e7.53 (13H, m, Ph), 7.63 (2H, d, J 7.3, Ph); d_C

(100 MHz, CDCl₃) 8.3 (C(3⁰)), 13.0 (C(2⁰)), 13.5 (C(3⁰)Me), 14.2 (C(1⁰)),

54.0 (N(CH₂Ph)₂), 60.7 (C(1)), 126.7, 126.8, 127.9, 128.2, 128.8, 128.8

(o,m,p-Ph),140.8,142.7 (i-Ph); m/z (ESI^þ) 342 ([MþH]^þ,100%); HRMS

(ESI^þ) C₂₀H₂₆N^þ([MþH]^þ) requires 342.2216, found 342.2215.

(1H, m, C(3⁰)H_A), 0.60e0.65 (1H, m, C(2⁰)H), 0.77e0.80 (1H, m, C(3⁰)

H_B), 0.98e1.01 (3H, m, C(2⁰)Me),1.33 (3H, s, C(1⁰)Me), 3.61 (1H, s, C(1)

H), 3.88 (2H, d, J 14.2, N(CH_APh)₂), 4.08 (2H, d, J 14.2, N(CH_BPh)₂),

7.30e7.52 (13H, m, Ph), 7.77 (2H, d, J 6.3, Ph); d_C(100 MHz, CDCl₃) 15.1

(C(2⁰)Me),19.4 (C(2⁰)), 20.8 (C(1⁰)), 22.8 (C(3⁰)), 23.3 (C(1⁰)Me), 53.8 (N

(CH₂Ph)₂), 65.0 (C(1)), 126.6, 126.7, 128.0, 128.2, 129.0, 129.5 (o,m,p-

Ph), 139.9, 142.6 (i-Ph); m/z (ESI^þ) 356 ([MþH]^þ, 100%); HRMS (ESI^þ)

C₂₆H₃₀N^þ([MþH]^þ) requires 356.2373, found 356.2375.

4.22. (1RS,1⁰SR)-N,N-Dibenzyl-1-(2⁰,2⁰-dimethylcyclopropyl)-

1-phenylmethanamine 33

4.24. (RS,RS)-N,N-Dibenzyl-1-phenyl-1-(1⁰,2⁰,2⁰-

trimethylcyclopropyl)methanamine 35

NBn₂Me

Ph

Me

NBn₂Me

Ph

Me

Following General procedure 2, 25 (171 mg, 0.50 mmol), ZnEt₂

(1.0 mL, 1.0 mmol), CH₂I₂(0.16 mL, 2.0 mmol) and TFA (70 L,

Me

m

Following General procedure 2, 27 (178 mg, 0.50 mmol), ZnEt₂

(1.0 mL, 1.0 mmol), CH₂I₂(0.16 mL, 2.0 mmol) and TFA (70 L,

1.0 mmol) in CH₂Cl₂(1.0 mL) were reacted for 1 h to give, after

puriﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢀC

petrol/Et₂O, 99:1), 33 as a white solid (156 mg, 88%, >99:1 dr); mp

60e62 ^ꢀC; n_max(ﬁlm) 3027 (CeH), 1493, 1453; d_H(400 MHz, CDCl₃)

0.47 (1H, app t, J 4.9, C(3⁰)H_A), 0.68 (3H, s, C(2⁰)Me_A), 0.85 (1H, dd, J

8.3, 4.3, C(3⁰)H_B), 1.14e1.20 (1H, m, C(1⁰)H), 1.18 (3H, s, C(2⁰)Me_B),

3.42 (1H, d, J 10.6, C(1)H), 3.63 (2H, d, J 13.6, N(CH_APh)₂), 3.82 (2H, d,

J 13.6, N(CH_BPh)₂), 7.22e7.30 (3H, m, Ph), 7.34 (4H, app t, J 7.4, Ph),

7.40 (2H, app t, J 7.6, Ph), 7.45 (4H, d, J 7.4, Ph), 7.52 (2H, app d, J 7.6,

Ph); d_C(100 MHz, CDCl₃) 13.6 (C(2⁰)), 20.0 (C(2⁰)Me_A), 20.4 (C(3⁰)),

22.1 (C(2⁰)Me_B), 27.4 (C(1⁰)), 53.9 (N(CH₂Ph)₂), 61.6 (C(1)), 126.6,

126.7, 127.8, 128.2, 128.6, 128.7 (o,m,p-Ph), 140.7, 143.0 (i-Ph); m/z

(ESI^þ) 356 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₆H₃₀N^þ([MþH]^þ) re-

quires 356.2372, found 356.2372.

m

1.0 mmol) in CH₂Cl₂(1.0 mL) were reacted for 1 h to give, after pu-

riﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢀC petrol/

Et₂O, 19:1), 35 as a yellow oil (68 mg, 37%, >99:1 dr); n_max(ﬁlm)

3027 (CeH), 1493, 1453; d_H(400 MHz, CDCl₃) 0.39 (1H, d, J 4.4, C(3⁰)

H_A), 0.44 (1H, d, J 4.4, C(3⁰)H_B), 0.93 (3H, s, C(2⁰)Me_A), 1.08 (3H, s, C

(2⁰)Me_B), 1.36 (3H, s, C(1⁰)Me), 3.68 (1H, s, C(1)H), 3.82 (2H, d, J 14.4,

N(CH_APh)₂), 4.00 (2H, d, J 14.4, N(CH_BPh)₂), 7.23e7.46 (13H, m, Ph),

7.63 (2H, app d, J 7.6, Ph); d_C(100 MHz, CDCl₃) 17.5 (C(1⁰)Me), 19.1 (C

(2⁰)), 22.7 (C(2⁰)Me_A), 23.3 (C(2⁰)Me_B), 25.0 (C(1⁰)), 29.2 (C(3⁰)), 53.9

(N(CH₂Ph)₂), 66.4 (C(1)), 126.5, 126.6, 127.9, 128.1, 128.8, 129.2

(o,m,p-Ph),140.0,142.8 (i-Ph); m/z (ESI^þ) 370 ([MþH]^þ,100%); HRMS

(ESI^þ) C₂₇H₃₂N^þ([MþH]^þ) requires 370.2529, found 370.2528.

4.25. (RS,RS)-N,N-Dibenzyl-1-(2⁰,2⁰-dimethylcyclopropyl)-2-

methylpropan-1-amine 36

4.22.1. X-ray crystal structure determination for 33. Data were col-

lected using an EnrafeNonius

k-CCD diffractometer with graphite

monochromated Mo K radiation using standard procedures at

a

150 K. The structure was solved by direct methods (SIR92); all non-

hydrogen atoms were reﬁned with anisotropic thermal parameters.

Hydrogen atoms were added at idealised positions. The structure

was reﬁned using CRYSTALS.⁶²

NBn₂Me

ⁱPr

Me

X-ray crystal structure data for 33 [C₂₆H₂₉N]: M¼353.51, or-

thorhombic, space group F 2 d d, a¼9.02980(10) Å, b¼19.3438(3) Å,

Following General procedure 2, 28 (307 mg, 1.00 mmol), ZnEt₂

(2.0 mL, 2.0 mmol), CH₂I₂(0.32 mL, 4.0 mmol) and TFA (0.15 mL,

2.0 mmol) in CH₂Cl₂(2.0 mL) were reacted for 1 h to give, after pu-

riﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢀC petrol),

36as awhite crystalline solid (252 mg, 79%, >99:1 dr); mp 63e65 ^ꢀC;

n_max(KBr) 3060, 3025, 2950 (CeH), 1495, 1455, 745, 700; d_H

(400 MHz, CDCl₃) 0.63e0.67 (2H, m, C(3⁰)H_A, C(1⁰)H), 0.70e0.74 (1H,

m,C(3⁰)H_B), 0.92(3H, s, C(2⁰)Me_A), 0.95(3H, d, J6.7, C(2)Me_A),1.08(3H,

d, J 6.7, C(2)Me_B), 1.15 (3H, s, C(2⁰)Me_B), 1.86e1.94 (1H, m, C(2)H),

2.07e2.12 (1H, m, C(1)H), 3.81 (2H, d, J 13.5, N(CH_APh)₂), 3.97 (2H, d, J

13.5, N(CH_BPh)₂), 7.28e7.32 (2H, m, Ph), 7.38 (4H, app t, J 7.4, Ph), 7.47

(4H, app d, J 7.4, Ph); d_C(100 MHz, CDCl₃) 14.3 (C(2⁰)),18.3 (C(3⁰)), 20.1,

21.5 (C(2)Me₂), 21.6 (C(2⁰)Me_A), 26.4 (C(1⁰)), 27.2 (C(2⁰)Me_B), 32.0 (C

(2)), 55.1 (N(CH₂Ph)₂), 61.9 (C(1)), 126.7, 128.1, 129.2 (o,m,p-Ph), 141.1

(i-Ph); m/z (CI^þ) 278 ([MꢁC₃H₇]^þ, 100%), 322 ([MþH]^þ, 10%); HRMS

(CI^þ) C₂₃H₃₂N^þ([MþH]^þ) requires 322.2535, found 322.2525.

c¼49.1328(3) Å, V¼8582.06(19) Å³, Z¼16,

m

¼0.063 mm^ꢁ1, colour-

less plate, crystal dimensions¼0.05ꢃ0.05ꢃ0.3 mm. A total of 2589

unique reﬂections were measured for 5<

were used in the reﬁnement. The ﬁnal parameters were wR₂¼0.042

(I)]. Crystallographic data (excluding struc-

q<27 and 2029 reﬂections

and R₁¼0.034 [I>3.0

s

ture factors) has been deposited with the Cambridge Crystallo-

graphic Data Centre as supplementary publication number CCDC

783812. Copies of the data can be obtained, free of charge, on ap-

plication to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: þ44

1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].

4.23. (1RS,1⁰SR,2⁰RS)-N,N-Dibenzyl-1-(1⁰,2⁰-

dimethylcyclopropyl)-1-phenylamine 34

NBn₂Me

Ph

Me

4.25.1. X-ray Crystal Structure Determination for 36. Data were

collected using an EnrafeNonius

k-CCD diffractometer with

graphite monochromated Mo K radiation using standard pro-

a

Following General procedure 2, 26 (171 mg, 0.50 mmol), ZnEt₂

(1.0 mL, 1.0 mmol), CH₂I₂(0.16 mL, 2.0 mmol) and TFA (70 mL,

1.0 mmol) in CH₂Cl₂(1.0 mL) were reacted for 1 h to give, after pu-

riﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢀC petrol/

Et₂O, 99:1), 34 as a colourless oil (127 mg, 71%, >99:1 dr); n_max(ﬁlm)

3061, 3027, 2960 (CeH), 1493, 1452; d_H(400 MHz, CDCl₃) 0.30e0.33

cedures at 150 K. The structure was solved by direct methods

(SIR92); all non-hydrogen atoms were reﬁned with anisotropic

thermal parameters. Hydrogen atoms were added at idealised po-

sitions. The structure was reﬁned using CRYSTALS.⁶²

X-ray crystal structure data for 36 [C₂₃H₃₁N]: M¼321.51, triclinic,

space group Pꢁ1, a¼9.3589(2) Å, b¼10.0571(2) Å, c¼10.6726(3) Å,

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

8433

a

¼102.2247(9)^ꢀ,

b

¼95.2451(9)^ꢀ,

g

¼92.1221(9)^ꢀ, V¼976.01(4) Å³,

4.28. (RS,RS)-N,N-Dibenzyl-1-(2⁰,2⁰-dideuteriocyclopropyl)-1-

phenylmethanamine 39

Z¼2,

m

¼0.062 mm^ꢁ1

,

colourless

plate,

crystal

dimen-

sions¼0.2ꢃ0.2ꢃ0.2 mm. A total of 4430 unique reﬂections were

NBn₂

measured for 5<

ﬁnement. The ﬁnal parameters were wR₂¼0.043 and R₁¼0.040

[I>3.0 (I)]. Crystallographic data (excluding structure factors) has

q<27 and 3112 reﬂections were used in the re-

Ph

s

D

been deposited with the Cambridge Crystallographic Data Centre as

supplementary publication number CCDC 783813. Copies of the

data can be obtained, free of charge, on application to CCDC, 12

Union Road, Cambridge CB2 1EZ, UK [fax: þ44 1223 336033 or e-

mail: deposit@ccdc.cam.ac.uk].

D

Following General procedure 2, 30 (157 mg, 0.50 mmol),

ZnEt₂(1.0 mL, 1.0 mmol), CD₂I₂(0.16 mL, 2.0 mmol) and TFA (70 L,

m

1.0 mmol) in CH₂Cl₂(1.0 mL) were reacted for 3 h to give, after

puriﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢀC

petrol/Et₂O, 19:1), 39 as a pale yellow oil (118 mg, 72%, 70:30 dr).

Data for mixture: n_max(ﬁlm) 3060, 3025, 2805 (CeH), 1600, 1495,

1455, 1120, 1070, 1030, 970, 910, 745, 700; m/z (ESI^þ) 330 ([MþH]^þ,

100%); HRMS (ESI^þ) C₂₄H₂₄D₂N^þ([MþH]^þ) requires 330.2185, found

330.2175.

Data for major isomer: d_H(400 MHz, CDCl₃) ꢁ0.02 (1H, app t, J

4.9, C(3⁰)H_A), 0.57 (1H, dd, J 8.3, 4.6, C(3⁰)H_B), 1.30e1.39 (1H, ddd, J

9.7, 8.3, 5.0, C(1⁰)H), 3.01 (1H, d, J 9.8, C(1)H), 3.67 (2H, d, J 13.8, N

(CH_APh)₂), 3.93 (2H, d, J 13.8, N(CH_BPh)₂), 7.27e7.34 (3H, m, Ph),

7.38 (4H, app t, J 7.6, Ph), 7.45 (2H, app t, J 7.6, Ph), 7.50 (4H, d, J 7.1,

Ph), 7.60 (2H, app d, J 7.3, Ph); d_C(100 MHz, CDCl₃) 3.0 (C(3⁰)),10.8 (C

(1⁰)), 54.1 (N(CH₂Ph)₂), 67.2 (C(1)), 126.8, 128.0, 128.2, 128.2, 128.7,

128.8 (o,m,p-Ph), 140.6, 142.4 (i-Ph).⁶⁸

Data for minor isomer: d_H(400 MHz, CDCl₃) 0.52e0.62 (1H, app t,

J 4.6, C(3⁰)H_A), 0.82 (1H, dd, J 7.7, 4.6, C(3⁰)H_B), 1.30e1.39 (1H, m, C

(1⁰)H), 3.01 (1H, d, J 9.8, C(1)H), 3.67 (2H, d, J 13.8, N(CH_APh)₂), 3.93

(2H, d, J 13.8, N(CH_BPh)₂), 7.27e7.34 (3H, m, Ph), 7.38 (4H, app t, J

7.6, Ph), 7.45 (2H, app t, J 7.6, Ph), 7.50 (4H, d, J 7.1, Ph), 7.60 (2H, app

d, J 7.3, Ph); d_C(100 MHz, CDCl₃) 6.7 (C(3⁰)), 10.8 (C(1⁰)), 54.1 (N

(CH₂Ph)₂), 67.2 (C(1)), 126.8, 128.0, 128.2, 128.2, 128.7, 128.8 (o,m,p-

Ph), 140.6, 142.4 (i-Ph).⁶⁸

4.26. (1RS,1⁰SR,2⁰SR)-N,N-Dibenzyl-1-[2⁰-methylcyclopropyl]-

1-phenylmethanamine 37

NBn₂

Ph

Me

Following General procedure 2, 29 (164 mg, 0.50 mmol),

ZnEt₂(1.0 mL, 1.0 mmol), CH₂I₂(0.16 mL, 2.0 mmol) and TFA

(70 mL, 1.0 mmol) in CH₂Cl₂(1.0 mL) were reacted for 1 h to give,

after puriﬁcation by ﬂash column chromatography (eluent

30e40 ^ꢀC petrol/Et₂O, 99:1), 37 as a pale yellow oil (102 mg,

60%, 89:11 dr).

Data for mixture: n_max(ﬁlm) 3060, 3025, 2950 (CeH), 1495, 1450,

1120, 1070, 1030, 745, 700; m/z (ESI^þ) 342 ([MþH]^þ, 100%); HRMS

(ESI^þ) C₂₅H₂₈N^þ([MþH]^þ) requires 342.2216, found 342.2213.

Data for major isomer: d_H(400 MHz, CDCl₃) 0.33e0.40 (1H, m, C

(2⁰)H), 0.61e0.65 (1H, m, C(3⁰)H_A), 0.70e0.74 (1H, m, C(3⁰)H_B),

1.03e1.10 (1H, m, C(1⁰)H),1.15 (3H, d, J 6.1, C(2⁰)Me), 3.11 (1H, d, J 9.8,

C(1)H), 3.68 (2H, d, J 13.6, N(CH_APh)₂), 3.88 (2H, d, J 13.6, N

(CH_BPh)₂), 7.26e7.51 (13H, m, Ph), 7.58 (2H, app d, J 7.3, Ph); d_C

(100 MHz, CDCl₃) 10.4 (C(2⁰)), 14.9 (C(3⁰)), 18.6 (C(1⁰)), 18.7 (C(2⁰)

Me), 54.0 (N(CH₂Ph)₂), 66.2 (C(1)), 126.7, 126.7, 127.9, 128.2, 128.7,

128.7 (o,m,p-Ph), 140.6, 142.7 (i-Ph).

4.29. (RS)-N,N-Dibenzyl-1-(1⁰-methylcyclopropyl)-1-

phenylmethanamine 40

NBn₂

Ph

Data for minor isomer: d_H(400 MHz, CDCl₃) [selected peaks] 1.30

(3H, d, J 6.1, C(2⁰)Me).

Following General procedure 2, 31 (164 mg, 0.50 mmol), ZnEt₂

(1.0 mL, 1.0 mmol), CH₂I₂(0.16 mL, 2.0 mmol) and TFA (70 mL,

1.0 mmol) in CH₂Cl₂(1.0 mL) were reacted for 1 h to give, after

puriﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢀC

petrol/Et₂O, 99:1), 40 as a yellow oil (160 mg, 94%); n_max(ﬁlm)

3026, 2951 (CeH), 1493, 1452; d_H(400 MHz, CDCl₃) 0.17e0.19 (1H,

m, C(2⁰)H_A), 0.46e0.52 (3H, m, C(2⁰)H_B, C(3⁰)H₂), 1.16 (3H, s, C(1⁰)

Me), 3.08 (1H, s, C(1)H), 3.72 (2H, d, J 14.5, N(CH_APh)₂), 3.98 (2H, d, J

14.5, N(CH_BPh)₂), 7.26e7.30 (2H, m, Ph), 7.33e7.38 (8H, m, Ph),

7.40e7.45 (3H, m, Ph), 7.52 (2H, app d, J 7.3, Ph); d_C(100 MHz, CDCl₃)

11.1 (C(2⁰)), 16.5 (C(3⁰)), 18.2 (C(1⁰)), 19.8 (C(1⁰)Me), 52.7 (N

(CH₂Ph)₂), 71.0 (C(1)), 126.7, 126.8, 127.9, 128.1, 129.2, 129.2 (o,m,p-

Ph), 138.9, 141.5 (i-Ph); m/z (ESI^þ) 342 ([MþH^þ],100%); HRMS (ESI^þ)

C₂₅H₂₈N^þ([MþH]^þ) requires 342.2216, found 342.2209.

4.27. (RS)-N,N-Dibenzyl-1-cyclopropyl-1-phenylmethanamine

38

NBn₂

Ph

Following General procedure 2, 30 (157 mg, 0.50 mmol), ZnEt₂

(1.0 mL, 1.0 mmol), CH₂I₂(0.16 mL, 2.0 mmol) and TFA (70 mL,

1.0 mmol) in CH₂Cl₂(1.0 mL) were reacted for 1 h to give, after

puriﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢀC

petrol/Et₂O, 19:1), 38 as a pale yellow oil (119 mg, 73%); n_max

(ﬁlm) 3026 (CeH), 1493, 1453; d_H(400 MHz, CDCl₃) 0.01e0.03

(1H, m, C(2⁰)H_A), 0.52e0.62 (2H, m, C(2⁰)H_B, C(3⁰)H_A), 0.81e0.88

(1H, m, C(3⁰)H_B), 1.30e1.39 (1H, m, C(1⁰)H), 3.01 (1H, d, J 9.8, C(1)

H), 3.67 (2H, d, J 13.8, N(CH_APh)₂), 3.93 (2H, d, J 13.8, N(CH_BPh)₂),

7.27e7.34 (3H, m, Ph), 7.38 (4H, app t, J 7.6, Ph), 7.45 (2H, app t, J

7.6, Ph), 7.50 (4H, app d, J 7.1, Ph), 7.60 (2H, app d, J 7.3, Ph); d_C

(100 MHz, CDCl₃) 3.0 (C(2⁰)), 6.7 (C(3⁰)), 10.8 (C(1⁰)), 54.1 (N

(CH₂Ph)₂), 67.2 (C(1)), 126.8, 128.0, 128.2, 128.2, 128.7, 128.8

(o,m,p-Ph), 140.6, 142.4 (i-Ph); m/z (ESI^þ) 328 ([MþH]^þ, 100%);

HRMS (ESI^þ) C₂₄H₂₆N^þ([MþH]^þ) requires 328.2060, found

328.2064.

4.30. (RS,RS)-N,N-Dibenzyl-1-(1⁰-methyl-2⁰,2⁰-

dideuteriocyclopropyl)-1-phenylmethanamine 41

NBn₂

Ph

D

Me

D

Following General procedure 2, 31 (164 mg, 0.50 mmol),

ZnEt₂(1.0 mL, 1.0 mmol), CD₂I₂(0.16 mL, 2.0 mmol) and TFA

8434

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

(70

mL, 1.0 mmol) in CH₂Cl₂(1.0 mL) were reacted for 3 h to give,

4.32. (1RS,2RS,3SR)-2-Phthalimidobicyclo[4.1.0]heptane 51

after puriﬁcation by ﬂash column chromatography (eluent

30e40 ^ꢀC petrol/Et₂O, 19:1), 41 as a pale yellow solid (108 mg, 63%,

58:42 dr).

NPhth

Data for mixture: mp 57e59 ^ꢀC; n_max(KBr) 3060, 3025, 2960,

2810 (CeH), 1600, 1495, 1450, 1120, 1070, 1030, 910, 775, 750, 700;

m/z (ESI^þ) 344 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₅H₂₆D₂N^þ

([MþH]^þ) requires 344.2342, found 344.2335.

PPh₃(1.44 g, 5.50 mmol), 52⁷⁰(561 mg, 5.00 mmol) and DEAD

(0.87 mL, 5.50 mmol) were added to a stirred solution of phthali-

mide (809 mg, 5.50 mmol) in THF (100 mL) at rt. The resulting

mixture was stirred at rt for 24 h then concentrated in vacuo. Pu-

riﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢀC pet-

rol/Et₂O, 19:1) gave 51 as a white solid (600 mg, 50%, >99:1 dr); mp

130e132 ^ꢀC.

Data for major isomer: d_H(400 MHz, CDCl₃) 0.46e0.52 (2H,

m, C(3⁰)H₂), 1.16 (3H, s, C(1⁰)Me), 3.08 (1H, s, C(1)H), 3.72

(2H, d, J 14.5, N(CH_APh)₂), 3.98 (2H, d, J 14.5, N(CH_BPh)₂),

7.26e7.30 (2H, m, Ph), 7.33e7.38 (8H, m, Ph), 7.40e7.45 (3H,

m, Ph), 7.52 (2H, app d, J 7.3, Ph); d_C(100 MHz, CDCl₃) 16.5 (C

(3⁰)), 18.2 (C(1⁰)), 19.8 (C(1⁰)Me), 52.7 (N(CH₂Ph)₂), 71.0 (C(1)),

126.7, 126.8, 127.9, 128.1, 129.2, 129.2 (o,m,p-Ph), 138.9, 141.5

(i-Ph).⁶⁸

Data for minor isomer: d_H(400 MHz, CDCl₃) 0.17e0.19 (1H, m,

C(3⁰)H_A), 0.46e0.52 (1H, m, C(3⁰)H_B), 1.16 (3H, s, C(1⁰)Me), 3.08

(1H, s, C(1)H), 3.72 (2H, d, J 14.5, N(CH_APh)₂), 3.98 (2H, d, J 14.5, N

(CH_BPh)₂), 7.26e7.30 (2H, m, Ph), 7.33e7.38 (8H, m, Ph), 7.40e7.45

(3H, m, Ph), 7.52 (2H, app d, J 7.3, Ph); d_C(100 MHz, CDCl₃) 11.1 (C

(3⁰)), 18.2 (C(1⁰)), 19.8 (C(1⁰)Me), 52.7 (N(CH₂Ph)₂), 71.0 (C(1)),

126.7, 126.8, 127.9, 128.1, 129.2, 129.2 (o,m,p-Ph), 138.9, 141.5

(i-Ph).⁶⁸

4.33. tert-Butyl (1RS,2SR,6SR)-bicyclo[4.1.0]heptan-2-

ylcarbamate 53

NHBoc

Following General procedure 1, 49^23,71(197 mg, 1.00 mmol),

ZnEt₂(2.0 mL, 2.0 mmol) and CH₂I₂(0.32 mL, 4.0 mmol) in CH₂Cl₂

(2.0 mL) were reacted for 3 h to give, after puriﬁcation by ﬂash

column chromatography (eluent 30e40 ^ꢀC petrol/Et₂O, 9:1), 53 as

a white solid (141 mg, 67%, >99:1 dr); mp 41e43 ^ꢀC; n_max(ﬁlm)

3343 (NeH), 2933 (CeH), 1701 (C]O); d_H(500 MHz, CDCl₃)

0.04e0.06 (1H, m, C(7)H_A), 0.48e0.52 (1H, m, C(7)H_B), 0.77 (1H, app

q, J 11.6, C(3)H_A), 1.02e1.07 (1H, m, C(6)H), 1.11e1.20 (2H, m, C(1)H,

C(4)H_A), 1.28e1.36 (2H, m, C(5)H_A, C(4)H_B), 1.42 (9H, br s, CMe₃),

1.69 (1H, br s, C(3)H_B), 1.84e1.87 (1H, m, C(5)H_B), 3.98 (1H, br s, C(2)

H), 4.53 (1H, br s, NH); d_C(125 MHz, CDCl₃) 7.8 (C(7)), 11.6 (C(6)),

15.5 (C(1)), 21.5 (C(4)), 23.0 (C(5)), 27.5 (C(3)), 28.4 (CMe₃), 46.5 (C

(2)), 78.8 (CMe₃), 155.3 (C]O); m/z (ESI^þ) 270 ([MþMeCNþNH₄]^þ,

4.31. (1RS,2SR,3SR)- and (1RS,2RS,3SR)-2-Phthalimidobicyclo

[4.1.0]heptane syn-50 and anti-51

NPhth

-50

syn

-51

anti

Following General procedure 2, 47^23,69(455 mg, 2.00 mmol),

ZnEt₂(4.0 mL, 4.0 mmol), CH₂I₂(0.64 mL, 8.0 mmol) and TFA

(0.30 mL, 4.0 mmol) in CH₂Cl₂(4.0 mL) were reacted for 3 h to

give a 17:83 mixture of syn-50 and anti-51, respectively, in addi-

tion to 38% returned starting material. Puriﬁcation by ﬂash col-

umn chromatography (eluent 30e40 ^ꢀC petrol/Et₂O, 9:1) gave

syn-50 (38 mg, 8%, >99:1 dr) and anti-51 (311 mg, 33%, >99:1 dr)

as white solids.

þ

100%); HRMS (ESI^þ) C₁₂H₂₁NNaO₂([MþNa]^þ) requires 234.1465,

found 234.1465.

4.34. tert-Butyl (1RS,2RS,6SR)-bicyclo[4.1.0]heptan-2-

ylcarbamate 54

Data for syn-50: mp 140e142 ^ꢀC; n_max(KBr) 2947 (CeH), 1707

(imide); d_H(400 MHz, CDCl₃) 0.65e0.71 (1H, m, C(7)H_A), 0.89 (1H,

app q, J 5.2, C(7)H_B), 1.03e1.12 (2H, m, C(1)H, C(6)H), 1.23e1.36 (1H,

m, C(4)H_A), 1.45e1.55 (2H, m, C(5)H_A, C(3)H_A), 1.63e1.72 (1H, m, C

(4)H_B), 1.97e2.02 (1H, m, C(5)H_B), 2.09e2.19 (1H, m, C(3)H_B),

4.72e4.77 (1H, m, C(2)H), 7.68e7.70 (2H, m, Ar), 7.81e7.83 (2H, m,

Ar); d_C(100 MHz, CDCl₃) 11.1 (C(6)), 11.2 (C(7)), 14.8 (C(1)), 23.0 (C

(5)), 23.3 (C(3)), 23.9 (C(4)), 49.6 (C(2)), 123.0 (C(3⁰), C(4⁰)), 132.2 (C

(2⁰), C(5⁰)), 133.7 (C(1⁰), C(6⁰)), _þ168.9 (C]O); m/z (FI^þ) 241 ([M]^þ,

100%); HRMS (FI^þ) C₁₅H₁₅NO₂([M]^þ) requires 241.1103, found

241.1111.

NHBoc

Following General procedure 2, 49⁷¹(197 mg, 1.00 mmol), ZnEt₂

(2.0 mL, 2.0 mmol), CH₂I₂(0.32 mL, 4.0 mmol) and TFA (150 mL,

2.0 mmol) in CH₂Cl₂(2.0 mL) were reacted for 3 h to give, after

puriﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢀC

petrol/Et₂O, 9:1), 54 as a white solid (148 mg, 70%, >99:1 dr); mp

40e42 ^ꢀC; n_max(ﬁlm) 3333 (NeH), 2933 (CeH), 1703 (C]O); d_H

(500 MHz, CDCl₃) ꢁ0.03e0.02 (1H, m, C(7)H_A), 0.52e0.57 (1H, m, C

(7)H_B), 0.70e0.74 (1H, m, C(1)H), 0.83e0.88 (1H, m, C(6)H),

0.99e1.03 (1H, m, C(4)H_A), 1.06e1.12 (1H, m, C(3)H_A), 1.24e1.32

(1H, m, C(4)H_B), 1.37 (9H, br s, CMe₃), 1.39e1.44 (1H, m, C(3)H_B),

1.51e1.56 (1H, m, C(5)H_A), 1.68e1.75 (1H, m, C(5)H_B), 3.71 (1H, br s,

C(2)H), 4.76 (1H, br s, NH); d_C(125 MHz, CDCl₃) 9.2 (C(7)), 9.7 (C(6)),

16.3 (C(1)), 16.9 (C(4)), 24.8 (C(5)), 28.0 (C(3)), 28.4 (CMe₃), 46.4 (C

(2)), 78.9 (CMe₃), 155.2 (C]O); m/z (ESI^þ) 270 ([MþMeCNþNH₄]^þ,

Data for anti-51: mp 130e132 ^ꢀC; n_max(KBr) 2940 (CeH),

1709 (imide); d_H(400 MHz, CDCl₃) 0.18 (1H, app q, J 5.3, C(7)

H_A), 0.62e0.68 (1H, m, C(7)H_B), 1.01e1.13 (2H, m, C(1)H, C(4)

H_A), 1.18e1.25 (1H, m, C(6)H), 1.51e1.58 (2H, m, C(4)H_B, C(3)H_A),

1.75e1.91 (3H, m, C(3)H_B, C(5)H₂), 4.28 (1H, app dd, J 11.5, 5.7,

C(2)H), 7.69e7.71 (2H, m, Ar), 7.82e7.84 (2H, m, Ar); d_C

(100 MHz, CDCl₃) 9.3 (C(7)), 11.3 (C(6)), 14.5 (C(1)), 18.1 (C(4)),

22.3 (C(5)), 27.0 (C(3)), 47.9 (C(2)), 123.1 (C(3⁰), C(4⁰)), 132.1 (C

(2⁰), C(5⁰)), 133.8 (C(1⁰), C(6⁰)), 168.2 (C]O); m/z (FI^þ) 241

([M]^þ, 100%); HRMS (FI^þ) C₁₅H₁₅NO₂([M]^þ) requires 241.1103,

þ

100%); HRMS (ESI^þ) C₁₂H₂₁NNaO₂([MþNa]^þ) requires 234.1465,

þ

found 241.1110.

found 234.1465.

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

8435

4.35. Methyl (RS)-cyclohex-2-en-1-ylcarbamate 59

4.38. (RS)-N-(Cyclohex-2-en-1-yl)benzamide 62

NHBz

NHMoc

Following General procedure 4, 46 (980 mg, 10.0 mmol), Bi

(OTf)₃(328 mg, 0.50 mmol), KPF₆(92 mg, 0.50 mmol), benzamide

(1.82 g, 15.0 mmol) and MgSO₄(w1.5 g) in THF (50 mL) were

reacted for 16 h to give, after puriﬁcation by ﬂash column chro-

matography (eluent 30e40 ^ꢀC petrol/Et₂O, 1:0 to 9:1 gradient elu-

tion), 62 as a white solid (570 mg, 28%);⁷⁴mp 96e98 ^ꢀC (lit.⁷⁴mp

102e104 ^ꢀC); d_H(400 MHz, CDCl₃) 1.57e1.72 (3H, m, CH₂),

1.93e2.02 (3H, m, CH₂), 4.64e4.70 (1H, m, C(1)H), 5.62e5.68 (1H,

m, C(2)H), 5.85e5.90 (1H, m, C(3)H), 6.34 (1H, d, J 7.5, NH),

7.36e7.40 (2H, m, Ph), 7.44e7.48 (2H, m, Ph), 7.75e7.78 (1H, m, Ph).

Following General procedure 4, 46 (980 mg, 10.0 mmol), Bi

(OTf)₃(328 mg, 0.50 mmol), KPF₆(92 mg, 0.50 mmol), methyl car-

bamate (1.13 g, 15.0 mmol) and MgSO₄(w1.5 g) in THF (50 mL)

were reacted for 16 h to give, after puriﬁcation by ﬂash column

chromatography (eluent 30e40 ^ꢀC petrol/EtOAc, 1:0 to 9:1 gradient

elution), 59 as a white solid (1.21 g, 78%);⁷²mp 25e26 ^ꢀC; d_H

(400 MHz, CDCl₃) 1.47e1.55 (1H, m, CH₂), 1.56e1.66 (2H, m, CH₂),

1.84e1.92 (1H, m, CH₂), 1.94e2.00 (2H, m, CH₂), 3.64 (3H, s, OMe),

4.18 (1H, br s, C(1)H), 4.75 (1H, br s, NH), 5.58 (1H, dd, J 9.9, 2.0, C(2)

H), 5.78e5.83 (1H, m, C(3)H).

4.39. Methyl (1RS,2SR,6SR)-bicyclo[4.1.0]hept-2-ylcarbamate 63

4.36. Phenyl (RS)-cyclohex-2-en-1-ylcarbamate 60

NHMoc

CO₂Ph

HN

Following General procedure 1, 59 (155 mg, 1.00 mmol), ZnEt₂

(2.0 mL, 2.0 mmol) and CH₂I₂(0.32 mL, 4.0 mmol) in CH₂Cl₂

(2.0 mL) were reacted for 1 h to give, after puriﬁcation by ﬂash

column chromatography (eluent 30e40 ^ꢀC petrol/Et₂O, 4:1), 63 as

a colourless oil (167 mg, 99%, >99:1 dr); n_max(ﬁlm) 3320 (NeH),

3015, 2930, 2855 (CeH), 1700 (C]O), 1540, 1460, 1250, 1045, 780,

645; d_H(400 MHz, CDCl₃) 0.05 (1H, app q, J 5.2, C(7)H_A), 0.49 (1H,

td, J 8.8, 4.7, C(7)H_B), 0.76 (1H, m, C(3)H_A),1.00e1.18 (3H, m, C(1)H, C

(4)H_A, C(6)H),1.24e1.38 (2H, m, C(4)H_B, C(5)H_A),1.64e1.72 (1H, m, C

(3)H_B), 1.82e1.89 (1H, m, C(5)H_B), 3.60 (3H, s, OMe), 3.97e4.04 (1H,

m, C(2)H), 4.78 (1H, br s, NH); d_C(100 MHz, CDCl₃) 7.8 (C(7)), 11.6 (C

(1)), 15.4 (C(6)), 21.5 (C(4)), 22.9 (C(5)), 27.3 (C(3)), 47.0 (C(2)), 51.7

(OMe), 156.4 (C]O); m/z (ESI^þ) 192 ([MþNa]^þ, 80%), 361

([2MþNa]^þ, 100%); HRMS (ESI^þ) C₉H₁₅NNaO₂^þ([MþNa]^þ) requires

192.0995, found 192.0998.

Following General procedure 4, 46 (980 mg, 10.0 mmol), Bi

(OTf)₃(328 mg, 0.5 mmol), KPF₆(92 mg, 0.5 mmol), phenyl carba-

mate (2.06 g, 15.0 mmol) and MgSO₄(w1.5 g) in THF (50 mL) were

reacted for 16 h to give, after puriﬁcation by ﬂash column chro-

matography (eluent 30e40 ^ꢀC petrol/Et₂O, 1:0 to 9:1 gradient elu-

tion), 60 as a white solid (1.23 g, 57%); mp 108e110 ^ꢀC; n_max(KBr)

3330 (NeH), 3020, 2930, 2870 (CeH), 1735 (C]O), 1530, 1495,

1340, 1210, 975, 725, 665; d_H(400 MHz, CDCl₃) 1.61e1.70 (3H, m, C

(5)H₂, C(6)H_A),1.95e2.04 (3H, m, C(4)H₂, C(6)H_B), 4.29e4.50 (1H, m,

C(1)H), 5.03 (1H, d, J 6.8, NH), 5.69e5.71 (1H, m, C(2)H), 5.88e5.93

(1H, m, C(3)H), 7.15 (2H, app d, J 7.7, Ph), 7.20 (1H, app t, J 7.5, Ph),

7.36 (2H, app t, J 7.7, Ph); d_C(100 MHz, CDCl₃) 19.6 (C(5)), 24.8 (C(6)),

29.6 (C(4)), 46.6 (C(1)), 127.4 (C(2)), 121.6, 125.2, 129.3 (o,m,p-Ph),

131.1 (C(3)), 151.0 (i-Ph), 153.8 (C]O); m/z (ESI^þ) 276

([MþMeCNþNH₄]^þ, 100%); HRMS (ESI^þ) C₁₃H₁₅NNaO₂^þ([MþNa]^þ)

requires 240.0995, found 240.0997.

4.40. Phenyl (1RS,2SR,6SR)-bicyclo[4.1.0]hept-2-ylcarbamate 64

4.37. Benzyl (RS)-cyclohex-2-en-1-ylcarbamate 61

CO₂Ph

HN

NHCbz

Following General procedure 1, 60 (217 mg, 1.0 mmol), ZnEt₂

(2.0 mL, 2.0 mmol) and CH₂I₂(0.32 mL, 4.0 mmol) in CH₂Cl₂

(2.0 mL) were reacted for 1 h to give, after puriﬁcation by ﬂash

column chromatography (eluent 30e40 ^ꢀC petrol/EtOAc, 1:0 to

9:1), 64 as a white solid (229 mg, 99%, >99:1 dr); mp 101e103 ^ꢀC;

n_max(KBr) 3310 (NeH), 2930 (CeH), 1705 (C]O), 1535, 1495, 1215,

1020, 990, 795, 665; d_H(400 MHz, CDCl₃) 0.17 (1H, app t, J 5.1, C(7)

H_A), 0.61 (1H, app t, J 8.7, 4.7, C(7)H_B), 0.86e0.95 (1H, m, C(3)H_A),

1.11e1.29 (3H, m, C(1)H, C(4)H_A, C(6)H), 1.33e1.45 (2H, m, C(4)H_B, C

(5)H_A), 1.81e1.89 (1H, m, C(3)H_B), 1.89e1.99 (1H, m, C(5)H_B),

4.11e4.19 (1H, m, C(2)H), 5.07e5.08 (1H, m, NH), 7.11e7.21 (3H, m,

Ph), 7.36 (2H, app t, J 7.8, Ph); d_C(100 MHz, CDCl₃) 7.9 (C(7)), 11.8 (C

(6)), 15.3 (C(1)), 21.4 (C(4)), 22.9 (C(5)), 27.3 (C(3)), 47.5 (C(2)), 121.6,

Following General procedure 4, 46 (980 mg, 10.0 mmol), Bi

(OTf)₃(328 mg, 0.5 mmol), KPF₆(92 mg, 0.5 mmol), benzyl carba-

mate (2.27 g, 15.0 mmol) and MgSO₄(w1.5 g) in THF (50 mL) were

reacted for 16 h to give, after puriﬁcation by ﬂash column chro-

matography (eluent 30e40 ^ꢀC petrol/EtOAc, 1:0 to 9:1 gradient

elution), 61 as a white solid (1.92 g, 83%);⁷³mp 65e67 ^ꢀC; d_H

(400 MHz, CDCl₃) 1.01e1.93 (3H, m, CH₂), 1.45e1.64 (3H, m, CH₂),

4.22 (1H, br s, C(1)H), 5.02e5.09 (2H, m, OCH₂Ph), 5.39 (1H, br s,

NH), 5.58 (1H, d, J 9.9, C(2)H), 5.74e5.79 (1H, m, C(3)H), 7.23e7.29

(5H, m, Ph).

8436

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

125.1, 129.2 (o,m,p-Ph), 151.1 (i-Ph), 153.9 (C]O); m/z (ESI^þ) 23_þ2

([MþH]^þ, 40%), 485 ([2MþNa]^þ, 100%); HRMS (ESI^þ) C₁₄H₁₇NNaO₂

([MþNa]^þ) requires 254.1151, found 254.1154.

solid (90 mg, 83%, 98:2 dr); mp 50e52 ^ꢀC; n_max(KBr) 3305 (NeH),

1690 (C]O), 1540, 1255, 1095, 665; d_H(400 MHz, CDCl₃) 0.01e0.05

(1H, m, C(7)H_A), 0.59 (1H, td, J 9.2, 4.9, C(7)H_B), 0.73e0.79 (1H, m, C

(1)H), 0.87e0.95 (1H, m, C(6)H), 1.00e1.09 (1H, m, C(4)H_A),

1.13e1.22 (1H, m, C(3)H_A), 1.27e1.37 (1H, m, C(4)H_B), 1.42e1.49 (1H,

m, C(3)H_B), 1.55e1.61 (1H, m, C(5)H_A), 1.77 (1H, app dq, J 13.7, 6.9, C

(5)H_B), 3.62 (3H, s, OMe), 3.79e3.85 (1H, br m, C(2)H), 5.08 (1H, br s,

NH); d_C(100 MHz, CDCl₃) 9.2 (C(7)), 9.7 (C(6)), 16.1 (C(1)), 16.7 (C

(4)), 22.6 (C(5)), 27.9 (C(3)), 46.8 (C(2)), 51.7 (OMe), 156.3 (C]O);

m/z (ESI^þ) 170 ([MþH]^þ, 25%), 192 ([MþNa]^þ, 40%), 339 ([2MþH]^þ,

4.41. Benzyl (1RS,2SR,6SR)-bicyclo[4.1.0]hept-2-ylcarbamate 65

NHCbz

þ

30%), 361 ([2MþNa]^þ, 100%); HRMS (ESI^þ) C₉H₁₅NNaO₂

([MþNa]^þ) requires 192.0995, found 192.0999.

Following General procedure 1, 61 (231 mg, 1.00 mmol), ZnEt₂

(2.0 mL, 2.0 mmol) and CH₂I₂(0.32 mL, 4.0 mmol) in CH₂Cl₂(2.0 mL)

were reacted for 1 h to give, after puriﬁcation by ﬂash column

chromatography (eluent 30e40 ^ꢀC petrol/Et₂O, 4:1), 65 as a white

solid (206 mg, 84%, >99:1 dr); mp 48e50 ^ꢀC; n_max(KBr) 3330 (NeH),

2935, 2360 (CeH), 1695 (C]O), 1530, 1240, 1045, 695, 665; d_H

(400 MHz, CDCl₃) 0.09 (1H, q, J 5.1, C(7)H_A), 0.51e0.57 (1H, m, C(7)

H_B), 0.78e0.87 (1H, m, C(3)H_A), 1.06e1.14 (1H, m, C(6)H), 1.14e1.25

(2H, m, C(1)H, C(4)H_A), 1.28e1.42 (2H, m, C(5)H_A, C(4)H_B), 1.70e1.79

(1H, m, C(3)H_B),1.86e1.96 (1H, m, C(5)H_B), 4.06e4.15 (1H, m, C(2)H),

4.88 (1H, d, J 6.3, NH), 5.11 (2H, s, CH₂Ph), 7.30e7.37 (5H, m, Ph); d_C

(100 MHz, CDCl₃) 7.9 (C(7)),11.7 (C(6)),15.4 (C(1)), 21.5 (C(4)), 22.9 (C

(5)), 27.4 (C(3)), 47.2 (C(2)), 66.4 (OCH₂Ph),128.0,128.2,128.5 (o,m,p-

Ph), 136.7 (i-Ph), 155.7 (C]O); m/z (ESI^þ) 268 ([MþNa]^þ, 40%), 304

([MþNH₄þMeCN]^þ, 100%), 513 ([2MþNa]^þ, 30%); HRMS (ESI^þ)

C₁₅H₁₉NNaO₂^þ([MþNa]^þ) requires 268.1308, found 268.1309.

4.44. Phenyl (1RS,2RS,6SR)-bicyclo[4.1.0]hept-2-ylcarbamate 68

CO₂Ph

HN

Following General procedure 2, 60 (100 mg, 0.46 mmol), ZnEt₂

(1.38 mL, 1.38 mmol), CH₂I₂(0.22 mL, 2.76 mmol) and TFA (0.11 mL,

1.38 mmol) in CH₂Cl₂(1.5 mL) were reacted for 4 h to give, after

puriﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢀC

petrol/Et₂O, 1:0 to 9:1 gradient elution), 68 as a white solid (80 mg,

75%, 95:5 dr); mp 110e112 ^ꢀC; n_max(KBr) 3320 (NeH), 2930 (CeH),

1710 (C]O), 1540, 1490, 1215, 690, 665; d_H(400 MHz, CDCl₃) 0.12

(1H, app q, J 5.3, C(7)H_A), 0.69 (1H, td, J 9.2, 5.0, C(7)H_B), 0.87e0.93

(1H, m, C(1)H), 0.97e1.05 (1H, m, C(6)H), 1.11e1.20 (1H, m, C(4)H_A),

1.25e1.37 (1H, m, C(3)H_A), 1.37e1.46 (1H, m, C(4)H_B), 1.54e1.73 (2H,

m, C(3)H_B, C(5)H_A), 1.87 (1H, app dq, J 13.7, 6.8, C(5)H_B), 3.97 (1H,

app q, J 6.3, C(2)H), 5.36 (1H, br d, J 6.9, NH), 7.14e7.21 (3H, m, Ph),

7.36 (2H, app t, J 7.8, Ph); d_C(100 MHz, CDCl₃) 9.4 (C(7)), 9.7 (C(6)),

16.0 (C(1)), 16.8 (C(4)), 22.7 (C(5)), 27.7 (C(3)), 47.1 (C(2)), 121.6,

125.2, 129.2 (o,m,p-Ph), 151.1 (i-Ph), 153.8 (C]O); m/z (ESI^þ) 232

([MþH]^þ, 30%), 290 ([MþMeCNþNH₄]^þ, 60%), 485 ([2MþNa]^þ,

4.42. (1RS,2SR,6SR)-N-(Bicyclo[4.1.0]hept-2-yl)benzamide 66

NHBz

Following General procedure 1, 62 (201 mg, 1.0 mmol), ZnEt₂

(2.0 mL, 2.0 mmol) and CH₂I₂(0.32 mL, 4.0 mmol) in CH₂Cl₂(2.0 mL)

were reacted for 1 h to give, after puriﬁcation by ﬂash column chro-

matography (eluent 30e40 ^ꢀC petrol/EtOAc, 7:3 to 1:1 gradient elu-

tion), 66 as a white solid (215 mg, quant, >99:1 dr); mp 122e124 ^ꢀC;

n_max(KBr) 3295 (NeH), 1625 (C]O), 1535, 665; d_H(400 MHz, CDCl₃)

0.21 (1H, app q, J 5.2, C(7)H_A), 0.62(1H, td, J 8.7, 4.6, C(7)H_B), 0.87e0.96

(1H, m, C(3)H_A), 1.13e1.22 (1H, m, C(6)H), 1.24e1.35 (2H, m, C(1)H, C

(5)H_A), 1.40e1.48 (2H, m, C(4)H₂), 1.85e1.92 (1H, m, C(5)H_B),

1.95e2.01 (1H, m, C(3)H_B), 4.51e4.58 (1H, m, C(2)H), 6.07 (1H, br s,

NH), 7.42e7.52 (3H, m, Ph), 7.77e7.80 (2H, m, Ph); d_C(100 MHz, CDCl₃)

8.0 (C(7)), 11.6 (C(6)), 15.4 (C(1)), 21.6 (C(4)), 23.0 (C(5)), 27.0 (C(3)),

46.0(C(2)),127.0,128.4,131.1(o,m,p-Ph),135.0(i-Ph),166.9 (C]O);m/z

(ESI^þ) 216 ([MþH]^þ, 40%), 238 ([MþNa]^þ, 40%), 453 ([2MþNa]^þ,

100%), 668 ([3MþNa]^þ, 60%); HRMS (ESI^þ) C₁₄H₁₇NNaO^þ([MþNa]^þ)

requires 238.1202, found 238.1200.

þ

100%); HRMS (ESI^þ) C₁₄H₁₇NNaO₂([MþNa]^þ) requires 254.1151,

found 254.1163.

4.45. Benzyl (1RS,2RS,6SR)-bicyclo[4.1.0]hept-2-ylcarbamate 69

NHCbz

Following General procedure 2, 61 (231 mg, 1.00 mmol), ZnEt₂

(2.0 mL, 2.0 mmol), CH₂I₂(0.32 mL, 4.0 mmol) and TFA (150 mL,

2.0 mmol) in CH₂Cl₂(2.0 mL) were reacted for 4 h to give, after

puriﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢀC

petrol/Et₂O, 4:1), 69 as a white solid (218 mg, 89%, 98:2 dr); mp

44e45 ^ꢀC; n_max(KBr) 3330 (NeH), 2935 (CeH), 1700 (C]O), 1530,

1240, 1090, 695, 665; d_H(400 MHz, CDCl₃) 0.09 (1H, app d, J 5.0, C

(7)H_A), 0.63e0.68 (1H, m, C(7)H_B), 0.80e0.85 (1H, m, C(1)H),

0.92e0.97 (1H, m, C(6)H), 1.06e1.13 (1H, m, C(4)H_A), 1.20e1.26 (1H,

m, C(3)H_A), 1.37 (1H, dd, J 13.2, 6.9, C(4)H_B), 1.50e1.54 (1H, m, C(3)

H_B), 1.60e1.66 (1H, m, C(5)H_A), 1.79e1.84 (1H, m, C(5)H_B),

3.89e3.93 (1H, m, C(2)H), 5.08e5.18 (3H, m, NH, OCH₂Ph),

7.29e7.37 (5H, m, Ph); d_C(100 MHz, CDCl₃) 9.3 (C(7)), 9.7 (C(6)), 16.1

(C(1)), 16.8 (C(4)), 22.7 (C(5)), 27.9 (C(3)), 46.9 (C(2)), 66.5 (OCH₂Ph),

128.0, 128.1, 128.5 (o,m,p-Ph), 136.7 (i-Ph), 155.7 (C]O); m/z (ESI^þ)

268 ([MþNa]^þ, 60%), 304.2 ([MþNH₄þMeCN]^þ, 100%), 513

4.43. Methyl (1RS,2RS,6SR)-bicyclo[4.1.0]hept-2-ylcarbamate 67

NHMoc

Following General procedure 2, 59 (100 mg, 0.64 mmol), ZnEt₂

(1.93 mL, 1.93 mmol), CH₂I₂(0.31 mL, 3.87 mmol), TFA (0.15 mL,

1.93 mmol) in CH₂Cl₂(2.0 mL) were reacted for 4 h to give, after

puriﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢀC

petrol/Et₂O, 1:0 to 9:1 gradient elution), 67 as a white crystalline

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

8437

([2MþNa]^þ, 80%); HRMS (ESI^þ) C₁₅H₁₉NNaO₂^þ([MþNa]^þ) requires

procedures at 150 K. The structure was solved by direct methods

(SIR92); all non-hydrogen atoms were reﬁned with anisotropic

thermal parameters. Hydrogen atoms were added at idealised po-

sitions. The structure was reﬁned using CRYSTALS.⁶²

268.1308, found 268.1308.

4.46. (1RS,2RS,6SR)-N-(Bicyclo[4.1.0]hept-2-yl)benzamide 70

X-ray crystal structure data for 72 [C₁₄H₁₉NO₂S]: M¼263.36,

monoclinic, space group P 2₁/c, a¼10.0211(5) Å, b¼12.9160(7) Å,

NHBz

c¼11.1049(6) Å,

b

¼105.377(4)^ꢀ, V¼1385.88(13) Å³, Z¼4,

m

¼0.228

mm^ꢁ1, colourless plate, crystal dimensions¼0.12ꢃ0.24ꢃ0.37 mm. A

total of 3073 unique reﬂections were measured for 5<q<27 and 2129

reﬂections were used in the reﬁnement. The ﬁnal parameters were

(I)]. Crystallographic data (exclud-

wR₂¼0.068 and R₁¼0.083 [I>1.5

s

Following General procedure 2, 62 (201 mg, 1.0 mmol), ZnEt₂

(2.0 mL, 2.0 mmol), CH₂I₂(0.32 mL, 4.0 mmol) and TFA (0.15 mL,

2.0 mmol) in CH₂Cl₂(2.0 mL) were reacted for 6 h to give, after

puriﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢀC

petrol/EtOAc, 7:3 to 1:1 gradient elution), 70 as a white solid

(173 mg, 80%, >99:1 dr); mp 128e130 ^ꢀC; n_max(KBr) 3310 (NeH),

3060, 2930 (CeH), 1630 (C]O), 1540, 1490, 1320, 1270, 695, 665; d_H

(400 MHz, CDCl₃) 0.10 (1H, app q, J 5.3, C(7)H_A), 0.64 (1H, td, J 9.2,

4.9, C(7)H_B), 0.81e0.87 (1H, m, C(1)H), 0.91e0.98 (1H, m, C(6)H),

1.06e1.14 (1H, m, C(4)H_A), 1.26e1.43 (2H, m, C(3)H_A, C(4)H_B),

1.53e1.67 (2H, m, C(3)H_B, C(5)H_A), 1.75e1.84 (1H, m, C(5)H_B),

4.25e4.30 (1H, m, C(2)H), 6.74 (1H, d, J 7.6, NH), 7.34e7.38 (2H, m,

Ph), 7.41e7.45 (1H, m, Ph), 7.78e7.80 (2H, m, Ph); d_C(100 MHz,

CDCl₃) 9.3 (C(7)), 9.9 (C(1)), 15.9 (C(6)), 17.1 (C(4)), 22.7 (C(5)), 27.8

(C(3)), 45.8 (C(2)), 127.0, 128.4, 131.2 (o,m,p-Ph), 135.0 (i-Ph), 166.7

(C]O); m/z (ESI^þ) 274 ([MþNH₄þMeCN]^þ, 100%), 453 ([2MþNa]^þ,

70%); HRMS (ESI^þ) C₁₄H₁₇NNaO^þ([MþNa]^þ) requires 238.1202,

found 238.1209.

ing structure factors) has been deposited with the Cambridge Crys-

tallographic Data Centre as supplementary publication number CCDC

783814. Copies of the data can be obtained, free of charge, on appli-

cation to CCDC,12 Union Road, Cambridge CB21EZ, UK[fax: þ441223

336033 or e-mail: deposit@ccdc.cam.ac.uk].

4.48. (1RS,2SR,3RS)-N-Benzylbicyclo[4.1.0]heptan-2-amine 73

NHBn

Pd/C (10% wt, 29 mg) was added to a degassed solution of 9

(58 mg, 0.20 mmol) in MeOH/H₂O/AcOH (40:4:1, 2 mL) and the re-

sultantsuspensionwasstirred underH₂(1 atm) for 16 h. Thereaction

mixture was then ﬁltered through Celite (eluent MeOH) and the ﬁl-

trate was concentrated in vacuo. The residue was dissolved in CH₂Cl₂

(10 mL) and the resultant solution was washed with satd aq NaHCO₃

(3ꢃ10 mL) then dried and concentrated in vacuo to give 73 as a pale

yellowoil(28 mg, 65%, >99:1dr); n_max(ﬁlm)2930, 2857 (CeH),1454;

d_H(400 MHz, CDCl₃) 0.19 (1H, app q, J 5.3, C(7)H_A), 0.53e0.59 (1H, m,

C(7)H_B), 0.78e0.90 (1H, m, C(3)H_A),1.06e1.22 (3H, m, C(1)H and C(6)

H, C(4)H_A), 1.35e1.45 (2H, m, C(5)H_A, C(4)H_B), 1.52 (1H, br s, NH),

1.62e1.68 (1H, m, C(3)H_B),1.88e1.94 (1H, m, C(5)H_B), 3.08e3.13 (1H,

m, C(2)H), 3.88 (1H, d, J 12.9, NCH_APh), 3.96 (1H, d, J 12.9, NCH_BPh),

7.24e7.27 (1H, m, Ph), 7.32e7.38 (4H, m, Ph); d_C(100 MHz, CDCl₃) 7.5

(C(7)), 11.6 (C(1)), 15.7 (C(6)), 21.6 (C(4)), 23.8 (C(5)), 27.9 (C(3)), 50.8

(NCH₂Ph), 51.8 (C(2)), 126.8, 128.2, 128.4 (o,m,p-Ph), 141.0 (i-Ph); m/z

(ESI^þ) 202 ([MþH]^þ, 100%); HRMS (ESI^þ) C₁₄H₂₀N^þ([MþH]^þ) re-

quires 202.1590, found 202.1588.

4.47. (1RS,2RS,6SR)-N-(Bicyclo[4.1.0]heptan-2-yl)-4⁰-

methylbenzenesulfonamide 72

NHTs

Method A: Following General procedure 1, 71^23,75(251 mg,

1.00 mmol), ZnEt₂(2.0 mL, 2.0 mmol) and CH₂I₂(0.32 mL,

4.0 mmol) in CH₂Cl₂were reacted for 1 h to give, after puriﬁcation

by ﬂash column chromatography (eluent 30e40 ^ꢀC petrol/Et₂O, 1:0

to 3:1 gradient elution), 72 as a white solid (160 mg, 60%, >99:1 dr);

mp 68e70 ^ꢀC; n_max(KBr) 3260 (NeH), 3065, 3005, 2935, 2860

(CeH), 1600, 1450, 1325 (SO₂N), 1160 (SO₂N), 1095, 1070, 930, 815,

670; d_H(400 MHz, CDCl₃) 0.09 (1H, app q, J 5.3, C(7)H_A), 0.42 (1H,

app td, J 8.8, 4.9, C(7)H_B), 0.82e0.93 (2H, m, C(1)H, C(3)H_A),

0.96e1.13 (2H, m, C(4)H_A, C(6)H), 1.20e1.36 (2H, m, C(4)H_B,C(5)H_A),

1.56e1.62 (1H, m, C(3)H_B), 1.77e1.84 (1H, m, C(5)H_B), 2.41 (3H, s, C

(4⁰)Me), 3.69 (1H, ddt, J 10.5, 7.8, 5.5, C(2)H), 4.90 (1H, d, J 7.7, NH),

7.28 (2H, d, J 8.4, C(3⁰)H, C(5⁰)H), 7.81 (2H, d, J 8.4, C(2⁰)H, C(6⁰)H); d_C

(100 MHz, CDCl₃) 8.1 (C(7)), 12.4 (C(6)), 15.8 (C(1)), 21.5 (C(4)), 21.6

(C(4⁰)Me) 22.6 (C(5)), 28.3 (C(3)), 50.3 (C(2)), 127.0 (C(2⁰),_ꢁC(6⁰)),

129.6 (C(3⁰), C(5⁰)), 138.7 (C(4⁰)), 143.0 (C(1⁰)); m/z (ESI ) 264

([MꢁH]^ꢁ, 100%); HRMS (ESI^þ) C₁₄H₁₉NNaO₂S^þ([MþNa]^þ) requires

288.1029, found 288.1032.

4.49. (1RS,2SR,3RS)-Bicyclo[4.1.0]heptan-2-amine

triﬂuoroacetate 74

NH₂·TFA

Method A: Pd/C (50 mg, 10% wt) was added to a degassed solu-

tion of 9 (100 mg, 0.34 mmol) in MeOH/H₂O/AcOH (40:4:1, 0.6 mL).

The vessel was charged with H₂(5 atm) and the reaction mixture

was stirred rapidly at rt for 16 h, after which time the solution was

ﬁltered through a pad of Celite (eluent MeOH) and TFA (1.0 mL) was

added. The resultant mixture was concentrated in vacuo to give 74

as a pale yellow oil (77 mg, quant, >99:1 dr); n_max(ﬁlm) 3425

(NeH), 2935 (CeH),1680,1205,1140; d_H(400 MHz, CDCl₃) 0.38 (1H,

app q, J 5.0, C(7)H_A), 0.66e0.71 (1H, m, C(7)H_B), 1.05e1.10 (1H, m, C

(3)H_A), 1.15e1.26 (3H, m, C(1)H, C(6)H, C(4)H_A), 1.35e1.43 (1H, m, C

(5)H_A), 1.47e1.52 (1H, m, C(4)H_B), 1.74e1.79 (1H, m, C(3)H_B),

1.92e1.97 (1H, m, C(5)H_B), 3.70e3.80 (1H, m, C(2)H), 7.62 (3H, br s,

NH₃); d_C(100 MHz, CDCl₃) 8.1 (C(7)), 12.1 (C(1)), 13.0 (C(6)), 20.8 (C

(4)), 22.1 (C(5)), 24.7 (C(3)), 49.0 (C(2)); m/z (FI^þ) 112 ([MþH]^þ,

Method B: Following General procedure 2, 71 (126 mg,

0.50 mmol), ZnEt₂(1.0 mL, 1.0 mmol), CH₂I₂(0.16 mL, 2.0 mmol)

and TFA (0.07 mL, 1.0 mmol) in CH₂Cl₂were reacted for 1 h to give,

after puriﬁcation by ﬂash column chromatography (eluent

30e40 ^ꢀC petrol/Et₂O, 1:0 to 3:1 gradient elution), 72 as a white

solid (70 mg, 53%); mp 66e68 ^ꢀC.

4.47.1. X-ray Crystal Structure Determination for 72. Data were

collected using an EnrafeNonius

k-CCD diffractometer with

graphite monochromated Mo

Ka radiation using standard

8438

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

100%); HRMS (FI^þ) C₇H₁₄N^þ([MþH]^þ) requires 112.1126, found

cyclohexylamine (1.14 mL, 10.0 mmol) in THF (100 mL) at 0 ^ꢀC. The

resultant mixture was stirred for 16 h at rt then washed with brine

(100 mL). The aqueous layer was extracted with CH₂Cl₂(2ꢃ50 mL)

and the combined organic extracts were dried and concentrated in

vacuo to give 77 as a white solid (2.32 g, 99%);⁷⁶mp 82e84 ^ꢀC (lit.⁷⁶

mp 79e80 ^ꢀC); d_H(400 MHz, CDCl₃) 1.08e1.22 (3H, m, 3ꢃCH₂),

1.31e1.40 (2H, m, 2ꢃCH₂), 1.56e1.64 (1H, m, 1ꢃCH₂), 1.66e1.74 (2H,

m, 2ꢃCH₂), 1.93e1.96 (2H, m, 2ꢃCH₂), 3.51e3.53 (1H, m, CHN), 4.66

(1H, br s, NH), 5.09 (2H, br s, OCH₂Ph), 7.30e7.40 (5H, m, Ph).

112.1124.

Method B: N₂H₄$H₂O (8 mL, 0.16 mmol) was added to a stirred

solution of 50 (34 mg, 0.15 mmol) in MeOH (2 mL) at rt and the re-

sultant suspensionwas heated at reﬂux for 16 h. The reaction mixture

was then allowed to cool to rt, ﬁltered and concentrated in vacuo. The

residue was triturated with CHCl₃(3ꢃ10 mL) and the organic wash-

ings were acidiﬁed to pH 2 with TFA (e1 mL) then concentrated in

vacuo to give 74 as a pale yellow oil (32 mg, quant, >99:1 dr).

Method C: Pd/C (4 mg, 10% wt) was added to a degassed solution

of 65 (12 mg, 0.05 mmol) in MeOH/EtOAc (4:1, 0.5 mL) and the

resultant mixture was stirred under H₂(1 atm) for 1 h. The reaction

4.52. (RS,RS)-1-Phenylbicyclo[4.1.0]heptane 79

mixture was then ﬁltered through Celite (eluent EtOAc), TFA (50 mL)

was added to the ﬁltrate and the resultant mixture was concen-

trated in vacuo to give 74 as a yellow oil (10 mg, quant, >99:1 dr).

Ph

Method D: TFA (30 mL, 0.43 mmol) was added to a stirred solu-

tion of 53 (30 mg, 0.14 mmol) in CH₂Cl₂(1.0 mL) at 0 ^ꢀC and the

resultant mixture was stirred at 0 ^ꢀC for 3 h. The reaction mixture

was then allowed to warm to rt and concentrated in vacuo to give

74 as a yellow oil (32 mg, quant, >99:1 dr).

Following General procedure 1, 76 (154 mg, 0.50 mmol), ZnEt₂

(0.5 mL, 0.5 mmol) and CH₂I₂(81 mL, 1.0 mmol) in CH₂Cl₂(0.5 mL)

were reacted for 1 h to give 79 as a colourless oil (160 mg, 60%,

>99:1 dr);^13cd_H(400 MHz, CDCl₃) 0.64 (1H, dd, J 5.6, 4.3, C(7)H_A),

0.95 (1H, dd, J 9.4, 4.5, C(7)H_B), 1.21e1.42 (4H, m, 3ꢃCH₂, C(6)H),

1.45e1.52 (1H, m,1ꢃCH₂),1.92e1.99 (1H, m,1ꢃCH₂), 2.03e2.12 (2H,

m, 2ꢃCH₂), 7.14e7.18 (1H, m, Ph), 7.27e7.29 (4H, m, Ph).

4.50. (1RS,2RS,3SR)-Bicyclo[4.1.0]heptan-2-amine

triﬂuoroacetate 75

NH₂·TFA

Acknowledgements

The authors would like to thank the Oxford Chemical Crystal-

lography Service for the use of their X-ray diffractometers.

Method A: N₂H₄$H₂O (11 mL, 0.23 mmol) was added to a stirred

solution of 51 (50 mg, 0.21 mmol) in MeOH (2 mL) at rt and the re-

sultant suspensionwas heated at reﬂux for 16 h. The reaction mixture

was then allowed to cool to rt, ﬁltered and concentrated in vacuo. The

residue was triturated with CHCl₃(3ꢃ10 mL) and the organic wash-

ings were acidiﬁed to pH2 with TFA (w1 mL) then concentrated in

vacuo to give 75 as a pale yellow oil (47 mg, quant, >99:1 dr); n_max

(ﬁlm) 3440 (NeH), 1680 (C]O), 1440, 1205, 1140; d_H(400 MHz,

CDCl₃) 0.13 (1H, app d, J 4.6, C(7)H_A), 0.72e0.77 (1H, m, C(7)H_B),

0.87e0.91 (1H, m, C(1)H),1.06e1.12 (2H, m, C(6)H, C(4)H_A), 1.28e1.37

(1H, m, C(3)H_A),1.44e1.49(1H, m, C(4)H_B),1.65e1.71 (2H, m, C(5)H_A, C

(3)H_B), 1.80e1.88 (1H, m, C(5)H_B), 3.44e3.48 (1H, m, C(2)H), 7.89 (3H,

brs,NH₃);d_C(100 MHz,CDCl₃)9.0(C(7)),10.1(C(6)),12.9 (C(1)),15.7 (C

(4)), 21.9 (C(5)), 26.3 (C(3)), 48.2 (C(2)); m/z (FI^þ) 112 ([MþH]^þ,100%);

HRMS (FI^þ) C₇H₁₅N^þ([MþH]^þ) requires 111.1126, found 111.1124.

Method B: Pd/C (10% wt, 30% w/w, 12 mg) was added to

a degassed solution of 69 (39 mg, 0.16 mmol) in MeOH/EtOAc (4:1,

2.0 mL) and the resultant mixture was stirred under H₂(1 atm) for

1 h. The reaction mixture was then ﬁltered through Celite (eluent

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EtOAc), TFA (159 mL) was added to the ﬁltrate and the resultant

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Method C: TFA (30 mL, 0.43 mmol) was added to a stirred solu-

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a yellow oil (32 mg, quant, >99:1 dr);

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4.51. Benzyl (RS)-cyclohexylcarbamate 77

NHCbz

NEt₃(1.53 mL, 11.0 mmol) and benzyl chloroformate (1.57 mL,

11.0 mmol) were sequentially added to a stirred solution of

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

8439

12. Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1959, 81, 4256.

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V. K.; Fang, G. Y.; Charmant, J. P. H.; Meek, G. Org. Lett. 2003, 5, 1757.

18. A single example of the Simmons-Smith cyclopropanation of an allylic amine

had previously been reported prior to 1993, although no experimental details

were provided, see: Perraud, R.; Arnaud, P. Bull. Soc. Chim. Fr. 1968, 1540.

19. Aggarwal, V. K.; Fang, G. Y.; Meek, G. Org. Lett. 2003, 5, 4417.

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Asymmetry 2006, 17, 1157.

21. For cyclopropanation studies, see: (a) Davies, S. G.; Ling, K. B.; Roberts, P. M.;

Russell, A. J.; Thomson, J. E. Chem. Commun. 2007, 4029; (b) Csatayová, K.;

Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Org. Lett.

2010, 12, 3152.

22. For epoxidation studies, see: (a) Aciro, C.; Claridge, T. D. W.; Davies, S. G.;

Roberts, P. M.; Russell, A. J.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3751; (b)

Aciro, C.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.

Org. Biomol. Chem. 2008, 6, 3762; (c) Bond, C. W.; Cresswell, A. J.; Davies, S. G.;

Fletcher, A. M.; Kurosawa, W.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Smith, A.

D.; Thomson, J. E. J. Org. Chem. 2009, 74, 6735; (d) Bagal, S. K.; Davies, S. G.; Lee,

J. A.; Roberts, P. M.; Russell, A. J.; Scott, P. M.; Thomson, J. E. Org. Lett. 2010, 12,

136.

36. Meier, H.; Antony-Mayer, C.; Schulz-Popitz, C.; Zerban, G. Liebigs Ann. Chem.

1987, 12, 1087.

37. For the anti-selective epoxidation of cis-cyclooct-2-en-1-ol, see: (a) Itoh, T.;

Kaneda, K.; Teranishi, S. J. Chem. Soc., Chem. Commun. 1976, 421; (b) Cope, A. C.;

Keough, A. H.; Peterson, P. E.; Simmons, H. E.; Wood, G. W. J. Am. Chem. Soc.

1957, 79, 3900.

38. For a discussion of the conformation of cyclooctane derivatives, such as cis-

cyclooctene see: Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981.

39. Crystallographic data (excluding structure factors) have been deposited with

the Cambridge Crystallographic Data Centre as supplementary publication

number CCDC 733890, see also Ref. 22c.

40. Poulter, C. D.; Friedrich, E. C.; Winstein, S. J. Am. Chem. Soc. 1969, 91, 6892.

41. Molander, G. A.; Harring, L. S. J. Org. Chem. 1989, 54, 3525.

42. Leong, M. K.; Mastryukov, V. S.; Boggs, J. E. J. Mol. Struct. 1998, 445, 149.

43. Crystallographic data (excluding structure factors) have been deposited with

the Cambridge Crystallographic Data Centre as supplementary publication

number CCDC 733888, see also Ref. 22c.

44. Abraham, R. J.; Castellazzi, I.; Sancassan, F.; Smith, T. A. D. J. Chem. Soc., Perkin

Trans. 2 1999, 99.

45.

a-Benzotriazolyl substituted amine 22 was prepared on a multigram (>20 g)

scale in 87% yield by condensation of benzaldehyde with dibenzylamine and

benzotriazole. The corresponding reaction with isobutyraldehyde gave 23 in

81% yield, also on a >20 g scale, according to the procedure detailed in: Ka-

trizky, A. R.; Nair, S. K.; Qiu, Q. Synthesis 2002, 199.

23. For aziridination studies, see: Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A.

J.; Thomson, J. E.; Woods, P. A. Tetrahedron 2010, 66, 6806.

24. Allylic amine 8 was prepared according to the procedure detailed in Ref.

22a.

25. (a) Wittig, G.; Schwarzenbach, K. Angew. Chem. 1959, 20, 652; (b) Furukawa, J.;

Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24, 53.

26. Denmark, S.; O’Connor, S. P. J. Org. Chem. 1997, 62, 3390.

27. As determined by peak integration of the ¹H NMR spectrum of the crude re-

action mixture.

28. Attempts at N-methylation of 9 with either MeI or MeOTf were not successful,

even at elevated temperatures.

29. Alternative (iodomethyl)zinc acetate reagents were also screened, although it

was found that the yield of syn-9 increased with the reactivity of the carbenoid

used [CH₃CO₂ZnCH₂I, <10%; CH₂ClCO₂ZnCH₂I, 62%; CHCl₂CO₂ZnCH₂I, 89%;

CCl₃CO₂ZnCH₂I, 66%; CF₃CO₂ZnCH₂I, 92%].

30. Extended reaction times led to lower yields of the desired cyclopropane

product syn-9 [1 h, 92%; 6 h, 71%; 12 h, 64%].

46. In the cyclopropanation of (Z)-24 (91:9 dr) and (Z)-26 (96:4 dr), the di-

astereoisomeric purity of the starting material was maintained in the products.

Additionally, the observed minor diastereoisomer from the reaction of (Z)-24

matched the major product from the cyclopropanation of (E)-29 by ¹H NMR

spectroscopic analysis.

47. In each case the syn-conﬁgurations of the major diastereoisomers were ten-

tatively assigned assuming N-directed cyclopropanation via a conformation,

which minimises 1,2-allylic strain.

48. For studies on a related system, see: Ezzitouni, A.; Russ, P.; Marquez, V. E. J. Org.

Chem. 1997, 62, 4870.

49. Coote, S. C.; O’Brien, P.; Whitwood, A. C. Org. Biomol. Chem. 2008, 6, 4299.

50. Crystallographic data (excluding structure factors) have been deposited with

the Cambridge Crystallographic Data Centre as supplementary publication

number CCDC 644843; see also Ref. 21a.

51. The cyclopropanation of an allylic carbamate was ﬁrst reported in 1972. The

reaction of ethyl (RS)-cyclohex-2-en-1-ylcarbamate under SimmonseSmith

conditions was reported to give the syn-diastereoisomer in 75e95% yield,

see: Tardella, P. A.; Pellacani, L.; DiStazio, G. Gazz. Chim. Ital. 1972, 102, 822.

52. SimmonseSmith cyclopropanations of similar systems have been reported;

for the cyclopropanation of an allylic carbamate, see: (a) Pilar de Frutos, M.;

Fernández, M. D.; Fernández-Alvarez, E.; Bernabé, M. Tetrahedron Lett. 1991,

32, 541; (b) Newombe, N. J.; Simpkins, N. S. J. Chem. Soc., Chem. Commun.

1995, 831; (c) Mohapatra, D. K. J. Chem. Soc., Perkin Trans. 1 2001, 1851; (d)

Pietruszka, J.; Witt, A.; Frey, W. Eur. J. Org. Chem. 2003, 68, 3219. For the cy-

clopropanation of an allylic amide, see: (e) For the cyclopropanation of an

allylic phosphonamide, see: Russ, P.; Ezzitouni, A.; Marquez, V. E. Tetrahedron

Lett. 1997, 38, 723; Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc.

2003, 125, 761.

31. 4,4-Diphenylcyclohex-1-ene 12 was synthesised in two steps from commer-

cially available enone 84 in 74% overall yield. N,N-Dibenzyl cyclohexylamine 13

was synthesised by benzylation of cyclohexylamine 86 to give 13 in 84% yield,

according to the procedure detailed in: Ju, Y.; Varma, R. S. Green Chem. 2004, 6,

219.

NHTs

O

N

(i)

(ii)

Ph Ph

84

Ph Ph

85, 99%

Ph Ph

12, 75%

0

53. Substrates 59e61 were prepared in 57e83% yield via the Bi(OTf)₃-catalysed S_N

substitution of cyclohex-2-enol 46 with a range of carbamates, see: Qin, H.;

Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2007, 46, 409.

54. (a) McBriar, M. D.; Guzik, H.; Xu, R.; Paruchova, J.; Li, S.; Palani, A.; Clader, J. W.;

Greenlee, W. J.; Hawes, B. E.; Kowalski, T. J.; O’Neill, K.; Spar, B.; Weig, B. J. Med.

Chem. 2005, 48, 2274; (b) McBriar, M. D.; Guzik, H.; Shapiro, S.; Xu, R.; Par-

uchova, J.; Clader, J. W.; O’Neill, K.; Hawes, B.; Sorota, S.; Margulis, M.; Tucker,

K.; Weston, D. J.; Cox, K. Bioorg. Med. Chem. Lett. 2006, 16, 4262; (c) Kowalski, T.

J.; Spar, B. D.; Weig, B.; Farley, C.; Cook, J.; Ghibaudi, L.; Fried, S.; O’Neill, K.; Del

Vecchio, R. A.; McBriar, M.; Guzik, H.; Clader, J.; Hawes, B. E.; Hwa, J. Eur. J.

Pharmacol. 2006, 535, 182; (d) Kanuma, K.; Omodera, K.; Nishiguchi, M.; Fu-

nakoshi, T.; Chaki, S.; Nagase, Y.; Iida, I.; Yamaguchi, J.; Semple, G.; Tran, T.-A.;

Sekiguchi, Y. Bioorg. Med. Chem. 2006, 14, 3307; (e) McBriar, M. D.; Guzik, H.;

Shapiro, S.; Paruchova, J.; Xu, R.; Palani, A.; Clader, J. W.; Cox, K.; Greenlee, W. J.;

Hawes, B. E.; Kowalski, T. J.; O’Neill, K.; Spar, B. D.; Weig, B.; Weston, D. J.; Farley,

C.; Cook, J. J. Med. Chem. 2006, 49, 2294.

NH₂

NBn₂

(iii)

86

13, 84%

Reagents and conditions: (i) TsNHNH₂, MeOH/PhMe (2:1), rt, 16 h; (ii) catechol

borane, CHCl₃, 0 ^ꢀC to rt, 2 h then NaOAc$H₂O, 60 ^ꢀC, 1 h; (iii) BnBr, NaOH (0.5 M

aq), 80 ^ꢀC, 30 min.

32. It is known that external ligands, such as DME, signiﬁcantly reduce the rate of

reaction of the WittigeFurukawa reagent [Zn(CH₂I)₂]. See: Denmark, S. E.;

Edwards, J. P.; Wilson, S. R. J. Am. Chem. Soc. 1992, 114, 2592.

33. Transition state 15 is analogous to the corresponding proposed transition states

for the cyclopropanation of allylic alcohols with zinc carbenoid reagents, see:

(a) Wittig, G.; Wingler, F. Chem. Ber. 1964, 97, 2146; (b) Nakamura, M.; Hirai, A.;

Nakamura, E. J. Am. Chem. Soc. 2003, 125, 2341; (c) Blanchard, E. P.; Simmons,

H. E. J. Am. Chem. Soc. 1964, 86, 1337.

55. As in the previous mechanistic investigations concerning the cyclopropanation

of N,N-dibenzyl protected allylic amine 8, the use of cyclohexene as an external

oleﬁn to mimic the cyclopropanation of allylic carbamate 61 was not practical

due to its relatively high volatility (bp 83 ^ꢀC).

56. Carbamate 77 was readily synthesised from cyclohexylamine 86 in 99% yield by

reaction with benzyl chloroformate.

34. Allylic amines 16e18 were prepared according to the procedures detailed in

Ref. 22c.

57. The relative conﬁguration within syn-80 was established by single crystal X-ray

analysis. Crystallographic data (excluding structure factors) have been

35. Several instances of syn-selective osmylation and epoxidation reactions of 3-

substituted cyclopentenes which proceed in the absence of any obvious

8440

K. Csatayová et al. / Tetrahedron 66 (2010) 8420e8440

deposited with the Cambridge Crystallographic Data Centre as supplementary

publication number CCDC 779449; see also Ref. 21b.

66. Katritzky, A. R.; Yannakopoulou, K.; Lue, P.; Rasada, D.; Urogdi, L. J. Chem. Soc.,

Perkin Trans. 1 1989, 225.

58. The observation that the total conversion is greater than 100% may indicate

that the deprotonation step does not proceed to 100% conversion. This would

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Article Doi

Chemo- and diastereoselective cyclopropanation of allylic amines and carbamates

DOI: 10.1016/j.tet.2010.08.055

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