Sml2-mediated carbon-carbon bond fragmentation in a-aminomethyl malonates

Article abstract of DOI:10.1021/ol901608k

A new and efficient samarium diiodide-promoted carbon-carbon bond fragmentation reaction of α-aminomethyl malonates, taking place normally at room temperature and generating the corresponding deaminomethylation products In 74-94% yields, is reported. The presence of the amino group Is necessary for the success of the current transformation.

Full text of DOI:10.1021/ol901608k

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4136-4138
SmI2-Mediated Carbon-Carbon Bond
Fragmentation in r-Aminomethyl
Malonates
Qiongfeng Xu,†,‡ Bin Cheng,‡,§ Xinshan Ye,*,† and Hongbin Zhai*,†,‡
The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking UniVersity, 38 Xue Yuan Road, Beijing 100083, China, The Key
Laboratory of Synthetic Chemistry of Natural Substances and the State Key Laboratory
of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, China, and Hefei National
Laboratory for Physical Science at Microscale and Department of Chemistry,
UniVersity of Science and Technology of China, Hefei, Anhui 230026, China
zhaih@mail.sioc.ac.cn; xinshan@mail.bjmu.edu.cn
Received July 18, 2009
ABSTRACT
A new and efficient samarium diiodide-promoted carbon-carbon bond fragmentation reaction of r-aminomethyl malonates, taking place
normally at room temperature and generating the corresponding deaminomethylation products in 74-94% yields, is reported. The presence
of the amino group is necessary for the success of the current transformation.
Samarium diiodide, or SmI2, was first introduced by Kagan
in the late 1970s as a powerful one-electron reducing agent
for a variety of organic functional groups.1 Since then, it
has been extensively employed to mediate many processes
ranging from functional group interconversion to complex
carbon-carbon bond-forming sequences.2 Among those
transformations, a number of fragmentation reactions have
been investigated, the majority of which have been aimed
at carbon-heteroatom bond fragmentation such as dehalo-
genation, deoxygenation, and deamination.2k,3 In contrast,
relatively few endeavors have been devoted to the carbon-
carbon bond fragmentation reactions although they just started
to gain increasing popularity in recent years.4 For the latter
category, the presence of a ring-strained system5 or a leaving
group6 (such as halo atoms, dithiocarbonyl group, etc.) is usually
required to trigger the reaction, while certain 1,4-diketones,
† Peking University.
‡ Shanghai Institute of Organic Chemistry.
§ University of Science and Technology of China.
(1) (a) Namy, J. L.; Girard, P.; Kagan, H. B. NouV. J. Chim. 1977, 1, 5.
(b) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102,
2693.
(2) For reviews on the use of SmI2 in organic synthesis, see: (a)
Gopalaiah, K.; Kagan, H. B. New J. Chem. 2008, 32, 607. (b) Ebran, J.-P.;
Jensen, C. M.; Johannesen, S. A.; Karaffa, J.; Lindsay, K. B.; Taaning, R.;
Skrydstrup, T. Org. Biomol. Chem. 2006, 4, 3553. (c) Edmonds, D. J.;
Johnston, D.; Procter, D. J. Chem. ReV. 2004, 104, 3371. (d) Kagan, H. B.
Tetrahedron 2003, 59, 10351. (e) Steel, P. G. J. Chem. Soc., Perkin Trans.
1 2001, 2727. (f) Kagan, H.; Namy, J. L. Lanthanides: Chemistry and Use
in Organic Synthesis; Kobayashi, S., Ed.; Springer: Berlin, 1999; p 155.
(g) Krief, A.; Laval, A.-M. Chem. ReV. 1999, 99, 745. (h) Molander, G. A.;
Harris, C. R. Tetrahedron 1998, 54, 3321. (i) Molander, G. A.; Harris, C. R.
Chem. ReV. 1996, 96, 307. (j) Molander, G. A. Org. React. 1994, 46, 211.
(k) Molander, G. A. Chem. ReV. 1992, 92, 29. (l) Soderquist, J. A.
Aldrichimica Acta 1991, 24, 15.
(3) For a comprehensive account of carbon-heteroatom bond fragmen-
tation, see: (a) Concellon, J. M.; Rodriguez-Solla, H. Eur. J. Org. Chem.
2006, 7, 1613. (b) Dahlen, A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004,
3393. For some recent work, see: (c) Honda, T.; Hisa, C. Tetrahedron Lett.
2009, 50, 4654. (d) Lam, K.; Marko, I. E. Org. Lett. 2009, 11, 2752. (e)
Honda, T.; Aranishi, E.; Kaneda, K. Org. Lett. 2009, 11, 1857. (f) Wang,
X.; Mao, H.; Xie, G.; Du, J. Synth. Commun. 2008, 38, 2908. (g) Molander,
G. A.; Stengel, P. J. J. Org. Chem. 1995, 60, 6660. (h) Enholm, E. J.;
Schreier, J. A. J. Org. Chem. 1995, 60, 1110
(4) Williams, D. B. G.; Blann, K.; Caddy, J. Org. Prep. Proc. 2001,
33, 565.
.
10.1021/ol901608k CCC: $40.75
Published on Web 08/21/2009
 2009 American Chemical Society

within either ring-strained or strain-free systems, have been
found to undergo carbon-carbon bond fragmentation.7
Recently, we investigated the reaction of SmI2 with a series
of R-aminomethyl malonates, a type of strain-free substrate
containing a quaternary carbon center adjacent to the
alkoxycarbonyl groups. Upon treatment with freshly prepared
SmI2 (1.1 equiv), approximately 50% of diester 1a was
converted into 2a within 20 min (Table 1, entry 1), through
Table 2. SmI2-Mediated Carbon-Carbon Bond Fragmentation of 1
Table 1. Optimization of Reaction Conditions with 1a
entry
SmI2 (equiv)
time
yielda (%)
1
2
3
4
1.1
2.0
2.2
5.0
20 minb
20 minb
2 h
ca. 50c
88
94
a Isolated yield. b SmI2 (5 equiv) was added while the substrate was heated
in THF, and the mixture was then heated at reflux for an additional 0.5 h.
2 h
87
a Isolated yield. b The reaction mixture turned from blue to yellow after
about 20 min, indicating that SmI2 was completely consumed. c Estimated
yield based on a TLC analysis.
derivatives (dibenzyl, dimethyl, or diethyl malonates, or a
lactone) underwent clean and smooth fragmentation to form
the corresponding products in good to excellent yields
(74-94%, entries 1-5, 7, 8, and 10). (iii) The presence of
the amino group is necessary for the success of the reaction.
For example, it can be a dimethylamino, diethylamino,
dibenzylamino, piperidinyl, morpholinyl, or anilino group.
No reaction occurred in the case of amide 1i (entry 9), and
a messy mixture was generated from ammonium 1f (entry
6). In addition, as demonstrated by further studies, replace-
ment of the amino group with an iodo, ethoxy, or phenyl
did not bring about the desired fragmentation. (iv) While
tertiary amine substrates reacted readily at room temperature,
a secondary amine counterpart 1h (entry 8) required both
harsher reaction conditions and extra SmI2 to secure a useful
transformation.
a new and intriguing type of carbon-carbon bond fragmen-
tation. If the quantity of SmI2 was increased to 2.0 equiv,
the reaction was complete in 20 min, affording 2a in 88%
yield (entry 2). When the substrate was treated with more
SmI2 (2.2 and 5.0 equiv) for longer reaction time (2 h), the
yields were found to be 94% and 87%, respectively (entries
3 and 4). Therefore, the quantity of SmI2 and the reaction
time were fixed at 2.2 equiv and 2 h, respectively, for most
of the subsequent experiments.
To examine the generality and scope of the SmI2-mediated
carbon-carbon bond fragmentation method, a series of
R-aminomethyl malonates8 were scrutinized (Table 2). The
following observations have been made. (i) The R1 group in
1 (Table 2) can be a methyl, a benzyl, or a methylene within
a lactone ring. (ii) Except for 1f and 1i, all malonate
The current fragmentation seems to proceed via a free
radical reaction pathway. To collect pertinent evidence, the
following experiment was executed. As shown in Scheme 1,
(5) For examples of SmI2-promoted C-C bond in ring-strain systems,
see: (a) Lange, G. L.; Gottardo, C.; Merica, A. J. Org. Chem. 1999, 64,
6738. (b) Lange, G. L.; Merica, A. Tetrahedron Lett. 1999, 40, 7897. (c)
Lange, G. L.; Furlan, L.; MacKinnon, M. C. Tetrahedron Lett. 1998, 39,
5489. (d) Lange, G. L.; Gottardo, C. Tetrahedron Lett. 1994, 35, 6607. (e)
Comins, D. L.; Zheng, X. J. Chem. Soc., Chem. Commun. 1994, 2681. (f)
Molander, G. A.; McKie, J. A. J. Org. Chem. 1991, 56, 4112. (g) Batey,
R. A.; Motherwell, W. B. Tetrahedron Lett. 1991, 32, 6649. (h) Beerli, R.;
Bruner, E. J.; Broschberg, H. J. Tetrahedron Lett. 1992, 33, 6449. (i) Hwang,
J. T.; Liao, C. C. Tetrahedron Lett. 1991, 32, 6583.
Scheme 1. Reaction of 1b with 1.2 Equiv of SmI2
(6) (a) Ananthanarayan, T. P.; Gallagher, T.; Magnus, P. J. Chem. Soc.,
Chem. Commun. 1982, 709. (b) Honda, T.; Naito, K.; Yamane, S.; Suzuki,
Y. J. Chem. Soc., Chem. Commun. 1992, 1218. (c) Molander, G. A.; Etter,
J. B.; Zinke, P. W. J. Am. Chem. Soc. 1987, 109, 453.
(7) (a) Haque, A.; Ghosh, S. Chem. Commun. 1997, 2039. (b) Williams,
D. B. G.; Blann, K.; Holzapfel, C. W. J. Chem. Soc., Perkin Trans. 1 2001,
219. (c) Camps, P.; Lukach, A. E.; Vazquez, S. Tetrahedron 2001, 57, 2419.
(8) Compounds 1a-g and 1j were prepared according to: (a) Miller,
R. B.; Smith, B. F. Synth. Commun. 1973, 3, 359. Compound 1h was
prepared according to: (b) Desai, P.; Schildknegt, K.; Agrios, K. A.;
Mossman, C.; Milligan, G. L.; Aube, J. J. Am. Chem. Soc. 2000, 122, 7226.
The detailed preparation for these compounds can also be found in the
Supporting Information.
careful addition of SmI2 (1.2 equiv) to a solution of compound
1b in THF did provide the homocoupling product 3b (63%) in
addition to the fragmentation product 2a (57%). Successful
isolation of dimer 3b has thus confirmed our hypothesis that
the reaction involves free radical intermediates.
Org. Lett., Vol. 11, No. 18, 2009
4137

On the basis of all the information described above, a
tentative mechanism has been proposed for the fragmentation
reaction of R-aminomethyl malonates (Scheme 2). Com-
and the carbonyl oxygen of the other ester group. Fragmen-
tation of 4b leads to Sm(III) enolate 5b and radical 6b.
Primary radical 6b can either undergo dimerization via
homocoupling to give 3b or be further reduced to afford
anion 7b in the presence of excess SmI2. After aqueous
workup, 5b and 7b are transformed into 2a and 8b,
respectively. Alternatively, radical 6b could attract a proton
from the solvent to afford 8b.11
Scheme 2. Proposed Mechanism
In conclusion, we have developed a novel and efficient
SmI2-promoted carbon-carbon bond fragmentation reaction
of R-aminomethyl malonates, which takes place normally
at room temperature and generates the deaminomethylation
products in 74-94% yields. The presence of the amino group
is necessary for the success of the transformation. The current
fragmentation can be considered conceptually as a retro-
Mannich reaction (although no aldehydes or imines would
be obtained from this reaction), which should find potential
applications in organic synthesis.
Acknowledgment. Financial support was provided by
the grants from NSFC (20625204; 20632030; 90713007;
20772141) and MOST_863 (2006AA09Z405; 2006AA09Z446).
We are indebted to Professor Xueshun Jia of Shanghai
University for enlightening discussions.
pound 1b is taken as an example here to illustrate the reaction
pathways. Upon treatment with SmI2, simultaneous coordi-
nation9,10 of samarium to an electron-rich nitrogen atom and
two carbonyl oxygen atoms might take place to form 1b′.
Unsuccessful transformation of 1f and 1i presumably resulted
from failure in prior tridentate coordination to samarium.
Subsequently, partial reduction of 1b′ is realized through
single electron transfer (SET) to produce a ketyl radical anion
4b, in which Sm(III) might also coordinate to the nitrogen
Supporting Information Available: Experimental pro-
1
cedures, analytical data, and copies of H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL901608K
(9) (a) Guazzelli, G.; Grazia, S. D.; Collins, K. D.; Matsubara, H.; Spain,
M.; Procter, D. J. J. Am. Chem. Soc. 2009, 131, 7214. (b) Duffy, L. A.;
Matsubara, H.; Procter, D. J. J. Am. Chem. Soc. 2008, 130, 1136
.
(11) Katritzky, A. R.; Wang, J.; Henderson, S. A. Heterocycles 1998,
48, 1567.
(10) Flowers, R. A., II. Synlett 2008, 10, 1427
.
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Org. Lett., Vol. 11, No. 18, 2009