Radical Multicomponent Carboamination of [1.1.1]Propellane

Article abstract of DOI:10.1021/jacs.7b11865

Three-dimensional, small-ring scaffolds are very important in modern drug discovery to expand the available drug-like chemical space and to optimize drug candidates. Among them, bicyclo[1.1.1]pentane (BCP) is regarded as a high-value bioisostere for a phenyl ring or tert-butyl group; it provides an option to generate drug-like molecules with good passive permeability, high aqueous solubility, and improved metabolic stability, though the lack of methodology to functionalize BCP remains a significant challenge. Here we present an efficient method, developed with the aid of density functional theory calculations, for the synthesis of multifunctionalized BCP derivatives by means of a radical multicomponent carboamination of [1.1.1]propellane. This reaction features mild conditions, one-pot operation, and gram-scale synthetic capability, and opens up a unique and highly efficient route for the synthesis of multifunctionalized BCP derivatives, including synthetically useful 3-substituted BCP-amines.

Full text of DOI:10.1021/jacs.7b11865

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Communication
Radical Multicomponent Carboamination of [1.1.1]Propellane
Junichiro Kanazawa, Katsuya Maeda, and Masanobu Uchiyama
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b11865 • Publication Date (Web): 13 Nov 2017
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Journal of the American Chemical Society
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Radical Multicomponent Carboamination of [1.1.1]Propellane
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,
†,‡
†
,‡,#
Junichiro Kanazawa,* Katsuya Maeda, and Masanobu Uchiyama*
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†
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1ꢀ1 Murasakiꢀcho, Takatsuki, Osaka 569ꢀ1125, Japan.
Elements Chemistry Laboratory, RIKEN, 2ꢀ1 Hirosawa, Wakoꢀshi, Saitama 351ꢀ0198, Japan.
‡
#
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7ꢀ3ꢀ1 Hongo, Bunkyoꢀku, Tokyo 113ꢀ0033, Japan.
Supporting Information Placeholder
A ~ C: Pioneering Synthetic Work of Bicyclo[1.1.1]pentane (BCP) Derivatives
ABSTRACT: Threeꢀdimensional, smallꢀring scaffolds
are very important in modern drug discovery to expand
the available drugꢀlike chemical space and to optimize
drug candidates. Among them, bicyclo[1.1.1]pentane
2
H N
C
[
1.1.1]Propellane
1ꢀAminoꢀBCP
(BCPꢀamine)
(2)
Symmetric
Disubstitution
Lack of
Methodology
(BCP) is regarded as a highꢀvalue bioisostere for a pheꢀ
This Work
nyl ring or tertꢀbutyl group; it provides an option to genꢀ
erate drugꢀlike molecules with good passive permeabilꢀ
ity, high aqueous solubility, and improved metabolic
stability, though the lack of methodology to functionalꢀ
ize BCP remains a significant challenge. Here we preꢀ
sent an efficient method, developed with the aid of denꢀ
sity functional theory (DFT) calculations, for the syntheꢀ
sis of multiꢀfunctionalized BCP derivatives by means of
A, B
X
2
H N
X
X
Unsymmetrization
Unsymmetric
Disubstituted BCPs
Disubstituted BCPs
Multi-step Transformation
A Michl et al. (1988)7
O
O
3 steps
HO
Cl
2 steps
3
H N
MeCOCOMe
OMe
OMe
hv
O
B Adsool et al. (2015)9
O
O
Cl
1
. TBACB, AIBN,
Benzene, Air Flow
I
NaN
N
3
3
H N
I
2
3
I
I
2. TTMSS, AIBN, HCl
a
radical
multicomponent
carboamination
of
C Baran et al. (2016)1c,1d
Bn NMgCl—LiCl Pd(OH)
Cl
[1.1.1]propellane. This reaction features mild conditions,
oneꢀpot operation, and gramꢀscale synthetic capability,
and opens up a unique and highly efficient route for the
synthesis of muliꢀfunctionalized BCP derivatives, inꢀ
cluding synthetically useful 3ꢀsubstituted BCPꢀamines.
2
2
/C, H
2
3
H N
D This Work
Boc
Boc
HN
N
N
N
H
2 3
Fe(Pc) / TBHP / Cs CO
N
H
2
N
X
Radical Multicomponent
Carboamination
Boc
Boc
X
X = COOMe, Ar, HetAr, Alkyl
Figure 1. (A), (B), (C) Synthesis of BCPꢀamine and 3ꢀ
substituted BCPꢀamines. (D) Oneꢀpot radical multicomꢀ
ponent strategy.
In modern drug discovery, threeꢀdimensional smallꢀ
ring scaffolds are increasingly being employed to exꢀ
pand the available drugꢀlike chemical space and to optiꢀ
mize drug candidates. A representative example is bicyꢀ
clo[1.1.1]pentane (BCP, 1), which was first utilized in
5
for synthesis of BCP derivatives, but access to 3ꢀ
substituted BCPꢀamines is still difficult. For example, 3ꢀ
aminobicyclo[1.1.1]pentaneꢀ1ꢀcarboxylic acid has conꢀ
siderable potential as an unnatural amino acid in the
1
the MGluR1 antagonists developed by Novo Nordisk in
6
pharmaceutical sciences, but is extremely costly (meꢀ
2
1996. BCP is considered as a bioisostere of the phenyl
thyl ester: ~$300,000/kg) due to the complex multiꢀstep
synthetic procedure, including photoreaction as the first
3
4
ring and tertꢀbutyl group, and its introduction can sigꢀ
nificantly improve passive permeability, aqueous soluꢀ
bility, metabolic stability, and other properties (Chart 1).
7
step (Figure 1A). 3ꢀAryl BCPꢀamines are also synthetiꢀ
cally inaccessible, though they are of interest in drug
Chart 1. Bicyclo[1.1.1]pentane
discovery as a bioisostere of biarylamine to escape the
8
“
flatland” of multiple aryl systems. So far, there is the
only one example of the synthesis of 3ꢀphenyl BCPꢀ
9
amine (Figure 1B) and there has been no report on the
introduction of substituted aryl groups into BCPꢀamine.
Bunker et al. demonstrated that Carreira’s hydroaminaꢀ
1
ꢀAminobicyclo[1.1.1]pentane (BCPꢀamine) derivaꢀ
10
tion could be applied to [1.1.1]propellane to give BCPꢀ
tives are already a pharmaceutically important scafꢀ
fold,
use of [1.1.1]propellane (2) has opened up new avenues
11
1c,1d
amine. Baran has reported a strainꢀreleaseꢀtype transꢀ
but they remain synthetically challenging. The
formation of [1.1.1]propellane by turboꢀamidoꢀGrignard
reagents to give BCPꢀamine (Figure 1C).
1c,1d
Also,
Knochel developed an elegant practical method to synꢀ
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Journal of the American Chemical Society
Page 2 of 5
thesize bisꢀarylated BCPs by combining Grignard reaꢀ unsuccessful. Thus, we focused on screening of other
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gentꢀmediated ringꢀopening of [1.1.1]propellane and
Negishi coupling after transmetalation with ZnCl2.
catalysts/oxidants/additives and on optimization of the
reaction conditions for the radical multicomponent carꢀ
boamination of [1.1.1]propellane (2), as summarized in
Table 1. We found that the combination of tertꢀbutyl
hydroperoxide (TBHP) and iron(II) phthalocyanine
12
However, the applicability of these protocols to syntheꢀ
13
size 3ꢀfunctionalized BCPꢀamines remains unclear.
Taking account of the facts that [1.1.1]propellane conꢀ
14
(
Fe(Pc)) (cat.) was most effective; on the other hand,
tains a characteristic fragile central bond and bicyꢀ
clo[1.1.1]pentꢀ1ꢀyl radical (BCPꢀradical) is kinetically
FeCl , Fe(OAc) , CuBr, or CuCl did not catalyze this
2
2
1
5
transformation. Other terminal oxidants, such as diꢀtertꢀ
butyl peroxide (TBP), benzoyl peroxide (BPO), and cuꢀ
mene hydroperoxide (CHP), gave the desired product in
moderate yield. Addition of inorganic base to the reacꢀ
stable (energy barrier to ring opening: ~26 kcal/mol),
we hypothesized that a oneꢀpot radical multicomponent
carboamination (radical addition / central bond cleavage
/ radical trapping) protocol (Figure 1D) might provide
direct methodology to form C–C and C–N bonds simulꢀ
taneously on a BCP scaffold and generate 3ꢀ
functionalized BCPꢀamines. In radical reactions involvꢀ
ing [1.1.1]propellane, it is usually difficult to control
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tion mixture was effective, and Cs CO gave the best
2
3
result (Entry 7). Use of K CO or K PO gave comparaꢀ
2
3
3
4
ble results, but organic bases and NaHCO decreased the
3
yield of 5. The reaction temperature/time, solvent, and
ratio of substrates also influenced the yield of this radiꢀ
cal multicomponent carboamination. Examination of
several solvents showed acetonitrile to be greatly supeꢀ
rior to etheric solvents, nonꢀpolar solvents, or aromatic
16
polymerization as a side reaction. However, our model
calculations indicated that diꢀtertꢀbutyl azodicarboxylate
(3) can act as a radical acceptor of the intermediary 3ꢀ
substituted BCPꢀradical (INT1) to give a more stable
2
0
1
0,11a
solvents. Finally, the set of conditions shown in Entry
19 was found to be optimal.
radical intermediate (INT2a).
The C–N bond forꢀ
‡
mation (∆G = 6.6 kcal/mol) is kinetically preferred by
a
3
[
[
.6 kcal/mol over ‡ radical oligomerization of
Table 1. Optimization of Reaction Conditions
1.1.1]propellane (∆G = 10.2 kcal/mol) to give
n]staffanes (Figure 2). INT2a contains an intrinsically
Catalyst
Oxidant
Additive
Boc
HN
N
Boc
H
N
N
N
OMe
H
2
N
Boc
OMe
stable amidyl radical, resulting in a highly exothermic
process. Therefore, if we can find an appropriate precurꢀ
sor that generates radical species by hydrogen abstracꢀ
tion with INT2a, an efficient radical chain reaction
might be possible.
Boc
O
MeCN, Temp., Time
2
3
4
5
O
Time Yieldb
Entry
Catalyst
(mol%)
Oxidant
(equiv.)
Additive
(equiv.)
Temp.
(°C)
(h)
(%)
1
2
3
4
5
6
7
8
9
FeCl
2
(20)
H
H
2
O
O
2
(4.0)
(2.0)
none
none
none
0
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
1
28
18
40
47
47
29
52
42
30
39
33
37
44
8
Fe(Pc) (20)
Fe(Pc) (20)
Fe(Pc) (20)
Fe(Pc) (20)
Fe(Pc) (20)
Fe(Pc) (20)
Fe(Pc) (20)
Fe(Pc) (20)
Fe(Pc) (20)
Fe(Pc) (20)
Fe(Pc) (20)
Fe(Pc) (20)
2
2
0 to r.t.
0 to r.t.
0 to r.t.
0 to r.t.
0 to r.t.
0 to r.t.
0 to r.t.
0 to r.t.
0 to r.t.
0 to r.t.
0 to r.t.
0 to r.t.
0 to r.t.
0 to r.t.
0 to r.t.
0 to r.t.
–20
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
K
K
2
CO
PO
3
(1.0)
(1.0)
∆
G (Kcal/mol)
3
4
TS1b
+10.2
TBHP (2.0) NaHCO
3
(1.0)
(1.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBP (2.0)
BPO (2.0)
CHP (2.0)
TBHP (2.0)
2 3
Cs CO
–
35.2
TS1a
Boc
DMAP (1.0)
Pyridine (1.0)
+6.6
Boc
10
11
12
Et
3
N (1.0)
N
N
N
N
Cs CO (1.0)
OMe
OMe
2
3
INT2b
INT2a
Boc
Cs CO (1.0)
2
2
2
3
3
3
Boc
OMe –52.2
O
INT1
O
13
Cs
Cs
CO
CO
(1.0)
(1.0)
INT2b
2
FeCl (20)
Fe(OAc)2 (20) TBHP (2.0)
O
14
[
n]Staffanes
INT2a
Target Molecule
Cs CO (1.0)
7
6
5
15
16
17
18
19
20
2
2
2
2
3
3
3
3
CuBr (20)
CuCl (20)
Fe(Pc) (5)
Fe(Pc) (5)
Fe(Pc) (5)
TBHP (2.0)
TBHP (2.0)
TBHP (2.0)
TBHP (1.5) Cs
TBHP (1.0) Cs
Cs
Cs
Cs
CO
CO
CO
(1.0)
(1.0)
(1.0)
(1.0)
(1.0)
Figure 2. Our model calculation at the UM062X/6ꢀ
58
61(57)
39
c
CO
3
–20
–20
1
1
3
1G* level (∆G in kcal/mol).
2
2
CO
3
a
Based on this working hypothesis, we initially selectꢀ
Reaction conditions: 2 in pentane (1.0 mmol), 2.0 equiv. of 3 and 4, cataꢀ
b 1
lyst, oxidant, additive in acetonitrile (6.0 mL). Determined by H NMR
using benzyl benzoate as an internal standard. Isolated yield.
ed methyl carbazate (4) as a methoxycarbonyl radical
c
17
precursor. The initial hydrogen abstraction step from 4
proceeds in the presence of oxidant and transition metal
catalyst, and the use of toxic tin reagents or photoirradiaꢀ
Scheme 1. Gram-scale Synthesis and Transformation
to Amine
18
Fe(Pc) (5 mol%)
TBHP (1.5 equiv.)
tion equipment is not necessary. We then investigated
Boc
H
N
N
N
OMe
H
2
N
2 3
Cs CO (1.0 equiv.)
the radical multicomponent carboamination of
Boc
O
MeCN, –20 °C, 1 h
[
1.1.1]propellane (2) freshly prepared in pentane soluꢀ
19
2
3
4
[Xꢀray]
tion in the presence of 3 and 4 to determine the best
(
6.4 mmol) (2.0 equiv.) (2.0 equiv.)
5 1.6 g (71%)
reaction conditions (Table 1).
Cl
Cl
H
PtO
2
(10 mol%)
3
H N
N
H
2
(1 atm)
Gratifyingly, an initial attempt under typical Fenton
HCl
3
H N
OMe
O
OMe
AcOEt, r.t., 36 h
MeOH, r.t., 12 h
reaction conditions (H O /FeCl (cat.) system; MeCN, 0
2
2
2
O
°C, 12 h) afforded the desired product 5 in 28% yield
(Entry 1). However, attempts improve the yield of 5 in
the FeCl /H O system under various conditions were
6
7 92% (2 steps)
Notably, the reaction could be conducted on gram scale
to provide 5 in 71% yield. The structure of 5 was deterꢀ
2
2
2
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Journal of the American Chemical Society
amined alkyl hydrazine substrates. When 2,2,2ꢀ
mined unequivocally by singleꢀcrystal Xꢀray diffraction
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
analysis, and the methoxycarbonyl group and the hydraꢀ
zine moiety were found to be installed at the 1ꢀ and 3ꢀ
positions of the BCP skeleton, respectively, as expected.
The hydrazine moiety is a versatile platform for further
chemical elaborations. Treatment of 5 with 4 N HCl in
AcOEt gave the hydrazine hydrochloride salt (6). Reꢀ
duction of the N–N bond under hydrogenation condiꢀ
tions in the presence of PtO2 gave methyl 3ꢀ
aminobicyclo[1.1.1]pentaneꢀ1ꢀcarboxylate hydrochloꢀ
trifluoroethyl)hydrazine was used, 9s was obtained in
moderate yield. This result suggests that the present radꢀ
ical multicomponent carboamination is applicable to
3
C(sp )–substrates on the BCP scaffold. To our
knowledge, this is the first example of oneꢀpot radical
multicomponent carboamination of [1.1.1]propellane (2)
to afford highly multiꢀfunctionalized BCPs.
A
Fe(Pc) (5 mol%)
Boc
HN
N
Boc
H
TBHP (1.5 equiv.)
Cs2CO3 (1.0 equiv.)
TEMPO (2.0 equiv.)
N
N
N
OMe
H
2
N
Boc
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OMe
2
1
Boc
O
ride salt (7) in 92% yield (over 2 steps) (Scheme 1).
O
MeCN, –20 °C, 1 h
2
3
4
5 Not Detected
by LCꢀMS Analysis
Table 2. Radical Multicomponent Carboamination of
(
1 mmol) (2.0 equiv.) (2.0 equiv.)
a
Boc
[1.1.1]Propellane
B
Radical Addition
and
Central Bond Cleavage
N
N
3
Radical Trapping
Fe(Pc) (5 mol%)
TBHP (1.5 equiv.)
Cs CO (n + 1.0 equiv.) Boc
2 3
Boc
Boc
OMe
O
OMe
Boc
Boc
nCl
HN
N
N
N
H
N
N
+
∆G‡ = +9.1
∆G = –28.3
∆G‡ = +6.6
∆G = –52.2
N
nH H
2
N
X
Boc
X
HN
N
MeCN, –20 °C, 1 ~ 3 h
O
2
3
8
9
INT1
(
1 mmol)
(2.0 equiv.)
(2.0 equiv.)
Boc
OMe
Boc
Boc
Boc
Boc
Boc
OMe
2
N
N
INT3
O
HN
N
HN
HN
N
HN
N
N
O
Boc
OMe
Fe(Pc)
TBHP
OMe ref. 18
Boc
Boc
Boc
Boc
12
CF
3
F
INT2a
O
N
2
N
HN
4
Cl
a: 53%b
9b (ortho): 66%b
9e (ortho): 49%b
9f (meta): 57%
9g (para): 53%b
9h: 42%d
O
9
∆G‡ = +1.5
∆G = –27.8
∆G‡ = +7.0 10
c
b
N
OMe
9
9
c (meta): 38%
d (para): 44%
N
INT3 ∆G = –33.6
c
Fe(Pc)/TBHP
O
G‡ = +5.9
∆
Boc
Boc
Boc
Boc
HN
Boc
11
HN
N
HN
HN
N
12
HN
N
N
Regeneration
of
Methoxycarbonyl Radical
Boc
Boc
Boc
Boc
N
F
Boc
OMe
Hydrogen Abstraction
O
Br
NO2
5
O
9
i: 41%d
Boc
9j: 71%
b
F
9k: 57%d
OMe
HN
9l: 43%c
Boc
Figure 3. (A) Radical trapping experiment with
TEMPO. (B) DFT calculation on radical chain cylcle at
the UM062X/6ꢀ31G* level (∆G in kcal/mol).
Boc
HN
N
HN
N
N
Boc
Boc
Boc
Boc
OCF
3
CN
m: 64%d
9n: 72%b
9o: 42%d
To reach a better understanding of the present radical
multicomponent carboamination, a mechanistic investiꢀ
gation was performed. When 2.0 equiv. of TEMPO was
added to the reaction mixture as a radical inhibitor, the
desired product (5) was not obtained at all and the
TEMPOꢀCOOMe, and TEMPOꢀBCPꢀCOOMe adducts
were detected by LCꢀMS analysis (Figure 3A), supportꢀ
ing the free radical mechanism. Density functional theoꢀ
ry (DFT) calculations (UM062X/6ꢀ31G*) were then
employed to corroborate the experimental results and to
comprehensively unveil the radical chain cycle (Figure
3B). Firstly, addition of methoxycarbonyl radical (12)
(generated in situ by oxidative denitrogenation of methyl
carbazate (4)) to [1.1.1]propellane (2) with a small actiꢀ
vation energy of 9.1 kcal/mol, led to cleavage of the cenꢀ
tral bond to give BCPꢀradical intermediate (INT1) with
a high stabilization energy of 28.3 kcal/mol. Diꢀtertꢀ
butyl azodicarboxylate (3) acts as an excellent radical
acceptor of INT1 to give a stable amidyl radical
9
Boc
Boc
HN
Boc
HN
N
HN
N
HN
Cl
N
N
N
Boc
Boc
Boc
Boc
CF
3
N
N
N
N
Me
e
9q: 56%b
9r: 60%f
9s: 56%b
9
p: 46%
a
Reaction conditions: 2 in pentane (1.0 mmol), 2.0 equiv. of 3 and 8,
Fe(Pc), TBHP, Cs CO in acetonitrile (6.0 mL) at –20 °C. Yields were
2
3
1
determined by H NMR using benzyl benzoate as an internal standard.
b
c
hydrazine monohydrochloride (n = 1), time (1 h). hydrazine (n = 0), time
d
e
(
3 h). hydrazine monohydrochloride (n = 1), time (3 h). hydrazine
f
dihydrochloride (n = 2), time (1 h). hydrazine (n = 0), time (1 h).
We next applied this radical multicomponent carboꢀ
amination to the synthesis of 3ꢀaryl BCPꢀamine equivaꢀ
lents (Table 2). A wide range of arylhydrazines could be
employed: both electronꢀdonating and ꢀwithdrawing
substituents at the orthoꢀ, metaꢀ, and paraꢀpositions of
the aryl ring were well tolerated (9b–g, o). Halogens on
the aryl ring (F, Cl, and Br) were not deleterious to the
reaction; the desired products were obtained (9e–j), and
radicalꢀmediated dehalogenation reactions were not obꢀ
served. Various functional groups were also compatible,
including trifluoromethyl (9b–d), methyl ester (9k), niꢀ
tro (9l), trifluoromethyl ether (9m), nitrile (9n), and tertꢀ
butyl (9o). The reaction also allowed introduction of
heterocyclic groups, such as pyrazolyl (9p), pyridinyl
‡
(INT2a) (∆G = 6.6 kcal/mol) with a very large stabiliꢀ
zation energy of 52.2 kcal/mol. INT2a undergoes hyꢀ
‡
drogen abstraction from 10 (∆G = 7.0 kcal/mol) with a
large exothermicity to provide the unsymmetrically diꢀ
substituted BCP product (5) and diazenyl radical (11),
which smoothly produces 12 with the release of molecuꢀ
‡
(9q), and pyrazyl (9r). To access further synthetically
lar nitrogen (∆G = 1.5 kcal/mol). In this hydrogen abꢀ
useful radical multicomponent carboamination, we exꢀ
straction step, there are multiple candidates for hydrogen
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sources in the reaction mixture, such as H O, tBuOH,
Makoto Shiozaki, and Mr. Kazuyuki Hirata (JT) for their
support, Mr. Ryuhei Okura (JT) for assistance with Xꢀray
crystallographic analysis of 5, Mr. Mitsumasa Takahashi
and Ms. Toshimi Yamada (JT) for the NMR measurements,
and Mr. Eita Nagao (JT) for the ESIꢀMS measurements.
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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4
4
4
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5
5
5
5
5
5
5
5
5
6
TBHP, and CH CN. Based on the activation energies, 10
3
appears to be the most energetically favorable subꢀ
22
strate. This means that the hydrazine moiety is an ideal
precursor to prevent generation of highly reactive oxyꢀ
18,23
gen free radicals.
The whole of this catalytic cycle
REFERENCES
turned out to be kinetically and thermodynamically faꢀ
vorable, in good accordance with the experimental obꢀ
servation (the reaction proceeds under very mild condiꢀ
tions, and is generally completed within 1 h at –20 °C).
(
1) (a) Burkhard, J. A.; Guérot, C.; Knust, H.; Carreira, E. M. Org.
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0
1
2
3
4
5
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9
0
1
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9
0
1
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8
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0
1
2
3
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0
1
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3
4
5
6
7
8
9
0
We have developed the first radical multicomponent
carboamination of [1.1.1]propellane with hydrazyl reaꢀ
gents as a radical precursor and diꢀtertꢀbutyl azodicarꢀ
boxylate as a radical acceptor. This multicomponent carꢀ
boamination features mild reaction conditions, a tinꢀ
free/photoirradiationꢀfree system, oneꢀpot operation, and
gramꢀscale synthetic capability, and thus provides a
highly efficient method for synthesizing a wide range of
novel multiꢀfunctionalized bicyclo[1.1.1]pentane derivaꢀ
tives. These products can be easily transformed into a
variety of synthetically useful 3ꢀsubstituted BCPꢀ
amines, which have many potential applications in
pharmaceutical chemistry, agricultural chemistry, and
materials sciences. We also obtained a comprehensive
reaction profile of the present radical multicomponent
carboamination, by employing a combination of experiꢀ
mental and computational methods. Further studies to
expand the scope of this radical multicomponent methꢀ
odology to activated/inactivated olefins, benzyne, and
other types of propellanes are ongoing in our laboratory.
(
2) Pellicciari, R.; Raimondo, M.; Marinozzi, M.; Natalini, B.; Cosꢀ
tantino, G.; Thomsen, C. J. Med. Chem. 1996, 39, 2874.
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(
O’Sullivan, T. J.; Dirico, K. J.; McDonald, W. S.; Won, A.; Dorff, P.
H.; Nolan, C. E.; Becker, S. L.; Pustilnik, L. R.; Riddell, D. R.;
Kauffman, G. W.; Kormos, B. L.; Zhang, L.; Lu, Y.; Capetta, S. H.;
Green, M. E.; Karki, K.; Sibley, E.; Atchison, K. P.; Hallgren, A. J.;
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Chem. 2012, 55, 3414.
(4) Westphal, M. V.; Wolfstädter, B. T.; Plancher, J.ꢀM.; Gatfield, J.;
Carreira, E. M. ChemMedChem 2015, 10, 461.
(
5) For reviews of [1.1.1]propellane, see: (a) Levin, M. D.; Kaszynski,
P.; Michl, J. Chem. Rev. 2000, 100, 169. (b) Dilmaç, A. M.; Spuling,
E.; de Meijere, A.; Bräse, S. Angew. Chem. Int. Ed. 2017, 56, 5684.
(
6) Pätzel, M.; Sanktjohanser, M.; Doss, A.; Henklein, P.; Szeimies,
G. Eur. J. Org. Chem. 2004, 493.
(7) Kaszynski, P.; Michl, J. J. Org. Chem. 1988, 53, 4593.
(
6
(
2
8) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52,
752.
9) Thirumoorthi, N. T.; Shen, C. J.; Adsool, V. A. Chem. Commun.
015, 51, 3139.
10) Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J. Am. Chem.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on
the ACS Publications website at DOI:
(
Soc. 2006, 128, 11693.
(11) (a) Bunker, K. D.; Sach, N. W.; Huang, Q.; Richardson, P. F.
Org. Lett. 2011, 13, 4746. (b) For syntheses of BCPꢀamine other than
ref 1c, 1d, and 11a, see: Bunker, K. D. Patent WO 2015/089170 A1
Experimental details and characterization data (PDF)
Xꢀray data for compound 5 (CCDC 1570594) (CIF)
(
12) Makarov, I. S.; Brocklehurst, C. E.; Karaghiosoff, K.; Koch, G.;
Knochel, P. Angew. Chem. Int. Ed. 2017, 56, 12774.
AUTHOR INFORMATION
Corresponding Author
(13) For synthesis of 3ꢀalkyl BCPꢀamines, see: Bunker, K. D.; Guo,
C.; Grier, M. C.; Hopkins, C. D.; Pinchman, J. R.; Slee, D. H.; Huang,
Q.; Kahraman, M. Patent WO 2016/044331 A1
*junichiro.kanazawa@jt.com
(
14) Wu, W.; Gu, J.; Song, J.; Shaik, S.; Hiberty, P. C. Angew. Chem.
*uchiyama@mol.f.uꢀtokyo.ac.jp
Int. Ed. 2009, 48, 1407.
(15) Della, E. W.; Schiesser, C. H.; Taylor, D. K.; Walton, J. C. J.
Chem. Soc., Perkin Trans. 2 1991, 0, 1329.
Notes
The authors declare no competing financial interest.
(16) Wiberg, K. B.; Waddell, S. T. J. Am. Chem. Soc. 1990, 112,
2
194.
ACKNOWLEDGMENT
(
17) We examined other methods for the generation of Cꢀradicals, but
Financial support for experimental work was provided by
Japan Tobacco Inc. (JT). This work was also supported by
JSPS GrantꢀinꢀAid for Scientific Research on Innovative
Areas (No. 17H05430), JSPS KAKENHI (S) (No.
these were not applicable the present multicomponent reaction, and
did not afford the target molecule; see Supporting Information.
(18) Taniguchi, T.; Sugiura, Y.; Zaimoku, H.; Ishibashi, H. Angew.
Chem. Int. Ed. 2010, 49, 10154.
(
19) We synthesized 2 in pentane by slightly modified relevant experꢀ
1
7H06173), and grants from Asahi Glass Foundation and
iments reported in ref 1c and 1d, see Supporting Information.
(20) For details of optimizations, see Supporting Information.
Kobayashi International Scholarship Foundation (to M.U.).
The DFT calculations were performed on the RIKEN
HOKUSAI GreatWave (GW). We gratefully acknowledge
the Advanced Center for Computing and Communication
(
21) We confirmed the conversion of some of the arylꢀsubstituted
hydrazines to the corresponding amines; see Supporting Information.
For reaction conditions, refer to ref. 11a.
(
(
22) For details of DFT calculation, see Supporting Information.
23) (a) Liu, W.; Li, Y.; Liu, K.; Li, Z. J. Am. Chem. Soc. 2011, 133,
(
RIKEN) for providing computational resources. We also
thank Dr. Hiromasa Hashimoto, Dr. Motohide Sato, Dr.
10756. (b) Cheng, J.ꢀK.; Loh, T.ꢀP. J. Am. Chem. Soc. 2015, 137, 42.
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