Novel intramolecular rearrangement of tertiary propargylamine N-oxides

Full text of DOI:10.1021/jo0104779

J . Org. Chem. 2001, 66, 7219-7222
7219
Novel In tr a m olecu la r Rea r r a n gem en t of
Sch em e 1. Rea r r a n gem en t P r od u cts of P a r gylin
N-Oxid e (1) in Ap r otic a n d P r otic Med iu m
Ter tia r y P r op a r gyla m in e N-Oxid es
Anna Szab o´ and Istv a´ n Hermecz*
Chinoin Pharmaceutical and Chemical Works Ltd.,
Budapest, T o´ utca 1-5, Hungary H-1045
istvan.hermecz@sanofi-synthelabo.com.
Received May 9, 2001
In medicinal chemistry, propargylamines are consid-
ered to be suicide inhibitors,1 and their outstanding
representatives (e.g., pargyline2 and selegiline ) have
been introduced into human therapy, or used as phar-
macological tools, as selective monoamine oxidase inhibi-
3
4
tors (e.g., clorgiline ) or to produce experimental parkin-
5
sonism (tremorine ). When we studied the chemical
behavior of pargyline N-oxide (1) in protic media, we
recognized novel type of a solvent-dependent rearrange-
When the hydrochloride of 1 was heated in 5% aqueous
NaHCO solution at 70 °C for 1.5 h, besides enamino
3
ment of tertiary propargylamine N-oxides. Pargyline
N-oxide (1),6 a metabolite7 of the monoamine oxidase
aldehyde 3 (55%), acrylamide 4 (1.1%) could be isolated
from the reaction mixture. Compound 4 was identical to
the product of the reaction of N-methylbenzylamine and
acryloyl chloride. Compounds 3 and 4 were also obtained
in 24% and 6% yields, respectively, when 1 was heated
in boiling ethanol for 3 h.
From both aqueous and ethanolic media, 1-2% and
0-12% benzaldehyde (the hydrolytic product of N-
benzylidenemethylamine), respectively, could be identi-
fied with p-nitrophenylhydrazine.
8
inhibitor pargyline, and similar tertiary propargylamine
N-oxides9
-12
are known to undergo thermal Meisen-
heimer-type13 concerted [2,3] sigmatropic transformation
2 2 4
in aprotic media (CH Cl , THF, and CCl ), for example,
to yield O-propadienyl hydroxylamine (2), which readily
furnishes N-benzylidenemethylamine and propenal by a
1
[1,5] hydrogen shift.
Resu lts a n d Discu ssion
In protic media, however, two new products (3 and 4)
were isolated, whose formation can be interpreted only
by an assumption of new rearrangement (Scheme 1).
Whereas 1 was stable under acidic conditions (pH 1),
heating in a phosphate buffer at pH 7 at 90 °C for 2 h
led to the formation of enamino aldehyde 3 (66%) and
its hydrolytic product, N-methylbenzylamine (28%).
For the verification of the proposed mechanism, de-
picted in Scheme 3, we carried out isotope labeling and
repeated the same experiment with the methyl deriva-
tives 5 and 6.
No 18O isotope incorporation into products was ob-
1
8
served when 1 was heated in O-labeled water (10%),
but deuterium-labeled enamino aldehyde 7 and acryla-
mide 8 could be isolated from deutero derivative of 1 (R
) D), prepared in situ, in deuterium oxide. (The deute-
rium on C(2) in 7 could be easily changed for hydrogen
in water.)
(Enamino aldehyde 3 was also prepared from N-meth-
ylbenzylamine with propiolaldehyde in aqueous ethanol;
its spectroscopic properties are identical to those of the
product isolated from the above reaction mixture of 1.)
14
Two methyl derivatives (5 and 6 ) of pargyline N-oxide
were also included in the mechanistic studies. From 5,
only enamino ketone 9 (54%) was isolated, and no
formation of amide derivative could be detected (Scheme
2).
*
To whom correspondence should be addressed. Fax: 36-13-70-55-
9
7.
(
(
1) Abeles, R. H.; Maycock, A. L. Acc. Chem. Res. 1976, 9, 313-319.
2) Swett, L. R.; Martin, W. B. ; Taylor, J . D.; Everett, G. M.; Wykers,
A. A.; Gladish, Y. C. Ann. NY Acad. Sci. 1963, 107, 891-898.
The results of experiments in deuterium oxide and with
(
3) Knoll, J .; Ecsery, Z.; Magyar, K.; S a´ tory, EÄ . Biochem. Pharmacol.
5
indicate that the formation of enamino aldehyde/ketone
1
978, 27, 1739-1747.
(
(
4) J ohnston, J . P. Biochem. Pharmacol. 1968, 17, 1285-1297.
5) Everett, G. M.; Blockus, L. E.; Shepperd, I. M. Science 1956, 124,
(3, 9) does not involve propargyl group migration, which
10
is the case in the Meisenheimer rearrangement.
7
9.
(
6) Hallst o¨ m, G.; Lindeke, B.; Khuthier, A. H.; Al-Iraqi, M. A.
Because of the presence of the â hydrogens, compound
6 readily participates14 in Cope elimination
15-17
to give
Tetrahedron Lett. 1980, 21, 667-670.
7) Weli, A. M.; Lindeke, B. Biochem. Pharmacol. 1985, 34, 1993-
998.
8) Fowler, C. J .; Oreland, L.; Callingham, B. A. J . Pharm. Phar-
(
hydroxylamine 10 and vinylacetylene in CH
2
Cl
2
at 37 °C.
1
(
From an aqueous solution of the N-oxide 6 (where Cope
macol. 1981, 33, 341-347.
18
elimination is suppressed by solvation of the N-oxide)
(
(
9) Khuthier, A. H.; Al-Iraqi, M. A. Chem. Commun. 1979, 9-10.
10) Craig, J . C.; Ekwuribe, N. N.; Gruenke, L. D. Tetrahedron Lett.
1
979, 20, 4025-4028.
11) Khuthier, A. H.; Sheat, M. A. J . Prakt. Chem. 1989, 331, 187-
94.
12) Khuthier, A. H.; Sheat, M. A.; Al-Rawi, J . M. A.; Salih, Z. S. J .
Chem. Res., Synop. 1987, 184-185.
13) J ohnstone, R. A. W. Mech. Mol. Migr. 1969, 2, 249-266.
(14) Weli, A. M.; H o¨ o¨ k, B. B.; Lindeke, B. Acta Pharm. Suec. 1985,
22, 249-264.
(
1
(15) Cope, A. C.; Foster, T. T.; Towle, P. H. J . Am. Chem. Soc. 1949,
71, 3929-3935.
(
(16) Cope, A. C.; Trumbull, E. R. Org. React. 1960, 11, 361-370.
(17) DePuy, C. H.; King, R. W. Chem. Rev. 1960, 60, 448-451.
(
1
0.1021/jo0104779 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/18/2001

7
220 J . Org. Chem., Vol. 66, No. 21, 2001
Notes
Sch em e 2. Rea r r a n gem en t P r od u cts of P a r gylin
curred. The amide minor products 19 may form via
O-propadienyl hydroxylamine (17) through oxaziridinium
(
1) in D
2
O a n d Its Meth yl Der iva tives 5 a n d 6 in
P r otic Med iu m
1
8. This is supported by the formation of deuterated 8
in deuterium oxide. A similar mechanism was recently
described23 for the rearrangement of O-propargyl ke-
toximes to N-1-alkenylacrylamides. Rearrangement of a
condensed oxaziridinium salt into a lactam has also been
reported.24
In conclusion, the formation of enamino aldehydes and
acryl amides from tertiary propargylamine N-oxides in
protic media can be interpreted as a novel prototropic
rearrangement. The proposed rearrangement mechanism
is supported by isotopic labeling experiments and by
relevant literature data.
Exp er im en ta l Section
Gen er a l In for m a tion . All reagents were of com-
mercial quality. Phosphate buffer, pH 7.00, was pur-
chased from Merck. Organic extracts were dried with
6
anhydrous Na
2
SO
4
. Pargilin N-oxide (1), N-(1-butin-3-
at pH 12 at 80 °C, besides hydroxylamine 10 (53%), an
increased amount of crotonamide 11 (28%) was isolated.
When this reaction was carried out at pH 7, the signals
of enamino aldehyde 12 could be detected in the H NMR
spectrum of the crude reaction product [400.13 MHz,
14
yl)-N-methylbenzylamine N-oxide HCl (6‚HCl), and
25
1
-bromo-2-butyne were prepared according to the lit-
erature. Silica gel 60 (230-400 mesh, Merck) was used
1
for column chromatography, and precoated Kieselgel
6
0F254 preparative plates (2 mm, 20 × 20, Merck) were
used for preparative TLC. NMR spectra were recorded
in CDCl solution with TMS as an anternal reference at
00.13 MHz ( H), and 100.61 MHz ( C).
N-Ben zyl-N-m eth yl-3-a m in oa cr olein (3). To a solu-
CDCl , δ 5.30d (dCHCO) and 9.59d (CHO, J ) 8.1 Hz)].
3
Both the novel rearrangement and the previously
known [2,3] sigmatropic rearrangement depend on the
negatively charged oxide oxygen to attack the triple bond
as a nucleophile (see Scheme 3). At pH 1, this oxygen is
protonated so it is only very weakly nucleophilic, and
therefore, N-oxide is stable under acidic conditions.
The above experimental data suggest that the forma-
tion of enamino aldehyde/ketone-type derivatives 16 from
3
1
13
4
tion of propiolaldehyde, prepared from propiolaldehyde
diethyl acetal (640 mg, 5 mmol) in 0.2 N hydrochloric acid
solution (5 mL) at 40 °C for 0.5 h was added dropwise a
solution of N-methylbenzylamine (610 mg, 5 mmol) in
EtOH (5 mL). After being stirred for 2 h at 50 °C, the
reaction mixture was diluted with H O (20 mL), and
2
EtOH was distilled off. The pH of the aqueous phase was
adjusted to 12 with 1 N NaOH solution, and the reaction
1
3 involves a cyclic transition state 14, similar to 14′ in
1
0
the case of the Meisenheimer rearrangement (path B);
however, in protic medium instead of propargyl group
migration by splitting of the N-C bond, the cleavage of
the N-O bond (path A) occurs. After protonation, an
isoxazoline 15 formed, from which by a subsequent
deprotonation 16 formed. (It is interesting to note that
in the case of acetylenic ammonium ylide Ollis and co-
workers pointed out that beside the sigmatropic rear-
rangement in protic media, similar to path A, a betain
cyclic structure is formed.1 ) The suggested mechanism,
depicted in Scheme 3, is supported by the fact that the
yield of enamino aldehyde 3 in water is higher than in
ethanol as a consequence of the higher anion-solvating
mixture was extracted with Et
2
O. The ethereal solution
was washed with H O. The evaporation of the dried
2
organic phase gave an oil (830 mg) that was purified by
column chromatography (benzene-acetone, 9:1) to afford
3
enamino aldehyde 3 (500 mg, 57%). In CDCl , 3 exists
26
as a 7:3 mixture of s-trans and s-cis rotamers: IR (KBr)
-1
1
ν
4
0
6
6
max 1613 cm ; H NMR δ 2.77 (s, 2.1H), 3.10 (s, 0.9H),
.44 (s, 0.6H), 4.34 (s, 1.4H), 5.22 (dd, J ) 8.0, 12.0 Hz,
.7H), 5.29 (dd, J ) 8.0, 12.0 Hz, 0.3H), 7.19-7.38 (m,
9,20
13
H), 9.16 (d, J ) 8.0 Hz, 1H); C NMR δ 35.4, 43.0, 53.7,
1.6, 101.3, 126.9, 127.7, 128.4, 135.1, 159.9, 189.0.
2
1
tendency of water (acity ) than that of ethanol.
N-Ben zyl-N-m eth yla cr yla m id e (4). To a solution of
N-methylbenzylamine (610 mg, 5 mmol) in acetone (10
mL) was added dropwise a solution of acryloyl chloride
N-Methyl-4-isoxazolinium salts (20), prepared by quat-
ernization of neutral isoxazolines, were recently reported
to give enamino ketones 21 and enones 22 in competing
(490 mg, 5 mmol) in acetone (5 mL) in the presence of
reactions, through deprotonation of the 5-CH
methyl, respectively, under basic conditions22 (Scheme
).
During the formation of amide minor products 19,
migration of both oxygen and the propargyl group oc-
2
and N-
K
2
CO (690 mg) at ambient temperature. After being
3
stirred for 1 h, the reaction mixture was filtered and the
filtrate was treated with 1 N NaOH solution (20 mL).
4
The aqueous layer was extracted with CHCl
3
. The
chloroformic solution was washed with H O, dried, and
2
evaporated in vacuo to dryness. The oily residue was
treated with 0.1 N hydrochloric acid for 15 min at room
(
18) Sahyon, M. R. N.; Cram, D. J . J . Am. Chem. Soc. 1963, 85,
263-1268.
19) Ollis, W. D.; Sutherland, I. O.; Thebtaranonth, Y. J . Chem. Soc.,
Chem. Commun. 1973, 657-658.
20) Mageswaran, S.; Ollis, W. D.; Sutherland, I. O.; Thebtaranonth,
Y. J . Chem. Soc., Chem. Commun. 1971, 1494-1495.
21) Swain, C. G.; Swain, M. S.; Powell, A. L.; Alunni, S. J . Am.
Chem. Soc. 1983, 105, 502-513.
22) Chiacchio, U.; Casuscelli, F.; Liguori, A.; Rescifina, A.; Romeo,
G.; Sindona, G.; Uccella, N. Heterocycles 1993, 36, 585-600.
1
(
(23) Tromifov, B. A.; Tarasova, O. A.; Sigalov, M. V.; Mikhaleva, A.
I. Tetrahedron Lett. 1995, 36, 9181-9184.
(24) Pocalyko, D. J .; Coope, J . L.; Carchi, A., J .; Boen, L.; Madison,
S. A. J . Chem. Soc., Perkin Trans. 2 1997, 117-121.
(25) Marson, C. M.; Grabowska, U. ; Walsgrove, T.; Eggleston, D.
S.; Baures, P. W. J . Org. Chem. 1994, 59, 284-290.
(26) O¨ ki, M. Top. Stereochem. 1985, 14, 1-81.
(
(
(

Notes
J . Org. Chem., Vol. 66, No. 21, 2001 7221
Sch em e 3. P r op osed Mech a n ism of th e Rea r r a n gem en t of Ter tia r y P r op a r gyla m in e N-Oxid es
Sch em e 4
aldehyde 3 (20 mg, 4%). From the acidic aqueous solution,
after adjustment of pH to 12 with 1 N NaOH solution,
by extraction with benzene, and by evaporation of dried
organic phase a second corp of enamino aldehyde 3 (100
mg, 20%) was obtained from the oily residue (170 mg)
by preparative TLC.
Rea r r a n gem en t of 1 in Na HCO
tion of 1‚HCl (4.23 g, 20 mmol) and NaHCO
mmol) in H O (40 mL) was stirred at 70 °C for 1.5 h.
The aqueous reaction mixture was cooled to room tem-
perature and extracted with CHCl . The dried organic
layer was evaporated in vacuo to dryness. Column
chromatography (benzene-acetone, 9:1) of the oily resi-
due (2.89 g) gave benzaldehyde (70 mg), acrylamide 4 (40
mg, 1.1%), and enamino aldehyde 3 (1.92 g, 55%).
N-(2-Bu t in -1-yl)-N-m et h ylb en zyla m in e N-Oxid e
Hyd r och lor id e (5‚HCl). To a solution of N-methylben-
zylamine (3.63 g, 30 mmol) in acetone (40 mL) was added
dropwise a solution of 1-bromo-2-butyne25 (4.4 g, 33
3
Solu tion . A solu-
2
temperature, and then it was extracted with Et O. The
dried organic solution was evaporated in vacuo to dryness
to give colorless oily acrylamide 4 (610 mg, 69%). In
3
(2.02 g, 24
2
CDCl
rotamers:26 IR (KBr) νmax 1648 cm ; H NMR δ 2.99 (s,
.5H), 3.01 (s, 1.5H), 4.60 (s, 1H), 4.66 (s, 1H), 5.68 (dd,
J ) 10.4, 1.3 Hz, 0.5H) 5.75 (dd, J ) 10.4, 1.3 Hz, 0.5H),
.38 (dd, J ) 16.7, 1.3 Hz, 0.5H), 6.41 (dd, J ) 16.7, 1.3
Hz, 0.5H), 6.60 (dd, J ) 10.4, 16.7 Hz, 0.5H), 6.63 (dd, J
10.4, 16.7 Hz, 0.5H), 7.17-7.36 (m, 5H); 13C NMR δ
3
, 4 exists as a 1:1 mixture of s-trans and s-cis amide
-1
1
3
1
6
)
3
1
3.8, 34.6, 50.8, 53.1, 126.1,127.0, 128.0, 127.4, 128.0,
28.2, 128.7, 136.4, 136.9, 166.3, 166.8.
Rea r r a n gem en t of 1 in a P h osp h a te Bu ffer , p H
.00. A solution of 1‚HCl (430 mg, 2 mmol) and NaOH
mmol) in acetone (20 mL) in the presence of K
g), and the reaction mixture was stirred at room tem-
perature for 5 h. The excess of K CO was filtered off.
2 3
CO (8.28
7
(
80 mg, 2 mmol) in a phosphate buffer, pH 7.00 (100 mL),
was stirred at 90 °C for 2 h. The reaction mixture was
cooled to room temperature and extracted with CH Cl
The dried organic extract was evaporated in vacuo to
dryness. The residue was treated with Et O (15 mL).
2
3
The filtrate was evaporated in vacuo to dryness. The
residue was dissolved in 1 N hydrochloric acid solution
2
2
.
(
60 mL), which was extracted with ethyl acetate, then
the pH of aqueous solution was adjusted to 12 with 1 N
NaOH solution and extracted with CHCl . The dried
organic phase was evaporated in vacuo to dryness, and
the residue was treated with Et O (100 mL). The de-
2
Decanted ethereal solution was evaporated to give oily
enamino aldehyde 3 (230 mg, 66%). From the aqueous
phase, after adjustment of pH to 13 with 10% NaOH
3
2
solution, and extraction with CH
of the dried organic extract N-methylbenzylamine HCl
90 mg, 28%, mp 263 °C (lit.27 mp 262-263 °C)) was
2 2
Cl , then evaporation
canted ethereal solution was evaporated to give N-(2-
butin-1-yl)-N-methylbenzylamine (2.69 g, 55%) as a
colorless oil.
N-(2-Butin-1-yl)-N-methylbenzylamine (2.04 g, 11.8
3
mmol) was oxidized in CHCl (40 mL) with m-CPBA (4.46
g, 13 mmol) at 5 °C for 1.5 h. To the reaction mixture
was added EtOH saturated with HCl gas (15 mL), and
the reaction mixture was evaporated. The residue was
(
obtained by the treatment of the ethereal solution of the
residue with HCl gas.
Rea r r a n gem en t of 1 in Eth a n ol. A solution of 1 (500
mg, 2.9 mmol) in EtOH (10 mL) was heated at reflux for
3
h. After evaporation of the reaction mixture, the residue
was dissolved in 0.1 N hydrochloric acid (10 mL), and
the aqueous phase was extracted with benzene. The dried
organic phase was evaporated in vacuo to dryness. The
first treated with Et
tallized from a 1:1 mixture of Et
2
O (40 mL), and then it was recrys-
O and acetone and
2
finally from acetone to afford HCl salt of N-oxide 5 (820
residue was treated with Et
real solution was concentrated. The preparative TLC
benzene-acetone, 3:1) of the light brown oil gave ben-
zaldehyde, acrylamide 4 (30 mg, 6%), and enamino
2
O (30 mL). Decanted ethe-
mg, 31%. mp 132-133 °C): 1H NMR δ 2.01 (s, 3H), 3.61
(s, 3H), 4.32 (d, J ) 16.1 Hz, 1H), 4.48 (d, J ) 16.1 Hz,
(
1
7
H), 4.88 (d, J ) 12.8 Hz, 1H), 5.03 (d, J ) 12.8 Hz, 1H),
.35-7.67 (m, 5H), 12.7 (brs, 1H).
Rea r r a n gem en t of 5‚HCl in Wa ter in th e P r es-
(
27) Meidl, W. R.; von Angerer, E.; Sch o¨ nenberger, H.; Ruckdeschel,
G. J . Med. Chem. 1984, 27, 1111-1118.
en ce of NEt . A solution of 5‚HCl (450 mg, 2 mmol) and
3

7
222 J . Org. Chem., Vol. 66, No. 21, 2001
Notes
NEt
3
(242 mg, 2.4 mmol) in H
2
O (10 mL) was stirred at
s-trans and s-cis amide rotamers:26 1H NMR δ 1.85 (d, J
) 7.0 Hz, 1.5H), 1.91 (d, J ) 7.0 Hz, 1.5H), 2.98 (s, 3H),
4.49 (s, 2H), 4.65 (s, 2H), 6.28 (d, J ) 15.0 Hz, 0.5H),
6.33 (d, J ) 15.0 Hz, 0.5H), 6.97 (m, 1H), 7.17-7.39 (m,
5H); 13C NMR δ 18.2, 34.0, 34.8, 51.0, 53.3, 121.5, 126.2-
128.8, 141.9, 166.8, 167.4.
7
0 °C for 1.5 h. The reaction mixture was cooled to room
temperature and extracted with ethyl acetate (3 × 10
mL). The combined organic solution was washed with
brine and H
was dissolved in Et
2
O, dried, and evaporated. The oily residue
O (20 mL), the ethereal solution was
2
filtered and evaporated. The residue was purified on
preparative TLC (toluene-acetone, 3:1) to give enamino
ketone 9 (200 mg, 54%) as yellow oil: 1H NMR δ 2.09 (s,
Hydroxylamine HCl, 10‚HCl (160 mg, 53%, mp 132-
28
1
33 °C, base mp 40 °C (lit. mp 40-41 °C)) was obtained
from the aqueous layer after the adjustment of the pH
to 12 with a 1 N NaOH solution, and extraction with CH
Cl , then evaporation the dried organic phase, and the
3
7
H), 2.69 (s, 3H), 4.36 (s, 2H), 5.14 (d, J ) 12.0 Hz, 1H),
.09-7.30 (m, 5H), 7.66 (d, J ) 12.0 Hz, 1H).
Rea r r a n gem en t of N-(1-Bu tin -3-yl)-N-m eth ylben -
2
-
2
saturation of the ethereal solution of the residue with
HCl gas.
zyla m in e N-Oxid e HCl (6‚HCl) in a n Aqu eou s 0.025
1
4
N Na OH Solu tion . A solution of 6‚HCl (330 mg, 1.46
mmol) in an aqueous 0.025 N NaOH solution (100 mL)
was stirred at 80 °C for 2 h. The pH of the reaction
mixture was adjusted to 1 with 1 N hydrochloric acid (40
Ack n ow led gm en t. The authors are indebted to Drs.
G e´ za Tim a´ ri and David Durham for their invaluable
suggestions and helpful comments.
2
mL), and the aqueous solution was extracted with Et O.
The dried organic phase was evaporated, and the oily
residue was purified on preparative TLC (toluene-
acetone, 3:1) to afford crotonamide 11 (80 mg, 28%) as a
J O0104779
(28) Hassan, A.; Wazeer, M. I. M.; Perzanowski, H. P.; Ali, Sk. A.
3
colorless oil. In CDCl , 11 exists as a 1:1 mixture of
J . Chem. Soc., Perkin Trans. 2 1997, 411-418.