Formation of carbon-carbon bonds using aminal radicals

Article abstract of DOI:10.1021/ol3029912

Aminal radicals were generated by radical translocation processes. For the first time, it is shown that they participate in carbon-carbon bond forming reactions. Either stannane or silane hydrogen atom donors are suitable for the reaction. More than 30 su

Full text of DOI:10.1021/ol3029912

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Formation of CarbonÀCarbon Bonds
Using Aminal Radicals
David A. Schiedler, Jessica K. Vellucci, and Christopher M. Beaudry*
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis,
Oregon 97331, United States
christopher.beaudry@oregonstate.edu
Received October 30, 2012
ABSTRACT
Aminal radicals were generated by radical translocation processes. For the first time, it is shown that they participate in carbonÀcarbon bond
forming reactions. Either stannane or silane hydrogen atom donors are suitable for the reaction. More than 30 substrate combinations are
reported, and chemical yields are as high as 91%.
Nitrogenous molecules are ubiquitous in Nature. Phar-
maceuticals, molecular catalysts, and secondary meta-
bolites often contain nitrogen. As a result, nitrogenous
molecules, such as alkaloids, make compelling targets for
synthesis. However, alkaloid synthesis is inherently compli-
cated by the nitrogen atom.1 The Lewis basic lone pair found
on amines, the presence of weakly acidic NÀH hydrogens, and
the readiness of amines to quaternize often lead to undesired
reactivity. These factors conspire against the synthetic chemist.
Figure 1. Selected nitrogen-rich alkaloids; aminals indicated by *.
Traditional strategies used to circumvent the Lewis
acidÀbase reactivity of nitrogen include: using protecting
groups,2 installing nitrogen at the end of a synthesis,3 or
packaging the nitrogen in a less reactive functional group
(e.g., as a nitrile4 or nitro5 group). Such strategies have
enjoyed widespread success in synthesis. However, a con-
ceptually different approach to avoid the acidÀbase
properties of nitrogen is to use single electron processes
(1) Hesse, M. Alkaloid Chemistry, WILEY, New York, 1981, pp 175À200.
(2) Wuts, P. G. M.; Greene, T. W. Protective Groups in Organic
Synthesis, 4th Ed. WILEY, Hoboken, NJ, 2007, pp 696À926.
(3) For example: (a) Nicolaou, K. C.; Chakraborty, T. K.; Piscopio,
A. D.; Minowa, N.; Bertinato, P. J. Am. Chem. Soc. 1993, 115, 4419–
4420. (b) Ge, H. M.; Zhang, L.ÀD.; Tan, R. X.; Yao, Z.ÀJ. J. Am.
Chem. Soc. 2012, 134, 12323–12325.
€
(7) For review, see: (a) Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S.
Angew. Chem., Int. Ed. 2007, 46, 6586–6594. (b) Heasley, B. Eur. J. Org.
Chem. 2009, 1477–1489. (c) Zhang, D.; Song, H.; Qin, Y. Acc. Chem.
Res. 2011, 44, 447–457.
(8) (a) Bhonde, V. R.; Looper, R. E. J. Am. Chem. Soc. 2011, 133,
20172–20174. (b) Iwamoto, O.; Shinohara, R.; Nagasawa, K. Chem.
Asian J. 2009, 4, 277–285. (c) Fleming, J. J.; McReynolds, M. D.; Du
Bois, J. J. Am. Chem. Soc. 2007, 129, 9964–9975. (d) Jacobi, P. A.;
Martinelli, M. J.; Polanc, S. J. Am. Chem. Soc. 1984, 106, 5594–5598.
(e) Tanino, H.; Nakata, T.; Kaneko, T.; Kishi, Y. J. Am. Chem. Soc.
1977, 99, 2818–2819. (f) Jessen, H. J.; Gademann, K. Angew. Chem., Int.
Ed. 2010, 49, 2972–2974. (g) Seiple, I. B.; Su, S.; Young, I. S.; Lewis,
C. A.; Yamaguchi, J.; Baran, P. S. Angew. Chem., Int. Ed. 2010, 49,
1095–1098. (h) Zuo, Z.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2010, 132,
13226–13228. (i) Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc.
2007, 129, 13794–13795. (j) Liu, P.; Seo, J. H.; Weinreb, S. M. Angew.
Chem., Int. Ed. 2010, 49, 2000.
(4) Tennant, G. in Comp. Org. Synth., Vol. 2 (Eds: Barton, D.; Oates,
W. D.), Pergamon Press, Oxford, 1979, pp 383À590.
(5) Ono, N. The Nitro Group in Organic Synthesis, WILEY-VCH,
New York, 2001.
(6) For selected recent examples of radical reactions as key steps in
alkaloid synthesis, see: (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.
r
10.1021/ol3029912
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(i.e., radical reactions) to build the CÀC bonds of alka-
loid molecular architectures.6
radical translocation results in a benzyl-protected amine
product.
Figure 1 shows a selection of alkaloids that has attracted
considerable interest from the synthetic community.7,8
Although more than half of the 55 carbons depicted in
Figure 1 bear heteroatoms, only five are disubstituted with
nitrogen (i.e., diamino or aminal carbons). Harnessing
reactivity specific to the aminal carbon in the presence of
heteroatom-bearing carbons could be useful in alkaloid
synthesis. Toward this end, we envisioned creating an aminal
radical intermediate that could be used in the formation of
CÀC bonds. We expected such a radical would be unreactive
toward acidic NÀH bonds and Lewis basic lone pairs,9 and it
would be well suited to forging CÀC bonds in nitrogen-rich
molecular architectures. Aminal radicals have been gener-
ated, and their spectral and physical properties have been
studied.10 However, to the best of our knowledge, they have
not been used in synthesis.11 Herein, we describe bond-
forming reactions of aminal radicals for the first time.
Scheme 2. Initial Investigations of Aminal Radical Reactivity
Scheme 1. Radical Translocation
Computational methods estimate the stabilization of an
aminal radical to be approximately 2 kcal/mol relative to
the R-amino radical.14 Thus, it should be possible to selec-
tively form an aminal radical in the presence of other nitrogen-
bearing carbons. The first substrate chosen to evaluate this
hypothesis was aminal 6, prepared in two steps from diamine
7 (Scheme 2).
Reaction of aminal 6 with methyl acrylate as a radical
acceptor led to the formation of the desired addition product
8, presumably via the route shown. Unreacted starting
material, isomer 9, overaddition product 10, and the pro-
duct of deiodination (11) were present in the reaction
mixture. Attempts to improve the yield of 8 by adjusting
reagent stoichiometry, concentration, or the hydrogen-atom
source were unsuccessful. We suspect that competitive for-
mation of 9 is the result of the additional stabilization at the
benzylic position (vide infra).
We next prepared substrate 12 in order to block reactiv-
ity at the benzylic position and simplify the product
mixture (Table 1, entry 1). Substrate 12 is prepared in
two steps and 70% overall yield from inexpensive anthra-
nilamide. Gratifyingly, 12 showed cleaner reactivity giving
61% yield of the desired products (49% yield of 13, accom-
panied by 12% of the corresponding lactam 14). The in-
creased yield may be partially attributable to the capto-dative
effect: one nitrogen is relatively electron poor, and one
nitrogen is relatively electron rich.15
Carbon-centered radicals bearing one nitrogen (R-amino
radicals) are well-known.12 A convenient method for
their generation is by radical translocation (Scheme 1).
For example, homolytic cleavage of a CÀI bond in 1 gen-
erates intermediate 2, which undergoes hydrogen-atom trans-
fer to generate stabilized R-amino radical 3.13 The stability
provided by the neighboring nitrogen atom is 11 kcal/mol.14
Addition to a radical acceptor such as methyl acrylate
leads to 4, which receives a hydrogen atom from Bu3SnH
to form the product (5). Use of iodobenzyl to initiate
(9) NÀH bonds, OÀH bonds, and lone pairs are known to be
spectators in radical reactions. For example, see: (a) Urry, W. H.;
Juveland, O. O.; Stacey, F. W. J. Am. Chem. Soc. 1952, 74, 6155.
(b) Bongini, A.; Cardillo, G.; Orena, M.; Sandri, S.; Tomasini, C. J. Org.
€
Chem. 1986, 51, 4905–4910. (c) Sibi, M. P.; Ji, J.; Wu, J. H.; Gurtler, S.;
Porter, N. A. J. Am. Chem. Soc. 1996, 118, 9200–9201.
ꢀꢁ
ꢁ
(10) (a) Yao, C.; CuadradoÀPeinado, M. L.; Polasek, M.; Turecek,
F. Angew. Chem., Int. Ed. 2005, 44, 6708–6711. (b) Novais, H. M.;
Steenken, S. J. Am. Chem. Soc. 1986, 108, 1–6.
Thiols are used as polarity-reversal catalysts in radical
reactions and may assist in hydrogen atom transfer events,16
and the addition of BnSH increased reaction yields (entry 2).
Further increasing the stoichiometry of the thiol had little
effect on the overall yield (entry 3), but 13 was formed as the
(11) Fragementation and protonation reactions of aminal radicals
have been reported. See: (a) CabreraÀRivera, F. A.; OrtızÀNava, C.;
´
ꢀ
ꢀ
^
Escalante, J.; HernandezÀPerez, J. M.; Ho, M. Synlett 2012, 23, 1057–
1063. (b) Steenken, S.; Telo, J. P.; Novais, H. M.; Candeias, L. P. J. Am.
Chem. Soc. 1992, 114, 4701–4709.
(12) For review, see: (a) Aurrecoechea, J. M.; Suero, R. Arkivoc 2004,
14, 10–35. (b) Renaud, P.; Giraud, L. Synthesis 1996, 8, 913–926.
(13) Williams, L.; Booth, S. E.; Undheim, K. Tetrahedron 1994, 50,
13697–13708.
(15) Leroy, G.; Dewispelaere, J.ÀP.; Benkadour, H.; Riffi Temsamani,
D.; Wilante, C. Bull. Soc. Chim. Belg. 1994, 103, 367–378.
(16) Roberts, B. P. Chem. Soc. Rev. 1999, 28, 25–35.
(14) Song, K.ÀS.; Liu, L.; Guo, Q.ÀX. Tetrahedron 2004, 60, 9909–
9923.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Reactivity of Aminal 12
combined
yield
entry
RÀH
additive
(13:14)
1
2 equiv of Bu3SnH
2 equiv of Bu3SnH
2 equiv of Bu3SnH
none
none
61% (80:20)
2a
3
0.1 equiv of BnSH 86% (30:70)
0.9 equiv of BnSH 75% (100:0)
0.9 equiv of BnSH 0%
4
5b
6
2 equiv of Bu3SnH
0.9 equiv of BnSH 18% (100:0)
2 equiv of (TMS)3SiH none
48% (48:52)
7a
8
2 equiv of (TMS)3SiH 0.1 equiv of BnSH 91% (77:23)
2 equiv of (TMS)3SiH 0.9 equiv of BnSH 89% (81:19)
a 5 equiv of methyl acrylate used. b AIBN was omitted from the
reaction mixture.
sole product. No product formation occurs in the absence
of stannane (entry 4), suggesting the thiol is not the
terminal hydrogen atom donor. We also performed a
control experiment by omitting the AIBN and observed
only modest product formation (entry 5). We speculate
that in hot benzene some homolytic cleavage of the CÀI
bond may occur. The aminal radical reaction is also
successful using (TMS)3SiH as a hydrogen atom donor
(entry 6). The yield of the reaction is improved by adding
BnSH (entries 7 and 8).
The aminal radical reaction was examined with various
aminals and radical acceptors. The aminals were made by
condensing the corresponding amino amide with formalin
(see Supporting Information). Use of acrylonitrile, tert-butyl
acrylate, and acrolein as radical acceptors in the reaction
with 12 results in good yields of the addition products 15, 16,
and 17, respectively (Figure 2). Use of Bu3SnH as a hydro-
gen atom source gives superior yields compared with
(TMS)3SiH. However, use of the silane often gives synthe-
tically useful yields without the use of heavy metals, and we
report yields with both reagents. Attachment of the iodo-
benzyl group at the amide nitrogen also resulted in produc-
tive reactions with methyl acrylate, acrylonitrile, or tert-butyl
acrylate to give products 18, 19, and 20, respectively.
Aliphatic six-membered ring aminals participated in the
reaction, provided one nitrogen bears an electron-with-
drawing group. The acetamide-derived aminal added to
methyl acrylate to give 21 in good yield. We found that
trifluoroacetamides also participate in the reaction giving
22. Notethattheaminalradicalisgeneratedinthe presence
of the amino-substituted carbon. In these cases, products
derived from formation of the R-amino radicals are not
observed. It appears that, in the absence of benzylic stabili-
Figure 2. Scope of the aminal radical reaction. a Method A:
5.0 equiv of alkene, 2.0 equiv of Bu3SnH, 0.1 equiv of BnSH,
0.2 equiv of AIBN, 0.10 M PhH, reflux, 3 h. b Method B: 5.0 equiv
of alkene, 2.0 equiv of (TMS)3SiH, 0.1 equiv of BnSH, 0.2 equiv of
AIBN, 0.10 M PhH, reflux, 12 h. c 0.9 equiv of BnSH. d 3.0 equiv of
methyl acrylate. e 10 equiv of methyl acrylate. f 0.2 equiv of BnSH.
groups did not participate in the reaction; they gave only
complex intractible product mixtures.
Intramolecular reactions were possible, and compound
23 was produced as a single diastereomer, whereas 24
was formed as a diastereomeric mixture. Bicyclic five-
membered aminals are competent substrates in the reaction.
Pipecolic acid derived aminals react with methyl acrylate
and acrylonitrile in good yields and selectivities to form
25 and 26, respectively. Finally, proline-derived aminals
undergo diastereoselective reactions giving 27 and 28,
respectively.
The relative stereochemistry of 23 was determined by 1H
NMR methods. First, methyne hydrogen Ha is positioned
axial as evidenced by NOESY crosspeaks to the indicated
hydrogens (Scheme 3). The small (2 Hz) coupling constant
between Ha and Hb suggests Hb is equatorial. The diaster-
eoselectivity in the formation of 23 may be a result of the
model shown in Scheme 3. The favored conformation of 29
positions the ester away from the methylene groups on
the tetrahydropyrimidone ring. The favored conforma-
tion leads to formation of 23. As the steric size of the
ꢂ
zation (vis-a-vis with substrate 6), aminal radicals selec-
tively form in the presence of amino-substituted carbons.
Substrates that lacked electron-withdrawing carbonyl
Org. Lett., Vol. XX, No. XX, XXXX
C

react with radical acceptors in CÀC bond-forming reac-
tions in good yields with both Bu3SnH and (TMS)3SiH as
hydrogen atom donors. Aminals can be formed from
aromatic or aliphatic diamines, provided that one nitro-
gen bears an electron-withdrawing carbonyl group. The
reactivity of the aminal radical is different from that of the
R-amino radical; specifically it can be formed in the presence
of amino-substituted carbon atoms. We believe this reactiv-
ity will be useful in the synthesis of nitrogen-rich alkaloids,
and efforts to apply this chemistry in synthesis are underway
in our laboratory.
Scheme 3. Plausible Model for Formation of 23
Acknowledgment. Financial support from Oregon
State University is acknowledged. The National Science
Foundation (CHE-0722319) and the Murdock Charita-
ble Trust (2005265) are acknowledged for support of the
NMR facility.
pyrimidone ring decreases, the selectivity should de-
crease. This hypothesis is consistent with the observation
that 24 is produced as a diastereomeric mixture. The favored
diastereomer of the bicyclic aminal products 25À28 likely
results from addition to the convex face of the bicycle. The
relative stereochemistry was confirmed using NOESY
methods.
Supporting Information Available. Experimental pro-
cedures, spectroscopic data, 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.
In conclusion, aminal radicals are formed via radical
translocation reactions. These carbon-centered radicals
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX