Tetrabutylammonium decatungstate (chemo)selective photocatalyzed, radical C-H functionalization in amides

Article abstract of DOI:10.1002/adsc.200800378

Photoamidation of electron-poor olefins has been achieved bymeans of a radical-induced C-H functionalization in amides. Tetrabutylammonium decatungstate was used as photocatalyst of the reaction and allowed the smooth generation of different carbon-centered radicals depending on the amide structure.

Full text of DOI:10.1002/adsc.200800378

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DOI: 10.1002/adsc.200800378
Tetrabutylammonium Decatungstate (Chemo)selective
À
Photocatalyzed, Radical C H Functionalization in Amides
Simone Angioni,a Davide Ravelli,a Daniele Emma,a Daniele Dondi,b
Maurizio Fagnoni,a,* and Angelo Albinia
a
Department of Organic Chemistry, University of Pavia. Via Taramelli 10, 27100 Pavia, Italy
Fax : (+39)-0382-987-323; e-mail: fagnoni@unipv.it
Department of General Chemistry, University of Pavia. Via Taramelli 12, 27100 Pavia, Italy
b
Fax : (+39)-0382-528-544
Received: June 16, 2008; Revised: July30, 2008; Published online: August 29, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800378.
Abstract: Photoamidation of electron-poor olefins
has been achieved bymeans of a radical-induced
À
C H functionalization in amides. Tetrabutylammo-
nium decatungstate was used as photocatalyst of
the reaction and allowed the smooth generation of
different carbon-centered radicals depending on the
amide structure.
Figure 1.
À
Keywords: amides; conjugate alkylation; electron-
poor olefins; photochemical reactions; radical reac-
tions
as the C H a to the carbonyl in higher homologues
(e.g., acetamides, path c). A selective functionaliza-
À
tion is not trivial because these C H bonds mayhave
a similar bond dissociation energy(BDE). As an ex-
À
ample, in the DMF molecule the BDE of the C H
bond was calculated as 89.7 kcalmolÀ1 and 89.1 kcal
molÀ1 for the formyl and for the methyl group, re-
[4a]
À
Simple amides are the least reactive carbonyl-contain- spectively.
ing functionalities. These derivatives are virtuallynon
The N H bond (BDE=108.5 kcal
molÀ1)[4b] and, when present, the C H a to the car-
À
basic, poor C-electrophiles and poor N H acids, so bonyl (BDEꢀ94 kcalmolÀ1)[4c] are stronger. More-
that formation of the corresponding enolates requires over, in non-symmetrical amides, the selective trans-
strong bases. Actually, DMF or N-methyl-2-pyrroli- formation of different N-alkyl groups is a further
done are convenient solvents for the generation of issue (path b and d).
À
most enolates. An increased reactivityhas been ob-
tained bya structure modification through the intro-
duction of Weinreb amides about 20 years ago, but in functionalization of amides. In the first method, the
Homolytic hydrogen abstraction and electrochemi-
cal oxidation[5] have been reported to afford the C H
À
this case the amide functionalityis lost in the reac-
tion. Metal-catalyzed activation of the N H bond of plished byusing thermallygenerated radicals (such as
formation of a carbon-centered radical was accom-
À
primaryand secondaryamides for the formation of
t-BuOC[6a] or ethyl radicals[6b]) or byFe(II) salt-mediat-
C N bond has recentlyemerged, with the N-arylation ed reactions.[6c,d] The nucleophilic radicals thus formed
of amides,[1] the synthesis of enamides via N-vinyla- have been exploited for the amidation of electron-
tion,[2] and N-alkynylation reactions[3] as representa- poor olefins or of (protonated) heterocyclic bases.
À
tive examples.
Unfortunately, in all of these cases the amide must be
À
The (chemo)selective functionalization of a C H used in a large excess (as the solvent in most cases),
rather than an N H bond in amides is, however, more which obviouslylimits the synthetic significance. Elec-
demanding. As summarized in Figure 1, both the C
H adjacent to the carbonyl (path a) and that a to the involves formation of the radical cations of the
nitrogen (path b) could be functionalized in forma- amides and then of carbon radicals from them byde-
mides (e.g., N,N-dimethylformamide, DMF), as well protonation. Under the oxidative conditions em-
À
À
trochemical oxidation is an interesting alternative and
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Simone Angioni et al.
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ployed, however, radicals were easily transformed fective even for unreactive substrates, such as alkanes,
into the corresponding cations and thus the reaction for the introduction of oxygen functionalities[9] as well
took a different course giving alcohols or ethers by as for C-alkylation reactions.[8,10] Tetrabutylammoni-
addition to water or alcohols. A wayto overcome this
problem was recentlyintroduced byYoshida and co-
workers bymeans of the “cation pool” method.
um decatungstate (TBADT) has been recentlyintro-
duced and has been found to promote the photocata-
[7]
lyzed alkylation of enones, unsaturated esters and ni-
[11]
Thus, the amides (carbamates) were electrochemically triles starting directlyfrom alkanes.
A selective
oxidized and the acyliminium cations accumulated. In transformation was obtained through the same
a later step, the last intermediates were reduced to a- method in the alkylation by aliphatic alcohols and
amido radicals, which were trapped byelectron-poor
alkenes. This method requires the availabilityof an
electrochemical equipment, establishing a low temper-
ethers[12] and in the acylation by aliphatic alde-
hydes.[13]
We surmised that TBADT might be conveniently
ature (À728C) and using a large excess both of the applied for the (chemo)selective photocatalyzed func-
amide (at least 5 equiv.) and of triflic acid (50 equiv.). tionalization of amides. We thus explored the reaction
At anyrate, the reaction was limited to the amidoal- of a varietyof amides and carbamates in the presence
kylation of a,b-unsaturated esters or lactones. Thus, of electrophilic alkenes under TBADT photocatalysis.
some drawbacks remained in the above methods and
this fostered the interest for new C C bond forming formamide (1a, 4 equiv.) was irradiated (24 h, lirr =
reactions via radicals from amides, and thus for the 310 nm) in an acetonitrile solution of cyclohexenone
The results obtained are gathered in Table 1. Thus,
À
selectivityof the keyhydrogen abstraction step.
(2a, 1 equiv.) and TBADT (2% mol) and gave 3-oxo-
Photocatalysis[8] is a mild alternative for the func- cyclohexanecarboxamide (3) as the onlydetected
À
tionalization of C H bonds that has proven to be ef- product. This compound was isolated in a 51% yield
Table 1. Photocatalyzed amidation of electron-poor olefins.
Amide
Olefin
Product
Yield [%][a,b]
51
1a
2a
3
1a
1b
1b
1b
1b
2b
2c
2d
2e
2f
4
5
6
7
8
76
86
71
61
47
1c
2f
9
47
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À
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Table 1. (Continued)
Amide
Olefin
Product
Yield [%][a,b]
1c
2e
2b
10
11
60
46
1d
1d
1e
2c
12
60[c]
2d
13
56[d]
13’
14
1e
2e
50[e]
14’
1f[f]
1g[f]
2d
2c
15
16
59
51[g]
1g[f]
2e
2d
17
26
1h[h]
18
44
28
18’
[a]
Conditions: Amide (0.4M), electron-poor olefin (0.1M), TBADT (2”10À3 M), irradiated in acetonitrile.
Isolated yields.
See text.
13/13’ ca. 13:1 ratio.
[b]
[c]
[d]
[e]
[f]
14/14’ ca. 13:1 ratio.
About 70–75% of the carbamate recovered based on consumed 1f–g.
Two diastereoisomers formed in ca. 1:1 ratio.
About 73% of the silyl amide recovered based on consumed 1h.
[g]
[h]
bya two-step procedure involving elimination of
excess 1a under vacuum followed bychromatographic
sluggish reaction and a marked decrease of the prod-
uct yield. Likewise, the succinamic ester derivative 4
separation. No reaction took place in the absence of was obtained under the same conditions in 76% yield
TBADT. Using a lower amount of the amide led to a from the reaction of 1a and methyl crotonate (2b).
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A tertiaryamide, DMF ( 1b), was next tested and stereoisomeric mixture (16). The alkylation of methyl
found likewise to react under TBADT photocatalysis. vinyl ketone, on the other hand, gave only a modest
A fullychemoselective transformation of the
methyl C H bond resulted, with no competition by
N- yield of carbamate 17.
À
A final reaction was carried out with the N-trime-
the formyl group. Accordingly, w-functionalized N- thylisilylmethyl acetamide 1h, in order to ascertain
methyl-N-propylformamides 5–8 were obtained in whether the silyl group may be cleaved competitively
yields ranging from 47–86% by using a,b-unsaturated with a hydrogen atom. In the experiment, the photo-
ketones, esters and nitriles (2c–f) as the olefins. A 4 catalyzed reaction of 1h with 2d gave two silicon-con-
to 1 excess amide was likewise used and was distilled taining products (18 and 18’), resulting from the func-
off after the reaction (toluene azeotrope). Changing tionalization of the N-methylene and methyl groups,
the proportion of the reagents gave no satisfactoryre-
respectively. The same reaction, when carried out in
sults, for example, using excess of the alkene lowered acetonitrile-water 7:1 (water 7M), was slightlyslower
the yield, as shown in the formation of 5 in the re- than that in neat MeCN but led to the same products
duced 46% yield in the reaction between 1b (1 equiv.) distribution.
and 2c (4 equiv.). This is due to the formation of by-
The above results fit with the mechanism in
products that, as far as can be judged from the mass Scheme 1.[14] The radicals from amides add to electro-
spectrum, resulted from the addition of two or more philic alkenes and the catalytic cycle is terminated by
olefin units.
In the case of N,N-dimethylacetamide (1c), func-
tionalization of the N-methyl group was likewise ex-
clusive and w-functionalized N-methyl-N-propylacet-
amides 9 and 10 were formed in a satisfactoryyield
(ca. 50–60%) from methyl vinyl ketone and ethyl ac-
rylate respectively.
A complete change in the chemoselectivitywas ob-
served when passing to a secondaryamide, N-methyl-
formamide (1d). In this case, the photocatalytic trans-
formation involved onlythe formyl group. According-
ly, the succinamic ester derivative 11 and succinimide
12 were obtained from methyl crotonate and dimethyl
maleate, respectively. In the latter case, the isolated
product contained an imide function formed byintra-
molecular condensation upon heating during the dis-
À
Scheme 1. Photocatalyzed functionalization of C H bonds
in amides.
tillation under vacuum of the excess 1d.
The non-symmetrical lactam 1e (N-methyl-2-pyrro-
lidone) was chosen as a test for assessing the potential
À
of the method since three different C H bonds were back H transfer to adduct radical 2C. Functionalization
potentiallysusceptible to functionalization under pho-
of amides bythe excited photocatalyst involves either
tocatalytic conditions. In the experiment, homolytic hydrogen transfer (path a) or electron transfer (ET)
+
abstraction from the N-methylene group greatly pre- followed bydeprotonation of the radical cation ( 1C ,
dominated with respect to that of the N-methyl group path a’). In fact, although amides are not easilyoxi-
(ca. 13:1), while the methylene a to the amide func- dized (e.g., E1/2ox =2.29 V vs. SCE for DMF),[17] the
tion had no role. Thus, the alkylated pyrrolidones 13 highlypositive reduction potential of excited TBADT
and 14 predominated over isomeric 13’ and 14’ in the [E
amidation of 2d and 2e (see Table 1).
redA
vs. SCE][16,18a] makes the ET process conceivable next
Carbamates were next considered as a logical ex- to the thermoneutral one.[18b] There is evidence in the
tension of the work on amides. Positive results were literature for the operation of a photochemical ET
obtained in the reaction of tert-butyl pyrrolidinyl car- path when using a strong photochemical oxidant such
bamate 1f in the presence of acrylonitrile, where ni- as 1,2,4,5-tetracyanobenzene (TCB)[22a] or the dicya-
trile 15 was synthesized in 59% isolated yield. The re- noanthracene/biphenyl system.[22b] Thus we decided to
action was successful despite the competitive absorp- explore this issue byusing the sillyated amide
1h,
+
tion of 1f that caused a lengthening of the reaction since the loss of the good electrofugal group SiMe3
+
[22b]
time (ca. 40 h). The product was isolated bycolumn
from radical cation 1hC is largelyfavored
and thus
chromatography, which further allowed recovering desilylation would reveal the ET mechanism. How-
excess 1f (about 70–75%). The diethylamino carba- ever, the products obtained with TBADT conserved
mate 1g likewise gave an alkylation product with di- the silyl group even in the presence of water (a
methyl maleate in a medium yield as a ca. 1 to 1 dia- protic/nucleophilic cosolvent) that should favor the
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desilylation step[22b,c] supporting that path a, not a’,
was operative. In contrast, we found that the photo-
chemistryof 1d in the presence of TCB, a bona-fide
ET sensitizer, gave N-(2,4,5-tricyanobenzyl)forma-
mide as the exclusive product (see Supporting Infor-
mation). It should further be noticed that a different
reaction course involving a transformation of the
methyl rather than the formyl group was previously
observed in the electrochemical reaction of 1d.[23]
From the synthetic point of view, the key character-
photolyzed solution and the products isolated by elimination
of the excess amide by(azeotropic) distillation and purifica-
tion of the residue bycolumn chromatography(cyclohex-
ane/ethyl acetate as eluants) or distillation. In the case of
carbamates 1f, g and amide 1h, column chromatographic
separation of the raw photolysate allowed the separation of
the alkylated olefins and a partial recovery of the starting
reagent.
Supporting Information
1
Experimental details and H and 13C NMR spectra of com-
À
istic is the chemoselective functionalization of C H
bonds byelectrophilic TBADT*. With tertiary
pounds 3–18 are available as Supporting Information.
amides, onlya hydrogen a to the amide nitrogen is
À
abstracted, not a formyl C H from formamides or the
electrophilic H a to the carboxamide group.[24] On the
À
other hand, the presence of an N H group prevents
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