Rhodium-Catalyzed Addition of Aryl Boronic Acids to 2,2-Disubstituted Malononitriles

Article abstract of DOI:10.1002/anie.201703471

β-Ketonitriles bearing a quaternary carbon at the 2-position were prepared through Rh-catalyzed addition of aryl boronic acids to 2,2-disubstituted malononitriles. In contrast to the previously described transnitrilative cyanation of aryl boronic acids with dialkylmalononitriles, the present reaction avoids retro-Thorpe collapse of the intermediate addition product through the use of a milder base. The reaction was amenable to a variety of aryl boronic acids and disubstituted malononitriles, providing a diverse array of β-ketonitriles. The products could be further derivatized to valuable chiral α,α-disubstituted-β-aminonitriles through addition reactions to the corresponding N-tert-butanesulfinyl imines.

Full text of DOI:10.1002/anie.201703471

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201703471
German Edition: DOI: 10.1002/ange.201703471
Homogeneous Catalysis
Rhodium-Catalyzed Addition of Aryl Boronic Acids to 2,2-
Disubstituted Malononitriles
Christian A. Malapit, Donald R. Caldwell, Irungu K. Luvaga, Jonathan T. Reeves,*
Ivan Volchkov, Nina C. Gonnella, Zhengxu S. Han, Carl A. Busacca, Amy R. Howell, and
Chris H. Senanayake
Abstract: b-Ketonitriles bearing a quaternary carbon at the 2-
position were prepared through Rh-catalyzed addition of aryl
boronic acids to 2,2-disubstituted malononitriles. In contrast to
the previously described transnitrilative cyanation of aryl
boronic acids with dialkylmalononitriles, the present reaction
avoids retro-Thorpe collapse of the intermediate addition
product through the use of a milder base. The reaction was
amenable to a variety of aryl boronic acids and disubstituted
malononitriles, providing a diverse array of b-ketonitriles. The
products could be further derivatized to valuable chiral a,a-
disubstituted-b-aminonitriles through addition reactions to the
corresponding N-tert-butanesulfinyl imines.
b-Ketonitriles are valuable compounds in organic syn-
thesis.[1] They may be used in Knoevenagel condensations,[2]
as building blocks for heterocycles,[3] and as components of
copolymers with tunable hydrophilic or hydrophobic proper-
ties.[4] Stereoselective reduction of b-ketonitriles gives access
to chiral b-hydroxynitriles or 1,3-aminoalcohols that have
significant synthetic utility.[5] b-Ketonitriles or their deriva-
tives are present in numerous natural products[6] and phar-
maceuticals.[7]
Figure 1. Methods for 2,2-disubstituted b-ketonitrile synthesis and
reaction pathways for aryl boronic acid addition to malononitriles.
b-Ketonitriles bearing 2,2-disubstitution are less prevalent
than mono- and unsubstituted homologues, most likely due to
the limited methods described for their preparation.[8] The
addition of a,a-disubstituted nitrile anions to acylbenzotria-
zoles was reported by Katritzky and co-workers (Fig-
ure 1A).[9] More recently, Skrydstrup and Beller described
a Pd-catalyzed carbonylative arylation of nitrile anions to give
b-ketonitriles (Figure 1B).[10] We recently reported the Rh-
catalyzed cyanation of aryl boronic acids by a transnitrilation
with dimethylmalononitrile (Figure 1C).[11] We postulated
that this reaction proceeds through initial addition of the aryl
boronic acid to one of the nitrile groups, and subsequent
retro-Thorpe fragmentation of the N-protonated iminonitrile
adduct A to give the aryl nitrile product as well as
isobutyronitrile.[12] During optimization studies for this reac-
tion, we found varying amounts of b-ketonitrile byproduct B
were formed depending on the reaction conditions. The b-
ketonitrile would result from either hydrolysis of adduct A
prior to retro-Thorpe fragmentation, or from a lack of retro-
Thorpe fragmentation of A and subsequent hydrolysis during
workup.[13] Given the potential utility of a one-step synthesis
of valuable 2,2-disubstituted b-ketonitriles from widely avail-
able aryl boronic acids and disubstituted malononitriles, we
re-examined the reaction conditions employed for trans-
nitrilation, with the goal of suppressing the retro-Thorpe
fragmentation pathway and making b-ketonitrile B the
exclusive product (Figure 1D). Herein, we describe the
development of reaction conditions that offer a new dis-
connection for accessing structurally diverse 2,2-disubstituted
b-ketonitriles.
[*] Dr. J. T. Reeves, Dr. I. Volchkov, Dr. Z. S. Han, Dr. C. A. Busacca,
Dr. C. H. Senanayake
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc.
900 Ridgebury Road, Ridgefield, CT 06877-0368 (USA)
E-mail: jonathan.reeves@boehringer-ingelheim.com
Dr. N. C. Gonnella
Material and Analytical Sciences
Boehringer Ingelheim Pharmaceuticals, Inc.
900 Ridgebury Road, Ridgefield, CT 06877-0368 (USA)
C. A. Malapit, D. R. Caldwell, I. K. Luvaga, Prof. Dr. A. R. Howell
Department of Chemistry, University of Connecticut
55 North Eagleville Road, Storrs, CT 06269-3060 (USA)
We began with a screen of parameters in the reaction of
phenyl boronic acid with dimethylmalononitrile to give either
benzonitrile (1) or 2,2-dimethyl-3-oxo-3-phenylpropaneni-
trile (2; Table 1). The optimized conditions for transnitrilation
are given in entry 1 (1 mol% [RhCl(cod)]2, 2 equiv Cs2CO3,
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201703471.
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Table 1: Screening of catalysts and additives, and the effect of temper-
Table 2: Scope with respect to the malononitrile.[a]
ature.[a]
Entry Catalyst
Additive (2 equiv) Yield 1 [%][b] Yield 2 [%][b]
1
2
3
4
[RhCl(cod)]2
Cs2CO3; 1008C
K3PO4
ZnCl2
93 (89)
25
8
7
8
3
5
5
2
5
71
36
30
55
28
30
[RhCl(cod)]2
[RhCl(cod)]2
[RhCl(cod)]2
[RhCl(cod)]2
Rh(nor)2BF4
Rh(cod)2OTf
[Rh(OH)(cod)]2 K3PO4; 1 equiv H2O
[Rh(OH)(cod)]2 i-Pr2NEt
[Rh(OH)(cod)]2 Proton sponge
CuI
5
K3PO4; 1 equiv H2O
K3PO4; 1 equiv H2O
K3PO4; 1 equiv H2O
6[c]
7[c]
8
68 (55)
90
9
10
11
0
0
98 (95)[d]
95[d]
[RhCl(cod)]2
Proton sponge
[a] Reaction conditions: 0.75 mmol PhB(OH)2, 0.50 mmol DMMN,
1 mol% catalyst and 1 mmol additive in 1 mL dioxane at 808C, 20 h.
[b] HPLC assay yields; values in parentheses are isolated yields.
[c] 2 mol% catalyst. [d] Reaction time of 4 h. cod=1,5-cyclooctadiene,
nor=norbornene, Proton sponge=1,8-bis(dimethylamino)naphtha-
lene.
[a] Reaction conditions: 1.5 equiv PhB(OH)2, 1.0 equiv malononitrile,
1 mol% [Rh(OH)cod]2 and 2.0 equiv proton sponge in 2 mL dioxane at
808C, 6 h; yields of isolated product are given. [b] Reaction was done at
1008C. [c] Reaction time of 24 h.
dioxane, 1008C). Under these conditions, the transnitrilation
pathway is predominant, and 1 and 2 are formed in 93% and
5% assay yields, respectively.[11] It was noted that the use of
K3PO4 as the base resulted in a shift towards favoring the b-
ketonitrile product 2 (71% assay yield, entry 2). We thought
the addition of water to the reaction mixture would facilitate
hydrolysis of the putative iminonitrile adduct and potentially
further increase the amount of b-ketonitrile formation.
However, the inclusion of 1 equiv of water in reactions with
different Rh catalysts resulted in reduced assay yields of 2 and
1 (entries 5–8). The use of [RhOH(cod)]2 as the catalyst
provided the best ratio of 2 to 1 of 68:5 (entry 8). A
breakthrough in both yield and selectivity occurred when
organic amine bases were employed instead of inorganic
bases. When Hꢀnigꢁs base was used (entry 9), the b-ketoni-
trile product 2 was formed in 90% assay yield, while only 2%
assay yield of 1 was detected. The best results were obtained
with a proton sponge. Under these conditions, the reaction
was completely selective for 2. With either [RhOH(cod)]2 or
[RhCl(cod)]2 as the catalyst, the reaction was complete after
just 4 h, and 2 was formed in 98% and 95% assay yields,
respectively (entries 10 and 11). Due to the slightly higher
yield obtained with [RhOH(cod)]2, the conditions of entry 10
were chosen as optimal.
With the optimized reaction conditions in hand, the scope
of b-ketonitrile formation was examined with respect to the
dialkylmalononitrile (Table 2). The reaction was compatible
with both cyclic (3–6) and acyclic (7–10) malononitriles,
giving b-ketonitrile products in yields ranging from 68–93%.
The reaction was sensitive to steric hindrance, since reduced
yields were obtained with acyclic malononitriles relative to
the tied-back cyclic malononitriles. The lowest yield of 68%
was observed for the bulkiest malononitrile 9 (product 17), for
which the reaction time was extended from 6 to 24 h. Notably,
the use of mono-substituted malononitrile 10, which bears an
acidic a-proton, was possible and gave b-ketonitrile 18 in
82% yield.
The reaction scope was next explored with respect to
variation of the aryl boronic acid structure (Table 3). The
presence of p-methyl, p-methoxy, p-phenoxy, or m-methoxy
substituents on the aryl boronic acid resulted in excellent
yields of products 19–23. 2-Methoxy substitution of the
boronic acid was tolerated (product 24), though the reaction
was run at increased temperature. The sterically hindered 2,6-
disubstituted product 25 could also be formed in good yield at
1008C. Halogens such as fluoride and chloride were amenable
(products 26 and 27), as were functional groups such as amine
(28), acetamide (29), ester (30), and ketone (31) groups.
Importantly, the presence of the ester and ketone functional
groups would likely not be tolerated by the nitrile anion
carbonylation method of Skrydstrup and Beller.[10] Finally, the
reaction was possible with a heterocyclic boronic acid, giving
indolyl product 32 in 77% yield.
The utility of the b-ketonitrile products was demonstrated
by diastereoselective additions to the derived tert-butanesul-
finyl ketimines to give b-aminonitriles. The requisite keti-
mines were prepared through condensation of (S)-tert-buta-
nesulfinamide with the b-ketonitrile in the presence of neat
Ti(OEt)4 (Scheme 1).[14] Imines 33–35 were obtained as single
geometrical isomers in good yields.
With the b-ketiminonitriles in hand, the diastereoselective
addition of nucleophiles was explored (Table 4). Reduction
with NaBH4 gave b-aminonitrile 36 in > 97:3 diastereoselec-
tivity and 94% yield. The addition of MeLi proceeded in high
yield and diastereoselectivity, giving the a-quaternary-b-
quaternary aminonitrile 37. The production of such a sterically
hindered system in a diastereoselective manner is, to the best
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Table 3: Scope with respect to the aryl boronic acid.[a]
Table 4: Diastereoselective additions to b-(N-tert-butanesulfinylimino)-
nitriles.[a]
[a] Reaction conditions: 1.5 equiv aryl boronic acid, 1.0 equiv malono-
nitrile, 1 mol% [Rh(OH)cod]2 and 2.0 equiv proton sponge in 2 mL
dioxane at 808C, 6 h; yields of isolated product are given. [b] Reaction
was done at 1008C.
[a] Reaction conditions: 1.2–3.0 equiv Nu-M, 1.0 equiv N-tert-butane-
sulfinyl imine, THF, À788C; see the Supporting Information for details;
yields of isolated product are given. [b] Yield of isolated product for the
major diastereomer after purification. [c] Diastereomeric ratio as
1
determined by H NMR of the crude product.
Scheme 1. Conversion of b-ketonitriles into b-(N-tert-butanesulfinylimi-
no)nitriles. Reaction conditions: 1.0 equiv b-ketonitrile, 1.5 equiv (S)-
tert-butanesulfinamide, 6 equiv Ti(OEt)4, 858C, 4 h; yields of isolated
product are given.
sulfinyl ketimines.[15,17,18] The addition of a thiocarbamoyl
anion was also possible, giving thioamide 42 in 72% yield and
> 97:3 diastereoselectivity. Finally, a Mannich-type addition
of tert-butyl acetate lithium enolate proceeded smoothly to
give the b-amino-g-cyanoester 43 in 89% yield and > 97:3
diastereoselectivity.
The proposed mechanism of the Rh-catalyzed b-ketoni-
trile formation is shown in Scheme 2. Transmetallation of the
boronic acid with catalyst A would give the arylrhodium B.
Carbometallation of the malononitrile with B would give the
Rh-ketimine C. Protonolysis of the imine nitrogen would
generate the b-iminonitrile E as well as the rhodium borate D.
Species D could regenerate the arylrhodium B or undergo
hydrolysis to give catalyst A and aryl boronic acid. Due to the
use of a proton sponge as a base instead of Cs2CO3, retro-
Thorpe fragmentation of E does not occur, and the N-H imine
is hydrolyzed during workup to give the b-ketonitrile product
F.
of our knowledge, not easily accomplished by alternative
methods. The addition of lithium phenylacetylide gave adduct
38 in near quantitative yield and > 97:3 diastereoselectivity.
Addition of PhLi gave the differentially arylated adduct 39 in
excellent yield and selectivity. The addition of 2-thienyl-
lithium gave heterocyclic adduct 40 in good yield with 94:6
diastereoselectivity. We described the highly diastereoselec-
tive addition of carbamoyl anions to N-sulfinyl aldimines and
ketimines in 2013.[15] The present b-(N-tert-butanesulfinylimi-
no)nitrile substrates were also compatible with carbamoyl
anion nucleophiles. The addition of N,N-diisopropylcarba-
moyllithium gave the sterically congested a-amino-b-cyano
amide 41 in 79% yield and > 97:3 diastereoselectivity. The
stereochemistry of 41 was confirmed by X-ray crystal
structure analysis and shown to be (S) for the newly formed
stereocenter.[16] This mode of addition is consistent with our
observations for the addition of carbamoyllithiums to N-
In conclusion, we have described the synthesis of b-
ketonitriles through the Rh-catalyzed addition of arylboronic
acids to 2,2-disubstituted malononitriles. This unique discon-
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
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[1] a) M. H. Elnagdi, M. R. H. Elmoghayar, G. E. H. Elgemeie,
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Scheme 2. Proposed mechanism for the rhodium-catalyzed addition of
aryl boronic acids to malononitriles. Ligands on the rhodium were
omitted to simplify the representation.
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[7] F. F. Fleming, L. Yao, P. C. Ravikumar, L. Funk, B. C. Shook, J.
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nection enables the synthesis of structurally diverse b-
ketonitriles with sterically demanding a,a-disubstitution.
The reaction was also possible with a mono-substituted
malononitrile. The process offers complimentary starting
materials compared with the Katritzky[9] and Skrydstrup/
Beller[10] methods, and proceeds under less strongly basic
reaction conditions. The addition of nucleophiles to the
derived N-tert-butanesulfinyl imines gave access to sterically
demanding a,a-disubstituted-b-aminonitriles with high dia-
stereoselectivity.
[8] Selected approaches to b-ketonitriles: a) K. Kiyokawa, T.
Nagata, S. Minakata, Angew. Chem. Int. Ed. 2016, 55, 10458;
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Zhou, J. Xu, Eur. J. Org. Chem. 2014, 6380; e) A. Park, S. Lee,
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Senanayake, Angew. Chem. Int. Ed. 2016, 55, 326; Angew. Chem.
2016, 128, 334.
[12] J. T. Reeves, C. A. Malapit, F. G. Buono, K. P. Sidhu, M. A.
Marsini, C. A. Sader, K. R. Fandrick, C. A. Busacca, C. H.
Senanayake, J. Am. Chem. Soc. 2015, 137, 9481.
[13] Selected Rh-catalyzed additions of boronic acids to nitriles:
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[14] a) M. T. Robak, M. A. Herbage, J. A. Ellman, Chem. Rev. 2010,
110, 3600; b) G. Liu, D. A. Cogan, T. D. Owens, T. P. Tang, J. A.
Ellman, J. Org. Chem. 1999, 64, 1278.
Experimental Section
Typical procedure: Under a nitrogen atmosphere, a mixture of
phenylboronic acid (366 mg, 3.0 mmol), DMMN (188 mg, 2.0 mmol),
[Rh(OH)cod]2 (9.1 mg, 0.02 mmol), and proton sponge (857 mg,
4.0 mmol) in dioxane (4 mL) was stirred at 808C for 4 h. After
cooling, the reaction mixture was partitioned between aqueous 1m
HCl (4 mL) and MTBE, and the layers were separated. The aqueous
phase was extracted twice more with MTBE (4 mL), and the
combined organic phases were dried with anhydrous Na2SO4, filtered,
and then concentrated under reduced pressure. Purification of the
crude residue by silica column chromatography using MTBE/hexane
as the eluent afforded 2,2-dimethyl-3-oxo-3-phenylpropanenitrile 2
(328 mg, 95% yield) as a colorless oil.
[15] J. T. Reeves, Z. Tan, M. A. Herbage, Z. S. Han, M. A. Marsini, Z.
Li, G. Li, Y. Xu, K. R. Fandrick, N. C. Gonnella, S. Campbell, S.
Ma, N. Grinberg, H. Lee, B. Z. Lu, C. H. Senanayake, J. Am.
Chem. Soc. 2013, 135, 5565.
Acknowledgements
We thank Dr. Heewon Lee for HRMS analysis.
[16] CCDC 1540107 (41) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
[17] D. A. Cogan, J. A. Ellman, J. Am. Chem. Soc. 1999, 121, 268.
[18] The stereochemistry of all products in Table 4 was assigned in
analogy to the stereochemistry of adduct 41.
Conflict of interest
The authors declare no conflict of interest.
Keywords: boronic acids · homogeneous catalysis · rhodium ·
sulfinimines · b-ketonitriles
Manuscript received: April 3, 2017
Final Article published: && &&, &&&&
4
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Angew. Chem. Int. Ed. 2017, 56, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Homogeneous Catalysis
C. A. Malapit, D. R. Caldwell, I. K. Luvaga,
J. T. Reeves,* I. Volchkov, N. C. Gonnella,
Z. S. Han, C. A. Busacca, A. R. Howell,
C. H. Senanayake
&&&& — &&&&
Rhodium-Catalyzed Addition of Aryl
Boronic Acids to 2,2-Disubstituted
Malononitriles
All about that base: In the presence of
a Rh catalyst, aryl boronic acids add to
2,2-disubstituted malononitriles to give
b-ketonitriles. A change of base from
Cs2CO3, which was employed in a previ-
ous transnitrilation reaction, to a proton
sponge prevents retro-Thorpe fragmen-
tation of the intermediate b-iminonitrile.
The utility of the b-ketonitriles was dem-
onstrated by highly diastereoselective
additions to the corresponding N-tert-
butanesulfinyl imines.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
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5
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