Polarity-mismatched addition of electrophilic carbon radicals to an electron-deficient acceptor: Cascade radical addition-cyclization-trapping reaction

Article

pubs.acs.org/joc

Polarity-Mismatched Addition of Electrophilic Carbon Radicals to an

Electron-Deﬁcient Acceptor: Cascade Radical Addition−Cyclization−

Trapping Reaction

Eito Yoshioka, Shigeru Kohtani, Kaori Sawai, Kentefu, Eri Tanaka, and Hideto Miyabe*

School of Pharmacy, Hyogo University of Health Sciences, Minatojima, Chuo-ku, Kobe 650-8530, Japan

S

* Supporting Information

ABSTRACT: The polarity-mismatched perﬂuoroalkyl radical addition to

electron-deﬁcient alkenes was studied. For this study, several substrates

having two polarity-diﬀerent radical acceptors were employed to

investigate the regiochemical courses of cascade reaction. In the case of

substrate 1 having a methacryloyl moiety, we found polarity-mismatched

perﬂuoroalkylation giving 15a−e as a major course over the polarity-

matched perﬂuoroalkylation giving 16a−e. Moreover, in the case of

substrates 2−7, perﬂuoroalkyl radicals selectively added to an electron-

deﬁcient alkene moiety of 2−7, to give polarity-mismatched perﬂuoro-

alkylation products without the formation of regioisomers. Next, the

control of enantioselectivity was studied. In the case of substrates 1 and 3, the reaction proceeded with good enantioselectivities

by employing a chiral Lewis acid, prepared from chiral box ligand 24 and Zn(OTf)₂. For direct comparison, we also studied the

reaction with other carbon radicals, derived from ICH₂CO₂Et, ICH₂CN, BrC(CO₂Et)₂Me, and CCl₃Br, which have electrophilic

character.

perﬂuoroalkyl radicals to electron-deﬁcient alkenes was

discovered by Hu’s group.^3a,bBurton’s group also reported

that polarity-mismatched perﬂuoroalkyl radical addition

proceeded eﬀectively under photochemical conditions using

low intensity 254 nm light.^3fRecently, Yajima reported

photoinduced diastereoselective addition to electron-deﬁcient

alkenes in the presence of an aqueous solution of Na₂S₂O₃.^3h

However, to the best of our knowledge, there have been no

reports on the cascade carbon−carbon bond-forming reactions

involving the polarity-mismatched perﬂuoroalkyl radical

addition process and on their stereocontrol. In this context,

we have been interested in achieving the electronically

unfavorable cascade transformation.

INTRODUCTION

■

Perﬂuoroalkyl radicals, which are classiﬁed into electrophilic

radicals, have played a signiﬁcant role in free radical chemistry.¹

Although the use of perﬂuoroalkyl radicals in organic synthesis

has continued to increase, the reported studies have

concentrated on the polarity-matched reaction with electron-

rich alkenes including π-suﬃcient aromatic compounds (Figure

1).²In contrast, the polarity-mismatched additions of

perﬂuoroalkyl radicals to electron-deﬁcient alkenes are rare,³

which are frequently plagued by the formation of dimeric or

polymeric byproducts. In 1991, the reductive addition of

Electrophilic perﬂuoroalkyl radicals exhibit extraordinary

reactivity, relative to their hydrocarbon counterparts.^4,5The

eﬀect of ﬂuorine atoms on the reactivity of radicals is usually

considered to derive from ﬂuorine’s electronic nature, because

of the small size of ﬂuorine atom. The main inﬂuence of

ﬂuorine substituents is the ﬂuorine’s potent σ-inductive

electron-withdrawing eﬀect, which gives rise to stabilizing

polarization of the transition state B (b in Figure 1).⁶

Additionally, the pyramidal perﬂuoroalkyl σ-radicals A have

an energetic advantage over the planar nucleophilic alkyl π-

radicals, because further bending is not required in the

transition state for radical addition. Therefore, it is expected

that the unique reactivity of perﬂuoroalkyl radicals would allow

for a wide variety of cascade reactions.

Received: July 24, 2012

Published: September 10, 2012

Figure 1. Properties of perﬂuoroalkyl radicals.

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As presumed from the electrophilic property of perﬂuoro-

alkyl radicals, the polarity-matched addition−cyclization

reactions of the substrates C having two electron-rich radical

acceptors were studied (a in Figure 2).⁷However, the cascade

Scheme 1. Preparation of Substrates

Figure 2. Cascade reaction using perﬂuoroalkyl radicals.

reaction of substrates E having two polarity-inverted radical

acceptors has remained unstudied (b in Figure 2). In this

reaction, two competitive reaction pathways, path a and path b,

are presumed. Particularly, the selective synthesis of the

product F via polarity-mismatched perﬂuoroalkylation (path

a) is a challenging task. We recently reported the cascade

addition−cyclization−trapping reaction involving the polarity-

mismatched interaction of perﬂuoroalkyl radicals.⁸In this

paper, we report in details of the addition of electrophilic

carbon radicals to electron-deﬁcient radical acceptors, together

with the control of enantioselectivities on the basis of our

cyclization strategy.⁹

acid in CH₂Cl₂gave the deprotected amines, which were then

subjected to reaction with methacryloyl chloride or acryloyl

chloride to aﬀord substrates 1−4. N-Propargylation of 8 in the

presence of NaH gave 12−14, which were converted into

substrates 5−7.

At ﬁrst, we investigated the regiochemical course of the

cascade reaction by employing the substrate 1 having a

methacryloyl moiety (Scheme 2). All reactions were performed

with readily available perﬂuoroalkyl iodides and Et₃B as a

radical initiator at 20 °C under tin-free iodine atom-transfer

conditions.¹¹The reaction was evaluated by checking the

competitive formation of three cyclic products cis-15a−d, trans-

15a−d, and 16a−d.

We studied the reaction using n-heptaﬂuoropropyl iodide (n-

C₃F₇I) as a primary perﬂuoroalkyl radical source (Table 1). In

the presence of a stoichiometric amount of Zn(OTf)₂, n-C₃F₇I

(5 equiv) and Et₃B (5 equiv) were added to a solution of 1 in

CH₂Cl₂and then the solution was stirred for 2 h (entry 1). The

cyclic products cis-15a, trans-15a, and 16a were obtained in

71% combined yield.¹²These products could be separated. The

ratio of 15a and 16a was 73:27; thus, we were gratiﬁed to ﬁnd

polarity-mismatched perﬂuoroalkylation giving 15a was a

preferred course over the polarity-matched perﬂuoroalkylation

giving 16a. Among several Lewis acids tested, Cu(OTf)₂led to

an enhancement of the 15a:16a ratio to 94:6, although the

chemical yield diminished to 54% (entries 2−4).¹³In our

previous study,^9awe reported that the reaction of substrate 1

with nucleophilic alkyl radicals did not proceed eﬀectively in

the absence of a Lewis acid. In marked contrast, the cyclic

RESULTS AND DISCUSSION

■

Reaction of Substrates Having Polarity-Inverted

Radical Acceptors. To compare the eﬀect of radical acceptors

on the reactivity and regiochemical courses, our experiments

began with the investigation of cascade addition−cyclization−

trapping reaction of several substrates 1−7 (Figure 3).

Diﬀerent types of substrates, 1−7, were synthesized from N-

(tert-butoxycarbonyl)-O-benzylhydroxylamine 8,¹⁰which was

prepared from O-benzylhydroxylamine hydrochloride (Scheme

1). In the presence of Cs₂CO₃as a base, the reaction of 8 with

allyl bromide derivatives in DMF gave the synthetic

intermediates 9−11. Treatment of 9−11 with triﬂuoroacetic

Figure 3. Substrates for this study.

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electrophilicities greater than those of primary perﬂuoroalkyl

radicals.¹⁴The use of secondary perﬂuoroalkyl iodide iso-C₃F₇I

had a moderate impact on the two competitive reaction

pathways. As expected, the formation of 16c slightly increased

via polarity-matched perﬂuoroalkylation. In contrast to n-C₃F₇I,

the cyclic products 15c and 16c were obtained in 78:22 ratio

even in the presence of Cu(OTf)₂(entry 4 in Table 2 vs entry

4 in Table 1). Similar regioselectivity and chemical eﬃciency

were observed when secondary cyclo-C₆F₁₁I was employed

(entry 5). For direct comparison, the previously reported result

using nucleophilic isopropyl radical has shown high selectivity,

aﬀording the product 15e with high cis selectivity (entry 6).^9a

Additionally, a large excess of the isopropyl iodide (30 equiv)

was required for the successful reaction (entry 6). Therefore, it

is important to note that the reaction with perﬂuoroalkyl

radicals proceeded eﬀectively by employing only 5 equiv of

perﬂuoroalkyl iodides (entries 1−5). This is probably due to

the extraordinary reactivity of perﬂuoroalkyl radicals, relative to

their hydrocarbon counterparts.^4,5

Scheme 2. Regiochemical Course of Cascade Reaction

Two competitive reaction pathways are shown in Figures 4

and 5. The cyclic products 15a−d were formed through

mismatched addition (path a), whereas the cyclic product 16a−

d were formed through matched addition (path b). As shown in

Tables 1 and 2, polarity-mismatched perﬂuoroalkylation (path

a) giving the cyclic products 15a−d was observed as a major

course. Here, two factors directing regiochemical courses are

discussed. First of all, the regiochemical courses are controlled

by the stability of intermediate radicals (Figure 4). The

stabilization of an intermediate radical by resonance promotes

polarity-mismatched addition to electron-deﬁcient acceptor

(path a) giving the resonance-stabilized radical H over the

polarity-matched addition (path b) to electron-rich acceptor

giving the unstable radical I.

We next consider the polar eﬀect by ﬂuorine’s potent σ-

inductive electron-withdrawing property on transition states

(Figure 5). As the possible transition states, we also have

presumed the polar transition states J and K in which weak

radical character has been transferred to radical acceptors.^1,2bIn

particular, these polarizations are assumed to play an important

role in the cyclization step. In other words, the matched

addition (path b) leads to the polarity-mismatched interaction

in the cyclization step as shown in the transition state K (the

mismatched cyclization path d), whereas the facile cyclization

products cis-15a, trans-15a, and 16a were formed in the

reaction with electrophilic n-C₃F₇radical even without

geometry control by the Lewis acid (entry 5). Next, the

amount of Et₃B was checked (entries 6 and 7). Decreasing the

amount of Et₃B to 1.0 or 0.5 equiv resulted in an acceptable

chemical eﬃciency. The desired products were obtained in 56%

combined yield, accompanied by 14% yield of the recovered

starting material 1 (entry 7). In regard to the solvent eﬀect, the

replacement of CH₂Cl₂with DMF or CH₃OH led to an

increase in the chemical yields, although solvents did not

inﬂuence the regiochemical courses and cis/trans selectivities of

15a so much (entries 8−13). The use of DMF improved the

chemical yield to 89% (entry 12). In these reactions, cis/trans

diastereoselectivities of 15a were low, although the polarity-

matched product 16a was obtained as a single cis-isomer.

We next studied the reaction using other perﬂuoroalkyl

radicals. Several trends in Table 2 are noteworthy. The cyclic

products 15b and 16b were obtained in 74% combined yield

and 72:28 ratio when primary n-C₄F₉I was employed in the

presence of Zn(OTf)₂(entry 1). This ratio is analogous to that

of n-C₃F₇I (entry 1 in Table 1). As shown in Scheme 2, the

branched secondary perﬂuoroalkyl radicals are known to exhibit

a

Table 1. Cascade Radical Reaction of 1 with n-C₃F₇Radical

b

c

b

entry

Lewis acid

solvent

Et₃B (equiv)

time (h)

ratio of 15a:16a

yield (%)

cis:trans of 15a

cis:trans of 16a

1

Zn(OTf)₂

Mg(OTf)₂

Yb(OTf)₃

Cu(OTf)₂

none

CH₂Cl₂

toluene

Et₂O

5.0

1.0

0.5

5.0

2

73:27

79:21

73:27

94:6

71

59:41

48:52

58:42

60:40

54:46

61:39

57:43

58:42

55:45

65:35

59:41

62:38

>98:2

2

2.5

2

41

3

60 (8)

54 (3)

49

4

7

5

3

72:28

71:29

74:26

78:22

76:24

73:27

6

Zn(OTf)₂

2

65 (3)

56 (14)

70 (7)

62

7

2.5

2

8

9

2

10

11

12

13

THF

2

72 (4)

67

CH₃CN

DMF

2

89

CH₃OH

2

81

a

b

1

Reactions were carried out with n-C₃F₇I (5 equiv), Lewis acid (1 equiv), and Et₃B in hexane (1.0 M) at 20 °C. Determined by H NMR

c

spectroscopic analysis. Combined yield of the isolated products; the yield in parentheses is for the recovered starting material 1.

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Table 2. Reaction of 1 with Perﬂuoroalkyl Radicals

a

b

a

entry

RI

Lewis acid

time (h)

product (ratio)

yield (%)

cis:trans of 15b−e

cis:trans of 16b−e

c

1

n-C₄F₉I (5 equiv)

i-C₃F₇I (5 equiv)

c-C₆F₁₁I (5 equiv)

Zn(OTf)₂

Yb(OTf)₃

Cu(OTf)₂

Zn(OTf)₂

2

15b + 16b (72:28)

15c + 16c (62:38)

15c + 16c (60:40)

15c + 16c (78:22)

15d + 16d (61:39)

15e

74

63:37

79:21

75:25

81:19

77:23

>98:2

c

2

2.5

3

77

c

3

42 (5)

74

c

4

8

c

5

2.5

4

66 (6)

41 (42)

d

6

i-C₃H₇I (30 equiv)

a

b

1

Determined by H NMR spectroscopic analysis. Combined yield of the isolated products; the yield in parentheses is for the recovered starting

c

d

material 1. Reactions were carried out with perﬂuoroalkyl iodides (5 equiv), Lewis acid (1 equiv), and Et₃B in hexane (1.0 M, 5 equiv). Reaction

was carried out with isopropyl iodides (30 equiv), Zn(OTf)₂(1 equiv), and Et₃B in hexane (1.0 M, 5 equiv): see ref 9a.

Figure 6. Reversibility and reaction rate.

Figure 4. Stability of intermediate radicals in the addition step.

nucleophilic isopropyl radical (entry 6 in Table 2), we observed

erosion of cis/trans diastereoselectivities of 15a−d in

perﬂuoroalkyl radical reactions. Although the change in stability

of alkyl radicals by ﬂuorination does not show a clear trend, the

diﬀerence in stability between the fully ﬂuorinated alkyl radicals

and alkyl radicals show a clear trend.^1,15We simulated the

stability of the fully ﬂuorinated alkyl radicals and alkyl radicals

by calculating the bond dissociation energies for F₃C−H,

H₃C−H, (F₃C)₂FC−H, (H₃C)₂HC−H, F₃CF₂CF₂C−H, and

H₃CH₂CH₂C−H, which are reported in Supporting Informa-

tion.¹⁶In our calculation studies, the most striking observation

is that in which the H_mC_n−H bonds are evidently made 6−4.5

kcal mol⁻¹stronger by the full substitution with ﬂuorine atoms.

Therefore, the ﬁnal iodine atom-transfer process giving cis-

15a−d or trans-15a−d is relatively slow (Figure 6).¹⁷

Figure 5. Polar eﬀect on the cyclization process.

Additionally, the matched interaction in the polar transition

state J could enhance the rate for the cyclization step (Figure

proceeds through mismatched addition (path a) as shown in

the matched interaction in the transition state J (the matched

cyclization path c). Therefore, these electronically disparate

interactions between addition step and cyclization step direct

regiochemical courses, although the net impact on regiochem-

ical courses is derived from a complex interplay involving the

activation by Lewis acid.

Moreover, the stability of the intermediate radical and the

polar eﬀect on transition states aﬀect the reversibility in the

cyclization step as well as the rate-determining step (Figure 6).

In comparison with high cis selectivity in the reaction using a

5). Consequently, the slow iodine atom-transfer step, the fast

cyclization step, and the high stability of the intermediate

radical H allow the reversibility between the two cyclized

radicals cis-L and trans-L, leading to low cis/trans diaster-

eoselectivity. Therefore, it assumes that the ﬁnal iodine atom-

transfer process would be a rate-determining step in this

pathway. In contrast, another pathway gave the cyclic products

16a−d as a single cis-isomer. In this pathway, the rate for the

cyclization step is smaller than that for iodine atom-transfer

step, probably due to the lower stability of intermediate radical

I and the polarity-mismatched interaction in the cyclization

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step as indicated by K (Figure 5). Thus, the unstable radical I

gave the cyclic intermediate radical M without equilibration,

leading to high diastereoselectivity. Probably, in this pathway,

the cyclization step is a rate-determining step, which suppressed

the initial polarity-mismatched perﬂuoroalkyl radical addition

step.

competitive polymerization of 2 having a labile acrylamide

moiety.

We next studied the substituent eﬀect of an electron-rich

acceptor on regiochemical courses by employing substrates 3

and 4 (Scheme 4 and Table 4). As expected, the introduction of

To learn about the eﬀect of an electron-deﬁcient acceptor on

regiochemical courses, the cascade reaction was next studied by

employing the substrate 2 having an acryloyl moiety (Scheme 3

Scheme 4. Regioselective Reaction of 3 and 4

Scheme 3. Cascade Radical Reaction of 2

a methyl substituent at the allyl moiety had an impact on the

perﬂuoroalkyl radical addition step. At ﬁrst, the cascade

reaction of substrate 3 (R = H) was studied (entries 1−3).

The regiochemical course was controlled well because of the

steric eﬀect of the substituent. The four stereoisomeric cyclic

products were formed via polarity-mismatched perﬂuoroalky-

lation. In other words, the products cis-18 and trans-18 were

respectively obtained as two diastereomeric mixtures regarding

the newly generated stereocenter at the iodinated carbon. In

the presence of Zn(OTf)₂, cis-18 (major), cis-18 (minor), trans-

18 (major), and trans-18 were obtained in 74% combined yield

in a 38:31:22:9 ratio (entry 1). Next, the cascade reaction of the

substrate 4 (R = Me) was studied. However, the formation of

cyclic products was not observed under similar conditions. This

result indicates that the iodine atom-transfer from perﬂuoro-

alkyl iodide (n-C₃F₇I) to stable tertiary radical N (R = Me),

generated from 4, was a less eﬀective process, although the

iodine atom-transfer to secondary radical N (R = H) proceeded

eﬀectively. Thus, Bu₃SnH was used as an additive for trapping

stable tertiary radical N (R = Me) (entries 4 and 5). As

expected, the desired cyclic products cis-19 and trans-19 were

formed in low chemical yield.

To understand the generality and practicality of the cascade

reaction induced by the polarity-mismatched addition of

perﬂuoroalkyl radicals, the next substrate of choice was 5

having a carbon−carbon triple bond (Scheme 5 and Table 5).

The reaction of alkyne 5 with n-C₃F₇I proceeded with high

regioselectivity to give the polarity-mismatched perﬂuoroalky-

lation products Z-20a and E-20a without the formation of

cyclic product via matched perﬂuoroalkylation (entries 1−7). In

the presence of Zn(OTf)₂, Z-20a and E-20a were obtained in

79% combined yield and 82:18 ratio (entry 1). Other Lewis

acids Mg(OTf)₂, Yb(OTf)₃, and Cu(OTf)₂promoted the

reaction of 5 with similar Z/E selectivities (entries 2−4). The

replacement of CH₂Cl₂with toluene, THF, or CH₃CN did not

inﬂuence the chemical eﬃciency and Z/E selectivity (entries

5−7). We tested the isomerization of the Z-isomer to the E-

isomer by treating pure Z-20a under radical conditions using n-

C₃F₇I and Et₃B. However, the formation of E-20a was not

observed, and the starting substrate Z-20a was recovered. The

secondary perﬂuoroalkyl iodide iso-C₃F₇I also worked well

a

Table 3. Reaction of 2 with n-C₃F₇Radical

c

trans:cis

b

entry

Lewis acid

solvent

CH₂Cl₂

T (°C) yield (%)

of 17

1

2

3

4

5

Zn(OTf)₂

Mg(OTf)₂

Yb(OTf)₃

20

53

62:38

66:34

67:33

64:36

−

toluene

THF

28 (21)

30 (6)

40

CH₂Cl₂

d

CH₂Cl₂/THF

(4:1, v/v)

ND (57)

6

7

Cu(OTf)₂

Zn(OTf)₂

CH₂Cl₂

20

28 (12)

46

64:36

62:38

−20

a

Reactions were carried out with n-C₃F₇I (5 equiv), Lewis acid (1

equiv), and Et₃B in hexane (1.0 M, 5 equiv). Combined yield of trans-

b

17 and cis-17; the yield in parentheses is for the recovered starting

c

d

material 2. Determined by ¹H NMR spectroscopic analysis. Not

detected.

and Table 3). In contrast to the substrate 1 having a

methacryloyl moiety, the cyclization proceeded under the

conditions of geometry control by a Lewis acid. The addition of

Zn(OTf)₂remarkably promoted the desired cascade reaction in

CH₂Cl₂at 20 °C due to the Lewis acid-induced geometry

control (entry 1). Interestingly, the regiochemical course of the

cascade reaction of 2 was controlled well. The 5-exo cyclization

products trans-17 and cis-17 was obtained in 53% combined

yield and 62:38 ratio via the polarity-mismatched radical

addition to the acryloyl moiety. In this reaction, the formation

of products starting from the polarity-matched perﬂuoroalky-

lation was not observed. Chemical yields decreased by changing

the solvent from CH₂Cl₂to toluene or THF; instead, the

starting material 2 was recovered (entries 2 and 3). In regard to

the eﬀect of the Lewis acid, the use of Mg(OTf)₂, Yb(OTf)₃, or

Cu(OTf)₂led to a decrease in the chemical yields (entries 4−

6). Next, the reaction was conducted at −20 °C in the presence

of Zn(OTf)₂(entry 7). As expected, a 41% combined yield of

trans-17 and cis-17 was formed. As compared with the substrate

1 having the methacryloyl moiety, the reaction of 2 showed the

lower chemical eﬃciency. The moderate chemical yields of

trans-17 and cis-17 were attributed to the side reactions such as

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a

Table 4. Reaction of 3 and 4 with n-C₃F₇Radical

b

entry

substrate

additive

Lewis acid

time (h)

product

yield (%)

ratio

d

1

2

3

4

none

Zn(OTf)₂

Yb(OTf)₃

Cu(OTf)₂

Zn(OTf)₂

Yb(OTf)₃

2.5

3.5

4.5

12

18

19

74

38:31:22:9

37:32:22:9

d

none

59

d

none

52 (16)

23 (12)

19 (18)

38:31:21:10

c

e

4

Bu₃SnH

36:64

c

5

12

−

a

b

Reactions were carried out with perﬂuoroalkyl iodides (5 equiv), Lewis acid (1 equiv), and Et₃B in hexane (1.0 M, 5 equiv). Combined yield of the

isolated products; the yield in parentheses is for the recovered starting material 3 or 4. Bu₃SnH (1.5 equiv) was employed. Determined by H

NMR spectroscopic analysis. The ratio for cis-18 (major):cis-18 (minor):trans-18 (major):trans-18 (minor). Determined by isolated yields. The

c

d

1

e

ratio for cis-19:trans-19.

Scheme 5. Cascade Radical Reaction of 5

Scheme 6. Reaction of 6 and 7

Table 5. Reaction of 5 with Perﬂuoroalkyl Radicals

product

time

(h)

(%

a

b

entry

RI

Lewis acid

Zn(OTf)₂

solvent

CH₂Cl₂

yield)

Z:E

c

1

n-C₃F₇I

(5 equiv)

5

2

5

20a (79) 82:18

20a (79) 83:17

20a (88) 85:15

20a (75) 84:16

20a (73) 82:18

20a (61) 85:15

20a (75) 85:15

20b (59) 84:16

c

2

n-C₃F₇I

(5 equiv)

Mg(OTf)₂

Yb(OTf)₃

Cu(OTf)₂

Zn(OTf)₂

CH₂Cl₂

toluene

THF

c

3

n-C₃F₇I

(5 equiv)

a

c

Table 6. Reaction of 6 and 7 with n-C₃F₇Radical

4

n-C₃F₇I

(5 equiv)

c

time

(h)

product

(% yield)

5

n-C₃F₇I

(5 equiv)

b

entry substrate

Et₃B

ratio

c

1

2

3

4

6

7

5 equiv

5

21 (81)

Z-21:E-21 =

6

n-C₃F₇I

(5 equiv)

d

76:24

c

5 equiv

1

22 (45)

Z-22:E-22 =

7

n-C₃F₇I

(5 equiv)

CH₃CN

CH₂Cl₂

d

>98:2

c

5 equiv

5

22 (63) + 23 Z-22:E-22 =

(8)

8

i-C₃F₇I

(5 equiv)

d

>98:2

c

d

5 equiv × 2

12

22 (8) + 23

(45)

E-23:Z-23 =

9

i-C₃H₇I

(30 equiv)

20c (80) >98:2

e

73:27

a

b

1

Reactions were carried out with n-C₃F₇I (5 equiv), Zn(OTf)₂(1

Combined yield of the isolated products. Determined by H NMR

b

c

equiv), and Et₃B in hexane (1.0 M). Combined yield of the isolated

products. Et₃B (5 equiv) was employed twice. Determined by H

NMR spectroscopic analysis. Determined by isolated yields.

spectroscopic analysis. Reactions were carried out with perﬂuoroalkyl

iodides (5 equiv), Lewis acid (1 equiv), and Et₃B in hexane (1.0 M, 5

equiv). Reaction was carried out with isopropyl iodides (30 equiv),

c

d

1

e

d

Zn(OTf)₂(1 equiv), and Et₃B in hexane (1.0 M, 5 equiv).

contrast to substrate 6, the reaction of 7 gave the product Z-22

in >98:2 ratio (entry 2). Interestingly, the formation of the

reduction products E-23 and Z-23 was newly observed after

being stirred for 5 h, although a hydrogen atom donor is still

unclear (entry 3). The high Z selectivity of 22 was maintained.

The products E-23 and Z-23 are assumed to be generated by

the hydrogen atom transfer from substrate, products, reagents,

or solvent into intermediate π-radicals. Actually, when an excess

amount of Et₃B (5 equiv × 2) was employed, the reduction

products E-23 and Z-23 were obtained in a 73:27 ratio as major

products (entry 4).

(entry 8). The products Z-20b and E-20b were obtained in

59% combined yield and 84:16 ratio. In contrast, high Z/E

selectivity was observed to give the product Z-20c in >98:2

ratio when iso-C₃H₇I was employed as an alkyl radical source

(entry 9).

To gain further insight into the eﬀect of a carbon−carbon

triple bond as a radical acceptor, we next explored the reaction

of substrates 6 and 7 having substituents at the terminal

position of the triple bond (Scheme 6 and Table 6). As

expected, the polarity-mismatched perﬂuoroalkylation pro-

ceeded exclusively. In the presence of Zn(OTf)₂, the reaction

of 6 (R = Me) with n-C₃F₇I gave the products Z-21 and E-21 in

81% combined yield and 76:24 ratio (entry 1). Next, the

reaction of 7 (R = Ph) was carried out for 1 h (entry 2). In

The E,Z selectivities are determined when vinyl radicals are

captured by atom-transfer reagents. Particularly, the E,Z

selectivities of 20a-23 would be inﬂuenced by the steric

hindrance between the substituents on α-carbon atom of

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intermediated radicals O-Q and perﬂuoroalkyl iodides (Figure

7). The vinyl radicals generated from 5 are σ-radicals, which are

Scheme 7. Cascade Reaction of 1 Using a Chiral Lewis Acid

ity was still low, the major product cis-15a was isolated in 76%

ee along with trans-16a in 88% ee. These results indicate that

the three-dimensional arrangement of two radical acceptors was

eﬃciently controlled by a ternary complex of ligand, Lewis acid,

and substrate at low temperature. In regard to the solvent eﬀect,

the addition of hexaﬂuoro-2-propanol (HFIP) as an acidic

solvent led to lower product ratio and enantioselectivity (entry

2). In contrast, the replacement of CH₂Cl₂with CH₂Cl₂−

toluene (1:1, v/v) led to an increase in enantioselectivities

(entry 4), although the nearly racemic products were obtained

when reaction was carried out in toluene (entry 3). The use of

CH₂Cl₂−toluene (1:1, v/v) improved the enantioselectivity of

cis-15a into 87% and the enantioselectivity of trans-16a into

90% (entry 4). When primary n-C₄F₉I was employed, similar

improvement of the product ratio was also observed to give the

products 15b and 16b in 95:5 ratio (entry 5). The

enantioselectivity and cis/trans diastereoselectivity were in-

creased by changing the primary perﬂuoroalkyl radicals to

secondary iso-C₃F₇radical (entry 6). The reaction with

secondary iso-C₃F₇radical in CH₂Cl₂gave the cyclic product

cis-15c with 90% ee in 92:8 cis/trans selectivity. However, the

product ratio of 15c and 16c diminished to 82:18 due to higher

electrophilicity of secondary iso-C₃F₇radical. When the ligand

25 was employed instead of ligand 24, the product ratio, cis/

trans diastereoselectivity, and enantioselectivity were all

lowered (entry 7). Decreasing the amount of chiral Lewis

acid to 0.5 equiv resulted in a low enantioselectivity (entry 8).

Again, the improvement in enantioselectivity was observed,

when reaction was carried out in CH₂Cl₂−toluene (1:1, v/v)

(entry 9). Additionally, the enantioselectivity of cis-15c

increased to 92% by using the activated 4 Å molecular sieves

(entry 10). Under analogous reaction conditions, outstanding

levels of enantio- and diastereoselectivities were also obtained

by employing cyclo-C₆F₁₁iodide as a radical precursor (entry

11).

Figure 7. Z and E selectivity.

in very fast equilibrium between E- and Z-isomers O and P.

Thus, it assumes that the small steric eﬀect around σ-radicals on

an sp²-carbon atom would lead to low Z/E selectivity. In

contrast, the reaction of 7 gave a stable intermediate π-radical

Q conjugated with the aromatic ring; thus, π-radical Q on an

sp-carbon atom was strongly inﬂuenced by the steric hindrance

and directed the Z selectivity.

Enantioselective Cascade Reaction Using a Chiral

Lewis acid. The control of stereochemistry in free radical-

mediated reactions has been of great importance to organic

synthesis.¹⁸Hence, in recent years, signiﬁcant progress has

been observed in enantioselective radical addition reactions,

allylation, H-atom transfer reactions, and so on.¹⁹⁻²¹However,

the enantiocontrol in radical cyclizations still remains a major

challenge,²²although signiﬁcant progress has been made

recently by several approaches.²³⁻²⁹Only a handful of reports

describes chiral Lewis acid-mediated enantioselective radical

cyclizations.^23,24Moreover, less is known about enantioselective

reactions of perﬂuoroalkyl radicals,³⁰and there have been no

studies on perﬂuoroalkyl radical-mediated enantioselective

cyclizations. Thus, we have studied the chiral Lewis acid-

mediated enantioselective reaction with perﬂuoroalkyl radicals

based on our approaches to control stereochemistry of the

cascade radical addition−cyclization reaction by taking

advantage of the hydroxamate ester.⁹

At ﬁrst, we investigated the chiral Lewis acid-mediated

reactions of 1 with perﬂuoroalkyl iodides at −78 °C (Scheme

7). The enantiomeric purities of products were checked by

chiral HPLC analysis. The combinations of chiral box ligands

24 or 25 and Lewis acids Zn(OTf)₂promoted the polarity-

mismatched perﬂuoroalkylation of the electron-deﬁcient

acceptor in 1 (Table 7).³¹Because the enantioselective radical

reaction at −78 °C was slow, elongation of the reaction time

improved the chemical yields. The use of chiral Lewis acid,

prepared from ligand 24 and Zn(OTf)₂, led to not only an

enhancement in product ratio but also an improvement in cis/

trans diastereoselectivity. In the presence of ligand 24, the

reaction with a n-C₃F₇radical in CH₂Cl₂proceeded eﬀectively

to form the products 15a and 16a in 95:5 ratio and 88%

combined yield (entry 1). Although cis/trans diastereoselectiv-

We next explored the enantioselective reaction of substrate 3

having a methyl group at a terminal position of the electron-

rich acceptor (Scheme 8). In this case, polarity-mismatched

perﬂuoroalkylation proceeded exclusively to give four isomers.

As expected, the circumstances in the presence of a chiral Lewis

acid led to an enhancement in diastereoselectivity (dr cis-18

(major)/cis-18 (minor)/trans-18 (major)/trans-18 (minor) =

50:23:21:6), as compared with the reaction in the absence of

ligand (entry 1 in Table 4). The reaction with a n-C₃F₇radical

gave the cyclic products in 91% combined yield. The major

isomer of cis-18 was obtained with 87% ee, along with the

minor isomer of cis-18 (75% ee) and the major isomer of trans-

18 (87% ee). In the case of secondary iso-C₃F₇radical, the

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a

Table 7. Enantioselective Reaction of 1 with Perﬂuoroalkyl Radicals

d

ee(%)

b

c

b

entry

RI

solvent

time (d)

ratio of 15:16

yield (%)

cis:trans of 15

cis-15

trans-15

1

2

3

4

5

6

n-C₃F₇I

n-C₄F₉I

i-C₃F₇I

c-C₆F₁₁I

CH₂Cl₂

2

3

1

2

5

2

5

3

95:5

88

78

84

78

72

44

45

46

40

73

62:38

86:14

81:19

64:36

66:34

92:8

76

6

88

13

0

CH₂Cl₂/HFIP (9:1, v/v)

78:22

91:9

toluene

1

CH₂Cl₂/toluene (1:1, v/v)

97:3

87

77

90

51

65

91

92

91

90

85

CH₂Cl₂

95:5

CH₂Cl₂

82:18

72:28

79:21

81:19

79:21

74:26

e

7

CH₂Cl₂

88:12

94:6

f

8

CH₂Cl₂

9

CH₂Cl₂/toluene (1:1, v/v)

CH₂Cl₂

92:8

g

10

94:6

11

CH₂Cl₂

92:8

a

Reactions were carried out with perﬂuoroalkyl iodides (5 equiv), Zn(OTf)₂(1 equiv), ligand 24 (1 equiv), and Et₃B in hexane (1.0 M, 5 equiv) at

b

c

d

e

−78 °C. Determined by ¹H NMR spectroscopic analysis. Combined yield of the isolated products. Determined by HPLC analysis. The ligand 25

was employed instead of ligand 24. Reaction was carried out with Zn(OTf)₂(0.5 equiv) and ligand 24 (0.5 equiv). In the presence of activated 4 Å

f

g

molecular sieves.

Scheme 8. Enantioselective Cascade Reaction of 3

Scheme 9. Reductive Deiodination of Four Stereoisomers

reaction proceeded with better diastereoselectivity (dr cis-26

(major)/cis-26 (minor)/trans-26 (major)/trans-26 (minor) =

81:13:5:1) to give the major isomer of cis-26 with 91% ee.

The conﬁguration of cis- and trans-isomers was conﬁrmed by

the reduction of four stereoisomers (Scheme 9). Four isomers

cis-26 (major), cis-26 (minor), trans-26 (major), and trans-26

(minor) were prepared in 40:38:17:5 ratio under the racemic

reaction conditions. The cis-conﬁguration was conﬁrmed by

converting cis-26 (major) and cis-26 (minor) into the same

product cis-27. The reduction of trans-26 (major) and trans-26

(minor) gave trans-27.

Next, the enantioselective reaction of substrates having a

triple bond was tested (Scheme 10). Although the reaction of 6

with a n-C₃F₇radical proceeded eﬀectively at −78 °C, moderate

enantioselectivity and low Z/E selectivity were observed. The

major product E-21 was formed in 33% ee along with Z-21 in

48% ee. In the case of substrate 7, high Z selectivity was

obtained. However, enantioselectivity of Z-22 was low. In

contrast to the reaction in the absence of ligand (entry 3 in

Table 6), the formation of the reduction products E-23 and Z-

23 was not observed under enantioselective reaction con-

ditions.

Reaction with Other Electrophilic Carbon Radicals.

Carbon radicals having electron-withdrawing groups possess

electrophilic character.³²We next studied the reaction of 1 with

the moderately electron-deﬁcient radicals derived from

ICH₂CO₂Et, ICH₂CN, and BrC(CO₂Et)₂Me (Scheme 11). In

the presence of Zn(OTf)₂, the reaction proceeded eﬀectively by

employing only 5 equiv of alkyl iodides as well as perﬂuoroalkyl

iodides (Table 8). These radicals selectively added to an

electron-deﬁcient alkene moiety of 1, to give cis-28a−c and

trans-28a−c without the formation of regioisomers. This

regiochemical course is similar to that using a nucleophilic

isopropyl radical (Table 2, entry 6). The diﬀerence between

these electron-deﬁcient radicals and an isopropyl radical is the

cis/trans diastereoselectivity. The cis/trans selectivities of 28a−

c were low (Table 8, entries 1−3), whereas high cis selectivity

was observed in the reaction with an isopropyl radical (Table 2,

entry 6). Thus, the cis/trans selectivities of 28a−c are similar to

those using perﬂuoroalkyl radicals (Tables 1 and 2). These

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and 28c also supports reversibility in the cyclization step as a

rate-determining step.

Scheme 10. Enantioselective Cascade Reaction of 6 and 7

Finally, we investigated the reaction of 1 with a

trichloromethyl radical, which has electrophilicity lower than

that of perﬂuoroalkyl radicals (Scheme 12 and Table 9).³³As

Scheme 12. Regiochemical Course of Reaction with BrCCl₃

expected, polarity-mismatched radical addition was observed as

a major pathway. Compared with n-C₃F₇radical (Table 1, entry

1), the low electrophilicity of trichloromethyl radical led to a

slight enhancement of ratio of 29:30 to 79:21 (Table 9, entry

1). However, the chemical yield was low probably because of a

less eﬀective bromine-atom transfer process as a ﬁnal step. The

use of Cu(OTf)₂led to the selective formation of 29 (29:30 =

96:4 ratio), although the chemical yield diminished to 24%

(entry 2). We next explored the enantioselective reaction with

CCl₃Br (entries 3 and 4). However, the reaction did not

proceed eﬀectively at −78 °C to give cis-29 in 8% yield and

77% ee (entry 3). Chiral Lewis acid accelerated the reaction at

20 °C to improve the chemical yield to 60%, although the

enantioselectivity of cis-29 was 49% ee (entry 4).

Scheme 11. Regiochemical Course of Reaction with Other

Radicals

CONCLUSION

■

We have demonstrated that cascade radical reactions, starting

from polarity-mismatched perﬂuoroalkylation of an electron-

deﬁcient acceptor, proceeded eﬀectively. These cascade radical

reactions involve a cyclization process, which proceed with

good chemical eﬃciency by using a hydroxamate ester as a

coordination site with a Lewis acid, providing the synthetic

approach to chiral γ-lactams. In certain cases, they proceed with

good enantio- and diastereoselectivities by employing a chiral

Lewis acid, prepared from a chiral box ligand and Zn(OTf)₂.

observations indicate reversibility in the cyclization step. It is

important to note that the reaction with BrC(CO₂Et)₂Me

proceeded eﬀectively via the bromine-atom transfer process due

to the high stability of C(CO₂Et)₂Me radical (Table 8, entry 3).

As expected, the brominated products cis-28c and trans-28c

were obtained in 84% yield and 81:19 ratio. We also

investigated the enantioselective reaction (entries 4 and 5)

and found moderate enantioselectivities and cis/trans selectiv-

ities of the reaction. The erosion of these selectivities of 28a

EXPERIMENTAL SECTION

■

1

General. Melting points are uncorrected. H NMR spectra were

measured at 400 or 600 MHz. ¹³C NMR spectra were measured at 101

Table 8. Reaction of 1 with Other Radicals

c

ee (%)

a

b

entry

RX

ligand

T (°C)

time (h)

yield (%)

cis:trans of 28

cis-28

trans-28

d

1

ICH₂CO₂Et

none

24

20

1.5

2

89

90

84

83

88

47:53

81:19

66:34

79:21

d

2

ICH₂CN

20

d

3

BrC(CO₂Et)₂Me

ICH₂CO₂Et

20

1.5

70

40

e

4

−78

55

51

54

27

e

5

BrC(CO₂Et)₂Me

24

a

b

c

d

Combined yield of the isolated products. Determined by ¹H NMR spectroscopic analysis. Determined by HPLC analysis. Reactions were carried

e

out with RX (5 equiv), Zn(OTf)₂(1 equiv), and Et₃B in hexane (1.0 M) in CH₂Cl₂at 20 °C. Reactions were carried out with RX (5 equiv),

Zn(OTf)₂(1 equiv), ligand 24 (1 equiv), and Et₃B in hexane (1.0 M, 5 equiv) in CH₂Cl₂at −78 °C.

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Table 9. Reaction of 1 with Other Radicals

a

b

a

c

entry

Lewis acid

ligand

T (°C)

time

ratio of 29:30

yield (%)

cis:trans of 29

ee (%)

d

1

Zn(OTf)₂

Cu(OTf)₂

Zn(OTf)₂

none

24

20

4.5 h

20 h

1.5 d

70 d

79:21

96:4

−

38

85:15

91:9

−

d

2

20

24 (8)

8 (46)

60

e

3

−78

20

77

49

e

4

Zn(OTf)₂

24

86:14

a

b

1

Determined by H NMR spectroscopic analysis. Combined yield of the isolated products; the yield in parentheses is for the recovered starting

c

d

material 1. Determined by HPLC analysis. Reactions were carried out with BrCCl₃(5 equiv), Zn(OTf)₂(1 equiv), and Et₃B in hexane (1.0 M) in

CH₂Cl₂. Reactions were carried out with BrCCl₃(5 equiv), Zn(OTf)₂(1 equiv), ligand 24 (1 equiv), and Et₃B in hexane (1.0 M, 5 equiv) in

e

CH₂Cl₂.

or 126 MHz. ¹⁹F NMR spectra were measured at 376 MHz with C₆F₆

as an internal standard (−162.2 ppm). The commercial reagents were

used without further puriﬁcation. HRMS measurements using

electrospray ionization (ESI) were performed with a time-of-ﬂight

(TOF) mass analyzer. HRMS measurements using electron ionization

(EI) were performed with a magnetic sector mass analyzer.

General Procedure for the Preparation of Allylamines 9 and

10. To a stirred suspension of 8 (1.00 g, 4.48 mmol) and Cs₂CO₃

(2.04 g, 6.27 mmol) in DMF (15 mL) was added allyl bromide

derivative (5.38 mmol) at room temperature. After being stirred at

same temperature for 12 h, the reaction mixture was diluted with water

and then extracted with AcOEt. The organic phase was dried over

MgSO₄and concentrated under reduced pressure. Puriﬁcation of the

residue by ﬂash silica gel column chromatography (AcOEt:hexane =

1:15) aﬀorded the products 9 (1.121 g, 95%), 10 (1.193 g, 96%), and

11 (1.174 g, 90%).

(CDCl₃) δ 7.45−7.40 (2H, m), 7.38−7.30 (3H, m), 4.93 (2H, s), 4.11

(2H, d, J = 2.4 Hz), 2.23 (1H, t, J = 2.4 Hz), 1.49 (9H, s). ¹³C NMR

(CDCl₃) δ 156.6, 135.6, 129.5, 128.6, 128.4, 82.3, 78.5, 77.8, 71.8,

40.2, 28.1. MS (EI⁺): m/z 261 (M⁺, 0.1), 91 (100). HRMS (EI⁺):

calcd for C₁₅H₁₉NO₃(M⁺): 261.1359, Found: 261.1366.

N-2-Butyn-1-yl-N-(phenylmethoxy)carbamic Acid 1,1-Dimethy-

1

lethyl Ester (13). A colorless oil. IR (CHCl₃) 1707 cm⁻¹. H NMR

(CDCl₃) δ 7.46−7.41 (2H, m), 7.38−7.31 (3H, m), 4.93 (2H, s), 4.09

(2H, q, J = 2.1 Hz), 1.82 (3H, t, J = 2.1 Hz), 1.50 (9H, s). ¹³C NMR

(CDCl₃) δ 156.7, 135.7, 129.5, 128.5, 128.3, 81.9, 79.3, 77.6, 73.6,

40.4, 28.1, 3.4. MS (FAB⁺): m/z 276 (M + H⁺, 12), 91 (100). HRMS

(FAB⁺): calcd for C₁₆H₂₂NO₃(M + H⁺): 276.1594, Found: 276.1607.

N-(Phenylmethoxy)-N-(3-phenyl-2-propyn-1-yl)carbamic Acid

1,1-Dimethylethyl Ester (14). A colorless oil. IR (CHCl₃) 1705

1

cm⁻¹. H NMR (CDCl₃) δ 7.48−7.40 (4H, m), 7.37−7.31 (3H, m),

7.30−7.25 (3H, m), 5.00 (2H, s), 4.38 (2H, s), 1.52 (9H, s). ¹³C NMR

(CDCl₃) δ 156.5, 135.6, 131.7, 129.5, 128.5, 128.4, 128.3, 128.2, 122.8,

84.0, 83.4, 82.1, 77.9, 41.0, 28.1. MS (EI⁺): m/z 337 (M⁺, 0.1), 57

(100). HRMS (EI⁺): calcd for C₂₁H₂₃NO₃(M⁺): 337.1672, Found:

337.1651.

N-(Phenylmethoxy)-N-2-propenylcarbamic Acid 1,1-Dimethy-

1

lethyl Ester (9). A colorless oil. IR (CHCl₃) 1699 cm⁻¹. H NMR

(CDCl₃) δ 7.41−7.30 (5H, m), 5.87 (1H, m), 5.22 (1H, dd, J = 17.1,

1.6 Hz), 5.17 (1H, dd, J = 10.4, 1.6 Hz), 4.83 (2H, s), 4.00 (2H, br d, J

= 6.1 Hz), 1.49 (9H, s). ¹³C NMR (CDCl₃) δ 156.6, 135.6, 132.7,

129.3, 128.4, 128.3, 118.0, 81.3, 77.1, 52.7, 28.1. MS (EI⁺): m/z 263

(M⁺, 0.2), 91 (100). HRMS (EI⁺): calcd for C₁₅H₂₁NO₃(M⁺):

263.1516, Found: 263.1519.

N-(Phenylmethoxy)-N-2-butenylcarbamic Acid 1,1-Dimethylethyl

Ester (10). A colorless oil. IR (KBr) 2976, 1704, 1454 cm⁻¹. ¹H NMR

(CDCl₃) δ 7.43−7.24 (5H, m), 5.70−5.61 (1H, m), 5.56−5.47 (1H,

m), 4.82 (2H, s), 3.92 (2H, d, J = 6.4 Hz), 1.69 (3H, dd, J = 6.4, 1.4

Hz), 1.50 (9H, s). ¹³C NMR (CDCl₃) δ 156.7, 135.7, 129.7, 129.4,

128.4 (2C), 125.3, 81.3, 77.2, 52.1, 28.3, 17.8. HRMS (ESI⁺): calcd for

C₁₆H₂₃NO₃Na (M + Na⁺): 300.1570, Found: 300.1566.

General Procedure for the Preparation of Substrates 1−7.

To a solution of 9−14 (3.0 mmol) in CH₂Cl₂(15 mL) was added

TFA (2.3 mL, 30 mmol) under argon atmosphere at 0 °C. After being

stirred at room temperature for 5 h, the reaction mixture was

neutralized with saturated aqueous NaHCO₃and then extracted with

CH₂Cl₂. The organic phase was dried over MgSO₄and concentrated

under reduced pressure to give crude amine. To a solution of crude

amine and Et₃N (1.25 mL, 9.0 mmol) in CH₂Cl₂(15 mL) was added

acid chloride (3.3 mmol) under argon atmosphere at room

temperature. After being stirred at the same temperature for 3 h, the

reaction mixture was diluted with water and then extracted with

AcOEt. Puriﬁcation of the residue by ﬂash silica gel column

chromatography (AcOEt:hexane = 1:6−1:3) aﬀorded the products 1

(555 mg, 80%), 2 (495 mg, 76%), 3 (626 mg, 85%), 4 (653 mg, 84%),

5 (488 mg, 71%), 6 (555 mg, 76%), and 7 (733 mg, 80%).

2-Methyl-N-(phenylmethoxy)-N-2-propen-1-yl-2-propenamide

(1). A colorless oil. IR (CHCl₃) 1655, 1631 cm⁻¹. ¹H NMR (CDCl₃) δ

7.45−7.30 (5H, m), 5.88 (1H, m), 5.34 (1H, s), 5.29 (1H, dd, J = 17.1,

1.3 Hz), 5.28 (1H, s), 5.23 (1H, br d, J = 10.1 Hz), 4.84 (2H, s), 4.23

(2H, d, J = 6.1 Hz), 1.98 (3H, s). ¹³C NMR (CDCl₃) δ 171.9, 140.6,

134.8, 132.3, 129.4, 128.9, 128.6, 118.5, 117.5, 77.4, 50.7, 19.9. MS

(EI⁺): m/z 231 (M⁺, 45), 159 (100). HRMS (EI⁺): calcd for

C₁₄H₁₇NO₂(M⁺): 231.1254, Found: 231.1252.

N-(Phenylmethoxy)-N-2-propen-1-yl-2-propenamide (2). A color-

less oil. IR (CHCl₃) 1653, 1618 cm⁻¹. ¹H NMR (CDCl₃) δ 7.42−7.32

(5H, m), 6.74 (1H, dd, J = 17.1, 10.4 Hz), 6.42 (1H, dd, J = 17.1, 1.8

Hz), 5.90 (1H, m), 5.73 (1H, dd, J = 10.4, 1.8 Hz), 5.28 (1H, dd, J =

17.1, 1.2 Hz), 5.23 (1H, dd, J = 10.4, 1.2 Hz), 4.86 (2H, s), 4.31 (2H,

d, J = 6.1 Hz). ¹³C NMR (CDCl₃) δ 166.9, 134.3, 132.1, 129.4, 129.2,

129.0, 128.7, 126.3, 118.6, 77.5, 49.4. MS (EI⁺): m/z 217 (M⁺, 4), 91

(100). HRMS (EI⁺): calcd for C₁₃H₁₅NO₂(M⁺): 217.1097, Found:

217.1098.

N-2-Buten-1-yl-2-methyl-N-(phenylmethoxy)-2-propenamide (3).

A colorless oil. IR (KBr) 2984, 1738, 1461 cm⁻¹. ¹H NMR (CDCl₃) δ

7.40−7.30 (5H, m), 5.75−5.65 (1H, m), 5.56−5.47 (1H, m), 5.32

(1H, br s), 5.26 (1H, br s), 4.83 (2H, s), 4.15 (2H, d, J = 5.0 Hz), 1.97

(3H, t, J = 1.4 Hz), 1.71 (3H, br dd, J = 6.4, 1.4 Hz). ¹³C NMR

N-(Phenylmethoxy)-N-(3-methyl-2-butenyl)carbamic Acid 1,1-

Dimethylethyl Ester (11). A colorless oil. IR (KBr) 2976, 1704,

1

1453 cm⁻¹. H NMR (CDCl₃) δ 7.40−7.29 (5H, m), 5.29 (1H, m),

4.81 (2H, s), 3.98 (2H, d, J = 6.9 Hz), 1.72 (3H, br s), 1.65 (3H, br s),

1.50 (9H, s). ¹³C NMR (CDCl₃) δ 156.8, 136.3, 135.7, 129.4, 128.4,

128.3, 118.8, 81.2, 77.2, 47.7, 28.3, 25.8, 17.9. MS (EI⁺): m/z 291 (M⁺,

0.4), 91 (100). HRMS (EI⁺): calcd for C₁₇H₂₅NO₃(M⁺): 291.1829,

Found: 291.1849.

General Procedure for the Preparation of Propargylamines

12−14. After NaH (60% oil suspension, 470 mg 11.7 mmol) was

washed with hexanes three times under argon atmosphere, THF (10

mL) was added. To this stirred suspension was added a solution of 8

(2.50 g, 11.2 mmol) in THF (10 mL) at 0 °C. After being stirred at

same temperature for 20 min, propargyl bromide derivative (13.4

mmol) or 3-chloro-1-phenyl-1-propyne (1.4 mL, 10.2 mmol) was

added to the reaction mixture. In the case of propargyl bromide

derivatives, the reaction mixture was stirred at the room temperature

for 12 h. In the case of 3-chloro-1-phenyl-1-propyne, the reaction

mixture was stirred at 50 °C for 5 h. The reaction mixture was diluted

with water and then extracted with AcOEt. The organic phase was

dried over MgSO₄and concentrated under reduced pressure.

Puriﬁcation of the residue by ﬂash silica gel column chromatography

(AcOEt:hexane = 1:20) aﬀorded the products 12 (2.693 g, 92%), 13

(2.837 g, 92%), and 14 (1.058 g, 28%).

N-(Phenylmethoxy)-N-2-propyn-1-ylcarbamic Acid 1,1-Dimethy-

1

lethyl Ester (12). A colorless oil. IR (CHCl₃) 1702 cm⁻¹. H NMR

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(CDCl₃) δ 171.6, 140.6, 134.7, 130.1, 129.3, 128.7, 128.5, 124.9, 117.2,

77.2, 50.1, 19.9, 17.8. MS (EI⁺): m/z 245 (M⁺, 0.6), 91 (100). HRMS

(EI⁺): calcd for C₁₅H₁₉NO₂(M⁺): 245.1410, Found: 245.1438.

2-Methyl-N-(3-methyl-2-buten-1-yl)-N-(phenylmethoxy)-2-pro-

aﬀorded the isolated products, cis-15a (110 mg, 48%), trans-15a (61

0.7 mg, 27%) and 16a (5.3 mg, 2%) [entry 4 in Table 7], cis-15b (112

mg, 45%), trans-15b (57.7 mg, 23%), and 16b (8.9 mg, 4%) [entry 5

in Table 7], cis-15c (67.3 mg, 30%), trans-15c (4.3 mg, 2%), and 16c

(19.0 mg, 8%) [entry 10 in Table 7], cis-15d (137 mg, 50%), trans-15d

(11.9 mg, 4%), and 16d (52.2 mg, 19%) [entry 11 in Table 7], cis-18

(major, 106 mg, 46%), cis-18 (minor, 48.7 mg, 21%), trans-18 (major,

44.5 mg, 19%), and trans-18 (minor, 12.7 mg, 5%) [Scheme 8], Z-21

(68.6 mg, 30%) and E-21 (103 mg, 44%) [Scheme 10], Z-22 (191 mg,

74%) [Scheme 10], cis-26 (major, 147 mg, 63%), cis-26 (minor, 23.6

mg, 10%), trans-26 (major, 9.1 mg, 4%), and trans-26 (minor, 1.8 mg,

1%) [Scheme 8], cis-28a (105 mg, 55%) and trans-28a (54.0 mg, 28%)

[entry 4 in Table 8], cis-28c (145 mg, 70%) and trans-28c (38.5 mg,

18%) [entry 5 in Table 8], and cis-29 (82.2 mg, 44%), trans-29 (13.4

mg, 7%), and 30 (15.6 mg, 8%) [entry 4 in Table 9]. As regards the

1

penamide (4). A colorless oil. IR (KBr) 2921, 1658, 1452 cm⁻¹. H

NMR (CDCl₃) δ 7.40−7.30 (5H, m), 5.31 (1H, br s), 5.28 (1H, m),

5.26 (1H, br s), 4.83 (2H, s), 4.22 (2H, d, J = 7.4 Hz), 1.97 (3H, t, J =

1.4 Hz), 1.74 (3H, s), 1.68 (3H, s). ¹³C NMR (CDCl₃) δ 171.5, 140.6,

136.8, 134.7, 129.3, 128.7, 128.5, 118.4, 117.1, 46.0, 25.8, 19.9, 17.9.

One peak of ¹³C NMR was missing due to overlap with carbon peaks

of CDCl₃. MS (EI⁺): m/z 259 (M⁺, 7.6), 91 (100). HRMS (EI⁺): calcd

for C₁₆H₂₁NO₂(M⁺): 259.1567, Found: 259.1574.

2-Methyl-N-(phenylmethoxy)-N-2-propyn-1-yl-2-propenamide

(5). A colorless oil. IR (CHCl₃) 1659, 1639 cm⁻¹. ¹H NMR (CDCl₃) δ

7.43−7.30 (5H, m), 5.41 (1H, s), 5.33 (1H, s), 4.98 (2H, s), 4.38 (2H,

d, J = 2.4 Hz), 2.30 (1H, t, J = 2.4 Hz), 1.98 (3H, s). ¹³C NMR

(CDCl₃) δ 172.1, 139.8, 134.5, 129.4, 128.9, 128.6, 118.3, 77.9, 77.7,

72.3, 38.3, 19.5. MS (EI⁺): m/z 229 (M⁺, 10), 92 (100). HRMS (EI⁺):

calcd for C₁₄H₁₅NO₂(M⁺): 229.1097, Found: 229.1109.

1

ratio of products, slight diﬀerences between H NMR analysis of the

mixture (the ﬁrst puriﬁcation) and the isolated yields (the second

puriﬁcation) were observed.

(3S,4R)-3-(2,2,3,3,4,4,4-Heptaﬂuorobutyl)-4-(iodomethyl)-3-

methyl-1-(phenylmethoxy)-2-pyrrolidinone (cis-15a). Colorless crys-

N-2-Butyn-1-yl-2-methyl-N-(phenylmethoxy)-2-propenamide (6).

1

A colorless oil. IR (CHCl₃) 1657, 1639 cm⁻¹. H NMR (CDCl₃) δ

1

tals. mp 99−99.5 °C (hexane). IR (KBr) 2948, 1717, 1458 cm⁻¹. H

7.45−7.32 (5H, m), 5.38 (1H, s), 5.30 (1H, s), 4.98 (2H, s), 4.33 (2H,

q, J = 2.4 Hz), 1.97 (3H, s), 1.83 (3H, t, J = 2.4 Hz). ¹³C NMR

(CDCl₃) δ 171.9, 140.0, 134.7, 129.4, 128.8, 128.5, 118.0, 80.0, 77.6,

73.2, 38.8, 19.6, 3.4. MS (FAB⁺): m/z 244 (M + H⁺, 100). HRMS

(FAB⁺): calcd for C₁₅H₁₈NO₂(M + H⁺): 244.1332, Found: 244.1333.

2-Methyl-N-(phenylmethoxy)-N-(3-phenyl-2-propyn-1-yl)-2-pro-

penamide (7). A colorless oil. IR (CHCl₃) 1659, 1631 cm⁻¹. ¹H NMR

(CDCl₃) δ 7.45−7.29 (10H, m), 5.43 (1H, t, J = 1.2 Hz), 5.34 (1H, t, J

= 1.4 Hz), 5.06 (2H, s), 4.63 (2H, s), 2.00 (3H, t, J = 1.4 Hz). ¹³C

NMR (CDCl₃) δ 171.9, 139.9, 134.6, 131.8, 129.4, 128.8, 128.6, 128.5,

128.3, 122.5, 118.2, 84.0, 83.4, 77.9, 39.3, 19.7. HRMS (ESI⁺): calcd

for C₂₀H₂₀NO₂(M + H⁺): 306.1489, Found: 306.1489.

General Procedure for Radical Reaction in the Absence of

Ligand. A solution of substrate (0.43 mmol) and Zn(OTf)₂(156 mg,

0.43 mmol) in CH₂Cl₂(4.3 mL) was stirred for 30 min under Ar

atmosphere at 20 °C. In the case of 8, Bu₃SnH (0.65 mmol) was

added. To a reaction mixture were added RX (2.15 mmol) and Et₃B

(1.05 M in hexane, 2.05 mL, 2.15 mmol) at 20 °C. After being stirred

at the same temperature for 2−20 h, the reaction mixture was diluted

with saturated NaHCO₃and then extracted with CH₂Cl₂. The organic

phase was dried over Na₂SO₄and concentrated at reduced pressure.

The residue was roughly puriﬁed by preparative TLC (hexane:AcOEt

= 3:1) to give the mixture of products. The ratio of products was

determined by ¹H NMR analysis of the mixture. Second puriﬁcation of

the mixture by preparative TLC (benzene:AcOEt = 10:1 or

hexane:AcOEt = 6:1, 2-fold development) aﬀorded the isolated

products, trans-17 (72.5 mg, 33%) and cis-17 (44.4 mg, 20%) [entry 1

in Table 3], cis-19 (15.3 mg, 8%) and trans-19 (27.2 mg, 15%) [entry

4 in Table 4], Z-20a (146 mg, 65%) and E-20a (32.1 mg, 14%) [entry

1 in Table 5], Z-20b (112 mg, 50%) and E-20b (21.3 mg, 9%) [entry 8

in Table 5], Z-20c (138 mg, 80%) [entry 9 in Table 5], Z-22 (20.7 mg,

8%), E-23 (67.1 mg, 33%) and Z-23 (24.8 mg, 12%) [entry 4 in Table

6], and cis-28b (72.4 mg, 42%) and trans-28b (81.7 mg, 48%) [entry 2

in Table 8]. As regards the ratio of products, slight diﬀerences between

¹H NMR analysis of the mixture (the ﬁrst puriﬁcation) and the

NMR (CDCl₃) δ 7.50−7.38 (5H, m), 5.04 (1H, d, J = 11.0 Hz), 5.02

(1H, d, J = 11.0 Hz), 3.50 (1H, dd, J = 9.2, 6.6 Hz), 3.30−3.19 (2H,

m), 2.73 (1H, t, J = 11.4 Hz), 2.58−2.39 (2H, m), 2.26 (1H, br dd, J =

37.0, 16.0 Hz), 1.32 (3H, d, J = 1.6 Hz). ¹³C NMR (CDCl₃) δ 170.8,

134.7, 129.6, 129.3, 128.7, 118.3 (tt, J = 257, 31 Hz), 117.5 (qt, J =

289, 34 Hz), 108.4 (tsex, J = 265, 36 Hz), 76.9, 51.1, 44.5, 44.2, 31.0

(t, J = 21 Hz), 22.2, 4.1. ¹⁹F NMR (CDCl₃) δ −80.6 (3F, t, J = 19.5

Hz), −106.2 (1F, dm, J = 273 Hz), −116.0 (1F, dm, J = 273 Hz),

−128.3 (2F, br s). MS (EI⁺): m/z 528 (M + H⁺, 25), 91 (100). HRMS

(EI⁺): calcd for C₁₇H₁₈F₇INO₂(M + H⁺): 528.0265, Found: 528.0260.

Elemental analysis (%) calcd for C₁₇H₁₇F₇INO₂: C, 38.73; H, 3.25; N,

2.66, found: C, 38.74, H, 3.22, N, 2.60. HPLC (Chiralcel AD-H,

hexane/2-propanol = 95/5, 1.0 mL/min, 254 nm) t_r(major) = 6.7

min, t_r(minor) = 8.9 min. A sample of 87% ee by HPLC analysis gave

[α]²⁴+28.3 (c 0.40, CHCl₃).

D

(3S,4S)-3-(2,2,3,3,4,4,4-Heptaﬂuorobutyl)-4-(iodomethyl)-3-

methyl-1-(phenylmethoxy)-2-pyrrolidinone (trans-15a). A colorless

oil. IR (KBr) 2973, 1717, 1457 cm⁻¹. ¹H NMR (CDCl₃) δ 7.47−7.37

(5H, m), 5.03 (1H, d, J = 10.5 Hz), 4.96 (1H, d, J = 10.5 Hz), 3.51

(1H, t, J = 8.3 Hz), 3.29 (1H, dd, J = 9.6, 4.1 Hz), 2.95 (2H, t, J = 10.5

Hz), 2.76 (1H, m), 2.59−2.27 (2H, br m), 1.07 (3H, s). ¹³C NMR

(CDCl₃) δ 172.0, 134.6, 129.6, 129.2, 128.6, 118.0 (tt, J = 258, 32 Hz),

117.7 (qt, J = 289, 34 Hz), 108.4 (tsex, J = 265, 36 Hz), 77.2, 51.4,

43.6, 40.5 (d, J = 3 Hz), 35.0 (t, J = 20 Hz), 17.5, 0.6. ¹⁹F NMR

(CDCl₃) δ −80.6 (3F, t, J = 10 Hz), −108.9 (1F, dm, J = 269 Hz),

−115.2 (1F, dm, J = 269 Hz), −128.0 (1F, dd, J = 289, 8 Hz), −128.5

(1F, dd, J = 289, 6 Hz). HRMS (ESI⁺): calcd for C₁₇H₁₈F₇INO₂(M +

H⁺): 528.0265, Found: 528.0271. HPLC (Chiralcel AD-H, hexane/2-

propanol = 95/5, 1.0 mL/min, 254 nm) t_r(major) = 13.6 min, t_r

(minor) = 8.2 min. A sample of 90% ee by HPLC analysis gave [α]²⁴

D

+28.8 (c 0.23, CHCl₃).

cis-4-(2,2,3,3,4,4,4-Heptaﬂuorobutyl)-3-(iodomethyl)-3-methyl-1-

(phenylmethoxy)-2-pyrrolidinone (16a). A colorless oil. IR (KBr)

1

2968, 2932, 1714, 1455 cm⁻¹. H NMR (CDCl₃) δ 7.47−7.34 (5H,

m), 5.09 (1H, d, J = 11.0 Hz), 5.04 (1H, d, J = 11.0 Hz), 3.48 (1H, t, J

= 8.5 Hz), 3.37 (1H, dd, J = 8.5, 1.8 Hz), 3.23 (1H, d, J = 11.0 Hz),

3.05 (1H, d, J = 11.0 Hz), 2.45 (1H, m), 2.42−2.26 (2H, br m), 1.30

(3H, s). ¹³C NMR (CDCl₃) δ 170.1, 134.7, 129.5, 129.1, 128.6, 117.6

(qt, J = 288, 34 Hz), 117.4 (tt, J = 256, 32 Hz), 108.4 (tsex, J = 265, 38

Hz), 77.2, 50.1 (d, J = 5 Hz), 44.0, 33.9, 28.1 (t, J = 21 Hz), 25.0, 6.4.

¹⁹F NMR (CDCl₃) δ −80.9 (3F, t, J = 9 Hz), −113.7 (1F, dm, J = 273

isolated yields (the second puriﬁcation) were observed.

General Procedure for Enantioselective Radical Reaction. A

solution of substrate (0.43 mmol), Zn(OTf)₂(156 mg, 0.43 mmol),

and ligand (153 mg, 0.43 mmol) in CH₂Cl₂(4.3 mL) was stirred for 1

h under Ar atmosphere at 20 °C. To a reaction mixture were added

RX (2.15 mmol) and Et₃B (1.05 M in hexane, 2.05 mL, 2.15 mmol) at

−78 °C. After being stirred at the same temperature for 1−5 days, the

reaction mixture was diluted with saturated NaHCO₃and then

extracted with CH₂Cl₂. The organic phase was dried over Na₂SO₄and

concentrated at reduced pressure. The residue was roughly puriﬁed by

preparative TLC (hexane:AcOEt = 3:1) to give the mixture of

Hz), −116.0 (1F, dm, J = 273 Hz), −127.8 (1F, dd, J = 290, 5 Hz),

−128.2 (1F, dd, J = 290, 5 Hz). HRMS (ESI⁺): calcd for

C₁₇H₁₈F₇INO₂(M + H⁺): 528.0265, Found: 528.0269.

(3S,4R)-4-(Iodomethyl)-3-methyl-3-(2,2,3,3,4,4,5,5,5-nonaﬂuoro-

pentyl)-1-(phenylmethoxy)-2-pyrrolidinone (cis-15b). Colorless crys-

tals. mp 95−96 °C (hexane). IR (KBr) 2975, 2949, 1717, 1458 cm⁻¹.

¹H NMR (CDCl₃) δ 7.45−7.37 (5H, m), 5.02 (1H, d, J = 11.4 Hz),

1

products. The ratio of products was determined by H NMR analysis

of the mixture. Second puriﬁcation of the mixture by preparative TLC

(benzene:AcOEt = 10:1 or hexane:AcOEt = 6:1, 2-fold development)

4.99 (1H, d, J = 11.4 Hz), 3.48 (1H, dd, J = 9.6, 6.8 Hz), 3.24−3.18

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(2H, m), 2.71 (1H, t, J = 9.6 Hz), 2.57−2.37 (2H, br m), 2.26 (1H, br

dd, J = 37.1, 16.0 Hz), 1.29 (3H, d, J = 2.8 Hz). ¹³C NMR (CDCl₃) δ

170.8, 134.7, 129.5, 129.2, 128.7, 118.8 (tt, J = 256, 31 Hz), 117.2 (qt,

J = 287, 33 Hz), 110.0 (tquin, J = 264, 33 Hz), 108.6 (tsex, J = 267, 37

Hz), 76.8, 51.1, 44.5, 44.2, 31.2 (t, J = 21 Hz), 22.2, 4.0. ¹⁹F NMR

(CDCl₃) δ −81.5 (3F, br s), −105.4 (1F, dm, J = 272 Hz), −115.0

(1F, dm, J = 272 Hz), −124.8 (1F, dm, J = 298 Hz), −125.0 (1F, dm, J

= 298 Hz), −125.9 (1F, dm, J = 295 Hz), −126.6 (1F, dm, J = 295

Hz). MS (EI⁺): m/z 578 (M + H⁺, 0.6), 91 (100). HRMS (EI⁺): calcd

for C₁₈H₁₈F₉INO₂(M + H⁺): 578.0233, Found: 578.0239. Elemental

analysis (%) calcd for C₁₈H₁₇F₉INO₂: C, 37.45; H, 2.97; N, 2.43,

found: C, 37.45, H, 2.94, N, 2.42. HPLC (Chiralcel AD-H, hexane/2-

propanol = 95/5, 1.0 mL/min, 254 nm) t_r(major) = 6.8 min, t_r

(1H, br t, J = 15.1 Hz), 2.26 (1H, br t, J = 15.1 Hz), 1.04 (3H, br s).

¹³C NMR (CDCl₃) δ 171.6, 134.6, 129.5, 129.1, 128.6, 120.8 (qd, J =

288, 28 Hz), 120.6 (qd, J = 288, 29 Hz), 91.4 (dseq, J = 241, 33 Hz),

77.2, 51.3, 45.0, 40.2 (d, J = 5 Hz), 32.1 (d, J = 18 Hz), 18.6, 0.6. ¹⁹F

NMR (CDCl₃) δ −77.5 (3F, br quin, J = 9 Hz), −78.3 (3F, dq, J = 9, 7

Hz), −186.9 (1F, m). HRMS (ESI⁺): calcd for C₁₇H₁₈F₇INO₂(M +

H⁺): 528.0265, Found: 528.0269.

cis-3-(Iodomethyl)-3-methyl-1-(phenylmethoxy)-4-[2,3,3,3-tetra-

ﬂuoro-2-(triﬂuoromethyl)propyl]-2-pyrrolidinone (16c). A colorless

1

oil. IR (KBr) 2966, 2930, 1715, 1456 cm⁻¹. H NMR (CDCl₃) δ

7.46−7.36 (5H, m), 5.08 (1H, d, J = 11.0 Hz), 5.02 (1H, d, J = 11.0

Hz), 3.46 (1H, dd, J = 9.2, 6.9 Hz), 3.32 (1H, m), 3.23 (1H, d, J = 11.0

Hz), 3.06 (1H, d, J = 11.0 Hz), 2.44−2.24 (3H, br m), 1.29 (3H, s).

¹³C NMR (CDCl₃) δ 169.8, 134.6, 129.5, 129.1, 128.6, 120.8 (qd, J =

288, 29 Hz), 120.6 (qd, J = 288, 28 Hz), 91.7 (dseq, J = 206, 32 Hz),

76.9, 50.1 (d, J = 6 Hz), 44.4, 35.3, 26.1 (d, J = 19 Hz), 25.0, 6.1. ¹⁹F

NMR (CDCl₃) δ −76.0 (3F, br quin, J = 9 Hz), −78.2 (3F, dq, J = 9, 7

Hz), −185.3 (1F, m). HRMS (ESI⁺): calcd for C₁₇H₁₈F₇INO₂(M +

H⁺): 528.0265, Found: 528.0266.

(minor) = 7.7 min. A sample of 77% ee by HPLC analysis gave [α]¹⁹

D

+20.0 (c 0.49, CHCl₃).

(3S,4S)-4-(Iodomethyl)-3-methyl-3-(2,2,3,3,4,4,5,5,5-nonaﬂuoro-

pentyl)-1-(phenylmethoxy)-2-pyrrolidinone (trans-15b). A colorless

1

oil. IR (KBr) 2973, 2944, 1717, 1458 cm⁻¹. H NMR (CDCl₃) δ

7.45−7.36 (5H, m), 5.02 (1H, d, J = 11.0 Hz), 4.95 (1H, d, J = 11.0

Hz), 3.50 (1H, t, J = 8.2 Hz), 3.23 (1H, dd, J = 9.6, 4.1 Hz), 2.94 (2H,

t, J = 10.1 Hz), 2.75 (1H, m), 2.51 (1H, br dd, J = 38.5, 15.1 Hz),

2.42−2.26 (1H, br m), 1.07 (3H, s). ¹³C NMR (CDCl₃) δ 172.0,

134.6, 129.6, 129.2, 128.6, 118.6 (tt, J = 259, 32 Hz), 117.3 (qt, J =

290, 33 Hz), 109.8 (tquin, J = 267, 36 Hz), 108.6 (tsex, J = 271, 34

Hz), 77.2, 51.4, 43.6, 40.5 (d, J = 3 Hz), 35.2 (t, J = 20 Hz), 17.5, 0.6.

¹⁹F NMR (CDCl₃) δ −81.5 (3F, t, J = 10 Hz), −108.1 (1F, dm, J =

269 Hz), −114.3 (1F, dm, J = 269 Hz), −124.9 (2F, br s), −126.0 (1F,

ddd, J = 295, 16, 9 Hz), −126.5 (1F, dt, J = 295, 15 Hz). MS (EI⁺): m/

z 578 (M + H⁺, 0.7), 91 (100). HRMS (EI⁺): calcd for C₁₈H₁₈F₉INO₂

(M + H⁺): 578.0233, Found: 578.0224. HPLC (Chiralcel AD-H,

hexane/2-propanol = 95/5, 1.0 mL/min, 254 nm) t_r(major) = 11.2

min, t_r(minor) = 8.0 min. A sample of 85% ee by HPLC analysis gave

(3S,4R)-4-(Iodomethyl)-3-methyl-1-(phenylmethoxy)-3-

[(1,2,2,3,3,4,4,5,5,6,6-undecaﬂuorocyclohexyl)methyl]-2-pyrrolidi-

none (cis-15d). Colorless crystals. mp 154−155 °C (hexane). IR

1

(KBr) 2979, 2939, 1713, 1461 cm⁻¹. H NMR (CDCl₃) δ 7.46−7.38

(5H, m), 5.04 (1H, d, J = 11.2 Hz), 5.01 (1H, d, J = 11.2 Hz), 3.48

(1H, dd, J = 9.7, 6.4 Hz), 3.35 (1H, dd, J = 9.7, 3.2 Hz), 3.24 (1H, dd,

J = 9.7, 2.6 Hz), 2.77 (1H, dd, J = 11.5, 9.7 Hz), 2.64 (1H, br t, J =

17.6 Hz), 2.39 (1H, br m), 2.15 (1H, br t, J = 17.6 Hz), 1.29 (3H, t, J

= 2.9 Hz). ¹³C NMR (CDCl₃) δ 171.0, 134.8, 129.5, 129.3, 128.7,

111−106 (5C, m), 92.5 (dquit, J = 205, 26 Hz), 76.9, 51.3, 45.8, 44.9,

26.4 (d, J = 20 Hz), 22.8, 3.1. ¹⁹F NMR (CDCl₃) δ −117.2 (1F, br d, J

= 295 Hz), −118.3 (1F, br d, J = 295 Hz), −122.8 (2F, br d, J = 279

Hz), −124.4 (1F, br d, J = 284 Hz), −131.7 (1F, br d, J = 295 Hz),

−132.3 (1F, br d, J = 295 Hz), −139.0 (2F, br d, J = 279 Hz), −142.5

(1F, br d, J = 284 Hz), −184.9 (1F, br s). HRMS (ESI⁺): calcd for

C₂₀H₁₈F₁₁INO₂(M + H⁺): 640.0201, Found: 640.0215. HPLC

(Chiralcel AD-H, hexane/2-propanol = 95/5, 1.0 mL/min, 254 nm) t_r

(major) = 6.0 min, t_r(minor) = 8.3 min. A sample of 91% ee by HPLC

[α]²²+33.6 (c 0.56, CHCl₃).

D

cis-3-(Iodomethyl)-3-methyl-4-(2,2,3,3,4,4,5,5,5-nonaﬂuoropen-

tyl)-1-(phenylmethoxy)-2-pyrrolidinone (16b). A colorless oil. IR

1

(KBr) 2969, 2933, 1715, 1456 cm⁻¹. H NMR (CDCl₃) δ 7.48−7.34

(5H, m), 5.08 (1H, d, J = 10.5 Hz), 5.03 (1H, d, J = 10.5 Hz), 3.48

(1H, t, J = 8.7 Hz), 3.37 (1H, m), 3.22 (1H, d, J = 11.0 Hz), 3.04 (1H,

d, J = 11.0 Hz), 2.49−2.25 (3H, br m), 1.30 (3H, s). ¹³C NMR

(CDCl₃) δ 170.1, 134.7, 129.6, 129.1, 128.6, 118.0 (tt, J = 257, 32 Hz),

117.2 (qt, J = 290, 34 Hz), 110.1 (tquin, J = 267, 36 Hz), 108.6 (tsex, J

= 271, 39 Hz), 77.2, 50.1 (d, J = 5 Hz), 44.0, 33.9, 28.3 (t, J = 22 Hz),

25.0, 6.4. ¹⁹F NMR (CDCl₃) δ −81.5 (3F, t, J = 9 Hz), −112.9 (1F,

dm, J = 257 Hz), −115.1 (1F, dm, J = 257 Hz), −124.7 (2F, br s),

−126.5 (2F, m). HRMS (ESI⁺): calcd for C₁₈H₁₈F₉INO₂(M + H⁺):

578.0233, Found: 578.0224.

analysis gave [α]²²+27.9 (c 0.52, CHCl₃).

D

trans-4-(Iodomethyl)-3-methyl-1-(phenylmethoxy)-3-

[(1,2,2,3,3,4,4,5,5,6,6-undecaﬂuorocyclohexyl)methyl]-2-pyrrolidi-

none (trans-15d). A colorless oil. IR (KBr) 2972, 2878, 1720, 1458

1

cm⁻¹. H NMR (CDCl₃) δ 7.45−7.36 (5H, m), 5.04 (1H, d, J = 11.0

Hz), 4.95 (1H, d, J = 11.0 Hz), 3.55 (1H, t, J = 7.8 Hz), 3.21 (1H, dd, J

= 9.6, 4.2 Hz), 2.94 (1H, br t, J = 7.8 Hz), 2.92 (1H, br t, J = 9.6 Hz),

2.75 (1H, m), 2.62 (1H, br dd, J = 19.7, 15.0 Hz), 2.36 (1H, br t, J =

15.0 Hz), 1.06 (3H, s). ¹³C NMR (CDCl₃) δ 171.6, 134.6, 129.5,

129.1, 128.6, 113−103 (5C, m), 91.8 (dquit, J = 233, 28 Hz), 76.9,

51.3, 44.9, 40.1, 29.6 (d, J = 19 Hz), 18.7, 0.3 (d, J = 2 Hz). ¹⁹F NMR

(CDCl₃) δ −118.1 (2F, br t, J = 265 Hz), −122.7 (2F, br d, J = 288

Hz), −124.1 (1F, br d, J = 288 Hz), −132.7 (1F, br d, J = 295 Hz),

−134.2 (1F, br d, J = 295 Hz), −139.1 (2F, br d, J = 270 Hz), −142.5

(1F, br m), −185.5 (1F, br s). HRMS (ESI⁺): calcd for

C₂₀H₁₈F₁₁INO₂(M + H⁺): 640.0201, Found: 640.0211.

(3S,4R)-4-(Iodomethyl)-3-methyl-1-(phenylmethoxy)-3-[2,3,3,3-

tetraﬂuoro-2-(triﬂuoromethyl)propyl]-2-pyrrolidinone (cis-15c).

Colorless crystals. mp 95.5−96.5 °C (hexane). IR (KBr) 2946, 1719,

1496, 1458 cm⁻¹. ¹H NMR (CDCl₃) δ 7.49−7.36 (5H, m), 5.04 (1H,

d, J = 11.0 Hz), 5.00 (1H, d, J = 11.0 Hz), 3.48 (1H, dd, J = 9.6, 4.0

Hz), 3.31 (1H, dd, J = 10.1, 3.2 Hz), 3.23 (1H, dd, J = 9.6, 2.8 Hz),

2.73 (1H, dd, J = 11.9, 10.1 Hz), 2.64 (1H, br t, J = 17.5 Hz), 2.39

(1H, m), 2.15 (1H, br t, J = 17.5 Hz), 1.27 (3H, br s). ¹³C NMR

(CDCl₃) δ 171.0, 134.7, 129.5, 129.3, 128.7, 121.0 (qd, J = 287, 29

Hz), 120.6 (qd, J = 291, 29 Hz), 92.1 (dseq, J = 210, 33 Hz), 76.9,

51.1, 46.1, 44.8, 28.5 (d, J = 19 Hz), 22.0, 3.5. ¹⁹F NMR (CDCl₃) δ

−76.7 (3F, dq, J = 10, 7 Hz), −77.0 (3F, br quin, J = 9 Hz), −185.2

(1F, m). HRMS (ESI⁺): calcd for C₁₇H₁₈F₇INO₂(M + H⁺): 528.0265,

Found: 528.0259. Elemental analysis (%) calcd for C₁₇H₁₇F₇INO₂: C,

38.73; H, 3.25; N, 2.66, found: C, 38.73, H, 3.22, N, 2.65. HPLC

(Chiralcel AD-H, hexane/2-propanol = 95/5, 1.0 mL/min, 254 nm) t_r

(major) = 6.2 min, t_r(minor) = 8.8 min. A sample of 92% ee by HPLC

cis-3-(Iodomethyl)-3-methyl-1-(phenylmethoxy)-4-

[(1,2,2,3,3,4,4,5,5,6,6-undecaﬂuorocyclohexyl)methyl]-2-pyrrolidi-

none (16d). Colorless crystals. mp 97−98 °C (hexane). IR (KBr)

1

2970, 2885, 1715, 1456 cm⁻¹. H NMR (CDCl₃) δ 7.46−7.35 (5H,

m), 5.08 (1H, d, J = 11.0 Hz), 5.03 (1H, d, J = 11.0 Hz), 3.45 (1H, m),

3.35 (1H, m), 3.23 (1H, d, J = 11.0 Hz), 3.10 (1H, d, J = 11.0 Hz),

2.52−2.42 (3H, m), 1.29 (3H, s). ¹³C NMR (CDCl₃) δ 169.7, 134.6,

129.4, 129.0, 128.5, 113−105 (5C, m), 91.7 (dquit, J = 203, 24 Hz),

76.9, 50.1 (d, J = 6 Hz), 44.5, 35.4, 25.0, 23.2 (d, J = 20 Hz), 6.1. ¹⁹F

NMR (CDCl₃) δ −118.0 (1F, br d, J = 295 Hz), −118.3 (1F, br d, J =

295 Hz), −122.7 (1F, br d, J = 280 Hz), −123.1 (1F, br d, J = 280

Hz), −124.5 (1F, br d, J = 280 Hz), −132.3 (1F, br d, J = 295 Hz),

−134.2 (1F, br d, J = 295 Hz), −139.5 (2F, br d, J = 280 Hz), −142.4

(1F, br d, J = 285 Hz), −185.1 (1F, br s). HRMS (ESI⁺): calcd for

C₂₀H₁₈F₁₁INO₂(M + H⁺): 640.0201, Found: 640.0211.

analysis gave [α]²⁴+33.0 (c 0.40, CHCl₃).

D

trans-4-(Iodomethyl)-3-methyl-1-(phenylmethoxy)-3-[2,3,3,3-tet-

raﬂuoro-2-(triﬂuoromethyl)propyl]-2-pyrrolidinone (trans-15c). A

1

colorless oil. IR (KBr) 2929, 1721, 1458 cm⁻¹. H NMR (CDCl₃) δ

7.46−7.36 (5H, m), 5.04 (1H, d, J = 11.0 Hz), 4.94 (1H, d, J = 11.0

Hz), 3.55 (1H, t, J = 8.2 Hz), 3.22 (1H, dd, J = 9.2, 3.7 Hz), 2.94 (1H,

br t, J = 10.1 Hz), 2.91 (1H, dd, J = 12.4, 10.1 Hz), 2.75 (1H, m), 2.54

trans-3-(2,2,3,3,4,4,4-Heptaﬂuorobutyl)-4-(iodomethyl)-1-(phe-

nylmethoxy)-2-pyrrolidinone (trans-17). A colorless oil. IR (KBr)

8599

dx.doi.org/10.1021/jo3015227 | J. Org. Chem. 2012, 77, 8588−8604

The Journal of Organic Chemistry

Article

1

2949, 2884, 1716, 1434, 1353 cm⁻¹. H NMR (CDCl₃) δ 7.45−7.35

CHCl₃). A minor isomer: A white solid. IR (KBr) 2973, 2878, 1722,

1457 cm⁻¹. ¹H NMR (CDCl₃) δ 7.45−7.34 (5H, m), 5.03 (1H, d, J =

11.0 Hz), 4.92 (1H, d, J = 11.0 Hz), 3.93 (1H, m), 3.33 (1H, t, J = 7.8

Hz), 3.00−2.82 (3H, m), 2.62 (1H, dd, J = 38.0, 15.6 Hz), 1.84 (3H, d,

J = 6.8 Hz), 1.18 (3H, s). ¹³C NMR (CDCl₃) δ 172.5, 134.9, 129.6,

129.0, 128.6, 118.0 (tt, J = 259, 31 Hz), 117.8 (qt, J = 289, 35 Hz),

108.3 (tsex, J = 266, 34 Hz), 77.1, 48.6, 43.9, 43.2, 34.1 (t, J = 19 Hz),

27.1, 20.5, 17.6. ¹⁹F NMR (CDCl₃) δ −80.5 (3F, br m), −105.5 (1F,

dm, J = 270 Hz), −114.3 (1F, dm, J = 270 Hz), −128.1 (1F, dm, J =

288 Hz), −128.6 (1F, dm, J = 288 Hz). HRMS (ESI⁺): calcd for

C₁₈H₂₀F₇INO₂(M + H⁺): 542.0421, Found: 542.0420.

(5H, m), 5.00 (2H, dd, J = 10.8, 9.6 Hz), 3.42 (1H, t, J = 8.7 Hz), 3.35

(1H, dd, J = 10.1, 3.7 Hz), 3.13−3.07 (2H, m), 2.89−2.74 (1H, m),

2.54 (1H, ddd, J = 10.1, 7.3, 2.8 Hz), 2.29−2.00 (2H, m). ¹³C NMR

(CDCl₃) δ 169.0, 134.6, 129.5, 129.1, 128.6, 117.6 (qt, J = 289, 34

Hz), 117.6 (tt, J = 256, 31 Hz), 108.4 (tsex, J = 266, 35 Hz), 76.9, 52.3,

39.8 (d, J = 1.9 Hz), 37.7, 31.4 (t, J = 21 Hz), 7.9 (d, J = 4.8 Hz). ¹⁹F

NMR (CDCl₃) δ −80.8 (3F, t, J = 9.6 Hz), −112.2 (1F, dm, J = 268

Hz), −114.6 (1F, dm, J = 268 Hz), −128.1 (2F, dd, J = 290, 6.0 Hz).

HRMS (ESI⁺): calcd for C₁₆H₁₆F₇INO₂(M + H⁺): 514.0108, Found:

514.0104.

cis-3-(2,2,3,3,4,4,4-Heptaﬂuorobutyl)-4-(iodomethyl)-1-(phenyl-

cis-3-(2,2,3,3,4,4,4-Heptaﬂuorobutyl)-3-methyl-4-(1-methyleth-

methoxy)-2-pyrrolidinone (cis-17). A colorless oil. IR (KBr) 2942,

yl)-1-(phenylmethoxy)-2-pyrrolidinone (cis-19). A white solid. IR

1

2913, 1711, 1444, 1354 cm⁻¹. H NMR (CDCl₃) δ 7.45−7.40 (5H,

1

(KBr) 2966, 2881, 1716, 1458 cm⁻¹. H NMR (CDCl₃) δ 7.46−7.33

m), 5.27 (2H, dd, J = 11.2, 3.6 Hz), 3.47 (1H, dd, J = 9.6, 5.3 Hz), 3.31

(1H, d, J = 9.6 Hz), 3.23 (1H, dd, J = 9.2 1.4 Hz), 2.85−2.63 (4H, m),

2.25−2.10 (1H, m). ¹³C NMR (CDCl₃) δ 167.9, 134.7, 129.5, 129.3,

128.8, 117.6 (qt, J = 289, 34 Hz), 117.6 (tt, J = 255, 31 Hz), 108.4

(tsex, J = 265, 35 Hz), 77.0, 52.2, 37.7, 36.4, 25.8 (t, J = 22 Hz), 3.8 (d,

J = 2.9 Hz). ¹⁹F NMR (CDCl₃) δ −80.8 (3F, t, J = 9.6 Hz), −114.2

(1F, dm, J = 270 Hz), −116.0 (1F, dm, J = 270 Hz), −128.1 (2F, dd, J

= 290, 6.2 Hz). HRMS (ESI⁺): calcd for C₁₆H₁₆F₇INO₂(M + H⁺):

514.0108, Found: 514.0102.

(5H, m), 5.03 (1H, d, J = 11.0 Hz), 4.95 (1H, d, J = 11.0 Hz), 3.30

(1H, t, J = 9.2 Hz), 3.13 (1H, dd, J = 9.2, 4.6 Hz), 2.52−2.23 (2H, m),

1.85 (1H, m), 1.78 (1H, m), 1.33 (3H, s), 0.93 (3H, d, J = 6.9 Hz),

0.74 (3H, d, J = 6.9 Hz). ¹³C NMR (CDCl₃) δ 171.8, 135.2, 129.3,

128.9, 128.5, 118.2 (tt, J = 258, 32 Hz), 117.8 (qt, J = 289, 34 Hz),

108.5 (tsex, J = 266, 37 Hz), 76.5, 47.9, 46.6, 42.7, 31.3 (t, J = 20 Hz),

27.1, 24.5, 22.0, 18.1. ¹⁹F NMR (CDCl₃) δ −80.6 (3F, t, J = 10 Hz),

−106.6 (1F, dm, J = 272 Hz), −114.8 (1F, dm, J = 272 Hz), −128.2

(2F, br s). HRMS (ESI⁺): calcd for C₁₉H₂₃F₇NO₂(M + H⁺):

430.1612, Found: 430.1606.

(3S,4R)-3-(2,2,3,3,4,4,4-Heptaﬂuorobutyl)-4-(1-iodoethyl)-3-

methyl-1-(phenylmethoxy)-2-pyrrolidinone (cis-18). A major iso-

trans-3-(2,2,3,3,4,4,4-Heptaﬂuorobutyl)-3-methyl-4-(1-methyl-

1

mer: A colorless oil. IR (KBr) 2948, 1715, 1458 cm⁻¹. H NMR

ethyl)-1-(phenylmethoxy)-2-pyrrolidinone (trans-19). A white solid.

1

IR (KBr) 2970, 2879, 1722, 1458 cm⁻¹. H NMR (CDCl₃) δ 7.45−

(CDCl₃) δ 7.49−7.34 (5H, m), 5.10 (1H, d, J = 11.0 Hz), 5.02 (1H, d,

J = 11.0 Hz), 4.06 (1H, m), 3.43 (1H, br t, J = 9.6 Hz), 3.30 (1H, dd, J

= 9.6, 2.3 Hz), 2.75−2.44 (2H, br m), 1.92 (3H, d, J = 6.8 Hz), 1.78

(1H, br m), 1.30 (3H, s). ¹³C NMR (CDCl₃) δ 170.3, 134.9, 129.4,

129.0, 128.5, 118.6 (tt, J = 256, 31 Hz), 117.6 (qt, J = 289, 35 Hz),

108.4 (tsex, J = 266, 36 Hz), 76.7, 49.4, 47.8, 43.6, 30.9 (t, J = 20 Hz),

28.0, 25.8, 24.5. ¹⁹F NMR (CDCl₃) δ −80.5 (3F, br m), −105.7 (1F,

dm, J = 273 Hz), −115.3 (1F, dm, J = 273 Hz), −128.2 (2F, br m).

MS (EI⁺): m/z 542 (M + H⁺, 0.6), 91 (100). HRMS (EI⁺): calcd for

C₁₈H₂₀F₇INO₂(M + H⁺): 542.0421, Found: 542.0430. HPLC

(Chiralcel AD-H, hexane/2-propanol = 95/5, 1.0 mL/min, 254 nm)

t_r(major) = 8.2 min, t_r(minor) = 9.4 min. A sample of 87% ee by

HPLC analysis gave [α]²⁴_D+59.2 (c 0.86, CHCl₃). A minor isomer: A

7.34 (5H, m), 5.01 (1H, d, J = 11.0 Hz), 4.92 (1H, d, J = 11.0 Hz),

3.25 (1H, t, J = 8.2 Hz), 2.92 (1H, t, J = 8.2 Hz), 2.85 (1H, dd, J =

39.9, 16.0 Hz), 2.21−2.00 (2H, m), 1.72−1.62 (1H, m), 1.08 (3H, s),

0.98 (3H, d, J = 6.4 Hz), 0.82 (3H, d, J = 6.9 Hz). ¹³C NMR (CDCl₃)

δ 173.1, 135.0, 129.6, 128.9, 128.5, 117.9 (tt, J = 258, 32 Hz), 117.8

(qt, J = 289, 34 Hz), 108.2 (tsex, J = 267, 36 Hz), 76.8, 49.2, 42.2

(2C), 35.7 (t, J = 20 Hz), 28.2, 21.5 (t, J = 2 Hz), 21.0, 18.4. ¹⁹F NMR

(CDCl₃) δ −80.6 (3F, t, J = 10 Hz), −104.3 (1F, dm, J = 270 Hz),

−115.8 (1F, dm, J = 270 Hz), −127.9 (1F, ddd, J = 289, 10, 5 Hz),

−128.7 (1F, dd, J = 289, 9 Hz). HRMS (ESI⁺): calcd for C₁₉H₂₃F₇NO₂

(M + H⁺): 430.1612, Found: 430.1608.

(3S,4Z)-3-(2,2,3,3,4,4,4-Heptaﬂuorobutyl)-4-(iodomethylene)-3-

1

colorless oil. IR (KBr) 2950, 1719, 1457 cm⁻¹. H NMR (CDCl₃) δ

methyl-1-(phenylmethoxy)-2-pyrrolidinone (Z-20a). A colorless oil.

1

IR (KBr) 2934, 2878, 1722, 1453, 1353 cm⁻¹. H NMR (CDCl₃) δ

7.47−7.33 (5H, m), 5.06 (1H, d, J = 11.0 Hz), 4.99 (1H, d, J = 11.0

Hz), 4.34 (1H, br qt, J = 6.8, 5.5 Hz), 3.45 (1H, dd, J = 10.1, 6.9 Hz),

3.40 (1H, dd, J = 10.1, 3.6 Hz), 2.72 (1H, m), 2.61 (1H, ddd, J = 32.5,

16.0, 9.6 Hz), 2.22 (1H, br dd, J = 37.5, 16.0 Hz), 1.64 (3H, d, J = 6.8

Hz), 1.35 (3H, d, J = 2.3 Hz). ¹³C NMR (CDCl₃) δ 171.3, 134.9,

129.3, 129.1, 128.6, 118.1 (tt, J = 257, 31 Hz), 117.6 (qt, J = 289, 34

Hz), 108.4 (tsex, J = 266, 36 Hz), 76.7, 50.0, 48.0, 43.7, 30.9 (t, J = 21

Hz), 24.0, 23.8, 23.6. ¹⁹F NMR (CDCl₃) δ −80.5 (3F, t, J = 9.7 Hz),

−106.3 (1F, dm, J = 271 Hz), −114.9 (1F, dm, J = 271 Hz), −128.2

(2F, br s). MS (EI⁺): m/z 542 (M + H⁺, 0.3), 91 (100). HRMS (EI⁺):

calcd for C₁₈H₂₀F₇INO₂(M + H⁺): 542.0421, Found: 542.0411.

HPLC (Chiralcel AD-H, hexane/2-propanol = 95/5, 1.0 mL/min, 254

nm) t_r(major) = 5.8 min, t_r(minor) = 6.9 min. A sample of 75% ee by

7.45−7.37 (5H, m), 6.37 (1H, t, J = 2.5 Hz), 5.06 (1H, d, J = 11.0 Hz),

4.98 (1H, d, J = 11.0 Hz), 3.86 (2H, ddd, J = 15.5, 14.2, 2.8 Hz), 2.73

(1H, ddd, J = 31.6, 15.5, 4.0 Hz), 2.29 (1H, ddd, J = 31.6, 15.5, 7.5

Hz), 1.33 (3H, s). ¹³C NMR (CDCl₃) δ 170.5, 144.6, 134.5, 129.5,

129.1, 128.5, 117.6 (qt, J = 289, 34 Hz), 116.9 (tt, J = 258, 31 Hz),

108.1 (tsex, J = 265, 37 Hz), 76.8, 73.0 (d, J = 2.9 Hz), 54.9, 45.5, 37.6

(t, J = 20 Hz), 26.7. ¹⁹F NMR (CDCl₃) δ −80.6 (3F, t, J = 9.8 Hz),

−110.8 (1F, dm, J = 271 Hz), −113.8 (1F, dm, J = 271 Hz), −128.3

(2F, dd, J = 30, 6.7 Hz). HRMS (ESI⁺): calcd for C₁₇H₁₆F₇INO₂(M +

H⁺): 526.0108, Found: 526.0101.

(3S,4E)-3-(2,2,3,3,4,4,4-Heptaﬂuorobutyl)-4-(iodomethylene)-3-

methyl-1-(phenylmethoxy)-2-pyrrolidinone (E-20a). A colorless oil.

HPLC analysis gave [α]²⁴+22.1 (c 0.42, CHCl₃).

1

IR (KBr) 2976, 2936, 1721, 1454, 1352 cm⁻¹. H NMR (CDCl₃) δ

D

(3S,4S)-3-(2,2,3,3,4,4,4-Heptaﬂuorobutyl)-4-(1-iodoethyl)-3-

7.43−7.35 (5H, m), 6.24 (1H, t, J = 1.8 Hz), 5.04 (1H, d, J = 11.0 Hz),

4.96 (1H, d, J = 11.0 Hz), 3.95 (1H, dd, J = 12.8, 1.8 Hz), 3.87 (1H,

dd, J = 12.8, 1.8 Hz), 3.19 (1H, ddd, J = 29.7, 15.5, 9.2 Hz), 2.61 (1H,

ddd, J = 31.3, 15.5, 6.5 Hz), 1.54 (3H, s). ¹³C NMR (CDCl₃) δ 171.2,

140.4, 134.8, 129.5, 129.1, 128.6, 117.7 (qt, J = 289, 34 Hz), 117.2 (tt,

J = 258, 32 Hz), 108.3 (tsex, J = 266, 36 Hz), 76.9, 73.0 (d, J = 2.9

Hz), 52.9, 44.8, 33.6 (t, J = 20 Hz), 22.6. ¹⁹F NMR (CDCl₃) δ −80.7

(3F, t, J = 9.8 Hz), −113.5 (2F, dm, J = 193 Hz), −128.5 (2F, br s).

HRMS (ESI⁺): calcd for C₁₇H₁₆F₇INO₂(M + H⁺): 526.0108, Found:

526.0103.

methyl-1-(phenylmethoxy)-2-pyrrolidinone (trans-18). A major

1

isomer: A white solid. IR (KBr) 2974, 2878, 1722, 1455 cm⁻¹. H

NMR (CDCl₃) δ 7.44−7.35 (5H, m), 5.02 (1H, d, J = 11.0 Hz), 4.94

(1H, d, J = 11.0 Hz), 4.14 (1H, m), 3.48 (1H, t, J = 8.2 Hz), 2.97 (1H,

t, J = 8.2 Hz), 2.90 (1H, dd, J = 39.4, 15.6 Hz), 2.78 (1H, q, J = 10.1

Hz), 2.10 (1H, m), 2.03 (3H, d, J = 6.4 Hz), 1.06 (3H, s). ¹³C NMR

(CDCl₃) δ 172.1, 134.6, 129.6, 129.1, 128.5, 117.7 (tt, J = 258, 32 Hz),

117.6 (qt, J = 289, 35 Hz), 108.1 (tsex, J = 266, 37 Hz), 77.0, 53.6,

44.8, 42.9, 35.7 (t, J = 20 Hz), 28.0, 25.3, 17.6. ¹⁹F NMR (CDCl₃) δ

−80.5 (3F, br m), −104.4 (1F, dm, J = 270 Hz), −115.7 (1F, dm, J =

270 Hz), −127.8 (1F, dm, J = 289 Hz), −128.6 (1F, dm, J = 289 Hz).

HRMS (ESI⁺): calcd for C₁₈H₂₀F₇INO₂(M + H⁺): 542.0421, Found:

542.0419. HPLC (Chiralcel AD-H, hexane/2-propanol = 95/5, 1.0

mL/min, 254 nm) t_r(major) = 11.0 min, t_r(minor) = 7.0 min. A

(3S,4Z)-4-(Iodomethylene)-3-methyl-1-(phenylmethoxy)-3-

[2,3,3,3-tetraﬂuoro-2-(triﬂuoromethyl)propyl]-2-pyrrolidinone (Z-

1

20b). A colorless oil. IR (KBr) 2976, 2935, 1731, 1456 cm⁻¹. H

NMR (CDCl₃) δ 7.45−7.35 (5H, m), 6.33 (1H, t, J = 2.3 Hz), 5.05

(1H, d, J = 10.8 Hz), 4.96 (1H, d, J = 10.8 Hz), 3.80 (2H, ddd, J =

15.8, 14.2, 2.4 Hz), 2.72 (1H, br t, J = 15.1 Hz), 2.34 (1H, br t, J =

sample of 87% ee by HPLC analysis gave [α]²⁴+32.6 (c 0.50,

D

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15.3 Hz), 1.33 (3H, s). ¹³C NMR (CDCl₃) δ 171.1, 144.2, 134.5,

129.4, 129.0, 128.5, 120.5 (br qd, J = 289, 26 Hz), 90.6 (dsep, J = 209,

33 Hz), 76.7, 76.5, 54.8 (d, J = 2.9 Hz), 46.7 (d, J = 4.8 Hz), 34.8 (d, J

= 18 Hz), 28.2; One carbon peak was missing due to overlapping. ¹⁹F

NMR (CDCl₃) δ −77.7 (6F, dq, J = 36, 8.4 Hz), −187.7 (1F, sep, J =

7.1 Hz). HRMS (ESI⁺): calcd for C₁₇H₁₆F₇INO₂(M + H⁺): 526.0108,

Found: 526.0104.

J = 289, 34 Hz), 117.2 (tt, J = 258, 31 Hz), 108.1 (tsex, J = 266, 36

Hz), 97.8, 76.8, 58.4, 45.0, 36.6 (t, J = 19 Hz), 25.9. ¹⁹F NMR

(CDCl₃) δ −80.6 (3F, t, J = 9.7 Hz), −113.3 (2F, dm, J = 77 Hz),

−128.3 (2F, br s). HRMS (ESI⁺): calcd for C₂₃H₂₀F₇INO₂(M + H⁺):

602.0421, Found: 602.0427. Elemental analysis (%) calcd for

C₂₃H₁₉F₇INO₂: C, 45.94; H, 3.18; N, 2.33, found: C, 45.88; H,

3.28; N, 2.20. HPLC (Chiralcel AD-H, hexane/2-propanol = 95/5, 1.0

mL/min, 254 nm) t_r(major) = 6.8 min, t_r(minor) = 8.1 min. A

(3S,4E)-4-(Iodomethylene)-3-methyl-1-(phenylmethoxy)-3-

sample of 39% ee by HPLC analysis gave [α]²⁴−16.0 (c 0.55,

[2,3,3,3-tetraﬂuoro-2-(triﬂuoromethyl)propyl]-2-pyrrolidinone (E-

D

1

20b). A colorless oil. IR (KBr) 2978, 2937, 1725, 1455 cm⁻¹. H

CHCl₃).

NMR (CDCl₃) δ 7.42−7.36 (5H, m), 6.23 (1H, t, J = 1.8 Hz), 5.02

(1H, d, J = 11.0 Hz), 4.94 (1H, d, J = 11.0 Hz), 3.93 (1H, dd, J = 12.8,

2.3 Hz), 3.78 (1H, dd, J = 12.8, 1.0 Hz), 3.17 (1H, br t, J = 15.4 Hz),

2.58 (1H, br t, J = 16.5 Hz), 1.57 (3H, s). ¹³C NMR (CDCl₃) δ 171.0,

140.1, 134.9, 129.4, 129.0, 128.6, 120.7 (qd, J = 291, 28 Hz), 120.5

(qd, J = 287, 28 Hz), 91.0 (dsep, J = 208, 33 Hz), 76.9, 73.3, 53.1 (d, J

= 3.8 Hz), 45.8 (d, J = 3.8 Hz), 31.2 (d, J = 18 Hz), 24.4. ¹⁹F NMR

(CDCl₃) δ −77.2 (6F, dm, J = 138 Hz), −187.7 (1F, m). HRMS

(ESI⁺): calcd for C₁₇H₁₆F₇INO₂(M + H⁺): 526.0108, Found:

526.0109.

(3S,4Z)-3-(2,2,3,3,4,4,4-Heptaﬂuorobutyl)-3-methyl-1-(phenylme-

thoxy)-4-(1-phenylmethylene)-2-pyrrolidinone (Z-23). A colorless

1

oil. IR (KBr) 2973, 2932, 2876, 1723, 1452, 1353 cm⁻¹. H NMR

(CDCl₃) δ 7.46−7.28 (8H, m), 7.13 (2H, br d, J = 7.3 Hz), 6.47 (1H,

br s), 5.07 (1H, d, J = 10.8 Hz), 5.00 (1H, d, J = 10.8 Hz), 4.39 (1H,

dd, J = 13.3, 2.5 Hz), 4.26 (1H, dd, J = 13.3, 2.3 Hz), 2.83 (1H, ddd, J

= 33.2, 15.4, 4.0 Hz), 2.35 (1H, ddd, J = 30.9, 15.4, 7.6 Hz), 1.44 (3H,

s). ¹³C NMR (CDCl₃) δ 170.7, 135.4, 134.7, 133.2, 129.5, 129.0,

128.7, 128.5, 128.1, 127.7, 125.9, 117.7 (qt, J = 293, 33 Hz), 117.2 (tt,

J = 258, 31 Hz), 108.3 (tsex, J = 251, 36 Hz), 76.7, 50.2, 43.7, 38.1 (t, J

= 20 Hz), 27.1. ¹⁹F NMR (CDCl₃) δ −80.7 (3F, t, J = 9.8 Hz), −110.6

(1F, dm, J = 271 Hz), −113.9 (1F, dm, J = 271 Hz), −128.4 (2F, ddd,

J = 289, 83, 6.5 Hz). HRMS (ESI⁺): calcd for C₂₃H₂₁F₇NO₂(M +

H⁺): 476.1455, Found: 476.1454.

(3S,4Z)-4-(Iodomethylene)-3-methyl-3-(2-methylpropyl)-1-(phe-

nylmethoxy)-2-pyrrolidinone (Z-20c). A colorless oil. IR (CHCl₃)

1

3019, 1711, 1418, 1363 cm⁻¹. H NMR (CDCl₃) δ 7.48−7.33 (5H,

m), 6.11 (1H, t, J = 2.8 Hz), 5.05 (1H, d, J = 10.7 Hz), 5.01 (1H, d, J =

10.7 Hz), 3.77 (2H, m), 1.75 (1H, dd, J = 13.4, 6.4 Hz), 1.50−1.35

(2H, m), 1.20 (3H, s), 0.79 (3H, d, J = 6.7 Hz), 0.76 (3H, d, J = 6.4

Hz). ¹³C NMR (CDCl₃) δ 173.5, 148.0, 134.9, 129.5, 129.1, 128.6,

76.9, 74.3, 55.5, 49.9, 47.6, 27.0, 25.3, 24.2, 23.2. MS (CI⁺): m/z 400

(M + H⁺, 4), 91 (100). HRMS (CI⁺): calcd for C₁₇H₂₃INO₂(M +

H⁺): 400.0774, Found: 400.0775.

(3S,4E)-3-(2,2,3,3,4,4,4-Heptaﬂuorobutyl)-3-methyl-1-(phenylme-

thoxy)-4-(1-phenylmethylene)-2-pyrrolidinone (E-23). A colorless

1

oil. IR (KBr) 2973, 2937, 2877, 1726, 1454, 1352 cm⁻¹. H NMR

(CDCl₃) δ 7.48−7.29 (8H, m), 7.15 (2H, d, J = 7.3 Hz), 6.64 (1H, br

s), 5.08 (1H, d, J = 11.0 Hz), 5.00 (1H, d, J = 11.0 Hz), 4.15 (1H, dd, J

= 12.4, 2.3 Hz), 4.02 (1H, dd, J = 12.4, 1.8 Hz), 2.57 (1H, ddd, J =

29.3, 15.1, 8.2 Hz), 2.01 (1H, ddd, J = 28.7, 15.1, 9.8 Hz), 1.19 (3H,

s). ¹³C NMR (CDCl₃) δ 171.9, 136.0, 135.0, 133.8, 129.5, 128.9,

128.5, 128.3, 127.6, 117.7 (qt, J = 289, 34 Hz), 117.4 (tt, J = 257, 31

Hz), 108.3 (tsex, J = 266, 37 Hz), 76.8, 51.9, 42.8, 37.3 (t, J = 20 Hz),

25.9; two carbon peaks were missing because of overlapping. ¹⁹F NMR

(CDCl₃) δ −80.7 (3F, t, J = 9.7 Hz), −113.3 (2F, dm, J = 107 Hz),

−128.4 (2F, br s). HRMS (ESI⁺): calcd for C₂₃H₂₁F₇NO₂(M + H⁺):

476.1455, Found: 476.1455.

(3S,4Z)-3-(2,2,3,3,4,4,4-Heptaﬂuorobutyl)-4-(1-iodoethylidene)-3-

methyl-1-(phenylmethoxy)-2-pyrrolidinone (Z-21). A colorless oil.

1

IR (KBr) 2980, 2937, 1727, 1454, 1352 cm⁻¹. H NMR (CDCl₃) δ

7.46−7.36 (5H, m), 5.06 (1H, d, J = 10.6 Hz), 4.97 (1H, d, J = 10.6

Hz), 3.86 (2H, ddd, J = 20.5, 13.5, 1.9 Hz), 2.90 (1H, br dd, J = 34.8,

15.6 Hz), 2.61 (3H, br t, J = 1.8 Hz), 2.48 (1H, br ddd, J = 29.8, 15.6,

8.7 Hz), 1.42 (3H, s). ¹³C NMR (CDCl₃) δ 171.3, 134.9, 134.4, 129.4,

128.9, 128.4, 117.5 (qt, J = 289, 34 Hz), 116.8 (tt, J = 257, 31 Hz),

108.1 (tsex, J = 229, 37 Hz), 97.6 (d, J = 1.9 Hz), 76.5, 57.8, 44.5 (d, J

= 1.9 Hz), 35.7 (t, J = 20 Hz), 30.0 (d, J = 1.9 Hz), 24.6. ¹⁹F NMR

(CDCl₃) δ −80.7 (3F, t, J = 9.7 Hz), −113.1 (1F, ddq, J = 273, 35, 9.3

Hz), −116.3 (1F, ddt, J = 275, 29, 8.3 Hz), −128.4 (2F, ddd, J = 289,

113, 7.3 Hz). HRMS (ESI⁺): calcd for C₁₈H₁₈F₇INO₂(M + H⁺):

540.0265, Found: 540.0265. HPLC (Chiralcel AD-H, hexane/2-

propanol = 95/5, 1.0 mL/min, 254 nm) t_r(major) = 7.2 min, t_r

(minor) = 11.6 min. A sample of 48% ee by HPLC analysis gave

(3S,4R)-4-(1-Iodoethyl)-3-methyl-1-(phenylmethoxy)-3-[2,3,3,3-

tetraﬂuoro-2-(triﬂuoromethyl)propyl]-2-pyrrolidinone (cis-26). A

major isomer: Colorless crystals. mp 58−59 °C (hexane). IR (KBr)

1

2979, 2945, 1717, 1457 cm⁻¹. H NMR (CDCl₃) δ 7.47−7.34 (5H,

m), 5.12 (1H, d, J = 10.9 Hz), 5.02 (1H, d, J = 10.9 Hz), 4.15 (1H, m),

3.40 (1H, dd, J = 10.0, 7.6 Hz), 3.29 (1H, dd, J = 10.0, 3.2 Hz), 2.67

(1H, t, J = 17.6 Hz), 2.54 (1H, t, J = 17.6 Hz), 1.94 (3H, d, J = 7.0

Hz), 1.77 (1H, m), 1.27 (3H, s). ¹³C NMR (CDCl₃) δ 170.5, 135.0,

129.4, 129.0, 128.6, 121.1 (qd, J = 287, 29 Hz), 120.7 (qd, J = 293, 28

Hz), 92.4 (tseq, J = 209, 33 Hz), 76.8, 49.6, 48.7, 45.2, 28.2 (d, J = 19

Hz), 28.0, 25.4, 24.6. ¹⁹F NMR (CDCl₃) δ −76.6 (3F, dq, J = 11, 7

Hz), −77.1 (3F, br quin, J = 11 Hz), −185.0 (1F, m). HRMS (ESI⁺):

calcd for C₁₈H₂₀F₇INO₂(M + H⁺): 542.0421, Found: 542.0419.

HPLC (Chiralcel AD-H, hexane/2-propanol = 95/5, 1.0 mL/min, 254

nm) t_r(major) = 7.3 min, t_r(minor) = 8.8 min. A sample of 91% ee by

HPLC analysis gave [α]²⁴_D+57.4 (c 0.55, CHCl₃). A minor isomer: A

colorless oil. IR (KBr) 2947, 1718, 1496, 1457 cm⁻¹. ¹H NMR

(CDCl₃) δ 7.47−7.35 (5H, m), 5.05 (1H, d, J = 10.9 Hz), 4.98 (1H, d,

J = 10.9 Hz), 4.47 (1H, m), 3.42 (2H, d, J = 4.7 Hz), 2.72 (1H, t, J =

16.8 Hz), 2.69 (1H, m), 2.14 (1H, br t, J = 16.8 Hz), 1.61 (3H, d, J =

7.0 Hz), 1.29 (3H, s). ¹³C NMR (CDCl₃) δ 171.5, 134.9, 129.3, 129.1,

128.6, 121.0 (qd, J = 288, 28 Hz), 120.7 (qd, J = 291, 31 Hz), 92.2

(tseq, J = 210, 33 Hz), 76.7, 50.5, 48.0, 45.3, 28.2 (d, J = 19 Hz), 23.7

(2C), 23.6. ¹⁹F NMR (CDCl₃) δ −76.7 (3F, m), −76.9 (3F, br quin, J

= 9.3 Hz), −184.9 (1F, m). HRMS (ESI⁺): calcd for C₁₈H₂₀F₇INO₂

(M + H⁺): 542.0421, Found: 542.0418.

[α]²⁴−10.4 (c 0.42, CHCl₃).

D

(3S,4E)-3-(2,2,3,3,4,4,4-Heptaﬂuorobutyl)-4-(1-iodoethylidene)-3-

methyl-1-(phenylmethoxy)-2-pyrrolidinone (E-21). A colorless oil. IR

(KBr) 2930, 2873, 1726, 1453, 1354 cm⁻¹. ¹H NMR (CDCl₃) δ 7.44−

7.35 (5H, m), 5.07 (1H, d, J = 11.0 Hz), 4.96 (1H, d, J = 11.0 Hz),

3.96 (2H, ddd, J = 21.1, 12.8, 1.4 Hz), 3.34−3.21 (1H, m), 2.53 (1H,

br ddd, J = 29.5, 15.3, 8.1 Hz), 2.39 (3H, br t, J = 1.1 Hz), 1.52 (3H,

s). ¹³C NMR (CDCl₃) δ 171.9, 134.7, 133.1, 129.4, 129.0, 128.5, 117.7

(qt, J = 289, 34 Hz), 117.3 (tt, J = 258, 31 Hz), 108.3 (tsex, J = 266, 36

Hz), 90.9 (d, J = 1.9 Hz), 76.7, 50.6, 45.1, 33.2 (t, J = 20 Hz), 31.3,

22.8. ¹⁹F NMR (CDCl₃) δ −80.7 (3F, t, J = 9.7 Hz), −113.9 (2F, dm, J

= 101 Hz), −128.5 (2F, br s). HRMS (ESI⁺): calcd for C₁₈H₁₈F₇INO₂

(M + H⁺): 540.0265, Found: 540.0263. HPLC (Chiralcel AD-H,

hexane/2-propanol = 95/5, 1.0 mL/min, 254 nm) t_r(major) = 5.7

min, t_r(minor) = 6.2 min. A sample of 33% ee by HPLC analysis gave

[α]²⁴−4.7 (c 0.21, CHCl₃).

D

(3S,4Z)-3-(2,2,3,3,4,4,4-Heptaﬂuorobutyl)-4-(1-iodo-1-phenyl-

methylene)-3-methyl-1-(phenylmethoxy)-2-pyrrolidinone (Z-22).

Colorless crystals. mp 98−101 °C (hexane). IR (KBr) 3033, 2940,

trans-4-(1-Iodoethyl)-3-methyl-1-(phenylmethoxy)-3-[2,3,3,3-tet-

raﬂuoro-2-(triﬂuoromethyl)propyl]-2-pyrrolidinone (trans-26). A

major isomer: Colorless crystals. mp 87−89 °C (hexane). IR (KBr)

1

2878, 1728, 1455, 1353 cm⁻¹. H NMR (CDCl₃) δ 7.50−7.21 (10H,

m), 5.11 (1H, d, J = 10.5 Hz), 5.01 (1H, d, J = 10.5 Hz), 3.86 (2H, dd,

J = 13.7, 12.4 Hz), 2.41 (1H, ddd, J = 26.8, 15.4, 10.4 Hz), 2.02 (1H,

ddd, J = 28.4, 15.4, 9.8 Hz), 1.14 (3H, s). ¹³C NMR (CDCl₃) δ 171.0,

142.0, 138.7, 134.6, 129.5, 129.1, 128.9, 128.6, 128.4, 128.0, 117.6 (qt,

1

2973, 2933, 1726, 1455 cm⁻¹. H NMR (CDCl₃) δ 7.46−7.35 (5H,

m), 5.04 (1H, d, J = 10.8 Hz), 4.92 (1H, dd, J = 10.8 Hz), 4.14 (1H,

m), 3.57 (1H, t, J = 8.2 Hz), 2.99 (1H, td, J = 8.9, 1.2 Hz), 2.77 (1H, t,

8601

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J = 8.9 Hz), 2.75 (1H, dd, J = 32.8, 15.8 Hz), 2.23 (1H, dd, J = 16.5,

9.2 Hz), 2.02 (3H, dd, J = 6.9, 1.4 Hz), 1.10 (3H, s). ¹³C NMR

(CDCl₃) δ 171.7, 134.7, 129.4, 129.0, 128.6, 120.7 (qd, J = 288, 28

Hz), 120.5 (qd, J = 288, 28 Hz), 91.9 (dsep, J = 208, 33 Hz), 76.9,

53.3, 44.4, 44.0 (d, J = 5.8 Hz), 33.5 (d, J = 18 Hz), 28.0 (d, J = 2.9

Hz), 25.9, 19.4. ¹⁹F NMR (CDCl₃) δ −75.4 (3F, br quin, J = 9.8 Hz),

−78.0 (3F, m), −183.5 (1F, m). HRMS (ESI⁺): calcd for

C₁₈H₂₀F₇INO₂(M + H⁺): 542.0421, Found: 542.0416. A minor

J = 10.9 Hz), 4.21 (1H, m), 4.18−4.11 (3H, m), 3.48 (1H, dd, J =

10.3, 4.4 Hz), 3.36 (1H, dd, J = 8.8, 7.0 Hz), 3.28−3.20 (2H, m), 2.45

(1H, d, J = 14.4 Hz), 2.27 (1H, m), 1.75 (1H, d, J = 14.4 Hz), 1.64

(3H, s), 1.28 (3H, s), 1.25 (3H, t, J = 7.3 Hz), 1.23 (3H, t, J = 7.1 Hz).

¹³C NMR (CDCl₃) δ 172.7, 172.3, 171.4, 135.2, 129.4, 128.9, 128.5,

76.8, 61.7 (2C), 53.2, 49.1, 47.9, 44.6, 35.2, 30.0, 23.1, 20.6, 13.9, 13.8.

HRMS (ESI⁺): calcd for C₂₂H₃₁⁷⁹BrNO₆(M + H⁺): 484.1329, Found:

484.1322. HRMS (ESI⁺): calcd for C₂₂H₃₁⁸¹BrNO₆(M + H⁺):

486.1309, Found: 486.1300. HPLC (Chiralcel AD-H, hexane/2-

propanol = 95/5, 1.0 mL/min, 254 nm) t_r(major) = 28.9 min, t_r

(minor) = 71.0 min. A sample of 51% ee by HPLC analysis gave

1

isomer: A colorless oil. IR (KBr) 2970, 2929, 1724, 1458 cm⁻¹. H

NMR (CDCl₃) δ 7.44−7.36 (5H, m), 5.05 (1H, d, J = 11.0 Hz), 4.91

(1H, d, J = 11.0 Hz), 3.96 (1H, quin, J = 7.1 Hz), 3.49−3.41 (1H, m),

2.99−2.87 (3H, m), 2.46 (1H, dd, J = 27.5, 16.0 Hz), 1.84 (3H, d, J =

6.4 Hz), 1.21 (3H, s). ¹³C NMR (CDCl₃) δ 172.0, 134.9, 129.4, 129.0,

128.6, 120.8 (qd, J = 289, 28 Hz), 120.7 (qd, J = 288, 28 Hz), 91.9

(dsep, J = 208, 32 Hz), 77.2, 48.4, 44.6, 43.5 (d, J = 4.8 Hz), 31.8 (d, J

= 19 Hz), 26.9, 20.9, 19.0. ¹⁹F NMR (CDCl₃) δ −76.0 (3F, br quin, J

= 9.8 Hz), −77.3 (3F, m), −184.9 (1F, m). HRMS (ESI⁺): calcd for

C₁₈H₂₀F₇INO₂(M + H⁺): 542.0421, Found: 542.0414.

[α]²⁴+13.7 (c 0.18, CHCl₃).

D

2-[(3S,4S)-4-(1-Iodoethyl)-3-methyl-2-oxo-1-(phenylmethoxy)-3-

pyrrolidinyl]-2-methylpropanedioic Acid 1,3-Diethyl Ester (trans-

28c). A colorless oil. IR (KBr) 2965, 2933, 1727, 1456 cm⁻¹. ¹H NMR

(CDCl₃) δ 7.45 (2H, m), 7.44−7.33 (3H, m), 5.01 (1H, d, J = 10.9

Hz), 4.93 (1H, d, J = 10.9 Hz), 4.27 (1H, m), 4.22−4.11 (3H, m), 3.61

(1H, t, J = 8.8 Hz), 3.57 (1H, dd, J = 9.7, 3.5 Hz), 3.12 (1H, dd, J =

11.8, 9.7 Hz), 2.98 (1H, t, J = 8.8 Hz), 2.47 (1H, m), 2.37 (1H, d, J =

15.3 Hz), 2.24 (1H, d, J = 15.3 Hz), 1.37 (3H, s), 1.29 (3H, t, J = 7.0

Hz), 1.25 (3H, t, J = 7.0 Hz), 0.93 (3H, s). ¹³C NMR (CDCl₃) δ

173.4, 172.2, 171.8, 135.0, 129.4, 129.0, 128.5, 76.6, 61.9 (2C), 52.7,

49.5, 44.6, 39.0, 38.8, 30.6, 20.1, 20.0, 14.0, 13.9. HRMS (ESI⁺): calcd

for C₂₂H₃₁⁷⁹BrNO₆(M + H⁺): 484.1329, Found: 484.1326. HRMS

(ESI⁺): calcd for C₂₂H₃₁⁸¹BrNO₆(M + H⁺): 486.1309, Found:

486.1304. HPLC (Chiralcel AD-H, hexane/2-propanol = 95/5, 1.0

mL/min, 254 nm) t_r(major) = 22.4 min, t_r(minor) = 46.5 min. A

sample of 27% ee by HPLC analysis gave [α]²⁴_D−4.6 (c 0.05, CHCl₃).

(3S,4R)-4-(1-Bromoethyl)-3-methyl-1-(phenylmethoxy)-3-(2,2,2-

trichloroethyl)-2-pyrrolidinone (cis-29). Colorless crystals. mp 129−

(3S,4R)-4-(1-Iodoethyl)-3-methyl-2-oxo-1-(phenylmethoxy)-3-

pyrrolidinepropanoic Acid Ethyl Ester (cis-28a). A colorless oil. IR

1

(KBr) 2977, 1729, 1711, 1456 cm⁻¹. H NMR (CDCl₃) δ 7.45−7.35

(5H, m), 5.01 (1H, d, J = 11.0 Hz), 4.96 (1H, d, J = 11.0 Hz), 4.11

(2H, q, J = 7.3 Hz), 3.45 (1H, dd, J = 8.9, 7.3 Hz), 3.22 (1H, dd, J =

10.1, 4.6 Hz), 2.99 (2H, br t, J = 10.1 Hz), 2.46 (1H, m), 2.41−2.31

(2H, m), 1.73−1.64 (1H, m), 1.59−1.51 (1H, m), 1.25 (3H, t, J = 7.3

Hz), 1.17 (3H, s). ¹³C NMR (CDCl₃) δ 173.1, 172.3, 134.7, 129.5,

129.0, 128.5, 76.6, 60.4, 51.2, 46.2, 44.6, 28.7, 26.5, 20.9, 14.1, 1.5. MS

(EI⁺): m/z 445 (M⁺, 0.2), 91 (100). HRMS (EI): calcd for

C₁₈H₂₄INO₄(M⁺): 445.0745, Found: 445.0761. HPLC (Chiralcel

AD-H, hexane/2-propanol = 95/5, 1.0 mL/min, 254 nm) t_r(major) =

44.0 min, t_r(minor) = 48.3 min. A sample of 55% ee by HPLC analysis

1

131 °C (hexane). IR (KBr) 2970, 2883, 1716, 1456 cm⁻¹. H NMR

gave [α]²⁴+19.2 (c 0.21, CHCl₃).

(CDCl₃) δ 7.46−7.36 (5H, m), 5.04 (1H, d, J = 11.4 Hz), 5.01 (1H, d,

J = 11.4 Hz), 3.73 (1H, ddd, J = 10.1, 3.2, 0.9 Hz), 3.48 (1H, ddd, J =

9.6, 5.9, 0.9 Hz), 3.46 (1H, d, J = 16.5 Hz), 3.36 (1H, dd, J = 9.6, 0.9

Hz), 2.96 (1H, dd, J = 11.0, 10.1 Hz), 2.92 (1H, d, J = 16.5 Hz), 2.61−

2.55 (1H, m), 1.44 (3H, s). ¹³C NMR (CDCl₃) δ 170.7, 134.7, 129.6,

129.3, 128.7, 97.0, 76.9, 53.6, 48.8, 47.4, 43.9, 33.0, 20.1. HRMS

(ESI⁺): calcd for C₁₅H₁₈BrCl₃NO₂(M + H⁺): 427.9581, Found:

427.9590. HPLC (Chiralcel AD-H, hexane/2-propanol = 95/5, 1.0

mL/min, 254 nm) t_r(major) = 14.0 min, t_r(minor) = 35.8 min. A

D

(3S,4S)-4-(1-Iodoethyl)-3-methyl-2-oxo-1-(phenylmethoxy)-3-

pyrrolidinepropanoic Acid Ethyl Ester (trans-28a). A colorless oil. IR

1

(KBr) 2975, 1727, 1714, 1456 cm⁻¹. H NMR (CDCl₃) δ 7.45−7.36

(5H, m), 5.01 (1H, d, J = 11.0 Hz), 4.96 (1H, d, J = 11.0 Hz), 4.14

(2H, q, J = 7.3 Hz), 3.46 (1H, br t, J = 8.7 Hz), 3.19 (1H, dd, J = 9.6,

4.1 Hz), 2.92 (1H, t, J = 8.7 Hz), 2.89 (1H, dd, J = 11.4, 9.6 Hz),

2.39−2.25 (3H, m), 1.94−1.78 (2H, m), 1.27 (3H, t, J = 7.3 Hz), 0.96

(3H, s). ¹³C NMR (CDCl₃) δ 173.3, 173.0, 134.8, 129.6, 129.1, 128.6,

76.8, 60.7, 51.4, 45.6, 41.2, 31.0, 29.3, 16.9, 14.2, 2.3. MS (EI⁺): m/z

445 (M⁺, 0.2), 91 (100). HRMS (EI): calcd for C₁₈H₂₄INO₄(M⁺):

445.0745, Found: 445.0761. HPLC (Chiralcel AD-H, hexane/2-

propanol = 95/5, 1.0 mL/min, 254 nm) t_r(major) = 50.5 min, t_r

(minor) = 36.4 min. A sample of 54% ee by HPLC analysis gave

sample of 77% ee by HPLC analysis gave [α]²⁴+10.8 (c 0.17,

D

CHCl₃).

trans-4-(1-Bromoethyl)-3-methyl-1-(phenylmethoxy)-3-(2,2,2-tri-

chloroethyl)-2-pyrrolidinone (trans-29). A white solid. IR (KBr)

1

2928, 2877, 1714, 1650, 1457 cm⁻¹. H NMR (CDCl₃) δ 7.45−7.32

[α]²⁴+17.7 (c 0.28, CHCl₃).

(5H, m), 5.01 (1H, d, J = 11.0 Hz), 4.95 (1H, d, J = 11.0 Hz), 3.70

(1H, t, J = 8.3 Hz), 3.62 (1H, dd, J = 9.2, 2.8 Hz), 3.52 (1H, d, J = 15.6

Hz), 3.35−3.27 (1H, m), 3.23 (1H, dd, J = 11.4, 9.2 Hz), 3.09 (1H, t, J

= 8.3 Hz), 2.79 (1H, d, J = 15.6 Hz), 1.00 (3H, s). ¹³C NMR (CDCl₃)

δ 172.3, 134.8, 129.4, 129.0, 128.5, 96.1, 76.7, 56.7, 49.2, 46.0, 36.9,

29.7, 18.7. HRMS (ESI⁺): calcd for C₁₅H₁₈BrCl₃NO₂(M + H⁺):

427.9581, Found: 427.9583.

D

cis-4-(1-Iodoethyl)-3-methyl-2-oxo-1-(phenylmethoxy)-3-pyrroli-

dinepropanenitrile (cis-28b). A colorless oil. IR (KBr) 2966, 2935,

2247, 1707, 1455 cm⁻¹. ¹H NMR (CDCl₃) δ 7.48−7.38 (5H, m), 5.04

(1H, d, J = 11.0 Hz), 4.96 (1H, d, J = 11.0 Hz), 3.49 (1H, dd, J = 9.2,

7.8 Hz), 3.17 (1H, dd, J = 9.8, 4.6 Hz), 2.98 (1H, t, J = 9.2 Hz), 2.91

(1H, dd, J = 11.5, 9.8 Hz), 2.53−2.30 (3H, m), 1.65−1.58 (2H, m),

1.20 (3H, s). ¹³C NMR (CDCl₃) δ 171.4, 134.5, 129.6, 129.4, 128.7,

119.5, 77.2, 51.1, 46.0, 44.4, 28.0, 20.4, 12.2, 0.2. MS (EI⁺): m/z 398

(M⁺, 2.1), 91 (100). HRMS (EI): calcd for C₁₆H₁₉IN₂O₂(M⁺):

398.0486, Found: 398.0509.

cis-3-(1-Bromoethyl)-3-methyl-1-(phenylmethoxy)-4-(2,2,2-tri-

chloroethyl)-2-pyrrolidinone (30). A colorless oil. IR (KBr) 2965,

1

2929, 1713, 1648, 1457 cm⁻¹. H NMR (CDCl₃) δ 7.48−7.43 (2H,

m), 7.41−7.36 (3H, m), 5.10 (1H, d, J = 10.6 Hz), 5.03 (1H, d, J =

10.6 Hz), 3.67 (1H, t, J = 8.7 Hz), 3.60 (1H, t, J = 8.7 Hz), 3.58 (1H,

d, J = 11.0 Hz), 3.23 (1H, d, J = 11.0 Hz), 3.18 (1H, dd, J = 14.7, 10.1

Hz), 2.92 (1H, dd, J = 14.7, 1,8 Hz), 2.65−2.57 (1H, br m), 1.31 (3H,

s). ¹³C NMR (CDCl₃) δ 169.8, 134.8, 129.4, 129.0, 128.6, 98.2, 76.9,

52.8, 51.6, 46.0, 38.8, 34.5, 23.6. HRMS (ESI⁺): calcd for

C₁₅H₁₈BrCl₃NO₂(M + H⁺): 427.9581, Found: 427.9582.

trans-4-(1-Iodoethyl)-3-methyl-2-oxo-1-(phenylmethoxy)-3-pyr-

rolidinepropanenitrile (trans-28b). A colorless oil. IR (KBr) 2967,

1

2936, 2247, 1708, 1456 cm⁻¹. H NMR (CDCl₃) δ 7.45−7.38 (5H,

m), 5.00 (1H, d, J = 11.0 Hz), 4.97 (1H, d, J = 11.0 Hz), 3.50 (1H, dd,

J = 9.2, 7.8 Hz), 3.14 (1H, dd, J = 10.1, 5.0 Hz), 2.93 (1H, t, J = 9.2

Hz), 2.92 (1H, t, J = 10.1 Hz), 2.50−2.31 (3H, m), 2.01−1.93 (1H,

m), 1.89−1.80 (1H, m), 1.00 (3H, s). ¹³C NMR (CDCl₃) δ 172.3,

134.5, 129.5, 129.2, 128.6, 119.3, 76.7, 51.0, 45.0, 41.1, 32.0, 16.4, 12.3,

0.7. HRMS (ESI⁺): calcd for C₁₆H₂₀IN₂O₂(M + H⁺): 399.0564,

Found: 399.0562.

Typical Procedure for Reductive Deiodination. To a stirred

solution of major isomer of cis-26 (130 mg 0.241 mmol) and Bu₃SnH

(126 μL, 0.482 mmol) in CH₂Cl₂(4.8 mL) was added Et₃B (1.05 M in

hexane, 1.15 mL, 1.21 mmol) at room temperature. After being stirred

at the same temperature for 3 h, the reaction mixture was diluted with

saturated NaHCO₃and then extracted with CH₂Cl₂. The organic

phase was dried over Na₂SO₄and concentrated at reduced pressure.

The residue was roughly puriﬁed by short column chromatography

2-[(3S,4R)-4-(1-Iodoethyl)-3-methyl-2-oxo-1-(phenylmethoxy)-3-

pyrrolidinyl]-2-methylpropanedioic Acid 1,3-Diethyl Ester (cis-28c).

1

A colorless oil. IR (KBr) 2980, 2937, 1728, 1454 cm⁻¹. H NMR

(CDCl₃) δ 7.48−7.33 (5H, m), 4.98 (1H, d, J = 10.9 Hz), 4.96 (1H, d,

8602

dx.doi.org/10.1021/jo3015227 | J. Org. Chem. 2012, 77, 8588−8604

The Journal of Organic Chemistry

Article

(hexane) to give a mixture of products. Further puriﬁcation of the

mixture by preparative TLC (hexane:AcOEt = 6:1, 2-fold develop-

ment) aﬀorded the isolated products cis-27 (94.7 mg, 94%). Under

similar reaction conditions, the product cis-27 (41.6 mg, 89%) was

obtained from a minor isomer of cis-26 (60.7 mg 0.111 mmol), the

product trans-27 (16.9 mg, 72%) was obtained from a major isomer of

trans-26 (30.0 mg 0.0550 mmol), and the product trans-27 (10.7 mg,

73%) was obtained from a minor isomer of trans-26 (19.3 mg 0.0357

mmol).

(g) Uenoyama, Y.; Fukuyama, T.; Morimoto, K.; Nobuta, O.; Nagai,

H.; Ryu, I. Helv. Chim. Acta 2006, 89, 2483. (h) Petrik, V.; Cahard, D.

Tetrahedron Lett. 2007, 48, 3327. (i) Tomita, Y.; Ichikawa, Y.; Itoh, Y.;

Kawada, K.; Mikami, K. Tetrahedron Lett. 2007, 48, 8922. (j) Nomoto,

A.; Ogawa, A. Fluorine-Containing Reagents. In Handbook of Reagents

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(f) Qiu, Z.-M.; Burton, D. J. J. Org. Chem. 1995, 60, 3465. (g) Yajima,

T.; Nagano, H.; Saito, C. Tetrahedron Lett. 2003, 44, 7027. (h) Yajima,

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Yajima, T.; Nagano, H.; Mikami, K. Eur. J. Org. Chem. 2008, 1331.

(j) Ueda, M.; Iwasada, E.; Miyabe, H.; Miyata, O.; Naito, T. Synthesis

2010, 1999.

(4) Smart, B. E. In Chemistry of Organic Fluorine Compounds II; ACS

Monograph 187; Hudlicky, M.; Pavlath, S. E., Eds.; American

Chemical Society: Washington DC, 1995; pp 979−1010.

(5) For studies on reactivity and structure of perﬂuoroalkyl radicals,

see (a) Krusic, P. J.; Bingham, R. C. J. Am. Chem. Soc. 1976, 98, 230.

(b) Bernardi, F.; Cherry, W.; Shaik, S.; Epiotis, N. D. J. Am. Chem. Soc.

1978, 100, 1352. (c) Dewar, M. J. S.; Olivella, S. J. Am. Chem. Soc.

1978, 100, 5290. (d) Wong, M. W.; Pross, A.; Radom, L. J. Am. Chem.

Soc. 1994, 116, 11938.

(6) The ﬂuorine atom not only has a σ-inductive eﬀect but is also a

potentially strong π-electron donor to SOMO of a carbon radical as a

disparate interaction. The π-electron-donating ability can be attributed

to the good math up in size of the lone pair 2p orbital of ﬂuorine with

radical orbital.

(7) (a) Brace, N. O. J. Am. Chem. Soc. 1964, 86, 523. (b) Brace, N. O.

J. Org. Chem. 1966, 31, 2879. (c) Piccardi, P.; Modena, M.; Cavalli, L.

J. Chem. Soc. C 1971, 3959. (d) Piccardi, P.; Massardo, P.; Modena,

M.; Santoro, E. J. Chem. Soc., Perkin Trans. 1 1974, 1848.

(8) Yoshioka, E.; Kentefu; Wang, X.; Kohtani, S.; Miyabe, H. Synlett

2010, 1341.

(9) We reported the strategy using the hydroxamate ester as a

coordination tether with a chiral Lewis acid. See (a) Miyabe, H.;

Asada, R.; Toyoda, A.; Takemoto, Y. Angew. Chem., Int. Ed. 2006, 45,

5863. (b) Miyabe, H.; Toyoda, A.; Takemoto, Y. Synlett 2007, 1885.

(c) Miyabe, H.; Asada, R.; Takemoto, Y. Org. Biomol. Chem. 2012, 10,

3519.

(10) Sulsky, R.; Demers, J. P. Tetrahedron Lett. 1989, 30, 31.

(11) The radical reactions were initiated using triethylborane and

oxygen. For reviews on alkylborane, see (a) Yorimitsu, H.; Shinokubo,

H.; Oshima, K. Synlett 2002, 674. (b) Ollivier, C.; Renaud, P. Chem.

Rev. 2001, 101, 3415.

(12) The structures of cis-15a−e, trans-15a−d, and 16a−d were

conﬁrmed by HMQC, HMBC, and NOESY experiments. See

Supporting Information.

cis-4-Ethyl-3-methyl-1-(phenylmethoxy)-3-[2,3,3,3-tetraﬂuoro-2-

(triﬂuoromethyl)propyl]-2-pyrrolidinone (cis-27). A colorless oil. IR

1

(KBr) 2969, 2942, 1716, 1460 cm⁻¹. H NMR (CDCl₃) δ 7.44−7.35

(5H, m), 4.98 (2H, dd, J = 28.4, 11.0 Hz), 3.33 (1H, dd, J = 9.3, 6.9

Hz), 2.95 (1H, dd, J = 9.3, 3.9 Hz), 2.55 (1H, br t, J = 16.5 Hz), 2.12

(1H, dd, J = 21.1, 16.5 Hz), 1.87−1.83 (1H, m), 1.51−1.42 (1H, m),

1.24 (3H, d, J = 1.8 Hz), 1.01 (1H, m), 0.77 (3H, t, J = 7.3 Hz). ¹³C

NMR (CDCl₃) δ 172.1, 135.2, 129.5, 129.0, 128.5, 121.1 (qd, J = 290,

28 Hz), 120.9 (qd, J = 287, 28 Hz), 92.2 (dsep, J = 210, 32 Hz), 76.8,

48.7, 44.7, 44.4, 28.9 (d, J = 19 Hz), 21.7, 21.0, 11.9. ¹⁹F NMR

(CDCl₃) δ −76.8 (3F, br quin, J = 9.8 Hz), −77.2 (3F, m), −184.8

(1F, m). HRMS (ESI⁺): calcd for C₁₈H₂₁F₇NO₂(M + H⁺): 416.1455,

Found: 416.1439.

trans-4-Ethyl-3-methyl-1-(phenylmethoxy)-3-[2,3,3,3-tetraﬂuoro-

2-(triﬂuoromethyl)propyl]-2-pyrrolidinone (trans-27). A colorless oil.

1

IR (KBr) 2971, 2939, 1721, 1460 cm⁻¹. H NMR (CDCl₃) δ 7.44−

7.36 (5H, m), 5.02 (1H, d, J = 11.0 Hz), 4.91 (1H, d, J = 11.0 Hz),

3.37 (1H, br t, J = 8.0 Hz), 2.87 (1H, td, J = 8.8, 1.6 Hz), 2.57 (1H, br

dd, J = 21.1, 16.0 Hz), 2.32−2.25 (1H, m), 2.15 (1H, br t, J = 14.9

Hz), 1.55−1.45 (1H, m), 1.25−1.14 (1H, m), 1.01 (3H, s), 0.85 (3H,

t, J = 7.6 Hz). ¹³C NMR (CDCl₃) δ 172.6, 135.1, 129.5, 128.9, 128.5,

120.9 (qd, J = 287, 28 Hz), 120.7 (qd, J = 288, 28 Hz), 91.6 (dsep, J =

208, 33 Hz), 76.7, 49.7, 43.8, 38.2 (d, J = 3.9 Hz), 32.0 (d, J = 19 Hz),

20.7, 19.5, 11.8. ¹⁹F NMR (CDCl₃) δ −77.0 (3F, br quin, J = 9.6 Hz),

−78.2 (3F, m), −186.6 (1F, m). HRMS (ESI⁺): calcd for

C₁₈H₂₁F₇NO₂(M + H⁺): 416.1455, Found: 416.1446.

ASSOCIATED CONTENT

■

S

* Supporting Information

HMQC, HMBC, and NOESY experiments for cis-15a, trans-

15a, 16a, cis-15c, trans-15c, 16c, trans-17, and cis-17, H, ¹³C,

1

and ¹⁹F NMR spectra for all new compounds, and HPLC

chromatograms for chiral products. This material is available

free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

*E-mail: miyabe@huhs.ac.jp.

■

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This work was supported in part by Grant-in-Aid for Scientiﬁc

Research (C) (H.M.) from Japan Society for the Promotion of

Science.

(13) In general, the copper (II) Lewis acids are unsuitable for radical

reactions due to extinction of radical species. For a successful example

of radical reaction using copper (II) Lewis acids, see (a) Friestad, G.

K.; Shen, Y.; Ruggles, E. L. Angew. Chem., Int. Ed. 2003, 42, 5061.

(b) Sibi, M. P.; Chen, J. J. Am. Chem. Soc. 2001, 123, 9472.

(14) The electrophilicity of perﬂuoroalkyl radicals followed the order

primary < secondary < tertiary; see ref 1.

(15) The stability of radicals was stimulated by the lower dissociation

energy of the C−H bond of C_nH_m−H compared with that of the C−H

bond of C_nF_m−H. For examples, see BDE (C−H) for F₃C−H = 106.7

1 kcal mol⁻¹vs BDE (C−H) for H₃C−H = 104.8 0.2 kcal mol⁻¹;

BDE (C−H) for F₃CF₂C−H = 102.7 0.5 kcal mol⁻¹vs Me₂HC−H

= 98.6 kcalmol⁻¹; see (a) McMillen, D. F.; Golden, D. M. Annu. Rev.

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dx.doi.org/10.1021/jo3015227 | J. Org. Chem. 2012, 77, 8588−8604

Article Doi

Polarity-mismatched addition of electrophilic carbon radicals to an electron-deficient acceptor: Cascade radical addition-cyclization-trapping reaction

DOI: 10.1021/jo3015227

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