Katritzky et al.
SCHEME 5
For this study, the benzotriazolyl adducts 8b-i prepared
by the addition of benzotriazole to the corresponding
enamines 7b-i were treated directly with various nu-
cleophiles, without isolation or purification, to give
tertiary alkyl carbinamines 9, propargylamines 10, and
R-heteroarylamines 11 (Scheme 5).
Preparation of Tertiary Alkyl Carbinamines 9a-
h. Previously, the most common approach for the syn-
thesis of tertiary alkyl carbinamines has been the
Bryulants reaction of R-aminonitriles (Scheme 6).16 Start-
ing R-aminonitriles are generated by Strecker reaction
of an aldehyde, amine, and a cyanide source17a and
quaternary centers R to the cyano substituent are often
created by lithiation-substitution.17b Although, the direct
preparation of such substrates from unhindered cyclic
ketones and a secondary amine18a,b proceeds smoothly at
20 °C, reactions using aliphatic acyclic ketones require
prolonged heating periods.15d Recently, the use of high
pressures for the preparation of R-aminonitriles from
relatively hindered aliphatic ketones and aromatic sec-
ondary amines has been reported.14 Most examples of
Bryulants substitution of a nitrile group by a Grignard
reagent utilize R-aminonitriles derived from aldehydes
or cyclic ketones.18 This methodology has been used for
the preparation of several compound classes of great
pharmaceutical interest including analgesics,18c,f,19a
anesthetics,19b CNS agents19c,d and tools for the study of
(18) (a) Thurkauf, A.; De Costa, B.; Mattson, M. V. France, C. P.;
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Med. Chem. 1990, 33, 2211. (b) Lednicer, D.; Von Voigtlander, P. F. J.
Med. Chem. 1979, 22, 1157. (c) Sundermann, B.; Hennies, H.-H.;
Englberger, W.; Koegel, B.-Y. PCT Int. Appl. 2003080557, 2003; Chem.
Abstr. 2003, 139, 291992. (d) Bacque, E.; Paris, J.-M.; Le Bitoux, S.
Synth. Commun. 1995, 25, 803. (e) Brine, G. A.; Boldt, K. G.; Coleman,
M. L.; Carroll, F. I. Org. Prep. Proced. Int. 1983, 15, 371. (f) Lednicer,
D.; Von Voigtlander, P. F.; Emmert, D. E. J. Med. Chem. 1981, 24,
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(19) (a) Al-Deeb, O. A. Arzneim.-Forsch. 1996, 46, 505; Chem. Abstr.
1996, 125, 104251. (b) Kudzma, L. V.; Severnak, S. A.; Benvenga, M.
J.; Ezell, E. F.; Ossipov, M. H.; Knight, V. V.; Rudo, F. G.; Spencer, H.
K.; Spaulding, T. C. J. Med. Chem. 1989, 32, 2534. (c) Eiden, F.;
Wu¨ensch, B.; Schuu¨nemann, J. Arch. Pharm. (Weinheim) 1990, 323,
481. (d) Eiden, F.; Wu¨ensch, B. Arch. Pharm. (Weinheim) 1990, 323,
393. (e) Linders, J. T. M.; De Costa, B. R.; Grayson, N. A.; Rice, K. C.
J. Labelled Compd. Radiopharm. 1992, 31, 671. (f) Alme, P.; Law, F.
C. P. J. Labelled Compd, Radiopharm. 1982, 19, 455.
(20) Jakobi, H.; Cramp, S. M.; Dickhaut, J.; Lindell, S.; Tiebes, J.;
Asuncion, C. M.; Jans, D.; Hempel, W.; Royalty, R. N.; McComb, S.
M.; Thoenessen, M.-T.; Waibel, J. M.; Salgado, V. L. Ger. Offen.
10141339, 2003; Chem. Abstr. 2003, 138, 204710. (b) Patel, M.;
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(c) Magnus, N. A., Confalone, P. N.; Storace, L. Tetrahedron Lett. 2000,
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dopamine re-uptake complex.19e 1-(1-Phenylcyclohexyl)-
piperidine (PCP) and its analogues constitute a special
class of compounds prepared by this methodology.19f
While complementary to Bryulants reaction of R-ami-
nonitriles, benzotriazole methodology is of wider scope
and avoids side reactions due to nucleophilic attack on
the nitrile substituent. Stirring benzotriazole and a ketone-
derived enamine at rt for 30 min in Et2O/THF forms ben-
zotriazolyl adducts which can be used for further amino-
alkylation of appropriate nucleophiles. The results shown
in Table 1 demonstrate that a wide range of Grignard
reagents can be employed for which the replacement of
the benzotriazolyl group by an alkyl group proceeded
smoothly. Treatment of the adduct 8e prepared in situ
with benzylmagnesium bromide gave the corresponding
product 9a in 47% yield (Scheme 5, Table 1). Similarly,
reaction of the adduct 8f with phenyl- or benzylmagne-
sium bromide gave 9b and 9c in 50% and 60% yields,
respectively. Nucleophilic replacement of the benzotria-
zolyl moiety from adduct 8g using phenyl-, benzyl-, and
n-butylmagnesium bromide gave novel compounds 9d-f
in 61%, 47%, and 48% yields, respectively. Importantly,
reaction of the adduct 8g with vinyl- or allylmagnesium
bromide provided an easy access to allylic and homoallylic
amines 9g and 9h, respectively, in 51% and 56% yields.
The structures of all of the novel tertiary alkyl carbi-
namines 9a-h were fully characterized by their 1H and
13C NMR spectra and elemental analysis.
(21) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed.
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Alkynylation of Benzotriazolyl Adducts 8a-i with
Lithium Phenylacetylide: Preparation of Propar-
gylamines 10a-i. Propargylamines are biologically
active20a-d and are important synthetic intermediates.20e
The most common preparative methods for propargy-
lamines include copper-catalyzed alkynylation of enam-
288 J. Org. Chem., Vol. 70, No. 1, 2005