Tandem multi-step synthesis of C-carboxyazlactones promoted by N-heterocyclic carbenes

Article abstract of DOI:10.1039/b806816j

Cascade reaction sequences incorporating N-heterocyclic carbene-based organocatalysis have been developed that allow the direct preparation of a range of (±)-4-phenoxycarbonylazlactones in good isolated yields (66-84%) from the corresponding N-p-anisoyl amino acids. The Royal Society of Chemistry.

Full text of DOI:10.1039/b806816j

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Tandem multi-step synthesis of C-carboxyazlactones promoted by
N-heterocyclic carbenesw
Craig D. Campbell,a Nicolas Duguet,a Katherine A. Gallagher,a Jennifer E. Thomson,a
Anita G. Lindsay,b AnnMarie C. O’Donoghueb and Andrew D. Smith*a
Received (in Cambridge, UK) 22nd April 2008, Accepted 20th June 2008
First published as an Advance Article on the web 7th July 2008
DOI: 10.1039/b806816j
Cascade reaction sequences incorporating N-heterocyclic car-
bene-based organocatalysis have been developed that allow the
direct preparation of a range of (Æ)-4-phenoxycarbonylazlac-
tones in good isolated yields (66–84%) from the corresponding
N-p-anisoyl amino acids.
The development of tandem reaction processes that permit the
Fig. 1 Proposed two-step carbonate formation–rearrangement pro-
efficient introduction of molecular complexity from simple
tocol.
starting materials in a single reaction sequence is highly
desirable. Many such sequential transformations have been
used in synthesis, with several reviews dedicated to this topic.1
rearrangement to give (Æ)-7 from azlactone 4 in the presence
of 5 mol% of triazolium salt 5 (pKa in aqueous solution
17.7).13–15 Addition of phenyl chloroformate (1.1 equiv.) to a
The area of organocatalysis has enjoyed immense popularity
in the last decade,2 and a number of organocatalytic processes
THF solution of triazolium salt 5 (5 mol%), NEt3 (1.3 equiv.)
that incorporate tandem reaction sequences have been devel-
oped.3 N-heterocyclic carbenes (NHCs) are commonly used as
ligands in organometallic processes,4 and in recent years have
and azlactone 4 (1 equiv.) gave a 33 : 67 ratio of 6 : (Æ)-7
(Table 1, entry 1), with optimal conversion to (Æ)-7 observed
upon increasing the molar equivalents of NEt3 and phenyl
been employed as organocatalysts in a remarkably diverse
chloroformate (entry 2). Approximately 20% of carbamate 8
series of reactions.5 As part of a programme of research
concerned with developing alternative organocatalytic uses
of NHCs,6 we have previously shown that triazolinylidenes,
generated by deprotonation of a triazolium salt with a metal-
lated base such as KHMDS, can efficiently promote the
Steglich rearrangement7,8 of oxazolyl carbonates.9 As rela-
tively limited studies concerning multi-component reactions
incorporating NHC-mediated catalysis have been disclosed,10
the inclusion of this rearrangement procedure in a tandem
reaction sequence was investigated. Oxazolyl carbonates 2 are
readily prepared from the corresponding azlactone 1 by treat-
ment with a chloroformate under basic conditions, and given
the ability to generate NHCs by deprotonation of an azolium
salt, the amalgamation of these two steps into a tandem
process was envisaged (Fig. 1).11,12
was observed as a by-product of this optimised process,16 with
purification affording (Æ)-7 in 81% yield. Increased quantities
of NEt3 and phenyl chloroformate were detrimental to the
formation of (Æ)-7 (entry 3), giving increased amounts
(B70%) of carbamate 8. A simple control experiment showed
that excluding triazolium salt 5 from the reaction manifold
gave oxazolyl carbonate 6 and carbamate 8 as the sole reaction
products, consistent with the need for in situ NHC generation
to promote rearrangement of carbonate 6 to (Æ)-7.
Table 1 Optimisation of a two-step tandem reaction protocol
Herein we demonstrate that sub-stoichiometric quantities of
NHCs (5 mol%) promote the formation of C-carboxyazlac-
tones (Æ)-3 from azlactones 1 in a two-step tandem reaction
process, and extend this protocol to multi-step reaction
sequences.
Conversiona
Ratio
6 : (Æ)-7a
Primary model studies focused upon optimising the use of
NEt3 to promote carbonate formation and the desired
Entry
NEt3
(equiv.)
PhOCOCl
(equiv.)
1
2
1.3
1.5
1.1
1.3
75%
495%
33 : 67
10 : 90
(81%)b
65 : 35
a EaStCHEM, School of Chemistry, University of St Andrews, North
Haugh, St Andrews, UK KY16 9ST. E-mail: ads10@st-
andrews.ac.uk
3
2.3
1.3
495%
b Department of Chemistry, University of Durham, University Science
Laboratories, South Road, Durham, UK DH1 3LE
w Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data for all new products. See DOI:
10.1039/b806816j
a
Reaction conversions and product ratios were judged by 1H NMR
spectroscopic analysis of the crude reaction product and were mea-
b
sured with respect to azlactone 4. Isolated yield of homogeneous
(Æ)-7 after chromatographic purification.
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Table 2 Probing the generality of the two-step tandem reaction
protocol
Table 3 Tandem reaction protocol incorporating DCC coupling,
carbonate formation and NHC-promoted O- to C-carboxyl transfer
Entry
1
Acid
Product
Yield (%)a
71
Entry
1
Azlactone
Product
Yield (%)a
81
2
3
4
5
69
70
73
84
2
3
4
5
81
85
75
81
a
Isolated yield of homogeneous product after chromatographic
purification.
a
Isolated yield of homogeneous product after chromatographic
purification.
after chromatography (entry 1). This process also allowed
N-p-anisoyl amino acids 20–23 to be readily converted to the
corresponding C-phenoxycarbonylazlactones in 69–84%
isolated yields (entries 2–5).
The generality of this two-step tandem reaction process was
next established, with azlactones 9–12 readily converted to
their corresponding C-phenoxycarbonylazlactones under
these optimised conditions (Table 2), with chromatographic
purification giving (Æ)-15–(Æ)-18 in 75–85% isolated yields
(entries 2–5).17 Monitoring the consumption of azlactone 9 in
this tandem reaction sequence by 1H NMR spectroscopic
analysis confirmed full conversion to oxazolyl carbonate 13
as the sole reaction product after short reaction times (1 to 15
min), with subsequent rearrangement of carbonate 13 to (Æ)-
15. This reaction profile is consistent with oxazolyl carbonate
13 being an intermediate in this reaction pathway rather than
direct C-carboxylation of azlactone 9 promoted by NHC 14
under the reaction conditions.
As an alternative one-pot procedure for the direct prepara-
tion of C-phenoxycarbonylazlactones from N-p-anisoyl amino
acids, the use of phenyl chloroformate to promote cyclisation
and participate in oxazolyl carbonate formation was at-
tempted.19 It was anticipated that an excess of phenyl chloro-
formate would be necessary in this protocol to sequester the
phenoxide generated upon azlactone formation in this reaction
cycle, generating inert diphenyl carbonate.20 Addition of
phenyl chloroformate (3 equiv.) to a solution of N-p-anisoyl
norleucine 22, NEt3 (3.5 equiv.) and triazolium salt 5 (5 mol%)
proceeded with complete conversion to (Æ)-24 within 10 min,
giving diphenyl carbonate in 95% yield and (Æ)-24 in 75%
yield after chromatography (Table 4, entry 1). To further
exemplify this one-pot multi-step protocol, N-p-anisoyl amino
acids 19, 20 and 25 were directly converted to their corre-
sponding C-phenoxycarbonylazlactones (Æ)-7, (Æ)-15 and
(Æ)-26 in 66-78% isolated yield. Notably, N-p-anisoyl tyrosine
25 could be utilised in this protocol to give directly
O-phenoxycarbonyl protected azlactone (Æ)-26 in 66% iso-
lated yield, involving a reaction sequence that presumably
involves initial acid activation and cyclisation, phenolic
As azlactones such as 4 and 9–12 are typically prepared
from the corresponding N-p-anisoyl amino acids by carboxy-
late activation and cyclisation, the incorporation of this
transformation into a cascade reaction sequence was investi-
gated (Table 3). Treatment of N-p-anisoyl phenylalanine 19
with DCC in THF,8a,c,18 followed by filtration of the urea by-
product after 2 h, and sequential addition of triazolium salt 5,
NEt3 and phenyl chloroformate directly to the filtrate gave
good conversion to (Æ)-7, allowing its isolation in 71% yield
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Table
NHC-promoted O- to C-carboxyl transfer
4
Tandem multi-step reaction protocol incorporating
and L. Moisan, Angew. Chem., Int. Ed., 2004, 43, 5138; P. I. Dalko
and L. Moisan, Angew. Chem., Int. Ed., 2001, 40, 3726.
3. For reviews see G. Guillena, D. J. Ramon and M. Yus,
Tetrahedron: Asymmetry, 2007, 18, 693; D. Enders, C. Grondal
and M. R. M. Huttl, Angew. Chem., Int. Ed., 2007, 46, 1570.
4. For recent reviews see D. Bourissou, O. Guerret, F. P. Gabbaı and
G. Bertrand, Chem. Rev., 2000, 100, 39; W. A. Herrmann, Angew.
Chem., Int. Ed., 2002, 41, 1290; N. M. Scott and S. P. Nolan, Eur.
J. Inorg. Chem., 2005, 1815; M. C. Perry and K. Burgess, Tetra-
hedron: Asymmetry, 2003, 14, 951.
5. For recent reviews see D. Enders, O. Niemeier and A. Henseler,
Chem. Rev., 2007, 107, 5606; N. Marion, S. Dıez-Gonzalez and
S. P. Nolan, Angew. Chem., Int. Ed., 2007, 46, 2988.
6. N. Duguet, C. D. Campbell, A. M. Z. Slawin and A. D. Smith,
Org. Biomol. Chem., 2008, 6, 1108.
Entry
1
Acid
Product
Yield (%)a
75
7. W. Steglich and G. Hofle, Tetrahedron Lett., 1970, 4727.
8. For asymmetric versions of this reaction see (a) J. C. Ruble and
G. C. Fu, J. Am. Chem. Soc., 1998, 120, 11532; (b) S. A. Shaw,
P. Aleman and E. Vedejs, J. Am. Chem. Soc., 2003, 125, 13368;
(c) S. A. Shaw, P. Aleman, J. Christy, J. W. Kampf, P. Va and
E. Vedejs, J. Am. Chem. Soc., 2006, 128, 925; (d) H. Y. Nguyen,
D. C. Butler and C. J. Richards, Org. Lett., 2006, 8332, 769;
(e) J. G. Seitzberg, C. Dissing, I. Søtofte, P.-O. Norrby and
M. Johannsen, J. Org. Chem., 2005, 70, 8. Application to indolyl
and benzofuranyl carbonate derivatives: I. D. Hills and G. C. Fu,
Angew. Chem., Int. Ed., 2003, 42, 3921.
9. J. E. Thomson, K. Rix and A. D. Smith, Org. Lett., 2006, 8, 3785;
J. E. Thomson, C. D. Campbell, C. Concellon, N. Duguet, K. Rix,
A. M. Z. Slawin and A. D. Smith, J. Org. Chem., 2008, 73, 2784.
For amidine promoted catalysis of this reaction see C. Joannesse,
C. Simal, C. Concellon, J. E. Thomson, C. D. Campbell, A. M.
Z. Slawin and A. D. Smith, Org. Biomol. Chem., 2008, DOI:
10.1039/b805850d.
2
71
78
66
3
4b
10. For selected examples see V. Nair, S. Bindu and V. Sreekumar,
Angew. Chem., Int. Ed., 2004, 43, 5130; V. Nair, C. Rajesh,
A. U. Vinod, S. Bindu, A. R. Sreekanth, J. S. Mathen and
L. Balagopal, Acc. Chem. Res., 2003, 36, 899; H. A. Duong,
M. J. Cross and J. Louie, Org. Lett., 2004, 6, 4679;
A. R. Bharadwaj and K. A. Scheidt, Org. Lett., 2004, 6, 1465.
11. For related tandem protocols involving stoichiometric DMAP
promoted catalysis see T. H. Black, S. M. Arrivo, J. S. Schumm
and J. M. Knobeloch, J. Org. Chem., 1987, 52, 5425; C. J. Moody,
K. J. Doyle, M. C. Elliott and T. J. Mowlem, J. Chem. Soc.,
Perkin Trans. 1, 1997, 2413.
a
Isolated yield of homogeneous product after chromatographic
b
purification. Reaction conditions employed: NEt3 (5.5 equiv.),
PhOCOCl (5 equiv.), salt 5 (10 mol%), THF, rt.
O-protection, oxazolyl carbonate formation and subsequent
chemoselective NHC mediated rearrangement to give the
desired product.21 Both of these multi-step reaction protocols
are chemically robust as they proceed without employing an
inert atmosphere or rigorously dried THF or reagents.
In conclusion, we have shown that NHC 14, generated from
triazolium salt 5 with NEt3, can promote the rearrangement of
oxazolyl carbonates to their corresponding C-carboxyazlac-
tones, allowing this NHC mediated rearrangement protocol to
be incorporated into tandem multi-step reaction sequences.
Current studies are focused upon developing efficient enantio-
selective versions of these reaction processes alongside develop-
ing alternative applications of NHCs in asymmetric catalysis.
The authors would like to thank the Royal Society for a
University Research Fellowship (ADS), The Carnegie Trust
for the Universities of Scotland for a scholarship (CDC), The
Leverhulme Trust (ND), EaStCHEM and the University of
St Andrews (JET) for funding.
12. For a related tandem diastereoselective procedure see G. Peris and
E. Vedejs, J. Org. Chem., 2008, 73, 1158.
13. Attempted use of KHMDS as a base to promote the two-step
tandem formation of (Æ)-7 from azlactone 4 (1 equiv.) using salt 5
(10 mol%), KHMDS (1.1 equiv.) and PhOCOCl (1.3 equiv.) in
THF at rt gave only B40% conversion to (Æ)-7.
14. T. L. Amyes, S. T. Diver, J. P. Richard, F. M. Rivas and K. Toth,
J. Am. Chem. Soc., 2004, 126, 4366.
15. See supporting information for full details of the methods used for
this pKa determination.
16. An authentic sample of carbamate 8 was prepared by treatment of
phenyl chloroformate with NEt3 in THF at rt, giving carbamate 8
in 68% isolated yield. See supporting information for full details.
17. In each case, the crude reaction product also contained 10–20% of
carbamate 8.
18. M. Tokunaga, J. Kiyosu, Y. Obora and Y. Tsuji, J. Am. Chem.
Soc., 2006, 128, 4481; B. M. Trost and C. Lee, J. Am. Chem. Soc.,
2001, 123, 12191; D. Obrecht, M. Altorfer, C. Lehmann,
P. Schoenholzer and K. Muller, J. Org. Chem., 1996, 61, 4080.
19. For the preparation of azlactones from N-acyl amino acids using
chloroformates see F. M. F. Chen, M. Slebioba and
N. L. Benoiton, Int. J. Peptide Res., 1988, 31, 339; M. Hugener
and H. Heimgartner, Helv. Chim. Acta, 1995, 78, 1863.
20. Attempts to use diphenyl carbonate as an alternative to phenyl
chloroformate to generate oxazolyl carbonates from azlactones in
the presence of NEt3 returned only starting material.
Notes and references
1. See L. F. Tietz and U. Beifuss, Angew. Chem., Int. Ed. Engl., 1993,
32, 131; L. F. Tietze, Chem. Ind., 1995, 453; L. F. Tietze, Chem.
Rev., 1996, 96, 115; S. E. Denmark and A. Thorarensen, Chem.
Rev., 1996, 96, 137; P. J. Parsons, C. S. Penkett and A. J. Shell,
Chem. Rev., 1996, 96, 195; M. Malacria, Chem. Rev., 1996, 96,
289.
21. Fries type rearrangement was not observed in this reaction
sequence. Furthermore, treatment of diphenyl carbonate with
NHC 14 (9 mol%) derived from salt 5 (10 mol%) and KHMDS
(9 mol%) returned only starting material after prolonged reaction
times or upon heating.
2. For reviews see A. M. Walji and D. W. C. MacMillan, Synlett,
2007, 1477; H. Pellissier, Tetrahedron, 2007, 63, 9267; P. I. Dalko
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3530 | Chem. Commun., 2008, 3528–3530