Chemistry of dicationic electrophiles: superacid-catalyzed reactions of amino acetals.

Article abstract of DOI:10.1021/jo0111558

Amino acetals are shown to form highly electrophilic systems in Bronsted superacids. It is proposed that amino acetals give dicationic electrophiles, and this proposal is supported by the direct observation of a dication by low-temperature (13)C NMR. When reacted with C(6)H(6) and superacidic CF(3)SO(3)H, amino acetals are shown to provide 1-(3,3-diphenylpropyl)amines and 1-(2,2-diphenylethyl)amines as condensation products in good yields (50-99%).

Full text of DOI:10.1021/jo0111558

direct observation of a dicationic intermediate by low-
temperature 13C NMR.
Ch em istr y of Dica tion ic Electr op h iles:
Su p er a cid -Ca ta lyzed Rea ction s of Am in o
Aceta ls
Douglas A. Klumpp,* Gregorio V. Sanchez, J r.,
Sharon L. Aguirre,† Yun Zhang, and Sarah de Leon
Department of Chemistry, California State Polytechnic
University, 3801 West Temple Avenue,
Pomona, California 91768
daklumpp@csupomona.edu
Received December 17, 2001
Although a number of amino acetal compounds are
commercially available, these compounds can be readily
prepared by the reaction of amines with brominated
acetals and Na2CO3 in anhydrous DMF.7 To compare two
common acetals, the dimethoxy acetals 4a -7a and the
dioxolane derivatives 4b-7b were prepared and reacted
with benzene in triflic acid (CF3SO3H, TfOH; Table 1).8
Although both types of amino acetals give fair yields of
the condensation products, the dimethoxy acetals give
better yields of the 1-(3,3-diphenylpropyl)amines (2, 14,
15). Amino acetals 8-12 react with C6H6 in TfOH to give
good yields of the 1-(2,2-diphenylethyl)amines 16-20. In
a typical reaction, the reagents (3 mmol of acetal, 20
mmol of TfOH, and 2 mL of C6H6) are stirred for 2 h at
room temperature. Longer reaction times and heat
caused reduction of yields for some of the acetals. Acetals
9, 10, and 12 were also reacted with H2SO4 and C6H6.
Although some condensation products could be detected
if the reactions were done at 90 °C, the H2SO4-catalyzed
conversions were generally poor. Even at elevated tem-
peratures, the condensation reactions do not proceed in
CF3CO2H. In the patent literature, there is a report of
amino acetals reacting with arenes in polyphosphoric acid
or H2SO4.4 However, in these earlier studies, the con-
densation reactions are done with strongly activated
arenes, such as phenols and catechols. For less reactive
arenes such as C6H6, the condensation reactions of amino
acetals work best in superacidic TfOH. Interestingly for
the TfOH reactions, the acetaldehyde derivatives (8-13)
give slightly better yields than the propionaldehyde
derivatives (4a ,b-7a ,b). When the formamide derivative
22 or the butyraldehyde derivative 23 are reacted under
similar conditions, however, the expected condensation
products are not formed.9 Compound 13 reacted in TfOH
and C6H6 to give product 21 as the only major product
(eq 1) in about 50% yield (after column chromatography).
Product 21 is the result of condensation and oxidation
chemistry; however, it is not immediately clear if the
benzylic position is oxidized during the TfOH reaction
or during the workup.
Abstr a ct: Amino acetals are shown to form highly electro-
philic systems in Bronsted superacids. It is proposed that
amino acetals give dicationic electrophiles, and this proposal
is supported by the direct observation of a dication by low-
temperature 13C NMR. When reacted with C6H6 and su-
peracidic CF3SO3H, amino acetals are shown to provide
1-(3,3-diphenylpropyl)amines and 1-(2,2-diphenylethyl)-
amines as condensation products in good yields (50-99%).
The 1-(3,3-diarylpropyl)amines are compounds having
a variety of pharmacological activities.1 In clinical ap-
plications, fenpiprane 1 and prozapine 2 are spasmolytics
and tolpropamine 3 is an antihistaminic.2 The 1-(3,3-
diarylpropyl)amines have been prepared by a variety of
synthetic routes,2,3 yet there is only one report (in the
patent literature) of these compounds being prepared by
electrophilic aromatic substitution chemistry.4 We have
been studying the chemistry of reactive, dicationic elec-
trophilic systems and recently reported a synthetic route
to diarylpiperidines by the superacid-catalyzed reactions
of piperidones with arenes.5 The diarylpiperidines were
prepared in good yields (80-99%). It was proposed that
dicationic electrophiles are generated from piperidones
by the protonation of the carbonyl and nitrogen base
sites. Since it is well-known that acetal and ketal groups
can form carboxonium ions in acid-catalyzed reactions,6
we have explored the possibility of generating dicationic
electrophiles from amino acetals with the goal of prepar-
ing compounds such as the 1-(3,3-diarylpropyl)amines.
In this paper, we describe a general synthetic route to
1-(3,3-diarylpropyl)amines and related products, propose
the formation of dicationic intermediates, and report the
† American Chemical Society Scholar, 2001-2002.
(1) (a) Giringauz, A. Medicinal Chemistry; Wiley-VHC: New York,
1997. (b) Pharmaceuticals; McGuire, J . L., Ed.; Wiley-VHC: New York,
2000; Vol. 2.
(2) (a) Andersson, P. G.; Schink, H. E.; Osterlund, K. J . Org. Chem.
1998, 63, 8067. (b) Reference 1b.
(3) Rische, T.; Eilbracht, P. Tetrahedron 1999, 55, 1915.
(4) Watanabe, Y.; Kamochi, Y.; Kido, K.; Kudo, T.; Nose, A. Chem.
Abstr. 1974, 81, 91256z.
(5) Klumpp, D. A.; Garza, M.; J ones, A.; Mendoza, S. J . Org. Chem.
1999, 64, 6702.
(6) (a) March, J . Advanced Organic Chemistry, 4th ed.; Wiley: New
York, 1992; pp 373-376. (b) Fukuzawa, S.; Tsuchimoto, T.; Hiyama,
T. J . Org. Chem. 1997, 62, 151. (c) For an example of a superacid-
catalyzed Friedel-Crafts reaction involving a heterocyclic acetal, see
ref 7.
(7) Wardani, A.; Lhomme, J . Tetrahedron Lett. 1993, 34, 6411.
(8) (a) For a review of TfOH chemistry, see: Stang, P. J .; White, M.
R. Aldrichim. Acta 1983, 16, 15. (b) Olah, G. A.; Prakash, G. K. S.;
Sommer, J . In Superacids; Wiley: New York, 1985. (c) TfOH may be
quantitatively recycled; for a procedure, see: Booth, B. L.; El-Fekky,
T. A. J . Chem. Soc., Perkin Trans. 1 1979, 2441.
(9) Compound 23 was also reacted with a large excess of TfOH and
C6H6 at 90 °C for 2 h with no conversion.
10.1021/jo0111558 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/18/2002
5028
J . Org. Chem. 2002, 67, 5028-5031

TABLE 1. P r od u cts fr om th e Rea ction s of Am in o Aceta ls 4-12 w ith CF 3SO3H a n d C6H6
a
Reference 5.
SCHEME 1
Acetal 9 reacts in TfOH with fluorobenzene, chloroben-
zene, or 1,2-dichlorobenzene to give products (24-26).
mediates (Scheme 1). The dicationic electrophiles are the
carboxonium-ammonium dication (27) and the carbe-
nium-ammonium dication (28). Both of these dications
are sufficiently electrophilic to react with benzene and
halogen-substituted arenes.
In comparing the different types of amino acetals, the
propionaldehyde and acetaldehyde derivatives give good
yields of products, while the formamide (22) and butyral-
dehyde (23) derivatives give no condensation products.
These results suggest that 22 does not form the dicationic
intermediate 29, due to the unfavorable proximity of the
two charge centers. On the other hand, the condensation
chemistry appears to work best with the acetaldehyde
derivatives, while the propionaldehyde and (especially)
the butyraldehyde derivatives yield poorer results. This
trend may reflect the relative reactivities of the dicationic
intermediates. Thus, the 1,3-dication (27) from the ace-
taldehyde derivative is more reactive than the analogous
1,4-dication (30) and the 1,5-dication (31) from the
respective propionaldehyde and butyraldehyde deriva-
tives. In the chemistry of dicationic electrophiles, proxim-
ity of the charge centers can influence the reactivity of
The reactions give mixtures of regioisomers, and the
yields parallel the relative deactivation of the arenes
(nitrobenzene did not react). Despite the fact that 1,2-
dichlorobenzene is a significantly deactivated arene,10
a
fair amount of the condensation products are formed.
Therefore, acetal 9 must form highly electrophilic inter-
mediates upon solvation in superacid. We propose a
mechanism involving the formation of dicationic inter-
(10) (a) Taylor, R. Electrophilic Aromatic Substitution; Wiley: New
York, 1990; Chapter 2. (b) Olah, G. A. Friedel-Crafts and Related
Reactions; Wiley: New York, 1964; Vol. 2; pp 597-640.
J . Org. Chem, Vol. 67, No. 14, 2002 5029

F IGURE 1. 13C NMR of ions 33 and 34 in FSO3H/SbF5/SO2ClF at -80 °C.
the intermediates. Proximity effects were also observed
in two other recent studies involving dicationic electro-
philes.11
To characterize the cationic intermediates arising from
the amino acetals, acetal 5b was studied in acidic solution
by NMR. When 5b is dissolved in CF3CO2H and analyzed
by 13C NMR at -10 °C (acetone-d6 external standard),
the spectrum is consistent with that of the monoproto-
nated, ammonium cation.12 Seven resonance signals
appear: 20.1, 22.4, 25.8, 52.4, 54.1, 64.5, and 101.4 ppm.
In a mixture of SbF5:FSO3H (ca. 1:1) with SO2ClF at -80
°C, compound 5b gives a 13C NMR spectrum (Figure 1)
consistent with that of a dicationic intermediate. Upon
ionization, the acetal carbon signal disappears and a new
signal forms at 231 ppm. Close examination of the
downfield signal reveals that it is split into a pair of
peaks. This suggests the formation of the isomeric
dicationic structures 33 and 34. Two other carbon atoms
also appear to give split peaks for the isomeric struc-
tures: one carbon at about 89 ppm and one carbon at 70
ppm. These peaks are likely the methylene groups
adjacent to the caboxonium ion. The remaining 13C
signals are isochronous for structures 33 and 34. It is
well known that carboxonium ions can form cis and trans
isomers.13 Although there are very few published 13C
NMR spectra of carboxonium ions similar to 33 and 34,
the 13C NMR spectrum of methylated trifluoroacetone
35 was recently reported and the carboxonium carbon
appeared at 222 ppm.14 These data are consistent with
When the acetal derivative of octanal (32) is reacted
with TfOH and C6H6, a complex mixture of products is
formed and 1,1-diphenyloctane is not present in the
mixture. Acetal 32 and the amino acetals (4-13) exhibit
much different chemistry in the superacid-catalyzed
reactions. This suggests that acetal 32 reacts primarily
through monocationic intermediates, and if any dicationic
intermediates are formed, they form in very low concen-
trations.
(12) 13C NMR data for 5b: (δ, CDCl3) 24.6, 26.2, 31.6, 54.3, 54.8,
65.1, 103.8
(13) Olah, G. A.; Prakash, G. K. S.; Laali, K.; Li, Q. in Onium Ions;
Wiley: New York, 2000.
(14) Olah, G. A.; Burrichter, A.; Rasul, G.; Yudin, A. K.; Prakash,
G. K. S. J . Org. Chem. 1996, 61, 1934.
(11) (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, G.; Sanchez, G. V.; Lau, S.; DeLeon, S. J . Org.
Chem. 2000, 65, 8997. (c) See also: Prakash, G. K. S.; Rawdah, T. N.;
Olah, G. A. Angew. Chem., Int. Ed. Engl. 1983, 22, 390.
5030 J . Org. Chem., Vol. 67, No. 14, 2002

published analytical data. Low-temperature NMR experiments
were done according to published procedures.15
the proposed structures (33 and 34) as the ionization
product from amino acetal 5b.
Typ ica l P r oced u r e. 2-Meth yla m in o-1,1-d ip h en yleth a n e
(20). Methylaminoacetaldehyde dimethyl acetal (12) (0.37 g, 3.11
mmol) was dissolved in 2.0 mL of benzene, and 3.0 mL of TfOH
was slowly added. After 4 h of stirring, the mixture was poured
over ice and neutralized with NaOH. The product was then
extracted into CHCl3 and the organic phase washed with water
and then brine, dried with MgSO4, and concentrated in vacuo.
Crude 20 (0.58 g, 2.75 mmol, 88%) was isolated as a clear oil.
1H NMR and GC analysis of the crude product indicates a purity
in excess of 95%. Further purification was achieved by vacuum
distillation.
2-(2,2-Dip h en yleth yl)-2,3-d ih yd r oisoin d ol-1-on e (21). In
anhydrous DMF, aminoacetaldehyde dimethyl acetal (11) was
reacted with exactly 1 equiv of R,R′-dibromo-o-xylene to yield
crude 13. Crude 13 (ca. 0.2 g) was dissolved in 2 mL of C6H6,
and 2 mL of TfOH was added slowly. Following 2 h of reaction,
the mixture was poured over several grams of ice, made basic
with 12 M NaOH, and extracted twice by CHCl3. The organic
extracts were washed with water, washed with brine, and dried
with MgSO4. Concentration under reduced pressure and puri-
fication by column chromatography (1:1, hexane/ether) afforded
compound 21 (0.17 g) as a white, crystalline solid: mp 162-
164 °C (hexane/ether); 1H NMR (300 MHz, CDCl3) δ 4.04 (s, 2H),
4.24 (d, 2H, J ) 8.1 Hz), 4.51 (t, 1H, J ) 8.1 Hz), 7.15-7.35 (m,
11H), 7.40-7.50 (m, 2H), 7.80 (d, 1H, J ) 6.6 Hz); 1H NMR (125
MHz, CDCl3) δ 47.8, 50.4, 50.8, 122.8, 123.9, 127.1, 128.1, 128.3,
128.9, 131.4, 132.8, 141.5, 142.1, 169.0; IR (NaCl, cm-1) 1685;
MS (m/z) 313 (M+), 165, 146, 91. HRMS (DEI) m/z 313.147164,
calcd C22H19NO 313.146664.
We have found that amino acetal compounds 4-13
react with benzene in superacidic triflic acid to give
condensation products in good yields. It is proposed that
the reactions occur through dicationic, electrophilic in-
termediates. The acetal functional groups react in acid
to form carboxonium ions (27, Scheme 1) and the adjacent
ammonium cations induce an electrostatic or inductive
effect upon the carboxonium ions. The resulting desta-
bilized carboxonium ions are sufficiently electrophilic to
react with benzene, chlorobenzene, and 1,2-dichloroben-
zene.
Ack n ow led gm en t. Financial support from the Na-
tional Institutes of Health (SO6GM53933-0251) is grate-
fully acknowledged. The assistance of Mr. Siufu Lau is
appreciated and we thank Professors Olah and Prakash
at the University of Southern California for the use of
their NMR instrument.
Exp er im en ta l Section
Su p p or tin g In for m a tion Ava ila ble: General procedure
for the preparation of amino acetals 4a -7a and 4b-7b;
analytical data for compounds 14-20. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Compounds 8-12 and the bromoacetals were purchased from
commercial sources and used as received. Trifluoromethane-
sulfonic acid was purchased from a commercial source and
distilled under a dry, inert atmosphere immediately prior to its
use. Benzene was dried with sodium prior to use. All products
were fully characterized by 1H and 13C NMR and mass spec-
troscopy. Known compounds were found to be consistent with
J O0111558
(15) (a) Laali, K. K.; Okazaki, T.; Kumar, S.; Galembeck, S. E. J .
Org. Chem. 2001, 66, 780. (b) Prakash, G. K. S., Schleyer, P. v. R.,
Eds. Stable Carbocation Chemistry; Wiley: New York, 1997; pp 137-
163.
J . Org. Chem, Vol. 67, No. 14, 2002 5031