Reductive C?C Coupling from α,β-Unsaturated Nitriles by Intercepting Keteniminates

Article abstract of DOI:10.1002/anie.201904530

We present an atom-economic strategy to catalytically generate and intercept nitrile anion equivalents using hydrogen transfer catalysis. Addition of α,β-unsaturated nitriles to a pincer-based Ru?H complex affords structurally characterized κ-N-coordinated keteniminates by selective 1,4-hydride transfer. When generated in situ under catalytic hydrogenation conditions, electrophilic addition to the keteniminate was achieved using anhydrides to provide α-cyanoacetates in high yields. This work represents a new application of hydrogen transfer catalysis using α,β-unsaturated nitriles for reductive C?C coupling reactions.

Full text of DOI:10.1002/anie.201904530

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Accepted Article
Title: Reductive C-C Coupling from α,β-Unsaturated Nitriles by
Intercepting Keteniminates
Authors: Lillian V. A. Hale, N. Marianne Sikes, and Nathaniel Kolnik
Szymczak
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201904530
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10.1002/anie.201904530
Angewandte Chemie International Edition
COMMUNICATION
Reductive C–C Coupling from α,β-Unsaturated Nitriles by
Intercepting Keteniminates
Lillian V. A. Hale,‡ N. Marianne Sikes,‡ and Nathaniel K. Szymczak*[a]
Abstract: We present a new atom economic strategy to catalytically
generate and intercept nitrile anion equivalents using hydrogen
transfer catalysis. Addition of α,β-unsaturated nitriles to a pincer-
based Ru–H complex affords structurally characterized κ-N-
coordinated keteniminates via selective 1,4-hydride transfer. When
generated in situ under catalytic hydrogenation conditions,
electrophilic addition to the keteniminate was achieved using
anhydrides to afford α-cyanoacetates in high yields. This work
represents a new application of hydrogen transfer catalysis for
selective 1,4 addition to α,β-unsaturated nitriles.
Despite the potential for rapid multi-functionalization, this mode of
activation is virtually unexplored for catalytic applications.
To contextualize the significance of expanding the pool of
available pro-nucleophiles, it is useful to compare with well-
established enolate chemistry; identifying new catalytic routes to
form enolates or silyl enol ethers in situ has led to significant
advances in selective reduction[6] and reductive C–C bond
forming reactions.[7] In particular, Krische and co-workers have
developed reductive C–C coupling reactions using hydrogen
transfer catalysts and π-unsaturated substrates.[7c;7e] They
reported that under catalytic hydrogenation conditions, α,β-
unsaturated ketones generate enolates capable of participating in
aldol condensations (Scheme 1b).[7b] Our current work parallels
these discoveries based on α,β-unsaturated ketones and is the
first example of using alkenyl nitriles as pro-nucleophiles for
hydrogenative C–C bond forming reactions.
Nitrile anions are a diverse class of synthetic intermediates
that provide access to highly functionalized products through
nucleophilic addition and substitution reactions.[1] Analogous to
enolates, nitrile anions are ambident nucleophiles that can react
either as carbanions to provide α-functionalized cyano
products,[1b-d] or as keteniminates to provide neutral
ketenimines.[1d;2] Each product class has further synthetic utility as
building blocks for natural products and pharmaceuticals; while α-
cyano groups are easily derivatized, ketenimines further undergo
nucleophilic, electrophilic, and/or cyclization reactions. To access
the diverse chemical space of these nitrogen containing
compounds, new methods to generate and control the reactivity
of nitrile anions are highly desirable.
(a) metalated nitriles generated from alkyl and alkenyl nitrile pro-nucleophiles
[M]
[M]
[M]–Base
[M]–H
N
R1
CN
CN
C
NC
R1
R2
alkyl nitrile
deprotonation
alkenyl nitrile
conjugate addition
R2
not reported
(b) hydrogenative C–C coupling using -unsaturated pro-nucleophiles
The synthetic utility of nitrile anions is hindered by a lack of
catalytic strategies available to generate them in situ from simple
pro-nucleophiles.[1b;1c;3] Alkyl nitriles are currently the major
precursors to C- or N-metalated nitriles used in catalytic
prior art: reductive generation of enolates for aldol condensation
via
O
OH
O
O
[Rh]
[Rh]
H2
O
transformations
(Scheme
1a,
left).[1c]
Base-assisted
+
R1
R2
R1
R1
H
R2
deprotonation of alkyl nitriles with transition-metal catalysts has
been successfully applied in a number of α-functionalization
reactions; however, significant challenges remain. Methods that
deliver products with all-carbon quaternary centers and/or occur
with high stereoselectivities are rare.[1b;1c;4] These challenges may
be addressed by designing new catalytic methods using pro-
nucleophiles with distinct modes of activation. α,β-Unsaturated
nitriles can generate nitrile anions through conjugate addition
(Scheme 1b, right) and are easily accessed from the
corresponding ketone, aldehyde, or alkene in a single step.[5]
CH3
enolate
CH3
precursor
this work: reductive generation of keteniminates for -cyanoalkylation

O
via
H
[Ru]
N
CN
R1
O
[Ru]–H
H2
H
H
CN
R3
+
R2
C
R3
2O
R2
R1
R2
R1
keteniminate
precursor
Scheme 1. (a) Formation of nitrile anions with alkyl nitrile or alkenyl nitrile pro-
nucleophiles. (b) Hydrogen mediated reductive coupling using π-unsaturated
substrates.
Lillian V. A. Hale, N, Marianne Sikes and Prof. Nathaniel K. Szymczak
Department of Chemistry
University of Michigan
930 N. University, Ann Arbor, MI 48109
E-mail: nszym@umich.edu
Although nitriles may undergo insertion into metal-hydrides
to afford imine type products,[8] a second site of unsaturation may
promote isomerization to form the resonance stabilized nitrile
[‡] These authors contributed equally
anion/keteniminate.
HRu(bMepi)(PPh3)2
We
(1,
previously
bMepi
reported
1,3-bis(6ʹ-methyl-2ʹ-
that
=
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10.1002/anie.201904530
Angewandte Chemie International Edition
COMMUNICATION
pyridylimino)isoindoline)) is an excellent catalyst for reversible
hydrogen transfer reactions of alcohols and amines.[9] For nitrile
substrates, hydride insertion readily occurs to form imine
coordinated species, and the catalytically active Ru–H can be
directly (re)generated from H2. 1 exhibits unique reactivity with
amines and nitriles, and has a high binding affinity for the
intermediate imine.[9d;10] We hypothesized that this reactivity
would provide an entry point for evaluating hydrogenative C–C
coupling with α,β-unsaturated nitriles.
We evaluated the insertion chemistry of α,β-unsaturated
nitriles to Ru–H through stoichiometric addition of α-
phenylcinnamonitrile (2a) to 1 (Scheme 2). When 2a (1.2 equiv)
was added to a toluene-d8 solution of 1 at room temperature,
quantitative conversion to a new species occurred within 5
minutes. 31P NMR spectroscopy confirmed the disappearance of
1 (51 ppm), concomitant with the appearance of free PPh3 and a
new resonance at 39 ppm. 1 was also absent in the 1H NMR
spectrum, with no detectable H2 or hydride-containing byproducts,
consistent with a hydride insertion reaction. A phase sensitive 1H–
13C correlation experiment (HSQC) revealed the presence of a –
CH2 group (1H δ: 3.20; 13C δ: 34.7), consistent with hydride
addition to the least substituted carbon of α-phenylcinnamonitrile
(Figure S5).
X-ray diffraction of single crystals unambiguously confirmed
the insertion product as the Ru-keteniminate complex 3a. The N-
coordinated keteniminate has an elongated C1−N1 bond of
1.190(7) Å and a shortened C1–C2 bond length of 1.369(7) Å.
Analysis by IR spectroscopy revealed a bathochromic shift in the
C–N stretching frequency between 2a (νCN = 2218 cm-1) and 3a
(νCN = 2210 cm-1), consistent with C–N bond elongation upon
formation of the C2=C1=N1 unit. These bond distances and IR
frequencies are consistent with known metal-keteniminate
complexes and reflect the electronic delocalization from the
partially negative C2 atom into the adjacent C1–N1 group.[11][12][13]
A distinct feature of 3a is the bent Ru–N1–C1 angle (= 141°),
which is highly unusual for metalated keteniminates — only four
structurally characterized keteniminate complexes exhibit M–N–
C1 angles <145°.[14],[13;15] Moreover, all reported κ-N-Ru-
keteniminate complexes exhibit nearly linear coordination (Ru–
N1–C1 Avg. 173°).[16] In addition to a base-free route to form a
keteniminate, the unique binding mode to Ru offers a new
framework to develop subsequent reactivity.[17]
The linear geometry of substituted keteniminates allow for
facile electrophilic additions to the C2 site, resulting in products
with new all-carbon quaternary centers. Highly substituted
carbons are desirable motifs for drug design and multi-step
syntheses.[18] When the electrophile is a carbonyl or acetate
group, the resulting α-cyano compounds can be modified at either
functional group to provide pharmaceutically relevant structural
cores.[19] The most common entry point into α-cyano carbonyl
products are through lithiated alkyl nitriles; however, in most
cases, stoichiometric addition of lithium diisopropylamide (LDA)
or n-BuLi is required to unmask the nucleophilic carbon.[4a;20] Silyl
ketenimines are precursors to quaternary α-cyano carbonyl
groups; however, stoichiometric base is also required.[2f]
Interception of Ru-keteniminates with a carbonyl electrophile
under hydrgonative reductive coupling conditions could provide α-
functionalized cyano compounds while avoiding stoichiometric
waste (eq 1).
The addition of carbonyl electrophiles to α,β-unsaturated
nitriles in the presence of H2 presents a key challenge: both C=C
and C≡N groups are susceptible to hydrogenation using 1. Prior
to evaluating reductive coupling with 2a, we interrogated
hydrogenation reactivity using H2 (100 psig) and 1 (1 mol %)
(Table 1, entry 1). Complete hydrogenation of 2a (0.25 mmol) to
amine 6a occurred at 80 °C.[21] Reductive C–C coupling was
evaluated using anhydrides based on the precedent for their
electrophilic addition to α-cyano carbanions.[2f;22] When di-tert-
butyl dicarbonate (Boc2O,
1 equiv) was added to the
hydrogenation reaction above under analogous conditions
(80 °C), acylation of 2a occurred to provide 4a in 29% yield and
the remaining mixture (71%) was composed of hydrogenation
products 5a and 6a (entry 2). Hydrogenative acylation was
promoted with the addition of base, where 10 mol % LiOtBu at
80 °C increased the selectivity for 4a over hydrogenation products
(53:47; entry 3). Further optimization revealed that a higher
temperature (100 °C), catalyst loading (2 mol % 1) and
concentration of Boc2O (4 equiv) improved acylation selectivity,
affording 4a in 70% chemical yield (entry 4).
PPh3
N
N
N
HRu(bMepi)(PPh3)2
N
Ru1
N1
Ru
CN
N
toluene-d8
H
25 °C, < 5 min
C1
PPh

3
N
C
> 99% NMR yield
(78% isolated)
C2
2a
(1.2 eq)
3a
H
H
Ru1-N1-C1 = 141


Scheme 2. Formation of Ru-keteniminate 3a via selective 1,4-hydride transfer.
The solid-state structure is displayed with 50% probability ellipsoids. PPh3
phenyl groups and hydrogen atoms, except for the –CH2 group, are omitted for
clarity.
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10.1002/anie.201904530
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COMMUNICATION
2g (R1 = H, R2 = CH3) using DBU and (C6H5CO)2O. In contrast,
di-substituted 2,3-dimethylacrylonitrile (2h, R1 = R2 = CH3) was
reactive toward acylation with (C6H5CO)2O at 100 °C to provide
4h (81%).
Table 1. Hydrogenative acylation of 2a with 1. Conversion and product
ratios were determined by NMR analysis with PhSi(CH3)3 as an internal
standard.
1 (2 mol %)
H2 (100 psig)
O
CN
R1
O
DBU (10 mol %)
toluene
+
R3
R2
R3
2O
100 C, 15 h


R1 CN
4a-4h
R2
2a-2h
(4 equiv)
O
O
O
tBuO
tBuO
tBuO
Entry
Temp
(°C)
Additive
(10 mol %)
Anhydride
% conv
4:5+6
CN
CN
CN
X2
1a
80
80
None
None
LiOtBu
LiOtBu
None
DBU
None
Boc2O
>99
>99
>99
>99
>99
>99
>99
>99
0:99
29:71
53:47
70:30
93:7
X1
X1 = OMe 4b, 83%
4a, 95%
X2 = OMe 4d, 78%
X2 = CF3 4e, 85%
2b
3b
4c
5c
6c
7
X1 = CF3 4c, 74%
O
O
O
80
Boc2O
Ph
Ph
Ph
CN
CN
4h, 81%
CN
100
100
100
100
100
Boc2O
a4f, 84%
a4g, 79%
(CF3CO)2O
Boc2O
Scheme 3. Synthesis of α-cyanoacetates 4a-4h with Boc2O or ((C6H5CO)2O),
DBU and 1. Isolated yields following chromatography are reported. aReaction
performed at 150 °C in mesitylene.
95:5
DBU
Ac2O
89:11
92:8
8
DBU
(C6H5CO)2O
Finally, we examined the functional group compatibility of
the hydrogenative acylation reaction using 1 in the presence of
several common functional groups (eq 2, Table 2).[25] Using 2e
and Boc2O, the NMR yield of 4e was assessed under standard
conditions in the presence of potentially reactive additives.
Notably, most additives tested did not decrease the yield of 4e
(entries 2-6). One limitation, however, was the incompatibility with
hydrogen acceptors such as 2-vinylnaphthalene (entry 7),
consistent with competitive hydrogenation by 1.
areaction conditions: 1 (1 mol %) b reaction conditions: 1 (2 mol %), Boc2O
(2 equiv). creaction conditions: 1 (2 mol %), Boc2O or (CF3CO)2O (4 equiv)
The improved selectivity toward acylation with the addition
of LiOtBu may be due to 1) base-assisted H2 heterolysis, or 2)
electrophilic activation of Boc2O by Li+. To determine whether a
more activated electrophile further improves the reaction
selectivity, we evaluated trifluoracetic anhydride (CF3CO)2O) in
place of Boc2O. Under base-free conditions, (CF3CO)2O provided
excellent selectivity for the acylated product 4a′ (93: 7, entry 5).
Anhydride reagents with decreased reactivity (such as Boc2O)
may be further activated with an appropriate nucleophile to
promote hydrogenative acylation. We previously identified 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) as a compatible base
under hydrogenation conditions with 1.[23] When DBU was used in
place of LiOtBu to activate Boc2O, the selectivity for 4a
dramatically improved (95:5, entry 6). These data indicate that the
electrophilicity of the acylating agent influences reaction
selectivity. Finally, the reductive acylation reaction is general to
several representative anhydride reagents and, in addition to
Boc2O and (CF3CO)2O, we observed high yields using both acetic
anhydride (89%, entry 7) and benzoic anhydride (92%, entry 8).[24]
To assess the reaction scope and functional group
compatibility, we examined α,β-unsaturated nitriles 2b-2h with
varying aryl and alkyl substitution (Scheme 3). Under optimized
conditions with DBU and Boc2O, diaryl α-cyanoacetates 4a-4e
were obtained in high isolated yields ranging from 78-95%. Alkyl
substitution was also tolerated, although higher temperatures
(150 °C) were required to obtain 4f (84%) and 4g (79%) from
monoalkyl substituted alkenyl nitriles 2f (R1 = H, R2 = C6H6) and
Table 2. Compatibility screening for hydrogenative acylation of 2e in the
presence of additives (1 equiv) containing common functional groups. R3
=
OtBu. Yields were determined by NMR spectroscopy using PhSi(CH3)3 as
an internal standard.
Entry
Additive (1 eq)
None
% conv
>99
% yield
86
1
2
3
4
N-benzylpyrrole
2,4,6-collidine
methyl benzoate
>99
88
>99
88
>99
86
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10.1002/anie.201904530
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COMMUNICATION
Acknowledgments
5
N-methyl-N-
phenylacetamide
>99
87
This work was supported by the NSF (CHE-1350877 to N.K.S and
CHE 1625543 for the X-ray diffractometers). L.V.A.H. and N.M.S
acknowledge funding from a Rackham Graduate Student
6
7
chlorobenzene
>99
57
86
0
2-vinylnapthalene
Research Grant. N.K.S. is a Camille and Henry Dreyfus Fellow.
Keywords: keteniminate • ruthenium • α,β-unsaturated nitriles •
Because saturated nitriles are products under
hydrogenative acylation • catalytic reductive C–C coupling
hydrogenation conditions with 1 and α,β-unsaturated nitriles, a
feasible pathway to α-cyanoacetate products may first involve
C=C hydrogenation followed by deprotonation of the acidic α-C–
H bond (by base or 1) prior to acylation. To evaluate this
possibility, we subjected saturated nitrile 5a to our reaction
conditions (Scheme 4). No 4a was formed as assessed by NMR
spectroscopy (see Figures S54-56). This suggests that 5a does
not undergo a base-assisted acylation. We attribute this result to
competitive activation of the Boc2O by DBU compared to
deprotonation.[26] We also found that stoichiometric reactions
between 3a and Boc2O quantitatively affords 4a, and that 3a is a
competent pre-catalyst. Under analogous conditions, 3a provided
identical yields of 4a compared to reactions employing 1,
consistent with the intermediacy of 3a during catalysis.
Collectively, these results suggest that 1 provides a unique entry
point to nitrile anions for catalysis, which is distinct from the
previously reported deprotonation pathways of alkyl nitriles.
Selective 1,4-hydride addition to α,β-unsaturated nitriles is a key
step for generating catalytically competent keteniminate
intermediates for hydrogenative C–C coupling reactions.
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(a) R. R. Huddleston, M. J. Krische, Org. Lett. 2003, 5, 1143-1146; (b)
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Scheme 4. Acylation of 5a does not proceed under reductive C–C coupling
conditions with 1 and DBU.
This work has introduced a new strategy to use catalytic
hydrogen mediated reductive coupling to generate and intercept
nitrile nucleophiles. Hydride transfer to α,β-unsaturated nitriles
from 1 affords Ru-keteniminates that can be converted to α-
cyanoacetate products under a H2 atmosphere using catalytic
DBU and 1. Hydrogenative acylation enables the use of α,β-
unsaturated nitriles as a new substrate class to access products
containing all-carbon quaternary centers. Mechanistically distinct
modes of nitrile activation are needed to discover new reactivity
that parallels their oxygen containing counterparts. We predict
that the diverse reactivity available to keteniminates and nitrile
carbanions may be accessible following H− insertion by 1 to α,β-
unsaturated nitriles. Current work is focused on exploring the
scope in substrate and electrophile, as well as enantioselective
acylation protocols.
[8]
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Chem. Soc. 2013, 135, 16352-16355; (c) K.-N. T. Tseng, S. Lin, J. W.
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COMMUNICATION
[12] Hydride insertion to afford Ru-coordinated keteniminates with similar
spectroscopic features was general for other α-phenyl substituted alkenyl
nitriles. For instance, varying the para substituent of either phenyl group
with OMe or CF3 provided Ru-keteniminate products with similar IR
stretches and 1H, 31P, and 13C resonances to 3a (See SI, section III).
[13] L. Becker, M. Haehnel, A. Spannenberg, P. Arndt, U. Rosenthal, Chem.
Eur. J. 2015, 21, 3242-3248.
[14] Cambridge Structural Database, version 5.38, August 2018
[15] (a) D. A. Culkin, J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 9330-9331;
(b) K. Chainok, S. M. Neville, C. M. Forsyth, W. J. Gee, K. S. Murray, S.
R. Batten, CrystEngComm 2012, 14, 3717-3726; (c) W. X. Jing-Min Shi,
Su-Qiao Lu, Chang-Ju Wu, Jie-Chao Ge, Zhi-De Zhang, Chinese J.
Struc. Chem. 2002, 640-642.
[16] For comparison, N-aryl and N-alkyl ketenimines typically have C–N–R (R
= Ar or alkyl) bond angles between 117-129°. See reference 11a
[17] No reactivity studies have been reported based on known discrete Ru-
ketenimine complexes. 3a was investigated using density functional
theory. See SI for the optimized structure, NBO analysis, and depiction
of the HOMO for 3a (Figure S11-S12).
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10.1002/anie.201904530
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Lilian V. A. Hale, N. Marianne Sikes, and
Nathaniel K. Szymczak*
Page No. – Page No.
Reductive C–C Coupling from α,β-
Unsaturated Nitriles by Intercepting
Keteniminates
We present a new application of hydrogen transfer catalysis to intercept
keteniminate intermediates from α,β-unsaturated nitriles for a net hydrogenative
acylation reaction.
This article is protected by copyright. All rights reserved.