Reductive synthesis of aminal radicals for carbon-carbon bond formation

Article abstract of DOI:10.1021/ol500024q

Aminal radicals were generated by reduction of the corresponding amidine or amidinium ion. The intermediate radicals participate in C-C bond-forming reactions to produce fully substituted aminal stereocenters. No toxic additives or reagents are required. More than 30 substrate combinations are reported, and chemical yields are as high as 99%.

Full text of DOI:10.1021/ol500024q

Letter
pubs.acs.org/OrgLett
Reductive Synthesis of Aminal Radicals for Carbon−Carbon Bond
Formation
David A. Schiedler, Yi Lu, and Christopher M. Beaudry*
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, Oregon 97331, United States
S
* Supporting Information
ABSTRACT: Aminal radicals were generated by reduction of the corresponding
amidine or amidinium ion. The intermediate radicals participate in C−C bond-
forming reactions to produce fully substituted aminal stereocenters. No toxic
additives or reagents are required. More than 30 substrate combinations are
reported, and chemical yields are as high as 99%.
such as 2. The aminal radicals add to electron-poor alkenes to
iologically active molecules commonly contain one or
Bmore nitrogen atoms. As a result, nitrogenous molecules, give products of carbon−carbon bond formation (3). Radical
such as alkaloids, make compelling targets for synthesis.1
translocation selectively activates the aminal position in the
presence of carbons bearing only one nitrogen atom.
Intermolecular and intramolecular reactions are possible, and
diastereoselectivities can be quite high.
However, synthesis of molecules containing Lewis basic
nitrogen atoms or Bronsted acidic nitrogenous functional
groups is not trivial. For example, the Lewis basic reactivity of
amines, the weakly acidic N−H hydrogens, and the ability of
amines to quaternize represent considerable challenges for the
synthetic chemist.
Single-electron processes (i.e., radical reactions) can be used
to circumvent the acid−base reactivity of nitrogen.2 Carbon-
centered radicals are generally tolerant of heteroatom lone pairs
and N−H bonds. Thus, chemoselective reactions of nitrogen-
rich functional groups would enjoy useful application in
synthesis. The aminal functional group was identified as a
particularly attractive substrate for radical-based bond-forming
reactions.
Aminals are conveniently prepared from condensation
reactions of readily available starting materials. Furthermore,
calculations suggested that carbon-centered aminal radicals
could be prepared in the presence of other nitrogen-containing
carbon atoms.3
We recently reported the first use of aminal radical
intermediates in synthetic reactions (Scheme 1).4 Iodobenzyl-
substituted aminals (1) undergo radical translocation5 (i.e.,
hydrogen atom abstraction) to give aminal radical intermediates
Despite the potential of the aminal radical reaction in
synthesis, a complementary approach for the formation of the
aminal radical intermediates was desired. Such a reaction would
avoid the use of toxic or foul-smelling reagents. Starting
materials that are convenient to prepare and do not require an
iodobenzyl group would be particularly useful. An amidine
reduction reaction (Scheme 1; 4 → 3) satisfies these criteria
and was selected for further study.
The success of substrate 1 in the translocation reaction
indicated that if presumptive intermediate radical 2 was
produced under different conditions then the desired product
3 could be formed. Amidine 4 was prepared and subjected to
reductive conditions in the presence of acrylonitrile (Scheme
2). Reductions with Zn and LiDBB6 did not give the desired
product (entries 1−4). Gratifyingly, treatment of 4 with the
Scheme 2. Development of the Amidine Reduction Reaction
Scheme 1. Formation of C−C Bonds with Aminal Radicals
Received: January 3, 2014
Published: February 10, 2014
© 2014 American Chemical Society
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single-electron reducing agent SmI2,7 camphorsulfonic acid
(CSA), and acrylonitrile as a radical acceptor gave product 3
(entry 5). The reaction is operationally easy, requires no
noxious reagents, is high yielding, and occurs rapidly at rt. The
reaction yield decreased if an acid was not present (entry 6).
After a screen of several acids, ammonium chloride was
identified as a convenient and effective proton source that
generally gives higher yields than CSA (entry 7).8
Scheme 3. Scope of the Amidine Reduction Reaction
The amidine reduction reaction was examined with various
substrates and acceptors (Scheme 3). Quinazolinones have
important medicinal properties,9 are easy to prepare,10 and have
an acylamidine substructure. Substrate 4 reacted with acrylates
to form products 5 and 6, respectively. In the amidine
reduction reaction, a benzyl group is not required. Thus, phenyl
substitution is tolerated, and 7 reacts with acrylonitrile, methyl
acrylate, and tert-butyl acrylate to give 8, 9, and 10, respectively.
Unsubstituted quinazolinone 11 reacted to give 12−14 in good
yield. The presumptive aminal radical intermediate does not
add to unactivated alkenes. Thus, substrate 15 preferentially
undergoes bimolecular addition to acrylonitrile and acrylates
giving 16−18 rather than unimolecular 5-exo-trig cyclizations of
the pendent alkene. Gratifyingly, substituted amidines also
participate in the reaction in good yields. Substrate 19 gave
products 20−22 which contain fully substituted carbon
stereocenters. Benzyl-substituted amidine 23 reacted to give
fully substituted aminals 24−26. Even the tert-butyl-substituted
amidine 27 reacts to give product 28, which contains vicinal
fully substituted carbon atoms. Cyclopropyl groups are
tolerated in the substrate (29), provided they are distant
from the carbon-centered radicals, to give product 30. A
sterically hindered amidine appended with a cyclohexyl group
(31) participated giving product 32. Electron-rich arenes are
tolerated in the reaction, and 33 reacts to form 34 in high yield.
Disubstituted alkenes are reactive acceptors, and 4 added to
ethyl crotonate to give 35 in good yield, but the
diastereoselectivity was modest.11 However, intramolecular
reactions proceeded in good yield and high diastereocontrol.
Substrate 36 reacted to form a six-membered ring product 37.
This reaction also demonstrates that the amidine can be
substituted at either nitrogen atom. Compound 38 contains a
trisubstituted alkene acceptor, and it reacts smoothly in high
yield and high diastereoselectivity to give 39, which contains a
quaternary carbon stereocenter. The relative stereochemistry
was confirmed by NOE methods.
Acyl amidines that are not quinazolinones are suprisingly rare
in the literature. Nevertheless, we found that they also
participate in the reaction (Scheme 4). Spiro-fused amidine
40 reacted to produce 41. Substituted amidine substrate 42
reacted under the conditions to give 43. Bicyclic amidine 44
gave 45, which contains a fully substituted stereocenter. The
acyl substiutent may be present as an acetyl group on the
amidine, and substrate 46 reacted with acrylonitrile to give 47.
Pyrimidinone 48 underwent dearomatizative reductive bond
formation to give substituted product 49.
The mechanism of the amidine reduction reaction may
involve initial protonation of the amidine to form an amidinium
ion, followed by single-electron reduction to give the aminal
radical. If this is the case, then amidinium ions should
participate in the reaction.
Various amidinium ions were formed using standard
transformations of the corresponding amidine.10 Subjection of
the amidinium ions to SmI2, acid, and a radical acceptor led to
carbon−carbon bond formation in good yields (Scheme 5).12
a
Reaction was performed with CSA.
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Aliphatic amidinium ions also participated in the reduction.
Known amidinium 58 underwent reductive bond formation
with acryonitrile to form product 59. Phenyl-substituted
amidinium 60 reacted to form 61.
Scheme 4. Scope of Amidine Substrates
Mechanistically, amidine 4 may receive a proton and an
electron to form neutral aminal radical 2 (Scheme 6, eq 1). The
Scheme 6. Mechanistic Investigations
Scheme 5. Amidinium Reduction
aminal radical could react with the electron-poor acceptor to
give radical 62. This radical would be further reduced and
protonated to give the product 3. Alternatively, the acrylate
may be reduced to radical 63 (Scheme 6, eq 2). Addition to the
amidine would give intermediate 64. This intermediate could
be reduced and protonated to give the product 3. Related
radical mechanisms have been proposed in the literature.13
To distinguish between these mechanistic possibilities,
amidine substrate 65 was prepared, which contains a cyclo-
propyl group attached directly to the amidine. Reduction of 65
by SmI2 in the absence of a radical acceptor leads to
fragmentation of the cyclopropane and formation of 66
(Scheme 6, eq 3). Reduction of 65 in the presence of an
Quinazolinone-derived amidinium ion 50 participated in the
reaction with standard radical acceptors to give 51−53.
Substituted amidinium ion 54 also particpated in the reduction,
giving a product (55) with a fully substituted carbon
stereocenter. The monocyclic amidinium substrate 56 also
participated in the reaction giving good yield of the desired
product (57).
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(5) (a) Rowlands, G. J. Tetrahedron 2010, 66, 1593−1636.
(b) Aurrecoechea, J. M.; Suero, R. ARKIVOC 2004, 14, 10−35.
(c) Renaud, P.; Giraud, L. Synthesis 1996, 8, 913−926. (d) Snieckus,
V.; Cuevas, J.-C.; Sloan, C. P.; Liu, H.; Curran, D. J. Am. Chem. Soc.
1990, 112, 896−898.
acceptor gave addition product 67 and formation of ring-
fragmentation product 68 (Scheme 6, eq 4).14
Cyclopropyl-containing radical acceptors were also inves-
tigated. Amidine 4 reacted with cyclopropyl acrylate 69 to form
addition product 70 (Scheme 6, eq 5). The balance of the
material was the reduction product 71 and unreacted starting
material. Control experiments indicated the acrylate acceptors
(acrylonitrile, methyl acyrlate, tert-butyl acrylate, and 69) did
not react under the reaction conditions in the absence of the
amidine. This suggests that the amidine is reduced prior to
reactions with the alkene acceptor. Reduction of the aminal
radical such as 2 to carbanion intermediates is unlikely in the
presence of strong acids (CSA and NH4Cl). On the basis of
these experiments, we believe the first mechanism is operative
(i.e., 4 → 2 → 62 → 3, Scheme 6, eq 1).
In conclusion, aminal radicals are formed via reduction of the
corresponding amidine and amidinium ions in the presence of a
proton source. The putative radical intermediates react with
radical acceptors in C−C bond-forming reactions in good yields
without the use of heavy metal hydrides or thiols. The reaction
can be performed in inter- and intramolecular contexts in high
yield. Furthermore, fully substituted aminal stereocenters are
formed in good yields with this chemistry. We believe this
reactivity will be useful in the synthesis of nitrogen-rich
alkaloids, and efforts to apply this chemistry in synthesis are
underway in our laboratory.
(6) (a) Freeman, P. K.; Hutchinson, L. L. Tetrahedron Lett. 1976, 17,
1849−1852. (b) Donohoe, T. J.; House, D. J. Org. Chem. 2002, 67,
5015−5018.
(7) (a) Gopalaiah, K.; Kagan, H. B. Chem. Rec. 2013, 13, 187−208.
(b) Kagan, H. B. Tetrahedron 2003, 59, 10351−10372.
(8) The reaction stoichiometry requires 2 equiv of acid, but our
optimized conditions use 1.1 equiv of H+. We speculate that upon
aqueous workup an anionic intermediate (e.g., an enolate) is
protonated.
(9) (a) Chawla, A.; Batra, C. Int. Res. J. Pharm. 2013, 4, 49−58.
(b) Rajput, R.; Mishra, A. P. Int. J. Pharm. Pharma. Sci. 2012, 4, 66−70.
(c) Rajput, C. S.; Bora, P. S. Int. J. Pharma. Bio. Sci. 2012, 3, 119−132.
(10) See the Supporting Information.
(11) The configuration of the major diastereomer was not
determined.
(12) The amidinium reduction stoichiometry requires 1 equiv of acid,
and the reaction yield drops substantially if acid is omitted.
(13) Ishida, T.; Tsukano, C.; Takemoto, Y. Chem. Lett. 2012, 41, 44−
46.
(14) SmI2 is known to induce fragmentation of strained rings with
incorporation of iodide, likely giving intermediate 72, which would
undergo intramolecular substitution to give 68. See: (a) Kwon, D. W.;
Kim, Y. H. J. Org. Chem. 2002, 67, 9488−9491. (b) Park, H. S.; Kwon,
D. W.; Lee, K.; Kim, Y. H. Tetrahedron Lett. 2008, 49, 1616−1618.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, spectroscopic data, and depiction of
1H and 13C NMR spectra 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: christopher.beaudry@oregonstate.edu.
Author Contributions
The manuscript was written through contributions of all
authors.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from Oregon State University is acknowl-
edged.
REFERENCES
■
(1) Hesse, M. Alkaloid Chemistry; Wiley: New York, 1981; pp 175−
200.
(2) Selected recent examples of radical reactions in alkaloid synthesis:
(a) Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C.
A.; Gallagher, J. D. J. Am. Chem. Soc. 2006, 128, 8678−8693.
(b) Movassaghi, M.; Schmidt, M. A. Angew. Chem., Int. Ed. 2007, 46,
3725−3728. (c) Zhang, H.; Curran, D. P. J. Am. Chem. Soc. 2011, 133,
10376−10378. (d) Palframan, M. J.; Parsons, A. F.; Johnson, P.
Tetrahedron Lett. 2011, 52, 1154−1156.
(3) The aminal radical is predicted to be 1−2 kcal/mol more stable
than the α-amino radical. See: Song, K.-S.; Liu, L.; Guo, Q.-X.
Tetrahedron 2004, 60, 9909−9923.
(4) Schiedler, D. A.; Vellucci, J. K.; Beaudry, C. M. Org. Lett. 2012,
14, 6092−6095.
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