An efficient method to convert lactams and amides into 2,2-dialkylated amines

Article abstract of DOI:10.1021/ol800145h

(Chemical Equation Presented) A practical method for the synthesis of gem-2,2-disubstituted tertiary amines from the corresponding lactams (or amides) is reported. It is based on the reaction of thioiminium ions, easily prepared from lactams and amides wi

Full text of DOI:10.1021/ol800145h

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1417-1420
An Efficient Method To Convert Lactams
and Amides into 2,2-Dialkylated Amines†
Alessandro Agosti, Sebastian Britto,‡ and Philippe Renaud*
UniVersita¨t Bern, Departement fu¨r Chemie und Biochemie, Freiestrasse 3,
3012-Bern, Switzerland
philippe.renaud@ioc.unibe.ch
Received January 21, 2008
ABSTRACT
A practical method for the synthesis of gem-2,2-disubstituted tertiary amines from the corresponding lactams (or amides) is reported. It is
based on the reaction of thioiminium ions, easily prepared from lactams and amides with organometallic reagents such allylmagnesium,
benzylmagnesium, and primary alkylcerium reagents.
Geminal 2,2-bisalkylated cyclic amines are interesting build-
ing blocks for natural product synthesis as well as important
Scheme 1. Yoshida’s Procedure for the Preparation of
pharmacophores. For instance, 2,2-bisallylated pyrrolidines
and piperidines have been used as starting material for the
synthesis of azaspirononanes and azaspirodecanes that are
present in a variety of natural products such as cephalotaxine,
pinnaic acid, and halichlorine.1
Azaspirononanes
and ring-closing metathesis (Scheme 1).2 However, the
interest of this procedure is limited by the use of very strong
bases such as sec-butyllithium to prepare the bis-silylated
derivative and by the use of different N-protecting groups
for the silylation and for the allylation steps.
Luke and Cerny reported an efficient procedure to convert
piperidinone into 2,2-diallylpiperidine.3 This procedure was
applied later by Semmelhack to prepare 2,2-diallylpyrroli-
dine.4 The azaspirocyclic system was prepared via an acyloin
condensation and converted into cephalotaxine. Bubnov5 and
Yoshida reported an interesting method to prepare aza-
spirononanes starting from pyrrolidines protected as car-
bamates via 2,2-bissilylation, electrochemical bisallylation,
† Part of the projected Ph.D. theses of A.A. (organomagnesium chemistry,
metathesis) and S.B. (organocerium chemistry).
‡ Research fellow at Universita¨t Bern, on leave from the School of
Chemistry, Bharathidasan University, Tiruchirappalli-620 024, India.
(1) For a recent review on the synthesis of 1-azaspirocycles, see: Dake,
G. Tetrahedron 2006, 62, 3467-3492.
(2) Suga, S.; Watanabe, M.; Yoshida, J. J. Am. Chem. Soc. 2002, 124,
14824-14825.
(3) Lukes, R.; Cerny, M. Collect. Czech. Chem. Commun. 1961, 26, 2886.
10.1021/ol800145h CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/04/2008

Zhang6 developed the direct conversion of lactams into the
gem-diallylderivatives via reaction with triallylborane and
allylsamarium bromide, respectively. However, none of the
reported approaches (Semmelhack, Bubnov, and Zhang) is
compatible with the presence of an alkyl substituent at the
nitrogen atom. Therefore, an extra N-alkylation step is
required for most application in natural product synthesis.
The conversion of amides into tertiary 2,2-dimethylamines
has been reported by Denton and Wood by direct treatment
of amides with methylmagnesium bromide in the presence
of zirconium or titanium tetrachloride.7 So far, this reaction
is limited to the introduction of a methyl group. Takahata8
and more recently Murai9 have investigated the reactivity
of thioiminium salts derived from thioamides and thiolactams
with nucleophiles leading to 2-monosubstituted and 2,2-
disubstituted amines (Scheme 2). The reaction is promising
Scheme 3. Optimized Conditions for the Preparation of
2,2-Diallyl-N-benzylpyrrolidine from N-Benzylpyrrolidinone
In contrast to Klaver et al.,10 neither the solvent nor the
temperature influences the product distribution. For instance,
when the reaction of 3a was performed with only one
equivalent of allylmagnesium bromide in dichloromethane
at -78 °C, no monoallylation was observed. Instead, the bis-
allylated amine 4a was obtained in 40% yield together with
lactam 1a arising from the aqueous workup.
Scheme 2. Takahata and Murai Alkynylation of Thioiminium
Ions
With allylic organomagnesium reagents, the mechanism
presumably involves an initial addition to the thioiminium
salt leading to the N,S-acetal I followed by a fast fragmenta-
tion, favored by the Lewis acidity of magnesium(II), leading
to the iminium ion II (Scheme 4). The iminium ion II is
Scheme 4. Mechanism of the Double-Allylation Reaction
when alkynyllithium reagents are used first as the nucleo-
phile. The reaction of a thioiminium salt derived from a
[3.2.1] bicyclic amide with a substituted alkyl Grignard
reagent has been investigated by Klaver, Speckamp, and
Hiemstra.10 In THF, the reaction afforded the gem-dialkylated
product in low yield. However, when the reaction was run
in dichloromethane, a good yield of the monoalkylated
product was obtained. In this paper, we report that thio-
iminium salts, easily prepared from lactams and amides, can
be converted into 2,2-disubstitued amines by reaction with
simple nucleophiles such as organomagnesium and organo-
cerium reagents.
gem-Diallylation and gem-Dibenzylation. The thio-
iminium iodide 3a is prepared from N-benzylpyrrolidinone
1a (Scheme 3). Treatment of 1a with the Lawesson’s reagent
affords the thiolactam 2a that is converted into the thio-
iminium salt 3a by treatment with methyl iodide in THF at
room temperature. Treatment of the thioiminium salt 3a with
allylmagnesium bromide affords the desired gem-diallylated
pyrrolidine 4a. Best results are obtained with 3 equiv of
allylmagnesium bromide in THF at room temperature.
more electrophilic than the thioiminium ion 3a, and therefore,
the second nucleophilic addition takes place more rapidly
than the reaction with the thioiminium ion.
The reaction sequence was applied to N-benzylpiperidi-
none 1b and N-benzylazepanone 1c. As nucleophiles, both
allylmagnesium bromide and benzylmagnesium chloride
were successfully tested (Scheme 5). In all cases, the gem-
dialkylated products 4 and 5 are obtained in excellent yields
over the three steps from the parent lactams. The reaction
was also tested with the acetamide 6. Successive treatment
with Lawesson’s reagent, methyl iodide, and benzylmagne-
sium chloride affords the tertiary amine 8 in 66% overall
yield.
Ring-Closing Metathesis (RCM). The bisallylated cyclic
amines 4a-c were then subjected to the RCM reaction.
Despite their high functional group tolerance, ruthenium
carbenes catalysts do not work well in the presence of basic
nitrogen atoms.11 Running the reaction on the free amine
led to low conversion (e20%) after 5 h in refluxing toluene
(4) Semmelhack, M. F.; Chong, B. P.; Stauffer, R. D.; Rogerson, T. D.;
Chong, A.; Jones, L. D. J. Am. Chem. Soc. 1975, 97, 2507-2516.
(5) Nieczypor, P.; Mol, J. C.; Bespalova, Y.; Bubnov, N. Eur. J. Org.
Chem. 2004, 812-819.
(6) Li, Z.; Zhang, Y. Tetrahedron 2002, 58 (26), 5301-5306.
(7) Denton, M. S.; Wood, A. Synlett 1999, 55-56.
(8) Takahata, H.; Takahashi, K.; Wang, E. C.; Yamazaki, T. J. Chem.
Soc., Perkin Trans. 1 1989, 1211-1214.
(9) Murai, T.; Toshio, R.; Mutoh, Y. Tetrahedron 2006, 62, 6312-6320.
(10) Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am. Chem. Soc.
1989, 111, 2588-2595.
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Org. Lett., Vol. 10, No. 7, 2008

rather than undergoing the desired addition. Organocerium
derivatives are offen used to avoid the undesired deproto-
nation during the addition of organolithium and organomag-
nesium reagents to ketones.15 Therefore, methylcerium
dichloride and n-butylcerium dichloride, easily prepared from
the commercially available organolithium derivatives, were
tested. Both reagents react cleanly with the thioiminium
iodides 3a-c and afford the gem-dimethyl and gem-dibutyl
derivatives 10a, 11a-c in good yield (Scheme 7). Interest-
Scheme 5. gem-Dialkylation of Lactams and Amides with
Allylic and Benzylic Organomagnesium Reagents
Scheme 7. gem-Dialkylation with Organocerium Reagents
with 10 mol % of Grubbs second-generation catalyst.12
However, when the corresponding hydrochlorides were used,
the RCM reactions took place in refluxing CH2Cl2 and afford
the 1-azaspirocycles 9a-c in higher yield and shorter reaction
time (90 min) in the presence of 5 mol % of Grubbs II
catalyst (Scheme 6).13
ingly, the reaction in the presence of 1 equiv of n-butylcerium
with 3a affords 11a as single isolated product in 20% yield.
Accordingly to the results of the organomagnesium allylation,
no product resulting from the monoaddition was detected.16
The gem-dialkylation process can also be applied to
amides. For instance, we prepared N-tert-butyltetrahydroiso-
quinoline 14 from the acetamide 12 via the thioiminium ion
13. The acetylation-gem-dimethylation process represents
a useful method for the conversion of secondary amines into
tert-butyl tertiary amines. In the literature, the tert-butylation
of secondary amines is scarcely reported, low yielding, and
requires drastic reaction conditions.7,17,18
Scheme 6. Preparation of Azaspiro Derivatives by RCM
Secondary and tertiary alkylcerium reagents do not add
to the thioiminium salts and after aqueous work up the parent
lactams are recovered. It is unclear whether this result is due
to a lack of reactivity or to a competitive depronation.
gem-Dialkylation. Extension of the allylation-benzylation
process to the introduction of geminal dialkyl group proved
not to be feasible by using either alkylmagnesium halides
or alkyllithium derivatives, despite the isolated example
reported by Klaver et al.10,14 Indeed, these reagents are
presumably too basic and deprotonate the thioiminium salts
(14) All our attempts to apply Klaver’s procedure to monocyclic
thioiminium salts bearing acidic H-atoms, such as 3a, failed to give the
expected monoalkylated or dialkylated products due to competitive depro-
tonation of the thioiminium salts.
(15) Liu, H.; Shia, K.; Shang, X.; Zhu, B. Tetrahedron 1999, 3803-
3830.
(16) Recently, the monoalkylation of thioiminium ion with alkylcuprates
has been reported by Amat et al.: Amat, M.; Llor, N.; Hidalgo, J.; Escolano,
C.; Bosch, J. J. Org. Chem. 2003, 68, 1919-1928.
(17) Direct reaction of secondary amines with tert-butyl halides did not
afford the tert-butyl amines in useful yields: Drake, W. V.; McElvain, S.
M. J. Am. Chem. Soc. 1933, 55, 1155-1158.
(11) Deiters, A.; Martin, S. F Chem. ReV. 2004, 104, 2199-2238.
(12) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(13) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-388.
Org. Lett., Vol. 10, No. 7, 2008
1419

In conclusion, we have developed a practical method for
the synthesis of gem-2,2-disubstituted amines from the
corresponding lactams and amides. So far, the reaction allows
the introduction of allyl, benzyl and primary alkyl chains.
Further investigation of this chemistry as well as applications
in alkaloid synthesis are underway.
Acknowledgment. We thank the Swiss National Science
Foundation (Project No. 200020-112250) and the State
Secretariat for Education and Research (Project No. C03.0047,
COST D28) for funding. S.B. is very grateful to the Federal
Commission for Scholarships for Foreign Students (FCS) for
a scholarship.
Supporting Information Available: Full experimental
(18) For examples of multistep tert-butylation of a secondary amines,
see: Knabe, J.; Grund, G. Arch. Pharm. 1963, 296, 820-828. Lattes, A.;
Perie, J. J. Tetrahedron Lett. 1967, 5165-5168. Suzuki, K.; Okano, K.;
Nakai, K.; Terao, Y.; Sekiya, M. Synthesis 1983, 723-725. Guan, H.;
Saddoughi, S. A.; Shaw, A. P.; Norton, J. R. Organometallics 2005, 24,
6358-6364.
1
procedures, spectral data, and H and 13C NMR spectra for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
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