Synthesis of 2-Alkenyl-Tethered Anilines

SYNTHESIS

0

3

9

-

7

8

1

4

3

7

-

2

1

0

X

2017, 49, A–P

psp

A

en

S. E. Denmark, H. M. Chi

PSP

Synthesis

Synthesis of 2-Alkenyl-Tethered Anilines

olefin

metathesis

3-aza-Cope

rearrangement

R'

Scott E. Denmark*

Hyung Min Chi

R

n

NHTs

BF₃•OEt₂or TsOH

(then tosylation)

for n = 1

R = alkyl, aryl

4 examples

N

R

NHTs

R

H

n = 1,2,3

n = 1, 2

R = aryl

4 examples

Roger Adams Laboratory, Department of Chemistry,

University of Illinois, Urbana, IL 61801, USA

sdenmark@illinois.edu

C–N cross-coupling

(then tosylation)

n = 1–3

R = H, alkyl

4 examples

R

n

X

Received: 03.02.2017

Accepted after revision: 22.03.2017

Published online: 04.05.2017

In the course of the reaction development, N-tosyl-pro-

tected anilines with pendant olefins at the 2-position were

identified as viable substrates for the sulfenoamination

process. Specifically, these reactions were found to be high-

ly enantioselective and site-selective with E-disubstituted

and terminal alkenes.¹Therefore, a rapid and versatile pro-

tocol for the preparation of these 2-alkenyl-substituted ani-

lines was necessary. As no single method could provide all

of the different substitution patterns and tether lengths,

developing a number of different methods to arrive at the

substrates was necessary. Specifically, three different routes

were developed that control the geometry of the double

bond in the tether and the introduction of the amino group

by rather different means, namely: (1) vinylmagnesium

chloride addition to imines followed by 3-aza-Cope rear-

rangement of the resulting N-allylic anilines, (2) cross-

metathesis of 2-substituted anilines bearing a terminal

alkene, and (3) palladium-catalyzed C–N coupling of 2-sub-

stituted halobenzenes (Scheme 2).

DOI: 10.1055/s-0036-1589002; Art ID: ss-2017-n0071-psp

Abstract Three general routes for the synthesis of (E)-2-alkenyl-teth-

ered anilines have been developed. The first route involves a 3-aza-

Cope rearrangement of N-allylic anilines in the presence of a Lewis acid.

The requisite N-allylic anilines were prepared by the addition of vinyl-

magnesium reagents to the corresponding aldimines. The second route

details a direct cross-metathesis of 2-allylic or 2-homoallylic anilines

with styrenes. The third route involves a palladium-catalyzed C–N

cross-coupling of aryl halides. Taken together, these three strategies al-

lowed access to the requisite aniline substrates with pendant alkenes at

the 2-position with excellent trans selectivities.

Key words 2-alkenylanilines, 3-aza-Cope rearrangement, olefin me-

tathesis, C–N cross-coupling, trans olefins

Recent studies in these laboratories have described the

catalytic, enantioselective, intramolecular sulfenoamina-

tion of 2-alkenyl-tethered anilines¹as a general method to

access enantioenriched N-containing heterocycles (Scheme

1), such as indolines, tetrahydroquinolines, and tetrahydro-

benzazepines, which represent important classes of com-

pounds exhibiting a range of biological activities.²

Through application of these three strategies, twelve 2-

alkenylaniline compounds 1a–l were prepared as substrates

for the sulfenoamination reaction (Figure 1). 2-Allylic ani-

lines 1a–d were synthesized by the addition of vinylmagne-

PhthS(2,6-i-Pr₂C₆H₃)

SAryl

catalyst

n

R

n

or

MsOH, CH₂Cl₂

NHTs

N

R

N

R

Ts

n = 1, 2

indolines (n = 1)

R = H, alkyl

tetrahydroquinolines (n = 1)

tetrahydrobenzazepines (n = 2)

R = aryl

Me

N

Se

P

N(i-Pr)₂

N

Me

selenophosphoramide

catalyst

Scheme 1

B

S. E. Denmark, H. M. Chi

PSP

Synthesis

R¹

3-aza-Cope

rearrangement

R¹

vinyl Grignard

addition

R²

N

R²

N

R²

BF₃•OEt₂or TsOH

MgCl

H

NHTs

R¹= H, OMe, F, CH=CH–C=CH

R²= alkyl, aryl

then tosyl protection

olefin metathesis

n

+

R

Grubbs catalyst

NHTs

R = H, OMe, Br

n = 1 or 2

C—N cross-coupling

R

tosyl protection

Pd(II), ligand

R

n

(NH₄)₂SO₄, base

TsCl

NH₂

Br

NHTs

n = 1–3; R = H, alkyl

Scheme 2

Cope rearrangement

sium chloride followed by a tandem 3-aza-Cope rearrange-

ment. While the preparations of 1e–g were also viable

through the first route, those compounds are also accessible

by a more direct olefin cross-metathesis reaction that re-

quires only a single step. 2-Homoallylic aniline 1h was also

prepared via the second route, showing its ability to deri-

vatize alkenylanilines with longer chains. Compounds 1i–l

were made by C–N cross-coupling to demonstrate its com-

plementary ability to access dialkyl-substituted alkene sub-

strates with different tether lengths.

Claisen rearrangement

O

3-aza-Cope rearrangement

1-aza-Cope rearrangement

HN

Scheme 3

3-Aza-Cope Rearrangement

The aza-Cope rearrangement is a heteroatom variant of

the Cope rearrangement, replacing a carbon with a nitrogen

atom in one of the allyl components (Scheme 3).³This reac-

tion is often referred to as an amino-Claisen or an aza-

Claisen rearrangement because of its structural similarity

to the Claisen rearrangement.

The 3-aza-Cope rearrangement reactions have received

less attention than Cope or Claisen rearrangements owing

to the higher reaction temperatures needed, which inevita-

bly leads to the formation of side products by thermal de-

composition.³Much effort has been invested to lower the

activation barrier for the rearrangement by employing

Brønsted or Lewis acids.⁴Ward and co-workers were able to

promote the rearrangement of 1,1-disubstituted N-allylic

anilines at significantly reduced temperature (65 °C)

through the addition of a catalytic amount of toluenesul-

fonic acid (Scheme 4).^4a

Grignard Addition/3-Aza-Cope

F

MeO

Ph

NHTs

1a

1b

1c

1d

NHTs

Olefin Metathesis

Ph

1e

1h

NHTs

OMe

NHTs

Br

NHTs

1f

1g

C–N Cross-Coupling

NHTs

n-Pr

CN

1i

1j

1k

1l

NHTs

Figure 1 Three approaches for the preparation of 2-alkenylanilines

C

S. E. Denmark, H. M. Chi

PSP

Synthesis

acid catalyzed the 3-aza-Cope rearrangement of α-aryl-

substituted allylic aniline 3a under much milder reaction

conditions (Conditions B, entry 2).^4aOther allylic anilines

3b and 3c also successfully rearranged to 5b and 5c, respec-

tively (entries 3 and 4). Protection of the resulting primary

aniline with tosyl chloride afforded the desired substrates

1a, 1b, and 1c.

CH₃

3-aza-Cope

rearrangement

CH₃

TsOH (10 mol%)

MeCN/H₂O

65 °C, 6 h

N

H

NH₂

70% yield

Scheme 4

A similar strategy was employed for the construction of

the isopropyl-substituted allylic aniline (Scheme 5). Aniline

and isobutyraldehyde were first condensed to afford aldi-

mine 2d, which was subsequently treated with vinylmag-

nesium chloride and 1-(trimethylsilyl)benzotriazole using

Katritzky’s 1,2-addition protocol for imines bearing acidic

α-protons.⁸The resulting α-substituted allylic aniline 3d

was then treated with boron trifluoride–diethyl ether com-

plex to generate the expected primary aniline 5d, which

was subsequently protected with tosyl chloride to furnish

tosylamide 1d. Interestingly, in this case p-toluenesulfonic

acid failed to promote the rearrangement.

In our case, the 2-cinnamylanilines 5 were synthesized

by 3-aza-Cope rearrangement of α-substituted allylic ani-

lines 3, which were prepared by the addition of vinylmag-

nesium chloride to the corresponding imines 2. This [3,3]-

sigmatropic rearrangement was especially attractive due to

its inherent high stereospecificity, furnishing trans-alkenes

exclusively. This three-step sequence (imine formation/

Grignard addition/rearrangement) was very effective for

the synthesis of 2-cinnamylaniline derivatives.

The imines 2 were prepared by a straightforward con-

densation of the appropriate anilines and aldehydes,⁵which

was followed by a subsequent addition of vinylmagnesium

chloride in the presence of zinc chloride to afford α-substi-

tuted allylic anilines 3 (Table 1).⁶Initially, vinylmagnesium

bromide was tested with zinc bromide as an additive, but

no product formation was observed (entry 1). Interestingly,

a slight excess (1.3 equiv) of the vinylmagnesium chloride

was insufficient and resulted in production of only reduc-

tion product 4a (entry 2).⁶However, successful addition of

the vinyl moiety to the aldimines 2 was observed with 2

equivalents of the Grignard reagent (entries 3–5).

vinylMgCl (2 equiv)

BtTMS (1 equiv)

H

N

H

toluene

reflux, 20 h

68%

2d

3d

BF₃•OEt₂

(conditions A)

TsOH

(conditions B)

57%

TsCl, pyridine

NHTs

1d

CH₂Cl₂, r.t., 24 h

90%

NH₂

5d

Table 1 Addition of Vinylmagnesium Reagents to Aldimines 2

Scheme 5

vinylMgX (x equiv)

ZnY₂(x equiv)

H

R

+

R

N

Ph

N

Ph

N

Ph

THF, r.t., 16 h

H

Olefin Cross-Metathesis

2

4

3, α-substituted allylaniline

Olefin cross-metathesis is arguably one of the most

powerful methods of olefin synthesis in modern organic

chemistry.⁹This process redistributes the double bonds of

olefins allowing the formation of more highly functional-

ized olefins from simple alkene precursors. Pronounced

functional group compatibility and mild reaction condi-

tions render these reactions highly valuable and contribute

to their wide application in many fields including polymer

chemistry and natural product synthesis.¹⁰

Cross-metathesis of precursors bearing terminal

alkenes was attempted to access disubstituted substrates,

which would allow a one-step synthesis of diverse alkene

substitution patterns and tether lengths. N-Tosyl-2-(2-pro-

penyl)aniline (6)¹¹and N-tosyl-2-(3-butenyl)aniline (7)¹²

were combined with several terminal olefins in the pres-

ence of a number of different ruthenium catalysts (Scheme

6). Although styrenyl products were formed with high E-se-

lectivity, dialkyl-substituted products were formed as mix-

tures of geometrical isomers.

Entry

R

VinylMgX

(equiv)

ZnY₂(equiv)

Yield (%)^a

3

4

1

2

3

4

5

4-FC₆H₄

X = Br (1.3)

X = Cl (1.3)

X = Cl (2.0)

Y = Br (0.1)

Y = Cl (0.1)

Y = Cl (0.2)

–

4-FC₆H₄

–

4a, 79

4-FC₆H₄

3a, 83

3b, 82

3c, 95

–

4-MeOC₆H₄

2-naphthyl

^aYield of isolated, purified products.

α-Substituted allylic anilines 3 were then subjected to

aza-Cope rearrangement conditions (Table 2). When α-

aryl-substituted allylic aniline 3a was treated with boron

trifluoride–diethyl ether complex, it rearranged to afford

the desired trans-alkene 5a upon heating (Conditions A, en-

try 1).⁷However, because of the unsatisfying yield of the re-

arrangement with generation of many side products, a sim-

plified reaction protocol was employed. p-Toluenesulfonic

D

S. E. Denmark, H. M. Chi

PSP

Synthesis

Table 2 Preparation of 2-Alkenylanilines by 3-Aza-Cope Rearrangement

3-aza-Cope

tosyl

rearrangement

protection

R

conditions A (BF₃•OEt₂)

or conditions B (TsOH)

Ph

TsCl, pyridine

CH₂Cl₂, r.t., 12 h

N

H

Ph

NH₂Ph

NHTs

3

5

1

Entry

Substrate

Conditions^a

Yield (%)^b

F

1

2

A

B

5a, 45

5a, 71

3a

3b

1a, 86

N

H

Ph

MeO

3

4

B

5b, 81

5c, 81

1b, 83

1c, 83

N

Ph

H

3c

N

H

Ph

^aReaction conditions A: BF₃·OEt₂(1.2 equiv), xylenes (0.5 M), 180 °C, 17 h; Reaction conditions B: TsOH (0.2 equiv), MeCN/H₂O (10:1, 0.1 M), 65 °C, 6–36 h.

^bYield of isolated, purified products.

Table 3 Optimization of Olefin Cross-Metathesis Conditions

R

n

Grubbs catalyst

n

+

R

NHTs

Grubbs catalyst (3 mol%)

CH₂Cl₂, temp, time

R

6, n = 1

7, n = 2

R = aryl, alkyl

R = aryl; exclusively E olefin

R = alkyl; E/Z mixture

+

R

(10 equiv)

NHTs

6 (0.5 mmol)

1

Scheme 6

Entry

R

Catalyst^a

G–H 2^nd

Temp, time

Yield (%)^btrans/cis^c

Next, the Grubbs–Hoveyda 2^ndgeneration catalyst was

examined for an initial survey of cross-metathesis, but a

rapid homodimerization of styrenes was observed with no

desired product (Table 3, entry 1). In contrast, Grubbs 1^st

generation indenylidene catalyst showed strong cross-

metathesis by affording trans-olefin 1e with excellent geo-

metrical selectivity (entry 2). Despite the excess amount of

styrene added, substrate olefin 6 still remained after 18

hours. Extended reaction times showed a slight increase in

yield (entry 3). Whereas metathesis with styrene afforded

trans-olefin exclusively, metathesis with 1-pentene gave

approximately a 2:1 mixture of trans- and cis-disubstituted

olefins (entry 4). Neohexene, which has significant steric

bulk adjacent to the olefin, was stable under the metathesis

conditions (entry 5). Interestingly, the reaction with 4-pen-

tenenitrile failed to give any products (entry 6). This reac-

tion was repeated with the more reactive Grubbs–Hoveyda

2^ndgeneration catalyst to promote metathesis, and higher

temperature was needed to initiate the reaction (entry 7).

However, a complex mixture of E- and Z-olefins was ob-

tained along with some olefin isomerization products.

1

2

3

4

5

6

7

Ph

reflux, 12 h

r.t., 18 h

r.t., 48 h

r.t., 18 h

reflux, 18 h

–

Ph

G 1^st

1e, 43

1e, 58

1m, 62

–

>20:1

2:1

–

Ph

G 1^st

n-Pr

t-Bu

G 1^st

(CH₂)₂CN

G 1^st

–

G–H 2^nd

–

d

^aG 1^st: Grubbs 1^stgeneration indenylidene catalyst; G–H 2^nd: Grubbs–

Hoveyda 2^ndgeneration catalyst.

^bIsolated yield.

^cThe trans/cis ratios were determined by ¹H NMR spectroscopy of the crude

mixtures.

^dA complex mixture was obtained.

Encouraged by the positive screening result with sty-

rene, the reaction was repeated on a gram scale which af-

forded the desired 2-cinnamyl-N-tosylaniline (1e) with the

expected trans selectivity (Table 4, entry 1). In a similar

manner, other styrenes were also examined. Metathesis

with 4-vinylanisole and 4-bromostyrene produced the 2-

cinnamylaniline derivatives 1f and 1g, respectively, in ex-

cellent selectivities (entries 2 and 3). Since these aniline

E

S. E. Denmark, H. M. Chi

PSP

Synthesis

compounds 1f, 1g can also be accessed through the aza-

Cope rearrangement route, cross-metathesis of 2-homoal-

lylaniline 7 was performed to demonstrate the advantage of

this strategy (entry 4). Gratifyingly, the cross-metathesis of

olefin 7 and styrene furnished longer-tethered compound

1h in good yield with exclusive trans selectivity.

a)

R

NfCl

Pd/TsNH₂

ONf

OH

NHTs

R = tethered olefin

b)

R

TsCl

Pd/(NH₄)₂SO₄

Table 4 Preparation of Substrates 1e–h by Cross-Metathesis

NHTs

NH₂

Br/Cl

Scheme 7

n

G i^st(3 mol%)

CH₂Cl₂, rt, 48 h

R

n

R

+

NHTs

1

6 (n = 1) or 7 (n = 2)

(2 or 4 mmol)

(10 equiv)

Between these two routes, the palladium-catalyzed C–N

coupling of aryl nonaflates with tosylamide appeared more

attractive because the starting phenols are readily available

(Scheme 7, a).^14aHowever, whereas the nonaflate derived

from o-cresol could be converted into the tosylaniline in ex-

cellent yield, this approach failed to afford any product for

substrates bearing an ortho-tethered olefin (Scheme 8).

This failure suggested a possible inhibition through binding

of the palladium catalyst by the alkene.

Entry Substrate

Product

Yield trans/

(%)^acis^b

6

1

1e

1f

47

54

>20:1

R = Ph

NHTs

6

2

R = 4-MeOC₆H₄

OMe

Pd₂(dba)₃(0.5 mol%)

CH₃

ONf

CH₃

t-BuXPhos (1.2 mol%)

6

3

4

1g 50

1h 49

>20:1

TsNH₂(1.2 equiv)

K₃PO₄, t-AmOH

R = 4-BrC₆H₄

NHTs

Br

96%

Ph

identical

conditions

7

R = Ph

NHTs

no reaction

ONf

NHTs

^aIsolated yield.

^bThe trans/cis ratios were determined by ¹H NMR spectroscopy of the crude

Scheme 8

mixtures.

In the alternative route, aryl halides are cross-coupled

with ammonium sulfate under palladium catalysis to gen-

erate N-unsubstituted anilines, which can be subsequently

tosylated (Scheme 7, b).^14bThis strategy was suitable for the

synthesis of two- and three-methylene-tethered substrates.

The configuration of the double bond in the 2-substitut-

ed haloarene was established with a Knoevenagel–Doebner

condensation of malonic acid with 3-(2-chlorophenyl)pro-

panal (8) to afford the nonconjugated carboxylic acid 9

(Scheme 9).¹⁵Then, reduction of 9 to primary alcohol 10,^15a

followed by mesylation and displacement with cyanide,

furnished nitrile intermediate 11 for the aryl amination.

Aryl chloride 11 was coupled with ammonium sulfate to

form aniline 12 following the palladium-catalyzed C–N

coupling developed by Hartwig and co-workers.^14bThe de-

sired product was generated in modest yield along with

isomerized side products. Tosylation of 12 afforded nitrile

1i which was reduced with LiAlH₄to the free amine. Subse-

quent tosyl protection of the amine furnished bistosyl-

amide 1j.

Palladium-Catalyzed Amination

Although the aza-Cope rearrangement approach was

successful for the preparation of aliphatic alkene tethers,

the scope is limited to one-methylene-tethered substrates.

For longer tethers, olefin metathesis is suitable for styrenes,

but aliphatic alkenes were formed in poor geometrical se-

lectivity. Accordingly, a different route was needed for the

aliphatic substituents.

The synthesis of aniline derivatives has been tremen-

dously facilitated by advances in transition-metal-catalyzed

coupling of aryl halides with various nitrogen sources. The

palladium-catalyzed C–N cross-coupling strategy was addi-

tionally appealing because the requisite, 2-substituted phe-

nols were readily available with high geometrical purity.¹³

The phenols could then be converted into anilines in two

simple steps by either a direct installation of the tosylamide

or by an amination followed by a tosyl protection (Scheme

7).¹⁴

F

S. E. Denmark, H. M. Chi

PSP

Synthesis

O

OH

O

malonic acid

piperidine

O

MgBr

OH

AcOH, DMSO

65 °C, 4 h

79%

8

14

9

THF, r.t., 1 h

Cl

Br

13

Br

Cl

LiAlH₄

(EtO)₃CMe, EtCO₂H

140 °C, 12 h

61% (2 steps)

THF, r.t., 2 h

89%

1) MsCl, Et₃N, CH₂Cl₂

0 °C, 1 h, 95%

O

LiAlH₄, Et₂O

CN

OH

r.t., 8 h, 90%

OH

OEt

16

Cl

2) NaCN, DMF

40 °C, 12 h, 90%

Br

11

10

Cl

15

Br

1) MsCl, Et₃N, 0 °C, 1 h, 85%

2) LiAlH₄, THF, 0 °C, 4 h, 92%

[P(o-tol)₃]₂, Josiphos

(NH₄)₂SO₄, NaOt-Bu

dioxane, 100 °C, 12 h

35%

[P(o-tol)₃]₂

Josiphos

17

(NH₄)₂SO₄

NaOt-Bu

dioxane

18

Br

NH₂

TsCl, pyridine

CN

TsCl, pyridine

CH₂Cl₂, r.t., 12 h

87%

CH₂Cl₂

r.t., 24 h, 86%

1i

NHTs

NH₂

12

1i

100 °C, 12 h

65%

1) LiAlH₄, THF

0 °C, 3 h, 79%

NHTs

2) TsCl, pyridine

CH₂Cl₂, r.t., 4 h

86%

1j

NHTs

1k

NHTs

Scheme 9

Scheme 10

As was observed previously with the shorter tether,

synthesis of the alkyl-substituted olefin side chain by cross-

metathesis was only modestly trans-selective. A more se-

lective synthesis of the trans-dialkyl-substituted alkene

with a two-methylene tether entailed a Johnson orthoester

Claisen rearrangement to set the configuration of the dou-

ble bond in 1k (Scheme 10). Synthesis of the aniline sub-

strate 1k was accomplished in a few steps from the alcohol

intermediate 16, which was prepared by following a report-

ed protocol by Wolfe and co-workers.¹⁶Addition of vinyl-

magnesium bromide to aldehyde 13 afforded allylic alcohol

14, which was followed by heating with triethyl orthoace-

tate in the presence of a catalytic amount of acid to pro-

mote a [3,3]-sigmatropic rearrangement.¹⁶Reduction of the

resulting ester 15 to alcohol 16,¹⁶followed by a two-step

sequence of mesylation and hydride reduction, afforded the

aryl bromide 17.¹⁷The aryl bromide 17 was then subjected

to Hartwig’s C–N coupling method.^14bGratifyingly, in con-

trast to the one-methylene-tethered system, the reaction

proceeded cleanly with no olefin migration observed. Tosyl

protection of the resulting primary aniline 18 furnished the

target substrate 1k.

moiety,^14band the resulting primary aniline 21 was pro-

tected with a tosyl group to furnish the target sulfonamide

1l.

In conclusion, three routes to accomplish the trans-se-

lective preparation of 2-olefin-tethered anilines have been

developed. The first method combines ZnCl₂-assisted

Grignard addition to aldimines with 3-aza-Cope rearrange-

ment to access single-methylene-tethered 2-olefinic ani-

lines with high efficiency. The second method is a more di-

rect olefin cross-metathesis approach, which is especially

effective for styrenyl substrates. The third method involves

a C–N cross-coupling reaction that is complementary to the

other methods, and allows access to dialkyl olefinic anilines

containing longer tethers. These N-tosylanilines are suit-

able substrates for general electrophilic addition reactions,

Br

, THF

BrMg

CuI, 2,2'-bipyridyl, toluene

r.t., 4 h, 55%

20

Br

19

[P(o-tol)₃]₂

Josiphos, (NH₄)₂SO₄

NaOt-Bu, dioxane

100 °C, 12 h, 61%

Encouraged by the satisfying results, the palladium-

catalyzed C–N coupling method was then applied to the

preparation of even-longer-tethered substrates. 2-(4-Pent-

enyl)aniline was prepared from 2-bromobenzyl bromide

(19) by initial addition of 3-butenylmagnesium bromide

with catalytic assistance of copper(I) iodide to afford the 2-

pentenylaryl bromide 20 (Scheme 11).¹⁸Hartwig’s C–N

coupling method was then employed to install the amine

TsCl, pyridine

NHTs

CH₂Cl₂, reflux, 12 h

85%

NH₂

21

1l

Scheme 11

G

S. E. Denmark, H. M. Chi

PSP

Synthesis

specifically designed for the enantioselective, catalytic

sulfenoamination reaction that has been recently devel-

oped.

IR (neat): 3413 (w), 3029 (w), 1612 (w), 1506 (s), 1452 (m), 1401 (w),

1312 (m), 1217 (s), 1156 (m), 1139 (w), 1108 (w), 1066 (w), 1028 (w),

991 (w), 817 (s), 779 (m), 748 (m) cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 7.46–7.38 (m, 4 H, HC(10,11)), 7.34 (tt,

J = 6.5, 1.5 Hz, 1 H, HC(12)), 6.93–6.87 (m, 2 H, HC(7)), 6.61–6.55 (m, 2

H, HC(6)), 6.09 (ddd, J = 16.5, 10.0, 6.0 Hz, 1 H, HC(4)), 5.37–5.26 (m, 2

H, HC(5)), 4.93 (d, J = 6.0 Hz, 1 H, HC(3)), 3.99 (s, 1 H, HN(2)).

¹³C NMR (126 MHz, CDCl₃): δ = 155.8 (d, J = 235.2 Hz, C8), 143.5 (C1),

141.7 (C9), 139.0 (C4), 128.7 (C10), 127.5 (C12), 127.0 (C11), 116.1

(C5), 115.5 (C7), 114.4 (C6), 61.5 (C3).

All reactions were performed in oven-dried (140 °C) and/or flame-

dried glassware under an atmosphere of dry argon, unless otherwise

noted. Column chromatography was performed using Merck silica gel

60 (40–63 μm particle size) purchased from Aldrich. Analytical TLC

was performed on Merck silica gel plates with QF-254 indicator. R_f

values reported were measured using 10 × 2 cm TLC plates in a devel-

oping chamber containing the solvent system described. Visualiza-

tion was accomplished with UV light (254 nm) and/or KMnO₄. Boiling

points for Kugelrohr distillations correspond to corrected air bath

temperatures. Melting points were determined in sealed tubes under

vacuum on a Thomas Hoover capillary melting point apparatus, and

are corrected. IR spectra were recorded on a Perkin-Elmer FT-IR sys-

tem. ¹H, ¹³C, and ¹⁹F NMR spectra were recorded on an Inova spec-

trometer (500 MHz, ¹H; 126 MHz, ¹³C; 470 MHz, ¹⁹F). ¹H and ¹³C NMR

spectra were acquired in CDCl₃referenced to residual CHCl₃at 7.26

and 77.00 ppm, respectively. Assignments were obtained by reference

to COSY, HSQC, and HMBC correlations; atom numbering is shown in

the Supporting Information. Mass spectrometry was performed by

the University of Illinois Mass Spectrometry Center. ESI mass spectra

were performed on a Waters or Micromass Q-Tof Ultima instrument.

EI mass spectra were performed on a 70-VSE instrument. Elemental

analyses were performed by the University of Illinois Microanalytical

Service Laboratory and Robertson Microlit Laboratories, Inc.

¹⁹F NMR (470 MHz, CDCl₃): δ = –128.2.

MS (ESI): m/z (%) = 117 (27), 145 (24), 183 (16), 200 (18), 228 (12) [M

+ H]⁺, 280 (15), 290 (100), 291 (32), 317 (24), 342 (15), 370 (21), 404

(19).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₅H₁₅FN: 228.1189; found:

228.1197.

4-Methoxy-N-(1-phenylallyl)aniline (3b)⁶

To a flame-dried, 100-mL Schlenk flask was added a solution of vinyl-

magnesium chloride in THF (18.8 mL, 1.6 M, 30 mmol, 2 equiv) and a

solution of ZnCl₂in THF (3 mL, 1.0 M, 3 mmol, 0.2 equiv). After the

solution was stirred for 20 min at r.t., imine 2b^5b(3.17 g, 15 mmol)

was added under positive argon pressure. The solution was stirred at

r.t. for 16 h. The reaction was quenched with sat. aqueous NH₄Cl solu-

tion (30 mL) and extracted with EtOAc (3 × 30 mL). The organic layers

were combined, washed with brine (30 mL), dried over MgSO₄, and

filtered. The filtrate was concentrated under reduced pressure (30 °C,

10 mmHg) to afford a dark brown oil. Purification by silica gel flash

chromatography (18 × 5 cm; 1000 mL of 93:5:2 hexane/EtOAc/Et₃N,

500 mL of 95:5 hexane/EtOAc, 300 mL of 93:7 hexane/EtOAc, 300 mL

of 90:10 hexane/EtOAc) afforded 2.93 g (82%) of 3b as a brown liquid;

R_f= 0.44 (hexanes/EtOAc, 4:1) [UV]. The spectroscopic data matched

those reported previously.¹⁹

Reaction solvents THF (Fisher, HPLC grade), Et₂O (Fisher, BHT-stabi-

lized ACS grade), and CH₂Cl₂(Fisher, unstabilized HPLC grade) were

dried by passage through two columns of neutral alumina in a solvent

dispensing system. Reaction solvent toluene (Fischer, ACS grade) was

dried by percolation through a column packed with neutral alumina

and a column packed with Q5 reactant, a supported copper catalyst

for scavenging oxygen, under a positive pressure of argon. Reaction

solvent DMF (Fisher, HPLC grade) was dried by percolation through a

column packed with molecular sieves in a solvent dispensing system.

Solvents for chromatography, filtration, and recrystallization [CH₂Cl₂

(Aldrich, ACS grade), EtOAc (Fisher, ACS grade), Et₂O (Fisher, ACS

grade), hexanes (Fisher, Optima)] were used as received. Et₃N (Alfa

Aesar) and pyridine (Fisher) were freshly distilled from CaH₂. ‘Brine’

refers to a saturated aqueous solution of sodium chloride.

IR (neat): 3394 (w), 3027 (w), 2831 (w), 1617 (w), 1508 (s), 1463 (m),

1451 (m), 1442 (w), 1406 (w), 1308 (w), 1290 (w), 1240 (s), 1229 (s),

1178 (m), 1156 (w), 1139 (w), 1114 (w), 1094 (w), 1034 (m), 991 (w),

923 (m), 817 (s), 764 (m), 746 (m) cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 7.42–7.32 (m, 4 H, HC(10,11), 7.31–

7.24 (m, 1 H, HC(12)), 6.78–6.72 (m, 2 H, HC(7)), 6.61–6.54 (m, 2 H,

HC(6)), 6.04 (ddd, J = 17.2, 10.2, 6.0 Hz, 1 H, HC(4)), 5.32–5.19 (m, 2 H,

HC(5)), 4.87 (d, J = 6.1 Hz, 1 H, HC(3)), 3.82 (s, 1 H, HN(2)), 3.73 (s, 3 H,

HC(13)).

¹³C NMR (126 MHz, CDCl₃): δ = 152.4 (C8), 142.3 (C9), 141.7 (C1),

139.7 (C4), 128.9 (C11), 127.6 (C12), 127.4 (C10), 116.1 (C6), 115.1

(C5), 114.9 (C7), 61.0 (C3), 55.9 (C13).

Addition of Grignard Reagent to Aldimines (Table 1)

4-Fluoro-N-(1-phenylallyl)aniline (3a)⁶

To a flame-dried, 50-mL Schlenk flask was added a solution of vinyl-

magnesium chloride in THF (18.8 mL, 1.6 M, 30 mmol, 2 equiv) and a

solution of ZnCl₂in THF (3 mL, 1.0 M, 3 mmol, 0.2 equiv). After the

solution was stirred for 20 min at r.t., imine 2a^5a(2.99 g, 15 mmol)

was added under positive argon pressure. The solution was stirred at

r.t. for 16 h. The reaction was quenched with sat. aqueous NH₄Cl solu-

tion (30 mL) and extracted with EtOAc (3 × 40 mL). The organic layers

were combined, washed with brine (30 mL), dried over MgSO₄, and

filtered. The filtrate was concentrated under reduced pressure (30 °C,

10 mmHg) to afford 3.05 g of a dark brown oil. Purification by silica

gel flash chromatography (16 × 5 cm; 800 mL of 93:5:2 hexane/

EtOAc/Et₃N, 200 mL of 90:10 hexane/EtOAc, 200 mL of 85:15

hexane/EtOAc, 200 mL of 80:20 hexane/EtOAc) afforded 2.84 g (83%)

of 3a as a brown liquid; R_f= 0.54 (hexanes/EtOAc, 9:1) [UV]. The spec-

troscopic data matched those reported previously.¹⁹

MS (ESI): m/z (%) = 117 (33), 217 (25), 240 (75) [M + H]⁺, 241 (13), 262

(22), 270 (21), 328 (100), 329 (29), 371 (96), 372 (31), 479 (23).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₆H₁₈NO: 240.1388; found:

240.1393.

N-(1-Phenylallyl)naphthalen-2-amine (3c)⁶

To a flame-dried, 50-mL Schlenk flask was added a solution of vinyl-

magnesium chloride in THF (18.8 mL, 1.6 M, 30 mmol, 2 equiv) and a

solution of ZnCl₂in THF (3 mL, 1.0 M, 3 mmol, 0.2 equiv). After the

solution was stirred for 20 min at r.t., imine 2c^5c(3.47 g, 15 mmol)

was added under positive argon pressure. The solution was stirred at

r.t. for 16 h. The reaction was quenched with sat. aqueous NH₄Cl solu-

tion (30 mL) and extracted with EtOAc (3 × 40 mL). The organic layers

were combined, washed with brine (30 mL), dried over MgSO₄, and

H

S. E. Denmark, H. M. Chi

PSP

Synthesis

filtered. The filtrate was concentrated under reduced pressure (30 °C,

10 mmHg) to afford 3.05 g of a dark brown oil. Purification by silica

gel flash chromatography (16 × 5 cm; 800 mL of 93:5:2 hexane/EtOAc/

Et₃N, 200 mL of 90:10 hexane/EtOAc, 200 mL of 85:15 hexane/EtOAc,

200 mL of 80:20 hexane/EtOAc) afforded 3.70 g (95%) of 3c as a brown

liquid; R_f= 0.35 (hexanes/EtOAc, 4:1) [UV]. The spectroscopic data

matched those reported previously.²⁰

¹³C NMR (126 MHz, CDCl₃): δ = 156.7 (d, J = 235.9 Hz, C1), 141.1 (C4),

137.3 (C10), 132.0 (C13), 128.9 (C12), 127.8 (C9 or C11), 127.0 (C9 or

C11), 126.5 (C8), 126.2 (d, J = 6.6 Hz, C5), 116.9 (d, J = 5.7 Hz, C3),

116.7 (d, J = 20.4 Hz, C6), 114.1 (d, J = 22.1 Hz, C2), 35.6 (C7).

MS (ESI): m/z (%) = 124 (41), 228 (100) [M + H]⁺, 229 (29).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₅H₁₅FN: 228.1189; found:

228.1192.

IR (neat): 3409 (w), 3056 (w), 3026 (w), 2847 (w), 1627 (s), 1601 (m),

1519 (s), 1478 (m), 1451 (m), 1424 (w), 1396 (m), 1358 (m), 1301

(w), 1265 (w), 1223 (m), 1188 (m), 1157 (w), 1145 (w), 1125 (w),

1094 (w), 1066 (w), 1028 (w), 1018 (w), 990 (w), 967 (w), 954 (w),

(E)-N-(2-Cinnamyl-4-fluorophenyl)-4-methylbenzenesulfon-

amide (1a)¹¹

To a flame-dried, 50-mL Schlenk flask equipped with a magnetic stir

bar, purged with a positive pressure of argon, were added aniline 5a

(1.13 g, 5.0 mmol) and CH₂Cl₂(15 mL, 0.3 M). The solution was cooled

to 0 °C and pyridine (2.0 mL, 25.0 mmol, 5.0 equiv) and TsCl (1.43 g,

7.5 mmol, 1.5 equiv) were added. The reaction mixture was warmed

to r.t. and stirred for 12 h. Then, brine (30 mL) was added and the

solution was extracted with CH₂Cl₂(3 × 30 mL). The organic layers

were combined, dried over MgSO₄, filtered, and concentrated under

reduced pressure (30 °C, 10 mmHg). The crude solid was purified by

silica gel flash chromatography (8 × 5 cm; 500 mL of 90:10 hex-

ane/EtOAc, 200 mL of 85:15 hexane/EtOAc, 200 mL of 80:20 hex-

ane/EtOAc, 200 mL of 75:25 hexane/EtOAc, 200 mL of 50:50 hex-

ane/EtOAc) to afford 1.88 g (98%) of a brown liquid. Crystallization of

the brown liquid was achieved by dissolving in boiling EtOAc (10 mL)

and cooling the solution to r.t. and then to –20 °C in a freezer. The 1^st

crop was collected by filtration, and the mother liquor was concen-

trated and recrystallized (boiling EtOAc, 5 mL). After cooling at –20 °C

and filtration, a combined yield of 1.63 g (86%) of 1a was obtained;

fluffy solid; mp 128–129 °C (sealed tube); R_f= 0.32 (hexanes/EtOAc,

4:1) [UV].

924 (m), 909 (m), 865 (w), 827 (s), 806 (s), 743 (s) cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 7.65 (d, J = 8.1 Hz, 1 H, HC(11)), 7.62 (d,

J = 8.8 Hz, 1 H, HC(13)), 7.54 (dd, J = 8.3, 1.1 Hz, 1 H, HC(8)), 7.54 (d, J =

8.2 Hz, 1 H, HC(16)), 7.43 (d, J = 7.5 Hz, 2 H, HC(16)), 7.45–7.41 (m, 2

H, HC(17)), 7.37 (t, J = 7.6 Hz, 1 H, HC(9)), 7.34–7.27 (m, 1 H, HC(18)),

7.18 (ddd, J = 8.1, 6.8, 1.2 Hz, 1 H, HC(10)), 6.92 (dd, J = 8.8, 2.4 Hz, 1 H,

HC(14)), 6.77 (d, J = 2.4 Hz, 1 H, HC(6)), 6.10 (ddd, J = 17.1, 10.2, 5.8

Hz, 1 H, HC(4)), 5.33 (dt, J = 17.1, 1.4 Hz, 1 H, HC(5)), 5.27 (dt, J = 10.2,

1.3 Hz, 1 H, HC(5)), 5.08 (t, J = 5.5 Hz, 1 H, HC(3)), 4.22 (d, J = 5.2 Hz, 1

H, HN(2)).

¹³C NMR (126 MHz, CDCl₃): δ = 144.7 (C1), 141.6 (C15), 138.7 (C4),

134.9 (C7), 128.8 (C13,17), 127.6 (C11), 127.5 (C18), 127.5 (C12),

127.2 (C16), 126.2 (C9), 126.0 (C8), 122.1 (C10), 118.1 (C14), 116.2

(C5), 105.9 (C6), 60.8 (C3).

MS (ESI): m/z (%) = 117 (100), 156 (63), 234 (48), 260 (60) [M + H]⁺,

274 (31), 400 (20), 415 (19), 517 (34).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₉H₁₈N: 260.1439; found:

260.1445.

IR (neat): 3270 (w), 3028 (w), 2924 (w), 1614 (w), 1598 (w), 1494

(m), 1448 (w), 1435 (w), 1392 (w), 1328 (w), 1305 (w), 1273 (w),

1200 (w), 1184 (w), 1157 (s), 1120 (w), 1092 (w), 1019 (w), 963 (w),

904 (w), 814 (w), 754 (w), 730 (w), 706 (w), 692 (w), 664 (m), 595

Preparation of 2-Alkenylanilines by 3-Aza-Cope Rearrangement

(Table 2)

(E)-2-Cinnamyl-4-fluoroaniline (5a)^4a

(w), 548 (m), 527 (m), 493 (w) cm^–1

.

To a 500-mL Schlenk flask equipped with a magnetic stir bar were

added 4-fluoro-N-(1-phenylallyl)aniline (3a) (2.05 g, 9.0 mmol),

TsOH·H₂O (352 mg, 1.8 mmol, 0.2 equiv), and a mixed solution of

MeCN (90 mL) and H₂O (10 mL). The solution was heated to 65 °C in

an oil bath while the reaction was monitored by NMR spectroscopy

(the reaction stalled after 36 h). Volatiles were removed under re-

duced pressure and the residue was extracted with Et₂O (3 × 30 mL).

The combined organic layer was washed with 1 M NaOH (30 mL) and

H₂O (30 mL), dried over Na₂SO₄, and concentrated under reduced

pressure (30 °C, 10 mmHg). Purification of the residue by silica gel

flash chromatography (9.5 × 5 cm; 500 mL of 88:10:2 hexane/EtOAc/

Et₃N, 200 mL of 90:10 hexane/EtOAc, 200 mL of 80:20 hexane/EtOAc,

250 mL of 50:50 hexane/EtOAc) afforded 1.45 g (71%) of 5a as a brown

liquid; R_f= 0.26 (hexanes/EtOAc, 4:1) [UV]. The spectroscopic data

matched those reported previously.²⁰

¹H NMR (500 MHz, CDCl₃): δ = 7.57 (d, J = 8.3 Hz, 2 H, HC(16)), 7.31–

7.26 (m, 6 H, HC(3,11,12,13)), 7.21 (d, J = 8.1 Hz, 2 H, HC(17)), 6.89

(ddd, J = 19.0, 8.6, 3.0 Hz, 2 H, HC(2,6)), 6.32 (s, 1 H, HN(14)), 6.27 (dt,

J = 16.2, 0.9 Hz, 1 H, HC(9)), 6.04 (dt, J = 15.9, 6.5 Hz, 1 H, HC(8)), 3.18

(d, J = 6.01 Hz, 2 H, HC(7)), 2.39 (s, 3 H, HC(19).

¹³C NMR (126 MHz, CDCl₃): δ = 162.3 (C1), 144.2 (C18), 136.7 (C15),

136.6 (C4), 132.7 (C9), 130.6 (C5 or C10), 130.5 (C5 or C10), 129.9

(C17), 128.8 (C6), 128.0 (d, J = 6.0 Hz, C3), 127.9 (C12), 127.8 (C13),

127.4 (C16), 126.5 (C11), 126.4 (C8), 117.3 (d, J = 22.7 Hz, C6), 114.6

(d, J = 22.2 Hz, C2), 35.2 (C7), 21.8 (C19).

¹⁹F NMR (470 MHz, CDCl₃): δ = –115.2.

MS (ESI): m/z (%) = 226 (21), 227 (100) [M – Ts + H]⁺, 228 (18), 382

(72) [M + H]⁺, 399 (36), 404 (17).

HRMS (ESI): m/z [M + H]⁺calcd for C₂₂H₂₁FNO₂S: 382.1271; found:

382.1273.

IR (neat): 3444 (w), 3367 (w), 3032 (w), 1624 (m), 1610 (w), 1596

(w), 1577 (w), 1494 (s), 1448 (w), 1436 (s), 1420 (m), 1352 (w), 1332

(w), 1277 (w), 1261 (m), 1197 (m), 1144 (m), 1081 (w), 1070 (w),

1055 (w), 1028 (w), 990 (m), 983 (m), 972 (w), 951 (s), 859 (s), 822

Anal. Calcd for C₂₂H₂₀FNO₂S (381.46): C, 69.27; H, 5.28; N, 3.67.

Found: C, 69.36; H, 5.20; N, 3.70.

(m), 807 (s), 751 (s) cm^–1

.

(E)-2-Cinnamyl-4-methoxyaniline (5b)^4a

¹H NMR (500 MHz, CDCl₃): δ = 7.45–7.23 (m, 5 H, HC(11,12,13)), 6.88

(ddt, J = 19.9, 8.5, 2.7 Hz, 2 H, HC(2,6)), 6.65 (dd, J = 8.7, 4.9 Hz, 1 H,

HC(3)), 6.50 (d, J = 15.9 Hz, 1 H, HC(9)), 6.35 (dtd, J = 15.8, 6.3, 1.8 Hz,

1 H, HC(8)), 3.59 (s, 2 H, HN(14)), 3.45 (d, J = 6.3 Hz, 2 H, HC(7)).

To a 100-mL Schlenk flask equipped with a magnetic stir bar were

added 4-methoxy-N-(1-phenylallyl)aniline (3b) (239 mg, 1 mmol),

TsOH·H₂O (39 mg, 0.2 mmol, 0.2 equiv), and a mixed solution of

MeCN (10 mL) and H₂O (1 mL). The solution was heated to 65 °C in an

oil bath while the reaction was monitored by NMR spectroscopy (the

I

S. E. Denmark, H. M. Chi

PSP

Synthesis

reaction stalled after 36 h). Volatiles were removed under reduced

pressure and the residue was extracted with Et₂O (3 × 10 mL). The

combined organic layer was washed with 1 M NaOH (10 mL) and H₂O

(10 mL), dried over MgSO₄, and concentrated under reduced pressure

(30 °C, 10 mmHg). Purification of the residue by silica gel flash chro-

matography (16 × 2 cm; 500 mL of 95:5 hexane/EtOAc with 10 mL of

Et₃N, 200 mL of 90:10 hexane/EtOAc, 200 mL of 50:50 hexane/EtOAc)

afforded 195 mg (81%) of a brown liquid. Crystallization of the brown

liquid was achieved by dissolving in boiling Et₂O (0.5 mL), followed by

slow addition of pentane (3 mL). The solution was cooled to r.t. and

then to –20 °C in a freezer. Filtration over glass wool afforded 170 mg

(71%) of 5b; white needle-like crystals; mp 63–64 °C (sealed tube);

R_f= 0.25 (hexanes/EtOAc, 4:1) [UV].

¹H NMR (500 MHz, CDCl₃): δ = 7.58 (d, J = 8.2 Hz, 2 H, HC(16)), 7.31–

7.27 (m, 4 H, HC(11,12)), 7.24–7.20 (m, 3 H, HC(17,13)), 7.19 (d, J = 8.7

Hz, 1 H, HC(3)), 6.72 (dd, J = 8.7, 3.0 Hz, 1 H, HC(2)), 6.69 (d, J = 2.9 Hz,

1 H, HC(6)), 6.31 (s, 1 H, HN(14)), 6.22 (dt, J = 15.8, 1.7 Hz, 1 H, HC(9)),

6.06 (dt, J = 15.9, 6.5 Hz, 1 H, HC(8)), 3.77 (s, 3 H, HC(20)), 3.17 (dd, J =

6.5, 1.6 Hz, 2 H, HC(7)), 2.39 (s, 3 H, HC(19)).

¹³C NMR (126 MHz, CDCl₃): δ = 158.7 (C1), 143.9 (C18), 137.02 (C4),

136.99 (C5), 132.0 (C9), 129.8 (C17), 128.8 (C12), 128.5 (C3), 127.73

(C13), 127.69 (C10 or C15), 127.5 (C16), 127.4 (C10 or C15), 127.3

(C8), 126.5 (C11), 116.0 (C6), 112.6 (C2), 55.6 (C20), 35.4 (C7), 21.8

(C19).

MS (ESI): m/z (%) = 239 (100) [M – Ts + H]⁺, 240 (18), 394 (45) [M +

H]⁺, 395 (12), 411 (10).

IR (neat): 3358 (w), 3024 (w), 2998 (w), 2936 (w), 2906 (w), 2831

(w), 1607 (w), 1500 (s), 1465 (m), 1448 (m), 1432 (m), 1323 (w), 1286

(w), 1242 (s), 1211 (w), 1189 (w), 1154 (m), 1075 (w), 1040 (m), 969

(m), 940 (w), 870 (w), 854 (w), 811 (m), 747 (m), 732 (m), 692 (s),

HRMS (ESI): m/z [M + H]⁺calcd for C₂₃H₂₄NO₃S: 394.1471; found:

394.1479.

Anal. Calcd for C₂₃H₂₃NO₃S (393.50): C, 70.20; H, 5.89; N, 3.56. Found:

C, 69.85; H, 5.81; N, 3.59.

566 (m), 498 (w), 475 (m) cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 7.35 (d, J = 7.0 Hz, 2 H, HC(11)), 7.31–

7.27 (m, 2 H, HC(12)), 7.24–7.17 (m, 1 H, HC(13)), 6.72 (d, J = 2.8 Hz, 1

H, HC(6)), 6.67 (dd, J = 8.4, 2.9 Hz, 1 H, HC(2)), 6.65 (d, J = 8.5 Hz, 1 H,

HC(3)), 6.45 (dt, J = 16.0, 1.4 Hz, 1 H, HC(9)), 6.33 (dt, J = 15.8, 6.2 Hz, 1

H, HC(8)), 3.75 (s, 3 H, HC(14)), 3.45 (d, J = 7.3 Hz, 4 H, HC(7) and

HN(15)).

¹³C NMR (126 MHz, CDCl₃): δ = 153.2 (C1), 138.5 (C4), 137.4 (C5),

131.6 (C9), 128.8 (C12), 127.7 (C8), 127.5 (C13), 126.4 (C11), 126.2

(C10), 117.3 (C3), 116.3 (C6), 113.0 (C2), 56.0 (C14), 36.0 (C7).

(E)-1-Cinnamylnaphthalen-2-amine (5c)^4a

To a 50-mL Schlenk flask equipped with a magnetic stir bar were add-

ed N-(1-phenylallyl)naphthalen-2-amine (3c) (259 mg, 1.0 mmol),

TsOH·H₂O (39 mg, 0.2 mmol, 0.2 equiv), and a mixed solution of

MeCN (10 mL) and H₂O (1 mL). The solution was heated to 65 °C in an

oil bath for 6 h. The solution was cooled to r.t. at which point a solid

started to form. To this suspension were added 2 M NaOH (10 mL) and

Et₂O (20 mL). The organic layer was separated, washed with brine (10

mL), dried over MgSO₄, and then concentrated under reduced pres-

sure (30 °C, 10 mmHg). Purification of the residue by silica gel flash

chromatography (16 × 2 cm; 300 mL of 95:5 hexane/EtOAc, 200 mL of

90:10 hexane/EtOAc, 250 mL of 50:50 hexane/EtOAc) afforded 210

mg (81%) of a brown liquid. Crystallization of the brown liquid was

achieved by dissolving in boiling Et₂O (0.5 mL), followed by slow addi-

tion of pentane (2 mL). The solution was cooled to r.t. and then to

–20 °C in a freezer. Filtration over glass wool afforded 192 mg (74%) of

5c; white crystals; mp 66–68 °C (sealed tube); R_f= 0.40 (hexanes/EtOAc,

4:1) [UV].

MS (ESI): m/z (%) = 136 (51) [M – styrene + H]⁺, 239 (12), 240 (100) [M

+ H]⁺, 241 (17).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₆H₁₈NO: 240.1388; found:

240.1391.

Anal. Calcd for C₁₆H₁₇NO (239.31): C, 80.30; H, 7.16; N, 5.85. Found: C,

80.25; H, 7.05; N, 5.93.

(E)-N-(2-Cinnamyl-4-methoxyphenyl)-4-methylbenzenesulfon-

amide (1b)¹¹

IR (neat): 3023 (w), 1622 (s), 1600 (m), 1496 (m), 1473 (m), 1446 (m),

1435 (m), 1393 (m), 1356 (w), 1282 (m), 1259 (m), 1222 (w), 1164

(w), 964 (s), 908 (m), 857 (w), 811 (s), 782 (m), 731 (s), 691 (s), 672

(m), 648 (m), 617 (m), 599 (m), 586 (m), 545 (m), 518 (m), 500 (m),

To a flame-dried, 25-mL Schlenk flask equipped with a magnetic stir

bar, purged with a positive pressure of argon, were added aniline 5b

(1.17 g, 4.9 mmol) and CH₂Cl₂(15 mL, 0.3 M). The solution was cooled

to 0 °C and pyridine (1.97 mL, 24.5 mmol, 5.0 equiv) and TsCl (1.4 g,

7.35 mmol, 1.5 equiv) were added. The reaction mixture was warmed

to r.t. and stirred for 12 h. Then, brine (30 mL) was added and the

solution was extracted with CH₂Cl₂(3 × 30 mL). The organic layers

were combined, dried over MgSO₄, filtered, and concentrated under

reduced pressure (30 °C, 10 mmHg). The crude solid was purified by

recrystallization by dissolving in boiling EtOAc (10 mL) and cooling

the solution to r.t. and then to –20 °C in a freezer. The 1^stcrop was

collected by filtration, and the mother liquor was concentrated and

recrystallized (boiling EtOAc, 5 mL). After cooling at –20 °C and filtra-

tion, a combined yield of 1.6 g (83%) of 1b was obtained; white solid;

mp 114–115 °C (sealed tube); R_f= 0.30 (hexanes/EtOAc, 4:1) [UV].

477 (m) cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 7.88 (d, J = 8.6 Hz, 1 H, HC(10)), 7.75

(dt, J = 8.1, 0.7 Hz, 1 H, HC(13)), 7.64 (d, J = 8.7 Hz, 1 H, HC(2)), 7.45

(ddd, J = 8.5, 6.8, 1.4 Hz, 1 H, HC(11)), 7.28 (tt, J = 5.4, 1.5 Hz, 3 H,

HC(12,15)), 7.26–7.22 (m, 2 H, HC(16)), 7.17 (tt, J = 7.2, 2.2 Hz, 1 H,

HC(17)), 6.99 (d, J = 8.7 Hz, 1 H, HC(3)), 6.44–6.34 (m, 2 H, HC(8,9)),

3.86 (d, J = 4.5 Hz, 4 H, HC(7) and HN(18)).

¹³C NMR (126 MHz, CDCl₃): δ = 142.3 (C4), 137.4 (C14), 133.6 (C6),

130.7 (C9), 128.9 (C13), 128.8 (C1), 128.7 (C16), 128.3 (C2), 127.4

(C17), 127.3 (C8), 126.8 (C11), 126.3 (C12), 122.5 (C10), 122.4 (C15),

119.1 (C3), 114.7 (C5), 29.9 (C7).

IR (neat): 3271 (w), 3027 (w), 2957 (w), 2837 (w), 1599 (m), 1581

(w), 1496 (s), 1464 (w), 1448 (w), 1433 (w), 1399 (m), 1327 (m), 1304

(m), 1290 (m), 1215 (m), 1185 (w), 1159 (s), 1092 (m), 1038 (m), 968

(m), 945 (w), 899 (m), 814 (m), 753 (m), 731 (m), 693 (m), 665 (m),

MS (ESI): m/z (%) = 156 (100) [M – styrene + H]⁺, 157 (11), 260 (43) [M

+ H]⁺, 261 (10).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₉H₁₈N: 260.1439; found:

260.1441.

596 (w), 550 (m) cm^–1

.

Anal. Calcd for C₁₉H₁₇N (259.35): C, 87.99; H, 6.61; N, 5.40. Found: C,

87.76; H, 6.44; N, 5.50.

J

S. E. Denmark, H. M. Chi

PSP

Synthesis

(E)-N-(1-Cinnamyl-2-naphthyl)-4-methylbenzenesulfonamide

H₂O (2 × 30 mL). The resulting organic layer was dried over Na₂SO₄,

filtered, and concentrated under reduced pressure (30 °C, 10 mmHg).

Purification by silica gel flash chromatography (40 g, 25 mm ∅; hex-

anes to hexanes/EtOAc, 19:1) afforded 595 mg (68%) of 3d as a pale

yellow oil. An analytically pure sample was obtained by Kugelrohr

distillation (60 °C/0.01 mmHg), affording 550 mg (63%) of 3d as a col-

orless oil; bp 60 °C/0.01 mmHg; R_f= 0.58 (hexanes/EtOAc, 4:1) [UV].

The spectroscopic data matched those reported previously.¹⁹

¹H NMR (500 MHz, CDCl₃): δ = 7.18 (t, J = 8.0 Hz, 2 H, HC(3)), 6.69 (t,

J = 7.5 Hz, 1 H, HC(4)), 6.63 (d, J = 8.5 Hz, 2 H, HC(2)), 5.76 (ddd, J =

17.0, 10.5, 6.0 Hz, 1 H, HC(6)), 5.27–5.16 (m, 2 H, HC(7)), 3.75–3.63

(br s + m, 2 H, HN + HC(5)), 1.90 (dq, J = 13.5, 6.5 Hz, 1 H, HC(8)), 1.01

(dd, J = 15.0, 7.0 Hz, 6 H, HC(9)).

(1c)¹¹

To a flame-dried, 50-mL Schlenk flask equipped with a magnetic stir

bar, purged with a positive pressure of argon, were added aniline 5c

(1.43 g, 5.5 mmol) and CH₂Cl₂(17 mL, 0.3 M). The solution was cooled

to 0 °C and pyridine (2.2 mL, 27.5 mmol, 5.0 equiv) and TsCl (1.57 g,

8.25 mmol, 1.5 equiv) were added. The reaction mixture was warmed

to r.t. and stirred for 12 h. Then, brine (30 mL) was added and the

solution was extracted with CH₂Cl₂(3 × 30 mL). The organic layers

were combined, dried over MgSO₄, filtered, and concentrated under

reduced pressure (30 °C, 10 mmHg) to afford a dark brown oil. The

crude product was dissolved in Et₂O and a yellow solid precipitated

immediately. Recrystallization was undertaken by dissolving the yel-

low solid in boiling EtOAc (10 mL) and then cooling the solution to r.t.

and subsequently to –20 °C in a freezer. The 1^stcrop was collected by

filtration, and the mother liquor was concentrated and recrystallized

(boiling EtOAc, 5 mL). After cooling at –20 °C and filtration, a com-

bined yield of 1.9 g (83%) of 1c was obtained; yellow solid; mp 148–

149 °C (sealed tube); R_f= 0.38 (hexanes/EtOAc, 4:1) [UV].

¹³C NMR (126 MHz, CDCl₃): δ = 147.8 (C1), 137.9 (C6), 129.1 (C3),

117.0 (C4), 116.0 (C7), 113.3 (C2), 61.4 (C5), 32.4 (C8), 18.8 (C9), 18.5

(C9).

MS (ESI): m/z (%) = 94 (20), 97 (22), 98 (15), 106 (14), 114 (56), 118

(28), 138 (16), 140 (13), 142 (26), 148 (34), 150 (28), 176 (78) [M +

H]⁺, 188 (50), 202 (43), 219 (100), 220 (17), 230 (16), 235 (69), 248

(16), 251 (19), 258 (25), 262 (14), 274 (40).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₈N: 176.1439; found:

176.1440.

IR (neat): 3283 (w), 1598 (m), 1512 (w), 1496 (w), 1468 (w), 1447

(w), 1407 (m), 1367 (m), 1320 (m), 1304 (m), 1234 (w), 1185 (w),

1159 (s), 1092 (m), 1067 (w), 1019 (w), 966 (m), 907 (m), 864 (w),

847 (w), 813 (m), 763 (m), 733 (s), 706 (m), 691 (m), 669 (s), 598 (m),

552 (s), 532 (m), 494 (w) cm^–1

.

(E)-2-(4-Methyl-2-pentenyl)aniline (5d)

¹H NMR (500 MHz, CDCl₃): δ = 7.92 (d, J = 8.5 Hz, 1 H, HC(10)), 7.84 (d,

J = 8.1 Hz, 1 H, HC(2)), 7.75 (d, J = 8.8 Hz, 1 H, HC(13)), 7.66 (d, J = 8.8

Hz, 1 H, HC(12)), 7.61 (d, J = 8.1 Hz, 2 H, HC(20)), 7.53–7.42 (m, 2 H,

HC(11,3)), 7.24 (dd, J = 7.2, 1.2 Hz, 2 H, HC(16)), 7.22–7.17 (m, 3 H,

HC(15,17)), 7.13 (d, J = 7.9 Hz, 2 H, HC(21)), 6.64 (s, 1 H, HN(18)), 6.19

(dtd, J = 16.1, 5.1, 1.1 Hz, 1 H, HC(8)), 6.13 (d, J = 16.1 Hz, 1 H, HC(9)),

3.65 (dd, J = 5.4, 1.3 Hz, 2 H, HC(7)), 2.31 (s, 3 H, HC(23)).

¹³C NMR (126 MHz, CDCl₃): δ = 144.1 (C22), 136.9 (C14), 136.8 (C19),

132.7 (C6), 132.6 (C1), 132.4 (C5), 131.6 (C9), 129.9 (C21), 129.8 (C4),

128.9 (C2), 128.7 (C16), 128.4 (C13), 127.7 (C17), 127.4 (C20), 127.0

(C11), 126.8 (C8), 126.4 (C15), 125.8 (C3), 124.5 (C10), 123.6 (C12),

30.0 (C7), 21.8 (C23).

By adopting the described procedure,^7,11to an oven-dried, 38-mL

pressure tube with a side arm in the neck, equipped with a magnetic

stir bar, were added allylaniline 3d (350 mg, 2.0 mmol) and xylenes (4

mL, 0.5 M). The tube was capped with a septum and purged with a

positive pressure of argon. The solution was cooled to –40 °C in a

MeCN/dry ice bath under positive argon pressure. To the tube was

added BF₃·OEt₂(48% solution, 0.62 mL, 2.4 mmol, 1.2 equiv). The reac-

tion mixture was warmed to r.t. and the septum was replaced with a

pressure screw cap under a positive stream of argon. Then, the mix-

ture was heated to 180 °C and stirred for 17 h. After completion, the

reaction mixture was cooled to 0 °C with continuous vigorous stirring

and quenched with 2 M NaOH (15 mL) at 0 °C. The resulting biphasic

layer was extracted with Et₂O (3 × 15 mL). The organic layers were

combined, filtered over Celite, and concentrated under reduced pres-

sure (30 °C, 10 mmHg). The crude solid was purified by silica gel flash

chromatography (30 g, 20 mm ∅; hexanes to hexanes/EtOAc, 6:1) to

afford 199 mg (57%) of 5d as a yellow oil. An analytically pure sample

was obtained by Kugelrohr distillation (80 °C/0.01 mmHg), affording

179 mg (51%) of 5d as a colorless oil; bp 80 °C/0.01 mmHg; R_f= 0.43

(hexanes/EtOAc, 4:1) [UV].

¹H NMR (500 MHz, CDCl₃): δ = 7.14–7.07 (m, 2 H, HC(3,5)), 6.80 (tt, J =

7.5, 1.5 Hz, 1 H, HC(4)), 6.72 (dd, J = 7.5, 1.5 Hz, 1 H, HC(6)), 5.63–5.50

(m, 2 H, HC(8,9)), 3.75 (br s, 2 H, H₂N), 3.30 (d, J = 5.5 Hz, 2 H, HC(7)),

2.35 (hept d, J = 6.5, 2.0 Hz, 1 H, HC(10)), 1.04 (dd, J = 7.0, 2.0 Hz, 6 H,

HC(11)).

¹³C NMR (126 MHz, CDCl₃): δ = 144.9 (C1), 139.5 (C9), 129.9 (C5),

127.3 (C3), 125.1 (C2), 124.3 (C8), 118.7 (C4), 115.7 (C6), 35.4 (C7),

31.0 (C10), 22.5 (C11).

MS (ESI): m/z (%) = 258 (22), 259 (100) [M – Ts + H]⁺, 260 (18), 436

(25) [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺calcd for C₂₆H₂₃NO₂SNa: 436.1342; found:

436.1347.

Anal. Calcd for C₂₆H₂₃NO₂S (413.53): C, 75.52; H, 5.61; N, 3.39. Found:

C, 75.19; H, 5.63; N, 3.51.

N-(1-Isopropyl-2-propenyl)aniline (3d) (Scheme 5)

By adopting the described procedure,⁸to an oven-dried, 100-mL,

round-bottomed flask equipped with a magnetic stir bar were added

imine 2d^5d(736 mg, 5 mmol) and toluene (30 mL, 0.17 M). After a

condenser was installed, the flask was purged with argon and 1-

(trimethylsilyl)benzotriazole (BtTMS; 957 mg, 5 mmol, 1 equiv) was

added by syringe. After the reaction mixture was stirred for 30 min at

r.t., it was cooled to 0 °C in an ice bath and a solution of vinylmagne-

sium chloride in THF (6.25 mL, 1.6 M, 10 mmol, 2 equiv) was added by

syringe. To the resulting yellow turbid mixture was added Et₂O (10

mL). The reaction mixture was refluxed under heat (bath temperature

90 °C) for 20 h. After the reaction mixture was cooled to r.t., it was

quenched by pouring into ice–water (30 mL), and then the mixture

was extracted with Et₂O (3 × 60 mL). The organic layers were com-

bined and washed with aqueous 2 M NaOH solution (2 × 20 mL) and

MS (ESI): m/z (%) = 106 (100), 114 (27), 176 (13) [M + H]⁺, 177 (13).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₂H₁₈N: 176.1439; found:

176.1443.

Anal. Calcd for C₁₂H₁₇N (175.27): C, 82.23; H, 9.78; N, 7.99. Found: C,

82.25; H, 10.00; N, 7.80.

K

S. E. Denmark, H. M. Chi

PSP

Synthesis

(E)-4-Methyl-N-[2-(4-methyl-2-pentenyl)phenyl]benzenesulfon-

dle-punctured septum, was thoroughly sealed with Parafilm. The

black mixture was stirred for 48 h at r.t. The mixture was filtered

through a plug of silica gel, then rinsed with CH₂Cl₂(2 × 25 mL) and

EtOAc (2 × 25 mL) to afford a dark solution. The filtrate was concen-

trated under reduced pressure (30 °C, 10 mmHg) to afford a black sol-

id. Purification by silica gel flash chromatography (40 g, 25 mm ∅;

hexanes to hexanes/EtOAc, 6:1) afforded 685 mg (47%) of 1e as a

white solid. Recrystallization of the solid with hot pentane (36 °C, 30

mL) afforded 630 mg (43%) of 1e as white crystals; mp 159–160 °C

(sealed tube). The spectroscopic data matched those reported previ-

ously.²²

amide (1d)¹¹

To an oven-dried, 50-mL, round-bottomed flask equipped with a

magnetic stir bar were added aniline 5d (876 mg, 5.0 mmol) and CH₂-

Cl₂(10 mL, 0.5 M) under positive argon pressure. The solution was

cooled to 0 °C and pyridine (1.21 mL, 15.0 mmol, 3.0 equiv) and TsCl

(1.05 g, 5.5 mmol, 1.1 equiv) were added. The reaction mixture was

warmed to r.t. and stirred for 24 h. To quench the reaction, H₂O (20

mL) was added and then the solution was extracted with CH₂Cl₂(3 ×

20 mL). The organic layers were combined, dried over Na₂SO₄, filtered,

and concentrated under reduced pressure (30 °C, 10 mmHg). The

crude solid was purified by silica gel flash chromatography (40 g, 25

mm ∅; hexanes to hexanes/EtOAc, 6:1) to afford 1.48 g (90%) of 1d as

a yellow solid. An analytically pure sample was obtained by recrystal-

lization (boiling pentane, 50 mL). The solution was cooled to r.t. and

then to –20 °C in a freezer. The 1^stcrop was collected by filtration, and

the mother liquor was concentrated and recrystallized (boiling pen-

tane, 10 mL). After cooling at –20 °C and filtration, a combined yield

of 1.34 g (82%) of 1d was obtained; white crystalline solid; mp 128–

129 °C (sealed tube); R_f= 0.32 (hexanes/EtOAc, 4:1) [UV].

IR (neat): 3280 (m), 1492 (m), 1448 (w), 1403 (m), 1333 (s), 1305 (w),

1291 (w), 1278 (w), 1184 (w), 1165 (s), 1119 (w), 1090 (s), 1053 (w),

1040 (w), 1019 (w), 969 (m), 954 (w), 907 (s), 810 (m), 756 (m) cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 7.60 (d, J = 8.0 Hz, 2 H, HC(9)), 7.43 (d,

J = 8.0 Hz, 1 H, HC(6)), 7.35–7.21 (m, 6 H, HC(aryl)), 7.21–7.13 (m, 4 H,

HC(aryl)), 6.52 (br s, 1 H, HN), 6.29 (dt, J = 16.0, 1.5 Hz, 1 H, HC(14)),

6.11 (dt, J = 16.0, 6.5 Hz, 1 H, HC(13)), 3.25 (dd, J = 6.5, 1.5 Hz, 2 H,

HC(12)), 2.39 (s, 3 H, HC(11)).

¹³C NMR (126 MHz, CDCl₃): δ = 143.8 (C10), 136.6 (C7), 136.6 (C15),

134.9 (C1), 132.2 (C2), 131.9 (C14), 130.5 (C3), 129.6 (C9), 128.6

(C17), 127.8, 127.6, 127.2 (C8), 127.0 (C13), 126.2 (C16), 126.2, 124.2

(C6), 35.2 (C12), 21.5 (C11).

IR (neat): 3286 (m), 2963 (w), 1489 (m), 1458 (w), 1391 (m), 1334 (s),

1307 (w), 1291 (w), 1275 (w), 1187 (w), 1166 (s), 1119 (w), 1090 (s),

1045 (w), 1021 (w), 969 (m), 901 (m), 834 (w), 810 (m), 762 (s) cm^–1

.

¹H NMR (500 MHz, CDCl₃): δ = 7.60 (d, J = 8.0 Hz, 2 H, HC(8)), 7.43 (d,

J = 8.0 Hz, 1 H, HC(6)), 7.22 (d, J = 8.0 Hz, 2 H, HC(9)), 7.19 (t, J = 7.5 Hz,

1 H, HC(5)), 7.09 (t, J = 7.5 Hz, 1 H, HC(4)), 7.04 (d, J = 7.5 Hz, 1 H,

HC(3)), 6.69 (s, 1 H, HN), 5.44 (dd, J = 15.5, 6.5 Hz, 1 H, HC(14)), 5.31

(dt, J = 15.5, 6.0 Hz, 1 H, HC(13)), 2.93 (d, J = 6.0 Hz, 2 H, HC(12)), 2.39

(s, 3 H, HC(11)), 2.34–2.22 (m, 1 H, HC(15)), 0.99 (d, J = 7.0 Hz, 6 H,

HC(16)).

¹³C NMR (126 MHz, CDCl₃): δ = 143.7 (C10), 140.7 (C14), 136.9 (C7),

135.3 (C1), 132.2 (C2), 130.3 (C3), 129.6 (C9), 127.6 (C5), 127.0 (C8),

125.9 (C4), 124.0 (C13), 123.9 (C6), 35.5 (C12), 31.0 (C15), 22.3 (C16),

21.5 (C11).

MS (ESI): m/z (%) = 208 (15), 209 (100), 210 (24), 364 (28) [M + H]⁺,

381 (44), 382 (13), 386 (17).

HRMS (ESI): m/z [M + H]⁺calcd for C₂₂H₂₂NO₂S: 364.1371; found:

364.1373.

(E)-N-{2-[3-(4-Methoxyphenyl)-2-propenyl]phenyl}-4-methyl-

benzenesulfonamide (1f)

By adopting the described procedure,²¹an oven-dried, 25-mL Schlenk

flask equipped with a magnetic stir bar was introduced into a glove-

box. Grubbs 1^stgeneration indenylidene catalyst (CAS no. 250220-36-

1; 55 mg, 0.06 mmol, 0.03 equiv) was loaded into the flask, which was

sealed with a septum and removed from the glovebox. The Schlenk

flask was hooked up to a Schlenk manifold and was purged thorough-

ly with argon. To a separate 25-mL, round-bottomed flask were added

sulfonamide 6¹¹(575 mg, 2.0 mmol, 1 equiv), 4-vinylanisole (2.66 mL,

20.0 mmol, 10 equiv), and CH₂Cl₂(10 mL, 0.2 M, degassed with ar-

gon); then, the flask was sealed with a septum. The mixture turned

into a solution while being degassed for an additional 30 min with ar-

gon (needle and a bubbler outlet attached). The premixed, degassed

solution of the two olefin substrates was transferred to the Schlenk

flask by syringe. The top area of the Schlenk flask, including the nee-

dle-punctured septum, was thoroughly sealed with Parafilm. The

black mixture was stirred for 48 h at r.t. The mixture was filtered

through a plug of silica gel, then rinsed with CH₂Cl₂(2 × 15 mL) and

EtOAc (2 × 15 mL) to afford a dark solution. The filtrate was concen-

trated under reduced pressure (30 °C, 10 mmHg) to afford a black sol-

id. Purification by silica gel flash chromatography (25 g, 20 mm ∅;

hexanes to hexanes/EtOAc, 6:1) afforded 425 mg (54%) of 1f as a

white solid. Recrystallization of the solid with hot pentane (36 °C, 30

mL) afforded 396 mg (50%) of 1f as white crystals; mp 117–118 °C

(sealed tube); R_f= 0.20 (hexanes/EtOAc, 4:1) [UV].

MS (ESI): m/z (%) = 118 (52), 132 (22), 146 (13), 160 (39), 174 (17),

175 (100), 176 (14), 330 (36) [M + H]⁺, 352 (42).

HRMS (ESI): m/z [M + H]⁺calcd for C₁₉H₂₄NO₂S: 330.1528; found:

330.1526.

Anal. Calcd for C₁₉H₂₃NO₂S (329.46): C, 69.27; H, 7.04; N, 4.25. Found:

C, 69.42; H, 7.23; N, 4.26.

Olefin Cross-Metathesis (Table 4)

(E)-4-Methyl-N-[2-(3-phenyl-2-propenyl)phenyl]benzenesulfon-

amide (1e)

By adopting the described procedure,²¹an oven-dried, 50-mL Schlenk

flask equipped with a magnetic stir bar was introduced into a glove-

box. Grubbs 1^stgeneration indenylidene catalyst (CAS no. 250220-36-

1; 111 mg, 0.12 mmol, 0.03 equiv) was loaded into the flask, which

was sealed with a septum and removed from the glovebox. The

Schlenk flask was hooked up to a Schlenk manifold and was purged

thoroughly with argon. To a separate 50-mL, round-bottomed flask

were added sulfonamide 6¹¹(1.15 g, 4.0 mmol, 1 equiv), styrene (4.60

mL, 40.0 mmol, 10 equiv), and CH₂Cl₂(20 mL, 0.2 M, degassed with

argon); then, the flask was sealed with a septum. The mixture turned

into a solution while being degassed for an additional 30 min with ar-

gon (needle and a bubbler outlet attached). The premixed, degassed

solution of the two olefin substrates was transferred to the Schlenk

flask by syringe. The top area of the Schlenk flask, including the nee-

IR (neat): 3271 (m), 3005 (w), 2965 (w), 1739 (w), 1606 (m), 1578

(w), 1510 (m), 1488 (m), 1469 (w), 1456 (w), 1437 (w), 1406 (m),

1332 (m), 1308 (w), 1292 (m), 1275 (w), 1251 (s), 1177 (w), 1160 (s),

1121 (w), 1109 (w), 1089 (m), 1066 (w), 1032 (m), 1018 (w), 969 (m),

908 (m), 862 (w), 820 (m), 812 (m), 778 (w), 761 (m), 754 (m) cm^–1

.

L

S. E. Denmark, H. M. Chi

PSP

Synthesis

¹H NMR (500 MHz, CDCl₃): δ = 7.58 (d, J = 8.5 Hz, 2 H, HC(8)), 7.42 (d,

J = 8.0 Hz, 1 H, HC(6)), 7.25–7.13 (m, 7 H), 6.84 (d, J = 8.5 Hz, 2 H,

HC(17)), 6.56 (br s, 1 H, HN), 6.22 (d, J = 16.0 Hz, 1 H, HC(14)), 5.94 (dt,

J = 16.0, 6.5 Hz, 1 H, HC(13)), 3.81 (s, 3 H, HC(19)), 3.19 (dd, J = 6.5, 2.0

Hz, 2 H, HC(12)), 2.37 (s, 3 H, HC(11)).

¹³C NMR (126 MHz, CDCl₃): δ = 159.1 (C18), 143.7 (C10), 136.6 (C7),

134.9 (C1), 132.3 (C2), 131.3 (C14), 130.5 (C3), 129.6 (C9), 129.4,

127.6, 127.4 (C8), 127.1 (C16), 126.1, 124.7 (C13), 124.0 (C6), 113.9

(C17), 55.3 (C19), 35.1 (C12), 21.5 (C11).

(E)-4-Methyl-N-[2-(4-phenyl-3-butenyl)phenyl]benzenesulfon-

amide (1h)

By adopting the described procedure,²¹an oven-dried, 50-mL Schlenk

flask equipped with a magnetic stir bar was introduced into a glove-

box. Grubbs 1^stgeneration indenylidene catalyst (CAS no. 250220-36-

1; 110 mg, 0.12 mmol, 0.03 equiv) was loaded into the flask, which

was sealed with a septum and removed from the glovebox. The

Schlenk flask was hooked up to a Schlenk manifold and was purged

thoroughly with argon. To a separate 25-mL, round-bottomed flask

were added sulfonamide 7¹²(1.21 g, 4.0 mmol, 1 equiv), styrene (4.60

mL, 40.0 mmol, 10 equiv), and CH₂Cl₂(16 mL, 0.25 M, degassed with

argon); then, the flask was sealed with a septum. The mixture turned

into a solution while being degassed for an additional 30 min with ar-

gon (needle and a bubbler outlet attached). The premixed, degassed

solution of the two olefin substrates was transferred to the Schlenk

flask by syringe. The top area of the Schlenk flask, including the nee-

dle-punctured septum, was thoroughly sealed with Parafilm. The

black mixture was stirred for 48 h at r.t. The mixture was filtered

through a plug of silica gel, then rinsed with CH₂Cl₂(2 × 30 mL) and

EtOAc (2 × 30 mL) to afford a dark solution. The filtrate was concen-

trated under reduced pressure (30 °C, 10 mmHg) to afford a black sol-

id. Purification by silica gel flash chromatography (40 g, 25 mm ∅;

hexanes to hexanes/EtOAc, 6:1) afforded 740 mg (49%) of 1h as a gray

solid. Recrystallization of the solid (boiling EtOAc/pentane, 1:10; 20

mL) afforded 649 mg (43%) of 1h as white crystals; mp 110–111 °C

(sealed tube); R_f= 0.25 (hexanes/EtOAc, 4:1) [UV].

MS (ESI): m/z (%) = 238 (17), 239 (100), 240 (37), 297 (34), 394 (52)

[M + H]⁺, 395 (16), 411 (79), 412 (25).

HRMS (ESI): m/z [M + H]⁺calcd for C₂₃H₂₄NO₃S: 394.1477; found:

394.1484.

Anal. Calcd for C₂₃H₂₃NO₃S (393.50): C, 70.20; H, 5.89; N, 3.56. Found:

C, 70.05; H, 5.81; N, 3.55.

(E)-N-{2-[3-(4-Bromophenyl)-2-propenyl]phenyl}-4-methylben-

zenesulfonamide (1g)

By adopting the described procedure,²¹an oven-dried, 25-mL Schlenk

flask equipped with a magnetic stir bar was introduced into a glove-

box. Grubbs 1^stgeneration indenylidene catalyst (CAS no. 250220-36-

1; 55 mg, 0.06 mmol, 0.03 equiv) was loaded into the flask, which was

sealed with a septum and removed from the glovebox. The Schlenk

flask was hooked up to a Schlenk manifold and was purged thorough-

ly with argon. To a separate 25-mL, round-bottomed flask were added

sulfonamide 6¹¹(575 mg, 2.0 mmol, 1 equiv), 4-bromostyrene (2.62

mL, 20.0 mmol, 10 equiv), and CH₂Cl₂(10 mL, 0.2 M, degassed with