Light-enabled synthesis of anhydrides and amides

Article abstract of DOI:10.1021/acs.joc.5b00003

Recently, we have demonstrated that the photogeneration of Vilsmeier-Haack reagents is possible using only dimethylformamide (DMF) and tetrabromomethane (CBr₄) in the bromination of alcohols. Extending these findings to carboxylic acid substrates has produced a mild and facile approach to the in situ formation of symmetric anhydrides, which were conveniently converted to amide derivatives in a one-pot process. The efficient protocols discussed herein are marked by use of UVA LEDs (365 nm), which have reduced the reaction times and come with a low setup cost.

Full text of DOI:10.1021/acs.joc.5b00003

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Note
Light-enabled Synthesis of Anhydrides and Amides
Terry McCallum, and Louis Barriault
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00003 • Publication Date (Web): 17 Feb 2015
Downloaded from http://pubs.acs.org on February 18, 2015
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Light-enabled Synthesis of Anhydrides and Amides
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Terry McCallum and Louis Barriault*
Centre for Catalysis, Research and Innovation, Department of Chemistry, University of Ottawa, Ottawa,
Ontario, Canada.
Eꢀmail: lbarriau@uottawa.ca
ABSTRACT: Recently, we have demonstrated that the photogeneration of VilsmeierꢀHaack reagents
are possible using only dimethylformamide (DMF) and tetrabromomethane (CBr4), in the bromination
of alcohols. Extending these findings to carboxylic acid substrates has produced a mild and facile apꢀ
proach to the in situ formation of symmetric anhydrides, which were conveniently converted to amide
derivatives in a oneꢀpot process. The efficient protocols discussed herein are marked by use of UVA
LEDs (365 nm) which have reduced reaction times and come with a low setup cost.
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The activation of carboxylic acids has been paramount to the synthesis of peptides in coupling reacꢀ
tions with amines.1 A variety of methods make carboxylic acids more electrophilic either by transformꢀ
ing the carboxylic acid into the corresponding acyl halide, or through the addition of coupling agents.2
Symmetric anhydrides have also seen great use in peptide chemistry as they provide electrophilic activaꢀ
tion of the carboxylic moiety without forming coupling byꢀproducts, as both electrophilic sites are idenꢀ
tical. However, these anhydrides are often formed through the same procedures that apply to the amide
couplings3 (acyl halide formation and then addition of carboxylates). New protocols offering the forꢀ
mation of anhydrides directly from the corresponding carboxylic acids along with the direct formation
of amides in a oneꢀpot process are of interest for development.4
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Photoredox catalysis has emerged as a powerful tool in the development of new organic transforꢀ
mations, especially in forming CꢀC, CꢀN, and CꢀO bonds.5 VilsmeierꢀHaack reagents for useful organic
transformations can be generated with photoredox catalysis,6,7 however, studies among our group found
that generation of the Vilsmeier-Haack reagent without use of a photocatalyst is possible from the irraꢀ
diation of CBr4 with UVA light (365 nm LED) in DMF under air atmosphere.8 Notably, visible light in
comparison was unable to achieve this transformation. This was used as a synthetically facile route to
bromoalkanes from alcohols, which was applicable to a oneꢀpot deoxygenation protocol.8b,9 Taking this
into consideration, we sought to apply the photogeneration of VilsmeierꢀHaack reagents from UVA and
CBr4 in a oneꢀpot protocol for the synthesis of amides from readily available carboxylic acids and
amines.
The formation of symmetric anhydrides was first optimized in order to minimize reagents used (Taꢀ
ble 1). Treating pꢀanisic acid with one equivalent of CBr4 and two equivalents of 2,4,6ꢀtrimethylpyridine
(collidine) in DMF were the conditions that gave anhydride product in the most reagent minimizing proꢀ
tocol, among the best yields (entries 1ꢀ3). The reaction was found to occur quickly, within 30 minutes,
as indicated by the precipitation of collidine hydrobromide. Removal of collidine resulted in little prodꢀ
uct formation (entry 4). Control experiments were performed which demonstrated that no reaction ocꢀ
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curred upon heating to 80°C without light irradiation in presence of CBr4 (entry 5) or UVA irradiation in
the absence of CBr4 (entry 7). Notably, the transformation does not react under visible light irradiation
(410 nm LED, entry 6).
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Table 1. Optimization of symmetric anhydrides.
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Entry
CBr4 (equiv.)
Collidine (equiv.)
(%)a
95
1
2
3
4
5
6
7
1.0
0.5
1.0
0.5
1.0
1.0
ꢀꢀꢀ
5.0
5.0
2.0
ꢀꢀꢀ
78
91
9
2.0
2.0
2.0
n.r.b
n.r.c
n.r.
a1H NMR yield with mesitylene as internal standard. bWithout irradiation, 80 oC overnight. n.r. = no reꢀ
action. cUsing visible light.
Having these conditions in hand, we established the scope of the transformation using a wide array of
carboxylic acids (Table 2). Nonꢀaromatic carboxylic acids including long chains, primary, secondary,
and tertiary αꢀcenters were converted in nearly quantitative yields, forming stable anhydrides 2b-d and
2h (entries 1ꢀ3 and 7). The reaction proved to be tolerant to alkenes and alkynes, the corresponding anꢀ
hydrides 2d-f were obtained in 75% to 98% yields (entries 4ꢀ6)
Table 2. Formation of symmetric anhydrides from carboxylic acids.a
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Entry
1
Subs.
(%)b
99
Entry
Subs.
(%)b
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X = H
4ꢀtBu
88, 68c
70
4ꢀF
54
2
3
4
99
99
75
4ꢀBr
95
4ꢀCF3
42
3ꢀBr
53
2ꢀOMe
2ꢀBr
81
54
3,4,5ꢀOMe
3,5ꢀCF3
2,4,6ꢀMe
65
59
45
5
6
98
78
21
22
85
62
7
8
80
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45
63
Deg.
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25
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aGeneral conditions: Carboxylic acid (1 equiv.), DMF (0.2 M), collidine (2 equiv.), and lastly CBr4 (1
equiv.) added to screw top vial, sealed, irradiated for 0.5 h w/365 nm LED. b1H NMR yield with mesityꢀ
lene as standard. c1.0 g scale of benzoic acid in 150 mL cylindrical Pyrex vessel.
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Interestingly, NꢀBoc and NꢀCBz protected Lꢀalanine showed only degradation (entry 8) however, Cbz
protected Lꢀproline was fully converted to the corresponding anhydride 2j (entry 9).10 This may be atꢀ
tributed instability of the anhydride formed. Various aromatic carboxylic acids were screened; a wide
variety of functionality is tolerated in good yields, including OMe, tBu, halides, CF3, naphthyl, and to
some extent, ortho and meta substitution (entries 10ꢀ20 and 24). 2ꢀCarboxylic acid substituted heterocyꢀ
cles thiophene 2v, furan 2w, and Nꢀmethylpyrrole 2x were also compatible with this method (entries 21ꢀ
23). Phthalic acid also converted quantitatively to phthalic anhydride 2z (entry 25), in an intramolecular
version of this transformation.
The method showed a robust general applicability; however isolation of many aromatic anhydrides reꢀ
sulted in some degradation or loss of product. Often, these compounds are used in amide couplings as
the coupling partner for an amine. It was reasoned that a oneꢀpot procedure for the coupling of these anꢀ
hydrides to an amine should be developed to avoid degradation of the anhydride through work up steps.
An optimization of the bases added to the reaction (Table 3) showed that three equivalents of carboxylic
acid, five equivalents of collidine and one equivalent of DMAP furnished the best yield of amide forꢀ
mation (3) in the coupling of carboxylic acid 1c and piperidine using CBr4 with UVA LED light in
DMF (entry 9). The analogous method using [Ru(bpy)3](PF6)2 (5 mol%) with visible light (CFL light)
gave little formation of either anhydride or amide product, 9% (entry 11). More importantly, the same
reaction without [Ru(bpy)3](PF6)2 gave a similar yield, 7% (entry 12). This may be due to the intensity
of these lights being relatively weak compared to high powered LED systems. A high powered 410 nm
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LED was used, giving 12% yield with [Ru(bpy)3](PF6)2, but also yielded 8% without the photocatalyst
(entries 13 and 14). One aspect of using more powerful lighting sources is that background activation
(reaction with light source in absence of photocatalyst, as shown in this study) may occur, which cir-
cumvents the need for photoredox catalysts. Also, the excited state of [Ru(bpy)3](PF6)2, may be
quenched by the amine in solution, which does not result in product forming pathways. For these reaꢀ
sons, a photoꢀmediated method for the combination of carboxylic acids with amines without a photoꢀ
catalyst gives the best conditions for amide synthesis.
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Table 3. Optimization of oneꢀpot amide formation.
Entry
1
Base
Collidine
DMAP
(%)a
22
2
22
3
DABCO
Imidazole
Pyridine
DBU
16
4
6
10
5
6
5
7
DIPEA
11
8
Collidine
Collidine
Collidine
2,6ꢀLutidine
2,6ꢀLutidine
27b
61b,c, 38d
11b,e
9f
9
10
11
12
7g
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2,6ꢀLutidine
2,6ꢀLutidine
12h
8i
1
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3
4
5
a1H NMR yield with mesitylene as standard, based on amine. 1 equiv. DMAP added. 3 equiv. 1c, 5
b
c
6
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8
d
equiv. collidine, 1.5 equiv. CBr4. 1.0 g scale of piperidine in 150 mL cylindrical Pyrex vessel using
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e
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same equiv. as in entry 9. 3 equiv. piperidine, 5 equiv. collidine, yield based on carboxylic acid.
g
f[Ru(bpy)3](PF6)2 5mol%, Ar degas, CFL light 97 h. No photocatalyst, Ar degas, CFL light 97 h.
h[Ru(bpy)3](PF6)2 5 mol%, Ar degas, 410 nm LED, 0.5 h. iNo photocatalyst, Ar degas, 410 nm LED, 0.5
h.
An extension of the amide protocol also showed promising results, (Table 4). Carboxylic acids funcꢀ
tionalized with cyclohexane, phenyl, and 4ꢀCF3ꢀphenyl were chosen to represent alkyl, aryl, and elecꢀ
tron withdrawing functionality. These were matched with nꢀbutylamine, piperidine and aniline to repreꢀ
sent primary, secondary and aromatic amines. Couplings of these compounds all proceeded in yields
ranging from 34 to 98%. Interestingly, the examples using 4ꢀCF3ꢀbenzoic acid for amide couplings obꢀ
tained much higher yields of the amide products 4f-h (entries 6ꢀ8) as compared to the isolation correꢀ
sponding anhydride 2n (cf. Table 2, entry 14). Benzoic acid was coupled with LꢀalaꢀOMe, which
showed that amino acid derivatives 4i retain their configuration throughout the reaction with 99:1 e.r.
(entry 9), where racemization plagues many protocols.11 Using NꢀCbzꢀLꢀala as carboxylic acid coupled
with nꢀbutylamine, conservation of enantiopurity was also observed with e.r. = 99:1, in 92% yield (entry
10). Coupling of LꢀalaꢀOMe and NꢀCbzꢀLꢀala as carboxylic acid demonstrated that the chirality of both
centres are retained with d.r. >20:1, in 94% yield.
Table 4. Oneꢀpot amidation protocol.
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Entry
R
Cy
N(R’)R”
nꢀBuNH2
PhNH2
Product (yield %)a
4a (98)
1
2
3
4
5
6
1
2
Cy
4b (63)
7
8
9
3
Ph
piperidine
nꢀBuNH2
PhNH2
4c (80)
4
Ph
4d (86)
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5
Ph
4e (75)
6
4ꢀCF3Ph
4ꢀCF3Ph
4ꢀCF3Ph
Ph
piperidine
nꢀBuNH2
PhNH2
4f (90)
7
4g (98)
8
4h (94)
9
LꢀalaꢀOMe
nꢀBuNH2
LꢀalaꢀOMe
4i (34)b
10
11
NꢀCbzꢀLꢀala
NꢀCbzꢀLꢀala
4j (92)b
4k (94)c
aIsolated yield, based on amine. be.r. = 99:1. cd.r. = >20:1 determined by 1H NMR analysis.
Mechanistic consideration of this transformation is described in Scheme 1. Irradiation of CBr4 proꢀ
.
duces an electrophilic radical CBr3 which, upon addition to DMF, generates the radical intermediate 5.
Under these reaction conditions, 5 is readily oxidized to produce the VilsmeierꢀHaack reagents 6 or 7.6ꢀ8
In the presence of carboxylic acid, the latter is converted to intermediate 8. At this point, intermediate 8
can be converted to corresponding anhydride 2 or amide 4. The formation of amide 4 through a transient
anhydride intermediate 2 could be also considered.
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Scheme 1. Proposed Mechanism.
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In summary, the photogeneration of VilsmeierꢀHaack reagents from irradiation of CBr4 with UVA
light in DMF has been shown to be a useful method for the generation of symmetric anhydrides. This
process is conveniently applicable to a oneꢀpot synthesis of amides from readily available carboxylic
acids and amines, without need of a photoredox catalyst. These studies not only exhibit the importance
of photochemical transformations in the synthesis of amide bonds but also the power of conducting conꢀ
trol reactions and lightꢀsource optimization in developing fast, efficient, and reagent minimizing methꢀ
ods in organic synthesis.
Experimental Section
General Information. All reactions were performed under atmospheric air (unless otherwise noted) in
Pyrex glassware equipped with a magnetic stir bar, capped with a septum. DMF was filtered using a puꢀ
rification system. Commercial reagents were used without further purification. Reactions were moniꢀ
tored by thin layer chromatography (TLC) analysis. TLC plates were viewed under UV light and stained
1
with potassium permanganate or pꢀanisaldehyde staining solution. H NMR spectra were recorded on
300 MHz or 400 MHz in chloroformꢀd and chemical shifts are reported in ppm referenced to residual
undeuterated solvent. Data are reported as follows: chemical shift, multiplicity, coupling, integration.
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13C NMR spectra were recorded on 75 MHz or 101 MHz. Optical rotations were recorded at 589 nm
with 0.1 dm/2 mL sample cell. Retention of configuration was determined by running an analogous reꢀ
action with racemic mixtures of either amine or acid with respect to the amide couplings, with workꢀup
in the usual way. Samples were diluted with 5% iPrOH in hexane, and run on a chiral HPLC, chromatoꢀ
graphs available in the supporting information (column: ADꢀH, 5%iPrOH/Hexanes, 1.0 mL/min, over
60 minutes).
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General Procedure 1 (GP1). Preparation of symmetric anhydrides from carboxylic acids. To an 8 mL
pyrex screwꢀtop reaction vessel was added substrate (0.3 mmol, 1.0 equiv.), Dimethylformamide (1.5
mL, 0.2 M), then 2,4,6ꢀtrimethylpyridine (0.6 mmol, 2.0 equiv.) and carbontetrabromide (0.3 mmol, 1.0
equiv.). The reaction mixture was capped and irradiated with a UVA (365 nm) LED at a distance of a
centimetre, for 30 minutes. The resulting mixture was poured into a separatory funnel containing 25 mL
of a 3:1 mixture of diethyl ether and hexanes (ethyl acetate added for compounds which needed further
solubility). This was washed with water, where the combined aqueous fractions were reꢀextracted with
25 mL of diethyl ether. The combined organic portions were washed with saturated sodium bicarbonate,
brine, and dried over sodium sulfate. The solution was concentrated in vacuo and products were
weighed for crude yields and then were added an internal standard (mesitylene), where yields were deꢀ
termined with proton NMR by comparison to literature precedence.
General Procedure 2 (GP2). Preparation of amides from carboxylic acids and amines. To an 8 mL
pyrex screwꢀtop reaction vessel was added carboxylic acid (0.6 mmol, 3.0 equiv.), amine, (0.2 mmol,
1.0 equiv.), Dimethylformamide (1.0 mL, 0.2 M), then 2,4,6ꢀtrimethylpyridine (1.0 mmol, 5.0 equiv.),
DMAP (0.2 mmol, 1.0 equiv.), and carbontetrabromide (0.3 mmol, 1.5 equiv.). The reaction mixture
was capped and irradiated with a UVA (365 nm) LED at a distance of one cm, for 30 minutes. The reꢀ
sulting mixture was poured into a separatory funnel containing 25 mL of ethyl acetate. This was washed
with 1 M HCl, where the combined aqueous fractions were reꢀextracted with 25 mL of ethyl acetate.
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The combined organic portions were washed with saturated sodium bicarbonate, brine, and dried over
sodium sulfate. Products were further purified by column chromatography (0ꢀ100% EtOAc:Hex), releꢀ
vant fractions combined, concentrated in vacuo, and characterized by NMR by comparison to literature
precedence.
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Compounds 2a-g and 2k-z were synthesized according to GP1 and characterized by NMR compariꢀ
son.12 Compounds 3, 4a-k were synthesized according to GP2 and characterized by NMR compariꢀ
son.12
4-(3,4-dimethoxyphenyl)butanoic anhydride (2h): Synthesized according to GP1.
IR (neat, cmꢀ1): 2933(m), 2836(w), 1813(s), 1745(s), 1648(m), 1591(s), 1514(vs), 1450(s), 1416(s). 1H
NMR (300 MHz, CDCl3)
δ = 6.82 ꢀ 6.75 (m, 2 H), 6.75 ꢀ 6.65 (m, 4 H), 3.87 (s, 6 H), 3.85 (s, 6 H), 2.63
(t, J=7.5 Hz, 4 H), 2.44 (t, J=7.3 Hz, 4 H), 1.97 (quint, J=7.4 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3)
δ
= 169.2 (2 X C), 148.8 (2 X C), 147.3 (2 X C), 133.4 (2 X C), 120.2 (2 X CH), 111.6 (2 X CH), 111.2
(2 X CH), 55.8 (2 X CH3), 55.7 (2 X CH3), 34.2 (2 X CH2), 34.2 (2 X CH2), 25.8 (2 X CH2) ppm.
HRMS (EI) m/z calcd for C24H30O7 [M+] 430.1992, found 430.1993.
(R)-1-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic anhydride (2j): Synthesized according to GP1.
IR (neat, cmꢀ1): 2995(m), 2882(w), 1827(s), 1745(s), 1697(vs) (overlapping), 1411(s), 1352(vs). 1H
NMR (400 MHz, CDCl3):
δ = 7.45 ꢀ 7.23 (m, 10 H), 5.25 ꢀ 5.03 (m, 4 H), 4.51 ꢀ 4.28 (m, 2 H), 3.72 ꢀ
3.42 (m, 4 H), 2.22 ꢀ 1.84 (m, 8 H) ppm. 13C NMR (101 MHz, CDCl3):
δ
= 167.7, 167.6, 167.5, 167.4 (2
X C, rotamers), 155.9, 154.8, 154.6, 153.9 (2 X C, rotamers), 136.8, 136.6, 136.4, 136.2 (2 X C, rotaꢀ
mers), 128.4, 128.4, 128.2, 128.0, 128.0, 127.9, 127.9, 127.8, 127.7, 127.5, 127.4 (10 X CH, rotamers),
67.3, 67.3, 67.2, 67.1 (2 X CH2, rotamers), 59.7, 59.6, 59.3, 59.2 (2 X CH, rotamers), 46.9, 46.9, 46.4,
46.3 (2 X CH2, rotamers), 31.0, 30.2, 30.2, 30.1, 29.6, 29.5, 29.0, 28.9 (2 X CH2, rotamers), 24.2, 24.2,
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23.4, 23.3 (2 X CH2, rotamers) ppm. HRMS (EI) m/z calcd for C26H28N2O7 [M+] 480.1897, found prodꢀ
uct was unstable. [α]20D = ꢀ32.1o (c 1.0, EtOH).
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methyl benzoyl-L-alaninate (4i): Synthesized according to GP2 and characterized according to NMR
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comparison.12 [α]20D = +30.2o (c 1.0, CHCl3).
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benzyl (S)-(1-(butylamino)-1-oxopropan-2-yl)carbamate (4j): Synthesized according to GP2 and charꢀ
acterized according to NMR comparison.12 [α]20D = ꢀ6.8o (c 1.0, EtOH).
Z-L-ala-L-ala-OMe (4k): Synthesized according to GP2 and characterized according to NMR compariꢀ
son.12 [α]20D = ꢀ49.0o (c 1.0, MeOH).
Supporting Information
1
ChiralꢀHPLC data for hydrolysis of 2j yielding Zꢀ
L
ꢀproline and compounds 4i-k along with H NMR
and 13C NMR for compounds 2h, 2j, 3 and 4a-k. This material is available free of charge via the Interꢀ
net at http://pubs.acs.org/
Author Information
Author Contributions
The manuscript was written through contributions of all authors. / All authors have given approval to the
final version of the manuscript.
Acknowledgment
We thank the Natural Sciences and Engineering Research Council (for Accelerator, Discovery and
CREATE grants to L.B.), and the University of Ottawa (for a University Research Chair to L.B.) for
support of this research. Acknowledgement is also made to the donor of the American Chemical Socieꢀ
ty Petroleum Research Fund for support of this research. T.M. thanks NSERC (CREATE on medicinal
chemistry and biopharmaceutical development).
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References
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