N-Alkenylation of hydroxamic acid derivatives with ethynyl benziodoxolone to synthesizecis-enamides through vinyl benziodoxolones

Article abstract of DOI:10.1039/d1ob00055a

The stereoselective synthesis ofcis-β-N-alkoxyamidevinyl benziodoxolones (cis-β-N-RO-amide-VBXs) fromO-alkyl hydroxamic acids in the presence of an ethynyl benziodoxolone-acetonitrile complex (EBX-MeCN) is reported herein. The reaction was performed under mild conditions including an aqueous solvent, a mild base, and room temperature. The reaction tolerated variousO-alkyl hydroxamic acids derived from carboxylic acids, such as amino acids, pharmaceuticals, and natural products. Vinyl dideuteratedcis-β-N-MeO-amide-VBXs were also synthesized using deuterium oxide as the deuterium source. Valine-derivedcis-β-N-MeO-amide-VBX was stereospecifically derivatized to hydroxamic acid-derivedcis-enamides without the loss of stereoselectivity or reduction in the deuterium/hydrogen ratio.

Full text of DOI:10.1039/d1ob00055a

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N-Alkenylation of hydroxamic acid derivatives with
ethynyl benziodoxolone to synthesize cis-
enamides through vinyl benziodoxolones†
a
Cite this: Org. Biomol. Chem., 2021,
19, 2442
Daisuke Shimbo,a Toshifumi Maruyama,b Norihiro Tada *a and Akichika Itoh
*
The stereoselective synthesis of cis-β-N-alkoxyamidevinyl benziodoxolones (cis-β-N-RO-amide-VBXs)
from O-alkyl hydroxamic acids in the presence of an ethynyl benziodoxolone–acetonitrile complex
(EBX–MeCN) is reported herein. The reaction was performed under mild conditions including an aqueous
solvent, a mild base, and room temperature. The reaction tolerated various O-alkyl hydroxamic acids
derived from carboxylic acids, such as amino acids, pharmaceuticals, and natural products. Vinyl dideuter-
ated cis-β-N-MeO-amide-VBXs were also synthesized using deuterium oxide as the deuterium source.
Valine-derived cis-β-N-MeO-amide-VBX was stereospecifically derivatized to hydroxamic acid-derived
cis-enamides without the loss of stereoselectivity or reduction in the deuterium/hydrogen ratio.
Received 12th January 2021,
Accepted 26th February 2021
DOI: 10.1039/d1ob00055a
rsc.li/obc
which are difficult to obtain using other methods.12b,14
Enamides are synthetically useful building blocks and impor-
Introduction
Hypervalent iodine compounds have been widely used as a key tant structural motifs of natural products (e.g., salicylihala-
reagents to afford various valuable products.1,2 For instance, mide and oximidine).14,15 We recently reported an ethynyl ben-
due to their inherent high reactivity and versatility, hypervalent ziodoxolone–organic solvent complex (EBX–solvent).16 Due to
iodine compounds can be utilized in functionalization plat- the high reactivity of EBX,17 cis-β-amide-VBXs could be syn-
form strategies to chemoselectively functionalize complex thesized from the EBX–chloroform and sulfonamides derived
molecules, such as peptides and proteins.3 Recently, from various amines, including amino acids, which are impor-
β-heteroatom (S, O, N, Cl)-substituted vinyl benziodoxolones tant structural motifs of pharmaceuticals, agrochemicals, and
(VBXs) have emerged as powerful tools to functionalize various chemical biology tools (Scheme 1b).12c To further expand the
nucleophiles, which readily react with highly reactive ethynyl
benziodoxolones (EBXs) to yield β-heteroatom-substituted-
VBXs under mild conditions. The obtained VBXs can then be
derivatized using various approaches, e.g., cross-coupling reac-
tions (Scheme 1a).4–13 Waser et al. reported a cysteine biocon-
jugation method to synthesize Z-β-thiol-VBXs, which were deri-
vatized to various alkenes.10a Nevertheless, owing to the low
nucleophilicity of the nitrogen atom in the nucleophiles and
low stability of β-nitrogen-substituted VBXs, the synthesis of
β-nitrogen-substituted VBXs is limited. Kitamura et al.
reported
a pioneering study involving the synthesis of
β-nitrogen-substituted VBXs using an azide as a nucleophi-
le.12a Recently, Waser et al. described the preparation of Z-
β-amide-VBXs and their derivatization to various enamides,
aGifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
E-mail: ntada@gifu-pu.ac.jp
bGifu University, Yanagido 1-1, Gifu 501-1193, Japan
†Electronic supplementary information (ESI) available. CCDC 2052251 and
2052252. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d1ob00055a
Scheme 1 Synthesis of β-amidevinyl benziodoxolone.
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possible applications of β-nitrogen-substituted VBXs as
functionalization platforms, N-functionalization of C-terminal
amides of amino acids and peptides is desirable. However, as
has been previously reported, amides and carbamates did not
afford the expected products, which was attributed to the low
acidity of these compounds (Scheme 1c).12c,18 We speculated
that to overcome these limitations, more acidic carboxylic
acid-derived amides were needed. Hydroxamic acid is an
attractive structural motif in organic synthesis and medicinal
chemistry.19,20 Intriguingly, due to the presence of an α-oxygen
on their nitrogen atom, hydroxamic acid derivatives exhibit
high acidity, which is comparable to that of sulfonamide
(Scheme 1c).18 Thus, we envisaged that hydroxamic acid
derivatives could be synthesized from simple carboxylic acids
to afford cis-β-N-alkoxyamidevinyl benziodoxolones (cis-β-N-RO-
amide-VBXs) under mild conditions. This study reports the
N-alkenylation of O-alkyl hydroxamic acids using EBX
(Scheme 1d).
Fig. 1 ORTEP drawing of EBX–H2O (thermal ellipsoids set at 50% prob-
ability). Selected bond lengths [Å] and angles [°]: I1–C1, 2.125(2); I1–C2,
2.055(3); I1–O1, 2.363(2); C2–C3, 1.157(5); C3–H1, 0.930; I1⋯O3, 2.923
(3); I1⋯O1’, 3.632(2); H2’⋯O2, 1.87(5); C1–I1–O1, 75.29(9); C1–I1–C2,
90.8(1); C2–I1–O1, 166.1(1); C1–I1⋯O3, 163.10(8); C1–I1⋯O1’, 132.90
(8); O3’–H2’⋯O2, 179(5).
Results and discussion
Waser et al. recently studied the stability of in situ-generated
EBX in an aqueous solvent.10d Nonetheless, the structure of an
EBX–H2O complex has not been reported before.21 To investi-
gate the stability and reactivity of EBX–H2O in the solid state,
we initially attempted to synthesize the complex. Agreeably,
recrystallization from wet chloroform and hexane yielded a
single crystal of EBX, wherein no organic solvent was detected
Table 1 Reaction optimization for the synthesis of cis-β-N-MeO-
amide-VBXa
1
by H NMR. The synthesized EBX–H2O complex was stable at
room temperature. No decomposition was observed when it
was left under ambient conditions for five days. Intriguingly,
elemental analysis indicated that EBX–H2O contained water in
a 1 : 1 ratio. This differed from the 3 : 1 ratio of the EBX–MeCN
complex, which exhibited a honeycomb structure. To elucidate
the solid-state structure of EBX–H2O, we conducted X-ray crys-
tallographic analysis (CCDC 2052251; †Fig. 1, Fig. S1 and S2,
†Tables S6 and S7†). The X-ray structure revealed that EBX–
H2O formed a dimer of EBX with two water molecules. The dis-
similar structure of this complex to EBX–MeCN was attributed
to the high donor and hydrogen bonding ability of water.22
We subsequently evaluated our previously reported reaction
conditions using N-methoxyamide derived from glycine (1a)
and the EBX–MeCN complex (2a). Pleasingly, cis-β-N-MeO-
amide-VBX (3a) was obtained in a moderate yield (Table 1,
entries 1 and 2).12c Encouraged by these results, we optimized
the reaction conditions (Table 1, Tables S1–S3†). A solvent
screen using K2CO3 as a base revealed that the reaction pro-
gressed at room temperature in both protic and aprotic sol-
vents, albeit in modest to moderate yields (Table 1, entries 3
and 4; Table S1†). K2CO3 was insoluble in these solvents; there-
fore, we subsequently conducted the reaction with water as the
co-solvent (Table 1, entries 5 and 6; Table S1†). Consequently,
1,2-dimethoxyethane and 1,2-dichloroethane (DCE)/H2O at a
ratio of a 9 : 1 afforded the highest yields (62%) (Table 1,
entries 3 and 6). Investigation of the base and the amount of
Entry
Change from the above conditions
Yield (%)
1
2
3
4
MeCN : IPA = 1 : 1, instead of DCE
IPA, instead of DCE
(MeOCH2)2, instead of DCE
—
(MeOCH2)2 : H2O = 9 : 1, instead of DCE
DCE : H2O = 9 : 1, instead of DCE
—
With brown flask
Irradiated with a fluorescent lamp
Air, instead of Ar
37
53
62
28
49
62
72
72
70
72
68
36
50
66
60
62
68
61
0
5
6
7b
8b
9b
10b
11b
12b
13b
14b
15b
16b
17b
18b
19b
20c
1 h
0 °C
35 °C
EBX·1/3MeCN (1.1 equiv.)
EBX·1/3MeCN (1.5 equiv.)
EBX·1/6CHCl3 (1.3 equiv.)
EBX·1/6EtOAc (1.3 equiv.)
EBX·H2O (1.3 equiv.)
TMS-EBX (1.3 equiv.)
0.1 mmol scale, DCE (2 mL)
(84)
a Reaction conditions: 1a (0.05 mmol), 2a (1.3 equiv.), K2CO3 (0.1
equiv.), DCE (1 mL), rt, 30 min, argon atmosphere. Yields were deter-
mined by 1H NMR spectroscopy using 1,1,2,2-tetrachloroethane as the
internal standard. Numbers in parentheses indicate isolated yields. b 1
M aq. K2CO3 (10 μL, 0.2 equiv.) was used instead of K2CO3 (0.1 equiv.).
c 1 M aq. K2CO3 (20 μL, 0.2 equiv.) was used instead of K2CO3 (0.1
equiv.).
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the base and water demonstrated that using 1 M aqueous
K2CO3 (10 μL, 0.2 equiv.) afforded the product in a higher yield
(72%) (Table 1, entry 7; Tables S2 and S3†). To further improve
the yield and examine the scope of the reaction, we further
studied the various conditions. We found that exposure to
light and oxygen had almost no effect (entries 8–10). Argon
gas was used to maintain the same reaction atmosphere in
subsequent experiments. Changes in the reaction time, temp-
erature, and the amount of 2a did not improve the product
yield (entries 11–15). Moreover, changing the organic solvent
in the EBX–solvent complex resulted in marginally lower yields
(entries 16 and 17). Notably, when EBX–H2O was used in the
reaction, 3a was obtained in a respectable yield (entry 18). In
contrast, the addition of TMS–EBX instead of 2a yielded no
product, indicating the importance of β-unprotected EBX (2a)
in this reaction (entry 19). Importantly, other amides did not
afford the corresponding VBXs; this was ascribed to the low
acidity of the amides (Table S6,† entries 1–3). Furthermore,
utilization of hydroxamic acid and O-pivaloyl-protected hydro-
xamic acid resulted in the formation of a complex mixture and
no desired products were isolated (Table S6,† entries 4 and 5).
Hence, the presence of alkoxy groups on the nitrogen atom
was essential for a successful alkenylation. Finally, the best
result was afforded when the reaction scale was increased to
0.1 mmol. Specifically, treatment of 1a (0.1 mmol) with 2a (1.3
equiv.) and 1 M aq. K2CO3 (20 μL, 0.2 equiv.) in DCE (2 mL) at
room temperature for 30 min afforded 3a in 84% isolated yield
(entry 20).
With the optimized reaction conditions, we examined the
scope and limitations of the reaction (Scheme 2). Aromatic car-
boxylic acid-derived N-methoxyamides containing electron-
withdrawing groups (Cl, Br, I, and NO2) and an electron-donat-
ing group (Me) on the benzene ring afforded the products in
good to high yields, regardless of the position of the substitu-
ent (3b–3i). Notably, both thiophene and pyridine rings were
tolerated in this reaction (3j and 3k). Additionally, using
O-benzyl hydroxamic acid afforded the product (3l) in a high
yield. The structure of 3l was unambiguously determined by
X-ray crystallographic analysis (CCDC 2052252; †Fig. 2, S3, and
S4; †Tables S8 and S9†). Interestingly, the oxygen atom of the
benzyl moiety internally interacted with the iodine center,
whereas the oxygen atom on the carbonyl group of the amide
exhibited no interactions with the iodine center. Aliphatic car-
boxylic acid derivatives also afforded the desired products in
moderate to good yields, even in the case of sterically bulky
pivalic acid derivatives (3m–3s). The optimized conditions
were subsequently employed in the reactions of amino acid
derivatives. We initially investigated different protecting
groups. The Boc-protected substrate afforded the product in a
modest yield (3t). Moreover, the phthaloyl substrate did not
afford the corresponding product (3u). Note that the
β-substituted n-Bu-EBX and Ph-EBX afforded no products and
the substrates were recovered unchanged (3v, 3w). Pleasingly,
however, various amino acid derivatives afforded the corres-
ponding cis-β-N-MeO-amide-VBXs in good to high yields
(3x–3ab). Under optimized conditions, the dipeptide afforded
Scheme 2 Synthesis of cis-β-N-RO-amide-VBX. Reaction conditions: 1
(0.1 mmol), 2a (1.3 equiv.), 1 M aq. K2CO3 (20 μL, 0.2 equiv.), DCE (2 mL),
rt, argon atmosphere. Isolated yields. a1 mmol scale. bIPA was used as
the solvent. cEBX–H2O was used instead of 2a.
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Fig. 2 ORTEP drawing of cis-β-N-BnO-amide-VBX (3l) (thermal ellip-
soids set at 50% probability). Selected bond lengths [Å] and angles [°]:
I1–C1, 2.129(3); I1–C2, 2.106(2); I1–O1, 2.468(2); C2–C3, 1.317(4);
I1⋯O2, 3.147(2); I1⋯O3’, 2.780(2); C1–I1–O1, 74.01(8); C1–I1–C2, 96.48
(9); C2–I1–O1, 170.41(8); C1–I1⋯O2, 71.51(7); C1–I1⋯O3’, 176.45(8);
C1–I1−C2–C3, −66.1(3); I1–C2–C3–N1, 5.6(4).
the product in a low yield (3ac, 29%) due to poor solubility.
Nonetheless, an improved yield was obtained using isopropyl
alcohol (IPA) as the solvent as well as by substituting 2a for
EBX–H2O. Notably, the reaction could also be applied to phar-
maceuticals (e.g., felbinac, ibuprofen, ketoprofen, and indo-
methacin) and natural products, such as cholic acid-derived
N-methoxyamides (3ad–3ah). Some VBXs (3b, 3l, 3z) could also
be synthesized in a high yield on a 1 mmol scale, demonstrat-
Scheme 3 Synthesis
of
dideuterated
cis-β-N-MeO-amide-VBX.
Reaction conditions: 1 (0.05 mmol), 2a (1.3 equiv.), K2CO3 (0.2 equiv.),
DCE/D2O = 9 : 1 (1 mL), rt, 24 h, argon atmosphere. Isolated yields.
a1 mmol scale.
ing the scalability of the reaction. None of the above VBXs (3a– were stereoselectively obtained by a Sonogashira reaction
3ah) have been previously reported (Scheme 2). without loss of stereoselectivity or reduction in the deuterium/
Considering the usefulness of deuterium-labeled com- hydrogen ratio (Scheme 4a).12b Furthermore, as reported by
pounds in various fields,23 different reaction conditions were Waser, difunctionalization of the diazo compounds afforded
then investigated to afford dideuterated VBXs. Alanine-derived the corresponding highly functionalized amino acid-derived
N-methoxyamide 1x afforded dideuterated VBX (3x-d2) in a enamides (6z and 6z-d2) (Scheme 4b).25 The use of ligand B
high yield and deuterium incorporation (Scheme 3, 81% yield; resulted in a slightly improved diastereomeric ratio (1.2 : 1).
α: 94%D; β: 97%D) using DCE/D2O (9 : 1) as the solvent in the These results demonstrated the potential for further application
presence of K2CO3 (0.2 equiv.). The reaction conditions could of cis-β-N-RO-amide-VBXs (3) as a functionalization platforms
be applied to various amino acids and pharmaceutical deriva- for various carboxylic acid-derived O-alkyl hydroxamic acids.
1
tives to produce novel dideuterated VBXs in moderate to good
Unfortunately, no intermediates were observed by H NMR
yields and high deuterium incorporation (Scheme 3). Note that analysis; however, based on the above results and previously
no deuterium was incorporated at the α-positions of these pro- reported outcomes, we proposed a plausible mechanism for
ducts (3x-d2–3ac-d2). Furthermore, almost the same specific the synthesis of cis-β-N-RO-amide-VBXs (Scheme 5). As shown
rotation was observed in the case of hydrogen- and deuterium- in the scheme, the reaction could proceed via two possible
containing products ([α]D22 = + 154.8 for 3z, +157.5 for 3z-d2 [C pathways. Initially, N-methoxyamide 1 underwent an addition
= 0.1 in MeOH]). Regrettably, the enantiomeric excess could reaction onto the β-carbon of 2a in the presence of a base to
not be determined by HPLC analysis due to the instability of form a vinyl anion 7 through the coordination of the nitrogen
the products. However, deuterium labeling and optical atom of N-methoxyamide to the iodine center (8) (Path A).12b
rotation analysis suggested no or little racemization of the pro- Subsequently, 7 effectively captured the proton to afford VBX
ducts. In addition, unlike in the case of sulfonamide-derived 3. However, under mild basic conditions, the elimination of
VBX, the H–D exchange reaction of the vinylic α-hydrogen 2-iodobenzoic acid to ynamide 9 proceeded via a high-energy
atom of 3z did not proceed,12c indicating that 3z could decom- pathway.12b Nonetheless, the perfect cis-selectivity of VBX
pose via an irreversible β-elimination reaction (Table S7†).24
could be explained by Path A. In contrast, nucleophilic oxygen
Valine-derived VBXs (3z and 3z-d2) could be used for further atom of deprotonated 1 attacked the electrophilic iodine of 2a
derivatization. cis-β-Alkynyl enamides (4z, 5z, 4z-d2, and 5z-d2) to form intermediate 10, which underwent a [3,3]-rearrange-
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oxygen of N-methoxyamide anion to the iodine center (12) to
afford 7 via a six-membered transition state was also poss-
ible.27 High deuterium incorporation of dideuterated VBX
(Scheme 3) implied that the deprotonation of the acetylene
proton of 2a was fast and reversible. In contrast, unlike in the
case of sulfonamide-derived VBXs, the H–D exchange reaction
of the α-proton of 3 hardly proceeded,12c indicating that 3
decomposed through an irreversible β-elimination to afford an
unstable ynamide 9, which could not be isolated.
Conclusions
In summary, we developed an approach for the stereoselective
synthesis of cis-β-N-alkoxyamidevinyl benziodoxolones from
the ethynyl benziodoxolone–acetonitrile complex and O-alkyl
hydroxamic acids derived from various carboxylic acids,
including amino acids, pharmaceuticals, and natural products,
under mild conditions. The vinyl dideuterated cis-β-N-MeO-
amide-VBXs were also synthesized using deuterium oxide due
to the high electron-withdrawing ability of hypervalent iodine.
Valine-derived cis-β-N-MeO-amide-VBX was stereospecifically
derivatized to hydroxamic acid-derived cis-enamides.
Furthermore, the X-ray structure and reactivity of EBX–H2O
was revealed. The results of the present study demonstrate the
potential of cis-β-heteroatom-substituted VBXs as functionali-
zation platforms for mild nucleophiles in complex molecules.
Scheme 4 Derivatization of valine derived cis-β-N-MeO-amide-VBX.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Number
19K06977 and Grants for Research from SIS (The Society of
Iodine Science). The authors would like to thank Enago for the
English language review.
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