Three-component reaction of small-ring cyclic amines with arynes and acetonitrile

Article abstract of DOI:10.1039/c3cc42854k

A novel stereospecific three-component reaction of aziridines and azetidines with arynes and acetonitrile has been developed. The reaction affords N-aryl γ-aminobutyronitriles and δ-aminovaleronitriles that can be used as precursors and congeners of a number of bioactive compounds, such as pregabalin and lergotrile.

Full text of DOI:10.1039/c3cc42854k

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Three-component reaction of small-ring cyclic amines
with arynes and acetonitrile†
Cite this: Chem. Commun., 2013,
49, 6558
David Stephens, Yu Zhang, Mathew Cormier, Gabriel Chavez, Hadi Arman and
Oleg V. Larionov*
Received 18th April 2013,
Accepted 30th May 2013
DOI: 10.1039/c3cc42854k
www.rsc.org/chemcomm
A novel stereospecific three-component reaction of aziridines and
azetidines with arynes and acetonitrile has been developed. The
reaction affords N-aryl c-aminobutyronitriles and d-aminovaleronitriles
that can be used as precursors and congeners of a number of bioactive
compounds, such as pregabalin and lergotrile.
Arynes have emerged as versatile and highly reactive intermediates
en route to diverse aromatic and heteroaromatic compounds.1 Recently,
multicomponent reactions of arynes have attracted significant attention
due to the ability of arynes to react with a variety of functional groups.2
In particular, the ability of arynes to engage both electrophilic and
nucleophilic reagents in a consecutive fashion has led to a number of
efficient syntheses of polycyclic (hetero)aromatic frameworks, such as
xanthenes,3 benzisoxazoles,4 isoquinolines,5 and coumarins.6
Scheme 1 General mechanistic proposal for the dual activation of aziridines
and pronucleophiles by arynes.
We envisaged that the reaction of benzyne with aziridines 1 of multicomponent reactions have been limited. Recently, Cheng and
would give rise to the corresponding zwitterionic intermediates co-workers have reported a three-component coupling of arynes,
2 (Scheme 1). The anionic residue in 2 could be sufficiently N-heteroaromatics and acetonitrile that involves deprotonation of
basic to generate a carbon nucleophile that would otherwise be acetonitrile by a zwitterionic intermediate.20 Similarly, benzyne-initiated
inaccessible under these mild conditions. Subsequent nucleo- ring-opening reactions of cyclic ethers by acidic methines have been
philic attack would produce N-arylated amines 4. We report observed by Okuma and co-workers.21 On the other hand, reactions of
herein the first example of such a three-component reaction arynes with allylamines have been shown to give rise to the products
with acetonitrile as a pronucleophile.
of aza-Claisen reaction.22 Reactions of arynes with aziridines and
Nitriles are versatile synthetic intermediates. They can be readily azetidines have not been described, but related azirines are known to
transformed into carboxylic acids,7 amides,8 amines9 and ketones.10 give rise to substituted indoles upon reaction with benzyne.23
Furthermore, the cyano group is present in a number of natural
products11 and pharmaceuticals,12 including antiparkinsonian nucleophiles.24 Recent approaches for activation of aziridines have
lergotrile13 and antidiabetic drug vildagliptin.14 focused on N-methylation with toxic methyl triflate,25 use of electron
Substituted aziridines and azetidines react sluggishly with carbon
Nucleophilic activation of alkyl nitriles remains a challenging task deficient N-acyl and N-arylsulfonylaziridines,26 and activation with
due to their low acidity (pKa 31.1 in DMSO for CH3CN15) and reduced stoichiometric amounts of Lewis acid.27 In addition to diminished
stability of the carbanion in the presence of strong bases.16 Several reactivity, control of the regioselectivity of the nucleophilic ring-opening
methods have been developed that rely on activation of nitriles by reactions of substituted aziridines remains a challenge.28
transition metals,17 as well as strong non-nucleophilic bases (Vercade’s
Reaction with arynes represents a new mode of activation of
proazaphosphatrane18 or cesium and potassium tert-butoxides19). N-alkylaziridines. Thus, aryne plays a dual role by activating
Despite this progress, generation and use of alkyl nitriles in the context both the aziridine and the pronucleophile.
Initial experiments with aziridine 5, benzyne precursor 6 and
Department of Chemistry, University of Texas at San Antonio, San Antonio,
cesium fluoride in acetonitrile afforded the three-component reaction
product 7 in 34% yield, asserting feasibility of the process (Table 1).
TX 78249, USA. E-mail: oleg.larionov@utsa.edu
† Electronic supplementary information (ESI) available: Experimental procedures
Subsequent attempts to identify a better fluoride source have led to
suboptimal results, as neither of the other salts provided an
and characterization data. CCDC 934181. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c3cc42854k
c
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Table
1
Optimization study of the reaction of aziridine 5 with benzyne
improvement over CsF. On the other hand, use of toluene as a co-
solvent at a lower temperature has led to a cleaner reaction with a
much improved yield of 86%.
precursor 6 and acetonitrilea
Less promising results have been observed with other co-solvents,
including tetrahydrofuran, 1,2-dimethoxyethane and dioxane. Attempts
to replace triflate 6 and cesium fluoride as a source of benzyne with
benzenediazonium-2-carboxylate29 have produced the desired g-amino-
nitrile 7 in 25% yield. Although synthetically less attractive, this
experiment supports our hypothesis that the nitrile carbanion is
generated via proton abstraction by zwitterionic intermediate 2 and
not by the fluoride, in line with the deuterium-labelling experiments
performed by Cheng et al.20 and Greaney et al.22 for their systems.
After completion of the optimization study we sought to explore the
scope of the new three-component reaction with respect to the structure
of the amine component. A number of N-substituents in the aziridine
ring are well tolerated, including primary and secondary alkyl, and
phenyl groups (Fig. 1). The yields of g-aminonitriles 7–9 and 11–15
are generally high. Bicyclic aziridines are also viable substrates, as
exemplified by the indene-derived product 8. The reaction proceeds in a
stereoselective fashion and affords 7 with >95 : 5 dr. The nucleophilic
attack by the nitrile carbanion generally occurred at the benzylic or
allylic position of the aziridines, placing the substituent at the b-position
in the corresponding products. Azetidines30 readily undergo the
Entry Fluoride source Solvent
Temperature (1C) Yield (%)
1
2
3
4
5
6
7
8c
9
CsF
NaF
TBAF
TAS-F
KF
CsF
CsF
—
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
80
80
80
80
65
34
10
7
5
24
86
31
25
16
PhCH3–CH3CNb 65
THF–CH3CNb
PhCH3–CH3CNb 65
DME–CH3CNb
65
65
CsF
a
Reaction conditions: aziridine 5 (0.25 mmol), fluoride (6 equiv.), 6
b
(3 equiv.), solvent (2 mL), 3 Å molecular sieves (30 mg). Solvent/CH3CN
c
ratio: 3 : 1. Benzenediazonium-2-carboxylate was used as a benzyne
precursor instead of 5 and CsF.
Table 2 Scope of the aryne precursors
Entry Aryne precursor
N-aryl-g-amino nitrile
Yield (%)
1
81
2
86
3
4
75
93
Fig. 1 N-Aryl-g-amino nitriles prepared from aziridines or azetidines, acetonitrile
and triflate 6.
c
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10 was isolated in 74% yield. Five- and six-membered cyclic
amines, on the other hand, gave mixtures of unidentified
products under these conditions.
In an effort to determine the stereochemical outcome of the
reaction, several chiral aziridines were prepared from (1S)-phenyl-
ethylamine, and the absolute configuration of one of the diaster-
eomers has been established by single-crystal X-ray crystallography.31
These chiral aziridines afforded corresponding products (S,R)-11 and
(S,S)-11, as well as (S,S)-15 with >95 : 5 dr.
In addition, we have also explored the influence of the aryne
structure on the reaction. Substituted aryne precursors 16–19 have
been subjected to the reaction with aziridines and nitrile products 20–
23 have been isolated in good yields (Table 2). Both m- and p-isomers
of nitrile 22 have been formed in equal amounts with triflate 18 as an
aryne precursor. Other substituted alkyl nitriles have yielded complex
mixtures of products, highlighting the importance of steric and
electronic factors in this reaction. Work is underway to expand the
scope of the reaction to other carbon and heteroatom pronucleo-
philes, as well as non-benzylic/allylic aziridines and azetidines. The
g-aminobutyronitrile framework that is readily accessed by this
three-component reaction is widely observed among molecules of
biomedical interest. In addition, hydrolysis of the nitrile products
to the corresponding carboxylic acids can afford chiral b-substituted
g-aminobutyric acids. This class of compounds has recently yielded a
number of new psychoactive small-molecule therapeutics, including
the blockbuster drug pregabalin (Lyricat), as well as vigabatrin,32
gabapentin,33 and atagabalin, currently in clinical development for
treatment of insomnia.34
In conclusion, we have developed a new three-component reac-
tion between aziridines and azetidines, arynes and acetonitrile that
leads to N-aryl-g-amino nitriles. The reaction proceeds with a high
degree of stereoselectivity and allows for transfer of chirality from
aziridine to the product. The aryne plays a crucial role by effecting
dual activation of the small-ring tertiary amine and the nitrile in a
stepwise fashion via zwitterionic intermediate 2.
Financial support from the Welch Foundation (AX-1788), the
Max and Minnie Tomerlin Voelcker Fund, the San Antonio Life
Sciences Institute (SALSI) and the University of Texas at San
Antonio is gratefully acknowledged.
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6560 Chem. Commun., 2013, 49, 6558--6560
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