Dearomatizing radical cyclizations and cyclization cascades triggered by electron-transfer reduction of amide-type carbonyls

Article abstract of DOI:10.1021/jacs.6b12077

Highly selective dearomatizing radical cyclizations and cyclization cascades, triggered by single electron transfer to amide-type carbonyls by SmI₂-H₂O-LiBr, provide efficient access to unprecedented spirocyclic scaffolds containing

Full text of DOI:10.1021/jacs.6b12077

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Article
Dearomatizing radical cyclizations and cyclization cascades
triggered by electron-transfer reduction of amide-type carbonyls
Huan-Ming Huang, and David J. Procter
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b12077 • Publication Date (Web): 20 Dec 2016
Downloaded from http://pubs.acs.org on December 20, 2016
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Journal of the American Chemical Society
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Dearomatizing radical cyclizations and cyclization cascades
triggered by electron-transfer reduction of amide-type car-
bonyls
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Huan-Ming Huang and David J. Procter*
School of Chemistry, Oxford Road, University of Manchester, Manchester, M13 9PL, United Kingdom
ABSTRACT: Highly selective dearomatizing radical cyclizations and cyclization cascades, triggered by single electron-
transfer to amide-type carbonyls by SmI2-H2O-LiBr provide efficient access to unprecedented spirocyclic scaffolds con-
taining five stereocenters with high diastereocontrol. The first dearomatizing radical cyclizations involving radicals de-
rived from the amide carbonyls by single electron-transfer take place under mild conditions and engage a range of aro-
matic and heteroaromatic systems present in the barbiturate substrates. The radical cyclizations deliver new polycyclic
hemiaminals or enamines selectively, depending on the conditions employed, that are based on a medicinally proven
scaffold and can be readily manipulated.
Scheme 1. (A) Known dearomatizating radical cyclizations
1. INTRODUCTION
of aldehydes and ketones. Unknown dearomatizating radi-
cal cyclizations of amides. (B) Dearomatizing radical cycli-
zations and cyclization cascades of barbiturates. (C) The
importance of spiro-heterocyclic scaffolds.
Dearomatization is a powerful strategy for the construction
of diverse three dimensional structures, including complex,
polycyclic scaffolds and natural products, from simple ar-
omatic starting materials.1 Successful approaches to
dearomatization involve, for example, oxidation, cycloaddi-
tion, alkylation, arylation and C-H activation.2 Radical cy-
clizations can also be used to achieve dearomatization,3
and, although major advances have been made in this field,
the development of new strategies for dearomatization by
radical addition, particular those that deliver novel hetero-
cyclic architectures, is an important goal.1-3 SmI2 is a highly
versatile, commercially available or readily-prepared elec-
tron transfer (ET) reductant.4 SmI2-mediated dearomatiz-
ing cyclizations and cyclization cascades have recently
been developed, with seminal contributions coming from
the teams of Schmalz,5 Reissig,6 Fang,7 Tanaka,8 Yamashi-
ta,9 Wang and Li.10 Of particular note, Reissig has exploited
an impressive SmI2-induced dearomatizing cyclization cas-
cade in a concise total synthesis of Strychnine.6p,s,v Despite
the progress made, until now, SmI2-mediated dearomatiz-
ing reactions are limited to radicals derived from ketone or
aldehyde substrates (Scheme 1A). Furthermore, few exam-
ples of radical cascade cyclizations involving dearomatiza-
tion have been reported.6d,f,p,q,s,v,9 The amide functional
group is widely found in biological molecules, pharmaceu-
ticals, natural products and functional materials.11 However,
because of their resistance to reduction, developing cycli-
zations and cascades involving ET reduction of amide car-
bonyls is challenging.12 Herein, we demonstrate the feasi-
bility of SmI2-mediated dearomatizing cyclizations and
cyclization cascades involving radicals 1 formed by ET re-
duction of amide-type carbonyls (Scheme 1B).
A. Dearomatizing radical cyclizations: R = alkyl/H – known; R = NR2 – unknown
Ar/HetAr
Ar/HetAr
X
Y
X
Y
X
1 e
1 e
HO
O
O
Y
2 H+
R
R
R
B. This work: dearomatizing radical cyclizations and cyclization cascades of amides
n first amide dearomatizing radical cyclizations
XH
Ar/HetAr
O
Y
O
Y
1 e
1 e
HO
Me
Me
Me
N
N
X
N
R
O
R
O
R
O
2 H+
O
N
N
O
O
N
1
Me
Me
Me
n first amide dearomatizing radical cyclization cascades
H
X
SmIII
O
O
Y
HO
N
X
1 e
X
1 e
N
N
R
O
R
O
R
Y
Y
2 H+
N
O
O
Ar/HetAr
N
Ar/HetAr
O
N
O
R'
R'
R'
• 2 electron cascades • 2 new C–C bonds • 4 stereocentres • highly diastereoselective
C. The importance of spirocyclic scaffolds
Me
Me
H
H
Me
Me Me
H
N
OMe
Me
O
O
O
O
O
MeO
O
HO
MeO
OH
Me
H
Cl
griseofulvin
NH
morphine
stachybotrylactam
O
O
NH
N
H
N
N
MeO2C
MeO2C
H
O
CO2Me
CO2Me
grandilodine A
N
N
CO2Me
CO2Me
OMe
grandilodine B
phosphodiesterase
(PDE4) Inhibitor
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The processes involve two ET events, and thus require ap- reduction to the anion under the SmI2-H2O/LiBr condi-
proximately two equivalents of the commercial reagent, tions and radical cyclization is more efficient. A hindered
and construct complex medicinally-relevant, polycyclic approach of Sm(II), in the modified reagent system, to the
barbiturates containing up to five stereocenters with high radicals may result in a slower outer-sphere ET process.
diastereoselectivity.13 The spirocyclic scaffolds accessible
1
2
3
4
5
6
7
8
are related to those found in biologically active products, Scope of dearomatizing radical cyclizations of amides.
drug targets and natural products (Scheme 1C).14
We next examined the scope of the dearomatizing radical
cyclization of amides 2 (Scheme 2). Benzofuran substrates
bearing hindered alkyl groups, such as isobutyl (3a) and
methylcyclohexyl (3b), and aryl-containing substituents
(3c-e) on the barbituric acid ring, exhibited excellent reac-
tivity and dearomatized spirocyclic products were isolated
in good yield and essentially as single diastereoisomers.
The relative stereochemistry in 3a-e was confirmed by X-
ray crystallographic analysis.20
2. RESULTS AND DISCUSSION
9
Optimization of the first dearomatizing radical cycli-
zations of amides – the key role of LiBr. Barbiturate 2a
is available in three steps from commercially available 1,3-
dimethylbarbituric acid and was selected as a model sub-
strate for optimization studies. Treatment of 2a with SmI2
in THF returned only starting material (Table 1, entry 1).
Upon activation of SmI2 by H2O,15 the desired product of
dearomatizing cyclization 3a was obtained in 20% yield,
with 32% of 2a recovered (entry 2). The addition of LiBr to
SmI216 gave 3a in 40% NMR yield (entry 3). However, when
LiBr was added to SmI2 and H2O, the reaction delivered
cyclized product 3a in 78% isolated yield with excellent
diastereocontrol (> 95:5 dr) (entry 4). Increasing the
amount of H2O did not have a beneficial effect on the reac-
tion (entry 5).
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Scheme 2. Scope of the dearomatizing radical cyclization
of amides.a,b
O
R
O
n
X
Me
O
R
n
N
H
Me
O
Y
N
SmI2–H2O–LiBr
THF, rt, 2 h
X
N
OH
N
O
Y
Me
Me
O
2
3
O
N
Cy
iBu
X-ray
crystal structure
Me
O
Me
N
N
of 3a
Table 1. Optimizating the dearomatizing radical cycliza-
N
O
tion of amide 2aa,b
OH
OH
O
O
Me
Me
Me
Me
3b
3a
O
84% > 95:5 dr
78% > 95:5 dr
Me
O
Me
Me
X-ray
X-ray
N
Me
see
O
Ph
N
Me
Ph
O
O
N
table
OH
O
O
N
O
N
O
O
Me
Ph
Me
O
Me
N
Me
Me
N
N
2a
3a
O
N
O
N
OH
O
OH
OH
O
Yield/%b
O
Me
Me
Me
SmI2
H2O
Entry
3c
3d
3e
(equiv)
(equiv)
2a
3a
76% > 95:5 drc
72% > 95:5 dr
83% > 95:5 dr
X-ray
X-ray
X-ray
1
3
3
3
3
3
–
100
32
-
0
Ph
O
O
O
Cy
iBu
Me
O
2
100
–
20
Me
Me
N
N
N
3c
4c
5c
40
N
NH
NH
NH
O
N
O
OH
N
S
OH
OH
S
Me
S
Me
80 (78)d
73
Me
100
200
–
-
3f
3g
3h
75% > 95:5 dr
78% > 95:5 dr
47% > 95:5 dr
Ph
O
O
a Reaction conditions: 2a (0.1 mmol, in 2 mL THF) at room
iBu
Me
O
Me
O
N
N
OH
temperature under N2, was added H2O, followed by SmI2 and
NH
b
1
N
N
the reaction quenched after 2 h. Yield was determined by H
NMR spectroscopy using 2,3,5,6-tetrachloronitrobenzene as an
internal standard. c LiBr (20 equiv wrt SmI2) was used. d isolat-
ed yield. > 95:5 dr - determined by 1H NMR on the crude prod-
uct mixture.
OH
O
S
Me
Me
3j
3i
47% > 95:5 dr
X-ray
crystal structure
27% > 95:5 dr
of 3j
X-ray
a Reaction conditions: To a solution of 2a (0.1 mmol), in THF
(2 mL) at room temperature under N2, was added H2O, fol-
lowed by a mixture of SmI2 and LiBr. The reaction was
quenched after 2 h. b Isolated yields, > 95:5 dr - determined by
1H NMR on the crude product mixtures. c major product 3c is a
75:25 mixture of diastereoisomers at the remote stereocenter.
Flowers has proposed that the combination of SmI2 and
LiBr generates a soluble form of SmBr2 in situ.17 Thus, the
addition of LiBr may generate SmBr2-H2O or the ate com-
plex SmBr3–Li+-H2O.18,19 SmBr2 (approx. –1.55 V vs SCE) has a
higher reduction potential than SmI2 (–0.9 V vs SCE).17,18 It
is therefore surprising that the radical intermediates in
dearomatizing cyclizations (cf. 1 in Scheme 1) and cycliza-
tion cascades (cf. 13 in Scheme 7) appear less susceptible to
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Benzothiazole-containing substrates also underwent complex scaffolds in a single operation (Table 2).22 Treat-
smooth dearomatizing radical spirocyclization to give 3f-i ment of 7a with SmI2 returned only starting material (entry
in moderate to high yield and high diastereocontrol. The 1), thus confirming the importance of H2O and LiBr for
relative stereochemistry in 3f was assigned by nOe studies activation of the reductant. Addition of H2O (100 equiv.) to
and inferred for analogous products.21 Finally, barbiturate SmI2 and 7a led to formation of the desired cascade prod-
3j, the product of a 6-exo-trig amide dearomatizing radical uct 9a (60% NMR yield), after acid-mediated dehydration
cyclization was isolated in modest yield and as a single dia- of hemiaminal product 8a, but little diastereocontrol was
stereoisomer. The structure of 3j was confirmed by X-ray observed (45:55 dr) (entry 2). Addition of LiBr to SmI2 gave
1
2
3
4
5
6
7
8
crystallographic analysis (Scheme 2).20
9a in 40% NMR yield (entry 3). However, when LiBr was
added to SmI2 and H2O at room temperature, both the
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Proposed mechanism for the dearomatizing radical yield and diastereoselectivity of the reaction were increased
cyclizations of amides. A mechanism for the dearomatiz- (71%, 63:27 dr) (entry 4). We next investigated the effect of
ing radical cyclization of amides is shown in Scheme 3. temperature on the radical cascade. The use of SmI2-H2O-
Radical 4 is formed by ET to the amide-type carbonyl from LiBr at 0 °C delivered optimal results and the cascade
Sm(II). Subsequent 5-exo-trig dearomatizing radical cy- product 9a was obtained in good yield and with high dia-
clization, via transition structure 5, and a second ET gives stereocontrol (80% isolated yield, 92:8 dr) and only 10% of
dianion 6, which, after protonation, gives 3 (Scheme 3). For monocyclization byproduct 10 (entry 5). Lower reaction
benzofuran substrates (Y = O, X = CH) the preference for temperatures gave lower yields of 9a and a greater propor-
transition structure 5 may arise from the minimization of tion of 10 (entry 6). Without acidic work up, the corre-
dipole-dipole interactions. For benzothiazole substrates (Y sponding hemiaminal product 8a was isolated in 76% yield
= S, X = N) coordination of Sm(III) to nitrogen may lead to and 93:7 dr (entry 7). X-ray crystallographic analysis con-
a preference for transition structure 5. To date our studies firmed the structure of major diastereoisomer 9a and the
have focused specifically on the chemistry of activated am- corresponding minor diastereoisomer 9a’ (not shown).2o
ide-type carbonyls in medicinally-relevant barbituric acid
substrates although we expect the process to extend to Table 2. Optimization of the dearomatizing radical cycliza-
other cyclic imides.12c,d Analogous chemistry of simple am- tion cascade of amide 7a.a
ides and lactams will likely require the future development
H
of more-reducing Sm(II) reagent systems.12f
see
Table
O
N
O
OH
iPr
O
iPr
O
iPr
O
O
N
O
O
N
O
N
N
N
Scheme 3. Proposed mechanism for the dearomatizing
R'
O
Me
radical cyclizations of amides.
R'
R'
7a
8a
9a
iPr
N
O
O
[R' = benzofuran-2-yl]
N
O
O
X
O
N
X
R
R'
R
10
Me
O
Me
O
Y
N
Y
N
1 e
OSmIII
N
O
Yield/% (dr)b
Me
Me
4
2
entry
T/°C
5-exo-trig
7a
8a
9a
10
R
R
O
O
Me
SmIII
Me
1c
rt
rt
100
24
-
-
-
N
N
N
O
O
SmIII
N
O
O
Me
Me
60
(45:55)
40
N
2d
-
-
-
-
-
20
15
7
Y
Y
dipoles near
antiparallel
chelation
control
when
X= CH2
when
X = N
5
3e
4
5
rt
rt
-
-
-
-
-
1 e
O
R
(48:52)
71
O
R
O
Me
Me
N
H
SmIII
N
2 x H+
X
O
N
X
O
N
(63:27)
85 (80)f
(92:8)
57
OH
Y
Me
Y
Me
SmIII
6
3
0
10
34
8
Optimization of the dearomatizing radical cascade
cyclizations of amides. Having established the feasibility
of dearomatizing radical cyclizations involving radical ani-
ons derived from amides by ET, we sought to develop re-
lated radical-radical cyclization cascades involving
dearomatization of aryl and heteroaryl substituents. Model
substrate 7a, readily synthesized from diethyl-2-
methylmalonate in three steps, was used to explore novel
dearomatizing radical cascades capable of delivering more
6
−15
0
(95:5)
7
80 (76)f
(93:7)
7g
(93:7)
a
Reaction conditions: To 7a (0.1 mmol), in THF (2 mL) un-
der N2, was added H2O (100 equiv), followed by a mixture of
SmI2 (3 equiv) and LiBr (20 equiv wrt SmI2). After 2 h, HCl (2
M, 1 mL) was added and the reaction stirred for 20 min. b Yield
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determined by 1H NMR spectroscopy using 2,3,5,6-
tetrachloronitrobenzene as internal standard. dr was deter-
Condition A
SmI2-H2O-LiBr
THF, 0 oC, 2 h
H
R1
1
2
3
4
5
6
O
N
O
OH
N
R'
1
c
R1
O
R1
O
R2
mined by H NMR on crude product mixtures. Without H2O
O
O
N
O
O
d
e
f
g
N
Condition B
SmI2-H2O-LiBr
THF, 0 oC, 2 h
then
R2
N
and LiBr. Without LiBr. Without H2O. Isolated yield.
Without HCl. T = temperature.
N
R'
O
R'
O
8
7
9
Condition A
Condition B
HCl (2 M, 1 mL)
20 min
R2
7
8
9
Condition A
Scheme 4. Scope of the dearomatizing radical cyclization
H
H
H
cascade.a,b
OH
iPr
OH
N
OH
N
Me
iBu
O
O
O
O
N
O
N
O
O
N
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
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58
59
60
N
O
R'
R'
R'
8a
8b
8c
76% 92:8 dr
[R' = benzofuran-2-yl]
73% 69:31 dr
[R' = benzofuran-2-yl]
52% 89:11 dr
[R' = benzofuran-2-yl]
H
H
H
Me
OH
F
Br
OH
OH
N
iPr
O
iPr
iPr
O
O
N
O
O
O
N
O
O
N
O
N
N
R'
R'
R'
8f
8e
8d
59% 91:9 dr
[R' = 5-Me-benzofuran-2-yl]
80% 94:6 dr
[R' = 5-F-benzofuran-2-yl]
73% 93:7 dr
[R' = 5-Br-benzofuran-2-yl]
Me
H
H
H
OH
OH
O
OH
N
iPr
O
iPr
O
iPr
O
O
O
N
O
N
O
O
O
N
O
N
N
Me
Br
R'
R'
R'
8g
8h
8i
72% 91:9 dr
[R' = 5-MeO-benzofuran-2-yl]
66% 96:4 dr
68% > 95:5 dr
[R' = 6-MeO-benzofuran-2-yl] [R' = 7-Br-benzofuran-2-yl]
H
OH
iPr
O
N
O
O
N
R'
8j
X-ray
crystal structure
of 8j
81% 91:9 dr
[R' = naphtho[2,1-b]furan-2-yl]
X-ray
Condition B
iBu
O
Me
O
iPr
O
O
N
O
O
N
O
O
N
O
N
N
N
R'
R'
9a
R'
9b
9c
80% 92:8 dr
[R' = benzofuran-2-yl]
74% 69:31 dr
[R' = benzofuran-2-yl]
54% 89:11 dr
[R' = benzofuran-2-yl]
X-ray
X-ray
Me
iPr
F
Br
iPr
O
iPr
O
O
N
O
O
O
N
O
O
N
O
N
N
N
R'
R'
R'
9f
9d
9e
65% 91:9 dr
[R' = 5-Me-benzofuran]
80% 93:7 dr
[R' = 5-Br-benzofuran]
85% 94:6 dr
[R' = 5-F-benzofuran]
X-ray
X-ray
Me
O
iPr
iPr
O
iPr
O
O
N
O
O
O
O
N
O
N
O
O
N
N
N
Br
Me
R'
R'
9i
R'
9h
9g
79% > 95:5 dr
[R' = 7-Br-benzofuran-2-yl]
68% 95:5 dr
[R' = 6-MeO-benzofuran-2-yl]
74% 91:9 dr
[R' = 5-MeO-benzofuran-2-yl]
X-ray
X-ray
iPr
O
X-ray
crystal structure
of 9i
O
N
O
N
R'
9j
85% 91:9 dr
[R' = naphtho[2,1-b]furan-2-yl]
X-ray
a
Reaction conditions A: To a solution of 7 (0.1 mmol), in THF
(2 mL) under N2, was added H2O, followed by a mixture of
SmI2 and LiBr, the reaction was quenched after 2 h. Reaction
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Journal of the American Chemical Society
conditions B: To a solution of 7 (0.1 mmol), in THF (2 mL)
the barbituric acid ring were tolerated, including bulky
1
2
3
4
5
6
7
8
under N2, was added H2O, followed by a mixture of SmI2 and
LiBr, after 2 h, HCl (2 M, 1 mL) was added and stirred for 20
isopropyl and isobutyl substituents, and the corresponding
cascade products (8a-c and 9a-c) were obtained in good
yield. Substrates bearing the hindered isopropyl substitu-
ent gave the highest yields and diastereoselectivities. Next
we investigated the scope with regards to the benzofuran
motif undergoing dearomatization. Benzofurans bearing
bromo (8d, 8i and 9d, 9i), fluoro (8e and 9e), methyl (8f
and 9f) and methoxy (8g, 8h and 9g, 9h) groups, as well as
naphthylfused furans (8j and 9j) were compatible with the
cascade process and gave polycyclic products in good to
excellent isolated yield (59-85%) and with excellent dia-
stereocontrol (91:9 to 95:5 dr). The relative stereochemistry
of the major products 8j and 9a, 9c-e, 9h-j was confirmed
by X-ray crystallographic analysis.20
1
min. b Isolated yield. Dr determined from H NMR of crude
product mixtures.
Scheme 5. Radical cyclization cascades involving dearoma-
tization of various heteroaromatic and aromatic rings.a,b
9
Condition A
H
H
H
R1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SmI2-H2O-LiBr
THF, 0 oC, 2 h
O
N
O
X
OH
N
X
R'
R1
O
R1
O
R2
O
Y
N
O
Y
N
Condition B
SmI2-H2O-LiBr
THF, 0 oC, 2 h
then
R2
N
N
R'
O
R'
Y
8
7
9
X
Condition A
Condition B
HCl (2 M, 1 mL)
20 min
R2
We further investigated the scope of the radical cyclization
cascade by varying the aromatic moiety undergoing
dearomatization (Scheme 5). Pleasingly, benzothiophene
(8k and 9k), naphthalene (8l and 9l), benzoxazole (8m-p),
benzothiazole (8q) were compatible with the process and
provided diverse barbiturates bearing spiro-heterocyclic
motifs with essentially complete diastereocontrol (> 95:5
dr). Attempts to engage simple benzene substituents in the
dearomatizing process have so far proved unsuccessful.
Again, fluoro (8n), chloro (8o) and bromo (8p) substitu-
ents on the heterocyclic ring were tolerated in the process.
The relative stereochemistry in 8o was assigned by nOe
studies and inferred for analogous products.21
H
H
OH
N
OH
iPr
O
iPr
O
N
S
N
N
O
R'
O
R'
8k
35% > 95:5 dr
[R' = benzo[b]thiophen-2-yl]
8l
40% > 95:5 dr
[R' = naphthalen-1-yl]
X-ray
crystal structure
of 8k
X-ray
H
H
H
H
H
H
OH
N
N
OH
N
F
OH
N
N
iPr
O
iPr
O
iPr
O
O
N
O
O
N
O
O
Cl
N
N
R'
R'
O
R'
8m
52% > 95:5 dr
[R' = benzo[d]oxazol-2-yl] [R' = 5-F-benzo[d]oxazol-2-yl]
8n
8o
47% > 95:5 dr
43% > 95:5 dr
[R' = 6-Cl-benzo[d]oxazol-2-yl]
Attempted cascade reactions involving two dearomatiza-
tion events were unsuccessful. We believe that the high
stability and ease of reduction of the benzylic radicals
formed during the first dearomatization event (factors that
are also key to driving the dearomatization event), rule out
trapping of the radical by a second radical acceptor, wheth-
er it be another aromatic unit or a simple alkene or alkyne.
H
H
H
N
H
N
Br
OH
N
OH
iPr
O
iPr
O
iPr
O
S
N
O
O
N
S
N
N
N
R'
O
R'
O
R'
8p
49% > 95:5 dr
8q
30% > 95:5 dr
9k
40% > 95:5 drc
[R' = 5-Br-benzo[d]oxazol-2-yl] [R' = benzo[d]thiazol-2-yl]
[R' = benzo[b]thiophen-2-yl]
X-ray
iPr
Dearomatizing cyclization cascades of amides involv-
ing 7-endo-trig processes. When a benzofuran and ben-
zothiophene moiety were attached to nitrogen of the barbi-
turic acid unit through the 3-position of the heterocycle,
dearomatizing radical-radical cyclization cascades involv-
ing 5-exo-trig and 7-endo-trig processes were observed and
azepine-containing products 11a and 11b were obtained in
moderate yield with excellent diastereocontrol (Scheme 6).
N
O
N
X-ray
crystal structure
of 9l
O
R'
9l
43% > 95:5 drc
[R' = naphthalen-1-yl]
X-ray
a
Reaction conditions A: To a solution of 7 (0.1 mmol), in THF
(2 mL) under N2, was added H2O, followed by a mixture of
SmI2 and LiBr, the reaction was quenched after 2 h. Reaction
conditions B: To a solution of 7 (0.1 mmol), in THF (2 mL)
under N2, was added H2O, followed by a mixture of SmI2 and
LiBr, , after 2 h, HCl (2 M, 1 mL) was added and stirred for 20
Scheme 6. Dearomatizing radical cyclization cascades in-
volving 7-endo-trig processes.a,b
b
1
min. Isolated yield. Dr determined by H NMR of crude
product mixtures. c Prepared using Condition B.
Scope of the dearomatizing radical cyclization cascade
of amides. With optimal conditions established, the gen-
erality of the dearomatizing radical cascade cyclization for
the construction of tetracyclic hemiaminals 8 or enamines
9 was investigated (Scheme 4). Focusing initially on the
dearomatization of benzofurans, various alkyl groups on
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iPr
iPr
iPr
O
N
O
O
N
O
O
N
O
SmI2–H2O–LiBr
THF, rt, 2 h
SmI2–H2O–LiBr
THF, rt, 2 h
R'
R'
R'
1
IIISm
O
O
O
1 e
N
N
N
2
X
X
X
3
4
5
6
7
8
9
7 or 10
12
10a X = O
10b X = S
5-exo-trig
H
H
iPr
N
iPr
N
O
O
H
O
iPr
H
S
H
O
HO
H
HO
H
N
R'
N
R'
heterocycle attached
via C2
IIISm
O
N
N
X
O
O
6-exo-trig
dearomatizing
spirocyclization
R'
O
11a (from 10a)
45% > 95:5 dr
[R' = benzofuran-3-yl]
11b (from 10b)
38% > 95:5 dr
[R' = benzo[b]thiophen-3-yl]
13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
heterocycle attached
via C3
X-ray
7-endo-trig
dearomatizing
cyclization
iPr
O
SmIII
O
H
X-ray
crystal structure
of 11b
H
14
15
H
OSmIII
X
iPr
X
N
N
N
O
N
R'
O
1 e
2 x H+
1 e
2 x H+
O
a
R'
Reaction conditions: To a solution of 10 (0.1 mmol), in THF
(2 mL) under N2, was added H2O, followed by a mixture of
SmI2 and LiBr. The reaction was quenched after 2 h. Isolated
yield. Dr was determined by H NMR of the crude product
H
H
iPr
O
b
OH
N
H
iPr
O
1
HO
X
X
N
N
N
mixture.
H
8
11
O
R'
O
R'
In dearomatizing radical cyclization cascades, ET from
Sm(II) to the amide-type carbonyl forms radicals 12. 5-Exo-
trig cyclization then forms radical intermediates 13 which
undergo either 6-exo-trig or 7-endo-trig dearomatizing cy-
clization, depending on the site of attachment of the het-
eroaryl unit to the barbituric acid scaffold. When the het-
eroaromatic group is attached via C2, spirocyclization takes
place via chair transition structure 14 in which dipole-
dipole interactions are minimized. Further ET reduction
and protonation then delivers 8. In contrast, when the het-
eroaryl unit is attached via C3, 7-endo-trig radical cycliza-
tion via transition structure 15 leads to 11 (Scheme 7).
Manipulation of the products of dearomatizing amide
radical cyclizations and cyclization cascades. The
dearomatizing radical cyclizations and cyclization cascades
can be carried out on larger scale to deliver products such
as 3b and 9a with excellent diastereocontrol in good isolat-
ed yield (Scheme 8).
Scheme 8. Larger scale dearomatizing radical cyclizations
and cyclization cascades of amides.
O
Cy
O
Cy
Me
O
N
Me
O
O
SmI2–H2O–LiBr
THF, rt, 2 h
N
N
OH
O
N
O
Me
Me
2 mmol, 0.80 g
0.62 g
2b
3b
78% > 95:5 dr
Scheme 7. Proposed mechanisms for the dearomatizing
radical cyclization cascades.
SmI2–H2O–LiBr
THF, 0 °C, 2 h
iPr
N
O
N
O
R'
iPr
O
then
HCl (2 M, 15 mL)
1 h
O
N
O
O
N
O
R'
9a
70% 92:8 dr
1 mmol, 0.48 g
7a
0.34 g
[R' = benzofuran-2-yl]
The unusual hemiaminal products arising from dearoma-
tizing amide radical cyclization can be readily manipulated.
For example, iminium ion generation, upon exposure of 3b
to BF3•OEt2, and addition of various carbon nucleophiles,
delivers complex tertiary amine products 16a-c with high
stereocontrol (Scheme 9).23
Scheme 9. Manipulation of the hemiaminal products of
the dearomatizing radical cyclization of amides.
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Journal of the American Chemical Society
O
Cy
O
Cy
Supporting Information
Me
O
Me
O
1
2
BF3•Et2O
N
The Supporting Information is available free of charge on the
ACS Publications website. Experimental details, characteriza-
tion data and spectra, X-ray structures, and NOE studies
(PDF).
N
N
CH2Cl2, rt
N
OH
Nu
O
O
Nucleophile
Me
3
4
Me
(Nu–
)
16a–d
major
3b
5
6
7
8
AUTHOR INFORMATION
O
Cy
O
O
N
Cy
O
O
Cy
O
Me
O
Me
O
Me
N
N
N
Corresponding Author
N
O
N
*david.j.procter@manchester.ac.uk
9
Me
Me
Me
•
Cl
16c
10
11
12
13
14
15
16
17
18
19
Notes
16a
96% > 95:5 dr
(with allylTMS)
16b
66% > 95:5 dr
(with propargylTMS)
The authors declare no competing financial interest.
55% > 95:5 dr
(with 2-chloromethylallylTMS)
ACKNOWLEDGMENT
O
N
Cy
Me
N
X-ray crystal
structure
of major
diastereoisomer
of 16d
We thank the EPSRC (EPSRC Established Career Fellowship to
D. J. P.), the Leverhulme Trust (Research Fellowship to D. J.
P.), and the University of Manchester (President’s Scholarship
to H. H.).
O
H
O
Me
16d
99% 68:32 dr
(with Et3SiH)
REFERENCES
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1) For selected reviews on dearomatization, see (a) Pape, A. R.;
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Similarly, the products of dearomatizing amide radical cy-
clization cascades can be further elaborated. For example,
selective allylic oxidation of tetracyclic enamine 9a gave
ketone 17 in moderate yield (Scheme 10).24 The cyclic urea
moiety in the cascade products can be reduced. For exam-
ple, reduction of 9a with DIBALH gave new hemiaminal 18
which can be reduced further by excess reagent to give pol-
ycyclic aminal 19.
Scheme 10. Manipulation of the novel polycyclic spiro-
barbiturates.
O
iPr
iPr
CAN (6 equiv)
O
N
O
O
O
N
O
O
CH3CN:H2O
45%
N
N
17
9a
R'
R'
[R' = benzofuran-2-yl]
DIBAL-H (3 equiv)
iPr
O
N
OH
THF, –78 oC to rt
68%
N
18
O
R'
iPr
O
N
O
N
iPr
9a
DIBAL-H (8 equiv)
O
R'
O
N
THF, –78 oC to rt
95%
N
19
R'
3. CONCLUSION
The first dearomatizing radical cyclizations and cyclization
cascades triggered by ET reduction of amide-type carbonyls
provide access to unprecedented polycyclic molecular ar-
chitectures containing up to five stereocenters with high C. S. J. Am. Chem. Soc. 2015, 137 (47), 14858.
(3) For recent examples of dearomatizing radical cyclization,
diastereocontrol. The mild process exploits activation of
SmI2 with H2O and LiBr, exhibits wide scope with regard to
the aromatic system undergoing dearomatization, and de-
livers novel scaffolds based on a medicinally-proven struc-
tural platform. While the current method is limited to am-
ide-type carbonyls in cyclic imides, future studies will focus
on extending the method to simple lactam substrates.
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1517645 for 3j, CCDC 1517646 for 8j, CCDC 1517647 for 8k, CCDC
1517649 for 9a, CCDC 1517648 for 9a’, CCDC 1517650 for 9c, CCDC
1517651 for 9d, CCDC 1517652 for 9e, CCDC 1517653 for 9h, CCDC
1517654 for 9i, CCDC 1517655 for 9j, CCDC 1517656 for 9k, CCDC
1517657 for 9l, CCDC 1517638 for 11b, CCDC 1517639 for 16d).
(21) See Supporting Information for nOe studies on 3f, 8o and
18.
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B. E.; Zhang, H. C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A.
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(24) Nair, V.; Deepthi, A. Chem. Rev. 2007, 107, 1862.
O
O
SmII
R
R
Me
Me
N
N
2
O
O
N
O
O
N
OH
O
Me
Me
up to >95:5 dr
ET reduction
n dearomatizing radical cyclizations & cascades
n amides n high stereocontrol n up to 5 stereocenters
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