Titanium-Catalyzed Cyano-Borrowing Reaction for the Direct Amination of Cyanohydrins with Ammonia

Article abstract of DOI:10.1021/acs.orglett.9b03194

α-Aminonitrile was an important building block in natural products and key intermedia in organic chemistry. Herein, the direct amination of cyanohydrins with the partner of ammonia to synthesis N-unprotected α-aminonitriles is developed. The reaction proceeds via titanium-catalyzed cyano-borrowing reaction, which features high atom economy and simple operation. A broad range of ketone or aldehyde cyanohydrins was tolerated with ammonia, and the N-unprotected α-aminonitriles were synthesis with moderate to high yields under mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.9b03194

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Titanium-Catalyzed Cyano-Borrowing Reaction for the Direct
Amination of Cyanohydrins with Ammonia
Qing-Hua Li,*,† Zhao-Feng Li,† Jing Tao,† Wan-Fang Li,‡ Li-Qing Ren,† Qian Li,† Yun-Gui Peng,†
and Tang-Lin Liu*,†
†School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
‡College of Science, University of Shanghai for Science and Technology, Shanghai 200093, China
S
* Supporting Information
ABSTRACT: α-Aminonitrile was an important building
block in natural products and key intermedia in organic
chemistry. Herein, the direct amination of cyanohydrins with
the partner of ammonia to synthesis N-unprotected α-
aminonitriles is developed. The reaction proceeds via
titanium-catalyzed cyano-borrowing reaction, which features
high atom economy and simple operation. A broad range of
ketone or aldehyde cyanohydrins was tolerated with ammonia,
and the N-unprotected α-aminonitriles were synthesis with
moderate to high yields under mild reaction conditions.
s an atom-economic nitrogen source in organic synthesis,
ammonia is the simplest and useful molecule.1 Amination
formation. However, the Strecker reaction of NH-imine to
synthesis of N-unprotected α-aminonitriles is rare.12 Other
procedures to deliver N-protected α-aminonitriles were also
developed: (a) α−C-H cyanation of primary amines13 and (b)
electrophilc amination of stabilized carbanions.14 Herein, we
developed the first amination of ketone cyanohydrins (3°
alcohols) with the partner of ammonia15 via titanium-catalyzed
cyano-borrowing reaction. Additionally, the aldehyde cyanohy-
drins (2° alcohols) could be aminated by ammonia under mild
reaction conditions as well.
On the basis of our ongoing research on the cyano-
borrowing reaction,16 we selected acetophenone cyanohydrin
1a as the starting material with the partner of ammonia (7 M
in methanol). In the presence of Ti(Oi‑Pr)4, the amination was
carried out in the media of toluene, and the corresponding 2a
was obtained with 25% yield (Table 1, entry 1). We used
TBME instead and delivered the product with 41% yield
(Table 1, entry 2), and other solvents, such as THF, CH3CN,
DCM, CPME, and MeOH, did not improve the reactivity of
this transformation (Table 1, entries 3−7 vs 2). Benzoic acid
was added as the additive, and 64% of 2a was obtained. Other
carbonyl acids, such as p-nitrobenzoic acid, p-methoxylbenzoic
acid, and acetic acid, gave moderate yields (40−54%) (Table 1,
entries 9−11). When the reaction temperature was increased
to 80 °C, the reactivity of this cyano-borrowing reaction was
almost the same as at 60 °C (Table 1, entry 12), and a lower
yield was obtained while the reaction was carried out at 40 °C
(Table 1, entry 13). The optimized condition was the ketone
A
of alcohols with the partner of ammonia represents an
important direct procedure to synthesis primary amines.2
Conventional procedure to transfer alcohols to amines involves
oxidation, imine formation, and reduction or reductive
amination, which need an excess amount of oxidants and
reductants, and meanwhile, a large amount of wastes could be
formed (Scheme 1a).3 A direct and atom-economical process
is transition-metal catalyzed hydrogen borrowing reaction; in
this transformation, water is the sole byproduct.4 In 2008,
Milstein reported the first amination of primary alcohols with
the partner of ammonia catalyzed by Ru/PNP pincer
complex.5 The pioneering work of amination of secondary
alcohols with ammonia was developed by Vogt6 and Beller7
using ruthenium8 as the catalysts, respectively. Other
procedures on the amination of alcohols with the partner of
ammonia via hydrogen borrowing were also explored.9 The
major challenge of the amination of alcohols with ammonia is
the lack of selectivity. However, we notice that the hydrogen
borrowing reaction just aminates the primary and secondary
alcohols with ammonia, and we wonder whether the tertiary
alcohols with a cyano group could be aminated by ammonia
with the analogous mechanism of hydrogen borrowing to
produce the primary amines with a quaternary carbon center.
α-Aminonitriles are important structural building blocks of
pharmacy and drugs.10 The Strecker reaction, the hydro-
cyanation of imines, was the most efficiently procedure to
access the N-protected α-aminonitriles.11 Deprotection is
necessary to prepare the N-unprotected α-aminonitriles
containing free pri-mary amines, which could produce lots of
byproducts and lower the atom-economy of the trans-
Received: September 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03194
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
cyanohydrins reacted with 3.5 equipment of ammonia in
methanol in the presence of 10 mol % of Ti(Oi‑Pr)4 and 40
mol % of benzoic acid with TBME as the reaction media at 60
°C.
Scheme 1. Amination of Alcohols Using Ammonia
Then we turned our attention to other ammonia sources,
such as ammonia in dioxane and ammonium acetate, and
found that these ammonias were also compatible in this cyano-
borrowing reaction but delivered the target compound with
low isolated yields (20% and 25%) (Scheme 2a). The
Scheme 2. Control Experiments
inorganic salt, ammonium chloride, was found not suitable
for this transformation. When this reaction was carried out
without titanium catalyst and benzoic acid, the design product
was obtained with 29% yield, which indicated that the catalyst
was indispensable to improve reactivity. Meanwhile, the result
suggested that this transformation may undergo nucleophilic
substitution pathway; however, as Boc (tert-Butyloxy carbonyl)
protected acetophenone cyanohydrin 3, the more reactivity
substrate in nucleophilic substitution reaction did not improve
the reactivity. The free imine 4 was subjected to reaction with
acetophenone cyanohydrin 1a under standard reaction
condition, and 2a was obtained with 74% yield (Scheme
2b), indicating cleavage of the C−CN bond instead of the C−
O bond of ketone cyanohydrins in this titanium-catalyzed
transformation.
a
Table 1. Optimization of Reaction Conditions
Having identified optimal conditions, we then evaluated the
substrate scope of ketone cyanohydrins with the partner of
ammonia in methanol on 0.4 mmol scale, and the results are
listed in Scheme 3. Ketone cyanohydrins bearing both
electron-donating, electron-deficient and electron-neutral
groups on the aromatic moiety were well tolerated and
delivered the corresponding unprotected α-aminonitriles with
moderate to good isolated yields (2b−2k). Substitution on the
phenyl ring did not affect the reaction of titanium-catalyzed
cyano-borrowing (2g−2j vs 2a−2f). Nevertheless, heterocycle-
containing such as benzo[b]thiophen-3-yl underwent direct
amination to furnish the corresponding α-aminonitrile (2l) in
synthetically useful yield. The reaction of propiophenone
cyanohydrin gave the desired product 2m bearing ethyl
substitute in 68% yield. In general, aliphatic substituted
cyanohydrins also proved suitable substrates (2n−2r). The
methyl ketone cyanohydrins bearing ethyl, cyclopropyl, and
chloromethyl (2p) were applicable in this cyano-borrowing
reaction (2n−2p). Even the cyanohydrins derived from the
symmetric ketone, such as 3-pentanone (2q) and cyclo-
pentanone (2r), performed well to deliver the corresponding
entry
solvent
additives
yield (%)
1
2
3
4
5
6
7
8
toluene
TBME
THF
CH3CN
DCM
CPME
MeOH
TBME
TBME
TBME
TBME
TBME
TBME
25
41
trace
30
21
trace
trace
64
54
51
PhCO2H
9
p-NO2C6H4CO2H
p-MeOC6H4CO2H
AcOH
PhCO2H
PhCO2H
10
11
40
63
42
b
12
c
13
a
Reaction was carried out with 0.4 mmol of 1, 0.2 mL of ammonia (7
M in methol), and 10 mol % Ti(Oi‑Pr)4, in 0.8 mL of solvent at 60 °C
b
for 18 h. The yields are isolated yields. Reaction was carried out at 80
c
°C. Reaction was carried out at 40 °C.
B
DOI: 10.1021/acs.orglett.9b03194
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Organic Letters
Letter
Scheme 3. Scope of Ketone Cyanohydrins for Cyano-
Borrowing Reaction
Scheme 4. Scope of Aldehyde Cyanohydrins for Cyano-
a
a
Borrowing Reaction
a
Reaction was carried out with 0.4 mmol of 1, 0.2 mL of ammonia
(7M in methanol), 40 mol % PhCO2H, and 10 mol % Ti(Oi‑Pr)4, in
0.8 mL of TBME at 40 °C for 18 h. The yields are isolated yields.
a
Reaction was carried out with 0.4 mmol of 1, 0.2 mL of ammonia
(7M in methol), and 10 mol % Ti(Oi‑Pr)4, in 0.8 mL of MeOH at 40
°C for 18 h. The yields are isolated yields.
quaternary center-containing α-aminonirtiles in moderate yield
(57% and 63%).
Subsequently, this titanium-catalyzed cyano-borrowing
reaction was also applicable to aldehyde cyanohydrins with
the partner of ammonia in methanol. To our surprise, the
aldehyde cyanohydrins could be transferred to the correspond-
ing α-aminonitriles at the absence of benzoic acid in methanol,
and the reaction temperature could be lower to 40 °C without
any loss of reactivity. As is shown in Scheme 4, aromatic
aldehyde cyanohydrins bearing various functional groups, such
as halogen, methyl, methoxyl, nitride, ester, and trifluorometh-
yl on the phenyl rings, were well-tolerated to deliver the
corresponding products 6a−6m in moderate to high yields.
Naphthalenyl was tolerated in this cayno-borrowing reaction
and gave the desired product with synthetically useful isolated
yields (70% for 6n and 72% for 6o). Notably, the disubstituted
cyanohydrins were also effective in the transformation (6p and
6q). The amination product 6r, containing a furanyl group,
was formed with 58% yield. To our satisfaction, several
synthetically useful alkyl groups were tolerated in this
transformation. α,β-Unsaturated cyanohydrin proved to be a
viable substrate, providing the desired product with 54% yield.
Aliphatic aldehyde cyanohydrins derived from hexanal and
cyclohexanecarbaldehyde worked well in this cyano-borrowing
reaction and gave the corresponding α-aminonitriles (6t and
6u) with 87% and 85% yield, respectively. Cyanohydrin 5v, an
aliphatic substrate containing a sulfur atom, reacted smoothly
with the partner of ammonia and provided product 6v in 37%
yield.
mmol, 1.47 g) with ammonia afforded 0.83 g (5.7 mmol) of
the product 2a. A gram-scale synthesis of α-aminonitrile 6a
was conducted, and high yield (87%) was retained (Scheme 5).
Scheme 5. Gram Scale Reaction
In conclusion, we have presented a new and scalable
procedure for the direct amination of cyanohydrins with the
partner of ammonia via titanium-catalyzed cyano-borrowing
reaction. Under the optimized conditions, a wide range of
cyanohydrins were tolerated in this transformation and
afforded the unprotected α-aminonitriles in good to high
yields under mild reaction conditions. Additionally, α-amino-
nitriles containing a quaternary center were obtained via this
cyano-borrowing process.
To demonstrate the applicability of this direct amination of
cyanohydrins with ammonia, the reaction also proceeded on
gram-scale; the reaction of acetophenone cyanohydrin 1a (10
C
DOI: 10.1021/acs.orglett.9b03194
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03194.
■
S
̈
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General information; procedures for titanium-catalyzed
cyano-borrowing reaction and gram scale reaction;
analytical and spectral characterization data; NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: liqinghua@swu.edu.cn.
*E-mail: liuschop@swu.edu.cn.
ORCID
Wan-Fang Li: 0000-0002-2544-1756
Tang-Lin Liu: 0000-0002-7318-4520
Notes
The authors declare no competing financial interest.
(6) Pingen, D.; Muller, C.; Vogt, D. Direct Amination of Secondary
Alcohols Using Ammonia. Angew. Chem., Int. Ed. 2010, 49, 8130−
8133.
ACKNOWLEDGMENTS
■
We are grateful for the financial support provided by National
Natural Science Foundation of China (21801209 and
21801210), the Fundamental Research Funds for the Central
Universities (SWU118117, XDJK2018C044, SWU118028, and
XDJK2019AA003), and Venture & Innovation Support
Program for Chongqing Overseas Returnees (cx2018085).
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catalyzed amination of secondary alcohols with ammonia. Angew.
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Beller, M. Improved ruthenium-catalyzed amination of alcohols with
ammonia: synthesis of diamines and amino esters. Angew. Chem., Int.
Ed. 2011, 50, 7599−7603.
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DOI: 10.1021/acs.orglett.9b03194
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