Enantioselective functionalization of indoles and pyrroles via an in situ-formed spiro intermediate

Article abstract of DOI:10.1021/ja403535a

Herein we report a highly enantioselective synthesis of polycyclic indoles and pyrroles with up to 99% ee by an iridium catalyst system consisting of a commercially available iridium precursor and a readily accessible ligand. Investigation of the reaction mechanism led to the discovery of an unprecedented dearomatized spiro intermediate and its in situ migration phenomenon. The new reaction mode features switching of the substituent from the indole C-3 position to the C-2 position (from the C-2 position to the C-3 position in the case of pyrrole) without loss of the enantiomeric purity, providing a novel concept in designing the asymmetric construction of enantiopure polycyclic indoles and pyrroles.

Full text of DOI:10.1021/ja403535a

Subscriber access provided by University of South Dakota
Communication
Enantioselective Functionalization of Indoles and
Pyrroles via An in-situ Formed Spiro-intermediate
Chun-Xiang Zhuo, Qing-Feng Wu, Qiang Zhao, Qing-Long Xu, and Shu-Li You
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 14 May 2013
Downloaded from http://pubs.acs.org on May 15, 2013
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Enantioselective Functionalization of Indoles and Pyrroles via
An in-situ Formed Spiro-intermediate
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
ChunꢀXiang Zhuo, QingꢀFeng Wu, Qiang Zhao, QingꢀLong Xu, and ShuꢀLi You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, China
Supporting Information Placeholder
some cases, spiroꢀindolenine compounds were proposed as the
intermediates and the alkylation at the Cꢀ2 position was attributed
as a result of alkylation at the Cꢀ3 position followed by migration
(Scheme 1, Path a)9. Evidences on the existence of the spiroꢀ
intermediate were also documented in the literature10. However, it
remains a controversial topic whether asymmetric PictetꢀSpengler
reaction of indole substrates proceeds through dearomatized spiroꢀ
indolenine intermediates (B, Scheme 1)11. In addition, in the
asymmetric intramolecular alkylation reactions of indoles, the
spiroꢀindolenine formation received little attention. The fact that
spiroꢀintermediate was overlooked could cause misunderstanding
of the reaction mechanism and even the incorrect assignment of
the alkylation products12.
ABSTRACT: Herein we report a highly enantioselective
synthesis of polycyclic indoles and pyrroles with up to 99% ee by
an iridiumꢀcatalytic system comprised of commercially available
iridium precursor and readily accessible ligand. Investigation of
the reaction mechanism led to the discovery of an unprecedented
dearomatized spiroꢀintermediate and its inꢀsitu migration
phenomenon. The new reaction mode features the switch of the
substituent from the Cꢀ3 position of indole to the Cꢀ2 position (Cꢀ
2 position to Cꢀ3 position in the case of pyrrole) without loss of
the enantiomeric purity, providing a novel concept in designing
asymmetric construction of enantiopure polycyclic indoles and
pyrroles.
Path
NH
R
a
a
N
H
Indoles and pyrroles are among the most widely distributed heterꢀ
ocyclic compounds in nature and many enantiopure natural and
synthetic derivatives thereof including tryptophan, an essential
amino acid, display interesting biological activities1. Representaꢀ
tive examples, such as yohimbine, tadalafil (Cialis), and styꢀ
loguanidine, all have polycyclic indole or pyrrole structures (Figꢀ
ure 1)2,3. Consequently, the synthesis of enantiomerically pure
polycyclic indoles and pyrroles are in great demand in both organꢀ
ic and medicinal chemistry.
b
N
H
A
B
spiroindolization
R
N
H
Path a
migration
NH
NH
N
N
H
-
H
H
R
H
R
C
Scheme 1. Two alternative reaction pathways of PictetꢀSpengler
reaction.
As our continuous efforts to study transitionꢀmetalꢀcatalyzed alꢀ
lylic alkylation reactions, we found that both indoles and pyrroles
undergo allylic dearomatization reaction in an intramolecular
fashion, providing various heterocycles bearing a quaternary carꢀ
bon center13,14. Interestingly, the isolated fiveꢀmembered spiroꢀ
indolenine products could further proceed allyl group migration in
a highly stereoselective manner under acid catalysis (Scheme 2,
Path a)13d. The allyl group was speculated to have higher migratoꢀ
ry aptitude compared to the methylene group. With this inforꢀ
mation in hands, we envisaged that by enhancing the migratory
aptitude of the methylene portion, an alternative migration pathꢀ
way might be observed, even in a tandem dearomatizaꢀ
tion/migration sequence (Scheme 2, Path b). Herein, we report an
unprecedented FriedelꢀCrafts type allylic alkylation reaction in
which the alkylation of indole at the Cꢀ3 position proceeds to
afford spiroꢀindolenine followed by the migration of methanamine
Figure 1. Selected naturally occurring compounds containing
polycyclic indole or pyrrole units.
The PictetꢀSpengler reaction has been recognized as one of the
most direct and efficient methods for construction of tetrahydroꢀ
carboline frameworks4. Catalytic enantioselective PictetꢀSpengler
reaction witnessed significant progress during the past decade5. In
addition, asymmetric intramolecular alkylation of indoles and
pyrroles provide another straightforward access to polycyclic
indole and pyrrole structures6. In this regard, transitionꢀmetalꢀ
catalyzed allylic alkylation reactions prove to be quite successꢀ
ful7,8. For the intramolecular alkylation of 3ꢀindolyl substrates, in
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
1
2
3
4
5
6
7
8
group to the Cꢀ2 position of indole (methanamine migration from
Cꢀ2 position to Cꢀ3 position in pyrrole system). The process feaꢀ
tures the wellꢀpreserved enantiomeric purity during the migration
process and provides a general strategy in construction of enantiꢀ
opure polycyclic indoles and pyrroles.
entry ligand
base
t (h)
16
16
19
19
16
18
34
18
29
conv. (%)b,c
ee (%)d
87
1
2
3
4
5
6
7
8
9
Cs2CO3
K3PO4
K2CO3
Li2CO3
DBU
72
1a
1a
1a
1a
1a
1b
1c
1d
1e
>95
78
89
89
92
85
9
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
60
85
K3PO4
K3PO4
K3PO4
K3PO4
64
88
>95 (80)
36
98
87
Scheme 2. Dearomatization of indole and controllable migration.
>95
94
Our studies began with a serendipitous discovery during our atꢀ
tempts on Irꢀcatalyzed intramolecular allylic FriedelꢀCrafts alꢀ
kylation reactions of 2ꢀpyrrolyl allylic carbonate 2a15,16. In the
presence of 2 mol % of [Ir(cod)Cl]2, 4 mol % of ligand 1a, and
1.0 equiv of Cs2CO3, the reaction of 2a in THF for 16 h did not
lead to the direct alkylated product 3a’. Instead, product 3a, feaꢀ
turing the migration of the original substituent at the Cꢀ2 position
to the Cꢀ3 position, was obtained in 72% conversion and 87% ee
(entry 1, Table 1). Encouraged by these results, we carried out
further optimization of the reaction conditions. Various bases such
as K3PO4, K2CO3, Li2CO3 and DBU were screened (entries 2ꢀ5,
Table 1), and K3PO4 was found the optimal base for the process.
Catalysts generated from ligands 1b and 1d could enable the
dearomatization/migration reaction of 2a with good ee, but in
only moderate conversions (entries 6 and 8, Table 1). Interestingly,
ligands 1c and 1e, developed in this group17, led to efficient cataꢀ
lysts with [Ir(cod)Cl]2 to provide product 3a in good yields and
excellent enantioselectivity (98% ee and 94% ee respectively,
entries 7 and 9, Table 1). After the optimization study, the best
conditions were obtained as the following: 2a in THF (0.1 M), 2
mol % of [Ir(cod)Cl]2, 4 mol % of 1c, 1.0 equiv of K3PO4 at 50 oC.
Under these reaction conditions, product 3a was obtained in 80%
yield and 98% ee (entry 7, Table 1).
a Reaction conditions: 2 mol % of [Ir(cod)Cl]2, 4 mol % of ligand,
o
0.1 mmol of 2a, 0.1 mmol of base in solvent (1.0 mL) at 50 C. b
1
c
Determined by H NMR of the crude reaction mixture. Isolated
yield in the parentheses. d Determined by HPLC analysis.
Table 2. The reaction substrate scopea.
entry 2, R1, R2
time (h) 3, yield ee
(%)b
3a, 80
3b, 57
3c, 91
3d, 95
3e, 89
(%)c
1
2a, Bn, H
34
58
34
34
98
98
99
96
98
2
2b, allyl, 4ꢀMeꢀC6H4
2c, Bn, Ph
3
4d
5
2d, Bn, 4ꢀMeOꢀC6H4
Table 1. Optimization of the reaction conditions a.
2e, Bn, 3,4ꢀ(MeO)2ꢀ 34
C6H3
6
2f, Bn, 4ꢀFꢀC6H4
2g, Bn, 4ꢀClꢀC6H4
2h, Bn, 4ꢀBrꢀC6H4
2i, Bn, Et
33
33
48
33
48
3f, 88
3g, 88
3h, 75
3i, 89
3j, 61
99
99
98
97
96
7
8
9
10
2j,
11
33
3a, 86
97
2k,
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
a Reaction conditions: 2 mol % of [Ir(cod)Cl]2, 4 mol % of 1c, 0.2
reaction are the following: 2 mol % of [Ir(cod)Cl]2, 4 mol % of 1c,
0.2 mmol of 4a, 0.4 mmol of K3PO4 in refluxed THF (see the
Supporting Information for details). Under these conditions, the
substrate scope was then investigated for the asymmetric allylic
dearomatization/migration reaction. The results are summarized in
Table 3. Reactions of allylic carbonates varying protecting group
(Bn, allyl) on nitrogen atom both gave the corresponding products
in good yields with high levels of enantiocontrol (63ꢀ80% yields,
88ꢀ96% ee, entries 1ꢀ2, Table 3). Meanwhile, substrates bearing
either electronꢀwithdrawing group (5ꢀF, 5ꢀCl, 5ꢀBr, 6ꢀCl) (entries
3ꢀ6, Table 3) or electronꢀdonating group (5ꢀMe, 5ꢀMeO, 6ꢀMeO)
(entries 7ꢀ9, Table 3) on the indole core all led to their correꢀ
sponding products in good to excellent yields and ee (72ꢀ93%
yields, 94ꢀ96% ee). The structure and stereochemistry of the
products were determined by an Xꢀray crystallographic analysis
of a crystal of enantiopure 5e. The absolute configuration was
determined as (R).
o
b
mmol of 2, 0.2 mmol of K3PO4 in THF (2.0 mL) at 50 C. Isoꢀ
c
lated yield of 3. Determined by HPLC analysis. d 3.5 mol % of
[Ir(cod)Cl]2, 7 mol % of 1c, 2 equiv of K3PO4 were used.
With the above optimized reaction conditions in hand, various 2ꢀ
pyrrolyl allylic carbonates were explored to examine the generaliꢀ
ty of the process. The results are summarized in Table 2. Reacꢀ
tions of allylic carbonates containing different protecting groups
(Bn, allyl) on the amine moiety in the tether both gave the correꢀ
sponding products in good yields and excellent ee (57ꢀ80% yields,
98% ee, entries 1ꢀ2, Table 2). Substrate bearing a phenyl group on
the pyrrole core (R2) reacted smoothly affording desired product
3c in 91% yield and 99% ee (entry 3, Table 2). Next, the electron
effect on the pyrrole core was probed. Substrates bearing either
electronꢀdonating [4ꢀMeO, 3,4ꢀ(MeO)2] (entries 4ꢀ5, Table 2) or
electronꢀwithdrawing groups (4ꢀF, 4ꢀCl, 4ꢀBr) (entries 6ꢀ8, Table
2) on the 5ꢀphenyl moiety (R2) on the pyrrole core all reacted to
form their corresponding products in good to excellent yields and
ee (75ꢀ95% yields, 97ꢀ99% ee). Notably, reaction occurred
smoothly for substrates 2i and 2j in which alkyl goups are present
at the pyrrole core (61ꢀ89% yields, 96ꢀ97% ee, entries 9ꢀ10, Table
2). Interestingly, when 3ꢀpyrrolyl allylic carbonate 2k was utilized,
the reaction went smoothly affording product 3a (the same prodꢀ
uct obtained when 2a was used as a substrate) in excellent yield
and ee (86% yield, 97% ee, entry 11, Table 2). The structure and
stereochemistry of the products were confirmed unambiguously
by an Xꢀray crystallographic analysis of a crystal of enantiopure
3h. The absolute configuration was determined as (S).
9
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
Based on the obtained experimental results, we proposed a plausiꢀ
ble reaction pathway using indoleꢀderived substrate 4a as an exꢀ
ample, as depicted in Scheme 3. Firstly, with the preformed iridiꢀ
um(I) catalyst, the oxidative addition of 4a proceeds to generate
Ir(III)ꢀπꢀallyl complex. Ir(III)ꢀπꢀallyl moiety receives the nucleoꢀ
philic attack of the Cꢀ3 indole with the assistance of a base to lead
to the formation of dearomatized spiroꢀindolenine intermediate I,
which inꢀsitu converted to intermediate II, and the latter yields the
corresponding product 5a after aromatization. The proposed inꢀ
termediate I is highly reactive and difficult to isolate. By using the
inꢀsitu IR, the formation of the intermediate I could be observed
(see the Supporting Information for details).
Table 3. The reaction substrate scopea.
NBn
NBn
aromatization
N
H
N
H
5a' (Not observed)
path b
x
NBn
NBn
NBn
Ir-catalyst
base
dearomatization
4, R3, R4
5, yield (%)b
5a, 80
5b, 63
5c, 88
ee (%)c
96
N
N
Ir
b
a
entry
H
H
N
OCO2Me
4a
base
I
1
2
3
4
5
6
7
8
9
4a, Bn, H
path a
4b, allyl, H
4c, Bn, 5ꢀF
4d, Bn, 5ꢀCl
4e, Bn, 5ꢀBr
4f, Bn, 6ꢀCl
4g, Bn, 5ꢀMe
4h, Bn, 5ꢀMeO
4i, Bn, 6ꢀMeO
88
aromatization
NBn
NBn
96
N
N
H
H
5a
5d, 80
5e, 74
94
II
94
Scheme 3. Plausible reaction pathway
5f, 93
95
In summary, we have developed a highly efficient synthesis of
enantioenriched polycyclic indoles and pyrroles (up to 99% ee)
through an Irꢀcatalyzed intramolecular asymmetric allylic alkylaꢀ
tion reaction. Studies of the reaction mechanism led to the discovꢀ
ery of an unprecedented dearomatized spiroꢀintermediate and the
inꢀsitu migration pathway. The switch of the substituent from the
Cꢀ3 position of indole to the Cꢀ2 position (Cꢀ2 position to Cꢀ3
position in the case of pyrrole) provides a novel concept in develꢀ
oping novel asymmetric construction of enantiopure polycyclic
indoles and pyrroles in asymmetric catalysis. Further mechanistic
studies on the dearomatization/migration process, design of new
migration pattern and application of this methodology are currentꢀ
ly underway in our laboratory.
5g, 75
5h, 80
5i, 72
96
94
95
a Reaction conditions: 2 mol % of [Ir(cod)Cl]2, 4 mol % of 1c, 0.2
b
mmol of 4, 0.4 mmol of K3PO4 in THF (2.0 mL), refluxed. Isoꢀ
lated yield of 5. c Determined by HPLC analysis.
Next, we examined the generality of this asymmetric dearomatizaꢀ
tion/migration process with indole system. After a systematic
study of the reaction conditions, the optimized conditions for the
ASSOCIATED CONTENT
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
1
2
3
4
5
6
7
8
13. For a recent review, see: (a) Zhuo, C.ꢀX.; Zhang, W.; You, S.ꢀL.
Supporting Information
Angew. Chem. Int. Ed. 2012, 51, 12662. Selected examples from our
group: (b) Wu, Q.ꢀF.; He, H.; Liu, W.ꢀB.; You, S.ꢀL. J. Am. Chem.
Soc. 2010, 132, 11418. (c) Zhuo, C.ꢀX.; Liu, W.ꢀB.; Wu, Q.ꢀF.; You,
S.ꢀL. Chem. Sci. 2012, 3, 205. (d) Wu, Q.ꢀF.; Zheng, C.; You, S.ꢀL.
Angew. Chem. Int. Ed. 2012, 51, 1680. (e) Zheng, C.; Wu, Q.ꢀF.;
You, S.ꢀL. J. Org. Chem. 2013, 78, 4357.
Experimental procedures and spectral data. Single crystal Xꢀray
diffraction data for compounds 3a, 3h, 5e, 5g. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
slyou@sioc.ac.cn
14. Selected examples for transitionꢀmetalꢀcatalyzed allylic substitution
reactions with indoles and pyrroles: (a) Bandini, M.; Melloni, A.;
UmaniꢀRonchi, A. Org. Lett. 2004, 6, 3199. (b) Kimura, M.;
Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc. 2005, 127,
4592. (c) Trost, B. M.; Dong, G. J. Am. Chem. Soc. 2006, 128, 6054.
(d) Kimura, M.; Fukasaka, M.; Tamaru, Y. Heterocycles 2006, 67,
535. (e) Cheung, H. Y.; Yu, W.ꢀY.; Lam, F. L.; AuꢀYeung, T. T.ꢀL.;
Zhou, Z.; Chan, T. H.; Chan, A. S. C. Org. Lett. 2007, 9, 4295. (f)
Liu, W.ꢀB.; He, H.; Dai, L.ꢀX.; You, S.ꢀL. Org. Lett. 2008, 10, 1815.
(g) Kagawa, N.; Malerich, J. P.; Rawal, V. H. Org. Lett. 2008, 10,
2381. (h) Sundararaju, B.; Achard, M.; Demerseman, B.; Toupet, L.;
Sharma, G. V. M.; Bruneau, C. Angew. Chem. Int. Ed. 2010, 49,
2782. (i) Trost, B. M.; Osipov, M.; Dong, G. J. Am. Chem. Soc. 2010,
132, 15800. (j) Hoshi, T.; Sasaki, K.; Sato, S.; Ishii, Y.; Suzuki, T.;
Hagiwara, H. Org. Lett. 2011, 13, 932. (k) Cao, Z.; Liu, Y.; Liu, Z.;
Feng, X.; Zhuang, M.; Du. H. Org. Lett. 2011, 13, 2164. (l) Trost, B.
M.; Osipov, M.; Dong, G. Org. Lett. 2012, 14, 2254. (m) Liu, Y.;
Cao, Z.; Du. H. J. Org. Chem. 2012, 77, 4479. (n) Bandini, M.; Botꢀ
toni, A.; Chiarucci, M.; Cera, G.; Miscione, G. P. J. Am. Chem. Soc.
2012, 134, 20690. (o) Liu, Y.; Du. H. Org. Lett. 2013, 15, 740. (p)
Montgomery, T. D.; Zhu, Y.; Kagawa, N.; Rawal, V. H. Org. Lett.
2013, 15, 1140.
9
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
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The authors thank Dr. Wei Zhang for helpful discussions and the
National Basic Research Program of China (973 Program
2009CB825300) and National Natural Science Foundation of
China (20923005, 21025209, 21121062) for generous financial
support.
REFERENCES
1. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 2000, 4th ed., Blackꢀ
well Science: Oxford.
15. For reviews, see: (a) Miyabe, H.; Takemoto, Y. Synlett 2005, 1641.
(b) Takeuchi, R.; Kezuka, S. Synthesis 2006, 3349. (c) Helmchen, G.;
Dahnz, A.; Dübon, P.; Schelwies, M.; Weihofen, R. Chem. Commun.
2007, 675. (d) Helmchen, G. In Iridium Complexes in Organic Syn-
thesis; (Eds. Oro, L. A.; Claver, C.), WileyꢀVCH: Weinheim, Gerꢀ
many 2009, p 211. (e) Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res.
2010, 43, 1461. (f) Hartwig, J. F.; Pouy, M. J. Top. Organomet.
Chem. 2011, 34, 169. (g) Liu, W.ꢀB.; Xia, J.ꢀB.; You, S.ꢀL. Top. Or-
ganomet. Chem. 2012, 38, 155. (h) Tosatti, P.; Nelson, A.; Marsden,
S. P. Org. Biomol. Chem. 2012, 10, 3147.
2. O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23, 532.
3. Kato, T.; Shizuri, Y.; Izumida, H.; Yokoyama, A.; Endo, M. Tetra-
hedron Lett. 1995, 36, 2133.
4. Pictet, A.; Spengler, Theod. Ber. Dtsch. Chem. Ges. 1911, 44, 2030.
5. For a recent review, see: Stöckigt, J.; Antonchick, A. P.; Wu, F.;
Waldmann, H. Angew. Chem. Int. Ed. 2011, 50, 8538.
6. For recent reviews, see: (a) Bandini, M.; Melloni, A.; Umaniꢀ
Ronchi, A. Angew. Chem. Int. Ed. 2004, 43, 550. (b) Poulsen, T. B.;
Jørgensen, K. A. Chem. Rev. 2008, 108, 2903.
16. Selected recent examples: (a) Stanley, L. M.; Bai, C.; Ueda, M.;
Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 8918. (b) Gärtner, M.;
Mader, S.; Seehafer, K.; Helmchen, G. J. Am. Chem. Soc. 2011, 133,
2072. (c) Teichert, J. F.; FañanásꢀMastral, M.; Feringa, B. L. Angew.
Chem. Int. Ed. 2011, 50, 688. (d) Gao, N.; Zheng, S.; Yang, W.;
Zhao, X. Org. Lett. 2011, 13, 1514. (e) Tosatti, P.; Campbell, A. J.;
House, D.; Nelson, A.; Marsden, S. P. J. Org. Chem. 2011, 76, 5495.
(f) Chen, W.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 15249. (g)
Roggen, M.; Carreira, E. M. Angew. Chem. Int. Ed. 2012, 51, 8652.
(h) Schafroth, M. A.; Sarlah, D.; Krautwald, S.; Carreira, E. M. J.
Am. Chem. Soc. 2012, 134, 20276. (i) Hamilton, J. Y.; Sarlah, D.;
Carreira, E. M. J. Am. Chem. Soc. 2013, 135, 994. (j) Chen, W.;
Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 2068.
7. For reviews, see: (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev.
1996, 96, 396. (b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003,
103, 2921. (c) Lu, Z.; Ma, S. Angew. Chem. Int. Ed. 2008, 47, 258.
8. Selected examples: (a) Bandini, M.; Melloni, A.; Piccinelli, F.;
Sinisi, R.; Tommasi, S.; UmaniꢀRonchi, A. J. Am. Chem. Soc. 2006,
128, 1424. (b) Namba, K.; Yamamoto, H.; Sasaki, I.; Mori, K.;
Imagawa, H.; Nishizawa, M. Org. Lett. 2008, 10, 1767. (c) Bandini,
M.; Eichholzer, A. Angew. Chem. Int. Ed. 2009, 48, 9533. (d) Xu,
Q.ꢀL.; Dai, L.ꢀX.; You, S.ꢀL. Chem. Sci. 2013, 4, 97.
9. (a) Ferrer, C.; Echavarren, A. M. Angew. Chem. Int. Ed. 2006, 45,
1105. (b) Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem. Eur.
J. 2007, 13, 1358. (c) Ferrer, C.; EscribanoꢀCuesta, A.; Echavarren,
A. M. Tetrahedron 2009, 65, 9015. (d) England, D. B.; Padwa, A.
Org. Lett. 2008, 10, 3631. (e) Lu, Y.; Du, X.; Jia, X.; Liu, Y. Adv.
Synth. Catal. 2009, 351, 1517. (f) Loh, C. C. J.; Raabe, G.; Enders,
D. Chem. Eur. J. 2012, 18, 13250. For examples on Cꢀ3 to Cꢀ2 funcꢀ
tional group migration during a cyclization step, see: (g) Broggini,
G.; Barbera, V.; Beccalli, E. M.; Borsini, E.; Galli, S.; Lanza, G.;
Zecchi, G. Adv. Synth. Catal. 2012, 354, 159. (h) Hashmi, A. S. K.;
Yang, W.; Rominger, F. Adv. Synth. Catal. 2012, 354, 1273.
17. (a) Liu, W.ꢀB.; He, H.; Dai, L.ꢀX.; You, S.ꢀL. Synthesis 2009, 2076.
(b) Liu, W.ꢀB.; Zheng, C.; Zhuo, C.ꢀX.; Dai, L.ꢀX.; You, S.ꢀL. J.
Am. Chem. Soc. 2012, 134, 4812.
10. (a) Jackson, A. H.; Smith, P. J. Chem. Soc. Chem. Commun. 1967,
264. (b) Jackson, A. H.; Smith, P. Tetrahedron 1968, 24, 403. (c)
Jackson, A. H.; Smith, P. Tetrahedron 1968, 24, 2227.
11. Maresh, J. J.; Giddings, L.ꢀA.; Friedrich, A.; Loris, E. A.; Panjikar,
S.; Trout, B. L.; Stöckigt, J.; Peters, B.; O’Connor, S. E. J. Am.
Chem. Soc. 2008, 130, 710.
12. The structures of allylic alkylation products of 2a, 4a and 4g were
assigned incorrectly in the literature. For details, see reference 8a
and page 18 in the supporting information of reference 13b.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
Graphic for TOC
4
5
6
7
8
9
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
5
ACS Paragon Plus Environment