Oxidative homologation of aldehydes to α-ketoaldehydes by using iodoform, o-iodoxybenzoic acid, and dimethyl sulfoxide

Article abstract of DOI:10.1002/ejoc.201101835

An efficient three-step synthetic route to α-ketoaldehydes starting from aryl aldehydes is reported. The aldehydes were treated with iPrMgCl and iodoform to obtain β-diiodoalcohols, which were then oxidized with o-iodoxybenzoic acid at room temperature to the corresponding β-diiodoketones. Subsequent reaction of the β-diiodoketone to the α-ketoaldehyde occurred under oxygen transfer from dimethyl sulfoxide. These sensitive products were in situ cyclized with o-phenylenediamine to form the stable monosubstituted quinoxalines, which could be characterized and isolated easily. α-Ketoaldehydes are a versatile, highly reactive moiety for the synthesis of heterocyclic compounds. We investigated the transformation of aldehydes into α-ketoaldehydes via β-diiodoketone intermediates and finally applied the procedure to the synthesis of peptidic substrates. Copyright

Full text of DOI:10.1002/ejoc.201101835

FULL PAPER
DOI: 10.1002/ejoc.201101835
Oxidative Homologation of Aldehydes to α-Ketoaldehydes by using Iodoform,
o-Iodoxybenzoic Acid, and Dimethyl Sulfoxide
Andrea Zall,[a] Dennis Bensinger,[a] and Boris Schmidt*[a]
Keywords: Homologation / Aldehydes / Oxidation / Synthetic methods
An efficient three-step synthetic route to α-ketoaldehydes
starting from aryl aldehydes is reported. The aldehydes were
treated with iPrMgCl and iodoform to obtain β-diiodoalco-
Subsequent reaction of the β-diiodoketone to the α-keto-
aldehyde occurred under oxygen transfer from dimethyl sulf-
oxide. These sensitive products were in situ cyclized with o-
hols, which were then oxidized with o-iodoxybenzoic acid phenylenediamine to form the stable monosubstituted quin-
at room temperature to the corresponding β-diiodoketones.
oxalines, which could be characterized and isolated easily.
Introduction
Results and Discussion
Here we report the efficient three-step synthetic route to
α-ketoaldehydes starting from aryl aldehydes. Initially, the
aldehydes were treated with iPrMgCl and iodoform to ob-
tain desired β-diiodoalcohols 2, which were then oxidized
with o-iodoxybenzoic acid (IBX) at room temperature to
the corresponding β-diiodoketones 3. Compounds 3 are a
valuable reactive species on there own. Subsequent reaction
of β-diiodoketones 3 with α-ketoaldehydes 4 occurred un-
der oxygen transfer from dimethyl sulfoxide. These sensitive
products were then cyclized in situ with o-phenylenediamine
to form stable monosubstituted quinoxalines 5, which could
be characterized and isolated easily (Scheme 1).
α-Ketoaldehydes are a versatile, highly reactive moiety
for the synthesis of heterocyclic compounds.[1] Cyclization
of α-ketoaldehydes has been utilized in the design of pepti-
dyl α-ketoaldehydes, which inhibit the 20 S proteasome,[2]
and various synthetic approaches to such desirable peptidic
α-ketoaldehydes have been established. A frequently em-
ployed method, the oxidation of α-diazoketones by using
dimethyldioxirane (DMD), imposes a potential hazard in
the scale up of the synthesis.[3] Another versatile method,
recently developed by Rademann et al., starts with the C-
acylation of polymer-supported 2-phosphoranylidene acet-
ates linked to protected amino acids, which is followed by
saponification of the ester, decarboxylation, and oxidation
with DMD.[4]
The majority of the documented syntheses of α-keto-
aldehydes rely on the oxidation of acetophenone by SeO2.[5]
The alternative iodination of acetophenone under acidic
conditions and subsequent oxidation of the phenacyl
iodides with dimethyl sulfoxide has distinct merits.[6] How-
ever, all these methods are unfavorable with respect to rea-
gent toxicity, or require harsh reaction conditions or suffer
from insufficient yields. An alternative approach to non-
peptidic aldehydes utilizes dihalide compounds and di-
methyl sulfoxide under mild conditions.[7] Motivated by this
method, we investigated the transformation of aldehydes
into α-ketoaldehydes via β-diiodoketone intermediates and
finally applied the procedure to the synthesis of peptidic
substrates.
Scheme 1. Synthesis route to α-ketoaldehydes/quinoxalines.
[a] Technische Universität Darmstadt, Clemens Schöpf-Institut für
Organische Chemie und Biochemie,
The synthesis of β-diiodoalcohols from simple aromatic
aldehydes was described by Braun et al.[8] and was extended
to substituted benzaldehydes. A diverse array of commer-
cial, substituted benzaldehydes 1 was subjected to the reac-
tion conditions, and the corresponding products were iso-
Petersenstr. 22; 64287 Darmstadt, Germany
Fax: +49-6151-163278
E-mail: schmidt_boris@t-online.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101835.
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A. Zall, D. Bensinger, B. Schmidt
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Table 1. Scope of the reaction.[a]
Table 1. (Continued)
[a] Reagents and conditions: 1 (1.0 mmol), iPrMgCl (2 m in THF,
3.0 mmol), CHI3 (3.0 mmol) in THF at –78 °C for 15 min, then at
0 °C for 1–2 h. [b] Yield of isolated product.
lated in moderate to good yields with excellent functional
group tolerance (Table 1, Entries 1–8, 11–14). The forma-
tion of the β-diiodoalcohols was achieved in a single step
from the aldehyde and avoids expensive or sensitive rea-
gents such as diazomethane and SmI2.[5a]
In general, it was observed that aldehydes containing
either electron-withdrawing or electron-donating groups re-
acted smoothly to give the corresponding β-diiodoalcohols
in good yields. These transformations occurred readily
when the benzaldehyde was substitted in the ortho, meta,
and para positions with a variety of substituents including
methoxy, alkoxy, alkyl, hydroxy, and nitro groups (com-
pounds 2b, 2c, 2g, 2h, 2m, 2n; Table 1). However, the reac-
tion of aldehyde 1i did not provide the desired product
Scheme 2. Reaction of amines with β-diiodoalcohols.
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Oxidative Homologation of Aldehydes to α-Ketoaldehydes
upon workup. Desired product 2i formed in the course of mixture. A reason for the decomposition may be the strong
the reaction as monitored by HPLC–MS, but disintegrated nucleophilicity and basicity of tertiary amines, producing
during removal of the solvent to leave a complex product conjugated enol 7 by deprotection at Cα and elimination of
Table 2. Scope of the reaction.[a,b]
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Table 2. (Continued)
[a] Reagents and conditions: 2 (1.0 mmol), IBX (2.0 mmol) in DMSO at room temperature for 12–19 h. [b] Compound 3 (1.0 mmol) in
DMSO at 60 °C for 2 d, then AcOH, o-phenylenediamine (1.0 mmol) in EtOH at 90 °C for 1 h. [c] Yield of isolated product. [d] Detected
by HPLC; in situ cyclization with o-phenylenediamine.
iodide. Enol 7 is in tautomeric equilibrium with β-diiodo- determination. Thus, in a one-pot reaction the α-ketoal-
ketone 8, which generates stable quaternary ammonium salt dehydes were treated with o-phenylenediamine to give stable
9 by nucleophilic substitution (Scheme 2).
quinoxalines 5, which facilitate yield comparison (Table 2).
Phenolic precursor 1j did not participate in the reaction The transformation of gem-dihalomethylarenes into alde-
and was recovered upon workup of the reaction mixture. hydes by dimethyl sulfoxide as an oxygen donor was de-
Reduced acidity and nucleophilicity, which is realized in scribed to occur under neutral conditions for bromine and
imidazole 1k and amide 1l, result in good to excellent yield, chlorine derivatives.[7] Wei Li et al. proposed that the con-
which supports the proposed hypothesis, illustrated in version proceeds via an alkoxysulfonium species, which un-
Scheme 2.
dergoes 1,2-elimination to give the desired product and a
Subsequent oxidation of β-diiodoalcohols with 2-iodoxy- halodimethylsulfonium halide as a byproduct. Therefore,
benzoic acid (IBX)[9] delivered the desired β-diiodoketones we assumed that the reaction of the α-diiodoketones to af-
(Table 2). IBX is a selective and mild oxidizing agent for ford the corresponding α-ketoaldehydes involved such an
primary and secondary alcohols and has been applied to oxygen transfer from DMSO. This reaction mechanism was
the oxidation of peptidic substrates previously.[10]
confirmed for substrate 3a by NMR spectroscopy in [D6]-
1
The β-diiodoalcohols were oxidized with IBX (2 equiv.) DMSO. The H NMR spectrum included a significant sig-
in DMSO at room temperature within 12–19 h. Most β- nal of the resulting aldehyde at δ ≈ 9.55 ppm and the 13C
diiodoalcohols reacted smoothly irrespective of the elec- NMR spectrum showed signals at δ ≈ 196 and 189 ppm,
tronic nature of the groups in the ortho, meta, and para typical for carbonyl groups of ketoaldehydes. The 13C
positions or multiple substitutions to provide the β-diiodo- NMR signal of the diiodinated carbon atom at δ ≈
ketones in good yields (56–94%, 3b–g, 3j; Table 2) except –22.4 ppm disappeared at the same speed as the new signals
for p-phenol 2n. This substrate was consumed rapidly as arose.
monitored by HPLC–MS, but gave a complex reaction mix-
We tested the potential and general applicability of this
ture. This observation was rationalized by the ability to give method by synthesizing peptidic and peptidometic α-keto-
a cyclohexadienone intermediate and the known IBX-medi- aldehydes 13 and 18, which are versatile intermediates and
ated demethylation of 2-methoxyphenol.[11] The oxidation may be used in protease inhibition (Scheme 3). Peptide al-
of alcohols 2h and 2l proceeded so fast that resulting dehydes 10 and 15 were converted into peptidyl β-diiodoal-
ketones 3h and 3i could not be isolated because they imme- cohols 11 und 16 in analogy to the aryl aldehydes, and this
diately reacted further to the corresponding α-ketoal- process was reported to occur without epimerization of the
dehydes 4h and 4i. These were then cyclized with o-phenyl- α-carbon.[8] Subsequent oxidation by IBX provided peptidyl
enediamine in situ to provide quinoxalines 5h and 5i as the β-diiodoketones 12 and 17. Reaction to peptidyl α-ketoal-
final products. Isolated β-diiodoketones 3a–g and 3j were dehydes 13 and 18 was carried out in DMSO at 50 °C and
converted into desired α-ketoaldehydes 4 by DMSO at was monitored by HPLC–MS. A structurally related ana-
60 °C. The reaction progress was monitored by HPLC until logue of ketoaldehyde 18 was identified recently as a potent
complete. The targeted, labile α-ketoaldehydes form hy- inhibitor of the 20 S proteasome with a novel mode of ac-
drates and ketals easily and thus give rise to errors in yield tion.[2] Cyclocondensation with o-phenylenediamine at
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Oxidative Homologation of Aldehydes to α-Ketoaldehydes
Scheme 3. Synthesis route to peptidyl quinoxalines.
tion (λ = 254 nm). The chromatographic method employed the fol-
lowing: column Zorbax Eclipse XDB-C18; 4.6ϫ150 mm; mobile
phase A H2O (0.1% TFA), mobile phase B acetonitrile, flow rate
1 mL/min, gradient elution 30 to 100% B over 15 min. According
to these methods the purities for all compounds were Ն95% if not
indicated otherwise in the experimental details. Thin-layer
chromatography (TLC) was carried out by using aluminum sheets
precoated with silica gel 60 F254 (0.2 mm; E. Merck). Chromato-
graphic spots were visualized by UV and/or by spraying with a
methanolic solution of vanillin/H2SO4 or aq. KMNO4 solution fol-
lowed by heating. Silica gel chromatography was carried out by
using Merck silica gel 60 (0.063–0.2 mm). Melting points were de-
termined with a Mettler FP 51 melting point apparatus. All rea-
gents and solvents (THF, DMF, CH2Cl2, ethyl acetate, MeOH,
DMSO) were purchased from ABCR, Acros and Alfa Aesar, TCI,
Sigma Aldrich, and VWR.
70 °C afforded peptidyl quinoxalines 14 and 19 in good
yields. Compound 19 was isolated as a single diastereomer
with Ͼ95%dr as assigned by 1H NMR spectroscopic analy-
sis of the quinolyl 3H, which gave one signal only (see spec-
trum 19 in the Supporting Information).
Conclusions
In summary, we have developed a simple and mild syn-
thetic method to transform aldehydes into the correspond-
ing α-ketoaldehydes via β-diiodoketones. This is the first
example involving the use of DMSO as a single reagent/
solvent to convert β-diiodoketones into α-ketoaldehydes.
The synthetic route was applied to the straightforward syn-
thesis of peptidyl α-ketoaldehydes from peptidic β-diiodo-
ketones, which are versatile intermediates that can lead to
structures for protease inhibition.
Typical Procedure (TP I) for the Synthesis of β-Diiodoalcohols from
Aldehydes: iPrMgCl (2.0 m in THF, 1.5 mL, 3.0 mmol) was added
dropwise to a solution of iodoform (1.18 g, 3.0 mmol) in THF
(10 mL, abs.) at –78 °C under an argon atmosphere. A solution of
aldehyde 1 (1.00 mmol) in THF (1 mL, abs.) was added, and the
resulting mixture was stirred at the same temperature for 15 min
and at 0 °C for 1–2 h. The mixture was quenched with aqueous
NH4Cl (10 mL, sat.) and extracted with CH2Cl2 (3ϫ20 mL). The
combined organic layers were dried with Na2SO4 and concentrated
in vacuo. Crude product 2 was purified by LC.
Experimental Section
1
General Methods: H NMR and 13C NMR spectra were recorded
with a Bruker AC 300 (300 MHz) and AC 500 (500 MHz) spec-
trometer. Chemical shifts are reported in δ (ppm) adjusted to the
central line of the deuterated solvent (MeOD, CDCl3, [D6]DMSO).
Mass spectrometry was performed with a Bruker-Franzen Esquire
LC mass spectrometer (ESI) and a double-focused MAT 95 (EI).
HPLC analysis was performed with an Agilent 1100 system. The
purity of the final compounds was determined by using UV detec-
Typical Procedure (TP II) for the Oxidation of β-Diiodoalcohols
with IBX: To a solution of β-diiodoalcohol 2 (1.0 mmol) in DMSO
(5 mL) was added IBX (0.56 g, 2.0 mmol), and the mixture was
stirred at room temperature for 19 h. The reaction mixture was
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A. Zall, D. Bensinger, B. Schmidt
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quenched with water (50 mL) and CH2Cl2 (70 mL) was added. The
precipitate was filtered off, and the organic layer was extracted with
water (2ϫ50 mL), washed with NaHCO3 (50 mL, sat.), dried with
Na2SO4, and concentrated in vacuo. Crude product 3 was purified
by LC.
HPLC: tR = 5.90 min (99%). 1H NMR (300 MHz, CDCl3): δ =
6.63 (s, 2 H), 5.30 (d, J = 4.4 Hz, 1 H), 4.62 (t, J = 4.1 Hz, 1 H),
3.88 (s, 6 H), 3.85 (s, 3 H), 2.95 (d, J = 4.0 Hz, 1 H) ppm. 13C
NMR (75 MHz,CDCl3): δ = 153.3, 138.2, 134.5, 103.8, 79.7, 60.8,
56.3, –11.2 ppm. MS (EI): m/z = 464 [M]+.
Typical Procedure (TP III): Synthesis of Quinoxalines from β-Di-
iodoketones over α-Ketoaldehydes: β-Diiodoketone 3 (0.25 mmol)
was dissolved in DMSO (2.5 mL) and stirred at 60 °C for 40 h
(HPLC control). Glacial acetic acid (0.6 mL) and a solution of o-
phenylenediamine (27 mg, 0.25 mmol) in EtOH (1.5 mL) was
added to the reaction mixture, which was stirred at 90 °C for 1 h.
After cooling, water (10 mL) was added, and the mixture was ex-
tracted with CH2Cl2 (2ϫ15 mL). The combined organic layer was
2,2-Diiodo-1-(2,4,6-trimethoxyphenyl)ethanol (2e): According to
typical procedure TP I, 2,4,6-trimethoxybenzaldehyde (1e; 0.30 g,
1.53 mmol), CHI3 (1.8 g, 4.59 mmol), and iPrMgCl (2.3 mL,
4.59 mmol). Yield: 700 mg (99%) of 2e as a brown solid. Rf
(CHCl3) = 0.50. HPLC: tR = 7.20 min (93%). 1H NMR (300 MHz,
CDCl3): δ = 6.06 (s, 2 H), 5.46 (d, J = 7.8 Hz, 1 H), 5.19 (t, J =
8.4 Hz, 1 H), 4.83 (s, 1 H), 3.79 (s, 6 H), 3.75 (s, 3 H) ppm. 13C
NMR (75 MHz,CDCl3): δ = 161.4, 158.7, 107.2, 91.1, 75.0, 55.9,
washed with water (2ϫ30 mL), dried with Na2SO4, and concen- 55.4, –11.2 ppm. MS (EI): m/z = 464 [M]+.
trated in vacuo. Crude product 5 was purified by LC.
1-(Benzo[d][1,3]dioxol-5-yl)-2,2-diiodoethanol (2f): According to
2-Iodoxybenzoic Acid: 2-Iodobenzoic acid (4.0 g, 16.13 mmol) was
added all at once to a solution of oxone (12.9 g, 20.97 mmol) in
water (52 mL). The reaction mixture was warmed slowly to 73 °C
and stirred at this temperature for 3 h. The suspension was than
cooled to 5 °C and left at this temperature for 1.5 h with slow stir-
ring. The mixture was filtered, and the solid was repeatedly rinsed
with water (3ϫ15 mL) and acetone (20 mL). The white, crystalline
solid (4.26 g, 94%) was dried under reduced pressure. 1H NMR
(300 MHz, [D6]DMSO): δ = 8.01 (m), 8.42 (s) ppm.13C NMR
(75 MHz, [D6]DMSO): δ = 167.5, 146.6, 133.3, 132.9, 131.4, 130.1,
125.0 ppm.
typical procedure TP I, piperonal (1f; 0.30 g, 2.0 mmol), CHI3
(2.36 g, 5.99 mmol), and iPrMgCl (3.0 mL, 5.99 mmol). The crude
product was purified by LC (CHCl3). Yield: 683 mg (82%) of 2f as
1
a brown oil. Rf (CHCl3) = 0.71. HPLC: tR = 6.53 min (97%). H
NMR (300 MHz, CDCl3): δ = 7.27–6.86 (m, 2 H), 6.79 (d, J =
8 Hz, 1 H), 5.99 (m, 2 H), 5.25 (d, J = 4.7 Hz, 1 H), 4.61 (d, J =
4.6 Hz, 1 H), 2.89 (s, -OH) ppm. 13C NMR (75 MHz,CDCl3): δ =
147.8, 133, 120.5, 108.2, 106.9, 101.3, 79.4, –10.3 ppm. MS (EI):
m/z = 418 [M]+.
2,2-Diiodo-1-(4-isopropylphenyl)ethanol (2 g): According to typical
procedure TP I, 4-isopropylbenzaldehyde (1g; 0.30 g, 2.02 mmol),
CHI3 (2.39 g, 6.06 mmol), and iPrMgCl (3.0 mL, 6.06 mmol). The
crude product was purified by LC (CHCl3). Yield: 590 mg (71%)
2,2-Diiodo-1-phenylethanol (2a): According to typical procedure
TP I, benzaldehyde (1a; 0.30 g, 2.83 mmol), CHI3 (3.34 g,
8.48 mmol), and iPrMgCl (4.2 mL, 8.48 mmol). The crude product
was purified by LC (CHCl3). Yield: 834 mg (79%) of 2a as a brown
oil. Rf (CHCl3) = 0.67. HPLC: tR = 6.52 min (97%). 1H NMR
(300 MHz, CDCl3): δ = 7.44–7.36 (m, 5 H), 5.35 (d, J = 3.6, 2.0 Hz,
1 H), 4.71 (t, J = 3.9 Hz, 1 H), 2.85 (d, J = 3.8 Hz, 1 H, -OH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 139.1, 128.8, 128.6, 126.5,
79.7, –10.8 ppm. MS (EI): m/z = 374 [M]+.
of 2g as orange oil. Rf (CH/CHC,l31:1) = 0.21. HPLC: tR
=
1
7.91 min (90%). H NMR (300 MHz, CDCl3): δ = 7.35–7.22 (dd,
J = 31.8, 8.2 Hz, 4 H), 5.33 (d, J = 4.6 Hz, 1 H), 4.69 (d, J =
4.5 Hz, 1 H), 2.92 (hept., J = 6.3 Hz, 1 H), 2.81 (s, 1 H, -OH), 1.26
(d, J = 6.9 Hz, 6 H) ppm.13C NMR (75 MHz, CDCl3): δ = 149.6,
136.4, 126.6, 126.5, 79.7, 33.9, 23.8, –10.4 ppm. MS (EI): m/z =
416 [M]+.
2,2-Diiodo-1-(4-methoxyphenyl)ethanol(2b): According to typical
procedure TP I, anisaldehyde (1b; 0.272 g, 2.0 mmol), CHI3 (2.36 g,
6.0 mmol), and iPrMgCl (3.0 mL, 6.0 mmol).The crude product
was purified by LC (CHCl3). Yield: 775 mg (96%) of 2b as a brown
oil. Rf (CHCl3) = 0.59. HPLC: tR = 6.42 min (98%). 1H NMR
(300 MHz, CDCl3): δ = 7.36–7.32 (m, 2 H), 6.81 (d, J = 8.0 Hz, 2
H), 5.28 (d, J = 4.7 Hz, 1 H), 4.65 (d, J = 4.4 Hz, 1 H), 3.82 (s, 3
2,2-Diiodo-1-(4-nitrophenyl)ethanol (2h): According to typical pro-
cedure TP I, 4-nitrobenzaldehyde (1h; 0.27 g, 1.79 mmol), CHI3
(2.12 g, 5.38 mmol), and iPrMgCl (2.7 mL, 5.38 mmol). The crude
product was purified by LC (CHCl3). Yield: 609 mg (73%) of 2h
as a yellow solid. Rf (CHCl3) = 0.42. HPLC: tR = 6.76 min (95%).
1H NMR (300 MHz, CDCl3): δ = 8.18–8.14 (m, 2 H), 7.57–7.54
(m, 2 H), 5.28 (d, J = 4.1 Hz, 1 H), 4.76 (d, J = 4.1 Hz, 1 H), 2.96
H), 2.88 (s, 1 H, -OH) ppm. 13C NMR (75 MHz, CDCl3): δ = (s, 1 H, -OH) ppm.13C NMR (75 MHz, CDCl3): δ = 147.9, 145.8,
159.8, 131.2, 127.8, 113.9, 79.3, 55.3, –9.5 ppm. MS (EI): m/z =
127.7, 123.7, 78.6, –14.2 ppm. MS (EI): m/z = 419 [M]+.
404 [M]+.
N-[4-(1-Hydroxy-2,2-diiodoethyl)phenyl]acetamide (2l): According
to typical procedure TP I, 4-acetamidobenzaldehyde (1l; 0.30 g,
1.84 mmol), CHI3 (2.17 g, 5.51 mmol), and iPrMgCl (2.8 mL,
5.51 mmol). The crude product was purified by LC (CHCl3/MeOH,
20:1). Yield: 604 mg (76%) of 2l as a yellow solid. Rf (CHCl3/
MeOH, 20:1) = 0.28. HPLC: tR = 4.262 min (98%). 1H NMR
(300 MHz, CDCl3): δ = 7.15 (dd, J = 43.5, 8.6 Hz, 4 H), 5.03 (d,
2,2-Diiodo-1-(2-methoxyphenyl)ethanol (2c): According to typical
procedure TP I, o-methoxybenzaldehyde (1c; 0.30 g, 2.2 mmol),
CHI3 (2.60 g, 6.6 mmol), and iPrMgCl (3.3 mL, 6.6 mmol). The
crude product was purified by LC (CH/CHCl3, 1:1). Yield: 654 mg
(73%) of 2c as a brown oil. Rf (CH/CHCl3, 1:1) = 0.55. HPLC: tR
= 6.982 min (81%). 1H NMR (300 MHz, CDCl3): δ = 7.52–7.49
(m, 1 H), 7.39–7.33 (m, 1 H), 7.01 (td, J = 7.5, 1.0 Hz, 1 H), 6.88 J = 4.4 Hz, 2 H), 4.3 (d, J = 4.4 Hz, 1 H), 4.25 (s, 3 H) ppm. 13C
(dd, J = 8.3, 0.9 Hz, 1 H), 5.66 (d, J = 3.8 Hz, 1 H), 4.51 (d, J = NMR (75 MHz, CDCl3): δ = 169.8, 137.9, 135.8, 126.7, 119.1, 78.3,
3.6 Hz, 1 H), 3.88 (s, 3 H), 4.04 (s, OH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 156.0, 129.6, 128.6, 127.5, 120.7, 110.5, 76.3, 55.5,
–11.0 ppm. MS (EI): m/z = 404 [M]+.
22.8, –12.3 ppm. MS (EI): m/z = 431 [M]+.
1-(3-Bromo-4-methoxyphenyl)-2,2-diiodoethanol (2m): According to
typical procedure TP I, 3-bromo-4-methoxybenzaldehyde (1m;
0.30 g, 1.40 mmol), CHI3 (1.65 g, 4.19 mmol), and iPrMgCl
(2.1 mL, 4.19 mmol). The crude product was purified by LC
2,2-Diiodo-1-(3,4,5-trimethoxyphenyl)ethanol (2d): According to
typical procedure TP I, 3,4,5-trimethoxybenzaldehyde (1d; 0.35 g,
1.78 mmol), CHI3 (2.1 g, 5.34 mmol), and iPrMgCl (2.7 mL, (CHCl3). Yield: 633 mg (94%) of 2m as a brown oil. Rf (CHCl3) =
1
5.4 mmol). The crude product was purified by LC (CHCl3). Yield:
550 mg (67%) of 2d as a brown-orange oil. Rf (CHCl3) = 0.14.
0.51. HPLC: tR = 7.317 min (95%). H NMR (300 MHz, CDCl3):
δ = 7.61 (d, J = 2.2 Hz, 1 H), 7.34 (ddd, J = 8.5, 2.2, 0.5 Hz, 1 H),
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Oxidative Homologation of Aldehydes to α-Ketoaldehydes
6.88 (d, J = 8.5 Hz, 1 H), 5.26 (d, J = 4.5 Hz, 1 H), 4.62 (d, J = 1-(Benzo[d][1,3]dioxol-5-yl)-2,2-diiodoethanone (3f): According to
4.2 Hz, 1 H), 3.91 (s, 3 H), 2.89 (s, 1 H, -OH) ppm. 13C NMR typical procedure TP II, 1-(benzo[d][1,3]dioxol-5-yl)-2,2-diiodo-
(75 MHz, CDCl3): δ = 156.1, 132.5, 131.5, 126.9, 117.8, 111.6, 78.6,
ethanol (2f; 0.62 g, 1.49 mmol) and IBX (0.84 g, 2.98 mmol). The
crude product was purified by LC (CHCl3). Yield: 523 mg (84%)
of 3f as a brown solid. HPLC: tR = 7.51 min (80%). 1H NMR
(300 MHz, CDCl3): δ = 7.65 (dd, J = 8.3, 1.8 Hz, 1 H), 7.49 (d, J
= 1.8 Hz, 1 H), 6.86 (d, J = 8.3 Hz, 1 H), 6.45 (s, 1 H), 6.08 (s, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 185.3, 151.3, 147.1,
124.5, 121.3, 107.9, 106.8, 100.8, –29.3 ppm. MS (EI): m/z = 416
[M]+. HRMS (EI): calcd. for C9H6O3I2 [M]+ 415.8405; found
415.8404
56.3, –10.7 ppm. MS (EI): m/z = 482 [M]+.
4-(1-Hydroxy-2,2-diiodoethyl)-2-methoxyphenol (2n): According to
typical procedure TP I, 4-hydroxy-3-methoxybenzaldehyde (1n;
0.30 g, 1.97 mmol), CHI3 (2.33 g, 5.91 mmol), and iPrMgCl
(3.0 mL, 6.0 mmol). The crude product was purified by LC
(CHCl3). Yield: 555 mg (67%) of 2m as a brown oil. Rf (CHCl3) =
1
0.18. HPLC: tR = 4.89 min (100%). H NMR (500 MHz, CDCl3):
δ = 6.9 (d, J = 2 Hz, 1 H), 6.82 (d, J = 8.0 Hz, 1 H), 6.79 (dd, J =
8, 2 Hz, 1 H), 5.6 (s, 1 H), 5.2 (d, J = 4.5 Hz, 1 H), 4.55 (t, J = 2,2-Diiodo-1-(4-isopropylphenyl)ethanone (3g): According to typical
4.0 Hz, 1 H), 3.85 (s, 3 H), 2.76 (s, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 146.5, 145.9, 130.9, 119.9, 114.3, 109.0, 79.51, 56.1,
–9.67 ppm. MS (EI): m/z = 420 [M]+.
procedure TP II, 2,2-diiodo-1-(4-isopropylphenyl)ethanol (2g;
0.59 g, 1.27 mmol) and IBX (0.71 g, 2.54 mmol). Yield: 330 mg
(56%) of 3g as a brown oil. Rf (CH/CHCl3, 1:1) = 0.56. HPLC: tR
1
= 8.69 min (61%). H NMR (300 MHz, CDCl3): δ = 7.89 (d, J =
2,2-Diiodo-1-phenylethanone (3a): According to typical procedure
TP II, 2,2-diiodo-1-phenylethanol (2a; 0.57 g, 1.51 mmol) and IBX
(0.85 g, 3.03 mmol). The crude product was purified by LC
8.5 Hz, 2 H), 7.25 (d, J = 8.3 Hz, 2 H), 6.43 (s, 1 H), 2.91 (hept.,
J = 6.3 Hz, 1 H), 1.20 (d, J = 6.9 Hz, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 187.9, 156.0, 129.8, 127.2, 126.3, 34.4, 23.6,
–28.5 ppm. MS (EI): m/z = 414 [M]+.
(CHCl3). Yield: 460 mg (82%) of 3a as a brown oil. HPLC: tR
7.486 min (97%). H NMR (300 MHz, CDCl3): δ = 8.07–8.00 (m,
=
1
2 H), 7.67–7.58 (m, 1 H), 7.53–7.44 (m, 2 H), 6.52 (s, 1 H) ppm. 1-(3-Bromo-4-methoxyphenyl)-2,2-diiodoethanone (3j): According to
13C NMR (75 MHz, CDCl3): δ = 188.3, 134.1, 129.5, 129.0, 128.7, typical procedure TP II, 1-(3-bromo-4-methoxyphenyl)-2,2-diiodo-
–28.9 ppm. MS (EI): m/z = 372 [M]+.
ethanol (2m; 0.19 g, 0.39 mmol) and IBX (0.22 g, 0.79 mmol).
Yield: 178 mg (94%) of 3j as a brown oil. HPLC: tR = 8.28 min
(60%). 1H NMR (500 MHz, CDCl3): δ = 8.25 (d, J = 2.2 Hz, 1 H),
8.02 (dd, J = 8.7, 2.3 Hz, 1 H), 6.94 (d, J = 8.7 Hz, 1 H), 6.42 (s,
1 H), 3.99 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 184.9,
159.0, 133.5, 129.9, 120.9, 111.5, 111.3, 55.5, –29.7 ppm. MS (EI):
m/z = 480 [M]+.
2,2-Diiodo-1-(4-methoxyphenyl)ethanone (3b): According to typical
procedure TP II, 2,2-diiodo-1-(4-methoxyphenyl)ethanol (2b;
0.19 g, 0.47 mmol) and IBX (0.26 g, 0.94 mmol). The crude prod-
uct was purified by LC (CHCl3). Yield: 176 mg (93%) of 3b as a
1
brown solid. Rf (CHCl3) = 0.65. HPLC: tR = 7.55 min (97%). H
NMR (300 MHz, CDCl3): δ = 7.95 (d, J = 9.1 Hz, 2 H), 6.88 (d,
J = 9.1 Hz, 2 H), 6.40 (s, 1 H), 3.82 (s, 3 H) ppm. 13C NMR
2-Phenylquinoxaline (5a): According to typical procedure TP III,
(75 MHz, CDCl3): δ = 186.9, 164.3, 132.0, 121.0, 114.3, 55.6, 2,2-diiodo-1-phenylethanone (3a; 66 mg, 0.18 mmol) and o-phenyl-
–28.6 ppm. MS (EI): m/z = 402 [M]+. HRMS (EI): calcd. for
enediamine (19 mg, 0.18 mmol). The crude product was purified by
LC (CHCl3). Yield: 30 mg (81%) of 5a as a white solid. Rf (CHCl3)
= 0.41. HPLC: tR = 6.67 min (99%). 1H NMR (300 MHz, CDCl3):
δ = 9.34 (s, 1 H), 8.14–8.10 (m, 4 H), 7.82–7.72 (m, 2 H), 7.61–7.50
(m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 151.9, 143.4,
142.3, 141.6, 136.8, 130.0, 130.2, 129.7, 129.6, 129.2, 127.6 ppm.
C9H8O2I2 [M]+ 401.8605; found 401.8612.
2,2-Diiodo-1-(2-methoxyphenyl)ethanone (3c): According to typical
procedure TP II, 2,2-diiodo-1-(2-methoxyphenyl)ethanol (2c;
0.65 g, 1.62 mmol) and IBX (0.91 g, 3.24 mmol). The crude prod-
uct was purified by LC (CHCl3). Yield: 415 mg (64%) of 3c as a
brown solid. HPLC: tR = 7.75 min (98%). 1H NMR (300 MHz,
2-(4-Methoxyphenyl)quinoxaline (5b): According to typical pro-
CDCl3): δ = 7.86–7.83 (m, 1 H), 7.52 (ddd, J = 8.4, 7.3, 1.8 Hz, 1 cedure TP III, 2,2-diiodo-1-(4-methoxyphenyl)ethanone (3b;
H), 7.07–6.99 (m, 2 H), 6.78 (s, 1 H), 3.96 (s, 3 H) ppm. 13C NMR
85 mg, 0.21 mmol) and o-phenylenediamine (23 mg, 0.21 mmol).
(75 MHz, CDCl3): δ = 190.1, 158.1, 134.8, 132.9, 121.4, 119.9, The crude product was purified by LC (CH/CHCl3, 1:1). Yield:
111.6, 56.0, –20.1 ppm. MS (EI): m/z = 402 [M]+. HRMS (EI):
42 mg (84%) of 5b as a brown solid. Rf (Cy/CHCl3 = 1:1) = 0.23.
HPLC: tR = 6.81 min (93%). 1H NMR (300 MHz, CDCl3): δ =
9.31 (s, 1 H), 8.17 (m, 4 H), 7.76 (m, 2 H), 7.09 (m, 2 H), 3.91 (s,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.5, 151.5, 143.1,
142.3, 141.2, 133.9, 130.2, 129.4, 129.1, 114.6, 113.9, 55.4 ppm. MS
(EI): m/z = 236 [M]+.
calcd. for C9H8O2I2 [M]+ 401.8606; found 401.8612.
2,2-Diiodo-1-(3,4,5-trimethoxyphenyl)ethanone (3d): According to
typical procedure TP II, 2,2-diiodo-1-(3,4,5-trimethoxyphenyl)eth-
anol (2d; 0.35 g, 0.75 mmol) and IBX (0.42 g, 1.51 mmol). The
crude product was purified by LC (CHCl3). Yield: 250 mg (71%)
of 3d as a brown solid. Rf (CHCl3) = 0.65. HPLC: tR = 7.41 min 2-(2-Methoxyphenyl)quinoxaline (5c): According to typical pro-
1
(92%). H NMR (300 MHz, CDCl3): δ = 7.24 (s, 2 H), 6.39 (s, 1
cedure TP III, 2,2-diiodo-1-(2-methoxyphenyl)ethanone (3c;
H),3.88 (s, 3 H), 3.85 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): 100 mg, 0.25 mmol) and o-phenylenediamine (27 mg, 0.25 mmol).
δ = 187.2, 153.1, 143.7, 123.3, 107.4, 61.1, 56.4, –29.7 ppm. MS
(EI): m/z = 462 [M]+.
The crude product was purified by LC (CHCl3). Yield: 52 mg
(88%) of 5c as a yellow solid. HPLC: tR = 6.56 min (99%). 1H
NMR (500 MHz, CDCl3): δ = 9.36 (s, 1 H), 8.05–8.04 (m, 2 H),
7.84–7.82 (dd, J = 7.6, 1.8 Hz, 2 H), 7.70–7.65 (m, 2 H), 7.42–7.39
(ddd, J = 8.3, 7.4, 1.8 Hz, 1 H), 7.10–7.00 (td, J = 7.1, 1.0 Hz, 1
H), 6.98 (d, J = 8.0 Hz, 1 H), 3.83 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 157.4, 152.2, 147.3, 142.7, 141.0, 131.6,
131.4, 129.8, 129.6, 129.4, 129.1, 126.6, 121.6, 111.5, 55.7 ppm. MS
(EI): m/z = 236 [M]+. HRMS (EI): calcd. for C15H12N2O [M]+
236.0931; found 236.0950.
2,2-Diiodo-1-(2,4,6-trimethoxyphenyl)ethanone (3e): According to
typical procedure TP II, 2,2-diiodo-1-(2,4,6-trimethoxyphenyl)eth-
anol (2e; 1.00 g, 2.15 mmol) and IBX (1.20 g, 4.40 mmol). The
crude product was purified by LC (CHCl3/CH, 2:1). Yield: 813 mg
(88%) of 3e as a yellow solid. Rf (CHCl3/CH) = 0.49. HPLC: tR
=
7.49 min (94%). 1H NMR (300 MHz, CDCl3): δ = 6.34 (s, 1 H),
6.12 (s, 2 H), 3.85 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
188.3, 163.9, 159.8, 104.3, 90.7, 56.0, 55.5, –17.8 ppm. MS (EI):
m/z = 462 [M]+. HRMS (EI): calcd. for C11H12O4I2 [M]+ 461.8796;
found 461.8823.
2-(3,4,5-Trimethoxyphenyl)quinoxaline (5d): According to typical
procedure TP III, 2,2-diiodo-1-(3,4,5-trimethoxyphenyl)ethanone
Eur. J. Org. Chem. 2012, 1439–1447
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1445

A. Zall, D. Bensinger, B. Schmidt
FULL PAPER
(3d; 250 mg, 0.54 mmol) and o-phenylenediamine (59 mg,
0.54 mmol). The crude product was purified by LC (CHCl3/MeOH,
50:1). Yield: 130 mg (81%) of 5d as a brown solid. Rf (CHCl3/
MeOH = 50:1) = 0.67. HPLC: tR = 6.30 min (76%). 1H NMR
(300 MHz, CDCl3): δ = 9.28 (s, 1 H), 8.14–8.10 (m, 2 H),7.81–7.71
2-(3-Bromo-4-methoxyphenyl)quinoxaline (5j): According to typical
procedure
TP III,
1-(3-bromo-4-methoxyphenyl)-2,2-diiodo-
ethanone (3j; 95 mg, 0.20 mmol) and o-phenylenediamine (21.0 mg,
0.20 mmol). The crude product was purified by LC (CHCl3). Yield:
56 mg (90%) of 5j as a white solid. Rf (CHCl3) = 0.455. HPLC: tR
1
(m, 2 H), 7.43 (s, 2 H), 4.01 (s, 6 H), 3.94 (s, 3 H) ppm. 13C NMR = 7.84 min (99%). H NMR (300 MHz, CDCl3): δ = 9.26 (s, 1 H),
(75 MHz, CDCl3): δ = 153.8, 151.4, 143.2, 142.2, 141.5, 140.2, 8.47 (d, J = 2.2 Hz, 1 H), 8.15–8.07 (m, 3 H), 7.82–7.68 (m, 2 H),
132.2, 130.3, 129.5, 129.1,104.8, 61.0, 56.4 ppm. MS (EI): m/z =
7.05 (d, J = 8.6 Hz, 1 H), 3.90 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 157.6, 150.0, 142.6, 142.2, 141.4, 132.5, 130.5, 130.4,
129.4, 129.1, 127.7, 112.8, 112.0, 56.4 ppm. MS (EI): m/z = 314
[M]+. HRMS (EI): calcd. for C15H11N2OBr [M]+ 314.00243; found
314.0055.
296 [M]+.
2-(2,4,6-Trimethoxyphenyl)quinoxaline (5e): According to typical
procedure TP III, 2,2-diiodo-1-(2,4,6-trimethoxyphenyl)ethanone
(3e; 120 mg, 0.26 mmol) and o-phenylenediamine (28 mg,
0.26 mmol). The crude product was purified by LC (CHCl3). Yield:
65 mg (84%) of 5e as a yellow solid. HPLC: t = 5.89 min (89%).
1H NMR (300 MHz, CDCl3): δ = 8.85 (s, 1 H), 8.30–8.08 (m, 2
H), 7.82–7.71 (m, 2 H), 6.27 (s, 2 H), 3.90 (s, 3 H), 3.76 (s, 6 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 162.7, 159.5, 148.6, 140.8,
129.7, 129.4, 129.0, 91.0, 55.9, 55.5 ppm.
N1-[(2S)-3-Hydroxy-4,4-diiodo-1-phenylbutan-2-yl]-N3,N3-dipropyl-
isophthalamide (11): iPrMgCl (2.0 m in THF, 2.50 mL, 5.05 mmol)
was added dropwise to a solution of iodoform (1988 mg,
5.05 mmol) in THF (25 mL, abs.) at –78 °C under an argon atmo-
sphere. A solution of aldehyde 10 (358 mg, 1.01 mmol) in THF
(5 mL, abs.) was added, and the resulting mixture was stirred at the
same temperature for 15 min and at 0 °C for 2 h. The mixture was
quenched with aqueous NH4Cl (30 mL, sat.) and extracted with
CH2Cl2 (3ϫ35 mL). The combined organic layer was dried with
Na2SO4 and concentrated in vacuo. The crude product was purified
by LC (CHCl3) to give β-diiodoalcohol 11 (470 mg, 77%) as a yel-
low solid. Rf (CHCl3) = 0.31. HPLC: tR = 7.62 min (98%). 1H
NMR (300 MHz, CDCl3): δ = 7.70 (td, J = 7.0, 1.9 Hz, 1 H), 7.62–
7.61 (m, 1 H), 7.44–7.35 (m, 2 H), 7.28–7.18 (m, 5 H), 6.87 (d, J
= 8.5 Hz, 1 H), 5.02 (d, J = 8.5 Hz, 1 H), 4.87 (dq, J = 7.9, 2.2 Hz,
1 H), 3.72 (dd, J = 8.5, 2.6 Hz, 1 H), 3.55–3.37 (m, 2 H), 3.12–3.06
(m, 2 H), 2.98–2.01 (m, 2 H), 1.68–1.49 (m, 4 H), 1.09–0.84 (m, 3
H), 0.83–0.59 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
171.1, 167.5, 137.3, 137.2, 134.5, 129.5, 129.3, 128.8, 128.7, 128.2,
126.8, 125.1, 76.8, 52.8, 50.9, 46.7, 39.0, 21.9, 20.8, 11.5, 11.1,
–17.0 ppm. MS (ESI): m/z = 649 [M + H]+.
2-(Benzo[d][1,3]dioxol-5-yl)quinoxaline (5f): According to typical
procedure TP III, 1-(benzo[d][1,3]dioxol-5-yl)-2,2-diiodoethanone
(105 mg, 0.25 mmol) and o-phenylenediamine (27 mg, 0.25 mmol).
The crude product was purified by LC (CHCl3). Yield: 57 mg
(90%) of 5f as a white solid. HPLC: tR = 6.85 min (95%). 1H NMR
(500 MHz, CDCl3): δ = 9.17 (s, 1 H), 8.03–8.00 (m, 2 H), 7.70–
7.61 (m, 4 H), 6.91 (d, J = 8.1 Hz, 1 H), 5.99 (s, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 150.2, 148.6, 147.7, 142.0, 141.2,
140.3, 130.1, 129.2, 128.4, 128.2, 128.0, 121.0, 107.8, 106.7,
100.6 ppm. MS (EI): m/z = 250 [M]+. HRMS (EI): calcd. for
C15H10N2O2 [M]+ 250.0722; found 250.0742.
2-(4-isopropylphenyl)quinoxaline (5g): According to typical pro-
cedure TP III, 2,2-diiodo-1-(4-isopropylphenyl)ethanone (3g;
110 mg, 0.54 mmol) and o-phenylenediamine (58.5 mg, 0.54 mmol).
The crude product was purified by LC (CHCl3/MeOH, 50:1).
Yield: 130 mg (81%) of 5g as a brown solid. Rf (CH/CHC,l31:1) =
(S)-N1-(4,4-Diiodo-3-oxo-1-phenylbutan-2-yl)-N3,N3-dipropyliso-
phthalamide (12): To a solution of β-diiodoalcohol 11 (94 mg,
0.14 mmol) in DMSO (5 mL) was added IBX (78 mg, 0.28 mmol),
and the mixture was stirred at room temperature for 15 h. The reac-
tion mixture was quenched with water (50 mL) and MTBE (methyl
tert-butyl ether) (70 mL) was added. The precipitate was filtered
off, and the organic layer were extracted with water (2ϫ50 mL),
dried with Na2SO4, and concentrated in vacuo. The crude product
was purified by LC [cyclohexane (CH)/ethyl acetate (EE), 1:1] to
give β-diiodoketone 12 (86 mg, 91%) as a yellow solid. Rf (CH/EE,
1:1) = 0.68. HPLC: tR = 8.26 min (95%). 1H NMR (300 MHz,
CDCl3): δ = 7.75–7.64 (m, 2 H), 7.47–7.38 (m, 2 H), 7.35–7.24 (m,
5 H), 7.13 (d, J = 7.7 Hz, 1 H), 5.68 (s, 1 H), 5.46 (q, J = 7.3 Hz,
1 H), 3.55–3.38 (m, 2 H), 3.24 (dd, J = 7.2, 1.4 Hz, 2 H), 3.18–3.03
(m, 2 H), 1.82–1.61 (m, 2 H), 1.60–1.41 (m, 2 H), 1.06–0.89 (m, 3
H), 0.83–0.61 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
195.9, 170.8, 166.5, 137.6, 135.7, 133.6, 129.9, 129.2, 129.1, 128.9,
127.9, 127.5, 125.2, 53.3, 50.8, 46.6, 38.9, 21.9, 20.8, 11.5, 11.1,
–26.2 ppm. MS (EI): m/z = 647 [M + Na]+.
1
0.36. HPLC: t = 8.26 min (81%). H NMR (300 MHz, CDCl3): δ
= 9.23 (s, 1 H), 8.07–8.01 (m, 4 H), 7.71–7.35 (m, 2 H), 7.35–7.31
(m, 2 H), 2.92 (hept., J = 6.3 Hz, 1 H), 1.23 (d, J = 6.9 Hz, 6 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 151.9, 151.4, 143.4, 142.4,
141.4, 134.4, 131.5, 130.2, 129.6, 129.3, 129.1, 127.6, 127.3, 34.1,
23.9 ppm. MS (EI): m/z = 248 [M]+.
2-(4-Nitrophenyl)quinoxaline (5h): According to typical procedure
TP II and TP III (one pot), 2,2-diiodo-1-(4-nitrophenyl)ethanol
(2h; 100 mg, 0.24 mmol), IBX (134 mg, 0.48 mmol), and o-phenyl-
enediamine (26.0 mg, 0.24 mmol). The crude product was purified
by LC (CHCl3). Yield: 56 mg (93%) of 5h as a brown solid. Rf
(CHCl3) = 0.66. HPLC: tR = 7.19 min (90%). 1H NMR (300 MHz,
CDCl3): δ = 9.40 (s, 1 H), 8.42 (s, 4 H), 8.14–8.08 (m, 2 H), 7.80–
7.73 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 149.3,148.7,
142.8, 142.6, 142.2, 142.1, 130.9, 130.7, 129.9, 129.3, 128.4,
124.3 ppm. MS (EI): m/z = 251 [M]+. HRMS (EI): calcd. for
C14H9N3O2 [M]+ 251.0685; found 251.0695.
N-[4-(Quinoxalin-2-yl)phenyl]acetamide (5i): According to typical
procedure TP II and TP III (one pot), N-[4-(1-hydroxy-2,2-diiodo-
ethyl)phenyl]acetamide (2l; 200 mg, 0.46 mmol), IBX (260 mg,
0.93 mmol), and o-phenylenediamine (50.0 mg, 0.47 mmol). The
crude product was purified by LC (CHCl3/MeOH, 20:1). Yield:
102 mg (83%) of 5i as a white solid. HPLC: tR = 4.60 min (97%).
1H NMR (300 MHz, CDCl3): δ = 9.31 (s, 1 H), 8.20 (d, J = 8.6 Hz,
(S)-N1-[2-Phenyl-1-(quinoxalin-2-yl)ethyl]-N3,N3-dipropylisophthal-
amide (14): β-Diiodoketone 12 (65 mg, 0.11 mmol) was dissolved
in DMSO (2.5 mL) and stirred at 60 °C for 2 d (HPLC control).
Glacial acetic acid (1.0 mL) and a solution of o-phenylenediamine
(12 mg, 0.11 mmol) in EtOH (2.0 mL) was added to the reaction
mixture, which was stirred at 90 °C for 1 h. After cooling, water
2 H), 8.16–8.08 (m, 2 H), 7.81–7.69 (m, 4 H), 7.39 (s, 1 H), 2.24 (s, (10 mL) was added, and the mixture was extracted with CH2Cl2
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.4, 151.1, 143.0,
142.3, 141.4, 139.9, 132.4, 130.4, 129.5, 129.4, 129.1, 128.4, 120.0,
24.8 ppm. MS (EI): m/z = 263 [M]+.
(2ϫ15 mL). The combined organic layer was washed with water
(2ϫ30 mL), dried with Na2SO4, and concentrated in vacuo. The
crude product was purified by LC (EE/CH, 1:2) to give compound
1446
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1439–1447

Oxidative Homologation of Aldehydes to α-Ketoaldehydes
14 (22 mg, 45%) as a brown solid. Rf (CH/EE, 1:1) = 0.38. HPLC:
(10 mL) was added, and the mixture was extracted with CH2Cl2
tR = 7.61 min (96%);1H NMR (300 MHz, CDCl3): δ = 8.51 (s, 1 (2ϫ15 mL). The combined organic layer was washed with water
H), 8.17–8.08 (m, 2 H), 7.85–7.73 (m, 4 H), 7.60–7.45 (m, 3 H),
7.42–7.35 (m, 1 H), 7.21–7.16 (m, 2 H), 7.43–7.35 (m, 2 H), 5.80
(2ϫ30 mL), dried with Na2SO4, and concentrated in vacuo. The
crude product was purified by LC (EE/CH, 1:2) to give compound
(td, J = 7.9, 5.8 Hz, 1 H), 3.54 (dd, J = 13.4, 5.7 Hz, 1 H), 3.51– 19 (51 mg, 82%) as a yellow solid. Rf (EE/CH = 1:2) = 0.21. HPLC:
1
3.42 (m, 2 H), 3.30 (dd, J = 13.4, 8.2 Hz, 1 H), 3.24–3.09 (m, 2 H),
tR = 8.301 min (95%). H NMR (500 MHz, CDCl3): δ = 8.83 (s, 1
1.87–1.48 (m, 4 H),1.01–0.89 (m, 3 H), 0.84–0.65 (m, 3 H) ppm. H), 8.11–8.07 (m, 1 H), 8.06–8.04 (m, 1 H), 7.79–7.70 (m, 2 H),
13C NMR (75 MHz, CDCl3): δ = 169.8, 165.3, 153.1, 143.6, 142.2, 7.38–7.26 (m, 5 H, Hphenyl), 7.14 (d, J = 7.7 Hz, 1 H, NH), 6.53
141.9, 137.9, 136.1, 134.6, 130.7, 130.1, 129.5, 129.3, 129.2, 128.9,
128.8, 128.6, 127.8, 127.1, 125.2, 54.1, 46.5, 42.2, 21.9, 20.7, 11.5,
11.1 ppm. MS (EI): m/z = 480 [M]+. HRMS (EI): calcd. for
C30H32N4O2 [M]+ 480.2526; found 480.2486.
(d, J = 7.3 Hz, 1 H, NH), 5.45–5.31 (m, 1 H), 5.26 (d, J = 7.6 Hz,
1 H, NH), 5.11 (s, 2 H), 4.61–4.44 (m, 1 H), 4.23–4.01 (m, 1 H),
1.94–1.45 (m, 9 H), 1.05–0.86 (m, 18 H) ppm; 13C NMR (125 MHz,
CDCl3): δ = 172.7, 171.2, 156.3, 156.0, 144.4, 142.0, 141.8, 136.1,
130.2, 129.7, 129.3, 129.0, 128.6, 128.3, 128.1, 67.2, 53.6, 51.9, 51.1,
45.2, 41.4, 40.9, 29.7, 25.0, 24.7, 23.0, 22.9, 22.8, 22.7, 22.3, 22.2,
22.0 ppm. MS (EI): m/z = 575 [M]+. HRMS (EI): calcd. for
C33H45N5O4 [M]+ 575.3472; found 575.3382.
Benzyl (2S)-1-{(2S)-1-[(3S)-2-Hydroxy-1,1-diiodo-5-methylhexan-3-
ylamino]-4-methyl-1-oxopentan-2-ylamino}-4-methyl-1-oxopentan-2-
ylcarbamate (16): iPrMgCl (2.0 m in THF, 1.05 mL, 2.11 mmol)
was added dropwise to a solution of iodoform (829 mg, 2.11 mmol)
in THF (10 mL, abs.) at –78 °C under an argon atmosphere. A
solution of aldehyde 15 (200 mg, 0.42 mmol) in THF (1 mL, abs.)
was added, and the resulting mixture was stirred at the same tem-
perature for 15 min and at 0 °C for 1 h. The mixture was quenched
with aqueous NH4Cl (10 mL, sat.) and extracted with CH2Cl2
(3ϫ20 mL). The combined organic layer was dried with Na2SO4
and concentrated in vacuo. The crude product was purified by LC
(CHCl3/MeOH, 20:1) to give peptidic β-diiodoalcohol 16 (249 mg,
80%) as a yellow solid. Rf (CHCl3/MeOH, 20:1) = 0.60. HPLC: tR
= 8.30 min (9 %), 8.60 min (70 %). Diastereomeric mixture: 1H
NMR (500 MHz, CDCl3): δ = 7.38–7.31 (m, 5 H, Hphenyl), 6.95–
6.92 (m, 1 H, NH), 6.72 (d, J = 6.5 Hz, 1 H, NH), 5.53 (d, J =
7.3 Hz, 1 H, NH), 5.04 (m, 2 H), 4.95 (d, J = 8.3 Hz, 1 H), 4.40–
4.35 (m, 2 H), 4.13 (m, 1 H), 3.61–3.59 (m, 1 H),1.86 (s, OH),
1.56–1.18 (m, 9 H), 0.94–0.83 (m, 18 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 172.7, 127.6, 156.4, 136.0, 128.6, 128.3, 128.1, 79.1,
78.9, 67.4, 67.3, 53.8, 52.4, 52.1, 49.2, 41.6, 41.3, 40.6, 40.5, 25.0,
24.8, 24.7, 22.9, 22.9, 22.7, 22.4, 22.1, 21.4, –16.5 ppm. MS (ESI):
m/z = 766 [M + Na]+.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H NMR and 13C NMR spectra.
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Benzyl (S)-1-{(S)-1-[(S)-1,1-Diiodo-5-methyl-2-oxohexan-3-yl-
amino]-4-methyl-1-oxopentan-2-ylamino}-4-methyl-1-oxopentan-2-
ylcarbamate (17): To a solution of β-diiodoalcohol 16 (60 mg,
0.08 mmol) in DMSO (5 mL) was added IBX (45 mg, 0.16 mmol),
and the mixture was stirred at room temperature for 15 h. The reac-
tion mixture was quenched with water (50 mL) and MTBE (70 mL)
was added. The precipitate was filtered off, and the organic layer
was extracted with water (2ϫ50 mL), dried with Na2SO4, and con-
centrated in vacuo. The crude product was purified by LC (CH/
EE, 1:1) to give peptidic β-diiodoketone 17 (52 mg, 87%) as a yel-
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174.7, 158.6, 138.2, 129.5, 129.0, 128.8, 67.7, 55.4, 55.2, 54.9, 53.1,
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Benzyl (S)-4-Methyl-1-{(S)-4-methyl-1-[(S)-3-methyl-1-(quinoxalin-
2-yl)butylamino]-1-oxopentan-2-ylamino}-1-oxopentan-2-ylcarb-
amate (19): β-Diiodoketone 17 (80 mg, 0.11 mmol) was dissolved
in DMSO (2.5 mL) and stirred at 50 °C for 24 h (HPLC control).
Glacial acetic acid (1.0 mL) and a solution of o-phenylenediamine
(12 mg, 0.11 mmol) in EtOH (2.0 mL) was added to the reaction
mixture, which was stirred at 70 °C for 1 h. After cooling, water
Received: December 21, 2011
Published Online: January 24, 2012
Eur. J. Org. Chem. 2012, 1439–1447
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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