Organocerium additions to proline-derived hydrazones: Synthesis of enantiomerically enriched amines

Tetrahedron: Asymmetry 21 (2010) 1278–1302

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Tetrahedron: Asymmetry

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

Organocerium additions to proline-derived hydrazones: synthesis

of enantiomerically enriched amines

*

Scott E. Denmark , James P. Edwards, Theodor Weber, David W. Piotrowski

245 Roger Adams Laboratory, Department of Chemistry, University of Illinois, 600 S. Mathews Ave., Urbana, IL 61801, USA

a r t i c l e i n f o

a b s t r a c t

Article history:

The addition of organocerium reagents (from both organolithium and organomagnesium precursors) to

chiral aldehyde hydrazones prepared from 1-aminoproline derivatives has been studied. The additions

proceed in good yield and high diastereoselectivity and with good nucleophile (Me, n-Bu, i-Pr, t-Bu, Ph,

etc.) and substrate scope (alkyl, alkenyl and aryl). The resulting hydrazines can be converted to amines

by N–N bond cleavage through hydrogenolysis (Raney nickel) or by acylation and cleavage with Li/

NH₃. The inﬂuence of the side chain on the diastereoselectivity was investigated through variation of

the substituents to include more coordinating atoms (oxygen and nitrogen) as well as the removal of

coordinating atoms. The SAMEMP auxiliary bearing a 2-methoxyethoxymethyl group gave the highest

diastereoselectivities. Remarkably, auxiliaries bearing simple methyl and isobutyl substituents gave high

selectivities as well. Hypotheses for the origin of the selectivity are presented.

Received 11 February 2010

Accepted 1 April 2010

Available online 16 June 2010

Dedicated to Professor Henri Kagan,

stereochemist extraordinaire, on the

occasion of his 80th birthday

1. Introduction

discriminating nitrenoid (path c⁰). Finally, hydroamination of al-

kenes should be mentioned as a fourth disconnection.

Organic compounds containing nitrogen atoms on one or more

stereogenic centers are ubiquitous in nature and are of unparal-

leled importance in pharmaceutical substances. From amino acids

and amino sugars to alkaloids and penicillins, chiral nitrogen-con-

taining compounds are of signiﬁcant synthetic and biological inter-

est. Because chiral amines have been traditionally available from

classical resolution, the development of general methods for the

enantioselective construction of stereogenic carbons bearing nitro-

gen substituents lagged behind that for the synthesis of chiral alco-

hols. Indeed, the generation of chiral alcohols followed by

displacement with a nitrogen nucleophile represented one of the

earliest methods for the synthesis of chiral amines. However, the

past two decades have witnessed an enormous increase in the

development of new methods for the direct formation of chiral

amines by asymmetric transformations of azomethine precursors.¹

The two most general approaches are (1) the enantioselective

reduction of azomethines bearing two non-hydrogen substituents

(path a) and (2) the enantioselective addition of carbon nucleo-

philes (path b), Scheme 1. A third type of disconnection involves

a conceptually distinct approach in which the C–N bond is formed

in the stereodetermining step. The possibilities illustrated would

require an enantioface discriminating reagent of either nucleo-

philic or electrophilic character (path c) or an enantiotopic group

H

or

R¹R²

path c

path c'

path a

hydride

path b

R²Met

NH₂

C

X

H

c

N

H

R²

R¹

R¹R²

a

b

or H₂

or R²•

R¹

Scheme 1.

The number of methods for the catalytic, enantioselective

reduction of imines and imine derivatives is legion and beyond

the scope of the current overview. Although excellent reviews

are available,²seminal contributions from Mukaiyama (cobalt),³

Burk (rhodium),⁴Buchwald (titanium),⁵Noyori (ruthenium),⁶

Pfaltz (iridium),⁷Lipshutz (copper),⁸and Toste (rhenium)⁹should

be noted.

The earliest studies on (and still today some of the most effec-

tive methods for) the asymmetric addition of carbon nucleophiles

to azomethines involved the use of chiral auxiliaries wherein the

nitrogen carries a stereodirecting group.¹⁰Subsequent advances

involved the use of chiral additives and catalysts for the addition

of a myriad of organometallic reagents based primarily on zinc

and copper. These reagents are versatile and have good functional

group compatibility, but because of their lower reactivity, more

activated azomethines are generally required. Accordingly, to

* Corresponding author. Tel.: +1 (217) 333 0066; fax: +1 (217) 333 3984.

E-mail address: sdenmark@illinois.edu (S.E. Denmark).

doi:10.1016/j.tetasy.2010.04.042

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

1279

facilitate the nucleophilic addition of these reagents, a host of nitro-

gen derivatives has been extensively examined. The collection of

substrates shown in Chart 1 represents a vast spectrum of reactivity,

from the weakly electrophilic imines that only react with strong

organometallic reagents to the highly electrophilic acyliminium

salts that react with alkenes and arenes.¹¹Among these, the acyli-

mines,¹²sulfonylimines,¹³and especially the phosphinoylimines¹⁴

have found extensive use in catalytic, enantioselective additions of

copper and zinc reagents and this ﬁeld has been extensively

reviewed.^15,16

papers by Yoshimura et al.²⁸These investigators attempted to

determine the factors involved in relative stereocontrol in the

addition of phenylmagnesium bromide and phenyllithium to

a-alkoxy aldimines. Since these early reports, studies of organome-

tallic additions to azomethine compounds derived from chiral

aldehydes have been scarce.^19a,c,29

The ﬁrst examples of auxiliary-based stereocontrol in additions

to imine derivatives were reported by Kagan and Fiaud,²⁵who

studied the addition of organomagnesium and organocadmium

reagents to glyoxylate-derived imines. Although moderate diaste-

reoselectivity was observed, much better diastereoselectivity

(90:10–99:1 dr) was subsequently observed in chiral acetal- and

aminal-directed additions to hydrazones³⁰and oximes.³¹

O

N

O

N

–

X

–

+

N

X

Chiral auxiliaries attached to the nitrogen of the azomethine

function offer the potential advantage of much greater generality

of substrate structure. At the outset of our work, the only studies

on N-bound, chiral-auxiliary-directed additions of alkyllithium or

-magnesium reagents to azomethines came from Takahashi

et al.²⁶These workers described the addition of organomagnesium

and organolithium reagents to chiral imines derived from chiral

amino-alcohols generally with high diastereoselectivity. However,

an excess of the Grignard reagent is required for complete reaction,

and the yields are poor (<50%) for enolizable alkyl imines. Simi-

larly, additions to imines with organocerium reagents have been

reported by Pridgen^24cand Enders.³²Finally, Coates and Chang³³

have disclosed an extensive study on the addition of Grignard

reagents to chiral nitrones bearing stereodirecting groups on the

nitrogen atom. Additions to chiral nitrones derived from phenyl-

glycine are highly diastereoselective (90:10–95:5 dr).

By far the most successful azomethine derivatives in use today

are the tert-butylsulﬁnylimines introduced and extensively devel-

oped by Ellman et al.^10dThese stable, often crystalline derivatives

(from both aldehydes and ketones) can be easily prepared from

the readily available suﬁnamide³⁴and undergo highly diastereose-

lective additions with Grignard reagents, titanium enolates, cya-

nide, and triﬂuoromethyl groups. Cleavage of the sulﬁnyl group

is effected with HCl in methanol to produce the amine hydrochlo-

ride salts.

imines

iminium salts

N-acylimines N-acyliminium salts

+

N

hydrazones

O^–

nitrones

OR

oximes

N

S

R

N

SR

O

SO₂R

sulfenylimines N-sulfinylimines sulfonylimines

N

SiMe₃

P

O

R

N-silylimines N-phosphinylimines

Chart 1.

Although organolithium reagents were among the ﬁrst to be

studied they have received less attention in recent years, primarily

because of their hyperreactivity and lesser functional group com-

patibility. For the purposes of this report, the background setting

will focus on the addition of organolithium reagents to chiral imi-

nes and hydrazones.¹⁷

2. Background

Among the other azomethine derivatives, chiral hydrazones

also offer the advantage of auxiliary removal and recovery by

reductive N–N bond cleavage of the products. This tactic was ﬁrst

demonstrated by Takahashi et al. who reported the addition of

organolithium and organomagnesium reagents to hydrazones de-

rived from chiral amino alcohols.²⁷This method is limited to aryl

imines and the magnitude and the sense of stereocontrol are nucle-

ophile dependent. In 1986, Enders et al.³⁵reported highly diaste-

reoselective additions of alkyllithium reagents to (S)-1-Amino-2-

MethoxymethylPyrrolidine (SAMP)- and RAMP hydrazones.³⁶

Removal of the pyrrolidine auxiliary by cleavage of the N–N bond³⁷

of the labile hydrazines by hydrogenation over Raney nickel affords

enantiomerically enriched primary amines in 41–73% yield and

90:10–96:4 er.

2.1. Enantioselective organolithium additions to chiral

azomethines

Despite the obvious advantages of direct addition of carbon

nucleophiles to the C@N double bonded functional groups this ap-

proach suffers from a number of limitations. First, the attenuated

electrophilicity of imine derivatives (compared to carbonyl com-

pounds) leads to deprotonation of substrates bearing

a-hydro-

gens.¹⁸Second, simple alkyl aldimines are difﬁcult to prepare

and are hydrolytically labile. The problem of competing enolization

has been addressed by the use of less basic nucleophiles such as

allylic organometallic reagents¹⁹and metal enolates.^20,21The latter

reagents have been employed in synthetic approaches to b-lactam

antibiotics.²⁰A second strategy employs modiﬁcations of the imine

function to make it more susceptible to nucleophilic attack (and

simultaneously address the problem of imine lability). Many such

azomethine derivatives have been introduced including oximes

and nitrones,²²iminium ions,¹¹N-acyl imines,¹²sulfonylimines,¹³

phosphinoylimines,¹⁴and sulﬁnylimines.^10d

In 1987 we reported a new protocol that addresses the impor-

tant issues (as outlined above) in the additions to azomethine

derivatives, namely: stability of substrates, facile addition of vari-

ous carbon nucleophiles, stereochemical control, and removal of

the auxiliary.³⁸We found that the addition of organocerium

reagents^39,40to SAMP-aldehyde hydrazones proceeded in high

yield and with high levels of diastereoselectivity. Subsequent stud-

ies have addressed various experimental and mechanistic aspects

of organocerium additions including: (1) the optimization of the

auxiliary structure,^41a(2) improved methods for the cleavage and

The crucial issue of stereocontrolled addition was ﬁrst addressed

by chiral modiﬁcation of the substrates to produce enantiomeri-

cally enriched amines with good to excellent levels of diastereose-

lectivity. However, those methods were limited to either allylic

nucleophiles^19,23,24or nonenolizable imines^25,26and hydrazones.²⁷

One of the earliest systematic studies concerning stereoselectiv-

ity in additions to chiral imines is reported in a pioneering series of

recovery of the auxiliary,^41b(3) synthesis of

a-amino alcohols

and aldehydes,^41c(4) an extensive examination of the stoichiome-

try and composition of the organocerium (and lanthanum) re-

agents,^41dand studies on the addition of organocerium reagents

1280

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

Table 1

metallic reagents (RLi, RMgX, and R₂CuLi) alone and in conjunction

Optimization of CH₃Li/CeCl₃additions to hydrazone 1a^a

with additives (BF₃ꢀOEt₂and TMEDA) were disappointing (0–43%

yield). However, we ultimately discovered that organocerium re-

agents³⁹afforded good to excellent yields in additions to a variety

of SAMP hydrazones. Because the resulting hydrazines were prone

to air-oxidation, the reaction mixtures were quenched with methyl

or benzyl chloroformate to afford the air stable, isolable carba-

mates. Using the SAMP hydrazone 1a derived from hydrocinnamal-

dehyde as a test substrate, an initial optimization study was

conducted for the reagent derived from methyllithium and cerium

chloride (Table 1). A number of conclusions can be drawn from this

early study: (1) at least 2 equiv of RLi is needed to obtain good

yields in the addition (entry 1 vs entry 2),⁴⁴(2) excess reagent

afforded lower yields (entry 2 vs entry 3), (3) a 1:1 ratio of

CH₃Li/CeCl₃(‘CH₃CeCl₂’⁴⁵) resulted in the optimal yield and diaste-

reoselectivity (entry 2 vs entry 4), (4) formation of the putative

organocerium reagent before addition of the hydrazone was crucial

to obtain high yields (entry 4 vs entry 5), and (5) THF is superior to

DME or Et₂O as the reaction solvent (entry 2 vs entries 6 and 7).

To survey substrate generality we selected four types of alde-

O

N

H

N

1. CH₃Li/CeCl₃

2. CH₃OCOCl

N

CH₃O

Ph

N

OCH₃

CH₃

Ph

H

5a

Yield^b(%)

1a

Entry

CH₃Li (equiv)

CeCl₃(equiv)

Solvent

dr^c

d

e

1

2

3

4

5^f

6

7

1.2

2.0

5.0

3.0

2.0

1.2

2.0

5.0

1.0

2.0

THF

DME

Et₂O

80

61

75

28

80

44

98:2

e

89:11

94:6

86:14

95:5

a

b

c

For details, see Section 6.

Yield after chromatography.

Determined by capillary GC analysis. The minor diastereomer was identiﬁed-

see text.

d

Mostly unreacted starting material was recovered. Up to 25% of unprotected

hydrazine could be isolated by quenching with H₂O.

e

hyde hydrazones: aliphatic 1a, benzylic 2a, aromatic 3a, and

a,b-

Diastereomeric excess not determined.

f

CeCl₃was stirred with 1 at rt for 2 h then treated with CH₃Li at ꢁ78 °C.

unsaturated 4a. The results of the addition of CH₃Li/CeCl₃to 1–4

are collected in Table 2. For comparison, the results of the addition

of CH₃Li in THF⁴⁶are also tabulated. All the substrates reacted

readily with the methylcerium reagent and afforded good yields

of adducts with high diastereomeric excesses. In several cases (en-

tries 2 and 3) the benzyl carbamates (R²= Bn) were obtained in high-

er yield (yield in parentheses). Notably, reactions using CH₃Li alone

afforded signiﬁcantly lower yields, but the diastereoselectivities

were comparable (entries 5–7). In the case of highly enolizable

hydrazone 2, exclusive enolization was observed with CH₃Li (entry

6),⁴⁷whereas CH₃Li/CeCl₃added cleanly in high yield (entry 2).

The diastereoselectivity and absolute conﬁgurations of the

products were established for 5a–7a by LiAlH₄reduction of the

corresponding methyl ketone SAMP-hydrazones 9a (R¹= PhCH₂-

CH₂), 10a (R¹= PhCH₂), and 11a (R¹= Ph), and protection of the

resulting hydrazines as their methyl carbamates (Scheme 2). In

each case a mixture of diastereomers was obtained with selectivi-

ties reversed compared to CH₃Li/CeCl₃addition (5a, 21:79; 6a,

6:94; 7a, 28:72). The predominant products from these reductions

have been shown to possess S conﬁguration, thus the major prod-

ucts in the CH₃Li/CeCl₃additions have R conﬁguration. These

assignments were veriﬁed by correlation of the N–N bond cleavage

products from 5a to 7a with the speciﬁc rotations of the known

amines.

to a

-alkoxyhydrazones.^41eThe advantages of the organolanthanide

additions to hydrazones have been further demonstrated in a ser-

ies of disclosures from the Enders laboratories.⁴²In two separate

reports, extremely high diastereoselectivities were found in the

additions to a,a- and b,b-dialkoxyhydrazones: a dramatic temper-

ature effect was noted as well.^42bThe special reactivity of organoyt-

terbium reagents have been demonstrated by Enders in the

stereoselective synthesis of (S)-(+)-coniine.^42c

In this article we describe, in full, our studies on the factors gov-

erning the high levels of diastereoselectivity observed in the addi-

tions with SAMP-hydrazones.

3. Results

3.1. Additions to SAMP-hydrazones

The preparation of SAMP-hydrazones and their use in diastereo-

selective a-alkylations have been extensively developed by Enders

et al.³⁶In the context of a total synthesis of (+)-nepetalactone, we

observed the diastereoselective addition of n-BuLi to an aldehyde

SAMP-hydrazone as a byproduct of enolization.⁴³Initial attempts

to improve the yield of the addition by the use of various organo-

Table 2

Additions of CH₃Li and CH₃Li/CeCl₃to SAMP-hydrazones 1a–4a^a

O

N

R²O

N

R²O

N

1. CH₃Met

+

OCH₃

R¹

H

CH₃

2. R²OC(O)Cl

CH₃

H

1a-4a

R¹

5a-8a

5a'-8a'

Entry

Educt

R²

Nucleophile

Product

Yield^b(%)

dr^c(%)

1

2

3

4

5

6

7

1a

2a

3a

4a

1a

2a

4a

PhCH₂CH₂

PhCH₂

Ph

(E)-CH₃CH@CH

PhCH₂CH₂

CH₃

CH₃(Bn)

CH₃

CH₃Li/CeCl₃

CH₃Li

5a

81

98:2

96:4

91:9^d

96:4

98:2

–

6a (6aa)

7a (7aa)

8a^e

5a

6a

66 (83)

59 (75)

82

59

0

PhCH₂

(E)-CH₃CH@CH

CH₃

CH₃Li

7a

52

95:4

a–c

See Table 1.

Determined by HPLC analysis (5

The assignment of absolute conﬁguration is by analogy to 5–7.

d

l

m SiO_2,250 ꢂ 4.5 mm).

e

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

1281

O

N

R²O

N

R²O

N

1. LiAlH₄

+

OCH₃

R¹

R¹CH₃

H

CH₃

2. R²OC(O)Cl

CH₃

H

9a-11a

5a-7a

5a'-7a'

Scheme 2.

With these results in hand, the structural diversity of the nucle-

ophile was surveyed for substitution level and hybridization. The

results in Table 3 demonstrate that nearly all types of simple orga-

nometallic reagents may be employed. Organocerium reagents de-

rived from primary, tertiary, vinyl, and aryllithium reagents

(entries 1, 3, and 5–7) were all employed effectively, as were

organocerium reagents derived from primary and secondary Grig-

nard reagents (entries 2 and 4). Only the acetylenic reagent (entry

8) derived from either metal failed to add. Because the individual

diastereomers of 12a–17a have not been independently prepared,

the indicated diastereoselectivities are minimal values calculated

by comparison with the next largest peak in the GC trace. The abso-

lute conﬁguration of the newly created stereogenic center was as-

sumed to arise from Re face approach of the nucleophile to the

azomethine by analogy with the results with CH₃Li/CeCl₃and the

results of the addition of various nucleophiles to other hydrazones

(vide infra). These data show that the structure of the incoming

nucleophile has only a slight effect on the diastereoselectivity of

the reaction. The same holds true for origin (magnesium or lith-

ium) of the organocerium reagent. The ability to use Grignard re-

agents in these additions greatly increases the generality of the

process.

anol. The air-sensitive hydrazines were isolated by extractive

workup and distillation and then subjected to hydrogenation in

methanol at 60 °C and 375 psi (autoclave). At this stage, separation

of the desired amine and the auxiliary is problematic. The Enders

procedure involves selective Schiff-base formation, chromatogra-

phy, and subsequent hydrolysis.³⁵Following these steps (ꢁ)-2-ami-

no-4-phenylbutane and (ꢁ)-2-amino-1-phenylpropane (amphet-

amine) were obtained from 1a and 2a, respectively, in 45% and

52% overall yield. The absolute conﬁgurations of these materials

were established as R by comparison of a_Dwith the literature val-

ues.⁵⁰The preferred addition to the Re-face of the SAMP-hydrazone

was conﬁrmed. This has been shown to be general in addition to

a,a-

dialkoxy SAMP-hydrazones as well.^41c

Although usually successful, this N–N bond cleavage protocol

suffers from a number of disadvantages. Primarily, the conditions

are rather harsh and reduction or hydrogenolysis of unsaturated

residues can become competitive. Further, certain chiral auxiliaries

cannot be cleaved, and under still more forcing hydrogenolytic

conditions, epimerization of the amine and the auxiliary occurred

(vide infra). A solution to some of these problems is provided by

the use of sonication in place of high pressure.^30cThe acylated

hydrazines can be cleaved using Li/NH₃for the preparation of pro-

tected amines that also allows for the ready recovery of the auxil-

iary in enantiomerically pure form.^41bBurk has also reported the

use of samarium diiodide for a similar cleavage.^4a

3.2. Hydrogenolysis of the N–N bond^37,48

The ultimate utility of this protocol for the synthesis of chiral

amines depends on the facility of cleavage of the N–N bond. The

efﬁciency of this process also will determine the practicality of

the method for recovery and reuse of the auxiliary. Initial attempts

to cleave the hydrazine carbamates were unsuccessful with a wide

range of reagents (H₂/Raney-Ni, H₂/Pd–C, Na(Hg), Zn/AcOH, TiCl₃,

and BH₃ꢀTHF). Ultimately it was found that the crude, air-sensitive

hydrazines could be hydrogenated over W-2 Raney nickel to afford

the free amines.⁴⁹Thus, after reaction with the organocerium re-

agent was deemed complete the reaction was quenched with meth-

3.3. Modiﬁed 2-alkoxypyrrolidine auxiliaries

To understand the origin of the high degree of diastereoselec-

tion observed in additions to SAMP-hydrazones and to develop a

more highly selective auxiliary, a series of (S)-proline-derived 2-

phenylethyl hydrazones was prepared and allowed to react with

the 1:1 combination of n-BuLi/CeCl₃. The auxiliary side chains were

chosen to evaluate various aspects of the side chain group: (1) the

spacing of potential metal complexing sites (methylene, ethylene

Table 3

RM/CeCl₃additions to hydrazone 1^a

O

N

H

1. RM/CeCl₃

CH₃O

Ph

N

CH₃O

Ph

N

OCH₃

+

2. CH₃OC(O)Cl

R

H

Ph

H

R

5a, 12a-17a

5a', 12a'-17a'

1a

Entry

R

M

Product

Yield^b(%)

dr^c(%)

1

2

3

4

5

6

7

8

CH₃

Li

MgBr

Li

MgBr

Li

5a

81

76

71

65

68

72

74

0

98:2

97:3

93:7

99:1^d

96:4

97:3

–

CH₃

n-Bu

i-Pr

t-Bu

Ph

12a

13a

14a^e

15a

16a

17a

(E)-i-Pr₃SiCH@CH

Ph(CH₃)₂SiCC

Li

a,b

See Table 1.

c

Determined by capillary GC analysis. See text for explanation.

GC analysis of crude hydrazine showed 15% of another material which may have been a diastereomer but did not protect.

Compound 14a is the unprotected hydrazine. The anionic hydrazine intermediate would not react with either CH₃OC(O)Cl or BnOC(O)Cl.

d

e

1282

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

Table 4

Addition of n-BuLi/CeCl₃to hydrazones 1a–1f^a

O

N

H

N

1. n -BuLi/CeCl₃

N

CH₃O

Ph

N

CH₃O

Ph

N

+

OR

n-Bu

H

Ph

2. CH₃OC(O)Cl

H

n-Bu

1a-1f

12a-12f

12a'-12f'

Entry

Hydrazone

R

Product

Yield^b(%)

dr^c(%)

1

2

3

4

1a

1b

1c

1d

1e

1f

CH₃

CH₂OCH₃

CH₂OCH₂CH₂OCH₃

CH₂CH₂OCH₃

CH₂CH₂N(CH₃)₂

H

12a

12b

12c

12d

12e

12f

71

70

75

72

61

75

93:7

85:15

97:3

5

90:10

6^d

70:30^e

a–c

See Table 1.

d

Reagent prepared from 3 equiv of n-BuLi, 2 equiv of CeCl₃. Isolated as the methyl carbonate. Yield refers to mixture of diastereomers.

Analyzed by HPLC (Supelco LC-CN, hexane/EtOAc/i-PrOH 98:1.5:0.5).

e

spacers), (2) the number of such sites (one to three), and (3) the ef-

reagents were combined with the ‘SAMEMP’ ((S)-1-Amino-2-(2⁰-

MethoxyEthoxy)MethylPyrrolidine) hydrazone 1d. The results are

shown in Table 5. Although t-BuLi/CeCl₃and n-BuLi/CeCl₃showed

increased selectivity, CH₃Li/CeCl₃and PhLi/CeCl₃afforded virtually

the same diastereoselectivity in additions to 1a and 1d.

Authentic samples of the minor diastereomers observed in

additions of the CH₃, t-Bu, and Ph cerium reagents to 1d were ob-

tained from the addition of PhCH₂CH₂Li/CeCl₃to the SAMEMP

hydrazones 19–21 followed by trapping with methyl chlorofor-

mate, as shown in Table 6. 2-Phenylethyllithium was prepared

by the addition of 2-phenylethyl iodide to an ethereal solution of

t-BuLi (2.0 equiv) at ꢁ100 °C.⁵³In each case, the major diastereo-

mer thus obtained was identical to the minor diastereomer ob-

served in the additions to 1d. The diastereoselectivities observed

in additions to 12–14 were uniformly high.

fects of non-ethereal sites (amine, alkoxide). The diastereoselectiv-

ity of the addition of n-BuLi/CeCl₃to each of the hydrazones 1b–1f

was compared to that of the parent SAMP-hydrazone 1a. The n-bu-

tyl nucleophile was chosen since it showed the lowest selectivity

in the study described above (Table 3). The required hydrazines

were prepared by standard methods in analogy with the prepara-

tion of SAMP reported by Enders.³⁶

The results of the addition of n-BuLi/CeCl₃to the hydrazones

1b–f are shown in Table 4, together with the result from the parent

system 1a. Adding a second ligating atom one methylene unit

away (1b, entry 2) had no effect on the selectivity of the reaction.

However, a third oxygen atom with an ethylene spacer (1c, entry 3)

lowered the selectivity. Reasoning that the methoxyethoxy unit

was an effective chelator, we moved that moiety two atoms closer

to the pyrrolidine ring (entry 4). Gratifyingly, hydrazone 1d reacted

more selectively than 1a. The lowest selectivity was observed with

hydrazone 1f bearing an alkoxide side-chain (entry 6).⁵¹Despite

the high afﬁnity of Ce(III) for nitrogen,⁵²n-BuLi/CeCl₃addition to

1e was less selective than that to the SAMP hydrazone 1a (entry

5). Authentic samples of each of the minor diastereomers observed

in the addition of n-BuLi/CeCl₃to 1b–f were obtained by reduction

of the corresponding ketone hydrazones, 18a–18f as described

above for the CH₃Li/CeCl₃addition to 1a (Scheme 3).

3.4. Additions to 2-alkylpyrrolidine hydrazones

The results of the foregoing study suggested the importance of

the side chain groups for high diastereoselectivity. A hypothesis

was formulated in which the approach of the nucleophile to the

azomethine linkage is directed by coordination of the cerium re-

agent to Lewis basic groups of the auxiliary side chain. To test this

hypothesis we examined the inﬂuence of 2-alkylpyrrolidine auxil-

iaries that bear no coordinating atoms in the side chain (e.g.,

methyl and isobutyl groups). The syntheses of the requisite hydra-

zones are outlined in Schemes 4 and 5. Thus, a methyl group was

incorporated by lithium aluminum hydride reduction of (S)-N,O-

bis(tosyl)prolinol⁵⁴22. Dissolving metal reductive detosylation of

To determine if the improved selectivity observed in the addi-

tion of n-BuLi/CeCl₃to 1d was general, a variety of organocerium

Table 5

Comparison of addition of RLi/CeCl₃to 1a and 1d^a

O

Table 6

N

H

N

1. RLi/CeCl₃

Addition of PhCH₂CH₂Li/CeCl₃to 19–21^a

N

CH₃O

Ph

N

O

R

CH₃O

2. CH₃OC(O)Cl

Ph

O

H

CH₃O

N

H

N

1d

1. PhCH₂CH₂Li/CeCl₃

2. CH₃OC(O)Cl

N

CH₃O

Ph

N

5d, 12d, 14d, 15d

O

H

CH₃O

R

Yield^b(%)

dr^c

97:3

>99:1

95:5

dr from 1a^d(%)

R

Entry

R

Product

CH₃O

1

2

3

4

CH₃

5d

78

72

87^e

78

98:2

93:7

96:4

5d', 14d', 15d'

19d-21d

n-Bu

t-Bu

Ph

12d

14d

15d

Entry

Hydrazone (R)

Product

Yield^b(%)

dr^c(%)

1

2

3

19d (CH₃)

20d (t-Bu)

21d (Ph)

5d⁰

14d⁰

15d⁰

53

96:4

98:2

97:3

a

b

c

See Section 6 for details.

60^d

80

Yield of pure major diastereomer after chromatography.

Determined by capillary GC (50 m, OV-17).

Results for reaction of 1a from Table 3.

d

e

a–c

See Table 5.

Compound 14d⁰is the unprotected hydrazine.

d

Compound 14d is the unprotected hydrazine.

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

1283

O

N

R²O

N

R²O

Ph

N

1. LiAlH₄

+

OR

H

n-C₄H₉

Ph

n-C₄H₉

2. R²OC(O)Cl

n-C₄H₉

H

18a-18f

12a-12f

12a'-12f'

Scheme 3.

23 afforded (R)-2-methylpyrrolidine 24.³⁶N-Nitrosation, reduc-

tion, and condensation of the resulting hydrazine with hydrocinna-

maldehyde afforded the 2-methylpyrrolidinyl hydrazone 25

(Scheme 4).

OH

ClCO₂Bn

95%

BH₃-THF

85%

CO₂H

N

H

N

Cbz

26

N

Cbz

27

CH₃

(COCl)₂

DMSO

Et₃N

H_2/Pd-C

75-85%

(CH₃)₂C=PPh₃

75-80%

OTs

Na/i -AmOH

LiAlH₄

CHO

N

Cbz

28

CH₃

N

Cbz

29

CH₃

N

Tos

22

N

H

24

~50%

Tos

23

77%

90-95%

CH₃

N

H

n -BuONO

~50%

CH₃

LiAlH₄

~50%

PhCH₂CH₂CHO

75-80%

1. n-BuONO

CH₃

N

CH₃

N

NO

N

NH₂

N

H

30

2. LiAlH₄

Ph

3.PhCH₂CH₂CHO

31

N

H

Scheme 5.

N

CH₃

and the amine thus obtained was derivatized with 3,5-dinitroben-

zoyl chloride to afford benzamide 33 in 51% overall yield from 25.

Comparison of the HPLC traces⁵⁶of 33 obtained from 25 and that of

an authentic sample of the racemate (prepared from the corre-

sponding N,N-dimethylhydrazone in 68% isolated yield) indicated

that this material consisted of a 94:6 mixture of enantiomers. That

the major product had the R conﬁguration was conﬁrmed by com-

parison with a sample of 33 obtained from n-BuLi/CeCl₃addition to

SAMP-hydrazone 1a (1a?33, 42% for three steps). The HPLC trace

of this sample was virtually identical to that obtained for the sam-

ple of 33 derived from 25. Thus, n-BuLi/CeCl₃addition to the 2-

methylpyrrolidine hydrazone 25 not only proceeded with the same

sense of asymmetric induction as n-BuLi/CeCl₃addition to SAMP-

hydrazone 1a but with the same magnitude as well!

Addition of n-BuLi/CeCl₃to 31 occurred readily, but trapping

with methyl chloroformate proved to be problematic.⁵⁷Efforts to

determine the diastereomeric ratio of the crude hydrazine product

by GC or HPLC were fruitless, as the compound was not stable to an

array of analytical conditions. Furthermore, the crude hydrazine

obtained from n-BuLi/CeCl₃addition was found to be remarkably

resistant to catalytic hydrogenation. Neither extremely high pres-

sure (2000 psi hydrogen) nor high temperatures (450 psi hydro-

gen, 100 °C) afforded acceptable (>30%) yields. Even more

disturbing was the ﬁnding that the recovered amine auxiliary 30

Ph

25

Scheme 4.

The 2-(isobutyl)pyrrolidinyl hydrazone 31 was also prepared al-

beit by a more lengthy route (Scheme 5). Borane reduction of the

(S)-N-carbobenzyloxyproline 26 followed by Swern oxidation of

Cbz-prolinol 27 afforded the aldehyde 28. Subsequent Wittig olef-

ination afforded the alkene 29. Hydrogenation of 29 over palla-

dium on carbon simultaneously reduced the alkene and removed

the carbobenzyloxy group affording 30. The amine 30 was typically

obtained in 80:20–90:10 er.⁵⁵N-Nitrosation, reduction, and con-

densation of the resulting hydrazine with hydrocinnamaldehyde

afforded the target hydrazone 31.

The 2-methylpyrrolidinyl hydrazone 25 was examined ﬁrst.

Treatment of 25 with n-BuLi/CeCl₃followed by trapping with

methyl chloroformate afforded 32 in 64% isolated yield (Scheme 6).

Both GC and HPLC analysis of the crude and isolated products

showed a single peak. In addition, the ¹H and ¹³C NMR spectra of

this material were consistent with the presence of only one diaste-

reomer. In a separate experiment, 25 was treated with n-BuLi/

CeCl₃and the reaction was quenched with methanol. The crude

product was then subjected to hydrogenation over Raney nickel,

O

N

1. n-BuLi/CeCl₃

CH₃O

Ph

N

CH₃

n-Bu

Ph

H

2. ClCO₂CH₃

64%

H

25

32

O

N

H

N

HN

Aryl

n -Bu

1. Raney Ni/H₂

2. 3,5-DNBCl

n-BuLi/CeCl₃

CH₂R

Ph

H

1a: R=OCH₃

25: R=H

33 Aryl = 3,5-C₆H₃(NO₂)₂

94:6 er from each

Scheme 6.

1284

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

was partially epimerized under the N–N bond cleavage conditions,

thus invalidating the connection between the enantiomeric ratio of

the products and the diastereomeric ratio of the hydrazines.

Fortunately, the crude hydrazine could be functionalized by

treatment with neat, thoroughly degassed, acetic anhydride at re-

ﬂux for 10 h. The acetyl hydrazide 34 was isolated in 83% yield

(Scheme 7). As with the carbamate 32 mentioned above, 34 ap-

peared to be a single diastereomer by GC and HPLC analyses. Cleav-

age of the N–N bond with 4 equiv of lithium metal in reﬂuxing

liquid ammonia afforded the crystalline amide 34 in greater than

95% yield.^41dTo avoid enantiomeric enrichment of this crystalline

material, it was not puriﬁed, but deprotected (ðCH₃Þ O^þBF ^ꢁ/DME,

these variables are depicted in Figure 1. For the purposes of discus-

sion, the azomethine nitrogen will be referred to as ‘digonal’ (two

covalently attached moieties), while the ring nitrogen will be re-

ferred to as ‘trigonal’ (three covalently attached moieties).

π

N

dig

N

R₁

H

R₁

trig

N

R

H

N

R

azomethine

ring

metal binding

sites

orientation

conformations

3

4

then 6 N HCl, reﬂux) and functionalized as its 3,5-dinitrobenzam-

ide 33 in 55% overall yield from 35. This amide had an 88:12 er

(R) from the pyrrolidine auxiliary of 90.5:9.5 er (S), indicating that

34 was a 97:3 mixture of diastereomers (i.e., 94% diastereospeciﬁc-

ity). Thus, the 2-(isobutyl)pyrrolidine auxiliary was shown to be as

effective as SAMEMP in controlling the diastereofacial selectivity in

the addition of n-BuLi/CeCl₃with the same sense of asymmetric

induction.

Figure 1. Hydrazone structural attributes for consideration.

Although little information is available on the conformation of

pyrrolidine hydrazones, other types of hydrazones have been stud-

ied. Of the two limiting conformations for N,N-dialkyl hydrazones,

i and ii (Fig. 2), it is generally accepted⁵⁸that the ground state con-

formation of aldehyde hydrazones (R¹= H) is i, because of favorable

overlap of the trigonal (‘trig’) nitrogen lone pair with the azomethine

p-system. For ketone hydrazones, ii is the preferred conformation

because of A^1,3strain between R¹and R². Enders et al.^58chave dem-

onstrated that this situation holds for SAMP-hydrazones as well. For

the sake of discussion, conformations similar to i will be referred to

as ‘0°’ conformations in recognition of the approximate torsional an-

gle between the carbon–nitrogen double bond and the nitrogen–al-

kyl single bond (i.e., N–R²). Likewise, conformations similar to ii will

be referred to as ‘90°’ conformations.

O

N

H

N

CH₃

N

CH₃

Ph

N

1. n-BuLi/CeCl₃

CH₃2. Ac₂O, heat

83%

Ph

n-Bu

H

31 (90.5:9.5 er)

34

O

HN

Aryl

n-Bu

HN

CH

-

Li/NH₃

³1. (CH₃)₃O⁺BF₄

2. HCl

n-Bu

R³

R²

R

N

Ph

R¹

N

H

R²

R³

3. 3,5-DNBCl

i

ii

33 Aryl = 3,5-C₆H₃(NO₂)₂

35

88:12 er

Figure 2. Limiting hydrazone azomethine conformations.

Scheme 7.

Several X-ray crystallographic analyses of pyrrolidine hydra-

zones have been reported. Enders et al. obtained the X-ray crystal

structure of SAMP-ketone–hydrazone 36 to verify a stereochemical

assignment.⁵⁹Ehlers and tom Dieck obtained the X-ray crystal

structure of the molybdenum tetracarbonyl-complexed RAMP-

aldehyde–hydrazone 37 in the context of planned enantioselective

catalysis studies (Fig. 3).⁶⁰Beck et al. prepared SAMP complexes of

a number of transition metals (Rh, Ru, Pd, and Ir) and obtained X-

ray crystallographic analyses on two such structures bound

through the NH₂group. These authors also prepared Ir, Ru, and

4. Discussion

These studies served to clarify the factors responsible for the

diastereoselectivity observed in the addition of organocerium re-

agents to chiral 2-alkylpyrrolidine hydrazones. The results ob-

tained with SAMEMP-hydrazones 1d and 19d–21d veriﬁed the

generality of the addition of organocerium reagents to hydrazones

of variable structure and demonstrated that the SAMEMP auxiliary

consistently affords products with greater than 95:5 dr with a wide

range of nucleophile structures. However, the results of the addi-

tion of n-BuLi/CeCl₃to 25 and 31 demonstrated that the origin of

diastereoselectivity cannot be due to delivery of the nucleophile

from reagent bound to the auxiliary side-chain, because 25 and

31 have no such binding sites, yet still undergo highly diastereose-

lective additions.

Pd complexes of SAMP hydrazones prepared from a-keto carboxyl-

ates and obtained an X-ray structural analysis of the iridium com-

plex, 38.⁶¹Finally, Albrecht et al. prepared complexes of seven

different lanthanide salts with bis-SAMP ligand 39. No X-ray crys-

tallographic analysis could be obtained, but the structures could be

secured by spectroscopic methods.⁶²

In formulating a rationalization of these results, a number of

variables can be discounted in light of the data obtained herein:

(1) the structure of the reagent: CH₃Li and various CH₃Ce reagents

afford approximately the same diastereoselection in additions to 1,

(2) the conformation of the auxiliary side-chain: addition of n-

BuLi/CeCl₃to 25 affords adduct with 94:6 dr, and (3) the hydrazone

alkyl backbone: addition of PhCH₂CH₂Li/CeCl₃to 21d affords ad-

duct with 96.5:3.5 dr. Any proposed rationale must not rely on

any of these variables to explain the observed stereoinduction.

Nevertheless, a number of other factors must be considered includ-

ing: (1) the conformation of the ﬁve-membered ring, (2) potential

binding sites for the organometallic reagent, (3) the orientation of

the azomethine moiety, (4) the conﬁguration of the pyrrolidine-

nitrogen atom of the hydrazone, and (5) intra- or inter-complex

delivery of the nucleophile. Examples of possibilities for each of

As expected, the hydrazone moiety in 36 adopts an approximate

‘90°’ conformation. In addition, the conformation of the pyrrolidine

ring is such that the nitrogen atom is the ‘ﬂap’ of the ‘envelope’ of

the ﬁve-membered ring, and both the methoxymethyl side-chain

and the azomethine are pseudo-equatorial. The structures 37 and

38 are particularly enlightening. In 37, the N–N bond adopts a

P

‘0°’ conformation and the ring nitrogen is planar

gles = 359.9°) whereas in 38 the N–N bond approximates a ‘90°’

(

an-

P

conformation, and the ring nitrogen is highly pyramidalized (

angles = 337.1°). Hydrazones bound to metal centers via the azo-

methine nitrogen (‘dig’) are known with both planar⁶³and pyrami-

dal⁶⁴nitrogen atoms, hence the binding of the digonal nitrogen

atom to a metal center does not always result in a planar trigonal

nitrogen atom. In addition, binding via the digonal nitrogen is obvi-

ously favored by the formation of the ﬁve-membered ring chelate,

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

1285

thus metal coordination to the trigonal nitrogen cannot be ruled

out. Nevertheless, the apparent lack of characterized hydrazone

(trigonal nitrogen-bound) metal complexes strongly suggests that

complexation to the digonal nitrogen is preferred.

only removes R¹farther from the azomethine, thus the ‘90°’ confor-

mations (vi and vii) seem even less likely to lead to highly selective

additions.

R¹

Met

N

Met

N

Met

N

R

H

R

H

R

H

N

R¹

OCH₃

OC CO

OCH₃

CH₃

OC Mo CO

Ir

N

R¹

Cl

vi

v

vii

N

O

N N

OCH₃

Figure 5. Proposed reactive complexes: dig nitrogen–bound metal/pyramidal trig

H

CH₃

Ph Ph

O

nitrogen.

37

38

36

As mentioned previously, binding of the metal center to the ring

nitrogen is also possible. In this scenario, the conﬁguration of the

ring nitrogen takes on added importance, as the metal can be

bound either syn to R¹or anti to R¹(Fig. 6, viii). In addition, in-

tra-complex delivery of the nucleophile is much more likely, as a

ﬁve-membered ring transition structure would be involved. Final-

ly, the favorable overlap between the lone pair of the ring nitrogen

N

H

39

CH₃O

OCH₃

Figure 3. Crystallographically characterized pyrrolidine hydrazones.

and the

p-system of the azomethine cannot contribute signiﬁ-

cantly to the energy of the complex, because the lone pair is in-

volved in the binding to the metal.

In the absence of detailed mechanistic data, it seems reasonable

to adopt known structural data to the reaction at hand to at least

determine if such data can rationalize experimental results. Unfor-

tunately, adaptation of the RAMP-hydrazone/molybdenum tetra-

carbonyl structure to an organocerium addition is not

encouraging (Fig. 4, iii). As can be seen in two different perspec-

tives of such a complex (iiia and iiib), the stereocenter is far re-

moved from the azomethine carbon and is unlikely to be able to

exert any inﬂuence over the approach of a nucleophile. However,

the metal center in this complex will undoubtedly be part of an

aggregate structure of some type and bear a number of ligands (al-

kyl, tetrahydrofuran, etc.) larger than the carbon monoxide ligands

on molybdenum in 37. Thus, steric interactions between the li-

gands on the metal center and R¹may destabilize iii. Maintaining

a ‘0°’ conformation while avoiding this interaction requires a

180° rotation about the N–N bond (iv). In this conformation, R¹is

obviously much closer to the azomethine carbon, effectively

shielding the Si-face. Addition of the nucleophile to the sterically

less-encumbered Re-face leads to the observed major diastereo-

mer. This scenario requires an external nucleophile that is an alkyl

group not bound to the metal attached to the digonal nitrogen.

Inspection of various complexes with the metal bound anti to R¹

does not lead to a clear-cut rationale for diastereofacial selectivity

even for intramolecular delivery of the nucleophile (Fig. 6, viii, for

example). However, for the complex in which the metal is bound

syn to R¹, the picture becomes much clearer. For intra-complex

delivery of the nucleophile, ix would obviously be preferred to

avoid the interactions of R¹with both the azomethine moiety

and the nucleophile in x. Transition structure ix correctly predicts

Re-face attack. Furthermore, reaction via x would lead to severe

steric interactions for even small R¹groups, such as the methyl

group in 24. Thus, this hypothesis does not require a speciﬁc re-

agent structure nor a particularly large side-chain.

R

Nuc

H

N

Met

N

Met

N

H

N

Nuc

R

Met

N

R¹

R

H

viii

ixb

ixa

Met

N

Nuc

R¹

H

Nuc

R¹

N

R¹

H

R

Met

N

R

H

Met

N

H

xa

xb

N

iiib

N

R¹

R

Figure 6. Proposed reactive complexes: trig nitrogen–bound metal.

iiia

It would be imprudent at best to suggest that a hypothesis con-

cerning an event with only two possible outcomes is somehow ver-

iﬁed by a correct prediction. However, any hypothesis that makes a

correct prediction in such a situation is at least worthy of discus-

sion. Both the digonal nitrogen-bound hydrazone complex iv

(Hypothesis A) and the trigonal nitrogen-bound hydrazone com-

plex x (Hypothesis B) appear to be reasonable proposals for ratio-

nalizing the observed diastereoselectivity in that both are

consistent with the data in hand. Furthermore, Hypothesis A is

consistent with the proposal of Reetz^29athat organocerium addi-

R

H

Met

N

Met

N

H

N

R¹

R

H

iva

ivb

Figure 4. Proposed reactive complexes: dig nitrogen–bound metal/planar trig

nitrogen.

However, if the ring nitrogen is pyramidal, a number of new

variables emerge. Both ‘0°’ and ‘90°’ conformations are accessible

and the trigonal nitrogen is pyramidal and is thus a stereogenic

center. If the azomethine moiety is in a ‘0°’ conformation, the anal-

ysis is analogous to that described above for a planar ring nitrogen

(Fig. 5, v). Inspection of molecular models, however, suggests that

R¹does not sufﬁciently block Si-face approach of nucleophiles. In

addition, rotation of the N–N bond away from the ‘0°’ conformation

tions to

a-amino imines proceed via a ‘Cram-chelate’ transition

state, which requires coordination of a digonal nitrogen atom with

the organocerium reagent.

The hypotheses described above became necessary due to the

surprisingly high level of diastereoselectivity exerted by a non-

chelating chiral auxiliary. This outcome is not without precedent.

Rawson and Meyers⁶⁵have demonstrated that a similar situation

1286

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

holds for alkyllithium additions to chiral 2-(1-naphthyl)-oxazo-

lines. Nucleophilic addition of various alkyllithiums to tert-leucin-

ol-derived 2-(1-naphthyl)-oxazoline 40 affords adducts with

greater than 95:5 dr (Scheme 8). These authors postulate that

Analytical thin-layer chromatography was performed on Merck

silica gel plates with F-254 indicator. Visualization was accom-

plished by UV light, iodine, or para-anisaldehyde solution. Solvents

for extraction and chromatography were of technical grade and

distilled from the indicated drying agents: dichloromethane

(CH₂Cl₂), pentane, hexane: CaCl₂; diethyl ether (Et₂O), t-butyl

methyl ether (TBME): CaSO₄/FeSO₄; ethyl acetate (EtOAc): K₂CO₃.

Column chromatography was performed by the method of Still⁶⁶

with 32–63 mm silica gel (Woelm). Analytical gas chromatography

(GC) was performed on either a Varian 3700 or a Hewlett–Packard

5890 gas chromatograph equipped with a variable-temperature

program and a ﬂame ionization detector. The columns used were

a Hewlett–Packard 50-m OV-17 capillary column (column A), a

Hewlett–Packard 50-m HP-5 capillary column (column B), and a

Hewlett–Packard 50-m HP-101 capillary column (column C). The

injector temperature was 225 °C, the detector temperature was

300 °C, and the column head pressure was 17.5 psi. Temperature

programs are reported in the following form: initial temperature,

°C (time, min), temperature ramp rate (deg/min), ﬁnal tempera-

ture, °C (time, min). Retention times (t_R) and integrated ratios were

obtained from either a Hewlett–Packard 3390A recorder (column

A) or a Hewlett–Packard 3393A recorder (columns B and C). Ana-

lytical high-pressure liquid chromatography (HPLC) was per-

formed on a Hewlett–Packard 1090 liquid chromatograph with a

Perkin-Elmer LC-75 Spectrophotometric Detector. The columns

used were a Supelco LC-CN 5-m column (column 1), a Pirkle Cova-

the lithium reagent coordinates to the

p-system of the oxazoline

on the face opposite the t-butyl group; delivery of the nucleophile

to this face affords the observed major diastereomer. Notably, the

alanine-derived oxazoline (methyl substituent instead of t-butyl)

affords only moderate selectivity (75:25 dr), in contrast to the re-

sults herein with a methyl substituent, 25 (94:6 dr).

Me

N

Me

N

Me

O

H₃C

1. RLi

R

2. CH₃I

40

Scheme 8.

Thus, it seems clear that there is now ample precedent for the

possibility that other stereoselective organic transformations be-

lieved to be under chelation control may instead be strictly under

steric approach control. The ramiﬁcations for the design of more

selective auxiliaries for such transformations are self-evident.

lent

L

-N-(2-napthyl)alanine (column 2),⁶⁷an experimental chiral

-N-(1-napthyl)leucine) (column

stationary phase derived from

L

3),⁶⁸and a Supelco LC-Si 5-m column (column 4). The detector

wavelength was set to 254 nm. Retention times (t_R) and integrated

ratios were obtained from a Hewlett–Packard 3390A recorder.

Melting points (mp) were determined on a Thomas–Hoover capil-

lary melting point apparatus and are uncorrected. Bulb-to-bulb

(‘Kugelrohr’) distillations were done on a Buchi GKR-50 Kugelrohr

and boiling points (bp) correspond to uncorrected air bath temper-

atures. Organolithium reagents were titrated by the method of

Gilman.⁶⁹All reactions were performed under a dry nitrogen or

argon atmosphere in oven- and/or ﬂame-dried glassware, except

for those reactions utilizing water as a solvent, which were run

in air. ‘Brine’ refers to a saturated aqueous solution of NaCl. Unless

otherwise speciﬁed, solutions of NH₄Cl, NaHCO₃, KOH, NaOH, and

Na₂S₂O₃are aqueous solutions.

5. Conclusions

The studies described above demonstrate that organocerium

additions to SAMP aldehyde hydrazones are very efﬁcient and

highly diastereoselective. Reductive cleavage of the carbamate or

hydrazide products affords enantiomerically enriched amines in

protected form in a straightforward fashion. The use of organoceri-

um reagents (as opposed to Grignard or organolithium reagents)

provides superior yields in the addition step. Since the initial re-

port, organocerium reagents have found widespread use in addi-

tions to a variety of imine derivatives, demonstrating that these

reagents have sparked renewed interest in organometallic addi-

tions to C–N double bonds as a route to a-branched amines.

6. Experimental

The following compounds were prepared by literature methods:

(S)-prolinol,^36f(S)-N-nitrosoprolinol,^36e(S)-N-formylprolinol,^36f

(S)-1-amino-2-methoxymethyl-pyrrolidine (SAMP),^36fdimethyl-

6.1. General experimental

phenylsilyl-acetylene,⁷⁰

(E)-2-triisopropylsilylethenyllithium,⁷¹

¹H and ¹³C NMR spectra were recorded on a General Electric QE-

300 (300 MHz ¹H, 75.5 MHz ¹³C) spectrometer in deuteriochloro-

form (CDCl₃) with either tetramethylsilane (TMS) (0.00 ppm ¹H,

0.00 ppm ¹³C) or chloroform (7.26 ppm ¹H, 77.00 ppm ¹³C) as an

internal reference unless otherwise stated. Data are reported in

the following order: chemical shifts are given (d); multiplicities

are indicated (br (broadened), s (singlet), d (doublet), t (triplet), q

(quartet), m (multiplet), exch (exchangeable)); coupling constants,

J, are reported (Hz); integration is provided; and assignment is

indicated. Infrared spectra were recorded on an IBM FTIR-32 spec-

trometer. Peaks are reported (cm^ꢁ1) with the following relative

intensities: s (strong, 67–100%), m (medium 40–67%), w (weak

20–40%), and br (broad). Mass spectra were obtained by the Uni-

versity of Illinois Mass Spectroscopy Center on a Varian MAT CH-

5 spectrometer with ionization voltages of 70 and 10 eV. Data are

reported in the form m/e (intensity relative to base = 100). Optical

(S)-N-carbobenzyloxyproline,⁷²isopropyl(triphenyl)-phosphonium

bromide,⁷³(S)-N,O-ditosylprolinol,⁵⁴(R)-2-methyl-1-tosylpyrro-

lidine.⁵⁴

6.2. General procedure for the preparation of the hydrazones

6.2.1. Procedure I (aldehydes)

To 1.00 mmol of the hydrazine 49 (see below) cooled to 0 °C in a

round-bottomed ﬂask was added slowly 1.5–2.0 equiv of the requi-

site aldehyde. The neat mixture was stirred for 15 min at 0 °C, then

7–8 h at room temperature. The reaction mixture was then poured

into 50 mL of EtOAc/H₂O, 6:1. The organic phase was separated,

dried (Na₂SO₄), and concentrated. The crude hydrazone was then

puriﬁed by silica gel column chromatography and/or distillation

to give the pure hydrazone.

rotations were obtained on a Jasco DIP-360 Digital Polarimeter and

6.2.2. Procedure II (ketones)

temperature

are reported as follows: ½

a

ꢃ

, (concentration in g/100 mL,

An equimolar mixture of the hydrazine 49 and ketone in anhy-

drous benzene (10 mL/ mmol of ketone) was heated under reﬂux

for ca. 20 h with water removal via a Dean Stark trap. The mixture

wavelentgh

solvent). Elemental analyses were performed by the University of

Illinois Microanalytical Service Laboratory.

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

1287

was then worked up and the product was isolated and puriﬁed as

in procedure I. For the hydrazone 3o, a THF solution of the hydra-

zine 2e, ketone 1h, and trimethyl orthoformate were heated under

reﬂux for ca. 20 h and then worked up as above.

3.3–3.75 (m, 4H, H₂C(1⁰), HC(2), HC(5)), 3.05 (m, 1H, HC(5)), 1.96

(m, 4H, H₂C(3), H₂C(4)); IR (neat) 3854 (w), 3671 (w), 3055 (m),

3024 (m), 2974 (s), 2878 (s), 2357 (w), 1734 (w), 1701 (w), 1684

(w), 1585 (s), 1558 (s), 1458 (m), 1447 (s), 1375 (m), 1340 (s), 1323

(m), 1306 (m), 1282 (m), 1242 (m), 1194 (s), 1151 (m), 1120 (s),

1070 (m), 1024 (m), 972 (m), 914 (m) cm^ꢁ1; MS (70 eV) m/z 218

(M⁺, 10), 174 (13), 173 (100), 77 (21), 70 (73), 43 (20), 41 (13),

32 (26); TLC R_f0.34 (hexane/EtOAc, 6:1). Anal. Calcd for C₁₃H₁₈N₂O:

C, 71.53; H, 8.31; N, 12.83. Found: C, 71.26; H, 8.17; N, 12.76.

6.2.3. (S)-2-Methoxymethyl-1-(3-phenylpropylidenamino)pyrro-

lidine 1a

From 1.335 g (10.0 mmol) of hydrocinnamaldehyde and 1.30 g

(10.0 mmol) of SAMP was obtained 1.84 g (75%) of 1a as a clear,

colorless oil after chromatography (hexane/EtOAc, 8:1) and distil-

lation. Data for 1a: bp 90 °C (0.03 mm Hg); ¹H NMR (200 MHz) d

7.25 (m, 5H, Ph), 6.65 (t, J = 5.3, 1H, HC@N), 3.37 (s, 3H, OCH₃),

3.55–3.25 (m, 4H, H₂C(1⁰), HC(2), HC(5)), 2.68 (m, 3H, HC(5),

H₂C(3⁰⁰)), 2.55 (m, 2H, 2HC(2⁰⁰)), 1.90 (m, 4H, H₂C(3), H₂C(4)); IR

(neat) 3085 (m), 3061 (m), 3024 (m), 2924 (s), 1734 (w), 1653

(w), 1559 (w); 1539 (w), 1452 (s), 1495 (s), 1338 (m), 1603 (m),

1302 (m), 1281 (m), 1196 (s), 1117 (s), 1030 (m), 972 (m), 904

(m) cm^ꢁ1; MS (70 eV) m/z 246 (M⁺, 4), 202 (15), 201 (100), 105

(12), 104 (13), 92(12), 91(32), 77 (10), 70 (46), 43 (13), 41 (12);

TLC R_f0.13 (hexane/EtOAc, 6:1). Anal. Calcd for C₁₅H₂₂N₂O: C,

73.13; H, 9.00; N, 11.37. Found: C, 72.99; H, 9.22; N, 11.24.

6.2.8. (S)-2-Methoxymethyl-1-(1-phenylethylidenamino)pyrro-

lidine 11a. Procedure II

From 1.32 g (11.0 mmol) of acetophenone and 1.15 g

(8.8 mmol) of SAMP was obtained 770 mg (40%) of 11a as a clear,

colorless oil after chromatography (hexane/EtOAc, 8:1). Data for

11a: ¹H NMR (200 MHz) d 7.80–7.70 (m, 2H, Ph), 7.40–7.30 (s,

3H, Ph), 3.60–3.20 (m, 4H, H₂C(1⁰), HC(2), HC(5)), 3.35 (s, 3H,

OCH₃), 2.60–2.50 (m, 1H, HC(5)), 2.25 (s, 3H, CCH₃), 3.25–1.60

(m, 4H, H₂C(3), H₂C(4)); TLC R_f0.28 (hexane/EtOAc, 6:1).

6.2.9. (S)-1-(E-2-Butenylidenamino)-2-(methoxymethyl)pyrroli-

dine 4a. Procedure I

6.2.4. (S)-(ꢁ)-1-[1-Methyl-3-phenylpropylideneamino]-2-(metho-

xymethyl)pyrrolidine 9a. Procedure II

From 1.65 mL (20.0 mmol) of (E)-2-butenal and 2.60 g

(20.0 mmol) of SAMP was obtained 2.06 g (57%) of 4a as a clear,

colorless oil after distillation. Data for 4a: bp 110 °C (0.3 mm Hg);

¹H NMR (300 MHz) d 6.99 (d, J = 9, 1H, HC@N), 6.23–6.15 (m, 1H,

HC(1⁰)), 5.82–5.70 (m, 1H, HC(2⁰)), 3.60–3.34 (m, 4H, CH₂O, HC(2),

HC(5)), 3.37 (s, 3H, OCH₃), 2.90–2.82 (m, 1H, HC(5)), 2.02–1.79

(m, 7H, H₂C(3), H₂C(4), CCH₃); ¹³C NMR (75 MHz) d 136.59, 130.39,

129.18, 74.51, 63.02, 59.09, 49.42, 26.58, 22.13, 18.13; IR (neat)

2966–2731 (s), 1716 (w), 1560 (s), 1448 (s), 1367 (m), 1340 (s),

1304 (m), 1282 (m), 1197 (s), 1120 (s), 1072 (m), 968 (s), 933 (m),

900 (m) cm^ꢁ1; MS (70 eV) m/z 182 (M⁺, 18), 138 (9), 137 (100),

From 0.60 g (4.0 mmol) of 4-phenyl-2-butanone and 0.53 g

(4.0 mmol) of SAMP was obtained 937 mg (90%) of 9a as a clear,

colorless oil after chromatography (hexane/EtOAc, 4:1) and distil-

lation. Data for 9a: bp 90 °C (0.01 mm Hg); ¹H NMR (200 MHz) d

7.28–7.17 (m, 5H, Ph), 3.32 (s, 3H, OCH₃), 3.3–3.0 (m, 4H,

H₂C(1⁰), HC(2), HC(5)), 2.85 (m, 2H, H₂C(3⁰⁰)), 2.55 (m, 2H,

H₂C(2⁰⁰)), 2.4–2.2 (m, HC(5)), 1.90 (s, 3H, CH₃), 1.70–2.1 (m, 4H,

H₂C(3), H₂C(4)); IR (neat) 3061 (w), 3026 (m), 2922 (s), 2874 (s),

1718 (w), 1635 (w), 1603 (w),1558 (w) 1495 (m), 1454 (s), 1358

(m), 1279 (w), 1197 (m), 1129 (s), 1063 (m), 1030 (w), 970 (w),

918 (w) cm^ꢁ1; MS (70 eV) m/z 260 (M⁺, 3), 216 (16), 215 (100),

117 (11), 105 (96), 91 (26), 79 (11), 45 (11); TLC R_f0.21 (hexane/

EtOAc, 4:1). Anal. Calcd for C₁₆H₂₄N₂O (260.38): C, 73.52; H,

9.64; N, 10.72. Found: C, 73.72; H, 9.59; N, 10.69.

70 (19); [

a

]

_D= ꢁ138.5 (c 1.58 CHCl₃). Anal. Calcd for C₁₀H₁₈N₂O:

C, 65.90; H, 9.95; N, 15.35. Found: C, 65.66; H, 10.05; N, 15.08.

6.2.10. (S)-2-(Methoxymethoxymethyl)-1-(3-phenylpropylidena-

mino)pyrrolidine 1b. Procedure I

From 0.493 g (3.67 mmol) of hydrocinnamaldehyde and 0.321 g

(2.0 mmol) of hydrazine 49b was obtained 389 mg (71%) of 1b as a

clear, colorless oil after chromatography (hexane/EtOAc, 5:1) and

distillation. Data for 1b: bp 140 °C (0.04 mm Hg); ¹H NMR

(300 MHz) d 7.30–7.10 (m, 5H, Ph), 6.63 (t, J = 5.3, 1H), 4.61 (s,

2H, H₂C(3⁰)), 3.75–3.55 (m, 2H, H₂C(1⁰)), 3.45–3.25 (m, 1H,

HC(5)), 3.33 (s, 3H, OCH₃), 2.80–2.65 (m, 4H), 2.54–2.45 (m, 2H),

2.00–1.70 (m, 4H, H₂C(3), H₂C(4)); ¹³C NMR (75 MHz) d 141.42,

137.16, 128.26, 128.13, 125.65, 96.52, 69.32, 63.15, 54.98, 49.91,

34.60, 33.92, 26.43, 21.83; IR (neat) 3062 (w), 3026 (m), 2926

(m), 2880 (m), 1603 (w), 1496 (m), 1453 (m), 1209 (m), 1149 (s),

1111 (s), 1044 (s), 965 (m), 918 (m) cm^ꢁ1; MS (70 eV) m/z 276

(M⁺, 7), 202 (15), 201 (100), 91 (22), 69 (20), 45 (19); TLC R_f0.18

(hexane/EtOAc, 5:1). Anal. Calcd for C₁₆H₂₄N₂O₂: C, 69.55; H,

8.75; N, 10.13. Found: C, 69.40; H, 8.85; N, 10.09.

6.2.5. (S)-2-Methoxymethyl-1-(3-phenylethylidenamino)pyrroli-

dine 2a. Procedure I

From 0.60 g (5.0 mmol) of phenylacetaldehyde and 0.65 g

(5.0 mmol) of SAMP was obtained 753 mg (66%) of 2a as a clear,

colorless oil after distillation. Data for 2a:^36a¹H NMR (200 MHz)

d 7.15 (m, 5H, Ph), 6.68 (t, J = 5, 1H, HC@N), 3.39 (s, 3H, OCH₃),

3.71–3.27 (m, 6H, H₂C(1⁰), HC(5), HC(2), H₂C(2⁰⁰)), 2.75 (m, 1H,

HC(5)), 1.90 (m, 4H, H₂C(3), H₂C(4)); IR (neat) 3065 (w), 3030

(m), 2976 (s), 2880 (s), 2828 (s), 1704 (m), 1635 (m), 1599 (m),

1495 (s), 1454 (s), 1429 (w), 1365 (m), 1340 (s), 1197 (s), 1120

(s), 1030 (w), 974 (m), 931 (w), 904 (w), 804 (w) cm^ꢁ1; TLC R_f

0.16 (hexane/ EtOAc, 6:1).

6.2.6. (S)-2-Methoxymethyl-1-(1-methyl-2-phenylethylidenamino)-

pyrrolidine 10a. Procedure I

From 0.402 g (3.0 mmol) of 1-phenyl-2-propanone and 0.38 g

(2.9 mmol) of SAMP was obtained 320 mg (49%) of 10a as clear col-

orless oil. The spectroscopic data matched those reported in the

literature.^36c

6.2.11. (S)-1-(1-Butyl-3-phenylpropylidenamino)-2-(methoxy-

methoxymethyl)pyrrolidine 18b. Procedure II

From 0.380 g (2.0 mmol) of 1-phenyl-3-heptanone 41 and

0.160 g (1.0 mmol) of hydrazine 49b was obtained 70 mg (21%)

of 18b as a clear, colorless oil after chromatography and distilla-

tion. Data for 18b: bp 150 °C (0.2 mm Hg); ¹H NMR: (300 MHz) d

7.27–7.16 (m, 5H, Ph), 4.70–4.60 (m, 2H, OCH₂O), 3.60–1.20 (m,

22H), 1.00–0.80 (m, 3H, CCH₃); IR (neat) 3063 (w), 3028 (w),

2955 (s), 2930 (s), 1605 (w), 1496 (w), 1454 (m), 1379 (w), 1213

(w), 1151 (m), 1113 (m), 1045 (s), 966 (w), 920 (m) cm^ꢁ1; MS

(70 eV) m/z 257 (6), 148 (12), 140 (100), 125 (12), 111 (14), 105

(19), 91 (11), 85 (14), 70 (22), 57 (14).

6.2.7. (S)-(ꢁ)-1-Benzylideneamino-2-(methoxymethyl)pyrroli-

dine 3a. Procedure I

From 0.182 g (1.7 mmol) of benzaldehyde and 0.203 g

(1.6 mmol) of SAMP was obtained 212 mg (62%) of 3a as a clear,

colorless oil after chromatography (hexane/EtOAc, 6:1) and distil-

lation. Data for 3a: bp 100 °C (0.01 mm Hg); ¹H NMR (200 MHz)

d 7.5 (s, 1H, HC@N), 7.25–7.56 (m, 5H, Ph), 3.4 (s, 3H, OCH₃),

1288

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

6.2.12. (S)-2-[(2-Methoxyethoxy)methoxymethyl)]-1-(3-phenyl-

propylidenamino)-pyrrolidine 1c. Procedure I

6.2.16. (S)-2-[(2-N,N-Dimethylaminoethoxy)methyl]-1-(3-phenyl-

propylidenamino)-pyrrolidine 1e. Procedure I

From 1.00 g (7.45 mmol) of hydrocinnamaldehyde and 0.817 g

(4.0 mmol) of hydrazine 49c was obtained 565 mg (44%) of 1c as

a clear, colorless oil after chromatography (hexane/EtOAc, 6:1)

and distillation. Data for 1d: bp 200 °C (0.5 mm Hg); ¹H NMR

(300 MHz) d 7.28–7.18 (m, 5H, Ph), 6.70–6.60 (m, 1H, HC@N),

4.80–4.70 (m, 2H, OCH₂O), 3.80–3.50 (m, 7H, HC(2), H₂C(1⁰),

H₂C(5⁰), H₂C(6⁰)), 3.39 (s, 3H, OCH₃), 3.39–3.30 (m, 1H, HC(5)),

2.90–2.70 (m, 3H, H₂C(3⁰⁰), HC(5)), 2.60–2.50 (m, 2H, H₂C(2⁰⁰)),

2.05–1.75 (m, 4H, H₂C(3), H₂C(4)); ¹³C NMR (75 MHz) d 141.49,

137.22, 128.30, 128.17, 125.70, 95.66, 71.66, 69.44, 66.60, 63.20,

58.88, 49.99, 34.66, 33.96, 26.45, 21.88; IR (neat) 3025 (m), 2924

(s), 2877 (s), 1603 (w), 1496 (m), 1453 (m), 1365 (w), 1340 (m),

1303 (w), 1279 (w), 1242 (w), 1199 (m), 1116 (s), 1046 (s), 933

(w), 850 (w) cm^ꢁ1; MS (10 eV) m/z 320 (M⁺, 3), 202 (15), 201

From 0.21 g (1.6 mmol) of hydrocinnamaldehyde and 0.19 g

(1.04 mmol) of hydrazine 49e was obtained 126 mg (41%) of 1e

as a clear, colorless oil after chromatography (CH₂Cl₂/MeOH/

NH₄OH, 9:1:0.1) and distillation. Data for 1e: bp 160 °C

(0.05 mm Hg); ¹H NMR (300 MHz) d 7.28–7.19 (m, 5H, Ph), 6.65–

6.60 (m, 1H, HC@N), 3.70–3.25 (m, 6H, CH₂OCH₂, HC(2), HC(5)),

2.85–2.70 (m, 3H, H₂C(3⁰⁰), HC(5)), 2.60–2.50 (m, 4H, H₂C(2⁰⁰),

H₂C(4⁰)), 2.26 (s, 6H, N(CH₃)₂), 2.00–1.70 (m, 4H, H₂C(3), H₂C(4));

¹³C NMR (75 MHz) d 141.58, 137.16, 128.42, 128.26, 125.79,

73.30, 69.57, 63.19, 58.78, 50.28, 45.91, 34.73, 34.11, 26.83,

22.11; IR (neat) 3027 (w), 2943 (s), 2817 (s), 2769 (m), 1604 (w),

1497 (w), 1459 (m), 1453 (s), 1341 (m), 1276 (w), 1202 (m),

1117 (s), 1042 (m) cm^ꢁ1; MS (70 eV) m/z 303 (M⁺, 1), 215 (17),

214 (74), 202 (40), 201 (100), 187 (41), 172 (20), 171 (100), 132

(13), 126 (53), 123 (10); TLC R_f0.11 (CH₂Cl₂/MeOH/NH₄OH,

9:1:0.1). Anal. Calcd for C₁₈H₂₉N₃O: C, 71.24; H, 9.63; N, 13.84.

Found: C, 70.91; H, 9.37; N, 13.64.

(100), 139 (32); TLC R_f0.27 (hexane/EtOAc, 1:1); [

0.72 CHCl₃). Anal. Calcd for C₁₈H₂₈N₂O₃: C, 67.47; H, 8.80; N,

a

]

_D= ꢁ76.4 (c

8.74. Found: C, 67.37; H, 8.59; N, 8.75.

6.2.13. (S)-1-(1-Butyl-3-phenylpropylidenamino)-2-[(2-methoxy-

ethoxy)methoxymethyl]-pyrrolidine 18c. Procedure II

6.2.17. (S)-1-(1-Butyl-3-phenylpropylidenamino)-2-[(2-N,N-

dimethylaminoethoxy)-methyl]pyrrolidine 18e. Procedure II

From 0.04 g (0.3 mmol) ketone 41 and 62 mg (0.33 mmol) of

hydrazine 49e was obtained 47 mg (40%) of 18e as a clear, colorless

oil after chromatography (CH₂Cl₂/MeOH/NH₄OH, 9:1/0.1) and dis-

tillation. Data for 18e: bp 180 °C (0.06 mm Hg); ¹H NMR (300 MHz)

d 7.27–7.19 (m, 5H, Ph), 3.70–1.10 (m, 23H), 2.27 and 2.25 (2s, 6H,

N(CH₃)₂)), 1.00–0.90 (m, 3H, CCH₃); IR (neat) 3062 (w), 3027 (w),

2957 (w), 2862 (s), 2816 (m), 2769 (w), 1653 (w), 1635 (w),

1496 (w), 1456 (m), 1272 (w), 1120 (s), 1043 (w) cm^ꢁ1; MS

(10 eV) m/z 257 (6), 190 (69), 148 (54), 133 (58), 105 (100), 91

(84), 85 (86); TLC R_f0.37 (CH₂Cl₂/MeOH/NH₄OH, 9:1:0.1).

From 0.208 g (1.0 mmol) of ketone 41 and 0.194 g (1.0 mmol) of

hydrazine 49c was obtained 88 mg (23%) of 18c as a clear, colorless

oil after chromatography (hexane/EtOAc, 2:1) and distillation. Data

for 18c: bp 160 °C (0.1 mm Hg); ¹H NMR (300 MHz) d 7.40–7.10 (m,

5H, Ph), 4.80–4.70 (m, 2H, OCH₂O), 3.80–1.20 (m, 23H), 3.38 (s, 3H,

OCH₃), 1.00–0.90 (m, 3H, CCH₃); IR (neat) 3063 (w), 3027 (m), 2955

(s), 2930 (s), 2872 (s), 1714 (s), 1604 (w), 1496 (m), 1454 (s), 1411

(w), 1282 (w), 1243 (w), 1199 (m), 1171 (m), 1121 (s), 1048 (s),

983 (w), 933 (w), cm^ꢁ1; MS (10 eV) m/z 376 (M⁺, 2), 257 (43), 190

(77), 148 (88), 133 (55), 130 (35), 105 (100), 91 (58), 85 (67); TLC

R_f0.42 (hexane/EtOAc, 1:1). Anal. Calcd for C₂₂H₃₆N₂O₃: C, 70.77;

H, 9.63; N, 7.43. Found: C, 70.44; H, 9.78; N, 7.17.

6.2.18. (S)-1-(3-Phenylpropylidenamino)-2-hydroxymethylpyrr-

olidine 1f

6.2.14. (S)-2-[(2-Methoxyethoxy)methyl]-1-(3-phenylpropylide-

namino)pyrrolidine 1d. Procedure I

In a 10-mL, one-necked ﬂask a neat solution of hydrazine 49f

(250 mg, 2.15 mmol) was cooled to 0 °C and hydrocinnamaldehyde

From 0.502 g (3.7 mmol) of hydrocinnamaldehyde and 0.348 g

(2.0 mmol) of hydrazine 49d was obtained 442 mg (76%) of 1d as

a clear, colorless oil after chromatography (hexane/EtOAc, 4:1)

and distillation. Data for 1d: bp 150 ^oC (0.05 mm Hg); ¹H NMR

(300 MHz) d 7.40–7.15 (m, 5H, Ph), 6.65 (t, J = 5.3, 1H, HC@N),

3.80–3.25 (m, 8H, HC(2), HC(5), H₂C(1⁰), H₂C(3⁰), H₂C(4⁰)), 3.38 (s,

3H, OCH₃), 2.90–2.70 (m, 3H, H₂C(3⁰⁰), HC(5)), 2.60–2.50 (m, 2H,

H₂C(2⁰⁰)), 2.10–1.70 (m, 4H, H₂C(3), H₂C(4)); ¹³C NMR (75 MHz) d

141.74, 136.67, 128.33, 128.08, 125.60, 73.25, 71.74, 70.41, 63.04,

58.77, 49.99, 34.51, 33.87, 26.66, 21.90; IR (neat) 3062 (w), 3025

(w), 2877 (m), 2722 (m), 1603 (m), 1496 (m), 1453 (m), 1339

(m), 1301 (m), 1279 (m), 1243 (m), 1199 (m), 1111(s), 1030 (m),

851 (m) cm^ꢁ1; MS (10 eV) m/z 290 (M⁺, 1), 202 (13), 201 (100),

133 (21), 132 (19), 118 (14), 117 (12), 92 (15), 91 (70), 83 (14),

(350 lL, 2.65 mmol, 1.23 equiv) was added neat. The reaction mix-

ture was allowed to warm to rt and stirred for 26 h. The reaction

mixture was diluted with Et₂O (10 mL), dried (MgSO₄), ﬁltered

through a pad of Celite, and concentrated to afford an orange oil.

Puriﬁcation by silica gel chromatography (hexane/EtOAc, 3:2)

and bulb-to-bulb distillation afforded the pure hydrazone 1f

(385 mg, 77%). This material decomposes within a matter of days

at ꢁ20 °C. Data for 1f: bp 170–180 °C (0.35 mm Hg). ¹H NMR

(300 MHz) 7.23 (m, 5H, Ph), 6.62 (t, J = 5.10, 1H, HC(1⁰)), 4.08 (br

s, 1H, HO), 3.79 (m, 1H, HC(2)), 3.67 (m, 1H, HC(5)), 3.33 (m, 2H,

H₂COH), 2.74 (m, 2H, H₂C(3⁰)), 2.66 (m, 1H, HC(5)), 2.53 (m, 2H,

H₂C(2⁰)), 1.98–1.80 (m, 3H, HC(3), H₂C(4)), 1.47 (m, 1H, HC(3)).

¹³C NMR (75.5 MHz) 141.21, 138.07, 128.31, 125.88, 66.82, 64.13,

49.16, 34.60, 33.60, 25.32, 21.63. IR (CCl₄) 3453 (br), 3028 (m),

2949 (s), 2878 (s), 1496 (m), 1454 (s), 1433 (m), 1342 (m), 1149

(m), 1090 (s), 1043 (s), 816 (s). MS (70 eV) 232 (7), 202 (15), 201

(100), 141 (6), 105 (8), 104 (9), 91 (22), 77 (7), 70 (30). TLC R_f

0.23 (hexane/EtOAc, 1:1). Anal. Calcd for C₁₄H₂₀N₂O (232.33): C,

72.38; H, 8.68; N, 12.06. Found: C, 72.37; H, 8.62; N, 12.08.

71 (88), 58 (20); TLC R_f0.08 (hexane/EtOAc, 4:1); [

(c = 1.0, CHCl₃). Anal. Calcd for C₁₇H₂₆N₂O₂: C, 70.31; H, 9.02; N,

a

]

_D= ꢁ92.0

9.64. Found: C, 70.29; H, 9.04; N, 9.45.

6.2.15. (S)-1-(1-Butyl-3-phenylpropylidenamino)-2-[(2-metho-

xyethoxy)methyl]pyrrolidine 18d. Procedure II

From 0.19 g (1.0 mmol) of ketone 41 and 0.087 g (0.5 mmol) of

hydrazine 49d was obtained 22 mg (12%) of 18d as a clear, color-

less oil after chromatography (hexane/EtOAc, 3:1). Data for 18d:

¹H NMR (300 MHz) d 7.40–7.10 (m, 5H, Ph), 3.70–1.20 (m, 26H),

1.00–0.80 (m, 3H, CCH₃); IR (neat) 3063 (w), 3026 (m), 2957 (s),

2930 (s), 2872 (s), 1716 (m), 1632 (w), 1605 (w), 1496 (m), 1454

(m), 1365 (w), 1246 (w), 1199 (w), 1111 (s), 1032 (m) cm^ꢁ1; MS

(70 eV) m/z 46 (M⁺, 2), 258 (19), 257 (100), 132 (25), 105 (34);

TLC R_f0.12 (hexane/EtOAc, 3:1).

6.3. General procedure for the preparation of SAMEMP

hydrazones 19d–21d

6.3.1. (S)-1-Methylidenamino-2-(2-methoxyethoxymethyl)pyrro-

lidine 19d

To a 1-dram vial was added SAMEMP (115 mg, 0.89 mmol)

which was cooled to 0 °C. Acetaldehyde (100 mL, 1.79 mmol,

2.00 equiv) was added dropwise and the reaction mixture was stir-

red for 1 h at 0 °C. The reaction mixture was allowed to warm to rt

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

1289

and react for 22 h. The reaction mixture was diluted with Et₂O

(20 mL), dried (Na₂SO₄), ﬁltered through a pad of Celite, and con-

centrated to afford an orange oil. Puriﬁcation by column chroma-

tography and bulb-to-bulb distillation afforded 65 mg (37%) of

the hydrazone 19d. Data for 19d: bp 60–65 °C (0.01 mm Hg); ¹H

NMR (300 MHz) 6.67 (q, 1H, J = 5.27, HC@N), 3.68 (m, 1H, HC(2)),

3.62, 3.53 (2 m, 4H, OCH₂CH₂OCH₃), 3.42 (m, 2H, NCHCH₂O), 3.32

(m, 1H, HC(5)), 3.37 (s, 3H, H₃CO), 2.71 (m, 1H, HC(5)), 1.95–1.78

(m, 4H, H₂C(3), H₂C(4)), 1.88 (d, 3H, J = 5.27, CH₃C@N). ¹³C NMR

(75.5 MHz) 134.29, 73.55, 71.86, 70.54, 63.30, 58.99, 50.48, 26.81,

22.12, 18.93. TLC R_f0.38 (hexane/EtOAc, 1:1). GC t_R12.86 (column

C; 100 (5), 20, 220 (10)). MS (70 eV) 200 (6), 112 (8), 111 (100), 70

(6). HRMS Calcd for C₁₀H₂₀N₂O₂(MW 200.27): 200.15248. Found:

200.15277.

allowed to warm to 20 °C over 2–3 h. Methyl chloroformate (4–

5 equiv) was added and the mixture was stirred at room tempera-

ture for 12 h. The reaction mixture was poured onto satd aq NH₄Cl

solution (2 mL/mL THF) and extracted with EtOAc (3ꢂ). The extracts

were washed with brine, combined, dried (Na₂SO₄) ﬁltered, and con-

centrated. The crude carbamate was puriﬁed by silica gel column

chromatography and bulb to bulb distillation.

6.4.1. (2S,2⁰⁰R)-1-[N-Methoxycarbonyl-N-(1-methyl-3-phenyl-

propyl)amino]-2-(methoxymethyl)pyrrolidine 5a

From 0.110 g (0.45 mmol) of hydrazone 1a, 220 mg (0.89 mmol)

of CeCl₃ꢀ7H₂O, 0.65 mL (0.89 mmol) of MeLi (1.38 M in Et₂O), and

76 lL (0.98 mmol) of ClCO₂Me was obtained 115 mg (80%) of 5a as

a clear, colorless oil after chromatography (hexane/EtOAc, 8:1) and

distillation. Data for 5a: bp 130 °C (0.01 mm Hg); ¹H NMR

(200 MHz, TMS) d 7.25 (m, 5H, Ph), 3.70 (br, 3H, CO₂CH₃), 3.25 (s,

3H, CH₂OCH₃), 3.40–3.00 (m, 5H, H₂C(1⁰), HC(5), HC(2) CHCH₃),

2.60 (m, 3H, HC(5), H₂C(3⁰⁰)), 1.60–2.20 (m, 6H, H₂C(3), H₂C(4),

H₂C(2⁰⁰)), 1.20 (d, 3H, CHCH₃); IR (neat) 3433 (m), 3299 (m), 3130

(m), 3082 (m), 3026 (m), 2953 (s), 2874 (s), 2361 (w), 1700 (s),

1653 (w), 1603 (w), 1539 (w), 1495 (m), 1439 (s), 1383 (m), 1317

(s), 1190 (m), 1048 (m) cm^ꢁ1; MS (70 eV) m/z 320 (M⁺, 1), 276

(18), 275 (100), 143 (50), 114 (10), 111 (49), 91 (34), 71 (11), 70

(14), 69 (21), 45 (13), 43 (11), 41 (15); TLC R_f0.20 (hexane/ethyl ace-

tate, 6:1). GC t_R5a, 12.66 min (98%); t_R5a⁰, 13.50min (2%) (columnA;

200 °C isothermal). Anal. Calcd for C₁₈H₂₈N₂O₃: C, 67.47; H, 8.81; N,

8.74. Found: C, 67.54; H, 8.70; N, 8.95.

6.3.2. (S)-1-(2,2-Dimethylpropylidenamino)-2-(2-methoxyethoxy-

methyl)pyrrolidine 20d

Following the general procedure for 19d, from SAMEMP (132 mg,

0.76 mmol) and pivalaldehyde (160 mL, 1.47 mmol, 1.94 equiv) was

obtained an orange oil. Puriﬁcation by column chromatography

(hexane/EtOAc, 4:1) and bulb-to-bulb distillation afforded 121 mg

(66%) of the pure hydrazone 20d. Data for 20d: bp 120–5 °C

(0.5 mm Hg) ¹H NMR (300 MHz) 6.54 (s, 1H, HC@N), 3.71 (m, 1H,

HC(2)), 3.60, 3.51 (2 m, 4H, OCH₂CH₂O), 3.42 (m, 1H, HC(5)), 3.35

(s, 3H, H₃CO), 3.25 (br m, 2H, NCHCH₂O), 2.64 (m, 1H, HC(5)),

1.96–1.73 (m, 4H, H₂C(3), H₂C(4)), 1.01 (s, 9H, (H₃C)₃C). ¹³C NMR

(75.5 MHz) 146.71, 73.39, 71.84, 70.45, 63.21, 58.93, 49.87, 34.29,

28.22, 26.74, 21.81. IR (CCl₄) 2959 (s), 2899 (s), 1701 (m), 1474

(m), 1458 (m), 1362 (m), 1339 (m), 1200 (m), 1115 (s), 808 (s). MS

(70 eV) 242 (M+, 6), 154 (11), 153 (100), 70 (10). TLC R_f0.32 (hex-

ane/EtOAc, 3:1). Anal. Calcd for C₁₃H₂₆N₂O₂(MW 242.35): C,

64.43; H, 10.81; N, 11.56. Found: C, 64.64; H, 10.73; N, 11.79.

6.4.2. (2S,2⁰⁰R)-1-[N-Methoxycarbonyl-N-(1-methyl-2-phenyl-

ethyl)amino]-2-(methoxymethyl)pyrrolidine 6a

From 0.232 g (1.0 mmol) of hydrazone 2a, 0.74 g (2.0 mmol) of

CeCl₃ꢀ7H₂O, 1.7 mL (2.0 mmol) of MeLi (1.18 M in Et₂O), and

0.25 mL (3.0 mmol) of ClCO₂CH₃was obtained 200 mg (66%) of 6a

as a clear, colorless oil after chromatography (hexane/EtOAc, 7:1)

and distillation. Data for 6a: bp 150 °C (0.5 mm Hg); ¹H NMR

(300 MHz) d 7.30–7.18 (m, 5H Ph), 4.35–4.10 (m, 1H, HC(2⁰⁰)), 3.71

(s, br, 3H, COOCH₃), 3.37–2.93 (m, 6H, H₂C(1⁰), HC(5), HC(2),

H₂C(3⁰⁰)); 3.29 (s, 3H, OCH₃); 2.74–2.71 (m, 1H, HC(5)), 2.20–1.60

(m, 4H, H₂C(3), H₂C(4)), 1.11 (d, J = 7, 3H, CH₃C(2⁰⁰)); ¹³C NMR

(75 MHz) d 139.51, 129.33, 128.16, 125.92, 61.81), 58.74, 57.18,

54.01, 52.00, 41.40, 27.45, 23.10, 17.67; IR (neat) 3026 (w), 2972

(w), 2874 (w), 1701 (s), 1496 (w), 1439 (m), 1384 (w), 1321 (m),

1279 (w), 1196 (w), 1111 (s), 1043 (w) cm ^ꢁ1; MS (10 eV) m/z 306

(M⁺, 2), 263 (2), 262 (16), 261 (100), 144 (2), 143 (24), 119 (3), 114

(10), 91 (4), 70 (3), 69 (8), 68 (5); TLC R_f0.18 (hexane/EtOAc, 7:1).

Anal. Calcd for C₁₇H₂₆N₂O₃: C, 66.64; H, 8.55; N, 9.14. Found: C,

66.49; H, 8.40; N, 9.27. GC t_R6a, 12.01 min (96%); t_R6a⁰12.74 min

(4%) (column A, 200 °C isothermal).

6.3.3. (S)-1-(Benzylidenamino)-2-(2-methoxyethoxymethyl)-

pyrrolidine 21d

Following the general procedure for 19d, from SAMEMP

(142 mg, 0.81 mmol) and benzaldehyde (97 mL, 0.96 mmol,

1.17 equiv) was obtained a pale yellow oil. Puriﬁcation by column

chromatography (hexane/EtOAc, 3:1) and bulb-to-bulb distillation

afforded 164 mg (77%) of the pure hydrazone 21d. Data for 21d: bp

190–5 °C (0.35 mm Hg) ¹H NMR (300 MHz) 7.53 (d, 2H, J = 7.53,

HC(2⁰), CH(6⁰)), 7.26 (m, 2H, HC(3⁰), HC(5⁰)), 7.20 (s, 1H, HC@N),

7.19 (m, 1H, HC(4⁰)), 3.81 (m, 1H, HC(2)), 3.78 (m, 1H, HC(5)),

3.66 (m, 2H, OCH₂CH₂OCH₃), 3.55 (m, 2H, CH₂CH₂OCH₃), 3.44 (m,

2H, RNCHCH₂O), 3.39 (s, 3H, H₃CO), 3.06 (m, 1H, HC(5)), 2.10–

1.89 (m, 4H, H₂C(3), H₂C(4)). ¹³C NMR (75.5 MHz) 137.25 (HC@N),

132.07 (C(1⁰), 128.38, 126.85, 125.21, 73.24, 71.93, 70.69, 62.94,

59.04, 48.90, 26.98, 22.20. IR (CCl₄) 2882 (s), 1589 (m), 1560 (m),

1449 (m), 1340 (m), 1242 (m), 1115 (s), 814 (s). MS (70 eV) 262

(11), 174 (13), 173 (100), 153 (5), 70 (19), 57 (3). TLC R_f0.25 (hex-

ane/EtOAc, 3:1). Anal. Calcd for C₁₅H₂₂N₂O₂(MW 262.34): C, 68.67;

H, 8.45; N, 10.68. Found: C, 68.70; H, 8.53; N, 10.70.

6.4.3. (2S,2⁰⁰S)-1-[N-Benzyloxycarbonyl-N-(1-methyl-2-phenyl-

ethyl)amino]-2-(methoxymethyl)pyrrolidine 6aa

From 232 mg (1.0 mmol) of hydrazone 2a, 0.85 g (2.3 mmol) of

CeCl₃ꢀ7H₂O, 1.7 mL of MeLi (1.18 M in Et₂O), and 0.3 mL (2.1 mmol)

of ClCO₂CH₂Ph was obtained 318 mg (83%) of 6aa as a clear, color-

less oil after chromatography (hexane/EtOAc, 6:1) and distillation.

Data for 6aa: bp 170 °C (0.5 mm Hg); ¹H NMR (200 MHz) d 7.36–

7.13 (m, 10H, Ph), 5.30–5.0 (m, 2H, PhCH₂), 4.30–4.10 (m, 1H,

HC(2⁰⁰)), 3.80–2.80 (m, 6H, H₂C(1⁰), HC(5), HC(2), H₂C(3⁰⁰)), 3.29

(s, 3H, OCH₃), 2.80–2.60 (m, 1H, HC(5)), 2.20–1.40 (m, 4H,

H₂C(3), H₂C(4)), 1.13 (d, J = 7, 3H, CH₃C(2⁰⁰)); IR (neat) 3028,

2970, 2876, 1697, 1496, 1454, 1390, 1311, 1277, 1199, 1109,

1037, 746 cm^ꢁ1; MS (70 eV) m/z 382 (M⁺, 1), 337 (23), 336 (100),

180 (8), 151 (10), 129 (9), 114 (8), 107 (20), 92 (10), 91 (50), 79

(9); TLC R_f0.23 (hexane/EtOAc, 9:1). GC t_R6aa, 24.97 min (96%);

t_R6aa⁰, 26.28 min (4%) (column A, 230 °C isothermal). Anal. Calcd

for: C, 72.22; H, 7.90; N, 7.32. Found: C, 71.93; H, 7.71; N, 7.25.

6.4. General procedure for the additions to hydrazones

In a three-necked, round-bottomed ﬂask ﬁtted with N₂inlet,

thermometer, magnetic stirrer, and rubber septum was placed

CeCl₃ꢀ7H₂O (2 equiv) which was dried (140 °C, 0.5 mm Hg) for 2 h.

The dried CeCl₃was stirred in dry THF (10 mL/mmol CeCl₃) for 2 h

at room temperature. For organolithium reagents, the suspension

was cooled to ꢁ78 °C, treated with the organometallic species

(2.0 equiv), and stirred at ꢁ78 °C for 1 h. For organomagnesium re-

agents, the suspension was cooled to 0 °C, treated with the Grignard

reagent (2.0 equiv), stirred at 0 °C for 1 h, and then cooled to ꢁ78 °C

for reaction. A solution of the hydrazone in THF (3 mL/mmol) was

added, and the suspension was stirred at ꢁ78 °C for 1 h and then

1290

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

6.4.4. (2S,2⁰⁰R)-2-Methoxymethyl-1-[N-methoxycarbonyl-N-(1-

phenylethyl)amino)pyrrolidine 7a

and distillation. Data for 12a: bp 150 °C (0.01 mm Hg); ¹H NMR

(200 MHz) d 7.74–7.4 (m, 5H, Ph); 3.7 (br, 3H, CO₂CH₃), 3.5 (m,

1H, HC(3⁰⁰)), 3.3 (m, 2H, H₂C(1⁰)), 3.2 (s, 3H, OCH₃), 3.2–2.9 (m,

4H, H₂C(2⁰⁰)_,HC(2), HC(5)), 2.6 (m, 2H, H₂C(2⁰⁰)), 1.9 (m, 1H,

HC(5)), 1.8–1.6 (m, 4H, H₂C(3), H₂C(4)), 1.3–1.2 (br, 6H, H₂C(4⁰⁰),

H₂C(5⁰⁰), H₂C(6⁰⁰)), 0.875 (t, 3H, CCH₃); IR (neat) 1698 (s), 2955

(s), 1439 (s), 1109 (s), 2874 (s), 910 (s), 1337 (m), 1383 (m),

1194 (m), 1285 (m), 1495 (m), 1250 (m), 3028 (w), 1030 (w),

970 (w), 2249 (w), 1603 (w), 997 (w) cm^ꢁ1; MS (70 eV) m/z 362

(M⁺, 1), 318 (18), 317 (82), 144 (13), 143 (100), 111 (42), 105

(17), 91 (39), 85 (16), 83 (14), 70 (12), 69 (41), 57 (29), 55 (23),

45 (12), 43 (13), 41 (29); TLC R_f0.41 (hexane/EtOAc, 4:1). Anal.

Calcd for C₂₁H₃₄N₂O₃: C, 69.58; H, 9.45; N, 7.73. Found: C, 69.57;

H, 9.64; N, 7.68. GC t_R12a, 22.86 min (93%); t_R12a⁰, 23.28 min

(7%) (column A, 210 °C isothermal).

From 0.11 g (0.5 mmol) of hydrazine 3a, 0.43 g (1.1 mmol) of

CeCl₃ꢀ7H₂O, 0.9 mL (1.1 mmol) of MeLi (1.18 M in Et₂O), and

0.3 mL (3.9 mmol) of ClCO₂Me was obtained 86 mg (89%) of 7a as

a clear, colorless oil after chromatography (hexane/EtOAc, 7:1)

and distillation. Data for 7a: bp 140 °C (1.0 mm Hg); ¹H NMR

(300 MHz) d 7.35–7.26 (m, 5H, Ph), 5.40 (s, br, 1H, HC(1⁰⁰)), 3.77

(s, 3H, COOCH₃), 3.40–3.13 (m, 4H, H₂C(1⁰), HC(2), HC(5)), 2.89 (s,

3H, OCH₃), 2.31–2.25 (m, 1H, HC(5)), 2.10–1.43 (m, 4H, H₂C(3),

H₂C(4)), 1.54 (d, J = 6, 3H, CH₃C(1⁰⁰)); IR (neat) 2970 (m), 2872

(m), 1701 (s), 1439 (s), 1375 (s), 1306 (s), 1192 (s), 1115 (s),

1047 (w), 1032 (w) cm^ꢁ1; MS (10 eV) m/z 292 (M⁺, 2), 247 (16),

246 (95), 187 (62), 143 (100), 114 (11), 112 (18), 111 (80), 105

(12), 80 (13), 71 (25), 45 (21); TLC R_f0.35 (hexane/EtOAc, 7:1).

Anal. Calcd for C₁₆H₂₄N₂O₃: C, 65.72; H, 8.27; N, 9.57. Found: C,

65.69; H, 8.50; N, 9.71. HPLC t_R7a⁰, 2.21 min (9%); t_R7a, 3.32

min (91%) (column 4, hexane/EtOAc, 20:1, 1 mL/min).

6.4.8. (2S,2⁰⁰S)-1-[N-(1-(1-Methylethyl)-3-phenylpropyl)-N-

methoxycarbonylamino]-2-(methoxymethyl)pyrrolidine 13a

From 246 mg (1.0 mmol) of hydrazone 1a, 850 mg (2.2 mmol)

of CeCl₃ꢀ7H₂O, 3.25 mL (2.01 mmol) of i-PrMgBr (0.62 M THF),

and 0.4 mL (5.1 mmol) of ClCO₂Me was obtained 225 mg (65%) of

13a as a clear, colorless oil after chromatography (hexane/EtOAc,

8:1) and distillation. Data for 13a: bp 140 °C (0.05 mm Hg); ¹H

NMR (300 MHz) d 7.30–7.10 (m, 5H, Ph), 3.90–3.00 (m, 6H), 3.70

(s, 3H, CO₂CH₃), 3.20 (s, 3H, CH₂OCH₃), 2.75–2.45 (m, 2H,

HC(3⁰⁰)), 2.35–2.15 (m, 1H, HC(4⁰⁰)), 2.10–1.60 (m, 6H, H₂C(2⁰⁰),

H₂C(3), H₂C(4)), 0.90–0.86 (m, 6H, C(CH₃)₂); ¹³C NMR (75 MHz) d

142.12, 128.28, 128.20, 125.67, 75.35, 65.30, 63.60, 58.70, 54.40,

52.20, 32.98, 30.72, 30.43, 27.52, 23.92, 20.71, 19.80; IR (neat)

3063 (w), 3026 (w), 2959 (s), 2874 (s), 2824 (m), 1699 (s), 1603

(w), 1496 (m), 1439 (s), 1375 (s), 1333 (s), 1279 (s), 1192 (m),

1109 (s), 1028 (m), 999 (w), 970 (w), 920 (w), 765 (m), 748 (m)

cm^ꢁ1; MS (70 eV) m/z 348 (M⁺, 2), 304 (20), 303 (100), 143 (80),

111 (18), 55 (11); TLC R_f0.48 (hexane/EtOAc, 4:1). GC t_R13a,

12.65 min (column A, 220 °C isothermal). Anal. Calcd for

6.4.5. (2S,2⁰⁰S)-1-[N-Benzyloxycarbonyl-N-(1-phenylethyl)amino]-

2-]-2-(methoxymethyl)pyrrolidine 7aa

From 440 mg (2.0 mmol) of 3a, 1.7 g (4.6 mmol) of CeCl₃ꢀ7H₂O,

3.4 mL (4.9 mmol) of MeLi (1.18 M in Et₂O), and 0.8 mL (6.0 mmol)

of ClCO₂Bn was obtained 555 mg (75%) of 7aa as a clear, colorless

oil after chromatography (hexane/EtOAc, 9:1) and distillation. Data

for 7aa: bp 170 °C (0.5 mm Hg); ¹H NMR (200 MHz) d 7.48–7.24

(m, 10H, Ph), 5.60–5.40 (m, 1H, HC(1⁰⁰)), 5.27 and 5.17 (2d, J = 14,

2H, PhCH₂), 3.50–3.14 (m, 5H, H₂C(1⁰), HC(5), H₂C(2)), 2.92 (s,

3H, OCH₃), 2.40–2.25 (m, 1H, HC(5)), 2.10–1.40 (m, 4H, H₂C(3),

H₂C(4)), 1.57 (d, J = 7, 3H, CH₃C(1⁰⁰)); IR (neat) 3030 (w), 2970

(m), 2874 (m), 1697 (s), 1496 (w), 1452 (m), 1388 (m), 1292 (s),

1213 (w), 1115 (m), 1043 (m), 1028 (m), 997 (w), 970 (w), 914

(w), 821 (w) cm^ꢁ1; MS (70 eV) m/z 368 (M⁺, 1), 324 (21), 323

(21), 263 (37), 219 (43), 187 (30), 129 (10), 118 (14), 114 (22),

111 (25), 91 (41), 70 (22); TLC R_f0.30 (hexane/EtOAc, 9:1). Anal.

Calcd for C₂₂H₃₂N₂O₃: C, 72.71; H, 7.65; N, 7.60. Found: C, 71.64;

H, 7.75; N, 7.63. GC t_R7aa, 19.20 min (91%); t_R7aa⁰, 17.87 min

(9%) (column A, 230 °C isothermal).

C₂₀H₃₂N₂O₃: C, 68.93; H, 9.25; N, 8.03. Found: C, 69.15; H, 9.19;

N, 8.04.

6.4.9. (2S,2⁰⁰S)-1-[N-(1-(1,1-Dimethylethyl)-3-phenylpropyl)amino]-

2-methoxymethyl-pyrrolidine 14a

6.4.6. (2S,2⁰⁰R)-1-[N-Methoxycarbonyl-N-(1-methyl-2-(E)-bute-

nyl)amino]-2-(methoxymethyl)pyrrolidine 8a

From 0.246 g (1.00 mmol) of hydrazone 1a, 0.85 g (2.00 mmol)

of CeCl₃ꢀ7H₂O, and 1.35 mL (2.00 mmol) of t-BuLi (1.48 M in pen-

tane) was obtained 204 mg (68%) of 14a as a clear, colorless oil

after distillation. Data for 14a: bp 160 °C (0.5 mm Hg); ¹H NMR

(300 MHz) d 7.32–7.17 (m, 5H, Ph), 3.71–3.64 (m, 1H, HC(3⁰⁰)),

3.42–3.31 (m, 2H), 3.36 (s, 3H, OCH₃), 2.95–1.15 (m, 13H), 0.90

(m, 9H, C(CH₃)₃); ¹³C NMR (75 MHz) d 142.66, 128.41, 128.32,

128.28, 128.23, 125.67, 75.23, 66.81, 66.42, 58.97, 57.83, 34.90,

34.73, 33.07, 27.08, 26.34, 20.77; IR (neat) 3084 (w), 3063 (w),

3026 (m), 2955 (s), 2872 (s), 2810 (m), 1603 (w), 1495 (m), 1454

(m), 1392 (w), 1361 (m), 1190 (w), 1124 (s), 1030 (w), 918 (w),

746 (m) cm^ꢁ1; MS (10 eV) m/z 304 (M⁺, 8), 259 (12), 248 (17),

129 (10), 114 (26), 70 (27). GC t_R14a, 7.76 min (column A,

220 °C isothermal). Anal. Calcd for C₁₉H₃₂N₂O: C, 74.95; H, 10.59;

N, 9.19. Found: C, 75.05; H, 10.49; N, 9.21.

From 364 mg (2.0 mmol) of 4a, 1.49g (4.0 mmol) of CeCl₃ꢀ7H₂O,

2.95 mL (4.0 mmol) of MeLi (1.36

M in Et₂O), and 0.8 mL

(10.0 mmol) of ClCO₂Me was obtained 420 mg (82%) of 8a as a

clear colorless oil after chromatography (hexane/EtOAc, 6:1) and

distillation. Data for 8a: bp 130 °C (1.4 mm Hg); ¹H NMR

(200 MHz) d 5.55–5.45 (m, 1H, HC(3⁰⁰), HC(4⁰⁰)), 4.50 (s, br, 1H,

HC(2⁰⁰)), 3.68 (s, 3H, COOCH₃), 3.55–3.05 (m, 5H, HC(2), H₂C(1⁰),

H₂C(5)), 3.29 (s, 3H, OCH₃), 2.10–1.57 (m, 4H, H₂C(3), H₂C(4)),

1.67 (d, J = 7, 3H, CH₃C(2⁰⁰)), 1.22 (d, J = 6.5, 3H, H₃CC(4⁰⁰)); ¹³C

NMR (75 MHz) d 132.87, 125.55, 75.41, 61.08, 58.67, 56.17,

53.87, 51.89, 27.49, 23.08, 18.60, 17.58; IR (neat) 2968 (w), 2874

(s), 1703 (s), 1439 (s), 1377 (s), 1307 (s), 1252 (m), 1192 (m),

1109 (s), 1037 (m), 970 (s), 918 (m) cm^ꢁ1; MS (10 eV) m/z 256

(M⁺, 10), 212 (14), 211 (86), 188 (14), 187 (82), 143 (100), 112

(12), 111(98), 71 (21), 44 (12); TLC R_f0.20 (hexane/EtOAc, 6:1).

Anal. Calcd for C₁₃H₂₄N₂O₃: C, 60.91; H, 9.43; N, 10.92. Found: C,

60.90; H, 9.54; N, 10.88. GC t_R8a⁰, 11.28 min (8%); t_R8a, 11.98

min (94%) (column A, 150 °C isothermal).

6.4.10. (2S,2⁰⁰S)-1-[N-(1⁰,3⁰-Diphenylpropyl)-N-methoxycarbonyl-

amino]-2-methoxymethylpyrrolidine 15a

From 0.246 g (1.00 mmol) hydrazone 1a, 0.85 g (2.20 mmol) of

CeCl₃ꢀ7H₂O, 1.0 mL (2.00 mmol) of PhLi (2.0 M in cyclohexane/

Et₂O), and 0.4 mL (5.1 mmol) of ClCO₂Me was obtained 275 mg

(72%) of 15a as a clear, colorless oil after chromatography (hexane/

EtOAc, 8:1) and distillation. Data for 15a: bp 160 °C (0.03 mm Hg);

¹H NMR (300 MHz) d 7.45–7.20 (m, 10H, Ph), 5.40–5.00 (m, 1H,

HC(1⁰⁰)), 3.77 (s, 3H, COOCH₃), 3.77–3.50 (m, 1H), 3.46–3.42 (m,

1H), 3.28 (s, 3H, CH₃OCC(2)), 3.28–3.20 (m, 1H), 2.67–2.30 (m, 5H),

6.4.7. (2S,3⁰⁰R)-1-[N-(1-Butyl-3-phenylpropenyl)-N-methoxycar-

bonylamino]-2-(methoxymethyl)pyrrolidine 12a

From 170 mg (0.69 mmol) of hydrazone 1a, 595 mg (1.60

mmol) of CeCl₃ꢀ7H₂O, 1.07 mL (1.41 mmol) of n-BuLi (1.32 M in

hexane), and 120

lL (1.55 mmol) of ClCO₂Me was obtained

177 mg (71%) of 12a after chromatography (hexane/EtOAc, 6:1)

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

1291

2.10–1.85 (m, 2H), 1.65–1.48 (m, 3H); ¹³C NMR (75 MHz) d 141.83,

140.21, 128.93, 128.80, 128.33, 128.28, 128.08, 127.45, 125.79,

75.33, 60.76, 60.70, 58.78, 53.20, 52.36, 33.04, 32.78, 27.41, 23.05;

IR (neat) 3028 (w), 2951 (m), 2874 (m), 1701 (s), 1496 (w), 1454

(m), 1439 (m), 1373 (m), 1313 (m), 1194 (m), 1111 (s), 1030 (w)

cm^ꢁ1; MS (10 eV) m/z 382 (M⁺, 3), 338 (22), 337 (100), 277 (16),

208 (5), 188 (17), 187 (66), 144 (8), 143 (94), 117 (7), 114 (5), 112

(4), 111 (39), 105 (4), 91 (16); TLC R_f= 0.15 (hexane/EtOAc, 8:1).

GC t_R15a, 15.57 min (96%); t_R15a⁰, 17.25 min (4%). Anal. Calcd for

12c as a clear, colorless oil after chromatography (hexane/EtOAc,

5:1) and distillation. Data for 12c: bp 200 °C (0.05 mm Hg); ¹H

NMR (300 MHz) d 7.40–7.10 (m, 5H, Ph), 4.70 and 4.61 (2s, br, H,

OCH₂O), 4.10–3.00 (m, 13H), 3.35 (s, 3H, CH₃OCC(2)), 2.70–2.50

(m, 2H), 2.30–1.10 (m, 12H), 1.00–0.80 (m, 3H, CCH₃); ¹³C NMR

(75 MHz) d 155.83 141.85 (br), 128.16, 128.11, 125.58, 95.39,

71.54, 70.22, 66.54, 63.64 (br), 62.71 (br), 58.80, 58.69, 55.13

(br), 54.11 (br), 51.91 (br), 34.46, 32.89, 32.70, 28.53, 27.55,

23.88, 22.60, 13.92; IR (neat) 3026 (w), 2932 (s), 2874 (m), 1697

(s), 1496 (w), 1439 (m), 1383 (m), 1334 (m), 1284 (m), 1248 (w),

1178 (m), 1116 (m), 1047 (s), 993 (w) cm ^ꢁ1; MS (70 eV) m/z 436

(M⁺, 3), 392 (23), 318 (21), 317 (100), 274 (26), 218 (20), 178

(44), 141 (22), 104 (20); TLC R_f0.37 (hexane/EtOAc, 2:1). GC t_R

12c, 15.20 min (85%); t_R12c⁰, 15.68 min (15%) (column A, 250 °C

isothermal). Anal. Calcd for C₂₄H₄₀N₂O₅: C, 66.02; H, 9.23; N,

6.41. Found. C, 66.26; H, 9.38; N, 6.56.

C₁₃H₃₀N₂O₃: C, 72.22; H, 7.90; N, 7.32. Found: C, 72.24; H, 7.91; N,

7.31.

6.4.11. (2S,2⁰⁰S)-1-[N-Methoxycarbonyl-N-(1-(2-triisopropylsilyl-

ethenyl)-3-phenylpropyl)amino]-2-methoxymethylpyrrolidine

16a

From 245 mg (1.0 mmol) of hydrazone 1a, 0.85 g (2.20 mmol) of

CeCl₃ꢀ7H₂O, 2.00 mmol of (E)-2-triisopropylsilylvinyllithium (pre-

pared by tin lithium exchange in THF at room temperature from

1.0 g (2.00 mmol) of (E)-2-triisopropylsilylethenyl tributylstann-

ane and 1.5 mL (2.20 mmol) of n-BuLi according to the literature

procedure), and 0.4 mL (5.10 mmol) of ClCO₂Me was obtained

360 mg (74%) of 16a as a clear, colorless oil after chromatography

(hexane/EtOAc, 6:1) and distillation. Data for 16a: bp 170 °C

(0.4 mm Hg); ¹H NMR (300 MHz) 7.23–7.08 (m, 5H, Ph), 6.09 (dd,

J = 19.0, 7.8, 1H, HC(1⁰⁰)), 5.61 (d, br, J = 19, HC(2⁰⁰)), 4.30–4.10 (m,

1H, HC(1⁰)), 3.70–2.90 (m, 11H), (3.62, s, CO₂CH₃), (3.18, s,

CH₃OCC(2)), 2.58–2.46 (m, 2H), 1.97–1.54 (m, 6H), 1.18–0.83 (m,

21H, (CH(CH₃)₂)₃); ¹³C NMR (75 MHz) d 147.10, 142.04, 128.31,

128.27, 126.97, 125.73, 76.57, 75.43, 65.66, 61.6 (br), 58.79, 54.0

(br), 52.10, 34.43, 32.76, 27.55, 23.23, 18.61, 10.82; IR (neat)

3026 (w), 2941 (s), 2864 (s), 1751 (w), 1705 (s), 1606 (w), 1496

(w), 1439 (m), 1369 (w), 1300 (m), 1194 (w), 1113 (m), 1030

(w), 997 (m), 918 (w), 883 (m) cm^ꢁ1; MS (10 eV) m/z 488 (M⁺,6),

444 (21), 443 (60), 188 (25), 187 (99), 143 (100), 111 (35); TLC R_f

0.53 (hexane/EtOAc, 4:1). GC t_R16a⁰, 15.77 min (3%); t_R16a,

17.48 min (97%) (column A, 260 °C isothermal). Anal. Calcd for

6.4.14. (2S,3⁰⁰R)-1-[N-(1-Butyl-3-phenylpropyl)-N-methoxycar-

bonylamino]-2-(2-methoxy ethoxymethyl)pyrrolidine 12d

From 0.16 g (0.55 mmol) of hydrazone 1d, 0.410 g (1.10 mmol)

of CeCl₃ꢀ7H₂O, 0.78 mL (1.09 mmol) of n-BuLi (1.40 M in hexane),

and 0.4 mL (5.1 mmol) of ClCO₂Me was obtained 161 mg (72%) of

12d as a clear, colorless oil after chromatography (hexane/EtOAc,

5:1) and distillation. Data for 12d: bp 180 °C (0.05 mm Hg); ¹H

NMR (300 MHz) d 7.35–7.10 (m, 5H, Ph), 4.20–3.00 (m, 13H),

3.33 (s, 3H, CH₃OCC(2)), 2.70–2.50 (m, 2H), 2.30–1.20 (m, 12H),

0.95–0.80 (m, 3H, CCH₃); ¹³C NMR (75 MHz) d 145.00 (br),

128.20, 125.65, 73.87, 71.80, 70.23, 64.00 (br), 62.6 (br), 58.92,

58.72, 55.00 (br), 54.10 (br), 52.00 (br), 34.60, 32.98, 32.78,

28.62, 27.59, 23.88, 23.62, 22.69, 13.99; IR (neat) 3026 (w), 2954

(s), 2933 (s), 2873 (s), 1699 (s), 1496 (w), 1454 (m), 1440 (s),

1384 (m), 1335 (m), 1284 (m), 1252 (m), 1195 (m), 1106 (s),

1032 (w) cm^ꢁ1; MS (70 eV) m/z 406 (M⁺, 1), 318 (22), 317 (100),

143 (37), 111 (11); TLC R_f0.33 (hexane/EtOAc, 3:1). GC t_R12d,

13.58 min (97%); t_R12d⁰, 13.93 min (3%) (column A, 240 °C isother-

mal). Anal. Calcd for C₂₃H₃₈N₂O₄: C, 67.94; H, 9.42; N, 6.88. Found:

C, 68.07; H, 9.45; N, 6.87.

C₂₈H₄₈N₂O₃Si: C, 68.80; H, 9.89; N 5.73. Found: C, 68.93; H, 9.72;

N, 5.62.

6.4.15. (2S,3⁰⁰R)-1-(N-(1-n-Butyl-3-phenylpropylamino)-2-(2-

N,N-dimethylamino-ethoxymethyl)pyrrolidine 12e

6.4.12. (2S,3⁰⁰R)-1-[N-(1-Butyl-3-phenylpropyl)-N-methoxycarbon-

ylamino]-2-(methoxymethoxymethyl)pyrrolidine 12b

From 65 mg (0.21 mmol) of hydrazone 1e, 160 mg (0.43 mmol)

of CeCl₃ꢀ7H₂O, and 0.31 mL (0.43 mmol) of n-BuLi (1.39 M in hex-

ane) was obtained 50 mg (61%) of 12e as a brown oil after distilla-

tion. Data for 12e: bp 180 °C (0.01 mm Hg); ¹H NMR (300 MHz) d

7.40–7.00 (m, 5H, Ph), 3.70–3.45 (m, 2H, OCH₂O), 3.50–3.30 (m,

1H, HC(3⁰⁰)), 3.00–1.10 (m, 22H), 2.45 (s, 6H, N(CH₃)₂), 1.00–0.80

(m, 3H, CCH₃); IR (neat) 3300 (m) (br), 3026 (w), 2932 (s), 2858

(s), 2816 (m), 2769 (m), 1496 (w), 1454 (m), 1377 (w), 1269 (w),

1120 (m), 1071 (w), 1041 (w), 746 (w), 699 (w) cm^ꢁ1; MS

(10 eV) m/z 361 (M⁺, 13), 260 (20), 259 (100), 171 (17), 98 (21),

86 (25), 84 (40), 72 (28), 71 (36). GC t_R12e⁰, 8.02 min (10%); t_R

12e, 8.23 min (90%) (column A, 250 °C isothermal). Anal. Calcd

for C₂₂H₃₉N₃O: C, 73.08; H, 10.87; N, 11.62. Found: C, 73.11; H,

10.60; N, 11.69.

From 0.256 g (0.93 mmol) of hydrazone 1b, 0.692 g (1.86 mmol)

of CeCl₃ꢀ7H₂O, 1.25mL (1.83 mmol) of n-BuLi (1.46 M in hexane),

and 0.4 mL (5.1 mmol) of ClCO₂Me was obtained 253 mg (70%) of

12b as a clear, colorless oil after chromatography (hexane/EtOAc,

6:1) and distillation. Data for 12b: bp 170 °C (0.05 mm Hg); ¹H

NMR (300 MHz) d 7.25–7.10 (m, 5H, Ph), 4.50 (s, br, 2H, OCH₂O),

4.20–3.00 (m, 7H), 3.66 (s, br, 3H, COOCH₃), 3.25 (s, 3H, OCH₃),

2.70–2.50 (m, 2H), 2.35–1.10 (m, 11H), 0.95–0.85 (m, 3H, CCH₃);

¹³C NMR (75 MHz) d 141.9 (br), 128.25, 128.19, 128.13, 125.61,

96.33, 70.04, 62.5 (br), 58.73, 54.94, 53.8 (br), 51.8 (br), 34.47,

32.98, 32.71, 28.54, 27.55, 23.95, 22.64, 13.97; IR (neat) 3063–

2822 (s), 1697 (s), 1603 (w), 1496 (m), 1439 (m), 1383 (m), 1334

(m), 1284 (s), 1221 (m), 1190 (m) 1151 (s), 1109 (s), 1078 (m),

1045 (s), 997 (w), 966 (w), 920 (m) cm^ꢁ1; MS (10 eV) m/z 392

(M⁺, 2), 318 (22), 317 (100), 143 (27); TLC R_f0.34 (hexane/EtOAc,

6:1). GC t_R12b, 21.51 min (93%); t_R12b⁰, 21.74 min (7%) (column

A, 220 °C isothermal). Anal. Calcd for C₂₂H₃₆N₂O₄: C, 67.31; H,

9.24; N, 7.13. Found: C, 67.38; H, 9.26; N, 6.96.

6.4.16. 1-(N-Methoxycarbonyl-N-3-(1-phenylheptylamino))-2-

(O-methoxycarbonyl)-2-(hydroxymethyl)pyrrolidine 12f

From 174 mg (0.75 mmol) of hydrazone 1f, 559 mg (1.50 mmol,

.

2.00 equiv) of CeCl₃7H₂O, 0.98 mL (1.51 mmol, 2.01 equiv) of n-

BuLi (1.55

1.00 equiv) and 400

M

in hexane) followed by n-BuLi (0.50 mmol,

L (5.2 mmol, 6.9 equiv) of methyl chlorofor-

6.4.13. (2S,3⁰⁰R)-1-[N-(1-Butyl-3-phenylpropyl)-N-methoxycar-

bonylamino)-2-(2-methoxyethoxymethoxymethyl)-pyrrolidine

12c

From 0.242 g (0.75 mmol) of hydrazone 1c, 558 mg (1.5 mmol)

of CeCl₃ꢀ7H₂O, 1.05 mL (1.5 mmol) of n-BuLi (1.43 M in hexane),

and 0.4 mL (5.1 mmol) of ClCO₂Me was obtained 243 mg (75%) of

l

mate was obtained 230 mg (76%) of 12f after silica gel chromatog-

raphy (hexane/EtOAc, 10:1). Data for 12f: ¹H NMR (300 MHz)

7.29–7.17 (m, 5H, Ph), 4.16–4.13 (br, 1H, HC(3⁰)), 3.92–3.66 (br,

3H, HC(2), CH₂OCO₂CH₃), 3.73 (s, 3H, H₃COCO₂), 3.66 (br s, 3H,

H₃CO(C@O)N), 3.3–3.0 (2br m, 2H, H₂C(5)), 2.64 (m, 2H, H₂C(1⁰)),

1292

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

2.24, 1.98 (2br m, 2H, H₂C(2⁰)), 1.74 (m, 4H, H₂C(3), H₂C(4)), 1.5–

1.2 (br m, 6H, H₂C(4⁰), H₂C(5⁰), H₂C(6⁰)), 0.87 (m, 3H, H₃C(7⁰)). ¹³C

NMR (75.5 MHz) 156.21, 155.64, 141.82, 128.32, 128.20, 125.66,

69.41, 61.57, 58.73, 54.63, 54.12, 52.08, 34.76, 32.86, 32.76,

28.58, 27.26, 23.86, 22.66, 13.99. MS (70 eV) 406 (5), 318 (9), 317

(42), 257 (8), 158 (53), 156 (13), 155 (8), 144 (11), 143 (100),

117 (8), 111 (22), 105 (16), 104 (9), 97 (9), 91 (63). HRMS

(m), 1454 (m), 1439 (m), 373 (m), 1313 (s), 1194 (m), 1109 (s),

1030 (m) cm^ꢁ1; MS (70 eV) m/z 427 (M⁺, 1), 338 (24), 337 (100),

230 (32), 143 (72), 111 (26); TLC R_f0.15 (hexane/EtOAc, 5:1); GC

t_R15d, 15.93 min (95%); t_R15d⁰17.31 min (5%) (column A;

250 °C isothermal). Anal. Calcd for C₂₅H₃₄N₂O₄(426.56): C, 70.39;

H, 8.03; N, 6.56. Found: C, 70.42; H, 8.04; N, 6.59.

C

₂₂H₃₄N₂O₅Calcd: 406.24677. Found: 406.24721. TLC R_f0.63 (hex-

6.4.20. 2-Phenylethyllithium

ane/EtOAc, 1:1). HPLC t_R12f, 4.1 min (70%), t_R12f⁰, 6.5 min (30%)

(column 1; hexane/EtOAc/i-PrOH, 98.0:1.5:0.5). Anal. Calcd for

A 10 mL two-necked ﬂask ﬁtted with septum and gas inlet was

ﬂame-dried. To this ﬂask t-BuLi (1.7 M in pentane, 2.34 mL,

3.98 mmol, 2.00 equiv) was added and the reaction vessel was

cooled to ꢁ120 °C (pentane/liquid N₂). Et₂O (3 mL) was added, fol-

lowed by the dropwise addition of 2-phenylethyliodide (459 mg,

1.98 mmol). GC analysis (column A) of an H₂O-quenched aliquot

indicated complete consumption of starting material in less than

5 min. The major (>90%) product observed by GC was ethylben-

zene, and no styrene was detected. Titration of this solution by

the method of Gilman⁶⁹indicated that 2-phenylethyllithium was

produced in >95% yield. This alkyl lithium reagent was found to

be unstable as a pentane/Et₂O solution at temperatures above

ꢄ0 °C and decomposed rapidly at rt. As this reagent was not

shelf-stable, samples were prepared as required and transferred

to the appropriate reaction vessel via cannula. Further evidence

for the formation of 2-phenylethyllithium is clean conversion of

12–14 to 11a⁰–c⁰as described below. Data for GC runs: 2-phenyle-

thyliodide, t_R10.24 (column A; 60(4), 20, 220 (10)) ethylbenzene,

t_R4.91 (column A; 60(4), 20, 220 (10)) styrene, t_R5.26 (column

A; 60(4), 20, 220 (10)).

C

₂₂H₃₄N₂O₅(406.53): C, 65.00; H, 8.43; N, 6.89. Found: C, 64.97;

H, 8.43; N, 7.00.

6.4.17. (2S,1⁰R)-2-(2-Methoxyethoxymethyl)-1-[N-(1-methyl-3-

phenylpropyl)-N-methoxycarbonylamino]pyrrolidine 5d

From 0.145 g (0.50 mmol) of hydrazone 1d, 0.372 g (1.00 mmol)

of CeCl₃ꢀ7H₂O, 0.66 mL (1.00 mmol) of MeLi (1.52 M in Et₂O), and

0.2 mL (0.25 mmol) of ClCO₂Me was obtained 131 mg (78%) of 5d

as a clear colorless oil after chromatography (hexane/EtOAc, 5:1)

and distillation. Data for 5d: bp 190 °C (0.05 mm Hg); ¹H NMR

(300 MHz) d 7.40–7.10 (m, 5H, Ph), 4.30–3.00 (m, 13H), 3.33 (s,

3H, CO₂CH₃), 2.70–2.50 (m, 2H), 2.30–1.60 (m, 6H), 1.16 (d,

J = 6.5, 3H, CCH₃); ¹³C NMR (75 MHz) d 141.78, 128.03, 125.49,

73.95, 71.63, 70.11, 62.0 (br), 58.72, 55.00 (br), 54.30, 51.88,

36.17, 32.72, 27.63, 23.41, 18.99; IR (neat) 3061 (w), 3026 (w),

2947 (s), 2876 (s), 1701 (s), 1605 (w), 1496 (m), 1439 (s), 1385

(m), 1319 (s), 1253 (w), 1196 (m), 1109 (s), 1049 (m) cm^ꢁ1; MS

(70 eV) m/z 364 (M⁺, 1), 276 (11), 275 (100), 143 (10); TLC R_f

0.10 (hexane/EtOAc, 5:1); GC t_R5d, 11.71 min (96.6%); t_R5d⁰,

12.45 min (3.4%) (column A, 230 °C isothermal); [

(c = 1.42, CHCl₃). Anal. Calcd for C₂₀H₃₂N₂O₄: C, 65.90; H, 8.84; N,

7.68. Found: C, 65.85; H, 8.87; N, 7.69.

a

]

_D= ꢁ50.0

6.5. General procedure for the addition of ’PhCH₂CH₂CeCl₂’ to

19d–21d

6.5.1. (2S,1⁰S)-1-(N-Methoxycarbonyl-N-(1-methyl-3-phenyl-

propyl)amino)-2-(2-methoxyethoxymethyl)pyrrolidine 5d⁰

To a 25-mL, two-necked ﬂask ﬁtted with septum and gas inlet

6.4.18. (2S,1⁰⁰S)-1-[N-(1,1-Dimethylethyl)-3-phenylpropylamino]-

2-(2-methoxyethoxymethyl)pyrrolidine 14d

From 0.145 g (0.50 mmol) of hydrazone 1a, 0.372 g (1.00 mmol)

of CeCl₃ꢀ7H₂O, and 0.60 mL (1.02 mmol) of t-BuLi (1.67 M in pen-

tane) was obtained 153 mg (87%) of 14d as a clear, colorless oil

after distillation. Data for 14d: bp 200 °C (0.2 mm Hg); ¹H NMR

(300 MHz) d 7.40–7.10 (m, 5H, Ph), 4.10–3.30 (m, 7H), 3.00–1.10

(m, 13H), 1.00–0.80 (s, br, 9H, C(CH₃)₃; IR (neat) 3450 (br), 3025

(w), 2954 (s), 2860 (s), 1605 (w), 1496 (m), 1476 (m), 1454 (m),

1392 (w), 1362 (m), 1320 (w), 1243 (w), 1201 (m), 1106 (s),

1030 (m) cm^ꢁ1; MS (10 eV) m/z 348 (M⁺, 7), 291 (88), 259 (100),

215 (65), 153 (63), 118 (24), 117 (38), 91 (91), 84 (24), 70 (30),

57 (34); TLC R_f0.75 (hexane/EtOAc, 4:1); GC t_R14d, 19.3 min

(1%); t_R14d⁰20.9 min (99%) (column A; 200 °C isothermal). Anal.

Calcd for C₂₁H₃₆N₂O₂: C, 72.37; H, 10.40; N, 8.03. Found: C,

74.10; H, 10.32; N, 7.71 (satisfactory analytical data could not be

obtained).

.

was added CeCl₃7H₂O (305 mg, 0.81 mmol, 2.7 equiv) which was

dried at 140 °C/0.2 mm Hg for 2 h. The ﬂask was allowed to cool

to rt, vented to dry N₂, and THF (5 mL) was added. The reaction

mixture was stirred for 2 h at rt and cooled to ꢁ78 °C (i-PrOH/

CO₂). A solution of 2-phenylethyllithium (0.81 mmol, 2.7 equiv,

freshly prepared as described above) was added slowly via syringe.

The reaction mixture was stirred for 1 h at ꢁ78 °C. A solution of the

hydrazone 19d (58 mg, 0.29 mmol) in THF (4 mL) was added

slowly via syringe and the reaction mixture was stirred for 1 h at

ꢁ78 °C. The reaction mixture was allowed to warm to rt and react

for 2 h. Methyl chloroformate (0.140 mL, 1.81 mmol, 6.2 equiv)

was added and the reaction mixture was stirred for 16 h. The reac-

tion mixture was poured into H₂O (15 mL) and extracted with

EtOAc (3 ꢂ 20 mL). The extracts were washed with brine

(1 ꢂ 15 mL), combined, dried (Na₂SO₄), ﬁltered through a pad of

Celite, and concentrated to afford an orange oil. GC (column A)

analysis of this crude product provided a ratio of 5d⁰:5d of

96.4:3.6 dr. Co-injection of this material with a sample of the crude

material obtained above in the addition of CH₃Li/CeCl₃to 1d

proved the diastereomeric relationship of the peaks being analyzed

and conﬁrmed the previous assignment of diastereomers in the GC

trace. Puriﬁcation by silica gel chromatography (hexane/EtOAc,

5:1) provided 56 mg (53%) of 5d⁰. Data for 5d⁰: ¹H NMR

(300 MHz) 7.21 (m, 5H, Ph), 4.3–4.0 (br m, 1H, HC(1⁰)), 3.69 (br s,

3H, H₃CO₂C), 3.55 (m, 6H, CH₂OCH₂CH₂OCH₃), 3.37 (s, 3H,

CH₂OCH₃), 3.4–3.0 (m, HC(2), H₂C(5)), 2.58 (t, 2H, J = 7.25,

H₂C(3⁰)), 2.2 (br m, 1H, HC(2⁰)), 1.90 (m, 2H, H₂C(3)), 1.7 (br m,

1H, HC(2⁰)), 1.66 (m, 2H, H₂C(4)), 1.19 (d, 3H, J = 6.63, H₃C). ¹³C

NMR (75.5 MHz) 142.05, 128.19, 125.70, 74.05, 71.89, 70.33,

58.97, 53.99, 52.06, 36.92, 32.98, 27.70, 23.33, 19.35. TLC t_R0.25

6.4.19. (2S,1⁰⁰S)-1-[N-(1,3-Diphenylpropyl)-N-methoxycarbonyl-

amino)-2-(2-methoxyethoxymethyl)pyrrolidine 15d

From 0.145 g (0.50 mmol) of hydrazone 1d, 0.327 g (1.00 mmol)

of CeCl₃ꢀ7H₂O, 0.5 mL (1.00 mmol) of PhLi (2.0 min Et₂O/cyclohex-

ane), and 0.2 mL (0.25 mmol) of ClCO₂Me was obtained 167 mg

(78%) of 15d as a clear, colorless oil after chromatography (hex-

ane/EtOAc, 5:1) and distillation. Data for 15d: bp 220 °C

(0.02 mm Hg); ¹H NMR (300 MHz) d 7.40–7.17 (m, 10H, 2 Ph),

5.40–5.00 (m, 1H, HC(1⁰)), 3.74 (s, 3H, CO₂CH₃), 3.70–3.40 (m,

6H), 3.35 (s, 3H, OCH₃), 3.30–3.20 (m, 1H, HC(2)), 2.70–1.80 (m,

6H, H₂C(2⁰⁰), H₂C(3⁰⁰), HC(5)), 1.70–1.40 (4H, H₂C(3), H₂C(4)); ¹³C

NMR (75 MHz) d 141.57, 139.98, 128.74, 128.22, 128.12, 127.87,

127.52, 127.42, 127.25, 125.60, 73.87, 71.67, 70.17, 62.00 (br),

60.43, 58.79, 53.00 (br), 52.15, 32.96, 32.56, 27.45, 22.90; IR (neat)

3061(w), 3026 (w), 2951 (m), 2874 (m), 1699 (s), 1603 (w), 1496

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

1293

(hexane/EtOAc, 5:1). GC t_R5d, 10.83 (3.6%); t_R5d⁰, 11.60 (96.4%)

(column A; 230 °C isothermal).

pale yellow solution was concentrated to ꢄ6 mL by careful frac-

tional distillation. The residue was dissolved in dry Et₂O (80 mL),

cooled to 0 °C, and treated with LiAlH₄(820 mg, 22 mmol,

0.6 equiv). This suspension was heated to reﬂux and allowed to re-

act for 24 h. The reaction mixture was cooled to 0 °C, excess LiAlH₄

was quenched with 20% KOH (3 mL), and the reaction mixture was

heated to reﬂux for 20 min. The reaction mixture was allowed to

cool to rt, ﬁltered through a pad of Celite, and the resulting solids

were extracted with reﬂuxing Et₂O (75 mL) for 1 h. The combined

ethereal layers were dried (Na₂SO₄), ﬁltered through a pad of Cel-

ite, and fractionally distilled to remove the Et₂O. The residue was

distilled bulb-to-bulb to afford 1.2 g (11 mmol, 35%) of impure

hydrazine. A neat solution of this crude hydrazine (200 mg,

2.0 mmol) was cooled to 0 °C, treated with hydrocinnamaldehyde

(330 mL, 2.5 mmol, 1.25 equiv), and allowed to warm to rt and re-

act for 24 h. The reaction mixture was diluted with Et₂O (20 mL),

dried (K₂CO₃), ﬁltered through a pad of Celite, and concentrated

to afford a yellow oil. Puriﬁcation by column chromatography

(hexane/EtOAc, 6:1) and bulb-to-bulb distillation afforded

238 mg (21% for the four steps) of the hydrazone 25 as a clear

oil. Data for 25: bp 155–165 °C (1.1 mm Hg). ¹H NMR (300 MHz)

7.24 (m, 5H, Ph), 6.62 (t, J = 5.25, 1H, H(C1⁰)), 3.26 (m, 2H, HC(2),

HC(5)), 2.80 (m, 2H, H₂(C3⁰)), 2.68 (m, 1H, HC(5)), 2.54 (m, 2H,

H₂C(2⁰)), 1.94 (m, 2H, H₂C(4)), 1.85 (m, 1H, HC(3)), 1.44 (m, 1H,

HC(3)), 1.22 (t, J = 6.14, 3H, H₃C). ¹³C NMR (75.5 MHz) 141.62,

137.80, 128.42, 128.26, 125.77, 59.44, 49.44, 34.90, 34.10, 31.09,

21.23, 19.62. MS (70 eV) 216 (18), 201 (14), 126 (8), 125 (100),

104 (6), 91 (20), 65 (7). TLC R_f0.49 (hexane/EtOAc, 2:1). Anal. Calcd

for C₁₄H₂₀N₂(MW 216.33): C, 77.73; H, 9.32; N, 12.95. Found: C,

77.89; H, 9.46; N, 12.86.

6.5.2. (2S,3⁰R)-1-(3-(4,4-Dimethyl-1-phenylpentlyamino)-2-(2-

methoxyethoxymethyl)pyrrolidine 14d⁰

Following the procedure above for the preparation of 5d⁰, from

.

CeCl₃7H₂O (320 mg, 0.85 mmol, 2.02 equiv), 2-phenylethyllithium

(0.85 mmol, 2.0 equiv, freshly prepared as described above), and

hydrazone 20d (102 mg, 0.42 mmol) in THF (11 mL) was obtained

an orange oil. GC (column A) analysis of this crude product pro-

vided a ratio of 14d⁰:14d of 98:2, in addition to 30% of unreacted

20d. Co-injection of this material with a sample of the crude mate-

rial obtained in the addition of ‘t-BuCeCl₂’ to 1d proved the diaste-

reomeric relationship of the peaks being analyzed and conﬁrmed

the previous assignment of diastereomers in the GC trace. Data

for 14d⁰: ¹H NMR (300 MHz) 7.24 (m, 5H, Ph), 6.48 (dd 1H, HN),

4.20 (d, 1H, HC(3⁰)), 4.0–2.4 (several m, 12H, CH₂OCH₂CH₂OCH₃,

HC(2), H₂C(5)), 2.9–2.6 (3 m, 4H, H₂C(1⁰), H₂C(2⁰)), 0.89 (s, 9H,

(H₃C)₃C). TLC t_R0.69 (hexane/EtOAc, 1:1). GC 14d⁰: t_R19.25

(98%); 14d: t_R20.89 (2%) (column A; 200 °C isothermal).

6.5.3. (2S,1⁰R)-1-(N-Methoxycarbonyl-N-(1,3-diphenylpropyl)-

amino)-2-(2-methoxyethoxy-methyl)pyrrolidine 15d⁰

Following the procedure above for the preparation of 5d⁰, from

.

CeCl₃7H₂O (501 mg, 1.34 mmol, 2.48 equiv), 2-phenylethyllithium

(1.31 mmol, 2.4 equiv, freshly prepared as described above), hydra-

zone 21d (142 mg, 0.54 mmol), and methyl chloroformate

(0.220 mL, 2.85 mmol, 4.0 equiv) in THF (11 mL) was obtained an

orange oil. GC (column A) analysis of this crude product provided

a ratio of 15d⁰:15d of 96.6:3.4. Co-injection of this material with

a sample of the crude material obtained above in the addition of

‘PhCeCl₂’ to 1d proved the diastereomeric relationship of the peaks

being analyzed and conﬁrmed the previous assignment of diaste-

reomers in the GC trace. Puriﬁcation by silica gel chromatography

(hexane/EtOAc, 8:1) and bulb-to-bulb distillation provided 184 mg

(80%) of 15d⁰as a clear oil. Data for 15d⁰: bp 190–200 °C/

0.01 mm Hg. ¹H NMR (300 MHz) 7.25 (m, 10H, Ph), 5.50–5.10

(2br m, 1H, HC(1⁰)), 3.78 (s, 3H, H₃CO₂), 3.36–3.16 (m, 3H, HC(2),

H₂COCH₂CH₂), 3.30 (s, 3H, H₃COCH₂), 3.29 (m, 2H, CH₂CH₂OCH₃),

3.07 (m 2H, CH₂CH₂OCH₃), 2.63 (m, 2H, H₂C(3⁰)), 2.30 (m, 3H,

H₂C(5), HC(3)), 2.08–1.81 (2br m, 2H, H₂C(2⁰)), 1.72 (m, 2H,

H₂C(4)), 1.49 (m, 1H, HC(3). ¹³C NMR (75.5 MHz) 140.74, 129.21,

128.37, 128.07, 127.56, 125.89, 73.06, 71.51, 69.78, 60.77, 58.96,

52.00, 32.85, 27.86. TLC t_R0.35 (hexane/EtOAc, 3:1). GC 15d: t_R

15.93 (3.4%); 15d⁰: t_R17.31 (96.6%) (column A; 250 °C isothermal).

6.5.5. (S)-(2l,3⁰u)-1-(N-Methoxycarbonyl-3⁰-(1-phenylheptylamino))-

2-methylpyrrolidine 32

To a 25-mL, two-necked ﬂask ﬁtted with septum and gas inlet

.

was added CeCl₃7H₂O (249 mg, 0.67 mmol, 2.03 equiv) which

was dried at 140 °C (0.2 mm Hg) for 2 h. The ﬂask was allowed

to cool to rt, vented to dry N₂, and THF (5 mL) was added. The

resulting slurry was stirred for 2 h at rt and cooled to ꢁ78 °C (i-

PrOH/CO₂). To this white suspension n-BuLi (1.55 M in hexane,

0.43 mL, 0.67 mmol, 2.03 equiv) was added dropwise via syringe

and the yellow reagent was stirred at ꢁ78 °C for 1 h. A solution

of the hydrazone 25 (72 mg, 0.33 mmol) in THF (5 mL) was added

slowly via syringe and the reaction mixture was stirred for 1 h at

ꢁ78 °C. The reaction mixture was allowed to warm to rt and react

for 2 h at rt. Methyl chloroformate (0.090 mL, 1.11 mmol,

3.5 equiv) was added slowly via syringe and the reaction mixture

was stirred for 26 h at rt. The reaction mixture was poured into

H₂O (30 mL) and extracted with Et₂O (3 ꢂ 40 mL). The extracts

were washed with brine (1 ꢂ 30 mL), combined, dried (Na₂SO₄), ﬁl-

tered through a pad of Celite, and concentrated to afford an orange

oil. Analysis of this crude material by GC (column A) or HPLC (col-

umns 1 or 4) showed a single peak. Puriﬁcation by column chroma-

tography (hexane/EtOAc, 16:1) and bulb-to-bulb distillation

afforded 70 mg (64%) of the carbamate 32. Data for 32: bp 145–

50 °C (0.08 mm Hg). ¹H NMR (300 MHz) 7.23 (m, 5H, Ph), 4.05,

3.95 (2br m, 1H, HC(3⁰)), 3.8–3.6 (br m, 1H, HC(2)), 3.66 (br s, 3H,

H₃CO), 3.6–3.0 (3 br m, 2H, H₂C(5)), 2.64 (m, 2H, H₂C(1⁰)), 2.2–

1.6 (br m, 6H, H₂C(2⁰), H₂C(3), H₂C(4)), 1.5–1.1 (br m, 6H,

H₂(C(4⁰), H₂(C(5⁰), H₂(C(6⁰)), 1.05 (d, J = 6.35, 3H, H₃C), 0.87 (m,

3H, H₃C(7⁰)). ¹³C NMR (75.5 MHz) 155.93, 142.2 (br), 128.30,

128.20, 125.60, 58.85, 57.57, 53.72, 51.88, 34.77, 33.05, 32.95,

32.19, 28.71, 23.23, 22.74, 21.63, 14.03. IR (CCl₄) 3028 (m), 2961

(s), 2872 (s), 1699 (s), 1496 (m), 1454 (s), 1439 (s), 1383 (m),

1331 (s), 1226 (m), 1190 (m), 1120 (m), 1101 (m). MS (70 eV)

332 (8), 158 (16), 157 (15), 143 (32), 125 (8), 91 (36), 85 (7), 84

(100). GC t_R14.75 (column A; 200 °C isothermal). TLC R_f0.62 (hex-

6.5.4. (R)-1-(3-Phenylpropylidenamino)-2-methylpyrrolidine 25

A 250-mL, one-necked ﬂask was ﬁtted with a reﬂux condenser

and gas inlet which was vented to a trap containing 6 N HCl. A

solution of 2-methyl-1-tosylpyrrolidine (23)⁵⁴(7.27 g, 30.3 mmol)

in isoamyl alcohol (100 mL) was heated to reﬂux and sodium metal

(7.5 g, 320 mmol, 10 equiv) was added in ꢄ200 mg portions. Upon

complete consumption of the sodium, the reaction mixture was

cooled to 0 °C and treated with 6 N HCl (45 mL). The contents of

the trap were added to the reaction mixture which was then

washed with Et₂O (2 ꢂ 200 mL). The ethereal layers were extracted

with 3 N HCl (2 ꢂ 100 mL). The aqueous layers were combined,

cooled to 0 °C, and Et₂O (150 mL) was added. This solution was

brought to pH 12 by the slow addition of solid NaOH (ꢄ40 g).

The layers were separated and the aqueous layer was extracted

with Et₂O (3 ꢂ 100 mL) and CH₂Cl₂(2 ꢂ 100 mL). The combined or-

ganic layers were concentrated to ꢄ10 mL by careful fractional dis-

tillation. The residue was dissolved in dry Et₂O (50 mL), cooled to

0 °C, and treated with n-BuONO (7.0 mL, 60 mmol, 2.0 equiv). The

reaction mixture was allowed to react for 30 min at 0 °C and then

allowed to warm to rt and react for 36 h at rt The resulting clear

1294

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

ane/EtOAc, 3:1). Anal. Calcd for C₂₀H₃₂N₂O₂(MW 332.49): C, 72.25;

H, 9.70; N, 8.43. Found: C, 72.30; H, 9.71; N, 8.46.

The organic layers were combined, dried (Na₂SO₄), ﬁltered through

a pad of Celite, and concentrated to afford a yellow oil. Puriﬁcation

by column chromatography (hexane/EtOAc, 8:1) afforded the

44 mg (51% for the three steps) of the amide 33 as white crystals.

Separation of the enantiomers was achieved on HPLC column 3 and

a 94:6 ratio of R to S enantiomers was indicated. The TLC, ¹H NMR,

and HPLC data matched those of the racemic sample prepared be-

low. Data for 33: HPLC t_R(S) 21.33 (6%), (R) 23.73 (94%) (column 3;

6.6. General procedure for the preparation of (R,S)-3-(3,5-dini-

trobenzamido)-1-phenylheptane 33 from Hydrazones 1a and 25

.

To a 20-mL, two-necked ﬂask was charged CeCl₃7H₂O (559 mg,

1.50 mmol, 1.50 equiv) which was dried at 140 °C/0.2 mm Hg for

2 h. The ﬂask was allowed to cool to rt, vented to dry nitrogen,

and THF (7 mL) was added. The reaction mixture was stirred for

2 h at rt and cooled to ꢁ78 °C (i-PrOH/CO₂). To this white suspen-

sion, n-BuLi (1.55 M in hexane, 0.98 mL, 1.52 mmol, 1.52 equiv)

was added dropwise via syringe and the reaction mixture was stir-

red for 1 h at ꢁ78 °C. A solution of hydrocinnamaldehyde dim-

ethylhydrazone 42 (176 mg, 1.00 mmol) in THF (5 mL) was added

via syringe and the reaction mixture was stirred for 1 h at

ꢁ78 °C. The reaction mixture was allowed to warm to rt and react

for 2 h at rt The reaction mixture was cooled to 0 °C, the reaction

was quenched with CH₃OH (3 mL), and the mixture was poured

into H₂O (20 mL), and extracted with Et₂O (3 ꢂ 30 mL). The ex-

tracts were washed with brine (1 ꢂ 20 mL), combined, dried

(MgSO₄), ﬁltered through a pad of Celite, and concentrated to af-

ford a clear oil. The residue was dissolved in CH₃OH (5 mL) and

treated with excess Raney Ni and stirred under a H₂atmosphere

(100 psi) for 12 h. The reaction mixture was ﬁltered through a

pad of Celite and concentrated to afford a clear oil which was dis-

solved in THF (5 mL). This solution was treated with a solution of

K₂CO₃(1 g) in H₂O (5 mL) and 3,5-dinitrobenzoylchloride

(465 mg, 2.01 mmol, 2.01 equiv) and stirred for 12 h at rt. The lay-

ers were separated and the aqueous layer was extracted with

CH₂Cl₂(2 ꢂ 10 mL). The organic layers were combined, dried

(Na₂SO₄), ﬁltered through a pad of Celite, and concentrated to af-

ford a yellow oil. Puriﬁcation by column chromatography (hex-

ane/EtOAc, 8:1) afforded 260 mg (68%) of the amide 33 as white

crystals. A sample was recrystallized from hexane/CH₂Cl₂for anal-

ysis. Separation of the enantiomers was achieved on HPLC column

3 (hexane/EtOAc, 99:1, 2 mL/min). Data for 33: mp 115–116 °C

hexane/i-PrOH, 99:1, 2 mL min^ꢁ1

)

6.6.2. (94%R,6%S)-3-(3,5-Dinitrobenzamido)-1-phenylheptane

33 from 1a

.

Following the general procedure described above, from CeCl₃7-

H₂O (373 mg, 1.00 mmol, 2.00 equiv), n-BuLi (1.55 M in hexane,

0.65 mL, 1.00 mmol, 2.00 equiv) and 1a (123 mg, 0.50 mmol) in

THF (11 mL) was obtained a clear oil. This material was dissolved

in dry CH₃OH, treated with excess Raney Ni, and stirred under an

atmosphere of H₂(350 psi) for 36 h at rt. The reaction mixture

was ﬁltered through a pad of Celite and concentrated to afford a

clear oil, which was dissolved in THF (5 mL). To this solution was

added a solution of K₂CO₃(ꢄ1 g) in H₂O (5 mL) and 3,5-dinitroben-

zoylchloride (240 mg, 1.04 mmol, 2.0 equiv). The resulting biphasic

reaction mixture was stirred for 2 h at rt. The layers were separated

and the aqueous layer was extracted with CH₂Cl₂(2 ꢂ 10 mL). The

organic layers were combined, dried (Na₂SO₄), ﬁltered through a

pad of Celite, and concentrated to afford a yellow oil. Puriﬁcation

by column chromatography (hexane/EtOAc, 8:1) afforded 80 mg

(42% for the three steps) of the amide 33 as white crystals. Separa-

tion of the enantiomers was achieved on HPLC column 3 and a 94:6

ratio of R to S enantiomers was indicated. The TLC, ¹H NMR, and

HPLC data matched those of the racemic sample prepared above.

Data for 33: HPLC t_R(S) 21.33 (6%), (R) 23.73 (94%) (column 3; hex-

ane/i-PrOH, 99:1, 2 mL min^ꢁ1).

6.6.3. (S)-1-Benzyloxycarbonyl-2-hydroxymethylpyrroldine 27

A 100-mL, three-necked ﬁtted with reﬂux condenser and rubber

septa was ﬂame-dried. A solution of (S)-1-benzyloxycarbonyl pro-

line (26) (850 mg, 3.41 mmol) in THF (35 mL) was cooled to 0 °C.

To this solution BH₃–THF (1.20 M, 2.90 mL, 3.48 mmol, 1.02 equiv)

was added slowly via syringe. The reaction mixture was stirred for

5 min at 0 °C, then slowly heated to a gentle reﬂux for 60 min. The

reaction mixture was cooled to 0 °C, THF/H₂O (2:1, 30 mL) was

added, and the reaction mixture was heated to reﬂux for 20 min.

The reaction mixture was poured into H₂O (40 mL) and extracted

with Et₂O (3 ꢂ 75 mL). The extracts were washed with a 10% solu-

tion of NaHCO₃(1 ꢂ 40 mL) and brine (1 ꢂ 40 mL), combined, dried

(K₂CO₃), ﬁltered through a pad of Celite, and concentrated. Puriﬁ-

cation by bulb-to-bulb distillation afforded 649 mg (81%) of analyt-

ically pure (S)-1-benzyloxycarbonyl-2-hydroxymethylpyrroldine

27 as a clear oil. Data for (S)-1-benzyloxycarbonyl-2-hydroxym-

ethylpyrroldine: bp 210–220 °C/0.5 mm Hg. ¹H NMR (300 MHz)

7.33–7.31 (br m, 5H, Ph), 5.11 (2 s, 2H, H₂CPh), 4.56 (exch, 1H,

HO), 3.98–3.92 (m, 1H, HC(2)), 3.61–3.33 (m, 4H, H₂C(5), H₂COH),

1.99–1.61 (m, 4H, H₂C(3), H₂C(4)). ¹³C NMR (75.5 MHz) 156.47,

136.26, 128.18, 128.05, 127.72, 127.56, 126.56, 66.82, 65.76,

63.43, 60.15, 58.39, 46.93, 28.09, 23.66. Most peaks have shoulders,

indicating several rotamers. IR (CCl₄) 3435 (br), 3036 (w), 2955

(w), 2882 (m), 1684 (s), 1559 (w), 1541 (w), 1499 (w), 1451 (m),

1418 (s), 1358 (m), 1339 (m), 1190 (m), 1109 (m). MS (10 eV)

235 (M+, 1.6), 204 (21), 160 (19), 92 (8), 91 (100). TLC R_f0.50

(CH₂Cl₂/CH₃OH, 10:1). Anal. Calcd for C₁₃H₁₇NO₃(MW 235.29):

C, 66.36; H, 7.28; N, 5.95. Found: C, 66.31; H, 7.29; N, 5.93.

1

(hexane/CH₂Cl₂) H NMR (300 MHz) 9.11 (s, 1H, HC(4⁰)), 8.76 (d,

J = 1.79, 2H, HC(2⁰), HC(6⁰)), 7.24 (m, 5H, Ph), 6.10 (d, J = 7.04, 1H,

HN), 4.28 (m, 1H, HC(3)), 2.75 (m, 2H, H₂C(1)), 1.95 (m, 2H,

H₂C(2)), 1.65 (m, 2H, H₂C(4)), 1.35 (br m, 4H, H₂C(5), H₂C(6)),

0.90 (m, 3H, H₃C(7)). ¹³C NMR (75.5 MHz) 162.07, 148.47,

141.51, 138.00, 128.63, 128.19, 126.95, 126.43, 51.18, 35.99,

34.83, 32.41, 28.12, 22.54, 13.97. MS (70 eV) 385 (12), 281 (61),

280 (18), 238 (30), 224 (8), 195 (64), 174 (23), 118 (12), 117

(88), 105 (12), 104 (60), 103 (14), 92 (15), 91 (100), 75 (26). IR

(KBr) 3266 (s), 3084 (s), 3029 (m), 2924 (s), 2851 (s), 2851 (s),

1640 (s), 1549 (s), 1449 (s), 1373 (s), 1308 (s), 1179 (s). HPLC

t_R= 25.0 (S) and 28.5 (R) (column 3; hexane/i-PrOH, 97:3,

1 mL min^ꢁ1). Anal. Calcd for C₂₀H₂₃N₃O₅(385.42): C, 62.33; H,

6.02; N, 10.90. Found: C, 62.21; H, 6.11; N, 10.80.

6.6.1. (94%R,6%S)-3-(3,5-Dinitrobenzamido)-1-phenylheptane

33 from 25

.

Following the general procedure described above, from CeCl₃7-

H₂O (269 mg, 0.72 mmol, 2.00 equiv), n-BuLi (1.33 M in hexane,

0.56 mL, 0.74 mmol, 2.04 equiv) and 25 (78 mg, 0.36 mmol) in

THF (11 mL) was obtained a clear oil. This material was dissolved

in dry CH₃OH, treated with excess Raney Ni. and stirred under an

atmosphere of H₂(100 psi) for 36 h at rt The reaction mixture

was ﬁltered through a pad of Celite and concentrated to afford a

clear oil which was dissolved in THF (5 mL). To this solution was

added a solution of K₂CO₃(ꢄ1 g) in H₂O (5 mL) and 3,5-dinitroben-

zoylchloride (166 mg, 0.72 mmol, 2.0 equiv) and the biphasic reac-

tion mixture was stirred at rt for 2 h. The layers were separated

and the aqueous layer was extracted with CH₂Cl₂(2 ꢂ 10 mL).

6.6.4. (S)-1-Benzyloxycarbonyl-2-formylpyrrolidine 28

To a 100-mL, three-necked ﬂask were added CH₂Cl₂(20 mL) and

oxalyl chloride (1.06 mL, 11.06 mmol, 1.11 equiv). This solution

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

1295

was cooled to ꢁ78 °C and

a

solution of DMSO (1.71 mL,

6.6.6. (75.0%R,25.0%S)-2-(2-Methylpropyl)pyrrolidine 30

24.09 mmol, 2.41 equiv) in CH₂Cl₂(15 mL) was added slowly via

addition funnel. The reaction mixture was stirred for 15 min at

ꢁ78 °C and a solution of (S)-1-benzyloxycarbonyl-2-hydroxymeth-

ylpyrroldine 27 (2.353 g, 10.00 mmol) in CH₂Cl₂(20 mL) was added

dropwise via addition funnel. The reaction mixture was stirred for

60 min at ꢁ78 °C and Et₃N (6.97 mL, 50.00 mmol, 5.00 equiv) was

added via syringe. The resulting suspension was stirred at ꢁ78 °C

for 20 min, allowed to warm to rt, and clariﬁed with H₂O (25 mL).

The layers were separated and the aqueous layer was extracted with

CH₂Cl₂(3 ꢂ 50 mL). The organic layers were washed with a 10%

solution of NaHCO₃(1 ꢂ 30 mL) and brine (1 ꢂ 30 mL), combined,

dried (Na₂SO₄), and concentrated to afford 2.336 g (quant) of the

aldehyde as a pale yellow oil. A portion (2.220 g) of this material

was distilled bulb-to-bulb to afford 2.0189 g (95%) of the aldehyde

28 as a thick, clear, colorless oil. The balance of the crude aldehyde

(216 mg) was puriﬁed by silica gel chromatography (hexane/EtOAc,

3:1) and bulb-to-bulb distillation to afford the analytical sample.

Data for 28: bp 155–160 °C (0.06 mm Hg). ¹H NMR (300 MHz)

9.48, 9.39 (2s, 1H, CHO), 7.31–7.24 (m, 5H, Ph), 5.09, 5.06 (2s, 2H,

H₂CPh), 4.21–4.10 (2m, 1H, HC(2)), 3.51–3.42 (m, 2H, H₂C(5)),

2.04–1.70 (m, 4H, H₂C(3), H₂C(4)). ¹³C NMR (75.5 MHz) 199.54,

199.49, 154.82, 153.96, 136.11, 135.91, 128.06, 127.85, 127.62,

127.46, 66.68, 64.85, 64.44, 46.85, 46.27, 27.26, 26.14, 24.05,

23.22. As the ¹H and ¹³C NMR spectra indicate, this material exists

primarily as two rotamers in solution. IR (CCl₄) 3924 (w), 3359

(w), 3069 (w), 3036 (w), 2955 (m), 2882 (m), 2809 (w), 2521 (w),

1738 (s), 1705 (s), 1549 (m), 1499 (m), 1451 (m), 1414 (s), 1356

(s), 1252 (m), 1211 (m), 1103 (s), 980 (m), 916 (w). MS (10 eV) 205

(3), 204 (17), 160 (13), 92 (8), 91 (100). TLC R_f0.35 (hexane/EtOAc,

1:1). Anal. Calcd for C₁₃H₁₅NO₃(233.27): C, 66.94; H, 6.48; N, 6.00.

Found: C, 66.67; H, 6.46; N, 5.92.

In a 125-mL Erlenmeyer ﬂask containing a magnetic stir bar, a

solution of the 29 (3.002 g, 11.57 mmol) in CH₃OH (50 mL) was

treated with AcOH (ꢄ5 drops). To this solution was added 5% pal-

ladium on carbon which had been pre-activated by exposure to an

H₂atmosphere (60 psi) for 15 min. The reaction vessel was placed

in a Parr bomb and saturated with H₂by evacuating to 60 mm Hg,

pressurizing to 100 psi H₂, and repeating this procedure three

times. The Parr bomb was pressurized to 100 psi H₂a ﬁnal time

and placed on a magnetic stirrer. The reaction mixture was stirred

for 16 h at rt, saturated with N₂(in analogy to the method of H₂

saturation described above), and ﬁltered through a pad of Celite.

The precipitates were washed with Et₂O (50 mL) and the resulting

solution was washed with NaOH (4 N in H₂O, 2 ꢂ 60 mL). The

aqueous layers were extracted with Et₂O (2 ꢂ 60 mL) and the ethe-

real layers were extracted with HCl (3 N in H₂O, 3 ꢂ 60 mL). The

combined aqueous layers were cooled to 0 °C, basiﬁed by the addi-

tion of solid NaOH, and extracted with Et₂O (3 ꢂ 100 mL). The ex-

tracts were washed with brine (1 ꢂ 100 mL), combined, dried

(K₂CO₃), ﬁltered through a pad of Celite, and concentrated at

60 mm Hg at rt to afford 1.252 g (85%) of the crude amine as a

clear, colorless liquid. Chiral HPLC analysis of the 3,5-dinitrobenz-

amide derived from a sample of this material (prepared in analogy

to the description below) indicated a 75.0:25.0 mixture of R/S

enantiomers. Amine 30 obtained from the four-step procedure

starting with N-Cbz proline outlined above had enantiomeric ex-

cesses that ranged from 67.5:33.5 er to 90.5:9.5 er, determined

by conversion to the 3,5-dinitrobenzamide. This volatile, air-sensi-

tive amine was not characterized, but the subsequent conversion

of 30 to the fully characterized hydrazone 31 veriﬁed the identity

of this material. Data for 30: ¹H NMR: (300 MHz) 3.05–2.80 (m, 3H,

HC(1), H₂C(5)), 1.90–1.10 (m, 7H, H₂C(3), H₂C(4), H₂(C(1⁰), HC(2⁰)),

0.94 (d, J = 6.8, 3H, H₃C(3⁰)), 0.98–0.92 (m, 3H, H₃C(4⁰)).

6.6.5. (S)-1-Benzyloxycarbonyl-2-(2-methyl-1-propenyl)pyrroli-

dine 29

6.6.7. (75.5%R,24.5%S)-2-(2-Methylpropyl)pyrrolidine 3,5-

To a 250-mL, three-necked ﬂask ﬁtted with two addition fun-

nels was charged isopropyl(triphenyl)phosphonium bromide

(5.619 g, 14.58 mmol, 1.30 equiv) and THF (35 mL). The reaction

mixture was cooled to 0 °C and n-BuLi (1.65 M in hexane,

7.14 mL, 11.78 mmol, 1.05 equiv) was added dropwise via addition

funnel. The reaction mixture was stirred for 30 min at 0 °C or until

the reaction mixture became homogeneous. To this burgundy-col-

ored ylide was added dropwise via addition funnel a solution of 28

(2.619 g, 11.22 mmol) in THF (35 mL). The reaction mixture was

stirred for 60 min at 0 °C, allowed to warm to rt, and H₂O

(20 mL) was added. The layers were separated and the aqueous

layer was extracted with Et₂O (2 ꢂ 60 mL). The extracts were

washed with brine (1 ꢂ 50 mL), combined, dried (K₂CO₃), ﬁltered

through a pad of Celite, and concentrated. The residue was puriﬁed

by silica gel chromatography (hexane/EtOAc, 16:1 to 2:1) and

bulb-to-bulb distillation to afford 2.590 g (89%) of the oleﬁn 29

as a clear oil. Data for 29: bp 135–145 °C (0.08 mm Hg). ¹H NMR

(300 MHz) 7.24 (br m, 5H, Ph), 5.08 (d, J = 12.4, 1H, HC(1⁰)), 5.04–

4.90 (br, H₂CPh), 5.50–5.30 (br m, HC(2)), 3.38 (br, 2H, H₂C(5)),

2.0–1.4 (br m, 10H, H₂C(3), H₂(4), H₃C(3⁰), H₃(4⁰)). ¹³C NMR

(75.5 MHz) 155, 137.03, 128.51, 128.17, 127.97, 127.92, 127.41,

126.90, 126.02, 125.94, 125.78, 125.69, 66.42, 55.56, 55.47, 55.26,

55.12, 46.54, 33.24, 32.57, 25.64, 24.08, 24.00, 23.48, 17.83,

17.74, 17.67. All peaks are broadened and have shadow peaks

due to rotamer equilibria. IR (CCl₄) 3035 (w), 2972 (m), 2877

(m), 1704 (s), 1448 (m), 1410 (s), 1376 (w), 1354 (s), 1335 (m),

1307 (w), 1185 (m), 1129 (m), 1102 (s). MS (70 eV) 260 (M+1,

0.8), 259 (M+, 5), 204 (8), 168 (19), 160 (5), 125 (3), 124 (35),

114 (10), 92 (8), 91 (100), 70 (5). TLC R_f0.47 (hexane/EtOAc,

1:1). Anal. Calcd for C₁₆H₂₁NO₂(259.35): C, 74.10; H, 8.16; N,

5.40. Found: C, 74.16; H, 8.18; N, 5.46.

dinitrobenzamide 43

In

a 20-mL, two-necked ﬂask, a solution of 30 (57 mg,

0.45 mmol) in THF (4 mL) was treated with a solution of K₂CO₃

(80 mg) in H₂O (4 mL). To this biphasic reaction mixture was added

3,5-dinitrobenzoyl chloride (155 mg, 0.67 mmol, 1.50 equiv). The

reaction mixture was stirred for 12 h at rt, Et₂O (5 mL), the layers

were separated, and the aqueous layer was extracted with Et₂O

(2 ꢂ 8 mL). The extracts were washed with brine (1 ꢂ 6 mL), com-

bined, dried (K₂CO₃), ﬁltered through a pad of silica gel, and con-

centrated to afford 102 mg (71%) of the crude amide as white

crystals. Separation of the enantiomers was achieved on HPLC col-

umn 2 (hexane/EtOAc/i-PrOH, 98.3:1.0/0.7, 0.8 mL min^ꢁ1), and a

75.5/24.5 ratio of R/S enantiomers was indicated. Data for 43: ¹H

NMR (300 MHz) 9.07 (br s, 1H, HC(4⁰⁰)), 8.68 (br s, 2H, HC(2⁰⁰),

HC(6⁰⁰)), 4.41–4.30 (br m, 1H, HC(2)), 3.53 (m, 1H, HC(5)), 3.38

(m, 1H, HC(5)), 2.21–1.60 (m, 6H, H₂C(3), H₂C(4), H₂C(1⁰)), 1.38–

1.22 (m, 1H, HC(2⁰)), 0.99 (t, 6H, J = 6.8, H₃C(3⁰), H₃C(4⁰)). HPLC

(S) t_R29.86, (R) t_R28.09 (column 2; hexane/EtOAc/i-PrOH,

98.3:1.0/0.7, 0.8 mL min^ꢁ1).

6.6.8. 1-(N-(3-Phenylethylideneamino))-2-(2-methylpropyl)-

pyrrolidine 31

A solution of 30 (1.010 g, 7.94 mmol) in Et₂O (30 mL) was cooled

to 0 °C and treated with n-BuONO (2.01 mL, 15.2 mmol, 1.9 equiv).

The reaction ﬂask was wrapped in aluminum foil to protect it from

light, allowed to warm to rt, and stirred at rt for 5 days. The reaction

mixture was poured into H₂O (15 mL) and extracted with Et₂O

(3 ꢂ 30 mL). The extracts were washed with H₂O (1 ꢂ 20 mL) and

brine (1 ꢂ 20 mL), combined, dried (K₂CO₃), ﬁltered through a pad

of Celite, and concentrated at 40 mm Hg to afford 1.115 g of an or-

ange liquid. The residue was dissolved in THF (40 mL), cooled to

1296

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

0 °C, and LiAlH₄(640 mg, 16 mmol, 2 equiv) was added in two equal

portions. The reaction mixture was heated to reﬂux and stirred for

24 h. The reaction mixture was cooled to 0 °C, and the reaction

was quenched by the sequential addition of H₂O (300 mL), a 20%

solution of KOH (300 mL), and then a second portion of H₂O

(1.0 mL). The reaction mixture was heated to reﬂux for 30 min,

cooled to rt, and ﬁltered through a pad of Celite. The salts were

washed with Et₂O (20 mL) and the ﬁltrate was concentrated at aspi-

rator pressure. Bulb-to-bulb distillation (120–130 °C/60 mm Hg)

afforded 698 mg (62%) of the crude hydrazine as a pale yellow oil.

In a 100-mL round-bottomed ﬂask ﬁtted with a Dean–Stark trap,

a solution of this crude hydrazine (420 mg, 3 mmol) in benzene

(30 mL) was treated with hydrocinnamaldehyde (400 mg, 3 mmol,

1.0 equiv) and heated to reﬂux with the azeotropic removal of

H₂O. The reaction mixture was heated at reﬂux for 24 h, allowed

to cool to rt, and concentrated. Puriﬁcation by silica gel chromatog-

raphy (hexane/EtOAc, 16:1) and bulb-to-bulb distillation afforded

451 mg (59%, 30% from 30) of the hydrazone 31 as a clear oil. Data

for 31: bp 155–165 °C (0.35 mm Hg). ¹H NMR (300 MHz) 7.26–

7.20 (m, 5H, Ph), 6.62 (t, J = 5.19, 1H, HC(1⁰)), 3.29 (m, 1H, HC(2)),

3.17 (m, 1H, HC(5)), 2.80 (m, 2H, H₂C(3’)), 2.68 (q, J = 7.93, 1H,

HC(5)), 2.55 (m, 2H, H₂C(2⁰)), 1.95–1.74 (m, 5H, H₂C(3), H₂C(4),

HC(2⁰⁰)), 1.47 (m, 1H, HC(1⁰⁰)), 1.18 (m, 1H, HC(1⁰⁰)), 0.94 (d, J = 7.58,

3H, H₃C(3⁰⁰)), 0.91 (d, J = 7.64, H₃C(4⁰⁰)). ¹³C NMR (75.5 MHz) 141.77,

137.20, 128.47, 128.27, 125.75, 65.52, 49.90, 43.73, 34.86, 34.02,

29.27, 25.71, 23.89, 22.22, 21.58. IR (CCl₄) 3850 (w), 3742 (w), 3440

(w), 3088 (w), 3065 (w), 3029 (w), 2957 (s), 2872 (m), 2363 (w),

1549 (s), 1497 (w), 1455 (w), 1368 (w), 1320 (w), 1250 (w), 1208

(w), 1163 (w), 1117 (w), 1005 (w), 978 (w). MS (70 eV) 258 (M+,

26), 202 (16), 201 (100), 167 (29), 124 (5), 111 (6), 104 (8), 91 (14).

TLC R_f0.38 (hexane/EtOAc, 1:1). GC t_R11.91 (column A; 140(4, 20,

200 (10)). Anal. Calcd for C₁₇H₂₆N₂(258.41): C, 79.02; H, 10.14; N,

10.84. Found: C, 79.08; H, 10.15; N, 10.80.

(m, 2H, H₂C(2)), 2.12, 1.92 (2 s, 3H, H₃C(C@O)N), 1.81 (m, 2H,

H₂C(4)), 1.35 (m, 4H, H₂C(5), H₂C(6)), 0.90 (m, 3H, H₃C(7)). ¹³C

NMR (75.5 MHz) 173.52, 141.99, 141.50, 128.52, 128.40, 128.31,

128.18, 126.07, 125.81, 61.42, 53.27, 45.08, 44.79, 44.03, 35.11,

34.12, 33.78, 33.00, 32.73, 32.19, 29.85, 29.01, 23.80, 22.99, 22.93,

22.83, 14.13, 14.07. MS (70 eV) 277 (M+1, 1), 276 (M+, 7), 234

(13), 233 (58), 129 (88), 128 (25), 117 (12), 105 (20), 102 (37), 101

(14), 91 (92), 86 (19), 85 (12), 60 (64), 59 (100). TLC R_f0.55 (hex-

ane/EtOAc, 1:1). Anal. Calcd for C₁₇H₂₈N₂O (276.43): C, 73.87; H,

10.21; N, 10.13. Found: C, 73.76; H, 10.29; N, 10.08.

6.6.10. (R,S)-N-Acetyl-1-phenyl-3-heptylamine 35

A 50-mL, three-necked ﬂask ﬁtted with a cold-ﬁnger was ﬂame-

dried. Both the ﬂask and the cold-ﬁnger were cooled to ꢁ78 °C, and

NH₃(20 mL) was distilled into the reaction vessel. Freshly cut lith-

ium metal (64 mg, 9.22 mmol, 4.00 equiv) was added to the reaction

vessel and a permanent blue color developed. A solution of (R,S)-

N-acetyl-N-dimethylamino-1-phenyl-3-heptylamine 44 (640 mg,

2.32 mmol) in THF (6 mL) was slowly added via syringe and the cold

bath was removed. The reaction mixture was stirred at reﬂux

(ꢁ33 °C) for 60 min and solid NH₄Cl (2 g) was added in approxi-

mately 400 mg portions. The cold-ﬁnger was removed and the ex-

cess NH₃was allowed to evaporate. The residue was dissolved in

H₂O (10 mL) and extracted with Et₂O (3 ꢂ 20 mL). The extracts were

washed with brine (1 ꢂ 15 mL), combined, dried (K₂CO₃), ﬁltered

through a pad of Celite, and concentrated. The residue was recrystal-

lized (hexane) to afford 495 mg (92%) of the amide 35. Data for 35:

mp 80–81 °C (hexane). ¹H NMR (300 MHz) 7.23 (m, 5H, Ph), 5.31

(d, J = 8.98, 1H, HN), 3.95 (m, 1H, HC(3)), 2.64 (t, J = 8.1, 2H, H₂C(1)),

1.95 (s, 3H, H₃C(C@O)N), 1.82, 1.65 (2 m, 2H, H₂C(2)), 1.50, 1.38 (2

m, 2H, H₂C(4)), 1.26 (m, 4H, H₂C(5), H₂C(6)), 0.88 (m, 3H, H₃C(7)).

¹³C NMR (75.5 MHz) 169.60, 141.95, 128.37, 128.23, 125.80, 49.28,

36.96, 34.98, 32.37, 27.97, 23.50, 22.60, 13.99. IR (KBr) 3310 (s),

3088 (s), 3028 (m), 1642 (s), 1592 (m), 1545 (s), 1495 (s), 1453 (s),

1347 (s), 1188 (m), 1111 (m), 1076 (m). MS (70 eV) 234 (M+1, 10),

233 (M+, 25), 174 (8), 134 (29), 129 (43), 128 (26), 117 (44), 105

(10), 104 (33), 100 (13), 92 (14), 91 (93), 87 (14), 86 (100). TLC R_f

0.10 (hexane/EtOAc, 1:1). Anal. Calcd for C₁₅H₂₃NO (233.36): C,

77.21; H, 9.93; N, 6.00. Found: C, 77.20; H, 9.97; N, 5.95.

6.6.9. (R,S)-N-Acetyl-N-dimethylamino-1-phenyl-3-heptylamine 44

To a 50-mL, three-necked ﬂask ﬁtted with an addition funnel was

.

charged CeCl₃7H₂O (1.677 g, 4.50 mmol, 1.50 equiv) which was

dried at 140 °C (0.2 mm Hg) for 2 h. The ﬂask was allowed to cool

to rt, vented to nitrogen, and THF (15 mL) was added. The reaction

mixture was stirred vigorously for 2 h at rt and cooled to ꢁ78 °C

(CO₂/i-PrOH). To this suspension n-BuLi (1.60 M in hexane,

2.82 mL, 4.51 mmol, 1.50 equiv) was added dropwise via syringe

and the reaction mixture was stirred for 1 h at ꢁ78 °C. To this golden

yellow suspension a solution of 42 (528 mg, 3.00 mmol) in THF

(8 mL) was added dropwise via addition funnel and the reaction

mixture was stirred for 1 h at ꢁ78 °C. The reaction mixture was al-

lowed to warm to 0 °C and CH₃OH (2 mL) was added slowly via syr-

inge. The reaction mixture was poured into H₂O (30 mL) and

extracted with Et₂O (3 ꢂ 40 mL). The extracts were washed with

brine (1 ꢂ 30 mL), combined, dried (MgSO₄), ﬁltered through a pad

of Celite, and concentrated. In a 50-mL round-bottomed ﬂask ﬁtted

with a reﬂux condenser, the residue was dissolved in Ac₂O (8 mL),

thoroughly degassed (3 freeze/thaw cycles), and heated to reﬂux

for 12 h. The reaction mixture was cooled to rt, diluted with Et₂O

(20 mL), and a 10% solution of NaHCO₃(15 mL) was slowly added

to the vigorously stirred reaction mixture. Solid NaHCO₃(2 g) was

added in approximately 200 mg portions. The reaction mixture

was poured into H₂O (20 mL) and extracted with Et₂O (3 ꢂ 30 mL).

6.6.11. (90.5%R,9.5%S)-(2l,3⁰u)-1-(N-Methoxycarbonyl-3-(1-

phenylheptylamino))-2-(2-methylpropyl)pyrrolidine 34

This reaction utilized a sample of 31 derived from amine 30 of

.

90.5:9.5 er. To a 20-mL two-necked ﬂask was charged CeCl₃7H₂O

(288 mg, 0.77 mmol, 2.00 equiv) which was dried at 140 °C/

0.2 mm Hg for 2 h. The ﬂask was allowed to cool to rt, vented to

nitrogen, and THF (4 mL) was added. The reaction mixture was

stirred for 2 h at rt and cooled to ꢁ78 °C (CO₂/i-PrOH). To this sus-

pension n-BuLi (1.60 M in hexane, 0.49 mL, 0.78 mmol, 2.02 equiv)

was added dropwise via syringe and the reaction mixture was stir-

red for 1 h at ꢁ78 °C. To this golden yellow suspension a solution of

31 (100 mg, 0.39 mmol) in THF (3 mL) was added slowly via syr-

inge and the reaction mixture was stirred for 1 h at ꢁ78 °C. The

reaction mixture was allowed to warm to rt and CH₃OH (1 mL)

was added. The reaction mixture was poured into H₂O (10 mL)

and extracted with Et₂O (3 ꢂ 15 mL). The extracts were washed

with brine (1 ꢂ 10 mL), combined, dried (MgSO₄), ﬁltered through

a pad of Celite, and concentrated. In a 20-mL round-bottomed ﬂask

ﬁtted with a reﬂux condenser, the residue was dissolved in Ac₂O

(5 mL), thoroughly degassed (three freeze/thaw cycles), and heated

to reﬂux for 10 h. The reaction mixture was cooled to rt, diluted

with Et₂O (10 mL), and a 10% solution of NaHCO₃(5 mL) was

slowly added to the vigorously stirred reaction mixture. Solid NaH-

CO₃(1 g) was added in approximately 200 mg portions. The reac-

tion mixture was poured into H₂O (12 mL) and extracted with

Et₂O (3 ꢂ 15 mL). The extracts were washed with a 10% solution

The extracts were washed with

a 10% solution of NaHCO₃

(1 ꢂ 25 mL) and brine (1 ꢂ 25 mL), combined, dried (K₂CO₃), ﬁltered

through a pad of Celite, and concentrated. The residue was puriﬁed

by silica gel chromatography (hexane/EtOAc, 4:1) and bulb-to-bulb

distillation to afford 737 mg (89%) of the amide as a clear, colorless

oil. Data for 44: bp 210–220 °C (0.5 mm Hg). ¹H NMR (300 MHz)

7.26–7.20 (m, 5H, Ph), 3.40, 3.20 (2 m, 1H, HC(3)), 2.88, 2.81 (2 s,

3H, H₃CN), 2.62 (m, 2H, H2C(1)), 2.49, 2.44 (2 s, 3H, H₃CN), 2.09

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

1297

of NaHCO₃(1 ꢂ 10 mL) and brine (1 ꢂ 10 mL), combined, dried

(K₂CO₃), ﬁltered through a pad of Celite, and concentrated. The res-

idue was puriﬁed by silica gel chromatography (hexane/EtOAc,

16:1) and bulb-to-bulb distillation to afford 116 mg (83%) of the

amide 34 as a clear, colorless oil. This sample appeared to be a sin-

gle diastereomer by GC (column A). Data for 34: bp 175–180 °C

(0.4 mm Hg). ¹H NMR (500 MHz) 7.26–7.15 (m, 5H, Ph), 2.95–2.35

(several m, 6H), 2.10–1.88 (several m, 7H), 1.80–1.60 (m, 2H),

1.58–1.50 (m, 2H), 1.48–1.39 (m, 1H), 1.37–1.10 (m, 6H), 0.91–

0.79 (m, 9H). This material exists as several rotamers in solution,

resulting in broadening of all of the peaks and making analysis dif-

ﬁcult. ¹³C NMR (125.8 MHz) 174.81 (C@O), 143.01, 128.31, 128.22,

128.19, 125.72, 58.13, 55.04, 50.44, 42.71 36.04, 34.01, 32.13, 29.80,

28.45, 26.18, 24.33, 22.98, 22.91, 21.92, 20.18, 14.11. IR (CCl₄) 3854

(m), 3679 (m), 3407 (m), 3306 (m), 3231 (m), 2959 (m), 2872 (m),

2319 (w), 1657 (s), 1549 (s), 1451 (m), 1366 (m), 1321 (w), 1250

(m), 1219 (m), 1098 (w), 1071 (w), 1003 (m), 978 (m), 897 (w).

MS (70 eV) 358 (M+, 1.4), 316 (19), 315 (70), 301 (16), 259 (38),

210 (34), 183 (13), 132 (11), 129 (15), 128 (29), 127 (100), 126

(100), 124 (16), 105 (37), 104 (23), 92 (23), 91 (100). TLC R_f0.21

(hexane/EtOAc, 8:1). Anal. Calcd for C₂₃H₃₈N₂O (358.57): C, 77.04;

H, 10.68; N, 7.81. Found: C, 76.94; H, 10.72; N, 7.73.

rator pressure. The residue was dissolved in THF (4 mL) and treated

with a solution of K₂CO₃(100 mg) in H₂O (5 mL) followed by the

addition of 3,5-dinitrobenzoyl chloride (60 mg). The reaction mix-

ture was stirred for 2 h at rt, extracted with Et₂O (3 ꢂ 10 mL), and

ﬁltered through a pad of silica gel. Concentration of the ethereal

solution afforded the 3,5-dinitrobenzamide 43 as off-white crys-

tals. The ¹H NMR, TLC, and HPLC data matched those of a previ-

ously prepared sample. Analysis by chiral HPLC (hexane/EtOAc/i-

PrOH, 98.3:1.3:0.7, 0.7 mL min^ꢁ1, column 2) indicated a 90.5:9.5

ratio of R/S enantiomers identical to the enantiomeric composition

of 30 before conversion to hydrazone 31, indicating that no epi-

merization of the auxiliary had occurred at any point in these

transformations. Data for 2-(2-methylpropyl)pyrrolidine 3,5-dini-

trobenzamide: HPLC (S) t_R31.6 (9.5%), (R) t_R33.5 (90.5%) (column

2; hexane/EtOAc/i-PrOH, 89.3:1.0/0.7, 0.8 mL min^ꢁ1).

6.6.13. (88.0%R,12.0%S)-3-(3,5-Dinitrobenzamido)-1-

phenylheptane 33 from 35

All transfers of trimethyloxonium tetraﬂuoroborate were con-

ducted in a glove bag under dry argon. Trimethyloxonium tetra-

ﬂuoroborate (60 mg, 0.41 mmol, 1.48 equiv) was dissolved in

DME (3 mL) in a 20 mL two-necked ﬂask. To this solution was

added

a solution of the amide 35 prepared above (64 mg,

6.6.12. (88%R,12%S)-N-Acetyl-1-phenyl-3-heptylamine 35 (from

34)

0.27 mmol) in DME (3 mL). The reaction mixture was stirred at rt

for 2 h, the reaction was quenched with a 20% solution of KOH,

and the mixture extracted with Et₂O (3 ꢂ 12 mL). The extracts

were washed with brine (1 ꢂ 15 mL), combined, dried (K₂CO₃), ﬁl-

tered through a pad of Celite, and concentrated. Inspection of the

¹H NMR spectrum of this pale yellow oil indicated the presence

of two imino-ether isomers. The residue was dissolved in CH₃OH

(6 mL) and 6 N HCl (1.5 mL) was added. The reaction mixture

was heated to reﬂux for 2 h, cooled to 0 °C, and basiﬁed with solid

NaOH. The amine was extracted with Et₂O (3 ꢂ 8 mL). The extracts

were washed with brine (1 ꢂ 10 mL), combined, dried (K₂CO₃), ﬁl-

tered through a pad of Celite, and concentrated. The residue was

dissolved in THF (5 mL) and treated with a solution of K₂CO₃

(100 mg) in H₂O (4 mL) followed by 3,5-dinitrobenzoyl chloride

(120 mg, 0.52 mmol, 1.93 equiv). The reaction mixture was stirred

for 1 h at rt, extracted with Et₂O (2 ꢂ 10 mL), washed with brine

(1 ꢂ 10 mL), dried (K₂CO₃), ﬁltered through a pad of Celite, and

concentrated. Puriﬁcation by silica gel chromatography (hexane/

EtOAc, 8:1) afforded 55 mg (52%) of the amide 33 as white crystals.

The TLC, ¹H NMR, and HPLC data of this material matched with

those of the previously prepared racemic sample. Chiral HPLC anal-

ysis of the enantiomers on HPLC column 3 (hexane/EtOAc, 97:3,

1 mL min^ꢁ1) indicated an 88.0:12.0 mixture of R/S enantiomers.

The amine 30 from which this sample was ultimately derived

A 50-mL, three-necked ﬂask ﬁtted with a cold-ﬁnger was ﬂame-

dried. Both the ﬂask and the cold-ﬁnger were cooled to ꢁ78 °C, and

NH₃(15 mL) was distilled into the reaction vessel. Freshly cut lith-

ium metal (7 mg, 1.0 mmol, 3.2 equiv) was added to the reaction

vessel and a permanent blue color developed. A solution of 34

(112 mg, 0.31 mmol) in THF (4 mL) was slowly added via syringe

and the cold bath was removed. The reaction mixture was stirred

at reﬂux (ꢁ33 °C) for 60 min and solid NH₄Cl (0.5 g) was added

in approximately 100 mg portions. The cold-ﬁnger was removed

and the excess NH₃was allowed to evaporate. The residue was dis-

solved in 1 N HCl (8 mL) and extracted with Et₂O (3 ꢂ 10 mL). The

extracts were washed with 1 N HCl (2 ꢂ 8 mL) a 10% solution of

NaHCO₃(1 ꢂ 10 mL), and brine (1 ꢂ 10 mL). The ethereal layers

were combined, dried (K₂CO₃), ﬁltered through a pad of Celite,

and concentrated to afford 66 mg (100%) of the amide 35 as white

crystals. The ¹H NMR and TLC data of this material matched that of

the previously prepared racemic sample.

The acidic extracts from the above-described experiment were

combined, cooled to 0 °C, and neutralized by the addition of solid

NaOH. The amine 30 was extracted with Et₂O (2 ꢂ 8 mL), and the

extracts were washed with brine (1 ꢂ 10 mL), combined, dried

(K₂CO₃), ﬁltered through a pad of Celite, and concentrated at aspi-

CH₃

N

O

N

CH₃

N

OCH₃

O

CH₃

C(O)NH₂

Ph

N

H

H₃C

O

42

48b

48c

48d

O

N

NH₂

N

NH₂

N

NH₂

O

N

CHO

O

CH₃

OCH₃

O

CH₃

CHO

H₃C

O

49b

49c

49d

46b

46c

46d

O

N

H

N

H

N

H

CH₃

N

NH₂

N

NH₂

O

CH₃

N

CH₃

H₃C

O

47b

47c

47d

49e

49f

Directory of compounds prepared, but not shown in text

1298

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

was of 90.5:9.5 er indicating that the addition of n-BuLi/CeCl₃to 31

had occurred with 97:3 diastereoselectivity. Data for 33: HPLC t_R

(S) 30.93 (12.0%), (R) 34.89 (88.0%) (column 3; hexane/i-PrOH,

97:3, 1 mL min^ꢁ1).

2.20–1.60 (m, 4H, H₂C(3), H₂C(4)); IR (neat) 2945 (m), 2883 (m),

1666 (s), 1460 (w), 1414 (m), 1383 (m), 1348 (w), 1215 (w),

1149 (m), 1111 (m), 1045 (s), 968 (w), 949 (w), 918 (w) cm^ꢁ1

;

[a]

_D= ꢁ42.4 (c 1.55, CHCl₃).

6.8.2. (S)-1-Formyl-2-(2-methoxyethoxymethoxymethyl)-

pyrrolidine 46c

6.6.14. (E)-3-Phenypropanal (N,N-dimethylhydrazone) 42

In a 15-mL one-necked ﬂask a neat solution of hydrocinnamal-

dehyde (2.686 g, 20.01 mmol) was cooled to 0 °C (ice/H₂O) and 1,1-

dimethylhydrazine (2.30 mL, 30 mmol, 1.50 equiv) was added

slowly via a syringe. The reaction mixture was allowed to warm to

rt, heated to 40 °C, and stirred for 18 h at 40 °C. The reaction mixture

was allowed to cool to rt, diluted with EtOAc (100 mL), and washed

with H₂O (2 ꢂ 100 mL) and brine (1 ꢂ 100 mL). The washings were

extracted with EtOAc (2 ꢂ 100 mL). The extracts were washed with

brine (1 ꢂ 100 mL). The organic layers were combined and dried

(Na₂SO₄), ﬁltered through a pad of Celite, and concentrated. The res-

idue was puriﬁed by silica gel chromatography (hexane/EtOAc, 3/1)

and bulb-to-bulb distillation to afford 3.477 g (95%) of hydrazone 42

as a single isomer as evidenced by ¹H NMR, ¹³C NMR, and GC (col-

umn A). Data for 42: bp: 100–110 °C (0.1 mm Hg) (air bath temper-

ature); ¹H NMR d (300 MHz, CDCl₃) 7.29–7.17 (m, 5H, Ph), 6.63 (t,

J = 5.32, 1H, HC(1)), 2.76 (m, 2H, H₂C(3)), 2.70 (s, 6H, N(CH₃)₂),

2.56 (m, 2H, H₂(C(2)); ¹³C NMR d (75.5 MHz, CDCl₃) 141.29 (C(1)),

137.64 (Ph-C(1⁰)), 128.29 (C(2⁰)), 128.20 (C(4⁰)), 125.73 (C(3⁰)),

43.13 (N(CH3)2), 34.62 (C(3)), 33.98 (C(2)); IR (CCl₄) 3028 (m),

2990 (s), 2955 (s), 2855 (m), 1497 (s), 1469 (s), 1454 (m), 1140

(m), 1030 (s) cm^ꢁ1; MS (70 eV) m/z 177 (2), 176 (13), 86 (5), 85

(100), 45 (4), 44 (13); GC t_R6.94 min (column A; 135 °C isothermal);

TLC R_f0.38 (hexane/EtOAc, 2:1). Anal. Calcd for C₁₁H₁₆N₂(176.26): C,

74.96; H, 9.15; N, 15.89. Found: C, 74.95; H, 9.06; N, 15.68.

From 6.46 g (50 mmol) of 45 and 7.47 g (60 mmol) of 2-

(methoxyethoxy)methoxymethyl chloride was obtained 7.27 g

(67%) of 46c after distillation. Data for 46c: bp 130 °C (0.3 mm Hg);

¹H NMR (300 MHz) d 8.29–8.22 (2 s, 1H, CHO), 4.80–4.65 (m, 2H,

OCH₂O), 4.20–3.90 (m, 1H, HC(2)), 3.80–3.30 (m, 5H), 3.34 (s, 3H,

OCH₃), 2.10–1.16 (m, 4H, H₂C(3), H₂C(4)); IR (neat) 2880 (s),

1666 (s), 1456 (m), 1414 (m), 1383 (s), 1348 (w), 1242 (w), 1197

(m), 1116 (s), 1047 (s), 933 (w), 848 (w) cm^ꢁ1

.

6.8.3. (S)-1-Formyl-2-((2-methoxyethoxy)methyl)pyrrolidine

46d

From 1.42 g (11 mmol) of the amide 45 and 2.22 g (12 mmol) 2-

iodoethylmethyl ether was obtained 0.830 g (40%) of 46d after dis-

tillation. Data for 46d: bp 125–130 °C (0.1 mm Hg); ¹H NMR

(300 MHz) d 8.36 (s, 0.75H, CHO), 8.25 (s, 0.25H, CHO), 4.22–4.13

(m, 0.25H, HC(2)), 4.05–3.96 (m, 0.75H, HC(2)), 3.70–3.45 (m, 6H,

H₂C(1⁰), H₂C(3⁰), H₂C(4⁰)), 3.38 (s, 3H, OMe), 3.45–3.33 (m, 2H,

H₂C(5)), 2.10–1.68 (m, 4H, H₂C(3), H₂C(4)); ¹³C NMR (75 MHz) d

161.62 (CHO), 160.77 (CHO), 73.78 (C(1⁰)), 71.65 (C(3⁰)), 71.63

(C(3⁰)), 70.50 (C(4⁰)), 70.33 (C(4⁰)), 58.88 (OMe), 58.77 (OMe),

56.53 (C(2)), 54.40 (C(2)), 46.68 (C(5)), 43.38 (C(5)), 27.63 (C(3)),

27.48 (C(3)), 23.52 (C(4)), 22.49 (C(4)); IR (CCl₄) 3403 (m), 2878

(s), 1673 (s), 1456 (m), 1416 (s), 1381 (s), 1244 (m), 1198 (m),

1113 (s) cm^ꢁ1; MS (70 eV) m/z 188 (M⁺+1, 2.3), 187 (M⁺, 2.5),

172 (M⁺-15, 1.6), 158 (M⁺-CHO, 1), 142 (2), 128 (10), 111 (34),

98 (100), 84 (6), 70 (77), 59 (10); R_f0.50 (CH₂Cl₂:MeOH, 10:1);

6.7. General procedure for the reduction of keto hydrazones

[

a

]

_D= ꢁ45.8 (c 1.0, CHCl₃). Anal. Cacld for C₉H₁₇NO₃(187.24): C,

A solution of the keto hydrazone in THF (1 mL/20 mg) was

added to a cold (0 °C) suspension of LiAlH₄(5 equiv) in THF

(1 mL/20 mg). The mixture was stirred for 1 h at 0 °C and until

the hydrazone was consumed, then the reaction was quenched

with excess ClCO₂Me (5–10 equiv) and stirred until the protection

was complete. After aqueous extractive workup (satd aq NH₄Cl

solution/EtOAc), the organic phase was dried (Na₂SO₄) and concen-

trated. Without further puriﬁcation the crude reaction product was

analyzed by capillary GC.

57.73; H, 9.15; N, 7.48. Found: C, 57.75; H, 9.17; N, 7.45.

6.9. General procedure for the preparation of the pyrrolidines

A solution of 80 mmol of KOH in 10 mL of H₂O was added at 0 °C

to 10 mmol of crude formamide 46 and the resulting mixture was

stirred at room temperature for 24 h. After saturation with 20 g of

K₂CO_3,the precipitated potassium salts were collected by suction

ﬁltration and the ﬁltrate was extracted with Et₂O. The combined

organic phases were washed with brine, dried (Na₂SO₄), and con-

centrated to afford the amine 47 as an oil, which was puriﬁed by

distillation.

6.8. General procedure for the preparation of the N-

formylpyrrolidine ethers

A magnetically stirred solution of 10 mmol of (S)-1-formyl-2-

hydroxymethylpyrrolidine 45 in 20 mL of THF under argon was

cooled to ꢁ50 °C to ꢁ60 °C and treated with 12 mmol of NaH, fol-

lowed by 11 mmol of the alkylating agent. The cooling bath was

then removed and the mixture allowed to warm to room temper-

ature. After being stirred, the mixture was heated at reﬂux for 1 h,

then cooled to room temperature, and neutralized with sat. NH₄Cl

solution. The reaction mixture was then extracted with EtOAc and

the organic phase was separated and dried (Na₂SO₄). Filtration and

evaporation of the solvent afforded the ether 46 as an oil, which

was puriﬁed by distillation.

6.9.1. (S)-2-((2-Methoxymethoxy)methyl)pyrrolidine 47b

From 5.30 g (31 mmol) of amide 46b, 2.40 g (55%) of 47b was

obtained after distillation. Data for 47b: bp 120 °C (0.5 mm Hg);

¹H NMR (300 MHz) d 4.61 (s, 2H, OCH₂O), 3.53–2.80 (m, 5H,

CH₂N, CHN, H₂C(1⁰)), 3.34 (s, 3H, CH₃O), 2.01 (s, 1H, NH), 1.90–

1.30 (m, 4H, H₂C(3), H₂C(4)); IR (neat) 3346 (w), 2947 (s), 2876

(s), 2824 (m), 1460 (m), 1404 (m), 1294 (w), 1215 (m), 1151 (s),

1111 (s), 1045 (s), 918 (m) cm^ꢁ1

.

6.9.2. (S)-2-((2-Methoxyethoxymethoxy)methyl)pyrrolidine 47c

From 7.52 g (34.6 mmol) of 46c, 4.39 g (67%) of 47c was ob-

tained after distillation. Data for 47c: bp 100 °C (0.3 mm Hg); ¹H

NMR (300 MHz) d 4.85–4.75 (m, 2H, OCH₂O), 3.80–3.70 (m, 2H);

3.65–3.55 (m, 2H), 3.50–3.40 (m, 1H), 3.40 (s, 3H, OCH₃), 3.37–

3.25 (m, 1H), 3.10–2.90 (m, 2H), 2.20 (s, br, 1H, NH), 1.90–1.30

(m, 4H, H₂C(3), H₂C(4)); IR (neat) 3346 (m), 2876 (s), 1456 (m),

6.8.1. (S)-1-Formyl-2-(methoxymethoxymethyl)pyrrolidine 46b

From 6.46 g (50 mmol) of amide 45 and 1.44 g (60 mmol) of

methoxymethyl chloride was obtained 5.30 g (60%) of 46b after

distillation. Data for 46b: bp 130 °C (0.5 mm Hg); ¹H NMR

(300 MHz) d 8.33 (m, 1H, CHO), 4.65–4.55 (m, 2H, OCH₂O), 4.25–

3.95 (m, 1H, HC(2)), 3.80–3.30 (m, 7H, H₂C(1⁰), H₂C(5) and OCH₃),

1199 (s), 1172 (m), 1118 (s), 1049 (s), 983 (m) cm^ꢁ1

.

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

1299

6.9.3. (S)-2-((2-Methoxyethoxy)methyl)pyrrolidine 47d

From 1.66 g (8.9 mmol) of 46d, 1.12 g (80%) of 47d was obtained

after distillation. Data for 47d: bp 80–90 °C (0.3 mm Hg); ¹H NMR

6.11. General procedure for the preparation of the pyrrolidine

hydrazines

(300 MHz)

d

3.63–3.58 (m, 2H, H₂C(3⁰)), 3.56–3.52 (m, 2H,

A solution of 10 mmol of urea 48 in 5–6 mL of H₂O was cooled

to 0 °C (ice/salt), and a precooled (0 °C) solution of 30 mmol of KOH

in 5–6 mL H₂O was introduced, followed by 15 mmol of an aque-

ous KOCl (from Ca(OCl)₂and K₂CO₃in H₂O).^36fThe temperature

of the exothermic reaction mixture should not exceed 5 °C. After

the addition was complete, the mixture was kept at 0 °C for

approximately 2 h, after which the cooling bath was removed

and stirring was continued for 12 h. Excess hypochlorite was de-

stroyed with about 0.7 g of sodium sulﬁte (Na₂SO₃). Acidiﬁcation

with 12 N HCl to pH 2 under ice cooling caused evolution of car-

bon-dioxide and stirring was continued for 1/2 h at room temper-

ature after which the solution was made alkaline by adding 1.7 mL

of a 50% aqueous KOH solution. The mixture was saturated with 5 g

of K₂CO₃and ﬁltered by suction. The salts were washed twice with

EtOH and the aqueous layer was extracted three times with 60 mL

of CH₂Cl₂/EtOH (1:1). The organic layers were collected, concen-

trated, and the resulting oil was taken up in 150 mL CH₂Cl₂, dried

(Na₂SO₄), and concentrated again to afford an oil, which after dis-

tillation gave the hydrazines 49 as clear colorless oils.

H₂C(2⁰)), 3.46 (ddt, J = 12.2, 8.7, 4.0, 1H, HC(2)), 3.38 (s, 3H, OMe),

3.36–3.28 (m, 2H, H₂C(1⁰)), 2.97 (dt, J = 10.1, 6.4, 1H, HC(5)), 2.87

(dt, J = 10.1, 7.1, 1H, HC(5)), 2.30–2.20 (s, br, 1H, NH), 1.86–1.67

(m, 3H, H₂C(3), HC(4)), 1.44–1.36 (m, 1H, HC(4)); ¹³C NMR

(75 MHz) d 74.36 (C(1⁰)), 71.43 (C(3⁰)), 69.95 (C(4’)), 58.50 (C(2)),

57.21 (OMe), 45.85 (C(5)), 27.34 (C(3)), 24.65 (C(2)); IR (CCl₄) 3359

(w), 2874 (s), 1653 (m), 1456 (m), 1410 (m), 1356 (m), 1291 (m),

1246 (w), 1200 (m), 1111 (s), 1048 (m), 875 (m) cm^ꢁ1; MS (10 eV)

m/z 128 (M⁺ꢁ31, 3), 112 (1.5), 84 (1.4), 71 (5), 70 (100); [

a]_D= +7.5

(c 1.0, CHCl₃). Anal. Calcd for C₈H₁₇NO₂(159.23): C, 60.35; H,

10.76; N, 8.80. Found: C, 60.10; H, 10.74; N, 8.90.

6.10. General procedure for the preparation of the ureas

The pyrrolidine 47 (10 mmol) was dissolved in 100 mL of Et₂O

acidiﬁed with 1.1 mL 12 N HCl at 0 °C. The ethereal solution was

extracted twice with 10 mL of water to afford an aqueous solution

of the amine hydrochloride. This solution was adjusted to pH 3

with a concd aq solution of KOH, and treated in one portion with

10.5 mmol of potassium cyanate at room temperature. The result-

ing solution was stirred for a minimum of 24 h at room tempera-

ture. The reaction mixture was then extracted with CH₂Cl₂

(2 ꢂ 30 mL). The organic phase was dried (Na₂SO₄), concentrated,

and the resulting crude urea 48 was used without further puriﬁca-

tion in the next step.

6.11.1. (S)-1-Amino-2-((methoxymethoxy)methyl)pyrrolidine

49b

From 2.56 g (13.6 mmol) of 48b, 0.671 g (31%) of 49b was ob-

tained after distillation. Data for 49b: bp 120 °C (0.4 mm Hg); ¹H

NMR (300 MHz) d 4.62 (s, 2H, OCH₂O), 3.70–3.50 (m, 2H, OCH₂),

3.50–3.00 (m, 6H, NH₂, OCH₃, HC(2)), 2.50–2.30 (m, 2H, H₂C(5),

2.00–1.50 (m, 4H, H₂C(3), H₂C(4)); IR (neat) 3341(w), 2945 (s),

2880 (s), 2822 (s), 1605 (w), 1462 (m), 1213 (m), 1149 (s), 1109

6.10.1. (S)-1-Carbamoyl-2-((methoxymethoxy)methyl)pyrroli-

dine 48b

(s), 1043 (s), 918 (s) cm^ꢁ1

.

From 1.97 g (13.6 mmol) of amine 47b, 2.45 g (95%) of crude

48b was obtained. Data for 48b: ¹H NMR (300 MHz) d 5.07 (s, br,

2H, NH₂), 4.60 (s, 2H, OCH₂O), 4.05–3.95 (m, 1H, HC(2)), 3.70–

3.30 (m, 7H, H₂C(5), H₂C(1⁰), OCH₃), 2.10–1.60 (m, 4H, H₂C(3),

H₂C(4)); IR (neat) 3346 (m), 3196 (m), 2947 (m), 2877 (m), 1652

(s), 1603 (s), 1443 (s), 1359 (m), 1213 (m), 1150 (m), 1079 (m),

6.11.2. (S)-1-Amino-2-((2-methoxyethoxy)methoxymethyl)-

pyrrolidine 49c

From 3.58 g (15.41 mmol) of 48c, 1.68 g (54%) of 49c was ob-

tained after distillation. Data for 49c: bp 140 °C (1 mm Hg); ¹H

NMR (300 MHz) d 4.80–4.60 (m, 2H, OCH₂O), 3.70–3.45 (m, 5H),

3.33 (s, 3H, OCH₃), 3.30–3.00 (m, 2H), 2.40–2.20 (m, 2H), 2.00–

1.50 (m, 4H, H₂C(3), H₂C(4)); IR (neat) 3345 (w), 2922 (s), 2878

(s), 2818 (m), 1606 (w), 1458 (m), 1365 (m), 1284 (w), 1244 (m),

1041 (s), 918 (m) cm^ꢁ1

.

6.10.2. (S)-1-Carbamoyl-2-((2-methoxyethoxy)methoxymethyl)-

pyrrolidine 48c

1199 (m), 1172 (m), 1115 (s), 1047 (s), 983 (m), 850 (m) cm^ꢁ1

.

From 4.38 g (23.1 mmol) of amine 47c, 3.67 g (67%) of crude 48c

was obtained. Data for 48c: ¹H NMR (300 MHz) d 5.00 (s, br, 2H,

NH₂), 4.75–4.65 (m, 2H, OCH₂O), 4.05–3.90 (m, 1H), 3.70–3.40

(m, 10H, (OCH₃as s at 3.37)), 3.37–3.30 (m, 1H), 2.10–1.60 (m,

4H, H₂C(3), H₂C(4)); IR (neat) 3358 (m), 2932 (m), 2878 (m),

6.11.3. (S)-1-Amino-2-((2-methoxyethoxy)methyl)pyrrolidine

49d

From 1.07 g (5.3 mmol) of 48d, 0.502 g (54%) of 49d was ob-

tained after distillation. Data for 49d: bp 80–85 °C (0.05 mm Hg);

¹H NMR (300 MHz) d 3.68–3.51 (m, 6H, H₂C(1⁰), H₂C(3⁰), H₂C(4⁰)),

3.38 (s, 3H, CH₃(6⁰)), 3.31–3.25 (m, 1H, HC(2)), 2.55–2.49 (m, 1H,

HC(5)), 2.39 (dq, J = 2.3, 9.1, 1H, HC(3)), 2.25–2.13 (m, 1H, NH),

2.02–1.90 (m, 1H, HC(5)), 1.82–1.71 (m, 2H, HC(3), HC(4)), 1.60–

1657 (s), 1605 (s), 1444 (s), 1116 (s), 1045 (s) cm^ꢁ1

.

6.10.3. (S)-1-Carbamoyl-2-((2-methoxyethoxymethyl)pyrroli-

dine 48d

13

From 3.23 g (20.5 mmol) of amine 47d, 3.72 g (90%) of crude

48d was obtained. Data for 48d: bp 175–180 °C (0.1 mm Hg); ¹H

NMR (300 MHz) d 5.30–5.00 (s, br, 2H, NH₂), 4.01–3.95 (m, 1H,

HC(2)), 3.66–3.59 (m, 3H, HC(5), H₂C(3⁰)), 3.59–3.41 (m, 4H,

H₂C(4⁰), H₂C(1⁰)), 3.36 (s, 3H, OMe), 3.30 (dt, J = 10.6, 5.7, 1H,

HC(5)), 2.03 (ddt, J = 16.3, 12.3, 8.4, 1H, HC(3)), 1.88–1.79 (m, 2H,

H₂C(4)), 1.80–1.70 (s, br, 1H, HC(3)); ¹³C NMR (75 MHz) d 159.19

(CONH₂), 74.58 (C(1⁰)), 71.42 (C(3⁰)), 70.21 (C(4⁰)), 58.60 (OMe),

58.11 (C(2)), 46.46 (C(5)), 28.79 (C(3)), 23.39 (C(4)); IR (CCl₄)

3492 (w), 3357 (w), 3195 (w), 2876 (m), 1667 (s), 1601 (s), 1435

(s), 1360 (m), 1244 (w), 1215 (m), 1200 (m), 1111 (s) cm^ꢁ1; MS

(10 eV) m/z 203 (M⁺+1, 1), 202 (M⁺, 2), 143 (3), 126 (23), 114 (6),

1.45 (m, 1H, HC(4)); C NMR (75 MHz) d 74.38 (C(1⁰)), 71.56

(C(3⁰)), 70.27 (C(4’)), 68.07 (C(6⁰)), 59.43 (C(2)), 58.72 (C(5)),

26.06 (C(3)), 20.65 (C(4)); IR (CCl₄) 3389 (w), 2926 (m), 2878

(m), 1456 (m), 1362 (w), 1246 (w), 1200 (m), 1109 (s), 853 (w)

cm^ꢁ1; MS (70 eV) m/z 174 (M⁺, 1.5), 125 (3), 97 (3), 85 (C₄H₉N₂

,

+

100), 70 (32), 68 (13), 56 (8), 41 (21); [

Anal. Calcd for C₈H₁₈N₂O₂(174.24): C, 55.15; H, 10.41; N, 16.08.

Found: C, 55.07; H, 10.38; N, 15.99.

a

]

_D= ꢁ6.7 (c = 1.07, CHCl₃).

6.11.4. (S)-1-Amino-2-[(2-(N,N-dimethylamino)ethoxy)methyl]-

pyrrolidine 49e

To a solution of 5.29 g (40 mmol) of (S)-1-nitrosoprolinol in

100 mL of THF was added at once 2.11 g (88 mmol) of NaH. The

mixture was then cooled to ꢁ50 °C and treated with a solution of

6.34 g (44 mmol) of 2-dimethylamino-ethylchloride hydrochlo-

83 (100), 70 (67); R_f0.20 (CH₂Cl₂/MeOH, 15:1); [

(c = 1.0, CHCl₃). Anal. Cacld for C₉H₁₈N₂O₃(202.25): C, 53.45; H,

a

]

_D= ꢁ33.8

8.97; N, 13.85. Found: C, 53.43; H, 9.00; N, 13.80.

1300

S. E. Denmark et al. / Tetrahedron: Asymmetry 21 (2010) 1278–1302

ride. The mixture was then slowly warmed up to room tempera-

ture and then heated at reﬂux for 25 h in the presence of

1.5 mol % of NaI. The mixture was neutralized with 10 mL of H₂O,

washed with brine, and the organic phase was dried (Na₂SO₄)

and concentrated. The residue was distilled to give 2.20 g (30%)

of the nitroso-prolinol ether. A solution of this compound in

50 mL of THF was then added slowly to a boiling suspension of

1.1 g (28 mmol) of LiAlH₄in 20 mL of THF over 1 h. The mixture

was then heated under reﬂux for 30 min, cooled to 0 °C and the

reaction was quenched with 0.4 g (24 mmol) KOH in 2 mL H₂O, fol-

lowed by 2 mL H₂O. The mixture was again heated under reﬂux for

2 h. The colorless salts were removed by suction ﬁltration and

washed twice with 20 mL of THF. The combined organic layers

were concentrated in vacuo to give a yellow oil. The oil was dis-

solved in 200 mL of CH₂Cl_2,dried (Na₂SO₄), concentrated, and dis-

tilled to give 1.81 g (80%) of the hydrazine 49e. Data for 49e: bp

75 °C (0.2 mm Hg); ¹H NMR (300 MHz) d 3.80–3.00 (m, 7H, NH₂,

CH₂OCH₂, HC(2)), 2.60–2.10 (m, 10H, (N(CH₃)₂as s at 2.20)),

2.00–1.30 (m, 4H, H₂C(3), H₂C(4)).

50 °C (0.05 mm Hg);

[

a

]

_D= ꢁ3.6 (c 1.58, EtOH). Lit (R)-51:⁷⁴

[a]

_D= ꢁ6.7 (c 0.5, CHCl₃).

6.12.2. (R)-(1-Methyl-2-phenyl)ethylamine 51

From 0.465 g (2.0 mmol) of hydrazone 2a, 0.142 g (52%) of the

amine 51 was obtained after distillation. Data for 51: bp 40 °C

(0.05 mm Hg);

[

a

]

_D= ꢁ35.8 (c 1.05, EtOH). Lit (S)-51:^50b

[a]

_D= +28.7 (EtOH).

6.13. General procedure for the preparation of the

dinitrobenzamides 52 and 53

To a solution of 0.5 mmol the amine in 5 mL of CH₂Cl₂were

added simultaneously 1 mmol of 3,5-dinitrobenzoyl chloride and

5 mL of 0.1 N NaOH. The mixture was stirred at 0 °C for 5 min

and 1 h at room temperature. The organic layer was then sepa-

rated, dried (Na₂SO₄), and concentrated to afford the crude benz-

amide which was used without further puriﬁcation for the

analyses. The er of the amides were determined by using column

2 (hexane/EtOH/1,2-dichloroethane, 13:5:2, 1.5 mL/min).

6.11.5. (S)-1-Amino-2-hydroxymethylpyrrolidine 49f

6.13.1. (R)-N-(1-Methyl-3-phenylpropyl)-3,5-dinitrobenzamide 52

From 0.075 g (0.5 mmol) of the amine 50, 0.148 g (86%) crude

benzamide 52 was obtained. Data for 52: ¹H NMR (300 MHz) d

9.00–8.70 (m, 3H, DNB), 7.20–6.90 (m, 5H, Ph), 5.60 (m, 1H, NH),

4.60–4,10 (m, 1H, HC(3)), 2.69–2.57 (m, 2H, H₂C(1)), 1.95–1.80

(m, 2H, H₂C(2)), 1.24 (d, J = 6, 3H, CCH₃); HPLC t_R(R)-52, 3.23

min (93%); t_R(S)-52, 4.85 min (7%) (column 2, hexane/EtOH/1,2-

dichloroethane, 13:5:2, 1.5 mL/min).

A 50-mL, two-necked ﬂask ﬁtted with a rubber septum and re-

ﬂux condenser was ﬂame-dried. To the ﬂask were added THF

(10 mL) and LiAlH₄(200 mg, 5.26 mmol, 2.10 equiv). This slurry

was cooled to 0 °C and a solution of N-nitrosoprolinol (326 mg,

2.50 mmol) in THF (8 mL) was added dropwise via a syringe. The

reaction mixture was stirred for 15 min at 0 °C, allowed to warm

to rt, and then heated to reﬂux for 3 h. The reaction mixture was

cooled to 0 °C, treated with 20% KOH (0.5 mL), and then heated

to reﬂux for 10 min. The reaction mixture was cooled to rt and ﬁl-

tered through a pad of Celite. The resulting solids were extracted

with reﬂuxing THF (15 mL) for 1 h. The combined organic layers

were concentrated and the residue was dissolved in CH₂Cl₂and

dried (Na₂SO₄). This material was ﬁltered through a pad of Celite

and concentrated to afford 272 mg (93%) of (S)-1-amino-2-hydrox-

ymethylpyrrolidine as a pale-yellow oil which was used without

further puriﬁcation. Data for (S)-1-amino-2-hydroxymethylpyrr-

olidine: ¹H NMR (300 MHz) 4.8–3.6 (br, 3H, H₂N, HO), 3.75, 3.60

(2 m, 2H, H₂COH), 3.24 (m, 1H, HC(2)), 2.50, 2.25 (2 m, 2H,

H₂C(5)), 1.77 (m, 3H, H₂C(3), HC(4)), 1.40 (m, 1H, HC(4).

6.13.2. (R)-N-(1-Methyl-2-phenylethyl)-3,5-dinitrobenzamide 53

From 0.03 g (0.22 mmol) of amine 51, and chromatography

(hexane/EtOAc, 2:1), 0.039 g (50%) of 53 was obtained. Data for

53: ¹H NMR (200 MHz) d 9.12–8.72 (m, 3H, DNB), 7.31–7.19 (m,

5H, Ph), 6.60–6.45 (m, 1H, NH), 4.65–4.40 (m, 1H, HC(2)), 2.94 (d,

J = 6.3, 2H, H₂C(3)), 1.32 (d, J = 6.6, 3H, CCH₃); TLC R_f= 0.42 (hex-

ane/EtOAc, 2:1); HPLC t_R(R)-53, 1.62 min (94.4%); t_R(S)-53, 2.31

min (5.5%) (column 2, hexane/EtOH/1,2-dichloroethane, 13:5:2,

1.5 mL/min).

Acknowledgment

6.12. General procedure for the isolation of the free amines

We are grateful to the Pharmacia and Upjohn Company for

ﬁnancial support.

After the addition of the organocerium reagent the reaction was

completed according to the general procedure and was quenched

with MeOH (1mL:10 mL THF). Aqueous workup and bulb-to-bulb

distillation afforded the crude, air-sensitive hydrazine, which was

dissolved in MeOH (10 mL/mmol hydrazine) and directly hydroge-

nated using Raney-Ni (W-2) at 60 °C and 375 psi. When the reac-

tion was completed (TLC), the catalyst was ﬁltered off though

Celite and the solvent was evaporated. The residue was then dis-

solved in ether (10 mL/mmol amine), ﬁltered, treated with 1,

5 equiv of 4-nitrobenzaldehyde, and stirred at room temperature

for 12 h. The formed Schiff-base (R_f>0.24 (hexane/EtOAc 5:1))

was separated by chromatography from the chiral auxiliary and

dissolved in ether (10 mL/mmol base). This solution was treated

with 1 N HCl (10 mL / mmol base) and stirred 2 h at room temper-

ature. The aqueous layer was then separated and made alkaline by

adding conc. KOH solution and extracted with ether. The organic

phase was then dried (Na₂SO₄), concentrated, and the afforded

crude amine was puriﬁed by distillation.

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Article Doi

Organocerium additions to proline-derived hydrazones: Synthesis of enantiomerically enriched amines

DOI: 10.1016/j.tetasy.2010.04.042

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