Heteroatom-nucleophile-induced C - C fragmentations: Synthesis of allenes and entry to domino reactions

Article abstract of DOI:10.1002/anie.201004795

Blessed are the piece-makers: Heteroatom nucleophiles (NuH) induce Grob-type fragmentations of vinyl triflates under mild conditions and provide-allene-functionalized carboxylic acid derivatives. These products are a versatile starting point for domino an

Full text of DOI:10.1002/anie.201004795

Communications
DOI: 10.1002/anie.201004795
Domino Reactions
ꢀ
Heteroatom-Nucleophile-Induced C C Fragmentations: Synthesis of
Allenes and Entry to Domino Reactions**
Tanguy Saget and Nicolai Cramer*
Dedicated to Professor Albert Eschenmoser on the occasion of his 85th birthday
Since their discovery by Burton and von Pechmann in 1887,[1]
allenes have metamorphosed from a laboratory curiosity to a
versatile and uniquely reactive functional group.[2] The C C
=
bond of allenes is around 10 kcalmolꢀ1 less stable than that of
simple alkenes,[3] rendering them significantly more reactive.
In transition-metal-catalyzed reactions their reactivity is
closer to that of alkynes than that of simple alkenes. None-
theless, allenes display a distinct and complementary reac-
tivity profile.[4] As consequence of their increasing synthetic
importance, greater emphasis has been placed on the devel-
opment of methods for their preparation.[5]
Owing to the seminal contribution from Eschenmoser in
1952[6] and subsequent studies by Grob,[7] carbonyl- and
olefin-generating C–C bond fragmentations have found
widespread applications in synthesis.[8] Nucleophile-induced
ꢀ
Scheme 1. C C fragmentation of ketone 1 and potential domino
Grob-type fragmentation reactions of vinylogous acyl triflates
reactions of the generated products 3. Tf=trifluoromethanesulfonyl.
leading to w-functionalized alkynes were developed by
Dudley et al.[9] Recently, Williams and co-workers reported
a related method for the synthesis of allenes from vinyl
triflates such as 1.[10] This method requires organolithium or
organocerium carbon nucleophiles and leads to carbonyl
moieties at the ketone or aldehyde oxidation level. In
contrast, heteroatom nucleophiles failed to react or led to
decomposition of the substrates. However, given their strong
synthetic potential,[11] w-heteroatom or carboxylic acid deriv-
ative functionalized allenes are the most valuable congeners.
Thus a convenient and robust approach to this class of
compounds is highly desirable.
The fragmentation was initially examined with ketone 1a
and benzyl alcohol as the prototypical nucleophile (Table 1).
The reactivity of 1a is strongly dependent on the solvent.
Even after prolonged heating, no conversion was observed in
nonpolar solvents like dichloroethane or toluene (Table 1,
entries 1 and 2), whereas fast conversions resulted in dipolar
aprotic solvents (Table 1, entries 3–5). The employed base
and its amount have a significant impact on the reactivity
Herein we report a straightforward method for the
heteroatom-induced Grob-type fragmentation of vinyl tri-
flates 1 (Scheme 1). The reaction leads to trisubstituted
allenes with a terminal carbonyl functionality at the oxidation
level of a carboxylic acid. Furthermore, the resulting products
3 are amenable to a broad set of downstream reactions and
can initiate domino reactions.
Table 1: Optimization of the fragmentation reaction.[a]
Entry
T [8C]
t [h]
Base
Solvent[b]
Conversion [%][c]
1
2
3
4
5
6
7
8
50
50
50
50
50
50
50
50
50
23
6
6
2
2
2
6
24
24
24
7
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
NaHCO3
NEt3
DCE
0
0
100
100
100
100
20
<5
toluene
DMSO
DMF
DMA
DMA
DMA
DMA
DMA
DMA
[*] T. Saget, Dr. N. Cramer
Laboratory of Organic Chemistry, ETH Zurich
Wolfgang-Pauli-Strasse 10, HCI H 304, 8093 Zurich (Switzerland)
Fax: (+41)446-321-328
E-mail: Nicolai.cramer@org.chem.ethz.ch
Homepage: http://www.cramer.ethz.ch
9
–
<5
10[d]
Cs2CO3
100 (70%)[e]
[**] We thank the SNF (21-119750.01) and Prof. Dr. E. M. Carreira for
generous support. N.C. thanks the Fonds der Chemischen Industrie
for a Liebig fellowship.
[a] Conditions: 0.10 mmol 1a, 5 equiv BnOH and base, 0.3m; [b] DCE=
dichloroethane, DMSO=dimethyl sulfoxide, DMA=N,N-dimethylacet-
amide. [c] Determined by NMR analysis. [d] 2 equiv BnOH and Cs2CO3.
[d] Yield of isolated product in parentheses.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004795.
8962
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Angewandte
Chemie
(Table 1, entries 5–9). The best results were obtained with
cesium carbonate. Potassium carbonate displayed significant
lower reactivity, and only very poor conversion was observed
with sodium bicarbonate, with triethylamine, and in the
absence of base. At ambient temperature, two equivalents of
benzyl alcohol and cesium carbonate were sufficient for
complete conversion, and benzyl ester 3a was obtained in
70% yield (Table 1, entry 10).[12]
Scheme 2. Selective reaction of p-aminophenol with ketone 1a.
With these optimized conditions, we then explored the
reactivity of different nucleophiles and ketones 1 (Table 2). In
addition to benzyl alcohol and phenol, thiphenol also
starting point for a range of subsequent reactions involving
both formed functionalities. In this context, we explored the
potential of the free carboxylic acids 3, which are smoothly
generated either in wet DMA or DMSO (Table 3). In the
Table 2: Scope of the fragmentation reaction.[a]
Table 3: Sequential reactions of carboxylic acids 3.[a]
Entry
R1
R2
R3
NuH
3
Yield [%][b]
1
2
3
4
5
6
7
Pr
Pr
Bn
Me
allyl
Pr
Ph
allyl
Ph
Pr
allyl
Bn
allyl
allyl
allyl
allyl
allyl
Pr
allyl
Bn
Me
Me
H
H
Me
Me
H
Me
H
BnOH
BnOH
BnOH
PhOH
PhOH
PhOH
PhSH
H2O
H2O
H2O
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
70
65
51
88
92
56
66
86
99
99
90
94
96
84
99
80
91
97
99
72
Me
Me
allyl
Pr
allyl
allyl
allyl
Pr
allyl
Me
allyl
allyl
allyl
allyl
allyl
Pr
Entry
Conditions
R1
R2
R3
Y
4
Yield [%][b]
1
2
3
4
5
6
7
8
A
A
B
B
B
C
C
C
Pr
Me
Pr
Me
Me
Pr
Me
Me
Pr
Bn
Pr
Bn
Me
Pr
Me
Bn
Me
H
Me
H
H
Me
H
H
H
I
I
I
Ph
Ph
Ph
4a
4b
5a
5b
5c
6a
6b
6c
99
69[c]
78
83[d]
72
8[c]
9[c]
10[c]
11[c]
12[d]
13[c]
14[c]
15[c]
16[e]
17[e]
18[c]
19[c]
20[c]
Me
Me
H
83
62
H2O
NH3
H
60[e]
Me
Me
Me
Me
Me
Me
Me
H
BnNH2
PhNH2
Bn(Me)NH
TsNH2
TsNH2
morpholine
morpholine
morpholine
[a] Conditions A: a) 0.10 mmol 1, 3 equiv K2CO3, 40 equiv H2O, 0.2m in
DMA, 508C, 20 h; b) CH2Cl2, TFA, 238C, 1 h; B: 0.10 mmol 1, 3 equiv
K2CO3, 40 equiv H2O, 0.1m in DMSO, 508C, 20 h, then 0.15 mmol I2,
238C, 2 h; C: 0.10 mmol 1, 3 equiv K2CO3, 40 equiv H2O, 0.2m in DMA,
608C, 20 h, then 0.15 mmol PhI, 5 mol% [Pd(dba)2], 7 mol% PCy3, 10 h.
[b] Yield of isolated product. [c] Z/E=1:2.3. [d] Z/E=1:1.3. [e] Z/E=
2.1:1.
allyl
Me
Me
3s
3t
H
[a] Conditions: 0.10 mmol 1, 0.20 mmol NuH, 0.2 mmol Cs2CO3, 0.3m
in DMA, 238C, 7–12 h. [b] Yield of isolated product. [c] With
0.20 mmolK2CO3, 0.2m in DMA, 508C, 20 h. [d] With 4 equiv NH3
(0.5m in dioxane), 32 h. [e] At 508C, 12 h.
presence of trifluoroacetic acid, carboxylic acids 3 cyclized to
give the corresponding five-membered allylic lactones 4a and
4b through protonation of the central carbon atom and
trapping of the formed allylic carbenium ion (Table 3,
entries 1 and 2). Another possibility is the addition of
iodine upon completion of the fragmentation step. This
iodolactonization led to the corresponding vinyl iodides 5,
which are amenable to further reactions, for example, cross-
coupling (Table 3, entries 3–5).[13] It is also possible to directly
obtain arylated tetrasubstituted olefins. In the presence of
catalytic amounts of [Pd(dba)2] (dba = dibenzylideneacetone)
and tricyclohexylphosphine, aryl iodides underwent arylative
cyclization leading to 6a–6c (Table 3, entries 6–8).[14] The
reaction proceeded in good yields, though the stereoselectiv-
ity of the formed olefins was only modest when R1 ¼ R2
(Table 3, entry 8).
provided the corresponding allenes 3a–3g (Table 2,
entries 1–7). When the reaction was performed in wet DMA
(40 equiv water), the free carboxylic acids 3h–3k (Nu = OH)
were obtained in excellent yields (Table 2, entries 8–11).
Nitrogen nucleophiles like ammonia, anilines, primary and
secondary amines, and sulfonyl amides also induce the
fragmentation. However, they required reaction temper-
atures of 508C and the use of potassium carbonate to afford
amides 3l–3t in high yields (Table 2, entries 12–20).
Remarkably, in the reaction with 4-aminophenol the
phenolic hydroxy group reacts with high selectivity
(Scheme 2). For instance, in the presence of cesium carbon-
ate, aryl ester 3u was formed in 70% yield, whereas amide 3v
was detected only in trace amounts.
When the fragmentation of 1a was conducted in the
presence of N-phenyl hydroxylamine, hydroxamic acid 3w
was obtained selectively (Scheme 3). Recently, the utility of
N-substituted hydroxamic acids was shown for intramolecular
The mild conditions and the broad spectrum of competent
nucleophiles should make the fragmentation a suitable
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Communications
entries 1–6). Along the same lines, thiocarbamate (13g) and
ureas (13h, 13i) can be prepared (Table 4, entries 7–9). To
avoid competition with the azide anion for the initial
fragmentation and to suppress formation of the correspond-
ing amides, amine and thiol nucleophiles had to be added
after complete generation of 12.
Remarkably, when substrate 1a was heated in the absence
of nucleophile in dry DMF at 1008C, enone 17 was obtained
as the sole product in good yield (Scheme 4). This observation
suggests that the solvent itself acts as the promoting
Scheme 3. Oxidative radical cyclization of allenic hydroxamic acid 3w.
oxidative radical cyclizations of olefins with molecular
oxygen.[15] Allenic hydroxamic acid 3w was converted under
comparable conditions (catalytic amounts of lauroyl peroxide
in acetic acid under an atmosphere of oxygen) to the densely
functionalized 1,2-oxazine 10.[16] We assume that the initially
formed oxygen-centered radical 7 cyclizes to give the vinyl
radical 8. The addition of molecular oxygen subsequently
leads to the putative hydroperoxide 9, which in turn,
rearranges into hydroxyketone 10, thus obviating reductive
workup.[17]
Scheme 4. Domino reaction consisting of a fragmentation and a
Friedel–Crafts reaction.
We next tried to induce the fragmentation of 1 with the
azide anion as a complementary nitrogen nucleophile. Our
hypothesis was to generate acyl azide 11, which under these
reaction conditions should undergo a Curtius rearrangement
to generate isocyanate 12 (Table 4). Indeed, heating 1 at
1008C for one hour in the presence of sodium azide in DMA
led to complete conversion of 1.[18] When alcohols were added
to the reaction mixture, the isocyanates 12 were intercepted
and converted directly to carbamates 13a–13 f (Table 4,
ꢀ
nucleophile to induce the C C bond fragmentation, thus
generating either 14 or acyl triflate 15 as highly potent
intermediates. However, neither of these intermediates could
be detected, presumably because a rapid intramolecular
Friedel–Crafts acylation leads via the putative allylic carbe-
nium ion 16 to the final product, enone 17.[19] At present, we
do not know whether acyl azide 11 is formed by the direct
attack of the azide anion, or whether the reaction proceeds
via intermediates 14 or 15.
In summary, we have developed a mild and operatively
simple method the preparation of synthetically versatile w-
heteroatom-functionalized allenes through Grob-type frag-
mentations of 3-keto vinyl triflates 1. The resulting products
can be utilized for further functionalizations of both the
allene and the carboxylic acid moieties, and they provide
direct access to a range of structurally diverse structural
motifs.
Table 4: Domino reaction consisting of fragmentation and Curtius
reaction.[a]
R1
R2
R3
NuH
13
Yield [%][b]
Received: August 2, 2010
Entry
Published online: October 6, 2010
1
2
3
4
5
6
Pr
Pr
Pr
Pr
Me
Me
Me
H
H
H
Me
Me
Me
BnOH
EtOH
13a
13b
13c
13d
13e
13 f
13g
13h
13i
77
80
75
54
68
56
38
67
69
Keywords: allenes · cyclization · domino reactions ·
allyl
Me
Me
allyl
Pr
allyl
Me
Bn
Ph
Pr
BnOH
BnOH
BnOH
BnOH
PhSH
.
fragmentation · radicals
7[c]
8[d]
9[d]
Pr
Pr
Pr
Pr
BnNH2
Me2NH
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Angewandte
Chemie
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