Synthesis of Chiral Piperazines via Hydrogenation of Pyrazines Activated by Alkyl Halides

Article abstract of DOI:10.1021/acs.orglett.6b01190

A facile method has been developed for the synthesis of chiral piperazines through Ir-catalyzed hydrogenation of pyrazines activated by alkyl halides, giving a wide range of chiral piperazines including 3-substituted as well as 2,3- and 3,5-disubstituted

Full text of DOI:10.1021/acs.orglett.6b01190

Letter
pubs.acs.org/OrgLett
Synthesis of Chiral Piperazines via Hydrogenation of Pyrazines
Activated by Alkyl Halides
Wen-Xue Huang,†,‡ Lian-Jin Liu,† Bo Wu,† Guang-Shou Feng,† Baomin Wang,‡ and Yong-Gui Zhou*,†
†State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian
116023, P. R. China
‡State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, 2
Linggong Road, Dalian 116024, P. R. China
S
* Supporting Information
ABSTRACT: A facile method has been developed for the synthesis
of chiral piperazines through Ir-catalyzed hydrogenation of pyrazines
activated by alkyl halides, giving a wide range of chiral piperazines
including 3-substituted as well as 2,3- and 3,5-disubstituted ones with
up to 96% ee. The high enantioselectivity, easy scalability, and
concise drug synthesis demonstrate the practical utility.
hiral piperazines have received much attention due to their
wide distribution in natural products and drugs (Figure 1).1
AH of pyrazines with a fairly narrow substrate scope: working
only for pyrazine-2-carboxylic acid derivatives (Scheme 1).15
C
Scheme 1. AH of Pyrazines and Pyrazinium Salts
Figure 1. Natural products and drugs containing chiral piperazines.
Some piperazines are also useful catalysts and ligands in
asymmetric catalysis.2 The commonly used methods to chiral
piperazines are reduction of ketopiperazines3 and classical
resolution.1d Recently, kinetic resolution and dynamic kinetic
resolution were employed to access chiral piperazines by Bode4a
and Guercio.4b Wolfe and Michael utilized Pd-catalyzed
carboamination or hydroamination of alkenes to synthesize
chiral piperazines.5 More recently, the asymmetric lithiation−
substitution of N-Boc piperazines provided a new approach.6
Other synthetic methods included asymmetric addition of a
Grignard reagent to pyrazine N-oxides,7a chiral pool synthesis,7b
asymmetric hydrogenation (AH) of partially reduced pyrazi-
nes,7c−e and so on.7f,g However, given the great importance of
chiral piperazines, there is still a great need to develop a more
direct, efficient, and general route to such motifs.
This is due to the fact that pyrazine not only is a single-ring
aromatic compound with relative high aromaticity but also has
two strong coordinative nitrogen atoms which easily poison the
catalyst. Furthermore, the piperazine product has two secondary
amines that deactivate the catalyst, too. Recently, a unique
strategy was developed by our group, which employed alkyl
halides to activate azaarenes to realize their AH.9b,11b Specially,
the asymmetric hydrogenation of pyrrolo[1,2-a]pyrazinium salts
had been realized using such a strategy.16 Considering the
structural similarity, we envisioned that such a strategy might be
applied to pyrazines. First, N-alkylation made the pyrazine ring
more electron deficient, weakened its coordination ability, and
AH of readily available pyrazines is among the most
convenient methods for chiral piperazines. But in sharp contrast
to other six-membered azaarenes8 such as pyridine,9 quinoline,10
isoquinoline,11 and others,12−14 there are only two reports on
Received: April 24, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01190
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
facilitated its reduction. Additionally, one nitogen of the product
was blocked by alkylation, and the more basic secondary
piperazine nitrogen formed a salt with in situ generated acid.
Thus, catalyst poisoning of the product was greatly inhibited.
Based on these considerations, herein we report the AH of
pyrazines using alkyl halides as avtivators with a broad substrate
scope.
Table 2. Substrate Scope: 3-Substituted Pyrazinium Salts
b
c
entry
R
yield (%)
ee (%)
To begin the study, pyrazinium salt 1a was employed as a
model substrate (Table 1). The hydrogenation of 1a was
1
2
3
4
5
Ph
90 (2b)
93 (2c)
92 (2d)
93 (2e)
86 (2f)
91 (2g)
80 (2h)
85 (2i)
91 (2j)
82 (2k)
87 (2l)
91 (S)
3-MeC6H4
4-MeC6H4
3,5-Me2C6H3
3-MeOC6H4
4-FC6H4
91 (−)
92 (−)
90 (−)
86 (−)
90 (−)
87 (−)
87 (−)
85 (−)
88 (−)
86 (−)
66 (+)
81 (+)
a
Table 1. Condition Optimization
d
6
7
4-ClC6H4
d
8
de
,
4-BrC6H4
9
4-CF3C6H4
4-PhC6H4
ef
,
10
11
12
13
b
c
entry
solvent
THF
ligand
conv (%)
ee (%)
2-naphthyl
2-Me-4-FC6H3
cyclopropyl
de
,
1
2
3
4
5
6
7
8
9
L1
L1
L1
L1
L1
L2
L3
L4
L5
L4
L4
L4
L4
L4
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
50
24
52
51
38
35
62
29
79
21
85
88
86
88
91
95 (2m)
68 (2n)
ef
,
toluene (T)
benzene
1,4-dioxane (D)
EtOAc
a
Conditions: 1 (0.2 mmol), [Ir(COD)Cl]2 (1.0 mol %), L4 (2.2 mol
%), H2 (1200 psi), toluene/1,4-dioxane (1/1), −20 °C, 36 h; if not
b
c
noted, Ar = 2-iPrO2CC6H4. Isolated yields. Determined by chiral
d
e
f
toluene
HPLC. −10 °C. Ar = Ph. 0 °C.
toluene
toluene
toluene
withdrawing groups were well tolerated, affording piperazines
with high yields and ee’s (entries 2−9). Meanwhile, products
with electron-donating groups tended to have slightly higher
enantioselectivities than those with electon-withdrawing groups.
Biphenyl and 2-naphthyl substituted substrates underwent
reduction smoothly, delivering 88% and 86% ee, respectively
(entries 10−11). Product 2m with a substitution pattern present
in drug Vestipitant1b was isolated with a diminished ee value,
which was possibly caused by the steric hindrance of the ortho
methyl group (entry 12). For 3-alkyl substituted 2n, moderate
yield and ee were obtained (entry 13).
d
10
toluene
e
11
toluene
f
12
13 ,
toluene
88
fg
toluene
>95
>95
fg
14 ,
T/D (1/1)
a
Conditions: 1a (0.20 mmol), [Ir(COD)Cl]2 (1.0 mol %), L* (2.2
b
mol %), H2 (600 psi), solvent (3.0 mL), 30 °C, 36 h. Determined by
c
d
e
f
1H NMR. Determined by chiral HPLC. 0 °C. −20 °C. −20 °C, H2
g
(1200 psi). 1b (0.20 mmol).
Next, we turned our attention to the AH of 3,5-disubstituted
pyrazinium salts. After a condition reoptimization (see the SI),
our strategy turned out to be successful, and a range of 3,5-
disubstituted pyrazinium salts could be well reduced (Table 3).
The electronic property and position of the substituent on the 5-
aryl ring had little effect on the yield and ee (entries 1−13, 82−
93% ee). All the products except 4i were delivered with excellent
d.r. (>20:1). Interestingly, product 4m with the more sterically
demanding 1-naphthyl group afforded a higher ee than 2-
naphthyl 4l (86% vs 78%). A longer alkyl or cyclopropyl group
instead of a methyl group at the 3-position led to slight erosion of
the ee, but a good yield and d.r. were maintained (entries 14−
18). When the hydrogenation of 3a was performed on a gram
scale, 90% yield and 89% ee were obtained with 0.5 mol %
catalyst loading (see the SI).
Encouraged by the successful AH of 3-substitued and 3,5-
disubstitued pyrazinium salts, we sought to further examine the
feasibility of the current strategy on 2,3-disubstituted pyrazines.
Being different from the former substrates, a high reaction
temperature and low hydrogen pressure were propitious to the
enantiocontrol (see the SI). Under the optimal conditions, a
range of 2,3-disubstituted piperazines were readily obtained with
high yields and ee’s (Table 4, entries 1−8). 2,3-Dimethyl
pyrazinium salt was also a suitable substrate, giving the desired
product 6i in 91% ee (entry 9). The 6j with a decahydroquinoxa-
line framework was obtained with 96% ee (entry 10). Notably, all
sensitive to solvent, and toluene was the best choice with respect
to enantioselectivity (entries 1−5). Subsequently, some
commercially available chiral diphosphine ligands were evaluated
to identify an efficient catalyst (entries 6−9). To our delight,
much better ee was obtained with ferrocene-derived JosiPhos L4
(79%). The substituent on the phosphine was crucial; a dramatic
drop of the ee was observed using L5 (21%). Decreasing the
temperature gradually improved the ee, albeit with some loss of
reactivity (entries 10−11). So, high pressure was employed
(entry 12). Then, different activation reagents such as iodo-
methane, benzyl chloride, or substituted benzyl bromide were
tested. It was found that both the alkyl group and counterion had
a great impact on the reactivity and enantioselectivity (for details,
see the Supporting Information (SI)). While the N-methyl group
gave poor reactivity, the 2-isopropoxycarbonyl substituted benzyl
group delivered full conversion with 88% ee (entry 13). Finally,
91% ee was achieved with a mixed solvent of toluene and 1,4-
dioxane (entry 14).
Having identified a highly enantioselective catalytic system, a
range of 3-substituted pyrazinium salts were hydrogenated to test
the generality (Table 2). Both electron-donating and electon-
B
DOI: 10.1021/acs.orglett.6b01190
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Substrate Scope: 3,5-Disubstituted Pyrazinium Salts
Scheme 2. Synthesis of Vestipitant
b
c
entry
R1
R2
yield (%)
ee (%)
1
2
3
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Ph
94 (4a)
93 (4b)
95 (4c)
81 (4d)
92 (4e)
95 (4f)
97 (4g)
93 (4h)
87 (4i)
94 (4j)
96 (4k)
94 (4l)
91 (3R,5S)
90 (−)
88 (−)
90 (−)
92 (−)
84 (−)
82 (−)
92 (+)
93 (−)
93 (−)
90 (−)
78 (−)
86 (+)
80 (+)
77 (+)
86 (+)
76 (+)
83 (+)
3-MeC6H4
4-MeC6H4
3,5-Me2C6H3
3-MeOC6H4
4-MeOC6H4
4-BnOC6H4
4-FC6H4
3-ClC6H4
4-CF3C6H4
4-PhC6H4
2-naphthyl
1-naphthyl
Ph
reported syntheses of 10 generally require 3−6 steps coupled
with chemical resolution.1d Starting from salt 1a, 10 was obtained
in five steps with just three column separations in an overall 47%
yield (Scheme 3).
d
4
5
6
7
8
Scheme 3. Formal Synthesis of (S)-Mirtazapine
de
,
9
d
10
11
12
13
14
15
16
17
18
d
91 (4m)
96 (4n)
90 (4o)
92 (4p)
86 (4q)
90 (4r)
nPr
nBu
iBu
Ph
Ph
d
f
Ph
cyclopropyl
Ph
a
Conditions: 3 (0.2 mmol), [Ir(COD)Cl]2 (1.0 mol %), L2 (2.2 mol
%), H2 (600 psi), toluene/DCE (1/1), −20 °C, 24 h. If not noted, the
To investigate the reaction pathway, an isotopic labeling
experiment was carried out by reducing 1a with D2 (Scheme 4).
b
c
d
d.r. > 20:1. Isolated yield. Determined by chiral HPLC. H2 (1000
e
f
psi). d.r. = 12:1. 0 °C.
Scheme 4. Mechanistic Investigation
a
Table 4. Substrate Scope: 2,3-Disubstituted Pyrazinium Salts
b
c
entry
R
yield (%)
ee (%)
1
2
Ph
96 (6a)
98 (6b)
93 (6c)
94 (6d)
95 (6e)
94 (6f)
92 (6g)
96 (6h)
95 (6i)
93 (6j)
94 (2R,3S)
92 (+)
93 (+)
95 (+)
93 (+)
82 (+)
81 (+)
93 (+)
91 (+)
96 (+)
3-MeC6H4
4-MeC6H4
3-MeOC6H4
4-FC6H4
d
3
d
4
5
6
7
3-ClC6H4
4-CF3C6H4
2-naphthyl
Me
d
8
e
9
It was determined that each atom of C3, C5, and C6 incorporated
one deuterium atom. Meanwhile, hydrogen/deuterium scram-
bling took place on the C2, which was possibly caused by
enamine−iminium tautomerization. The deuteration extent at
the two diastereotopic positions of C6 was slightly different (55%
vs 35%), indicating that deuterium incorporation at C6
happened after stereocenter formation. When the reduction of
1a was performed in deuterium solvent CD3OD, a deuterium
atom was only incorporated on C2, further confirming the
possible enamine−iminium tautomerization.
On the basis of above-mentioned experimental data, a
plausible reaction pathway was proposed in Scheme 5. The salt
1a first undergoes 1,4-hydride addition to give a 1,4-
dihydropyrazine intermediate. In the presence of HBr, the
right side enamine is prone to tautomerize due to the adjacent
e
10
-(CH2)4-
a
Conditions: 5 (0.2 mmol), [Ir(COD)Cl]2 (1.0 mol %), L* (2.2 mol
%), H2 (400 psi), THF/EtOAc (1/1), 50 °C, 24 h. In all cases, the d.r.
b
c
d
> 20:1 Isolated yields. Determined by chiral HPLC. H2 (200 psi),
60 °C. L*: (S,S)-f-Binaphane, H2 (600 psi), THF, 30 °C, 24 h; BnBr
was used as an activator.
e
the 2,3-disubstituted pyrazinium salts were reduced with
excellent d.r. (>20:1).
With readily available chiral piperazines in hand, we were keen
to synthesize piperazine-containing drugs. Vestipitant is a potent
and selective NK1 receptor antagonist, which is now under
development as an antiemetic and anxiolytic drug. Currently, the
syntheses of Vestipitant require 6−9 steps.17 Starting from the
piperazine 2m, Vestipitant can be obtained in just two steps,
significantly shortening the synthetic route (Scheme 2).
Mirtazapine is a tetracyclic antidepressant drug widely used as
a racemate. But recent biological investigations reveal that only
(S)-Mirtazapine shows potential in the treatment of insomnia
and climacteric symptoms. To obtain the (S)-Mirtazapine, 1-
methyl-3-phenylpiperazine 10 is an important intermediate. The
Scheme 5. Proposed Reaction Pathway
C
DOI: 10.1021/acs.orglett.6b01190
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(5) (a) Cochran, B. M.; Michael, F. E. Org. Lett. 2008, 10, 329.
(b) Nakhla, J. S.; Wolfe, J. P. Org. Lett. 2007, 9, 3279.
(6) (a) Firth, J. D.; O’Brien, P.; Ferris, L. J. Am. Chem. Soc. 2016, 138,
651. (b) McDermott, B. P.; Campbell, A. D.; Ertan, A. Synlett 2008,
2008, 875.
phenyl group, which leads to the stabilization of the iminium salt
via conjugation. Hydrogenation of the iminium salt delivers
chiral tetrahydropyrazine. The residual double bond is directly
hydrogenated for the lack of steric hindrance and stabilization.
In conclusion, an expedient method has been developed for
the synthesis of chiral piperazines from readily available
pyrazinium salts. The current system exhibits an impressively
broad substrate scope, and 3-substituted as well as 2,3- and 3,5-
disubstituted pyrazinium salts can be easily hydrogenated with
high yields and ee’s. The chiral products are mono-N-protected,
which is advantageous for synthetic modification on either
nitrogen. The practicability of the reaction has been demon-
strated by the easy scalability and drug synthesis. In addition,
preliminary mechanistic studies shed some light on the reaction
pathway, which involves an initial 1,4-hydride addition,
enamine−iminium tautomerization, and AH of an iminium
salt. Further efforts to apply the related method to other
challenging heteroaromatics are ongoing in our laboratory.
(7) (a) Andersson, H.; Banchelin, T. S.-L.; Das, S.; Gustafsson, M.;
Olsson, R.; Almqvist, F. Org. Lett. 2010, 12, 284. (b) Jida, M.; Laconde,
G.; Soueidan, O.-M.; Lebegue, N.; Revelant, G.; Pelinski, L.; Agbossou-
Niedercorn, F.; Deprez, B.; Deprez-Poulain, R. Tetrahedron Lett. 2012,
53, 5215. (c) Pye, P. J.; Rossen, K.; Reamer, R. A.; Tsou, N. N.; Volante,
R. P.; Reider, P. J. J. Am. Chem. Soc. 1997, 119, 6207. (d) Kuwano, R.; Ito,
Y. J. Org. Chem. 1999, 64, 1232. (e) Li, Y.; He, Y.; Chen, F.; Fan, Q. Chin.
J. Chem. 2014, 32, 991. (f) O’Reilly, M. C.; Lindsley, C. W. Org. Lett.
2012, 14, 2910. (g) Crestey, F.; Witt, M.; Jaroszewski, J. W.; Franzyk, H.
J. Org. Chem. 2009, 74, 5652.
(8) For reviews, see: (a) He, Y.-M.; Song, F.-T.; Fan, Q.-H. Top. Curr.
Chem. 2013, 343, 145. (b) Wang, D.-S.; Chen, Q.-A.; Lu, S.-M.; Zhou,
Y.-G. Chem. Rev. 2012, 112, 2557. (c) Zhou, Y.-G. Acc. Chem. Res. 2007,
40, 1357. (d) Glorius, F. Org. Biomol. Chem. 2005, 3, 4171. (e) Tang, W.;
Zhang, X. Chem. Rev. 2003, 103, 3029.
(9) (a) Chang, M.; Huang, Y.; Liu, S.; Chen, Y.; Krska, S. W.; Davies, I.
W.; Zhang, X. Angew. Chem., Int. Ed. 2014, 53, 12761. (b) Ye, Z.-S.;
Chen, M.-W.; Chen, Q.-A.; Shi, L.; Duan, Y.; Zhou, Y.-G. Angew. Chem.,
Int. Ed. 2012, 51, 10181. (c) Wang, X.-B.; Zeng, W.; Zhou, Y.-G.
Tetrahedron Lett. 2008, 49, 4922. (d) Rueping, M.; Antonchick, A. P.
Angew. Chem., Int. Ed. 2007, 46, 4562. (e) Legault, C. Y.; Charette, A. B.
J. Am. Chem. Soc. 2005, 127, 8966.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01190.
Experimental procedures, characterization data, X-ray
structures, data for the determination of ee, and NMR
spectra (PDF)
(10) (a) Shugrue, C. R.; Miller, S. J. Angew. Chem., Int. Ed. 2015, 54,
11173. (b) Tu, X.-F.; Gong, L.-Z. Angew. Chem., Int. Ed. 2012, 51, 11346.
(c) Wang, T.; Zhuo, L.-G.; Li, Z.; Chen, F.; Ding, Z.; He, Y.; Fan, Q.-H.;
Xiang, J.; Yu, Z.-X.; Chan, A. S. C. J. Am. Chem. Soc. 2011, 133, 9878.
(d) Wang, C.; Li, C.; Wu, X.; Pettman, A.; Xiao, J. Angew. Chem., Int. Ed.
2009, 48, 6524. (e) Rueping, M.; Antonchick, A. P.; Theissmann, T.
Angew. Chem., Int. Ed. 2006, 45, 3683. (f) Wang, W.-B.; Lu, S.-M.; Yang,
P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am. Chem. Soc. 2003, 125, 10536.
(11) (a) Iimuro, A.; Yamaji, K.; Kandula, S.; Nagano, T.; Kita, Y.;
Mashima, K. Angew. Chem., Int. Ed. 2013, 52, 2046. (b) Ye, Z.-S.; Guo,
R.-N.; Cai, X.-F.; Chen, M.-W.; Shi, L.; Zhou, Y.-G. Angew. Chem., Int.
Ed. 2013, 52, 3685. (c) Shi, L.; Ye, Z.-S.; Cao, L.-L.; Guo, R.-N.; Hu, Y.;
Zhou, Y.-G. Angew. Chem., Int. Ed. 2012, 51, 8286. (d) Lu, S.-M.; Wang,
Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2006, 45, 2260.
(12) For AH of quinoxaline, see: (a) Zhang, Z.; Du, H. Angew. Chem.,
Int. Ed. 2015, 54, 623. (b) Chen, Q.-A.; Wang, D.-S.; Zhou, Y.-G.; Duan,
Y.; Fan, H.-J.; Yang, Y.; Zhang, Z. J. Am. Chem. Soc. 2011, 133, 6126.
(c) Rueping, M.; Tato, F.; Schoepke, F. R. Chem. - Eur. J. 2010, 16, 2688.
(d) Tang, W.; Xu, L.; Fan, Q.-H.; Wang, J.; Fan, B.; Zhou, Z.; Lam, K.-
H.; Chan, A. S. C. Angew. Chem., Int. Ed. 2009, 48, 9135.
(13) For AH of pyrimidine, quinazoline, and indolizine, see:
(a) Kuwano, R.; Hashiguchi, Y.; Ikeda, R.; Ishizuka, K. Angew. Chem.,
Int. Ed. 2015, 54, 2393. (b) Kita, Y.; Higashida, K.; Yamaji, K.; Iimuro,
A.; Mashima, K. Chem. Commun. 2015, 51, 4380. (c) Ortega, N.; Tang,
D.-T. D.; Urban, S.; Zhao, D.; Glorius, F. Angew. Chem., Int. Ed. 2013, 52,
9500.
(14) For AH of 1,5-naphthyridine and 1,10-phenanthroline, see:
(a) Zhang, J.; Chen, F.; He, Y.-M.; Fan, Q.-H. Angew. Chem., Int. Ed.
2015, 54, 4622. (b) Wang, T.; Chen, F.; Qin, J.; He, Y.-M.; Fan, Q.-H.
Angew. Chem., Int. Ed. 2013, 52, 7172.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ygzhou@dicp.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science Foundation
of China (21532006 and 21372220) is acknowledged.
REFERENCES
■
(1) (a) Kohmoto, S.; Kashman, Y.; McConnell, O. J.; Rinehart, K. L.;
Wright, A.; Koehn, F. J. Org. Chem. 1988, 53, 3116. (b) Di Fabio, R.;
Griffante, C.; Alvaro, G.; Pentassuglia, G.; Pizzi, D. A.; Donati, D.; Rossi,
T.; Guercio, G.; Mattioli, M.; Cimarosti, Z.; Marchioro, C.; Provera, S.;
Zonzini, L.; Montanari, D.; Melotto, S.; Gerrard, P. A.; Trist, D. G.;
Ratti, E.; Corsi, M. J. Med. Chem. 2009, 52, 3238. (c) Dorsey, B. D.;
Levin, R. B.; McDaniel, S. L.; Vacca, J. P.; Guare, J. P.; Darke, P. L.;
Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Quintero, J. C.; Lin, J. H.; Chen,
I.-W.; Holloway, M. K.; Fitzgerald, P. M. D.; Axel, M. G.; Ostovic, D.;
Anderson, P. S.; Huff, J. R. J. Med. Chem. 1994, 37, 3443. (d) van der
Linden, M.; Borsboom, J.; Kaspersen, F.; Kemperman, G. Eur. J. Org.
Chem. 2008, 2008, 2989.
(2) (a) Barros, M. T.; Phillips, A. M. F. Eur. J. Org. Chem. 2007, 2007,
178. (b) Nakamura, D.; Kakiuchi, K.; Koga, K.; Shirai, R. Org. Lett. 2006,
8, 6139. (c) Shono, T.; Kise, N.; Shirakawa, E.; Matsumoto, H.; Okazaki,
E. J. Org. Chem. 1991, 56, 3063.
(3) For selected examples, see: (a) Yokoshima, S.; Watanabe, K.;
Uehara, F.; Usui, Y.; Tanaka, H. Bioorg. Med. Chem. Lett. 2014, 24, 5749.
(b) Ashton, K. S.; Denti, M.; Norman, M. H.; St. Jean, D. J., Jr.
(15) (a) Rossen, K.; Weissman, S. A.; Sager, J.; Reamer, R. A.; Askin,
D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1995, 36, 6419.
(b) Fuchs, R. EP 0803502, 1997.
(16) Huang, W.-X.; Yu, C.-B.; Shi, L.; Zhou, Y.-G. Org. Lett. 2014, 16,
3324.
(17) Guercio, G.; Bacchi, S.; Perboni, A.; Leroi, C.; Tinazzi, F.;
Bientinesi, I.; Hourdin, M.; Goodyear, M.; Curti, S.; Provera, S.;
Cimarosti, Z. Org. Process Res. Dev. 2009, 13, 1100.
Tetrahedron Lett. 2014, 55, 4501. (c) Maity, P.; Konig, B. Org. Lett. 2008,
10, 1473.
̈
(4) (a) Binanzer, M.; Hsieh, S.-Y.; Bode, J. W. J. Am. Chem. Soc. 2011,
133, 19698. (b) Guercio, G.; Bacchi, S.; Goodyear, M.; Carangio, A.;
Tinazzi, F.; Curti, S. Org. Process Res. Dev. 2008, 12, 1188.
D
DOI: 10.1021/acs.orglett.6b01190
Org. Lett. XXXX, XXX, XXX−XXX