Arylthio-metal exchange of α-arylthioalkanenitriles

Article abstract of DOI:10.1021/ol403020s

The addition of BuLi, Bu₃MgLi, Et₂ZnBuLi, or Me ₂CuLi to α-arylthioalkanenitriles triggers an arylthio-metal exchange. NMR spectroscopic analyses implicate organometallic attack on sulfur forming a three-coordinate sulfidate as the key intermediate. Electrophilic trapping affords tertiary and quaternary nitriles in high yield. The method addresses the challenge of improving the functional group tolerance and preventing polyalkylations.

Full text of DOI:10.1021/ol403020s

Letter
pubs.acs.org/OrgLett
Arylthio-Metal Exchange of α‑Arylthioalkanenitriles
Dinesh Nath,† Melanie C. Skilbeck,‡ Iain Coldham,‡ and Fraser F. Fleming*,†
†Department of Chemistry & Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282-1530, United States
‡Department of Chemistry, University of Sheffield, Sheffield S3 7HF, U.K.
S
* Supporting Information
ABSTRACT: The addition of BuLi, Bu3MgLi, Et2ZnBuLi, or Me2CuLi to α-
arylthioalkanenitriles triggers an arylthio-metal exchange. NMR spectroscopic
analyses implicate organometallic attack on sulfur forming a three-coordinate
sulfidate as the key intermediate. Electrophilic trapping affords tertiary and
quaternary nitriles in high yield. The method addresses the challenge of
improving the functional group tolerance and preventing polyalkylations.
etalated nitriles are powerful nucleophiles ideally suited
for sterically demanding alkylations.1 The exceptional
nucleophilicity originates from the nitrile’s small cylindrical
diameter2 and the high charge density on the formally anionic
carbon.3 The combination of small steric demand4 and high
nucleophilicity permits challenging alkylations even in cases
where comparable enolate alkylations are unsuccessful.5
Deprotonating alkanenitriles 1 with lithium amide bases
generate N-lithiated nitriles 2 in which the nitrile nitrogen is
coordinated to lithium (Scheme 1).1 A complementary
recently11 the development of arylsulfide-based exchange
reactions stalled, perhaps because preferential attack of the
organometallic on resident functionality can circumvent the
exchange.12
Arylthioalkanenitriles are attractive metalated nitrile pre-
cursors13 because deprotonation is facile,14 unlike sulfinylni-
triles15 they do not readily eliminate, and many are
commercially available or easily synthesized.16 Exploratory
forays employed arylthioalkanenitriles 7 that were readily
prepared by double alkylation of arylthioacetonitriles 6
(Scheme 2) or by sulfenylation of the corresponding
M
Scheme 1. Metalated Nitrile Syntheses
Scheme 2. Arylthioalkanenitrile Syntheses
alkanenitrile 8. These two strategies readily provided four-
through six-membered phenylthio-, o-methoxyphenylthio-, and
2-pyridinethiocarbonitriles.
Initial sulfide−metal exchange reactions employed phenyl-
thiocyclohexanecarbonitrile (7c) as a prototype because six-
membered nitriles feature in mechanistic studies17 and are a key
motif in several nitrile containing pharmaceuticals.18 Although
7c did not react with i-PrMgCl, even after 12 h at rt, BuLi
caused a complete exchange at −78 °C in less than 5 min.
Trapping the intermediate with benzyl bromide affords the
quaternary nitrile 3c in 98% yield (Figure 1). Presuming that
the successful exchange with BuLi stems from an increased
nucleophilicity relative to i-PrMgCl, the phenylthionitrile 7c
was treated with the magnesiate Bu3MgLi derived from Bu2Mg
and BuLi.19 Minimal exchange occurs at −78 °C, but warming
to room temperature allowed complete exchange after 1 h.
Cooling the reaction to −78 °C and addition of benzyl bromide
gave nitrile 3c in 86% yield.
approach to metalated nitriles employs an exchange with a
substituted nitrile 4, which allows selective generation of N-
metalated nitriles 2 or C-metalated nitriles 5. Organometallic
addition to α-haloalkanenitriles6 (4, Y = Cl, Br, I) or α-
sulfinylnitriles7 (4, Y = PhSO) provides N- or C-metalated
nitriles even in the presence of acidic esters, enoates, and
nitriles.7 Despite the versatility of exchange-based syntheses of
metalated nitriles, several challenges remain: greater precursor
stability, improved functional group tolerance, and increased
organometallic diversity.
Arylsulfides are attractive exchangeable groups because
arylsulfides are readily manipulated, tolerate numerous
reagents, and readily exchange with organometallics.8 Arylsul-
fides first served as organometallic precursors in the
serendipitous attack of NaSPh on a phenylthio ketone,9 and
were subsequently used to generate lactone enolates not
accessible by conventional metal amide deprotonation.10 Until
Received: October 21, 2013
© XXXX American Chemical Society
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a
Figure 2. Sequential ArS-lithium exchange alkylation. The reaction
was allowed to warm to rt over 2 h prior to addition of NH4Cl.
Addition of NH4Cl at −78 °C affords 3l (36%) and the uncyclized
isomer (49%).
a
Figure 1. Sequential PhS-lithium exchange alkylation. An 86% yield
was obtained when the exchange was performed with Bu3MgLi.
diagnostic for the coordination mode: N-lithiated nitriles
resonate downfield (δ = 142−164)20 whereas C-metalated
nitriles typically resonate upfield (δ = 120−140).21 The
addition of BuLi to 7c generates a signal for the nitrile carbon
at δ = 128.9, significantly upfield from that of lithiated
cyclohexanecarbonitrile (2c, δ = 163.6),22 and consistent with
formation of sulfidate 10c.
The efficiency of the exchange−alkylation of 7c with propyl
iodide to afford 3g in 87% yield (Figure 1) suggests that the
alkylation does not proceed through the sterically congested
sulfidate 10c. Although the sulfidate is the major solution
species, an equilibrium may exist with a small fraction of the
more nucleophilic lithiated nitrile 2c from which alkylation
occurs. The existence of an equilibrium between the sulfidate
and an N-lithiated nitrile was probed by preparing the lithiated
cyclohexanecarbonitrile 2c (Scheme 3) and adding butylphe-
nylsulfide. The diagnostic nitrile carbon signal at δ = 163.6 in
2c shifts upfield to δ = 128.3, close to the normal range for
neutral cyclohexanecarbonitriles (δ = 118−127).23 Consistent
with the rapid sulfidate-N-lithiated nitrile equilibration is the
loss of configuration at the nitrile-bearing stereocenter during
the exchange and benzylation of the norbornene carbonitrile
diastereomers 7f and 7g which converge to a single
stereoisomer 3h (eq 2).
Upon adopting BuLi as the optimal organometallic, a series
of phenylthioacetonitriles were subjected to the exchange and
alkylated with an array of electrophiles (Figure 1). Sequential
exchange−benzylations with four-, five-, and six-membered
phenylthioalkanenitriles afforded the benzyl-substituted nitriles
3a−c in uniformly excellent yield. Using the phenylthionitrile
7c as a prototype and varying the electrophile allowed
alkylations with reactive alkylbromide and carbonyl electro-
philes (3d−f) as well as with less reactive propyliodide (3g).
Modulating the electronic environment of the aryl sulfide
does not influence the exchange−alkylation efficiency.
Sequential treatment of the electron-rich 2-methoxyphenylsul-
fide 7d with BuLi and BnBr gave nitrile 3c in 91% yield (eq 1),
virtually the same yield as the phenyl sulfide (98%, Figure 1),
together with sulphide 9a.
Exchange−alkylations with the electron-deficient 2-pyridine-
thiocarbonitriles are particularly efficient (Figure 2). Sequential
treatment of 2-pyridinethiocarbonitriles with BuLi and alkyl
halide or carbonyl electrophiles efficiently installs quaternary
centers in 3c and 3i−l.
Mechanistically, adding BuLi to an arylthioalkanenitrile could
trigger an SN2 type displacement passing through a
tricoordinate sulfur as a transition state or as a discrete
intermediate (Scheme 3). Insight into the mechanism was
obtained by acquiring 13C NMR spectra from a −78 °C, THF
solution of 7c to which BuLi was added. Particularly revealing is
the signal for the nitrile carbon because the chemical shift is
A series of competitive sulfide exchanges were performed to
determine the relative exchange rates of phenylthio, 2-
pyridinethio, and 2-methoxyphenylthio substituents.24 The
exchange rate decreases in the order 2-pyridylsulfide > ortho-
methoxyphenylsulfide > phenylsulfide. Chelation of BuLi to the
pyridine nitrogen25 or the methoxy oxygen is likely responsible
for the rate acceleration, rather than electronic effects, because
the pyridinethionitriles are electron deficient relative to the
phenylthionitriles, whereas 7d is electron rich.
Scheme 3. Arylthio-Lithium Exchange Mechanism
With the propensity of pyridylsulfides toward exchange
discovered, a series of organometallics were screened and
Bu3MgLi was identified as the optimal reagent for the
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exchange.24 Acyclic and cyclic 2-pyridinethiocarbonitriles
exchange equally well, and the exchange−alkylation is effective
in generating the alkenenitrile 3q (Figure 3). Exchange−
does not cyclize onto, or eliminate adjacent to, the pendant
chloride (7o→3v). An analogous exchange−acylation, 7p→3w,
proceeds smoothly at the tertiary carbon without interference
from the pendant nitrile, despite the ease with which metalated
nitriles can equilibrate.26
The facile pyridinethio-magnesium exchange stimulated a
search for an exchange with less reactive organometallics.
Although BuZnCl·LiCl and Bu2Zn·LiCl do not react with 7e, a
clean exchange occurs in 5 min at 0 °C with Et2ZnBuLi.27 An
analogous exchange with Et2ZnBuLi·LiCl did not proceed
cleanly. The zincated nitrile derived from 7e smoothly alkylates
propyliodide and propylene oxide to afford 3g and 3x,
respectively (Scheme 4).
Scheme 4. Sulfur−Zinc and Sulfur−Copper Exchange
Despite there being scant precedent for arylthio-cuprate
exchange,28 Bu2CuLi triggers a complete exchange of 7e within
5 min at 0 °C. In a preparative experiment, trapping the copper
intermediate generated from 7e with allyl bromide very
efficiently affords 3y (Scheme 4). The analogous copper
exchange with piperidinecarbonitrile 7h generates a cuprated
nitrile that acylates methyl cyanoformate to afford 3k.
α-Arylthioalkanenitriles engage BuLi, Bu3MgLi, BuMgCl,
Et2ZnBuLi, and even Me2CuLi in a highly unusual arylthio-
metal exchange. NMR analysis suggests formation of a sulfidate
in equilibrium with a small fraction of the corresponding
lithiated nitrile. Trapping the metalated intermediates efficiently
affords tertiary, quaternary, and alkenenitriles even in the
presence of relatively acidic and electrophilic functionality. The
arylthio-metal exchange reactions of α-arylthioalkanenitriles
address several long-standing challenges with metalated nitriles:
selective access to N- or C-metalated nitriles, functional group
tolerance, and the formation of tertiary nitriles without
polyalkylation.
a
Figure 3. 2-Pyridinethionitrile exchange−alkylation. The yield was
92% when the exchange was performed with BuLi, and butyl(2-
pyridyl)sulfide was isolated in 96% yield. b A yield of 82% was obtained
from the diastereomeric nitrile.
benzylations with the diastereomeric norbornene carbonitriles
7f and 7g converge to the same carbonitrile 3h, indicating that
the intermediate magnesiated nitrile is configurationally labile.
The piperidinecarbonitrile 3k is readily generated from the
acylation with methyl cyanoformate. An analogous alkylation
with benzyl bromide affords the quaternary nitrile 3i in 54%
yield accompanied by 32% of the nitrile resulting from
exchange and protonation. Evidently the reactivity of the
intermediate magnesiated nitrile is diminished, at least in this
case, relative to the corresponding lithiated nitrile (cf. Figure 2).
Particularly remarkable are the exchange reactions with
nitriles 7m−7p (Figure 3, lower quadrant). Secondary nitriles
7m and 7n, bearing a relatively acidic methine proton,
efficiently undergo an exchange−alkylation forming tertiary
nitriles 3t and 3u without overalkylation. Bu3MgLi-induced
exchange with nitrile 7o generates a magnesiated nitrile that
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra and experimental procedures for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: flemingf@duq.edu.
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(25) For leading references, see: (a) Jeffrey, J. L.; Sarpong, R. Org.
Lett. 2012, 14, 5400. (b) Lee, J. I. Bull. Korean Chem. Soc. 2011, 32,
1765. (c) Furukawa, N.; Sagae, T.; Ogawa, S. Heterocycles 1991, 32,
679. (d) Meyers, A. I.; Comins, D. L. Tetrahedron Lett. 1978, 19, 5179.
(e) Araki, M.; Sakata, S.; Takei, H.; Mukaiyama, T. Bull. Chem. Soc.
Jpn. 1974, 47, 1777.
(26) (a) Taber, D. F.; Kong, S. J. Org. Chem. 1997, 62, 8575.
(b) Kieczykowski, G. R.; Schlessinger, R. H.; Sulsky, R. B. Tetrahedron
Lett. 1975, 464. (c) Watt, D. S. Tetrahedron Lett. 1974, 707.
(27) (a) Merkel, S.; Stern, D.; Henn, J.; Stalke, D. Angew. Chem., Int.
Ed. 2009, 48, 6350. (b) Hevia, E.; Chua, J. Z.; Garcia-Alvarez, P.;
Kennedy, A. R.; McCall, M. D. Proc. Natl. Acad. Sci. U.S.A. 2010, 107,
5294.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Science Foundation is
gratefully acknowledged (IR/D, CHE 1111406 and CHE-
0963450). Dr. Lujan Montelongo is thanked for assistance with
NMR experiments. The views expressed do not necessarily
reflect those of the NSF.
REFERENCES
(28) Posner, G. H.; Switzer, C. J. Am. Chem. Soc. 1986, 108, 1239.
■
(1) Fleming, F. F.; Zhang, Z. Tetrahedron 2005, 61, 747.
(2) The cylindrical diameter of the π-system is 3.6 Å: Sheppard, W.
A. In The Chemistry of the Cyano Group; Rappoport, Z., Ed.; Wiley:
1970; Chapter 5.
(3) (a) Richard, J. P.; Williams, G.; Gao, J. J. Am. Chem. Soc. 1999,
121, 715. (b) Bradamante, S.; Pagani, G. A. J. Chem. Soc., Perkin Trans.
2 1986, 1035.
(4) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; Wiley: New York, 1994; pp 696−7.
(5) (a) Pellissier, H.; Michellys, P.-Y.; Santelli, M. Steroids 2007, 72,
297. (b) Barton, D. H. R.; Bringmann, G.; Motherwell, W. B. Synthesis
1980, 68.
(6) (a) Pitta, B. R.; Fleming, F. F. Org. Lett. 2010, 12, 2810.
(b) Fleming, F. F.; Zhang, Z.; Liu, W.; Knochel, P. J. Org. Chem. 2005,
70, 2200.
(7) (a) Nath, D.; Fleming, F. F. Angew. Chem., Int. Ed. 2011, 50,
11790. (b) Nath, D.; Fleming, F. F. Chem.Eur. J. 2013, 19, 2023.
(8) (a) Cohen, T.; Daniewski, W. M.; Weisenfeld, R. B. Tetrahedron
Lett. 1978, 19, 4665. (b) Seebach, D. Angew. Chem., Int. Ed. 1967, 6,
442. (c) Brandsma, L. Rec. Trav. Chim. Pays-Bas. 1964, 83, 307.
(9) (a) Oki, M.; Funakoshi, W.; Nakamura, A. Bull. Chem. Soc. Jpn.
1971, 44, 828. (b) Oki, M.; Funakoshi, W. Bull. Chem. Soc. Jpn. 1971,
44, 832.
(10) Trost, B. M.; Mao, M. K. T.; Balkovec, J. M.; Buhlmayer, P. J.
Am. Chem. Soc. 1986, 108, 4965.
(11) (a) Unsinn, A.; Dunst, C.; Knochel, P. Beilstein J. Org. Chem.
2012, 8, 2202. (b) Stoll, A. H.; Krasovskiy, A.; Knochel, P. Angew.
Chem., Int. Ed. 2006, 45, 606.
(12) Leriverend, P.; Huard, C. Sulfur Lett. 1990, 11, 219.
(13) (a) Coldham, I.; Watson, L.; Adams, H.; Martin, N. G. J. Org.
Chem. 2011, 76, 2360. (b) Barriere, F.; Barriere, J. C.; Barton, D. H.
R.; Cleophax, J.; Gateau-Olesker, A.; Gero, S. D.; Toad, F. Tetrahedron
Lett. 1985, 26, 3119.
(14) Bordwell, F. G.; Van Der Puy, M.; Vanier, N. R. J. Org. Chem.
1976, 41, 1885.
(15) Resek, J. E.; Meyers, A. I. Tetrahedron Lett. 1995, 36, 7051.
(16) The parent phenylthioacetonitrile and (methylthio)acetonitrile
are commercially available.
(17) Fleming, F. F.; Gudipati, S.; Zhang, Z.; Liu, W.; Steward, O. W.
J. Org. Chem. 2005, 70, 3845.
(18) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C.
J. Med. Chem. 2010, 53, 7902.
(19) (a) Inoue, A.; Kondo, J.; Shinokubo, H.; Oshima, K. Chem.
Eur. J. 2002, 8, 1730. (b) Inoue, A.; Kitagawa, K.; Shinokubo, H.;
Oshima, K. J. Org. Chem. 2001, 66, 4333.
(20) (a) Carlier, P. R.; Lo, W.-S. J. Am. Chem. Soc. 2000, 122, 12819.
(b) Carlier, P. R.; Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1994,
116, 11602. (c) Crowley, P. J.; Leach, M. R.; Meth-Cohn, O.;
Wakefield, B. J. Tetrahedron Lett. 1986, 27, 2909.
(21) Sott, R.; Granander, J.; Hilmersson, G. Chem.Eur. J. 2002, 8,
2081.
(22) Purzycki, M.; Liu, W.; Hilmersson, G.; Fleming, F. F. Chem.
Commun. 2013, 49, 4700.
(23) Fleming, F. F.; Wei, G. J. Org. Chem. 2009, 74, 3551.
(24) See eq 1 and Table 1 in the Supporting Information.
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