Synthesis of functionalized allenamides from ynamides by enolate claisen rearrangement

Article abstract of DOI:10.1021/ol400402n

The Claisen rearrangement of N-Boc glycinates derived from ynamido-alcohols affords an efficient and stereoselective access to highly functionalized allenamides. These compounds undergo silver-catalyzed cyclization to 3-pyrrolines which are useful precurs

Full text of DOI:10.1021/ol400402n

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1626–1629
Synthesis of Functionalized Allenamides
from Ynamides by Enolate Claisen
Rearrangement
Julien Brioche, Christophe Meyer,* and Janine Cossy*
Laboratoire de Chimie Organique, ESPCI Paris Tech, CNRS, 10 rue Vauquelin,
75231 Paris Cedex 05, France
christophe.meyer@espci.fr; janine.cossy@espci.fr
Received February 11, 2013
ABSTRACT
The Claisen rearrangement of N-Boc glycinates derived from ynamido-alcohols affords an efficient and stereoselective access to highly
functionalized allenamides. These compounds undergo silver-catalyzed cyclization to 3-pyrrolines which are useful precursors for the synthesis
of substituted pyrrolidines.
Over the past decade, the chemistry of allenamides has
elicited considerable interest.1 These compounds, which
are more stable than allenamines, have emerged as useful
building blocks in a wide variety of transformations
cleverly exploiting their greater nucleophilic character
compared to nonheterosubstituted allenes and their ability
to introduce valuable nitrogen-based functionalities into
the resulting products.1,2 Several methods have been
developed for the synthesis of allenamides (Scheme 1)
and the most popular route involves the base-catalyzed
isomerization of N-propargyl amides A which only affords
terminal allenamides (Scheme 1, path a).3 Allenamides
have been prepared from other nitrogen-containing pre-
cursors byβ-elimination of enol triflates B(Scheme 1, path b)4
or reaction of metalated chiral N-propargyl oxazolidi-
nones C with aldehydes (Scheme 1, path c).5 Alternatively,
the nitrogen atom can be introduced by intramolecular
addition to a σ-allenylPd(II) complex generated from an app-
ropriate propargylic nucleofuge in compounds D (Scheme 1,
path d)6 or by copper-catalyzed cross-coupling between an
amide and an allenyl halide E (Scheme 1, path e).7 Another
strategy involves the [3,3]-sigmatropic rearrangement of a
propargyl alcohol derivative. This transformation was initially
reported for propargyl imidates,8a propargyloxy-oxazoles,8b
and purines,8c with a limited substrate scope. Recently
N-phosphoryl allenamides have been synthesized by
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r
10.1021/ol400402n
Published on Web 03/15/2013
2013 American Chemical Society

Pd(II)-catalyzed rearrangement of propargyl phosphori-
midates F (Scheme 1, path f).9 A complementary strategy
relies on the [2,3]-sigmatropic rearrangement of propargyl
sulfimides G leading to N-allenylsulfenimides (Scheme 1,
path g).10 Another recently investigated class of precursors
are ynamides11 possessing a propargylic alcohol (hereafter
referred to as “ynamido-alcohols”), as illustrated with the
[2,3]-sigmatropic rearrangement of phosphites H leading
to R-aminoallenylphosphonates (Scheme 1, path h)12 and
the Pd(0)-catalyzed coupling of propargylic carbonates I
with arylboronic acids (Scheme 1, path i).13 However, the
preparation of enantiomerically enriched functionalized
allenamides with respect to axial chirality has only been
achieved byroute (c) relying on a chiral auxiliary,5 route(e)
using enantioenriched allenyl halides whose preparation is
not trivial,7b and routes (f) and (g) by chirality transfer.9,10
rearrangement leading to aminodienes L.16 This work
prompted us to disclose our results, and we report herein
the first synthesis of highly functionalized allenamides O
using the ester-enolate Claisen rearrangement of glycinates17
M derived from N-sulfonyl ynamido-alcohols as well
as their use for the synthesis of substituted pyrrolidines
(Scheme 2).
Scheme 2. Claisen Rearrangement of Ynamido-Alcohol
Derivatives
Scheme 1. Synthetic Routes toward Allenamides
Propargylicglycinate2awas selectedasthetestsubstrate
and was readily prepared by copper-catalyzed cross-cou-
pling between bromoalkyne 1a, derived from but-3-yn-2-
ol, and N-benzyl sulfonamide.18 As reported recently,12
this coupling reaction could be carried out with the free
alcohol, but to avoid long reactions times and obtain
satisfactory yields of the coupling products in all the
investigated cases, we found that a 3-fold increase of the
copper salt and ligand loadings was beneficial. Subsequent
esterification of the intermediate ynamido-alcohol with
N-Boc glycine provided glycinate 2a (63%, two steps from
1a). The chelated R-amino zinc enolate P was generated
from glycinate 2a by treatment with LiHMDS (THF,
ꢀ78 °C) followed by the addition of ZnCl2.17b,c Subse-
quent enolate-Claisen rearrangement proceeded smoothly
(ꢀ78 °C, 2 h) and led to the corresponding stable car-
boxylic acid 3a which did not undergo decarboxylation, by
contrast with the behavior of compounds J.19 Carboxylic
acid 3a was converted to the corresponding methyl ester
(MeI, K2CO3, DMF, rt) to afford allenamide 4a, but the
diastereoselectivity of the rearrangement was difficult to
evaluate due to the presence of rotamers (Boc group).
Cyclization of the crude allenamide 4a could be accom-
plished under remarkably mild conditions by treatment
Despite the synthetic potential of Claisen rearrangements
involving derivatives of propargyl alcohols as a route to
allenes,14 the possibility to access allenamides by a [3,3]-
sigmatropic rearrangement involving ynamido-alcohol
derivatives has not been demonstrated yet.15 Recently,
Carbery and Heffernan reported that an IrelandꢀClaisen
rearrangement applied to arylacetates J did not lead to the
expected allenamide carboxylic acids K because these
compounds underwent spontaneous decarboxylative
(9) Danowitz, A. M.; Taylor, C. E.; Shrikian, T. M.; Mapp, A. K.
Org. Lett. 2010, 12, 2574–2577.
(10) (a) Armstrong, A.; Cooke, R. S.; Shanahan, S. E. Org. Biomol.
Chem. 2003, 1, 3142–3143. (b) Armstrong, A.; Emmerson, D. P. G. Org.
Lett. 2009, 11, 1547–1550.
(11) For reviews on ynamides, see: (a) DeKorver, K. A; Li, H.;
Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev.
2010, 110, 5064–5106. (b) Evano, G.; Coste, A.; Jouvin, K. Angew.
Chem., Int. Ed. 2010, 49, 2840–2859.
(16) Heffernan, S. J.; Carbery, D. R. Tetrahedron Lett. 2012, 53,
5180–5182. Rearrangement of a propionate derived from an ynamido-
alcohol also led to an aminodiene instead of an allenamide.
(12) Gomes, F.; Fadel, A.; Rabasso, N. J. Org. Chem. 2012, 77, 5439–
5444.
(17) (a) Castelhano, A. L.; Horne, S.; Taylor, G. J.; Billedeau, R.;
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Krantz, A. Tetrahedron 1988, 44, 5451–5466. (b) Kazmaier, U.; Gorbitz,
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Org. Biomol. Chem. 2012, 10, 9556–9561.
C. H. Synthesis 1996, 1489–1493. (c) Zumpe, F. L.; Kazmaier, U. Synlett
1998, 434–436. (d) Mitasev, B.; Brummond, K. M. Synlett 2006, 3100–
3104.
(18) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera,
E. L. Org. Lett. 2004, 6, 1151–1154.
(14) (a) The Claisen Rearrangement. Methods and Applications;
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(b) For a recent review, see: Trejedor, D.; Mendez-Abt, G.; Cotos, L.; García-
Tellado, F. Chem. Soc. Rev. 2013, 42, 458–471.
(19) The different reactivity seems to be due to the nature of
the electron-withdrawing group on the nitrogen atom since the
IrelandꢀClaisen rearrangement of an arylacetate derived from a
N-tosyl ynamido-alcohol was not followed by decarboxylation; see
Supporting Information for a comparison of the reactivity.
(15) For sigmatropic rearrangements of the related enamido allylic
alcohols, see: (a) Ylioja, P. M.; Mosley, A. D.; Charlot, C. E.; Carbery,
D. R. Tetrahedron Lett. 2008, 49, 1111–1114. (b) Barbazanges, M.;
Meyer, C.; Cossy, J.; Turner, P. Chem.;Eur. J. 2011, 17, 4480–4495.
Org. Lett., Vol. 15, No. 7, 2013
1627

with AgNO3 (5 mol %) (acetone, rt)20 to afford the
corresponding 3-pyrroline 5a which, as indicated by analysis
of its 1H NMR spectrum recorded at 395 K, was obtained
with high diastereoselectivity (dr = 95:5) and isolated in
excellent overall yield (70%, three steps from glycinate 2a).
After reduction of the ester moiety and cleavage of the Boc
group, the 2,5-cis relative configuration of pyrroline 6 was
established by NMR (NOESY). The observed stereochem-
ical outcome was consistent with a chairlike transition
state for the [3,3]-sigmatropic rearrangement of the zinc
enolate P in which the methyl substituent preferentially
occupies a pseudoequatorial position (Scheme 3).17bꢀd
Scheme 4. Chirality Transfer in the Rearrangement of 2a
allenamides 4b (54%) or 4c (57%), respectively, were
isolated in overall yields comparable to the one obtained
for 4a (65%). The substituents were then varied at the
propargylic position and at the nitrogen atom to provide
functionalized allenamides 4dꢀf in good overall yields
(67ꢀ73%) (Scheme 5).
Scheme 3. Preliminary Results with Glycinate 2a
Scheme 5. Scope of the [3,3]-Claisen Rearrangement
The presence of the nitrogen substituent on the alkyne
had no adverse effect on the stereochemical outcome of the
[3,3]-sigmatropic Claisen rearrangement by contrast with
previous observations with derivatives of the related
enamido allylic alcohols.15 Due the high diastereoselectivity
observed in the rearrangement of 2a, the absolute chirality
transfer was evaluated with glycinate (R)-2a (ee = 96%).
The enolate-Claisen rearrangement of this latter substrate
led to the enantioenriched allenamide 4a whose optical
purity confirmed that complete chirality transfer took
place, as previously observed with nonheterosubstituted
alkynes.17 Subsequent silver-catalyzed cyclization also
proceeded with chirality transfer though a slight erosion
of the measured optical purity (ee = 93%) was observed
for the corresponding 3-pyrroline 5a (Scheme 4).21
The scope of the enolate-Claisen rearrangement was
explored with a variety of substituted ynamido-propargylic
glycinates 2bꢀi, and the corresponding allenamides 4bꢀi
were isolated in satisfactory overall yields (53ꢀ73%, two
steps from 2bꢀi). For glycinates possessing a N-benzyl
N-sulfonylamino group on the alkyne, the substituent at
thepropargylicposition could bea benzyloxymethylgroup
(R0 = CH2OBn) or an isopropyl group (R0 = i-Pr) and
We also checked that glycinates 2gꢀi, derived from
primary ynamido-alcohols, were viable substrates that led
to the corresponding terminal allenamides 4gꢀi in similar
yields (53ꢀ60%) without competing deprotonation at the
unsubstituted propargylic position (R0 = H) (Scheme 5).
The cyclization of R-amino allenes to 3-pyrrolines can be
20
catalyzed by AgNO3 or AgBF4.22 When the nitrogen
(22) Claesson, A.; Sahlberg, C.; Luthman, K. Acta Chem. Scand. B
1979, 33, 309–310.
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4256.
(25) For the cyclization of N-sulfonyl R-amino allenes, see: (a) Okala
Amombo, M.; Hausherr, A.; Reissing, H.-U. Synlett 1999, 1871–1874.
(b) Ohni, H.; Toda, A.; Miwa, Y.; Taga, T.; Oswa, E.; Yamaoka, Y.;
Fujii, N.; Ibuka, T. J. Org. Chem. 1999, 64, 2992–2993. (c) Cai, S.;
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(20) Dieter, R. K.; Yu, H. Org. Lett. 2001, 3, 3855–3858.
(21) This difference may be due to the presence of the 2,5-trans-
diastereomer of pyrroline 5a which is at the limit of detection by 1H
NMR spectroscopy (dr = 95:5).
1628
Org. Lett., Vol. 15, No. 7, 2013

atom is substituted by an electron-withdrawing carbonyl
group, AgBF4 has often been used in large if not
stoichiometric quantities and the cyclization worked well
with terminal allenes;23 otherwise side reactions were also
observed.17d,24,25 Although gold-catalyzed cyclizations
have also been developed,26,27 the mild conditions ob-
served for the silver-catalyzed cyclization of N-Boc
R-amino allenamide 4a to 5a were noteworthy and thus
applied to the other allenamides 4bꢀf. In the case of
allenamide 4b, substituted by a benzyloxymethyl group
at C5, a 80:20 mixture of diastereomeric pyrrolines 5b/5b0
was obtained. In the particular case of 4b, anchimeric
assistance by the oxygen atom of the benzyl ether may
partially occur leading to the opposite configuration at C5
after intramolecular nucleophilic attack of the nitrogen
atom. The other 2,5-disubstituted 3-pyrrolines 5cꢀf were
obtained in excellent yields (82ꢀ90%) and with high
diastereoselectivities (dr g95:5) (Scheme 6).
Scheme 7. Synthesis of Substituted Pyrrolidines
was accompanied by isomerization to the corresponding
N-benzyl ketimine 8 which was not purified. Subsequent
reduction with NaBH4 led to the 2,3,5-cis-trisubstituted
pyrrolidine 9 (73%, two steps from 7) with high diaste-
reoselectivity (dr g95:5). By intramolecular nucleophilic
substitution of the mesylate derived from the primary
alcohol, compound 9 was converted to the substituted
2,6-diazabicyclo[3.2.0]heptane 10 (48%), a scaffold of
interest in medicinal chemistry.29 The addition of allylmag-
nesium chloride to ketimine 8 also proceeded with high
diastereoselectivity (dr g95:5) and provided the tetrasub-
stituted pyrrolidine 11 possessing a quaternary stereocenter
in 40% yield (unoptimized, two steps from 7) (Scheme 7).
In conclusion, we have reported that the Claisen rear-
rangement of N-Boc glycinates derived from ynamido-
alcohols offers an efficient and stereoselective access to
functionalized allenamides. These compounds underwent
silver-catalyzed cyclization to3-pyrrolines which are useful
building blocks for the synthesis of substituted pyrroli-
dines. Further work is in progress to expand the scope of
sigmatropic rearrangements involving ynamido-alcohol
derivatives.
Scheme 6. Silver-Catalyzed Cyclization of Allenamides 4aꢀf
Acknowledgment. The authors thank the ANR
(DYNAMITE ANR-2010-BLAN-704 project) for finan-
cial support.
To highlight the interest of the Claisen rearrangement of
glycinates derived from ynamido-alcohols and the subse-
quent silver-catalyzed cyclization, we briefly examined its
application to the preparation of substituted pyrrolidines.
One important issue was cleavage of the tosyl substituent
on the nitrogen atom of the enamide moiety. As illustrated
for pyrroline 7 (generated from 5a by reduction with
LiAlH4), this operation could be cleanly accomplished by
treatment with sodium naphthalenide (THF, ꢀ78 °C)28 and
Note Added after ASAP Publication. The uncorrected
version of this paper was published ASAP on March 15,
2013 the corrected version reposted later on March 15, 2013.
Supporting Information Available. Experimental pro-
1
cedures and H and 13C NMR data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Nersesian, D. L.; Schrimpf, M. R. U.S. Patent 2005/101602 A1, May 12,
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hydroxy group leads to dihydrofurans bearing a N,O-acetal; see:
Hyland, C. J. T.; Hegedus, L. S. J. Org. Chem. 2006, 71, 8658–8660.
(28) Ji, S.; Gortler, L. B.; Waring, A.; Battisti, A. J.; Bank, S.;
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The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
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