Free radical-mediated vinyl amination: A mild, general pyrrolidinyl enamine synthesis

Article abstract of DOI:10.1016/j.tet.2003.04.003

The complete scope of free radical-mediated vinyl amination is described, using 5-exo-trig cyclizations of vinyl radicals to the nitrogen of azomethines. The focus is primarily on N,N-dialkyl enamines since their nucleophilicity renders them the most challenging enamines to synthesize using redox conditions. These studies establish several encouraging precedents for the broader application of this strategy.

Full text of DOI:10.1016/j.tet.2003.04.003

Tetrahedron 59 (2003) 8877–8888
Free radical-mediated vinyl amination: a mild, general
pyrrolidinyl enamine synthesis
*
Benjamin M. Nugent, Amie L. Williams, E. N. Prabhakaran and Jeffrey N. Johnston
Department of Chemistry, Indiana University, Bloomington, IN 47405-7102, USA
Received 2 April 2003; accepted 28 April 2003
Abstract—The complete scope of free radical-mediated vinyl amination is described, using 5-exo-trig cyclizations of vinyl radicals to the
nitrogen of azomethines. The focus is primarily on N,N-dialkyl enamines since their nucleophilicity renders them the most challenging
enamines to synthesize using redox conditions. These studies establish several encouraging precedents for the broader application of this
strategy.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
cyclopropyl ketimines.6 Vinyl amination7 using an olefin
donor and an amine was reported only recently by
Barluenga8 using the palladium catalyst systems
popularized by Hartwig and Buchwald.9
The vinyl–nitrogen bond is a fundamental structural
building block ubiquitous within organic chemistry. When
part of an aromatic system, a substantial degree of stability
is imparted. However, in the absence of any resonance
stabilization for the olefin and nitrogen, a highly reactive
enamine results. These intermediates have often been
deployed in organic synthesis as enolate equivalents that
are neutral, yet still potently nucleophilic.1,2
Our examination of this problem begins not from the view in
which the nitrogen–hydrogen s bond of the amine is
activated (Eq. (1)), thereby necessitating the use of a base,
but instead by activation of a nitrogen–carbon p bond
(Eq. (2)). Our first solution was the addition of aryl (carbon)
radicals to an azomethine (Eq. (3)), a transformation first
documented by Takano10 and Warkentin11,12 but improved
and generalized by us.13 A typical requirement for
regioselective carbon–nitrogen bond formation is the use
of a ketimine bearing at least one radical-stabilizing
substituent as the azomethine acceptor.14 Our attention
toward pyrrolidinyl enamines stems from their pervasive-
ness in alkaloid natural products. By coupling the develop-
ment of a new method to direct the formation of
nucleophilic enamines with the pyrrolidine motif, we offer
a powerful platform from which alkaloids containing a
pyrrolidine subunit may be accessed.15,16
The vast majority of enamine syntheses are thermodyna-
mically-driven, often condensative processes.3 Methods that
can provide kinetic control, either formally or
ð1Þ
ð2Þ
Our approach to vinyl amination is by some measure an
extension of free radical-mediated aryl amination. Yet, a
closer examination of the process reveals significant new
issues that render this proposition non-trivial. For example,
the products of vinyl amination are N,N-dialkyl enamines
that are not resonance stabilized and consequently more
nucleophilic and reactive than aminoaryl products resulting
from aryl amination. Furthermore, vinyl radicals invert
rapidly and cannot cyclize when in the trans-form
(relationship between the radical and b-alkyl). However,
both stereoisomers are reactive toward hydrogen atom
transfer from stannane. Finally, although 5-membered
ð3Þ
otherwise, include metallocene-catalyzed alkyne hydro-
amination,4 Tebbe olefination of lactams,5 and pyrolysis of
Keywords: vinyl amination; free radicals; enamines; alkyne
aminostannation; b-stannyl enamine.
*
Corresponding author. Tel.: þ1-812-855-9266; fax: þ1-812-855-8300;
e-mail: jnjohnst@indiana.edu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.04.003

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B. M. Nugent et al. / Tetrahedron 59 (2003) 8877–8888
heterocyclic rings were again targeted, an additional degree
of freedom is introduced in many of the substrates examined
(c.f. A–B). Fortunately, the studies described below
demonstrated that none of these issues were ultimately
obstructive.
since the intermediate vinyl radicals produced during
cyclization readily epimerize.
a-Amino acid derivatives 3–4 were prepared from the
corresponding bromopropene and bromobutene derivatives
using phase transfer-catalyzed alkylation of glycine tert-
butyl ester 17.18 The amine (3) (Scheme 2) could be
retrieved after hydrolysis of the ketimine, but direct use of
the benzophenone imine provided a desirable level of
brevity for the synthesis of the derived proline derivatives.
2. Synthesis of the cyclization precursors
Cyclization precursors 1–10 were targeted for synthesis to
carefully evaluate the relative importance of conformational
and stereoelectronic effects. 1- and 2-bromopropene deriva-
tives 1–4 were readily prepared from 3-aminopropanol (11)
(Scheme 1). Protection of amine 11 as its phthalimide and
subsequent oxidation with the Dess–Martin periodinane
provided aldehyde 12 in 42% overall yield. Use of the
Smithers reagent17 derived from dibromomethane trans-
formed the aldehyde to terminal vinyl bromide 13 as a 4:1
mixture of Z/E isomers in 49% yield. The imide could then
be deprotected using hydrazine hydrate to liberate amine 1
in 71% yield. Similarly, the Smithers reagent derived from
1,1-dibromoethane enabled access to the 2-bromopropene
derivative 2 as a 4:1 mixture of Z/E stereoisomers. It is
significant to note that these low molecular weight amines
are often both water soluble and volatile, thereby, demand-
ing strict attention to the handling procedures outlined.
Although no convenient point to separate the olefin
stereoisomers was found, it was of little consequence
Scheme 2. Reagents and conditions: (a) NaOH, BnEt3NCl, H2O–CH2Cl2
(18, 80%; 19, 96%).
Phthalimide 20 was prepared from 5-chloro-1-pentyne
according to the Marks protocol (Scheme 3).4 Bromobora-
tion and subsequent treatment with protic acid returned the
a-olefin 21. Removal of the phthalimide with hydrazine
hydrate provided the desired, highly hygroscopic amine 5.
Scheme 3. Reagents and conditions: (a) BBr3, CH2Cl2, 2788C, then AcOH,
hexanes, K (81%); (b) NH2NH2, CH3OH, 658C (97%).
The benzophenone imine of 6 could be directly accessed as
described in Scheme 4. Both stereoisomers were syn-
thesized from cyclohexanone 22.19 Imine formation from
diphenylmethyl amine and reduction provided secondary
amine 23 in 50% yield for the two steps. Use of the Honek
protocol20 for DDQ oxidation to the corresponding imine
provided 24 in 78% yield. cis-24 and trans-24 were
separable on neutral alumina. Relative stereochemical
assignments are based on NOE measurements on the
derived cyclization products (vide infra).
˚
Scheme 4. Reagents and conditions: (a) (i) Ph2CHNH2, 4 A MS, C6H6,
(ii) NaBH4 (cis/trans¼3:1, 50%); (b) (i) DDQ, CH2Cl2, 558C (78%),
Chart 1.
(ii) chromatography (neutral Al2O3).
Vinyl bromide 7 was formed from ortho-iodobenzyl alcohol
in six steps by first using a Sonagashira coupling with
trimethylsilyl acetylene (Scheme 5). Subsequent alkyne
deprotection, treatment with carbon tetrabromide/triphenyl-
phosphine, and bromination with boron tribromide led to an
intermediate benzyl halide with adequate efficiency (72%
yield). This halide was then transformed to the required
amine (7) via a straightforward Gabriel amine synthesis.
Scheme 1. Reagents and conditions: (a) phthalic abhydride, DMAP, 128C
(64%); (b) Dess–Martin periodinane, CH2Cl2 (65%); (c) Ph3PCRBr2,
nBuLi, THF, 2788C (13, 49%; 14 39%); (d) NH2NH2, CH3OH, 658C (1,
71%; 2, 92%).

B. M. Nugent et al. / Tetrahedron 59 (2003) 8877–8888
8879
tography, the condensations are clean transformations, and
excess acetophenone can be removed slowly by application
of a high vacuum. In cases where acetophenone imine is
slow to form (for either steric or electronic reasons), or a
symmetrical ketimine is desired, transimination with
benzophenone imine is the method of choice. The
benzophenone ketimines that result can be chromato-
graphed on neutral alumina. It is particularly critical to
remove benzophenone, as it effectively halts the desired free
radical amination process.
Scheme 5. Reagents and conditions: (a) TMS–CuC–H, (Ph3P)4Pd, Cul,
TEA, 508C (quant); (b) K2CO3, CH3OH (quant); (c) Ph3P, CBr4, 2,6-
lutidine (93%); (d) (i) BBr3, CH2Cl2, 2788C, (ii) AcOH, hexanes, 608C
(72%); (e) KPhth, DMF, 608C (43%); (f) NH2NH2, CH3OH (84%).
Synthesis of aniline 8 (Scheme 6) commenced from ortho-
aminobenzyl alcohol by tert-butoxycarbonyl (Boc)
protection and oxidation to benzaldehyde derivative 28
with the Dess–Martin reagent (48% overall). Wittig
olefination using the Smithers reagent provided amine 8
after Boc deprotection with trifluoroacetic acid.
The ketimine derivatives of amines 1–10 described in
Chart 1 were individually optimized for vinyl radical
addition to the azomethine nitrogen (Eq. (4), Table 1).
Ketimines of 1–2 are analogous to the aryl aminations
described previously, yet they possess an additional degree
of freedom by virtue of the epimerizable vinyl radical
intermediate: when the radical is trans to the alkyl chain,
intermolecular hydrogen atom transfer is the only possible
direct functionalization. Notwithstanding, ketimines 32 and
18, which present little bias for either the Z- or E-vinyl
radical configurations, cleanly cyclized to their correspond-
ing enamines. Despite the reluctance of 39a to react cleanly
with any acylating agent, it was clear from 1H NMR
analysis that formation of 39a was quite selective. Again,
volatility of the the D2-pyrroline was evident throughout the
optimization process. In cases where enamine volatility is a
concern, care must be exercised to maintain a closed
refluxing benzene reaction mixture. Formation of the
analogous but less volatile vinylogous amide 41b in 54%
yield (Table 1, entry 3) supports this contention. The near
identical behavior of ketimines 33 and 19 (Table 1, entries 2
and 4) compared to their counterparts 32 and 18 (Table 1,
entries 1 and 3) suggests that the vinyl radical is indeed
epimerizing faster than cyclization. This result also
underscores an important advantage to free radical-
mediated amination in that mixtures of vinyl halide
stereoisomers can be used. Cyclizations of 33 and 19
uniformly produced exocyclic enamines 40a and 42a,
respectively, instead of the expected endocyclic isomers.
When these transformations were executed in refluxing
C6D6 so as to allow periodic monitoring of the reaction, no
spectroscopic evidence for the endocyclic enamine was
observed. Although the endocyclic isomer must be the first
intermediate, it is apparently quick to isomerize.21
Scheme 6. Reagents and conditions: (a) Boc2O, THF (92%); (b) Dess–
Martin periodinane, CH2Cl2 (52%); (c) Ph3PCBr2(CH3), nBuLi, THF,
2788C (44%); (d) TFA, CH2Cl2 (64%).
Two substrates were targeted as 6-exo-cyclization substrate
variants. The first of these, ketimine 30 was formed directly
via the glycine Schiff base alkylation protocol (Scheme 7).
Treatment of 17 with aqueous alkali and the benzylic
bromide synthesized en route to 7 provided the desired
benzophenone ketimine (30) in 63% yield.
Scheme 7. Reagents and conditions: (a) NaOH, BnEt3NCl, H2O–CH2Cl2
(63%).
The benzophenone imine of 10 (ketimine 38) was prepared
concisely from ortho-hydroxy aniline in 86% yield as
depicted in Scheme 8.
Following several trial cyclizations of ketimine 34 that lead
to uniformly low yields, the reaction was effected in C6D6 in
a sealed J-Young tube in order to monitor the reaction. Once
again, selective formation of the desired enamine was
evident, with little or no formation of the reduced vinyl
radical (comparison with an authentic sample). This
example is the most conformationally mobile example we
have cyclized successfully. A 36% yield over three steps
(condensation, cyclization, benzoylation) could be repro-
duced consistently, suggesting that amounts of the inter-
mediate enamine are again lost to the headspace of the
refluxing benzene solution during cyclization.
˚
Scheme 8. Reagents and conditions: (a) Ph2CvNH, 4 A MS, C6H6 (91%);
(b) NaH, 2-bromoallyl bromide, THF (95%).
3. Free radical-mediated vinyl amination
Our protocol for vinyl amination involves the traditional
generation of a vinyl radical using tri-n-butylstan-
nane/AIBN and its regioselective addition to the nitrogen
of a ketimine.15 Generally speaking, both acetophenone and
benzophenone ketimines work equally well in the context of
the cyclization. However, each offers unique practical
attributes. Acetophenone imines are formed via conden-
sation of the amine with acetophenone, facilitated by
The cis-fused pyrrolidine 43b was conveniently prepared
in 64% overall yield via the free radical amination
protocol (Table 1, entry 6). Similarly, the trans isomer
(trans-24) cyclized without event, delivering the trans-fused
˚
activated (at 4008C) 4 A MS at room temperature. Although
the resulting imine is not sufficiently inert toward chroma-

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B. M. Nugent et al. / Tetrahedron 59 (2003) 8877–8888
Table 1. 5-exo-Trig vinyl radical cyclizations to ketimine nitrogena
ð4Þ
Entry
Ketimine
Intermediate enamineb (A)
Isolated product (B)
Overall
yieldc/steps
1
32
33
39a
38d,e/2
2
3
40a
41a
40b
41b
34d/3
54/2
18
4
5
68/2
19
34
42a
40a
42b
40b
36d/3
6
7
64/2
57/2
8
35
44a
44b
31f/3
9
10
64/2
53/2
45
46
11
12
30
38
47
0
48
0
b
1
c
aSee Ref. 15 for complete experimental details. Observed by H NMR. Isolated yields from amine (2-3 steps depending on substrate) after trapping with
PhCOCl (39a–43a), maleimide 44a, or no trapping agent (45–46). dEnamines 39a, 40a, and 42a are volatile. eYield measured by 1H NMR relative to HMDS
as an internal standard. fA single diastereomer was observed and isolated after trapping.

B. M. Nugent et al. / Tetrahedron 59 (2003) 8877–8888
8881
indolizidine trans-43b in 57% yield for the two steps
(Table 1, entry 7). Insofar as substituted cyclohexanones are
readily prepared in enantiomerically pure form, this
procedure constitutes a versatile platform from which to
target indolizidine natural and unnatural products.
substrate lacking the intramolecular hydrogen atom transfer
pathway. Yet only complex product mixtures resulted.
The first demonstration that tandem bond-forming processes
could be based on free radical mediated vinyl amination
came in the form of a series of alkyne bisfunctionalization
reactions. Although aminoacylation and aminothiolation of
an alkyne were possible, only the aminostannation variant
was efficient (Table 2). As expected, the nucleophilicity of
the intermediate b-stannylenamine (C) was readily tapped
by acylation,
Ketimine 35 was expected to provide the exocyclic enamine
by analogy to the preceding cyclizations. Interestingly, only
isoindole 44a was observed spectroscopically (1H NMR) in
the crude reaction mixture.22 This isoindole could be
retrieved after rapid flash chromatography, yet its purity
was only marginally improved. As a result, the crude
reaction mixture was instead treated with maleimide and
placed in the freezer overnight. The precipitate that formed
was then filtered, dried, and found to be analytically pure
cycloadduct 44b. Although the yield for these three steps is
modest at best, it is significant to note both the mild
conditions used to produce the isoindole, as well as the
diastereomerically pure nature of the cycloadduct.
providing uniformly good yields (up to 60%) of vinylogous
amides 50a–j for the three steps (condensation, cyclization,
acylation). Unfortunately, attempts to form the homologous
azetidine and azirine ring systems using this tandem
functionalization protocol resulted in only hydrostannation
of the alkyne. Similarly, attempts to effect aminostannation
on substrates analogous to 47 and 48 in which the vinyl
bromide is replaced by a terminal alkyne were similarly
fruitless.
Our interest in the cyclization of ketimines 36–37 stemmed
primarily from the possibility that these ketimines were the
most likely, theoretically, to be reduced directly by stannane
via either radical or non-radical pathways using reducing
reaction conditions. Gratifyingly, no evidence for direct
reduction to the corresponding secondary amines was
obtained. Zanardi23 and Kim24 have demonstrated the
utility of aryl diazo and alkyl azides, respectively, to serve
as nitrogen sources for carbon radicals (Eqs. (5) and (6)).
4. Conclusions
The 5-exo-trig cyclizations of vinyl radicals to azomethine
nitrogen described here provide a strategically innovative
approach to the synthesis of highly nucleophilic N,N-dialkyl
enamines. With only two exceptions, the expected
kinetic enamine product was produced selectively and
under mild, non-dehydrative conditions. At the present
time, the cyclizations are generally limited to the
formation of pyrrolidine derivatives, yet within this class
there exists considerable generality in backbone construc-
tion. The examples described here also further demonstrate
the efficiency with which carbon radicals can be added
regioselectively to the nitrogen of an azomethine. Ryu
has described the complementary regioselective 6-endo-trig
ð5Þ
ð6Þ
Table 2. Vinylogous amides from an alkyne hydrostannation/acylation
sequencea
Yet both of these acceptors require either the use of aryl/
alkyl iodides and/or tris(trimethylsilyl)silane to minimize
products of direct reduction. Although we cannot exclude
reversible addition/elimination of stannane to the ketimines
studied here, it remains clear that the azomethine functional
group offers this clear advantage over both azo and azide
nitrogen sources for carbon radical amination.
Entry
R
Compound
Yield (3 steps, %)b
1
2
3
4
5
6
7
8
9
10
Me
Et
50a
50b
50c
50d
50e
50f
50g
50h
50i
51
54
57
53
60
49
36
28
54
27
iPr
iBu
Ph
Unfortunately, all attempts to effect 6-exo cyclization of a
vinyl radical to ketimine nitrogen were unsuccessful. Two
examples are shown in Table 1 (entries 11 and 12).
Treatment of 30 with stannane and AIBN furnished only
the product of direct reduction, presumably through
intramolecular 1,5-hydrogen atom transfer if not inter-
molecularly from stannane. A second attempt utilized 38, a
PhO
MeO2C
CH3CvCH
ClCH2
ClCH2CH2
50j
a
See Section 5 for complete details.
Isolated yield after silica gel chromatography.
b

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B. M. Nugent et al. / Tetrahedron 59 (2003) 8877–8888
cyclization of a vinyl radical to azomethine carbon
through the deployment of an aldimine instead of a
ketimine.25 This dramatic turnover in regioselection under-
scores the importance of steric effects in the control of
regioselectivity.
5.1.4. 2-(1-Bromo-vinyl)-benzylamine (7). Alcohol 26
(1.9 g, 14.4 mmol), CBr4 (8.61 g, 26.1 mmol), and 2,6-
lutidine (8.2 mL, 70.4 mmol) were combined in cold (58C)
dichloromethane (40 mL) and treated dropwise with a
solution of PPh3 (7.64 g, 29.1 mmol) in dichloromethane
(10 mL). The mixture was stirred for 12 h prior to
concentration, addition of ether, and removal of POPh3 by
filtration through Celite. The solution was washed with 1N
HCl, dried, and concentrated. The residual yellow oil was
purified by flash chromatography (neutral alumina, 5% ethyl
acetate in hexanes) to give the bromide as a yellow oil
(2.6 g, 93%), Rf¼0.66 (SiO2, 40% CH2Cl2/hexanes); IR
(film) 3292, 2109, 1488 cm21; 1H NMR (400 MHz, CDCl3)
d 7.53 (dd, J¼7.5, 1.2 Hz, 1H), 7.47 (dd, J¼7.8, 1.1 Hz,
1H), 7.36 (dt, J¼7.5, 1.5 Hz, 1H), 7.29 (dt, J¼7.5, 1.4 Hz,
1H), 4.71 (s, 2H), 3.44 (s, 1H); 13C NMR (100 MHz,
CDCl3) ppm 167.9, 140.1, 133.5, 130.0, 129.6, 128.7, 83.1,
80.9, 31.8; HRMS (EI): exact mass calcd for C9H7Br [M]þ,
193.9731. Found 193.9731. A cold (2788C) dichloro-
methane solution (20 mL) of ortho-ethynyl-benzyl bromide
(1.0 g, 5 mmol) was treated with boron tribromide (5 mL,
1 M in CH2Cl2) dropwise over 45 min. The solution was
warmed to room temperature and stirred for 45 min prior to
the addition of water and the final 10 min stirring period.
Following concentration, the crude oil was diluted with
hexanes (70 mL) and acetic acid (5.5 mL), and the solution
was refluxed for 3 h. The reaction mixture was cooled,
washed with water, dried and concentrated. Flash chroma-
tography (neutral alumina, 100% hexanes, then 10%
dichloromethane in hexanes) furnished the targeted vinyl
bromide (990 mg, 72%) as a yellow oil; Rf¼0.33 (100%
5. Experimental
5.1. Data for compounds
5.1.1. 4-Bromo-but-3-enylamine (1). To a 0.1 M solution
of phthalimide 13 (460 mg, 1.6 mmol) in methanol was
added hydrazine hydrate (160 mL, 3.3 mmol). The mixture
was refluxed for 1 h, during which a white precipitate
formed. The reaction mixture was cooled to room
temperature, concentrated, and diluted with ether. Filtration
of the white solid through Celite and concentration gave the
desired product (174 mg, 71%) as an inseparable 4:1
mixture of E/Z isomers; Rf¼0.07 (20% EtOAc in hexanes);
1
IR (film) 3345, 3263, 2932, 1654, 1624 cm21; H NMR
(400 MHz, CDCl3) d 6.25 (d, J¼7.0 Hz, 1H), 6.10 (dt,
J¼7.3, 7.0 Hz, 1H), 2.77 (t, J¼6.9 Hz, 2H), 2.32 (dt, J¼6.9,
7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) ppm 132.1,
110.2, 40.4, 33.3; HRMS (EI): exact mass calcd for
C4H9BrN [MþH]þ, 151.9898. Found 151.9895.
5.1.2. 4-Bromo-pent-3-enylamine (2). To a 0.1 M solution
of phthalimide 14 (256 mg, 0.87 mmol) in methanol was
added hydrazine hydrate (85 mL, 1.8 mmol). The mixture
was refluxed for 1 h resulting in the formation of a white
precipitate. The reaction mixture was cooled to room
temperature, concentrated and diluted with ether. Filtration
of the white solid through Celite and concentration gave the
desired amine (131.7 mg, 92%) as an inseparable 4:1
mixture of Z/E isomers, (Z)-isomer: Rf¼0.05 (20%
EtOAc/hexanes); IR (film) 3343, 1689, 1514, 1453, 1273,
hexanes); IR (film) 1630 cm21
;
1H NMR (400 MHz,
CDCl3) d 7.46 (dd, J¼7.6, 1.9 Hz, 1H), 7.37–7.32 (m,
3H), 6.01 (d, J¼1.7 Hz, 1H), 5.99 (d, J¼1.7 Hz, 1H), 4.65
(s, 2H); 13C NMR (100 MHz, CDCl3) ppm 140.5, 135.1,
131.2, 130.0, 129.7, 128.9, 122.8, 107.2, 31.0; HRMS (EI):
exact mass calcd for C9H7Br2 [M]þ, 273.8993. Found
273.8996. A solution of the bromide (2.5 g, 9.1 mmol) and
potassium phthalimide (4.2 g, 22.7 mmol) in DMF (40 mL)
was warmed (608C) for 12 h. The mixture was cooled,
concentrated in vacuo, diluted with CH2Cl2, and filtered.
The filtrate was concentrated, and the product purified by
chromatography (neutral alumina, 5% ethyl acetate in
hexanes) to give the desired product as a white solid
(1.3 g, 43% yield); Rf¼0.73 (30% EtOAc/hexanes); IR
1
1252, 1170 cm21; H NMR (400 MHz, CDCl3) d 6.00 (qt,
J¼10.4, 2.0 Hz, 1H), 3.63 (td, J¼9.2, 2.0 Hz, 2H), 2.94–
2.88 (m, 2H), 2.41 (d, J¼2.0 Hz, 3H), 1.43 (bs, 2H); 13C
NMR (100 MHz, CDCl3) ppm 129.8, 125.6, 41.5, 34.0,
29.1; HRMS (EI): exact mass calcd for C5H11BrN [MþH]þ,
164.0075. Found 164.0078; (E)- isomer: 1H NMR
(400 MHz, CDCl3) d 5.80 (ddd, J¼16.8, 7.6, 1.6 Hz, 1H),
2.91 (ddd, J¼15.2, 8.8, 1.6 Hz, 2H), 2.98–2.87 (m, 2H),
2.46 (d, J¼1.6 Hz, 3H), 1.43 (bs, 2H); 13C NMR (100 MHz,
CDCl3) ppm 126.5, 124.3, 41.2, 36.0, 29.1.
1
(film) 3059, 1983, 1770, 1721 cm21; H NMR (400 MHz,
CDCl3) d 7.88 (dd, J¼5.4, 3.1 Hz, 2H), 7.74 (dd, J¼8.5,
3.1 Hz, 2H), 7.34–7.31 (m, 1H), 7.26 (dd, J¼4.9, 3.9 Hz,
2H), 7.20 (dd, J¼3.9, 3.9 Hz, 1H), 6.01 (d, J¼1.5 Hz, 1H),
5.95 (d, J¼1.5 Hz, 1H), 5.05 (s, 2H); 13C NMR (100 MHz,
CDCl3) ppm 168.3, 139.9, 134.4, 133.7, 132.3, 129.6,
129.5, 127.8, 127.5, 127.3, 123.7, 122.7, 39.2; HRMS
(EI): exact mass calcd for C17H12BrNO2 [M]þ, 341.0051.
Found 341.0037. A solution of the phthalimide (273 mg,
0.86 mmol) and hydrazine monohydrate (85.6 mg,
1.71 mmol) in methanol (6 mL) was warmed (608C) for
12 h. The solvent was then removed under vacuum, and the
residue was treated with ether and filtered through Celite.
Concentration of the filtrate gave analytically pure amine
(153 mg, 84%) as a yellow oil; Rf¼0.18 (30% EtOAc/
5.1.3. 4-Bromo-pent-4-enylamine (5). A solution of
phthalimide 21 (1.78 g, 6.1 mmol) and hydrazine mono-
hydrate (0.588 mL, 12.1 mmol) in methanol (30 mL) was
heated to 658C for 1.5 h. The reaction mixture was cooled to
room temperature, concentrated, and diluted with CH2Cl2.
The solution was filtered to remove the white solid and
concentrated to give the amine (972 mg, 97%) as a yellow
liquid; Rf¼0.05 (20% EtOAc in hexanes); IR (film) 3362,
2938, 1629, 1585, 1431 cm21; 1H NMR (400 MHz, CDCl3)
d 5.59 (s, 1H), 5.40 (s, 1H), 2.73 (t, J¼7.0 Hz, 2H), 2.48 (t,
J¼7.5 Hz, 2H), 1.71 (quint, J¼7.3 Hz, 2H); 13C NMR
(100 MHz, CDCl3) ppm 134.4, 116.9, 41.2, 39.1, 32.1;
HRMS (CI): exact mass calcd for C5H11BrN [MþH]þ,
166.0054. Found 166.0049.
hexanes); IR (film) 3371, 3288, 3062 cm21 1H NMR
;
(400 MHz, CDCl3) d 7.39 (d, J¼7.4 Hz, 1H), 7.34 (ddd,
J¼8.7, 7.0, 1.9 Hz, 1H), 7.26 (dd, J¼5.3, 1.6 Hz, 1H), 7.24

B. M. Nugent et al. / Tetrahedron 59 (2003) 8877–8888
8883
(ddd, J¼7.8, 7.8, 1.3 Hz, 1H), 5.90 (d, J¼1.6 Hz, 1H), 5.79
(d, J¼1.6 Hz, 1H), 4.00 (s, 2H), 1.86–1.79 (bs, 2H); 13C
NMR (100 MHz, CDCl3) ppm 140.9, 139.6, 135.1, 129.6,
129.4, 128.28, 127.0, 121.7, 44.9; HRMS (EI): exact mass
calcd for C9H11N [MþH]þ, 212.0075. Found 211.9889.
with satd aq Na2S2O3. The crude product was dried,
concentrated and purified by flash chromotography (silica
gel, 30% ethyl acetate in hexanes) to furnish a white solid
(0.33 g, 65%), mp 119–1218C; Rf¼0.30 (30% EtOAc/
hexanes); IR (film) 3080, 2950, 1710, 1614, 1370 cm21; 1H
NMR (400 MHz, CDCl3) d 9.81 (s, 1H), 7.83 (dd, J¼5.4,
3.1 Hz, 2H), 7.71 (dd, J¼5.4, 3.1 Hz, 2H), 4.02 (t, J¼7 Hz,
2H), 2.86 (dt, J¼6.8, 1.1 Hz, 2H). 13C NMR (100 MHz,
CDCl3) ppm 199.7, 168.3, 134.4, 132.2, 123.6, 42.6, 31.9;
HRMS (EI): exact mass calcd for C11H9NO3 [M]þ,
203.0582. Found 203.05845.
5.1.5. 2-(2-Bromo-propenyl)-phenylamine (8). Smithers’
salt, Ph3PC(CH3)Br2 (6.99 g, 13.3 mmol) was warmed in a
round-bottom flask under vacuum for 10 min. After the flask
was flushed with nitrogen, THF (100 mL) was added, the
resulting suspension was cooled to 2788C, and nBuLi added
(4.25 mL, 2.5 M in hexanes, 10.6 mmol) over a 5 min
period. The dark red–brown solution was stirred 2 h prior to
addition of aldehyde 28 (1.18 g, 5.3 mmol). The solution
was stirred for 12 h, diluted with water, and extracted with
ether. The combined organic layers were dried and
concentrated, and the orange oily residue was purified by
flash chromatography (SiO2, 10% ethyl acetate in hexanes)
to furnish the Z-vinyl bromide (.95:5) as a yellow oil
(725 mg, 44%); Rf¼0.60 (20% EtOAc/ hexanes); IR (film)
3429, 2978, 1731 cm21; 1H NMR (400 MHz, CDCl3) d 7.95
(d, J¼7.0 Hz, 1H), 7.39–7.28 (m, 2H), 7.08 (dd, J¼7.4,
7.4 Hz, 1H), 6.64 (s, 1H), 6.39 (s, 1H), 2.56 (s, 3H), 1.55 (s,
9H); 13C NMR (100 MHz, CDCl3) ppm 153.0, 135.8, 134.1,
133.9, 129.9, 124.8, 123.2, 80.9, 30.0, 28.6; HRMS (EI):
exact mass calcd for C14H19BrNO2 [MþH]þ, 312.0582.
Found 312.0606. To a solution of protected amine (714 mg,
2.3 mmol) in CH2Cl2 (40 mL) was added trifluoroacetic
acid (2 mL) at 08C. The solution was warmed to room
temperature over 6 h, washed with 1 M NaOH, dried and
concentrated to an oil that was purified by flash chroma-
tography (SiO2, 10% ethyl acetate in hexanes) to furnish the
aniline as a yellow oil (308 mg, 64%); Rf¼0.22 (10%
5.1.7. 2-(4-Bromo-but-3-enyl)-isoindole-1,3-dione (13).
To a cooled (2788C) suspension of Ph3PCHBr2 (3.73 g,
n
7.2 mmol) in THF (30 mmol) was added BuLi (4.1 mL,
1.8 M in hexanes) dropwise. The solution was stirred for
2 h, after which a solution of aldehyde 12 (734 mg,
3.6 mmol) in THF (10 mL) was added and the reaction
mixture was stirred for 2 h. The mixture was warmed to
room temperature, quenched with water and extracted with
diethyl ether. The crude product was dried, concentrated,
and purified by flash chromatography (silica gel, 20% ethyl
acetate in hexanes) to give the vinyl bromide as a light
orange oil (496 mg, 49%); Rf¼0.12 (10% EtOAc/hexanes);
1
IR (film) 2941, 2336, 1773, 1711, 1396 cm21; H NMR
(400 MHz, CDCl3) d 7.85–7.83 (m, 2H), 7.71–7.70
(m, 2H), 6.22 (d, J¼7.1 Hz, 1H), 6.14 (dt, J¼13.3, 6.8 Hz,
1H), 3.81 (t, J¼6.8 Hz, 2H), 2.61 (ddd, J¼13.7, 6.8, 1.2 Hz,
2H); 13C NMR (100 MHz, CDCl3) ppm 134.7, 134.2,
131.0, 123.5, 110.9, 36.3, 32.2, 29.4; HRMS (EI): exact
mass calcd for C12H9NO2 [M2H]þ, 279.9796. Found
279.9787.
EtOAc/hexanes); IR (film) 3452, 3372, 3026 cm21
;
1H
5.1.8. 2-(4-Bromo-pent-3-enyl)-isoindole-1,3-dione (14).
To a cooled (2788C) suspension of Ph3PC(CH3)Br2 (5.77 g,
11 mmol) in THF (30 mL) was added nBuLi (6.8 mL, 1.6 M
in hexanes) dropwise. To this solution was added a solution
of the aldehyde 12 (1.11 g, 5.5 mmol) in THF (10 mL) and
the reaction mixture was stirred for 4 h. The mixture was
warmed to room temperature, quenched with water and
extracted with diethyl ether. The crude product was dried,
concentrated, and purified by flash column chromatography
to gave the vinyl bromides as an inseparable 4:1 mixture of
Z/Eisomers (636 mg, 39%); (E)-isomer: Rf¼0.32 (20%
EtOAc/hexanes); IR (film) 1771, 1710, 1612, 1437, 1396,
1355, 1186, 1063 cm21; 1H NMR (400 MHz, CDCl3) d 7.82
(dd, J¼5.4, 3.0 Hz, 2H), 7.70 (dd, J¼5.5, 3.1 Hz, 2H), 5.64
(ddd, J¼7.8, 7.8, 1.5 Hz, 1H), 3.75 (t, J¼6.8 Hz, 2H), 2.52
(ddd, J¼6.9, 6.1, 0.8 Hz, 2H), 2.21 (s, 3H); 13C NMR
(100 MHz, CDCl3) ppm 168.5, 134.1, 132.3, 127.8, 125.1,
123.4, 36.6, 31.1, 29.1; HRMS (CI): exact mass calcd for
C13H12NO2 [M]þ, 293.0051. Found 293.0050. (Z)-isomer:
1H NMR (400 MHz, CDCl3) d 7.82 (dd, J¼5.4, 3.0 Hz, 2H),
7.70 (dd, J¼5.5, 3.1 Hz, 2H), 5.84 (ddd, J¼7.8, 7.8, 1.2 Hz,
1H), 3.71 (t, J¼7.2 Hz, 2H), 2.40 (dd, J¼7.8, 7.5 Hz, 2H),
2.16 (s, 3H); 13C NMR (100 MHz, CDCl3) ppm 168.4,
134.3, 132.2, 127.8, 125.4, 123.5, 36.9, 31.1, 28.8.
NMR (400 MHz, CDCl3) d 7.27 (d, J¼6.4 Hz, 1H), 7.14
(ddd, J¼7.5, 7.5, 1.2 Hz, 1H), 6.80 (ddd, J¼7.5, 7.5, 0.9 Hz,
1H), 6.73 (dd, J¼7.9, 0.7 Hz, 1H), 6.61 (s, 1H), 2.53 (d,
J¼1.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) ppm 143.9,
130.1, 129.0, 126.0, 125.3, 123.2, 118.5, 115.7, 30.0; HRMS
(EI): exact mass calcd for C9H11BrN [MþH]þ, 210.9997.
Found 210.9995. Anal. calcd for C9H10BrN: C, 50.97; H,
4.75; N, 6.60. Found: C, 51.19; H, 4.80; N, 6.43.
5.1.6. 3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propional-
dehyde (12). A mixture of 3-aminopropan-1-ol (2.25 g,
30 mmol) (11), phthalic anhydride (4.44 g, 30 mmol), and
DMAP (402 mg, 3.0 mmol) were refluxed at 1208C for 2 h.
The mixture was then cooled to room temperature, diluted
with CH2Cl2 and washed with water. The crude residue was
dried and concentrated to give a thick paste that was purified
by column chromatography (silica gel, 30% ethyl acetate in
hexanes) to give the desired product (3.94 g, 64%) as a
white solid, mp 73–758C; Rf¼0.22 (40% EtOAc/hexanes);
1
IR (film) 3464, 2949, 1710, 1649, 1399 cm21; H NMR
(400 MHz, CDCl3) d 7.88–7.84 (m, 2H), 7.76–7.72 (m,
2H), 4.13 (t, J¼6.2 Hz, 2H), 3.82 (t, J¼6.9 Hz, 2H), 2.05
(quint, J¼6.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) ppm
168.5, 134.2, 132.2, 123.5, 62.1, 35.3, 27.7; HRMS (EI):
exact mass calcd for C11H11NO3 [M]þ, 205.0739. Found
205.0737. To a cooled (08C) mixture of alcohol (0.52 g,
2.5 mmol) in CH2Cl2 (7 mL) was added Dess–Martin
periodinane (1.08 g, 2.5 mmol). The mixture was warmed to
room temperature and stirred for 20 min prior to washing
5.1.9. 2-(Benzhydrylidene-amino)-5-bromo-pent-4-enoic
acid tert-butyl ester (18). To a solution of Schiff base 17
(383 mg, 1.30 mmol) in CH2Cl2 (3 mL) was added sodium
hydroxide (1.04 g, 26.0 mmol) in water (1.5 mL), and
benzyltriethylammonium chloride (59.1 mg, 260 mmol).

8884
B. M. Nugent et al. / Tetrahedron 59 (2003) 8877–8888
1,3-Dibromopropene (156 mL, 1.56 mmol, 1:1 Z/E) was
added, and the reaction mixture was stirred for 20 min and
then diluted with ether. The layers were separated, the
aqueous layer was extracted with ether, and the combined
organic layers were dried (Na2SO4), filtered, and concen-
trated. The crude oil was purified by flash chromatography
(neutral alumina, 10% CH2Cl2 in hexanes) to give a yellow
oil (430 mg, 80%) as an inseparable mixture (1:1) of Z/E
olefin stereroisomers: Rf¼0.58 (10% EtOAc/hexanes); IR
(film) 3292, 3058, 1619 cm21; 1H NMR (400 MHz, CDCl3)
d 7.66 (ddd, J¼7.0, 3.4, 1.5 Hz, 2H), 7.48–7.44 (m, 3H),
7.42–7.38 (m, 1H), 7.36 (dd, J¼7.5, 3.5 Hz, 2H), 7.19 (dt,
J¼7.1, 1.7 Hz, 2H), 6.22 (ddd, J¼12.5, 12.5, 6.7 Hz, 1H),
6.10 (d, J¼3.1 Hz, 1H), 4.10 (dd, J¼6.8, 5.5 Hz, 0.5H), 4.00
(dd, J¼7.0, 5.9 Hz, 0.5H), 2.86–2.77 (m, 0.5H), 2.76–2.70
(m, 0.5H), 2.64–2.60 (m, 1H), 1.47 (s, 4.5H), 1.46 (s, 4.5H);
13C NMR (100 MHz, CDCl3) ppm 171.8, 171.0, 170.7,
170.5, 139.8, 139.7, 136.7, 136.6, 134.4, 131.3, 130.64,
130.57, 129.06, 129.13, 128.9, 128.7, 128.31, 128.26,
128.05, 120.12, 107.1, 109.8, 64.8, 65.4, 37.1, 34.3;
HRMS (EI): exact mass calcd for C22H24BrNO2 [M]þ,
413.0990. Found 413.0987.
Following extraction with CH2Cl2 and concentration, the
orange/yellow oil was diluted with hexanes (50 mL) and
acetic acid (3 mL) and the suspension was refluxed for 3 h.
The reaction mixture was cooled, neutralized with sodium
bicarbonate, and washed with brine. The crude product was
dried, concentrated, and purified by flash chromatography
(SiO2, 5% ethyl acetate in hexanes) to give the vinyl
bromide (3.5 g, 81%) as a clear oil; Rf¼0.20 (5% EtOAc in
hexanes); IR (film) 3465, 3060, 2939, 1770, 1710, 1629,
1467, 1396, 1371 cm21; 1H NMR (400 MHz, CDCl3) d 7.86
(dd, J¼5.5, 3.1 Hz, 2H), 7.74 (dd, J¼5.4, 3.0 Hz, 2H), 5.66
(s, 1H), 5.44 (s, 1H), 3.74 (t, J¼7.1 Hz, 2H), 2.51 (t,
J¼7.3 Hz, 2H), 1.99 (quint, J¼7.4 Hz, 2H); 13C NMR
(ppm) (100 MHz, CDCl3) 168.6, 134.2, 133.1, 132.3, 123.5,
117.7, 39.0, 37.1, 27.2; HRMS (CI): exact mass calcd for
C13H13BrNO2 [MþH]þ, 296.0109. Found 296.0108.
5.1.12. Benzhydryl-[2-(2-bromo-allyl)-cyclohexyl]-
amine (23).
A
solution of ketone 2219 (0.981 g,
4.5 mmol), diphenylmethyl amine (794 mL, 4.6 mmol),
˚
and benzene (5 mL) was stirred with 4 A molecular sieves
at 808C for 24 h. The crude mixture was then cooled, filtered
through Celite, and concentrated to an orange oil (1.48 g,
;
85%); IR (film) 3060, 1710, 1629 cm21 1H NMR
5.1.10. 2-(Benzhydrylidene-amino)-5-bromo-hex-4-enoic
acid tert-butyl ester (19). To a solution of Schiff base 17
(200 mg, 0.68 mmol) in CH2Cl2 (2 mL) was added sodium
hydroxide (542 mg, 14 mmol) in water (1.1 mL), and
benzyltriethylammonium chloride (30.9 mg, 0.14 mmol).
1,3-Dibromopropene26 (229 mL, 2.0 mmol, 1:1 Z/E) was
added, and the reaction mixture was warmed to room
temperature, stirred for 12 h, and then diluted with ether.
The layers were separated, the aqueous layer was extracted
with ether, and the combined organic layers were dried
(Na2SO4), filtered, and concentrated. The crude oil was
purified by flash chromatography (neutral alumina, 4% ethyl
acetate in hexanes) to give the product as a yellow oil
(280 mg, 96%). The product was an inseparable mixture of
Z/E isomers (1:4); E isomer: Rf¼0.55 (5% EtOAc/hexanes);
(400 MHz, CDCl3) d 7.47–7.40 (m, 4H), 7.36–7.20 (m,
6H), 5.64 (s, 1H), 5.48 (s, 1H), 5.24 (s, 1H), 3.06–2.94 (m,
2H), 2.74–2.01 (m, 4H), 1.94–1.57 (m, 3H), 1.33–1.16 (m,
2H); 13C NMR (100 MHz, CDCl3) ppm 172.8, 145.9, 134.6,
128.8, 128.6, 127.73, 127.67, 127.23, 127.19, 119.0, 60.0,
48.6, 42.5, 41.4, 33.2, 28.2, 25.4; HRMS (EI): exact mass
calcd for C22H24BrN [M]þ, 381.1092. Found 381.1109. To
a solution of this imine (1.01 g, 2.6 mmol) in chilled
methanol (16 mL) was added sodium borohydride (101 mg,
2.6 mmol). The solution was stirred for 15 min, then
warmed to room temperature for an additional 2 h. The
solution was quenched with satd aq NH4Cl and extracted
with CH2Cl2. The organic layers were combined, dried with
Na2SO4, and concentrated. Flash chromatography (SiO2,
7% ethyl acetate in hexanes) provided the product as an
orange oil (602.2 mg, 59%) and an inseparable mixture of
cis/trans diastereomers (3:1); Rf¼0.57 (10% EtOAc/
hexanes); IR (film) 3330, 3060, 3025, 2926, 2853,
IR (film) 3058, 2976, 1729, 1620 cm21
;
1H NMR
(400 MHz, CDCl3) d 7.68 (dd, J¼7.8, 1.6 Hz, 2H), 7.49–
7.45 (m, 4H), 7.36 (dd, J¼7.5, 1.6 Hz, 2H), 7.22 (dd, J¼7.8,
1.6 Hz, 2H), 5.74 (ddd, J¼7.9, 7.9, 1.2 Hz, 1H), 4.01 (dd,
J¼7.6, 5.4 Hz, 1H), 2.62 (dd, J¼7.8, 7.8 Hz, 1H), 2.60 (dd,
J¼7.2, 2.8 Hz, 1H), 2.20 (s, 3H), 1.47 (s, 9H); 13C NMR
(100 MHz, CDCl3) ppm 170.8, 139.6, 136.7, 132.7, 130.6,
130.3, 129.1, 128.8, 128.7, 128.5, 128.4, 128.3, 128.2,
122.0, 81.5, 65.6, 33.7, 28.3, 23.8; HRMS (CI): exact mass
calcd for C23H27BrNO2 [MþH]þ, 428.1125. Found
1
1628 cm21; H NMR (400 MHz, CDCl3) d 7.44–7.41 (m,
3H), 7.32–7.28 (m, 5H), 7.25–7.20 (m, 2H), 5.55 (s, 1H),
5.42 (s, 1H), 4.97 (s, 1H), 2.71 (m, 1H), 2.61 (d, J¼4.6 Hz,
1H), 2.57 (d, J¼9.3 Hz, 1H), 2.07–2.04 (m, 1H), 1.74–1.73
(m, 2H), 1.56–1.50 (m, 2H), 1.43–1.28 (m, 5H); 13C NMR
(100 MHz, CDCl3) ppm 145.2, 144.4, 134.9, 128.8, 128.7,
128.0, 127.7, 127.5, 127.3, 118.0, 63.8, 53.7, 45.5, 42.2,
28.8, 26.4, 25.9, 22.4; HRMS (EI): exact mass calcd for
C22H25BrN [M2H]þ, 382.1170. Found 382.1170.
1
428.1234; Z isomer: H NMR (400 MHz, CDCl3) d 7.68
(dd, J¼7.8, 1.6 Hz, 2H), 7.49–7.45 (m, 4H), 7.36 (dd,
J¼7.5, 1.6 Hz, 2H), 7.22 (dd, J¼7.8, 1.6 Hz, 2H), 5.74 (ddd,
J¼7.9, 7.9, 1.2 Hz, 1H), 3.96 (dd, J¼7.8, 5.4 Hz, 1H),
2.67–2.58 (m, 2H), 2.20 (s, 3H), 1.47 (s, 9H); 13C NMR
(100 MHz, CDCl3) ppm 170.8, 139.6, 136.7, 132.7, 130.6,
130.3, 129.1, 128.8, 128.7, 128.5, 128.4, 128.3, 128.2,
122.0, 81.5, 65.6, 31.9, 28.3, 22.9.
5.1.13. Benzhydrylidene-[2-(2-bromo-allyl)-cyclohexyl]-
amine (24). Using the Honek protocol, a mixture of amine
23 (198 mg, 0.5 mmol), 2,3-dichloro-5,6-dicyano-1,4-
benzoquininone (119 mg, 0.5 mmol) and benzene (10 mL)
was stirred at 608C for 45 min, then cooled to room
temperature. The solvent was removed under vacuum and
the residue was chromatographed (neutral alumina, 3%
dichloromethane in hexanes) to give the ketimine as a
colorless oil (153.7 mg, 78%). This mixture of cis/trans
diastereomers (3:1) was separated by flash chromatography;
cis-diastereomer: Rf¼0.65 (Al2O3, 5% EtOAc/hexanes); IR
5.1.11. 2-(4-Bromo-pent-4-enyl)-isoindole-1,3-dione (21).
To a cold (2788C) solution of alkyne 20 (3.14 g,
14.7 mmol) in CH2Cl2 (12 mL) was added boron tribromide
(14.7 mL, 1.0 M in CH2Cl2) dropwise 20 min. The solution
was warmed to room temperature and stirred for an
additional 45 min prior to the addition of water (10 mL).

B. M. Nugent et al. / Tetrahedron 59 (2003) 8877–8888
8885
(film) 3059, 1626 cm21; 1H NMR (400 MHz, CDCl3) d 7.66
(dd, J¼6.6, 1.3 Hz, 2H), 7.48–7.42 (m, 3H), 7.38–7.32 (m,
3H), 7.15 (dd, J¼6.0, 1.7 Hz, 2H), 5.51 (s, 1H), 5.38 (s, 1H),
3.48 (m, 1H), 2.34 (ddd, J¼14.1, 14.1, 3.6 Hz, 1H), 2.31
(ddd, J¼14.5, 14.5, 8.1 Hz, 1H), 1.93–1.82 (m, 4H), 1.68–
1.63 (m, 1H), 1.58–1.50 (m, 2H), 1.44–1.40 (m, 2H); 13C
NMR (100 MHz, CDCl3) ppm 165.9, 140.5, 137.4, 134.4,
129.9, 128.6, 128.3, 128.2, 128.0, 117.8, 60.0, 45.0, 40.2,
33.9, 26.3, 25.8, 21.7; HRMS (EI): exact mass calcd for
C22H24BrN [M]þ, 380.1013. Found 380.1030; trans-dia-
stereomer: Rf¼0.53 (Al2O3, 5% EtOAc/hexanes); 1H NMR
(400 MHz, CDCl3) d 7.61 (dd, J¼7.8, 1.6 Hz, 2H), 7.47–
7.42 (m, 3H), 7.37–7.30 (m, 3H), 7.12 (dd, J¼7.8, 1.9 Hz,
2H), 5.47 (s, 1H), 5.39 (s, 1H), 2.90 (ddd, J¼9.9, 9.8,
4.3 Hz, 1H), 2.61 (dd, J¼14.1, 3.1 Hz, 1H), 2.13–2.05 (m,
1H), 1.86 (dd, J¼13.4, 2.4 Hz, 1H), 1.78–1.61 (m, 4H),
1.36–1.26 (m, 2H), 1.19–1.10 (m, 1H), 0.70 (dddd, J¼13.0,
13.0, 13.0, 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) ppm
167.1, 140.3, 137.7, 133.9, 130.0, 128.72, 128.67, 128.4,
128.3, 127.8, 117.8, 66.0, 46.1, 41.9, 34.1, 29.4, 25.8, 24.9.
1.3 Hz, 1H), 7.13 (dd, J¼7.5, 1.2 Hz, 1H), 7.00 (ddd, J¼7.4,
7.4, 0.8 Hz, 1H), 4.61 (d, J¼2.8 Hz, 2H), 2.90 (br s, 1H),
1.52 (s, 9H); 13C NMR (100 MHz, CDCl3) ppm 153.8,
138.1, 129.5, 129.24, 129.16, 123.4, 121.4, 80.7, 64.3, 28.6;
HRMS (EI): exact mass calcd for C12H17NO3 [M]þ,
223.1208. Found 223.1206. Anal. calcd for C12H17NO3:
C, 64.55; H, 7.67; N, 6.27. Found: C, 64.26; H, 7.72; N,
6.20. The benzyl alcohol (1.17 g, 5.2 mmol) in cold CH2Cl2
(35 mL) was treated with the Dess–Martin periodinane
(3.41 g, 8.0 mmol). The mixture was stirred at 08C for
20 min, then at room temperature for 30 min prior to a series
of washes with satd aq Na2S2O3, NaHCO3, and H2O. The
organic layer was dried, the solvent was removed, and the
residue was chromatographed (SiO2, 10% ethyl acetate in
hexanes) to give the aldehyde as a pale yellow solid
(605 mg, 52%), mp 57–588C; Rf¼0.52 (20% EtOAc/
hexanes); IR (film) 3291, 2980, 1732, 1670 cm21 1H
;
NMR (400 MHz, CDCl3) d 10.39 (br s, 1H), 9.91 (s, 1H),
8.47 (d, J¼8.5 Hz, 1H), 7.64 (dd, J¼7.7, 1.6 Hz, 1H), 7.58
(ddd, J¼7.7, 7.7, 1.6 Hz, 1H), 7.14 (ddd, J¼7.5, 7.5, 0.9 Hz,
1H), 1.55 (s, 9H); 13C NMR (100 MHz, CDCl3) ppm 195.3,
153.1, 142.0, 136.3, 136.2, 121.7, 121.4, 118.5, 81.2, 28.5;
HRMS (EI): exact mass calcd for C12H16NO3 [MþH]þ,
221.1052. Found 221.1045. Anal. calcd for C12H15NO3: C,
65.14; H, 6.83; N, 6.33. Found: C, 65.35; H, 6.73; N, 6.30.
5.1.14. (2-Ethynyl-phenyl)-methanol (26). A solution of
trimethylsilyl acetylene (2.82 mL, 20 mmol) and ortho-
iodobenzyl alcohol (2.33 g, 10 mmol) in triethylamine
(150 mL) was degassed using the freeze-pump-thaw method
and added to a flask containing Pd(PPh3)4 (150 mg,
196 mmol). The mixture was warmed to 408C for 5 h. The
solvent was removed in vacuo, and the residue was rinsed
over a Celite pad with Et2O. The organic washes were
concentrated to give an orange–yellow oil (2.0 g, 100%),
Rf¼0.16 (40% CH2Cl2/hexanes); IR (film) 3310, 3262,
2106 cm21; 1H NMR (400 MHz, CDCl3) d 7.47 (dd, J¼7.5,
0.8 Hz, 1H), 7.42 (d, J¼7.5 Hz, 1H), 7.33 (dt, J¼6.5,
1.2 Hz, 1H), 7.23 (dd, J¼7.5, 1.1 Hz, 1H), 4.82 (d,
J¼5.5 Hz, 2H), 2.70 (t, J¼5.5 Hz, 1H), 0.29 (s, 9H); 13C
NMR (100 MHz, CDCl3) ppm 143.8, 132.6, 129.2, 127.9,
127.8, 121.2, 102.3, 99.9, 63.9, 0.03; HRMS (EI): exact
mass calcd for C12H16OSi [M]þ, 204.0970. Found
204.0979. The alcohol (2.0 g, 9.9 mmol) and potassium
carbonate (691 mg, 5 mmol) in methanol (60 mL) was
stirred for 3 h. The solvent was removed, satd aq NH4Cl was
added, and the resulting mixture was extracted with ether.
The organic layers were combined, washed with water and
brine, dried, and concentrated to an analytically pure yellow
solid (1.3 g, 100%), mp 64–668C; Rf¼0.25 (SiO2, 60%
5.1.16. 2-(Benzhydrylidene-amino)-3-[2-(1-bromo-
vinyl)-phenyl]-propionic acid tert-butyl ester (30). To a
solution of Schiff base 17 (50.0 mg, 0.17 mmol) in CH2Cl2
(1 mL) was added NaOH (140.2 mg), 3.5 mmol), Et3BnNCl
(9.1 mg, 0.40 mmol) and H2O (1 mL). The biphasic mixture
was stirred for several minutes prior to addition of
dibromide 29 (47.2 mg, 0.17 mmol). The mixture was
stirred for 6 h, then diluted with CH2Cl2 and separated.
The organic layer was washed with H2O, dried and
concentrated to a yellow oil that was purified by flash
chromatography (neutral alumina, 5% ethyl acetate in
hexanes) to furnish the product as a colorless oil (52.3 mg,
63%); Rf¼0.33 (Al2O3, 10% EtOAc/hexanes); IR (film)
3059, 1733, 1625 cm21; 1H NMR (400 MHz, CDCl3) d 7.57
(d, J¼8.5 Hz, 2H), 7.35–7.33 (m, 1H), 7.28 (dd, J¼6.1,
5.8 Hz, 4H), 7.24–7.20 (m, 4H), 7.15–7.09 (m, 3H), 5.56
(s, 1H), 5.00 (s, 1H), 4.19 (dd, J¼9.8, 3.7 Hz, 1H), 3.49 (dd,
J¼13.7, 3.7 Hz, 1H), 3.20 (dd, J¼13.4, 9.8 Hz, 1H), 1.42 (s,
9H); 13C NMR (100 MHz, CDCl3) ppm 171.1, 170.5, 141.0,
139.7, 136.6, 136.0, 132.7, 132.0, 130.4, 130.3, 129.4,
129.0, 128.7, 128.5, 128.4, 128.3, 128.2, 127.9, 126.6,
121.8, 81.3, 67.2, 36.9, 28.3; HRMS (EI): exact mass calcd
for C28H28BrNO2 [M]þ, 489.1303. Found 489.1316.
CH2Cl2/hexanes); IR (film) 3313, 3262, 2101, 1963 cm21
;
1H NMR (400 MHz, CDCl3) d 7.51 (d, J¼7.6 Hz, 1H), 7.45
(d, J¼7.6 Hz, 1H), 7.37 (dd, J¼7.6, 7.4 Hz, 1H), 7.26 (dd,
J¼7.5, 7.4 Hz, 1H), 4.83 (s, 2H), 3.35 (s, 1H), 1.28 (br s,
1H); 13C NMR (100 MHz, CDCl3) ppm 143.5, 133.1, 129.5,
127.6, 127.5, 120.4, 82.2, 63.9, 30.0; HRMS (EI): exact
mass calcd for C9H8O [M]þ, 132.0575. Found 132.0580.
5.1.17. 1-[2-((1E-1-aza-2,2-diphenylvinyl)phenoxy)]-2-
bromoprop-2-ene (38). A mixture of ortho-aminophenol
(445 mg, 4.08 mmol) and benzophenone imine (739 mg,
4.08 mmol) in benzene (70 mL) was refluxed for 24 h under
a steady flow of nitrogen. The solvent was removed in vacuo
to give the analytically pure ketimine as a colorless oil
(1.00 g, 91%). Rf¼0.25 (5% EtOAc/hexanes); IR (film)
5.1.15. (2-Formyl-phenyl)-carbamic acid tert-butyl ester
(28). A THF solution (45 mL) of 2-aminobenzyl alcohol
(2.01 g, 16.3 mmol) and di-tert-butyl carbonate (3.7 g,
16.9 mmol) was stirred at 258C for 12 h. The solvent was
removed by vacuum and the residue purified by flash
chromatography (SiO2, 30% ethyl acetate in hexanes) to
give the carbamate as a yellow oil (3.3 g, 92%). Rf¼0.48
(40% EtOAc/hexanes); IR (film) 3358, 2979, 1729,
1
3460, 2980, 2116, 1672, 1291 cm21; H NMR (400 MHz,
CDCl3) d 7.78 (d, J¼7.1 Hz, 2H), 7.60 (d, J¼7.1 Hz, 1H),
7.52 (dd, J¼7.4, 4.2 Hz, 1H), 7.46–7.40 (m, 4H), 7.22 (dd,
J¼7.6, 1.3 Hz, 2H), 6.98 (d, J¼4.0 Hz, 2H), 6.50 (ddd,
J¼8.4, 4.0, 0.7 Hz, 1H), 6.23 (d, J¼7.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3) ppm 168.7, 151.9, 140.0, 136.6, 136.0,
1703 cm21
;
1H NMR (400 MHz, CDCl3) d 7.85 (d,
J¼8.1 Hz, 1H), 7.72 (br s, 1H), 7.29 (ddd, J¼8.7, 8.7,

8886
B. M. Nugent et al. / Tetrahedron 59 (2003) 8877–8888
132.8, 131.3, 130.6, 130.3, 129.7, 129.5, 129.3, 128.8,
128.6, 128.5, 127.0, 120.7, 119.4, 114.8; HRMS (EI): exact
mass calcd for C19H15NO [M]þ, 273.1154. Found 273.1162.
To a suspension of sodium hydride (33.2 mg, 1.39 mmol) in
THF (5.6 mL) at 2108C was added, while stirring
vigorously, a solution of the imino phenol (315 mg,
1.15 mmol) and 2,3-dibromopropene (143 mL, 1.38 mmol)
in THF (5.6 mL). After 10 min the mixture was warmed to
room temperature and stirred for and additional 12 h. The
reddish brown solution was then quenched with H2O
(0.3 mL), concentrated, redissolved in CH2Cl2 (15 mL)
and washed with H2O. The resulting product was dried
(Na2SO4), concentrated and purified by flash chromato-
graphy (SiO2, 10% ethyl acetate in hexanes) to furnish the
product as a reddish brown oil (428 mg, 95%). Rf¼0.48
(10% EtOAc/hexanes); IR (film) 3058, 2912, 1955, 1882,
1627, 1481 cm21; 1H NMR (400 MHz, CDCl3) d 7.79 (dd,
J¼8.2, 1.2 Hz, 2H), 7.75 (dd, J¼8.6, 1.5 Hz, 1H), 7.57 (tt,
J¼7.3, 2.5 Hz, 2H), 7.46 (dd, J¼8.0, 0.7 Hz, 4H), 7.38 (t,
J¼7.6 Hz, 1H), 7.22 (t, J¼7.0 Hz, 2H), 6.83 (dtd, J¼22.9,
8.2, 1.5 Hz, 1H), 6.69 (dt, J¼6.4, 1.6 Hz, 1H), 5.80 (dd,
J¼3.7, 1.5 Hz, 1H), 5.52 (dd, J¼3.7, 1.5 Hz, 1H), 4.46 (t,
J¼1.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) ppm 167.8,
137.8, 132.6, 131.0, 130.3, 129.6, 129.0, 128.5, 128.4,
127.9, 124.4, 121.9, 117.3, 113.9, 70.4; HRMS (EI): exact
mass calcd for C22H18BrNO [M]þ, 391.0572. Found
391.0585.
538C; Rf¼0.18 (20% EtOAc/hexanes); IR (film) 3063, 1729,
1631 cm21; 1H NMR (400 MHz, CDCl3) d 7.52 (dd, J¼7.1,
1.5 Hz, 2H), 7.42–7.40 (m, 1H), 7.39 (d, J¼7.9 Hz, 2H),
7.36–7.30 (m, 6H), 7.28 (d, J¼7.2 Hz, 2H), 7.23 (d,
J¼7.4 Hz, 2H), 5.95 (s, 1H), 5.68 (s, 1H), 4.11 (dd, J¼9.3,
1.3 Hz, 1H), 3.78 (dd, J¼18.2, 8.7 Hz, 1H), 3.25 (td, J¼9.5,
9.3 Hz, 1H), 2.35 (ddt, J¼12.9, 11.1, 9.3 Hz, 1H), 2.07 (dd,
J¼12.8, 8.8 Hz, 1H), 1.29 (s, 9H); 13C NMR (100 MHz,
CDCl3) ppm 188.7, 171.4, 166.5, 141.8, 139.6, 138.3,
130.7, 130.5, 130.3, 129.1, 128.9, 128.4, 128.2, 127.9,
127.8, 127.5, 92.0, 81.9, 65.7, 64.8, 32.4, 28.0; HRMS (CI,
CH4): exact mass calcd for C30H31NO3 [M]þ, 453.2304.
Found 453.2288.
5.4. General procedure for b-stannyl enamine acylations
The crude b-stannyl enamine was dissolved in tetrahydro-
furan and cooled to 08C. To this 0.1 M solution, an acid
chloride (1 equiv.) was added dropwise. After 30 min, the
solvent was removed to afford the acylated enamine
product. The crude mixture was then diluted with diethyl
ether and stirred at room temperature while a saturated
solution of KF was added. The mixture was allowed to stir
for 4–6 h. The organic layer was separated and the aqueous
layer was extracted with diethyl ether. The combined
organic layers were dried over MgSO4, filtered, and
concentrated in vacuo to afford the crude product, which
was purified by flash column chromatography on silica
gel.
5.2. General procedure for ketimine condensations
A rapidly stirred benzene solution of the amine (0.5 M),
˚
5.4.1. 1-[1-(Phenylethyl)pyrrolidin-2-ylidene]butan-2-
one (50b). Following the general procedure, to the b-
stannyl enamine (0.841 g, 1.77 mmol) in cold THF
(08C) propionyl chloride (0.163 g, 1.77 mmol) were added
and stirred for 30 min to give the vinylogous amide in
54% yield of a clear oil. Rf¼0.42 (10% acetone/CH2Cl2);
IR (film) 3060, 3029, 2973, 2874, 1641, 1545, 1482,
1418, 1290, 1199, 1137, 1028, 958, 895, 759, 700 cm21; 1H
NMR (400 MHz, CDCl3) d 7.38–7.23 (m, 5H), 5.22 (s, 1H),
4.97 (q, J¼6.9 Hz, 1H), 3.43–3.29 (m, 2H), 3.22 (ddd,
J¼16.9, 8.1, 8.1 Hz, 1H), 3.10 (ddd, J¼8.5, 8.5, 5.2 Hz,
1H), 2.31 (q, J¼7.5 Hz, 2H), 1.99–1.81 (m, 2H), 1.58 (d,
J¼6.9 Hz, 3H), 1.08 (t, J¼7.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) ppm 198.3, 165.2, 140.3, 128.9, 127.8,
126.8, 89.3, 53.1, 47.1, 36.6, 33.8, 21.1, 17.0, 10.1; HRMS
(EI): exact mass calcd for C16H21NO [M]þ 243.1623. Found
243.1624.
ketone (0.5 M), and 4 A MS (1:1 w/w) was stirred at 258C
until complete conversion was achieved, as evidenced by 1H
NMR. The mixture was filtered through a pad of Celite and
washed with Et2O or benzene. The solvent was removed in
vacuo to give the analytically pure ketimine which was used
immediately. The same procedure was used when the
benzophenone ketimine was desired, except benzophenone
imine27 was used in place of the ketone.
5.3. Representative procedure for radical cyclizations28
5.3.1. tert-Butyl-1-(diphenylmethyl)-5-methylenepyrroli-
dine-2-carboxylate (42b). To a solution of 19 (43 mg,
100 mmol) and nBu3SnH (59.5 mL, 221 mmol) in hot (858C)
benzene (9.2 mL) was added a solution of AIBN (13.2 mg,
80.4 mmol) in benzene (0.8 mL) over 4 h. Thirty minutes
n
into the addition period, an additional amount of Bu3SnH
(59.5 mL, 221 mmol) was added to the reaction mixture. The
solution was refluxed for 1 h following complete AIBN
addition and cooled to room temperature. The intermediate
enamine could be observed by 1H NMR spectroscopy after
solvent removal. 1H NMR (400 MHz, CDCl3) d 7.42–7.20
(m, 10H), 5.62 (s, 1H), 3.84 (dd, J¼8.7, 1.3 Hz, 1H), 3.59 (s,
1H), 3.26 (s, 1H), 2.78 (ddd, J¼7.9, 3.7, 1.9 Hz, 1H), 2.59
(dd, J¼14.2, 7.1 Hz, 1H), 1.83 (dd, J¼12.5, 8.2 Hz, 1H),
1.75 (s, 9H). The crude benzene solution was cooled to 5 8C
and treated with triethylamine (140 mL, 1 mmol) and
benzoyl chloride (60 mL, 500 mmol). The solution was
allowed to warm to room temperature over 2 h. The solvent
was removed and the residue subjected to flash chromato-
graphy (SiO2, 22% ethyl acetate in hexanes) to furnish the
vinylogous amide as a white solid (31.6 mg, 69%), mp 51–
5.4.2. 3-Methyl-1-[1-(1-phenylethyl)pyrrolidin-2-ylid-
ene]butan-2-one (50c). Following the general procedure,
to the b-stannyl enamine (0.858 g, 1.81 mmol) in cold THF
(08C) iosbutyryl chloride (0.191 g, 1.81 mmol) were added
and stirred for 30 min to give the vinylogous amide in 57%
yield of a yellow oil. Rf¼0.48 (10% acetone/CH2Cl2); IR
(film) 3050, 2963, 2932, 2867, 1641, 1543, 1482, 1290,
1177, 1077, 990, 841, 772, 699 cm21; 1H NMR (400 MHz,
CDCl3) d 7.39–7.24 (m, 5H), 5.22 (s, 1H), 4.97 (q,
J¼6.9 Hz, 1H), 3.42–3.30 (m, 2H), 3.24 (ddd, J¼16.8,
7.8, 7.8 Hz, 1H), 3.11 (ddd, J¼9.8, 8.3, 5.2 Hz, 1H) 2.49
(septet, J¼6.8 Hz, 1H), 1.99–1.81 (m, 2H), 1.59 (d,
J¼6.9 Hz, 3H), 1.08 (d, J¼6.8 Hz, 3H) 1.06 (d, J¼6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) ppm 201.8, 165.7, 140.4,
128.9, 127.8, 126.8, 88.5, 53.2, 47.2, 41.1, 33.9, 21.1, 20.1,

B. M. Nugent et al. / Tetrahedron 59 (2003) 8877–8888
8887
20.0, 17.0; HRMS (CI): exact mass calcd for C17H23NO
[M]þ 257.1780. Found 257. 1783.
CDCl3) d 7.39–7.23 (m, 5H), 5.19 (s, 1H), 4.98 (q,
J¼6.9 Hz, 1H), 3.86–3.76 (m, 2H), 3.44–3.33 (m, 2H),
3.24 (ddd, J¼16.8, 8.0, 8.0 Hz, 1H), 3.13 (ddd, J¼8.4, 8.4,
5.1 Hz, 1H), 2.77 (dd, J¼6.9, 6.9 Hz, 2H), 2.07–1.85
(m, 2H), 1.60 (d, J¼6.9 Hz, 3H); 13C NMR (ppm)
(100 MHz, CDCl3) 192.4, 166.3, 140.0, 129.0, 127.9,
126.8, 89.7, 53.4, 47.4, 45.9, 41.2, 34.1, 20.9, 17.0;
HRMS (CI): exact mass calcd for C16HClNO [M]þ
277.1233. Found 277.1230.
5.4.3. 2-Oxo-3-[1-(1-phenylethyl)pyrrolidin-2-ylidene]-
propionic acid methyl ester (50g). Following the general
procedure, to the b-stannyl enamine (0.985 g, 2.06 mmol)
in cold THF (08C) methyl chlorooxoacetate (0.19 mL,
2.06 mmol) were added and stirred for 30 min to give
the vinylogous amide in 36% yield of an off white solid,
mp 75–76.58C; Rf¼0.40 (100% ethyl acetate); IR (film)
3000, 2948, 1719, 1627, 1542, 1454, 1296, 1199, 1113,
1
1001, 787, 765, 700 cm21; H NMR (400 MHz, CDCl3) d
Acknowledgements
7.42–7.25 (m, 5H), 6.08 (s, 1H), 5.19 (q, J¼6.9 Hz, 1H),
3.82 (s, 3H), 3.64–3.40 (m, 2H), 3.34 (ddd, J¼16.4, 7.9,
7.9 Hz, 1H), 3.15 (ddd, J¼10.6, 8.4, 5.5 Hz, 1H), 2.02–1.88
(m, 2H), 1.63 (d, J¼6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) ppm 176.8, 170.3, 166.0, 139.0, 129.1, 126.9, 86.5,
53.8, 52.6, 48.0, 34.8, 20.5, 16.6; HRMS (CI): exact
mass calcd for C16H19NO3 [M]þ 273.1365. Found
273.1356.
This work was supported by NIGMS (GM-63577-01) and
the Yamanouchi USA Foundation. Gratitude is expressed to
Amgen and Boehringer-Ingelheim for Young Investigator
Awards (J. N. J.). E. N. P., B. M. N., and A. L. W. were
supported in part as Boehringer-Ingelheim postdoctoral,
Paget (2000), and GAANN fellows (1999–2001), respect-
ively. Kristen Nailor (an IU STARS undergraduate research
participant) is acknowledged for early contributions to this
work. Acknowledgment is also made to the Donors of the
Petroleum Research Fund, administered by the American
Chemical Society, for partial support of this research.
5.4.4. 1-[1-(1-Phenylethyl)pyrrolidin-2-ylidene]pent-3-
en-2-one (50h). Following the general procedure, to the
b-stannyl enamine (0.301 g, 0.629 mmol) in cold THF
(08C) crotonyl chloride (0.104 g, 0.629 mmol) were added
and stirred for 30 min to give the vinylogous amide in 28%
of a yellow oil. Rf¼0.15 (40% ethyl acetate/hexanes); IR
(film) 2974, 2933, 1661, 1607, 1538, 1481, 1291, 1137,
1082, 700 cm21; 1H NMR (400 MHz, CDCl3) d 7.39–7.24
(m, 5H), 6.71 (dq, J¼15.3, 7.1 Hz, 1H), 6.14 (d, J¼15.3 Hz,
1H), 5.27 (s, 1H), 5.02 (q, J¼6.9 Hz, 1H), 3.51–3.42 (m,
1H), 3.39–3.26 (m, 2H), 3.15–3.09 (m, 1H), 1.99–1.86 (m,
2H), 1.82 (d, J¼6.9 Hz, 3H), 1.60 (d, J¼7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) ppm 186.4, 166.7, 140.2, 136.2,
134.6, 128.9, 127.9, 126.8, 90.4, 53.3, 47.4, 34.2, 21.1, 18.1,
17.0; HRMS (CI): exact mass calcd for C17H21NO [M]þ
255.1623. Found 255.1613.
References
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5.4.5. 1-Chloro-3-[1-phenylethyl)pyrrolidin-2-ylidene]-
propan-2-one (50i). Following the general procedure, to
the b-stannyl enamine (0.147 g, 0.31 mmol) in cold THF
(08C) 2-chloroethynyl chloride (24 mL, 0.31 mmol) were
added and stirred for 30 min to give the vinylogous amide of
a light yellow oil. Rf¼0.68 (20% acetone/CH2Cl2); IR (film)
3060, 3029, 2978, 2938, 2877, 1629, 1582, 1481, 1454,
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1
1417, 1314, 1295, 1205, 1176, 1001, 759, 700 cm21; H
NMR (400 MHz, CDCl3) d 7.39–7.42 (m, 5H), 5.55 (s, 1H),
5.04 (q, J¼6.9 Hz, 1H), 3.97 (s, 2H), 3.44–3.36 (m, 2H),
3.25 (ddd, J¼16.6, 8.1, 8.1 Hz, 1H), 3.16 (ddd, J¼10.2, 8.5,
5.3 Hz, 1H), 2.08–1.84 (m, 2H), 1.61 (d, J¼6.9 Hz, 3H);
13C NMR (ppm) (100 MHz, CDCl3) ppm 188.0, 168.0,
139.6, 129.0, 128.1, 126.8, 86.0, 53.6, 48.8, 47.8, 34.3, 20.7,
16.9; HRMS (CI): exact mass calcd for C15H18ClNO [M]þ
263.1077. Found 263.1079.
7. Vinyl bromide coupling with resonance stabilized amines:
(a) Lam, P. Y. S.; Duedon, S.; Averill, K. M.; Li, R.; He, M. Y.;
DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600.
(b) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.;
Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415. (c) Lebedev,
A. Y.; Izmer, V. V.; Kazyul’kin, D. N.; Beletskaya, I. P.;
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´ ´
8. Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valdes, C. Chem.
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5.4.6. 4-Chloro-1-[1-(phenylethyl)pyrrolidin-2-ylidene]-
butan-2-one (50j). Following the general procedure, to the
b-stannyl enamine (0.645 g, 1.35 mmol) in cold THF (08C)
3-chloropropionyl chloride (0.172 g, 1.35 mmol) were
added and stirred for 30 min to give the vinylogous amide
in light yellow oil. Rf¼0.71 (20% acetone/CH2Cl2); IR
(film) 3040, 2975, 2876, 1634, 1540, 1481, 1495, 1452,
1293, 1177, 1048, 993, 758, 700 cm21; 1H NMR (400 MHz,
9. (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
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8888
B. M. Nugent et al. / Tetrahedron 59 (2003) 8877–8888
2123. (b) Tomaszewski, M. J.; Warkentin, J.; Werstiuk, N. H.
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