Nitrile alkylations through sulfinyl-metal exchange

Article abstract of DOI:10.1002/anie.201105630

Triple alkylation: Phenylsulfinyl- and phenylthioacetonitrile can function as trianion equivalents of acetonitrile by sequential alkylation and sulfinyl-metal exchange (see scheme; mCPBA=meta-chloroperoxybenzoic acid). The metalated nitriles alkylate a range of electrophiles to obtain nitriles with quaternary centers. The sulfinyl-metal exchange proceeds under very mild conditions and has a high functional-group tolerance. Copyright

Full text of DOI:10.1002/anie.201105630

Communications
DOI: 10.1002/anie.201105630
Quaternary Carbon Centers
Nitrile Alkylations through Sulfinyl–Metal Exchange**
Dinesh Nath and Fraser F. Fleming*
Nitriles play pivotal roles in a diverse range of pharmaceut-
icals.[1] The nitrile pharmacophore often engages in key
hydrogen bonding, as in the blockbuster drug anastrazole
(1),[2] in other cases a covalent attachment occurs, as in the
anti-diabetic vildagliptin (2, Scheme 1).[3] Syntheses of many
nitrile-containing pharmaceuticals, particularly of those bear-
ing quaternary centers, such as anastrazole[1] and the cyclo-
hexylnitriles levocabastine (3)[4] and cilomilast (4),[5] typically
involve multiple alkylations.
Scheme 2. Multiple alkylations of an acetonitrile trianion equivalent.
M=metal.
sors. Recently reported halogen–metal exchange reactions of
bromo-, iodo-,[12] and even chloronitriles[13] with organo-
lithium and Grignard reagents allow the selective generation
of N-lithiated and C-magnesiated nitriles, respectively. Con-
ceptually, an analogous sulfinyl–metal exchange[14] represents
a significant advance by avoiding the aggressive reagents
typically required for the synthesis of halonitriles, allowing
the performance of two alkylations with mild base, and
introducing a greater functional-group tolerance.
Access to the symmetrical sulfinylnitrile 6a was achieved
by two complementary alkylations[15] of phenylsulfinylaceto-
nitrile[16] (5a; Scheme 3, conditions 1 and 2). In each case, 1,5-
dibromopentane was used as a prototypical bis-electrophile
Scheme 1. Representative nitrile-containing pharmaceuticals.
Most alkylations of nitriles employ alkyllithium or metal
amide bases,[6] in these cases, monoalkylation is often
complicated by overalkylation.[7] A conceptually appealing
solution for multiple controlled alkylations of acetonitrile
includes two sequential alkylations of an activated acetoni-
trile (5!6) with a mild base followed by a functional group/
metal exchange alkylation (6!7!8, Scheme 2). The execu-
tion of this strategy would allow three consecutive alkylations,
require only one equivalent of strong base, and install
quaternary centers, as can be found in numerous nitrile-
containing pharmaceuticals.
Scheme 3. Complementary routes 1, 2, and 3 to sulfinylnitrile 6a.
DMF=N,N-dimethylformamide, LDA=lithium diisopropylamine,
THF=tetrahydrofuran.
because the resulting nitrile 6a contains the core cyclo-
hexylnitrile motif embedded within several nitrile-containing
pharmaceuticals (see 3 and 4 in Scheme 1). Heating 5a and
1,5-dibromopentane with Cs2CO3 to reflux in THF smoothly
provides 6a, whereas the use of NaH in DMF allows the
analogous alkylation at ambient temperature. Alternatively,
the sulfinylnitrile 6a can be prepared by sulfinylating nitrile 9
with methyl phenylsulfinate.[17] Sequential alkylation and
oxidation of phenylthioacetonitrile provides another versatile
route to sulfinyl nitriles that is ideal for nonsymmetrical
substrates (see the Supporting Information for details).[18]
The sulfinyl–metal exchange of 6a is remarkably facile.
iPrMgCl triggers a rapid exchange that is complete within
5 minutes at ꢀ788C.[19] In sequential sulfinyl–magnesium
exchange alkylations, quaternary centers are efficiently
installed by the reaction of the magnesiated nitriles with a
diverse range of electrophiles (Table 1). Carbonyl-containing
ketone, ester, and acid chloride electrophiles all acylate
Metal-exchange reactions[8] usually employ halides,[9]
trialkylstannanes,[10] or sulfoxides[11] as transferrable precur-
[*] D. Nath, Prof. F. F. Fleming
Department of Chemistry and Biochemistry, Duquesne University
Pittsburgh, PA 15282-1530 (USA)
E-mail: flemingf@duq.edu
Homepage: http://www.scienceresearch.duq.edu/chem/chemfac/
ffleming/
[**] Financial support from the National Science Foundation (USA) is
gratefully acknowledged (CHE 1111406, 0808996, 0421252 HRMS,
and 0614785 for NMR facilities).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105630.
11790
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Angew. Chem. Int. Ed. 2011, 50, 11790 –11793

Table 1: Sulfinyl-exchange alkyations of nitriles 6.[a]
Entry Sulfinylnitrile
Electrophile Quaternary nitrile Yield[a] [%]
magnesiated nitriles efficiently (Table 1, entries 1–3 and 15–
17). Diphenyldisulfide (Table 1, entry 4), alkyl halides
(entries 5–6 and 9–14), and benzylidene malononitrile
(entry 8) similarly provide high yields in nucleophilic alkyla-
tions of nitriles.
Cyclic (Table 1, entries 1–13) and acyclic sulfinylnitriles
(entries 14–17) engage in sulfinyl exchange alkylations with
essentially the same efficiencies. The alkylation with isopro-
pyl iodide is particularly interesting because the exchange
installs vicinal tertiary–quaternary centers in 90% yield
(Table 1, entry 6). Unlike lithiated nitriles, the magnesiated
nitrile derived from 6a alkylates propylene oxide to afford
hydroxynitrile 8g without any observable formation of the
lactone that results from internal cyclization (Table 1,
entry 7).[20]
The sulfinyl–magnesium exchange is remarkably tolerant
toward functional groups. Addition of iPrMgCl to a solution
of methyl cyanoformate and the ester-containing sulfinyl
nitrile 6g (Table 1, entry 15) affords the bisester nitrile 8o in
94% yield without observable intramolecular or intermolec-
ular deprotonation or addition to the ester functionality. The
selective generation of a magnesiated nitrile in the presence
of an enolizable carbonyl functionality is highly unusual.[21]
The sulfinyl–magnesium exchange of bisnitrile 6h similarly
allows the selective formation and acylation of a magnesiated
nitrile in the presence of a potentially acidic alkylnitrile
(Table 1, entry 16). The incorporation of a remote chloride
within nitrile 6i does not interfere with the exchange
alkylation, despite the potential for intramolecular alkylation
or elimination (Table 1, entry 17). Functional-group tolerance
is further demonstrated by several in situ exchange alkyla-
tions in which iPrMgCl is added to a solution of the sulfinyl
nitrile and the electrophile in THF at ꢀ788C (Table 1,
entries 1–3, 5, and 15–17). A premature reaction of iPrMgCl
and the electrophile was not observed in any case.
1
2
3
4
5
6
7
6a
6a
6a
6a
6a
6a
6a
8a
8b
8c
8d
8e
8 f
92[b]
91[b]
90[b]
77
92[b]
90
8g
91
8
6a
8h
92
9
6b
6c
8i
8j
93
99
10
11
6d
8k
90
The sulfinylnitrile 6a readily engages in sulfinyl–metal
exchanges with other organometallic compounds (Scheme 4).
Sequential addition of BuLi and cinnamyl bromide efficiently
generates the alkylated nitrile 8r via a lithiated nitrile
intermediate. Lithium butyldiethylzincate[22] triggers a sulf-
oxide–metal exchange to form a putative zincate that acylates
methyl cyanoformate to afford ester nitrile 8b (Scheme 4).
The isolation of both phenylbutylsulfoxide and phenylethyl-
sulfoxide from the reaction indicates that either alkyl group of
the zincate can initiate the exchange.
12
13
6e
6e
8l
92
96
8m
14
15
6 f
8n
8o
94
6g
94[b]
16
17
6h
6i
8p
8q
91[b]
92[b]
[a] Reactions performed by sequential addition of iPrMgCl and electro-
phile to a solution of sulfinyl nitrile in THF at ꢀ788C, unless otherwise
noted. [b] Reaction performed by addition of iPrMgCl to a solution of
electrophile and sulfinyl nitrile in THF at ꢀ788C.
Scheme 4. Sulfinyl–lithium and sulfinyl–zinc exchange reactions.
Angew. Chem. Int. Ed. 2011, 50, 11790 –11793
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Communications
chromatography (EtOAc/hexanes) to afford analytically pure mate-
rial.
The exchange is presumed to occur via the sulfurane 10
(Scheme 5). Prior mechanistic studies of related exchange
processes demonstrate sulfoxide inversion,[23] which is con-
Received: August 8, 2011
Revised: October 12, 2011
Published online: November 4, 2011
Keywords: alkylation · metalation · nitriles · quaternary centers ·
.
sulfinyls
[1] F. F. Fleming, L. Yao, P. C. Ravikumar, L. Funk, B. C. Shook,
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Scheme 5. Sulfinyl–metal exchange mechanism.
sistent with an initial complexation between magnesium and
the sulfoxide oxygen atom, followed by an invertive attack on
the sulfur atom.[24] The interaction between the metal and the
nitrile in sulfurane 10 might transfer the metal from the
oxygen to the nitrogen atom with a minimal build-up of
charge. During the exchange with BuLi, the N-lithiated nitrile
11 would form directly from sulfurane 10. The analogous
exchange with iPrMgCl requires a rapid “conducted tour”[25]
equilibration from the N-magnesiated nitrile 11 (M = MgCl)
to the C-magnesiated nitrile 7 (M = MgCl). Consistent with
this sequence, near-quantitative isolation of iPrSOPh is
observed in all the exchange procedures employing iPrMgCl.
Alkylation products derived from this sulfoxide were not
observed despite the presence of acidic protons in iPrSOPh.
Sulfinylnitriles readily exchange with Grignard reagents,
organolithium reagents, and zincates in highly efficient
metalation–alkylation sequences. The requisite sulfinylni-
triles are prepared by several routes, which include the
consecutive alkylation of phenylsulfinylacetonitrile with
Cs2CO3; this route avoids the use of strong base typically
required in alkylations of alkane nitriles. The sulfinyl–
magnesium exchange is remarkably tolerant toward func-
tional groups and allows alkylations with ester-, nitrile-, and
chloro-substituted sulfinyl nitriles without competitive addi-
tion or deprotonation. A diverse range of electrophiles
efficiently installs quaternary centers as found in numerous
cyclohexylnitrile-containing pharmaceuticals. The sulfinyl–
metal exchange is rapid and allows sequential alkylations of
acetonitrile equivalents under very mild conditions.
[8] For an overview, see: J. Clayden in Organolithiums: Selectivity
for Synthesis, Elsevier, Dordrecht, 2002, chap. 3.
[9] P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F. Kopp,
T. Korn, I. Sapountzis, V. A. Vu, Angew. Chem. 2003, 115, 4438;
Angew. Chem. Int. Ed. 2003, 42, 4302.
[10] C. Rim, D. Y. Son, ARKIVOC 2006, 265.
[11] For a review, see: T. Satoh The Chemistry of Magnesium
Carbenoids in The Chemistry of Organomagnesium Compounds
(Eds.: Z. Z. Rappoport, I. Marek), Wiley, Chichester, 2008,
chap. 16. For recent references, see: a) S. Mitsunaga, T. Ohbaya-
shi, S. Sugiyama, T. Saitou, M. Tadokoro, T. Satoh, Tetrahedron:
Asymmetry 2009, 20, 1697; b) C. B. Rauhut, L. Melzig, P.
Knochel, Org. Lett. 2008, 10, 3891; c) P. R. Blakemore, M. S.
Burge, M. A. Sephton, Tetrahedron Lett. 2007, 48, 3999, and
references therein.
[12] F. F. Fleming, Z. Zhang, W. Liu, P. Knochel, J. Org. Chem. 2005,
70, 2200.
[13] B. R. Pitta, F. F. Fleming, Org. Lett. 2010, 12, 2810.
[14] For a related sulfinyl – magnesium exchange, see: D. C. Cruz, F.
Yuste, E. Dꢁaz, B. Ortiz, R. Sꢂnchez-Obregꢃn, F. Walls, J. L. G.
Ruano, ARKIVOC 2005, vi, 211.
[15] Surprisingly, the alkylation of phenylsulfinylacetonitrile has
been reported only twice to date: a) G. Maitro, G. Prestat, D.
Madec, G. Poli, Synlett 2006, 1055; b) F. Yuste, B. Ortiz, P. J.
Israel, A. Rodriguez-Hernandez, R. Sanchez-Obregon, F. Walls,
J. L. Garcia Ruano, Tetrahedron 2002, 58, 2613.
[16] Readily prepared from thiophenol and chloroacetonitrile fol-
lowed by oxidation with mCPBA: T. Ono, T. Tamaoka, Y. Yuasa,
T. Matsuda, J. Nokami, S. Wakabayashi, J. Am. Chem. Soc. 1984,
106, 7890.
Experimental Section
General deprotonation–alkylation procedure: A solution of the
Grignard reagent (1.05 equiv) in THF was added to a stirred solution
of the sulfinyl nitrile 6 in THF at ꢀ788C. After 5 minutes, neat
electrophile (1.0 equiv) was added to the mixture, the reaction was
allowed to warm to room temperature, and a saturated aqueous
solution of NH4Cl was added. The crude product was extracted with
EtOAc, dried over MgSO4, concentrated, and purified by radial
[17] a) J. E. Resek, A. I. Meyers, Tetrahedron Lett. 1995, 36, 7051;
b) R. Annunziata, M. Cinquini, S. Colonna, F. Cozzi, J. Chem.
Soc. Perkin Trans. 1 1981, 614.
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Angew. Chem. Int. Ed. 2011, 50, 11790 –11793

[18] The strategy was used to prepare sulfinyl nitriles 6g, 6h, and 6i.
[19] T. Satoh, K. Takano, Tetrahedron 1996, 52, 2349.
Alvarez, A. R. Kennedy, M. D. McCall, Proc. Natl. Acad. Sci.
USA 2010, 107, 5294.
[20] S. K. Taylor, D. De Young, L. J. Simons, J. R. Vyvyan, M. A.
Wemple, N. K. Wood, Synth. Commun. 1998, 28, 1691.
[23] a) T. Shibutani, H. Fujihara, N. Furukawa, Heteroat. Chem. 1991,
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LeBelle, R. van den Elzen, K.-C. Tin, Can. J. Chem. 1974, 52,
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[24] Nucleophilic attack on the sulfoxide may proceed through a s-
sulfurane intermediate or transition structure; a) C. Cardellic-
chio, V. Fiandanese, F. Naso, J. Org. Chem. 1992, 57, 1718;
b) J. G. Tillett, Chem. Rev. 1976, 76, 747.
[21] For a sole example with a magnesiated nitrile, see Ref. [13], and
for examples involving transition metals, see: a) A. Recio, J. A.
Tunge, Org. Lett. 2009, 11, 5630; b) A. Goto, K. Endo, Y. Ukai, S.
Irle, S. Saito, Chem. Commun. 2008, 2212; c) N. Kumagai, S.
Matsunaga, M. Shibasaki, Tetrahedron 2007, 63, 8598; d) L. Fan,
O. V. Ozerov, Chem. Commun. 2005, 4450.
[22] Prepared by addition of BuLi to Et2Zn; a) S. Merkel, D. Stern, J.
Henn, D. Stalke, Angew. Chem. 2009, 121, 6468; Angew. Chem.
Int. Ed. 2009, 48, 6350; b) E. Hevia, J. Z. Chua, P. Garcia-
[25] P. R. Carlier, Chirality 2003, 15, 340.
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