This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 8655–8657 8655

Cite this: Chem. Commun., 2012, 48, 8655–8657

Simple and convenient access to a,a,a-trisubstituted amides by double

addition of Grignard reagents to acyl cyanohydrinsw

Fatma Boukattaya,aAndrii Stanovych,

aPaul Setzer,

aSouhir Abid,

bHoucine Ammar,

b

Morwenna S. M. Pearson-Longaand Philippe Bertus*

a

Received 8th June 2012, Accepted 9th July 2012

DOI: 10.1039/c2cc34841a

The double addition of Grignard (alkyl, aryl, alkenyl, alkynyl)

reagents to acyl cyanohydrins was performed under unusually

smooth conditions with a concomitantO–N acyl transfer, providing

a very simple and general access to a,a,a-trisubstituted amides.

The addition of Grignard reagents to nitriles is a long time

known reaction, leading to ketones in fair to good yields

(Scheme 1).1 As described in most undergraduate textbooks,

the metallated imine intermediate was claimed to be unable to

undergo a second addition. The double nucleophilic addition

to nitriles, leading to a,a,a-trisubstituted amines, was however

attained only in specific cases. Thus, allyl Grignard reagents

have been known since 1939 to add twice to nitriles.2 Besides

aliphatic or aromatic nitriles, a-alkoxynitriles are more reactive3

and a sequential addition of Grignard reagents was performed

with a stoichiometric amount of Ti(Oi-Pr)4.4 Recently, the

method using Ti(Oi-Pr)4 was extended to aliphatic or aromatic

nitriles, but only in the presence of an excess of Grignard

reagent and at reflux of diethyl ether.5 In contrast to Grignard

reagents, organocerium reagents (prepared from RLi and

CeCl3) were able to add twice to various aromatic and aliphatic

nitriles, but this method is limited by the availability of

organolithium reagents.6

During our studies on the titanium-mediated addition of

Grignard reagents to nitriles7 and more especially to protected

cyanohydrins,8 we have shown that treatment of acyl cyano-

hydrins 2 with EtMgBr (2.1 equiv.) and Ti(Oi-Pr)4 in Et2O

afforded 1,4-dicarbonyl compounds 3 (Scheme 2, eqn 1).9

When the reaction was performed with the Grignard reagent

alone (i.e. without Ti(Oi-Pr)4), the expected tertiary alcohol 4

was obtained along with the amide 5 (Scheme 2, eqn 2).

Whereas the alcohol 4 resulted from the addition of the

Grignard reagent to the carboxylate moiety, the formation

of the amide 5 is less trivial. Obviously, the formation of 5

resulted from a two-fold Grignard addition to the nitrile

moiety, along with an acyl transfer. Since this last product

was obtained under outstandingly smooth conditions, and

should be of interest as a direct precursor of a,a-disubstitutedamino acids10,11 and 2-oxazolines,12,13 the optimization of the

conditions favoring the formation of 5 was investigated.

In the optimization phase, the solvent was found to play an

important role in the chemoselectivity of the reaction (Table 1).

When EtMgBr (2.2 equiv.) was added to cyanomethyl benzoate

(2a) in Et2O, the amide 5a was obtained in only 14% yield, the

main byproducts being the alcohol 4a (41%) and propiophe-

none (17%). Other apolar solvents such as toluene and CH2Cl2gave similar results (entries 2 and 3). In contrast, in THF,

the amide 5a was the major product (entry 4). The ratio was

slightly increased by using a Grignard reagent prepared in THF

(entry 5), and by using lower temperature (0 1C or �30 1C,

entries 6 and 7). In order to let the reaction go to completion,

the Grignard reagent was first added at 0 1C, then the reaction

was allowed to warm up to room temperature, and under these

optimized conditions, the amide 5a was obtained in 65%

isolated yield after column chromatography (entry 8). Finally,

1,4-dioxane solvent lies between Et2O and THF, giving an

equimolar mixture of 4a and 5a (entry 9).

Scheme 1 Addition of organometallic reagents to nitriles.

Scheme 2 Grignard addition to acyl cyanohydrins.

a LUNAM Universite, Universite du Maine, CNRS UMR 6283,Institut des Molecules et Materiaux du Mans (IMMM),Avenue Olivier Messiaen, 72085 Le Mans cedex 9, France.E-mail: philippe.bertus@univ-lemans.fr; Fax: +33 2 43 83 39 02

b Laboratory of Applied Chemistry HCGP, Faculty of Science,University of Sfax, 3000 Sfax, Tunisia

w Electronic supplementary information (ESI) available: Experimentalprocedure, characterization data, 1H and 13C NMR spectra ofcompounds 5a–5t. See DOI: 10.1039/c2cc34841a

ChemComm Dynamic Article Links

www.rsc.org/chemcomm COMMUNICATION

Dow

nloa

ded

by L

akeh

ead

Uni

vers

ity o

n 12

Mar

ch 2

013

Publ

ishe

d on

24

July

201

2 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

2CC

3484

1AView Article Online / Journal Homepage / Table of Contents for this issue

8656 Chem. Commun., 2012, 48, 8655–8657 This journal is c The Royal Society of Chemistry 2012

These unusual smooth conditions used for the double

nucleophilic addition to the cyanoester are mostly due to a

synergy between the ester and the nitrile moieties, as illustrated

by the following experiments.

When 2-benzyloxyacetonitrile3,4 was used under the conditions

of Table 1, entry 8, the amine resulting from the double addition

was obtained in low yield (10%), the main product being 1-benzyl-

oxybutan-2-one (6, 74%), underlining the importance of the ester

moiety. Moreover, the addition of EtMgBr (2.2 equiv.) to an

equimolar mixture of ethyl benzoate and 2-benzyloxyacetonitrile

led mainly to the formation of the conventional addition products

(4a and 6) without any trace of 5a, dismissing the possibility of

an intermolecular process. At last, when only one equivalent

of EtMgBr was used, the amide 5a and the starting cyanoester

2a were mainly obtained, indicating that the second addition

of EtMgBr is even faster than the first one.

In the light of the above result, the formation of the amide

can be explained by the following reaction pathway (Scheme 3).

The first addition of the Grignard reagent to the nitrile moiety

leads to a metallated imine A. In the case of aliphatic nitriles,

the metallated imine is poorly electrophilic and the reaction

stops at the first addition.With acyl cyanohydrins, a subsequent

acyl transfer would occur, leading to the formation of the

reactive N-acyl imine intermediate B, which is able to react

with the Grignard reagent, leading to the bismetallated species

C, and 5a after hydrolysis. Thus, this mechanism shows that

the second addition of the Grignard reagent is faster than the

first one, due to the formation of a more reactive electrophilic

intermediate.

Table 1 Solvent effect on the preparation of 5aa

Entry Conditions Yield (4a) Yield (5a) Ratio 4a : 5a

1 Et2O, rt 41 14 2.9 : 12 Toluene, rt 46 14 3.3 : 13 CH2Cl2, rt 48 3 16 : 14 THF, rt 22 59 1 : 2.75 THF, rtb 15 59 1 : 3.96 THF, 0 1Cb,c 8 56 1 : 77 THF, �30 1Cb,c 11 51 1 : 4.68 THF, 0 1C to rtb 16 79 (65) 1 : 4.99 1,4-dioxane, rt 39 36 1.1 : 1

a Yield estimated by the 1H NMR integration and the weight of the

crude product. Isolated yield is in parentheses. b Reaction performed

with EtMgBr prepared in THF (instead of Et2O). c Unreacted 2a was

also observed (8–17%).

Scheme 3 Postulated reaction pathway.

Table 2 Scope of the synthesis of a,a,a-trisubstituted amidesa

Entrya Cyanoester RMgBr Product (yield)

1 MeMgBr

2 2a n-BuMgBr

3 2a PhMgBr

4 2a

5

2a

6

7

8

9

EtMgBr

Ar = p-MeOC6H4 2b

10 Ar = p-BrC6H4 2c

11 EtMgBr

12 EtMgBr

13 EtMgBr

14

15

16

17 EtMgBr

a Reaction conditions: cyanoester (1.0 mmol), Grignard reagent (ca. 1M,

2.2 mmol), THF (5 mL), 0 1C to rt under Ar, 1 h. Isolated yields.

Dow

nloa

ded

by L

akeh

ead

Uni

vers

ity o

n 12

Mar

ch 2

013

Publ

ishe

d on

24

July

201

2 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

2CC

3484

1A

View Article Online

This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 8655–8657 8657

The reaction was performed with a large array of acyl cyano-

hydrins and Grignard reagents as shown in Table 2. Starting from

the cyanoester 2a, the corresponding a,a,a-trisubstituted amides

were obtained in fair to good yields, especially when phenyl-

magnesium bromide is used (entry 3). Heteroaromatic

Grignard reagents are also suitable as shown by the formation

of 5e (entry 4). o-Unsaturated Grignard reagents are particularly

good reagents and give the opportunity of further functionaliza-

tion (entries 5–8). The use of para-substituted aryl cyanoesters 2b

and 2c illustrates the reactivity difference between nitrile and

ester moieties (entries 9 and 10). With a donor group (MeO),

the ester is less electrophilic, and a good yield of 5j is obtained

(ratio 5/4 = 5 : 1). With an attractor group (Br), a lower yield

is obtained for 5k, due to a higher formation of the alcohol 4

(ratio 5/4= 2.5 : 1).14 Cyanoesters bearing aliphatic chains are

tolerated, and are insensitive to substitution, as exemplified by

the formation of amides 5l–n (entries 11–13). Unsaturated

esters are also well tolerated, and lead to polyunsaturated

amides when vinylmagnesium bromide is used (entries 14–16).

Finally, the reaction with 2j, bearing a methyl at the a position

of the nitrile led to a decrease in the yield of the amide, as

exemplified by the synthesis of 5r (entry 17). The concomitant

formation of a large amount of the alcohol 4a shows the steric

sensitivity near the nitrile moiety, leading to a preferential

attack of the Grignard reagent to the ester moiety.

Grignard reagents can also be prepared by metalation or

halogen–metal exchange,15 and diversely substituted amides would

be obtained by this way. For instance, the metalation of terminal

alkynes with EtMgBr followed by the addition of 2a gave the

amides 5s–t bearing two acetylenic units (Scheme 4). Here, the

temperature is important, since 2a was converted into 5s in only

16% conversion after 1 h at rt.

In summary, we have shown that Grignard reagents are able

to add twice to acyl cyanohydrins, via the supposed formation of a

reactive acylimine intermediate. This method represents a cheap,

simple and transition metal-free, access to a,a,a-trisubstitutedamine derivatives, some of them being not accessible by conven-

tional methods, i.e. the alkylation of glycinate Schiff bases.10 These

compounds can be valuable precursors of biologically relevant

compounds, as symmetrically a,a-disubstituted amino acids.

Work is ongoing to understand this unique reactivity and to

delimit the scope of this reaction.

Notes and references

1 M. S. Kharash and O. Reinmuth, Grignard reactions ofnonmetallic substances, Prentice-Hall, New York, 1954; See also:P. Canonne, G. B. Foscolos and G. Lemay, Tetrahedron Lett.,1980, 21, 155; C. G. Savarin, G. N. Boice, J. A. Murry, E. Corley,L. DiMichele and D. Hughes, Org. Lett., 2006, 8, 3903.

2 B. B. Allen and H. R. Henze, J. Am. Chem. Soc., 1939, 61, 1790;H. R. Henze, B. B. Allen and W. B. Leslie, J. Am. Chem. Soc.,1943, 65, 87.

3 H. R. Henze, B. B. Allen and W. B. Leslie, J. Am. Chem. Soc.,1943, 65, 1422; M. Chastrette, G. Axiotis and R. Gauthier, Tetra-hedron Lett., 1977, 23; R. Gauthier, G. P. Axiotis andM. Chastrette, J. Organomet. Chem., 1977, 140, 245.

4 A. B. Charrette, A. Gagnon, M. Janes and C. Mellon, TetrahedronLett., 1998, 39, 5147; A. B. Charrette and A. Gagnon, Tetrahedron:Asymmetry, 1999, 10, 1961.

5 O. Tomashenko, V. Sokolov, A. Tomashevskiy and A. de Meijere,Synlett, 2007, 652; See also: R. Wang, B. T. Gregg, W. Zhang,K. C. Golden, J. F. Quinn, P. Cui and D. O. Tymoshenko,Tetrahedron Lett., 2009, 50, 7070.

6 E. Ciganek, J. Org. Chem., 1992, 57, 4521; A. B. Charrette andC. Mellon, Tetrahedron, 1998, 54, 10525; J. Limanto, B. Dornerand P. N. Devine, Synthesis, 2006, 4143.

7 P. Bertus and J. Szymoniak, Synlett, 2007, 1346.8 P. Bertus and J. Szymoniak, Synlett, 2003, 265; C. Laroche,D. Harakat, P. Bertus and J. Szymoniak, Org. Biomol. Chem.,2005, 3, 3482; P. Bertus, C. Menant, C. Tanguy and J. Szymoniak,Org. Lett., 2008, 10, 777; M. S. M. Pearson-Long, A. Beauseigneur,P. Karoyan, J. Szymoniak and P. Bertus, Synthesis, 2010, 3410.

9 P. Setzer, A. Beauseigneur, M. S. M. Pearson-Long and P. Bertus,Angew. Chem., Int. Ed., 2010, 49, 8691.

10 For reviews dealing with the synthesis and the biological relevanceof a,a-disubstituted a-aminoacids, see: V. A. Soloshonok andA. E. Sorochinsky, Synthesis, 2010, 2319; H. Vogt and S. Brase,Org. Biomol. Chem., 2007, 5, 406; A. Giannis and T. Kolter,Angew. Chem., Int. Ed. Engl., 1993, 32, 1244.

11 For some recent syntheses of a,a-disubstituted a-aminoacids, see:C. Hartmann, T. Baumann, M. Bachle and S. Brase, Tetrahedron:Asymmetry, 2010, 21, 1341; J. S. Dickstein, M. W. Fennie,A. L. Norman, B. J. Paulose and M. C. Kozlowski, J. Am. Chem.Soc., 2008, 130, 15794; S. Cabrera, E. Reyes, A. Milelli,S. Kobbelgaard and K. A. Jorgensen, J. Am. Chem. Soc., 2008,130, 12031; T. K. Ellis, C. H. Martin, G. M. Tsai, H. Ueki andV. A. Soloshonok, J. Org. Chem., 2003, 68, 6208.

12 R. J. Bergeron, Chem. Rev., 1984, 84, 587.13 For some uses of 4,4-disubstituted oxazolines in catalysis, see:

A. Bugarin and B. T. Connell, Chem. Commun., 2011, 47, 7218;S. Trudeau and J. P. Morken, Tetrahedron, 2006, 62, 11470.

14 For a kinetic study of the addition of nucleophiles to aromaticesters, see: I.-H. Um, H.-J. Han, J.-A. Ahn, S. Kang and E. Bunce,J. Org. Chem., 2002, 67, 8475.

15 A. Krasovskiy and P. Knochel, Angew. Chem., Int. Ed., 2004,43, 3333; P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel,F. Kopp, T. Korn, I. Sapountzis and V. A. Vu, Angew. Chem., Int.Ed., 2003, 42, 4302; P. Knochel, A. Krasovskiy and I. Sapountzis,Polyfunctional magnesium organometallics for organic synthesis,in Handbook of Functionalized Organometallic, ed. P. Knochel,Wiley-VCH, Weinheim, Germany, 2005, vol. 1, p. 109.

Scheme 4 Preparation of a,a,a-trisubstituted amides by metalation

of alkynes.

Dow

nloa

ded

by L

akeh

ead

Uni

vers

ity o

n 12

Mar

ch 2

013

Publ

ishe

d on

24

July

201

2 on

http

://pu

bs.r

sc.o

rg |

doi:1

0.10

39/C

2CC

3484

1A

View Article Online