Asymmetric Hydrocyanation of Alkenes without HCN

Article abstract of DOI:10.1002/anie.201906111

A general and efficient rhodium-catalyzed asymmetric cyanide-free hydrocyanation of alkenes has been developed. Based on the asymmetric hydroformylation/condensation/aza-Cope elimination sequences, a broad scope of substrates including mono-substituted, 1,2-, and 1,1-disubstituted alkenes (involving natural product R- and S-limonene) were employed, and a series of valuable chiral nitriles are prepared with high yields (up to 95 %) and enantioselectivities (up to 98 % ee). Notably, the critical factor to achieve high enantioseletivies is the addition of catalytic amount of benzoic acid. This novel methodology provides an efficient and concise synthetic route to the intermediate of vildagliptin and anagliptin.

Full text of DOI:10.1002/anie.201906111

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Asymmetric Hydrocyanation of Alkenes without HCN
Authors: Xiuxiu Li, Cai You, Jiaxin Yang, Shuailong Li, Dequan Zhang,
Hui Lv, and Xumu Zhang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906111
Angew. Chem. 10.1002/ange.201906111
Link to VoR: http://dx.doi.org/10.1002/anie.201906111
http://dx.doi.org/10.1002/ange.201906111

10.1002/anie.201906111
Angewandte Chemie International Edition
COMMUNICATION
Asymmetric Hydrocyanation of Alkenes without HCN
Xiuxiu Li,+a Cai You,+a Jiaxin Yang,b Shuailong Li,b Dequan Zhang,a Hui Lvb,c* and Xumu Zhanga,b*
Abstract: A general and efficient rhodium-catalyzed asymmetric
hydrocyanation of mono-substituted, 1,2- and 1,1-disubstituted
alkenes, and chiral nitriles are achieved with high yields (up to
95%) and enantioselectivities (up to 98% ee, Scheme 2c).
cyanide-free hydrocyanation of alkenes has been developed. Based
on
the
asymmetric
hydroformylation/condensation/aza-Cope
elimination sequences, a broad scope of substrates including mono-
substituted, 1,2- and 1,1-disubstituted alkenes (involving natural
product R- and S-limonene) were employed, and a series of valuable
chiral nitriles are prepared with high yields (up to 95%) and
enantioselectivities (up to 98% ee). Notably, the critical factor to
achieve high enantioseletivies is the addition of catalytic amount of
benzoic acid. This novel methodology provides an efficient and
concise synthetic route to the intermediate of vildagliptin and
anagliptin.
The transition-metal-catalyzed hydrocyanation of olefins
represents an efficient access to nitriles, which has been
highlighted by the industrial production of adiponitrile from 1,3-
butadiene (> 106 tons per year) with Ni-catalyzed hydrocyanation
steps (Scheme 1).[1] Nitriles are one of the most versatile building
blocks in organic chemistry and can be readily used as
intermediates to other valuable functionalized compounds, such
as carboxylic acid derivatives, amines, aldehydes, ketones, N-
heterocycles.[2] In particular, chiral nitriles are important synthetic
intermediates for many biologically active compounds and
pharmaceuticals such as naproxen, ibuprofen and flurbiprofen.[3]
In addition, there are some pharmaceutical molecules with the
nitrile moiety as a key functional group, such as vildagliptin,[4]
anagliptin,[5] saxagliptin hydrate[6] and the CCR1 recaptor
antagonist (Scheme 2a).[7] Due to the significance of chiral nitriles,
the development of efficient asymmetric synthetic methods for
their preparation has attracted considerable attentions. To date,
the synthesis of chiral nitriles are based on the asymmetric
hydrocyanation of alkenes (Scheme 2b),[8] the Strecker reaction[9]
and other cyanation reactions.[7,10] Owing to the high toxicity and
volatile property of these cyanide reagents, the development of a
cyanide-free method to synthesize chiral nitriles is highly desired.
Herein, we report an asymmetric cyanide-free
Scheme 2. Transition-metal-catalyzed hydrocyanation of alkenes.
Rhodium-catalyzed hydroformylation of alkenes represents a
highly efficient route for the preparation of aldehydes.[11] Due to
the various transformation of the aldehyde group,
hydroformylation-initiated tandem reactions towards more
complex
molecules
have
been
achieved,
including
indole
hydroaminomethylation,[12]
hydroformylation/Fischer
synthesis,[13] hydroformylation/Wittig reaction[14] and other tandem
processes.[15] By contrast, asymmetric hydroformylation-triggered
cascade reactions have been rarely reported, although intensive
research efforts and much progress have been made in
asymmetric hydroformylation during the past decades.[16] The
main reason may lie in the racemization of chiral branched
aldehydes in the cascade process which usually led to the target
products with very low enantioselectivity. In 2013, Landis reported
one-pot AHF/Wittig olefination (AHF/WO) sequences with their
bis-diazophos as the chiral ligand for the AHF step.[17] Recently,
our group have developed the rhodium/YanPhos-catalyzed
asymmetric interrupted intramolecular hydroaminomethylation of
trans-1,2-disubstituted alkenes.[18] Inspired by these results, we
envisioned that the chiral aldehyde, generated from alkenes by
hydroformylation, can react with hydrazines to form relatively
stable hydrazones that can further undergo aza-Cope elimination
(accroding to the method reported by Lassaletta and co-workers
in 1993[19]) to give chiral nitriles. In contrast to Landis’ and our
previous tandem reaction in which the reaction conditions are
neutral, our reaction need to be carried out under alkaline
conditions, which is difficult to keep high enantioselectivities.
Therefore, to avoid racemization is the key factor in this
asymmetric tandem transformation.
Scheme 1. DuPont's production of adiponitrile via hydrocyanation.
[a]
Grubbs Institute and Department of Chemistry, Southern University
of Science and Technology, Shenzhen, Guangdong 518000, P. R.
China
E-mail: zhangxm@sustc.edu.cn
[b]
[c]
Key Laboratory of Biomedical Polymers of Ministry of Education &
College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan, Hubei 430072, China. E-mail: huilv@whu.edu.cn
Engineering Research Center of Organosilicon Compounds &
Materials, Ministry of Education, Sauvage Center for Molecular
Sciences, College of Chemistry and Molecular Sciences, Wuhan
University, Wuhan, Hubei, 430072, China.
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201906111
Angewandte Chemie International Edition
COMMUNICATION
We started our investigation using styrene (1a) as a model
substrate, 1-methylphenylhydrazine (A) as the N-source.
Excellent ee values of the corresponding arylhydrazone B were
achieved, but no desired 2a was produced, because the aza-
Cope elimination cannot realize for these arylhydrazones
(Scheme 3a). Then, 1-aminopiperidine (C) was used as the N-
source feedstock, the reaction underwent smoothly and the
desired chiral nitrile 2a was obtained in high yield, but the ee of
2a was only 30% (Scheme 3b). We also found that the ee of D is
as same as that of 2a. These results disclosed that the
condensation step is very important for keeping the ee values of
the final chiral nitrile. As shown in Scheme 3c, when 1-
methylphenylhydrazine A was employed, due to the strong
conjugation of the arylhydrazone, dehydration condensation can
undergo very fast, which is beneficial for the ee values. By
contrast, when 1-aminopiperidine (C) was used, because of the
weak conjugation of the corresponding hydrazone, dehydration
condensation undergoes slowly, which is detrimental to the ee
values of 2a.
we obtained chiral nitrile 2a with 92% yield and 92% ee (Table 1,
entry 7).
Table 1. Investigation of reaction conditions.[a]
C
Yield
[%][b]
ee
[%][c]
Entry
Solvent
Additive
(mmol)
1
2
0.75
0.75
0.75
0.75
0.55
1.5
toluene
toluene
toluene
THF
none
89
90
93
92
91
90
92
30
73
85
88
85
91
92
3Å MS
3
PhCOOH (10 mol%)
PhCOOH (10 mol%)
PhCOOH (10 mol%)
PhCOOH (10 mol%)
PhCOOH (10 mol%)
4
5
THF
6
THF
7[d]
1.5
THF
[a] Unless otherwise mentioned, all reactions were performed on a 0.5 mmol
scale at 70 °C in 1.0 mL solvent with substrate/Rh = 100:1, (S,S)-Ph-BPE/Rh =
3:1, 20 bar CO/H2 (1:1), a reaction time of 24 h, and MMPP·6H2O (1.0 mmol).
[b] Isolated yield of 2a. [c] Determined by HPLC analysis using a chiral
stationary phase. The absolute configuration was assigned by comparing the
sign of the optical rotation of (S)-2a with that reported in the literature.[20] [d]
60 °C, 2.5 mL THF.
Scheme 3. General one-pot AHF/condensation/aza-Cope elimination
sequence affording chiral nitriles.
Figure 1. Structures of the phosphine ligands for asymmetric cyanide-free
hydrocyanation.
To achieve higher ee values, we attempted to use some
additives which possesses the following properties: (1) the
additive can accelerate the dehydration condensation step to
avoid racemization; (2) the additive cannot interfere the foregoing
AHF step and the following aza-Cope elimination. As shown in
Table 1, when molecular sieves were used, the ee values
increased from 30% to 73%, which supports our hypothesis
(Table 1, entry 2). Next, we tried a class of acids as the additive.
When 10 mol% of benzoic acid was used, 85% ee was given
(Table 1, entry 3). Besides benzoic acid, other acids were also
investigated, which revealed benzoic acid to be superior to all
others tested (see SI). The evaluation of solvents disclosed that
THF should be the best solvent for this reaction (Table 1, entry 4).
Different equivalents of 1-aminopiperidine (C) were also tested,
and 3 equivalents give 90% ee (Table 1, entries 4-6). After
investigating the concentration of 1a and the reaction temperature,
To investigate the substrate scope and generality of this
asymmetric tandem transformation, various alkenes were tested
under the optimized conditions (Scheme 3). First, mono-
substituted alkenes were employed. A series of functional groups,
such as methyl (2b), methoxyl (2c), tertiary butyl (2d), isobutyl
(2e) and halides (2f-2h), at the para position of the phenyl group
are compatible with this transformation. Substrates with meta-
and ortho- substitution on the phenyl group are also tolerated very
well, and high yields with excellent ee values were achieved (2i-
2k). Moreover, substrates containing other aromatic fragments,
including naphthalenes, thiophenes, pyrroles and indoles (2l-2o),
were also tolerated. Next, protected allylic alcohols and allylic
amines were tested, and the corresponding chiral nitriles were
produced with good yields and excellent ee values.
This article is protected by copyright. All rights reserved.

10.1002/anie.201906111
Angewandte Chemie International Edition
COMMUNICATION
As exemplifed by 2r, 2s and 2t, this tandem reaction was also
effective for 1,2- disubstituted alkenes, and high yields with
excellent ee values can be achieved. To our delight, the
desymmetrizing strategy in current reaction is also efficient, and
high diastereo- and enantioselectivities were obtained (2u, >20:1
dr, 90% ee).
We found that a variety of 1,1-disubstituted alkenes can be
transformed to chiral nitriles in high ee’s, which have never been
reported before. When α-methylstyrene (1v) was employed, 2v
was produced in 88% yield with 86% ee. Substrates with methoxyl
(1w) or trifluoromethyl (1x) on the phenyl group were also
accommodated, and high ee values were obtained (2w and 2x).
Next, we introduced this tandem reaction to the modification of
(S)-limonene and (R)-limonene, and the corresponding chiral
nitriles were given with high diastereoselectivities (2z and 2aa).
developed. Using (R,S)-YanPhos as the chiral ligand, 1r
underwent the one-pot tandem reaction very smoothly to give (S)-
2r in 84% yield with 98% ee (Scheme 5a). Starting from (S)-2r,
vildagliptin and anagliptin can be synthesized readily following
literature procedures.[5,21] Furthermore, gram scale reaction of 1e
was achieved, affording the desired chiral nitrile 2e with excellent
yield and ee values (92% yield and 92% ee, Scheme 5b). Then,
the non-steroidal anti-inflammatory drug (S)-Ibuprofen 3 was
obtained in good yield with a high enantiomeric excess (92% ee)
through the nitrile hydrolysis of 2e. With NiCl2/NaBH4 in MeOH,
2e can be also readily converted to the chiral primary amine 4 in
good yield with no loss in ee.
Scheme 5. Synthetic transformations.
In conclusion, we have developed a general and efficient
rhodium-catalyzed
asymmetric
cyanide-free
formal
hydrocyanation of alkenes. In current tandem transformation, the
substrate scope, including mono-substituted, 1,2- and 1,1-
disubstituted alkenes, is broad. It should be pointed that catalytic
amount of benzoic acid is necessary to achieve high
enantioseletivies in the asymmetric reaction of mono- and 1,2-
disubstituted alkenes. Using the enantioselective one-pot
AHF/condensation/aza-Cope elimination sequences, a series of
valuable chiral nitriles are achieved with high yields (up to 95%)
and enantioselectivities (up to 98%). This method provides a
concise route to the synthesis of nitriles with α- or β-chirality,
which are important intermediates in organic synthesis.
Furthermore, a creative method for the synthesis of vildagliptin
and anagliptin has been also disclosed. Further investigations on
the asymmetric reactions in organic synthesis are in progress in
our lab.
Scheme 4. Substrate scope. Condition A: 1 (0.5 mmol), 1-aminopiperidine (1.5
mmol), PhCOOH (0.05 mmol), Rh(acac)(CO)2 (1.0 mol%), L1 (3.0 mol%), CO
(5 bar), H2 (5 bar), THF (2.5 ml), 60 °C, 24 h. MMPP·6H2O (1.0 mmol). Condition
B: 1 (0.5 mmol), 1-aminopiperidine (0.75 mmol), Rh(acac)(CO)2 (2.0 mol%), L4
(6.0 mol%), CO (2.5 bar), H2 (2.5 bar), toluene (0.5 ml), 80 °C, 48 h.
MMPP·6H2O (1.0 mmol). Isolated yields. Enantiomeric excesses (ee) were
Acknowledgements
adetermined by HPLC analysis using
diastereoselectivities were determined by 1H NMR or 13 C NMR analysis of the
a chiral stationary phase. The
We are grateful for financial support from Shenzhen Science and
Technology
Innovation
Committee
(Nos.
unpurified reaction mixture.
JSGG20160608140847864 and JSGG20170821140353405),
Shenzhen Nobel Prize Scientists Laboratory Project (C17213101),
National Natural Science Foundation of China (Nos. 21672094
and 21871212), SZDRC Discipline Construction Program and
Natural Science Foundation of Hubei Province (2018CFB430).
In order to further demonstrate the synthetic utility of the
current tandem methodology, several transformations were
conducted, as summarized in Scheme 5. A creative synthetic
route to the key intermediate of vildagliptin and anagliptin was
This article is protected by copyright. All rights reserved.

10.1002/anie.201906111
Angewandte Chemie International Edition
COMMUNICATION
Keywords: asymmetric synthesis
hydroformylation • nitriles • rhodium
•
hydrocyanation
•
[1]
[2]
a) C. A. Tolman, R. J. McKinney, W. C. Seidel, J. D. Druliner, W. R.
Stevens, Adv. Catal.1985,33, 1-46；b) C. A. Tolman, J. Chem. Educ.
1986, 63, 199-201.
M. B. Smith, J. March, in March's Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 6th ed., Wiley-Interscience,
Hoboken, 2007.
[3]
[4]
D. Lednicer, L. A. Mitscher, The Organic Chemistry of Drug Synthesis
Wiley, New York, 1980.
E. B. Villhauer, J. A. Brinkman, G. B. Naderi, B. F. Burkey, B. E. Dunning,
K. Prasad, B. L. Mangold, M. E. Russell, T. E. Hughes, J. Med. Chem.
2003, 46, 2774-2789.
[5]
N. Ervinna, T. Mita, E. Yasunari, K. Azuma, R. Tanaka, S. Fujimura, D.
Sukmawati, T. Nomiyama, A. Kanazawa, R. Kawamori, Y. Fujitani, H.
Watada, Endocrinology 2013, 154, 1260-1270.
[6] S. A. Savage, G. S. Jones, S. Kolotuchin, S. A. Ramrattan, T. Vu, R. E.
Waltermire, Org. Process Res. Dev. 2009, 13, 1169-1176.
[7]
[8]
W. Zhang, F. Wang, S. D. McCann, D. Wang, P. Chen, S. S. Stahl, G.
Liu, Science 2016, 353, 1014-1018.
a) P. S. Elmes, W. R. Jackson, J. Am. Chem. Soc. 1979, 101, 6128-
6129; b) A. L. Casalnuovo, T. V. RajanBabu, T. A. Ayers, T. H. Warren,
J. Am. Chem. Soc. 1994, 116, 9869-9882; c) T. V. RajanBabu, A. L.
Casalnuovo, J. Am. Chem. Soc. 1996, 118, 6325-6326; d) J. Wilting, M.
Janssen, C. Müller, D. Vogt, J. Am. Chem. Soc. 2006, 128, 11374-11375;
e) A. Falk, A.-L. Göderz, H.-G.Schmalz, Angew. Chem. Int. Ed. 2013, 52,
1576-1580; Angew.Chem. 2013, 125, 1617-1621.
[9]
H. Gröger, Chem. Rev. 2003, 103, 2795-2827.
[10] a) T. Mita, K. Sasaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2005,
127, 514-515; b) C. Mazet, E. N. Jacobsen, Angew. Chem. Int. Ed. 2008,
47, 1762-1765; Angew. Chem. 2008, 120, 1786-1789; c) Y. Tanaka, M.
Kanai, M. Shibasaki, J. Am. Chem. Soc. 2010, 132, 8862-8863; d) D.
Wang, F. Wang, P. Chen, Z. Lin, G. Liu, Angew. Chem. Int. Ed. 2017, 56,
2054-2058; Angew. Chem. 2017, 129, 2086-2090; e) D. Wang, N. Zhu,
P. Chen, Z. Lin, G. Liu, J. Am. Chem. Soc. 2017, 139, 15632-15635; f)
N. Kurono, T. Ohkuma, ACS Catal. 2016, 6, 989-1023.
[11] a) B. Breit, W. Seiche, Synthesis 2001, 1, 1-36; b) R. Franke, D. Selent,
A. Bꢀrner, Chem. Rev. 2012, 112, 5675-5732; c) S. S. Nurttila, P. R.
Linnebank, T. Krachko, J. N. H. Reek, ACS Catal. 2018, 8, 3469-3488.
[12]
a) D. Crozet, M. Urrutigoity, P. Kalck, ChemCatChem 2011, 3, 1102-
1118; b) C. Chen, X.-Q. Dong, X. Zhang, Org. Chem. Front. 2016, 3,
1359-1370; c) P. Kalck, M. Urrutigoïty, Chem. Rev. 2018, 118, 3833-
3861.
[13] a) P. Köhling, A. M. Schmidt, P. Eilbracht, Org. Lett. 2003, 5, 3213-3216;
b) M. Ahmed, R. Jackstell, A. M. Seayad, H. Klein, M. Beller, Tetrahedron
Lett. 2004, 45, 869-873; c) A. M. Schmidt, P. Eilbracht, J. Org. Chem.
2005, 70, 5528-5535; d) B. P. Bondzić, P. Eilbracht, Org. Lett. 2008, 10,
3433-3436.
[14] a) B. Breit, S. K. Zahn, Angew. Chem. Int. Ed. 1999, 38, 969-971; Angew.
Chem. 1999, 111, 1022-1024; b) A. Farwicka, & G. Helmchena, Adv.
Synth. Catal. 2010, 352, 1023-1032.
[15] a) B. P. Bondžić, J. Mol. Catal. A: Chem. 2015, 408, 310-334; b) W. Fang,
B. Breit, Angew. Chem. Int. Ed. 2018, 57, 14817-14821; Angew .Chem.
2018, 130, 15033-15037; c) J. Meng, L.-F. Fan, Z.-Y. Han, L.-Z. Gong,
Chem 2018, 4, 1047-1058.
[16] a) F. Agbossou, J. F. Carpentier, A. Mortreaux, Chem. Rev. 1995, 95,
2485-2506; b) J. Klosin, C. R. Landis, Acc. Chem. Res. 2007, 40, 1251-
1259; c) X. Jia, Z. Wang, C. Xia, K. Ding, Chin. J. Org. Chem. 2013, 33,
1369-1381; d) S. H. Chikkali, J. I. van der Vlugt, J. N. H. Reek, Coord.
Chem. Rev. 2014, 262, 1-15; e) A. C. Brezny, C. R. Landis, Acc. Chem.
Res. 2018, 51, 2344-2354.
[17] G. W. Wong, C. R. Landis, Angew. Chem. Int. Ed. 2013, 52, 1564-1567;
Angew. Chem. 2013, 125, 1604-1607.
[18] C. Chen, S. Jin, Z. Zhang, B. Wei, H. Wang, K. Zhang, H. Lv, X. Q. Dong,
X. Zhang, J. Am. Chem. Soc. 2016, 138, 9017-9020.
[19] R. Fernández, C. Gasch, J.-M. Lassaletta, J.-M. Llera, J. Vázquez,
Tetrahedron Lett. 1993, 34, 141-144.
[20] J. Guin, G. Varseev, B. List, J. Am. Chem. Soc. 2013, 135, 2100-2103.
[21] a) L. Pellegatti, J. Sedelmeier, Org. Process Res. Dev. 2015, 19, 551-
554; b) P. Rommelmann, T. Betke, H. Grꢀger, Org. Process Res. Dev.
2017, 21, 1521-1527.
This article is protected by copyright. All rights reserved.

10.1002/anie.201906111
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Xiuxiu Li,+a Cai You,+a Jiaxin Yang,b
Shuailong Li,b Dequan Zhang,a Hui
Lvb,c* and Xumu Zhanga,b
*
Page No. – Page No.
Asymmetric Hydrocyanation of
Alkenes without HCN
A general and efficient rhodium-catalyzed asymmetric cyanide-free hydrocyanation of alkenes has been developed. Based on the
asymmetric hydroformylation/condensation/aza-Cope elimination sequences, a broad scope of substrates including mono-substituted,
1,2- and 1,1-disubstituted alkenes were employed, and a series of valuable chiral nitriles are prepared with high yields (up to 95%) and
enantioselectivities (up to 98% ee). This method provides a concise route to the synthesis of nitriles with α- or β-chirality, which are
important intermediates in organic synthesis. Furthermore, a creative method for the synthesis of vildagliptin and anagliptin has been
also disclosed.
This article is protected by copyright. All rights reserved.