Dicationic electrophiles from olefinic amines in superacid

Article abstract of DOI:10.1021/jo030024z

This paper describes the superacid-catalyzed chemistry of olefinic amines and related compounds. A variety of olefinic amines are found to react with benzene in CF₃SO₃H (triflic acid) to give addition products in good yields (75-99%), including the pharmaceutical agents fenpiprane and prozapine. A general mechanism is proposed that invokes the formation of reactive, dicationic electrophiles and the direct observation of a diprotonated species is reported from low-temperature NMR experiments. This chemistry is also used to conveniently prepare functionalized polystyrene beads having pendant amine groups.

Full text of DOI:10.1021/jo030024z

Dica tion ic Electr op h iles fr om Olefin ic Am in es in Su p er a cid
Yun Zhang, Aaron McElrea, Gregorio V. Sanchez, J r., Dat Do, Alma Gomez,
Sharon L. Aguirre,† Rendy Rendy, and Douglas A. Klumpp*,§
Department of Chemistry, California State Polytechnic University, 3801 West Temple Avenue,
Pomona, California 91768
daklumpp@csupomona.edu
Received J anuary 17, 2003
This paper describes the superacid-catalyzed chemistry of olefinic amines and related compounds.
A variety of olefinic amines are found to react with benzene in CF3SO3H (triflic acid) to give addition
products in good yields (75-99%), including the pharmaceutical agents fenpiprane and prozapine.
A general mechanism is proposed that invokes the formation of reactive, dicationic electrophiles
and the direct observation of a diprotonated species is reported from low-temperature NMR
experiments. This chemistry is also used to conveniently prepare functionalized polystyrene beads
having pendant amine groups.
In tr od u ction
we reported that 1,2,5,6-tetrahydropyridines give dica-
tionic intermediates in the Bronsted superacid CF3SO3H
(triflic acid, TfOH; eq 1).4a The dicationic intermediates
It has been more than 100 years since Friedel and
Crafts first reported the chemistry of electrophilic aro-
matic substitution. Yet, this area of organic chemistry
continues to be active with research in both mechanistic
and synthetic studies.1 One recent development involves
the chemistry of superelectrophiles. The concept of su-
perelectrophilic activation was first proposed by Olah and
co-workers in 1975.2 In studies involving the nitration
of aromatic compounds, they observed that nitronium
salts exhibit enhanced reactivities in Bronsted superac-
ids. It was suggested that the nitronium electrophile is
protosolvated in superacid to give a dicationic electro-
phile, or superelectrophilic intermediate. The Olah group
also found similar electrophilic activation involving the
acylation of aromatic compounds.2 Following these pio-
neering studies, superelectrophilic activation has been
studied extensively by both theoretical and experimental
methods.3
react in good yields to give aryl-substituted piperidines
from electrophilic aromatic substitution. Similarly, we
found that piperidones condense with arenes in high
yields with TfOH.4b Both these studies suggested that
the ammonium cation plays a critical role in activating
the nearby electrophilic site. In the following report, we
describe further studies in the area of electrophilic
chemistry involving these reactive intermediates. We
show that a variety of olefinic amines and N-heterocycles
can yield reactive dicationic electrophiles in TfOH and
that these reactive intermediates can be used in electro-
philic aromatic substitution reactions, including the
functionalization of polystyrene resins. We also report the
direct observation of a diprotonated species by low-
temperature NMR.
We and others have recently reported several examples
of dicationic electrophilic systems which are analogous
to the superelectrophiles.4 There are also a number of
older reports in which dications were clearly involved in
the chemistry, but the role of these reactive species was
not generally appreciated.5 In one of our recent studies,
Resu lts
The 1-(3,3-diarylpropyl)amines belong to an important
class of biologically active compounds.6 For example,
Dedicated to Professor George A. Olah on the occasion of his 75th
birthday.
† American Chemical Society Scholar, 2001-2002.
§ Present address: Department of Chemistry and Biochemistry,
Northern Illinois University, DeKalb, IL 60115.
(4) (a) Klumpp, D. A.; Beauchamp, P. S.; Sanchez, G. S., J r.; Aguirre,
S.; de Leon, S. Tetrahedron Lett. 2001, 42 (34), 5821. (b) Klumpp, D.
A.; Garza, M.; J ones, A.; Mendoza, S. J . Org. Chem. 1999, 64, 6702.
(c) Klumpp, D. A.; Aguirre, S. L.; Sanchez, G. V., J r.; de Leon, S. J .
Org. Lett. 2001, 3 (17), 2781. (d) Zhang, Y.; Aguirre, S. A.; Klumpp, D.
A. Tetrahedron Lett. 2002, 43, 6837. (e) Koltunov, K. Y.; Prakash, G.
K. S.; Rasul, G.; Olah, G. A. J . Org. Chem. 2002, 67, 8943. (f) Koltunov,
K. Y.; Prakash, G. K. S.; Rasul, G.; Olah, G. A. Tetrahedron 2002, 58,
5423. (g) Klumpp, D. A.; Lau, S. J . Org. Chem. 1999, 64, 7309.
(5) (a) Palmer, D. C.; Strauss, M. J . Chem. Rev. 1977, 77, 1. (b)
Fuson, R. C.; Kozacik, A. P.; Eaton, J . T. J . Am. Chem. Soc. 1933, 55,
3799.
(1) (a) Hubig, S. M.; Kochi, J . K. J . Am. Chem. Soc. 2000, 122, 8279.
(b) Hubig, S. M.; Kochi, J . K. J . Org. Chem. 2000, 65, 6534. (c) Olah,
G. A.; Torok, B.; J oschek, J . P.; Bucsi, I.; Esteves, P. M.; Rasul, G.;
Surya Prakash, G. K. J . Am. Chem. Soc. 2002, 124, 11379. (d) Shorthill,
B. J .; Glass, T. E. Org. Lett. 2001, 3, 577. (e) Anderson, K. W.; Tepe,
J . J . Org. Lett. 2002, 4, 459. (f) Paras, N. A.; MacMillan, D. W. C. J .
Am. Chem. Soc. 2001, 123, 4370.
(2) Olah, G. A.; Germain, A.; Lin, H. C.; Forsyth, D. J . Am. Chem.
Soc. 1975, 97, 3928
(3) (a) Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 767. (b)
Prakash, G. K. S.; Schleyer, P. v. R., Eds. Stable Carbocation
Chemistry; Wiley: New York, 1997; Chapter 16.
(6) (a) Andersson, P. G.; Schink, H. E.; Osterlund, K. J . Org. Chem.
1998, 63, 8067. (b) Rische, T.; Eilbracht, P. Tetrahedron 1999, 55, 1915.
10.1021/jo030024z CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/30/2003
J . Org. Chem. 2003, 68, 5119-5122
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Zhang et al.
TABLE 1. Resu lts fr om th e Rea ction s of Olefin ic Am in es w ith C6H6 in TfOH
a
b
25 °C. 50 °C. c 80 °C.
SCHEME 1
fenpiprane (14) is an anti-allergic and anti-spasmodic
drug while prozapine (15) is an anti-spasmodic and
choleretic drug.7 Fenpiprane (14) can be prepared in good
yield from piperidine and cinnamyl bromide via the
olefinic amine (1). When compound 1 is reacted with CF3-
SO3H (TfOH, triflic acid) and benzene, 14 is formed in
high yield (Table 1). In general, cinnamyl-substituted
N-heterocycles (1-5) give the 1-(3,3-diarylpropyl)amines
(14-18) in good yields. Compounds 6 and 7 react to give
products 19 and 20, respectively, by protonation of the
nitrogen base-sites and the exo-cyclic double bonds. In
the case of 6, diprotonation occurs to give the 1,4-dication
(27), while 7 gives exclusively the 1,5-dication (28)
additions products in good yields, but in some cases the
conversions require heating (Table 1). When the vinyl-
substituted imidazole (10), pyridine (12), thiazole (13),
or aniline (11) is reacted with TfOH and C6H6, protona-
tion occurs at the 2-carbon of the vinyl group to give 1,1-
diarylethane products (23-26).
We propose that the olefinic compounds (1-13) react
through dicationic electrophilic intermedites. In the case
of vinylpyridine 12, protonation occurs at the nitrogen
to give the monocation (29) and a second protonation
gives the reactive dication (30, Scheme 1). The dicationic
intermediate then reacts with benzene to give the final
product (25). Despite the fact that TfOH catalyzes the
polymerization of styrene,8 there is no evidence for
polymerization or oligomerization of any of the olefinic
compounds (1-13) in the addition reactions. This sug-
gests that the dicationic intermediate (i.e., 30) is unable
to react with the cationic olefin (29) due to repulsive
electrostatic effects.
leading to product formation. These products are consis-
tent with the formation of the most highly stabilized
carbocation centers. Olefins 8 and 9 react by additions
to the 2-methyl-2-propenyl and allyl groups and they give
the respective addition products (21 and 22) in good
yields. The vinyl group also reacts with benzene in
superacid. The vinyl-substituted arenes 10-13 give the
To characterize the proposed dicationic intermediates,
low-temperature 13C NMR studies were done with olefinic
amines dissolved in FSO3H-SbF5-SO2ClF. Initial efforts
to observe dicationic species were not successful. For
(7) (a) Budavari, S.; O’Neil, M. J .; Smith, A.; Heckelman, P. E.;
Kinneary, J . F., Eds. The Merck Index, 12th ed.; Merck Company:
Whitehouse Station, NJ , 1996; No. 4031. (b) Keemann, A.; Engel, J .;
Kutscher, B.; Reichert, D. Pharmaceutical Substances, 4th ed.; Thi-
eme: Stutgart, Germany, 2001; pp 1750-1751.
(8) Stang, P. J .; White, M. R. Aldrichim. Acta 1983, 16, 15.
5120 J . Org. Chem., Vol. 68, No. 13, 2003

Olefinic Amines
F IGURE 1. 13C NMR of dication 32 in FSO3H:SbF5:SO2ClF (1:1:1) at -30 °C; the • denotes the external standard peak (d6-
acetone).
example, compound 1 is dissolved in FSO3H-SbF5-SO2-
ClF (1:1:1) at -30 °C, and a clean spectrum was not
obtained. Similar results occur when compound 8 dis-
solved the superacidic solution. However, when com-
pound 31 is dissolved in FSO3H-SbF5-SO2ClF (1:1:1)
trophile 35 is still capable of reaction with this arene.
The reactivity of this electrophilic system may stem from
two effects: an electrostatic effect arising from the two
charge centers on the electrophile and also a decreased
neighboring group stabilization of the carbcationic center.
at -30 °C, a clean 13C NMR spectrum results and the
olefinic carbons are replaced by a new signal in the
aliphatic region and another at 225 ppm (Figure 1). The
downfield signal is consistent with the formation of the
diphenyl-substituted carbocation center. The dication 32
shows no signs of decomposition at -30 °C in the
superacidic solution. The stability of 32 is evidently due
to the stabilization by the two phenyl groups and the
relatively large distance between the two charge centers.9
Neither olefin 33 or 34 gave spectra of the corresponding
dications in FSO3H-SbF5-SO2ClF at -30 °C, but instead
gave complex spectra. The difficulty in observing the
dications from 1, 8, 33, and 34 may be due to rapid
equilibration with the monocationic species.
In addition to the reactions with benzene, olefinic
amines can also be used to functionalize polystyrene
resins. Compounds 3, 5, and 8 can be reacted with
polystyrene beads in the presence of TfOH to give the
functionalized polymers 39, 40, and 41, respectively (eqs
2-4). Amine-functionalized resins have been useful as
In previous studies, we and others have shown that
dicationic electrophiles are often capable of reacting with
deactivated arenes.10 Compound 8 was reacted with
monosubstituted benzenes in TfOH and the results
indicate that the diprotonated species (35) is a fairly
reactive electrophile. When 8 is reacted with TfOH and
toluene, benzene, chlorobenzene, or o-dichlorobenzene,
the respective addition products 36, 21, 37, and 38 are
formed. Nitrobenzene is unreactive toward compound 8
in TfOH. The yields of products roughly correlate with
the deactivation of the arenes. Despite the high level of
deactivation of o-dichlorobenzene,11 the dicationic elec-
acid-scavenging reagents and reaction scaffolds for com-
binatorial synthesis.12 Although acid-catalyzed cleavage
of polystyrene is known, we found that the functionalized
polymers 39-41 can be prepared by using polystyrene
(9) We have found evidence that the distance between charge centers
can dramatically influence reactivity, see: Klumpp, D. A.; Garza, M.;
Sanchez, G. V.; Lau, S.; DeLeon, S. J . Org. Chem. 2000, 65, 8997.
(10) (a) Olah, G. A.; Wang, Q.; Sandford, G.; Oxyzoglou, A. B.;
Prakash, G. K. S. Synthesis 1993, 1077. (b) Reference 4g.
J . Org. Chem, Vol. 68, No. 13, 2003 5121

Zhang et al.
62.4, 126.0, 126.2, 128.5, 148.1 ppm. MS m/z (EI) 177 (M+),
91, 58. HRMS (DEI) calcd for C12H20N 178.159575 (MH+),
found 178.159111.
beads having a 2% cross-linking of divinylbenzene. Under
these reaction conditions, analysis with a bright-field,
optical microscope indicates there is little damage to the
polystyrene beads. However, if marcoporous beads (poly-
styrene-co-divinylbenzene) are used, the beads show
massive structural damage. Microscopic cracks and pit-
ting is evident on the surface of the porous beads.
Evidently, the macroporous beads absorb significant
quantities of TfOH prior to any amine functionalization
and the superacid cleaves some of the polystyrene
surface.
Eth yl(2-m eth yl-2-p h en ylp r op yl)a m in e (21). 1H NMR
(CDCl3, 300 MHz) δ 1.08 (t, J ) 7.5 Hz, 3H), 1.23 (s, 1H), 1.36
(s, 6H), 2.56 (q, J ) 7.5 Hz, 2H), 2.75 (s, 2H), 7.16-7.40 (m,
10H) ppm. 13C NMR (CDCl3, 125 MHz) δ 15.3, 27.7, 38.8, 45.0,
62.4, 126.0, 126.2, 128.5, 148.1 ppm. MS m/z (EI) 177 (M+),
162, 58. HRMS calcd for C12H20N 178.159575 (MH+), found
178.159111.
1-(2-P h en ylp r op yl)-1H-im id a zole (22). 1H NMR (CDCl3,
300 MHz) δ 1.27 (d, J ) 6.9 Hz, 3H), 3.02-3.10 (m, 1H), 4.02
(d, J ) 7.5 Hz, 3H), 6.72 (s, 1H), 6.97 (s, 1H), 7.60-7.23 (m,
2H), 7.18-7.36 (m, 3H) ppm. 13C NMR (CDCl3, 125 MHz) δ
18.8, 41.9, 54.5, 119.4, 127.2, 127.3, 129.0, 129.4, 137.6, 142.9
ppm. MS m/z (EI) 186 (M+), 105, 82. HRMS (EI+) calcd for
Con clu sion
In summary, we have found that olefinic amines and
heterocycles react with arenes in the Bronsted superacid,
CF3SO3H. We propose that olefinic amines are protonated
twice to generate reactive dicationic intermediates. These
doubly charged electrophiles are sufficiently reactive to
attack moderately deactivated arenes such as o-dichlo-
robenzene. Polystyrene beads can be conveniently func-
tionalized by olefinic amines in reactions catalyzed by
TfOH.
C
12H14N2 186.115699, found 186.115742.
4-Meth yl-5-(1-ph en yleth yl)th iazole (26). 1H NMR (CDCl3,
300 MHz) δ 1.67 (d, J ) 6.9 Hz, 3H), 2.35 (s, 3H), 4.38 (q, J )
6.9 Hz, 1H), 7.19-7.33 (m, 5H), 8.57 (s, 1H) ppm. 13C NMR
(CDCl3, 125 MHz) δ 15.5, 24.2, 37.8, 126.8, 127.2, 128.9, 129.5,
145.1, 149.4, 149.5 ppm. MS m/z (EI) 203 (M+), 188. HRMS
calcd for C12H13NS 203.076871, found 203.077637.
Cin n a m ylp ip er a zin e F u n ction a lized P olystyr en e 39.
A 1.0-g sample of polystyrene is suspended in 15 mL of CHCl3
and 0.2011 g (1.0 mmol) of trans-1-cinnamylpiperazine (3) is
added. To this solution is added 4 mL of triflic acid and the
solution is stirred overnight at room temperature and then
poured over about 50 g of ice. The solution is made basic with
1.0 M NaOH, and after an hour of stirring, the functionalized
polymer is filtered off and rinsed thoroughly with deionized
water. The solids are rinsed three times with anhydrous ether
and then dried with heating under vacuum to yield ap-
proximately 1.2 g of a granular, tan solid. Anal. Calcd for 1.0
mmol of cinnamylpiperazine/g of polystyrene: C, 89.77; H,
7.90; N, 2.32. Found: C, 81.26; H, 7.32; N, 0.93. FTIR (KBr,
cm-1) 3448, 3020, 1380.
1-Ben zoyl-4-cin n a m ylp ip er a zin e F u n ction a lized P oly-
styr en e 40. A 1.0-g sample of polystyrene is reacted with
0.2013 g (0.66 mmol) of 1-benzoyl-4-cinnamylpiperazine (5) and
4 mL of triflic acid in CHCl3, using the procedure described
above, to yield approximately 1.2 g of a granular, tan solid.
Anal. Calcd for 0.66 mmol of 1-benzoyl-4-cinnamylpiperazine/g
of polystyrene: C, 90.0; H, 7.57; N, 1.50. Found: C, 88.18; H,
7.45; N, 0.98. FTIR (KBr, cm-1) 3018, 2918, 1628, 1607, 1495,
1449.
Exp er im en ta l Section
Compounds 1 and 2 were prepared from the reactions of
cinnamyl bromide with the appropriate heterocycle; com-
pounds 6 and 7 were prepared from N-benzyl-4-piperidone
with use of CH3PPh3Br:NaNH2 and (C6H5)CH2PPh3Br:BuLi,
respectively, and standard Wittig reaction procedures.13 All
other olefinic amines were purchased from commercial sup-
pliers. Products 14, 16, 17, 19, 20, 23, 24, and 25 are known
compounds.14 Products 36, 37, and 38 were obtained as
inseparable mixtures of regioisomers. The triflic acid was
purchased from 3M and distilled from an argon atmosphere
prior to use. Polystyrene beads were purchased from com-
mercial suppliers. Microscopic analysis of functionalized poly-
mers was done with a Nikon Eclipse E-400 with Nikon Plan
lenses, using a Tungsten-halogen light source and an objective
of 40× (standard bright-field configuration).
Gen er a l Syn th etic P r oced u r e (P r od u cts 14-26). Ap-
proximately 0.2 g of the olefin is suspended in 2 mL of benzene
and 3 mL of TfOH is added. After being stirred for at least 3
h, the mixture is poured over ice, and it is made basic with
concentrated NaOH. The mixture is then extracted with CHCl3
and the organic phase is washed with brine, dried with MgSO4,
and concentrated under vacuum.
E t h yl(2-m et h yla llyl)a m in e F u n ct ion a lized P olyst y-
r en e 41. A 1.0-g sample of polystyrene is reacted with 0.20
mL (1.52 mmol) of ethyl(2-methylallyl)amine (5) and 1 mL of
triflic acid in 5 mL of CHCl3, using the procedure described
above, to yield approximately 1.1 g of a granular, tan solid.
Anal. Calcd for 1.52 mmol of ethyl(2-methylallyl)amine/g of
polystyrene: C, 89.75; H, 8.43; N, 1.82. Found: C, 88.60; H,
7.85; N, 0.71. FTIR (KBr, cm-1) 3438, 3022, 2914, 1603, 1490,
1445, 1386.
1-Ben zoyl-4-(3,3-d ip h en ylp r op yl)p ip er a zin e (18). 1H
NMR (CDCl3, 300 MHz) δ 2.20-2.26 (m, 8H), 3.38-3.50 (m,
2H), 3.71-3.88 (m, 2H), 4.03 (t, J ) 7.1 Hz, 1H), 7.00-7.51
(m, 15H) ppm. 13C NMR (CDCl3, 125 MHz) δ 32.8, 42.3, 47.9,
49.2, 53.1, 53.7, 56.9, 126.5, 127.3, 128.1, 128.7, 128.8, 129.9,
136.1, 144.9, 170.5 ppm. MS m/z (EI) 384 (M+), 203, 105.
HRMS (DEI) calcd for C26H28N2O 384.220164, found 384.220624.
Eth yl(2-m eth yl-2-p h en ylp r op yl)a m in e (21). 1H NMR
(CDCl3, 300 MHz) δ 1.01 (t, J ) 6.6 Hz, 3H), 1.23 (s, 1H), 1.36
(s, 6H), 2.56 (q, J ) 6.6 Hz, 2H), 2.75 (s, 2H), 7.15-7.40 (m,
5H) ppm. 13C NMR (CDCl3, 125 MHz) δ 15.3, 27.7, 38.8, 45.0,
Ack n ow led gm en t. We are grateful to the NIH for
support of this work (SO6GM53933-0251). We also
thank Ms. Sarah de Leon, Mr. Siufu Lau, and Mr. Kevin
Franke for their kind assistance and we are indebted
to Professors George A. Olah and G. K. Surya Prakash
for the use of their NMR instruments at the University
of Southern California. We thank the manuscript re-
viewers for their comments.
(11) (a) Taylor, R. Electrophilic Aromatic Substitution; Wiley: New
York, 1990; Chapter 2. (b) Olah, G. A. Friedel-Crafts and Related
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(12) Burgess, K. Solid-Phase Organic Synthesis; Wiley: New York,
1999.
Su p p or tin g In for m a tion Ava ila ble: Analytical data (1H
and 13C NMR spectra) for new compounds and literature
citations for known compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(13) Furniss, B. S.; Hannaford, A. J .; Smith, P. W. G.; Tatchell, A.
R. Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Wiley: New
York, 1989; pp 498-499.
(14) See Supporting Information.
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5122 J . Org. Chem., Vol. 68, No. 13, 2003