Organocatalytic synthesis of N-phenylisoxazolidin-5-ones and a one-pot synthesis of β-amino acid esters

Article abstract of DOI:10.1021/ol800003n

A novel N-heterocyclic carbene (NHC)-catalyzed C-N bond formation by the reaction of α,β-unsaturated aldehydes and nitrosobenzene to N-phenylisoxazolidin-5-ones, followed by an acid-catalyzed esterification and Bamberger-like rearrangement in a mild one-pot protocol leads to N-p-methoxyphenyl (N-PMP) protected β-amino acid esters.

Full text of DOI:10.1021/ol800003n

ORGANIC
LETTERS
2008
Vol. 10, No. 5
953-956
Organocatalytic Synthesis of
N-Phenylisoxazolidin-5-ones and a
One-Pot Synthesis of
Esters
â-Amino Acid
Jayasree Seayad, Pranab Kumar Patra, Yugen Zhang,* and Jackie Y. Ying*
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way,
The Nanos, Singapore 138669
ygzhang@ibn.a-star.edu.sg; jyying@ibn.a-star.edu.sg
Received January 1, 2008
ABSTRACT
A novel N-heterocyclic carbene (NHC)-catalyzed C−N bond formation by the reaction of
r,
â
-unsaturated aldehydes and nitrosobenzene to
N-phenylisoxazolidin-5-ones, followed by an acid-catalyzed esterification and Bamberger-like rearrangement in a mild one-pot protocol leads
to N-p-methoxyphenyl (N-PMP) protected -amino acid esters.
â
New catalytic methods for carbon-nitrogen (C-N) bond
formation are important for their broad applications in
organic synthesis, especially for pharmaceuticals and natural
products.1 Organocatalytic C-N bond formations that avoid
the use of toxic and expensive metal catalysts are of particular
interest. Proline-catalyzed direct R-aminations of carbonyl
compounds developed independently by List2 and Jørgensen
and co-workers3 are the first examples of organocatalytic
C-N bond formation. Yamamoto et al.4 and Maruoka and
co-workers5 subsequently reported N-nitroso aldol reaction
of enamines selectively forming N-hydroxyaminoketones.
The recent enantioselective conjugate addition of N-sily-
loxycarbamates to enals using imidazolidinone catalysts
developed by MacMillan and co-workers6 is an elegant
method for enantio-enriched â-amino aldehydes. Another
recent interesting example is the reaction of enals and
N-protected hydroxylamine in the presence of chiral pyrro-
lidine catalysts, forming 5-hydroxyisoxazolidines that were
further converted to the corresponding â-amino acids or
γ-amino alcohols.7 We report here a novel method for C-N
(1) (a) Xu, L.-W.; Xia, C. G. Eur. J. Org. Chem. 2005, 633-639. (b)
Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959-8960.
(c) Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 2134-2136.
(d) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed.
2004, 43, 3368-3398. (e) Hultzsch, K. C. AdV. Synth. Catal. 2005, 347,
367-391. (f) Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42, 4290-4299. (g)
Magriotis, P. A. Angew. Chem., Int. Ed. 2001, 40, 4377-4379.
(2) List, B. J. Am. Chem. Soc. 2002, 124, 5656-5657.
(4) (a) Yamamoto, H.; Momiyama, N. J. Am. Chem. Soc. 2005, 127,
1080-1081. (b) Yamamoto, H.; Momiyama, N. Chem. Commun. 2005,
3514-3525. (c) Momiyama, N.; Yamamoto, Y.; Yamamoto, H. J. Am.
Chem. Soc. 2007, 129, 1190-1195.
(5) Kano, T.; Ueda, M.; Takai, J.; Maruoka, K. J. Am. Chem. Soc. 2006,
128, 6046-6047.
(6) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc.
2006, 128, 9328-9329.
(3) (a) Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790-1793. (b) Marigo,
M.; Jørgensen, K. A. Chem. Commun. 2006, 2001-2011.
10.1021/ol800003n CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/05/2008

bond formation by the reaction of R,â-unsaturated aldehydes
with nitrosobenzene using N-heterocyclic carbene (NHC)
catalysis, forming N-phenylisoxazolidin-5-ones8 that are
converted to the corresponding N-p-methoxyphenyl (N-
PMP)-protected â-amino acid esters in a mild one-pot
synthetic protocol. â-amino acids possess biologically im-
portant properties, occur in natural products, and are key
building blocks to several bioactive compounds.9
Scheme 1. NHC Catalysis: Nitrosobenzene as an Electrophile
NHC-catalyzed activation of carbonyl compounds has
evolved as a potential method for metal-free C-C bond-
forming reactions via the nucleophilic “Breslow intermedi-
ate”10 or the homoenolate equivalent species i.11 We envi-
sioned that nitroso compounds could act as potential
electrophiles for such reactions, forming the corresponding
C-N bonds12 leading to amides or â-amino acid derivatives.
The coupling of the nitroso compound with the homoenolate
equivalent i (d3 nucleophile)13 would form intermediate
nitroxide species ii and iii (Path A, Scheme 1). The nitroxide
iii can then attack the carbonyl group of the activated
carboxylate intramolecularly, leading to isoxazolidin-5-ones,
returning the carbene catalyst back for further turnovers.
Potential competing reactions would be the reaction of the
d1 nucleophile with the nitroso compound to form the
N-hydroxycinnamamide (Path B, Scheme 1) and the self-
condensation of enal.11b The ability of thiamine-dependent
enzymes to convert aromatic nitroso compounds into hy-
droxamic acids has been investigated by Corbett et al.14
In our initial experiments, cinnamaldehyde and nitrosoben-
zene were found to rapidly react in the presence of NHC
catalysts generated from imidazolium salts (5-6), forming
2,3-diphenylisoxazolidin-5-one (3a). Optimization studies
using different imidazolium and triazolium salts indicated
that sterically more demanding imidazolium catalyst 5d
provided the highest selectivity toward 3a. On the other hand,
use of sterically less hindered catalysts such as 5c also formed
N-hydroxy-N-phenylcinnamamide (4a)15 (Table 1). The
NHCs derived from the triazolium salts 716 and 817 produced
(7) Ibrahem, I.; Rios, R.; Vesely, J.; Zhao, G.-L.; Cordova, A. Chem.
Commun. 2007, 849-851.
(8) (a) Mitsuru, S.; Kotaro, I.; Keiko, O.; Chinatsu, T.; Kozo, S. Synthesis
2003, 9, 1441-1445. (b) Shindo, M.; Itoh, K.; Tsuchiya, C.; Shishido, K.
Org. Lett. 2002, 4, 3119-3121. (c) Luisi, R.; Capriati, V.; Florio, S.; Vista,
T. J. Org. Chem. 2003, 68, 9861-9864.
(9) (a) Abdel-Magid, A. F.; Cohen, J. H.; Maryanoff, C. A. Curr. Med.
Chem. 1999, 6, 955-969. (b) Cole, D. C. Tetrahedron 1994, 50, 9517-
9582. (c) Juaristi, E., Ed. EnantioselectiVe Synthesis of â-Amino Acids;
Wiley-VCH: New York, 1997. (d) Ma, J.-A. Angew. Chem., Int. Ed. 2003,
42, 4290-4299. (e) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991-
8035.
Table 1. NHC-Catalyzed Synthesis of
2,3-Diphenylisoxazolidin-5-one: Catalyst Optimization
(10) (a) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726. (b) Zeitler,
K. Angew. Chem., Int. Ed. 2005, 44, 7506-7510. (c) Enders, D.; Balensiefer,
T. Acc. Chem. Res. 2004, 37, 534-541 and references therein. (d) Enders,
D.; Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107, 5606-5655 and
references therein. (e) Marion, N.; D´ıez-Gonza´lez, S.; Nolan S. P. Angew.
Chem., Int. Ed. 2007, 46, 2988-3000 and references therein. (f) Enders,
D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743-1745. (g) Kerr,
M. S.; de Alaniz, R. J.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298-
10299. (h) Kerr, M. S.; Rovis, T. Synlett 2003, 1934-1936. (i) Kerr, M.
S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876. (j) Vora, H. U.; Rovis, T.
J. Am. Chem. Soc. 2007, 129, 13796-13797. (k) Bode, J. W.; Sohn, S. S.
J. Am. Chem. Soc. 2007, 129, 13798-13799.
(11) (a) Burstein, C.; Tschan, S.; Xie, X.; Glorius, F. Synthesis 2006,
2418-2439. (b) Sohn, S. S.; Rosen, E. L.; Bode, J. F. J. Am. Chem. Soc.
2004, 126, 14370-14371. (c) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh,
E. J. Am. Chem. Soc. 2006, 128, 8736-8737. (d) Burstein, C.; Glorius, F.
Angew. Chem., Int. Ed. 2004, 43, 6205-6208. (e) He, M.; Struble, J. R.;
Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418-8420. (f) Chan, A.; Scheidt,
K. A. J. Am. Chem. Soc. 2007, 129, 5334-5335. (g) Phillips, E. M.;
Wadamoto, M.; Chan, A.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46,
1-5. (h) He, M.; Uc, G. J.; Bode, J. F. J. Am. Chem. Soc. 2006, 128, 15088-
15089. (i) Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc.
2007, 129, 3520-3521. (j) Wadamoto, M.; Phillips, E. M.; Reynolds, T.
E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 10098-10099.
(12) Duong, H. A.; Cross, M. J.; Louie, J. Org. Lett. 2004, 6, 4679-
4681 (cyclotrimerization of isocyanates using NHC catalysis).
(13) Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239-258.
(14) (a) Corbett, M. D.; Corbett, B. R.; Doerge, D. R. J. Chem. Soc.
Perkin Trans. I 1982, 345-350 and references therein. (b) Corbett, M. D.;
Doerge, D. R.; Corbett, B. R. J. Chem. Soc., Perkin Trans. I 1983, 765-
769.
entry
catalyst
solvent
base
yield (%)a
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
6
7
8
5d
5d
5d
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
C6H6
CH2Cl2
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
DBUc
14
5
60
80
10
b
-
-
b
82
50
48
10
a Yields determined by 1H NMR. b Over 95% formation of N-hydroxy-
N-phenylcinnamamide(4a)wasobserved. c DBU)1,8-diazabicyclo[5.4.0]undec-
7-ene.
954
Org. Lett., Vol. 10, No. 5, 2008

4a exclusively, irrespective of the steric bulk. The only other
observable side product was a small amount of azoxyben-
zene, which was effectively minimized by optimizing the
reaction parameters.
In attempts to cleave the N-O bond of the 2,3-diphenyl-
isoxazolidin-5-one (3a), we have developed an acid-catalyzed
esterification, followed by a Bamberger-like rearrangement18
to form N-p-methoxyphenyl â-phenethylamino acid ester
9a.19 This is an excellent method to create a nitrogen-
protecting group (PMP), which has been known to be
deprotected under mild oxidative conditions.20 More interest-
ingly, these two catalytic steps could be performed in a one-
pot process starting with the enal (Table 2). Thus, in the
A variety of aryl (1a-1j)- and alkyl (1k-1l)-substituted
R,â-unsaturated aldehydes were found to form the corre-
sponding N-phenylisoxazolidin-5-ones (3a-3l) and â-amino
acid esters (9a-9l) by this method (Table 2). In general,
those with an electron-withdrawing group provided higher
yields. Substrates with different functional groups, such as
ether, ester, nitro, and sulfonate, were readily accommodated
in this protocol. The intermediate N-phenylisoxazolidin-5-
one derivatives were not quite stable for isolation due to
potential decarboxylation and further hydrolysis.21 Hence,
their formations were monitored separately by H nuclear
magnetic resonance (NMR) studies.
Furthermore, we applied this methodology for the synthesis
of the natural product â-DOPA,22 starting from the com-
mercially available enal 10 (Scheme 2). Thus, 10 after
1
Table 2. NHC-Catalyzed One-Pot Synthesis of â-Amino Acid
Esters
Scheme 2. Application to â-DOPA Synthesis
entry
R
yield of 3 (%)a
yield of 9 (%)b
1
2
3
4
5
6
7
8
9
Ph (a)
82
98c
84
83
82
75
95
90
85
88
96
40
75
85
70
79
75
68
40d
80
72
78
84
30
4-NO2Ph (b)
2-NO2Ph (c)
3-Br-4-OTfPh (d)
4-COOMePh (e)
6-COOMe-2-Np (f)
4-CNPh (g)
4-CF3Ph (h)
C6F5 (i)
10
11
12
3,5-F2Ph (j)
EtCOO (k)
C4H9 (l)
triflation to 11, was allowed to react with nitrosobenzene
using our one-pot protocol, producing N-PMP protected
â-DOPA ester 12 (see Figure 1) in high yields.
1
a Yields determined by H NMR. b Overall isolated yields with respect
to aldehyde. c 10 mol % of catalyst. d Lower yield could be due to the
hydrolysis of cyano group under acidic conditions.
optimized protocol, 5d, KOtBu, nitrosobenzene, and the enal
were reacted for 1-6 h. After solvent evaporation, the residue
was diluted in methanol, HClO4 was added to the mixture,
and the reaction was continued to produce the N-PMP pro-
tected â-amino acid esters in good to excellent yields. Traces
of N-p-hydroxyphenyl â-amino acid ester and N-o-methox-
yphenyl â-amino acid ester were also formed in some cases.
(15) Zhang, Y.; Ying, J. Y.; Seayad, J.; Wong, F. T.; Patra, P. K. U.S.
Patent Application pending.
(16) Kerr, M. S.; de Alaniz, J. R.; Rovis, T. J. Org. Chem. 2004, 126,
5725-5728.
(17) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128,
8418-8422.
Figure 1. Crystal structure of 12.
(18) Bamberger, E. Chem. Ber. 1894, 1347 & 1548-1557.
(19) See Supporting Information for the proposed mechanism.
(20) (a) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L.
M.; Alsters, P. L.; van Delft, F. L.; Rutjes, F. P. J. T. Tetrahedron Lett.
2006, 47, 8109-8113. (b) Hata, S.; Iguchi, I.; Iwasawa, T.; Yamada, K.;
Tomioka, K. Org. Lett. 2004, 6, 1721-1723. (c) Porter, J. R.; Traverse, J.
F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 10409-
10410. (d) Ibrahem, I.; Casas, J.; Co´rdova, A. Angew. Chem., Int. Ed. 2004,
43, 6528-6531. (e) Hoffmann, S.; Nicoletti, M.; List, B. J. Am. Chem.
Soc. 2006, 128, 13074-13075.
A preliminary study on the enantioselective variant of this
methodology by the reaction of the enal 1h and nitrosoben-
zene resulted in 44.5% ee and 76% yield of 9h using the
(21) See Supporting Information.
(22) von Franz, N.; Peter, S.; Matthias, R.; Wolfgang, S.; Gerhard, W.;
Brandy, G.; Lorenzo, S.; Friedrich, E. W. Angew. Chem., Int. Ed. 1998,
37, 3292-3295.
Org. Lett., Vol. 10, No. 5, 2008
955

NHC catalyst derived from a chiral imidazolium salt 1323
(Scheme 3).
rangement of the intermediate N-phenylisoxazolidin-5-ones.
The reaction of the homoenolate with nitrosobenzene is
directed efficiently to either 1,4- or 1,2-addition by manipu-
lating the steric and electronic properties of the NHC catalyst.
This new organocatalytic protocol is attractive in terms of
both mechanistic and synthetic aspects, in addition to its
simplicity and advantages over the current approaches.
Further optimization of the enantioselective variant and
elaboration of the scope of the reaction are underway.
Scheme 3. NHC-Catalyzed Enantioselective Synthesis of
â-Amino Acid Esters
Acknowledgment. This work is funded by the Institute
of Bioengineering and Nanotechnology (Biomedical Re-
search Council, Agency for Science, Technology and Re-
search, Singapore).
Supporting Information Available: Experimental pro-
cedures, compound characterization, NMR spectra, HPLC
traces, X-ray crystallography data (PDF). This material
is available free of charge via the Internet at http://pubs.
acs.org.
In conclusion, we have developed a one-pot protocol for
N-PMP protected â-amino acid esters by a novel NHC-
catalyzed reaction of enals and nitrosobenzene, followed by
an acid-catalyzed esterification and Bamberger-like rear-
(23) Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C. Chem.
Commun. 2002, 2704-2705. See also Supporting Information for the
complete synthesis procedure.
OL800003N
956
Org. Lett., Vol. 10, No. 5, 2008