Heteroatom nucleophile induced C-C fragmentations to access functionalized allenes

Article abstract of DOI:10.2533/chimia.2012.205

The rich structural and reactivity profile of allenes render them versatile synthetic intermediates. However, application of allenes in organic chemistry is often attenuated by inconvenient methods of preparation. Herein we present an operationally simple

Full text of DOI:10.2533/chimia.2012.205

Laureates: awards and Honors, sCs FaLL Meeting 2011
CHIMIA 2012, 66, No. 4 205
doi:10.2533/chimia.2012.205
Chimia 66 (2012) 205–207 © Schweizerische Chemische Gesellschaft
Heteroatom Nucleophile Induced C–C
Fragmentations to Access Functionalized
Allenes
Tanguy Saget§ and Nicolai Cramer*
§SCS-Metrohm Foundation Award for best oral presentation
Abstract: The rich structural and reactivity profile of allenes render them versatile synthetic intermediates.
However, application of allenes in organic chemistry is often attenuated by inconvenient methods of preparation.
Herein we present an operationally simple route to functionalized allenes from vinyl triflate precursors through
a Grob-type fragmentation induced by heteroatom nucleophiles such as water, alcohols, thiols or amines. The
fragmentation occurs under mild conditions and is well suited for one-pot or domino processes allowing access
to a range of synthetically useful intermediates.
Keywords: Allenes · Cyclization · Domino reactions · Fragmentation · Radicals
The allene moiety is a versatile and
1).[6] However, their method is limited by was not required for this transformation.
uniquely reactive functional group which the use of hard carbon-nucleophiles such After careful examination of the reaction
has become popular in modern organic as organolithium or organocerium re- parameters, we found that 1a is quanti-
chemistry, especially in transition-metal agents. Moreover, only products with the tatively transformed into enone 6 when
catalysis.[1] Although several methods for carbonyl moiety at the ketone oxidation heated in DMF at 100 °C in the presence
their preparation are established, addi- level or tertiary alcohols resulting from a of potassium carbonate.[8] One can ratio-
tional and complementary methods to ac- second addition of the nucleophile are ac- nalize the formation of 6 by a mechanism
cess them are of synthetic significance.[2] cessible. Reactions induced by heteroatom which starts by a nucleophile-induced
Additionally, the use of mild reaction con- nucleophiles that would provide versatile Grob-fragmentation in which DMF acts
ditions is highly desirable since the reactive carbonyl bearing products at the carboxyl- as the attacking nucleophile. The resulting
profile of the allene would be well suited ic acid oxidation level are not possible with intermediate 4a or its acyl triflate equiva-
for one pot or domino processes. Such an the reported set of reaction conditions.
approach would lead to a rapid increase in Our group has a long-standing inter- molecular Friedel-Crafts acylation leading
molecular complexity from rather simple est in the development of metal-catalyzed to allylic carbenium 5 which gives 6 after
precursors.
C–H bond activations.[7] In this context, we proton elimination (Scheme 2). After this
The carbonyl-generating Grob frag- have prepared compounds such as vinyl initial discovery, we decided to follow up
lent 4b can subsequently undergo an intra-
mentation is a well-established cleaving triflate 1 as substrates to develop enanti- this reactivity and to explore the potential
process which has found widespread ap- oselective palladium-catalyzed C(sp3)-H of this transformation. First we reasoned
plication in synthesis.[3] Since the seminal functionalizations. Unexpectedly, 1a was that if DMF can promote the fragmenta-
work of Eschenmoser,[4] numerous related converted to product 6 under several reac- tion of 1, then other nucleophiles such as
reactions have been reported in the litera- tion conditions we tested. To our surprise,
alcohols and amines might be competent
ture. Dudleyandcoworkersstudiednucleo- we discovered that a palladium catalyst as well.
phile-induced Grob-type fragmentation re-
Scheme 1. Nucleo-
phile induced Grob-
type fragmentations
to access allenes.
actions of vinylogous acyl triflates leading
2
1
OTf
R
2
1
OTf
R
to ω-substituted alkynes.[5] Furthermore,
Williams and coworkers recently extended
this strategy to access allenes (Scheme
R
R
1
O
Nu
R
O
TfO
Nu
3 O
R
3
R
2
•
R
Nu
3
3
3
3
3
R
R
R
R
2
1
Scheme 2. Lead dis-
covery of a domino
reaction consisting
of a fragmentation
and a Friedel-Crafts
reaction.
Pr
TfO
O
•
Pr
Pr
Pr Pr
O
O
NMe
Pr
Pr
2
O
OTf
4a
D
MF,K2CO3
O
4AMS, 1 0°C
0
Pr
Me N
H
O
2
5
*Correspondence: Prof. Dr. N. Cramer
Ecole Polytechnique Fédérale de Lausanne
EPFL SB ISIC LCSA
DMF
1a
•
OTf
4b
Et
O
BCH 4305
CH-1015 Lausanne
Tel.: +41 21 693 9839
Fax: +41 21 693 9700
E-mail: nicolai.cramer@epfl.ch
Pr
6
99%
4,4:1 Z/E

206 CHIMIA 2012, 66, No. 4
Laureates: awards and Honors, sCs FaLL Meeting 2011
In this respect, the fragmentation was ing carboxylic acids 7e,f were obtained by standard cross-coupling reactions.
initially examined with substrate 1a and in high yields. Finally, thiophenol is also Alternatively, such tetrasubstituted ole-
benzyl alcohol as the promoter in the pres- competent to promote the reaction giving fins are directly obtained from allenes 7
ence of a base. We found that the reaction access to valuable thioester 7h, available through a one-pot fragmentation-arylative
proceeds equally well in polar aprotic sol- for further derivatization reactions, e.g. cyclization sequence.[11] The addition of a
vents such as DMF, DMA or DMSO while Liebeskind-couplings.
nonpolar solvents like toluene or DCE are To showcase the utility of this reac-
not competent. The influence of the base tion, we studied the lactonization of the allenes 7 induces lactonization to products
catalytic amount of [Pd(dba)2] and tricy-
clohexyl phosphine with phenyl iodide to
was also investigated. Cesium carbonate carboxylic acid products as the resulting 8e,f. From a mechanistic point of view,
gave the best results, allowing fast con- γ-butyrolactones represent an abundant oxidative addition of Pd0 to the aryl iodide
versions at room temperature. Potassium motif in natural products (Scheme 4).[9] generates an [Ar-PdII-X] species which can
carbonate displayed somewhat lower re- For instance, cyclization to the desired act as a π-Lewis acid to activate the allene
activity whereas poor conversions were five-membered allylic lactones 8a,b oc- moiety of 5, thus promoting a Wacker-type
observed with sodium bicarbonate, tri- curs in good yields in the presence of tri- cyclization followed by a reductive elimi-
ethylamine or in the absence of any base. fluoroacetic acid. The reaction proceeds
Under the optimized reaction conditions, presumably via protonation of the allene. a carbo-palladation of the allene to form
the desired allene 7a was obtained in 70% The resulting allylic carbocation is in turn
nation. A second possible mechanism is
a π-allyl palladium intermediate which is
yield (Scheme 3). Different allenes such as intramolecularly trapped by the carboxylic trapped by an intramolecular nucleophilic
7b could be synthesized with similar effi- acid moiety to give 8a,b. We found that attack of the carboxylic acid.[11]
ciency. The more acidic phenol works even
acids 7 also undergo iodolactonizations in
We then evaluated nitrogen-contain-
better as shown for 7c,d. Remarkably, the a one-pot process from 1 by simply add- ing nucleophiles as a second major class
ambident nucleophile 4-aminophenol re- ing iodine to the reaction mixture after of heteroatom nucleophiles for the frag-
acts selectively with the hydroxyl group to completion of the fragmentation step.[10] mentation. We were pleased that they ef-
give 7g in good yield. Moreover, water is a The resulting vinyl iodides 8c,d are valu-
ficiently promote the reaction with only
powerful promoter and by simply running able intermediates which can be further minor changes to the prior established
the reaction in wet solvent, the correspond- transformed into tetrasubstituted olefins reaction conditions. Both primary and
secondary amines lead to allenes 9a,b in
excellent yields (Scheme 5). Aniline and
even free ammonia are also competent nu-
cleophiles (9c,d). Moreover, significantly
less nucleophilic sulfonamides can pro-
Scheme 3. Oxygen
2
1
OTf
R
R
1
and sulfur nucleo-
philes induce the
fragmentation.
R
O
Nu
H
3 O
R
3
R
2
•
R
Pr
Pr
Cs2CO3,DMA, 23°C
Nu
3
3
mote the fragmentation provided that ce-
7
R
R
1
sium carbonate is used as base instead of
potassium carbonate. Interestingly, when
the fragmentation was conducted with the
ambident N-phenyl hydroxylamine, the
nitrogen atom selectively reacts to afford
hydroxamic acid derivative 9f.
Pr
Bn
Pr
O
O
O
•
•
Pr
Me
•
O
Bn
O
Bn
OPh
70 % 7
a
65% 7b
9
2 % 7c
Ph
Allyl
Pr
O
O
O
Inspired by a recent report on oxida-
•
Allyl
•
•
Allyl
O
H
O
Ph
OH
tive cyclization of unsaturated hydroxamic
86 %
acids,[12] 9f seemed to be an ideal precur-
8
8 % 7
d
7e
9
9 %
7f
sor for a further cyclization. Heating 9f
in acetic acid in the presence of oxygen
and lauroyl peroxide at 60 °C resulted in
the formation of 1,2-oxazinone 13 in fair
Allyl
Pr
NH2
O
O
•
•
Allyl
Pr
S
P
h
O
70 %
66%
7
g
7h
yield. From a mechanistic point of view,
we presume that the initially formed oxy-
gen centered radical 10 cyclizes to gener-
ate a highly reactive vinyl radical species
11, which in turn is trapped by molecular
Scheme 4. Lactoni-
zation reactions of
carboxylic acid inter-
mediates.
O
O
O
O
Me
Pr
Pr
H
Bn
H
oxygen. The resulting hydroperoxide 12
rearranges into hydroxyketone product 13
(Scheme 6). This radical cyclization rep-
resents a convenient approach to densely
functionalized 1,2-oxazinones which are
an important class of heterocycles encoun-
tered in several biologically active com-
pounds.
Finally, we turned our attention to so-
dium azide as another nitrogen-contain-
ing promoter for the fragmentation of 1
(Scheme 7). With the azide anion as nu-
8
b
9
9 %8
a
6
9%
O
1:2.3 Z/E
O
TFA
Pr
Pr
2
1
R
R
I
1
R
O
OTf
I
2
78 %
8c
3 O
R
H O,K2CO3
3
2
R
2
•
R
O
O
H
3
3
7
R
R
O
1
Me
Bn
8d
0
cat. Pd
PhI
I
8
3 %
1:1.3 Z/E
O
O
cleophile, this would lead to the formation
O
O
Me
Bn
Pr
Pr
of an acyl azide intermediates 14. These
derivatives are known to undergo Curtius-
rearrangements generating isocyanates 15.
Indeed, heating 1a in the presence of NaN3
H
H
6
0 % 8f
8e
2 %
6
2.1:1 Z/E

Laureates: awards and Honors, sCs FaLL Meeting 2011
CHIMIA 2012, 66, No. 4 207
Allene Chemistry’, Eds. N. Krause, A. S. K.
Hashmi, Wiley-VCH, Weinheim, 2004.
[2] a) K. M. Brummond, J. E. Deforrest, Synthesis
2007, 795; b) S. Yu, S. Ma Chem. Commun.
2011, 47, 5384.
[3] K. Pranz, J. Mulzer, Chem. Rev. 2010, 110,
Scheme 5. Frag-
mentation induced by
nitrogen containing
nucleophiles.
2
1
OTf
R
R
1
O
R
Nu
H
3 O
R
3
R
2
•
R
K2CO3,DMA, 50°C
Nu
3
3
R
R
9
1
3741.
Me
O
Allyl
Allyl
O
O
[4] A. Eschenmoser, A. Frey, Helv. Chim. Acta
1952, 35, 1660.
[5] a) S. Kamijo, G. B. Dudley, J. Am. Chem. Soc.
•
•
Bn
•
Allyl
Allyl
Allyl
Pr
N
NHBn
NHPh
9
9 % 9
b
96 %
O
84%
9
9
a
c
2005, 127, 5028; b) S. Kamijo, G. B. Dudley,
Org. Lett. 2006, 8, 175; c) D. M. Jones, S,
Kamijo, G. B. Dudley, Synlett 2006, 936;
d) S. Kamijo, G. B. Dudley, J. Am. Chem.
Soc. 2006, 128, 6499; e) S. Kamijo, G. B.
Dudley, Tetrahedron Lett. 2006, 47, 5629; f) J.
Allyl
Pr
Pr
O
O
O
•
•
•
Pr
Ph
N 2
H
N
HTs
N
OH
91 %
75% 9f
94 % 9
d
9e
Tummatorn, G. B. Dudley, J. Am. Chem. Soc.
2008, 130, 5050; g) D. M. Jones, M. P. Lisboa,
S. Kamijo, G. B. Dudley, J. Org. Chem. 2010,
75, 3260.
Scheme 6. Oxidative
radical cyclization of
allenic hydroxamic
acid 9f.
Ph
N
Pr
O
O
O
O
Pr
Pr
lauroylperoxide, O (1 atm)
2
•
Pr
Pr
Ph
[6] R. V. Kolakowski, M. Manpadi, Y. Zhang, T. J.
N
O
O
H
AcOH, 60°C
Emge, L. J. Williams, J. Am. Chem. Soc. 2009,
131, 12910.
[7] a) T. Seiser, O. A. Roth, N. Cramer, Angew.
9f
H
O
13
52 %
R
Chem. Int. Ed. 2009, 48, 6320; M. Albicker, N.
Cramer, Angew. Chem. Int. Ed. 2009, 48, 9139;
D. N. Tran, N. Cramer, Angew. Chem. Int. Ed.
2010, 49, 8181; D. N. Tran, N. Cramer, Angew.
Chem. Int. Ed. 2011, 50, 11098; T. Saget, S. J.
Lemouzy, N. Cramer, Angew. Chem. Int. Ed.
2012, 51, 2238.
Ph
Ph
Pr
O
O
N
N
O
O
Pr
Pr
O
Pr
Pr
2
•
Ph
N
O
10
O
11
OH
12
[8] T. Saget, N. Cramer, Angew. Chem. Int. Ed.
2010, 49, 8962.
[9] a) M. S. Maier, D. I. G. Marimon, C. A. Stortz,
Scheme 7. Domino
reaction consisting of
the fragmentation and
a Curtius rearrange-
ment.
Pr
Pr
M. T. Adler, J. Nat. Prod. 1999, 62, 1565; b)
S.-C. Lee, G. D. Brown, J. Nat. Prod. 1998, 61,
29; c) R. R. A. Kitson, A. Millemaggi, R. J. K.
Taylor, Angew. Chem. Int. Ed. 2009, 48, 9426.
1
R
•
3 O
3
R
R
2
•
14
R
2
1
N
R
R
3
O
OTf
H O
2
NaN
NH
3
-N
[10] X. Jiang, C. Fu, S. Ma, Chem. Eur. J. 2008, 14,
9656.
[11] R. D. Walkup, L. Guan, M. D. Mosher, S. W.
Kim, Y. S. Kim, Synlett 1993, 88.
[12] V. A. Schmidt, E. J. Alexanian, Angew. Chem.
Int. Ed. 2010, 49, 4491.
2
O
1
DMA, 100°C
R
N
H
3
3
3
3
R
R
R
R
99 %
2
•
R
N
•
1
15
O
•
16
Pr
Pr
R
O
H, RR1N
or R
H
S
H
O
O
O
HN
OBn
HN
OEt
HN
OBn
•
•
•
•
Pr
Pr
Me
17c 68 %
17b 80 %
17a 77 %
Pr
Pr
Bn
O
O
O
HN NMe
HN NHBn
HN
SPh
2
•
Pr
•
Pr
Pr
17e
17f 38 %
Pr
17d 67 %
69%
Pr
Pr
at 100 °C in DMF resulted in full conver- and well suited to be coupled to one-pot
sion to isocyanate 15a which was isolated or domino processes. In this case, one
as the symmetrical urea 16 upon aqueous can benefit from the inherent reactivity of
work-up. When alcohols are added to the allenes which allow transformations of
reaction mixture from the beginning, iso- these intermediates into a wide range of
cyanates 15 are directly trapped to the cor- synthetically useful compounds.
responding carbamates 17a,c. A similar
strategy can be used with amines or thiols
Acknowledgments
leading to ureas 17d,e and thiocarbamate
17f. In these cases, the nucleophile has to
be added after completion of the fragmen-
tation step.
In conclusion, we have reported a
practical and operationally simple syn-
thesis of functionalized allenes from read-
T. S. would like to cordially thank Metrohm
and the Swiss Chemical Society for the SCS-
Metrohm award. We thank the ETH Zurich
(ETH-16 09-3) and EPF Lausanne for funding.
Received: January 13, 2012
ily available vinyl triflate precursors. The
[1] a) ‘The Chemisty of Allenes’, Ed. S. R. Landor,
Academic Press, London, 1982; b) ‘Modern
employed reaction conditions are mild