A new route to 7-substituted derivatives of N-{4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl) -ethyl]benzoyl}-L-glutamic acid [ALIMTA (LY231514, MTA)]

Article abstract of DOI:10.1021/jo001580l

Alkylation of various primary amines with crotyl bromide, followed by DMAP-promoted acylation with methyl malonyl chloride to 4 and then manganic triacetate dihydrate/cupric acetate induced radical cyclization, gave 1-substituted-4-vinyl-3-carbomethoxy-2-pyrrolidinones (5). Thiation to the thiolactams 6 and guanidine cyclization then gave a series of 2-amino-3,4-dihydro-4-oxo-5-vinyl-7-substituted pyrrolo[2,3-d]pyrimidines (7). Palladium-catalyzed C-C coupling with diethyl 4-iodobenzoylglutamate led in one step via an unexpected redox reaction to the diethyl esters 9 of a series of 7-substituted derivatives of ALIMTA (LY231514, MTA), from which the target analogues 10 were readily prepared by saponification. Attempted deprotection at position 7 was successful in only one case (9d, R = CH₂C₆H₃(OMe)₂ (-3′,4′), which resulted in a known pentultimate precursor (9, R = H) of ALIMTA. The 7-substituted derivatives 10 proved to be inactive in vitro as inhibitors of cell division.

Full text of DOI:10.1021/jo001580l

3726
J . Org. Chem. 2001, 66, 3726-3738
A New Rou te to 7-Su bstitu ted Der iva tives of
N-{4-[2-(2-Am in o-3,4-d ih yd r o-4-oxo-7H-p yr r olo[2,3-d ]p yr im id in -5-yl)-
eth yl]ben zoyl}-L-glu ta m ic Acid [ALIMTA (LY231514, MTA)]1
Edward C. Taylor* and Bin Liu
Department of Chemistry, Princeton University, Princeton, New J ersey 08655
etaylor@princeton.edu
Received November 6, 2000
Alkylation of various primary amines with crotyl bromide, followed by DMAP-promoted acylation
with methyl malonyl chloride to 4 and then manganic triacetate dihydrate/cupric acetate induced
radical cyclization, gave 1-substituted-4-vinyl-3-carbomethoxy-2-pyrrolidinones (5). Thiation to the
thiolactams 6 and guanidine cyclization then gave a series of 2-amino-3,4-dihydro-4-oxo-5-vinyl-
7-substituted pyrrolo[2,3-d]pyrimidines (7). Palladium-catalyzed C-C coupling with diethyl 4-
iodobenzoylglutamate led in one step via an unexpected redox reaction to the diethyl esters 9 of a
series of 7-substituted derivatives of ALIMTA (LY231514, MTA), from which the target analogues
10 were readily prepared by saponification. Attempted deprotection at position 7 was successful in
only one case (9d , R ) CH2C6H3(OMe)2(-3′,4′), which resulted in a known pentultimate precursor
(9, R ) H) of ALIMTA. The 7-substituted derivatives 10 proved to be inactive in vitro as inhibitors
of cell division.
During our extensive program involving the design and
Phase III clinical trials for lung cancer and in multiple
additional trials, both as a single agent and in combina-
tion with other oncolytic agents. In the course of our
extensive SAR studies on this new drug, we had earlier
found that substitution at position 7 essentially elimi-
nated cell growth inhibitory activity.8 For example, the
N-7 methyl derivative of 1 exhibited only minimal
activity, and the N-7 phenylsulfonyl derivative was
synthesis of inhibitors of folate-dependent enzymes as
potential antitumor agents, we prepared N-{4-[2-(2-
amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl-
)ethyl]benzoyl}-L-glutamic acid (ALIMTA, 1).2 This com-
pound may be considered a structural analogue of
DDATHF (2a )3 and lometrexol (2b)4 in which the ring
junction position joining the ethano side-chain bridge to
the bicyclic heterocyclic ring is sp2 rather than sp3.
ALIMTA is a unique antifolate in that it has been shown
(5) Shih, C.; Chen, V. J .; Gossett, L. S.; Gates, S. B.; MacKellar, W.
C.; Habeck, L. L. Shackelford, K. A.; Mendelsohn, L. G.; Soose, D. J .;
Patel, V. F.; Andis, S. L.; Bewley, J . R.: Rayl, E. A.; Moroson, B. A.;
Beardsley, G. P.; Kohler, W.; Ratnam, M.; Schultz, R. M. Cancer Res.
1997, 57, 1116.
(6) (a) Taylor, E. C.; Kuhnt, D.; Shih, C. In Chemistry and Biology
of Pteridines and Folates; Pfleiderer, W., Rokos, H. Eds.; Blackwell
Science: Cambridge, MA, 1997; p 81. (b) Shih, C.; Beardsley, G. P.;
Chen, V. J .; Ehlhardt, W. J .; MacKellar, W. C.; Mendelsohn, L. G.;
Ratnam, M.; Schultz, R. M.; Taylor, E. C.; Worzalla, J . F. In Chemistry
and Biology of Pteridines and Folates; Pfleiderer, W., Rokos, H. Eds.;
Blackwell Science: Cambridge, MA, 1997; p 181. (c) Thornton, D. E.;
J ohn, W.; Loeher, P.; Eisenhauer, E. In Chemistry and Biology of
Pteridines and Folates; Pfleiderer, W., Rokos, H. Eds.; Blackwell
Science: Cambridge, MA, 1997; p 195. (d) Rinaldi, D. A.; Burris, H.
A.; Dorr, F. A.; Woodworth, J . R.; Kuhn, J . G.; Eckardt, J . R.; Rodriguez,
G.; Corso, S. W.; Fields, S. M.; Langley, C.; Clark, G.; Faries, D.; Lu,
P.; Van Hoff, D. D. J . Clin. Oncol. 1995, 13, 2842. (e) Calvert, A. H.;
Walling, J . M. Br. J . Cancer 1998, 78 (Suppl), 35. (f) Hammond, L.;
Baker, S. D.; Villalona-Calero, M.; Eckhardt, S. G.; Drengler, R.;
Aylesworth, C.; J ohnson, T.; Hidalgo, M.; Rodriguez, G.; Diab, S.;
Monroe, P.; Thornton, D.; J ohnson, R.; Von Hoff, D.; Rowinsky, E. Ann.
Oncol. 1998, 9 (Suppl), 160. (g) J ohnson, T.; Schwartz, G.; McCune,
D.; Stephenson, J .; Aylesworth, C.; Hammond, L.; Monroe, P.; Thorn-
ton, D.; Von Hoff, D.; Rowinsky, E. Ann. Oncol. 1998, 9 (Suppl), 160.
(h) J ohn, W.; Clark, J .; Burris, H.; Picus, J .; Schulman, L.; Thornton,
D.; Lochrer, P. Proc. Am. Soc. Clin. Oncol. 1997, 16, 292a-A1038. (i)
Cripps, M. C.; Burnell, M.; J olivet, J .; Lofters, W.; Fischer, B.; Panasci,
L.; Iglesias, J .; Eisenhauer, E. Eur. J . Cancer 1997, 33 (Suppl 8), S172-
a768. (j) Rusthoven, J .; Eisenhauer, E.; Butts, C.; Gregg, R.; Dancey,
J .; Fisher, B.; Iglesias, J . Eur. J . Cancer 1997, 33 (Suppl 8), S231-
a1045. (k) Thoedtmann, R.; Kemmerich, M.; Depenbrock, H.; Blatter,
J .; Ohnmacht, U.; Rastetter, J .; Hanauske, A. R. Eur. J . Cancer 1997,
33 (Suppl 8), S247-a1116.
to inhibit (following intracellular polyglutamylation) at
least five of the major folate-dependent enzymes (thymidy-
late synthase, dihydrofolate reductase, glycinamide ri-
bonucleotide formyltransferase, aminoimidazole ribonu-
cleotide formyltransferase, and C-1 tetrahydrofolate
synthetase). Its cell growth inhibition spectrum thus
contrasts sharply with those of DDATHF and lometrexol,
which function as effective inhibitors only of glycinamide
ribonucleotide formyltransferase.5-7 ALIMTA is an ex-
traordinarily effective antitumor agent that is now in
(1) This compound was originally referred to as LY231514, and later
as MTA (for MultiTargeted Antifolate). The disodium salt of this
compound has recently been given the proprietary name ALIMTA
(pemetrexed disodium).
(2) Taylor, E. C.; Kuhnt, D.; Shih, C.; Rinzel, S. M.; Grindey, G. B.;
Barredo, J .; J annatipour, M.; Moran, R. G. J . Med. Chem. 1992, 35,
4450.
(3) Taylor, E. C.; Harrington, P. J .; Fletcher, S. R.; Beardsley, G.
P.; Moran, R. G. J . Med. Chem. 1985, 28, 914.
(7) For a review and leading references, see: Taylor, E. C. Adv. Exp.
Med. Biol. 1993, 338, 387.
(4) Taylor, E. C.; Moran, R. G.; Baldwin, S. W.; Shih, C. J . Biol.
Chem. 1989, 264, 21047.
(8) Taylor, E. C.; Shih, C.; Gossett, L. S.; Meldelsohn, L. G.,
unpublished observations.
10.1021/jo001580l CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/09/2001

Substituted Derivatives of LY231514 (MTA)
J . Org. Chem., Vol. 66, No. 11, 2001 3727
Sch em e 1
Sch em e 2
totally inactive. A recent patent from Takeda Chemical
Industries, however, claims that a broad variety of
7-substituted derivatives of 1, including the two deriva-
tives above, are active antitumor agents.9 To resolve this
contradiction, we have prepared a number of 7-substi-
tuted derivatives by a new synthetic route and examined
their cell growth inhibitory activity. In addition, we
report on a number of surprisingly unsuccessful attempts
to remove a number of standard nitrogen protecting
groups from position 7, as well as a successful N-7
deprotection that exploits this new synthetic methodology
for an alternative preparation of ALIMTA itself.
Orena has described a manganic triacetate dihydrate
induced radical cyclization of methyl (S)-N-crotyl-N-(1-
phenyleth-1-yl)malonamide (2) to yield a diastereomeric
mixture of the 3-carbomethoxy-2-pyrrolidinones 3a ,b
(Scheme 1).10 Cyclization of a variety of N-substituted
malonamides 4 under the above conditions to malona-
mides 5,11 followed by guanidine annulation of 2-amino-
4(3H)-pyrimidinone rings unto the resulting 3-car-
bomethoxy-2-pyrrolidinones 7, palladium-catalyzed Heck
coupling with diethyl 4-iodobenzoylglutamate to 8, ap-
propriate manipulation of the oxidation states of the
bridge and the fused pyrroline ring to give 9, and final
hydrolysis would provide a straightforward route to our
target MTA analogues 10 bearing a variety of substitu-
ents on the pyrrole nitrogen (Scheme 2).
Sch em e 3
The pyrrolidinone 5a was prepared as described by
Orena through alkylation of racemic R-methylbenzy-
lamine with crotyl bromide, followed by DMAP-promoted
acylation with methyl malonyl chloride to give 4a , and
manganic triacetate dihydrate/cupric acetate hydrate
induced radical cyclization.10,12 Although the two diaster-
eomers could be isolated by column chromatography, we
employed the mixture of diastereomers for the next
reaction, since the stereogenic centers at positions 3 and
4 would be destroyed in the eventual conversion of this
proposed intermediate to a pyrrolopyrimidine. Pyrroli-
dinone 5a was thiated with P2S5 in THF to give the
thiolactam 6a , which was then converted in fair yield
with guanidine to the 5,6-dihydropyrrolo[2,3-d]pyrimi-
dine 7a . This appealing intermediate was then subjected
to a standard Pd-catalyzed Heck reaction with diethyl
4-iodobenzoylglutamate. The coupling product was not,
however, the anticipated vinyl-bridged pyrrolinopyrimi-
dine 8a but was the ethano-bridged pyrrolopyrimidine
9a . Since 7a itself does not undergo an analogous double
bond rearrangement under the reaction conditions (Pd-
(Oac)2, CuI, (o-tolyl)3P, Et3N, DMF), it appears (see
Scheme 3) that the PdII adduct initially formed in the
above Heck reaction (A) must undergo â-hydride elimi-
nation from the pyrroline ring bridgehead position more
rapidly than from the benzylic position. We suggest that
the resulting PdH complex then re-adds to give B faster
than it undergoes deprotonation. A second â-hydride
elimination from B would then lead to the pyrrolopyri-
midine 9a . This unexpected double bond rearrangement
obviated our anticipated need for reduction of the un-
saturated bridge and subsequent oxidation of the pyrro-
line ring. Saponification of the glutamate esters with
sodium hydroxide in aqueous THF then gave our first
target compound 10a .
Target compounds 10b and 10c were similarly pre-
pared starting with the appropriate malonamides 4b and
4c. However, the precursor crotylamines 13b and 13c
proved in our hands impossible to prepare by direct
alkylation of benzylamine and p-methoxybenzylamine
with crotyl bromide, since dialkylation inevitably oc-
curred. As a consequence, the above benzylamines were
(9) Akimoto, H.; Ootsu, K. Eur. Pat. Appl. 91-300266 910115.
(10) Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron 1996, 52, 1069.
(11) An alternative strategy for the preparation of trans-N-benzyl-
3-methoxycarbonyl-4-vinyl-2-pyrrolidinone (5b, vide infra) has recently
been described that involves a palladium(0)-catalyzed cyclization of
(Z)-[benzyl(malonyl)amino]-but-2-enyl acetate (Giambastiani, G.; Pa-
cini, B.; Porcelloni, M.; Poli, G. J . Org. Chem. 1998, 63, 804).
(12) (a) Cossy, J .; Leblanc, C. Tetrahedron Lett. 1989, 30, 4531. (b)
Cossy, J .; Bouzide, A.; Leblanc, C. J . Org. Chem. 2000, k, 7257.

3728 J . Org. Chem., Vol. 66, No. 11, 2001
Taylor and Liu
Sch em e 4
however, we were completely frustrated in our attempts
to deprotect 9c. Catalytic reduction with 10% Pd-C
under 50 psi of hydrogen resulted in partial reduction of
the pyrrole ring, with retention of the 4-methoxybenzyl
group, while no reaction whatsoever occurred upon
transfer hydrogenation using Pd-C and ammonium
formate. Acidic conditions (either with TFA alone or with
TFA/sulfuric acid)21,22 at room temperature or upon
heating again had no impact on 9c, which was recovered
unchanged. Ceric ammonium nitrate (CAN) oxidation
decomposed the substrate. Similar negative results were
obtained with the 2-pivaloyl derivative 16.
first acylated with methyl chloroformate,13 and the
resulting carbamates 11b and 11c were alkylated with
crotyl bromide to give 12b and 13c, respectively. These
compounds were then converted to the desired secondary
amines with aqueous hydrazine and potassium hydroxide
(Scheme 4).14
We then turned to removal of the above N-7 benzyl
protecting groups in an effort to utilize compounds 9a -c
as intermediates for a possible alternative preparation
of ALIMTA itself. To our surprise, all efforts to remove
the R-methylbenzyl protecting group from 9a proved
fruitless, despite encouraging precedents.15 Even under
forcing reductive conditions, only a miniscule yield could
be obtained of an impure deprotected derivative (14) in
which the fused pyrrole 5,6-double bond had simulta-
neously been reduced.16 Although reductive hydrogenoly-
sis of an N-benzyl group can be easier than hydrogeno-
lysis of an R-methylbenzyl protecting group,17 efforts to
deprotect 9b were also unsuccessful. Hydrogenolysis
using Pd-C in methanol at various temperatures and
pressures failed to give straightforward debenzylation;
only small amounts of the corresponding 5,6-dihydropy-
rrolopyrimidine still bearing the N-7 benzyl protecting
group were obtained. Benzoyl peroxide in methylene
chloride, either under reflux or in a sealed tube at 80
°C,18 brought about extensive decomposition of the sub-
strate, in contrast to encouraging literature precedents
with indoles. We also attempted to remove the N-7 benzyl
group from the precursor pyrrolidinone 5b. Transfer
hydrogenation with Pd-C and ammonium formate19
resulted (unsurprisingly) in quantitative reduction of the
vinyl side chain to give 15 but with no impact on the
N-benzyl grouping. Similar results were obtained upon
catalytic reduction with Pd-C in methanol under various
temperatures and pressures.
Neither the pyrrolidinone intermediate 5c nor the 5,6-
dihydropyrrolo[2,3-d]pyrimidine 7c was affected by TFA,
and both decomposed when treated with CAN. As was
the case with precursor 5b, the 4-methoxybenzyl pyrro-
lidinone 5c was also recovered unchanged upon treat-
ment with TFA, and it decomposed when treated with
ceric ammonium nitrate. The pyrrolinopyrimidine 7c was
also inert to TFA and also decomposed when treated with
CAN.
Since it was clear at this point that deprotection of the
N-7 benzyl derivatives 9a -c or their respective pyrroli-
dinone precursors was not promising, we looked at the
possibility that the methodology utilized for the initial
preparation of the vinyl pyrrolidinones 5a -c might be
applicable to the preparation of an N-unsubstituted
derivative. Thus, crotylamine hydrochloride was pre-
pared by the reported method involving silver iodide
promoted alkylation of lithium bis(trimethylsilyl)amine
with crotyl bromide followed by desilylation with dry HCl
in ether.23 In a one-pot procedure, crotylamine was
obtained from its hydrochloride by treatment with tri-
ethylamine in ethyl acetate; addition of methyl malonyl
chloride and DMAP then gave 4 (R ) H). Unfortunately,
no reaction took place when this material was treated
with manganic triacetate dihydrate in the presence of
cupric acetate; unchanged starting material was recov-
ered.
We thus had to consider the introduction of a nitrogen
protecting group that might be more readily removed
than the recalcitrant N-7 benzyl derivatives explored
above. A BOM protecting group was first examined.
Crotylamine was acylated with methyl chloroformate to
(17) See: Kocienski, P. J . Protecting Groups; Georg Thieme Verlag:
New York, 1994; p 221.
(18) Nakatsuka, S.-i.; Asano, O.; Goto, T. Heterocycles 1986, 24,
2791.
Utilization of 9c as a possible precursor to ALIMTA
seemed attractive, since the literature is replete with
various reductive and oxidative methods for removal of
4-methoxybenzyl groups from nitrogen.20 Once again,
(19) (a) Ram, S.; Spicer, L. D. Synth. Commun. 1987, 17, 415. (b)
Botta, M.; Summa, V.; Saladino, R.; Nicoletti, R. Synth. Commun. 1991,
21, 2181. (c) Kiguchi, T.; Kuninobu, N.; Takahashi, Y.; Yoshida, Y.;
Naito, T.; Ninomiya, I. Synthesis 1989, 778.
(20) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; J ohn Wiley & Sons, Inc.: New York, 1999.
(21) (a) Shimshock, S. J .; Waltermire, R. E.; DeShong, P. J . Am.
Chem. Soc. 1991, 113, 8791. (b) Smith, A. B., III; Rano, T. A.; Chida,
N.; Sulikowski, G. A.; Wood, J . L. J . Am. Chem. Soc. 1992, 114, 8008.
(22) J ones, M. I.; Froussios, C.; Evans, D. A. J . Chem. Soc., Chem.
Commun. 1976, 472.
(13) Corey, E. J .; Bock, M. G.; Kozikowski, A. P.; Rama Rao, A. V.;
Floyd, D.; Lipshutz, B. Tetrahedron Lett. 1978, 1051.
(14) (a) Shono, T.; Matsumura, Y.; Uchida, K.; Tsubata, K.; Makino,
A. J . Org. Chem. 1984, 49, 300. (b) Wee, A. G. H.; Liu, B.; Zhang, L. J .
Org. Chem. 1992, 57, 4404.
(15) (a) Marx, E.; El Bouz, M.; Ce´le´rier, J . P.; Lhommet, G.
Tetrahedron Lett. 1992, 30, 4307. (b) Haviari, G.; Ce´le´rier, J . P.; Petit,
H.; Lhommet, G.; Gardette, D.; Gramain, J . C. Tetrahedron Lett. 1992,
30, 4311.
(23) (a) Murai, T.; Yamamoto, M.; Kato, S. J . Chem. Soc., Chem.
Commun. 1990, 789. (b) Bestmann, H. J .; Wøolfel, G. Chem. Ber. 1984,
117, 1250.
(16) This compound has been prepared by a different strategy:
Barnett, C. J .; Wilson, T. M. Heterocycles 1993, 35, 925.

Substituted Derivatives of LY231514 (MTA)
J . Org. Chem., Vol. 66, No. 11, 2001 3729
Sch em e 5
give methyl N-crotylcarbamate (17a ). Attempted alky-
lation with BOM chloride in the presence of sodium
hydride gave an impure product that rapidly disente-
grated in the presence of KOH and hydrazine. With the
intention of introducing a carbamate that might be
cleaved under gentler conditions, crotylamine was acy-
lated with BOC anhydride to give tert-butyl N-crotylcar-
bamate (17b), but attempted alkylation with BOM
chloride at room temperature with NaH in THF again
was not a clean reaction, and subsequent attempts to
remove the tert-butoxycarbonyl group with acid again led
to extensive decomposition, with only a trace of com-
pletely deprotected crotylamine being recovered.
We next investigated the possible utility of a 2-ni-
trobenzyl protecting group, whose removal from nitrogen
by photolysis has been widely exploited. 2-Nitrobenzyl-
bromide was converted to 2-nitrobenzylamine with hex-
amethylenetetramine followed by HCl as previously
described.24 Acylation with methyl chloroformate pro-
ceeded uneventfully to give 18, but alkylation with crotyl
bromide under Finkelstein conditions (tetrabutylammo-
nium iodide and NaH) gave a low yield of 19 that rapidly
decomposed upon attempts to remove the carbamate
functionality with hydrazine and KOH. Since we sus-
pected that both the low yield in the alkylation step and
the failure of the carbamate cleavage step were due to
the acidity of the benzyl protons, we were intrigued by
the possibility of utilizing the 2,4-dinitrobenzenesulfona-
mide intermediate 20 for the alkylation step with crotyl
bromide, since alkylation could presumably be carried out
under much milder conditions, and a mild procedure for
removal of the 2,4-dinitrobenzenesulfonyl group has
recently been described.25 Thus, treatment of 2-nitroben-
zylamine with 2,4-dinitrobenzenesulfonyl chloride gave
20, which was smoothly alkylated to 21 with crotyl
chloride using potassium carbonate in DMF. The desired
secondary amine 22 was then easily obtained by treat-
ment of 21 with thioacetic acid in the presence of
triethylamine. DMAP-catalyzed acylation with methyl
malonyl chloride yielded 23, which underwent radical
cyclization in high yield to 24 upon treatment with
manganic triacetate and cupric acetate in acetic acid.
Thiation with P2S5 in THF then gave the thioamide 25.
Unfortunately, this intermediate instantly decomposed
when exposed to guanidine, probably again as a conse-
quence of the acidity of the o-nitrobenzyl protons. An
attempt to remove the o-nitrobenzyl protecting group
from the pyrrolidinone 24 by photolysis in MeOH met
with some success under very dilute conditions, but
preparative quantities of the deprotected pyrrolidinone
26 could never be obtained (Scheme 5).
with methyl chloroformate, and the resulting carbamate
11e was alkylated without incident with crotyl bromide
and sodium hydride to give 12e. Cleavage to the second-
ary amine 13e was achieved as before with KOH and
hydrazine. Acylation with methyl malonyl chloride pro-
ceeded in good yield to give 27, which was successfully
cyclized to the pyrrolidinone 28 with manganic triacetate
dihydrate/cupric acetate. Heck coupling of 28 with methyl
4-iodobenzoate gave 29 with no accompanying double
bond rearrangement as was observed earlier in the
conversion of 7 to 9. It appears that annulation of the
pyrimidinone ring is a requisite for this unexpected Pd-
promoted rearrangement reaction. Nitration of 29 with
TFAA/ammonium nitrate yielded a mixture of 2- and
4-mononitrated derivatives (30a ,b), but attempted depro-
tection with DBU then returned unchanged starting
material. Deprotonation of the 3-carbomethoxy-2-pyrro-
lidinone ring apparently blocks the reverse Michael
deprotection pathway (Scheme 6)
The above mixture of 2- and 4-mononitro derivatives
was separated by column chromatography, and the
predominant 4-nitro derivative 30a was thiated with P2S5
in THF to give the thiolactam 31. Methylation with
methyl iodide/potassium carbonate then gave the meth-
ylthiopyrroline 32, which no longer contained the acidic
R-methine proton positioned between the carbomethoxy
and pyrrolidinone carbonyl group. To our surprise,
however, treatment of this substrate with DBU resulted
in conversion to the pyrrole 33 in excellent yield. No
reaction whatsoever took place upon subsequent treat-
ment of 33 with an excess of DBU. To make the pyrrole
ring a potentially better leaving group for the reverse
Michael deprotection route, the methylthio substituent
was oxidized to the methylsulfonyl derivative 34 with
We next considered a 4-nitrophenethyl protecting
group, since there are encouraging reports of its use with
a deoxyguanosine derivative.26 However, since deprotec-
tion is achieved with DBU, and the preparation of the
necessary intermediate crotylamine requires base cleav-
age of an intermediate carbamate (see Scheme 3), we
chose to prepare the pyrrolinone 28 using phenethy-
lamine and to introduce the nitro group at a later step
in the synthesis. Thus, phenethylamine was acylated
(24) Ong-Lee, A.; Sylvester, L.; Wasley, J . W. F. J . Heterocycl. Chem.
1983, 20, 1565.
(25) (a) Fukuyama, T.; J ow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373. (b) Fukuyama, T.; Cheung, M.; J ow, C.-K.; Hidai, Y.;
Kan, T. Tetrahedron Lett. 1997, 38, 5831.
(26) Gaffney, B. L.; J ones, R. A. Tetrahedron Lett. 1982, 23, 2257.

3730 J . Org. Chem., Vol. 66, No. 11, 2001
Taylor and Liu
Sch em e 6
It is thus apparent that what appeared initially to be
an attractive alternative synthetic approach to the pyr-
rolopyrimidine oncolytic agent ALIMTA (1), starting from
the readily accessible N-protected pyrrolidinones 5a -c,
24, and 30, faltered at the projected deprotection steps.
However, the general strategy outlined in Scheme 2 was
eventually vindicated by successful deprotection of the
7-(3′,4′-dimethoxybenzyl) derivative 9d to 9 (R ) H),
which has been previously converted by saponification
to 1.27
In confirmation of our earlier studies8 and in contra-
diction to the Takeda claims,9 we have found that
compounds 10a -c are essentially devoid of cell growth
inhibitory activity and conclude that 7-substituted de-
rivatives of ALIMTA, which are easily prepared by the
above novel strategy, are not themselves of interest as
antitumor agents. We are currently exploring synthetic
applications of the intriguing double bond rearrangement
reaction that takes place under Heck-coupling conditions,
as exemplified by the conversions of 8a -d to 9a -d .
Exp er im en ta l Section
Gen er a l. All commercial reagents were used without
further purification. Tetrahydrofuran (THF) was distilled from
benzophenone ketyl. Methylene chloride, N,N-dimethylforma-
mide (DMF), and triethylamine were distilled from calcium
Sch em e 7
1
hydride. H and 13C NMR data were obtained with a Varian
INOVA-500 MHz, GE QE-300 MHz or J EOL-270 MHz
instrument. IR spectra were obtained on a Nicolet FT-IR
instrument. Melting points are uncorrected. High resolution
mass spectral data were determined at Princeton University
on AEI MS-920 and Kratos MS50TC spectrometers. Elemental
analyses and FABMS analyses were provided by Eli Lilly and
Co., Indianapolis, Indiana.
Meth yl N-Ben zylca r ba m a te (11b). The following repre-
sentative procedure was used for the preparation of all of the
carbamates described herein. To a solution of 10.7 g (100
mmol) of benzylamine in 150 mL of acetone were added 42.0
g (304 mmol) of potassium carbonate followed by 37.8 g (400
mmol) of methyl chloroformate. After stirring at reflux over-
night, the mixture was filtered, and the filtrate was concen-
trated under reduced pressure. The residual solid was washed
with water followed by petroleum ether and then dried under
vacuum to afford 14.4 g (87% yield) of 11b as a white solid:
IR (KBr) 3373, 1692, 1532, 1275, 1246, 1202, 739, 704, 611
hydrogen peroxide in TFA, but treatment of 34 with DBU
resulted only in rapid decomposition (Scheme 7).
cm-1; H (CDCl3) δ 7.37-7.26 (5 H, m), 5.05 (1 H, br s), 4.37
We finally turned to the 3,4-dimethoxybenzyl protect-
ing group that had been successfully employed (in
contrast to benzyl or 4-methoxybenzyl groups) for the
protection/deprotection of a pyrrole NH group.22 The
requisite urethane 11d (obtained in 94% yield by acyla-
tion of 3,4-dimethoxybenzylamine with methyl chloro-
formate) was alkylated with crotyl bromide to give 12d
in 95% yield in a procedure analogous to that employed
for the preparation of 12b,c. Cleavage of urethane 12d
with hydrazine hydrate/KOH gave the crotylamine 13d
in 90% yield, and subsequent acylation with methyl
malonyl chloride gave 4d in 87% yield. Manganic triac-
etate dihydrate/cupric acetate oxidation to the 4-vinyl-
2-pyrrolidinone 5d , thiation to 6d , guanidine cyclization
to 7d , and palladium diacetate mediated Heck coupling/
rearrangement to 9d were carried out as described above
for the conversions of 4a -c through to 9a -c. Compound
9 (R ) H), a known precursor of ALIMTA (1)27 was finally
obtained by deprotection of 9d (29.5% yield) with H2SO4/
TFA at room temperature22 (rapid decomposition took
place at higher temperatures).
1
(2 H, d, J ) 5.1 Hz), 3.71 (3 H, s).
Meth yl N-(4′-Meth oxyben zyl)ca r ba m a te (11c). Isolated
in 94% yield as a white solid: IR (KBr) 3323, 1692, 1515, 1512,
1
1273, 1256, 1033, 810, 691 cm-1; H NMR (CDCl3) δ 7.21 (2
H, d, J ) 7.8 Hz), 6.86 (2 H, d, J ) 8.4 Hz), 4.99 (1 H, br s),
4.29 (2 H, d, J ) 5.1 Hz), 3.79 (3 H, s), 3.68 (3 H, s).
Meth yl N-(3′,4′-Dim eth oxyben zyl)ca r ba m a te (11d ). Iso-
lated in 94% yield as a light yellow solid: IR (KBr) 3331, 2962,
2838, 1692, 1594, 1539, 1517, 1457, 1262, 1138, 1024, 993, 886,
1
807, 766, 667 cm-1; H NMR (CDCl3) δ 6.83 (3 H, m), 5.13 (1
H, br s), 4.30 (2 H, d, J ) 4.6 Hz), 3.87 (6 H, s), 3.70 (3 H, s)
Meth yl N-P h en eth ylca r ba m a te (11e). Isolated in 88%
yield as a yellow oil: IR (neat) 3335, 3060, 3022, 2941, 1699,
1456, 1257, 1194, 1144, 1031, 1000, 901, 769, 745, 695, cm-1
;
1H NMR (CDCl3) δ 7.33-7.18 (5 H, m), 4.69 (1 H, br s), 3.06
(3 H, s), 3.45 (2 H, m), 2.85 (2 H, t, J ) 6.5 Hz); EIMS m/z
179(M+), 164, 147, 132, 119, 104, 91, 88, 77.
Meth yl N-(2′-Nitr oben zyl)ca r ba m a te (18). Isolated in
85% yield as a light yellow solid: IR (KBr) 3337, 3194, 2950,
1
1705, 1610, 1520, 1455, 1348, 1259, 1077, 860, 783 cm-1; H
NMR (CDCl3) δ 8.03 (1 H, d, J ) 8.5 Hz), 7.62 (2 H, m), 7.47-
7.41 (1 H, m), 5.64 (1 H, br s), 4.60 (2 H, d, J ) 6.8 Hz), 3.65
(3 H, s); EIMS m/z 211 (MH+), 179, 164, 148, 136, 135, 133,
118, 108, 105, 104, 103, 92, 91, 79, 77, 76.
(27) Taylor, E. C.; Liu, B. Tetrahedron Lett. 1999, 40, 4023.

Substituted Derivatives of LY231514 (MTA)
J . Org. Chem., Vol. 66, No. 11, 2001 3731
Meth yl N-Cr otylca r ba m a te (17a ). To a mixture of 2.8 g
(26 mmol) of crotylamine hydrochloride and 12.6 g (91 mmol)
of potassium carbonate in 100 mL of acetone was added 7.4 g
(6.1 mL, 78 mmol) of methyl chloroformate at room temper-
ature. The resulting mixture was stirred at reflux overnight.
The mixture was filtered, concentrated, and dried under
vacuum at 0 °C to give 2.78 g (83% yield) of 17a as a yellow
oil that was used without further purification in the next
step: IR (neat) 3338, 3013, 2952, 1705, 1532, 1450, 1361, 1259,
1194, 1162, 1115, 1069, 1037, 968, 780 cm-1; 1H NMR (CDCl3)
δ 5.70-5.56 (1 H, m), 5.52-5.35 (1 H, m), 4.68 (1 H, br s),
3.79-3.62 (5 H, m), 1.67 (3 H, d, J ) 5.1 Hz); EIMS m/z 129
(M+), 114, 97, 88, 82, 70, 68.
(CDCl3) δ 5.68-5.61 (1 H, m), 5.52-5.41 (1 H, m), 4.58 (1 H,
br s), 3.70 (2 H, s), 1.71 (3 H, d, J ) 6.5 Hz), 1.48 (9 H, s); 13
C
NMR (CDCl3) δ 155.94, 127.80, 127.71, 79.29, 42.70, 28.56,
17.76; EIMS m/z 171(M+), 140, 111, 101, 83, 70, 68.
N-(2′-Nitr oben zyl)-2,4-din itr oben zen esu lfon am ide (20).
To a solution of 4.0 g (26.3 mmol) of 2-nitrobenzylamine and
8.0 mL (99 mmol) of pyridine in 150 mL of methylene chloride
was added 7.20 g (27.0 mmol) of 2,4-dinitrobenzenesulfonyl
chloride in 200 mL of methylene chloride, and the resulting
orange-colored mixture was stirred at room temperature
overnight. The mixture was washed with 200 mL of 0.2 N HCl
followed by 200 mL of water. The organic layer was separated,
dried with sodium sulfate, and concentrated under vacuum
to give 8.1 g (81% yield) of 20 as a light yellow solid that was
used for the next step without further purification. A small
amount of highly pure 20 was obtained by chromatography
(silica gel, hexane/methylene chloride/ethyl acetate 10:15:1):
IR (KBr) 3358, 3108, 1608, 1539, 1417, 1346, 1309, 1172, 1097,
Meth yl N-Cr otyl-N-ben zylca r ba m a te (12b). To a solu-
tion containing 15.9 g (100 mmol) of 85% pure crotyl bromide,
4.18 g (174 mmol) of sodium hydride, and 1.6 g (4.34 mmol) of
tetrabutylammonium iodide in 350 mL of dry THF at 0 °C was
added a solution of 14.4 g (87 mmol) of methyl N-benzyl
carbamate (11b) in 100 mL of dry THF via a cannula. The
resulting mixture was stirred at 0 °C for 1 h and then at room
temperature overnight. Some suspended solid was removed
by filtration, and the filtrate was evaporated to dryness under
reduced pressure. The residual solid was dissolved in 150 mL
of ethyl acetate, and the solution was washed with brine (2 ×
30 mL). After drying over sodium sulfate, the solvent was
evaporated under reduced pressure to give 17.7 g (93%) of 12b
as a light yellow oil: IR (neat) 3064, 3028, 2954, 2920, 2858,
1705, 1471, 1455, 1437, 1407, 1234, 1132, 1101, 969, 946, 770,
1
1049, 89 cm-1; H NMR (DMSO-d6) δ 9.18 (1 H, br s), 8.90 (1
H, d, J ) 2.0 Hz), 8.60 (1 H, dd, J ) 8.5 and 2.0 Hz), 8.21 (1
H, d, J ) 8.5 Hz), 8.03 (1 H, d, J ) 8.0 Hz), 7.72 (1 H, t, J )
7.5 Hz), 7.64 (1 H, d, J ) 7.5 Hz), 7.55 (1 H, t, J ) 7.5 Hz),
4.78 (2 H, s); 13C NMR (DMSO) δ 149.71, 147.65, 147.48,
137.58, 133.86, 132.25, 131.35, 130.07, 128.94, 127.28, 124.79,
120.12, 42.28; EIMS m/z 383 (MH+), 381, 352, 348, 231, 151,
135, 134, 133, 105, 104, 103, 93, 92, 91, 79, 78, 77.
N-Cr otyl-N-(2′-n itr oben zyl)-2,4-din itr oben zen esu lfon a-
m id e (21). The following procedure is representative for the
preparation of N-crotylsulfonamides. To a mixture of 7.8 g
(20.4 mmol) of N-(2′-nitrobenzyl)-2,4-dinitrobenzenesulfona-
mide (20) and 10.1 g (73 mmol) of potassium carbonate in 150
mL of DMF was added 5.1 g (32.0 mmol) of 85% pure crotyl
bromide at room temperature. The resulting dark orange
mixture was stirred for 1 h. The mixture was poured into 300
mL of methylene chloride, washed with concentrated aqueous
NaHCO3 (2 × 150 mL) and water (150 mL), dried with Na2-
SO4, and concentrated to give 6.98 g (79%) of crude 21 that
was used for the next step without further purification. A small
amount of 21 was purified by column chromatography (silica
gel, methylene chloride/hexane 1:1) to afford a light yellow
solid as a mixture of cis and trans isomers: IR (KBr) 3095,
1
700 cm-1; H NMR (CDCl3) δ 7.34-7.23 (5 H, m), 5.70-5.30
(2 H, m), 4.44 (2 H, s), 3.98-3.76 (5 H, br m), 1.68 (3 H, d, J
) 5.9 Hz); EIMS m/z 219 (M+), 204, 176, 164, 160, 132, 128,
121, 104, 96, 92, 91, 85; HRMS calcd for C13H17NO2 219.1259,
found 219.1246.
The following N-crotyl carbamates were prepared similarly.
Meth yl N-Cr otyl-N-(4′-m eth oxyben zyl)car bam ate (12c).
Isolated in 99.0% as a light yellow oil: IR (neat) 3002, 2955,
2857, 1701, 1612, 1512, 1472, 1405, 1302, 1230, 1175, 1132,
1
1036, 969, 840, 813, 772 cm-1; H NMR (CDCl3) δ 7.15 (2 H,
d, J ) 22 Hz), 6.84 (2 H, d, J ) 8.5 Hz), 5.53 (1 H, br s), 5.38
(1 H, br s), 4.37 (2 H, s), 3.78 (3 H, s), 3.73 (3 H, s), 3.68 (2 H,
s), 1.68 (2 H, d, J ) 6.5 Hz); EIMS m/z 249(M+), 194, 162,
151, 141, 128, 121, 91, 77; HRMS calcd for
249.1377, found 249.1372.
C14H19NO3
2909, 1667, 1603, 1528, 1349, 1165, 918, 791, 733 cm-1 1H
;
NMR (CDCl3) δ 8.51 (1 H, d, J ) 1.5 Hz), 8.46 (1 H, dd, J )
8.5 and 2.0 Hz), 8.20 (1 H, t, J ) 8.5 Hz), 7.99 (1 H, t, J ) 8.0
Hz), 7.72-7.63 (2 H, m), 7.46 (1 H, t, J ) 7.5 Hz), 5.66-5.45
(1 H, m), 5.25-5.20 (1 H, m), 4.90 (2 H, s), 4.03 and 3.91 (2 H,
two doublets, J ) 7.5 and J ) 6.5 Hz), 1.56 and 1.39 (3 H, two
doublets, J ) 5.0 and J ) 6.5 Hz); 13C NMR (CDCl3) δ 168.03,
149.98, 148.85, 139.08, 133.91, 133.37, 132.90, 131.51, 130.02,
129.01, 126.34, 125.30, 123.84, 122.78, 120.11, 51.12, 47.85,
17.86; EIMS m/z 436 (M+), 419, 381, 300, 254, 231, 205, 151,
138, 136, 120, 106, 92, 78.
Meth yl N-Cr otyl-N-(3′,4′-d im eth oxyben zyl)ca r ba m a te
(12d ). Isolated in 95% yield as a yellow oil: IR (neat) 3001,
2955, 2836, 1701, 1592, 1516, 1466, 1405, 1262, 1232, 1140,
1
1029, 969, 807, 767, 732 cm-1; H NMR (CDCl3) δ 6.88-6.75
(3 H, m), 5.60-6.50 (1 H, m), 5.50-5.30 (1 H, m), 4.41 (2 H,
s), 3.90 (6 H, s), 3.70 (3 H, s), 1.72 (3 H, d, J ) 6.5 Hz); EIMS
m/z 279 (M+), 248, 224, 192, 181, 167, 151, 141, 128, 107, 91,
77; HRMS calcd for C15H21NO4 279.1470, found 279.1481.
Meth yl N-Cr otyl-N-p h en eth ylca r ba m a te (12e). Isolated
in 88% yield as a yellow oil: IR (neat) 3019, 2938, 1702, 1470,
1400, 1296, 1232, 1116, 1092, 965, 768, 739, 693 cm-1; 1H NMR
(CDCl3) δ 7.33-7.29 (2 H, m), 7.24-7.22 (3 H, m), 5.58 (1 H,
m), 5.41 (1 H, m), 3.79 (2 H, m), 3.71 (3 H, s), 3.44 (2 H, m),
2.85 (2 H, m), 1.71 (3 H, d, J ) 6.0 Hz); EIMS m/z 233(M+),
142, 105, 91, 88, 77; HRMS calcd for C14H19NO2 233.1435,
found 233.1431.
Meth yl N-Cr otyl-N-(2′-n itr oben zyl)ca r ba m a te (19). Iso-
lated in 20% yield as a yellow oil: IR (neat) 3100, 2948, 2852,
1705, 1257, 1468, 1405, 1312, 1242, 1190, 1130, 961, 859, 769,
720 cm-1; 1H NMR (CDCl3) δ 8.07 (1H, m), 7.63 (1H, m), 7.45-
7.29 (2H, m), 5.66-5.44 (2H, m), 4.82 (2H, s), 4.02-3.70 (5H,
m), 1.68 and 1.56 (3H, two doublets, J ) 6.0 and J ) 5.0 Hz).
ter t-Bu tyl N-Cr otylca r ba m a te (17b). To a suspension of
7.34 g (68 mmol) of crotylamine hydrochloride in 100 mL of
methylene chloride were added 12 g (16.5 mL, 119 mmol) of
trimethylamine and 22.3 g (102 mmol) of di-tert-butyl carbon-
ate in 30 mL of methylene chloride at room temperature. The
resulting mixture was stirred at room temperature for 30 min
and then heated to 40 °C for 1.5 h. The mixture was filtered,
and solvent was evaporated under vacuum. The residue was
purified by column chromatography (silica gel, hexane/EtOAc
1:1) to afford 11.2 g (96%) of 17b as a colorless liquid: 1H NMR
N-Cr otylben zyla m in e (13b). The following procedure is
representative for the preparation of the N-substituted croty-
lamines. To a mixture of 8.76 g (40 mmol) of methyl N-benzyl-
N-(2-buten-1-yl)carbamate (12b) and 33.6 g (600 mmol) of
potassium hydroxide in 280 mL of ethylene glycol was added
10.0 g (200 mmol) of hydrazine monohydrate at room temper-
ature. The resulting mixture was heated to 110 °C for
overnight. After the mixture cooled to room temperature, 400
mL of ethyl ether was added, and the mixture was washed
with water (4 × 100 mL). The organic layer was separated,
dried over sodium sulfate, and concentrated. The residue was
purified by column chromatography (silica gel, EtOAc and then
EtOAc/MeOH 4:1) to give 5.54 g (86%) of 13b as a mixture of
cis and trans isomers as a light yellow oil: IR (neat) 2932,
1581, 1450, 961, 848, 740, 693 cm-1; 1H NMR (CDCl3) δ 7.39-
7.38 (4 H, m), 7.32-7.30 (1 H, m), 5.72-5.59 (2 H, m), 3.86
and 3.84 (2 H, two singlets), 3.36 and 3.26 (2 H, two doublets,
J ) 6.5 and J ) 5.0 Hz), 2.08 (1 H, br s), 1.76 and 1.67 (3 H,
two doublets, J ) 5.0 and J ) 6.0 Hz); 13C NMR (CDCl3) δ
140.20, 129.30, 128.56, 128.42, 127.92, 127.13, 53.30, 51.16,
45.41; EIMS m/z 161 (M+), 160, 146, 132, 120, 106, 91, 77, 70,
65; HRMS calcd for C11H15N 161.1204, found 161.1201.

3732 J . Org. Chem., Vol. 66, No. 11, 2001
Taylor and Liu
N-Cr otyl-(4′-m eth oxyben zyl)a m in e (13c). Isolated in
88% as a light yellow oil: IR (neat) 3312, 3002, 2913, 2834,
1612, 1512, 1456, 1301, 1247, 1175, 1105, 1037, 968 cm-1; 1H
NMR (CDCl3) δ 7.28 (2 H, d, J ) 8.0 Hz), 6.90 (2 H, d, J ) 8.5
Hz), 5.69-5.54 (2 H, m), 3.83 (3 H, s), 3.76 (2 H, s), 3.24 (2 H,
d, J ) 5.0 Hz), 1.74 (3 H, d, J ) 5.5 Hz), 1.39 (1 H, br s); 13C
NMR (CDCl3) δ 159.33, 133.30, 130.28, 130.08, 128.05, 114.48,
55.96, 53.46, 51,80, 18.55; EIMS m/z 191(M+), 190, 162, 137,
136, 135, 122, 91, 77, 70, 55; HRMS calcd for C12H17NO:
191.1310, found 191.1315. Anal. Calcd for C12H17NO: C, 75.35;
H, 8.96; N, 7.32. Found: C, 75.05; H, 8.84; N, 7.32.
N-Cr otyl-(3′,4′-d im eth oxyben zyl)a m in e (13d ). Isolated
in 90% yield as a light yellow oil: IR (neat) 3303, 2967, 2836,
1592, 1516, 1465, 1376, 1241, 1157, 1140, 1029, 969, 809, 764
cm-1; 1H NMR (CDCl3) δ 6.94 (1 H, d, J ) 7.5 Hz), 6.88-6.79
(2 H, m), 5.67-5.52 (2 H, m), 3.90 (3 H, s), 3.87 (3 H, s), 3.74
(2 H, s), 3.22 (2 H, d, J ) 5.0 Hz), 2.72 (1 H, br s), 1.71 (3 H,
d, J ) 5.5 Hz); 13C NMR (CDCl3) δ 149.69, 148.82, 132.90,
129.42, 128.87, 121.18, 112.28, 111.67, 56.61, 56.60, 53.49,
51.50, 18.53; EIMS m/z 221 (M+), 220, 206, 190, 178, 166, 151,
137, 121, 107, 95, 91, 84, 77, 70; HRMS calcd for C13H19NO2
221.1416, found 221.1412.
N-Cr otylp h en eth yla m in e (30). Isolated in 76% yield as
a light yellow oil: IR (neat) 3321, 3058, 3022, 2915, 2808, 1495,
1449, 1119, 970, 743, 696 cm-1; 1H NMR (CDCl3) δ 7.33-7.30
(2 H, m), 7.25-7.22 (3 H, m), 5.64-5.47 (2 H, m), 3.32 and
3.21 (2 H, d, J ) 6.5 and 6.0 Hz), 2.93-2.88 (2 H, m), 2.86-
2.82 (2 H, m), 1.71 and 1.66 (3 H, d, J ) 5.5 Hz), 1.14 (1 H, br
s); 13C NMR (CDCl3) δ 140.26, 129.59, 128.81, 128.54, 127.30,
126.20, 51.79, 50.72, 36.58, 17.87; EIMS m/z 176(MH+), 175-
(M+), 174, 147, 134, 120, 105, 104, 102, 91, 89, 81. N-
Crotylphenethylamine could also be prepared in 51% yield
from N-crotyl-N-phenethyl-2,4-dinitrobenzenesulfonamide as
described below for the preparation of 22.
N-Cr otyl-(2′-n itr oben zyl)a m in e (22). To a solution of 4.2
g (9.6 mmol) of N-crotyl-N-(2-nitrobenzyl)-2,4-dinitrobenzene-
sulfonamide and 2.12 g (21 mmol) of triethylamine in 50 mL
of methylene chloride was added 1.15 g (12.5 mmol) of
thioacetic acid at room temperature. After the dark brown
solution was stirred for 20 min, it was poured into 250 mL of
diethyl ether, washed with a saturated solution of K2CO3 (2
× 100 mL), dried with Na2SO4, and concentrated. The residue
was purified by column chromatography (silica gel, CH2Cl2/
EtOAc 7:3) to give 1.47 g (74%) of 22 as a mixture of cis and
trans isomers: IR (neat) 3346, 3066, 3018, 2908, 2854, 1527,
1444, 1347, 1109, 964, 855, 787, 729 cm-1; 1H NMR (CDCl3) δ
7.94 (1 H, d, J ) 8.0 Hz), 7.63-7.56 (2 H, m), 7.40 (1 H, t, J )
7.5 Hz), 5.65-5.49 (2 H, m), 4.02 and 4.01 (2 H, two singlets),
3.31 and 3.20 (2 H, two doublets, J ) 6.5 and J ) 6.0 Hz);
1.68 and 1.62 (3 H, two doublets J ) 6.0 and J ) 7.0 Hz), 1.67
(1 H, s); 13C NMR (CDCl3) δ 149.31, 135.92, 133.27, 131.50,
129.36, 128.58, 128.06, 128.02, 127.91, 126.86, 124.86, 51.42,
50.36, 50.17, 34.70, 17.94, 13.20; EIMS m/z 206 (M+), 205, 189,
158, 151, 144, 136, 135, 134, 118, 105, 91, 78; HRMS calcd for
Meth yl N-Cr otyl-N-ben zylm a lon yla m id e (4b). Isolated
in 77% yield as a light yellow oil that was a mixture of
isomers: IR (neat) 3028, 3005, 2953, 2920, 1751, 1652, 1473,
1326, 1262, 1202, 1160, 1027, 1013, 970, 952, 731, 701 cm-1
;
1H NMR (CDCl3) δ 7.43-7.29 (4 H, m), 7.25-7.22 (1 H, m),
5.75-5.59 (1 H, m), 5.51-5.34 (1 H, m), 4.66 and 4.55 (2 H,
two singlets), 3.82 and 3.77 (3 H, two singlets), 4.12-3.51 (4
H, m), 1.77-1.73 and 1.63-1.59 (3 H, m); 13C NMR(CDCl3) δ
168.41, 166.46, 137.25, 136.38, 129.81, 129.26, 129.16, 128.77,
128.31, 127.91, 127.58, 126.63, 126.52, 125.35, 125.10, 52.63,
50.66, 49.38, 48.37, 47.71, 44.60, 41.42, 41.24, 17.84; EIMS
m/e 261 (M+), 230, 206, 170, 162, 145, 120, 106, 96, 91, 77, 70,
65, 55; HRMS calcd for C15H19NO3 261.1365, found 261.1363.
Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N, 5.36. Found:
C, 68.75; N, 7.34; N, 5.30.
Meth yl N-Cr otyl-N-(4′-m eth oxyben zyl)m a lon yla m id e
(4c). Isolated in 82% yield as a light yellow oil that was a
mixture of cis and trans isomers: IR (neat) 2999, 2960, 1749,
1
1652, 1513, 1437, 1248, 1175, 1032, 971, 818 cm-1; H NMR
(CDCl3) δ 7.18 and 7.08 (2 H, two doublets, J ) 9.0 and J )
9.0 Hz), 6.87 and 6.83 (2 H, two doublets, J ) 8.5 and J ) 9.0
Hz), 5.70-5.51 (1 H, m), 5.43-5.25 (1 H, m), 4.52 and 4.41 (2
H, two singlets), 4.04-3.69 (5 H, m), 3.49 and 3.46 (2 H, two
singlets), 1.70-1.66 and 1.57-1.53 (3 H, m); 13C NMR (CDCl3)
δ 168.40 and 168.30, 166.3, 159.40 and 159.10, 129.71, 129.10,
127.86, 125.42 and 125.20, 114.5 and 114.1, 55.48 and 55.42,
52.56, 50.15, 49.10, 47.74 and 47.38, 41.39 and 41.42, 17.87
and 17.70; EIMS m/z 291(M+), 263, 162, 136, 121, 91, 70;
HRMS calcd for C16H21N1O4 291.1470, found 291.1462. Anal.
Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81. Found: C,
66.14; H, 7.36; N, 4.85.
Meth yl N-Cr otyl-N-(3′,4′-d im eth oxyben zyl)m a lon yla -
m id e (4d ). Isolated in 87% yield as a mixture of isomers, a
light yellow oil: IR (neat) 3001, 2954, 2837, 1742, 1649, 1517,
1441, 1417, 1324, 1261, 1238, 1208, 1155, 1140, 1027, 970, 920,
1
809, 732 cm-1; H NMR (CDCl3) δ 7.88-6.70 (3 H, m), 5.72-
5.56 (1 H, m), 5.47-5.30 (1 H, m), 4.55 and 4.40 (2 H, two
singlets), 3.89-3.88 (7 H, m), 3.77-3.74 (4 H, m), 3.54-3.49
(2 H, m), 1.74-1.69 and 1.61-1.53 (3 H, m); 13C NMR (CDCl3)
δ 168.95 and 168.84, 166.96 and 166.78, 150.20 and 149.95,
149.29 and 149.12, 130.35 and 130.25, 129.59, 125.73, 121.18
and 119.25, 112.85, 111.60, 56.62 (two carbons), 53.13, 51.06,
49.07, 48.63, 48.16, 41.85 and 41.70, 18.45 and 18.37; EIMS
m/z 321 (M+), 290, 266, 222, 192, 166, 151, 139, 132, 124, 107,
101, 87, 77, 70; HRMS calcd for C17H23N1O5 321.1576, found
321.1555.
Meth yl N-Cr otyl-N-(2′-n itr oben zyl)m a lon yla m id e (23).
Isolated in 82% yield as a light yellow oil that was a mixture
of isomers: IR (neat) 3004, 2945, 1733, 1653, 1525, 1437, 1337,
1198, 1160, 1009, 961, 860, 785, 726 cm-1; 1H NMR (CDCl3) δ
8.16 and 8.04 (1 H, two doublets, J ) 8.0 and J ) 8.0 Hz),
7.70 and 7.63 (1 H, two triplets, J ) 6.5 and J ) 6.5 Hz), 7.56-
7.50 (1 H, m), 7.44-7.39 (1 H, m), 5.73-5.52 (1 H, m), 5.45-
5.27 (1 H, m); 4.9 and 4.89 (2 H, two singlets), 3.96 and 3.84
(2 H, two br singlets), 3.80 and 3.69 (3 H, two singlets), 3.60
and 3.40 (2 H, m), 1.71-1.66 and 1.57-1.50 (3 H, m); 13C NMR
(CDCl3) δ 168.46 and 167.77, 166.92 and 166.80, 148.57 and
147.98, 134.41, 134.00, 132.95, 130.46, 129.80, 129.33, 128.84,
128.77, 128.08, 127.84, 125.91, 125.16, 124.75, 124.61, 124.43,
52.72 and 52.63, 50.78, 48.57 and 48.25, 46.51, 46.40, 45.85,
41.12, 40.97, 17.77, 12.99; EIMS m/z 307 (MH+), 291, 289, 175,
262, 233, 205, 189, 170, 151, 128, 119, 105, 95, 89, 70. Anal.
Calcd for C15H18N2O5: C, 58.82; H, 5.92; N, 9.15. Found: C,
58.95; N, 5.94; H, 9.03.
Meth yl N-Cr otyl-N-p h en eth ylm a lon yla m id e (27). Iso-
lated in 83% yield as a light yellow oil that was a mixture of
isomers: IR (neat) 3019, 2943, 1742, 1644, 1435, 1325, 1261,
1197, 1156, 1011, 971, 750, 698 cm-1; 1H NMR (CDCl3) δ 7.35-
7.27 (2 H, m), 7.24 (2 H, d, J ) 6.0 Hz), 7.17 (1 H, d, J ) 7.0
Hz), 5.74-5.54 (1 H, m), 5.49-5.29 (1 H, m), 4.11 and 3.98 (1
H, two doublets, J ) 7.0 and 6.0 Hz), 3.78 and 3.74 (3 H, two
singlets), 3.68-3.67 (1 H, m), 3.58-3.56 (1 H, m), 3.49-3.46
(2 H, m), 3.25 and 3.23 (1 H, two singlets), 2.92-2.84 (2 H,
m), 1.73-1.70 and 1.65-1.63 (3 H, m); 13C NMR (CDCl3) δ
168.35, 166.03, 165.80, 139.34, 138.18, 129.30, 129.04, 128.89,
C
11H14N2O2 206.1055, found 206.1050.
Meth yl N-Cr otyl-N-(r-m eth ylben zyl)m alon ylam ide (4a).
The following procedure is representative for the preparation
of the malonylamides used in this study. To a mixture of 4.1
g (23.4 mmol) of N-crotyl-R-methylbenzylamine, 0.32 g (2.6
mmol) of DMAP, and 2.9 g (4.0 mL, 28.7 mmol) of triethy-
lamine in 65 mL of dry ethyl acetate was added at 0 °C 4.1 g
(29 mmol) of 97% pure methyl malonyl chloride in 25 mL of
dry ethyl acetate. After stirring at 0 °C for 1 h and at room
temperature for 2 h, the reaction mixture was poured into 150
mL of ethyl acetate and washed with 100 mL of 2.0 N HCl
solution and then with 100 mL of 10% aqueous Na2CO3. The
organic layer was separated, dried over Na2SO4, and concen-
trated to afford crude 4a The product was purified by column
chromatography (silica gel, EtOAc) to give 5.66 g (88%) of 4a
as a light yellow oil that was a mixture of cis and trans
isomers: IR (neat) 3024, 2953, 1746, 1641, 1437, 1335, 1256,
1204, 1161, 1027, 970, 782, 748, 701 cm-1; 1H NMR (CDCl3) δ
7.38-7.26 (5 H, m), 6.08 (1 H, q, J ) 7.5 Hz), 5.52-5.41 (1 H,
m), 5.21-5.03 (1 H, m), 3.77 (3 H, s), 3.66-3.45 (4 H, m), 1.66-
1.60 (3 H, m), 1.54 (3 H, d, J ) 7.0 Hz).

Substituted Derivatives of LY231514 (MTA)
J . Org. Chem., Vol. 66, No. 11, 2001 3733
128.64, 127.04, 126.49, 125.85, 125.45, 52.55, 51.17, 49.30,
48.49, 47.43, 46.19, 41.38, 40.86, 35.13, 34.07, 17.88, 17.77;
EIMS m/z 275(M+), 274, 244, 202, 185, 184, 174, 148, 130, 105,
104, 101, 91, 84, 77; HRMS calcd for C16H21NO3 275.1517,
found 275.1515.
1-(4′-Meth oxyben zyl)-3-m eth oxycar bon yl-4-vin yl-2-pyr -
r olid in on e (5c). Isolated in 92% yield as a mixture of two
diastereomers as a light yellow oil: IR (neat) 3071, 3006, 2954,
1
1740, 1696, 1514, 1437, 1248, 1175, 1032, 924, 819 cm-1
; H
NMR (CDCl3) δ 7.16 (2 H, d, J ) 9.0 Hz), 6.85 (2 H, d, J ) 8.5
Hz), 5.75-5.68 (1 H, ddd, J ) 17.0, 10.0 and 3.5 Hz), 5.11 (1
H, d, J ) 17.5 Hz), 5.08 (1 H, d, J ) 10.5 Hz), 4.39 (2 H, AB,
J ) 7.0 Hz), 3.80 (3 H, s), 3.79 (3 H, s), 3.77-3.70 (1 H, m),
3.43-3.33 (2 H, m), 3.01-2.98 (1 H, m); 13C NMR (CDCl3) δ
169.99, 168.98, 159.42, 136.44, 129.74, 128.03, 117.51, 114.33,
55.47, 54.56, 52.90, 50.05, 46.52, 40.53; EIMS m/z 289 (M+),
230, 202, 176, 162, 149, 136, 121, 77, 55; HRMS calcd for
Meth yl N-Cr otylm a lon yla m id e (4, R ) H). To a suspen-
sion of 2.68 g (25 mmol) of crotylamine hydrochloride and 0.39
g (3.2 mmol) of DMAP in a mixture of 60 mL of dry EtOAc
and 6.24 g (8.6 mL, 62 mmol) of dry triethylamine was added
a solution of 3.96 g (3.1 mL, 29 mmol) of methyl malonyl
chloride in 20 mL of dry EtOAc at 0 °C. The resulting mixture
was stirred at 0 °C for 2 h and then at room temperature for
4 h. The mixture was poured into 150 mL of EtOAc and
washed with 100 mL of 2 N HCl followed by 100 mL of 10%
aqueous Na2CO3. The organic layer was separated, dried with
Na2SO4, and concentrated. The residue was purified by column
chromatography (silica gel, EtOAc/hexane 1:1) to afford 1.34
g (31% yield) of 4 (R ) H) as a white solid: IR (KBr) 3289,
3077, 2949, 1745, 1644, 1559, 1436, 1280, 1155, 1024, 979, 850,
C16H19NO4 289.1314, found 289.1310. Anal. Calcd for C16H19
-
NO4: C, 66.42; H, 6.62; N, 4.84. Found: C, 66.37; H, 6.72; N,
4.87.
1-(3′,4′-Dieth oxyben zyl)-3-m eth oxyca r bon yl-4-vin yl-2-
p yr r olid in on e (5d ). Isolated in 86% yield as a mixture of
isomers as a light yellow oil: IR (neat) 3081, 3009, 2954, 2838,
1741, 1694, 1593, 1516, 1437, 1358, 1262, 1157, 1140, 1027,
1
923, 854, 813, 766 cm-1; H NMR (CDCl3) δ 6.85-6.76 (3 H,
1
722, 614 cm-1; H NMR (CDCl3) δ 7.13 (1 H, br s), 5.69-5.62
m), 5.74-5.67 (1 H, ddd, J ) 17.5, 10.5 and 3.5 Hz), 5.14 (1 H,
d, J ) 17.5 Hz), 5.08 (1 H, d, J ) 10.5 Hz), 4.29 (2 H, s), 3.86
(3 H, s), 3.85 (3 H, s), 3.79 (3 H, s), 3.56-3.42 (1 H, m), 3.38-
3.32 (2 H, m), 3.04-2.99 (1 H, m); 13C NMR (CDCl3) δ 170.01,
169.08, 149.49, 148.87, 136.47, 128.50, 120.79, 117.49, 111.37,
111.24, 56.11, 56.09, 54.53, 52.90, 50.12, 46.90, 40.49; EIMS
m/z 319 (M+), 304, 288, 260, 232, 206, 192, 179, 166, 151, 136,
121, 127, 91, 77, 67; HRMS calcd for C17H21NO5 319.1420,
found 319.1426.
(1 H, m), 5.55-5.43 (1 H, m), 3.94 and 3.84 (2 H, two triplets
for cis and trans isomers), 3.75 (3 H, s), 3.33 (2 H, s), 1.69 (3
H, d, J ) 6.0 Hz); 13C NMR (CDCl3) δ 170.24, 164.70, 128.82,
126.53, 52.63, 41.68, 41.06, 17.89; EIMS m/z 171 (M+) 156,
142, 111, 96, 83, 70; HRMS calcd for C8H13NO3 171.0895, found
171.0884. Anal. Calcd for C8H13NO3: C, 56.13; H, 7.65; N, 8.18.
Found: C, 56.20; H, 7.49; N, 8.26.
1-(r-Meth ylben zyl)-3-m eth oxyca r bon yl-4-vin yl-2-p yr -
r olid in on e (5a ). The following procedure is representative
for the preparation of the 4-vinyl-2-pyrrolidinones reported
below. To a well degassed mixture of 4.82 g (18.0 mmol) of
manganese(III) acetate dihydrate and 1.8 g (9.0 mmol) of
copper(II) acetate monohydrate in 70 mL of acetic acid was
added a well degassed solution of 2.48 g (9.0 mmol) of methyl
N-crotyl-N-(R-methylbenzyl)malonylamide (4a ) in 20 mL of
acetic acid. The resulting mixture was stirred at room tem-
perature for 18 h. The sky-blue mixture was poured into 300
mL of ethyl ether and washed with 50 mL of 10% aqueous
sodium thiosulfate solution. The organic layer was separated,
and the aqueous layer was extracted with 100 mL of ethyl
ether. The combined organic solution was washed with satu-
rated aqueous Na2CO3, dried with Na2SO4, and concentrated.
The residue was purified by column chromatography (silica
gel, hexane/ethyl acetate 70:30) to afford 2.38 g (97%) of 5a
as a mixture of two diastereomers. Although the two diaster-
eomers can be separated by column chromatography, the
mixture of diastereomers was used for next step: IR (neat)
mixture of two diastereomers 3064, 3029, 2976, 2952, 1741,
1695, 1426, 1257, 1206, 1166, 701 cm-1; (a) Rf ) 0.40; 1H NMR
(CDCl3) δ 7.38-7.30 (5 H, m), 5.70-5.61 (1 H, ddd, J ) 17.0,
10.5 and 7.5 Hz), 5.51 (1 H, q, J ) 7.0 Hz), 5.11 (1 H, d, J )
17.0 Hz), 5.07 (1 H, d, J ) 10.5 Hz), 3.82 (3 H, s), 3.56-3.52
(1 H, m), 3.39-3.30 (2 H, m), 2.75-2.71 (1 H, m), 1.57 (3 H, d,
J ) 7.0 Hz); 13C NMR (CDCl3) δ 170.46, 169.21, 140.21, 136.96,
129.36, 128.47, 127.88, 117.93, 55.43, 53.35, 50.41, 46.65,
41.09, 16.85; (b) Rf ) 0.34; 1H NMR (CDCl3) δ 7.40-7.30 (5 H,
m), 5.83-5.76 (1 H, m), 5.50 (1 H, q, J ) 7.0 Hz), 5.17 (1 H,
dm, J ) 17.0 Hz), 5.14 (1 H, dm, J ) 10.0 Hz), 3.82 (3 H, s),
3.41-3.39 (1 H, m), 3.29 (1 H, quintet, J ) 8.5 Hz), 3.22 (1 H,
dd, J ) 9.5 Hz), 3.11-3.07 (1 H, m), 1.56 (3 H, d, J ) 7.0 Hz);
13C NMR (CDCl3) δ 170.49, 169.28, 140.26, 136.95, 129.37,
128.36, 127.66, 118.08, 55.37, 53.36, 50.22, 46.74, 41.23, 16.86.
1-(2′-Nitr oben zyl)-3-m eth oxyca r bon yl-4-vin yl-2-p yr r o-
lid in on e (24). Isolated as a mixture of isomers in 93% yield
as a yellow oil: IR (neat) 3079, 2955, 1739, 1699, 1653, 1528,
1436, 1343, 1253, 1169, 1046, 1005, 857, 791, 730 cm-1 1H
;
NMR (CDCl3) δ 8.01 (1 H, d, J ) 8.0 Hz), 7.62 (1 H, t, J ) 8.0
Hz), 7.47 (2 H, d, J ) 8.0 Hz), 5.82-5.75 (1 H, ddd, J ) 17.0,
10.0 and 7.0 Hz), 5.19 (1 H, d, J ) 17.0 Hz), 5.16 (1 H, d, J )
10.0 Hz), 4.94 (1 H, d, J ) 16.0 Hz), 4.73 (1 H, d, J ) 16.0 Hz),
3.83 (3 H, s), 3.63-3.57 (1 H, m), 3.43-3.39 (2 H, m), 3.16 (1
H, dd, J ) 9.5 and 7.5 Hz); 13C NMR (CDCl3) δ 170.00, 169.91,
148.82, 136.18, 134.12, 131.60, 129.91, 128.84, 125.26, 117.84,
54.10, 53.04, 51.18, 43.89, 40.68; EIMS m/z 305 (MH+), 289,
274, 273, 258, 170, 138, 136, 135, 119, 108, 95, 91, 79, 78;
HRMS calcd for C15H17N2O5 305.1137, found 305.1148.
1-P h en et h yl-3-m et h oxyca r b on yl-4-vin yl-2-p yr r olid i-
n on e (28). Isolated as a mixture of isomers in 87% yield as a
yellow oil: IR (neat) 3094, 3057, 3023, 2951, 1740, 1690, 1485,
1429, 1318, 1207, 1163, 1007, 918, 752, 702 cm-1 1H NMR
;
(CDCl3) δ 7.33-7.30 (2 H, m), 7.25-7.21 (3 H, m), 5.71 (1 H,
ddd, J ) 17.0, 10.5 and 7.5 Hz), 5.14 (1 H, d, J ) 17.0 Hz),
5.10 (1 H, d, J ) 10.5 Hz), 3.79 (3 H, s), 3.56 (2 H, t, J ) 7.5
Hz), 3.40 (1 H, t, J ) 9.0 Hz), 3.33 (1 H, t, J ) 8.0 Hz), 3.26 (1
H, d, J ) 8.5 Hz), 3.02 (1 H, dd, J ) 9.0 and 7.5 Hz), 2.87 (2
H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 169.92, 168.92, 138.58,
136.50, 128.84, 128.75, 126.74, 117.35, 54.45, 52.75, 51.38,
44.60, 40.60, 33.83; EIMS m/z 273(M+), 242, 214, 182, 151,
150, 132, 122, 121, 105, 104, 91, 77, 67; HRMS calcd for C16H19
NO3 273.1315, found 273.1350.
-
3-Meth oxyca r bon yl-4-vin yl-2-p yr r olid in on e (26). A so-
lution of 15 mg (0.049 mmol) of 1-(2′-nitrobenzyl)-3-methoxy-
carbonyl-4-vinyl-2-pyrrolidinone (24) in 15 mL of methanol (3.0
× 10-6 M) was degassed thoroughly and then irradiated with
a mercury vapor lamp in a quartz tube for 1.5 h. After
evaporation of the methanol, the product was purified by
column chromatography (silica gel, EtOAc/CH2Cl2 1:1) to give
1.1 mg (14%) of 26 as a yellow oil: 1H NMR (CDCl3) δ 6.22 (1
H, br s), 5.87 (1 H, ddd, J ) 17.0, 10.0 and 7.0 Hz), 5.23 (1 H,
d, J ) 17.0 Hz), 5.17 (1 H, d, J ) 10.0 Hz), 3.80 (3 H, s), 3.61
(1 H, q, J ) 8.5 Hz), 3.57 (1 H, t, J ) 8.0 Hz), 3.30 (1 H, d, J
) 8.5 Hz), 3.20 (1 H, t, J ) 8.0 Hz); 13C NMR (CDCl3) δ 168.21,
153.47, 136.26, 117.76, 53.45, 52.99, 45.85, 43.38; EIMS m/z
169 (M+), 138, 137, 113, 111, 110, 97, 82, 81, 80; HRMS calcd
for C8H11NO3 169.0739, found 169.0734.
1-Ben zyl-3-m eth oxyca r bon yl-4-vin yl-2-p yr r olid in on e
(5b). Isolated as a mixture of two diastereomers as a light
yellow oil in 94% yield: IR (neat) 3071, 3032, 2953, 1740, 1698,
1652, 1436, 1256, 1168, 1003, 924, 703 cm-1; 1H NMR (CDCl3)
δ 7.33-7.21 (5 H, m), 5.74-5.68 (1 H, m), 5.11 (1 H, d, J )
16.5 Hz), 5.06 (1 H, d, J ) 10.0 Hz), 4.44 (2 H, s), 3.76 (3 H, s),
3.43-3.39 (1 H, m), 3.36-3.34 (2 H, m), 3.02-2.99 (1 H, m);
13C (CDCl3) δ 169.60, 168.78, 136.09, 135.68, 128.62, 127.96,
127.61, 117.14, 54.10, 52.47, 49.78, 46.66, 40.29; EIMS m/z 259
(M+), 228, 206, 201, 200, 199, 172, 170, 162, 146, 136, 132,
119, 118, 117, 108, 106, 104, 92, 91, 81, 77, 65, 53; HRMS calcd
for C15H17NO3 259.1208, found 259.1196.
1-Ben zyl-3-m et h oxyca r b on yl-4-et h yl-2-p yr r olid in o-
n e (15). Meth od A. To a mixture of 0.259 g (1.0 mmol) of
1-benzyl-3-methoxycarbonyl-4-vinyl-2-pyrrolidinone (5b) and

3734 J . Org. Chem., Vol. 66, No. 11, 2001
Taylor and Liu
0.39 g of 10% Pd/C in 20 mL of methanol was added 0.64 g
(10.0 mmol) of ammonium formate in one portion. The result-
ing mixture was stirred at reflux overnight. The mixture was
cooled to room temperature and passed through a Celite pad.
The methanol was evaporated, and 50 mL of ethyl acetate was
added. The solution was washed with water (3 × 30 mL), dried
with Na2SO4, concentrated, and dried under vacuum to give
0.256 g (98% yield) of 15 as a colorless oil: IR (neat) 3059,
3031, 2953, 1741, 1696, 1493, 1435, 1349, 1263, 1168, 916, 733,
m/z 452 (M+), 421, 407, 393, 376, 361, 348, 316, 284, 256, 244,
216, 215, 184, 170, 155, 149, 143, 133, 129, 115, 104, 91, 77;
HRMS calcd for C24H24N2O7 452.1591, found 452.1578. 2′-
1
Nitr o p r od u ct (30b): H NMR (CDCl3) δ 8.00 (2 H, d, J )
8.5 Hz), 7.99 (1 H, d, J ) 7.5 Hz), 7.59 (1 H, t, J ) 7.0 Hz),
7.45 (2 H, d, J ) 7.5 Hz), 7.40 (2 H, d, J ) 8.5 Hz), 6.55 (1 H,
d, J ) 16.0 Hz), 6.22 (1 H, dd, J ) 16.0 and 8.0 Hz), 3.92 (3 H,
s), 3.81 (3 H, s), 3.70-3.55 (4 H, m), 3.41 (1 H, d, J ) 8.5 Hz),
3.29 (1 H, t, J ) 8.0 Hz), 3.18 (2 H, t, J ) 7.5 Hz); 13C NMR
(CDCl3) δ 169.70, 169.10, 166.90, 149.47, 140.76, 133.60,
132.93, 132.03, 130.22, 130.14, 129.56, 128.87, 128.20, 126.42,
125.21, 54.57, 52.98, 52.26, 51.50, 43.82, 40.30, 31.17.
1
702 cm-1; H NMR (CDCl3) δ 7.37-7.24 (5 H, m), 4.48 (2 H,
s), 3.81 (3 H, s), 3.44 (1 H, t, J ) 9.0 Hz), 3.21 (1 H, d, J ) 8.0
Hz), 2.88 (1 H, dd, J ) 9.0 and 7.0 Hz), 2.64 (1 H, q, J ) 7.0
Hz), 1.57-1.43 (2 H, m), 0.89 (3 H, t, J ) 7.5 Hz); 13C NMR
(CDCl3) δ 170.85, 169.73, 136.09, 128.90, 128.25, 127.87, 54.99,
52,78, 50.75, 47.06, 38.07, 26.90, 11.56; EIMS m/z 261(M+),
1-(r-Meth ylben zyl)-3-m eth oxyca r bon yl-4-vin yl-2-p yr -
r olid in eth ion e (6a ). The following procedure is representa-
tive for the preparation of the 2-pyrrolidinethiones described
herein. A mixture of 0.9 g (3.3 mmol) of 1-(R-methylbenzyl)-
3-methoxycarbonyl-4-vinyl-2-pyrrolidinone (5a ) and 0.88 g (4.0
mmol) of P4S10 in 45 mL of dry THF was heated to reflux. The
reaction was monitored by TLC. When the starting material
completely disappeared (about 2.5 h), the mixture was cooled
to room temperature, and solid was removed by filtration. The
solvent was evaporated, and the residue was purified by
column chromatography (silica gel, hexane/ethyl acetate 1:1)
to give 0.65 g (68%) of 6a as a light yellow oil that was a
mixture of two diastereomers: IR (neat) 3069, 3021, 2980,
2944, 1741, 1491, 1448, 1290, 1209, 1166, 1124, 1027, 920, 784,
230, 202, 172, 119, 106, 91, 77, 69; HRMS calcd for C15H19
NO3 261.1345, found 261.1363.
-
Meth od B. A mixture of 0.259 g (1.0 mmol) of 1-benzyl-3-
methoxycarbonyl-4-vinyl-2-pyrrolidinone and 0.39 g of 10%
Pd/C in 20 mL of methanol was hydrogenated at room
temperature under 50 psi for 4 h. The reduction mixture was
passed through a Celite pad, and the methanol was evaporated
under vacuum to give 0.261 g (100%) of the product as a
1
colorless oil that was >99% pure by H NMR.
1-P h en eth yl-3-m eth oxyca r bon yl-4-(4′-m eth oxyca r bo-
n ylstyr yl)-2-p yr r olid in on e (29). A mixture of 1-phenethyl-
3-methoxycarbonyl-4-vinyl-2-pyrrolidinone (1.2 g, 4.4 mmol),
Pd(OAc)2 (99 mg, 0.44 mmol), CuI (85 mg, 0.44 mmol), and
(o-toyl)3P (268 mg, 0.88 mmol) in 40 mL of DMF was degassed
and then purged with nitrogen. Methyl 4-iodobenzoate (2.31
g, 8.8 mmol) in 30 mL of DMF was degassed and added to the
above mixture by a cannula. The resulting mixture was stirred
at 70 °C under a nitrogen atmosphere for 18 h. The mixture
was poured into 300 mL of ethyl acetate and washed with
water (3 × 50 mL). The organic layer was separated, dried
with Na2SO4, and concentrated. The residue was purified by
column chromatography (silica gel, hexane/ethyl acetate 2:1
and then 1:1) to give 1.2 g (69%) of 29 as a yellow oil: IR (neat)
3054, 3022, 2947, 1733, 1696, 1598, 1484, 1435, 1278, 1175,
1110, 1040, 1013, 970, 867, 758, 693 cm-1; 1H NMR (CDCl3) δ
8.00 (2 H, d, J ) 8.0 Hz), 7.39 (2 H, d, J ) 8.5 Hz), 7.33 (2 H,
t, J ) 7.5 Hz), 7.29-7.24 (3 H, m), 6.52 (1 H, d, J ) 16.0 Hz),
6.16 (1 H, dd, J ) 16.0 and 8.5 Hz), 3.93 (3 H, s), 3.82 (3 H, s),
3.70-3.57 (2 H, m), 3.57-3.51 (1 H, m), 3.47 (1 H, t, J ) 8.5
Hz), 3.37 (1 H, d, J ) 8.5 Hz), 3.11 (1 H, t, J ) 7.5 Hz), 2.91
(2 H, t, J ) 6.5 Hz); 13C NMR (CDCl3) δ 169.74, 168.73, 166.87,
140.79, 138.50, 131.80, 130.51, 134.11, 129.51, 128.86, 128.81,
126.83, 126.37, 54.66, 52.92, 52.42, 51.56, 44.57, 40.22, 33.83;
EIMS m/z 407 (M+), 376, 348, 316, 284, 255, 244, 199, 187,
169, 155, 149, 143, 128, 115, 113, 104, 91, 77; HRMS calcd for
1
702 cm-1; H NMR (CDCl3) δ 7.43-7.34 (5 H, m), 6.42-6.33
(1 H, m), 5.82-5.61 (1 H, m), 5.22-5.15 (1 H, m), 5.10-5.07
(1 H, m), 3.86 (3 H, s), 3.90-3.75 and 3.60-3.51 (2 H, m), 3.40-
3.03 (2 H, m), 1.66 and 1.64 (3 H, d, J ) 7.0 Hz); 13C NMR
(CDCl3) δ 196.02 and 195.65, 170.77 and 170.73, 138.96, 136.16
and 136.05, 129.57 and 129.53, 128.98 and 128.83, 127.98 and
127.69, 118.67 and 118.34, 66.72 and 66.54, 55.00 and 54.84,
53.76 and 53.71, 53.52 and 53.50, 42.92 and 42.67, 15.71 and
15.65; EIMS m/z 289(M+), 256, 236, 176, 120, 105, 104, 79,
77; HRMS calcd for C16H19NO2S 289.1136, found 289.1153.
Anal. Calcd for C16H19NO2S: C, 66.41; H, 6.62; N, 4.84; S,
11.08. Found: C, 66.71; H, 6.69; N, 4.85; S, 11.09.
1-Ben zyl-3-m eth oxyca r bon yl-4-vin yl-2-p yr r olid in eth -
ion e (6b). Isolated as a mixture of two diastereomers as a
light yellow oil in 74% yield: IR (neat) 3084, 3060, 3023, 2951,
2864, 1740, 1506, 1453, 1436, 1330, 1250, 1209, 1165, 1029,
1000, 930, 741, 703 cm-1; 1H NMR (CDCl3) δ 7.45-7.34 (5 H,
m), 5.80-5.71 (1 H, m), 5.18 (1 H, d, J ) 16.0 Hz), 5.16 (1 H,
d, J ) 9.5 Hz), 5.07-4.99 (2 H, m), 3.88-3.82 (4 H, m), 3.78 (1
H, s), 3.44-3.39 (2 H. m); 13C NMR (CDCl3) δ 196.31, 170.16,
135.49, 129.09, 128.40, 128.36, 128.28, 118.03, 65.93, 57.51,
52.97, 51.78, 42.23; EIMS m/z 275 (M+), 244, 242, 217, 216,
188, 162, 148, 117, 106, 91, 77, 65; HRMS calcd for C15H17
-
NO2S 275.0980, found 275.0978. Anal. Calcd for C15H17NO2S:
C, 65.43; H, 6.22; N, 5.09; S, 11.64. Found: C, 65.15; H, 6.36;
N, 5.07; S, 12.17.
C
24H25NO5 407.1736, found 407.1735.
1-(4′-Nit r op h en et h yl)-3-m et h oxyca r b on yl-4-(4′-m et h -
oxyca r bon ylstyr yl)-2-p yr r olid in on e (30a ) a n d 1-(2′-Ni-
tr op h en eth yl)-3-m eth oxyca r bon yl-4-(4′-m eth oxy-ca r bo-
n ylstyr yl)-2-p yr r olid in on e (30b). To a mixture of 0.56 g
(1.38 mmol) of 29 and 0.122 g (1.52 mmol) of NH4NO3 in 10
mL of methylene chloride was added 2.89 g (13.8 mmol, 1.95
mL) of trifluoroacetic anhydride at room temperature. The
resulting mixture was stirred for 7 h. The reaction mixture
was poured into 150 mL of ethyl acetate, and the mixture was
washed with 60 mL of K2CO3 solution. The organic layer was
separated, dried with Na2SO4, and concentrated. The residue
was purified by column chromatography (silica gel, hexane/
ethyl acetate 1:1) to afford 457 mg (84%) of p-nitro and o-nitro
products as well as 40 mg of unchanged starting material. 4′-
Nitr o p r od u ct (30a ): IR (neat) 3070, 3037, 2951, 1701, 1604,
1518, 1437, 1340, 1281, 1206, 1136, 1109, 1017, 969, 850, 801,
1-(4′-Meth oxyben zyl)-3-m eth oxycar bon yl-4-vin yl-2-pyr -
r olid in eth ion e (6c). Isolated in 64% as a light yellow oil: IR
(neat) 3076, 2949, 2834, 1740, 1695, 1652, 1514, 1436, 1248,
1
1174, 1024, 924, 813 cm-1; H NMR (CDCl3) δ 7.31 (2 H, d, J
) 8.5 Hz), 6.93 (2 H, d, J ) 8.5 Hz), 5.79-5.70 (1 H, ddd, J )
17.5, 10.5 and 7.5 Hz), 5.18 (1 H, d, J ) 16.5 Hz), 5.15 (1 H, d,
J ) 10.0 Hz), 4.96 (2 H, s), 3.88 (3 H, s), 3.86 (3 H, s), 3.84-
3.78 (2 H, m), 3.41-3.37 (2 H, m); 13C NMR (CDCl3) δ 195.98,
170.28, 159.78, 135.62, 129.99, 126.87, 118.10, 114.52, 66.10,
57.47, 55.55, 53.07, 51.37, 42.31; EIMS m/z 305 (M+), 246, 192,
153, 121, 77; HRMS calcd for C16H19NO3S 305.1086, found
305.1082.
1-(3′,4′-Dim eth oxyben zyl)-3-m eth oxyca r bon yl-4-vin yl-
2-p yr r olid in eth ion e (6d ). Isolated in 85% yield as a mixture
of isomers, a yellow oil: IR (neat) 3070, 2950, 1742, 1690, 1438,
1
1
758, 721, 694 cm-1; H NMR (CDCl3) δ 8.20 (2 H, d, J ) 8.5
1244, 1167, 1023, 918, 770 cm-1; H NMR (CDCl3) δ 6.89 (1
Hz), 8.00 (2 H, d, J ) 8.0 Hz), 7.42 (2 H, d, J ) 9.0 Hz), 7.40
(2 H, d, J ) 8.0 Hz), 6.54 (1 H, J ) 16.0 Hz), 6.18 (1 H, dd, J
) 16.0 and 7.5 Hz), 3.96 (3 H, s), 3.82 (3 H, s), 3.75-3.53 (4 H,
m), 3.45-3.36 (1 H, m), 3.22-3.18 (1 H, m), 3.03 (2 H, t, J )
8.0 Hz); 13C NMR (CDCl3) δ 169.62, 169.22, 166.89, 156.51,
147.19, 146.07, 140.61, 132.23, 130.22, 129.99, 129.80, 126.43,
124.10, 54.43, 53.16, 52.34, 51.64, 44.01, 40.16, 33.63; EIMS
H, d, J ) 2.0 Hz), 6.85-6.80 (2 H, m), 5.70 (1 H, ddd, J )
17.5, 10.0 and 7.0 Hz), 5.12 (1 H, d, J ) 17.5 Hz), 5.10 (1 H, d,
J ) 10.0 Hz), 4.90 (2 H, AB), 3.86 (3 H, s), 3.85 (3 H, s), 3.81
(3 H, s), 3.79-3.71 (2 H, m), 3.37-3.28 (2 H, m); 13C NMR
(CDCl3) δ 196.01, 170.23, 149.53, 149.15, 135.58, 127.31,
120.95, 117.99, 111.45, 111.27, 66.01, 57.48, 56.13, 56.09,
52.99, 51.62, 42.19; EIMS m/z 335 (M+), 319, 302, 288, 276,

Substituted Derivatives of LY231514 (MTA)
J . Org. Chem., Vol. 66, No. 11, 2001 3735
H, s), 3.88 (3 H, s), 3.14 (2 H, t, J ) 7.0 Hz), 2.46 (3 H, s); 13
260, 242, 222, 208, 183, 166, 151, 135, 121, 107, 91, 77, 67;
HRMS calcd for C17H21NO4S 335.1191, found 335.1202.
1-(2′-Nitr oben zyl)-3-m eth oxyca r bon yl-4-vin yl-2-p yr r o-
lid in eth ion e (25). Isolated as a mixture of isomers as a yellow
oil in 70% yield: IR (neat) 3076, 2951, 1740, 1527, 1506, 1452,
1339, 1277, 1206, 1162, 992, 910, 855, 784, 724 cm-1; 1H NMR
(CDCl3) δ 8.15-8.10 (1 H, m), 7.70-7.63 (1 H, m), 7.53-7.46
(2 H, m), 5.85-5.71 (1 H, m), 5.65-5.52 (1 H, m), 5.27-5.14
(3 H, m), 4.19-3.80 (2 H, m), 3.87 (3 H, s), 3.55-3.44 (2 H,
m); 13C NMR (CDCl3) δ 198.44, 170.76, 149.16, 136.01, 134.80,
130.56, 129.72, 129.57, 126.06, 118.78, 66.20, 59.17, 53.65,
49.05, 42.86; EIMS m/z 321 (MH+), 289, 276, 275, 274, 214,
200, 188, 154, 151, 137, 136, 135, 123, 122, 121, 105, 97, 92,
91, 78, 67; HRMS calcd for C15H17N2O4S (MH) 321.0831, found
321.0885. Anal. Calcd. for C15H16N2O4S: C, 56.24; H, 5.03; N,
8.74; S, 10.01; Found: C, 56.41; H, 4.79; N, 8.61; N, 10.30.
1-(4′-Nit r op h en et h yl)-3-m et h oxyca r b on yl-4-(4′-m et h -
oxyca r bon ylstyr yl)-2-p yr r olid in eth ion e (31). A mixture of
210 mg (0.456 mmol) of 1-(4′-nitrophenethyl)-3-methoxycar-
bonyl-4-(4′-methoxycarbonylstyryl)-2-pyrrolidinone (30a ) and
0.6 g (1.3 mmol) of P4S10 in 15 mL of dry THF was stirred at
70 °C for 7 h. The mixture was cooled to room temperature,
and 30 mL of hexane was added. The resulting mixture was
passed through a column (silica gel, hexane/ethyl acetate 1:1)
to afford 165 mg (76%) of 31 as a yellow oil: IR (neat) 3070,
3037, 2945, 1720, 1607, 1518, 14955, 1346, 1261, 1178, 1111,
1018, 963, 912, 855, 765, 732, 691, 645 cm-1; 1H NMR (CDCl3)
δ 8.18 (2 H, d, J ) 8.0 Hz), 7.98 (2 H, d, J ) 8.0 Hz), 7.45 (2
H, d, J ) 8.5 Hz), 7.37 (2 H, d, J ) 8.0 Hz), 6.52 (1 H, d, J )
15.5 Hz), 6.16 (1 H, dd, J ) 15.5 and 8.0 Hz), 4.13-4.07 (1 H,
m), 4.01-3.94 (1 H, m), 3.91 (3 H, s), 3.89-3.83 (2 H, m), 3.82
(3 H, s), 3.57-3.49 (2 H, m), 3.24-3.11 (2 H, m); 13C NMR
(CDCl3) δ 195.88, 169.85, 166.77, 147.12, 145.70, 140.38,
132.46, 130.11, 129.91, 129.67, 129.09, 126.39, 124.04, 65.98,
59.50, 53.07, 52.25, 49.03, 42.12, 31.98; EIMS m/z 468 (M+),
437, 409, 332, 286, 260, 231, 215, 184, 149, 129, 128, 103, 91,
77; HRMS calcd for C24H24N2O6S 468.1384, found 468.1381.
1-(4′-Nitr oph en eth yl)-2-m eth ylth io-3-m eth oxycar bon yl-
4-(4′-m eth oxyca r bon ylstyr yl)-2-p yr r olin e (32). To a mix-
ture of 1-(4′-nitrophenethyl)-3-methoxycarbonyl-4-(4′-methoxy-
carbonylstyryl)-2-pyrrolidinethione (31) (100 mg, 0.214 mmol)
and K2CO3 (94 mg, 0.684 mmol) in 10 mL of acetone was added
97 mg (0.684 mmol) of methyl iodide at room temperature.
The resulting mixture was stirred at room temperature
overnight. Residual solid was removed by filtration, and the
solvent was evaporated under reduced pressure to give 97 mg
(94%) of 32 as a yellow oil: IR (neat) 2948, 1718, 1670, 1606,
1520, 1495, 1345, 1278, 1102, 1110, 971, 911, 851, 764, 733
C
NMR (CDCl3) δ 167.10, 164.93, 147.26, 145.34, 142.49, 130.12,
129.91, 128.58, 126.40, 126.16, 124.42, 124.40, 124.10, 120.36,
118.17, 52.19, 51.50, 48.34, 38.07, 20.49; EIMS m/z 408(M+),
433, 405, 344, 331, 312, 298, 284, 266, 256, 238, 225, 210, 150,
139, 120, 104, 103, 91, 77; HRMS calcd for C25H24N2O6S
480.1355, found 480.1344.
1-(4′-Nitr op h en eth yl)-2-m eth ylsu lfon yl-3-m eth oxyca r -
bon yl-4-(4′-m eth oxyca r bon ylstyr yl)p yr r ole (34). To a mix-
ture of 15 mg (0.031 mmol) of 1-(4′-nitrophenethyl)-2-methylthio-
3-methoxycarbonyl-4-(4′-methoxycarbonylstyryl)pyrrole in 1
mL of trifluoroacetic acid at 0 °C (ice-salt) was added 10 µL
of H2O2 (30% in H2O). The mixture changed immediately to a
deeper color. The progress of the reaction was monitored by
TLC. After 1 h, the starting material had completely disap-
peared. The TFA was evaporated under reduced pressure at
0 °C, and the residue was purified by column chromatography
(silica gel, ethyl acetate) to afford 4.6 mg (30%) of 34 as a light
pink oil: 1H NMR (CDCl3) δ 8.18 (2 H, d, J ) 8.0 Hz), 8.01 (2
H, d, J ) 8.5 Hz), 7.54 (1 H, d, J ) 16.5 Hz), 7.49 (2 H, d, J )
8.0 Hz), 7.41 (2 H, d, J ) 8.0 Hz), 6.96 (1 H, s), 6.76 (1 H, d,
J ) 16.5 Hz), 4.90 (1 H, m), 4.56 (1 H, m), 3.92 (3 H, s), 3.90
(3 H, s), 3.37 (1 H, m), 3.28 (1 H, m), 3.01 (3 H, s); EIMS m/z
512(M+), 496, 481, 465, 449, 433, 417, 401, 347, 333, 312, 300,
256, 196, 163, 155, 120, 104, 78; HRMS calcd for C25H24N2O8S
512.1253, found 512.1244.
2-Am in o-4-oxo-5-vin yl-7-(r-m et h ylb en zyl)-3,4,5,6-t et -
r a h yd r op yr r olo[2,3-d ]p yr im id in e (7a ). The following pro-
cedure is representative for the preparation of the 5,6-dihy-
dropyrrolo[2,3-d]pyrimidines reported herein. To a suspension
of 4.3 g (45 mmol) of guanidine hydrochloride in 20 mL of dry
methanol was added 2.43 g (45 mmol) of freshly made sodium
methoxide in methanol. After stirring at room temperature
for 30 min, the solution was filtered and added to a mixture
of 2.6 g (8.99 mmol) of 1-(a-methylbenzyl-3-methoxycarbonyl-
4-vinyl-2-pyrrolidinethione (6a ). The resulting mixture was
stirred for 5 min, concentrated in vacuo to remove most of the
methanol, and then slowly heated to 90 °C for 1 h under
reduced pressure (about 15 Torr). After cooling to ambient
temperature, 40 mL of water was added, and the mixture was
boiled for 30 min. The resulting suspension was cooled to room
temperature, adjusted to pH 7 by addition of 1 N HCl, filtered,
washed with water followed with ethyl ether, and dried under
vacuum to give 1.27 g (50% yield) of 7a as a white solid, mp
180 °C (decomp): IR (KBr) 3312, 3123, 2977, 2874, 1653, 1617,
1
1669, 1533, 1438, 1384, 1362, 1340, 1317, 775, 700 cm-1; H
NMR (DMSO-d6) δ 9.70 (1 H, s), 7.37-7.26 (5 H, m), 6.44 (2
H, s), 5.71 (1 H, ddd, J ) 17.0, 10.0 and 6.0 Hz), 5.32-5.28 (1
H, q, J ) 7.0 Hz), 4.91 (1 H, d, J ) 17.0 Hz), 4.86 (1 H, d, J )
10.0 Hz), 3.63-3.46 (2 H, m), 2.78 (1 H, m), 1.47 (3 H, d, J )
6.5 Hz); 13C NMR (DMSO-d6) δ 167.93, 159.81, 158.28, 142.50,
141.20, 129.52, 128.13, 127.89, 114.37, 88.68, 50.90, 50.31,
39.58, 17.49; EIMS m/z 282 (M+), 267, 178, 176, 177, 163, 151,
134, 105, 79; HRMS calcd for C16H18N4O 282.1481, found
282.1498.
1
cm-1; H NMR (CDCl3) δ 8.16 (2 H, d, J ) 8.5 Hz), 7.98 (2 H,
d, J ) 8.5 Hz), 7.39 (2 H, d, J ) 8.0 Hz), 7.38 (2 H, d, J ) 8.5
Hz), 6.41 (1 H, d, J ) 15.5 Hz), 6.26 (1 H, dd, J ) 15.5 and 7.5
Hz), 3.92 (3 H,. s), 3.84-3.79 (1 H, tm, J ) 10.5 Hz), 3.78-
3.58 (3 H, m), 3.32 (3 H, s), 3.32 (1 H, dd, J ) 10.0 and 3.5
Hz), 2.99-2.89 (2 H, m), 2.49 (3 H, s); 13C NMR (CDCl3) δ
167.04, 165.27, 160.89, 146.96, 146.51, 141.98, 134.18, 130.05,
129.91, 128.86, 128.64, 126.22, 123.94, 103.22, 57.45, 52.20,
50.69, 48.62, 42.99, 34.97, 18.25; EIMS m/z 482(M+), 480, 433,
376, 246, 330, 312, 266, 209, 175, 131, 104, 91; HRMS calcd
for C25H26N2O6S 482.1511, found 482.1355.
2-Am in o-4-oxo-5-vin yl-7-ben zyl-3,4,5,6-tetr a h yd r op yr -
r olo[2,3-d ]p yr im id in e (7b). Isolated in 74% yield as a white
solid, mp 220 °C (decomp): IR (KBr) 3410, 3302, 3107, 2851,
1654, 1616, 1545, 1449, 1366, 1325, 1234, 911, 773, 701 cm-1
;
1-(4′-Nitr oph en eth yl)-2-m eth ylth io-3-m eth oxycar bon yl-
4-(4′-m eth oxyca r bon ylstyr yl)p yr r ole (33). To a mixture of
135 mg (0.28 mmol) of 1-(4′-nitrophenethyl)-2-methylthio-3-
methoxycarbonyl-4-(4′-methoxycarbonylstyryl)-2-pyrroline (32)
in 20 mL of acetonitrile was added 0.47 g (3.0 mmol) of DBU
at room temperature. The resulting mixture was stirred for 7
h, and the color of the mixture changed slowly to brown. The
acetonitrile was evaporated under reduced pressure, and the
residue was purified by column chromatorgaphy (silica gel,
ethyl acetate/hexane 1:2 and then 1:1) to afford 74 mg (55%)
of 33 as a yellow oil: IR (neat) 3112, 3061, 2927, 2854, 1716,
1615, 120, 1473, 1437, 1346, 1314, 1276, 1213, 1177, 1108,
1059, 951, 854, 750 cm-1; 1H NMR (CDCl3) δ 8.14 (2 H, d, J )
8.5 Hz), 7.96 (2 H, d, J ) 8.5 Hz), 7.62 (1 H, d, J ) 16.5 Hz),
7.46 (2 H, d, J ) 8.5 Hz), 7.23 (2 H, d, J ) 8.5 Hz), 6.93 (1 H,
s), 6.69 (1 H, d, J ) 16.5 Hz), 4.38 (2 H, t, J ) 7.0 Hz), 3.89 (3
1H NMR (DMSO-d6) δ 9.82 (1 H, s), 7.36-7.28 (2 H, m), 7.26-
7.15 (3 H, m), 6.48 (2 H br s), 5.83-5.76 (1 H, m), 4.97 (1 H,
d, J ) 17.0 Hz), 4.90 (1 H, d, J ) 10.5 Hz), 4.41 (2 H, AB, J )
21.5 Hz), 3.58 (1 H, br s), 3.43 (1 H, t, J ) 9.8 Hz), 3.04 (1 H,
br s); 13C NMR (DMSO-d6) δ 167.36, 158.72, 157.20, 139.93,
137.72, 128.47, 127.50, 127.03, 113.32, 87.55, 54.03, 47.46,
38.68; EIMS m/z 268 (M+), 253, 241, 215, 201, 177, 175, 163,
149, 135, 133, 120, 106, 91, 78, 63; HRMS calcd for C15H16N4O
268.1324, found 268.1346. This compound was too insoluble
for recrystallization and purification, and it was therefore
converted to the much more soluble 2-p iva loyla m in o-4-oxo-
5-vin yl-7-ben zyl-3,4,5,6-tetr a h yd r op yr r olo[2,3-d ]p yr im i-
d in e. To a solution of 52 mg (0.19 mmol) of 7b in 5 mL of dry
pyridine was added 0.59 g (0.6 mL, 4.9 mmol) of pivaloyl
chloride. The resulting mixture was heated to 80-90 °C for 2
h. The solution was evaporated to dryness under vacuum, and

3736 J . Org. Chem., Vol. 66, No. 11, 2001
Taylor and Liu
the residue was dissolved in 3 mL of methanol followed by
addition of NH4OH to adjust the pH to 7. Methylene chloride
was added, and the mixture was washed with water (2 × 20
mL). The organic layer was separated, dried, and concentrated.
The residue was purified by column chromatography (silica
gel, EtOAc/CH2Cl2 1:1) to give 51 mg (76% yield) of the
2-pivaloyl derivative of 7b as a white solid, mp 150-152 °C:
IR (KBr) 3214, 2962, 1655, 1601, 1553, 1473, 1435, 1271, 1318,
DMF. After stirring for 15 min, a degassed solution of 0.84 g
(2.0 mmol) of diethyl 4-iodobenzoyl-L-glutamate in 10 mL of
DMF was added. The resulting mixture was stirred at 75 °C
under nitrogen for 48 h. The mixture was cooled to room
temperature, poured into 300 mL of ethyl acetate, and washed
with water (2 × 200 mL) followed with brine (50 mL). The
organic layer was separated, dried over sodium sulfate, and
then concentrated to give a dark solid that was purified by
chromatography (silica gel, 10% methanol in ethyl acetate) to
give 284 mg (68%) of 9a as a light pink solid as a mixture of
two diastereomers, mp 164-166 °C: IR (KBr) 3412, 3344,
2980, 2936, 1734, 1653, 1522, 1442, 1340, 1206, 1189, 1101,
1
1215, 1162, 926 cm-1; H NMR (CDCl3) δ 11.34 (1 H, s), 8.33
(1 H, s), 7.36-7.28 (3 H, m), 7.21 (2 H, d, J ) 7.0 Hz), 5.90 (1
H, ddd, J ) 17.0, 10.0 and 7.0 Hz), 5.14 (1 H, d, J ) 17.5 Hz),
5.05 (1 H, d, J ) 10.0 Hz), 4.44 (2 H, AB, J ) 13.5 Hz), 3.90-
3.86 (1 H, m), 3.54 (1 H, t, J ) 10.0 Hz), 3.18 (1 H, dd, J )
10.0 and 5.5 Hz), 1.32 (9 H, s); 13C NMR (CDCl3) δ 179.86,
165.99, 157.84, 152.05, 138.24, 137.07, 128.83, 127.76, 127.65,
114.91, 94.63, 54.89, 48.49, 40.36, 39.43, 27.14; EIMS m/z 352
(M+), 350, 337, 3255, 295, 268, 261, 225, 177, 175, 141, 91;
HRMS calcd for C20H24N4O2 352.1900, found 352.1901. Anal.
Calcd. for C20H24N4O2: C, 68.16; H, 6.86; N, 15.90. Found: C,
68.37; H, 6.88; N, 15.96.
1
1021, 766, 757, 700 cm-1; H NMR (CDCl3) δ 11.48 (1 H, s),
7.73 (2 H, d, J ) 8.0 Hz), 7.34-7.31 (2 H, m), 7.28 (1 H, d, J
) 8.0 Hz), 7.22 (2 H, d, J ) 8.0 Hz), 7.16 (2 H, d, J ) 7.5 Hz),
6.25 (1 H, s), 5.86 (1 H, q, J ) 7.0 Hz), 5.37 (2 H, s), 4.84 (1 H,
q, J ) 4.5 Hz), 4.27-4.20 (2 H, qm, J ) 7.5 Hz), 4.14-4.08 (2
H, qm, J ) 7.5 Hz), 3.06-2.92 (4 H, m), 2.59-2.44 (2 H, m),
2.40-2.29 (1 H, m), 2.32-2.15 (1 H, m), 1.75 (3 H, d, J ) 7.5
Hz), 1.31 (3 H, t, J ) 7.5 Hz), 1.22 (3 H, t, J ) 7.5 Hz); 13C
NMR (CDCl3) δ 173.98 and 173.97, 173.00 and 172.98, 168.00,
162.10, 152.47, 151.86, 147.39, 142.73 and 142.69, 131.75,
129.53, 129.30 and 129.28, 128.12 and 128.10, 127.78, 127.06,
119.01, 115.87, 100.15, 62.48, 61.57, 53.12, 52.43, 37.37, 31.30,
29.05, 28.04, 21.39, 14.92 and 14.89; EIMS m/z 587 (M+), 267,
163, 129, 105, 84, 69, 55; HRMS calcd for C32H37N5O6 587.2743,
found 587.2727. Anal. Calcd. for C32H37N5O6: C, 65.40; H, 6.35;
N, 11.92. Found: C, 65.28; H, 6.29; N, 11.90.
Dieth yl N-{4-[2-(2-Am in o-3,4-dih ydr o-4-oxo-7-ben zylpyr -
r olo[2,3-d]pyr i-m idin -5-yl)eth yl]ben zoyl}-L-glu tam ate (9b).
Starting with 2-amino-4-oxo-5-vinyl-7-benzyl-3,4,5,6-tetrahy-
dropyrrolo[2,3-d]pyrimidine (7b), the same procedure and
conditions were applied as in the preparation of 9a above
except that after the solvent was evaporated, the dark solid
was washed with ethyl acetate and then with diethyl ether,
and dried under vacuum to give 9b as a light pink solid in
51% yield, mp 192-194 °C: IR (KBr) 3439, 3327, 3182, 2934,
1734, 1650, 1525, 1502, 1454, 1376, 1338, 1203, 1009, 1023,
732, 701 cm-1; 1H NMR (DMSO-d6) δ 10.26 (1 H, s), 8.62 (1 H.
d, J ) 7.5 Hz), 7.77 (2 H, d, J ) 7.5 Hz), 7.29-7.20 (5 H, m),
7.03 (2 H, d, J ) 7.0 Hz), 6.38 (1 H, s), 6.19 (2 H, br s), 5.05 (2
H, s), 4.43 (1 H, td, J ) 9.5 Hz), 4.10 (2 H, q, J ) 6.0 Hz), 4.04
(2 H, q, J ) 7.0 Hz), 2.99 (2 H, t, J ) 7.3 Hz), 2.86 (2 H, t, J
) 7.3 Hz), 2.43 (2 H, t, J ) 7.5 Hz), 2.14-2.07 (1 H, m), 2.03-
1.96 (1 H, m), 1.18 (3 H, t, J ) 7.0 Hz), 1.16 (3 H, t, J ) 7.0
Hz); 13C NMR (DMSO-d6) δ 172.19, 171.82, 166.57, 159.11,
152.47, 150.49, 146.07, 138.44, 131.00, 128.42, 128.25, 127.34,
127.05, 126.70, 117.47, 117.23, 98.68, 60.53, 59.92, 51.94,
46.58, 35.87, 30.17, 27.85, 25.71, 14.07 (two carbons); EIMS
m/z 573 (M+), 527, 371, 286, 254, 253, 222, 207, 194, 186, 91,
84, 77; HRMS calcd for C31H35N5O7 573.2587, found 573.2613.
Anal. Calcd. for C31H35N5O7: C, 64.91; H, 6.15; N, 12.21.
Found: C, 64.87; H, 6.41; N, 11.95.
2-Am in o-4-oxo-5-vin yl-7-(4′-m eth oxyben zyl)-3,4,5,6-tet-
r a h yd r op yr r olo[2,3-d ]p yr im id in e (7c). Isolated in 72%
yield as a white solid, mp 208 °C (decomp): IR (KBr) 3407,
3310, 3110, 2836, 1653, 1616, 1541, 1515, 1443, 1386, 1361,
1324, 1250, 1174, 1036, 914, 773 cm-1; 1H NMR (DMSO-d6) δ
9.72 (1 H, s), 7.14 (2 H, d, J ) 8.5 Hz), 6.89 (2 H, d, J ) 8.0
Hz), 6.45 (2 H, s), 5.77 (1 H, quintet, J ) 7.5 Hz), 4.96 (1 H, d,
J ) 17.0 Hz), 4.89 (1 H, d, J ) 10.0 Hz), 4.34 (2 H, AB, J )
15.0 Hz), 3.72 (3 H, s), 3.56 (1 H, m), 3.39 (1 H, t, J ) 9.8 Hz),
3.00 (1 H, m); 13C NMR (DMSO-d6) δ 167.28, 158.64, 158.34,
157.14, 139.94, 129.42, 128.90, 113.84, 113.27, 87.61, 55.00,
53.82, 46.88, 38.63; EIMS m/z 298 (M+), 245, 177, 170, 141,
97, 85, 77, 57; HRMS calcd for C16H18N4O2 298.1430, found
298.1435. Anal. Calcd for C16H18N4O2: C, 64.40; H, 6.08; N,
18.79. Found: C, 63.99; H, 6.17; N, 18.13. 2-P iva loyla m in o-
4-oxo-5-vin yl-7-(4′-m eth oxyben zyl)-3,4,5,6-tetr a h yd r op y-
r r olo[2,3-d ]p yr im id in e was prepared from 7c as described
above as a further confirmation of its assigned structure; it
was isolated in 85% as a light yellow solid, mp 88-90 °C: IR
(KBr) 3218, 2968, 1653, 1603, 1559, 1540, 1512, 1437, 1246,
1
1168, 1031, 925 cm-1; H NMR (DMSO-d6) δ 11.42 (1 H, s),
10.94 (1 H, s), 7.17 (2 H, d, J ) 8.0 Hz), 6.92 (2 H, d, J ) 8.0
Hz), 5.82 (1 H, m), 5.00 (1 H, d, J ) 17.5 Hz), 4.96 (1 H, d, J
) 10.0 Hz), 4.47 (2 H, q, J ) 22.0 Hz), 3.74 (3 H, s), 3.70 (1 H,
br s), 3.50 (1 H, t, J ) 10.0 Hz), 3.10 (1 H, br s), 1.24 (9 H, s),
13C NMR (CDCl3) δ 179.86, 165.91, 159.19, 157.83, 152.04,
138.29, 129.12, 128.98, 114.85, 114.21, 94.66, 55.46, 54.72,
47.93, 40.38, 39.38, 27.16; EIMS m/z 382 (M+), 380, 261, 177,
122, 121, 91, 77, 57; HRMS calcd for C21H26N4O3 382.2005,
found 382.2013; Anal. Calcd. for C21H26N4O3: C, 65.95; H, 6.85;
N, 14.65. Found: C, 65.46; H, 6.44; N, 14.09.
2-Am in o-4-oxo-5-vin yl-7-(3′,4′-dim eth oxyben zyl)-3,4,5,6-
tetr a h yd r op yr r olo[2,3-d ]p yr im id in e (7d ). Isolated in 68%
yield as a white solid, mp 214 °C (decomp): IR (KBr) 3404,
3314, 3086, 2837, 1663, 1619, 1544, 1516, 1448, 1384, 1358,
Dieth yl N-{4-[2-(2-Am in o-3,4-d ih yd r o-4-oxo-7-(4′-m eth -
oxyben zyl)p yr r olo-2,3-d ]p yr im id in -5-yl)eth yl]ben zoyl}-
L-glu ta m a te (9c). From 2-amino-4-oxo-5-vinyl-7-(4′-methoxy-
benzyl)-3,4,5,6-tetrahydropyrrolo[2,3-d]pyrimidine (7c); prod-
uct isolated in 61% yield as a light pink solid, mp 220-222
°C: IR (KBr) 3470, 3329, 2981,2935, 1734, 1670, 1636, 1539,
1318, 1257, 1234, 1153, 1139, 1029, 911, 770, 659 cm-1 1H
;
NMR (DMSO-d6) δ 9.72 (1 H, s), 6.91 (1 H, d, J ) 8.5 Hz),
6.82 (1 H, d, J ) 1.0 Hz), 6.47 (1 H, d, J ) 8.5 Hz), 6.64 (2 H,
br s), 5.79 (1 H, ddd, J ) 17.5, 10.0 and 6.5 Hz), 4.97 (1 H, d,
J ) 17.5 Hz), 4.90 (1 H, d, J ) 10.0 Hz), 4.33 (2 H, AB, J )
32.5 Hz)), 3.72 (3 H, s), 3.70 (3 H, s), 3.57 (1 H, dt, J ) 9.5 and
6.0 Hz), 3.41 (1 H, t, J ) 10.0 Hz), 3.03 (1 H, dd, J ) 9.5 and
5.0 Hz); 13C NMR (DMSO-d6) δ 167.33, 158.66, 157.14, 148.69,
147.86, 139.95, 129.93, 119.69, 113.23, 111.76, 111.45, 87.66,
55.46, 55.37, 53.94, 47.26, 38.59; EIMS m/z 328 (M+), 313, 299,
275, 256, 241, 227, 213, 191, 177, 163, 151, 135, 121, 107, 91,
78, 69; HRMS calcd for C17H20N4O3 328.1535, found 328.1534.
Dieth yl N-{4-[2-(2-Am in o-3,4-d ih yd r o-4-oxo-7-(r-m eth -
ylben zyl)p yr r olo-[2,3-d ]p yr im id in -5-yl)eth yl]ben zoyl}-L-
glu ta m a te (9a ). To a well-degassed mixture of Pd(OAc)2 (22.4
mg, 0.1 mmol), CuI (19 mg, 0.1 mmol), and (o-toyl)3P (66 mg,
0.22 mmol) in 40 mL of dry DMF were added 1.1 g (1.5 mL,
11 mmol) of triethylamine and a degassed solution of 2-amino-
4-oxo-5-vinyl-7-(R-methylbenzyl)-3,4,5,6-tetrahydro-pyrrolo-
[2,3-d]pyrimidine (7a ) (200 mg, 0.71 mmol) in 10 mL of dry
1
1514, 1457, 1249, 1179, 1099, 1031, 785, 759 cm-1; H NMR
(DMSO-d6) δ 10.24 (1 H, s), 8.62 (1 H, d, J ) 7.5 Hz), 7.77 (2
H, d, J ) 8.0 Hz), 7.26 (2 H, d, J ) 8.5 Hz), 7.02 (2 H, d, J )
8.5 Hz), 6.85 (2 H, d, J ) 8.5 Hz), 6.37 (1 H, s), 6.18 (2 H, s),
4.96 (2 H, s), 4.44-4.40 (1 H, m), 4.10 (2 H, q, J ) 7.0 Hz),
4.04 (2 H, q, J ) 7.0 Hz), 3.70 (3 H, s), 2.97 (2 H, t, J ) 7.5
Hz), 2.84 (2 H, t, J ) 8.0 Hz), 2.41 (2 H, t, J ) 15 Hz), 2.14-
2.07 (1 H, m), 2.03-1.96 (1 H, m), 1.80 (3 H, t, J ) 7.0 Hz),
1.16 (3 H, t, J ) 7.0 Hz); 13C NMR (DMSO-d6) δ 172.18, 171.80,
166.58, 159.08, 158.40, 152.42, 150.33, 146.10, 131.02, 130.31,
128.27, 128.21, 127.35, 117.44, 116.96, 113.82, 98.65, 60.51,
59.90, 55.02, 51.95, 46.07, 35.93, 30.16, 27.88, 25.70, 14.05 (two
carbons); EIMS m/z 603 (M+), 303, 283, 225, 145, 121, 84, 63;
HRMS calcd for C32H37N5O7 603.2693, found 603.2717. Anal.
Calcd for C32H37N5O7: C, 63.57; H, 6.18; N, 11.60. Found: C,
63.53; H, 6.30; N, 11.40.

Substituted Derivatives of LY231514 (MTA)
J . Org. Chem., Vol. 66, No. 11, 2001 3737
Dieth yl
N-{4-[2-(2-Am in o-3,4-d ih yd r o-4-oxo-7-(3′,4′-
(1 mL) was added 1 mL of 1.0 N aqueous NaOH solution. The
resulting solution was stirred at room temperature for 3 h.
The THF was evaporated under reduced pressure, and the
residual solution was acidified with acetic acid. The resulting
light yellow precipitate was collected by filtration, washed
successively with water, hexane, and diethyl ether, and dried
under vacuum to give 65 mg (62%) of 10a as a light yellow
solid, mp 164-168 °C: IR (KBr) 3342, 3204, 2973, 1637, 1526,
1434, 1210, 1177, 1091, 782, 742, 697 cm-1; 1H NMR (DMSO-
d6) δ 12.52 (2 H, br s), 10.24 (1 H, s), 8.47 (1 H, d, J ) 6.0 Hz),
7.79 (2 H, d, J ) 7.5 Hz), 7.28-7.22 (5 H, m), 7.05 (2 H, d, J
) 7.0 Hz), 6.52 (1 H, s), 6.14 (2 H, br s), 5.68 (1 H, q, J ) 6.5
Hz), 4.40 (1 H, q, J ) 6.5 Hz), 3.02-2.84 (4 H, m), 2.36 (2 H,
m), 2.08 (1 H, m), 1.97 (1 H, m), 1.68 (3 H, d, J ) 6.5 Hz); MS
m/z 532 (MH+), 459, 385, 320, 301, 300, 154, 153, 152, 135,
119; FABMS calcd for C28H30N5O6 (MH+) 532.2196, found
(MH+) 532.2203.
d im et h oxyb en zyl)-p yr r olo[2,3-d ]p yr im id in -5-yl)et h yl]-
ben zoyl}-L-glu ta m a te (9d ). Isolated on column chromatog-
raphy (silica gel, EtOAc/MeOH 8:2) in 65% yield as a light
yellow solid, mp 203-205 °C: IR (KBr) 3345, 2935, 1735, 1668,
1629, 1596, 1516, 1452, 1419, 1378, 1261, 1237, 1188, 1156,
1097, 1026, 855, 785, 766, 687 cm-1; 1H NMR (CDCl3) δ 11.41
(1 H, s), 7.71 (2 H, d, J ) 8.0 Hz), 7.22 (2 H, d, J ) 8.0 Hz),
7.18 (1 H, d, J ) 7.5 Hz), 6.80 (1 H, d, J ) 8.0 Hz), 6.73 (1 H,
d, J ) 1.5 Hz), 6.65 (1 H, dd, J ) 8.0 and 1.5 Hz), 6.18 (1 H,
s), 5.41 (2 H, br s), 5.00 (2 H, s), 4.78 (1 H, q, J ) 5.5 Hz), 4.22
(2 H, q, J ) 7.5 Hz), 4.11 (2 H, q, J ) 7.0 Hz), 3.85 (3 H, s),
3.80 (3 H, s), 3.01 (2 H, m), 2.99 (2 H, m), 2.55-2.41 (2 H, m),
2.35-2.28 (1 H, m), 2.19-2.12 (1 H, m), 1.30 (3 H, t, J ) 7.0
Hz), 1.21 (3 H, t, J ) 7.0 Hz); 13C NMR (CDCl3) δ 173.37,
172.37, 167.43, 161.40, 152.01, 151.41, 149.20, 148.67, 146.75,
131.20, 130.06, 128.83, 127.23, 119.95, 118.66, 117.85, 111.37,
110.99, 99.59, 61.85, 60.94, 56.04 (two carbons), 52.54, 47.50,
36.73, 30.68, 28.25, 27.32, 14.27, 14.25; EIMS m/z 633 (M+),
615, 588, 566, 504, 476, 459, 418, 364, 341, 313, 191, 151, 122,
107, 90, 84, 78; HRMS calcd for C33H39N5O8 633.2798, found
633.2766.
N-{4-[2-(2-Am in o-3,4-d ih yr o-4-oxo-7-ben zylp yr r olo[2,3-
d ]p yr im id in -5-yl)eth yl]ben zoyl}-L-glu ta m ic Acid (10b).
From 89 mg of diethyl N-{4-[2-(2-amino-3,4-dihydro-4-oxo-7-
ben zylp yr r olo[2,3-d ]p yr im id in -5-yl)et h yl]ben zoyl}-L -
glutamate (9b), compound 10b was obtained in 88% yield as
a off-white solid, mp 196-198 °C: IR (KBr) 3424, 3317, 3192,
2936, 1694, 1631, 1519, 1494, 1457, 1339, 1257, 1207, 1095,
Dieth yl N-{4-[2-(2-P iva loyla m in o-3,4-d ih yd r o-4-oxo-7-
(4′-m eth oxyben zyl)-p yr r olo[2,3-d ]p yr im id in -5-yl)eth yl]-
ben zoyl}-L-glu ta m a te (16). Isolated in 71% yield as a
colorless oil: IR (neat) 3227, 2976, 2929, 1729, 1659, 1606,
1
776, 732, 695 cm-1; H NMR (DMSO-d6) δ 12.43 (2 H, br, s),
10.26 (1 H, s), 8.48 (1 H, d, J ) 8.0 Hz), 7.78 (2 H, d, J ) 8.0
Hz), 7.30-7.21 (5 H, m), 7.02 (2 H, d, J ) 7.5 Hz), 6.38 (1 H,
s), 6.18 (2 H, br s), 5.05 (2 H, s), 4.39 (1 H, q, J ) 8.5 Hz), 2.99
(2 H, t, J ) 7.5 Hz), 2.86 (2 H, t, J ) 7.5 Hz), 2.35 (2 H, t, J
) 7.5 Hz), 2.12-2.05 (1 H, m), 1.99-1.91 (1 H, m); 13C NMR
(DMSO-d6) δ 173.93, 173.52, 166.39, 159.11, 152.46, 150.51,
145.93, 138.45, 131.28, 128.44, 128.24, 127.31, 127.09, 126.71,
117.49, 117.27, 98.69, 51.92, 46.59, 35.88, 30.48, 27.87, 26.02;
EIMS m/z 518 (MH+), 459, 371, 339, 321, 308, 1554, 12, 135,
119; FABMS calcd for C27H28N5O6 (MH+) 518.2040, found
(MH+) 518.2046. Anal. Calcd for C27H27N5O6‚HOAc: C, 60.31;
H, 5.41; N, 12.12. Found: C, 60.63; H, 5.34; N, 12.36.
1537, 1447, 1240, 1170, 1094, 1024, 913, 785, 727 cm-1 1H
;
NMR (CDCl3) δ 11.65 (1 H, s), 7.96 (1 H, s), 7.66 (2 H, d, J )
8.0 Hz), 7.21 (2 H, d, J ) 8.5 Hz), 6.99 (2 H, d, J ) 8.5 Hz),
6.92 (1 H, d, J ) 7.5 Hz), 6.84 (2 H, d, J ) 8.5 Hz), 6.25 (1 H,
s), 5.03 (2 H, s), 4.78 (1 H, q, J ) 4.5 Hz), 4.26-4.21 (2 H, m),
4.14-4.06 (2 H, m), 3.78 (3 H, s), 2.53-2.47 (2 H, m), 2.44-
2.38 (2 H, m), 2.34-2.27 (2 H, m), 2.17-2.09 (2 H, m), 1.34 (9
H, s), 1.29 (3 H, t, J ) 7.0 Hz), 1.21 (3 H, t, J ) 7.0 Hz); 13C
NMR (CDCl3) δ 179.48, 173.42, 172.26, 167.31, 159.39, 158.14,
147.32, 146.85, 145.92, 131.16, 129.38, 129.15, 128.60, 127.12,
119.88, 119.59, 114.34, 103.72, 61.88, 60.99, 55.51, 52.49,
47.41, 40.33, 36.77, 30.70, 28.09, 27.57, 27.34, 14.37, 14.34;
EIMS m/z 687(M+), 485, 367, 207, 121, 84; HRMS calcd for
N-{4-[2-(2-Am in o-3,4-d ih yd r o-4-oxo-7-(4′-m eth oxyben -
zyl)pyr r olo[2,3-d]pyr im idin -5-yl)eth yl]ben zoyl}-L-glu tam -
ic Acid (10c). From 86 mg of diethyl N-{4-[2-(2-amino-3,4-
dihydro-4-oxo-7-(4′-methoxybenzyl)pyrrolo[2,3-d]pyrimidin-5-
yl)ethyl]benzoyl}-L-glutamate (9c), compound 10c was isolated
in 85% yield as a light yellow solid, mp 198-200 °C: IR (KBr)
3421, 3329, 2930, 1692, 1634, 1516, 14551, 1339, 1241, 1169,
C
C
37H45N5O8 687.2368, found 687.2366. Anal. Calcd for
37H45N5O8: C, 64.61; H, 6.59; N, 10.18. Found: C, 64.62; H,
6.48; N, 9.93.
Dieth yl N-{4-[2-(2-Am in o-4-oxo-3,4,5,6-tetr a h yd r o-7H-
p y r r o l o [ 2 ,3 -d ] p y r i m i d i n -5 -y l ) e t h y l ] b e n z o y l }-L -
glu ta m a te (14). A mixture of 230 mg (0.392 mmol) of diethyl
N-{4-[2-(2-amino-3,4-dihydro-4-oxo-7-(R-methylbenzyl)pyrrolo-
[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamate (9a ) and 200
mg of 10% Pd/C in 20 mL of methanol (or ethanol) was
hydrogenated under 55 psi. The reaction was monitored by
TLC. At room temperature, no reaction occurred after 24 h.
At 50 °C, after 24 h, new spots appeared, and the mixture was
continually hydrogenated for 3 days. The mixture was passed
through a Celite filter, concentrated, and then dried under
vacuum. The proton NMR spectrum of the crude mixture
showed considerable starting material. The residue was puri-
fied by column chromatography (silica gel, EtOAc/MeOH 9:1)
to give 11 mg (6% yield) of 14 as a white solid. Proton and
carbon NMR spectra are consistent with the reported data:16
1H NMR (DMSO-d6) δ 9.76 (1 H, s), 8.64 (1 H, d, J ) 5.5 Hz),
7.78 (2 H, d, J ) 7.5 Hz), 7.31 (2 H, d, J ) 7.5 Hz), 6.32 (1 H,
s), 6.28 (2 H, br s), 4.43 (1 H, m), 4.12 (2 H, q, J ) 7.0 Hz),
4.06 (2 H, q, J ) 7.0 Hz), 3.49 (1 H, m), 3.02 (2 H, m), 2.68 (2
H, t, J ) 6.5 Hz), 2.36 (2 H, t, J ) 7.5 Hz), 2.1-2.0 (3 H, m),
1.62 (1 H, m), 1.21 (3 H, t, J ) 7.0 Hz), 1.18 (3 H, t, J ) 7.0
Hz); 13C NMR (DMSO-d6) δ 172.70, 172.32, 170.04, 167.12,
159.53, 157.24, 146.99, 131.58, 128.71, 127.99, 89.32, 61.03,
60.42, 52.46, 49.75, 37.51, 36.43, 33.06, 30.68, 26.21, 14.56 (two
carbons).
1
1104, 1032, 782 cm-1; H NMR (DMSO-d6) δ 12.43 (2 H, s),
10.26 (1 H, s), 8.48 (1 H, d, J ) 7.5 Hz), 7.78 (2 H, d, J ) 7.5
Hz), 7.27 (2 H, d, J ) 8.0 Hz), 7.04 (2 H, d, J ) 8.5 Hz), 6.86
(2 H, d, J ) 8.5 Hz), 6.38 (1 H, s), 6.19 (2 H, br s), 4.97 (2 H,
s), 4.40 (1 H, m), 3.71 (3 H, s), 2.98 (2 H, t, J ) 8.0 Hz), 2.85
(2 H, t, J ) 8.0 Hz), 2.36 (2 H, t, J ) 7.5 Hz), 2.12-2.06 (1 H,
m), 1.99-1.92 (1 H, m); 13C NMR (DMSO-d6) δ 173.92, 173.49,
166.44, 159.10, 158.44, 152.41, 150.35, 145.97, 131.31, 130.33,
128.32, 128.21, 127.34, 118.95, 117.50, 116.99, 113.85, 55.05,
51.93, 46.09, 35.95, 30.48, 27.91, 26.00; MS m/z 548(MH+), 459,
428, 391, 339, 322, 321, 308, 154, 153, 135, 119; FABMS calcd
for C28H30N5O7 (MH+) 548.2152, found (MH+) 548.2138. Anal.
Calcd for C28H29N5O7: C, 61.42; H, 5.34; N, 12.79. Found: C,
61.31; H, 5.34; N, 12.59.
N-{4-[2-(2-Am in o-3,4-d ih yd r o-4-oxo-7-(3′,4′-d im eth oxy-
b en zyl)-p yr r olo[2,3-d ]p yr im id in -5-yl)et h yl]b en zoyl}-L-
glu ta m ic Acid (10d ). Isolated in 88% yield as a light yellow
solid: IR (KBr) 3355, 3215, 2935, 1636, 1517, 1451, 1420, 1339,
1262, 1237, 1141, 1024, 785, 763 cm-1; 1H NMR (DMSO-d6) δ
12.55 (2 H, br s), 10.24 (1 H, s), 8.46 (2 H, d, J ) 7.0 Hz), 7.89
(2 H, d, J ) 8.0 Hz), 7.26 (2 H, d, J ) 8.0 Hz), 6.89 (1 H, s),
6.83 (1 H, d, J ) 8.0 Hz), 6.51 (1 H, d, J ) 8.0 Hz), 6.39 (1 H,
s), 6.19 (2 H, s), 4.96 (2 H, s), 4.37 (1 H, q, J ) 3.5 Hz), 3.69 (6
H, s), 2.95(2 H, t, J ) 6.0 Hz), 2.86 (2 H, t, J ) 6.0 Hz), 2.10-
2.00 (1 H, m), 2.00-1.85 (1 H, m); 13C NMR (DMSO-d6) δ
173.95, 173.50, 166.39, 159.11, 152.41, 150.39, 148.61, 148.01,
145.98, 131.34, 130.71, 128.19, 127.33, 119.21, 117.48, 117.02,
111.81, 111.31, 98.67, 55.51, 55.45, 51.98, 46.47, 35.99, 30.55,
27.88, 26.07; EIMS m/z 578 (MH+), 562, 546, 528, 514, 504,
N-{4-[2-(2-Am in o-3,4-dih ydr o-4-oxo-7-(r-m eth ylben zyl)-
p yr r olo[2,3-d ]p yr im id in -5-yl)eth yl]ben zoyl}-L-glu ta m ic
Acid (10a ). The following procedure is representative for the
preparation of the glutamic acids described herein. To a
solution of 109 mg of diethyl N-{4-[2-(2-amino-3,4-dihydro-4-
oxo-7-(R-methylbenzyl)pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]ben-
zoyl}-L-glutamate (9a ) in a mixture of THF (2 mL) and H2O

3738 J . Org. Chem., Vol. 66, No. 11, 2001
Taylor and Liu
488, 476, 462, 446, 379, 313, 281, 215, 151, 135, 107, 86;
FABHRMS calcd for
578.2267.
solid: 1H NMR (DMSO-d6) δ 10.62 (1 H, s), 10.14 (1 H, s), 8.62
(1 H, d, J ) 7.0 Hz), 7.77 (2 H, d, J ) 8.0 Hz), 7.29 (2 H, d, J
) 8.0 Hz), 6.31 (1 H, s), 5.99 (2 H, br s), 4.43 (1 H, q, J ) 7.5
Hz), 4.11 (2 H, q, J ) 7.0 Hz), 4.06 (2 H, q, J ) 7.0 Hz), 2.98
(2 H, t, J ) 8.5 Hz), 2.85 (2 H, t, J ) 8.5 Hz), 2.42 (2 H, t, J
) 7.5 Hz), 2.13-2.05 (1 H, m), 2.03-1.95 (1 H, m), 1.18 (3 H,
t, J ) 7.0 Hz), 1.16 (3 H, t, J ) 7.0 Hz).27
C
29H32N5O8 (MH+) 578.2251, found
Dieth yl N-{4-[2-(2-Am in o-3,4-dih ydr o-4-oxo-7H-pyr r olo-
[2,3-d ]p yr im id in -5-yl)eth yl]ben zoyl}-L-glu ta m a te (9, R )
H). To a mixture of 40 mg (0.065 mmol) of diethyl N-{4-[2-(2-
amino-3,4-dihydro-4-oxo-7-(3′,4′-dimethoxybenzyl)pyrrolo[2,3-
d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamate in 0.3 mL of dry
trifluororacetic acid were added 0.05 mL of dry anisole and
0.6 mL of concentrated sulfuric acid. The resulting mixture
was stirred at room temperature for 4 h. Methylene chloride
(4 mL) was added, and the mixture was washed with water (4
× 1 mL) and dried over Na2SO4. Solvent was evaporated, and
the solid was washed with diethyl ether (2 × 0.5 mL) and ethyl
acetate (2 × 0.5 mL) and dried under reduced pressure. The
residue was purified by a TLC plate (silica gel, CH2Cl2/MeOH
9:1) to afford 9.0 mg (29.5% yield) of product as an off-white
Ack n ow led gm en t. We are indebted to Eli Lilly &
Company both for financial support of this work and
for the in vitro cell growth inhibition studies. We thank
Professor J effrey Schwartz of Princeton University for
stimulating discussions regarding the double bond rear-
rangement observed during the Heck reaction.
J O001580L