N-Hydroxyphthalimide-catalyzed chemoselective intermolecular benzylic C-H amination of unprotected arylalkanols

Article abstract of DOI:10.1039/d1cc03466a

N-Hydroxyphthalimide-catalyzed chemoselective benzylic C(sp³)-H amination of unprotected arylalkanols using bis(2,2,2-trichloroethyl)azodicarboxylate has been developed. The use of 1,1,1,3,3,3-hexafluoropropan-2-ol as a solvent plays a critical role in chemoselectivity. The conversion of an aminated product to the corresponding free amino alcohol was also demonstrated.

Full text of DOI:10.1039/d1cc03466a

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N-Hydroxyphthalimide-catalyzed chemoselective
intermolecular benzylic C–H amination of
unprotected arylalkanols†
Cite this: DOI: 10.1039/d1cc03466a
Received 29th June 2021,
Accepted 29th July 2021
Masatoshi Shibuya, * Takayuki Orihashi, Yamei Li and Yoshihiko Yamamoto
DOI: 10.1039/d1cc03466a
rsc.li/chemcomm
N-Hydroxyphthalimide-catalyzed chemoselective benzylic C(sp3)–H C(sp3)–H amination of unprotected alkanols has not been estab-
amination of unprotected arylalkanols using bis(2,2,2-trichloroethyl)- lished to the best of our knowledge. Focusing on the potential
azodicarboxylate has been developed. The use of 1,1,1,3,3,3-hexafluoro- usefulness of this reaction, we have developed a chemoselective
propan-2-ol as a solvent plays a critical role in chemoselectivity. The intermolecular benzylic C(sp3)–H amination of unprotected ary-
conversion of an aminated product to the corresponding free amino lalkanols (Fig. 1c).
alcohol was also demonstrated.
In 2012, Kamijo, Inoue and coworkers reported on C(sp3)–H
amination using N-hydroxyphthalimide (NHPI) and dialkyl
C(sp3)–H amination is a powerful reaction for the synthesis of azodicarboxylate, which enabled C–H amination across a
nitrogen compounds.1,2 The C–H amination of alkanols facili- broad range of substrates with high efficiency.11 Despite the
tates the synthesis of amino alcohols, which are important
components of biologically active compounds (Fig. 1a).3,4 The
intramolecular C–H amination of alkanol derivatives (e.g. car-
bamates, sulfamates, and imidates) shows promise for prepar-
ing 1,2- and 1,3-amino alcohols (Fig. 1b).5–7 In addition, Chang
and coworkers reported the intermolecular C–H amination of a
terminal CH3 group directed by ketoxime producing 1,2-amino
alcohol derivatives.8 More recently, Zuo and coworkers reported
d-selective amination of alkanols by photoinduced ligand-to-
metal charge transfer (LMCT) catalysis, which enables the
synthesis of 1,4-amino alcohols.9 These are effective strategies
for the preparation of amino alcohols that possess specific
chain lengths between hydroxy and amino groups. In contrast,
the non-directed regioselective intermolecular C(sp3)–H amina-
tion of alkanols facilitates the preparation of amino alcohols
possessing a diverse range of chain lengths between hydroxy
and amino groups. In particular, the reaction of unprotected
alkanols is a promising method for the straightforward pre-
paration of free amino alcohols; however, the C–H bond
proximal to the hydroxy group is susceptible to yielding a
non-desired product under amination conditions.10 Although
protected alkanols are often used to examine the scope of C–H
amination reactions,2g,11 a general strategy toward the successful
Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical
Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
E-mail: m-shibu@ps.nagoya-u.ac.jp
Fig. 1 Biologically active amino alcohols and the C–H amination of
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
alkanols or its derivatives.
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demonstration of benzylic C–H amination of protected pheny- trace amounts of 3a and no trace of either 4a or 5, although the
lalkanols (e.g. benzoates and a TBDPS ether), the reaction of an yield of 2a had slightly decreased (entry 4). These results
unprotected phenylalkanol was not examined. Hence, our suggest that alcohol oxidation, as well as the condensation of
research commenced with the application of their C–H amina- 2a and/or 1a with BTCEAD, are suppressed in HFIP.
tion method to an unprotected phenylalkanol. We examined
Having developed an effective protocol for the chemoselec-
the reaction of 4-phenylbutanol using NHPI (20 mol%) and tive benzylic C–H amination, the reactions of o-phenylalkanols
diethyl azodicarboxylate (DEAD) (2.4 equiv.) in DCE (Table S1, with various alkyl chain lengths were examined (Fig. 2). The
ESI†). The reaction was hampered by side reactions, resulting benzylic C–H bonds of o-phenylalkanols, including the long
in a moderate yield (42%) of the desired product. After initial alkyl chain bearing 1e, were efficiently aminated to produce the
solvent screening to improve the yield, we found that desired products 2b–2e. Note that the amination of 1b bearing a
1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) was an optimal sol- hydroxy group adjacent to the benzylic C–H bond also proceeded
vent for the chemoselective benzylic C(sp3)–H amination. The with high chemoselectivity to provide 2b in 83% yield.
conversion of the aminated product to the corresponding free
Next, a variety of 3-arylpropanols were subjected to the
amino alcohol, however, had failed (Scheme S1, ESI†).11,12 reaction to examine the effects of substituents bonded to an
Bis(2,2,2-trichloroethyl)azodicarboxylate (TrocN=NTroc, BTCEAD) aromatic ring (Fig. 3). The reactions of 4-tert-butyl-, 4-phenyl-
instead of DEAD was chosen as a nitrogen source and an oxidant and 4-fluoro-substituted phenylpropanols (1f–1h) produced
for the regeneration of phthalimide N-oxyl (PINO) (for the reaction 2f–2h in high yields (80–95%). The moderately electron-
mechanism; see Fig. S1, ESI†), under the expectation that the withdrawing 4-chloro and 4-bromo-substituted phenylpropa-
corresponding aminated products would convert to free amino nols (2i and 2j) were also obtained in high yields (85%).
alcohols.11
Although the reactions of strongly electron-withdrawing 4-
We treated 1a with NHPI (10 mol%) and BTCEAD (2.4 equiv.) trifluoromethyl- and 4-methoxycarbonyl-substituted phenyl
in HFIP at 60 1C for 5 h. The C–H amination efficiently propanols (1k and 1l) provided small amounts of pyrazolidines
proceeded to afford the desired product 2a in 89% yield 3k and 3l (6% and 10% yields), the desired products 2k and 2l
(Table 1, entry 1). The same reaction was then administered were obtained in 66% and 65% yields, respectively. The reac-
in DCE. 2a was produced in 43% yield with 11% of 1a remain- tion of 1-naphthylpropanol (1m) produced 28% yield of 6 which
ing unaffected. A small amount of pyrazolidine 3a was also was aminated on its aromatic ring along with the desired
produced through alcohol oxidation alongside several uniden- product 2m (23% yield), as HFIP enhanced the aromatic
tified side products (entry 2). Although 1a was fully consumed amination process.13 We found that benzylic C–H amination
after prolonging the reaction time to 24 h, the yield of 2a had of 1m selectively occurred in the mixed solvent of HFIP and
decreased to 24%. In contrast, the yield of 3a increased to 19%. DCE (1 : 1) to produce 2m in 70% yield. The mixed solvent
Small amounts of 4a and 5 which were formed from the was also effective for the chemoselective amination of 2-
condensation of 2a and BTCEAD, and/or the condensation of naphthylpropanol (1n) and strongly electron-donating
1a and BTCEAD and the subsequent C–H amination, were also methoxy-substituted phenylpropanols (1o–1q), and the desired
produced (entry 3). The reaction in HFIP after 24 h yielded only products (2n–2q) were afforded in good to high yields
(64–93%). The reaction of acetanilide 1r produced 2r in 46%
yield along with 14% of trichloroethyl carbonate 4r; however,
the reason for the formation of 4r remains unclear. When the
Table 1 Benzylic C–H amination of 3-phenylpropanol (1a) using NHPI
reaction of 1r was operated using the less amount of BTCEAD
(1.5 equiv.) in HFIP, 2r was produced in higher yield (63%).
and BTCEAD in HFIP and DCE
Yielda (%)
Entry
Solvent
t (1C)
T (h)
2a
3a
1
HFIP
DCE
DCE
HFIP
60
80
80
60
5
2
24
24
89
43
24
72
0
2
2b
3c
4
19
Trace
a
b
c
Isolated yields. 1a (11%) was recovered. 4a (6%) and 5 (4%) were
Fig. 2 C–H amination of o-phenylalkanols.
obtained. Troc = 2.2.2-trichloroethoxycarbonyl.
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Scheme 1 Additional scope of benzylic C–H amination.
to a hydroxy group afforded the desired product in 88% yield
(Scheme S2, ESI†).
To gain insight into the effects of HFIP, 13C NMR spectra of a
solution at different ratios of 1c and HFIP in CDCl3 were
collected (Fig. 4a).14 The signal assigned to the a-carbon of
1c was shifted downfield as the HFIP to 1c ratio increased.
Fig. 3 Scope on the aromatic ring of 3-arylpropanols for the benzylic
C–H amination. aIsolated yields. b3k was obtained in 6% yield. c3l was
obtained in 10% yield. d4r was produced in 14% yield (NMR). eBTCEAD (1.5
equiv.) was used and the reaction was operated in HFIP. f4r was produced
in 5% yield (NMR).
We additionally examined the C–H aminations of four
substrates to probe the substrate scope (Scheme 1). 7 bearing
a remote hydroxy group in a different substituent on its
aromatic ring, underwent the desired reaction to provide 8 in
89% yield. Methylarene 9 was also efficiently aminated to
provide 10 in 77% yield without overamination products affect-
ing the methylene C–H bond of 10. The amination of the
methine C–H bond in 11 was slow, and 12 was formed in
moderate yield (o42%) with inseparable unidentified bypro-
ducts after 24 h. Even though the BDE of the C–H bond
proximal to a secondary hydroxy group is generally higher than
that of the C–H bond proximal to a primary hydroxy group,10a
the benzylic C–H amination of secondary alkanol 13 proceeded
with high chemoselectivity to produce 14 in 74% yield with a
small amount of the aminated ketone 15 (5% yield). The
reaction of 13 was examined in DCE as a control experiment,
which was completed after 4 h to produce 15 as a major product
(39% yield) along with 14 (27% yield). As a side note, the
benzylic C–H amination of 1,1-dimethyl-3-phenylpropanol
Fig. 4 Control experiments to get insight into the effect of HFIP.
(a) 13C NMR spectra of a 1c and HFIP mixture in CDCl3. (b) Deactivation
by hydrogen bonding to the oxygen atom of alcohols. (c) C–H amination
(S3) which is a tertiary alkanol having no C–H bond proximal of benzoate 16.
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Scheme 2 Preparation of free amino alcohol 18 from 2c.
These results indicate the presence of hydrogen bonding from
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DCE, respectively, to compare the reaction rates (Fig. 4c and Fig. S2,
ESI†). The reaction in HFIP was completed within 3 h to produce 17
with 85% yield, whereas the reaction in DCE produced 17 in 41%
yield and a 39% yield of 16 remained after the same reaction time.
These results suggest that C–H amination is accelerated by HFIP.
The hydrogen bonding of HFIP to BTCEAD enhances the addition
of a benzyl radical intermediate to BTCEAD (Fig. S3, ESI†).
To demonstrate the usefulness of this method, 2c was
treated with Zn in AcOH in the presence of acetone, with a free
amino alcohol 18 being obtained in 78% yield (Scheme 2).
In conclusion, we have developed a method of NHPI-catalyzed
chemoselective benzylic C(sp3)–H amination of unprotected ary-
lalkanols. HFIP solvent deactivates the C–H bonds proximal to a
hydroxy group, enabling the chemoselective hydrogen atom
abstraction at the benzylic position. Benzylic C–H bonds of
primary alkanols as well as a secondary alkanol were chemoselec-
tively aminated. Benzylic methylene C–H bonds, as well as a
benzylic methyl C–H bond, were also efficiently aminated. Ami-
nated products can be converted to the corresponding free amino
alcohols via zinc reduction. Chemoselective amination enables a
direct conversion of arylalkanols to the corresponding amino
alcohols without the use of a protective group, which facilitates
a step- and atom-economic synthesis toward producing pharma-
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This work was partially supported by JSPS KAKENHI (no.
JP19K06973), and Platform Project for Supporting Drug Dis-
covery and Life Science Research (BINDS, no. JP21am0101099)
from AMED. We thank Shin-ichi Suzuki for experimental help.
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Conflicts of interest
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There are no conflicts to declare.
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