Nucleophilic transformations of azido-containing carbonyl compoundsviaprotection of the azido group

Article abstract of DOI:10.1039/d1cc01143j

Nucleophilic transformations of azido-containing carbonyl compounds are discussed. The phosphazide formation from azides and di(tert-butyl)(4-(dimethylamino)phenyl)phosphine (Amphos) enabled transformations of carbonyl groups with nucleophiles such as lithium aluminum hydride and organometallic reagents. The good stability of the phosphazide moiety allowed us to perform consecutive transformations of a diazide through triazole formation and the Grignard reaction.

Full text of DOI:10.1039/d1cc01143j

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Nucleophilic transformations of azido-containing
carbonyl compounds via protection of the azido
group†
Cite this: Chem. Commun., 2021,
57, 6062
Received 2nd March 2021,
Accepted 17th May 2021
a
Takahiro Aimi,a Tomohiro Meguro,a Akihiro Kobayashi,ab Takamitsu Hosoya
*
ab
and Suguru Yoshida
*
DOI: 10.1039/d1cc01143j
rsc.li/chemcomm
Nucleophilic transformations of azido-containing carbonyl com- a denitrogenation process. The deprotection was easily realized
pounds are discussed. The phosphazide formation from azides and by treating with elemental sulfur to afford azides in high yields.
di(tert-butyl)(4-(dimethylamino)phenyl)phosphine (Amphos) enabled Considering the significance of azides in synthetic organic
transformations of carbonyl groups with nucleophiles such as lithium chemistry, we focused on the stability of phosphazides under
aluminum hydride and organometallic reagents. The good stability of nucleophilic or radical conditions for transformations of
the phosphazide moiety allowed us to perform consecutive transfor- azides, which were still unclear due to the possible equili-
mations of a diazide through triazole formation and the Grignard brium liberation of azides from phosphazides under various
reaction.
conditions.9
We firstly examined denitrogenative reductions of azide 1a
Azides are of great significance in a broad range of research fields and phosphazide 4 (Fig. 2). As a result, aniline 2 was obtained
including synthetic organic chemistry, chemical biology, and
materials chemistry.1 Diverse reliable transformations of azides
such as copper-catalyzed azide–alkyne cycloaddition (CuAAC),2
strain-promoted azide–alkyne cycloaddition (SPAAC),3 the Stau-
dinger reaction,4 and reduction into amines5 have been used in
the synthesis of various organonitrogen compounds (Fig. 1A).
One drawback of azide chemistry is that an azido group is
easily damaged with various nucleophiles due to the high
electrophilicity.1,6,7 We herein disclose selective nucleophilic
transformations of a carbonyl group through the protection of
the azido group (Fig. 1B and C).
In the course of our studies on azide4d,e,8,9 and organophos-
phorus chemistry,9,10 we recently found a protection method
for the azido group from CuAAC and SPAAC reactions by
phosphazide formation with di(tert-butyl)(4-(dimethylamino)-
phenyl)phosphine (Amphos) (Fig. 1B).9 The phosphazide for-
mation took place smoothly without forming azaylides through
a Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai,
Chiyoda-ku, Tokyo 101-0062, Japan. E-mail: s-yoshida@rs.tus.ac.jp,
thosoya.cb@tmd.ac.jp
b Department of Biological Science and Technology,
Faculty of Advanced Engineering, Tokyo University of Science,
6-3-1 Niijuku, Katsushika-ku, Tokyo 125-8585, Japan
† Electronic supplementary information (ESI) available: Experimental proce-
Fig. 1 Backgrounds and plan of this study. (A) Conventional transforma-
tions of azides. (B) Our previous work. (C) This work.
dures, and characterization of new compounds including NMR spectra. See
DOI: 10.1039/d1cc01143j
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Fig. 2 Transformations of azide 1a and phosphazide 4 under reductive
conditions.
Fig. 3 Reduction of azido-substituted esters 1 with LiAlH4. (A) Reductions
with or without the protection of azide 1a. (B) Scope of synthesized azido-
substituted alcohols 6. See ESI† for the structures of 1.
by hydrogenation of azide 1a catalyzed by Pd/C under a hydrogen
atmosphere (Fig. 2, a-1) or radical-mediated reduction with tribu-
tylstannane and 2,20-azodiisobutyronitrile (AIBN) (Fig. 2, a-2). The
Staudinger reaction of azide 1a with triphenylphosphine furnished Amphos even in the presence of highly nucleophilic reagents
azaylide 3 in high yield (Fig. 2, a-3). In contrast, we found that such as LAH.
phosphazide 4 prepared from azide 1a with Amphos was stable
The good stability of phosphazides toward nucleophiles
under the reductive conditions using Pd/C and H2 (Fig. 2, b-1), allowed for alcohol synthesis from 4-azidobenzaldehyde (7a)
tributylstannane and AIBN (Fig. 2, b-2), or triphenylphosphine with organomagnesium or organolithium reagents (Fig. 4).7,12
(Fig. 2, b-3). These results obviously indicated that azides can The reaction between aldehyde 7a and ethylmagnesium bro-
be protected by phosphazide formation under various reduction mide furnished aniline 9 in moderate yield along with a trace
conditions, although azides can form in equilibrium from phos- amount of alcohol 8a due to the denitrogenation reduction of
phazides.9
the azido group (Fig. 4A, upper). In sharp contrast, we accom-
Ester-selective lithium aluminum hydride (LAH) reduction plished an efficient synthesis of alcohol 8a from aldehyde 7a
was achieved through the phosphazide formation (Fig. 3).6 and ethylmagnesium bromide without damaging the highly
While the treatment of azide 1a with LAH in tetrahydrofuran electrophilic aromatic azido group (Fig. 4A, lower). Indeed, the
(THF) at ꢀ20 1C provided 4-aminobenzyl alcohol (5) and phosphazide formation of azide 7a with Amphos proceeded
4-(ethoxycarbonyl)aniline (2) via reduction of the azido group smoothly leaving the formyl group. Then, the addition of
(Fig. 3A, upper), pretreatment of azide 1a with Amphos at room ethylmagnesium bromide to the resulting mixture followed by
temperature followed by the addition of LAH at ꢀ20 1C and the deprotection with elemental sulfur furnished alcohol 8a in
subsequent deprotection using elemental sulfur successfully high yield keeping the azido group unreacted. The reaction
afforded 4-azidobenzyl alcohol (6a) by selective reduction of the performed at a 1 mmol scale also proceeded efficiently to afford
ethoxycarbonyl group leaving the azido group untouched alcohol 8a in good yield. Thus, this simple single-purification
(Fig. 3A, lower).11 It is worth noting that the phosphazide procedure enabled the efficient Grignard reaction of the formyl
moiety tolerated highly nucleophilic LAH. We also succeeded group without damaging the azido group.
in the ester-selective LAH reduction of a broad range of azido-
A wide variety of carbanions successfully participated in the azido-
substituted esters 1 via the formation of phosphazides (Fig. 3B). substituted alcohol synthesis from aldehydes 7 (Fig. 4B and C).
Indeed, phosphazide formation, LAH reduction, and deprotec- For example, phenylation, 4-chloro- and 4-methoxyphenylation,
tion with elemental sulfur took place efficiently using esters 1 and 2-thienylation of aldehyde 7a efficiently proceeded to provide
to afford the corresponding alcohols 6b–6f in moderate to good alcohols 8b–8e possessing an azido group in good yields. Benzyla-
yields via the protection of the heteroaromatic and primary, tion and allylation of aldehyde 7a also took place smoothly to afford
secondary, and tertiary alkyl azido groups. These results clearly azido-substituted alcohols 8f and 8g in moderate to high yields.
show that a wide range of azido groups were protected using Bulky alkyl Grignard reagents such as isopropylmagnesium
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ethynylmagnesium bromide, furnishing azido-substituted propar-
gyl alcohol 8j in good yield, which will serve in click chemistry. Also,
organolithium reagents including n-butyllithium and phenyl-
lithium were applicable to the addition reaction without damaging
the phosphazide moiety.
The Grignard reactions of various aldehydes 7 bearing an azido
group were accomplished to provide alcohols 8l–8r in moderate to
good yields (Fig. 4B and D). A broad range of aldehydes 7
efficiently reacted with ethylmagnesium bromide at the formyl
group without damaging the azido group via phosphazide for-
mation to yield alcohols 8l–8p leaving methoxy, trifluoromethyl,
and bromo groups intact. The azide protection followed by the
Grignard reaction and deprotection uneventfully took place when
using o-azidobenzaldehyde to provide 8q in good yield. Synthesis
of secondary alcohol 8r was also achieved from an aliphatic
aldehyde (3-(4-azidophenyl)propanal) and ethylmagnesium bro-
mide via the azide protection with Amphos. These results clearly
show that nucleophilic additions of formyl-substituted azides with
a broad range of organomagnesium and organolithium reagents
through the robust phosphazides realized the preparation of
diverse alcohols having an azido group.
A synthetic utility of the Grignard reaction of aldehydes having
azido groups was showcased by the consecutive reactions between
diazide 10, cycloalkyne 12, and 4-methoxyphenylmagnesium bro-
mide (Fig. 5). Firstly, the treatment of diazide 10 with an equi-
molar amount of Amphos resulted in the selective protection of
the aromatic azido group by virtue of the stabilization by the
benzene ring without phosphazide formation at the benzyl azide
moiety. Secondly, the SPAAC reaction of phosphazide 11 with
cycloalkyne 12 at the remaining benzylic azido group proceeded
smoothly to afford cycloadduct 13. Thirdly, the Grignard reaction
of aldehyde 13 with 4-methoxyphenylmagnesium bromide fol-
lowed by the deprotection with elemental sulfur provided azide 14
in high yield. Since azides are of great importance in not only
synthetic chemistry but also chemical biology, this four-step two-
pot method will allow us to construct a vast chemical library of
a wide variety of triazoles having an aromatic azide moiety
from formyl-substituted diazide 10, alkynes, and organometallic
reagents through the phosphazide formation.
Fig. 4 Azido-substituted alcohol synthesis with organomagnesium or orga-
nolithium reagents. (A) Grignard reaction with or without the protection of
azide 7a. (B) General scheme. (C) Scope of synthesized azido-substituted
alcohols 8 from 7a. (D) Scope of synthesized azido-substituted alcohols 8
from various azido-substituted aldehydes 7. See ESI† for the structures of 7.
aThe isolated yield for the reaction conducted on a 0.2 mmol scale.
bThe isolated yield for the reaction conducted on a 1 mmol scale.
bromide and tert-butylmagnesium chloride reacted with aldehyde
7a avoiding the reaction at the azido group. Of note, we achieved
the introduction of a terminal alkyne moiety by the reaction using Fig. 5 Synthesis of azide 14 from diazide 10.
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In summary, we have accomplished nucleophilic transfor-
mations of diverse azides through phosphazide formation.
Good stability of the phosphazide intermediates realized
reduction of esters by LAH and addition reaction of aldehydes
with organometallic reagents to provide a wide variety of azido-
substituted alcohols. Further studies to examine detailed prop-
erties of phosphazides, especially equilibrium liberation of
azides, and to expand the applicability of the azide protection
method are underway in our group.
The authors thank Dr Takashi Niwa (RIKEN, Center for
Biosystems Dynamics Research (BDR)) and Dr Yuki Sakata
(Tokyo Medical and Dental University) for HRMS analyses
and Assoc. Prof. Dr Hiroki Tanimoto for helpful discussions.
This work was supported by JSPS KAKENHI Grant Numbers
JP19K05451 (C; S. Y.) and JP18H02104 (B; T. H.); the Naito
Foundation (S. Y.); the Japan Agency for Medical Research and
Development (AMED) under Grant Number JP20am0101098
(Platform Project for Supporting Drug Discovery and Life
Science Research, BINDS); and the Cooperative Research
Project of Research Center for Biomedical Engineering.
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Conflicts of interest
There are no conflicts to declare.
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