Additions of Cyclic Amides to Methylenecyclopropanes
Experimental Section
Representative Procedure for the Addition of Cyclic
Amides 16a to the Alkylidenecyclopropane 7c. To a
screw-capped Wheaton microreactor, containing Pd(PPh
3
)
4
(
17.3 mg, 0.015 mmol) and methylenecyclopropane (61.8 mg,
0.3 mmol), was added the cyclic amide (0.045 mL, 0.6 mmol)
under Ar atmosphere and the mixture was stirred at 120 °C
for the specified time. The reaction progress was monitored
with GC-MS. After completion, the turbid reaction mixture was
filtered through a short silica column with ethyl acetate as
eluent. Separation by passing through a florisil column (hex-
ane as the eluent) and purification by medium-pressure liquid
column chromatography (silica gel) with hexane as the eluent
afforded the allylation product 17a in 91% yield.
1
-(2-Methylene-3,3-diphenylpropyl)pyrrolidin-2-one
-
1 1
(
17a). IR (neat) 3352, 2939, 1680, 1597, 1490 cm . H NMR
CDCl , 400 MHz) δ 1.79 (t, J ) 5.0 Hz, 2H), 2.26 (t, J ) 8.2
Hz, 2H), 3.19 (t, J ) 5.4 Hz, 2H), 3.90 (s, 2H), 4.73 (d, J )
(
3
of σ-allylpalladium species, an intramolecular pallada-
ene reaction may take place as shown in 26, giving the
π-allylpalladium species 27. Reductive elimination of Pd-
1
3
1
6.4 Hz, 2H), 5.15 (s, 1H), 7.12-7.30 (m, 10H). C NMR
CDCl , 100 MHz) δ 44.3, 49.9, 55.2, 61.6, 116.3, 126.5, 128.3,
28.88, 128.89, 141.1, 146.2, 158.2. Anal. Calcd for C20
(
3
(
0) from 27 gives the intermediate 28, which leads to 25
1
H
21NO
upon deprotonation and bond rearrangement. We tested
(
291.39): C, 82.44; H, 7.26; N, 4.81; O, 5.49. Found: C, 82.38;
the effect of proton sources upon the yield of 25 (see the
20 21
H, 7.23; N, 4.79. HRMS (EI) Calcd for C H NO: m/z
Supporting Information). External addition of H
not exert any significant effects, but the use of CH
2
O did
CN
291.1623. Found: m/z 291.1618.
Representative Procedure for the Intramolecular
3
Hydroamination of Alkylidenecyclopropane 19a. To a
as a solvent was a key for the present interesting
cyclization. Other solvents, such as DMF and benzene,
were not suitable to the present reaction. The use of a
3 4 3
mixture of Pd(PPh ) (28.9 mg, 0.025 mmol) and P(O)n-Bu
(
(
8.4 mg, 0.075 mmol) was added methylenecyclopropane 19a
110.5 mg, 0.5 mmol), under Ar atmosphere in a screw-capped
+
strong H source was not suitable perhaps due to facile
Wheaton microreactor. After being heated at 120 °C for 2 days,
the mixture was filtered through a short florisil column with
ethyl acetate as an eluent. Separation by passing though a
florisil column (hexane/ethyl acetate as the eluent) and
purification by medium-pressure liquid column chromatogra-
phy (RP-18) with EtOAc as the eluent afforded adducts 20a
in 86% yield.
decomposition of the cyclopropyl derivatives
Conclusion
All cyclic amides reported here reacted with alky-
lidenecyclopropanes in good to high yields with high
regioselectivities. The intermolecular hydroamination of
methylenecyclopropanes with amines proceeds smoothly
in the presence of palladium catalyst, giving the ally-
lamines 11 or 15 in good to high yields. Here the
selectivity of the respective ring-opening position depends
on the substituents of methylenecyclopropanes. When the
amine pronucleophile was changed to cyclic amides, the
highly regioselective products 17 were obtained irrespec-
tive of the structure of the substituent of methylenecy-
clopropanes.
3-Methylene-4-phenyl-1,2,3,4-tetrahydroquinoline (20a).
-
1 1
IR (neat) 3397, 3077-2812, 1653, 1598, 1497, 1450 cm . H
NMR (CDCl , 400 MHz) δ 3.68 (d, J ) 12 Hz, 1H), 3.78 (d, J
12 Hz, 1H), 3.92 (br s, 1H), 4.69 (s, 1H), 5.00 (s, 1H), 5.06
s, 1H), 6.61 (d, J ) 8.0 Hz, 1H), 6.66 (t, J ) 7.3 Hz, 1H), 6.87
(d, J ) 6.6 Hz, 1H), 7.05 (t, J ) 7.4 Hz, 1H), 7.15-7.29 (m,
3
)
(
1
3
5H). C NMR (CDCl
117.9, 126.2, 127.4, 128.2, 128.3, 130.3, 144.0, 144.60, 144.64.
Anal. Calcd for C16 15N (221.29): C, 86.84; H, 6.83; N, 6.33.
Found: C, 86.81; H, 6.85; N, 6.31. HRMS (EI) Calcd for
15N: m/z 221.1204. Found: m/z 221.1199.
Representative Procedure for the Intramolecular
Hydroamination of Alkylidenecyclopropane 24. To a
mixture of Pd(PPh (28.9 mg, 0.025 mmol) in CH CN was
3
, 400 MHz) δ 46.1, 50.7, 110.9, 114.5,
H
16
C H
Furthermore, the intramolecular hydroamination of
alkylidenecyclopropanes 19 (or 24) proceeds smoothly in
the presence of Pd(0), giving the cyclic amines 20 (or 25)
in good yields. This reaction seems to be potentially
)
3 4
3
added methylenecyclopropane 24 (2.3 mg, 1.0 mmol), under
Ar atmosphere in a screw-capped Wheaton microreactor. After
being heated at 120 °C for 2 days, the mixture was filtered
through a short florisil column with ethyl acetate as an eluent.
Separation by passing though a florisil column (hexane/ethyl
acetate as the eluent) and purification by medium-pressure
liquid column chromatography (RP-18) with EtOAc as the
eluent afforded adducts 25 in 57% yield.
useful for the synthesis of various types of quinoline type
derivatives (eq 3),16 azepane type derivatives (eq 4),17 and
18
indolizine type derivatives (eq 5). This intramolecular
hydroamination reaction further seems to be desirable
from the eco-chemical point of view since most previous
syntheses of cyclic amines need a substitution process
and liberate a leaving group.1
1,2-Dimethylindolizine (25). IR (neat) 2919, 1716, 1628,
6-18
-1 1
6 6
1434 cm . H NMR (C D , 400 MHz) δ 1.77 (s, 3H), 1.79 (s,
3
H), 5.59-5.63 (m, 1H), 5.93-5.97 (m, 1H), 6.31 (s, 1H), 6.70-
13
6
3
.80 (m, 2H). C NMR (CDCl , 400 MHz) δ 8.4, 10.6, 108.8,
(
15) (a) Binger, P.; Schuchardt, U. Chem. Ber. 1980, 113, 3334. (b)
Nakamura, I.; Oh, B.-H.; Saito, S.; Yamamoto, Y. Angew. Chem., Int.
Ed. 2001, 40, 1298. (c) Oh, B.-H.; Nakamura, I.; Saito, S.; Yamamoto,
Y. Tetrahedron Lett. 2001, 42, 6203.
110.1, 114.9, 116. 6, 124,4, 128.4, 133.6, 133.8. HRMS (EI)
Calcd for C10 11N: m/z 145.0891. Found: m/z 145.0886.
H
(
16) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996,
2, 15031.
17) Gagan, J. M. F. Rodd’s Chemistry of Carbon Compounds, 2nd
Supporting Information Available: Experimental in-
formation including characterization data of all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
5
(
ed.; Coffey, S.. Ed.; Elsevier: Amsterdam, The Netherlands, 1979; Vol.
4
k, p 195.
(
18) Katritzky, A. R.; Qiu, G.; Yang, B.; He, H.-Y. J. Org. Chem.
999, 64, 7618.
1
JO050700S
J. Org. Chem, Vol. 70, No. 15, 2005 5937