Synthesis of unnatural amino acids from serine derivatives by β-fragmentation of primary alkoxyl radicals

Article abstract of DOI:10.1021/jo071155t

(Chemical Equation Presented) The fragmentation of primary alkoxyl radicals has been scarcely used in synthesis since other competing processes (such as oxidation or hydrogen abstraction) usually predominate. However, when serine derivatives were used as

Full text of DOI:10.1021/jo071155t

Synthesis of Unnatural Amino Acids from Serine Derivatives by
â-Fragmentation of Primary Alkoxyl Radicals
Alicia Boto,* Juan A. Gallardo, Da´cil Herna´ndez, and Rosendo Herna´ndez*
Instituto de Productos Naturales y Agrobiolog´ıa del CSIC, AVda. Astrof´ısico Francisco Sa´nchez 3,
38206-La Laguna, Tenerife, Spain
alicia@ipna.csic.es; rhernandez@ipna.csic.es
ReceiVed May 31, 2007
The fragmentation of primary alkoxyl radicals has been scarcely used in synthesis since other competing
processes (such as oxidation or hydrogen abstraction) usually predominate. However, when serine
derivatives were used as substrates, the scission took place in excellent yields. Tandem scission-allylation,
-alkylation, or -arylation reactions were subsequently developed. This one-pot methodology was applied
to the synthesis of unnatural amino acids, which are useful synthetic blocks or amino acid surrogates in
peptidomimetics.
Introduction
â-lactam antibiotics,5 glutamate antagonists,6 and other drugs.7
Besides, these amino acids have been incorporated into peptides8
to modulate their activity and to improve their hydrolytic
stability or bioavailability. Moreover, recent advances have
allowed incorporation of unnatural amino acids into proteins,
using cellular machinery, providing new tools to study protein
function and to create peptides and proteins with enhanced
properties.9
As a result, the methods to prepare these amino acids have
deserved much interest.10 The best known among them is the
Strecker reaction,11 because of its simplicity and the availability
of the starting aldehydes and amines. However, it requires toxic
cyanide reagents, so safer alternatives have been explored.
A competitive route should use readily available substrates
and proceed in few (ideally one) steps. We reasoned that the
fragmentation of O-radicals derived from serine derivatives
Nonproteinogenic amino acids are important building blocks
in the synthesis of alkaloids, peptides, and other biologically
active products.1 Thus, they have been used to prepare alkaloids
such as the antiviral castanospermine2 and the cytotoxic
dragmacidins.3 They are also components of glycopeptide4 and
(1) For reviews on the synthetic and therapeutic use of nonprotein-
ogenic amino acids, see: (a) Bridges, R. J.; Esselinger, C. S. Pharmacol.
Ther. 2005, 107, 271-285. (b) Van Bambeke, F. Curr. Opin. Pharmacol.
2004, 4, 471-478. (c) Johansen, T. N.; Greenwood, J. R.; Frydenvang, K.;
Madsen, U.; Krogsgaard-Larsen, P. Chirality 2003, 15, 167-179. (d) Beck,
G. Synlett 2002, 837-850. (e) Na´jera, C. Synlett 2002, 1388-1403. (f)
Sardina, F. J.; Rapoport, H. Chem. ReV. 1996, 96, 1825-1872.
(2) Bhide, R.; Mortezaei, R.; Scilimati, A.; Sih, C. J. Tetrahedron Lett.
1990, 31, 4827-4830.
(3) Kawasaki, T.; Enoki, H.; Matsumura, K.; Ohyama, M.; Inagawa, M.;
Sakamoto, M. Org. Lett. 2000, 2, 3027-3029.
(4) (a) For reviews, see: Pace, J. L.; Yang, G. Biochem. Pharmacol.
2006, 71, 968-980. (b) Walker, S.; Chen, L.; Hu, Y.; Rew, Y.; Shin, D.;
Boger, D. L. Chem. ReV. 2005, 105, 449-475. (c) Welzel, P. Chem. ReV.
2005, 105, 4610-4660. (d) Kahne, D.; Leimkuhler, C.; Lu, W.; Walsh, C.
Chem. ReV. 2005, 105, 425-448.
(5) (a) Mor´ın, R. B.; Gorman, M. Chemistry and Biology of â-Lactam
Antibiotics, Vols. 1-3; Academic: New York, 1982. (b) Townsend, C.
A.; Brown, A. M. J. Am. Chem. Soc. 1983, 105, 913-918.
(6) Moloney, M. G. Nat. Prod. Rep. 1999, 16, 485-498.
10.1021/jo071155t CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/15/2007
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J. Org. Chem. 2007, 72, 7260-7269

Amino Acids by Radical Fragmentation
SCHEME 1. Synthetic Strategy toward Nonproteinogenic
Amino Acids, Based on the Fragmentation of Primary
Alkoxyl Radicals Derived from Serine Derivatives
SCHEME 2. Fragmentation of Primary Alkoxyl Radicals in
Serine Derivatives
commercial methyl ester 5 (Scheme 2) was transformed into
the scission substrate 6.16 The latter was treated with (diac-
etoxyiodo)benzene (DIB) and iodine, at 26 °C and under visible
light irradiation (sunlight or 80-W tungsten-filament lamp), to
generate an alkoxyl radical, which underwent â-fragmentation.
Plausibly, the resulting C-radical reacted with iodine, to give
the unstable R-iodoglycine 7.17 Extrusion of iodide formed the
glycine cationic intermediate 3a, which was trapped by acetate
ions from the reagent (DIB), to give the R-acetoxy glycine 8 in
excellent yield (94%).
When dry methanol was added after the fragmentation step,
the R-methoxy glycine 918 (Table 1, entry 1) was formed in
93% yield. No side reactions (such as oxidation of the alkoxyl
radical to a carbonyl group or hydrogen abstraction) were
observed.
A similar strategy was used to introduce other heteroatom
functions: the scission of substrate 6 was followed by addition
of sulfur or nitrogen nucleophiles. Dissapointingly, when
thiophenol was added (entry 2), only acetate 8 was isolated.
The same result was obtained when pure acetate 8 was treated
with thiophenol in dichloromethane. Finally, the desired R-phe-
nylthioglycine 1019 was formed by addition of BF3‚OEt2 to the
reaction mixture (entry 3; 81% global yield for the two-step
procedure and 37% yield for the one-step method). The
R-phenylthioglycines are phenylglycine bioisosteres and have
been incorporated to peptides with anti-HIV20 or antibiotic
activity.21
When thiophenol was replaced by nitrogen nucleophiles such
as 2-oxazolidinone or 4-phenylurazole (entries 4-7), similar
results were obtained. In the absence of a Lewis acid (entries 4
and 6), the acetate 8 was the only product isolated. However,
the addition of BF3‚OEt2 to the reaction mixture afforded the
oxazolidinone 11 (entry 5) and the urazole 12 (entry 7). The
could match these requirements (Scheme 1). Although primary
alkoxyl radicals 1 undergo oxidation or hydrogen abstraction12
rather than scission, in the case of serine derivatives the
fragmentation would be favored, since the resulting C-radical
2 would be stabilized by the adjacent nitrogen function.13 Under
appropriate conditions, these radicals would undergo oxidation
to acyliminium ions 3,14 which could be trapped by nucleo-
philes,15 affording a variety of nonproteinogenic amino acids
4. The feasibility of this approach is discussed herein.
Results and Discussion
Fragmentation of Serine Derivatives. To explore the
â-fragmentation of primary O-radicals derived from serine, the
(7) (a) Chen, K. X.; Njoroge, F. G.; Arasappan, A.; Venkatraman, S.;
Vibulbhan, B.; Yang, W.; Parekh, T. N.; Pichardo, J.; Prongay, A.; Cheng,
K. C.; Butkiewicz, N.; Yao, N.; Madison, V.; Girijavallabhan, V. J. Med.
Chem. 2006, 49, 995-1005. (b) Sollis, S. L. J. Org. Chem. 2005, 70, 4735-
4740. (c) Stilz, H. U.; Guba, W.; Jablonka, B.; Just, M.; Klinger, O.; Ko¨nig,
W.; Wehner, V.; Zoller, G. J. Med. Chem. 2001, 44, 1158-1176.
(8) (a) For some reviews, see: Sewald, N.; Jakubke, H. D. Peptides:
Chemistry and Biology; Wiley-VCH: Weinheim, 2002. (b) Liskamp, R.
M. J. Angew. Chem., Int. Ed. Engl. 1994, 33, 305-307. (c) Gante, J. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1699-1720. (d) Giannis, A.; Kolter, T.
Angew. Chem., Int. Ed. Engl. 1993, 32, 1244-1267.
(9) Over 30 new amino acids have been genetically encoded, see: Wang,
L.; Schultz, P. G. Angew. Chem., Int. Ed. 2005, 44, 34-66.
(10) For some reviews, see: (a) Viso, A.; Ferna´ndez de la Pradilla, R.;
Garc´ıa, A.; Flores, A. Chem. ReV. 2005, 105, 3167-3196. (b) O’Donnell,
M. J. Acc. Chem. Res. 2004, 37, 506-517. (c) Erdik, E. Tetrahedron 2004,
60, 8747-8782. (d) Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem.
Res. 2003, 36, 10-19. (e) Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42, 4290-
4299. (f) Maruoka, K.; Ooi, T. Chem. ReV. 2003, 103, 3013-3028. (h)
Asymmetric Synthesis of Novel Sterically Constrained Amino Acids;
Symposium-in-Print, Hruby, V. J.; Soloshonok, V. A., Eds. Tetrahedron
2001, 57, 6329-6650 and references cited therein.
(11) Gro¨ger, H. Chem. ReV. 2003, 103, 2795-2827.
(12) (a) Cekovic, Z. Tetrahedron 2003, 59, 8073-8090. (b) Feray, L.;
Kuznetsov, N.; Renaud, P. In Radicals in Organic Synthesis; Renaud, P.;
Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2; pp 246-278 and
references cited therein.
(16) Easton, C. J.; Ivory, A. J.; Smith, C. A. J. Chem. Soc. Perkin Trans.
2 1997, 503-507.
(17) For the discussion on the reaction mechanism, see: Boto, A.;
Herna´ndez, R.; De Leo´n, Y.; Murgu´ıa, J. R.; Rodr´ıguez-Afonso, A. Eur. J.
Org. Chem. 2005, 673-682.
(18) (a) Ginzel, K. D.; Brungs, P.; Steckhan, E. Tetrahedron 1989, 45,
1691-1701. (b) Zoller, U.; Ben-Ishai, D. Tetrahedron 1975, 31, 863-866.
(19) Easton, C. J.; Peters, S. C. Aust. J. Chem. 1994, 47, 859-868.
(20) (a) Priem, G.; Rocheblave, L.; De Michelis, C.; Courcambeck, J.;
Kraus, J. L. J. Chem. Soc. Perkin Trans. 1 2000, 819-824. (b) Niddam,
V.; Camplo, M.; Le Nguyen, D.; Chermann, J. C.; Kraus, J. L. Bioorg.
Med. Chem. Lett. 1996, 6, 609-614.
(21) (a) Massie`re, F.; Badet-Denisot, M. A.; Rene´, L.; Badet, B. J. Am.
Chem. Soc. 1997, 119, 5748-5749. (b) Yaouancq, L.; Anissimova, M.;
Badet-Denisot, M. A.; Badet, B. Eur. J. Org. Chem. 2002, 3573-3579.
(13) For a preliminary communication of this work, see: Boto, A.;
Herna´ndez, R.; Montoya, A.; Sua´rez, E. Tetrahedron Lett. 2002, 43, 8269-
8272.
(14) (a) Boto, A.; Gallardo, J. A.; Herna´ndez, R.; Saavedra, C. J.
Tetrahedron Lett. 2005, 46, 7807-7811. (b) Boto, A.; De Leo´n, Y.;
Gallardo, J. A.; Herna´ndez, R. Eur. J. Org. Chem. 2005, 3461-3468. (c)
Boto, A.; Herna´ndez, R.; Montoya, A.; Sua´rez, E. Tetrahedron Lett. 2004,
45, 1559-1563. (d) Boto, A.; Herna´ndez, R.; Leo´n, Y.; Sua´rez, E. J. Org.
Chem. 2001, 65, 7796-7803. (e) Boto, A.; Herna´ndez, R.; Sua´rez, E. J.
Org. Chem. 2000, 64, 4930-4937.
(15) (a) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. ReV. 2004, 104, 1431-1628. (b) Speckamp, W.
N.; Hiemstra, H. In ComprehensiVe Organic Synthesis; Trost, B. M.;
Fleming, I. Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 1047-1082.
J. Org. Chem, Vol. 72, No. 19, 2007 7261

Boto et al.
TABLE 1. Scission and Addition of Oxygen, Sulfur, and Nitrogen Nucleophiles
a Yields for products purified by chromatography.
yields for the two-step procedure (70% and 27%, respectively)
were superior to those for the one-step method (43% and 14%).
The addition of nonaromatic carbon nucleophiles, such as
allylsilanes and enol ethers, was studied as well (Table 2). In
all cases, in the absence of the Lewis acid, only acetate 8 was
isolated (about 90% yield). When BF3‚OEt2 was added, products
13-19 were formed (entries 1-4). Using allylTMS as the
nucleophile (entry 1), the two-step process afforded the allyl
glycine 1322 in good yield (70%). However, the one-step method
initially gave complex product mixtures. The results improved
when the conversion of acetate intermediate 8 into the allyl
glycine 13 was not forced to completion. Thus, product 13 was
obtained (35%) together with acetate 8 (52%), which was later
transformed into the allylglycine.
dures gave similar yields. Thus, the tandem fragmentation-
allylation method with (chloromethyl)allylTMS gave the desired
allyl glycine 14 in 60% yield, while the two-step process
afforded compound 14 in 58% global yield. In both cases, trace
amounts of the proline derivative 15 were detected. The
conversion of compound 14 into product 15 by intramolecular
N-alkylation with NaH proceeded in quantitative yield. This
transformation exemplifies the utility of allyl glycines as
precursors of bioactive products, since racemic 4-methylene
proline (first isolated from the seeds of loquat) is a potent
enzyme inhibitor.23
The fragmentation-nucleophilic addition procedure is also
useful to obtain γ-oxo-R-amino acids (entries 3 and 4), which
are components of antibiotic, antiinflammatory, or antihyper-
tensive drugs.24 Thus, the tandem fragmentation-alkylation with
phenyl(trimethylsilyloxy)ethylene and BF3‚OEt2 (entry 3) af-
In contrast, when a more substituted allylsilane was used as
the nucleophile (entry 2), the two-step and the one-pot proce-
(22) (a) Easton, C. J.; Scharfbillig, I. M. J. Org. Chem. 1990, 55, 384-
386. (b) Tanaka, K.; Ahn, M.; Watanabe, Y.; Fuji, K. Tetrahedron:
Asymmetry 1996, 7, 1771-1782. (c) For related allyl glycines and their
therapeutic uses, see: Alco´n, M.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron: Asymmetry 1999, 10, 4639-4651. (d) Kazmaier, U.; Krebs,
A. Angew. Chem., Int. Ed. Engl. 1995, 34, 2012-2014 and references cited
therein.
(23) Panday, S. K.; Griffart-Brunet, D.; Langlois, N. Tetrahedron Lett.
1994, 35, 6673-6676.
(24) (a) D´ıez, D.; Garc´ıa, P.; Marcos, I. S.; Basabe, P.; Garrido, N. M.;
Broughton, H. B.; Urones, J. G. Tetrahedron 2005, 61, 11641-11648. (b)
Lygo, B.; Andrews, B. I. Tetrahedron Lett. 2003, 44, 4499-4502. (c)
Golubev, A. S.; Sewald, N.; Burger, K. Tetrahedron 1996, 52, 14757-
14776.
7262 J. Org. Chem., Vol. 72, No. 19, 2007

Amino Acids by Radical Fragmentation
forded the γ-oxo-homophenylalanine 1625 (30%), together with
the R-acetoxyglycine 8 (55%). In this case, the two-step
procedure gave better results, affording compound 16 in 67%
global yield.
To our satisfaction, although aromatic rings are poorer
nucleophiles than allylsilanes or enol silyl ethers, the scission-
arylation reaction provided different aryl glycines in moderate
to excellent yields. The arylation was favored by electron-
donating groups (EDG) on the aromatic ring. Thus, the reaction
yields increased from naphthyl glycine 2013,32 (63%, entry 1)
to the 2-methoxynaphthyl analogue 21 (95%, entry 2). Another
example is shown in entries 3 and 4. When phenyl acetate was
used as the nucleophile (entry 3), the desired phenyl glycine
was not isolated. However, when methoxy and (to a lesser
extent) alkyl groups were activating the ring (entry 4), the
arylation took place, affording products 22 and 23 in good global
yield. The p-methoxy derivative 22 predominated over the
o-methoxy product 23.
In most cases, the one-step process was similar to the two-
step procedure. An exception is biphenylglycine 24 (entry 5),
which was formed in low yield using the one-pot method, while
the two-step process gave moderate yields.
To study the directing effect of EDG, several aromatic
nucleophiles with ether, carbamate, and alkyl groups were
prepared (entries 6-11). The one-pot process afforded products
25-32 in good to excellent yields. When 2,3-dihydrobenzo-
[b][1,4]dioxine was used as the nucleophile (entry 6), benzo-
dioxolane 25 predominated over the more hindered analogue
26. In the case of the benzoxazolidinone nucleophile (entry 7),
the directing effect of the nitrogen function was superior to the
effect of the oxygen function, and only isomer 27 was formed.
In a similar way, product 28 (entry 8) was formed exclusively,
since the directing effect of the methoxy group predominated
over that of the alkyl group. It should be noted that amino acid
28 can be linked to other amino acids in modified peptides
through its side chain carboxylate group,33 inducing turns in
the peptidic chain.
If a bulky substituent is introduced ortho to the directing
group, the regioselectivity is improved (entries 9 and 10, the H
substituent is replaced by Br). Thus, when methyl 2-phenoxy-
acetate was used as the nucleophile (entry 9), a mixture of p-
and o-alkoxyphenylglycines 29 and 30 was formed. Using
methyl 3-bromo-2-phenoxyacetate (entry 10), the p-alkoxy
isomer 31 was formed exclusively; no ortho products were
detected. Similarly, when the nucleophile was 1-(allyloxy)-2-
iodobenzene (entry 11), only the p-allyloxyglycine 32 was
isolated (89%).
A variation of this reaction gave an unexpected result
(entry 4). The scission of substrate 6, followed by addition of
boron trifluoride and isopropenyl acetate, gave the methyl
ketone 17 as the minor product, and the azetidines 18 and 19
as the major products. The stereochemistry of â-lactamols 18
and 19 was determined by NOESY experiments26 and supported
by MMFF calculations.27 The reaction results can be explained
as shown in Table 2 (footnote b). The scission of the O-COMe
bond (route a) would generate a highly electrophilic [Me-CO]+
intermediate; therefore, the nucleophilic attack by the amide
function (route b) is preferred.
The â-lactamols 18 and 19 were hydrolyzed to the ketone
17 in excellent yield. However, azetidine carboxylic acids are
important on their own: these cyclic amino acids have been
incorporated into peptides to decrease their backbone flexibility
and to improve their bioactivity.28 In spite of their usefulness,
very few of these amino acids are commercially available and
are quite expensive. This route would provide a direct access
to these compounds,29 incorporating a variety of side-chains.
The N,O-acetal group would also allow to introduce new
functionalities. The synthesis of new azetidine carboxylic acids
is in progress and will be reported in due course.
Other nonproteinogenic amino acids with biological signifi-
cance are the aryl glycines, which are constituents of antibiotics
such as vancomycin4 and the nocardicins,5 antineurodegenerative
agents,6 and alkaloids.30 Therefore, the synthesis of new aryl
glycines has elicited much interest.31
The fragmentation of the serine derivative 6, followed by
treatment with boron trifluoride and different aromatic nucleo-
philes, is shown in Table 3. All the nucleophiles were com-
mercial products or were obtained therefrom. Most of the
unreacted reagent was recovered, being easily separated from
the desired products.
(25) For a very similar product, see: Werner, R. M.; Shokek, O.; Davis,
J. T. J. Org. Chem. 1997, 62, 8243-8246.
(26) In the NOESY experiment of compound 19, spatial correlations were
observed between δH 4.45 (1H, dd, 4-H) and δH 1.92 (3H, s, 2-Me). In the
NOESY experiment of compound 18, no correlations between δH 4.41 (1H,
dd, 4-H) and δH 1.96 (3H, s, 2-Me) were detected.
(27) (a) Theoretical coupling constants were calculated over the mini-
mized structures for both diastereomers, by using the Karplus-Altona
equation implemented in the Macromodel 7.0 program. The calculations
were performed with an MMFF force field, using high-quality parameters,
and repeated with an AMBER force field. Similar results were obtained in
both cases. (b) Theoretical J for the minimized structure corresponding to
diastereomer 18: J2,3 ) 5.2, 9.8 Hz (experimental: J2,3 ) 5.0, 12.6 Hz).
The minimized structure for diastereomer 19 showed J2,3 ) 3.9, 9.3 Hz
(experimental: J2,3 ) 3.7, 7.3 Hz). (c) For information on the Karplus-
Altona equation, see: Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona,
C. Tetrahedron 1980, 36, 2783-2792. (d) For more information on this
software, see: Mohamadi, F.; Richard, N. G. J.; Guida, W. C.; Liskamp,
R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrikson, T.; Stille, W. C. J.
Comput. Chem. 1990, 11, 440.
The preparation of halogenated aryl glycines such as com-
pounds 31 and 32 is quite interesting, since the halo substituent
can be replaced by aryl, vinyl, alkynyl, or alkyl groups using
sp2-sp2 coupling reactions.34 For instance, compound 32 (entry
11) underwent a Heck reaction affording the benzofuran glycine
33 in 71% yield. To our knowledge, it is the first time that a
5-methylene benzofuran glycine has been obtained. A variety
of alkyl chains could be introduced from differently substituted
allyl groups. These chains may belong to amino acid sequences
in peptidomimetics.
(28) For a review on the subject, see: Couty, F.; Evano, G.; Prim, D.
Mini-ReV. Org. Chem. 2004, 1, 133-148.
(32) Bretschneider, T.; Miltz, W.; Mu¨nster, P.; Steglich, W. Tetrahedron
1988, 44, 5403-5414.
(33) For related examples, see: Abbenante, G.; Bergman, D. A.;
Brinkworth, R. I.; March, D. R.; Reid, R. C.; Hunt, P. A.; James, I. W.;
Dancer, R. J.; Garnham, B.; Stoermer, M. L.; Fairlie, D. P. Bioorg. Med.
Chem. Lett. 1996, 6, 2531-2536.
(34) (a) Wang, W.; Zhang, J.; Xiong, C.; Hruby, V. J. Tetrahedron Lett.
2002, 43, 2137-2140. (b) Lutz, C.; Bleicher, K. H. Tetrahedron Lett. 2002,
43, 2211-2214. (c) Sammelson, R. E.; Kurth, M. J. Chem. ReV. 2001, 101,
137-202.
(29) (a) Only one example of the synthesis of 4-alkoxyazetidine
carboxylic acids has been reported: Akiyama, T.; Daidouji, K.; Fuchibe,
K. Org. Lett. 2003, 5, 3691-3693. (b) For the preparation of other azetidine
carboxylic acids, see: Morimoto, H.; Wiedemann, S. H.; Yamaguchi, A.;
Harada, S.; Chen, Z.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed.
2006, 45, 3146-3150 and references cited therein.
(30) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1-48.
(31) (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234-
245. (b) Williams, R. M.; Hendrix, J. A. Chem. ReV. 1992, 92, 889-917.
J. Org. Chem, Vol. 72, No. 19, 2007 7263

Boto et al.
TABLE 2. Addition of Nonaromatic Carbon Nucleophiles
The synthesis of heteroaryl glycines was studied as well. Two
representative examples are shown in entries 12 and 13. The
fragmentation of substrate 6, followed by arylation with furan,
gave the furyl glycine35 34 in good yield. The one-pot and the
two-step procedure gave similar results (80% versus 79%). The
scission-heteroarylation reaction was then tried with methyl
1-indolecarboxylate, affording the indole glycines 35 and 36,
which are tryptophan surrogates.36 In this case the two-step
procedure gave better results than the one-pot procedure, since
the indolic rings can be oxidized by the system DIB-iodine.
In summary, primary alkoxyl radicals derived from serine
(by treatment with (diacetoxyiodo)benzene and iodine) undergo
â-fragmentation in excellent yield. When no external nucleo-
philes are added, an R-acetoxy glycine is formed. However, the
fragmentation can be coupled with the addition of heteroatom
or carbon nucleophiles, providing uncommon amino acids such
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Amino Acids by Radical Fragmentation
TABLE 3. Synthesis of Aryl Glycines
a Yields for purified products.
as R-alkoxy, R-thiophenyl, R-amino, R-allyl, R-alkyl, and R-aryl
glycines. These amino acids can be used as synthetic intermedi-
ates for different bioactive compounds or as peptidomimetic
constituents.
Experimental Section
Methyl (Acetyloxy)(benzoylamino)acetate (8). The serine
derivative 616 (223 mg, 1 mmol) in dry dichloromethane (14 mL)
was treated with DIB (805 mg, 2.5 mmol) and iodine (254 mg, 1
J. Org. Chem, Vol. 72, No. 19, 2007 7265

Boto et al.
mmol). The mixture was stirred at room temperature (26 °C) under
visible light irradiation (sunlight or 80-W tungsten-filament lamp).
After 3 h, the solution was poured into aqueous 10% Na2S2O3 and
extracted with CH2Cl2. The residue was purified by chromatography
on silica gel (hexanes/EtOAc, 95:5), giving the acetate 8 (94%):
Crystalline solid; mp 87-88.5 °C (from EtOAc/n-hexane); IR 3441,
1754, 1682, 1513 cm-1; 1H NMR (500 MHz) δH 2.09 (3H, s), 3.79
(3H, s), 6.59 (1H, d, J ) 8.8 Hz), 7.42 (2H, dd, J ) 7.6, 7.9 Hz),
7.52 (1H, dd, J ) 7.4, 7.5 Hz), 7.75 (1H, d, J ) 8.8 Hz), 7.82 (2H,
d, J ) 7.3 Hz); 13C NMR (100.6 MHz) δC 20.4 (CH3), 53.1 (CH3),
72.5 (CH), 127.3 (2 × CH), 128.5 (2 × CH), 132.3 (CH + C),
166.8 (C), 167.2 (C), 170.2 (C); MS (EI) m/z (rel intensity) 251
(M+, <1), 192 (M+ - COOMe, 11), 105 (COPh, 100); HRMS
calcd for C12H13NO5, 251.0794; found, 251.0825; calcd for C7H5O,
105.0340; found, 105.0342. Anal. Calcd for C12H13NO5: C, 57.37;
H, 5.22; N, 5.58. Found: C, 57.14; H, 5.31; N, 5.53.
Methyl 2-Benzamido-2-methoxyacetate (9). The serine deriva-
tive 616 (223 mg, 1 mmol) in dry dichloromethane (14 mL) was
treated with DIB (805 mg, 2.5 mmol) and iodine (254 mg, 1 mmol).
The mixture was stirred at room temperature (26 °C) under visible
light irradiation. After 3 h, dry methanol (1 mL) was injected and
the solution was stirred for 1 h. Workup and purification as
previously described afforded compound 9 (207 mg, 93%).18
Standard Procedure for the Two-Step Decarboxylation-
Addition of Nucleophiles. The serine derivative 6 (223 mg, 1
mmol) underwent fragmentation to afford acetate 8 as previously
commented. Then compound 8 was dissolved in dry dichlo-
romethane and cooled to 0 °C, and BF3‚OEt2 (2 equiv) and an
excess of the nucleophile (5 equiv for compounds 10-19, 22-31,
and 35-36; 10 equiv. for compounds 20, 21, 32, and 34) were
added. The reaction was allowed to reach rt and stirred for 4 h.
Afterward, it was poured into aq NaHCO3 and extracted with CH2-
Cl2. The yields are given for products purified by chromatography
on silica gel.
Standard Procedure for the One-Pot Decarboxylation-
Addition of Nucleophiles Reaction. To a solution of methyl
N-benzoylserine 6 (223 mg, 1 mmol) in dry dichloromethane (14
mL) was added (diacetoxyiodo)benzene (805 mg, 2.5 mmol) and
iodine (254 mg, 1 mmol). The reaction was stirred at room
temperature (26 °C) and under visible light irradiation (sunlight or
80-W tungsten-filament lamp) for 2-3 h, till complete disappear-
ance of the starting material. Then the reaction mixture was cooled
to 0 °C with an ice bath and BF3‚OEt2 was added dropwise (2
mmol), followed by addition of an excess of the nucleophile (5 or
10 mmol). The reaction mixture was allowed to reach room
temperature and then was stirred for 4 h. Finally, it was poured
into 10% aqueous sodium thiosulfate containing sodium bicarbonate
and extracted with dichloromethane. The organic layers were dried
with sodium sulfate and filtered, and the solvent was removed under
vacuum. Then the residue was purified by column chromatography
on silica gel. The column was eluted with hexanes/ethyl acetate
mixtures to give the desired products in good to excellent yields
(see below).
as the nucleophile, afforded compound 10 (81%). The one-step
procedure also gave compound 10 (37%).19
Methyl 2-Benzamido-2-(2-oxooxazolidin-3-yl)acetate (11). The
two-step fragmentation-nucleophilic addition procedure, using
oxazolidin-2-one as the nucleophile, afforded compound 10 (70%).
The one-step procedure also gave compound 11 (43%). Colorless
oil; IR 3434, 3024, 1762, 1669 cm-1; 1H NMR (500 MHz) δH 3.83
(1H, ddd, J ) 7.1, 8.3, 8.8 Hz), 3.85 (3H, s), 4.01 (1H, ddd, J )
6.9, 8.5, 8.5 Hz), 4.36-4.43 (2H, m), 5.88 (1H, d, J ) 7.4 Hz),
7.45 (2H, dd, J ) 7.4, 7.9 Hz), 7.54 (1H, dd, J ) 7.4, 7.4 Hz),
7.77 (1H, br d, J ) 7.2 Hz), 7.85 (2H, d, J ) 8.0 Hz); 13C NMR
(125.7 MHz) δC 44.7 (CH2), 53.5 (CH3), 60.4 (CH), 63.1 (CH2),
127.3 (2 × CH), 128.7 (2 × CH), 132.4 (CH), 132.6 (C), 157.9
(C), 167.5 (2 × C); MS (FAB) m/z (rel intensity) 301 (M+ + Na,
12), 279 (M+ + H, 94), 192 (M+ + H - oxazolidin-2-one, 37),
158 (M+ - NHCOPh, 52), 105 (COPh, 100); HRMS m/z calcd for
C13H14N2O5Na, 301.0800; found, 301.0793; calcd for C7H5O,
105.0340; found, 105.0338. Anal. Calcd for C13H14N2O5: C, 56.11;
H, 5.07; N, 10.07. Found: C, 56.22; H, 5.34; N, 9.68.
Methyl 2-Benzamido-2-(3,5-dioxo-4-phenyl-1,2,4-triazolidin-
1-yl)acetate (12). The two-step fragmentation-nucleophilic addi-
tion procedure, using 4-phenylurazole as the nucleophile, afforded
the urazole glycine 12 (27%). The one-step procedure also gave
compound 12 (14%). White solid; mp 180-181 °C (from EtOAc/
n-hexane); IR 3433, 3306, 1749, 1720, 1656, 1601 cm-1; 1H NMR
(500 MHz) δH 3.88 (3H, s), 6.31 (1H, d, J ) 7.1 Hz), 7.37-7.50
(8H, m), 7.57 (1H, dd, J ) 7.4, 7.5 Hz), 7.70 (1H, br d, J ) 7.0
Hz), 7.84 (2H, d, J ) 7.2 Hz); 13C NMR (125.7 MHz) δC 54.0
(CH3), 63.0 (CH), 125.5 (2 × CH), 127.5 (2 × CH), 128.5 (CH),
128.8 (2 × CH), 129.2 (2 × CH), 130.8 (C), 132.0 (C), 132.8 (CH),
152.9 (C), 153.2 (C), 166.2 (C), 167.9 (C); MS m/z (rel intensity)
368 (M+, <1), 309 (M+ - COOCH3, <1), 249 (M+ + H -
NHCOPh, 5), 105 (COPh, 100), 77 (Ph, 49); HRMS m/z calcd for
C18H16N4O5, 368.1121; found, 368.1138; calcd for C7H5O, 105.0340;
found, 105.0339.
Methyl 2-Benzoylamino-4-pentenoate (13).22 The two-step
fragmentation-allylation procedure, using allyltrimethylsilane as
the nucleophile, afforded compound 13 (66%). The one-step
procedure gave compounds 13 (35%) and 8 (52%).
Methyl 2-Benzoylamino-4-(chloromethyl)-4-pentenoate (14).
The tandem scission-allylation procedure, using 2-(chloromethyl)-
allyltrimethylsilane as the nucleophile, afforded compound 14 (60%)
and trace amounts of the cyclic product 15 (0.6%). Compound 14:
crystalline solid; mp 64-66 °C (from EtOAc/n-hexane); IR (CHCl3)
3432, 1740, 1664, 1486, 1206 cm-1; 1H NMR (500 MHz) δΗ 2.65
(1H, dd, J ) 8.5, 14.6 Hz), 2.92 (1H, dd, J ) 5.1, 14.6 Hz), 3.78
(3H, s), 4.06 (1H, d, J ) 11.9 Hz), 4.16 (1H, d, J ) 11.9 Hz), 4.97
(1H, ddd, J ) 5.2, 8.1, 8.3 Hz), 5.08 (1H, s), 5.25 (1H, s), 6.71
(1H, br d, J ) 6.8 Hz), 7.42 (2H, dd, J ) 7.3, 7.9 Hz), 7.50 (1H,
dd, J ) 7.4, 7.4 Hz), 7.76 (2H, d, J ) 7.1 Hz); 13C NMR (125.7
MHz) δC 36.0 (CH2), 47.5 (CH2), 50.9 (CH), 52.6 (CH3), 118.6
(CH2), 127.0 (2 × CH), 128.6 (2 × CH), 131.8 (CH), 133.7 (C),
140.4 (C), 167.1 (C), 172.4 (C); MS m/z (rel intensity) 283/281
(M+, 3/1), 246 (M+ - Cl, 19), 105 (PhCO, 100), 77 (Ph, 24);
HRMS calcd for C14H1637ClNO3/C14H1635ClNO3, 283.0839/281.0819;
found, 283.0891/281.0815; calcd for C14H16NO3, 246.1130; found,
246.1126; calcd for C7H5O, 105.0340; found, 105.0347. Anal. Calcd
for C14H16ClNO3: C, 59.68; H, 5.72; N, 4.97. Found: C, 59.41;
H, 5.97, N, 4.95.
Methyl N-Benzoyl-4-methylenepyrrolidine-2-carboxylate (15).
To a solution of the amino acid 14 (60 mg, 0.21 mmol) in dry
DMF (5 mL) at 0 °C was added NaH (60% dispersion in mineral
oil, 12.6 mg, 0.32 mmol). The mixture was warmed to room
temperature (26 °C) and stirred for 14 h; then it was poured into
water and extracted with CH2Cl2. The organic layer was dried, and
the solvent was removed under vacuum. The residue was purified
by chromatography on silica gel (hexanes/EtOAc, 9:1), giving
pyrrolidine 15 (53 mg, 99%) as a colorless oil; two rotamers at 26
°C (3:1), one rotamer at 70 °C; IR (CHCl3) 3086, 1739, 1636, 1421
Methyl 2-Benzamido-2-(phenylthio)acetate (10). The two-step
fragmentation-nucleophilic addition procedure, using thiophenol
(35) (a) Drueckhammer, D. G.; Barbas, C. F., III; Nozaki, K.; Wong,
C.-H.; Wood, C. Y.; Ciufolini, M. A. J. Org. Chem. 1988, 53, 1607-1611.
(b) For related furan glycines in anticonvulsivant or sweetening compounds,
see: Kohn, H.; Sawhney, K. N.; LeGall, P.; Conley, J. D.; Robertson, D.
W.; Leander, J. D. J. Med. Chem. 1990, 33, 919-926. (c) Janusz, J. M.;
Young, P. A.; Blum, R. B.; Riley, C. M. J. Med. Chem. 1990, 33, 1676-
1682.
(36) (a) For the use of indolyl glycines as synthetic intermediates
(dragmacidins and dihydrohamacanthin A synthesis), see: Kawasaki, T.;
Ohno, K.; Enoki, H.; Umemoto, Y.; Sakamoto, M. Tetrahedron Lett. 2002,
43, 4245-4248. (b) For other related compounds, see: Zhao, J. L.; Liu,
L.; Zhang, H. B.; Wu, Y. C.; Wang, D.; Chen, Y. J. Synlett 2006, 96-100
and references cited therein.
7266 J. Org. Chem., Vol. 72, No. 19, 2007

Amino Acids by Radical Fragmentation
1
cm-1; H NMR (500 MHz, 70 °C) δΗ 2.70 (1H, d, J ) 15.9 Hz),
127.8 (2 × CH), 128.1 (2 × CH), 131.2 (CH), 132.6 (C), 154.1
(C), 168.4 (C), 172.0 (C); MS m/z (rel intensity) 291 (M+, 4), 232
(M+ - CO2Me, 45), 105 (PhCO, 100), 77 (Ph, 57); HRMS calcd
for C15H17NO5, 291.1107; found, 291.1096; calcd for C7H5O,
105.0340; found, 105.0338. Anal. Calcd for C15H17NO5: C, 61.85;
H, 5.88; N, 4.81. Found: C, 61.95; H, 6.05, N, 4.95.
Hydrolysis of Lactamols 18 and 19. To a solution of azetidine
18 (40 mg, 0.14 mmol) in dry methanol (4 mL) at 0 °C was added
MeONa (15 mg, 0.28 mmol), and the mixture was allowed to reach
room temperature and stirred for 30 min. Then the acid resin IR-
120 was added until pH ) 7, and the reaction mixture was filtered
and evaporated under vacuum, giving pure ketone 17 (34 mg, 99%).
The reaction was repeated with azetidine 19, affording ketone 17
(97%).
2.97 (1H, dd, J ) 11.5, 15.7 Hz), 3.71 (3H, s), 4.15 (1H, br b),
4.23 (1H, d, J ) 13.3 Hz), 4.85 (1H, br b), 4.97 (1H, br s), 5.01
(1H, br s), 7.35-7.42 (3H, m), 7.48 (2H, br d, J ) 6.2 Hz); 13C
(125.7 MHz, 70 °C) δC 36.0 (CH2), 52.1 (CH3), 52.8 (CH2), 59.4
(CH), 108.1 (CH2), 127.0 (2 × CH), 128.4 (2 × CH), 130.1 (CH),
136.6 (C), 142.9 (C), 170.1 (C), 172.0 (C); MS m/z (rel intensity)
245 (M+, 3), 186 (M+ - CO2Me, 28), 140 (M+ - PhCO, 28), 105
(PhCO, 100), 77 (Ph, 42); HRMS calcd for C14H15NO3, 245.1052;
found, 245.1042; calcd for C7H5O, 105.0340; found, 105.0342.
Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found:
C, 68.54; H, 6.38, N, 5.84.
Methyl 2-Benzoylamino-4-oxo-4-phenylbutanoate (16). The
two-step fragmentation-alkylation procedure, using 1-phenyl-1-
(trimethylsilyloxy)ethene as the nucleophile, afforded compound
16 (63%). The one-step procedure gave compounds 16 (30%) and
8 (55%). Compound 16: syrup; IR 3443, 1744, 1661, 1599, 1515,
Methyl 2-Benzoylamino-2-(1-naphthyl)acetate (20). The one-
step fragmentation-alkylation procedure, using naphthalene as the
nucleophile, afforded compound 20 (63%).13,32
1486 cm-1; H NMR (500 MHz) δH 3.72 (1H, dd, J ) 4.1, 18.3
1
Methyl 2-Benzoylamino-2-(2-methoxy-1-naphthyl)acetate (21).
The one-step fragmentation-arylation procedure, using 2-methox-
ynaphthalene as the nucleophile, afforded compound 21 (95%):
syrup; IR 3450, 1748, 1661, 1599, 1514, 1485, 1271 cm-1; 1H NMR
(500 MHz) δH 3.70 (3H, s), 3.99 (3H, s), 6.89 (1H, d, J ) 8.9 Hz),
7.29 (1H, d, J ) 9.0 Hz), 7.39 (1H, dd, J ) 6.8, 7.0 Hz), 7.40 (2H,
dd, J ) 7.0, 7.5 Hz), 7.41 (1H, d, J ) 8.8 Hz), 7.47 (1H, ddd, J )
1.2, 7.3, 7.5 Hz), 7.59 (1H, ddd, J ) 1.1, 7.0, 8.7 Hz), 7.79 (2H,
d, J ) 7.0 Hz), 7.82 (1H, d, J ) 7.3 Hz), 7.88 (1H, d, J ) 9.0 Hz),
8.34 (1H, d, J ) 8.7 Hz); 13C NMR (100.6 MHz) δC 48.6 (CH),
52.5 (CH3), 56.5 (CH3), 113.0 (CH), 118.9 (C), 122.7 (CH), 123.9
(CH), 127.1 (2 × CH), 127.6 (CH), 128.4 (2 × CH), 128.5 (CH),
129.3 (C), 130.6 (CH), 131.5 (CH), 132.3 (C), 134.0 (C), 155.1
(C), 166.8 (C), 172.0 (C); MS m/z (rel intensity) 349 (M+, 10),
317 (M+ - MeOH, 8), 290 (M+ - COOMe, 55), 105 (COPh, 100);
HRMS calcd for C21H19NO4, 349.1314; found, 349.1299; calcd for
C7H5O, 105.0340; found, 105.0346. Anal. Calcd for C21H19NO4:
C, 72.19; H, 5.48; N, 4.01. Found: C, 72.35; H, 5.64; N, 4.07.
Hz), 3.78 (3H, s), 3.86 (1H, dd, J ) 4.0, 18.3 Hz), 5.19 (1H, m),
7.35 (1H, d, J ) 7.8 Hz), 7.42 (2H, dd, J ) 7.3, 7.8 Hz), 7.46 (2H,
dd, J ) 7.6, 7.8 Hz), 7.49 (1H, dd, J ) 7.3, 7.4 Hz), 7.59 (1H, dd,
J ) 7.4, 7.5 Hz), 7.80 (2H, d, J ) 7.3 Hz), 7.95 (2H, d, J ) 7.5
Hz); 13C NMR (125.7 MHz) δC 40.5 (CH2), 48.6 (CH), 52.8 (CH3),
127.2 (2 × CH), 128.2 (2 × CH), 128.6 (2 × CH), 128.7 (2 ×
CH), 131.8 (CH), 133.6 (C), 133.9 (CH), 135.8 (C), 167.0 (C),
171.7 (C), 198.1 (C); MS (EI) m/z (rel intensity) 311 (M+, 1), 279
(M+ - MeOH, 1), 252 (M+ - COOMe, 9), 206 (M+ - COPh,
17), 105 (COPh, 100); HRMS calcd for C18H17NO4, 311.1158;
found, 311.1189; calcd for C7H5O, 105.0340; found, 105.0339.
Anal. Calcd for C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found:
C, 69.41; H, 5.88; N, 4.53.
Methyl 2-Benzamido-4-oxo-pentanoate (17), (2R*,4S*)-N-
Benzoyl-2-acetoxy-2-methyl-4-(methoxycarbonyl)azetidine (18),
and (2R*,4R*)-N-Benzoyl-2-acetoxy-2-methyl-4-(methoxycar-
bonyl)azetidine (19). The one-step scission-alkylation procedure,
using isopropenyl acetate as the nucleophile, afforded methyl ketone
17 (9%), and the azetidines 18 and 19 (11% and 44%, respectively).
Methyl ketone 17: colorless oil; IR (CHCl3) 3443, 1744, 1715,
1660 cm-1; 1H NMR (500 MHz) δΗ 2.18 (3H, s), 3.12 (1H, dd, J
) 4.2, 18.5 Hz), 3.31 (1H, dd, J ) 4.1, 18.5 Hz), 3.76 (3H, s),
4.98 (1H, ddd, J ) 4.1, 4.1, 8.1 Hz), 7.20 (1H, br d, J ) 7.5 Hz),
7.44 (2H, dd, J ) 7.2, 7.6 Hz), 7.51 (1H, dd, J ) 7.3, 7.5 Hz),
7.79 (2H, d, J ) 7.1 Hz); 13C NMR (125.7 MHz) δC 29.9 (CH3),
44.9 (CH2), 48.6 (CH), 52.8 (CH3), 127.2 (2 × CH), 128.6 (2 ×
CH), 131.9 (CH), 133.7 (C), 166.9 (C), 171.5 (C), 207.0 (C); MS
m/z (rel intensity) 249 (M+, 3), 206 (M+ - COMe, 14), 190 (M+
- CO2Me, 42), 105 (PhCO, 100), 77 (Ph, 77); HRMS calcd for
C13H15NO4, 249.1001; found, 249.0999; calcd for C7H5O, 105.0340;
found, 105.0338. Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07;
N, 5.62. Found: C, 62.65; H, 6.15, N, 5.58. Azetidine 18: Colorless
oil; IR (CHCl3) 3090, 1743, 1660, 1437 cm-1; 1H NMR (500 MHz)
δΗ 1.93 (1H, dd, J ) 12.6, 13.9 Hz), 1.96 (3H, s), 2.03 (3H, s),
2.80 (1H, dd, J ) 5.1, 14.0 Hz), 3.83 (3H, s), 4.41 (1H, dd, J )
5.0, 12.6 Hz), 7.38 (2H, dd, J ) 7.2, 7.8 Hz), 7.45 (1H, dd, J )
7.3, 7.4 Hz), 8.00 (2H, d, J ) 7.2 Hz); 13C NMR (125.7 MHz) δC
22.0 (CH3), 24.7 (CH3), 32.6 (CH2), 52.5 (CH3), 53.1 (CH), 100.7
(C), 127.7 (2 × CH), 128.1 (2 × CH), 131.2 (CH), 132.3 (C), 154.0
(C), 168.6 (C), 172.2 (C); MS m/z (rel intensity) 291 (M+, 6), 232
(M+ - CO2Me, 53), 105 (PhCO, 100), 77 (Ph, 12); HRMS calcd
for C15H17NO5, 291.1107; found 291.1110; calcd for C7H5O,
105.0340; found, 105.0340. Anal. Calcd for C15H17NO5: C, 61.85;
H, 5.88; N, 4.81. Found: C, 61.77; H, 5.99, N, 4.76. Azetidine 19:
Crystalline solid; mp 104-106 °C (from EtOAc/n-hexane); IR
(CHCl3) 3092, 1751, 1662, 1437, 1252 cm-1; 1H NMR (500 MHz)
δΗ 1.92 (3H, s), 1.93 (3H, s), 2.15 (1H, dd, J ) 7.3, 14.1 Hz),
2.88 (1H, dd, J ) 3.3, 14.2 Hz), 3.77 (3H, s), 4.45 (1H, dd, J )
3.7, 7.3 Hz), 7.38 (2H, dd, J ) 7.2, 7.7 Hz), 7.45 (1H, dd, J ) 7.3,
7.4 Hz), 8.00 (2H, d, J ) 7.1 Hz); 13C NMR (125.7 MHz) δC 21.8
(CH3), 24.7 (CH3), 32.7 (CH2), 52.4 (CH3), 53.1 (CH), 100.2 (C),
N-(7-Methoxy-3-oxoisochroman-4-yl)benzamide (22) and Meth-
yl 2-Benzoylamino-2-(4-(hydroxymethyl-2-methoxyphenyl)ac-
etate (23). The one-step fragmentation-arylation procedure, using
3-methoxybenzyl alcohol as the nucleophile, afforded compounds
22 (45%) and 23 (22%). Compound 22: white solid; mp 176-177
1
°C (from EtOAc/n-hexane); IR 3433, 3020, 1753, 1669 cm-1; H
NMR (500 MHz) δH 3.82 (3H, s), 5.25 (1H, d, J ) 13.7 Hz), 5.48
(1H, d, J ) 13.7 Hz), 5.83 (1H, d, J ) 5.6 Hz), 6.84 (1H, d, J )
2.4 Hz), 6.90 (1H, dd, J ) 2.5, 8.5 Hz), 7.17 (1H, br d, J ) 6.8
Hz), 7.19 (1H, dd, J ) 1.2, 8.5 Hz), 7.52 (2H, dd, J ) 7.2, 7.9
Hz), 7.59 (1H, dd, J ) 7.4, 7.4 Hz), 7.97 (2H, d, J ) 7.6 Hz); 13
C
NMR (125.7 MHz) δC 51.9 (CH), 55.5 (CH3), 69.5 (CH2), 111.0
(CH), 114.3 (CH), 124.1 (C), 125.1 (CH), 127.3 (2 × CH), 128.8
(2 × CH), 132.0 (C), 132.3 (CH), 133.2 (C), 159.6 (C), 167.9 (C),
170.6 (C); MS m/z (rel intensity) 297 (M+, 8), 192 (M+ - COPh,
100), 105 (COPh, 79), 77 (Ph, 64); HRMS m/z calcd for C17H15-
NO4, 297.1001; found, 297.0996; calcd for C10H10NO3, 192.0661;
found, 192.0661. Anal. Calcd for C17H15NO4: C, 68.68; H, 5.09;
N, 4.71. Found: C, 68.43; H, 5.35; N, 4.69. Compound 23:
1
Colorless oil; IR 3606, 3446, 3013, 1745, 1660 cm-1; H NMR
(500 MHz) δH 3.72 (3H, s), 3.88 (3H, s), 4.68 (2H, s), 5.94 (1H,
d, J ) 8.1 Hz), 6.95 (1H, d, J ) 7.6 Hz), 6.97 (1H, s), 7.31 (1H,
br d, J ) 8.0 Hz), 7.41 (1H, d, J ) 8.1 Hz), 7.42 (2H, dd, J ) 7.8,
8.0 Hz), 7.49 (1H, dd, J ) 7.2, 7.5 Hz), 7.78 (2H, d, J ) 7.2 Hz);
13C NMR (125.7 MHz) δC 52.7 (CH3), 53.5 (CH), 55.7 (CH3), 65.0
(CH2), 109.7 (CH), 119.3 (CH), 124.7 (C), 127.1 (2 × CH), 128.5
(2 × CH), 130.8 (CH), 131.6 (CH), 134.0 (C), 143.1 (C), 157.3
(C), 166.6 (C), 171.5 (C); MS m/z (rel intensity) 329 (M+, 2), 297
(M+ - CH3OH, 4), 270 (M+ - COOCH3, 39), 224 (M+ - COPh,
14), 105 (COPh, 100), 77 (Ph, 42); HRMS m/z calcd for C18H19-
NO5, 329.1263; found, 329.1258; calcd for C7H5O, 105.0340; found,
105.0345. Anal. Calcd for C18H19NO5: C, 65.64; H, 5.81; N, 4.25.
Found: C, 65.47; H, 5.87; N, 4.35.
J. Org. Chem, Vol. 72, No. 19, 2007 7267

Boto et al.
Methyl 2-Benzoylamino-2-(biphenyl-4-yl)acetate (24). The
one-step fragmentation-arylation procedure, using biphenyl as the
nucleophile, afforded compound 24 (8%). The two-step procedure
also gave product 24 (40%) as a white solid: mp 127-128 °C
(from EtOAc/n-hexane); IR 3434, 3013, 1740, 1664 cm-1; 1H NMR
(500 MHz) δH 3.80 (3H, s), 5.84 (1H, d, J ) 6.9 Hz), 7.21 (1H, br
d, J ) 6.8 Hz), 7.36 (1H, dd, J ) 7.3, 7.4 Hz), 7.44 (2H, dd, J )
7.4, 7.8 Hz), 7.45 (2H, dd, J ) 7.2, 7.8 Hz), 7.51 (1H, m), 7.52
(2H, d, J ) 8.4 Hz), 7.57 (2H, d, J ) 8.1 Hz), 7.60 (2H, d, J ) 8.3
Hz), 7.85 (2H, d, J ) 7.8 Hz); 13C NMR (125.7 MHz) δC 53.0
(CH3), 56.6 (CH), 127.1 (2 × CH), 127.2 (2 × CH), 127.5 (CH),
127.7 (2 × CH), 127.8 (2 × CH), 128.6 (2 × CH), 128.8 (2 ×
CH), 131.9 (CH), 133.6 (C), 135.5 (C), 140.4 (C), 141.6 (C), 166.5
175 (M+ - H - COOCH3 - COPh, 40), 105 (COPh, 100); HRMS
m/z calcd for C18H16N2O5, 340.1059; found, 340.1057; calcd for
C7H5O, 105.0340; found, 105.0339. Anal. Calcd for C18H16N2O5:
C, 63.52; H, 4.74; N, 8.23. Found: C, 63.51; H, 4.72; N, 8.45.
Methyl 2-Benzoylamino-2-[5-(methoxycarbonyl)methyl-2-
methoxyphenyl]acetate (28). The one-step fragmentation-aryla-
tion procedure, using methyl 4-methoxyphenylacetate as the
nucleophile, afforded compound 28 (82%): syrup; IR 3448, 1740,
1662, 1510, 1484, 1326, 1257 cm-1; 1H NMR (500 MHz) δH 3.56
(2H, s), 3.66 (3H, s), 3.70 (3H, s), 3.83 (3H, s), 5.93 (1H, d, J )
8.2 Hz), 6.86 (1H, d, J ) 8.4 Hz), 7.23 (1H, dd, J ) 2.2, 8.4 Hz),
7.31 (1H, d, J ) 8.0 Hz), 7.32 (1H, d, J ) 2.3 Hz), 7.39 (2H, dd,
J ) 7.5, 7.7 Hz), 7.47 (1H, dd, J ) 7.3, 7.4 Hz), 7.78 (2H, d, J )
7.5 Hz); 13C NMR (125.7 MHz) δC 39.9 (CH2), 51.9 (CH3), 52.6
(CH3), 53.5 (CH), 55.7 (CH3), 111.3 (CH), 125.3 (C), 126.5 (C),
127.1 (2 × CH), 128.4 (2 × CH), 130.5 (CH), 131.6 (2 × CH),
133.9 (C), 156.2 (C), 166.5 (C), 171.3 (C), 171.9 (C); MS m/z (rel
intensity) 371 (M+, 4), 339 (M+ - MeOH, 6), 312 (M+ - COOMe,
67), 266 (M+ - COPh, 23), 105 (COPh, 100); HRMS calcd for
C20H21NO6, 371.1369; found, 371.1402; calcd for C7H5O, 105.0340;
found, 105.0349. Anal. Calcd for C20H21NO6: C, 64.68; H, 5.70;
N, 3.77. Found: C, 64.64; H, 5.57; N, 3.87.
(C), 171.5 (C); MS m/z (rel intensity) 345 (M+, 4), 313 (M+
-
CH3OH, 9), 286 (M+ - COOCH3, 14), 240 (M+ - COPh, 27),
180 (M+ - H - COOCH3 - COPh, 26), 105 (COPh, 100), 77
(Ph, 47); HRMS m/z calcd for C22H19NO3, 345.1365; found,
345.1380; calcd for C7H5O, 105.0340; found, 105.0349. Anal. Calcd
for C22H19NO3: C, 76.50; H, 5.54; N, 4.06. Found: C, 76.42; H,
5.60; N, 4.30.
Methyl 2-Benzamido-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-
acetate (25) and Methyl 2-Benzamido-2-(2,3-dihydrobenzo-
[b][1,4]dioxin-5-yl)acetate (26). The one-step fragmentation-
arylation procedure, using 2,3-dihydrobenzo[b][1,4]dioxine as the
nucleophile, afforded compounds 25 (60%) and 26 (19%). Com-
pound 25: white solid; mp 134-135 °C (from EtOAc/n-hexane);
Methyl 2-Benzamido-2-(4-[2-methoxy-2-oxoethoxy]phenyl)-
acetate (29) and Methyl 2-Benzamido-2-(2-[2-methoxy-2-oxo-
ethoxy]phenyl)acetate (30). The one-step fragmentation-arylation
procedure, using methyl 2-phenoxyacetate as the nucleophile,
afforded compounds 29 (61%) and 30 (31%). Compound 29: white
solid; mp 130-131 °C (from EtOAc/n-hexane); IR 3441, 3013,
1742, 1663 cm-1; 1H NMR (500 MHz) δH 3.77 (3H, s), 3.80 (3H,
s), 4.62 (2H, s), 5.71 (1H, d, J ) 7.0 Hz), 6.89 (2H, d, J ) 9.0
Hz), 7.09 (1H, br d, J ) 7.0 Hz), 7.37 (2H, d, J ) 8.5 Hz, Ar),
7.44 (2H, dd, J ) 7.5, 7.5 Hz, Ar), 7.51 (1H, dd, J ) 7.0, 7.5 Hz,
Ar), 7.81 (2H, d, J ) 7.5 Hz, Ar); 13C NMR (125.7 MHz) δC 52.3
(CH3), 52.9 (CH3), 56.2 (CH), 65.3 (CH2), 115.1 (2 × CH), 127.1
(2 × CH), 128.6 (2 × CH), 128.7 (2 × CH), 129.9 (C), 131.9
(CH), 133.6 (C), 158.0 (C), 166.5 (C), 169.2 (C), 171.6 (C); MS
m/z (rel intensity) 357 (M+, 3), 325 (M+ - CH3OH, 13), 298 (M+
- COOCH3, 18), 252 (M+ - COPh, 47), 192 (M+ - COOCH3 -
COPh, 19), 105 (COPh, 100), 77 (Ph, 35); HRMS m/z calcd for
C19H19NO6, 357.1212; found, 357.1211; calcd for C7H5O, 105.0340;
found, 105.0344. Anal. Calcd for C19H19NO6: C, 63.86; H, 5.36;
N, 3.92. Found: C, 63.88; H, 5.37; N, 4.05. Compound 30: white
solid; mp 122-123 °C (from dryness); IR 3433, 3020, 1748, 1662
1
IR 3435, 3022, 1739, 1662 cm-1; H NMR (500 MHz) δH 3.77
(3H, s), 4.24 (4H, s), 5.66 (1H, d, J ) 6.9 Hz), 6.85 (1H, d, J )
8.3 Hz), 6.92 (1H, dd, J ) 2.1, 8.3 Hz), 6.95 (1H, d, J ) 2.1 Hz),
7.08 (1H, br d, J ) 6.7 Hz), 7.43 (2H, dd, J ) 7.3, 7.8 Hz), 7.51
(1H, dd, J ) 7.3, 7.5 Hz), 7.81 (2H, d, J ) 7.8 Hz); 13C NMR
(125.7 MHz) δC 52.8 (CH3), 56.2 (CH), 64.3 (2 × CH2), 116.2
(CH), 117.8 (CH), 120.4 (CH), 127.1 (2 × CH), 128.6 (2 × CH),
129.6 (C), 131.8 (CH), 133.7 (C), 143.8 (C), 143.9 (C), 166.5 (C),
171.5 (C); MS m/z (rel intensity) 327 (M+, 10), 295 (M+ - CH3-
OH, 28), 268 (M+ - COOCH3, 20), 222 (M+ - COPh, 69), 162
(M+ - H -CO2Me - COPh, 36), 105 (COPh, 100); HRMS m/z
calcd for C18H17NO5, 327.1107; found, 327.1100; calcd for C7H5O,
105.0340; found, 105.0344. Anal. Calcd for C18H17NO5: C, 66.05;
H, 5.23; N, 4.28. Found: C, 66.02; H, 5.22; N, 4.28. Compound
26: colorless oil; IR 3446, 3020, 1745, 1662 cm-1; 1H NMR (500
MHz) δH 3.75 (3H, s), 4.27-4.31 (3H, m), 4.35 (1H, m), 5.99 (1H,
d, J ) 8.0 Hz), 6.83-6.88 (2H, m), 6.98 (1H, dd, J ) 2.4, 6.7
Hz), 7.21 (1H, br d, J ) 7.7 Hz), 7.43 (2H, dd, J ) 7.2, 7.8 Hz),
7.51 (1H, dd, J ) 7.3, 7.7 Hz), 7.81 (2H, d, J ) 7.8 Hz); 13C NMR
(125.7 MHz) δC 52.6 (CH), 52.8 (CH3), 64.2 (CH2), 64.5 (CH2),
117.8 (CH), 121.4 (CH), 122.0 (CH), 125.3 (C), 127.2 (2 × CH),
128.5 (2 × CH), 131.7 (CH), 134.0 (C), 141.5 (C), 143.8 (C), 166.6
1
cm-1; H NMR (500 MHz) δH 3.72 (3H, s), 3.77 (3H, s), 4.64
(1H, d, J ) 16.0 Hz), 4.73 (1H, d, J ) 16.0 Hz), 6.00 (1H, d, J )
8.5 Hz), 6.81 (1H, d, J ) 8.0 Hz), 7.04 (1H, dd, J ) 7.5, 8.0 Hz),
7.30 (1H, ddd, J ) 2.0, 7.5, 8.0 Hz), 7.41 (2H, dd, J ) 7.0, 7.5
Hz), 7.48 (1H, dd, J ) 7.5, 7.5 Hz), 7.49 (1H, dd, J ) 2.0, 7.5
Hz), 7.91 (2H, d, J ) 7.8 Hz), 8.01 (1H, br d, J ) 8.5 Hz); 13C
NMR (125.7 MHz) δC 52.4 (CH3), 52.7 (CH3), 54.4 (CH), 65.0
(CH2), 111.6 (CH), 122.4 (CH), 126.4 (C), 127.5 (2 × CH), 128.3
(2 × CH), 129.8 (CH), 131.5 (CH), 131.8 (CH), 134.1 (C), 155.3
(C), 166.7 (C), 169.2 (C), 171.2 (C); MS m/z (rel intensity) 357
(M+, 1), 325 (M+ - CH3OH, 3), 298 (M+ - COOCH3, 71), 252
(M+ - COPh, 18), 192 (M+ - COOCH3 - COPh, 5), 105 (COPh,
100), 77 (Ph, 44); HRMS m/z calcd for C19H19NO6, 357.1212;
found, 357.1196; calcd for C7H5O, 105.0340; found, 105.0337.
Anal. Calcd for C19H19NO6: C, 63.86; H, 5.36; N, 3.92. Found:
C, 63.47; H, 5.74; N, 4.01.
(C), 171.4 (C); MS m/z (rel intensity) 327 (M+, 9), 295 (M+
-
CH3OH, 6), 268 (M+ - COOCH3, 74), 222 (M+ - COPh, 21),
105 (COPh, 100), 77 (Ph, 47); HRMS m/z calcd for C18H17NO5,
327.1107; found, 327.1105; calcd for C7H5O, 105.0340; found,
105.0343. Anal. Calcd for C18H17NO5: C, 66.05; H, 5.23; N, 4.28.
Found: C, 66.31; H, 5.38; N, 4.34.
Methyl 2-Benzamido-2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]-
oxazol-6-yl)acetate (27). The one-step fragmentation-arylation
procedure, using 3-methylbenzo[d]oxazol-2(3H)-one as the nucleo-
phile, afforded compound 27 (59%) as a white solid: mp 144-
145 °C (from EtOAc/n-hexane); IR 3431, 3022, 1778, 1739, 1664
Methyl 2-Benzamido-2-(3-bromo-4-(2-methoxy-2-oxoethoxy)-
phenyl)acetate (31). The one-step fragmentation-arylation pro-
cedure, using methyl 2-(2-bromophenoxy)acetate as the nucleophile,
afforded compound 31 (63%) as a white solid: mp 128-129 °C
(from EtOAc/n-hexane); IR 3440, 3022, 1741, 1664 cm-1; 1H NMR
(500 MHz) δH 3.78 (3H, s), 3.80 (3H, s), 4.70 (2H, s), 5.69 (1H,
d, J ) 7.0 Hz), 6.78 (1H, d, J ) 8.5 Hz), 7.18 (1H, br d, J ) 6.5
Hz), 7.34 (1H, dd, J ) 2.0, 8.0 Hz), 7.45 (2H, dd, J ) 7.5, 8.0
Hz), 7.53 (1H, dd, J ) 7.5, 7.5 Hz), 7.63 (1H, d, J ) 2.5 Hz), 7.81
(2H, d, J ) 7.8 Hz); 13C NMR (125.7 MHz) δC 52.4 (CH3), 53.1
1
cm-1; H NMR (500 MHz) δH 3.38 (3H, s), 3.78 (3H, s), 5.77
(1H, d, J ) 6.8 Hz), 6.95 (1H, d, J ) 8.0 Hz), 7.28 (1H, br d, J )
6.5 Hz), 7.30 (1H, d, J ) 2.0 Hz), 7.32 (1H, dd, J ) 1.5, 8.0 Hz),
7.45 (2H, dd, J ) 7.0, 8.0 Hz), 7.52 (1H, dd, J ) 7.5, 7.5 Hz),
7.82 (2H, d, J ) 7.0 Hz); 13C NMR (100 MHz) δC 28.2 (CH3),
53.1 (CH3), 56.6 (CH), 108.2 (CH), 109.0 (CH), 123.3 (CH), 127.1
(2 × CH), 128.7 (2 × CH), 131.7 (2 × C), 132.0 (CH), 133.4 (C),
142.9 (C), 154.6 (C), 166.5 (C), 171.2 (C); MS m/z (rel intensity)
340 (M+, 9), 281 (M+ - COOMe, 12), 235 (M+ - COPh, 90),
7268 J. Org. Chem., Vol. 72, No. 19, 2007

Amino Acids by Radical Fragmentation
(CH3), 55.7 (CH), 66.2 (CH2), 112.9 (C), 113.6 (CH), 127.1 (2 ×
CH), 127.7 (CH), 128.7 (2 × CH), 131.5 (C), 132.0 (CH), 132.4
(CH), 133.4 (C), 154.6 (C), 166.5 (C), 168.8 (C), 171.1 (C); MS
(FAB) m/z (rel intensity) 437/435 (M+, 2/2), 405/403 (M+ - CH3-
OH, 6/5), 376 (M+ - COOCH3, 5), 332/330 (M+ - COPh, 28/
28), 105 (COPh, 100), 77 (Ph, 26); HRMS m/z calcd for
C19H1881BrNO6/C19H1879BrNO6, 437.0297/435.0317; found, 437.0295/
435.0304; calcd for C18H1481BrNO5/C18H1479BrNO5, 405.0035/
403.0055; found, 405.0025/403.0060; calcd for C7H5O, 105.0340;
found, 105.0343. Anal. Calcd for C19H18BrNO6: C, 52.31; H, 4.16;
N, 3.21. Found: C, 52.44; H, 4.13; N, 3.37.
MHz) δH 3.80 (3H, s), 5.97 (1H, d, J ) 8.0 Hz), 6.38 (1H, d, J )
3 Hz), 6.44 (1H, d, J ) 3 Hz), 7.07 (1H, d, J ) 8.0 Hz), 7.39 (1H,
s), 7.44 (2H, dd, J ) 8.0, 8.0 Hz), 7.52 (1H, dd, J ) 8.0, 8.0 Hz),
7.82 (2H, d, J ) 8.0 Hz); 13C NMR (100.6 MHz) δC 50.6 (CH),
53.1 (CH3), 109.0 (CH), 110.8 (CH), 127.2 (2 × CH), 128.6 (2 ×
CH), 132.0 (CH), 133.4 (C), 142.9 (CH), 148.5 (C), 166.7 (C),
169.4 (C); MS m/z (rel intensity) 259 (M+, 4), 227 (M+ - MeOH,
6), 200 (M+ - COOMe, 12), 154 (M+ - COPh, 75), 105 (COPh,
100); HRMS calcd for C14H13NO4, 259.0845; found, 259.0839;
calcd for C7H5O, 105.0340; found, 105.0351. Anal. Calcd for
C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found: C, 64.79; H, 5.18;
N, 5.32.
Methyl (4-Allyloxy-3-iodophenyl)-(benzoylamino)acetate (32).
The one-step fragmentation-arylation procedure, using 1-allyloxy-
2-iodobenzene as the nucleophile, gave compound 32 (86%):
crystalline solid; mp 161.5-162.5 °C (from EtOAc/n-hexane); IR
3432, 1740, 1663, 1510, 1484 cm-1; 1H NMR (500 MHz) δH 3.72
(3H, s), 4.52 (2H, d, J ) 4.9 Hz), 5.26 (1H, dd, J ) 1.4, 10.7 Hz),
5.47 (1H, dd, J ) 1.6, 17.3 Hz), 5.64 (1H, d, J ) 6.9 Hz), 5.98
(1H, m), 6.71 (1H, d, J ) 8.5 Hz), 7.34 (1H, dd, J ) 2.3, 8.5 Hz),
7.35 (2H, dd, J ) 7.8, 8.1 Hz), 7.38 (1H, d, J ) 6.5 Hz), 7.46 (1H,
dd, J ) 7.3, 7.5 Hz), 7.78 (2H, dd, J ) 1.3, 7.2 Hz), 7.82 (1H, d,
J ) 2.3 Hz); 13C NMR (100.6 MHz) δC 52.8 (CH3), 55.4 (CH),
69.5 (CH2), 86.8 (C), 112.2 (CH), 117.5 (CH2), 127.0 (2 × CH),
128.3 (2 × CH), 128.6 (CH), 130.6 (C), 131.7 (CH), 132.1 (CH),
133.2 (C), 137.9 (CH), 157.1 (C), 166.4 (C), 171.1 (C); MS m/z
Methyl 3-(1-Benzamido-2-methoxy-2-oxoethyl)-1H-indole-1-
carboxylate (35) and Methyl 2-(1-Benzamido-2-methoxy-2-
oxoethyl)-1H-indole-1-carboxylate (36). The one-step fragmen-
tation-arylation procedure, using methyl 1H-indole-1-carboxylate
as the nucleophile, afforded compounds 35 (43%) and 36 (20%).
Compound 35: white solid; mp 162-163 °C (from dryness); IR
1
3440, 3022, 1740, 1664 cm-1; H NMR (500 MHz) δH 3.77 (3H,
s), 4.04 (3H, s), 6.06 (1H, d, J ) 7.0 Hz), 7.03 (1H, br d, J ) 7.0
Hz), 7.29 (1H, dd, J ) 7.5, 8.0 Hz), 7.38 (1H, dd, J ) 7.0, 8.0
Hz), 7.43 (2H, dd, J ) 7.5, 8.0 Hz), 7.51 (1H, dd, J ) 7.5, 7.5
Hz), 7.70 (1H, s), 7.71 (1H, d, J ) 7.5 Hz), 7.80 (2H, d, J ) 7.0
Hz), 8.20 (1H, br d, J ) 8.0 Hz); 13C NMR (125.7 MHz) δC 49.5
(CH), 53.0 (CH3), 54.0 (CH3), 115.5 (CH), 116.8 (C), 119.4 (CH),
123.5 (CH), 124.5 (CH), 125.2 (CH), 127.2 (2 × CH), 128.1 (C),
128.6 (2 × CH), 132.0 (CH), 133.5 (C), 135.7 (C), 151.1 (C), 166.8
(rel intensity) 451 (M+, <1), 419 (M+ - MeOH, 7), 392 (M+
-
COOMe, 5), 346 (M+ - COPh, 28), 105 (COPh, 100); HRMS
calcd for C19H18INO4, 451.0281; found, 451.0273; calcd for C7H5O,
105.0340; found, 105.0332. Anal. Calcd for C19H18INO4: C, 50.57;
H, 4.02; N, 3.10. Found: C, 50.32; H, 4.14; N, 3.20.
(C), 171.1 (C); MS m/z (rel intensity) 366 (M+, 12), 334 (M+
-
CH3OH, 15), 307 (M+ - COOCH3, 15), 261 (M+ - COPh, 81),
201 (M+ - H - COOCH3 - COPh, 15), 105 (COPh, 100), 77
(Ph, 34); HRMS m/z calcd for C20H18N2O5, 366.1216; found,
366.1210; calcd for C7H5O, 105.0340; found, 105.0348. Anal. Calcd
for C20H18N2O5: C, 65.57; H, 4.95; N, 7.65. Found: C, 65.36; H,
5.14; N, 7.40. Compound 36: colorless oil; IR 3421, 3022, 1742
Methyl 2-Benzoylamino-2-(3-methylene-2,3-dihydro-[benzo-
furan-5-yl])acetate (33). To a solution of Pd(OAc)2 (11 mg, 0.05
mmol) in DMF (1 mL) was added triphenylphosphine (26 mg, 0.1
mmol). After stirring for 15 min, the solution was added to a mixture
of the iodoarylglycine 32 (225 mg, 0.5 mmol) and silver carbonate
(1.35 g, 5 mmol) in dry DMF (5 mL). The reaction mixture was
stirred at room temperature under nitrogen for 30 min, and then it
was heated at 80 °C for 18 h. Additional Pd(OAc)2 (10 mg) was
added after the first 12 h. The mixture was cooled to room
temperature, filtered through celite, diluted with water, and extracted
twice with ether. The combined organic layers were washed with
water, dried, and evaporated under vacuum. The residue was
purified by column chromatography (hexanes/EtOAc, 95:5), giving
compound 33 (114.5 mg, 71%): crystalline solid; mp 105.0-107.0
1
cm-1; H NMR (500 MHz) δH 3.76 (3H, s), 4.10 (3H, s), 6.46
(1H, d, J ) 9.0 Hz), 6.89 (1H, br s), 7.26 (1H, dd, J ) 7.7, 7.9
Hz), 7.33 (1H, dd, J ) 7.5, 7.8 Hz), 7.44 (2H, dd, J ) 7.5, 7.5
Hz), 7.51 (1H, dd, J ) 7.5, 7.5 Hz), 7.55 (1H, d, J ) 8.0 Hz), 7.63
(1H, br d, J ) 9.0 Hz), 7.81 (2H, d, J ) 7.5 Hz), 7.97 (1H, d, J )
8.0 Hz); 13C NMR (125.7 MHz) δC 51.5 (CH), 52.9 (CH3), 54.2
(CH3), 113.9 (CH), 115.8 (CH), 121.4 (CH), 123.6 (CH), 125.2
(CH), 127.2 (2 × CH), 128.6 (2 × CH), 128.8 (C), 131.8 (CH),
133.8 (C), 134.6 (C), 135.8 (C), 153.2 (C), 166.5 (C), 169.8 (C);
MS m/z (rel intensity) 366 (M+, 8), 334 (M+ - CH3OH, 12), 307
(M+ - COOCH3, 12), 261 (M+ - COPh, 72), 201 (M+ - H -
COOCH3 - COPh, 9), 105 (COPh, 100), 77 (Ph, 34); HRMS m/z
calcd for C20H18N2O5, 366.1216; found, 366.1227; calcd for C7H5O,
105.0340; found, 105.0345. Anal. Calcd for C20H18N2O5: C, 65.57;
H, 4.95; N, 7.65. Found: C, 65.62; H, 5.04; N, 7.69.
°C (from EtOAc/n-hexane); IR 3433, 1740, 1662, 1510, 1483 cm-1
;
1H NMR (500 MHz) δH 3.77 (3H, s), 5.02 (1H, dd, J ) 2.7, 2.8
Hz), 5.10 (2H, dd, J ) 3.0, 3.0 Hz), 5.43 (1H, dd, J ) 3.2, 3.2
Hz), 5.71 (1H, d, J ) 6.8 Hz), 6.83 (1H, d, J ) 8.3 Hz), 7.16 (1H,
d, J ) 6.4 Hz), 7.27 (1H, dd, J ) 2.0, 8.4 Hz), 7.43 (2H, dd, J )
7.4, 7.4 Hz), 7.46 (1H, d, J ) 2.0 Hz), 7.51 (1H, dd, J ) 7.4, 7.4
Hz), 7.82 (2H, d, J ) 7.5 Hz); 13C NMR (100.6 MHz) δC 52.9
(CH3), 56.4 (CH), 75.4 (CH2), 100.6 (CH2), 111.1 (CH), 120.1 (CH),
126.6 (C), 127.1 (2 × CH), 128.5 (2 × CH), 129.0 (C), 129.7 (CH),
131.8 (CH), 133.5 (C), 143.0 (C), 163.9 (C), 166.5 (C), 171.7 (C);
MS m/z (rel intensity) 323 (M+, 14), 291 (M+ - MeOH, 17), 264
(M+ - COOMe, 10), 218 (M+ - COPh, 32), 158 (M+ - [AcOH
+ COOMe], 43), 105 (COPh, 100); HRMS calcd for C19H17NO4,
323.1158; found, 323.1179; calcd for C7H5O, 105.0340; found,
105.0337. Anal. Calcd for C19H17NO4: C, 70.58; H, 5.30; N, 4.33.
Found: C, 70.37; H, 5.68; N, 4.26.
Acknowledgment. This work was supported by the Inves-
tigation Programs PPQ2000-0728 and PPQ2003-01379 (Plan
Nacional de I + D, Ministerios de Ciencia y Tecnolog´ıa and
Educacio´n y Ciencia, Spain) and 2004-8-0E211 (Proyecto
Intramural del CSIC). We also acknowledge financial support
from FEDER funds. D.H. thanks the Ministerio de Educacio´n
y Ciencia for an FPU fellowship. J.A.G. thanks the Consejer´ıa
de Industria del Gobierno de Canarias and the CSIC for a
postdoctoral contract.
Methyl 2-Benzoylamino-2-(2-furyl)acetate (34). The one-step
fragmentation-arylation procedure, using furan as the nucleophile,
gave compound 34 (79%). This compound was previously synthe-
sized by another method35 but the spectroscopic data were poorly
described: IR 3436, 1747, 1666, 1513, 1483 cm-1; 1H NMR (500
Supporting Information Available: The 1H and 13C NMR
spectra for compounds 8, 11, 12, 14-19, 21-36. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO071155T
J. Org. Chem, Vol. 72, No. 19, 2007 7269