Access to α-Cyano Carbonyls Bearing a Quaternary Carbon Center by Reductive Cyanation

Article abstract of DOI:10.1021/acs.orglett.1c00465

Reductive cyanation of tertiary alkyl bromides using electrophilic cyanating reagent and zinc reductant was developed, providing various α-cyano ketones, esters, and carboxamides containing a nitrile-bearing all-carbon quaternary center in good to excellent yields under mild reaction conditions. The corresponding reaction mechanism involving in situ generated organozinc reagent and reactivity distinction was elucidated by density functional theory computation.

Full text of DOI:10.1021/acs.orglett.1c00465

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Letter
Access to α‑Cyano Carbonyls Bearing a Quaternary Carbon Center
by Reductive Cyanation
Xinyi Ren, Chaoren Shen, Guangzhu Wang, Zhanglin Shi, Xinxin Tian,* and Kaiwu Dong*
Cite This: Org. Lett. 2021, 23, 2527−2532
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ABSTRACT: Reductive cyanation of tertiary alkyl bromides using electrophilic cyanating reagent and zinc reductant was
developed, providing various α-cyano ketones, esters, and carboxamides containing a nitrile-bearing all-carbon quaternary center in
good to excellent yields under mild reaction conditions. The corresponding reaction mechanism involving in situ generated
organozinc reagent and reactivity distinction was elucidated by density functional theory computation.
Scheme 1. Strategies for Synthesis of α-Cyano-Carbonyls
Bearing a Quaternary Carbon Center
iven by the indispensability of α-cyano carbonyl
1,2
Gcompounds to constructing bioactive molecules,
the
challenge of constructing congested all-carbon quaternary
centers in organic synthesis3 and the unique role of all-carbon
quaternary center in metabolic stability of pharmaceuticals,4
developing practical methods of synthesizing α-cyano carbonyl
compounds with nitrile-bearing all-carbon quaternary center is
a long-lasting attractive issue. Despite the significant advance-
ments in the synthesis of α-cyano carbonyl compounds,5−8
most of them focus on the preparation of simple α-cyano
ketones, whereas the accesses to the ketones with nitrile-
bearing all-carbon quaternary center is still limited. The
reported protocols include the substitution of deprotonated
α,α-disubstituted nitriles with N-acylbenzotriazoles,5 palladi-
um-catalyzed carbonylation of aryl iodide with deprotonated
α,α-disubstituted nitriles,6 electrophilic cyanation of enol
boronate with N-cyano-N-phenyl-p-toluenesulfonamide
(NCTs),7 and rhodium-catalyzed addition of aryl boronic
acids to α,α-disubstituted malononitriles (Scheme 1).8 Never-
theless, these approaches demand high temperature and
pressure conditions, use air/moisture-sensitive reagents or
costly noble metal catalyst, or display confined functional-
group tolerance. On the other side, the development on
preparing methods of other α-cyano carbonyls manifests sharp
contrast to the diverse strategies to obtain α-cyano ketones. As
we know, only one elegant pathway to α-cyano carboxamides
via copper-catalyzed cyanation of tertiary bromides with zinc
cyanide was reported by Nishikata and Kuninobu recently.9
Therefore, the reaction protocol, which can be simultaneously
applicable for the synthesis of α-cyano ketones, esters, and
carboxamides bearing a quaternary center, has yet to be
established. Considering the thriving progress on oxidative
cyanation with nucleophilic cyanating reagent,10 we envisioned
that reductive cyanation with two electrophilic partners and
opposite reaction mode might offer an efficient and convenient
solution to construct C−CN bond, which would not only
Received: February 7, 2021
Published: March 24, 2021
https://doi.org/10.1021/acs.orglett.1c00465
© 2021 American Chemical Society
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eliminate the usage of poisonous cyanide and vulnerable
organometallic reagents but also exhibit both impressive
robustness and remarkable flexibility.
completely stopped the proceeding of desired cyanation
(entries 3−6). In some of these cases (entries 4 and 5),
reductive debromination of 1a was determined as the major
side reaction. Adding Ni(acac)2 or NiBr2·glyme (10 mol %),
which mimicked the reported protocol of alkene hydro-
cyanation,22 hindered the reaction, decreasing the yield
(entries 7 and 8). Using other metal reductants like indium
or manganese dust resulted in no bromide conversion (entry
9) or lower yield (entry 10). When DMF was switched to
either THF or Et2O, nearly quantitative amount of starting
material was recovered (entry 11), which implied that without
employing Rieke-type activated zinc23 or reflux conditions,24
the formation of Reformatsky reagent in ether-type solvent was
rather sluggish at ambient temperature.
As an organometallic reagent easily available from zinc dust
and α-halogen ester, Reformatsky reagent is equipped with
better functional-group tolerance than organolithium or
Grignard reagent.11−13 The Zn−C addition of organozinc
reagent onto electrophilic C−X (X = C, N, and O) π bonds
represents a classic mode of building C−C bonds.12,13 Blaise
reaction, which goes through the Zn−C addition onto C≡N
bond, can transform nitrile to either carbon-chain elongated
ketone/imine or nitrogen-containing heterocycles in different
terminating manner.12−14 As we know, the β-carbon or β-
heteroatom elimination following Zn−C addition to C≡N
bond was unexploited. In addition, the ketone- and amide-type
of organozinc reagent, which could be generated from zinc and
α-halogenated ketones or N,N′-disubstituted amides, was an
far less cultivated field in organic synthesis.14a,15 These inspired
us to explore the potential application of Reformatsky reagent
in the reductive cyanation by combining the Zn−C addition of
Blaise reaction and β-atom elimination (i.e., retro-Thorpe
fragmentation).16 Herein, we presented treating tertiary alkyl
halides and electrophilic cyanation reagents with zinc dust
provided a practical and safe route to α-cyano carbonyls
(Scheme 1).
With the optimized reaction conditions in hand, the
substrate scope and functional group tolerance were
extensively inspected (Figure 1). For various substituted α,α-
dimethyl α-bromo acetophenones, the reaction afforded the
At the beginning of our studies, cyanation of sterically
demanding α-bromoketone 1a was selected as the model
reaction to survey the reaction parameters (Table 1). The
1
Table 1. Optimization of Reaction Conditions
entry
deviation from standard conditions
none
2a
1
90% (88%)
2
3
4
MPMN instead of NCTs
DMMN instead of NCTs
CBX instead of NCTs
40%
0
0
5
6
7
8
4-cyanopyridine 1-oxide instead of NCTs
butyronitrile instead of NCTs
adding 10% mol NiBr2·glyme
adding 10% mol Ni(acac)2
Mn instead of Zn
0
0
64%
75%
0
9
10
11
In instead of Zn
THF or Et2O instead of DMF
86%
0
1
Reaction conditions: 1a (0.50 mmol, 1.0 equiv), NCTs (0.60 mmol,
1.20 equiv), zinc (0.60 mmol, 1.20 equiv), DMF (2.0 mL). Yield
determined by GC using n-decane as internal standard. In the
parentheses is the isolated yield of 2a.
combination of electrophilic NCTs and reductive zinc dust
delivered the desired nitrile 2a in 90% yield after 2 h reaction
at room temperature in DMF (entry 1, standard reaction
conditions). 2-Methyl-2-phenylmalononitrile (MPMN),17 2,2-
dimethylmalononitrile (DMMN),18 cyanobenziodoxolone
(CBX),19 4-cyanopyridine 1-oxide,20 and butyronitrile21 are
five kinds of reported cyanating reagents. Replacing NCTs
with them led to significant lower yield of 2a (entry 2) or
Figure 1. Reductive cyanation of α-bromo ketones, esters, and
carboxamides. Unless otherwise noted, reaction conditions: substrate
(0.50 mmol, 1.0 equiv), zinc dust (0.60 mmol, 1.20 equiv), DMF (2.0
mL), rt, 2 h. For 1 or 3, adding NCTs (0.60 mmol, 1.20 equiv). For 5,
adding MPMN (0.60 mmol, 1.20 equiv). Isolated yields. (a) 80 °C.
(b) 0.2 mmol scale. (c) 0.2 mmol scale, NCTs (0.24 mmol, 1.20
equiv), zinc dust (0.24 mmol, 1.20 equiv), THF (2.0 mL), 100 °C, 12
h.
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desired nitriles 2b−2i in moderate to excellent yields (Section
A). The electron-donating or -withdrawing nature of
substituent has little impact on the reactivity. The bromo or
chloro substituents on the phenyl ring remain inert. Both cyclic
and acyclic alkyl units at the α-position of the halides were
tolerated, resulting in 64−94% yields of 2j−2q. Tertiary
bromide 1r derived from 2-methyl-1-indanone was smoothly
transformed into the nitrile with 94% yield under standard
conditions. The remarkable versatility of this approach was
further demonstrated by reductive cyanation of α-bromo
phenol esters 3 (Section B) and α-bromo carboxamides 5
(Section C). Isobutyrates of phenol, nathpanol, benzyl alcohol,
and allylic alcohol 3a−3n were converted to the corresponding
nitriles 4a−4n in reasonable to excellent yields. Among these
cases, bromo or iodo substituents on the aryl ring (4e, 4g, 4h,
4l) and C=C bond of cinnamyl group (4n) were preserved.
For carboxylic ester of p-cresol with longer aliphatic chain (3o-
3s) or cyclic substituent (3t−3v), the protocol also achieved
good cyanation yields in most of the cases. In some cases, using
N-cyano-N-phenylbenzenesulfonamide (NCPs) instead of
NCTs facilitated the isolation of cyanation products (4b−4h,
4j−4n). By using MPMN instead of NCTs, α-bromo N-aryl or
N-alkyl isobutyramides as well as cyclobutanecarboxylic amide
smoothly underwent reductive cyanation, resulting in the
products 6a−6o with high yields in most of the scenarios. The
molecular structure of 6a was identified by X-ray crystallog-
raphy. Thanks to the noble-metal-free and neutral conditions,
boronic acid pinacol ester group (Bpin), methyl sulfide group,
dimethylamino group, and piperonyl group did not impose
negative impact on this reductive cyanation (6j, 6k, 6m, and
6n). The merit demonstrated by 6j is beneficial to further
transformation with the miscellaneous tools of transition-
metal-catalyzed cross coupling. More impressively, this
protocol can be applied to introducing nitrile group and
quaternary carbon center into β-lactams at the same time by
employing α-halo-β-lactams as the substrates (6p and 6q).
Notably, α,α-difluorinated α-bromo acetate amide can also be
cyanated (6r) in acceptable yield, along with unwanted
reductive debromination of 5r. The above-mentioned results
of products 4q−4v and 6o demonstrated an practical
alternative of avoiding the selectivity obstacle in the
preparation of α,α-disubstituted β-amino amides via the
dialkylation or cycloalkylation of cyanoacetate with two
different alkyl halides or terminal dihalogenated alkanes.25
Encouraged by these results, we further demonstrated the
benefits of this synthetic tool from the following aspects: (i)
varied transformation of cyanation products (Scheme 2); (ii)
the late-stage functionalization of pharmaceuticals and
bioactive molecules (Scheme 3); (iii) gram-scale synthesis
(Scheme 4). The synthetic utility of this reductive cyanation
was projected on the diverse transformation of products. A
variety of transformations from nitriles to molecules, including
3-amino alcohol, 1,3-diamines with two primary amine
moieties with different N-protecting groups, α,α-disubstituted
malonamide with different N-terminus, and β-hydroxy26 or
-amino amide, were accomplished in moderate to high yields
(Scheme 2). Late-stage functionalization represents an
opportunity to expand the toolbox in hands of medicinal
chemists and in turn increase the chemical space explored in
drug discovery efforts.27 Because of the facile accessibility of α-
ketone substituted tertiary alkyl bromides by brominating the
corresponding ketone with hydrogen bromide, we achieved the
cyanative modification of acetylcholinesterase inhibitor Done-
Scheme 2. Transformation of α-Cyanocarbonyls Reaction
Conditions
1
1
(a) 2a (0.5 mmol, 1.0 equiv), CoCl2 (1.5 mmol, 3.0 equiv), (Boc)2O
(3.0 mmol, 6.0 equiv), NaBH4 (5.0 mmol, 10.0 equiv), MeOH (5
mL), 0 °C, overnight. (b) 2a (0.5 mmol, 1.0 equiv), BnNH2 (0.6
mmol, 1.2 equiv), Ti(OEt)4 (2 mL), 85 °C, 6 h; then with the
conditions of panel (a). (c) 6a (0.5 mmol, 1.0 equiv), LiAlH4 (2.5
mmol, 5.0 equiv), 80 °C, overnight. (d) 6a (0.5 mmol, 1.0 equiv),
K2CO3 (1.0 mmol, 2.0 equiv), 30 wt % H2O2 solution (2.5 mmol, 5.0
equiv), DMSO (2 mL), rt, 20 h. (e) 6a (0.5 mmol, 1.0 equiv) with the
conditions of (a). (f) 2a, with the method reported in ref 26.
Scheme 3. Late-Stage Modification of Pharmaceuticals
Scheme 4. Gram-Scale Synthesis
pezil (8a) by transforming Donepezil to its tertiary alkyl
bromide derivative and then implanting nitrile group with this
method (Scheme 3). Anesthetic Propofol, antihistamine drug
Desloratadine, antidepressant Fluoxetine, steroid Estrone, and
quetiapine’s active metabolite norquetiapine were converted to
the corresponding α-bromo esters or amides, and after
applying this cyanation method, products 8b−8f were
delivered in reasonable to high yields. The 2,2-dimethyl
cyanoacetyl group can be installed as a degradation-resistant
“tether” into these pharmaceuticals through this process. By
further transformation of implanted nitrile group to amino
group, these pharmaceuticals could be affixed to bioactive
peptides or proteins, providing potent option to explore the
vast potential of well-established drugs. Larger-scale reaction of
tertiary alkyl bromides with NCTs or MPMN and zinc dust
was performed. The corresponding α-cyano molecules were
produced gram-scale in 89−91% yields without any
modification of the optimized conditions (Scheme 4).
To validate the reaction pathway, a couple of control
experiments were designed and conducted (Scheme 5). No
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Scheme 5. Control Experiments of Probing the Mechanism
Scheme 6. Reaction Model for Reductive Cyanation of α-
Bromo Ketone 1a Using NCTs as the Cyanating Reagent
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00465.
reaction occurred between tertiary halides and nucleophilic
cyanide (Scheme 5A), precluding the involvement of
nucleophilic substitution. NCTs was inert to zinc dust
reductant in the absence of alkyl halides (Scheme 5B), ruling
out the reductive cleavage of N−CN or C−CN bonds by zinc
dust. When the α-bromo carboxamide was poured into the
zinc dust suspension of DMF for 2 h stirring and then adding
NCTs, similar yield of cyanation product was attained
(Scheme 5C). When using D2O instead of NCTs, deuterated
carboxamide was afforded in high yield and 95% deuterium
incorporation, suggesting the in situ formation of Reformatsky
reagent (Scheme 5D).
In the course of optimizing reaction conditions, the distinct
reactivity of electrophilic cyanation reagents NCTs, MPMN,
and DMMN (entries 1−3 in Table 1) has been observed.
When the α-bromo ketone and esters were utilized as the
substrates, NCTs as the cyanating reagent is more reactive
than MPMN. For the reductive cyanation of the α-bromo
amides, NCTs and MPMN showed the similar reactivity.
These patterns and the intrinsic transient properties of
organozinc intermediates led us to analyze the detailed
reaction mechanism, to investigate the reactivity difference of
cyanating reagent and elucidate the influence of substituent on
cyanation reagent by the tool of density functional theory
(DFT) based theoretical computation.28 Given by the reported
good performance for the description of elimination and
treating the imine system,16b hybrid generalized-gradient-
approximation (GGA) exchange−correlation functional
PBE029 with the D3 version of Grimme’s dispersion
correction30a and Becke−Johnson damping (D3BJ)30b was
adopted in our DFT computation. The distinct reactivity of
different cyanating reagents in the reductive cyanation of α-
bromo ketone and the good reactivity of Reformatsky reagent
derived from ketone 1a with NCTs at room temperature were
revealed (Scheme 6, for detailed description see Supporting
Information).
■
sı
Experimental details, DFT computation, characterization
data, NMR spectra (PDF)
Accession Codes
CCDC 2054231 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Xinxin Tian − Institute of Molecular Science, Key Laboratory
of Materials for Energy Conversion and Storage of Shanxi
Province, Shanxi University, Taiyuan 030006, P. R. China;
Email: tianxx@sxu.edu.cn
Kaiwu Dong − Chang-Kung Chuang Institute, and Shanghai
Key Laboratory of Green Chemistry and Chemical Processes,
School of Chemistry and Molecular Engineering, East China
Normal University, Shanghai 200062, P. R. China;
orcid.org/0000-0001-6250-2629; Email: kwdong@
chem.ecnu.edu.cn
Authors
Xinyi Ren − Chang-Kung Chuang Institute, and Shanghai Key
Laboratory of Green Chemistry and Chemical Processes,
School of Chemistry and Molecular Engineering, East China
Normal University, Shanghai 200062, P. R. China
Chaoren Shen − Chang-Kung Chuang Institute, and Shanghai
Key Laboratory of Green Chemistry and Chemical Processes,
School of Chemistry and Molecular Engineering, East China
Normal University, Shanghai 200062, P. R. China;
orcid.org/0000-0002-2849-7990
Guangzhu Wang − Chang-Kung Chuang Institute, and
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, School of Chemistry and Molecular Engineering,
East China Normal University, Shanghai 200062, P. R.
China
In conclusion, an efficient and convenient route to a variety
of sterically demanding α-cyano ketones, esters, and amides
was established. Various functional groups, including halogen
atom, lactam, amine, ether, alkene, sulfide, sulfone, and borate,
can be well tolerated. Late-stage modification of pharmaceut-
ical and bioactive molecules demonstrated the potential
application of this cyanating method in organic synthesis.
Zhanglin Shi − Chang-Kung Chuang Institute, and Shanghai
Key Laboratory of Green Chemistry and Chemical Processes,
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Site-specific Allylic C-H Bond Functionalization with a Copper-
Bound N-Centred Radical. Nature 2019, 574, 516−521.
School of Chemistry and Molecular Engineering, East China
Normal University, Shanghai 200062, P. R. China
(11) Reformatsky, S. Neue Synthese zweiatomiger einbasischer
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00465
̈
Sauren aus den Ketonen. Ber. Dtsch. Chem. Ges. 1887, 20, 1210−1211.
(12) Hirose, T.; Kodama, K. Recent Advances in Organozinc
Reagents. In Comprehensive Organic Synthesis II, 2nd ed.; Elsevier,
2014; Vol. 1, pp 204−266.
Notes
(13) Baba, A.; Yasuda, M.; Nishimoto, Y. Zinc Enolates: The
Reformatsky and Blaise Reactions. In Comprehensive Organic Synthesis
II, 2nd ed.; Elsevier, 2014; Vol. 2, pp 523−542.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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■
DFT calculation was financially supported by the Natural
Science Foundation of China (No. 21903049 for X.T.). C.S.
thanks Yuan-He Li from Peking University for providing PES
drawing tool EnergyProfiles 3.3.
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