Further studies on vinamidinium salt amine exchange reactions, borohydride reductions, and subsequent transformations

Article abstract of DOI:10.1016/j.tet.2010.08.075

Studies directed at the amine exchange reaction of vinamidinium salts followed by sodium borohydride reduction to secondary and tertiary allylic amines are described. The tertiary allylic amines were alkylated and subjected to base mediated rearrangement to yield a variety of highly functionalized tertiary homoallylic amines.

Full text of DOI:10.1016/j.tet.2010.08.075

Tetrahedron 66 (2010) 8485e8493
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Further studies on vinamidinium salt amine exchange reactions, borohydride
reductions, and subsequent transformations
,
a
a
a
a
a
John T. Gupton a , Nakul Telang , Xin Jia , Benjamin C. Giglio , James E. Eaton , Peter J. Barelli ,
Mona Hovaizi a, Kayleigh E. Hall a, R. Scott Welden a, Matthew J. Keough a, Eric F. Worrall a, Kara L. Finzel a,
Emily J. Kluball a, Rene P.F. Kanters a, Timothy M. Smith a, Stanton Q. Smith b, Shane R. Nunes b,
Mathew T. Wright b, Jennifer M. Birnstihl c
*
a Department of Chemistry, University of Richmond, Richmond, VA 23173, USA
b Department of Chemistry, Virginia Military Institute, Lexington, VA 24450, USA
c Department of Chemistry, University of Central Florida, Orlando, FL 32816, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 July 2010
Received in revised form 30 August 2010
Accepted 31 August 2010
Available online 8 September 2010
Studies directed at the amine exchange reaction of vinamidinium salts followed by sodium borohydride
reduction to secondary and tertiary allylic amines are described. The tertiary allylic amines were alky-
lated and subjected to base mediated rearrangement to yield a variety of highly functionalized tertiary
homoallylic amines.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Vinamidinium salt
Allylic amine
Reduction
2,3-Sigmatropic rearrangement
1. Introduction
the respective vinamidinium salts are in the range of 60e90% and
such salts form very well defined solids and have a very good shelf
life. The preparation of these salts is normally accomplished by
We have previously reported1 the sodium borohydride re-
duction of 2-aryl-N,N,N,N-tetramethylvinamidinium salts (1) to
give 2-aryl-3-N,N-dimethylaminopropenes (5) in good yield. We
have suggested that the reaction proceeds according to the steps
presented in Scheme 1.
The reduction reaction gives extremely pure 2-aryl-N,N-dime-
thylallylic amines (5) from the 2-arylvinamidinium salts (1) and the
salts themselves are available2,3 in good yield from arylacetic acids
or arylacetic acid chlorides. Vinamidinium salts function as masked
1,3-dicarbonyl compounds and the 2-substituted systems can be
prepared in general from acetic acids or acetic acid chlorides that
have electron withdrawing groups or aromatic groups attached at
the alpha carbon. Davies3 and his group at Merck have recently
prepared such compounds on large scale as a result of their need for
significant amounts of a new class of COX-2 inhibitors. Some ex-
amples of successful alpha substituents on acetic acids are Cl,4 Br,4
F,4 CF3,5 NO2,3 phenyl,4 substituted phenyl,4 naphthyl,4 phenyl-
sulfonyl,6 benzotriazolyl,7 and carbethoxy.4 The isolated yields of
heating the respective acids under VilsmeiereHaack conditions
with
a mixture of DMF and phosphorous oxychloride and
quenching the reaction mixture with an aqueous solution of so-
dium hexafluorophosphate or similar salt. The formation of these
salts is presumed to proceed through a ketene4 type intermediate
and it is thought that electron withdrawing groups and aromatic
groups at the 2-position of the acetic acid facilitate ketene forma-
tion from the acid chloride precursor. For this reason, yields of
2-alkylvinamidinium salts3 by the indicated procedure are usually
quite low. The 1-substituted vinamidinium salts are available8 from
chloropropenimium salts but a large part of our focus has been to
examine the reactions of the 2-substitued systems as a conse-
quence of their ready availability and the often unique properties6
imparted by location of a particular substituent at the 2 position.
Allylic amines are known to be useful reagents9 and have
functioned as important building blocks in organic chemistry. Some
examples involve the cross-linking of proteins,10 rhodium catalyzed
ylide formation,11 directed metalation reactions12 and the prepa-
ration of GABA uptake inhibitors.13 The quaternary salts derived
from such amines can function as useful alkylating agents14,15 for
* Corresponding author. Tel.: þ1 804 287 6498; fax: þ1 804 287 1897; e-mail
address: jgupton@richmond.edu (J.T. Gupton).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.075

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J.T. Gupton et al. / Tetrahedron 66 (2010) 8485e8493
NaBH4
H
Ar Me
PF6
Me Ar Me
B
6
N
N
N
H
NMe2
+
Me
Me
Me
i-PrOH and heat
5
1
Ar Me
H
H
H
Me Ar Me
B
4
N
H3B
Me
Me
N
N
NMe2
Me
3
H
H
2
Scheme 1. Sodium borohydride reduction of vinamidinium salts.
a variety of nucleophilic species and when properly functionalized
can undergo base mediated 2,3-sigmatropic rearrangement to give
homoallylic amines.16 Jorgensen9 and Johannsen have recently
reviewed the preparation of allylic amines and have suggested that
the direct approach to such systems involves either (1) nucleophilic
substitution of an allylic halide or allylic halide equivalent with an
amine or (2) direct allylic amination of alkenes. The allylic sub-
stitution reaction occasionally suffers from over alkylation pro-
cesses and there are certainly regiochemical issues associated with
direct allylic amination of unsymmetrical alkenes. Since our pre-
viously demonstrated reduction chemistry had no such issues, we
decided to examine extending the generality of our reduction se-
quence (Scheme 1) to a variety of tertiary and secondary allylic
amine systems and thereby further define the scope and limitation
of this methodology.
With this strategy in mind, we have carried out amine exchange
reactions with the parent vinamidinium salt (1, Ar¼4-methoxy-
phenyl) with a variety of amines as presented in Table 1. The re-
action is carried out by heating excess primary or secondary amines
with the parent vinamidinium salt in methanol or ethanol for
several hours in which case dimethylamine gas is evolved and the
exchange reaction is driven to completion in very high yield with
excellent purity. Cyclic secondary amines in addition to acyclic
secondary amines work very well in the transformation and pri-
mary amine exchanged salts also undergo the process very effi-
ciently. In addition, we have examined several different aromatic
substituents on the vinamidinium salts (10jem in Table 1) and such
functional group changes do not impact the yield or purity of the
amine exchanged products.
Table 1
Amine exchange reactions of vinamidinium salts
2. Results and discussions
Amine
PF6
Me Ar Me
In order to make the conversion of vinamidinium salt to allylic
amine of greater utility, it is necessary to have access to vinamidi-
nium salts (1) with diverse amine functionality. It is known17 that
vinamidinium salts (1) can undergo amine exchange reactions and
we have previously used this concept for the preparation of
2,4-disubstitutedpyrroles2 (9) as depicted in Scheme 2.
PF6
Ar
10
N
N
Z
Z
Me
Me
MeOH or ETOH
and heat
1
Compound Amine group (Z)
Ar group
%Yield of
exchanged
salt (10)
10a
10b
10c
10d
10e
10f
10g
10h
10i
Pyrrolidinyl
Morpholinyl
Piperidinyl3
Diethylamino
Dipropylamino
Butylamino
Hexylamino
s-Butylamino
2,4-Dimethoxybenzylamino 4-Methoxyphenyl
Butylamino
Butylamino
Butylamino
Butylamino
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
99
99
89
96
93
71
97
50
50
98
H
Cl
N
H
CO2Et
Ar
Me
PF6
7
CO2Et
Me Ar Me
N
N
N
NaH, DMF and Heat
Me
Me
Me
9
1
80% yield
10j
10k
10l
4-Chlorophenyl
3,4-Dimethoxyphenyl 97
4-Methylphenyl
1-Naphthyl
97
97
10m
Ar Me
N
Me
With a variety of amine exchanged vinamidinium salts in hand,
these materials were subjected to sodium borohydride reduction in
refluxing isopropanol (Table 2) and the corresponding allylic
amines (11) were produced in very good yield with excellent purity.
It is interesting to note that the primary amine exchanged vina-
midinium salts underwent the reduction in an equally efficient
N
Me
CO2Et
8
Scheme 2. Preparation of 2,4-disubstitutedpyrroles from vinamidinium salts.

J.T. Gupton et al. / Tetrahedron 66 (2010) 8485e8493
8487
Table 2
Other types of allylic ammonium salts have been carefully
studied16 with regard to base mediated 2,3-sigmatropic rear-
rangements and we anticipated it would be useful to examine some
of our tertiary allylic amines in such an application (Table 3). The
pyrrolidine allylic amine (11a) was subsequently alkylated with
Sodium borohydride reduction of amine exchanged vinamidinium salts
Ar
NaBH4
PF6
Ar
Z
Z
ethyl a-bromoacetate in THF to yield the corresponding quaternary
Z
i-PrOH and heat
salt (17a) in good yield and high purity. This material (17a) was fully
characterized but, as was the case for all of our salts, the crude
product was nearly analytically pure and it was used immediately
in the rearrangement step after isolation by solvent removal. All of
quaternary salts (17aen) resulting from such alkylations were
treated with sodium hydride or sodium tert-butoxide in acetoni-
trile at room temperature and after work up very pure homoallylic
products (18) were obtained (Table 3). A variety of different aryl
group analogs (18beg) were prepared in this manner and it is
notable that these compounds represent some uniquely function-
10
11
Compound Amine group (Z)
Ar group
%Yield
of allylic
amine (11)
11a
11b
11c
11d
11e
11f
11g
11h
11i
Pyrrolidinyl
Morpholinyl13
Piperidinyl
Diethylamino
Dipropylamino
Butylamino
Hexylamino
s-Butylamino
2,4-Dimethoxybenzylamino 4-Methoxyphenyl
Butylamino
Butylamino
Butylamino
Butylamino
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
89
97
97
96
99
62
99
62
60
99
alized a-substituted amino acid esters (18beg).
With the indicated results in hand, we assumed that other alky-
lating agents could be utilized in this sequence if electron with-
drawing groups (EWG) were present in the alkylating agent.
11j
11k
11l
4-Chlorophenyl
3,4-Dimethoxyphenyl 99
4-Methylphenyl
1-Naphthyl
94
98
For example when
were employed as alkylating agents, uniquely functionalized
noketones (18jel) and -substituted benzylic amines (18men) were
a-haloacetophenones and nitrobenzyl halides
11m
a-ami-
a
obtained, respectively, in modest to reasonable yields.
manner (11fem, Table 2) as did the secondary amine exchanged
salts (11aee, Table 2) thereby making such secondary allylic amines
available by this route for the first time. The crude products were
nearly analytically pure and often utilized in subsequent reactions
without additional purification.
As was mentioned earlier, one of the very significant reactions of
tertiary allylic amines is conversion to quaternary ammonium salts,
which in turn can undergo a variety of useful reactions. We have
previously reported such reactions of 2-aryl-N,N-dimethylallylic
amines (5) and these are depicted in Scheme 3. Reduction of the
quaternary salts (12) to styrenes14 (13), Grignard alkylation to
highly functionalized styrenes14 (14) and enolate alkylations to
highly functionalized allylic systems15 (15) were accomplished in
good yield and in high purity.
3. Conclusions
We have described herein a very practical, efficient, and general
high yielding preparation of amine exchanged vinamidinium salts
(10) along with their reduction to the corresponding allylic amines
(11). Some of the tertiary allylic amines were treated with a variety
of electron deficient haloalkane derivatives and under basic con-
ditions the quaternary salts rearranged to uniquely functionalized
homoallylic systems (18). Such transformations continue to dem-
onstrate the general synthetic utility of vinamidinium salts and
their derivatives and offer an alternative to the traditional prepa-
ration of highly functionalized allylic amines.
4. Experimental
4.1. General
Ar
13
All chemicals were used as received from the manufacturer
(Aldrich Chemicals and Fisher Scientific). All solvents were dried
over 4 Å molecular sieves prior to their use. NMR spectra were
obtained on either a Bruker 300 MHz spectrometer, a Bruker
500 MHz spectrometer or a Varian Gemini 200 MHz spectrometer
in either CDCl3, DMSO-d6 or acetone-d6 solutions. IR spectra were
recorded on a Nicolet Avatar 320 FT-IR spectrometer with an HATR
attachment. High resolution mass spectra were provided on a Bio-
tof Q electrospray mass spectrometer at the University of Richmond
or by the Midwest Center for Mass Spectrometry at the University
of Nebraska at Lincoln. Low resolution GCeMS spectra were
obtained on a Shimadzu QP 5050 instrument. Melting points and
boiling points are uncorrected. Chromatographic separations were
carried out on a Harrison Chromatotron (equipped with a silica
plate) or Biotage SP-1 instrument (equipped with a silica cartridge)
and ethyl acetate/hexane was used as the eluant in both instances.
The reaction products were eluted within the range of 6e8 column
volumes of eluant with a gradient of 60e80% ethyl acetate in
hexane. TLC analyses were conducted on silica plates with hexane/
ethyl acetate as the eluant. Vinamidinium salts utilized for the
described studies were prepared according to standard
procedures.2e4 All purified reaction products gave TLC results,
GCeMS spectra, and 13C NMR spectra consistent with a sample
purity of >95%. When the preparation of an analytical sample is
NaBH4
Ar
Ar
Ar
MeI in THF at rt
PhMgCl
I
N Me
Me
NMe2
Me
12
Ph
14
5
Ph
CO2Et
NaH in CH3CN
Ar
Ph
CO2Et
15
Scheme 3. Reaction of quaternary salts with nucleophiles and reducing agents.

8488
J.T. Gupton et al. / Tetrahedron 66 (2010) 8485e8493
Table 3
Alkylation and rearrangement of tertiary allylic amines
EWG
X
Ar
Ar
Ar
NaH or NaOt-Bu
CH3CN at rt
16
THF at rt
X
Z
Z
EWG
Z
18
EWG
17
11
Compound
Amine group (Z)
Ar group
EWG
%Yield of rearranged
amine (18)
18a
18b
18c
18d
18e
18f
18g
18h
18i
18j
18k
18l
18m
18n
Pyrrolidinyl
4-Methoxyphenyl
4-Chlorophenyl
4-Methoxyphenyl
4-Bromophenyl
Phenyl
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
4-bromobenzoyl
Benzoyl
4-Nitrobenzoyl
2-Nitrophenyl
4-Nitrophenyl
83
90
54
70
67
62
72
40
20
49
76
82
21
53
Dimethylamino
Dimethylamino
Dimethylamino
Dimethylamino
Dimethylamino
Dimethylamino
Piperidinyl
Dipropylamino
Dimethylamino
Dimethylamino
Dimethylamino
Dimethylamino
Dimethylamino
3,4-Dimethoxyphenyl
Naphthyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
reported, the crude reaction product was of sufficient purity to be
used in subsequent steps without further purification.
28.8, 25.6, 23.5; IR (neat) 1561 cmꢂ1; HRMS (ES) m/z calcd for
C20H29N2O 313.2274, found 313.2296.
4.1.1. 1-(2-(4-Methoxyphenyl)-3-pyrrolidin-1-yl-allylidene)pyrrolidi-
nium hexafluorophosphate (10a). To a 100 mL round bottom flask
equipped with a magnetic stirring bar and reflux condenser, was
added 4-methoxyphenylvinamidinium salt (1, 1.00 g, 2.64 mmol),
pyrrolidine (1.12 g, 15.9 mmol), and 40 mL of anhydrous ethanol.
The resulting reaction mixture was refluxed for 24 h and then
cooled to room temperature at which point a solid precipitated. The
solid was vacuum filtered with a Buchner funnel and was washed
with 2ꢀ20 mL of cold ethanol. The resulting material was dried
using a Kugelrohr apparatus to give a light yellow solid (1.12 g, 99%
yield). The resulting solid exhibited the following physical prop-
4.1.4. N-(3-(Diethylamino)-2-(4-methoxyphenyl)allylidene)-N-ethyl-
ethanaminium hexafluorophosphate (10d). This compound was
prepared by the above procedure with the exception that diethyl-
amine was used in place of pyrrolidine in which case a 96% yield of
an orange solid was obtained. This material exhibited the following
physical properties: mp 105e107 ꢁC; 1H NMR (CDCl3)
d 0.87 (t,
J¼7.0 Hz, 6H), 1.33 (t, J¼7.0 Hz, 6H), 2.88 (q, J¼7.0 Hz, 4H), 3.49 (q,
J¼7.0 Hz, 4H), 3.87 (s, 3H), 6.95 (d, J¼6.5 Hz, 2H), 7.25 (d, J¼6.5 Hz,
2H), 7.64 (s, 2H); 13C NMR (CDCl3)
d 163.8, 160.3, 132.2, 124.3, 114.5,
105.0, 55.4, 53.2, 42.9, 14.3 and 13.2; IR (neat) 1570 cmꢂ1; HRMS
(ES) m/z calcd for C18H29N2O 289.2274, found 289.2338.
erties: mp 158e159 ꢁC; 1H NMR (CDCl3)
d 1.84 (m, 8H), 2.71 (t,
J¼6.0 Hz, 4H), 3.82 (t, J¼6.0 Hz, 4H), 3.87 (s, 3H), 6.89 (d, J¼8.5 Hz,
4.1.5. N-(3-(Dipropylamino)-2-(4-methoxyphenyl)allylidene)-N-pro-
pylpropan-1-aminium hexafluorophosphate (10e). This compound
was prepared by the above procedure with the exception that di-
propylaminewasused inplace of pyrrolidine inwhich casea 93% yield
of a solid was obtained. This material exhibited the following physical
2H), 7.18 (d, J¼8.5 Hz, 2H), 7.79 (s, 2H); 13C NMR (CDCl3)
d 160.1,
133.8, 124.4, 113.8, 113.3, 106.3, 56.5, 55.3, 49.3, 26.0, 23.7; IR (neat)
1572 cmꢂ1; HRMS (ES) m/z calcd for C18H25N2O 285.1961, found
285.1967.
properties: mp 95e97 ꢁC;1H NMR(CDCl3)
d
0.45(t, J¼7.5 Hz, 6H), 0.98
4.1.2. 1-(2-(4-Methoxyphenyl)-3-morpholinoallylidene)morpholin-
4-ium hexafluorophosphate (10b). This compound was prepared by
the above procedure with the exception that morpholine was used
in place of pyrrolidine in which case a 99% yield of a tan solid was
obtained. This material exhibited the following physical properties:
(t, J¼7.5Hz, 6H),1.35(m, 4H),1.71 (m, 4H), 2.71(t, J¼7.5Hz,4H), 3.41 (t,
J¼7.5 Hz, 4H), 3.87 (s, 3H), 6.98 (d, J¼8.0 Hz, 2H), 7.22 (d, J¼8.0 Hz, 2H),
7.65 (s, 2H); 13C NMR (CDCl3)
d 169.2, 160.3, 132.4, 124.1, 114.6, 104.8,
60.5, 55.6, 50.2, 22.2, 21.3, 10.6, and 10.5; IR (neat) 1565 cmꢂ1; HRMS
(ES) m/z calcd for C22H37N2O 345.2900, found 345.2960.
mp 194e197 ꢁC; 1H NMR (CDCl3)
d
2.97 (t, J¼5.0 Hz, 4H), 3.45 (t,
J¼5.0 Hz, 4H), 3.68 (t, J¼5.0 Hz, 4H), 3.84 (t, J¼5.0 Hz, 4H), 3.87 (s,
4.1.6. N-(3-(Butylamino)-2-(4-methoxyphenyl)allylidene)butan-1-
aminium hexafluorophosphate (10f). This compound was prepared
by the above procedure with the exception that butylamine was
used in place of pyrrolidine in which case a 71% yield of a solid was
obtained. This material exhibited the following physical properties:
3H), 6.98 (d, J¼4.0 Hz, 2H), 7.18 (d, J¼4.0 Hz, 2H), 7.70 (s, 2H); 13C
NMR (CDCl3) d 163.4, 160.5, 132.0, 123.9, 115.5, 104.8, 67.1, 65.7, 57.2,
55.4, 48.1; IR (neat) 1557 cmꢂ1
C18H25N2O3 317.1860, found 317.1876.
; HRMS (ES) m/z calcd for
mp 163e165 ꢁC; 1H NMR (CDCl3)
d
0.94 (t, J¼7.5 Hz, 6H), 1.34 (m,
4.1.3. 1-(2-(4-Methoxyphenyl)-3-piperidin-1-yl-allylidene)piper-
idinium hexafluorophosphate (10c)3. This compound was prepared
by the above procedure with the exception that piperidine was
used in place of pyrrolidine in which case a 89% yield of a brown
solid was obtained. This material exhibited the following physical
4H), 1.58 (m, 4H), 3.49 (q, J¼7.0 Hz, 4H), 3.89 (s, 3H), 6.11 (br s, 2H),
7.13 (d, J¼5.5 Hz, 2H), 7.14 (d, J¼5.5 Hz, 2H), 7.96 (d, J¼15.0 Hz, 2H);
13C NMR (CDCl3)
d 162.9, 160.7, 131.2, 119.4, 116.6, 107.1, 55.5, 49.6,
32.0, 19.4, and 13.5; IR (neat) 1584 cmꢂ1; HRMS (ES) m/z calcd for
C18H29N2O 289.2274, found 289.2301.
properties: mp 235e238 ꢁC; 1H NMR (CDCl3)
d 1.34 (m, 4H),1.61 (m,
4H), 1.78 (m, 4H), 2.88 (t, J¼6.0 Hz, 4H), 3.59 (t, J¼6.0 Hz, 4H), 3.87
4.1.7. N-(3-(Hexylamino)-2-(4-methoxyphenyl)allylidene)hexan-1-
aminium hexafluorophosphate (10g). This compound was prepared
by the above procedure with the exception that hexylamine was
(s, 3H), 6.98 (d, J¼7.0 Hz, 2H), 7.16 (d, J¼7.0 Hz, 2H), 7.60 (s, 2H); 13C
NMR (CDCl3) d 162.6, 160.2, 131.7, 125.0, 115.1, 103.9, 59.2, 55.4, 48.2,

J.T. Gupton et al. / Tetrahedron 66 (2010) 8485e8493
8489
used in place of pyrrolidine in which case a 97% yield of a solid was
obtained. This material exhibited the following physical properties:
used in place of the 4-methoxy-phenylvinamidinium salt in which
case a 97% yield of a solid was obtained. This material exhibited the
following physical properties: mp 133e135 ꢁC; 1H NMR (CDCl3)
mp 173e176 ꢁC; 1H NMR (CDCl3)
d
0.86 (t, J¼6.6 Hz, 6H), 1.26 (br s,
12H), 1.58 (t, J¼7.2 Hz, 4H), 3.44 (t, J¼7.2 Hz, 4H), 3.83 (s, 3H), 6.40
d
0.93 (t, J¼7.5 Hz, 6H), 1.33 (m, 4H), 1.57 (m, 4H), 2.43 (s, 3H), 3.47
(br s, 2H), 7.07 (d, J¼9.0 Hz, 2H), 7.13 (d, J¼9.0 Hz, 2H), and 7.80 (br s,
(t, J¼7.5 Hz, 4H), 7.10 (d, J¼8.1 Hz, 2H), 7.39 (d, J¼8.1 Hz, 2H), and
2H); 13C NMR (CDCl3)
d
162.6, 160.6, 131.1, 119.3, 116.5, 107.2, 55.4,
7.90 (s, 2H); 13C NMR (CDCl3)
d 162.5, 140.0,131.7,129.5, 124.7,107.4,
49.9, 31.1, 30.0, 25.8, 22.4, and 13.8; IR (neat) 1602 cmꢂ1; HRMS (ES)
49.6, 32.0, 21.2, 19.4, and 13.4; IR (neat) 1600 cmꢂ1; HRMS (ES) m/z
m/z calcd for C22H37N2O 345.2900, found 345.2935.
calcd for C18H29N2 273.2325, found 273.2334.
4.1.8. N-(3-(sec-Butylamino)-2-(4-methoxyphenyl)allylidene)butan-
2-aminium hexafluorophosphate (10h). This compound was pre-
pared by the above procedure with the exception that sec-butyl-
amine was used in place of pyrrolidine in which case a 50% yield of
a solid was obtained after flash chromatography. This material
exhibited the following physical properties: mp 142e144 ꢁC; 1H
4.1.13. N-(3-(Butylamino)-2-(naphthalen-1-yl)allylidene)butan-1-
aminium hexafluorophosphate (10m). This compound was prepared
by the above procedure with the exception that butylamine was
used in place of pyrrolidine and the 2-naphthylvinamidinium salt
was used in place of the 4-methoxyphenylvinamidinium salt in
which case a 97% yield of a solid was obtained. This material
exhibited the following physical properties: mp 176e178 ꢁC; 1H
NMR (CDCl3)
d
0.93 (t, J¼7.5 Hz, 6H), 1.28 (d, J¼5.5 Hz, 6H), 1.54 (m,
4H), 3.64 (m, 2H), 3.90 (s, 3H), 5.86 (br s, 2H), 7.13 (s, 4H), and 8.07
NMR (CDCl3)
d
0.87 (t, J¼7.5 Hz, 6H), 1.25 (sextet, J¼7.5 Hz, 4H), 1.50
(d, J¼15.5 Hz, 2H); 13C NMR (CDCl3)
d
161.3,160.4, 131.0, 119.6,116.5,
(quintet, J¼7.5 Hz, 4H), 3.42 (t, J¼7.5 Hz, 4H), 7.43 (dd, J¼1.2, 6.9 Hz,
106.9, 57.8, 55.3, 29.6, 20.3, and 10.1; IR (neat) 1585 cmꢂ1; HRMS
1H), 7.58e7.69 (m, 4H), 7.98e8.01 (m, 2H), and 8.12 (br s, 2H); 13C
(ES) m/z calcd for C18H29N2O 289.2274, found 289.2258.
NMR (CDCl3) d 163.0, 134.6, 130.8, 130.5, 129.8, 129.3, 127.8, 127.2,
126.8, 124.7, 123.7, 104.9, 49.7, 31.9, 19.3, and 13.4; IR (neat)
1604 cmꢂ1; HRMS (ES) m/z calcd for C21H29N2 309.2325, found
309.2440.
4.1.9. N-(3-(2,4-Dimethoxybenzyl)amino)-2-(4-(methoxyphenyl)allyli-
dene)-1-(20,4-dimethoxyphenyl)methanaminium hexafluorophosphate
(10i). This compound was prepared by the above procedure with the
exception that 2,4-dimethoxybenzylamine was used in place of
pyrrolidine in which case a 50% yield of a solid was obtained after
flash chromatography. This material exhibited the following physical
4.1.14. 1-(2-(4-Methoxyphenyl)allyl)pyrrolidine (11a). To a 100 mL
round bottom flask equipped with a magnetic stir bar and con-
denser was added the amine exchanged vinamidinium salt (10a)
(1.00 g, 2.64 mmol), sodium borohydride (0.300 g, 7.93 mmol), and
50 mL of anhydrous isopropanol. The resulting reaction mixture
was refluxed for 24 h, allowed to cool to room temperature and was
concentrated in vacuo. The crude residue was diluted with 100 mL
of ethyl acetate and the organic layer was washed with water
(3ꢀ50 mL) and brine (2ꢀ50 mL). The organic phase was dried over
anhydrous Na2SO4 and was filtered and concentrated in vacuo to
give a viscous oil. This material was subjected to flash chromato-
graphic purification on a silica column using a Biotage SP-1 in-
strument and a hexane/ethyl acetate gradient in which case 0.510 g
(89% yield) of an oil was obtained. This material exhibited the fol-
lowing physical properties: bp 148e150 ꢁC at 1.6 Torr; 1H NMR
properties: mp 70e72 ꢁC; 1H NMR (CDCl3)
d 3.76 (s, 6H), 3.82 (s, 6H),
3.86 (s, 3H), 4.53 (s, 4H), 6.44 (br s, 2H), 6.47 (dd, J¼2.0, 8.5 Hz, 2H),
7.19 (d, J¼8.5 Hz, 2H), 8.05 (br s, 2H); 13C NMR (CDCl3)
d 162.1, 161.6,
160.4, 158.5, 131.1, 130.8, 119.9, 116.1, 115.8, 106.7, 104.6, 98.7, 60.4,
55.4, 53.5, 49.7; IR (neat) 1584 cmꢂ1; HRMS (ES) m/z calcd for
C28H33N2O5 477.2384, found 477.2341.
4.1.10. N-(3-(Butylamino)-2-(4-chlorophenyl)allylidene)butan-1-
aminium hexafluorophosphate (10j). This compound was prepared
by the above procedure with the exception that butylamine was
used in place of pyrrolidine and the 4-chorophenylvinamidinium
salt was used in place of the 4-methoxyphenylvinamidinium salt in
which case a 98% yield of a solid was obtained. This material
exhibited the following physical properties: mp 156e158 ꢁC; 1H
(CDCl3)
5.19 (s, 1H), 5.36 (s, 1H), 6.88 (d, J¼8.5 Hz, 2H), and 7.49 (d, J¼8.5 Hz,
2H); 13C NMR (CDCl3)
159.0, 145.1, 133.1, 127.3, 113.6, 112.7, 61.0,
d 1.78 (br s, 4H), 2.55 (br s, 4H), 3.46 (br s, 2H), 3.83 (s, 3H),
NMR (CDCl3)
d
0.92 (t, J¼7.5 Hz, 6H), 1.33 (m, 4H), 1.60 (m, 4H), 3.47
d
(br s, 4H), 6.42 (br s, 2H), 7.19 (d, J¼6.5 Hz, 2H), 7.54 (d, J¼6.5 Hz, 2H),
55.2, 54.2 and 23.6; HRMS (ES) m/z calcd for C14H20NO 218.1539,
found 218.1550.
and 7.81 (d, J¼14.5 Hz, 2H); 13C NMR (CDCl3)
d
162.5, 135.8, 131.3,
131.2, 126.3, 106.0, 49.9, 31.9, 19.4, and 13.4; IR (neat) 1602 cmꢂ1
;
HRMS (ES) m/z calcd for C17H26ClN2 293.1779, found 293.1790.
4.1.15. 1-(2-(4-Methoxyphenyl)allyl)morpholine (11b)13. This com-
pound was prepared according to the previous procedure with the
exception that amine exchanged vinamidinium salt 10b was used.
Chromatographic purification of the crude reaction product resul-
ted in a 97% yield of a viscous oil, which exhibited the following
physical properties: bp 85e86 ꢁC at 0.19 Torr; 1H NMR (CDCl3)
4.1.11. N-(3-(Butylamino)-2-(3,4-dimethoxyphenyl)allylidene)butan-
1-aminium hexafluorophosphate (10k). This compound was pre-
pared by the above procedure with the exception that butylamine
was used in place of pyrrolidine and the 3,4-dimethoxy-
phenylvinamidinium salt was used in place of the 4-methoxy-
phenylvinamidinium salt in which case a 97% yield of a solid was
obtained. This material exhibited the following physical properties:
d
2.50 (br s, 4H), 3.34 (br s, 2H), 3.71 (t, J¼5.0 Hz, 4H), 3.84 (s, 3H),
5.18 (s, 1H), 5.44 (s, 1H), 6.88 (d, J¼9.0 Hz, 2H), and 7.52 (d, J¼9.0 Hz,
2H); 13C NMR (CDCl3)
164.6, 148.5, 137.5, 132.6, 118.6, 118.3, 71.8,
d
mp 115e117 ꢁC; 1H NMR (CDCl3)
d
0.94 (t, J¼7.2 Hz, 6H),1.34 (sextet,
68.6, 59.8, and 58.7; HRMS (ES) m/z calcd for C14H20NO2 234.1489,
found 234.1498.
J¼7.2 Hz, 4H), 1.60 (q, J¼7.2 Hz, 4H), 3.50 (t, J¼7.2 Hz, 4H), 3.90 (s,
3H), 3.94 (s, 3H), 6.68 (d, J¼1.8 Hz, 1H), 6.76 (dd, J¼1.8, 8.1 Hz, 1H),
7.05 (d, J¼8.1 Hz, 1H), and 7.92 (b s, 2H); 13C NMR (CDCl3)
d
162.6,
4.1.16. 1-(2-(4-Methoxyphenyl)allyl)piperidine (11c). This com-
pound was prepared according to the previous procedure with the
exception that amine exchanged vinamidinium salt 10c was used.
Chromatographic purification of the crude reaction product resul-
ted in a 97% yield of a viscous oil, which exhibited the following
150.5, 149.8, 122.6, 120.1, 113.2, 112.3, 107.2, 55.9, 55.8, 49.6, 31.9,
19.4, and 13.4; IR (neat) 1598 cmꢂ1; HRMS (ES) m/z calcd for
C19H31N2O2 319.2380, found 319.2389.
4.1.12. N-(3-(Butylamino)-2-(p-tolyl)allylidene)butan-1-aminium
hexafluorophosphate (10l). This compound was prepared by the
above procedure with the exception that butylamine was used in
place of pyrrolidine and the 4-methylphenylvinamidinium salt was
physical properties: bp 95e96 ꢁC at 0.2 Torr; 1H NMR (CDCl3)
d 1.45
(m, 2H), 1.57 (m, 4H), 2.42 (broad absorption, 4H), 3.28 (s, 2H), 3.10
(s, 3H), 5.16 (s, 1H), 5.39 (s, 1H), 6.87 (d, J¼9.0 Hz, 2H), and 7.51 (d,
J¼9.0 Hz, 2H); 13C NMR (CDCl3)
d 159.1, 143.9, 133.3, 127.5, 113.5,

8490
J.T. Gupton et al. / Tetrahedron 66 (2010) 8485e8493
113.3, 64.0, 55.2, 54.6, 26.1, and 24.6; HRMS (ES) m/z calcd for
C15H22NO 232.1696, found 232.1717.
procedure with the exception that amine exchanged vinamidinium
salt 10i was used. Chromatographic purification of the crude re-
action product resulted in a 60% yield of a viscous oil, which
exhibited the following physical properties: bp 128e129 ꢁC at
4.1.17. Diethyl-[2-(4-methoxyphenyl)-allyl]amine (11d). This com-
pound was prepared according to the previous procedure with the
exception that amine exchanged vinamidinium salt 10d was used.
Chromatographic purification of the crude reaction product resulted
in a 96% yield of a viscous oil, which exhibited the following physical
0.81 Torr; 1H NMR (CDCl3)
d 3.59 (s, 3H), 3.81 (s, 3H), 3.84 (s, 2H),
3.86 (s, 3H), 4.10 (s, 2H), 6.41 (d, J¼2.5 Hz, 1H), 6.47 (dd, J¼2.5,
8.0 Hz, 1H), 6.96 (d, J¼8.5 Hz, 2H), 7.15 (d, J¼8.0 Hz, 1H), and 7.32 (d,
J¼8.0 Hz, 2H); 13C NMR (CDCl3)
d 162.4, 160.3, 158.6, 138.1, 132.2,
properties: bp 72e73 ꢁC at 0.37 Torr; 1H NMR (CDCl3)
d
1.04 (t,
128.3, 127.4, 119.1, 114.6, 110.5, 105.1, 98.4, 60.5, 55.4, 55.2, 50.5, and
47.8; IR (neat) 3228 cmꢂ1; HRMS (ES) m/z calcd for C19H24NO3
314.1751, found 314.1747.
J¼7.0 Hz, 6H), 2.57 (q, J¼7.0 Hz, 4H), 3.42 (s, 2H), 3.83 (s, 3H), 5.22 (s,
1H), 5.38(s,1H), 6.88 (d, J¼6.5 Hz, 2H), 7.49 (d, J¼6.5 Hz, 2H);13C NMR
(CDCl3)d159.1,145.2,133.2,127.5,113.5,113.3,57.9, 55.2, 46.8and11.5;
HRMS (ES) m/z calcd for C14H22NO 220.1696, found 220.1714.
4.1.23. n-Butyl-[2-(4-chlorophenyl)-allyl]amine (11j). This com-
pound was prepared according to the previous procedure with
the exception that amine exchanged vinamidinium salt 10j was
used. Chromatographic purification of the crude reaction product
resulted in a 99% yield of a viscous oil, which exhibited the fol-
lowing physical properties: bp 72e73 ꢁC at 0.25 Torr; 1H NMR
4.1.18. Dipropyl-[2-(4-methoxyphenyl)-allyl]amine (11e). This com-
pound was prepared according to the previous procedure with the
exception that amine exchanged vinamidinium salt 10e was used.
Chromatographic purification of the crude reaction product resul-
ted in a 99% yield of a viscous oil, which exhibited the following
physical properties: bp 80e81 ꢁC at 0.12 Torr; 1H NMR (CDCl3)
(CDCl3)
d
0.91 (t, J¼11.0 Hz, 3H), 1.33 (m, 2H), 1.46 (sextet,
J¼7.0 Hz, 2H), 2.62 (t, J¼7.0 Hz, 2H), 3.63 (s, 2H), 5.26 (s, 1H), 5.39
d
0.87 (t, J¼7.5 Hz, 6H), 1.5 (sextet, J¼7.5 Hz, 4H), 2.43 (t, J¼7.5 Hz,
(s, 1H), 7.30 (d, J¼11.0 Hz, 2H), and 7.38 (d, J¼11.0 Hz, 2H); 13C
4H), 3.42 (s, 2H), 3.85 (s, 3H), 5.24 (s, 1H), 5.39 (s, 1H), 6.89 (d,
NMR (CDCl3) d 145.2, 138.3, 133.4, 128.5, 127.5, 113.9, 53.3, 48.9,
J¼8.5 Hz, 2H), and 7.51 (d, J¼8.5 Hz, 2H); 13C NMR (CDCl3)
d
159.1,
31.9, 20.4, and 13.9; HRMS (ES) m/z calcd for C13H19ClN 224.1201,
found 224.1204.
145.5, 133.2, 127.6, 113.4, 113.1, 59.5, 55.9, 55.2, 20.1 and 11.9; HRMS
(ES) m/z calcd for C16H26NO 248.2009, found 248.1973.
4.1.24. n-Butyl-[2-(3,4-dimethoxyphenyl)-allyl]amine
(11k). This
4.1.19. n-Butyl-[2-(4-methoxyphenyl)-allyl]amine (11f). This com-
pound was prepared according to the previous procedure with the
exception that amine exchanged vinamidinium salt 10f was used.
Chromatographic purification of the crude reaction product resulted
in a 62% yield of a solid, which exhibited the following physical
compound was prepared according to the previous procedure with
the exception that amine exchanged vinamidinium salt 10k was
used. Chromatographic purification of the crude reaction product
resulted in a 99% yield of a viscous oil, which exhibited the fol-
lowing physical properties: bp 82e83 ꢁC at 0.58 Torr; 1H NMR
properties: mp 140e145 ꢁC; 1H NMR (CDCl3)
d
0.89 (t, J¼7.5 Hz, 3H),
(CDCl3)
d
0.87 (t, J¼7.2 Hz, 3H), 1.28 (m, 2H), 1.47 (quintet, J¼7.2 Hz,
1.28 (m, 2H),1.63 (quintet, J¼7.5 Hz, 2H), 2.98 (t, J¼7.5 Hz, 2H), 3.85 (s,
2H), 2.67 (t, J¼7.2 Hz, 2H), 3.70 (s, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 5.21
3H), 4.20 (s, 2H), 5.47 (s, 1H), 5.64 (s, 1H), 6.98 (d, J¼8.4 Hz, 2H), and
(s, 1H), 5.37 (s, 1H), 6.82 (d, J¼9.0 Hz, 1H), and 6.96 (m, 2H); 13C
7.37 (d, J¼8.4 Hz, 2H); 13C NMR (CDCl3)
d
162.6, 160.5, 131.5, 119.5,
NMR (CDCl3) d 149.1, 149.0, 144.3, 132.0, 118.5, 113.7, 111.2, 109.6,
116.4,107.1, 55.4, 49.6, 32.0,19.4, and 13.4;IR(neat) 3258cmꢂ1; HRMS
55.9, 53.0, 48.5, 31.1, 20.2, and 13.8; HRMS (ES) m/z calcd for
(ES) m/z calcd for C14H22NO 220.1696, found 220.1714.
C15H24NO2 250.1802, found 250.1807.
4.1.20. n-Hexyl-[2-(4-methoxyphenyl)-allyl]amine (11g). This com-
pound was prepared according to the previous procedure with the
exception that amine exchanged vinamidinium salt 10g was used.
Chromatographic purification of the crude reaction product resul-
ted in a 99% yield of a viscous oil, which exhibited the following
physical properties: bp 68e69 ꢁC at 0.83 Torr; 1H NMR (CDCl3)
4.1.25. n-Butyl-[2-(4-methylphenyl)-allyl]amine (11l). This com-
pound was prepared according to the previous procedure with the
exception that amine exchanged vinamidinium salt 10l was used.
Chromatographic purification of the crude reaction product resul-
ted in a 94% yield of a viscous oil, which exhibited the following
physical properties: bp 82e83 ꢁC at 0.48 Torr; 1H NMR (CDCl3)
d
0.87 (t, J¼6.9 Hz, 3H), 1.25 (br s, 6H), 1.49 (m, 2H), 2.71 (t, J¼7.5 Hz,
d
0.90 (t, J¼7.5 Hz, 3H), 1.35 (sextet, J¼7.5 Hz, 2H), 1.48 (quintet,
2H), 3.79 (s, 2H), 3.81 (s, 3H), 5.25 (s, 1H), 5.43 (s, 1H), 6.89 (d,
J¼7.5 Hz, 2H), 2.32 (s, 3H), 2.64 (t, J¼7.5 Hz, 2H), 3.67 (s, 2H), 3.80 (s,
1H), 5.22 (s, 1H), 5.39 (s, 1H), 7.17 (d, J¼8.0 Hz, 2H), 7.36 (d, J¼8.0 Hz,
J¼9.0 Hz, 2H), and 7.35 (d, J¼9.0 Hz, 2H); 13C NMR (CDCl3)
d 159.8,
142.5, 130.7, 127.3, 114.8, 114.3, 55.3, 52.4, 48.4, 31.4, 28.2, 26.5, 24.4,
and 13.9; IR (neat) 3200 cmꢂ1; HRMS (ES) m/z calcd for C16H26NO
248.2014, found 248.2080.
2H); 13C NMR (CDCl3)
d 146.8, 137.4, 136.9, 128.8, 126.0, 111.3, 53.3,
48.7, 32.1, 20.2, and 13.4; IR (neat) 3262 cmꢂ1; HRMS (ES) m/z calcd
for C14H22N 204.1747, found 204.1736.
4.1.21. s-Butyl-[2-(4-methoxyphenyl)-allyl]amine (11h). This com-
pound was prepared according to the previous procedure with the
exception that amine exchanged vinamidinium salt 10h was used.
Chromatographic purification of the crude reaction product resul-
ted in a 62% yield of a viscous oil, which exhibited the following
physical properties: bp 78e79 ꢁC at 0.23 Torr; 1H NMR (CDCl3)
4.1.26. n-Butyl-(2-naphthalen-1-yl-allyl)amine (11m). This com-
pound was prepared according to the previous procedure with the
exception that amine exchanged vinamidinium salt 10m was used.
Chromatographic purification of the crude reaction product resul-
ted in a 98% yield of a viscous oil, which exhibited the following
physical properties: bp 82e83 ꢁC at 0.24 Torr; 1H NMR (CDCl3)
d
0.84 (t, J¼4.5 Hz, 3H), 1.29 (d, J¼3.9 Hz, 3H), 1.56 (m, 1H), 1.68 (m,
d
0.90 (t, J¼7.2 Hz, 3H), 1.34 (m, 2H), 1.46 (m, 2H), 2.71 (t, J¼7.2 Hz,
1H), 3.00 (m, 1H), 3.86 (s, 3H), 4.04 (d, J¼14.4 Hz, 1H), 4.18 (d,
J¼14.4 Hz, 1H), 5.43 (s, 1H), 5.58 (s, 1H), 6.97 (d, J¼8.7 Hz, 2H), and
2H), 3.69 (s, 2H), 5.27 (s, 1H), 5.62 (s, 1H), 7.33 (d, J¼6.9 Hz, 1H),
7.44e7.52 (m, 3H), 7.81 (d, J¼8.1 Hz, 1H), 7.86e7.89 (m, 1H), and
7.38 (d, J¼8.7 Hz, 2H); 13C NMR (CDCl3)
d
160.4, 138.2, 128.4, 127.5,
8.05 (m, 1H); 13C NMR (CDCl3)
d 145.7, 139.1, 133.8, 131.4, 128.4,
119.2,114.9, 56.0, 55.4, 49.0, 26.2, 15.7, and 9.4; IR (neat) 3227 cmꢂ1
;
127.7, 126.1, 125.4, 125.3, 116.7, 55.4, 48.7, 31.6, 20.4, and 13.9; HRMS
HRMS (ES) m/z calcd for C14H22NO 220.1696, found 220.1730.
(ES) m/z calcd for C17H22N 240.1747, found 240.1789.
4.1.22. (2,4-Dimethoxybenzyl)-[2-(4-methoxyphenyl)-allyl]amine
4.1.27. 1-Ethoxycarbonylmethyl-1-[2-(4-methoxyphenyl)-allyl]pyr-
(11i). This compound was prepared according to the previous
rolidinium bromide (17a). To a round bottom flask equipped with

J.T. Gupton et al. / Tetrahedron 66 (2010) 8485e8493
8491
a
magnetic stir bar was added allylic amine 11a (0.250 g,
128.1, 116.0, 66.5, 60.4, 41.9, 36.2, and 14.6; IR (neat) 1726 cmꢂ1
;
1.15 mmol), 10 mL of THF, and 0.992 g (1.15 mmol) of ethyl
bromoacetate. The reaction mixture was stirred overnight at room
temperature and the solvent was then removed in vacuo leaving
0.376 g (85% yield) of a light yellow solid, which exhibited the
following physical properties: mp 134e136 ꢁC; 1H NMR (CDCl3)
HRMS (ES) m/z calcd for C15H21ClNO2 282.1253, found 282.1255.
4.1.30. 4-(4-Methoxyphenyl)-2-dimethylaminopent-4-enoic
acid
ethyl ester (18c). This compound was prepared according to the
previous procedure with the exception that 2-(4-methoxyphenyl)-3-
(N,N-dimethylamino)-1-propene1 was used as the allylic amine
substrate.Chromatographicpurificationofthecrudereactionproduct
resulted in a 54% yield of a viscous oil, which exhibited the following
d
1.24 (t, J¼7.0 Hz, 3H), 2.20 (m, 2H), 2.31 (m, 2H), 3.84 (s, 3H), 4.03
(m, 2H), 4.14 (q, J¼7.0 Hz, 2H), 4.51 (s, 1H), 4.82 (s, 1H), 6.94 (d,
J¼8.5 Hz, 2H), and 7.37 (d, J¼8.5 Hz, 2H); 13C NMR (CDCl3)
d 165.1,
160.2, 137.9, 130.7, 127.9, 127.1, 114.6, 63.6, 62.6, 62.5, 58.3, 21.3,
and 13.7; HRMS (ES) m/z calcd for C18H26NO3 304.1907, found
304.1964.
physicalproperties:bp89e90ꢁC at0.13Torr; 1HNMR (CDCl3)
d1.19(t,
J¼7.1 Hz, 3H), 2.32 (s, 6H), 2.79 (dd, J¼5.7,14.0 Hz,1H), 2.90 (dd, J¼9.0,
14.0 Hz, 1H), 3.22 (dd, J¼5.7, 9.0 Hz,1H), 3.78 (s, 3H), 4.07 (q, J¼7.1 Hz,
2H), 5.01 (s, 1H), 5.20 (s, 1H), 6.83 (d, J¼8.9 Hz, 2H), and 7.31 (d,
4.1.28. 4-(4-Methoxyphenyl)-2-pyrrolidin-1-yl-pent-4-enoic
acid
J¼8.9 Hz, 2H); 13C NMR (CDCl3)
d 172.2,159.8,144.7,133.4,127.8,114.2,
ethyl ester (18a). To a 100 mL round bottom flask equipped with
a magnetic stir bar and condensor was added 0.029 g (1.18 mmol)
of sodium hydride, and 30 mL of anhydrous acetonitrile. tert-
Butanol (0.197 g 2.34 mmol) was added to the flask and the
resulting mixture was allowed to react until gas evolution was no
longer observed. Quaternary salt 17a (0.351 g, 0.913 mmol) was
added to the reaction mixture and the resulting solution was
allowed to stir overnight. The reaction mixture was quenched
with several mL of ethanol and the solvent was removed from the
reaction mixture in vacuo. The resulting residue was dissolved in
ethyl acetate (30 mL) and the ethyl acetate phase was then
extracted with water (2ꢀ30 mL) and brine (2ꢀ30 mL) and dried
over anhydrous sodium sulfate. After the ethyl acetate phase was
filtered and concentrated in vacuo, the resulting residue was
subjected to flash chromatographic purification on a silica column
using a Biotage SP-1 instrument and a hexane/ethyl acetate gra-
dient in which case 0.270 g (98% yield) of an oil was obtained. This
material exhibited the following physical properties: bp 95e96 ꢁC
114.0, 66.8, 60.4, 55.6, 42.1, 36.3, and 14.6; IR (neat) 1726 cmꢂ1; HRMS
(ES) m/z calcd for C16H24NO3 278.1751, found 278.1734.
4.1.31. 4-(4-Bromophenyl)-2-dimethylaminopent-4-enoic acid ethyl
ester (18d). This compound was prepared according to the previous
procedure with the exception that 2-(4-bromophenyl)-3-(N,N-
dimethylamino)-1-propene1 was used as the allylic amine substrate.
Chromatographic purification of the crude reaction product resulted
in a 70% yield of a viscous oil, which exhibited the following physical
properties: bp 98e99 ꢁC at 0.40 Torr; 1H NMR (CDCl3)
d 1.20 (t,
J¼7.1 Hz, 3H), 2.31 (s, 6H), 2.78 (dd, J¼6.0, 14.0 Hz, 1H), 2.90 (dd,
J¼9.0,14.0 Hz,1H), 3.18 (dd, J¼6.0, 9.0 Hz,1H), 4.08 (q, J¼7.1 Hz, 2H),
5.12 (s, 1H), 5.27 (s, 1H), 7.23 (d, J¼8.6 Hz, 2H), and 7.43 (d, J¼8.6 Hz,
2H); 13C NMR (CDCl3)
d 172.0, 144.5, 140.0, 132.0, 128.5, 122.0, 116.1,
66.5, 60.5, 42.0, 36.1, and 14.6; IR (neat) 1728 cmꢂ1; HRMS (ES) m/z
calcd for C15H21BrNO2 326.0750, found 326.0759.
4.1.32. 4-(Phenyl)-2-dimethylaminopent-4-enoic acid ethyl ester
(18e). This compound was prepared according to the previous
procedure with the exception that 2-(phenyl)-3-(N,N-dimethyl-
amino)-1-propene1 was used as the allylic amine substrate. Chro-
matographic purification of the crude reaction product resulted in
a 67% yield of a viscous oil, which exhibited the following physical
at 0.63 Torr; 1H NMR (CDCl3)
d
1.23 (t, J¼7.0 Hz, 3H), 1.79 (br s,
4H), 2.63 (m, 2H), 2.80 (m, 2H), 2.93 (dd, J¼10.0, 13.5 Hz, 1H), 3.00
(dd, J¼5.0, 13.5 Hz, 1H), 3.30 (dd, J¼5.0, 10.0 Hz, 1H), 3.83 (s, 3H),
4.09 (q, J¼7.0 Hz, 2H), 5.06 (s, 1H), 5.27 (s, 1H), 6.87 (d, J¼7.0 Hz,
2H), and 7.35 (d, J¼7.0 Hz, 2H); 13C NMR (CDCl3)
d 172.0, 159.2,
144.0,132.9, 127.4, 113.9, 113.7, 65.7, 60.3, 55.3, 50.7, 37.7, 23.4, and
14.3; IR (neat) 1720 cmꢂ1; HRMS (ES) m/z calcd for C18H26NO3
304.1907, found 304.1911.
properties: bp 77e78 ꢁC at 0.20 Torr; 1H NMR (CDCl3)
d 1.18 (t,
J¼7.2 Hz, 3H), 2.31 (s, 6H), 2.82 (dd, J¼5.8, 14.0 Hz, 1H), 2.93 (dd,
J¼9.0, 14.0 Hz, 1H), 3.22 (dd, J¼5.8, 9.0 Hz, 1H), 4.06 (q, J¼7.2 Hz,
2H), 5.09 (s, 1H), 5.26 (s, 1H), and 7.22e7.39 (m, 5H); 13C NMR
4.1.29. 4-(4-Chlorophenyl)-2-dimethylaminopent-4-enoic acid ethyl
ester (18b). Into a 50 mL round bottom flask equipped with a mag-
netic stir bar was placed 4.10 g (0.0210 mol) of 2-(4-chlorophenyl)-3-
(N,N-dimethylamino)-1-propene1 and 3.50 g (0.0210 mol) ethyl
bromoacetate, and 25 mL of THF. The resulting mixture was stirred
overnight at room temperature and the solvent was removed in
vacuo leaving 8.13 g (100% yield) of a solid. Into a 250 mL 3-necked
round bottom flask equipped with stir bar and condensor was placed
0.249 g (6.23 mmol) of a 60% dispersion of sodium hydride along
with 50 mL of anhydrous acetonitrile. A 1.12 g sample (3.09 mmol) of
the solid material from the previous step was dissolved in 50 mL of
anhydrous acetonitrile and added to the reaction mixture. After
stirring for 4 h at room temperature, the reaction mixture was
concentrated in vacuo and the residue was partitioned between
water (50 mL) and chloroform (50 mL) and the aqueous phase was
extracted with additional chloroform (2ꢀ50 mL). The combined or-
ganic phases were dried over anhydrous MgSO4, filtered and con-
centrated to yield a dark oil. The oil was purified by radial
chromatography on a Harrison chromatotron using a 50:50 gradient
of hexane/ethyl acetate in which case 1.05 g (90% yield) of an amber
oil was obtained, which exhibited the following physical properties:
(CDCl3) d 172.1, 145.5, 141.1, 128.9, 128.1, 126.8, 115.5, 66.7, 60.3, 42.0,
36.2, and 14.6; IR (neat) 1730 cmꢂ1; HRMS (ES) m/z calcd for
C15H22NO2 248.1645, found 248.1649.
4.1.33. 4-(3,4-Dimethoxyphenyl)-2-dimethylaminopent-4-enoic acid
ethyl ester (18f). This compound was prepared according to the
previous procedure with the exception that 2-(3,4-dimethoxy-
phenyl)-3-(N,N-dimethylamino)-1-propene1 was used as the allylic
amine substrate. Chromatographic purification of the crude re-
action product resulted in a 62% yield of a viscous oil, which
exhibited the following physical properties: bp 95e96 ꢁC at
0.20 Torr; 1H NMR (CDCl3)
d
1.20 (t, J¼7.0 Hz, 3H), 2.32 (s, 6H), 2.78
(dd, J¼5.9, 14.0 Hz, 1H), 2.91 (dd, J¼9.0, 14.0 Hz, 1H), 3.24 (dd, J¼5.9,
9.0 Hz, 1H), 3.85 (s, 3H), 3.86 (s, 3H), 4.08 (q, J¼7.0 Hz, 2H), 5.03 (s,
1H), 5.21 (s, 1H), 6.79 (d, J¼8.0 Hz, 1H), 6.90 (s, 1H), and 6.92 (d,
J¼8.0 Hz, 1H); 13C NMR (CDCl3)
d 172.2, 149.2, 145.0, 133.8, 119.0,
114.3, 111.2, 110.0, 66.8, 60.4, 56.2, 42.0, 36.3, and 14.7; IR (neat)
1734 cmꢂ1; HRMS (ES) m/z calcd for C17H26NO4 308.1856, found
308.1861.
4.1.34. 4-(1-Naphthyl)-2-dimethylaminopent-4-enoic acid ethyl es-
ter (18g). This compound was prepared according to the previous
procedure with the exception that 2-(1-naphthyl)-3-(N,N-di-
methylamino)-1-propene1 was used as the allylic amine substrate.
Chromatographic purification of the crude reaction product
bp 82e83 ꢁC at 0.13 Torr; 1H NMR (CDCl3)
d
1.20 (t, J¼7.1 Hz, 3H), 2.31
(s, 6H), 2.78 (dd, J¼5.8,14.0 Hz,1H), 2.90 (dd, J¼9.0,14. 0 Hz,1H), 3.18
(dd, J¼5.8, 9.0 Hz, 1H), 4.08 (q, J¼7.1 Hz, 2H), 5.11 (s, 1H), 5.25 (s, 1H),
and 7.28 (br s, 4H); 13C NMR (CDCl3)
d 171.9,144.4,139.5,133.9,129.0,

8492
J.T. Gupton et al. / Tetrahedron 66 (2010) 8485e8493
resulted in a 72% yield of a viscous oil, which exhibited the fol-
159.8, 144.9, 136.7, 133.4, 132.2, 130.5, 128.5, 127.9, 114.6, 114.2, 65.9,
55.6, 41.8, and 31.4; IR (neat) 1686 cmꢂ1; HRMS (ES) m/z calcd for
C20H23BrNO2 388.0907, found 388. 0891.
lowing physical properties: bp 100e101 ꢁC at 0.10 Torr; 1H NMR
(CDCl3)
d
1.20 (t, J¼7.3 Hz, 3H), 2.26 (s, 6H), 2.81 (dd, J¼5.5, 14.0 Hz,
1H), 3.01 (dd, J¼9.0,14.0 Hz,1H), 3.19 (dd, J¼5.5, 9.0 Hz,1H), 4.08 (q,
J¼7.3 Hz, 2H), 5.13 (s, 1H), 5.45 (s, 1H), 7.28 (m, 1H), 7.46 (m, 3H),
4.1.38. 2-Dimethylamino-4-(4-methoxyphenyl)-1-phenylpent-4-en-
1-one (18k). This compound was prepared according to the pre-
vious procedure with the exception that 2-bromoacetophenone was
used as the alkylating agent. Chromatographic purification of the
crude reaction product resulted in a 76% yield of a viscous oil, which
exhibited the following physical properties: 146e147 ꢁC at 0.8 Torr;
7.80 (m, 2H), and 8.02 (m, 1H); 13C NMR (CDCl3)
d 171.9,145.5, 140.7,
134.3, 131.9, 128.8, 128.0, 126.4, 126.2, 125.9, 125.7, 118.5, 66.2, 60.4,
41.8, 38.9, and 14.7; IR (neat) 1728 cmꢂ1; HRMS (ES) m/z calcd for
C19H24NO2 298.1802, found 298.1795.
4.1.35. 4-(4-Methoxyphenyl)-2-piperidin-1-yl-pent-4-enoic acid ethyl
ester (18h). This compound was prepared according to the previous
procedure with the exception that 1-(2-(4-methoxyphenyl)-allyl)
piperidine was used as the allylic amine substrate. Chromatographic
purification of the crude reaction product resulted in a 40% yield of
a viscous oil, which exhibited the following physical properties: bp
1H NMR (CDCl3)
d
2.23 (s, 6H), 2.88 (dd, J¼4.0,13.9 Hz,1H), 3.07 (dd,
J¼9.5, 13.9 Hz, 1H), 3.79 (s, 3H), 4.20 (dd, J¼4.0, 9.5 Hz, 1H), 4.96 (s,
1H), 5.11 (s, 1H), 6.82 (d, J¼9.0 Hz, 2H), 7.26 (d, J¼9.0 Hz, 2H), 7.35 (t,
J¼7.0 Hz, 2H), 7.48 (t, J¼7.0 Hz, 1H), and 7.78 (d, J¼7.0 Hz, 2H); 13C
NMR (CDCl3)
d 199.8, 159.7, 145.0, 138.2, 133.6, 133.4, 129.0, 128.9,
127.9, 114.5, 114.2, 65.5, 55.6, 41.9, and 31.6; IR (neat) 1684 cmꢂ1
;
82e83 ꢁC at 1.05 Torr; 1H NMR (CDCl3)
d
1.24 (t, J¼7.0 Hz, 3H), 1.43
HRMS (ES) m/z calcd for C20H24NO2 310.1802, found 310. 1792.
(m, 2H),1.56 (m, 4H), 2.50 (br s, 2H), 2.63 (br s, 2H), 2.86 (m,1H), 2.95
(m, 1H), 3.28 (m, 1H), 3.83 (s, 3H), 4.12 (q, J¼7.0 Hz, 2H), 5.04 (s, 1H),
5.21 (s, 1H), 6.87 (d, J¼7.0 Hz, 2H), and 7.34 (d, J¼7.0 Hz, 2H); 13C
4.1.39. 2-Dimethylamino-4-(4-methoxyphenyl)-1-(4-nitrophenyl)-
pent-4-en-1-one (18l). This compound was prepared according to
the previous procedure with the exception that 40-nitro-2-bromo-
acetophenone was used as the alkylating agent. Chromatographic
purification of the crude reaction product resulted in an 82% yield of
a viscous oil, which exhibited the following physical properties:
NMR (CDCl3) d 171.6, 159.1, 144.7, 133.4, 127.4, 113.6, 113.4, 67.2, 59.8,
55.2, 53.4, 50.9, 35.8, 26.4, 24.6, and 14.7; IR (neat) 1709 cmꢂ1; HRMS
(ES) m/z calcd for C19H28NO3 318.2064, found 318. 2057.
4.1.36. 4-(4-Methoxyphenyl)-2-dipropylaminopent-4-enoic
acid
128e129 ꢁC at 0.4 Torr; 1H NMR (CDCl3)
d
2.32 (s, 6H), 2.90 (dd, J¼4.0,
ethyl ester (18i). This compound was prepared according to the
previous procedure with the exception that dipropyl-[2-(4-
methoxy-phenyl)-allyl]amine was used as the allylic amine sub-
strate. Chromatographic purification of the crude reaction product
resulted in a 20% yield of a viscous oil, which exhibited the fol-
lowing physical properties: bp 81e82 ꢁC at 0.93 Torr; 1H NMR
14.0 Hz, 1H), 3.07 (dd, J¼9.5,14.0 Hz,1H), 3.79 (s, 3H), 4.10 (dd, J¼4.0,
9.5 Hz, 1H), 4.96 (s, 1H), 5.14 (s, 1H), 6.84 (d, J¼8.8 Hz, 2H), 7.25 (d,
J¼8.8 Hz, 2H), 7.95 (d, J¼9.0 Hz, 2H), and 8.19 (d, J¼9.0 Hz, 2H); 13C
NMR (CDCl3)
d 197.8, 159.8, 150.5, 144.8, 142.5, 133.2, 130.0, 127.8,
124.1, 114.8, 114.3, 67.1, 55.8, 42.0, and 30.7; IR (neat) 1694 cmꢂ1
;
HRMS (ES) m/z calcd for C20H23N2O4 355.1652, found 355.1541.
(CDCl3)
d
0.85 (t, J¼7.5 Hz, 6H), 1.25 (t, J¼7.5 Hz, 3H), 1.35 (m, 4H),
2.43 (m, 2H), 2.57 (m, 2H), 2.75 (dd, J¼6.0, 14.5 Hz, 1H), 3.00 (dd,
J¼8.0, 14.5 Hz, 1H), 3.45 (dd, J¼6.0, 8.0 Hz, 1H), 4.12 (m, 2H), 5.04 (s,
1H), 5.24 (s, 1H), 6.88 (d, J¼9.0 Hz, 2H) and 7.36 (d, J¼9.0 Hz, 2H);
4.1.40. [3-(4-Methoxyphenyl)-1-(2-nitrophenyl)-but-3-enyl]di-
methylamine (18m). This compound was prepared according to the
previous procedure with the exception that 2-nitrobenzyl bromide
was used as the alkylating agent. Chromatographic purification of
the crude reaction product resulted in an 21% yield of a viscous oil,
which exhibited the following physical properties: 129e130 ꢁC at
13C NMR (CDCl3)
d 172.9, 159.1, 144.6, 133.1, 127.4, 113.6, 113.3, 62.0,
59.9, 55.3, 53.1, 36.3, 21.8,14.5, and 11.7; IR (neat) 1729 cmꢂ1; HRMS
(ES) m/z calcd for C20H32NO3 334.2377, found 334.2356.
0.9 Torr; 1H NMR (CDCl3)
d
2.21 (s, 6H), 2.76 (dd, J¼10.0, 14.0 Hz,
4.1.37. 1-(4-Bromophenyl)-2-dimethylamino-4-(4-methoxyphenyl)-
pent-4-en-1-one (18j). Into a 50 mL round bottom flask equipped
with a magnetic stir bar was placed 0.700 g (3.66 mmol) of 2-(4-
1H), 3.21 (dd, J¼4.8, 14.0 Hz, 1H), 3.79 (s, 3H), 4.14 (dd, J¼4.8,
10.0 Hz, 1H), 4.74 (s, 1H), 5.07 (s, 1H), 6.79 (d, J¼9.0 Hz, 2H), 7.18 (d,
J¼9.0 Hz, 2H), 7.27 (t, J¼7.0 Hz, 1H), 7.42 (t, J¼7.0 Hz, 1H), 7.50 (d,
methoxyphenyl)-3-(N,N-dimethylamino)-1-propene,1 0.994
g
J¼8.0 Hz, 1H), and 7.56 (d, J¼8.0 Hz, 1H); 13C NMR (CDCl3)
d 159.7,
(3.58 mmol) of 20,40-dibromo-2-bromoacetopheneone, and 50 mL
of THF. The resulting mixture was stirred for 2 h at room temper-
ature and vacuum filtered to yield 1.65 g (98%yield) of a white solid,
which was used without further purification. Into a 250 mL
3-necked round bottom flask equipped with stir bar and condensor
was placed 0.086 g (3.60 mmol) of a 60% dispersion of sodium
hydride along with 50 mL of anhydrous acetonitrile. A 1.30 g
sample (2.77 mmol) of the solid material from the previous step
was dissolved in 10 mL of anhydrous acetonitrile and added to the
reaction mixture. After stirring for 2 h at room temperature, the
reaction mixture was concentrated in vacuo and the residue was
partitioned between water (50 mL) and chloroform (30 mL) and the
aqueous phase was extracted with additional chloroform
(2ꢀ30 mL). The combined organic phases were dried over anhy-
drous MgSO4, filtered and concentrated to yield a dark oil. The oil
was purified by radial chromatography on a Harrison chromatotron
using a 50:50 gradient of hexane/ethyl acetate in which case
0.637 g (49% yield) of an amber oil was obtained, which exhibited
the following physical properties: 130e131 ꢁC at 1.20 Torr; 1H NMR
151.9, 144.9, 136.1, 133.7, 132.0, 129.9, 128.1, 127.7, 124.2, 114.4, 114.1,
62.4, 55.6, 42.9, and 37.7; IR (neat) 1527 and 1360 cmꢂ1; HRMS (ES)
m/z calcd for C19H23N2O3 327.1703, found 327.1711.
4.1.41. [3-(4-Methoxyphenyl)-1-(4-nitrophenyl)-but-3-enyl]di-
methylamine (18n). This compound was prepared according to the
previous procedure with the exception that 4-nitrobenzyl chloride
was used as the alkylating agent. Chromatographic purification of the
crude reaction product resulted in an 53% yield of a viscous oil, which
exhibited the following physical properties: 128e129 ꢁC at 0.9 Torr;
1H NMR (CDCl3)
d
2.19 (s, 6H), 2.68 (dd, J¼11.4, 14.7 Hz, 1H), 3.33 (m,
2H), 3.81(s, 3H), 4.63(s,1H), 4.94(s,1H), 6.82(d, J¼8.0 Hz, 2H), 7.13 (d,
J¼8.0 Hz, 2H), 7.20 (d, J¼8.0 Hz, 2H), and 8.08 (d, J¼8.0 Hz, 2H); 13C
NMR (CDCl3)
d 159.8, 149.0, 147.6, 144.9, 133.4, 129.8, 128.0, 123.6,
114.9, 114.2, 69.2, 55.6, 43.4, and 40.1; IR (neat) 1513 and 1346 cmꢂ1
;
HRMS (ES) m/z calcd for C19H23N2O3 327.1703, found 327.1722.
Acknowledgements
(CDCl3)
d
2.31 (s, 6H), 2.88 (dd, J¼4.0, 14.0 Hz, 1H), 3.04 (dd, J¼9.0,
We thank the National Institutes of Health (grant no. R15-
CA67236) for support of this research. We are exceedingly grateful
to Mr. Dave Patteson formerly of Biotage Inc. for the generous do-
nation of a Horizon HFC and SP-1 flash chromatography systems,
14. 0 Hz, 1H), 3.80 (s, 3H), 4.10 (dd, J¼4.0, 9.0 Hz, 1H), 4.94 (s, 1H),
5.11 (s, 1H), 6.82 (d, J¼9.0 Hz, 2H), 7.24 (d, J¼9.0 Hz, 2H), 7.48 (d,
J¼8.7 Hz, 2H), and 7.77 (d, J¼8.7 Hz, 2H); 13C NMR (CDCl3)
d 198.8,

J.T. Gupton et al. / Tetrahedron 66 (2010) 8485e8493
8493
3. Davies, I.; Taylor, M.; Marcoux, J.; Wu, J.; Dormer, P.; Hughes, D.; Reider, P. J. Org.
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which were used in the majority of sample purifications. Recent
grants from the MRI program of the National Science Foundation
for the purchase of a 500 MHz NMR spectrometer (CHE-0116492)
and an electrospray mass spectrometer (CHE-0320669) are also
gratefully acknowledged. We thank the Arnold and Mabel Beckman
Foundation for fellowship support to B.C.G. and Professors Wade
Downey, Jeff Seeman and Kristine Nolan for making helpful sug-
gestions as to the nature of this manuscript.
Katritzky, A. Tetrahedron 1993, 49, 10205.
8. Gupton, J.; Krolikowski, D.; Yu, R.; Vu, P.; Sikorski, J.; Dahl, M.; Jones, C. J. Org.
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Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.08.075.
14. Gupton, J.; Layman, J. J. Org. Chem. 1987, 52, 3683.
15. Gupton, J.; Krolikowski, D.; Russler, M. Synth. Commun. 1989, 19, 2415.
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References and notes
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