Olefinic-amide and olefinic-lactam cyclizations

Article abstract of DOI:10.1021/ol901448n

Image Presented Olefinic-amide and olefinic-lactam cyclization reactions that result in the generation of cyclic enamides are described.

Full text of DOI:10.1021/ol901448n

ORGANIC
LETTERS
2
009
Vol. 11, No. 16
774-3776
Olefinic-Amide and Olefinic-Lactam
Cyclizations
3
Jie Zhou and Jon D. Rainier*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East,
Salt Lake City, Utah 84112
rainier@chem.utah.edu
Received June 25, 2009
ABSTRACT
Olefinic-amide and olefinic-lactam cyclization reactions that result in the generation of cyclic enamides are described.
Small molecules that contain electron-rich olefins (enol ethers
and enamides) are both valuable in their own right and are
here, Bennasar and co-workers have successfully carried out
two-step olefinic-amide cyclizations to enamides. The
6
1
,2
interesting precursors to more elaborate substrates. Over
the past few years we have been interested in the generation
and use of cyclic enol ethers and have recently described
their synthesis from olefinic-ester and olefinic-lactone cy-
clizations using an in situ generated Ti reagent that is
Bennasar chemistry involves the initial conversion of amides
into mixtures of cyclic and acyclic enamides using dimeth-
yltitanocene followed by the conversion of the acyclic
enamides into the corresponding cyclic enamides using the
7
second generation Grubbs catalyst. With a limited number
3
presumed to be a Ti ethylidene. Although the corresponding
of substrates they observed a mixture of cyclic and acyclic
products from the dimethyltitanocene reaction. Representa-
tive of their results was the generation of indole 2 in 40%
overall yield from olefinic-amide 1. In addition to synthesiz-
ing indoles, they also generated dihydroquinolines and
dihydroisoquinolines using this chemistry. More problematic
was the use of the two-step protocol to generate seven-
membered ring substrates as olefin isomerization competed
4
olefinic-amide cyclizations would be synthetically useful,
to the best of our knowledge there are only two reports of
related reactions that employ amides. Takeda has described
Ti(II)-promoted cyclizations of dithianes having pendant
5
amides, and in work more closely related to that proposed
(
1) For representative examples of the use of enol ethers in synthesis,
see: (a) Castro, A. M. M. Chem. ReV. 2004, 104, 2939–3002. (b) Johnson,
H. W. B.; Majumder, U. J. Am. Chem. Soc. 2005, 127, 848–849
2) For representative examples of the use of enamides in synthesis,
.
(6) (a) Bennasar, M. L.; Roca, T.; Monerris, M.; Garc ´ı a-Diaz, D. J. Org.
Chem. 2006, 71, 7028–7034. (b) Bennasar, M.-L.; Roca, T.; Monerris, M.;
Garcia-Diaz, D. Tetrahedron Lett. 2005, 46, 4035–4038.
(
see: (a) Carbery, D. R. Org. Biomol. Chem. 2008, 6, 3455–3460. (b) Song,
Z.; Lu, T.; Hsung, R. P.; Al-Rashid, Z. F.; Ko, C.; Tang, Y. Angew. Chem.,
Int. Ed. 2007, 46, 4069–4072. (c) Huang, Y.; Iwama, T.; Rawal, V. H.
J. Am. Chem. Soc. 2000, 122, 7843–7844. (d) Harrison, T. J.; Patrick, B. O.;
(7) For examples of RCM cyclizations of enamides generated using non-
carbonyl olefination strategies, see: (a) Kinderman, S. S.; van Maarseveen,
J. H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, P. J. T. Org. Lett. 2001, 3,
2045–2048. (b) Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A. Angew.
Chem., Int. Ed. 2002, 41, 4732–4734. (c) Van Otterlo, W. A. L.; Pathak,
R.; de Koning, C. B. Synlett 2003, 1859–1861. (d) Rosillo, M.; Dominguez,
G.; Casarrubios, L.; Amador, U.; P e´ rez,-Castells, J. J. Org. Chem. 2004,
69, 2084–2093. (e) Katz, J. D.; Overman, L. E. Tetrahedron 2004, 60, 9559–
9568. (f) Manzoni, L.; Colombo, M.; Scolastico, C. Tetrahedron Lett. 2004,
45, 2623–2625. (g) Van Ortterlo, W. A. L.; Morgans, G. L.; Khanye, S. D.;
Aderibigbe, B. A. A.; Michael, J. P.; Billing, D. G. Tetrahedron Lett. 2004,
45, 9171–9175. Liu, G.; Tai, W.-Y.; Li, Y.-L.; Nap, F.-J. Tetrahedron Lett.
2006, 47, 3295–3298. (h) Toumi, M.; Couty, F.; Evano, G. J. Org. Chem.
2008, 73, 1270–1281.
Dake, G. R. Org. Lett. 2007, 9, 367–370
3) (a) Iyer, K.; Rainier, J. D. J. Am. Chem. Soc. 2007, 129, 12604–
2605. (b) Rohanna, J.; Rainier, J. D. Org. Lett. 2009, 11, 493–495. (c)
Zhang, Y.; Rainier, J. D. Org. Lett. 2009, 11, 237–239.
4) For reviews on the generation of heterocycles using a combination
.
(
1
(
of metathesis and alkylidenation, see: (a) Hartley, R. C.; Li, J.; Main, C. A.;
McKiernan, G. J. Tetrahedron 2007, 63, 4825–4864. (b) Hartley, R. C.;
Mckiernan, G. J. J. Chem. Soc., Perkin Trans. 1 2002, 2763–2793.
(
5) (a) Takeda, T.; Saito, J.; Tsubouchi, A. Tetrahedron Lett. 2003, 44,
5
571–5574. (b) Takeda, T.; Yatsumonji, Y.; Tsubouchi, A. Tetrahedron
Lett. 2005, 46, 3157–3160.
10.1021/ol901448n CCC: $40.75
Published on Web 07/23/2009
 2009 American Chemical Society

with cyclization. With some substrates they were able to
overcome this problem by adding dihydroquinone to the
reaction mixture.
enamide 9A. Bennasar’s procedure was more competitive here;
they were able to isolate a 50% overall yield of the seven-
membered ring substrate along with 7% of the corresponding
dihydroquinoline from olefin isomerization and cyclization.
Olefin isomerization does not appear to be a problem with the
titanium reagent.
Having established the viability of the olefinic-amide
cyclizations to aromatic substrates, we next explored the
cyclization of nonaromatic olefinic-lactams. When ε-capro-
lactam substrates 10, 11, and 12 were subjected to the
titanium ethylidene reagent, we isolated cyclic enamides 14C,
15C, and 16C as the exclusive products (Table 2, entries
8
When combined with our experience with olefinic-ester
and olefinic-lactone cyclizations, the Bennasar chemistry
outlined above peaked our interest in studying olefinic-amide
and olefinic-lactam cyclization reactions. Described here is
the successful use of in situ generated titanium ethylidenes
in this context.
To compare the titanium ethylidene reagent with Benna-
sar’s two-step protocol, we decided to initially examine the
cyclization of aromatic substrates 4-6. Concerned about
the potential reaction of carbonyl protecting groups with the
titanium reagent, i.e., Boc, CBz, etc., we opted to initially
avoid this potential problem by employing a Ts group in
this capacity. As illustrated in Table 1, the cyclization of
Table 2. Olefinic-Lactam Cyclizations
Table 1. Olefinic-Amide Cyclizations to Benzyl Fused
Enamides
a
b
c
entry
amide
n
enamide
yield (%)
C:A
1
2
3
4
a
10
11
12
13
1
2
3
4
14
15
16
17
70
80
82
70
b
>95:5
>95:5
>95:5
86:14
d
a
b
entry
amide
n
enamide
yield (%)
C:A
Combined yield of cyclic and acyclic enamide. From isolated cyclic
and acyclic enamides. Characterized as the corresponding aminal and/or
ketone (see Scheme 2). Minor product was the corresponding lactam in
c
1
2
3
a
4
5
6
0
1
2
7
8
9
70
78
76
b
>95:5
>95:5
76:24
d
which the alkene had undergone metathesis (see Supporting Information).
Combined yield of cyclic and acyclic enamides. From isolated cyclic
and acyclic enamide.
1
-3). Noteworthy because it is unlikely that this substrate
could be formed from an acyclic olefinic-enamide cyclization
was the fact that this chemistry was successful in the
ene-amide 5 gave a 78% yield of dihydroquinoline 8C (entry
9,10
generation of four-membered ring substrate 14C.
As with
2). Bennasar’s two-step protocol on a related substrate resulted
the aromatic substrate 6, lactam 13 gave a mixture of the
cyclized seven-membered enamide 17C and an uncyclized
product (entry 4).
in a 41% overall yield. The cyclization to indole 7C was also
successful, giving it in 70% yield versus 40% overall using the
two-step procedure (entry 1 and Scheme 1). Finally, the use of
Scheme 2. Enamide Derivatization
Scheme 1. Bennasar Synthesis of Indole 2 via RCM
Not surprisingly enamide 14C was not stable to SiO
chromatography. For characterization purposes, we converted
2
(
8) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2005, 127, 17160–17161.
9) In their synthesis of capnellene, the Grubbs group generated a
(
cyclobutene from a related ring-opening metathesis, carbonyl olefination
reaction. See: (a) Stille, J. R.; Grubbs, R. H. J. Am. Chem. Soc. 1986, 108,
ene-amide 6 resulted in a 58% yield of seven-membered ring
substrate 9C along with 18% of the corresponding acyclic
8
55–856. (b) Stille, J. R.; Santarsiero, B. D.; Grubbs, R. H. J. Org. Chem.
1990, 55, 843–862
.
Org. Lett., Vol. 11, No. 16, 2009
3775

1
4C into cyclobutanone 18 by subjecting it to aqueous acid
1
1
(
Scheme 2). Additionally, bromoaminal 19 was generated
1
2
Scheme 3. Olefinic-Amide Cyclizations
from the treatment of 14C with NBS in MeOH.
The lactam cyclizations are not limited to ε-caprolactam
substrates. Cyclic enamides 22C and 23C were the major
products from the cyclization of 2-pyrrolidinone 20 and
δ-valerolactam 21, respectively (entries 2 and 3, Table 3).
Table 3. Olefinic-Lactam Cyclizations
synthetically useful quantities but as a mixture with the
corresponding acyclic enamides. As a mechanistic test, we
did not observe the formation of 26C when we resubjected
acyclic enamide 26A to the reaction conditions. This is
consistent with the notion that cyclic enamide results from
a
b
entry
amide
n
enamide
yield (%)
C:A
1
3
an olefin-metathesis, carbonyl-olefination pathway.
1
2
3
a
12
20
21
3
1
2
16
22
23
82
75
78
b
>95:5
87:13
90:10
In summary, we have demonstrated that titanium eth-
ylidenes can be utilized in olefinic-amide and olefinic-lactam
cyclization reactions and that the efficiency of the reaction
depends somewhat on the nature of the substrate. We plan
to continue examining the scope of olefinic-carbonyl cy-
clizations and their use in total synthesis efforts.
combined yield of cyclic and acyclic enamine. ratio determined by
H NMR of the crude reaction mixture.
1
In contrast to the cyclization of ε-caprolactam substrate 12
to give 16C, however, these reactions did result in the
formation of small amounts of acyclic enamide.
As a final test of the methodology, we examined the
cyclization of methyl- and ethyl-substituted amides 24 and
Acknowledgment. We are grateful to the National Insti-
tutes of Health, General Medical Sciences (GM56677) for
support of this work. We would like to thank the support
staff at the University of Utah and especially Dr. Peter Flynn
(NMR) and Dr. Jim Muller (mass spectrometry) for help in
2
5 (Scheme 3) When these substrates were subjected to the
obtaining data.
titanium ethylidene reagent, cyclic enamide was isolated in
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
10) For selected examples of the use of four-membered rings in ring-
opening metathesis, see: (a) Maughon, B. R.; Grubbs, R. H. Macromolecules
1
2
997, 30, 3459–3469. (b) White, B. H.; Snapper, M. L. J. Am. Chem. Soc.
003, 125, 14901–145904. (c) Mori, M.; Wakamatsu, H.; Tonogaki, K.;
Fujita, R.; Kitamura, T.; Sato, Y. J. Org. Chem. 2005, 70, 1066–1069.
(
11) (a) Marion, F.; Coulomb, J.; Courillon, C.; Fensterbank, L.;
OL901448N
Malacria, M. Org. Lett. 2004, 6, 1509–1511. (b) Baktharaman, S.;
Selvakumar, S.; Singh, V. K. Org. Lett. 2006, 8, 4335–4338.
(
12) For related reactions of enamines see Hurley, P. B.; Dake, G. R. J.
(13) Allwein, S. P.; Cox, J. M.; Howard, B. E.; Johnson, H. W. B.;
Org. Chem. 2008, 73, 4131–4138.
Rainier, J. D. Tetrahedron 2002, 58, 1997–2009.
3776
Org. Lett., Vol. 11, No. 16, 2009