Palladium-Catalyzed Ring-Opening Reaction of Methyleneaziridines with Carboxylic Acids: Synthesis of α-Amidoketones

Article abstract of DOI:10.1021/jo035739g

In the presence of palladium catalysts, the reaction of methyleneaziridines 1 with carboxylic acids 2 proceeded smoothly to give the corresponding α-amidoketones 3 in good to high yields.

Full text of DOI:10.1021/jo035739g

P a lla d iu m -Ca ta lyzed Rin g-Op en in g
Rea ction of Meth ylen ea zir id in es w ith
Ca r boxylic Acid s: Syn th esis of
r-Am id ok eton es
Byoung Ho Oh, Itaru Nakamura, and
Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science,
Tohoku University, Sendai 980-8578, J apan
yoshi@yamamoto1.chem.tohoku.ac.jp
Received November 26, 2003
F IGURE 1. The reaction of methyleneaziridines with (A)
strong electrophiles and organometallics, (B) carbon mono-
oxide, and (C) active methynes.
Abstr a ct: In the presence of palladium catalysts, the
reaction of methyleneaziridines 1 with carboxylic acids 2
proceeded smoothly to give the corresponding R-amido-
ketones 3 in good to high yields.
of a palladium catalyst to give the R-amidoketones 3 in
good to high yields (eq 1).
Small ring compounds, such as oxiranes, aziridines,
vinylcyclopropanes, and methylenecyclopropanes, have
been widely utilized as synthetic intermediates for
organic synthesis. Recently a series of methyleneaziri-
dines 1 has been focused on as a new substrate of small
heterocycles. Generally, the reaction of methyleneaziri-
dines with strong electrophiles and organometallics
The results are summarized in Table 1. In the presence
of catalytic amounts of Pd
2
(dba)
3
‚CHCl
3
(5 mol %) and
PPh (10 mol %), the reaction of 1-benzyl-2-methylene-
3
aziridine 1a (0.75 mmol) with acetic acid 2a (0.5 mmol)
in THF at 100 °C gave R-amidoketone 3a in 75% yield
proceeds through ring opening at the N-C3 bond (Figure
,2
1
, A).1 Although the transition metal-catalyzed reactions
(entry 1). The use of Pd(PPh
less effective, and Pd(PPh
promote the reaction at all. The reaction of 1a and 2a
with other phosphine ligands, such as P(o-tolyl) , P(2-
furyl) , dppf, and P(O)Bu , instead of PPh afforded 3a
3
)
2
Cl
2
/PPh
3
as a catalyst was
of a wide variety of small-ring compounds have been
studied for the last several years, the catalytic reactions
of methyleneaziridines rarely have been investigated.
Alper’s group reported palladium-catalyzed carbonylation
of methyleneaziridines, which proceeded through N-C2
3
)
2
Cl
2
and Pd(OAc)
2
did not
3
3
3
3
in a lower yield. The reaction in other solvents, such as
toluene and acetonitrile, proceeded sluggishly. The reac-
tion of 1a and 2a at 60 °C gave 3a in 51% yield along
with a trace amount of the starting material 1a . In the
absence of palladium catalysts, the reaction of 1a with
2a in THF at 100 °C gave a complex mixture of unidenti-
fied products, indicating that a palladium catalysts is
essential to the transformation of 1a to 3a . The reactions
of 1a with benzoic acid 2b and pentenoic acid 2c afforded
3b and 3c in yields of 87% and 71%, respectively (entries
3
bond cleavage (B). Quite recently, we found that the
hydrocarbonation reaction of the double bond of meth-
yleneaziridines 1 with carbon pronucleophiles proceeded
smoothly in the presence of catalytic amounts of pal-
ladium giving the non-ring-opened products (C).4
We now report that methyleneaziridines 1 react with
carboxylic acids 2, as a pronucleophile, in the presence
*
Address correspondence to this author. Phone: +81-22-217-6581.
Fax: +81-22-217-6784.
1) For ring-opening reactions of methyleneaziridines through N-C3
2
and 3). The reaction of 1a with hippuric acid 2d
(
proceeded smoothly and the corresponding R-amido-
ketone 3d was produced in 57% yield (entry 4). The
reaction of 1-hexyl-2-methyleneaziridine 1b and 1-butyl-
bond cleavage. See: (a) Bottini, A. T.; Roberts, J . D. J . Am. Chem.
Soc. 1957, 79, 1462. (b) J ongejan, E.; Steinberg, H.; De Boer, T. J . Recl.
Trav. Chim. Pays-Bas 1978, 97, 146. (c) J ongejan, E.; Steinberg, H.;
De Boer, T. J . Recl. Trav. Chim. Pays-Bas 1979, 98, 66. (d) Ince, J .;
Shipman, M.; Ennis, D. S. Tetrahedron Lett. 1997, 38, 5887. (e) Ennis,
D. S.; Ince, J .; Rahman, S.; Shipman, M. J . Chem. Soc., Perkin Trans.
2
-methyleneaziridine 1c with 2b afforded 3e and 3f in
yields of 69% and 66%, respectively (entries 5 and 6).
Methyleneaziridines bearing a methoxy group (1d ) and
or an acetal group (1e), upon treatment with 2b, were
converted to 3g and 3h in 62% and 67% yield, respec-
tively (entries 7 and 8).
1
2000, 2047. (f) Quast, H.; Weise Velez, C. A. Angew. Chem., Int. Ed.
Engl. 1974, 13, 342. (g) Hayes, J . F.; Shipman, M.; Twin, H. Chem.
Commun. 2000, 1791. (h) Hayes, J . F.; Shipman, M.; Twin, H. Chem.
Commun. 2001, 1784. (i) Hayes, J . F.; Shipman, M.; Twin, H. J . Org.
Chem. 2002, 67, 935. (j) Bottini, A. T.; Roberts, J . D. J . Am. Chem.
Soc. 1962, 84, 195.
(
2) For ring-opening reaction of methyleneaziridines through N-C2
A plausible mechanism for the ring-opening reaction
is illustrated in Scheme 1. The oxidative addition of
palladium(0) into an O-H bond of the carboxylic acid 2
would give the hydridopalladium complex 4. The hydro-
palladation of a double bond of methyleneaziridines 1
with 4 would give 5. Reductive elimination of palladium-
(0) would give the N,O-acetal 6. Thermal rearrangement
bond cleveage see: Crandall, J . K.; Crawley, L. C.; Komin, J . B. J . Org.
Chem. 1975, 40, 2045.
(3) Pd-catalyzed ring-expansion reaction of methyleneaziridine with
carbon monoxide: Pd(0) catalyst inserts into the N-C2 bond of
methyleneaziridines: Alper, H.; Hamel, N. Tetrahedron Lett. 1987, 28,
237.
(
3
4) Oh, B. H.; Nakamura, I.; Yamamoto, Y. Tetrahedron Lett. 2002,
4
3, 9625.
1
0.1021/jo035739g CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/11/2004
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856
J . Org. Chem. 2004, 69, 2856-2858

TABLE 1. P a lla d iu m -Ca ta lyzed Rin g-Op en in g Rea ction of Meth ylen ea zir id in es 1 w ith Ca r boxylic Acid s 2a
a
The reaction of 1 (0.75 mmol) and 2 (0.5 mmol) was carried out in the presence of 5 mol % of Pd2(dba)3‚CHCl3 and 10 mol % of PPh3
in THF at 100 °C. b Isolated yield based on 2.
SCHEME 1
carried out. The reaction of 1a with 2a -d under the same
reaction conditions as above gave 3a -d in 70% yield in
which the deuterium content at the R-position of 3a -d
was 93% (eq 2). This result is in good agreement with
the proposed mechanism.
We and other groups reported the transition metal-
catalyzed addition of carboxylic acids to carbon-carbon
6
7
8
multiple bonds such as 1,3-dienes, alkynes, enynes, and
(
(
5) Sato, S.; Kato, H.; Ohta, M. Bull. Chem. Soc. J pn. 1967, 40, 2938.
6) (a) Walker, W. E.; Manyik, R. M.; Atkins, K. E.; Farmer, M. L.
of 6 would cleave a N-C2 bond giving R-amidoketone
Tetrahedron Lett. 1970, 11, 3817. (b) Rose, D.; Lepper, H. J . Organomet.
Chem. 1973, 49, 473.
products 3.5
(7) (a) Mitsudo, T.; Hori, Y.; Yamakawa, Y.; Watanabe, Y. J . Org.
To lend support to the proposed mechanism, the
reaction with deuterated acetic acid (2a -d, 98% D) was
Chem. 1987, 52, 2230. (b) Doucet, H.; Martin-Vaca, B.; Bruneau, C.;
Dixneuf, P. H. J . Org. Chem. 1995, 60, 7247.
J . Org. Chem, Vol. 69, No. 8, 2004 2857

9
allenes. It is most probable that the ring-opening reac-
methodology is applicable for such biologically active
molecules.10
tion of methyleneaziridines 1 occurs via the palladium-
catalyzed addition of carboxylic acids 2 to the CdC double
bond of 1. Accordingly, it seems that the addition of
carboxylic acids to reactive unsaturated C-C multiple
bonds is of a class of reactions widely seen in the presence
of transition metal catalysts.
Exp er im en ta l Section
Gen er a l P r oced u r e of th e Rin g-Op en in g Rea ction of
Meth ylen ea zir id in es 1 w ith Ca r boxylic Acid s 2. To a
mixture of Pd
2
(dba)
3
3
‚CHCl (25.9 mg, 0.025 mmol) and tri-
phenylphosphine (13.9 mg, 0.05 mmol) and the carboxylic acid
2 (0.5 mmol) in THF (1 mL) was added methyleneaziridine
1
2
It is clear that the palladium-catalyzed ring-opening
reaction of methyleneaziridines proceeds through a to-
tally different reaction pathway from the Brønsted acid-
promoted ring-opening reaction of methyleneaziridines
. The Brønsted acid-promoted reaction proceeds through
protonation of a nitrogen atom of methyleneaziridines
1
(0.75 mmol) under Ar atmosphere in a pressure vial. After being
heated at 100 °C for 2-5 h, the reaction mixture was filtered
through a silica gel column, using ethyl acetate as an eluent.
Separation by passage through a silica gel column and purifica-
tion by middle-pressure liquid column chromatography (silica
gel) and recrystallization afforded R-amidoketone 3.
1
followed by nucleophilic attack to the aziridine ring (7)
leading to ring opening at the N-C3 bond (8).
N-Ben zyl-N-(2-oxop r op yl)a ceta m id e (3a ). White solid: IR
(KBr) 3035-2937, 1728, 1633, 1494, 1469, 1454, 1419, 1359
1
a-c
-
1 1
3
cm . H NMR (CDCl , 500 MHz) δ 2.03 (s, 3H, minor), 2.08 (s,
3
H, minor), 2.11 (s, 3H, major), 2.22 (s, 3H, major), 4.00 (s, 2H,
minor), 4.12 (s, 2H, major), 4.58 (s, 2H, major), 4.60 (s, 2H,
1
3
minor), 7.17-7.38 (m, 5H, major and m, 5H, minor). C NMR
CDCl , 125 MHz, M ) major conformer, m ) minor conformer)
δ 21.1 (M), 21.3 (m), 27.0 (m), 27.2 (M), 49.5 (m), 52.8 (M), 54.8
(
3
(
(
(
M), 57.1 (m), 126.6 (M), 127.6 (m), 127.8 (M), 128.3 (m), 128.6
m), 128.9 (M), 136.0 (M), 136.7 (m), 171.0 (m), 171.2 (M), 202.7
m), 203.1 (M). Anal. Calcd for C12H15NO (205.25): C, 70.22;
2
In conclusion, we have developed a new method for the
synthesis of R-amidoketones via hydrocarboxylation of
methyleneaziridines in the presence of a palladium
catalyst. The structural unit of R-amidoketones is often
H, 7.37; N, 6.82. Found: C, 70.03; H, 7.50; N, 6.56. HRMS (EI)
Calcd for C12 : m/z 205.1103. Found: m/z 205.1104.
H
15NO
2
Su p p or tin g In for m a tion Ava ila ble: Experimental in-
formation including characterization data of all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
found in biologically important compounds such as
enzyme inhibitors.10 It is expected that the present
J O035739G
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(
(
9) Al-Masum, M.; Yamamoto, Y. J . Am. Chem. Soc. 1998, 120, 3809.
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9
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