Toward the synthesis of biologically important chlorins, isobacteriochlorins, and corrins. Cyclic enamides from acetylenic amides

Article abstract of DOI:10.1021/jo960428+

Cyclic enamides 1 of a type useful in the synthesis of naturally occurring chlorins, isobacteriochlorins, and corrins have been prepared by a process involving 5-exo-dig cyclization of the appropriate acetylenic amides 11. The desired cyclization is catalyzed by either n-Bu₄NF or LiAl-(NHBn)₄.

Full text of DOI:10.1021/jo960428+

J . Org. Chem. 1996, 61, 5013-5023
5013
Tow a r d th e Syn th esis of Biologica lly Im p or ta n t Ch lor in s,
Isoba cter ioch lor in s, a n d Cor r in s. Cyclic En a m id es fr om
Acetylen ic Am id es
Peter A. J acobi,* Harry L. Brielmann, and Sheila I. Hauck
Hall-Atwater Laboratories, Wesleyan University, Middletown, Connecticut 06459-0180
Received March 1, 1996X
Cyclic enamides 1 of a type useful in the synthesis of naturally occurring chlorins, isobacterio-
chlorins, and corrins have been prepared by a process involving 5-exo-dig cyclization of the
appropriate acetylenic amides 11. The desired cyclization is catalyzed by either n-Bu4NF or LiAl-
(NHBn)4.
In tr od u ction
chenmoser et al. published an improved synthesis of 7
that made elegant use of enamide derivatives 3-5 and
pyrroline 6 for assembling the corrin skeleton.2a Not
surprisingly, highly substituted ring systems of type 3-6
are themselves a significant synthetic challenge. For
example, the simplest member of this group, enamide 5,
was prepared in nine steps from acyclic starting materi-
als in an overall yield of ∼2% (including resolution).2a
Alternatively, 5 could be derived in seven steps by
degradation of (+)-camphor.2b,c Similar difficulties have
been encountered in the syntheses of related enamides
of type 1, particularly those in which Y ) H.
Numerous strategies have been employed for the
synthesis of enamide derivatives of general structure 1.3
However, most approaches make use of keto amide
cyclizations of type 9 f 10, in which carbinolamide
formation is followed by dehydration (Scheme 1). This
last step frequently requires forcing conditions (T > 150
°C), which can cause decomposition of the highly sensitive
1. Also, substituted keto amides of type 9 are themselves
difficult to prepare, in particular in enantiomerically pure
form. In this paper we describe an alternative strategy
for the synthesis of enamides 1 (Y ) H, CO2Me) that
involves direct cyclization of acetylenic amides of type
11. This route has the advantage of proceeding under
mild conditions from readily available starting materials
(vide infra),4,5a and it has been utilized in efficient
syntheses of two potential ring C precursors of vitamin
B12.4c
Cyclic enamides of type 1 are an important functional-
ity in natural products chemistry, and they have been
utilized in either free or protected form 2 in the synthesis
of species such as as prostaglandin analogs,1a -lactam
antibiotics,1b peptide mimics,1c angiotensin II antagonists,1d
and other biologically active compounds (Figure 1).1e In
addition, they form the skeleton of macrocyclic tetrapyr-
roles of the chlorin, isobacteriochlorin, and corrin oxida-
tion level. Members of the latter class serve important
biological functions as vitamins, cofactors, and light-
absorbing pigments, and the stereochemical complexities
associated with such ring systems can be enormous.1f
Sch em e 1
F igu r e 1.
A landmark study in this area was the early work of
Woodward and Eschenmoser,2b which culminated in the
total synthesis of cobyric acid (7), a known precursor to
vitamin B12 (8) (Figure 1), perhaps the most complicated
of the naturally occurring corrins. Subsequently, Es-
X Abstract published in Advance ACS Abstracts, J uly 1, 1996.
(1) (a) Barco, A.; Benetti, S.; Pollini, G. P. J . Org. Chem. 1979, 44,
1734. (b) Hashiguchi, S.; Natsugari, H.; Ochiai, M. J . Chem. Soc.,
Perkin Trans. 1 1988, 2345. (c) Abell, A. D.; Taylor, J . M. J . Org. Chem.
1993, 58, 14. (d) Murray, W. V.; Lalan, P.; Gill, A.; Addo, M. F.; Lewis,
J . M.; Lee, D. K. H.; Wachter, M. P.; Rampulla, R.; Underwood, D. C.
Bioorg. Med. Chem. Lett. 1993, 369, 785. (e) J ames, G. D.; Pattendon,
G.; Mills, S. D. Tetrahedron Lett. 1985, 26, 3617. (f) Flitsch, W. In
Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic
Press, Inc.: San Diego, 1988; Vol. 43, p 74 (Hydrogenated Porphyrin
Derivatives: Hydroporphyrins).
(2) (a) Eschenmoser, A.; Wintner, C. E. Science 1977, 196, 1410 and
references cited therein. See also: (b) Woodward, R. B. Pure Appl.
Chem. 1968, 17, 519; (c) 1971, 25, 283; (d) 1973, 33, 145. (e)
Eschenmoser, A. Q. Rev. 1970, 24, 366. (f) Eschenmoser, A. Pure Appl.
Chem. Suppl. 1971, 2, 69. (g) Eschenmoser, A. Naturwissenshaften
1974, 61, 513. (h) Eschenmoser, A. Angew. Chem., Int. Ed. Engl. 1988,
27, 5.
S0022-3263(96)00428-8 CCC: $12.00 © 1996 American Chemical Society

5014 J . Org. Chem., Vol. 61, No. 15, 1996
J acobi et al.
Discu ssion a n d Resu lts
The conversion of 14 to 15 provided reasonable prece-
dent for the desired 5-exo-dig cyclization leading from
acetylenic amide 11 to monocyclic enamide 1 (cf. Scheme
1). However, for the case of 14 f 15, intramolecular
nucleophilic addition is facilitated by the pyrroloester
substituent, which renders the alkyne relatively electron
deficient. It was uncertain whether such cyclizations
would be possible with simple unactivated alkynes. In
order to study this question, we prepared a series of
simple N-unsubstituted amides 18, which in the case of
18a -c were derived in 77-93% yield from the known
carboxylic acids 17a -c using isobutyl chloroformate
(IBCF) and NH3 (Scheme 3).9 Enantiomerically pure
We have recently reported that Pd(0)-mediated cou-
pling of acetylenic amides 12 with iodopyrroles 13 affords
excellent yields of acetylenic pyrroles of type 14,6,7 which
upon fluoride ion-catalyzed 5-exo-dig cyclization gave
dihydropyrromethenones 15 having the 5(Z)-stereochem-
istry (Scheme 2).4 These materials are attractive precur-
Sch em e 2
Sch em e 3
amides 18e,f and racemic amide 18d were prepared in
excellent overall yield as previously described for acety-
lenic amides 1 using the Nicholas-Schreiber method-
ology.4,5a Acetylenic amides 18 turned out to be relatively
unreactive toward direct cyclization to enamides 19,
affording at best a 10-20% yield of 19d and a 5-10%
yield of 19c upon heating with n-Bu4NF in refluxing THF
(65-67 °C, 24-48 h).4b It appears that cyclizations of
this type are feasible only with highly substituted
substrates, in particular those containing geminal di-
methyl substituents (Thorpe-Ingold effect10). No cy-
clization occurred with 18a or 18e,f. Also, higher reac-
tion temperatures and/or longer reaction times led to
substantial decomposition. These results are in marked
contrast to those obtained with activated alkynes of type
14, which afforded dihydropyrromethenones 15 in >85%
yields under identical conditions (cf. Scheme 1).4b In the
case of 14, the pyrroloester substituent undoubtedly
facilitates nucleophilic addition to the alkyne.
We next explored the possibility that enamides 19
might be derived by Pd(II)-catalyzed cyclization of 18 to
vinyl-Pd species 20, followed by protonolysis of the
carbon-Pd bond (Scheme 4).11a-c Since palladium is not
reduced in such cyclizations, no cooxidant is required.
Many such examples have been documented with related
systems,11a-c and we expended considerable effort in
investigating this route. However, this direct approach
was precluded by the extreme acid sensitivity of terminal
enamides 19, which rapidly decompose at pH < 4.
Equally discouraging results were obtained with a wide
range of reagents that have been successfully employed
sors for biologically important linear tetrapyrroles such
as phytochrome (16a ), phycocyanin (16b), and phyco-
erythrin (16c).8 The utility of this approach stems partly
from the fact that a wide variety of ring-A synthons 12
(and ent-12) are available by Nicholas-Schreiber reaction
of chiral ester enolates with cobalt-stabilized propargylic
cations (dashed line in 12).4,5 We expected that a similar
approach could be utilized for the synthesis of acetylenic
amides of type 11 (cf. Scheme 1).
(3) See, for example: (a) Walton, E. J . Chem. Soc. 1940, 439. (b)
Schulte, K. E.; Reisch, J . Arch. Pharm. 1959, 292, 51. (c) Schulte, K.
E.; Reisch, J .; Hobl, R. Arch. Pharm. 1960, 293, 687. (d) Eschenmoser,
A. Angew. Chem., Int. Ed. Engl. 1964, 3, 490; 1969, 8, 343. (e) Scheffold,
R.; Lo¨liger, J .; Blaser, H.; Geisser, P. Helv. Chim. Acta 1975, 58, 49.
(f) Gossauer, A.; Kuhne, G. Liebigs Ann. Chem. 1977, 664. (g)
Cannizarro, L. F.; Grubbs, R. H. J . Org. Chem. 1985, 50, 2316. (h)
Ribo, J . M.; Serra, X. Monatsh. Chem.1986, 117, 185. (i) J ones, R. C.
F.; Begley, M. J .; Peterson, G. E.; Sumaria, S. J . Chem. Soc, Perkin
Trans. 1 1990, 1959. (j) Micklefield, J .; Mackman, R. L.; Aucken, C.
J .; Beckmann, M.; Block, M. H.; Leeper, F. J .; Battersby, A. R. J . Chem.
Soc., Chem. Commun. 1993, 275. (k) Abell, A. D.; Oldham, M. D.;
Taylor, J . M. J . Org. Chem. 1995, 60, 1214 and references cited therein.
See also refs 4, 7a, 8a,e, and 2a,b.
(4) (a) J acobi, P. A.; Guo, J . Tetrahedron Lett. 1995, 36, 2717. (b)
J acobi, P. A.; Guo, J .; Zheng, W. Tetrahedron Lett. 1995, 36, 1197.
Preliminary communication: (c) J acobi, P. A.; Brielmann, H. L.; Hauck,
S. I. Tetrahedron Lett. 1995, 36, 1193. (d) J acobi, P. A.; Rajeswari, S.
Tetrahedron Lett. 1992, 33, 6231; (e) 1992, 33, 6235. (f) J acobi, P. A;
DeSimone, R. W. Tetrahedron Lett. 1992, 33, 6239. See also: (g) J acobi,
P. A.; Buddhu, S. C. Tetrahedron Lett. 1988, 29, 4823. (h) J acobi, P.
A.; Murphree, S.; Rupprecht, F.; Zheng, W. J . Org. Chem. 1996, 61, in
press.
(5) (a) Schreiber, S. L.; Klimas, M. T.; Sammakia, T. J . Am. Chem.
Soc. 1987, 109, 5749. (b) Lockwood, R. F.; Nicholas, K. M. Tetrahedron
Lett. 1977, 18, 4163.
(6) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467.
(7) (a) Bishop, J . E.; O’Connell, J . F.; Rapoport, H. J . Org. Chem.
1991, 56, 5079. (b) Barton, D. H. R.; Kervagoret, J .; Zard, S. Z.
Tetrahedron 1990, 46, 7587. (c) J ackson, A. H.; Kenner, G. W.; Smith,
K. M. J . Chem. Soc. C 1971, 502. See also: (d) J acobi, P. A.; Cai, G.
Heterocycles 1993, 35, 1103.
(8) (a) Gossauer, A.; Miehe, D. Liebigs Ann. Chem. 1974, 352. (b)
Weller, J .-P.; Gossauer, A. Chem. Ber. 1980, 113, 1603. (c) Gossauer,
A.; Weller, J .-P. Chem. Ber. 1978, 111, 486. (d) Schoenleber, R.; Kim,
Y.; Rapoport, H. J . Am. Chem. Soc. 1984, 106, 2645. (e) Bishop, J . E.;
Nagy, J . O.; O’Connell, J . F.; Rapoport, H. J . Am. Chem. Soc. 1991,
113, 8024 and references cited therein.
(9) (a) Acetylenic acid 17a : Aldrich Chemical Co., Milwaukee, WI.
(b) Acetylenic acid 17b: Magnus, P.; Slater, M. J .; Principe, L. M. J .
Org. Chem. 1989, 54, 5148. (c) Acetylenic acid 17c: Easton, N. R.;
Dillard, R. D. J . Org. Chem. 1962, 27, 3602. (d) Acetylenic acid 17d :
Crombie, L.; Mackenzie, K. J . Chem. Soc. 1958, 4417.
(10) (a) Beesley, R. M.; Ingold, C. K.; Thorpe, J . F. J . Chem. Soc.
1915, 107, 1080. Ingold, C. K. J . Chem. Soc. 1921, 119, 305. For more
recent interpretations of this effect, see: (b) Parrill, A. L.; Dolata, D.
P. Tetrahedron Lett. 1994, 35, 7319 and references cited therein. (c)
J ung, M. E.; Gervay, J . J . Am. Chem. Soc. 1991, 113, 224.
(11) Amide cyclizations: (a) Taylor, E. C.; Katz, A. H.; Salgado-
Zamora, H. Tetrahedron Lett. 1985, 26, 5963. (b) Knapp, S.; Levorse,
I. J . Org. Chem. 1988, 53, 4006. (c) Rudisill, D. E.; Stille, J . K. J . Org.
Chem. 1989, 54, 5856. (d) Arcadi, A.; Cacchi, S.; Marinelli, F.
Tetrahedron Lett. 1992, 33, 3915. See also refs 1 and 8c.

Cyclic Enamides from Acetylenic Amides
J . Org. Chem., Vol. 61, No. 15, 1996 5015
Sch em e 4
the enamide double bond is shielded by the neighboring
geminal methyl groups (i.e., C,D ) Me), and ester
hydrolysis is clean. In contrast, however, with 21a ,b and
21e,f all attempts at ester hydrolysis led to complex
mixtures of products, which appeared to arise by compet-
ing Michael addition followed by ring opening.
Much more satisfactory results were obtained with
acetylenic N-benzylamides of type 23-25 (R ) Bn,
4-MeOBN, and 3,4-di-MeOBn) and methyl carbazates 26,
which underwent cyclization to enamides 27-30 at a
greatly enhanced rate with n-Bu4NF (TBAF) (Scheme 5).
Sch em e 5
for the cyclization of related amides,11 amines,12 carbam-
ates,13 and acids.14 In many cases no reaction was
observed at all. Moreover, when cyclization did occur, it
often took place with participation of the amide carbonyl
group to produce lactones.
These difficulties were first circumvented with our
finding that 18 afforded moderate to excellent yields of
stable enamide esters 21 upon treatment with the
reagent system PdCl2/CO/CuCl2/MeOH (Scheme 4). Tsuji
et al. have employed similar conditions for effecting
methoxycarbonylation of terminal alkynes,15 and it is
possible that acetylenic esters are intermediates in the
formation of 21. However, at present we favor a mech-
anism in which 20 undergoes CO complexation, followed
by migratory insertion,16 and acyl substitution with
MeOH (cf. dashed arrow in Scheme 4). Stoichiometric
quantities of CuCl2 were necessary in order to reoxidize
Pd(0), obtained by reductive elimination of HCl, to Pd-
(II). Finally, we expected that esters 21 would afford
enamides 19 by a two-step sequence involving hydrolysis
to acids 22 followed by decarboxylation, and in certain
cases this procedure worked well. Thus, LiOH hydrolysis
of esters 21c,d afforded 90-93% yields of carboxylic acids
22c,d , which upon brief thermolysis gave >95% yields
of the corresponding enamides 19c,d . However, the
efficiency of this process depended in a critical fashion
upon the substitution pattern of esters 21. With 21c,d
For example, amides 23b-f (R ) Bn) gave essentially
quantitative yields of the corresponding enamides 27b-f
upon heating for 3 h with 1.0 equiv of TBAF at 66 °C
(THF). Even the least reactive member of this series,
23a (A-D ) H), afforded >80% yields of enamide 27a .
By way of comparison, N-unsubstituted acetylenic amides
18a -f, which have otherwise identical substituents,
afforded at best only trace amounts of enamides 19a -f
after heating for 24 h with 6.0 equiv of TBAF (cf. Scheme
3). Similar rate dependencies on the N-substitution
pattern have been observed with related amide and
carbamate cyclizations.11d,13 In analogous fashion, ben-
zylamide 24c (R ) 4-MeOBn) gave a 99% yield of
enamide 28c, and benzylamide 25c (R ) 3,4-di-MeOBn)
gave 99% of enamide 29c. Electron-rich aromatic rings
of the type found in enamides 28 (R ) 4-MeOBn) and 29
(R ) 3,4-di-MeOBn) have the potential advantage of
facilitating N-benzyl cleavage under either oxidative or
solvolytic conditions.17a Similarly, methyl carbazates 30
should be particularly susceptible to both reductive17a and
photochemical cleavage.4g,17b In any event, enamides
27b-d (R ) Bn) gave >80% yields of the corresponding
parent enamides 19 upon reductive cleavage with Na/
NH3.
(12) Amine cyclizations: (a) Arcadi, A.; Cacchi, S.; Marinelli, F.
Tetrahedron Lett. 1989, 30, 2581. (b) Fukuda, Y.; Matsubara, S.;
Utimoto, K. J . Org. Chem. 1991, 56, 5812 and references cited therein.
(c) McGrane, P. L.; J ensen, M.; Livinghouse, T. J . Am. Chem. Soc. 1992,
114, 5459.
We also tested the activity of several other reagents
for catalyzing cyclizations of type 23 f 27 (R ) Bn). As
in the case with simple acetylenic amides 18 (cf. Scheme
4), no cyclization was observed with benzylamides 23
employing various Pd(II) catalysts under conditions that
did not cause concomitant decomposition. In addition,
little effect was observed with numerous base catalysts
that have previously been employed for related carbam-
ate cyclizations.13 However, we found it interesting that
the reagent system LiAl(NHBn)4 (31), prepared in situ
from LiAlH4 and BnNH2,18 was highly effective in pro-
(13) Carbamate cyclizations: Kimura, M.; Kure, S.; Yoshida, Z.;
Tanaka, S.; Fugami, K.; Tamaru, Y. Tetrahedron Lett. 1990, 31, 4887.
(14) Acid cyclizations: (a) Chan, D. M. T.; Marder, T. B.; Milstein,
D.; Taylor, N. J . J . Am. Chem. Soc. 1987, 109, 6385. (b) Marder, T. B.;
Chan, D. M.-T.; Fultz, W. C.; Calabrese, J . C.; Milstein, D. J . Chem.
Soc., Chem. Commun. 1987, 1885. (c) Arcadi, A.; Burini, A.; Cacchi,
S.; Delmastro, M.; Marinelli, F.; Pietroni, B. R. J . Org. Chem. 1992,
57, 976 and references cited therein. (d) Reed, P. E.; Katzenellenbogen,
J . A. J . Org. Chem. 1991, 56, 2624.
(15) Tsuji, J .; Takahashi, M.; Takahashi, T. Tetrahedron Lett. 1980,
21, 849.
(16) (a) Klei, E.; Teuben, J . H. J . Organomet. Chem. 1981, 222, 79.
(b) Brix, H.; Beck, W. J . Organomet. Chem. 1982, 234, 151. (c) Casey,
C. P.; Miles, W. H.; Fagan, P. J .; Haller, K. J . Organometallics 1985,
4, 559. (d) Wong, A.; Pawlick, R. V.; Thomas, C. G.; Leon, D. R.; Liu,
L. K. Organometallics 1991, 10, 530. (e) Adams, H.; Bailey, N. A.;
Gauntlett, J . T.; Harkin, I. M.; Winter, M. J .; Woodward, S. J . Chem.
Soc., Dalton Trans. 1991, 1117. (f) Hneihen, A. S.; Fermin, M. C.; Mass,
J . J .; Bruno, J . W. J . Organomet. Chem. 1992, 429, 33.
(17) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley & Sons, Inc.: New York, 1991. (b)
Watteraon, A. C., J r.; Shama, S. A. J . Org. Chem. 1975, 40, 19.

5016 J . Org. Chem., Vol. 61, No. 15, 1996
J acobi et al.
moting cyclization. Reagent 31 has found considerable
utility for the conversion of esters and lactones to
benzylamides,18 and in the present case it provides a
convenient means for the direct transformation of -acet-
ylenic esters to cyclic enamides. For example, acetylenic
amide 23c afforded an 81% yield of enamide 27c after
warming for 2 h at 65 °C with 1 equiv of 31 (Scheme 6).
to enamide alcohol 43 by initial ring opening with excess
LiAl(NHBn)4 (31),18 followed by cyclization of the result-
ant acetylenic amide 42 at 65 °C (THF; 81% yield).
Although it was possible to isolate intermediate 42 in this
transformation, it proved to be advantageous to carry out
the cyclization in situ. Enamide alcohol 43 then gave a
78% yield of methyl ester 44 upon oxidation first with
CrO3/pyridine,21 followed by I2 in methanolic KOH.22 The
attractiveness of this approach resides in the ready
availability of both 39 and 40,4,5 each of which was
prepared in a single step from commercially available
starting materials. In addition, yields throughout the
synthesis are uniformly high.
Sch em e 6
Sch em e 8
In similar fashion, acetylenic ester 32d gave a 71% yield
of enamide 27d after 3 h at 65 °C (2 equiv of 31; 5% of
recovered acetylenic amide 23d by NMR). It is important
to note that no cyclization of intermediate amides 23c,d
was observed in the absence of excess 31 or with other
reagents known to convert esters to amides.19
This methodology was first exploited in a highly
efficient synthesis of enantiomerically pure enamide 38,
making use of the Nicholas-Schreiber methodology for
the synthesis of acetylenic acid 35 (Scheme 7).4,5 Thus,
condensation of Evans’ enolate 33 with cobalt complex
34 provided an 85% overall yield of 35 as a single
enantiomer, with syn-selectivity >98%.4,20a Acid 35 was
then converted in two steps to enamide 38 by initial
deprotection and lactonization to afford lactone 36 (P4S10,
88%),20b which upon treatment with 2 equiv of 31 at 25
°C gave a 96% yield of 38.20c In this case, transformation
of intermediate acetylenic amide 37 to enamide 38 was
rapid even at 0 °C.
An even more direct synthesis of a ring-c enamide was
realized beginning with the bis-silyl enol ether 45, itself
readily derived from dimethyl glutarate (Scheme 9).23
Thus, condensation of 45 with cobalt complex 40 afforded
a 94% yield of Nicholas adduct 46 (vide supra),4,5 which
was converted in a single step to benzyl-protected en-
amide 48 by reaction at 65 °C with excess LiAl(NHBn)4
(31) (81% yield). As in the case with 42 above (cf. Scheme
8), it proved unnecessary to isolate intermediate acety-
lenic bis-amide 47, although 47 could be obtained ad-
mixed with 48 upon reaction at lower temperatures (25
°C). Finally, we were pleased to find that the enamide
benzyl protecting group in 48 could be selectively cleaved
with Na/NH3, affording the parent enamide 49 in virtu-
ally quantitative yield.
Sch em e 7
Sch em e 9
Finally, we have utilized this methodology in two
syntheses of cyclic enamides, which are potential ring-c
precursors for cobyric acid (7) and related corrins. The
first of these began with silyl enol ether 39, which gave
a 92% yield of Nicholas adduct 41 upon BF3‚Et2O-
catalyzed condensation with cobalt complex 40, followed
by oxidative removal of cobalt (CAN) (Scheme 8).4,5
Interestingly, we observed no competing elimination of
MeOH from 40, a pathway that is frequently a problem
with Nicholas condensations involving tertiary carboca-
tions.4 Adduct 41, in turn, was converted in a single step
Su m m a r y
In this paper we described three procedures for con-
verting acetylenic amides of general structure 11 to cyclic
(18) Solladie´-Cavallo, A.; Bencheqroun, M. J . Org. Chem. 1992, 57,
5831.
(19) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(20) (a) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett.
1987, 28, 6141. (b) We are grateful to Dr. Robert DeSimone for initially
carrying out this reaciton. (c) We are grateful to Dr. Wanjun Zheng
for initially carrying out this reaction.
(21) Ratcliffe, R.; Rodenhurst, R. J . Org. Chem. 1970, 35, 4000 and
references cited therein.
(22) Yamada, S.; Morizono, D.; Yamamoto, K. Tetrahedron Lett.
1992, 33, 4329.
(23) Wallace, I. H. M.; Chan, T. H. Tetrahedron 1983, 39, 847.

Cyclic Enamides from Acetylenic Amides
J . Org. Chem., Vol. 61, No. 15, 1996 5017
19c as an unstable yellow solid, mp 72-73 °C, identical in all
respects with authentic 19c prepared following the method of
Dillard and Easton (mixed mp 72-73 °C):24a 1H NMR (300
MHz, CDCl3) 1.27 (s, 6H), 2.33 (s, 2H), 4.09 (d, J ) 1.9 Hz,
1H), 4.29 (d, J ) 1.9 Hz, 1H), 8.40 (br, 1H).
enamides of type 1: (1) Palladium-catalyzed cyclization
in the presence of CO and MeOH, which affords N-
unsubstituted enamide esters 21 in moderate to high
yields; (2) TBAF-catalyzed cyclization, which gives N-
substituted enamides 27-30 in excellent yields and at a
greatly enhanced rate relative to unsubstituted examples;
and (3) LiAl(NHBn)4-catalyzed cyclization of benzyl-
amides, which among other examples was employed in
the synthesis of the enantiomerically pure enamide 38
and in syntheses of the potential vitamin B12 precursors
44 and 49. With suitable modification, we believe that
the methodology described in this paper might be applied
to the synthesis of a wide range of cyclic enamides in
enantiomerically pure form, including those of a type
useful for the synthesis of biologically important chlorins,
isobacteriochlorins, and corrins. Experiments in this
direction are currently in progress.
Meth od B. Deben zyla tion of 27c. Approximately 5-10
mL of liquid NH3 was distilled from Na metal through a glass
tube into a flask containing 123 mg (0.57 mmol) of pyrrolidi-
none 27c and equipped with a dry ice/acetone condenser. The
reaction mixture was then treated with approximately 131 mg
(5.7 mmol, 10 equiv) of Na metal to give a dark blue solution.
This solution was maintained at -33 °C for 3 h (reflux) and
was then carefully quenched by slow addition of 786 mg (5.7
mmol, 10 equiv) of triethylamine hydrochloride to produce a
thick white suspension. The suspension was vigorously mixed
to ensure complete quenching of the Na (Wa r n in g: as with
all Na reductions, possible fire hazard). The NH3 was then
allowed to evaporate at rt, and the residue was partitioned
between 10 mL of EtOAc and 5 mL of H2O. The layers were
separated, and the aqueous layer was extracted with an
additional 2 × 10 mL of EtOAc. The combined organic layers
were then washed with brine (10 mL), dried over MgSO4, and
concentrated to give 62 mg (87%) of 19c as a white crystalline
solid, which rapidly turned yellow on standing at rt. The
material thus obtained was identical to 22c prepared using
method A above and also to an authentic sample.24a This
compound is very unstable and decomposes even during
storage at low temperatures.
Exp er im en ta l Section
Melting points were determined in open capillaries and are
uncorrected. 1H NMR spectra were recorded at either 300 or
400 MHz and are expressed as ppm downfield from tetra-
methysilane.
2,2-Dim eth yl-4-p en tyn a m id e (18b). A solution of 6.0 g
(48.0 mmol) of 2,2-dimethyl-4-pentynoic acid (17b)9b in 150 mL
of anhydrous THF was cooled to 0 °C and was treated in
dropwise fashion, with vigorous stirring, with 4.82 g (48.0
mmol, 1.0 equiv) of triethylamine, followed by 6.5 g (48.0 mmol,
1.0 equiv) of isobutyl chloroformate (IBCF). After addition was
complete, the resulting suspension was stirred at 0 °C for 30
min before cooling to -78 °C. The reaction was then treated
with 5.0 mL of condensed NH3, and stirring was continued at
-78 °C for 1 h and then at ambient temperature for an
additional 11 h (NH3 was allowed to evaporate). At the end
of this period the resulting mixture was diluted with 40 mL
of brine and extracted with 3 × 30 mL of EtOAc. The organic
layer was dried (MgSO4), concentrated under reduced pressure,
and chromatographed (silica gel, 50% EtOAc/hexanes) to afford
5.6 g (93%) of 18b as a white solid: mp 85-86 °C; Rf 0.52 (silica
gel, 75% EtOAc/hexanes; KMnO4 indicator); IR (KBr) 3402,
3282, 3205, 2976, 2116, 1650, 1619 cm-1; 1H NMR (400 MHz,
CDCl3) 1.27 (s, 6H), 2.04 (s, 1H), 2.41 (s, 2H), 5.4 (br, 1H),
5.8 (br, 1H); 13C NMR (100 MHz, CDCl3) 25.61, 30.29, 42.22,
71.62, 81.83, 179.65. Anal. Calcd for C7H11NO: C, 67.17; H,
8.86; N, 11.19. Found: C, 67.27; H, 8.86; N, 11.23.
3,4,4-Tr im et h yl-5-m et h ylen e-2-p yr r olid in on e (19d ).
Meth od A. Deca r boxyla tion of Acid (Z)-22d . This mate-
rial was prepared in 97% yield from 8.2 mg (0.048 mmol) of
acid (Z)-22d following method A described above (cf. 19c):
glassy yellow solid; Rf 0.24 (silica gel, 30% EtOAc/hexanes);
1
MS m/z 139 (M+); H NMR (300 MHz, CDCl3) 1.10 (s, 3H),
1.11 (d, J ) 6.8 Hz, 3H), 1.25 (s, 3H), 2.34 (q, J ) 7.4 Hz, 1H),
4.12 (d, J ) 1.4 Hz, 1H), 4.28 (d, J ) 1.6 Hz, 1H), 7.88 (br,
1H); IR (CDCl3) 3217, 2963, 1711, 1672 cm-1; exact mass calcd
for C8H13NO 139.0997, found 139.0996.
Met h od B. Deben zyla t ion of 27d . Alternatively, 19d
was prepared in 92% yield from 84 mg (0.37 mmol, 1 equiv) of
enamide 27d , 84 mg (3.7 mmol, 10 equiv) of Na metal, and 10
mL of liquid NH3 following method B described above (cf. 19c).
Workup afforded 47 mg (92%) of 19d as a white crystalline
solid, which rapidly turned yellow on standing.
3,3-Dim eth yl-5-m eth ylen e-2-pyr r olidin on e (19b).24b This
material was prepared in 82% yield from 86 mg (0.40 mmol)
of pyrrolidinone 27b, 92 mg (4.0 mmol, 10 equiv) of Na metal,
and 10 mL of liquid NH3 following method B described above
(cf. 19c). Workup afforded 41 mg (82%) of 19b as a white
crystalline solid, which rapidly turned yellow on standing: 1H
NMR (300 MHz, CDCl3) 1.22 (s, 6H), 2.56 (s, 2H), 4.11 (br s,
1H), 4.34 (d, J ) 1.4 Hz, 1H), 7.80 (br, 1H); exact mass calcd
for C7H11NO 125.0841, found 125.0839.
3,3-Dim eth yl-4-p en tyn a m id e (18c). This material was
prepared in 77% yield from 3.0 g (23.8 mmol) of 3,3-dimethyl-
4-pentynoic acid (17c)9c following a procedure identical to that
described above (cf. 18b). Chromatography (silica gel, 50%
EtOAc/hexanes) afforded 2.3 g (77%) of 18c as a white solid:
mp 56-57 °C; Rf 0.11 (silica gel, 10% EtOAc/hexanes; KMnO4
5-[(Met h oxyca r b on yl)m et h ylid en e]-2-p yr r olid in on e
(21a ).24c,d A mixture consisting of 3.7 g (38.0 mmol) of
acetylenic amide 18a , 674 mg (3.8 mmol, 0.1 equiv) of PdCl2,
and 20.6 g (152 mmol, 4.0 equiv) of CuCl2 in 300 mL of MeOH
was stirred at rt under an atmosphere of CO. After 2 h the
color of the reaction mixture had changed from green to black,
and after stirring for a total of 3 h the reaction was neutralized
by careful addition of powdered NaHCO3. The resulting light
green suspension was then filtered with vacuum through
Celite and concentrated under reduced pressure. The residue
was adsorbed onto silica gel and chromatographed (silica gel,
30% EtOAc/hexanes) to afford 2.1 g (36%) of (Z)-21a as a
colorless solid:24c,d Rf 0.41 (silica gel, 40:59:1 EtOAc/hexanes/
AcOH); MS m/z 137 (M+); IR (KBr) 3347, 2954, 1738, 1689,
1
indicator); H NMR (400 MHz, CDCl3) 1.35 (s, 6H), 2.28 (s,
1H), 2.38 (s, 2H), 5.7 (br, 1H), 6.2 (br, 1H). Anal. Calcd for
C7H11NO: C, 67.17; H, 8.86; N, 11.19. Found: C, 66.93; H,
8.92; N, 11.13.
2,3,3-Tr im eth yl-4-p en tyn a m id e (18d ). This material was
prepared in 93% yield from 1.0 g (7.1 mmol) of 2,3,3-trimethyl-
4-pentynoic acid (17d )9d following a procedure identical to that
described above (cf. 18b). Chromatography (silica gel, 50%
EtOAc/hexanes) afforded 921 mg (93%) of 18d as a white
solid: mp 63-64 °C; Rf 0.35 (silica gel, 50% EtOAc/hexanes;
1
KMnO4 indicator); H NMR (300 MHz, CDCl3) 1.30 (d, J )
7.1 Hz, 3H), 1.30 (s, 3H), 1.34 (s, 3H), 2.23-2.32 (m, 2H), 5.40
(br, 1H), 6.10 (br, 1H). Anal. Calcd for C8H13NO: C, 69.03;
H, 9.41; N, 10.06. Found: C, 68.96; H, 9.44; N, 10.13.
1
1643, 1438, 1195 cm-1; H NMR (400 MHz, CDCl3) 2.50-
2.60 (m, 2H), 2.85-2.94 (m, 2H), 3.69 (s, 3H), 5.00 (s, 1H), 9.85
4,4-Dim et h yl-5-m et h ylen e-2-p yr r olid in on e
(19c).
Meth od A. Deca r boxyla tion of Acid (Z)-22c. A total of
31 mg (0.18 mmol) of acid (Z)-22c (mp 141 °C) was heated
under nitrogen in an oil bath maintained at 180 °C for a period
of 3 min, at which point gas evolution ceased. Upon cooling
there was obtained 22 mg (99%) of pyrrolidinone 19c as a
glassy yellow solid. Recrystallization from pentane afforded
(24) (a) Easton, N., R.; Dillard, R. D. J . Org. Chem. 1962, 27, 3602.
(b) Stevens, R. V.; Christensen, C. G.; Edmonson, W. L.; Kaplan, M.;
Reid, E. B.; Wentland, M. P. J . Am. Chem. Soc. 1971, 93, 6629. (c)
Gossauer, A.; Hinze, R.-P.; Zilch, H. Angew. Chem., Int. Ed. Engl. 1977,
16, 418. (d) Bishop, J . E.; O’Connell, J . F.; Rapoport, H. J . Org. Chem.
1991, 56, 5079.

5018 J . Org. Chem., Vol. 61, No. 15, 1996
J acobi et al.
(br, 1H); 13C NMR (100 MHz, CDCl3) 25.8, 27.5, 50.9, 89.5,
157.5, 168.2, 177.3. Anal. Calcd for C7H9NO3: C, 54.19; H,
5.85; N, 9.03. Found: C, 54.27; H, 5.87; N, 8.96. Also isolated
was 1.5 g (25%) of (E)-21a as a yellow amorphous powder:24d
Rf 0.35 (silica gel, 40:59:1 EtOAc/hexanes/AcOH); MS m/z 137
(M+); 1H NMR (400 MHz, CDCl3) 2.50-2.62 (m, 2H), 3.22-
3.35 (m, 2H), 3.72 (s, 3H), 5.35 (s, 1H), 7.65 (br, 1H).
(Z)-5-(Ca r boxym eth ylid en e)-4,4-d im eth yl-2-p yr r olid i-
n on e ((Z)-22c). A solution of 183 mg (1.0 mmol, 1.0 equiv) of
ester (Z)-21c in 15 mL of CCl4 was treated with 500 mg (2.5
mmol, 2.5 equiv) of trimethylsilyl iodide (TMSI), and the
resulting mixture was stirred at 50 °C for 24 h. By the end of
this time the reaction had turned dark red and contained a
black precipitate. The reaction was then treated with 5 mL
of 0.5 N NaOH and 5 mL of CH2Cl2, and the resulting yellow
suspension was extracted with 3 × 5 mL of 0.5 N NaOH. The
aqueous extracts were then carefully acidified to pH 4 with
5% HCl and back-extracted with 3 × 5 mL of CH2Cl2. The
organic extracts were dried (MgSO4) and concentrated under
reduced pressure to afford 152 mg (90%) of (Z)-22c as a white
solid: mp 141 °C (with decarboxylation); IR (KBr) 3357, 1718,
5-[(Meth oxyca r bon yl)m eth ylid en e]-3,3-d im eth yl-2p yr -
r olid in on e (21b). This material was prepared in 51% yield
from 3.0 g (24.0 mmol, 1.0 equiv) of acetylenic amide 18b, 339
mg (1.9 mmol, 0.08 equiv) of PdCl2, and 9.72 g (72.0 mmol,
3.0 equiv) of CuCl2 in 300 mL of MeOH following a procedure
identical to that described above (cf. 21a ). Chromatography
(silica gel, 50% EtOAc/hexanes) afforded 2.24 g (51%) of 21b
as a 10:1 Z:E mixture. (E)-21b: mp 166-168 °C; Rf 0.31 (silica
gel, 75% hexanes/EtOAc); MS m/z 183 (M+); IR (KBr) 3182,
1
1701, 1595, 1227cm-1; H NMR (400 MHz, CDCl3) 1.36 (s,
6H), 2.40 (s, 2H), 5.02 (s, 1H) 9.82 (br s, 1H). Anal. Calcd for
C8H11NO3: C, 56.80; H, 6.55; N, 8.28. Found: C, 56.76; H,
6.54; N, 8.21.
2975, 1710, 1646, 1136 cm-1 1H NMR (400 MHz, CDCl3)
;
1.22 (s, 6H), 3.10 (s, 2H), 3.67 (s, 3H), 5.37 (s, 1H), 8.21 (br,
1H). (Z)-21b: mp 62-63 °C; Rf 0.21 (silica gel, 75% hexanes/
EtOAc); MS m/z 183 (M+); IR (KBr) 3350, 2965, 1748, 1688,
(Z)-5-(Ca r boxym eth ylid en e)-3,4,4-tr im eth yl-2-p yr r oli-
d in on e ((Z)-22d ). A solution consisting of 100 mg (0.51 mmol,
1.0 equiv) of ester (Z)-21d , 6 mL of 1.0 M aqueous LiOH, and
4 mL of MeOH was heated at reflux for a period of 30 min.
The reaction mixture was then concentrated to about 5 mL
under reduced pressure, cooled to 0 °C, and carefully acidified
to pH 2 with 10% HCl. The resulting solution was extracted
with 4 × 5 mL of EtOAc, and the combined extracts were dried
(MgSO4) and concentrated under reduced pressure. Chroma-
tography (silica gel, EtOAc) then afforded 86 mg (93%) of acid
(Z)-22d as a white solid: mp 126 °C (from EtOAc/hexanes;
melts with decarboxylation); IR (KBr) 3363, 2966, 1753, 1673,
1
1641, 1154, 1137 cm-1; H NMR (400 MHz, CDCl3) 1.22 (s,
6H), 2.67 (s, 2H), 3.67 (s, 3H), 4.96 (s, 1H), 9.6 (br, 1H). Anal.
Calcd for C9H13NO3: C, 59.00; H, 7.15; N, 7.65. Found: C,
58.85; H, 7.15; N, 7.53.
(Z)-5-[(Meth oxyca r bon yl)m eth ylid en e]-4,4-d im eth yl-2-
p yr r olid in on e ((Z)-21c). This material was prepared in 96%
yield from 2.0 g (16.0 mmol, 1.0 equiv) of acetylenic amide 18c,
227 mg (1.28 mmol, 0.08 equiv) of PdCl2, and 8.64 g (64.0
mmol, 4.0 equiv) of CuCl2 in 200 mL of MeOH following a
procedure identical to that described above (cf. 21a ). Chro-
matography (silica gel, 50% EtOAc/hexanes) afforded 2.80 g
(96%) of (Z)-21c as a light yellow solid: mp 74-76 °C; Rf 0.82
(silica gel, EtOAc); MS m/z 183 (M+); IR (melt) 3345, 2964,
1
1643, 1595, 1194 cm-1; H NMR (400 MHz, CDCl3) 1.06 (s,
6H), 1.14 (s, 3H) 2.35 (m, 1H), 5.02 (s, 1H) 9.70 (br s, 1H).
Gen er a l P r oced u r es for th e P r ep a r a tion of Acetylen ic
Am id es 23-26. Meth od A. A solution of 10.8 mmol (1.0
equiv) of the appropriate acetylenic acid 17 in 50 mL of
anhydrous THF was cooled to 0 °C under an atmosphere of
argon and was treated in dropwise fashion, with vigorous
stirring, with 11.8 mmol (1.1 equiv) of NEt3, followed by 11.8
mmol (1.1 equiv) of isobutyl chloroformate (IBCF). The
resulting white suspension was stirred at 0 °C for an additional
1 h and was then cooled to -78 °C. The resulting mixed
anhydride was then treated in dropwise fashion, and with
vigorous stirring, with 13.0 mmol (1.2 equiv) of the appropriate
amine, and the reaction was allowed to warm slowly to rt.
Stirring was continued at rt for an additional 16 h, and the
reaction was then partitioned between 50 mL of brine and 50
mL of EtOAc. The layers were separated, and the organic
phase was dried (MgSO4) and concentrated under reduced
pressure to an oil. The crude product was purified by flash
chromatography to afford acetylenic amides 23-26.
1750, 1684, 1634, 1168 cm-1 1H NMR (400 MHz, CDCl3)
;
1.31 (s, 6H), 2.40 (s, 2H), 3.71 (s, 3H), 4.98 (s, 1H); 13C NMR
(100 MHz, CDCl3) 28.4, 39.2, 43.7, 51.0, 87.3, 167.0, 168.6,
175.2. Anal. Calcd for C9H13NO3: C, 59.00; H, 7.15; N, 7.65.
Found: C, 58.72; H, 7.24; N, 7.41.
(Z)-5-[(Meth oxyca r bon yl)m eth ylid en e]-3,4,4-tr im eth -
ylp yr r olid in on e ((Z)-21d ). This material was prepared in
72% yield from 200 mg (1.43 mmol, 1.0 equiv) of acetylenic
amide 18d , 21 mg (0.12 mmol, 0.08 equiv) of PdCl2, and 388
mg (2.87 mmol, 2.0 equiv) of CuCl2 in 20 mL of MeOH
following a procedure identical to that described above (cf.
21a ). Chromatography (silica gel, 50% EtOAc/hexanes) af-
forded 203 mg (72%) of (Z)-21d as a colorless oil: Rf 0.72 (silica
gel, 50% EtOAc/hexanes); IR (neat) 3351, 2966, 1745, 1692,
1
1633, 1173cm-1; H NMR (400 MHz, CDCl3) 1.08 (d, J ) 8
Hz, 3H),1.08 (s, 3H), 1.20 (s, 3H), 2.30 (q, J ) 8 Hz, 1H), 3.66
(s, 3H), 5.01 (s, 1H), 9.85 (br, 1H); 13C NMR (100 MHz, CDCl3)
9.5, 24.1, 26.5, 42.5, 45.8, 50.9, 87.4, 166.5, 168.7, 178.1. Anal.
Calcd for C10H15NO3: C, 60.90; H, 7.67; N, 7.10. Found: C,
60.80; H, 7.68; N, 7.04.
Meth od B. A total of 2.18 mmol (1.0 equiv) of the
appropriate acetylenic acid 17 was covered with 34.4 mmol
(16.0 equiv) of oxalyl chloride, and the mixture was heated at
55 °C for a period of 3.5 h to afford a yellow solution. The
reaction was then cooled to rt and concentrated under reduced
pressure to remove excess oxalyl chloride. The crude acid
chloride was dissolved in 2.0 mL of anhydrous CH2Cl2 and
transferred by syringe to a cooled (0 °C), well-stirred solution
of 10.9 mmol (5.0 equiv) of the appropriate amine in 1.0 mL
of CH2Cl2. The resulting suspension was allowed to warm
slowly to rt, and stirring was continued for an additional 16
h. The reaction was then partitioned between 10 mL of brine
and 20 mL of CH2Cl2. The layers were separated, and the
organic phase was dried (MgSO4) and concentrated under
reduced pressure to an oil. The crude product was purified
by flash chromatography to afford acetylenic amides 23-26.
N-Ben zyl-4-p en tyn a m id e (23a ). This material was pre-
pared in 88% yield from 237 mg (2.41 mmol) of acid 17a and
0.32 mL (2.89 mmol, 1.2 equiv) of benzylamine using method
A described above. Purification by chromatography (silica gel,
50% EtOAc/hexanes, Rf 0.33) gave 398 mg of 23a as a white
crystalline solid: mp 69-70 °C (EtOAc/hexanes); IR (CDCl3)
(Z)-(3S,4S)-5-[(Meth oxyca r bon yl)m eth ylid en e]-3,4-d i-
m eth yl-2-p yr r olid in on e ((Z)-21f). This material was pre-
pared in 50% yield from 420 mg (3.36 mmol, 1.0 equiv) of
acetylenic amide 18f, 48 mg (0.26 mmol, 0.08 equiv) of PdCl2,
and 907 mg (6.72 mmol, 2.0 equiv) of CuCl2 in 25 mL of MeOH
following a procedure identical to that described above (cf.
21a ). Chromatography (silica gel, 10% EtOAc/hexanes) af-
forded 305 mg (50%) of (Z)-21f as a colorless oil: Rf 0.61 (silica
gel, 50% hexanes/EtOAc); MS m/z 183 (M+); IR (neat) 3351,
2969, 1748, 1688, 1643, 1192 cm-1; 1H NMR (400 MHz, CDCl3)
1.28 (d, J ) 10 Hz, 3H), 1.30 (d, J ) 8 Hz, 3H), 2.23 (m, 1H),
2.65 (m, 1H), 3.70 (s, 3H). 5.01 (s, 1H), 9.75 (br, 1H); 13C NMR
(100 MHz, CDCl3) 14.5, 17.1, 41.6, 42.4, 50.9, 88.4, 161.2,
168.4, 178.7; [R]25D ) -20.0° (c ) 10, MeOH); exact mass calcd
for C9H13NO3 183.0895, found 183.0896. Anal. Calcd for
C9H13NO3: C, 59.00; H, 7.15; N, 7.65. Found: C, 59.25; H,
7.22; N, 7.59.
(Z)-(3R,4R)-5-[(Meth oxyca r bon yl)m eth ylid en e]-3,4-d i-
m eth yl-2-p yr r olid in on e ((Z)-21e). This material was pre-
pared in 50% yield from acetylenic amide 18e following a
procedure identical to that described above for enantiomer
(Z)-21f: [R]25D ) +22.2° (c ) 10, MeOH), spectral data identical
to (Z)-21f.
1
3295, 1631, 1539 cm-1; H NMR (300 MHz, CDCl3) 2.00 (t,
J ) 2.5 Hz, 1H), 2.42-2.48 (m, 2H), 2.54-2.62 (m, 2H), 4.48
(d, J ) 5.7 Hz, 2H), 5.90 (br, 1H), 7.25-7.40 (m, 5H); 13C NMR
(75 MHz, CDCl3) 15.1, 35.5, 43.8, 69.6, 83.2, 127.7, 128.0,

Cyclic Enamides from Acetylenic Amides
J . Org. Chem., Vol. 61, No. 15, 1996 5019
128.8, 138.3, 171.0. Anal. Calcd for C12H13NO: C, 76.98; H,
7.00; N, 7.48. Found: C, 76.92; H, 7.05; N, 7.41.
N-(4-Meth oxyben zyl)-3,3-dim eth yl-4-pen tyn am ide (24c).
This material was prepared in 86% yield from 176 mg (1.39
mmol) of acid 17c and 0.22 mL (1.67 mmol, 1.2 equiv) of
p-methoxybenzylamine using method A described above. Pu-
rification by chromatography (silica gel, 30% EtOAc/hexanes,
Rf 0.22) gave 296 mg of 24c as a colorless, crystalline solid:
N-Ben zyl-2,2-d im eth yl-4-p en tyn a m id e (23b). This ma-
terial was prepared in 70% yield from 625 mg (4.95 mmol) of
acid 17b and 0.65 mL (5.94 mmol, 1.2 equiv) of benzylamine
using method A described above. Purification by chromatog-
raphy (silica gel, 20% EtOAc/hexanes, Rf 0.33) gave 746 mg of
23b as a white solid: mp 69-71 °C (EtOAc/hexanes); IR
(CDCl3) 3296, 2964, 1638, 1533; 1H NMR (300 MHz, CDCl3)
1.31 (s, 6H), 2.04 (t, J ) 2 Hz, 1H), 2.48 (d, J ) 2 Hz, 2H),
mp 55-57 °C; IR (CDCl3) 3295, 2929, 1648, 1543, 1513 cm-1
;
1H NMR (300 MHz, CDCl3) 1.34 (s, 6H), 2.19 (s,1H), 2.38 (s,
2H), 3.81 (s, 3H), 4.42 (d, J ) 5.5 Hz, 2H), 6.32 (br, 1H), 6.87
(d, J ) 8.0 Hz, 2H), 7.25 (d, J ) 8.0 Hz, 2H); 13C NMR (75
MHz, CDCl3) 29.2, 30.0, 43.1, 49.5, 55.3, 69.7, 91.0, 114.0,
129.1, 130.6, 159.0, 169.9. Anal. Calcd for C15H19NO2: C,
73.44; H, 7.81; N, 5.71. Found: C, 73.16; H, 7.75; N, 5.59.
4.48 (d, J ) 5.7 Hz, 2H), 6.12 (br, 1H), 7.27-7.40 (m, 5H); 13
C
NMR (75 MHz, CDCl3) 25.2, 30.2, 42.0, 43.9, 71.2, 81.6,
127.6, 127.9, 128.9, 138.6, 176.3. Anal. Calcd for C14H17NO:
C, 78.10; H, 7.96; N, 6.51. Found: C, 78.08; H, 7.94; N, 6.48.
N-(4-Met h oxyb en zyl-2,3,3-t r im et h yl-4-p en t yn a m id e
(24d ). This material was prepared in 71% yield from 305 mg
(2.18 mmol) of acid 17d and 1.4 mL (10.9 mmol, 5 equiv) of
p-methoxybenzylamine using method B described above. Pu-
rification by chromatography (silica gel, 30% EtOAc/hexanes,
Rf 0.34) gave 399 mg of 24d as a colorless solid: mp 70-72
N-Ben zyl-3,3-d im eth yl-4-p en tyn a m id e (23c). This ma-
terial was prepared in 87% yield from 338 mg (2.68 mmol) of
acid 17c and 0.35 mL (3.22 mmol, 1.2 equiv) of benzylamine
using method A described above. Purification by chromatog-
raphy (silica gel, 30% EtOAc/hexanes, Rf 0.27) gave 503 mg of
1
°C; IR (CDCl3) 3293, 2970, 1644, 1512, 1247 cm-1; H NMR
23c as a colorless oil: IR (CDCl3) 3295, 2966, 1643, 1543 cm-1
;
1H NMR (300 MHz, CDCl3) 1.35 (s, 6H), 2.19 (s,1H), 2.39 (s,
2H), 4.49 (d, J ) 5.6 Hz, 2H), 6.39 (br, 1H), 7.28-7.38 (m, 5H);
13C NMR (75 MHz, CDCl3) 29.3, 30.0, 43.7, 49.6, 69.8, 91.0,
(300 MHz, CDCl3) 1.28 (d, J ) 7.2 Hz, 3H), 1.28 (s, 3H),
1.30 (s, 3H), 2.19 (s, 1H), 2.26 (q, J ) 7.2 Hz, 1H), 3.81 (s,
3H), 4.40 (d, J ) 5.5 Hz, 2H), 6.30 (br, 1H), 6.87 (d, J ) 8.6
Hz, 2H), 7.23 (d, J ) 8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3)
13.9, 26.8, 27.6, 33.4, 42.7, 50.5, 55.1, 70.2, 90.1, 113.9, 129.0,
130.6, 158.8, 173.9. Anal. Calcd for C16H21NO2: C, 74.10; H,
8.16; N, 5.40. Found: C, 74.19; H, 8.20; N, 5.43.
127.5, 127.9, 128.7, 138.4, 170.1; exact mass calcd for C14H17
NO 215.1310, found 215.1311.
-
N-Ben zyl-2,3,3-tr im eth yl-4-p en tyn a m id e (23d ). This
material was prepared in 83% yield from 267 mg (1.9 mmol)
of acid 17d and 1.04 mL (9.5 mmol, 5 equiv) of benzylamine
using method B described above. Purification by chromatog-
raphy (silica gel, 30% EtOAc/hexanes, Rf 0.33) gave 364 mg of
23d as a colorless solid: mp 83-84 °C (EtOAc/hexanes); IR
(CH2Cl2) 3287, 1635, 1535 cm-1; 1H NMR (300 MHz, CDCl3)
1.29 (s, 3H), 1.30 (d, J ) 7.2 Hz, 3H), 1.32 (s, 3H), 2.21 (s,
1H), 2.29 (q, J ) 7.2 Hz, 1H), 4.48 (d, J ) 5.5 Hz, 2H), 6.30
(br, 1H), 7.29-7.39 (m, 5H); 13C NMR (75 MHz, CDCl3) 14.2,
27.6, 27.9, 33.6, 43.7, 51.5, 70.8, 90.2, 127.6, 128.0, 128.8, 138.6,
174.2. Anal. Calcd for C15H19NO: C, 78.56; H, 8.35; N, 6.11.
Found: C, 78.40; H, 8.31; N, 6.02.
N -(3,4-D im e t h o x y b e n zy l)-2,2-d im e t h y l-4-p e n t y n -
a m id e (25b). This material was prepared in 60% yield from
186 mg (1.47 mmol) of acid 17b and 0.27 mL (1.76 mmol, 1.2
equiv) of 3,4-dimethoxybenzylamine using method A described
above. Purification by chromatography (silica gel, 40% EtOAc/
hexanes, Rf 0.27) gave 242 mg of 25b as an off-white solid:
mp 98-99 °C (EtOAc/hexanes); IR (CDCl3) 3290, 2964, 1641,
1
1516, 1264 cm-1; H NMR (300 MHz, CDCl3) 1.30 (s, 6H),
2.03 (t, J ) 2.6 Hz, 1H), 2.47 (d, J ) 2.6 Hz, 2H), 3.87 (s, 3H),
3.88 (s, 3H), 4.40 (d, J ) 5.6 Hz, 2H), 6.07 (br, 1H), 6.80-6.88
(m, 3H); 13C NMR (75 MHz, CDCl3) 25.2, 30.2, 42.0, 43.8,
56.1, 56.2, 71.2, 81.7, 111.4, 111.5, 120.2, 131.3, 148.7, 149.4,
176.3. Anal. Calcd for C16H21NO3: C, 69.79; H, 7.67; N, 5.09.
Found: C, 69.71; H, 7.70; N, 5.06.
N-Ben zyl-2(R),3(R)-dim eth yl-4-pen tyn am ide (23e). This
material was prepared in 81% yield from 287 mg (2.27 mmol)
of acid 17e and 0.30 mL (2.72 mmol, 1.2 equiv) of benzylamine
using method A described above. Purification by chromatog-
raphy (silica gel, 20% EtOAc/hexanes, Rf 0.25) gave 394 mg of
23f as a colorless, crystalline solid: mp 64-65 °C (EtOAc/
N -(3,4-D im e t h o x y b e n zy l)-3,3-d im e t h y l-4-p e n t y n -
a m id e (25c). This material was prepared in 67% yield from
211 mg (1.67 mmol) of acid 17c and 0.30 mL (2.00 mmol, 1.2
equiv) of 3,4-dimethoxybenzylamine using method A described
above. Purification by chromatography (silica gel, 40% EtOAc/
hexanes, Rf 0.14 in 30% EtOAc/hexanes) gave 310 mg of 25c
as a white solid: mp 75-77 °C; IR (CDCl3) 3291, 2968, 1646,
hexanes); IR (CDCl3) 3288, 1643, 1549 cm-1 1H NMR (300
;
MHz, CDCl3) 1.23 (d, J ) 6.9 Hz, 3H), 1.25 (d, J ) 6.9 Hz,
3H), 2.10 (d, J ) 2.4 Hz, 1H), 2.35 (m, 1H), 2.78 (m, 1H), 4.40-
4.56 (m, 2H), 6.06 (br, 1H), 7.24-7.40 (m, 5H); 13C NMR (75
MHz, CDCl3) 15.4, 18.2, 29.3, 43.8, 46.7, 70.6, 87.2, 127.7,
1
1516, 1264 cm-1; H NMR (300 MHz, CDCl3) 1.34 (s, 6H),
2.19 (s, 1H), 2.38 (s, 2H), 3.87 (s, 6H), 4.42 (d, J ) 5.6 Hz,
2H), 6.35 (br, 1H), 6.80-6.90 (m, 3H); 13C NMR (75 MHz,
CDCl3) 29.1, 29.9, 43.2, 49.3, 55.76, 55.81, 69.5, 90.8, 111.1,
119.9, 131.0, 148.2, 149.0, 169.9. Anal. Calcd for C16H21NO3:
C, 69.79; H, 7.69; N, 5.09. Found: C, 69.72; H, 7.73; N, 5.04.
128.1, 128.9, 138.6, 174.4; [R]26 ) +12.69° (c ) 0.26, CH2-
D
Cl2). Anal. Calcd for C14H17NO: C, 78.10; H, 7.96; N, 6.51.
Found: C, 78.22; H, 7.98; N, 6.45.
N-Ben zyl-2(S),3(S)-d im eth yl-4-p en tyn a m id e (23f). This
material was prepared in 65% yield from 372 mg (2.95 mmol)
of acid 17f and 0.39 mL (3.54 mmol, 1.2 equiv) of benzylamine
using method A described above. Purification by chromatog-
raphy (silica gel, 20% EtOAc/hexanes, Rf 0.25) gave 410 mg of
23f as a colorless solid: mp 64-65 °C (EtOAc/hexanes);
N -(3,4-Dim e t h oxyb e n zyl)-2,3,3-t r im e t h yl-4-p e n t yn -
a m id e (25d ). This material was prepared in 77% yield from
252 mg (1.80 mmol) of acid 17d and 1.4 mL (9.0 mmol, 5 equiv)
of 3,4-dimethoxybenzylamine using method B described above.
Purification by chromatography (silica gel, 40% EtOAc/hex-
anes, Rf 0.21 in 30% EtOAc/hexanes) gave 400 mg of 25d as a
white solid: mp 104-105 °C (EtOAc/hexanes); IR (CDCl3)
3294, 2972, 1646, 1514, 1461 cm-1; 1H NMR (300 MHz, CDCl3)
1.28 (s, 3H), 1.29 (d, J ) 7.1 Hz, 3H), 1.34 (s, 3H), 2.20 (s,
1H), 2.28 (q, J ) 7.1 Hz, 1H), 3.87 (s, 6H), 4.39-4.43 (m, 2H),
6.28 (br, 1H), 6.80-6.90 (m, 3H); 13C NMR (75 MHz, CDCl3)
14.2, 27.4, 27.8, 33.6, 43.4, 51.3, 56.0, 56.1, 70.7, 90.2, 111.4,
120.1, 131.3, 148.5, 149.3, 174.0. Anal. Calcd for C17H23NO3:
C, 70.56; H, 8.01; N, 4.84. Found: C, 70.66; H, 8.07; N, 4.89.
spectral data identical to that of 23e; [R]26 ) -12.44° (c )
D
0.45, CH2Cl2). Anal. Calcd for C14H17NO: C, 78.10; H, 7.96;
N, 6.51. Found: C, 78.17; H, 8.00; N, 6.46.
N-(4-Meth oxyben zyl)-2,2-dim eth yl-4-pen tyn am ide (24b).
This material was prepared in 62% yield from 213 mg (1.68
mmol) of acid 17b and 0.26 mL (2.02 mmol, 1.2 equiv) of
p-methoxybenzylamine using method A described above. Pu-
rification by chromatography (silica gel, 30% EtOAc/hexanes,
Rf 0.27) gave 257 mg of 24b as a white solid: mp 75-77 °C
(EtOAc/hexanes); IR (CDCl3) 3300, 2964, 1641, 1512, 1247
3,3-Dim eth yl-4-p en tyn oic Acid , N ′-Meth yl-N ′-(m eth -
oxyca r bon yl)h yd r a zid e (26c). This material was prepared
in 79% yield from 369 mg (2.92 mmol) of acid 17c and a
solution of 366 mg (3.51 mmol, 1.2 equiv) of 1-(methoxycar-
bonyl)-1-methylhydrazine25 in 2 mL of anhydrous THF using
1
cm-1; H NMR (300 MHz, CDCl3) 1.29 (s, 6H), 2.03 (t, J )
2.7 Hz, 1H), 2.46 (d, J ) 2.7 Hz, 2H), 3.80 (s, 3H), 4.40 (d, J
) 5.5 Hz, 2H), 6.05 (br, 1H), 6.87 (d, J ) 8.6 Hz, 2H), 7.22 (d,
J ) 8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) 25.2, 30.2, 41.9,
43.4, 55.5, 71.2, 81.6, 114.3, 129.3, 130.7, 159.2, 176.3. Anal.
Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C,
73.36; H, 7.83; N, 5.65.
(25) Wadsworth, W. S. J . Org. Chem. 1969, 34, 2994.

5020 J . Org. Chem., Vol. 61, No. 15, 1996
J acobi et al.
method A described above. Purification by chromatography
(silica gel, 50% EtOAc/hexanes, Rf 0.45 in 70% EtOAc/hexanes)
gave 491 mg of 26c as a white crystalline solid: mp 79-81 °C
(EtOAc/hexanes); IR (CDCl3) 3274, 2964, 1715, 1676, 1450
mL (1.0 mmol, 1.0 equiv) of freshly prepared 1.0 M TBAF/
THF, following a procedure identical to that described above
for 27a (heating time 3.5 h). Chromatography (silica gel, 15%
EtOAc/hexanes) afforded 232 mg (98%) of 27d as a colorless
oil, identical to that obtained using method B below.
1
cm-1; H NMR (300 MHz, CDCl3) 1.37 (s, 6H), 2.30 (s, 1H),
2.39 (s, 2H), 3.19 (s, 3H), 3.73 (br s, 3H), 7.94 (br s, 1H); 13C
NMR (75 MHz, CDCl3) 29.1, 30.1, 37.9, 47.5, 53.4, 69.9, 90.7,
156.9, 169.0. Anal. Calcd for C10H16N2O3: C, 56.59; H, 7.60;
N, 13.20. Found: C, 56.51; H, 7.65; N, 13.13.
Meth od B. Cycliza tion w ith Rea gen t 31. A solution of
168 mg (1.0 mmol) of acetylenic ester 32d in 5 mL of
anhydrous THF was added to a solution of 2.0 mmol (2.0 equiv)
of reagent 31, prepared in situ from 76 mg (2.0 mmol) of
LiAlH4, 856 mg (8.0 mmol) of benzylamine, and 5 mL of
anhydrous THF following the general procedure of Solladie´-
Cavallo.18 After addition was complete, the reaction was
heated at reflux for a period of 3 h, cooled to rt, and carefully
quenched by sequential addition of 1 mL of H2O, 1 mL of 2 N
NaOH, and 3 mL of H2O. The mixture was stirred at rt until
a precipitate formed and was then extracted with 2 × 10 mL
CH2Cl2. The combined extracts were washed with brine, dried
over MgSO4, and concentrated under reduced pressure to
afford a yellow oil. Chromatography (silica gel, 20% EtOAc/
hexanes, Rf 0.32) afforded 162 mg (71%) of pyrrolidinone 27d
as a light yellow oil: MS m/z 229 (M+); IR (neat) 2968, 2870,
1720, 1663, 1635, 1395, 1160 cm-1; 1H NMR (300 MHz, CDCl3)
1.07 (s, 3H), 1.19 (d, J ) 7 Hz, 3H), 1.26 (s, 3H), 2.42 (q, J
) 7 Hz, 1H), 4.10-4.20 (m, 2H), 4.62 (d, J ) 15.4 Hz, 1H),
4.74 (d, J ) 15.4 Hz, 1H), 7.20-7.36 (m, 5H); 13C NMR (75
MHz, CDCl3) 10.4, 24.4, 27.4, 40.6, 43.9, 47.0, 83.8, 127.4,
N-Ben zyl-5-m eth ylen e-2-p yr r olid in on e (27a ). A solu-
tion of 107 mg (0.57 mmol, 1.0 equiv) of acetylenic amide 23a
in 5.7 mL of anhydrous THF was treated in dropwise fashion,
and with vigorous stirring, with a solution of 0.57 mL (0.57
mmol, 1.0 equiv) of freshly prepared 1.0 M tetra-n-butylam-
monium fluoride (TBAF) in THF. After addition was complete,
the reaction mixture was heated at reflux under an argon
atmosphere for a period of 8.5 h. At the end of this period the
reaction mixture was cooled, concentrated under reduced
pressure (bath temperature 25 °C), and chromatographed
(silica gel, 20% EtOAc/hexanes, Rf 0.37 in 30% EtOAc/hexanes)
to give 90 mg (84%) of 27a as a colorless oil: IR (CH2Cl2) 1719,
1664, 1393 cm-1; 1H NMR (300 MHz, CDCl3) 2.52-2.65 (m,
2H), 2.67-2.80 (m, 2H), 4.12 (d, J ) 1.8 Hz, 1H), 4.19 (d, J )
1.8 Hz, 1H), 4.68 (s, 2H), 7.20-7.39 (m, 5H); 13C NMR (75
MHz, CDCl3) 23.9, 29.2, 43.8, 85.5, 127.4, 127.5, 128.7, 136.2,
146.4, 176.1; exact mass calcd for C12H13NO 187.0997, found
187.0994.
127.5, 128.7, 136.6, 156.4, 177.3; exact mass calcd for C15H19
NO 229.1466, found 229.1467.
-
N-Ben zyl-3,3-d im et h yl-5-m et h ylen e-2-p yr r olid in on e
(27b). This material was prepared in 100% yield from 127
mg (0.59 mmol) of acetylenic amide 23b in 5.9 mL of anhy-
drous THF and 0.59 mL (0.59 mmol, 1.0 equiv) of freshly
prepared 1.0 M TBAF/THF, following a procedure identical
to that described above for 27a (heating time 3.5 h). Chro-
matography (silica gel, 10% EtOAc/hexanes, Rf 0.25) afforded
133 mg (100%) of 27b as a colorless oil that crystallized upon
standing: mp 33-36 °C; IR (CH2Cl2) 3413, 2954, 1719, 1666,
1396 cm-1; 1H NMR (300 MHz, CDCl3) 1.27 (s, 6H), 2.56 (br
s, 2H), 4.11 (d, J ) 2 Hz, 1H), 4.20 (d, J ) 2 Hz, 1H), 4.67 (s,
2H), 7.19-7.32 (m, 5H); 13C NMR (75 MHz, CDCl3) 25.5,
40.0, 40.6, 43.8, 85.8, 127.2, 127.4, 128.7, 136.5, 144.1, 181.2;
exact mass calcd for C14H17NO 215.1310, found 215.1311.
N-Ben zyl-4,4-d im et h yl-5-m et h ylen e-2-p yr r olid in on e
(27c). Meth od A. Cycliza tion w ith TBAF . This material
was prepared in 98% yield from 333 mg (1.55 mmol) of
acetylenic amide 23c in 15 mL of anhydrous THF and 1.55
mL (1.55 mmol, 1.0 equiv) of freshly prepared 1.0 M TBAF/
THF, following a procedure identical to that described above
for 27a (heating time 2.5 h). Chromatography (silica gel, 20%
EtOAc/hexanes, Rf 0.42) afforded 328 mg (98%) of 27c as a
N-Ben zyl-3(R),4(R)-d im eth yl-5-m eth ylen e-2-p yr r olid i-
n on e (27e). This material was prepared in 92% yield from
197 mg (0.92 mmol) of acetylenic amide 23e in 9.0 mL of
anhydrous THF and 0.92 mL (0.92 mmol, 1.0 equiv) of freshly
prepared 1.0 M TBAF/THF, following a procedure identical
to that described above for 27a (heating time 3.0 h). Chro-
matography (silica gel, 20% EtOAc/hexanes, Rf 0.47) afforded
182 mg (92%) of 27e as a colorless oil: 1H NMR (300 MHz,
CDCl3) 1.26 (d, J ) 6.8 Hz, 3H), 1.30 (d, J ) 7.2 Hz, 3H),
2.25 (m, 1H), 2.49 (m, 1H), 4.12 (m, 1H), 4.20 (m, 1H), 4.63 (d,
J ) 15.4 Hz, 1H), 4.72 (d, J ) 15.4 Hz, 1H), 7.19-7.36 (m, 5
H); exact mass calcd for C14H17NO 215.1310, found 215.1309.
N-Ben zyl-3(S),4(S)-d im eth yl-5-m eth ylen e-2-p yr r olid i-
n on e (27f). This material was prepared in 93% yield from
215 mg (1.0 mmol) of acetylenic amide 23f in 10 mL of
anhydrous THF and 1.0 mL (1.0 mmol, 1.0 equiv) of freshly
prepared 1.0 M TBAF/THF, following a procedure identical
to that described above for 27a (heating time 3.0 h). Chro-
matography (silica gel, 20% EtOAc/hexanes, Rf 0.47) afforded
201 mg (93%) of 27f as a colorless oil, with spectral data
identical to those of 27e: exact mass calcd for C14H17NO
215.1310, found 215.1309.
1
pale yellow oil: IR (CDCl3) 2966, 1719, 1660 cm-1; H NMR
(300 MHz, CDCl3) 1.27 (s, 6H), 2.44 (s, 2H), 4.11 (d, J ) 2
Hz, 1H), 4.14 (d, J ) 2 Hz, 1H), 4.69 (s, 2H), 7.20-7.35 (m,
5H); 13C NMR (75 MHz, CDCl3) 29.2, 36.5, 43.7, 45.0, 83.6,
127.1, 127.3, 128.6, 136.2, 156.7, 173.9; exact mass calcd for
C14H17NO 215.1310, found 215.1311.
N-(4-Meth oxyben zyl)-3,3-d im eth yl-5-m eth ylen e-2-p yr -
r olid in on e (28b). This material was prepared in 82% yield
from 274 mg (1.19 mmol) of acetylenic amide 24b in 12 mL of
anhydrous THF and 1.2 mL (1.2 mmol, 1.0 equiv) of freshly
prepared 1.0 M TBAF/THF, following a procedure identical
to that described above for 27a (heating time 3.0 h). Chro-
matography (silica gel, 20% EtOAc/hexanes, Rf 0.42 in 30%
EtOAc/hexanes) afforded 224 mg (82%) of 28b as a colorless
Meth od B. Cycliza tion w ith Rea gen t 31. A solution of
111 mg (0.52 mmol) of acetylenic amide 23c in 2 mL of
anhydrous THF was added to a solution of 0.52 mmol (1 equiv)
of reagent 31, prepared in situ from 20 mg (0.52 mmol, 1.0
equiv) of LiAlH4, 0.28 mL (2.58 mmol, 5.0 equiv) of benzyl-
amine, and 2 mL of anhydrous THF following the general
procedure of Solladie´-Cavallo.18 After addition was complete,
the reaction was heated at reflux for a period of 2 h, cooled to
rt, and carefully quenched by sequential addition of 1 mL of
H2O, 1 mL of 2 N NaOH, and 3 mL of H2O. The mixture was
stirred at rt until a precipitate formed and was then extracted
with 2 × 10 mL of CH2Cl2. The combined extracts were
washed with brine, dried over MgSO4, and concentrated under
reduced pressure to afford a yellow oil. Chromatography (silica
gel, 20% EtOAc/hexanes) afforded 90 mg of 27c (81%) as a
pale yellow oil, identical to that obtained using method A
above.
1
oil: IR (CDCl3) 2961, 1716, 1668, 1514, 1398, 1248 cm-1; H
NMR (300 MHz, CDCl3) 1.25 (s, 6H), 2.53 (t, J ) 1.8 Hz,
2H), 3.79 (s, 3H), 4.10 (d, J ) 1.8 Hz, 1H), 4.22 (d, J ) 1.8 Hz,
1H), 4.60 (s, 2H), 6.84 (d, J ) 8.7 Hz, 2H), 7.16 (d, J ) 8.7 Hz,
2H); 13C NMR (75 MHz, CDCl3) 25.4, 39.9, 40.6, 43.2, 55.2,
85.6, 114.0, 128.5, 128.6, 144.1, 158.9, 181.0; exact mass calcd
for C15H19NO2 245.1416, found 245.1417.
N-(4-Meth oxyben zyl)-4,4-d im eth yl-5-m eth ylen e-2-p yr -
r olid in on e (28c). This material was prepared in 100% yield
from 175 mg (0.71 mmol) of acetylenic amide 24c in 7.1 mL of
anhydrous THF and 0.71 mL (0.71 mmol, 1.0 equiv) of freshly
prepared 1.0 M TBAF/THF, following a procedure identical
to that described above for 27a (heating time 2.0 h). Chro-
matography (silica gel, 30% EtOAC/hexanes, Rf 0.42) afforded
175 mg (100%) of 28c as a colorless oil: IR (CDCl3) 2949, 1716,
N -Be n zyl-3,4,4-t r im e t h yl-5-m e t h yle n e -2-p yr r olid i-
n on e (27d ). Meth od A. Cycliza tion w ith TBAF . This
material was prepared in 99% yield from 234 mg (1.0 mmol)
of acetylenic amide 23d in 10 mL of anhydrous THF and 1.0
1
1665, 1511 1389 cm-1; H NMR (300 MHz, CDCl3) 1.24 (s,
6H), 2.42 (s, 2H), 3.79 (s, 3H), 4.11 (d, J ) 2.3 Hz, 1H), 4.17
(d, J ) 2.3 Hz, 1H), 4.61 (s, 2H), 6.84 (d, J ) 8.7 Hz, 2H), 7.16

Cyclic Enamides from Acetylenic Amides
J . Org. Chem., Vol. 61, No. 15, 1996 5021
(d, J ) 8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) 29.1, 36.6,
43.2, 45.0, 55.2, 83.5, 114.0, 128.4, 128.5, 156.8, 158.9, 173.9;
exact mass calcd for C15H19NO2 245.1416, found 245.1417.
3H total), 4.19 (d, J ) 2 Hz, 1H), 4.27 (d, J ) 2 Hz, 1H); exact
mass calcd for C10H16N2O3 215.1310, found 215.1309.
2(R),4(S)-Dim eth yl-3(R)-eth yn yl-γ-bu tyr ola cton e (36).
A solution of 95 mg (0.39 mmol, 1.0 equiv) of acetylenic acid
354h in 3.0 mL of CH2Cl2 was treated at rt, with vigorous
stirring, with 17.2 mg (0.39 mmol, 1.0 equiv) of P4S10 under
an atmosphere of N2. The reaction mixture was then stirred
at rt for 46 h before being diluted with 10 mL of H2O and
extracted with 3 × 6 mL of CH2Cl2. The combined organic
extracts were dried over anhydrous Na2SO4, concentrated
under reduced pressure, and chromatographed (silica gel, 30%
acetone/hexanes) to afford 47.3 mg (88%) of lactone 36 as a
white solid: mp 55-56 °C (acetone/hexanes); [R]26D ) -100.0°
(c ) 0.29, EtOAc). Similar yields were obtained for this
reaction on gram scales and larger but using 2 equiv) of
P4S10: Rf 0.52 (silica gel, 30% acetone/hexane); IR (CH2Cl2)
3053.7, 2986.3, 2305.2, 2253.7, 1774.3, 1421.7, 1265.1, 1181.4,
N-(4-Met h oxyb en zyl)-3,4,4-t r im et h yl-5-m et h ylen e-2-
p yr r olid in on e (28d ). This material was prepared in 98%
yield from 210 mg (0.81 mmol) of acetylenic amide 24d in 8.1
mL of anhydrous THF and 0.81 mL (0.81 mmol, 1.0 equiv) of
freshly prepared 1.0 M TBAF/THF, following a procedure
identical to that described above for 27a (heating time 3.0 h).
Chromatography (silica gel, 20% EtOAc/hexanes, Rf 0.39)
afforded 206 mg (98%) of 28d as a colorless oil: IR (CDCl3)
2962, 1716, 1659, 1511, 1395 cm-1; 1H NMR (300 MHz, CDCl3)
1.01 (s, 3H), 1.13 (d, J ) 7.4 Hz, 3H), 1.20 (s, 3H), 2.34 (q, J
) 7.4 Hz, 1H), 3.73 (s, 3H), 4.10 (d, J ) 2 Hz, 1H), 4.15 (d, J
) 2 Hz, 1H), 4.51 (d, J ) 15 Hz, 1H), 4.63 (d, J ) 15 Hz, 1H),
6.80 (d, J ) 8.6 Hz, 2H), 7.13 (d, J ) 8.6 Hz, 2H); 13C NMR
(75 MHz, CDCl3) 10.2, 24.1, 27.1, 40.3, 43.1, 46.7, 55.2, 83.5,
1
1054.6, 1014.8 cm-1; H NMR (400 MHz, CDCl3) 1.36 (d, J
113.9, 128.5, 156.1, 158.9, 176.9; exact mass calcd for C16H21
NO2 259.1572, found 259.1566.
-
) 8.5 Hz, 3H), 1.51 (d, J ) 5.9 Hz, 3H), 2.31 (d, J ) 2.0 Hz,
1H), 2.83 (dq, J ) 9.0, 8.5 Hz, 1H), 3.33 (m, 1H), 4.48 (dq, J )
6.0, 5.9 Hz, 1H); MS m/e 138 (M+), 123, 110, 94, 77, 66, 43, 39.
Anal. Calcd for C8H10O2: C, 69.55; H, 7.30. Found: C, 69.60;
H, 7.33.
N-(3,4-Dim eth oxyben zyl)-3,3-d im eth yl-5-m eth ylen e-2-
p yr r olid in on e (29b). This material was prepared in 89%
yield from 67 mg (0.24 mmol) of acetylenic amide 25b in 4.0
mL of anhydrous THF and 0.24 mL (0.24 mmol, 1.0 equiv) of
freshly prepared 1.0 M TBAF/THF, following a procedure
identical to that described above for 27a (heating time 3.0 h).
Chromatography (silica gel, 20% EtOAc/hexanes, Rf 0.24)
afforded 59 mg (89%) of 29b as a colorless oil: IR (CH2Cl2)
2960, 1715, 1666, 1517, 1398, 1261, 1140 cm-1; 1H NMR (300
MHz, CDCl3) 1.24 (s, 6H), 2.53 (m, 1H), 3.83 (s, 3H), 3.85 (s,
3H), 4.11 (d, J ) 1.5 Hz, 1H), 4.23 (d, J ) 1.5 Hz, 1H), 4.60 (s,
2H), 6.72-6.82 (m, 3H); 13C NMR (75 MHz, CDCl3) 25.4,
40.0, 40.7, 43.6, 55.9, 56.0, 85.7, 110.7, 111.3, 119.7, 129.2,
144.2, 148.5, 149.3, 181.2; exact mass calcd for C16H21NO3
275.1521, found 275.1521.
N-(3,4-Dim eth oxyben zyl)-4,4-d im eth yl-5-m eth ylen e-2-
p yr r olid in on e (29c). This material was prepared in 100%
yield from 110 mg (0.40 mmol) of acetylenic amide 25c in 4.0
mL of anhydrous THF and 0.40 mL (0.40 mmol, 1.0 equiv) of
freshly prepared 1.0 M TBAF/THF, following a procedure
identical to that described above for 27a (heating time 3.0 h).
Chromatography (silica gel, 30% EtOAc/hexanes, Rf 0.27)
afforded 111 mg (100%) of 29c as a colorless oil: IR (CDCl3)
2959, 1717, 1663, 1515, 1259 cm-1; 1H NMR (300 MHz, CDCl3)
1.25 (s, 6H), 2.42 (s, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 4.12 (d,
J ) 2.3 Hz, 1H), 4.19 (d, J ) 2.3 Hz, 1H), 4.62 (s, 2H), 6.75-
6.81 (m, 3H); 13C NMR (75 MHz, CDCl3) 29.1, 36.5, 43.4,
44.9, 55.9, 83.6, 110.5, 111.2, 119.6, 128.8, 148.3, 149.2, 156.7,
173.9; exact mass calcd for C16H21NO3 275.1521, found 275.1518.
N-(3,4-Dim eth oxyben zyl)-3,4,4-tr im eth yl-5-m eth ylen e-
2-p yr r olid in on e (29d ). This material was prepared in 100%
yield from 184 mg (0.64 mmol) of acetylenic amide 25d in 6.4
mL of anhydrous THF and 0.64 mL (0.64 mmol, 1.0 equiv) of
freshly prepared 1.0 M TBAF/THF, following a procedure
identical to that described above for 27a (heating time 3.0 h).
Chromatography (silica gel, 30% EtOAc/hexanes, Rf 0.31)
afforded 200 mg (100%) of 29d as a colorless oil: IR (CH2Cl2)
2962, 1716, 1659, 1517, 1459, 1395, 1260 cm-1; 1H NMR (300
MHz, CDCl3) 1.06 (s, 3H), 1.16 (d, J ) 7.3 Hz, 3H), 1.24 (s,
3H), 2.38 (q, J ) 7.3 Hz, 1H), 3.84 (s, 3H), 3.86 (s, 3H), 4.14
(d, J ) 2.1 Hz, 1H), 4.19 (d, J ) 2.1 Hz, 1H), 4.54 (d, J ) 15.2
Hz, 1H), 4.67 (d, J ) 15.2 Hz, 1H), 6.72-6.82 (m, 3H); 13C
NMR (75 MHz, CDCl3) 10.3, 24.1, 27.2, 40.4, 43.4, 46.8, 55.8,
55.9, 83.6, 110.5, 111.1, 119.7, 129.1, 148.3, 149.2, 156.1, 177.0;
exact mass calcd for C17H23NO3 289.1678, found 289.1671.
N-Ben zyl-3(R)-m eth yl-4(R)-(h ydr oxyeth yl)-5-m eth ylen e-
2-p yr r olid in on e (38). A solution of 850 mg (6.15 mmol, 1
equiv) of lactone 36 in 3.0 mL of anhydrous THF was added
to a solution of 6.15 mmol (1 equiv) of reagent 31, prepared in
situ from 246 mg (6.16 mmol, 1 equiv) of LiAlH4, 3.36 mL (30.8
mmol, 5 equiv) of benzylamine, and 5.0 mL of anhydrous THF
following the general procedure of Solladie´-Cavallo.18 After
addition was complete, the reaction mixture was stirred at rt
for 17 h and was then carefully quenched by sequential
addition of 0.24 mL of H2O, 0.24 mL of 10% KOH, and 0.71
mL of H2O. The mixture was then filtered through Celite and
washed with 5 × 3 mL of CH2Cl2. The organic layers were
dried over MgSO4, concentrated under reduced pressure, and
chromatographed (silica gel, 50% EtOAc/hexanes, Rf 0.33) to
afford 1.45 g (96%) of 38 as colorless crystals: mp 87-89 °C
(EtOAc/hexane); [R]26 ) -14.9° (c ) 0.35, EtOAc); IR 3607,
D
1
1715, 1637 cm-1; H NMR (400 MHz, CDCl3) 1.15 (d, J ) 6
Hz, 3H), 1.33 (d, J ) 6 Hz, 3H), 1.85 (m, 1H), 2.45-2.59 (m,
2H), 3.75 (m, 1H), 4.19 (s, 1H), 4.29 (s, 1H), 4.57 (d, J ) 16
Hz, 1H), 4.74 (d, J ) 16 Hz, 1H), 7.14-7.35 (m, 5H); exact
mass calcd for C15H19NO2 245.1416, found 245.1414.
3-(1,1-Dim et h yl-2-p r op yn yl)t et r a h yd r o-2H -p yr a n -2-
on e (41). A solution of 3.0 g (7.81 mmol, 1.0 equiv) of cobalt
complex 404h and 2.69 g (15.63 mmol, 2.0 equiv) of silyl enol
ether 3926 in 50 mL of anhydrous CH2Cl2 was cooled to -78
°C under nitrogen and was treated in dropwise fashion, with
vigorous stirring, with 2.22 g (15.6 mmol, 2.0 equiv) of BF3‚
Et2O. After addition was complete, the resulting solution was
stirred for an additional 30 min at -78 °C and then for 30
min at rt. The reaction was then carefully quenched with 20
mL of pH 7 buffer and extracted with 3 × 10 mL of CH2Cl2.
The combined extracts were dried (MgSO4) and concentrated
under reduced pressure. Chromatography (silica gel, 10%
EtOAc/hexanes, Rf 0.70) afforded 3.42 g (97%) of the interme-
diate cobalt-protected Nicholas adduct as a dark oil: 1H NMR
(300 MHz, CDCl3) 1.35 (s, 3H), 1.50 (s, 3H), 1.70-2.00 (m,
3H), 2.21 (m, 1H), 2.43 (m, 1H), 4.16-4.30 (m, 2H), 6.18 (s,
1H). Anal. Calcd for C16H14Co2O8: C, 42.50; H, 3.12.
Found: C, 42.59; H, 3.18.
A total of 3.42 g (7.56 mmol) of the cobalt-protected Nicholas
adduct described above was dissolved in 200 mL of acetone.
Ceric ammonium nitrate (CAN) was added in small portions
over 20 min, with vigorous stirring, until gas evolution ceased.
The solution was then concentrated under reduced pressure,
and the resulting red oil was diluted with 50 mL of H2O. This
now orange-colored solution was extracted with 6 × 20 mL of
Et2O, and the combined extracts were dried (MgSO4) and
concentrated under reduced pressure. Vacuum distillation of
the residue afforded 1.15 g (92%) of lactone 41 as a colorless
oil: bp0.75mm 98-101 °C; Rf 0.72 (silica gel, 10% EtOAc/
N -[N ′-Me t h yl-N ′-(m e t h oxyca r b on yl)a m in o]-4,4-d i-
m eth yl-5-m eth ylen e-2-p yr r olid in on e (30c). This material
was prepared in 90% yield from 115 mg (0.54 mmol) of
acetylenic hydrazide 26c in 5.4 mL of anhydrous THF and 0.54
mL (0.54 mmol, 1.0 equiv) of freshly prepared 1.0 M TBAF/
THF, following a procedure identical to that described above
for 27a (heating time 1.0 h). Chromatography (silica gel, 25%
EtOAc/hexanes, Rf 0.20) afforded 103 mg (90%) of 30c as a
colorless oil: IR (CDCl3) 2954, 1743, 1719, 1449, 1349 cm-1
;
1H NMR (300 MHz, CDCl3; mixture of rotomers) 1.29-1.35
(26) Fouque, E.; Rousseau, G.; Seyden-Penne, J . J . Org. Chem. 1990,
55, 4807.
(br, 6H), 2.34 (s, 2H), 3.19, 3.20 (2s, 3H total), 3.71, 3.81 (2s,

5022 J . Org. Chem., Vol. 61, No. 15, 1996
J acobi et al.
hexanes); MS m/z 151 (M+ - 15); IR (neat) 3285, 2972, 2109,
with 3 × 15 mL of Et2O. The combined organic extracts were
dried over MgSO4 and concentrated under reduced pressure.
Chromatography (silica gel, 20% EtOAc/hexanes, Rf 0.68) then
afforded 470 mg (78%) of ester 44 as a yellow oil: MS m/z 301
1
1732, 1131 cm-1; H NMR (300 MHz, CDCl3) 1.39 (s, 3H),
1.41 (s, 3H), 1.75-1.95 (m, 3H), 2.15 (s, 1H), 2.30 (m, 1H), 2.45
(m, 1H), 4.25-4.30 (m, 2H); 13C NMR (75 MHz, CDCl3) 22.0,
22.1, 26.1, 28.2, 33.4, 48.0, 67.7, 69.1, 89.4, 171.3. Anal. Calcd
for C10H14O2: C, 72.26; H, 8.49. Found: C, 72.04; H, 8.42.
N-Ben zyl-2-(3-h yd r oxyp r op yl)-3,3-d im eth yl-4-p en tyn -
a m id e (42). This material was prepared in 88% yield follow-
ing the general procedure outlined above for enamide 38,
employing 166 mg (1.0 mmol, 1.0 equiv) of lactone 41, and 2.0
mmol (2 equiv) of reagent 3118 in 10 mL of anhydrous THF
for 24 h at rt. Workup and chromatography (silica gel, 50%
EtOAc/hexanes, Rf 0.38) gave 241 mg (88%) of acetylenic amide
42 as a semisolid oil, which on crystallization (hexanes/EtOAc)
afforded 42 as colorless grains: mp 96-97 °C; IR (neat) 3299,
3065, 2972, 2109, 1650, 1245, 1058 cm-1; 1H NMR (300 MHz,
CDCl3) 1.25 (s, 6H), 1.42-1.60 (m, 2H), 1.70-1.80 (m, 2H),
1.86 (br, 1H), 2.10 (t, J ) 4.4 Hz, 1H), 2.12 (s, 1H), 3.59 (dt, J
) 2.5, 2.4 Hz, 2H), 4.41 (d, J ) 5.8 Hz, 2H), 6.38 (br, 1H),
7.19-7.32 (m, 5H). Anal. Calcd for C17H23NO2: C, 74.69; H,
8.48; N, 5.12. Found: C, 74.65; H, 8.52; N, 5.13.
1
(M+); H NMR (300 MHz, CDCl3) 1.09 (s, 3H), 1.26 (s, 3H),
1.82-1.93 (m, 2H), 2.29 (m, 1H), 2.64 (m, 1H), 2.82 (m, 1H)
3.67 (s, 3H), 4.13 (d, J ) 2.3 Hz, 1H), 4.15 (d, J ) 2.3 Hz, 1H),
4.59 (d, J ) 15.4 Hz, 1H), 4.69 (d, J ) 15.4 Hz, 1H), 7.18-
7.35 (m, 5H); exact mass calcd for C18H23NO3 301.1678, found
301.1672.
Dim eth yl 2-(1,1-Dim eth yl-2-p r op yn yl)glu ta r a te (46). A
solution of 9.30 g (24.0 mmol, 1.0 equiv) of colbalt complex 404h
and 18.50 g (61.0 mmol, 2.5 equiv) of bis-silyl enol ether 4523
in 200 mL of CH2Cl2 was cooled to -78 °C under nitrogen and
was treated in dropwise fashion, with vigorous stirring, with
8.63 g (61.0 mmol, 2.5 equiv) of BF3‚Et2O. After addition was
complete, the reaction was stirred for an additional 2 h at -78
°C and then for 30 min at 0 °C. The reaction was then
carefully quenched with 40 mL of pH 7 buffer and extracted
with 3 × 20 mL of CH2Cl2. The combined organic extracts
were dried (MgSO4) and concentrated under reduced pressure
to afford a dark residue. This material could either be purified
at this stage (chromatography, silica gel, 10% EtOAc/hexanes)
or deprotected directly with no change in yield: Rf 0.4 (silica
gel, 5% EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) 1.29
(s, 3H), 1.32 (s, 3H), 2.03-2.41 (m, 5H), 3.66 (s, 3H), 3.71 (s,
3H), 6.09 (s, 1H).
N-Ben zyl-3-(3-h yd r oxyp r op yl)-4,4-d im eth yl-5-m eth yl-
en e-2-p yr r olid in on e (43). This material was prepared in
81% yield following the general procedure outlined above for
enamide 38, employing 380 mg (2.29 mmol, 1.0 equiv) of
lactone 41 and 2.52 mmol (1.1 equiv) of reagent 3118 in 10 mL
of anhydrous THF at reflux for 12 h. Workup and chroma-
tography (silica gel, 50% EtOAc/hexanes, Rf 0.50) afforded 506
mg (81%) of enamide 43 as a viscous colorless oil. Alterna-
tively, 43 can be purified by vacuum distillation (bp0.4mm 174-
175 °C): IR (neat) 3418, 2962, 2869, 1715, 1662, 1634, 1065
A total of 12.23 g (23.0 mmol) of the cobalt-protected
Nicholas adduct described above was dissolved in 200 mL of
acetone. Ceric ammonium nitrate (CAN) was added in small
portions over 30 min, with vigorous stirring, until gas evolution
ceased. The solution was then concentrated under reduced
pressure, and the resulting red oil was diluted with 100 mL
of H2O. This now orange-colored solution was extracted with
6 × 20 mL of Et2O, and the combined extracts were dried
(MgSO4) and concentrated under reduced pressure. Chroma-
tography (silica gel, 10% EtOAc/hexanes) then afforded 4.77
g (94%) of diester 46 as a colorless oil. Alternatively, 46 could
be purified by vacuum distillation (bp0.15mm 81-82 °C): Rf 0.45
(silica gel, 40% EtOAc/hexanes); MS m/z 226 (M+); IR (neat)
3285, 2977, 2953, 2109, 1737, 1436, 1159 cm-1; 1H NMR (300
MHz, CDCl3) 1.25 (s, 3H), 1.27 (s, 3H), 2.04-2.14 (m, 2H),
1
cm-1; H NMR (300 MHz, CDCl3) 1.07 (s, 3H), 1.26 (s, 3H),
1.59-1.88 (m, 4H), 2.31 (m, 1H), 3.68-3.75 (m, 2H), 4.14 (d,
J ) 2 Hz, 1H), 4.17 (d, J ) 2 Hz, 1H), 4.61 (d, J ) 15.4 Hz,
1H), 4.72 (d, J ) 15.4 Hz, 1H), 7.19-7.38 (m, 5H); 13C NMR
(100 MHz, CDCl3) 22.2, 23.7, 27.0, 31.0, 40.5, 43.3, 50.9, 61.8,
83.5, 126.8, 126.9, 128.2, 135.9, 155.5, 176.6. Anal. Calcd for
C17H23NO2: C, 74.69; H, 8.48; N, 5.12. Found: C, 73.92; H,
8.44; N, 5.18.
N-Ben zyl-3-(3-ca r b om et h oxyp r op yl)-4,4-d im et h yl-5-
m eth ylen e-2-p yr r olid in on e (44). A solution of 950 mg (12.0
mmol, 12.0 equiv) of pyridine in 40 mL of CH2Cl2 was cooled
to 0 °C and was treated with 600 mg (6.0 mmol, 6.0 equiv) of
chromium(VI) oxide (CrO3) with vigorous stirring. Stirring
was continued for an additional 15 min at 0 °C, and the
resulting mixture was then treated in dropwise fashion with
a solution of 273 mg (1.0 mmol, 1.0 equiv) of alcohol 43 in 5
mL of CH2Cl2. After addition was complete, the reaction was
allowed to warm to rt and stirring was continued for a period
of 30 min. The chromium salts were then separated by
decanting, and the supernatant was concentrated under
reduced pressure. The residue was triturated with Et2O, and
the residual solid was removed by vacuum filtration through
Celite. The filtrate was then washed with 10% NaOH, dried
over MgSO4, and concentrated under reduced pressure to
afford 241 mg (90%) of aldehyde 43a as an unstable, light
yellow oil that was used without further purification: bp0.25mm
190-192 °C; Rf 0.70 (silica gel, 50% EtOAc/hexanes); MS m/z
271 (M+); IR (neat) 2962, 1715, 1666, 1643, 1260, 1091, 1027,
2.15 (s, 1H), 2.18-2.49 (m, 3H), 3.65 (s, 3H), 3.67 (s, 3H); 13
C
NMR (75 MHz, CDCl3) 23.8, 26.0, 28.0, 32.3, 51.3, 51.6, 54.3,
69.3, 89.2, 173.1, 173.6. Anal. Calcd for C12H18O4: C, 63.70;
H, 8.02. Found: C, 63.47; H, 7.95.
N -Be n zyl-3-[(N -b e n zyla m id o)e t h yl]-4,4-d im e t h yl-5-
m eth ylen e-2-p yr r olid in on e (48). A total of 114 mg (0.5
mmol, 1.0 equiv) of diester 46 was added to a solution of 2.0
mmol (4.0 equiv) of reagent 31, prepared in situ from 76 mg
(2.0 mmol, 4.0 equiv) of LiAlH4, 1.1 mL (10.0 mmol, 20.0 equiv)
of benzylamine, and 7.0 mL of anhydrous THF following the
general procedure of Solladie´-Cavallo.18 After addition was
complete, the reaction mixture was heated at reflux for a
period of 8 h. After being cooled to rt, the reaction mixture
was then carefully quenched by sequential addition of 1.0 mL
of H2O, 1.0 mL of 10% NaOH, and 3.0 mL of H2O. Stirring
was continued until the new precipitate became white and
powdered. The mixture was then filtered through Celite and
washed thoroughly with CH2Cl2. The combined organic
extracts were dried over MgSO4, concentrated under reduced
pressure, and chromatographed (silica gel, 50% EtOAc/hex-
anes, Rf 0.60) to afford 152 mg (81%) of enamide 48 as a
semisolid colorless oil: MS m/z 376 (M+); IR (neat) 3311, 3063,
1
801 cm-1; H NMR (300 MHz, CDCl3) 1.09 (s, 3H), 1.26 (s,
3H), 1.79-1.96 (m, 2H), 2.27 (dd, J ) 4.6, 9.2 Hz, 1H), 2.82
(m, 1H), 3.02 (m, 1H), 4.13 (d, J ) 2 Hz, 1H), 4.17 (d, J ) 2
Hz, 1H), 4.59 (d, J ) 15 Hz, 1H), 4.69 (d, J ) 15 Hz, 1H),
7.18-7.38 (m, 5H), 9.82 (s, 1H); exact mass calcd for C17H21
NO2 271.1572, found 271.1568.
-
2964, 1712, 1659, 1159 cm-1 1H NMR (300 MHz, CDCl3)
;
1.09 (s, 3H), 1.21 (s, 3H), 1.72 (m, 1H), 2.05 (m, 1H), 2.23 (m,
1H), 2.51-2.70 (m, 2H), 4.13 (d, J ) 2 Hz, 1H), 4.17 (d, J ) 2
Hz, 1H), 4.43-4.47 (m, 2H), 4.58 (d, J ) 15.4 Hz, 1H), 4.67 (d,
J ) 15.4 Hz, 1H), 6.48 (br, 1H), 7.15-7.36 (m, 10 H); 13C NMR
(75 MHz, CDCl3) 22.7, 23.4, 27.7, 34.1, 40.6, 43.4, 43.5, 49.9,
84.1, 127.0, 127.3, 127.7, 128.5, 136.1, 138.5, 155.5, 172.5,
176.6; exact mass calcd for C24H28N2O2 376.2151, found
376.2146.
A solution of 543 mg (2.0 mmol, 1.0 equiv) of aldehyde 43a
in 20 mL of anhydrous MeOH was cooled to 0 °C and was
treated portionwise, with vigorous stirring, with a solution of
292 mg (5.2 mmol, 2.6 equiv) of potassium hydroxide in 10
mL of MeOH, followed by 660 mg (2.6 mmol, 1.3 equiv) of
iodine in 5 mL of MeOH. The resulting solution was stirred
for 20 min at 0 °C, and the reaction was then quenched by
addition of 10 mL of H2O. The resulting dark solution was
decolorized by addition of 20 mg of Na2S2O3. Most of the
MeOH was then removed by concentration under reduced
pressure, and the aqueous solution remaining was extracted
3-[(N-Ben zyla m id o)eth yl]-4,4-d im eth yl-5-m eth ylen e-2-
p yr r olid in on e (49). Approximately 10 mL of liquid NH3 was
distilled from Na metal through a glass tube into a three-

Cyclic Enamides from Acetylenic Amides
J . Org. Chem., Vol. 61, No. 15, 1996 5023
necked flask containing 197 mg (0.52 mmol, 1.0 equiv) of
N-benzylenamide 48 and equipped with a dry ice/acetone
condenser. The reaction mixture was then treated with 48
mg (2.09 mmol, 4.0 equiv) of Na metal to give a dark blue
solution. This solution was maintained at -33 °C for 10 min
(reflux) and was then carefully quenched by slow addition of
ammonium chloride to produce a thick white suspension. The
suspension was vigorously mixed to ensure complete quench-
ing of the Na (Wa r n in g: as with all Na reductions, possible
fire hazard). The NH3 was then allowed to evaporate at rt,
and the residue was partitioned between 10 mL of CH2Cl2 and
10 mL of H2O. The layers were separated, and the aqueous
layer was extracted with an additional 2 × 10 mL of CH2Cl2.
The combined organic extracts were dried over MgSO4 and
concentrated under reduced pressure. Chromatography (silica
gel, CH2Cl2) then afforded 99 mg (98%) of the debenzylated
enamide 49 as an unstable colorless oil: Rf 0.6 (silica gel, 50%
EtOAc/hexanes); MS m/z 286 (M+); 1H NMR (300 MHz, CDCl3)
1.11 (s, 3H), 1.23 (s, 3H), 1.69 (m, 1H), 1.98 (m, 1H), 2.14
(m, 1H), 2.42-2.65 (m, 2H), 4.10 (d, J ) 2 Hz, 1H), 4.23 (d, J
) 2 Hz, 1H), 4.40-4.46 (m, 2H), 6.51 (br, 1H), 7.20-7.35 (m,
5 H), 7.49 (br, 1H).
Ack n ow led gm en t. Financial support of this work
by the National Institutes of Health, Grant No.
GM38913, is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for compounds 18b-d , 19b-d , (Z)-21a -f, (E)-
21a ,b, 23a -f, 24b-d , 25b-d , 26c, 27a -f, 28b-d , 29b-d ,
30c, 36, 38, 41-44, 43a , 46, 48, and 49 (43 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
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