Selective reduction of barbituric acids using SmI2/H 2O: Synthesis, reactivity, and structural analysis of tetrahedral adducts

Article abstract of DOI:10.1002/anie.201306484

Making a mark: Since the 1864 landmark discovery by Adolf von Baeyer, barbituric acids have played a prominent role in organic synthesis. Herein, the first chemoselective monoreduction of barbituric acids to the corresponding hemiaminals is described. The method delivers mono- and bicyclic hemiaminal products by a general single-electron-transfer polarity reversal mechanism. Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://angewandte.org/open.

Full text of DOI:10.1002/anie.201306484

Angewandte
Chemie
DOI: 10.1002/anie.201306484
Synthetic Methods
Selective Reduction of Barbituric Acids Using SmI /H O: Synthesis,
2
2
Reactivity, and Structural Analysis of Tetrahedral Adducts**
Michal Szostak,* Brice Sautier, Malcolm Spain, Maike Behlendorf, and David J. Procter*
[1]
Since the 1864 landmark discovery by Adolf von Baeyer,
barbituric acids have played a prominent role in medicine and
organic synthesis. The barbituric acid scaffold occurs in more
than 5000 pharmacologically active compounds, including
commonly used anticonvulsant, hypnotic, and anticancer
[
2]
agents (Figure 1a). Moreover, as an easily accessible feed-
stock material, it is an extremely useful building block for
[3]
organic synthesis. However, despite the fact that barbitu-
rates have been extensively studied for over a century, the
general monoreduction of barbituric acids remains
[
4]
unknown, even though it would have considerable potential
for the production and discovery of pharmaceuticals, materi-
als, and polymers. Interestingly, the barbiturate monoreduc-
tion products would formally constitute a new class of
tetrahedral intermediates of amide bond addition reactions,
only few of which have been successfully isolated to date
[
5]
because of their transient nature.
Single-electron-transfer reactions open up unexplored
reaction space charted with chemoselectivity and reactivity
[6]
levels difficult to access by ionic reaction mechanisms. The
generation of ketyl-type radicals with SmI is particularly
2
valuable in this regard because of the excellent chemo-
selectivity imparted by the reagent and the potential to effect
polarity reversal of the carbonyl group through a single-
Figure 1. a) Examples of pharmacologically active barbiturates.
b) Polarity inversion strategy using SET approach. c) This study.
[
7,8]
electron-reduction event (Figure 1b).
However, the selec-
tive reduction of amide carbonyls with SmI is challenging and
2
no general method to achieve this highly desirable trans-
the corresponding hemiaminals (Figure 1c). To our knowl-
edge these are the first general examples of monoreduction of
such systems as well as the reduction of amide-type
[
9]
formation is currently available.
Herein, we demonstrate that the SmI /H O reagent can
[
10]
[4]
2
2
[
7,8]
perform the selective monoreduction of barbituric acids to
carbonyls with SmI2.
ogous to tetrahedral intermediates derived from amide
The hemiaminal products are anal-
[5]
addition reactions. Moreover, the radical intermediates
formed by the one-electron reduction have been utilized in
intramolecular additions to alkenes. For the first time in any
SmI -mediated cross-couplings of acyl-type radicals, these
additions proceed with full control of diastereoselectivity.
[
+]
[+]
[
*] Dr. M. Szostak, B. Sautier, M. Spain, M. Behlendorf,
Prof. Dr. D. J. Procter
School of Chemistry, University of Manchester
Oxford Road, Manchester M13 9PL (UK)
E-mail: michal.szostak@manchester.ac.uk
david.j.procter@manchester.ac.uk
[
11]
2
[12]
Furthermore, experimental evidence is provided for the
isomerization of vinyl radical intermediates under SmI /H O
Homepage: http://people.man.ac.uk/~mbdssdp2/
] These authors contributed equally to this work.
2
2
+
[
reaction conditions. This discovery opens the door for the use
of SmI /H O in cascade reductive processes employing C-
[
**] We acknowledge the EPSRC and GSK for financial support. We thank
James Raftery for X-ray crystallography and Gareth Smith for mass
spectrometry assistance. Dedicated to Adolf von Baeyer on the
occasion of the 150th anniversary of the discovery of barbituric
acids.
2
2
[
13]
centered radicals. Overall, these studies provide a basis for
multiple methodologies to form versatile hemiaminal prod-
ucts (cf. hemiacetals) by a formal amide polarity reversal
[6]
event.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306484.
We hypothesized that single-electron reduction of barbi-
turic acids (cyclic 1,3-diimides) to their respective radical
anions could provide a benchmark for the development of
a general system for the reduction of a wide range of amide
functional groups. We considered that 1) in the barbituric acid
system the reduction of one of the imide carbonyls would be
ꢀ
2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
Angew. Chem. Int. Ed. 2013, 52, 12559 –12563
ꢀ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12559

.
Angewandte
Communications
enhanced because of its lower energy p*CO orbital, 2) the
reduction would be favored by anomeric stabilization of the
radical anion intermediate, and 3) the n !p* delocaliza-
a more thermodynamically powerful reductant required to
activate amide-type carbonyls. No over-reduction is seen,
[
14]
even in the presence of excess reagent. Other SmI -based
N
CO
2
[
15]
tion into the remaining carbonyl in a conformationally locked
system would provide access to stable, and unusual, hemi-
aminal products.
systems, including reductants with a higher redox potential
than SmI /H O, such as those with alcohols (MeOH, tBuOH,
2
2
EG), Lewis bases (HMPA, Et N), or salts (LiCl) did not
3
15]
[
After extensive optimization of the reaction conditions,
we determined that barbituric acids are reduced with SmI2/
provide the desired products.
(see the Supporting Information) illustrate that SmI /H O is
Competition experiments
2
2
H O to the corresponding hemiaminals in good yields and
diastereoselectivities (Table 1). Typically, a twofold excess of
selective for cyclic 1,3-diimides over reactive six-membered
lactones, thus suggesting that significant levels of selectivity
are possible with this reagent system.
2
To further evaluate the potential of our method, we
examined several substrates bearing an unactivated p system
tethered to the barbituric acid scaffold (Table 2). A broad
range of cyclic 1,3-diimides bearing alkene (entries 1–5) and
[
a]
Table 1: Reduction of barbituric acids using SmI2.
Entry 1,3-Diimide Product Yield [%] d.r. [%]
[
a]
Table 2: Reductive coupling of barbituric acids using SmI2.
1
2
Entry
3
R
R
4
Yield [%]
d.r. [%]
1
2
3
4
5
1a, R=iBu
2a
2b
2c
2d
2e
83
56
80
75
78
88:12
86:14
91:9
88:12
85:15
1b, R=C H
21
1
0
1c, R=(CH ) iPr
1d, R=(CH ) Ph
1e, R=(CH ) CHMePh
2
2
2
2
2
2
1
2
3
4
5
3a
3b
3c
3d
3e
iBu
iBu
iBu
C7H13
C4H7
H
Ph
4a
4b
4c
4d
4e
74
58
59
64
55
>95:5
>95:5
>95:5
>95:5
>95:5
4-MeOC H
Ph
H
6
4
6
7
8
1 f, X=MeO
1g, X=CF3
1h, X=Br
2 f
2g
2h
80
76
67
88:12
85:15
87:13
6
7
8
9
3 f
3g
3h
3i
iBu
iBu
iBu
C4H5
H
4 f
4g
4h
4i
63
66
90
82
>95:5
>95:5
63:37
>95:5
[
b]
[
TMS
Ph
H
c]
1
2
9
1
1
1
1
1i, R =Me, R =C H
2i
2j
71
50
55
76
58
77:23
87:13
–
87:13
88:12
1
0
21
1
2
0
1
2
3
1j, R =Me, R =iBu
1
2
2 2
[a] Reaction conditions: SmI (6 equiv), THF, H O, 1–15 min. See the
Supporting Information for full experimental details. [b] E isomer; >95:5
d.r. [c] Z/E geometry. TMS=trimethylsilyl.
1k, R ,R =-(CH ) CH=CH(CH ) - 2k
2
2
2 2
[
[
b]
b]
1
2
1l, R ,R = =C(OH)Bn
2l
2m
1
2
1m, R ,R = =CHiPr
[
a] Reaction conditions: SmI (4 equiv), THF, H O, 10–60 s. [b] Reaction
2
2
conditions: SmI (6–8 equiv), THF, H O, 10–60 s. See the Supporting
Information for full experimental details. THF=tetrahydrofuran.
alkyne (entries 6–9) substitutents underwent efficient radical
cyclizations, thus resulting in the formation of bicyclic hemi-
aminals in good to excellent yields. For the first time in any
radical cyclization mediated by SmI /H O, all products were
2
2
2
2
reagent was used to ensure that the reactions were complete.
A wide range of substrates exhibited excellent reactivity,
including those with sensitive a protons (entries 1–8), as well
as those with sterically hindered quaternary centers
formed with a high degree of stereoisomeric control around
the five-membered ring. We hypothesize that the increased
[
11]
half-life of the acyl-type radical, stabilized by the n !SOMO
N
[16]
conjugation (cf. esters), permits the alkene tether to adopt
the lowest energy conformation before the cyclization. This
finding bodes well for the development of other SmI2-
promoted radical cyclizations based on amide bond umpo-
lung.
(
entries 9–11). Importantly, the method tolerates functional
groups that are typically reduced under single-electron-trans-
fer conditions, including aromatic rings (entries 4 and 5),
ethers (entry 6), trifluoromethyl groups (entry 7), and halides
(
entry 8). The potential of the reaction to streamline synthetic
We have carried out preliminary studies to elucidate the
mechanism of the reaction (see the Supporting Information
for details): 1) The reduction of 1i with SmI /D O (> 98% D ;
routes by sequential reductive processes has also been
demonstrated (entries 12 and 13). Several products bear
close analogy to the pharmacologically active barbiturates
2
2
1
[
11a]
k /k = 1.5 ꢀ 0.1)
suggests that anions are generated and
H
D
(
entry 3: amobarbital, entry 10: butalbital).
protonated by H O in a series of electron-transfer steps and
2
We determined that the use of H O is critical for the
observed reactivity, which is in line with the formation of
that proton transfer is not involved in the rate-determining
step of the reaction. 2) Control experiments with a cyclic
2
[
17]
1
2560 www.angewandte.org
ꢀ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 12559 –12563

Angewandte
Chemie
1
,3-malonamide and DMPU demonstrate that activation of
well as with more powerful SmI -based reductants, SmI /LiCl
2 2
the amide carbonyl facilitates the reaction. 3) Intermolecular
competition experiments show that the rate of the reduction
can be modified by steric and electronic substitution at the a-
carbon atom. 4) Deuterium incorporation and KIE studies on
the reductive cyclizations suggest that proton transfer is not
involved in the rate-determining step (Figure 2). 5) The
and SmI /HMPA).
2
The a-amino alcohol moiety derived from barbituric acid
reduction is stabilized by a nonplanar arrangement of atoms
(Figure 3). The X-ray crystal structure of 4a reveals that the
C1ꢁO1 bond (1.407 ꢀ) is shorter than the average C ꢁO
sp3
[5a]
bond (1.432 ꢀ),
whereas the length of N1ꢁC1 bond is
1
.466 ꢀ, which corresponds to a typical C ꢁN bond
sp3
Figure 2. Reductive coupling of barbituric acids 3d, 3 f, and 3g using
SmI /D O (only products are shown).
2
2
Figure 3. X-ray structure of 4a. Selected bond lengths [ꢁ] and angles
8]: N1–C1 1.466, C1–O1 1.407, C1–C4 1.552, C1-H1 0.84, N1–C2
.354, C2–O2 1.218, N2–C2 1.421; C2-N1-C1-O1 155.1, C8-N1-C1-O1
[
1
reaction of 3d to give [D ]-4d (1:1 d.r.) demonstrates that
1
ꢁ
40.6, N1-C1-O1-H1 ꢁ52.1, C4-C1-O1-H1 70.8, C -N -C -N ꢁ6.9, C2-
1
1
2
2
the benzylsamarium(III) intermediate is not coordinated to
[23]
N2-C3-C4 ꢁ14.6, N1-C2-N2-C3 ꢁ3.6.
[
11a]
the hydroxy group (Figure 2).
3
6) The reactions of 3 f and
[18]
g indicate inversion of the vinyl radical
under the
[5a]
reduction conditions (Figure 2). 7) A gradual change in
(1.469 ꢀ). The C1ꢁC4 bond length of 1.552 ꢀ is slightly
[5a]
diastereoselectivity is observed in the cyclizations of 3h at
longer than the average C ꢁC bond (1.530 ꢀ).
The
sp3
sp3
[
10]
varied concentrations of H O, additionally suggesting that
torsion angle between Nlp (lp = lone pair) and C1ꢁO1 bond
2
the carbon-centered radicals do not undergo instantaneous
of 57.38 is consistent with the absence of Nlp!s*
CꢁO
[14]
reduction/protonation. 8) Finally, intermolecular competi-
tion experiments indicate that the rate of the cyclization is
governed by electronic and steric properties of the p accep-
interactions. However, there is a good overlap between the
O1lp1 and the N1ꢁC1 bond (ca. 1728) and between O1lp2
and the C1ꢁC4 bonds (ca. 1918). The shortened C1ꢁO1 bond
and the elongated C ꢁC bond are consistent with an
[
19]
tor,
suggesting significant levels of chemoselectivity in
1
4
[
8i]
these cyclizations.
anomeric effect resulting from Olp1!s*C1ꢁN1 and Olp2!
A proposed mechanism is shown in Scheme 1. We
hypothesize that the kinetic diastereoselectivity in the reduc-
tion results from the formation of an organosamarium(III) on
the less hindered face of the molecule. This is analogous to the
s*
ꢁ
C1 C4
interactions, while the geometry of the N1 atom
indicates the beginning of the decomposition of the tetrahe-
dral intermediate by the elimination of N(CO) group. It
should be noted that the a-amino alcohol function in this
system is stabilized by the reduced Nlp!s*C1ꢁO1 conjugation
because of the interaction of Nlp with the adjacent carbonyl
group.
Interestingly, the X-ray structure of the monocyclic
analogue 2 f shows kinetic rather than thermodynamic
stability (see the Supporting Information). The torsion
angles between Nlp and C1ꢁO1 of about 1758 and Olp and
C1ꢁN1 of about 378 indicate a significant Nlp!s*
ꢁ
C1 O1
interaction in this system, and the absence of Olp!s*C1ꢁN1
conjugation. The O1-C1-C4-H4 torsion angle of approxi-
mately 1808 reveals a perfect antiperiplanar arrangement
between the a-hydrogen atom and the hydroxy group. These
parameters are consistent with the beginning of the decom-
position of the a-amino alcohol moiety by the elimination of
a hydroxy group to give acyliminium. Overall, these features
seem to be characteristic of the a-amino alcohol function
stabilized by scaffolding effects in a barbituric acid system and
indicate that isolation of a range of analogues can be readily
achieved.
Scheme 1. Mechanism of the reduction and cyclization of barbituric
acids using SmI /H O.
2
2
classic reduction of cyclic ketones to equatorial alcohols by
[
10]
related SmI /H O systems. In the reductive cyclization, the
2
2
[20]
radical anion undergoes an anti addition to give the vinyl
radical intermediate, which isomerizes, depending on the
steric and electronic preferences of the p acceptor and the
reaction conditions. Control experiments (see the Supporting
Finally, we have preliminary results pertaining to the
reactivity of these hemiaminals (Scheme 2). We determined
that the alcohol could be directly displaced with a variety of
heteroatom and carbon nucleophiles under mild reaction
Information) point to the critical role of H O in stabilizing the
2
[14]
radical anion
and promoting cyclization (no reaction is
observed in the absence or at low concentration of H O as
2
Angew. Chem. Int. Ed. 2013, 52, 12559 –12563
ꢀ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 12561

.
Angewandte
Communications
Mori, S. Sueoka, T. Akiyama, J. Am. Chem. Soc. 2011, 133, 2424;
f) S. Reddy Chidipudi, I. Khan, H. W. Lam, Angew. Chem. 2012,
1
24, 12281; Angew. Chem. Int. Ed. 2012, 51, 12115; g) A. R.
Daniewski, W. Liu, M. Okabe, Org. Process Res. Dev. 2004, 8,
11; h) J. C. Ruble, A. R. Hurd, T. A. Johnson, D. A. Sherry,
4
M. R. Barbachyn, P. L. Toogood, G. L. Bundy, D. R. Graber,
G. M. Kamilar, J. Am. Chem. Soc. 2009, 131, 3991; i) X. Huang,
C. Li, S. Jiang, X. Wang, B. Zhang, M. Liu, J. Am. Chem. Soc.
2004, 126, 1322.
Scheme 2. Reactivity of the tetrahedral adducts 2. Reaction conditions:
a) MeOH, HCl, RT, 3 h, 99%. b) Et SiH, BF ·Et O, RT, 3 h, 96%.
3
3
2
c) Me Al, RT, 3 h, 78%. d) allyl-TMS, BF ·Et O, RT, 2 h, 86%.
3
3
2
[4] Ring scission and over-reduction have been observed in
reactions with other reductants: a) K. H. Dudley, I. J. Davis,
D. K. Kim, F. T. Ross, J. Org. Chem. 1970, 35, 147; b) See,
Ref. [2a].
5] For reviews, see: a) M. Adler, S. Adler, G. Boche, J. Phys. Org.
Chem. 2005, 18, 193; b) P. Deslongchamps, Stereoelectronic
Effects in Organic Chemistry, Pergamon Press, Elmsford, NY,
1983; examples of isolated tetrahedral intermediates: c) A. J.
Kirby, I. V. Komarov, N. Feeder, J. Am. Chem. Soc. 1998, 120,
conditions. We also showed that the N,N-phenobarbital-
derived hemiaminal undergoes an unprecedented 1,2-aryl
shift (see the Supporting Information). These results bode
well for accessing a wide range of biologically active uracil
[
[21]
derivatives.
7101; d) D. A. Evans, G. Borg, K. A. Scheidt, Angew. Chem.
In summary, we have developed the first general method
for the monoreduction of barbituric acids since their seminal
discovery in 1864 by von Baeyer. This reaction constitutes the
first general method for the reduction of amide-type carbon-
2002, 114, 3320; Angew. Chem. Int. Ed. 2002, 41, 3188; e) C. Cox,
H. Wack, T. Lectka, J. Am. Chem. Soc. 1999, 121, 7963; f) M.
Szostak, J. Aubꢃ, J. Am. Chem. Soc. 2010, 132, 2530; g) M. Adler,
M. Marsch, N. S. Nudelman, G. Boche, Angew. Chem. 1999, 111,
1345; Angew. Chem. Int. Ed. 1999, 38, 1261.
[22]
yls using SmI2.
The radicals formed by one-electron
reduction of the amide bond have been applied in intra-
molecular additions to alkenes. The cyclic hemiaminal
products are analogous to tetrahedral intermediates derived
from amide addition reactions and are formed in a formal
polarity reversal event. We fully expect that the present work
will provide the basis for the synthesis of novel barbituric acid
derivatives and will result in the development of an array of
modern synthetic methodologies to access reductive amide
umpolung by electron transfer events.
[6] Reviews on metal-mediated radical reactions: a) B. M. Trost, I.
Fleming, Comprehensive Organic Synthesis, Pergamon, New
York, 1991; b) A. Gansꢄuer, H. Blum, Chem. Rev. 2000, 100,
2771; c) M. Szostak, D. J. Procter, Angew. Chem. 2012, 124, 9372;
Angew. Chem. Int. Ed. 2012, 51, 9238; d) “Radicals in Synthesis I
and II”: A. Gansꢄuer in Topics in Current Chemistry, Vol. 263 –
264, Springer, Heidelberg, 2006; an excellent review on reduc-
tive umpolung: e) J. Streuff, Synthesis 2013, 45, 281.
[7] D. J. Procter, R. A. Flowers II, T. Skrydstrup, Organic Synthesis
using Samarium Diiodide: A Practical Guide, RSC Publishing,
Cambridge, 2010.
[
8] For reviews, see: a) G. A. Molander, C. R. Harris, Chem. Rev.
996, 96, 307; b) A. Krief, A. M. Laval, Chem. Rev. 1999, 99, 745;
Received: July 25, 2013
Published online: October 9, 2013
1
c) H. B. Kagan, Tetrahedron 2003, 59, 10351; d) D. J. Edmonds,
D. Johnston, D. J. Procter, Chem. Rev. 2004, 104, 3371; e) K. C.
Nicolaou, S. P. Ellery, J. S. Chen, Angew. Chem. 2009, 121, 7276;
Angew. Chem. Int. Ed. 2009, 48, 7140; f) M. Szostak, D. J.
Procter, Angew. Chem. 2011, 123, 7881; Angew. Chem. Int. Ed.
Keywords: electron transfer · heterocycles · reductive coupling ·
samarium iodide · synthetic methods
.
2011, 50, 7737; g) C. Beemelmanns, H. U. Reissig, Chem. Soc.
Rev. 2011, 40, 2199; h) B. Sautier, D. J. Procter, Chimia 2012, 66,
[
1] a) A. von Baeyer, Justus Liebigs Ann. Chem. 1864, 130, 129; for
the first mention of barbituric acid by von Baeyer, see: b) A.
von Baeyer, Justus Liebigs Ann. Chem. 1863, 127, 199; selected
historical perspectives: c) M. K. Carter, J. Chem. Educ. 1951, 28,
3
1
99; i) M. Szostak, M. Spain, D. J. Procter, Chem. Soc. Rev. DOI:
0.1039/c3cs60223k; extremely relevant review about chemo-
selective electron transfer using SmI2.
[
9] Skrydstrup and co-workers reported an elegant coupling of N-
524; d) G. B. Kauffmann, J. Chem. Educ. 1980, 57, 222; e) A.
acyl oxazolidinones by a radical addition mechanism: a) C. M.
Jensen, K. B. Lindsay, R. H. Taaning, J. Karaffa, A. M. Hansen,
T. Skrydstrup, J. Am. Chem. Soc. 2005, 127, 6544; b) A. M.
Hansen, K. B. Lindsay, P. K. S. Antharjanam, J. Karaffa, K.
Daasbjerg, R. A. Flowers II, T. Skrydstrup, J. Am. Chem. Soc.
de Meijere, Angew. Chem. 2005, 117, 8046; Angew. Chem. Int.
Ed. 2005, 44, 7836; f) A. W. Jones, Perspectives in Drug Discov-
ery, Linkçping, 2010.
[
2] Reviews: a) J. T. Bojarski, J. L. Mokrosz, H. J. Barton, M. H.
Paluchowska, Adv. Heterocycl. Chem. 1985, 38, 229; b) D. J.
Abraham, D. P. Rotella, Burgerꢀs Medicinal Chemistry, Drug
Discovery and Development, Wiley, Hoboken, 2010; c) F. Lꢁpez-
MuÇoz, R. Ucha-Udabe, C. Alamo, Neuropsychiatr. Dis. Treat.
2006, 128, 9616; c) R. H. Taaning, K. B. Lindsay, B. Schiøtt, K.
Daasbjerg, T. Skrydstrup, J. Am. Chem. Soc. 2009, 131, 10253;
d) J. P. Ebran, C. M. Jensen, S. A. Johannesen, J. Karaffa, K. B.
Lindsay, R. H. Taaning, T. Skrydstrup, Org. Biomol. Chem. 2006,
4, 3553; Namy reported coupling of imides via a fragmentation
mechanism: e) S. Farcas, J. L. Namy, Tetrahedron Lett. 2000, 41,
7299; Ha et al. and Farcas and Namy reported the addition of
organosamariums to imides: f) D. C. Ha, C. S. Yun, Y. Lee, J.
Org. Chem. 2000, 65, 621; g) S. Farcas, J. L. Namy, Tetrahedron
Lett. 2001, 42, 879.
2005, 1, 329; d) F. Seeliger, S. T. A. Berger, G. Y. Remennikov,
K. Polborn, H. Mayr, J. Org. Chem. 2007, 72, 9170.
[
3] Selected recent applications: a) K. Takenaka, N. Itoh, H. Sasai,
Org. Lett. 2009, 11, 1483; b) M. Holzwarth, A. Dieskau, M.
Tabassam, B. Plietker, Angew. Chem. 2009, 121, 7387; Angew.
Chem. Int. Ed. 2009, 48, 7251; c) S. Fujimori, E. M. Carreira,
Angew. Chem. 2007, 119, 5052; Angew. Chem. Int. Ed. 2007, 46,
4
964; d) M. U. Schmidt, J. Brꢂning, J. Glinnemann, M. W.
[10] For a recent review, see: M. Szostak, M. Spain, D. Parmar, D. J.
Procter, Chem. Commun. 2012, 48, 330.
Hꢂtzler, P. Mçrschel, S. N. Ivashevskaya, J. van de Streek, D.
Braga, L. Maini, M. R. Chierotti, R. Gobetto, Angew. Chem.
[11] For selected studies, see: a) D. Parmar, L. A. Duffy, D. V.
Sadasivam, H. Matsubara, P. A. Bradley, R. A. Flowers II, D. J.
2011, 123, 8070; Angew. Chem. Int. Ed. 2011, 50, 7924; e) K.
1
2562 www.angewandte.org
ꢀ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 12559 –12563

Angewandte
Chemie
Procter, J. Am. Chem. Soc. 2009, 131, 15467; b) K. D. Collins,
J. M. Oliveira, G. Guazzelli, B. Sautier, S. De Grazia, H.
Matsubara, M. Helliwell, D. J. Procter, Chem. Eur. J. 2010, 16,
[17] A value of 1.5 is likely to result from a secondary KIE arising
II
from differential coordination of D O/H O to Sm . For leading
2
2
references on KIE, see: a) M. L. Bender, E. J. Pollock, M. C.
Neveu, J. Am. Chem. Soc. 1962, 84, 595; b) “Theoretical and
Experimental Aspects of Isotope Effects in Chemical Kinetics”:
J. Bigeleisen, M. Wolfsberg in Advances in Chemical Physics,
Vol. 1 (Eds.: I. Prigogine, P. Debye), Wiley, Hoboken, 1958;
c) D. A. Singleton, A. A. Thomas, J. Am. Chem. Soc. 1995, 117,
9357; d) D. A. Singleton, M. J. Szymanski, J. Am. Chem. Soc.
1999, 121, 9455; e) J. G. Belasco, W. J. Albery, J. R. Knowles, J.
Am. Chem. Soc. 1983, 105, 2475; f) M. H. OꢅLeary, Annu. Rev.
Biochem. 1989, 58, 377. The absence of a primary KIE indicates
that proton transfer is not involved in the rate-determining step
of the reaction: g) K. B. Wiberg, Chem. Rev. 1955, 55, 713; h) M.
Wolfsberg, Acc. Chem. Res. 1972, 5, 225; i) L. Melander, W. H.
Saunders, Reaction Rates of Isotopic Molecules, Wiley, 1980;
j) E. M. Simmons, J. F. Hartwig, Angew. Chem. 2012, 124, 3120;
Angew. Chem. Int. Ed. 2012, 51, 3066.
10240; c) D. Parmar, K. Price, M. Spain, H. Matsubara, P. A.
Bradley, D. J. Procter, J. Am. Chem. Soc. 2011, 133, 2418; d) D.
Parmar, H. Matsubara, K. Price, M. Spain, D. J. Procter, J. Am.
Chem. Soc. 2012, 134, 12751; e) B. Sautier, S. E. Lyons, M. R.
Webb, D. J. Procter, Org. Lett. 2012, 14, 146.
II
[
[
12] For a classic review on Sm -mediated cascade cyclizations, see.
G. A. Molander, C. R. Harris, Tetrahedron 1998, 54, 3321.
13] a) L. A. Duffy, H. Matsubara, D. J. Procter, J. Am. Chem. Soc.
2008, 130, 1136; b) G. Guazzelli, S. De Grazia, K. D. Collins, H.
Matsubara, M. Spain, D. J. Procter, J. Am. Chem. Soc. 2009, 131,
7214; c) M. Szostak, M. Spain, D. J. Procter, Nat. Protoc. 2012, 7,
970; d) M. Szostak, M. Spain, D. J. Procter, Chem. Commun.
2011, 47, 10254; e) M. Szostak, M. Spain, D. J. Procter, Org. Lett.
2012, 14, 840; f) M. Szostak, K. D. Collins, N. J. Fazakerley, M.
Spain, D. J. Procter, Org. Biomol. Chem. 2012, 10, 5820; for
a related study on TmI /H O, see: g) M. Szostak, M. Spain, D. J.
Procter, Angew. Chem. 2013, 125, 7378; Angew. Chem. Int. Ed.
013, 52, 7237.
14] a) P. R. Chopade, E. Prasad, R. A. Flowers II, J. Am. Chem. Soc.
2
2
[18] R. W. Fessenden, R. H. Schuler, J. Chem. Phys. 1963, 39, 2147.
[19] a) D. P. Curran, N. A. Porter, B. Giese, Stereochemistry of
Radical Reactions, Wiley-VCH, Weinheim, 1996; b) C. Chatgi-
lialoglu, A. Studer, Encyclopedia of Radicals in Chemistry,
Biology and Materials, Wiley-Blackwell, Chichester, 2012.
[20] B. Giese, Angew. Chem. 1983, 95, 771; Angew. Chem. Int. Ed.
Engl. 1983, 22, 753.
2
[
2004, 126, 44; b) E. Prasad, R. A. Flowers II, J. Am. Chem. Soc.
2005, 127, 18093; c) M. Amiel-Levy, S. Hoz, J. Am. Chem. Soc.
2009, 131, 8280; d) E. Hasegawa, D. P. Curran, J. Org. Chem.
1993, 58, 5008.
[21] J. I. Bardagi, R. A. Rossi, Org. Prep. Proced. Int. 2009, 41, 479.
[
15] a) A. Dahlꢃn, G. Hilmersson, Eur. J. Inorg. Chem. 2004, 3393;
b) R. A. Flowers II, Synlett 2008, 1427.
16] a) V. Malatesta, K. U. Ingold, J. Am. Chem. Soc. 1981, 103, 609;
b) B. Giese, Angew. Chem. 1989, 101, 993; Angew. Chem. Int. Ed.
Engl. 1989, 28, 969; c) T. Cohen, M. Bhupathy, Acc. Chem. Res.
[22] For a detailed study on the preparation of SmI : M. Szostak, M.
2
Spain, D. J. Procter, J. Org. Chem. 2012, 77, 3049.
[23] CCDC 948382 (4a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[
1989, 22, 152.
Angew. Chem. Int. Ed. 2013, 52, 12559 –12563
ꢀ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 12563