Free radical-mediated vinyl amination: Access to N,N-dialkyl enamines and their β-stannyl and β-thio derivatives

Article abstract of DOI:10.1021/ol027064u

(Equation presented) The first examples of free radical-mediated vinyl amination are described by nonconventional vinyl radical addition to azomethine nitrogen. This new vinyl amination protocol is mild and provides convenient synthetic access to nonstabi

Full text of DOI:10.1021/ol027064u

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4197-4200
Free Radical-Mediated Vinyl Amination:
Access to N,N-Dialkyl Enamines and
Their â-Stannyl and â-Thio Derivatives
Erode N. Prabhakaran, Benjamin M. Nugent, Amie L. Williams,
Kristen E. Nailor, and Jeffrey N. Johnston*
Department of Chemistry, Indiana UniVersity, Bloomington, Indiana 47405-7102
jnjohnst@indiana.edu
Received October 9, 2002
ABSTRACT
The first examples of free radical-mediated vinyl amination are described by nonconventional vinyl radical addition to azomethine nitrogen.
This new vinyl amination protocol is mild and provides convenient synthetic access to nonstabilized N,N-dialkyl enamines and tandem bond-
forming processes.
In contrast to the growing number of methods that form
aryl-nitrogen bonds, almost exclusively from aryl halides
or triflates and an amine,1-3a,b the analogous vinyl amination
process has evolved at a relatively slow pace.3 This is despite
the fact that enamines occupy a prominent place as inter-
mediates in organic synthesis,4 target-oriented synthesis,5 and
as monomers for polymerization.6 Metal-mediated and
thermal vinyl-nitrogen bond-forming processes have been
reported to form both resonance-stabilized (N-acyl or N-aryl)1d,3
and highly nucleophilic enamines (N-alkyl).7 Approaches to
the latter must contend with the high degree of N,N-dialkyl
enamine nucleophilicity8 and the attendant potential for
single-electron transfer. As a result, methods for their
formation are few in number and dominated by dehydrative
protocols where selectivity, when an issue, is determined by
thermodynamic considerations.9 Alkyne hydroamination is
(1) Palladium-mediated amination, leading references: (a) Wolfe, J. P.;
Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,
805. (b) Hartwig, J. F. Pure Appl. Chem. 1999, 71, 1417-23. (c) Yang, B.
H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125-146.
(2) Other methods, leading references: (a) Copper-promoted: Lindley,
J. Tetrahedron 1984, 40, 1433-1456. Lam, P. Y. S.; Duedon, S.; Averill,
K. M.; Li, R.; He, M. Y.; DeShong, P.; Clark, C. G. J. Am. Chem. Soc.
2000, 122, 7600. Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett.
2002, 4, 581-584. (b) Nucleophilic aromatic substitution: Bunnett, J. F.
Acc. Chem. Res. 1978, 11, 413-420. Hattori, T.; Sakamoto, J.; Hayashizaka,
N.; Miyano, S. Synthesis 1994, 199-198.
(3) (a) Lam, P. Y. S.; Duedon, S.; Averill, K. M.; Li, R.; He, M. Y.;
DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600. (b) Lam, P.
Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron
Lett. 2001, 42, 3415-3418. (c) Lebedev, A. Y.; Izmer, V. V.; Kazyul’kin,
D. N.; Beletskaya, I. P.; Voskoboynikov, A. Z. Org. Lett. 2002, ASAP.
(4) (a) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.;
Terrell, R. J. Am. Chem. Soc. 1963, 85, 207-222. (b) Stork, G.; Terrell,
R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76, 2029.
(5) Stork, G. Med. Res. ReV. 1999, 19, 370-387.
(6) (a) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575. (b) Trofimov, B. A.;
Mikhaleva, A. I.; Morozova, L. V. Russ. Chem. ReV. 1985, 54, 1034.
(7) Cossy, J.; Belotti, D.; Bellosta, V.; Boggio, C. Tetrahedron Lett. 1997,
38, 2677-2680.
(8) (a) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker,
B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. J.
Am. Chem. Soc. 2001, 123, 9500-9512. (b) Mayr, H.; Patz, M. Angew.
Chem., Int. Ed. Engl. 1994, 33, 938-957.
(9) March, J. AdVanced Organic Chemistry, 4th ed.; Wiley: New York,
1992; pp 897-898 and references therein.
10.1021/ol027064u CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/05/2002

Table 1. Enamine Synthesis by Free Radical-Mediated Vinyl Amination of Vinyl Bromidesa
a See Supporting Information for individual experimental details. b Observed by 1H NMR. c Isolated yields from amine (2-3 steps depending on substrate)
after trapping with PhCOCl (9a-12a), maleimide (13a), or no trapping agent (14 and 15). d Enamine 12a is volatile. e A single diastereomer was observed
and isolated after trapping.
presently the most promising entry to nucleophilic enamines,
yet functional group tolerance remains a substantial issue
with lanthanide-based catalysts,10 as well as with methods
requiring oxidative11 or basic conditions.12 This Letter
describes our discovery that the addition of vinyl radicals to
the nitrogen of an azomethine provides a pH-neutral method
for directed, regioselective enamine formation. Furthermore,
the vinyl radical intermediate may be formed either directly
or as part of a tandem series of bond-forming events.
Departing from the conventional approaches that activate
an N-H σ-bond toward coupling, we recently investigated
the scope of aryl radical additions to the nitrogen of
azomethines.13-15 However, it was unclear whether nucleo-
philic enamines could be produced using this protocol since
(10) Li, T.; Marks, J. J. Am. Chem. Soc. 1998, 120, 1757-1771 and
references therein.
(11) Leonard, N. J.; Cook, A. G. J. Am. Chem. Soc. 1959, 81, 5627-
5631.
(12) Dimethyl titanocene: (a) Petasis, N. A.; Lu, S.-P. Tetrahedron Lett.
1995, 36, 2393-2396. (b) Pyrolysis of cyclopropyl ketimines: Cloke, J.
B. J. Am. Chem. Soc. 1929, 51, 1174-1187; Stevens, R. V.; Ellis, M. C.;
Wentland, M. P. J. Am. Chem. Soc. 1968, 90, 5576-5579 and 5580-5583.
(c) Pre´vost, N.; Shipman, M. Org. Lett. 2001, 3, 2383.
(13) Johnston, J. N.; Plotkin, M. A.; Viswanathan, R.; Prabhakaran, E.
N. Org. Lett. 2001, 3, 1009-1011.
(14) For prior related work, see: (a) Takano, S.; Suzuki, M.; Kijima,
A.; Ogasawara, K. Chem. Lett. 1990, 315. (b) Takano, S.; Suzuki, M.;
Ogasawara, K. Heterocycles 1994, 37, 149. (c) Bowman, W. R.; Stephenson,
P. T.; Terrett, N. K.; Young, A. R. Tetrahedron Lett. 1994, 35, 6369. (d)
Bowman, W. R.; Stephenson, P. T.; Terrett, N. K.; Young, A. R.
Tetrahedron 1995, 51, 7959. Review: (e) Friestad, G. K. Tetrahedron 2001,
57, 5461-5496.
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Org. Lett., Vol. 4, No. 24, 2002

the corresponding vinyl radicals possess a greater degree of
conformational and configurational freedom (eq 1).16 When
vinyl bromide 1 was treated with Bu3SnH and AIBN in
Furthermore, vinyl radicals might also be produced by the
addition of heteroatom-centered radicals to alkyne π-bonds.
Hence, aminostannation was achieved by addition of a
stannyl radical to the ketimine derived from alkyne 16 in a
highly regio- and stereoselective conversion to â-stannyl-
enamine 17 (eq 2).20-22 Not unexpectedly, enamine 17
acylated at low temperature without the use of additives.23
A variety of acid chlorides varying in oxidation state and
steric hindrance furnished vinylogous amides and carbamates
18a-d with comparable ease.24 Throughout both amination
and acylation, a single olefin stereoisomer is observed
spectroscopically.25 Overall yields ranged from 49 to 60%
(three steps) for the aminostannation sequence. Although less
efficient due to the propensity for thiyl and acyl radicals to
dimerize, both alkyne aminothiolation and aminoacylation
could be similarly effected. Aminothiolation of the interme-
diate iminoalkyne provided â-arylthioenamine 18e in 33%
yield (two steps) with diphenyl disulfide as the thiyl radical
precursor (eq 2).26 Similarly, phenylselenoacetate and tri-
butylstannane gave the product of aminoacylation (18f) in
29% yield (two steps).
In summary, vinylic free radicals add efficiently to the
nitrogen of an azomethine under conditions sufficiently mild
for regioselective production of even nonstabilized (N,N-
dialkyl) enamines. These kinetically controlled transforma-
tions constitute a reductive, nondehydrative method for
enamine formation. As a synthetic method, carbon radical
additions to the nitrogen of an azomethine are presently
unique in their ability to transcend aryl and vinyl amination,
as well as their tandem variants.
n
refluxing benzene, enamine 9a was formed and trapped as
its benzoylated adduct in 68% yield (two steps from the
imine); the product of direct reduction was not observed in
the 1H NMR spectrum of the reaction mixture. Terminal vinyl
bromide 2 was cyclized to enamine 10a and isolated as its
benzoylated adduct in good overall yield (54%, 2 steps).
Ketimines possessing additional conformational constraints
readily cyclized to a variety of heterocyclic products as well.
Indolizidine enamines 11a were accessed from vinyl bro-
mides 3, giving rise to their respective benzoylated deriva-
tives in 64% and 57% yield (entries 3 and 4).
Even vinyl bromides with increased conformational mo-
bility (4 and 5) readily cyclized to provide enamine 12 in
both cases. The lower overall yields of 34% and 36% after
benzoylation (3 steps from amine) most likely reflect a
combination of the volatility of the enamine and the use of
boiling benzene since direct analysis of the reaction when
performed in C6D6 revealed clean product formation. The
cyclization of 4 provided the exocyclic enamine isomer as
the first observable enamine in this transformation, presum-
ably resulting from thermal isomerization of the endocyclic
enamine.11,17
A rapid [1,5]-hydrogen shift followed enamine formation
from 6 to give isoindole 13a. This intermediate was observed
1
by H NMR spectroscopy and fully characterized as its
crystalline, diastereomerically pure maleimide cycloadduct.
Ketimines 7 and 8 cyclized to indoles 14 and 15 with
comparable ease, demonstrating that competitive direct
reduction of the azomethine by stannane is not problematic.18
Acknowledgment. This work was supported by NIGMS
(GM-63577-01). E.N.P., B.M.N., and A.L.W. were supported
(18) This observation is significant since alternative nitrogen sources for
radical-mediated amination are competitively reduced by stannane: Azo-
acceptors (a) Alberti, A.; Bedofni, N.; Benaglia, M.; Leardini, R.; Nanni,
D.; Pedulli, G. F.; Tundo, A.; Zanardi, G. J. Org. Chem. 1992, 57, 607-
13. (b) Leardini, R.; Lucarini, M.; Nanni, D.; Pedulli, G. F.; Tundo, A.;
Zanardi, G. J. Org. Chem. 1993, 58, 2419-23. (c) Benati, L.; Placucci, G.;
Spagnolo, P.; Tundo, A.; Zanardi, G. J. Chem. Soc. Perkin Trans. 1 1977,
1684-7. Azide acceptors: (d) Kin, S.; Joe, S. H.; Do, J. Y. J. Am. Chem.
Soc. 1994, 116, 5521-2.
Scheme 1. Free Radical-Mediated Tandem Addition/Vinyl
Amination (eq 2)
(19) Reviews on cascade radical cyclizations: (a) Wang, K. K. Chem.
ReV. 1996, 96, 207-222. (b) Curran, D. P. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, UK,
1991; Vol. 4, Chapter 4.2. (c) McCarroll, A. J.; Walton, J. C. Angew. Chem.,
Int. Ed. 2001, 40, 2224-2248. (d) Curran, D. P. ACS Symp. Ser. 1998,
685, 62-71.
(20) Radical-mediated hydrostannation, lead references: (a) Omae, I.
Organotin Chemistry; Elsevier: Amsterdam, The Netherlands, 1989; Vol.
21. (b) Ensley, H. E.; Buescher, R. R.; Lee, K. J. Org. Chem. 1982, 47,
404-408. (c) Jung, M. E.; Light, L. A. Tetrahedron Lett. 1982, 23, 3851-
3854. (d) Pereyre, M.; Quintard, J.-P.; Rahm, A. Tin in Organic Synthesis;
Butterworth & Co.: London, UK, 1987.
(21) Hydrostannation of ynamines favors (>9:1) the R-stannyl enamine
regioisomer: Minie`re, S.; Cintrat, J.-C. Synthesis 2001, 705-707.
(22) Vinyl stannanes have been used extensively in target-oriented
synthesis. Review: Farina, V.; Krishnamurthy, V.; Scott, W. J. Organic
Reactions; Wiley: New York, 1997; Vol. 50, Chapter 1.
An advantage to the use of vinyl radicals as a strategy for
amination is the potential for development of carbon-carbon
bond-forming reactions as part of a reaction cascade.19
(23) Cox, A. L.; Johnston, J. N. Org. Lett. 2001, 3, 3695-3697.
(24) For reviews on the synthesis and use of vinylogous amides
(enaminones) in synthesis, see: (a) Lue, P.; Greenhill, J. V. In AdVances
in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: New
York, 1997; Vol. 67, p 209. (b) Rappoport, Z., Ed. The Chemistry of
Enamines; Wiley: New York, 1994; Vol. 1.
(25) (a) Koenig, K. E.; Weber, W. P. Tetrahedron Lett. 1973, 2533-
2536. (b) Stork, G.; Mook, R., Jr. J. Am. Chem. Soc. 1987, 109, 2829.
(26) For an example of alkene aminothiolation, see: Newcomb, M.;
Deeb, T. M. J. Am. Chem. Soc. 1987, 109, 3163-3165.
(15) Acyl radical additions to azomethine nitrogen, although mechanisti-
cally distinct, proceed well with both aldimines and ketimines: Ryu, I.;
Matsu, K.; Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 1998, 120, 5838-
5839.
(16) The analogous vinyl radical cyclizations to aldimines give the
product of 6-endo carbon-carbon bond formation: Ryu, I.; Ogura, S.;
Minakata, S.; Komatsu, M. Tetrahedron Lett. 1999, 40, 1515.
(17) (a) Lukes, R.; Dedek, V.; Novotny, L. Collect. Czech. Chem.
Commun. 1959, 24, 1117-1126.
Org. Lett., Vol. 4, No. 24, 2002
4199

in part as Boehringer-Ingelheim postdoctoral, Paget (2000),
and GAANN fellows (1999-2001), respectively. K.E.N. was
an IU STARS undergraduate research participant. Acknowl-
edgment is made to Indiana University and the donors of
the Petroleum Research Fund, administered by the American
Chemical Society, for partial support of this research.
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
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