Cyano-borrowing: Titanium-catalyzed direct amination of cyanohydrins with amines and enantioselective examples

Article abstract of DOI:10.1039/c9cc08576a

The direct amination of cyanohydrins with amines via a catalytic cyano-borrowing reaction was developed. The transformation features broad substrate scope, excellent functional group compatibility, and very mild and simple operations. Moreover, a titanium

Full text of DOI:10.1039/c9cc08576a

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Cyano-borrowing: titanium-catalyzed direct
amination of cyanohydrins with amines and
Cite this:DOI: 10.1039/c9cc08576a
enantioselective examples†
Received 4th November 2019,
Accepted 5th December 2019
Tang-Lin Liu, *a Zhao-Feng Li,a Jing Tao,a Qing-Hua Li,a Wan-Fang Li,b Qian Li,b
Li-Qing Rena and Yun-Gui Peng*a
DOI: 10.1039/c9cc08576a
rsc.li/chemcomm
The direct amination of cyanohydrins with amines via a catalytic and all the other functionalities ended up in the target products.
cyano-borrowing reaction was developed. The transformation Recently, we have developed a direct amination of cyanohydrins
features broad substrate scope, excellent functional group compat- with the partner of ammonia to produce N-unprotected a-amino-
ibility, and very mild and simple operations. Moreover, a titanium nitriles.6 In view of the importance of a-aminonitriles1–3 and our
catalyst supported by quinine and (S)-BINOL ligands enabled an continued interest in cyano-borrowing reactions,6,7 herein, we
asymmetric cyano-borrowing reaction with moderate to high explored the direct amination of cyanohydrins with amines via
enantioselectivity.
the titanium-catalyzed cyano-borrowing reaction. Various types of
aromatic amines, aliphatic amines and sulfonyl amide were
a-Aminonitriles serve as conventional precursors for a-amino tolerated. The titanium-catalyzed enantioselectivity cyano-borrowing
acids, which constitute the fundamental building blocks for reaction was also developed (Table 3).
peptides and proteins.1 a-Aminonitriles are basic structures for
We started our investigation by the amination of commercially
the preparation of pharmaceuticals and agrochemicals and available mandelonitrile 1a with p-methoxybenzyl amine (PMPNH2)
drugs.2 In many organic transformations, a-aminonitriles also 2a to provide the desired a-aminonitrile 3, which could be synthe-
exhibit dual reactivity.3 The Strecker reaction – the hydrocyanation sized by the Strecker reaction. After careful studies on the reaction
of imines – represents one of the most direct and efficient routes to conditions, we discovered that the best results were obtained by
access a-aminonitriles (Scheme 1a).4 However, the usage of using Ti(Oi-Pr)4 as the catalyst in toluene at 40 1C (see ESI† for more
extremely toxic hydrogen cyanide (HCN) is a major obstacle in detailed screening).
traditional Strecker reactions. Owing to their lower explosion
The control experiments show that titanium was essential
hazard and easier handling, cyanohydrins have evolved into an for the envisioned transformation. We then focused on the scope
increasingly safe and versatile cyano source for organic synthesis.5 of the direct amination of cyanohydrins in a non-enantioselective
When cyanohydrins are used as the HCN source, carbonyl com- version. As shown in Table 1, various commercially available
pounds (such as ketones or aldehydes) are generally released as the aldehyde cyanohydrins were tolerated in this titanium-catalyzed
side products, which decreases the atom-economy of the process. amination procedure. Aldehyde cyanohydrins bearing various
Therefore, it would be a very valuable catalytic transformation if electron-withdrawing substituents, including halogens (4–6), ester
both the cyano group and the carbonyl side products could be (10), trifluoromethyl (11) and electron-donating groups (Table 1, 7
utilized. As hypothesized in Scheme 1b, the C–CN bond of the and 8) at the para-position of the phenyl ring reacted with amine 2
cyanohydrin was cleaved in the presence of titanium and the to deliver the corresponding a-aminonitrile in good to excellent
metal-cyano (A) and corresponding carbonyl compounds were yields (41–92%). Noticeably, a cyano group on the phenyl ring was
delivered (B), followed by imine formation via the condensation also tolerated and afforded the desired product (9) smoothly with a
of carbonyl compounds with amines, and then the cyano group moderate yield. The substrates containing an ortho or meta sub-
was transferred from the intermediate (A) to the imine (C) to stitute were still compatible in this transformation (Table 1, 12–14
give the a-aminonitriles. Overall, water was the sole byproduct and 17–18). Substrates with naphthyl (15 and 16) or heteroaryl
(19 and 20) underwent successful amination to deliver a range of
a-aminonitriles with isolated yields ranging from 56% to 92%.
A good chemical yield was achieved when cinnamaldehyde
cyanohydrin (21) was introduced to this transformation. Alkyl
substitutes, such as n-pentyl (22), cyclohexyl (23) and methyl
a School of Chemistry and Chemical Engineering, Southwest University,
Chongqing 400715, China. E-mail: liuschop@swu.edu.cn, pyg@swu.edu.cn
b College of Science, University of Shanghai for Science and Technology,
Shanghai 200093, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9cc08576a (24), were tested and the desired alkyl substituted cyano amines
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Table 1 Substrate scope with respect to the aldehyde cyanohydrins and
aminesa
Scheme 1 Amination of cyanohydrins via the cyano-borrowing reaction.
were obtained in moderate yields. Encouraged by the results
achieved with aldehyde cyanohydrins, we next expanded the
scope of the amine. Table 2 summarizes the amination of
mandelonitrile 1 with various amines. Aromatic amines bearing
electron-rich and electron-deficient substitutions at the para,
ortho and meta-positions were all well tolerated in this titanium-
catalyzed cyano-borrowing procedure with yields ranging from
47% to 92% (25–32). Additionally, an aliphatic amine, e.g.,
a
The reaction was carried out with 0.4 mmol of cyanohydrins, 0.2 mmol
of amines and 10 mol% Ti(Oi-Pr)4, in 1.0 mL of toluene at 40 1C for
b
18 h. The yields are isolated yields. o10% yield was obtained in the
absence of Ti(Oi-Pr)4.
benzylic amine was also tested in the transformation and the whereas the desired a-aminonitrile 3 was not observed. On the
corresponding a-aminonitrile 33 was obtained in 51% yield. On other hand, with the acetophenone cyanohydrin 36 which has
the other hand, a moderate yield could be achieved when the no a-hydrogen to ‘borrow’, the corresponding quaternary a-amino-
sulfonyl amide was tested in the titanium-catalytic transformation nitrile 37 was obtained in 62% yield.10 These results rule out the
(compound 34 in Table 1).
nucleophilic substitution and hydrogen-borrowing pathways.
Based on the previous reports from others and ourselves, Additionally, the crossover reaction between mandelonitrile
there could be three plausible mechanisms for this transformation: and N-PMP benzaldehyde imine (38) delivered the corres-
(1) nucleophilic substitution;8 (2) a catalytic hydrogen-borrowing ponding a-aminonitrile 3 with 93% yield. On the other hand,
mechanism;9 and (3) a catalytic cyano-borrowing mechanism.6,7 based on the control experiments, we found that a titanium
To shed some light on the reaction pathway, a series of studies catalyst improves the step of imine intermediate formation, and
were carried out under the standard reaction conditions (Scheme 2). the titanium catalyst was indispensable for the cleavage of the
Firstly, we found that the Boc (tert-butyloxy carbonyl) protected C–CN bond in cyanohydrins and the formation of C–CN in the
mandelonitrile which contained a more reactive leaving group, Strecker reaction under the optimal reaction conditions. And
did not react with amine 2a. Secondly, in order to know whether the fragment of Ti–CN was detected by HIMS (see ESI† for more
this transformation goes through the hydrogen-borrowing pathway, details and the proposed catalytic cycle). Taken together, these
we introduced the imine 35 under the standard reaction condition experimental results are in good accordance with our initial
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Table 2 Scope of ketone cyanohydrins with partner amine 2aa
Table 3 Scope of the asymmetric cyano-borrowing reactiona
a
The reaction was carried out with 0.4 mmol of 1, 0.2 mmol of 2a,
10 mol% of Ti(Oi-Pr)4, 10 mol% of (S)-BINOL and 25 mol% of quinine
in 1.0 mL of toluene at 40 1C for 36 h. The yields are isolated yields.
Ee was determined by chiral HPLC.
Under these conditions, acetophenone cyanohydrins with
either electron-deficient, electron-neutral or electron-rich groups
at all kinds of positions of the phenyl rings gave moderate
isolated yields (48–67%) (39–48). It is noteworthy that the
cyanohydrins derived from dialkyl ketones were also compatible.
The cyanohydrin from methyl ethyl ketone was well tolerated and
delivered 49 in 72% yield, and the cyclopropyl containing
a-aminonitrile 50 was obtained in 24% yield. Moderate yields
were obtained when the symmetric cyanohydrins, such as acetone
cyanohydrin, 3-pentanone cyanohydrin and cyclopentanone cyano-
hydrin, were subjected to the titanium-catalyzed cyano-borrowing
reaction under the optimized conditions (Table 2, 51–53).
a
The reaction was carried out with 0.4 mmol of cyanohydrins, 0.2 mmol
of PMPNH2 and 10 mol% Ti(Oi-Pr)4, in 1.0 mL of toluene at 60 1C for
18 h. The yields are isolated yields.
We next concentrated our attention on the development of
an asymmetric variant of the cyano-borrowing reaction. The
combination of titanium, dinaphthols and quinines was chosen
as the catalytic system for the asymmetric cyano-borrowing
reaction.11 After the screening of the reaction parameters, we
found that Ti(Oi-Pr)4 (10 mol%), (S)-BINOL (10 mol%) and
quinine (25 mol%) was the best combination as the catalyst,
and the optimal conditions were using mixed toluene/TBME
(v/v = 1 : 2) (TBME = tert-butyl methyl ether) and setting the
reaction temperature at 40 1C for 36 h (see ESI† for more details).
The absolute configurations were determined to be S by comparison
with known compounds. Then the scope of asymmetric cyano-
borrowing was tested, which is listed in Table 3. The aromatic
Scheme 2 Mechanism studies.
hypothesis on the direct amination of cyanohydrins with amines cyanohydrins with electron-deficient or electron-rich substitutes
via a cyano-borrowing process (Scheme 1b). on the phenyl rings were tolerated and delivered the corres-
Since the acetophenone cyanohydrin 37 reacted with the amine ponding chiral a-aminonitriles in moderate yields and moderate
2a smoothly and gave the corresponding product 37 in 62% yield, to good enantioselectivity excess (49–78% ee). To our delight,
we found that commercially available ketone cyanohydrins are also the ortho-chloride substituted product 12 was obtained with
suitable substrates for this titanium-catalyzed cyano-borrowing 87% ee. Additionally, the heteroarenes, e.g., thiophenyl con-
reaction. We then examined the scope of ketone cyanohydrins to taining product 20, could be successfully obtained albeit
the cyano-borrowing reaction with the partner of p-methoxyphenyl with moderate yields and 31% ee. The cyanohydrin from
amine 2a, as shown in Table 2. We also found a broad scope of caproaldehyde was tolerated in the titanium-catalyzed asym-
ketone cyanohydrins for this transformation. The other ketone metric cyano-borrowing reaction, and the alkyl substituted
cyanohydrins were subjected to the titanium-catalyzed cyano- product was formed with 57% ee. An attempt with acetophe-
borrowing procedure at 60 1C.
none cyanohydrin 36 was less efficient in the asymmetric
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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 Over-
seas Returnees (cx2018085).
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