Cyclic alkenenitriles: Chemoselective oxonitrile cyclizations

Article abstract of DOI:10.1021/jo026396+

Potassium tert-butoxide triggers the chemoselective cyclization between nitrile anions and remote, enolizable carbonyl groups, despite the acidity difference favoring enolate formation and addition to the nitrile group. Domino deprotonation, cyclization,

Full text of DOI:10.1021/jo026396+

Cyclic Alk en en itr iles: Ch em oselective Oxon itr ile Cycliza tion s
Fraser F. Fleming,* Lee A. Funk, Ramazan Altundas, and Vaqar Sharief
Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282-1530
flemingf@duq.edu
Received September 4, 2002
Potassium tert-butoxide triggers the chemoselective cyclization between nitrile anions and remote,
enolizable carbonyl groups, despite the acidity difference favoring enolate formation and addition
to the nitrile group. Domino deprotonation, cyclization, and dehydration efficiently transform a
diverse array of ω-oxonitriles into carbocyclic and heterocyclic five- and six-membered alkenenitriles
in a single synthetic operation.
SCHEME 2. Ch em oselective Oxon itr ile
Cycliza tion s
In tr od u ction
R,â-Alkenenitriles are versatile intermediates1 to an
array of heterocycles,2 carbocycles,3 and nitrile-containing
natural products.4 Cyclic alkenenitriles in particular are
ideal precursors to substituted alkanenitriles that often
exhibit unusual reactivity motifs that are inaccessible
with the corresponding carbonyl compounds. For ex-
ample, the cyclic nitrile 1 exhibits a unique solvent-
dependent cyclization to cis- and trans-decalins 2 and 3,5
whereas ester enolates cyclize to cis-decalins regardless
of the solvent6 (Scheme 1).
SCHEME 1. Nitr ile An ion Cycliza tion s
a nitrile anion despite the presence of a more acidic
carbonyl group (∆pKa ) 5-10)10 favoring enolate forma-
tion and addition to the nitrile group (8 or 9, Scheme 2).
(8) (a) Kunesch, N.; Francois, D.; Poupon, E.; Lallemand, M.;
Husson, H. J . Org. Chem. 2000, 65, 3209. (b) Tomoda, S.; Takeuchi,
Y.; Nomura, Y. J . Chem. Soc., Chem. Commun. 1982, 871. (c)
Hoffmann, H. M. R.; Giesel, K.; Lies, R.; Ismal, Z. M. Synthesis 1986,
548. (d) Kemp, D.S.; Carter, J . S. Tetrahedron Lett. 1987, 28, 4641. (e)
Kemp, D. S.; Carter, J . S. Tetrahedron Lett. 1987, 28, 4645. (f)
Merchant, J . R.; Dike, S. Y. Proc. Indian. Acad. Sci. 1978, 87 (A8),
229. (g) Prajapati, D.; Lekhok, K. C.; Sandhu, J . S.; Ghosh, A. C. J .
Chem. Soc., Perkin Trans. 1 1996, 959. (h) El Kaim, L.; Gacon, A.
Tetrahedron Lett. 1997, 38, 3391.
Despite the unique reactivity of cyclic nitriles, few are
commercially available. Alternatively, synthesizing7 cy-
clic alkenenitriles is attended by the inherent difficulty
in sequentially performing an efficient cyclization-ole-
fination sequence in a single synthetic operation.8
A
conceptually attractive solution9 (4f7, Scheme 2) is the
chemoselective condensation of a nitrile anion with a
remote carbonyl groupschemoselective in cyclizing via
(9) Deprotonation of â-ketonitriles,a-d â-cyanoesters,e-g â-cyano-
amides,h and arylacetonitrilesi-n permit analogous cyclizations al-
though the more challenging cyclizations of alkanenitriles typically
require two discreet synthetic operations.o-p (a) Fleming, F. F.; Guo,
J .; Wang, Q.; Weaver, D. J . Org. Chem. 1999, 64, 8568. (b) Fleming,
F. F.; Huang, A. Sharief, V.; Pu, Y. J . Org. Chem. 1999, 64, 2830 (c)
Haase-Held, M.; Hatzis, M.; Mann, J . J . Chem. Soc., Perkin Trans. 1
1993, 2907. (d) Haase-Held, M.; Hatzis, M.; Mann, J . J . Chem. Soc.,
Perkin Trans. 1 1992, 2999. (e) Kulkarni, B. A.; Ganesan, A. Angew.
Chem., Int. Ed. 1997, 36, 2454. (f) Kraus, G. A.; Roth, B. J . Org. Chem.
1980, 45, 4825. (g) Gorlitzer K. Arch. Pharm. 1975, 308, 700. (h) Ikeda,
M.; Uchino, T.; Maruyama, K.; Sato, A. Heterocycles 1988, 27, 2349 (i)
Bossio, R.; Marcaccini, S.; Pepino, R.; Torroba, T. Synthesis 1993, 783.
(j) Orlemans, E. O. M.; Schreuder, A. H.; Conti, P. G. M.; Verboom,
W.; Reinhoudt, D. N. Tetrahedron 1987, 43, 3817 (k) Verboom, W.;
Orlemans, E. O. M.; Berga, H. J .; Scheltinga, M. W.; Reinhoudt, D. N.
Tetrahedron 1986, 42, 5053 (l) Verboom, W.; Berga, H. J.; Trompenaars,
W. P.; Reinhoudt, D. N. Tetrahedron Lett. 1985, 685. (m) Stefancich,
G.; Artico, M.; Massa, S.; Vomero, S. J . Heterocyclic Chem. 1979, 16,
1443. (n) Flitsch, W.; Lerner, H.; Zimmermann, H. Chem. Ber. 1977,
110, 2765. (o) Nakashima, K.; Inoue, K.; Sono, M.; Tori, M. J . Org.
Chem. 2002, 67, 6034. (p) For a similar one-step cyclization see:
Elghamry, I.; Dopp, D.; Henkel, G. Synthesis 2001, 1223.
(1) Fatiadi, A. J . In The Chemistry of Functional Groups, Supple-
ment C; Patai, S., Rappoport, Z., Eds.; Wiley: New York, 1983; Chapter
26.
(2) Sharanin, Y. A.; Goncharenko, M. P.; Litvinov, V. P. Russ. Chem.
Rev. 1998, 67, 393.
(3) Fleming, F. F.; Shook, B. C.; J iang, T.; Steward O. W. Org. Lett.
1999, 1, 1547.
(4) Fleming, F. F. Nat. Prod. Rep. 1999, 16, 597.
(5) Fleming, F. F.; Shook, B. C. J . Org. Chem. 2002, 67, 2885.
(6) Stork, G.; Gardner, J . O.; Boeckman, R. K., J r.; Parker, K. A. J .
Am. Chem. Soc. 1973, 95, 2014.
(7) For existing syntheses of cyclic alkenenitriles see: (a) Couthon,
H.; Gourves, J .; Sturtz, G. Eur. J . Org. Chem. 1999, 3489. (b)
Bestmann, H. J .; Schmidt, M. Angew. Chem. 1987, 26, 79. (c) Flitsch,
W.; Lerner, H.; Zimmermann, H. Chem. Ber. 1977, 110, 2765. (d) Oda,
M.; Yamamuro, A.; Watabe, T. Chem. Lett. 1979, 1427. (e) Grierson,
D. S.; Sisti, N. J .; Zeller, E.; Fowler, F. W. J . Org. Chem. 1997, 62,
2093. (f) Henecka, H.; Aichinger, G.; Schubert, W. Angew. Chem. 1962,
74, 875.
10.1021/jo026396+ CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/05/2002
9414
J . Org. Chem. 2002, 67, 9414-9416

Cyclic Alkenenitriles
TABLE 1. Ch em oselective Oxon itr ile Cycliza tion s
Conceptually, several competitive cyclizations exist for
carbonyl-containing nitriles with only one mode leading
to cyclic alkenenitriles. The cyclization chemoselectivity
depends on the relative basicity and electrophilicity of
the ketone and nitrile groups with the later being more
critical.11 Despite a perception to the contrary, nitriles
are relatively poor electrophiles that often resist nucleo-
philic attack by organometallic reagents,12 even allowing
CtN incorporation within organolithium13 and Grignard
reagents!14 Ketones, by contrast, are excellent electro-
philes that condense rapidly with nitrile anions.15 The
combination of poor nitrile and high ketone electrophi-
licity favorably disposes carbonyl-containing nitriles
toward nitrile anion cyclization.
Resu lts a n d Discu ssion
Exploratory cyclizations with potassium tert-butoxide
(t-BuOK) and commercially available ketonitrile 4a
established the viability of chemoselectively cyclizing
oxonitriles (Table 1, entry 1). Base optimization revealed
a minimum requirement for 2-3 equiv16 of either t-
BuOK17 or i-BuOK, with 5 equiv permitting the complete
conversion to the alkenenitrile 7a within 5 h in refluxing
tetrahydrofuran (THF).
The alkoxide-promoted cyclization effectively assembles
a diverse range of carbocyclic and heterocyclic alkeneni-
triles. Acyclic and cyclic ketonitriles (Table 1, entries 1-2
and 3-8, respectively) cyclize equally efficiently, generat-
ing a variety of monocyclic and bicyclic five- and six-
membered alkenenitriles. Ketone electrophiles tolerate
aliphatic, olefinic, and aromatic substituents (Table 1,
entries 1 and 3-5, 6, and 2, respectively) with the
cyclization being favored over a potentially competitive
conjugate addition in the case of enone 4f (Table 1, entry
6). The cyclization is not limited to ketones,18 with imide
4g and lactam 4h readily cyclizing to the corresponding
indolizidine 7g and quinolizidine 7h .19 Cyclization of 4h
a
b
Reaction performed at ambient temperature.21 A 1 equiv
amount of t-BuOK was employed to prevent deleterious decyana-
(10) The pKa of acetone and acetonitrile are 20 and 25,a respectively,
with the pKa of acetonitrile being recently revised upward to ∼30.b (a)
Bordwell, F. G.; Matthews, W. S. J . Am. Chem. Soc. 1974, 96, 1214.
(b) Richard, J . P.; Williams, G.; Gao, J . J . Am. Chem. Soc. 1999, 121,
715.
d
tion.22 c Reaction time was 3 h. Brief exposure to aqueous HCl
was performed during workup to ensure complete dehydration of
the carbinol amine intermediate.
(11) Nitriles appear to exhibit an inherent propensity to react with
ketones or esters in the presence of base: Fleming, F. F.; Shook, B. C.
Tetrahedron 2002, 58, 1.
(12) Weiberth, F. J .; Hall, S. S. J . Org. Chem. 1987, 52, 3901.
(13) (a) Parham, W. E.; Nelson, J . H. A. J . Org. Chem. 1982, 15,
300. (b) Parham, W. E.; J ones, L. D. J . Org. Chem. 1976, 41, 1187. (c)
Tucker, C. E.; Majid, T. M.; Knochel, P. J . Am. Chem. Soc. 1992, 114,
3983.
(Table 1, entry 8), obtained by alkylating δ-valerolactam
with bromopentanenitrile, expediently provides a rapid
entry to alkaloids through quinolizidine 7h .20
Mechanistically the cyclization involves sequential
anion equilibration,23 cyclization, and elimination24
(14) (a) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J . Org.
Chem. 2001, 66, 4333. (b) Lee, J .-S.; Valerde-Ortiz, R.; Guijarro, A.;
Wurst, J . R.; Rieke, R. D. J . Org. Chem. 2000, 65, 5428. (c) Abarbri,
M.; Thibonnet, J .; Berillon, L.; Dehmel, F.; Rottla¨nder, M.; Knochel,
P. J . Org. Chem. 2000, 65, 4618. (d) Thibonnet, J .; Knochel, P.
Tetrahedron Lett. 2000, 41, 3319. (e) Kitagawa, K.; Ioue, A.; Shinokubo,
H.; Oshima, K. Angew. Chem. 2000, 39, 2481. (f) Burns, T. P.; Rieke,
R. D. J . Org. Chem. 1987, 52, 3674.
(19) For a related enolate-thiolactam condensation see: Guarna,
A.; Lombardi, E.; Machetti, F.; Occhiato, E. G.; Scarpi, D. J . Org. Chem.
2000, 65, 8093.
(20) Michael, J . P.; J ungmann, C. M. Tetrahedron 1992, 48, 10211.
(21) Performing the reaction at reflux causes partial nitrile hydroly-
sis to the corresponding amide.
(22) Use of excess t-BuOK (5 equiv) causes decyanation to 2-phen-
ylcyclohexadiene:
(15) DiBiase, S. A.; Lipisko, B. A.; Haag, A.; Wolak, R. A.; Gokel, G.
W. J . Org. Chem. 1979, 44, 4640.
(16) No observable reaction occurs with less than 2 equiv of t-BuOK.
(17) t-BuOK is estimated to have an acidity comparable to LiHMDS
in THF: Hartwig, J . F. Angew. Chem. 1998, 37, 2046. For recent
deprotonations of alkanenitriles with t-BuOK see: Bunlaksananusorn,
T.; Rodriguez, A. L.; Knochel, P. Chem. Commun. 2001, 745. For the
extremely high basicity in DMSO see: Cram, D. J .; Rickborn, B.; Knox,
G. R. J . Am. Chem. Soc. 1960, 82, 6412.
(18) Aldol condensation prevents the use of enolizable aldehydes.
For an excellent intermolecular addition to aromatic aldehydes see:
Kisanga, P. B.; Verkade, J . G. J . Org. Chem. 2002, 67, 426.
(23) A rapid proton transfer is observed with related ester enolate
nitriles: Stetter, H.; Marten, K. Liebigs Ann. Chem. 1982, 240.
(24) Cyclic â-hydroxynitriles are readily deprotonated adjacent to
the nitrile group: Wade, P. A.; Bereznak, J . F. J . Org. Chem. 1987,
52, 2973.
J . Org. Chem, Vol. 67, No. 26, 2002 9415

Fleming et al.
SCHEME 3. Cou n ter in tu itive Cycliza tion
Mech a n ism
SCHEME 4. Dom in o
Cycliza tion -Deh yd r a tion -Hyd r olysis
Alkoxide-induced cyclizations of ω-oxonitriles smoothly
generate cyclic R,â-alkenenitriles in a single synthetic
operation. Selective nitrile anion formation triggers facile
cyclization onto tethered ketone, enone, lactam, and
imide carbonyls, generating cyclic five- and six-membered
alkenenitriles. Performing the cyclization in t-BuOH,
rather than THF, enhances the nucleophilicity of the
ejected hydroxide, expediently triggering a cyclization,
dehydration, hydrolysis cascade to the corresponding
amide. Collectively, the chemoselective cyclizations afford
a diverse array of carbocyclic and heterocyclic nitriles
that are otherwise difficult to synthesize.
(Scheme 3). Evidence for anion equilibration with t-BuOK
emanates from the unusual cyclization of 4h with excess
KH (63% yield) that is anticipated to generate both the
enolate 9 and the nitrile anion 5 (Scheme 3). Complete
conversion to the cyclic alkenenitrile 7, without recovery
of 4, implies a relatively efficient inter- or intramolecular
proton transfer that converges the enolate 9 to the nitrile
anion 5. Cyclization (5f6), proton transfer (6f10), and
dehydration (10f7)25 then furnishes the respective cyclic
alkenenitriles.
Exp er im en ta l Section 28
Gen er a l Cycliza tion P r oced u r e. Solid t-BuOK (5 equiv)
was added to a refluxing, THF solution of the ketonitrile (1
equiv, 0.01-0.05 M). After 5 h the solution was cooled,
saturated, aqueous NH4Cl was added, the organic phase was
separated, and the aqueous phase was extracted with CH2Cl2
(3×). The combined organic extracts were dried (Na2SO4),
concentrated under reduced pressure, and then purified by
radial chromatography (EtOAc/hexanes).
Consistent with the proposed mechanism is the cy-
clization of 4f with i-BuOK rather than t-BuOK (Table
1, entry 6), which induces cyclization without concomi-
tant dehydration. Presumably the intermediate alkoxide
6 (Scheme 3) is generated in each case, with the subse-
quent protonation being more favorable from i-BuOH
than t-BuOH, allowing displacement of the equilibrium
toward the alkenenitrile 7.
Ejection of hydroxide during the cyclization generates
hydroxide ideally suited for nitrile hydrolysis. Performing
the cyclization in t-BuOH enhances the hydroxide nu-
cleophilicity,26 triggering a domino sequence in which
nitrile 4i is transformed into the cyclic amide 11i27
(Scheme 4). The overall sequence of proton transfers is
remarkably efficient for the deprotonation, cyclization,
dehydration, and nitrile hydrolysis cascade.
Ack n ow led gm en t . Financial support from the
J ohnson and J ohnson Focused Giving Program is grate-
fully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and 1H NMR and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O026396+
(25) The alcohol 10d is an observable intermediate in the cyclization
of 4d to 7d .
(26) Hall, J . H.; Gisler, M. J . Org. Chem. 1976, 41, 3769.
(27) Cyclopentanecarbonitriles seem prone to hydrolysis: J aroszew-
ski, J . W.; Olafsdottir, E. S.; Cornett, C.; Schaumberg, K. Acta Chem.
Scand. 1987, B41, 410.
(28) For general experimental procedures see: Fleming, F. F.;
Hussain, Z.; Weaver, D.; Norman, R. E. J . Org. Chem. 1997, 62, 1305.
The high-resolution mass spectra were recorded at The Ohio State
University Campus Chemical Instrumentation Center.
9416 J . Org. Chem., Vol. 67, No. 26, 2002