Enantioselective Allylation of Indoles: A Surprising Diastereoselectivity

Article abstract of DOI:10.1021/acs.joc.9b02573

Herein we show a novel approach toward the allylation of indoles. Thereby, we explore a class of bench-stable allylboronates and fine-tune their reactivity. The allylations of different substituted indoles proceed with negligible diastereo- and excellent enantioselectivities. This surprising selectivity (up to 99:1 er, up to ≈60:40 dr) is rationalized by DFT calculations.

Full text of DOI:10.1021/acs.joc.9b02573

Subscriber access provided by NEW MEXICO STATE UNIV
Article
Enantioselective Allylation of Indoles: A Surprising Diastereoselectivity
Patrick Ullrich, Julie Schmauck, Marcus Brauns, Marvin Mantel, Martin Breugst, and Jörg Pietruszka
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02573 • Publication Date (Web): 06 Jan 2020
Downloaded from pubs.acs.org on January 7, 2020
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 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 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.
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 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Enantioselective Allylation of Indoles:
A Surprising Diastereoselectivity
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
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
Patrick Ullrich†
Julie Schmauck‡
Marcus Brauns†
Marvin Mantel†
Martin Breugst‡*
†,§
Jörg Pietruszka *
†
Institut für Bioorganische Chemie (IBOC), Heinrich-Heine-Universität Düsseldorf im
Forschungszentrum Jülich, Stetternicher Forst, Geb. 15.8, 52426 Jülich, Germany
‡
Department für Chemie, Universität zu Köln, Greinstraße 4, 50939 Köln, Germany
§
Institut für Bio- und Geowissenschaften (IBG-1: Bioorganische Chemie), Forschungs-
zentrum Jülich, 52428 Jülich, Germany
mbreugst@uni-koeln.de
j.pietruszka@fz-juelich.de
Dedicated to the memory of Dieter Enders
1
/ 37
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 37
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
Graphical Abstract
F3C
CF3
Et
H
N
H
O
N
Et
O
B
B
+
H
N
O
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
O
Et
Et
6 examples
up to 83%
 60:40 dr
99:1 er
F3C
CF3
DFT-calculations
TS have
novel highly reactive
allylboronate
‡
comparable G
Abstract
Herein we show a novel approach towards the allylation of indoles. Thereby we explore
a class of bench-stable allylboronates and fine-tune their reactivity. The allylations of
different substituted indoles proceed with negligible diastereo- and excellent
enantioselectivities. This surprising selectivity (up to 99:1 er, up to ≈ 60:40 dr) is
rationalized by DFT-calculations.
2
/ 37
ACS Paragon Plus Environment

Page 3 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Introduction
Since first evidence for the extraordinary high stereoinduction of boronates in allylation
1
reactions was presented in 1978, this class of compounds has emerged as an
indispensable tool in synthetic organic chemistry.2-7 Thus asymmetric allylation
reactions have been investigated intensively in the last decades; research is mostly
concentrating on the stereoselective synthesis of homoallylic alcohols descending from
aldehydes and ketones.2, 8-9 However, addressing less reactive electrophiles remains
a challenging task, even though nitrogen-containing substrates such as indoles
represent an important class of compounds in many biologically active
pharmaceuticals and natural products, by implication a reliable portfolio for their
selective derivatisation is crucial.10-14 Underlining the demanding nature of this
synthetic issue, to the best of our knowledge, only two examples for the
enantioselective allylation of indoles have been reported so far. Namely, the groups of
Aggarwal and Szabó demonstrated elegant allylborations of indoles, providing high
dia- and enantioselectivity.15-16 On behalf of further improving the access to the
corresponding homoallylic amines, we now sought out to employ bench-stable boron-
based reagent 1 recently developed in our group. Easily used for the fully
stereodivergent allylation of aldehydes and ketones to the corresponding Z- and E-
configured homoallylic alcohols in high yields and with excellent stereoselectivities
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
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
(
scheme 1),17-18 application to the allylation of indoles seemed a promising endeavour.
3
/ 37
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 37
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
Scheme 1. Previously reported enantioselective allylborations of indole by Aggarwal and Szabó15-16 and
the outline of our attempt based on the highly enantioselective stereodivergent allylation of aldehydes
and ketones utilizing bench-stable boronate 1.17-18
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
Aggarwal, 2014:
H
a) n-BuLi, 15 min,
78 °C, THF
b) TFAA, 30 min
N
O
B
Et
–
O
c) –78 °C  rt,
THF  CH Cl ,
then indole,
74%
99:1 dr
98:2 er
Et
2
2
Ph
Ph
over night
Szabó, 2016:
indole,
3,3'-dibromo-BINOL
15 mol%)
OH
H
N
(
B
OH MeOH (3 equiv),
m.s. (3 Å), rt, 24 h
94%
97:3 dr
99.5:0.5 er
our approach:
O
OH
*
R1 R2
1
R2
Et
R
2
2
R  H or R  H
Ar  Ph or Ar = p-C6H4F
Et
Ar Ar
32 examples
up to 95%
>95:5 dr
highly enantio- and
diastereoselective
O
O
B
B *
O
*
>
99:1 er
*
*
O
Ar Ar
1
H
N
Et
H
N
Et
*
4
/ 37
ACS Paragon Plus Environment

Page 5 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Results and Discussion
We initially started our research with reported allylboronates 1a–b, attempting to
allylate indole in a similar fashion to aldehydes and ketones. Unfortunately, both
reported bench-stable reagents 1a–b were not capable of converting indole completely
within an adequate period, thus making modifications of reagent 1 mandatory. Prior
studies had revealed that introduction of electron donating or withdrawing groups in
para-position of the aromatic moieties modulate the reagents’ reactivity;
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
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
18
implementation of the latter led to an increased rate of the intended conversions. We
anticipated to extend this trend by introducing additional electron withdrawal and
designed boronates 1c–d bearing either a para-trifluoromethyl or two meta-fluoride
groups (scheme 2). Starting our attempt by the reagent’s synthesis in analogy to known
procedures with the addition of the corresponding Grignard-reagents to dimethyl
19
tartrate 2, followed by the condensation of the resulting tetraols 3a–d with boronic
acid 4. Vinylboronic acids 5a–c then underwent a stereoselective allylic substitution
reaction using copper(I) thiophene-2-carboxylate (6) and phosphoramidite ligand 7;20-
2
1
affording the bench-stable boronates 1a–c in three steps with good overall yields
61–74%) and in high regio- and stereoselectivities (>95:5). Their configuration can be
(
stipulated on the one hand by the choice of L- or D-tartrate 2 as starting material of the
sequence and by the selection of the phosphoramidite ligand 7 in the last synthetic
step shown in scheme 2. Unfortunately, compound 1d could not be isolated under
standard conditions likely due to its fast hydrolysis during the work-up procedure.
5
/ 37
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 37
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
Scheme 2. Three-step syntheses of allylboronates 1a–c. a one single regio- and stereoisomer was
detected in NMR (>95:5 dr), b instead of (R)-7 the (S)-enantiomer was used, c no product could be
1
isolated though H NMR reaction control showed full conversion
O
Ar Ar
OH
OMe
OH
OH
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
MeO
HO
7 equiv ArMgBr
HO
HO
Et O/THF,
2
0
°C to rt, 14 h
Ar Ar
O
(
R,R)-2
(
R,R)-3ad
2
.1 equiv 4,
toluene,
0 °C to rt, 14 h
Ar Ar
O
O
B
B
Cl
Cl
O
Cl
B(OH)2
O
Ar Ar
4
(
R,R)-5ad
O
S
2
.2 equiv EtMgBr,
O
3
mol% 6 and (R)-7,
Cu
CH Cl , –90 °C, 4 h
2
2
6
Ph
Ph
Et
Ar Ar
O
O
P
O
O
B (S)
(R)
(R)
(
S) B
O
O
Ar Ar
Et
(
R)-7
(
S,R,R,S)-1ac
entry
residue
compound
yield
1
2
3
(R,R)-3a
(R,R)-5a
66%
96%
98%a
(S,R,R,S)-1a
4
5
6
(R,R)-3b
(R,R)-5b
85%
94%
92%a
(S,R,R,S)-1b
F
7
8
9
(R,R)-3c
(R,R)-5c
66%
93%
99%a
(S,R,R,S)-1c
CF3
F
97%a,b
1
0
(R,R,R,R)-1c
11
2
(R,R)-3d
(R,R)-5d
68%
89%
1
c
13
(S,R,R,S)-1d
F
6
/ 37
ACS Paragon Plus Environment

Page 7 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
Next, H NMR kinetics were employed to illustrate the reactivity trend of compounds
1a–c by monitoring the formation of homoallyl amines 9a over time (figure 1). As
intended, the novel boronate 1c converted indole 8a much more rapidly – sixteen times
faster than boronate 1a and four times faster than fluorine-derivate 1b – to the
corresponding products 9a. The tautomerisation of indole 8a into its imine form seems
to be crucial for the reaction’s progress, as indicated by pseudo-zero order kinetics.
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
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
H
H
N
N
(R,S,S,R)-1ac
N
*
Et
CDCl3,
rt, up to 70 h
(
R,E)-9a and (S,Z)-9a
8
a'
8a
0.25
compound
1
1
1
a
b
c
0.20
0.15
0.10
0.05
4 ×
1
6 ×
4
×
0.00
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
reaction time / h
1
Figure 1. Model reaction for H-NMR kinetics and the progress of product formation over time.
Having achieved satisfying reactivity, our attention was drawn towards the
stereoselectivity of the allylation of indole 8a. As with its analogues 1a–b all four
stereoisomers of compound 1c are easily accessible (scheme 2). Unfortunately, the
extraordinary high stereoinduction generated by compound 1a–b in the reaction with
17
18
aldehydes and ketones could not be fully maintained when switching to indole 8a
as an electrophile. Hence, we investigated the variation of several reaction parameters
for the allylation of indole 8a – such as addition of Lewis acids, solvent and temperature
to improve the observed diastereoselectivities and the isolated yields. The rational for
the addition of external Lewis acids was the hope for a faster tautomerisation of indole
into its imine form and thereby a faster reaction. At the same time this could be used
as a handle for an additional induction of stereoselectivity when chiral Lewis acids
would be used. The beneficial influence of acid addition was prior reported.22-26 We
7
/ 37
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 37
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
also examined the addition of iodine as a halogen-bond donor.27-28 The reaction
proceeds optimal when refluxing dichloromethane is used as a solvent without any
additional Lewis acid present (scheme 3).
Scheme 3. Temperature, solvent and Lewis acid screening for the allylation of indole with boronates
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
1c. Reaction conditions: 0.15 mmol 1c, 0.60 mmol 8a were stirred until total conversion of 1c, monitored
1
a
1
b
c
by H NMR. determined by H-NMR, determined by HPLC, 0.1 mol% of the additional reagent and
only 2.1 eq. of 8a were used.
Et
Ar Ar
H
4
equiv 8a
O
N
O
B
B
[0.7 M]
*
Et
conditions
O
O
9a
Ar Ar
Ar = p-CF C H
6 4
Et
3
(S,R,R,S)-1c
dra
b
er (S:R)
entry T / °C solvent
additive
t / d yield
(
E:Z)
of E of Z
1c
2c
3c
4c
5c
6c
24
24
24
24
24
24
CH Cl2 HCl in Et O
5
5
5
2
2
5
32% 49:51 n.d. n.d.
31% 61:39 n.d. n.d.
15% 48:52 n.d. n.d.
decomposition of 1c
2
2
CH Cl2
AlCl3
2
CH Cl2
Sc(OTf)3
2
i
CH Cl2
Ti( PrO)4
2
CH Cl2
ZnCl2
decomposition of 1c
2
CH Cl2
Cu(OTf)2
36% 59:41 n.d. n.d.
2
7c
8
24
24
30
40
CH Cl2
I2
–
–
–
–
–
–
–
–
–
5
5
4
2
4
4
3
3
3
4
23% 50:50 n.d. n.d.
62% 63:37 2:98 97:3
42% 56:44 2:98 99:1
80% 48:52 1:99 98:2
38% 48:52 6:94 97:3
30% 43:57 6:94 97:3
11% 41:59 11:89 91:9
12% 40:60 14:86 89:11
42% 47:53 3:97 98:2
35% 43:57 6:94 97:3
2
CH Cl2
2
9
CH Cl2
2
10
CH Cl2
2
11
12
13
14
40 n-pentane
40
40
40
40
40
toluene
THF
EtOAc
CHCl3
DCE
15
1
6
7
1
40
40
40
40
tBuOH
–
–
–
–
3
3
4
3
29% 44:56 10:90 93:7
41% 45:55 4:96 97:3
46% 43:57 6:94 96:4
51% 54:46 6:94 97:3
18
CH CN
3
1
9
0
CH NO2
3
2
HFIP
Thus, the use of every stereoisomer of boronate 1c leads to a diastereomeric mixture
of homoallyl amines 9a (scheme 4). For example, both boronates (S,R,R,S)-1c and
(S,S,S,S)-1c deliver a 1:1-diastereomeric mixture of homoallylic amines (R,E)-9a and
(S,Z)-9a, albeit still excellent enantioselectivity for each diastereomer is given (up to
8
/ 37
ACS Paragon Plus Environment

Page 9 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
:99 er). Similarly, employment of (R,S,S,R)-1c and (R,R,R,R)-1c leads to the
enantiomeric products. The absolute configuration of all products 9a was determined
by reduction of the isolated double bond after separating the diastereomers and
comparing the optical rotational values to literature value.29-31
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
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
Scheme 4. Stereochemical outcome of the allylation of indole with boronates 1c. Reaction conditions:
for 40 h at 40 °C. a determined by H-NMR,
1
b
0
.15 mmol 1c, 0.60 mmol 8a were stirred in dry CH
determined by HPLC.
2
Cl
2
H
N
H
N
Et
(
R,E)-9a
Et
(S,Z)-9a
via
via
via
via
TS1-RE
TS2-RE
TS1-SZ
TS2-SZ
H
N
(
S,R,R,S)-1c
(S,S,S,S)-1c
(R,S,S,R)-1c
(
R,R,R,R)-1c
8a
H
N
H
N
Et
(R,Z)-9a
(S,E)-9a
Et
dra
b
er (S:R)
entry boronate
yield
(
E:Z)
of E of Z
1
2
3
4
(S,R,R,S)-1c 80% 48:52
(R,S,S,R)-1c 59% 62:38
1:99 98:2
97:3 2:98
(R,R,R,R)-1c 76% 58:42 90:10 6:94
(S,S,S,S)-1c 83% 61:39
5:95 88:12
To get a better understanding of the observed diastereoselectivity, density functional
theory calculations were performed employing M06-2X-D3/def2-TZVPP/IEFPCM
(CH Cl )//M06-L-D3/6-31+G(d,p). More precisely, we studied the allylation reactions of
2 2
indole using allylboronates (S,R,R,S)-1c and (S,S,S,S)-1c leading to the product
complexes via transition states TS1 and TS2 (table 1). The results of these calculations
are summarized in table 1 and selected structures are depicted in figure 2.
In line with experimental observations, the equilibrium between 1H- and 3H-indole lies
–1
completely on the side of the 1H-tautomer 8a (G = + 48 kJ mol ) and only very small
9
/ 37
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 37
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
concentrations of the reactive 3H-tautormer are present in solution. As tautomerization
reactions typically proceed quickly, even very small concentrations are sufficient for
the subsequent allylation reactions according to the Curtin-Hammett principle. The
reaction free energies for the allylation step are all highly exergonic with –82 kJ mol–1
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
–1
<
G < –66 kJ mol (see the Supporting Information for details) and indicate that the
stereochemistry for this reaction is dictated by kinetic control (i.e., relative activation
free energies). In comparison to the related allylation reactions involving aldehydes17
or ketones,18 the allylation of indoles is thermodynamically less favorable. This
furthermore indicates the lower reactivity of the latter compared to carbonyl derivatives.
As shown in table 1, the activation free energies for both (S,R,R,S)-1c and (S,S,S,S)-
1
c leading to the four different stereoisomers vary to a much larger extent (+81 < G‡
–1
<
+135 kJ mol ).
Table 1. Calculated activation barriers for the reactions of (S,R,R,S)-1c and (S,S,S,S)-1c
–1
with indole [kJ mol ].
‡
‡
‡
‡
Boronate
G (RE) G (RZ) G (SE) G (SZ)
F3C
CF3
Et
O
+99
+140
+130
+97
O
B
B
O
O
(TS1-RE) (TS1-RZ) (TS1-SE) (TS1-SZ)
Et
F3C
(
CF3
S,R,R,S)-1c
F3C
CF3
Et
O
+95
+119
+113
+85
O
B
B
O
O
(TS2-RE) (TS2-RZ) (TS2-SE) (TS2-SZ)
Et
F3C
(
CF3
S,S,S,S)-1c
For the allylboronate (S,R,R,S)-1c, the lowest barrier was calculated for the reactions
leading to (R,E)-9a and (S,Z)-9a via TS1-RE and TS1-SZ. In these transition states,
the six-membered ring adopts a chair conformation while for the higher-energy
transition states (TS1-RZ, TS1-SE) a boat conformation is preferred (figure 2). Due to
the fixed geometry of the imine no chair-like transition states are geometrically feasible
for these orientations. Interestingly, the ethyl group is located in the equatorial position
1
0 / 37
ACS Paragon Plus Environment

Page 11 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
for TS1-RE, while the axial position is preferred for TS1-SZ. Both transition states have
–1
almost identical activation energy (+99 vs +97 kJ mol ) which fits to the observation
of almost no diastereoselectivity (48:52, scheme 3). This indicates that the less favored
axial position of the ethyl group within TS1-SZ in combination with an unfavorable syn-
pentane-type interaction within the six-membered transition state (indole ↔ ethyl) is
counterbalanced by a smaller steric repulsion with the aryl group of the bisboronate
backbone compared to the equatorial orientation in TS1-RE. Obviously, the
contribution from the unfavorable steric interactions is much smaller in TS1-SZ
compared to TS1-RE.The calculated barrier also nicely agrees with the experimental
conditions (40 h at 40 °C). In line with the experimental data, the high enantioselectivity
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
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
for both the E- and Z- configured products is also reflected in the computational data
–1
(
e.g., 92 vs 125 kJ mol for TS1-RE and TS1-SE).
Figure 2. Calculated transition states TS1 for the reaction of allylboronate (S,R,R,S)-1c with
indole: complete structures (top) and simplified structures highlighting the chair- and boat-like
structures (bottom) with selected bond lengths (in Å).
For the isomeric allylboronate (S,S,S,S)-1c, the calculations predict a kinetic
preference for the formation of (S,Z)-9a followed by the formation of (R,E)-9a. Again,
1
1 / 37
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 37
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
these transition states adopt chair-like conformation and the energetically less favored
transition states (TS2-RZ, TS2-SE) are in boat-like conformations (figure 3). The
explanation for the relative activation energies is similar to that discussed for the
diastereometic allylboronate (S,R,R,S)-1c. The axial orientation of the ethyl group as
well as the syn-pentane interaction present in TS2-SZ are counterbalanced by the
smaller steric repulsion caused by the aryl substituents in the backbone. While the
enantioselectivity within each diastereomer (RE vs. SE and RZ vs. SZ) is nicely
paralleled in the computational investigations, the DFT calculations incorrectly predicts
a moderate kinetic preference of the Z-alkene over the E-alkene. Besides chair- and
boat-like conformations, we have also considered other orientations, which also
included “open” transition states without a direct interaction between the indole
nitrogen and the boron atoms. Furthermore, different functionals (e.g., B3LYP-D3BJ,
M06-L, TPSS-D3BJ, B97X-D) have also been tested and resulted in comparable
results (see the Supporting Information for more details). However, the experimentally
observed diastereoselectivity slightly varied during the optimization of the synthetic
procedure (see the Supporting Information). This indicates that the actual energy
difference between the transition states is relatively small. Small changes that are very
difficult to model computationally (e.g. specific interactions with the solvent) could
easily affect the experimental outcome.
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
1
2 / 37
ACS Paragon Plus Environment

Page 13 of 37
The Journal of Organic Chemistry
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
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
Figure 3. Calculated transition states TS2 for the reaction of allylboronate (S,S,S,S)-1c with
indole: complete structures (top) and simplified structures highlighting the chair- and boat-like
structures (bottom) with selected bond lengths (in Å).
After understanding the stereochemical outcome of the allylation of indole, we
investigated the scope of the cuprate catalyzed S 2’ reaction towards a broader
N
spectrum of α-chiral boronates 1c bearing other substituents than ethyl. The shown
20
method (scheme 5) provides excellent results for different primary alkyl residues, yet
appears to be unsuitable for the sufficient installation of further residues to bisboronate
5
c as it has been reported in literature previously.17 For n-pentyl α-substitued
boronates 1c’ the allylation of compound 8a was performed analoguosly to the
previously shown cases and the results are depicted in scheme 6. Both diastereo- and
enantioselectivity of the reaction are less pronounced than those of the ethyl substitued
reagents 1c.
Scheme 5. Copper-catalysed allylic substitutions of allyl chloride 5c with different commercially available
Grignard reagents.
1
3 / 37
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 37
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
Ar Ar
O
O
B
B
Cl
Cl
O
O
O
Ar Ar
S
(
R,R)-5c
O
Cu
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
2
.2 equiv Grignard reagent,
mol% 6 and (R)-7,
CH Cl , –90 °C, up to 6 h
6
3
2
2
Ph
Ph
O
R
Ar Ar
O
P
O
B (R)
O
(
R)
(
R)
(
R)
B
O
O
(R)-7
Ar Ar
(S,R,R,S)-1c
R
Ar = p-CF C H
6 4
3
entry
Grignard reagent
925-90-6
yield
1
2
BrMg
quant.
quant.
BrMg
693-25-4
O
–a
3
4
480438-44-6
BrMg
ClMg
O
Si
–a
13170-43-9
–a
5
6
7
8
9
ClMg
BrMg
2622-05-1
1826-67-1
100-58-3
–a
–a
–a
–a
BrMg Ph
ClMg
ClMg
Ph
6921-34-2
90878-19-6
Ph
Scheme 6. Allylation of indole with n-pentyl α-substitued boronates 1c’. Reaction conditions: 0.15 mmol
a
(
S,R,R,S)- or (R,R,R,R)-1c’, 0.60 mmol. 8a were stirred in dry CH
2
Cl
2
for 40 h at 40 °C. determined by
1
b
H-NMR, determined by HPLC
F3C
CF3
nPe
4 equiv 8a
CH Cl ,
2
2
O
4
0 °C, 40 h
O
B
*
B *
O
*
nPe
O *
H
N
nPe
*
F3C
CF3
1c'
9a'
dra
b
er (S:R)
entry compound yield
(
E:Z) of E of Z
1
2
(S,R,R,S)-1c' 45% 67:33 7:93 80:20
(R,R,R,R)-1c' 45% 45:55 67:33 12:88
1
4 / 37
ACS Paragon Plus Environment

Page 15 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Lastly, we studied the influence of the electrophile’s nature on the reaction. Therefore,
differently 5-substituted indoles 8b–g were converted into the corresponding homoallyl
amines as shown before (scheme 7). We presumed that an electron rich indole would
undergo allylation faster due to the increased nucleophilicity of the nitrogen. All
compounds 9b–e could be isolated in moderate yields (40–53%) when boronate
(S,R,R,S)-1c was used. The enantioselectivities are without exceptions very good to
excellent (96:4–99:1 er) while again diastereomeric ratios near 50:50 were observed.
Substrates 8f–g could not be converted in reasonable yields; which might be attributed
to the strong electron withdrawing character of the substituents. Comparing these to
the products resulting from an allylation with the diastereomeric reagent (R,R,R,R)-1c,
only low yields with worse enantioselectivities could be obtained. Nonetheless, all four
possible products can be addressed by converting indoles of different electronic
character with either (S,R,R,S)-1c or its enantiomer in excellent enantioselectivity;
upfront diastereomeric mixtures could be readily separated. It should be noted that due
to its negligible diastereoselectivity, the conversion of 1c with 3-substituted indoles
such as the natural product skatole led to a complex mixture of multiple, inseperable
stereoisomers in average yields (38%).
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
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
1
5 / 37
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 37
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
Scheme 7. Allylation of indoles with different functional groups. Reaction conditions: 0.15 mmol
a
(S,R,R,S)- or (R,R,R,R)-1c, 0.60 mmol. 8a–g were stirred in dry CH
2
Cl
2
for 40 h at 40 °C. determined
1
b
by H-NMR, determined by HPLC
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
F3C
CF3
Et
4 equiv 8ag
F3C
CF3
Et
CH Cl ,
2
2
40 °C, 40 h
H
O
O
N
O
B
B
O
B
B
*
Et
O
O
O
R
O
9
ag
Et
Et
4
equiv 8af
F3C
S,R,R,S)-1c
CF3
CH Cl ,
40 °C, 40 h
F3C
CF3
2
2
(
(R,R,R,R)-1c
dra
b
dra
b
er (S:R)
er (S:R)
entry compound yield
entry compound yield
(
E:Z) of E of Z
(E:Z) of E of Z
1
2
3
4
5
6
7
9a
H
80% 48:52 1:99 98:2
40% 47:53b 3:97 96:4
53% 46:54 3:97 96:4
46% 48:52 1:99 96:4
43% 49:51 2:98 98:2
8
9
9a
H
76% 58:42 90:10 6:94
43% 36:64b 91:9 8:92
30% 34:66 92:8 7:93
47% 44:56 83:17 8:92
35% 46:54 92:8 9:91
9b Me
9c OMe
9b Me
10 9c OMe
9d
9e
F
11 9d
12 9e
F
Br
Br
9f CO Me traces 49:51 2:98 98:2
13 9f CO Me traces 50:50 89:11 14:86
2
2
9g NO2
no conversion after 12 d
1
6 / 37
ACS Paragon Plus Environment

Page 17 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Conclusion
We have illustrated a straightforward approach towards the allylation of indoles. To this
end, the highly potent, bench-stable allylboronate 1c was established. Though the
allylboration of differently substituted indoles 8a–g proceeds only with negligible
diastereoselectivity, excellent enantioselectivities for all four possible homoallylic
amines (up to er 99:1) can be observed using only one diastereomeric form of the
allylation reagent 1c. The separation of diastereomeric mixtures is readily achievable.
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
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
DFT calculations furthermore provide insights into the geometries and relative
activation free energies of the relevant transition states. While the diastereoselectivity
for the (S,S,S,S)-1c was problematic probably due to specific interactions with the
solvent molecules, the more stable chair-like transition states are responsible for the
stereochemical outcome for the isomeric (S,R,R,S)-1c. For both allylboronates, the
experimentally observed enantioselectivity could also be rationalized by chair-like
transition states.
Based on the relatively broad functional group tolerance, albeit limited to non-electron-
withdrawing moieties, accompanied by high enantioselectivities, an air- and moisture-
insensitive allylation reagent was found with which natural products or intermediates
en route bearing an indole motif can be functionalised conveniently.
1
7 / 37
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 37
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
Experimental Section
General Information
If not otherwise mentioned all chemicals were obtained from commercial sources and
used without any further purification. The solvents CH Cl , Et O, THF and toluene were
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
2
2
2
purchased from commercial sources and dried using a MB-SPS-800 solvent
purification system. Furthermore all reactions were performed under inert conditions
(
N - or Ar-atmosphere) utilizing Schlenk-technique. The TLC-foil Polygram SilG/UV
2
2
5
4
by Macherey-Nagel was used as stationary phase in thin layer chromatography. TLC-plates
were stained using either a KMnO -solution or an I -chamber. Most products were isolated
4
2
using preparative column chromatography. The silica gel (0.040 mm to 0.063 mm) was
provided by Merck; as mobile phase mixtures of petrol ether and ethyl acetate or n-
pentane and diethyl ether were used. For determination of the enantiomeric excess
the Dionex UltiMate 3000 Column Comportment by Thermo Fisher Scientific was
utilized. More detailed information on the employed solvent mixtures as well as on the
used columns are mentioned in the corresponding Supporting Information section. For
the separation of diastereomeric homoallylamines a preparative Dionex HPLC by
Thermo Fisher Scientific with a Chiracel-IC column was used. Melting points were
determined using a Büchi Melting Point B-540. The specific rotation of optically active,
enantiomerically pure compounds was measured using a JASCO P-2000 polarimeter.
All shown NMR-spectra are recorded on a Bruker Avance DRX 600. The samples have
been solved in deuterated chloroform or dichloromethane. All spectra have been
referred to the solvent peak or the internal standard tetramethylsilane. IR spectra were
measured using a PerkinElmer SpectrumTwo spectrometer with attenuated total
reflection. High resolution ESI mass spectra were recorded on a Finnigen Model MAT
LC-Q by the Zentralinstitut für Engineering, Elektronik und Analytik (ZEA-3) at the
Forschungszentrum Jülich or on a MDS SCIEXQ Model Trap 4000 by the HHU Center
of Molecular and Structural Analytics (HHUCeMSA) at the Heinrich-Heine-Universität
Düsseldorf. For detailed information on the characterisation of the obtained products
and the enantiomeric analysis see the corresponding Supporting Information.
Synthesis of the Boronates 1a–c
The boronates 1a–c were synthesised according to the three step sequence published
by Brauns et al. with slight adaptations.17-18
1
8 / 37
ACS Paragon Plus Environment

Page 19 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
General procedure for the synthesis of tetraols 3a–d
Vacuum dried magnesium (0.1 mol, 7 equiv) is overlayed with dry Et O (0.1 M), after
2
which a solution of the aryl bromide (0.1 mol, 7 equiv) in dry THF (0.1 M) is slowly
added. Meanwhile the reaction is kept at rt with a water bath and stirred for 2 h at rt.
The dimethyl tartrate (14 mmol, 1 equiv) is solved in dry THF (0.5 M) and slowly added
to the Grignard reagent within 30 min. The reaction is stirred over night at rt.
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
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
Subsequently, the reaction was quenched by the addition of sat. aq. NH Cl-solution,
4
to remove the precipitate 1 M HCl is cautiously dripped into the reaction until solids
vanished. After phase separation, the aq. phase was extracted three times with ethyl
acetate. The combined organic layers were dried over MgSO and the solvent is
4
removed under reduced pressure. The crude product is purified either via column
chromatography or by recrystallization.
(2R,3R)-1,1,4,4-Tetraphenylbutan-1,2,3,4-tetraol [(R,R)-3a]
Yield: 78%, 8.3 g (19 mmol); white solid. R (PE:EE 80:20): 0.03. Mp: 147.7–149.2 °C.
f
1
[
α]D20 +157 (c 1.0, CHCl ). H NMR (600 MHz, CDCl ): δ 3.77 (d, J = 4.4 Hz, 2 H), 4.43
3
3
1
3
1
(d, J = 3.5 Hz, 2 H), 4.63 (s, 2 H), 7.13–7.37 (m, 20 H) ppm. C{ H} NMR (151 MHz,
CDCl ): δ 72.1, 81.7, 124.9, 126.0, 127.2, 127.3, 128.4, 128.6, 143.8, 144.1 ppm. IR
3
–1
(ATR): 휈 3391, 1493, 1449, 1061, 905, 733, 698, 603 cm . The analytics are in
alignment with the literature.17
(2R,3R)-1,1,4,4-Tetra(4-fluorophenyl)butan-1,2,3,4-tetraol [(R,R)-3b]
Yield: 85%, 2.1 g (4.2 mmol); white solid. R (PE:EE 80:20): 0.25. Mp: 128.1–132.2 °C.
f
1
[
α]D20 +128 (c 1.1, CHCl ). H NMR (600 MHz, CDCl ): δ 3.95 (d, J = 4.1 Hz, 2 H), 4.30
3
3
(d, J = 3.9 Hz, 2 H), 4.56 (s, 2 H), 6.94 (t, J = 8.7 Hz, 4 H), 7.04 (t, J = 8.7 Hz, 4 H),
7.19 (dd, J = 5.1, 8.5 Hz, 4 H), 7.25 (dd, J = 4.9, 8.5 Hz, 4 H) ppm. 13C{ H} NMR
1
(
(
(
151 MHz, CDCl ): δ 72.0, 81.2, 115.3 (d, J = 21.4 Hz), 115.6 (d, J = 21.4 Hz), 126.7
3
d, J = 8.0 Hz), 128.0 (d, J = 8.0 Hz), 139.3 (d, J = 3.3 Hz), 139.6 (d, J = 3.2 Hz), 161.9
d, J = 247.2 Hz) ppm. IR (ATR): 휈 3411, 1602, 1506, 1415, 1226, 1160, 1073, 1015,
–1
986, 907, 831, 730, 650, 601, 590, 561, 590 cm . The analytics are in alignment with
the literature.18
(2R,3R)-1,1,4,4-Tetra[4-(trifluoromethyl)phenyl]butan-1,2,3,4-tetraol [(R,R)-3c]
Yield: 66%, 6.2 g (8.9 mmol); pale yellow solid. R (PE:EE 80:20): 0.22. Mp: 104.6 °C.
f
1
[
α]D20 +83 (c 1.1, CHCl ). H NMR (600 MHz, CDCl ): δ 3.86 (d, J = 4.4 Hz, 2 H), 4.45
3
3
(d, J = 4.3 Hz, 2 H), 4.65 (s, 2 H), 7.37–7.45 (m, 8 H), 7.54 (d, J = 8.3 Hz, 4 H), 7.65
1
9 / 37
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 37
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
13
1
(
d, J = 8.2 Hz, 4 H) ppm. C{ H} NMR (151 MHz, CDCl ): δ 72.0, 81.6, 123.9 (d, J =
3
272.2 Hz), 125.5, 125.8 (q, J = 3.5 Hz), 126.1 (q, J = 3.4 Hz), 126.6, 130.3 (q, J =
3
1
6
2.8 Hz), 146.6, 146.8 ppm. IR (ATR): 휈 3417, 1618, 1415, 1321, 1164, 1119, 1067,
–1
–
017, 989, 909, 834, 773, 734, 710, 678, 630, 610 cm . HRMS: m/z [M – H] calcd.
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
97.1248 for C H F O ; found 697.1234.
32
21 12
4
(2R,3R)-1,1,4,4-Tetra(3,5-difluorophenyl)butan-1,2,3,4-tetraol [(R,R)-3d]
Yield: 58%, 3.2 g (5.6 mmol); pale yellow solid. R (PE:EE 80:20): 0.16. Mp: 133.2 °C.
f
1
[
α]D20 +152 (c 1.0, CHCl ). H NMR (600 MHz, CDCl ): δ 3.58 (d, J = 5.0 Hz, 2 H), 4.32
3
3
13
1
(d, J = 4.9 Hz, 2 H), 4.62 (s, 2 H), 6.62–6.90 (m, 12 H) ppm. C{ H} NMR (151 MHz,
CDCl ): δ 71.7, 80.8, 103.6 (t, J = 25.3 Hz), 104.0 (t, J = 25.1 Hz), 108.2 (d, J =
3
2
6.5 Hz), 109.0–109.5 (m), 146.2–146.4 (m), 163.1 (dd, J = 249.5 Hz, 12.6 Hz), 163.4
(
dd, J = 251.2 Hz, 12.7 Hz) ppm. IR (ATR): 휈 3412, 1620, 1597, 1438, 1304, 1118,
–1
–
980, 909, 850, 788, 768, 734, 705, 512 cm . HRMS: m/z [M – H] calcd. 569.0999 for
C H F O ; found 569.0992.
28 17
8
4
General procedure for the synthesis of allyl chlorides 5a–d
Tetraol 3 (2.9 mmol,1 equiv) and ground molecular sieves (3 Å, 0.5 g per mmol tetraol)
are stirred in dry toluene (40 mM). (E)-(3-Chloroprop-1-en-1-yl)boronic acid (6 mmol,
2
.05 equiv) is added to the suspension. The reaction is stirred at 0 °C for 1 h and
afterwards over night at rt. The solvent is removed under reduced pressure and the
crude product is purified by column chromatography.
(
4aR,8aR,1’E,1’’E)-2,6-Di(3-chloroprop-1-en-1-yl)-4,4,8,8-
tetraphenyltetrahydro[1,3,2]dioxaborinino[5,4-d][1,3,2]dioxaborinin [(R,R)-5a]
Yield: 96%, 2.9 g (4.9 mmol); white solid. R (n-pentane:Et O 90:10): 0.30. Mp: 164.3–
f
2
168.0 °C. [α]D20 +28 (c 1.2, CHCl ). H NMR (600 MHz, CDCl ): δ 4.08 (d, J = 5.9 Hz,
1
3
3
4
H), 4.82 (s, 2 H), 5.77 (dd, J = 1.7 Hz, 17.6 Hz, 2 H), 7.15–7.44 (m, 21 H) ppm.
1
3
1
C{ H} NMR (151 MHz, CDCl3): δ 46.3, 69.2, 80.9, 125.0, 126.3, 127.3, 128.0, 128.1,
1
29.1, 142.2, 143.5, 145.7 ppm. IR (ATR): 휈 3063, 3021, 1958, 1711, 1640, 1493,
–1
1450, 1386, 1328, 1266, 1219, 993, 822, 749, 697, 624 cm . The analytics are in
alignment with the literature.17
2
0 / 37
ACS Paragon Plus Environment

Page 21 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(
4aR,8aR,1’E,1’’E)-2,6-Di(3-chloroprop-1-en-1-yl)-4,4,8,8-tetrakis(4-fluoro-
phenyl)tetrahydro[1,3,2]dioxaborinino[5,4-d][1,3,2]dioxaborinin [(R,R)-5b]
Yield: 97%, 2.0 g (3.0 mmol); white solid. R (n-pentane:Et O 90:10): 0.36. Mp: 99.7–
f
2
02.3 °C. [α]D20 +38 (c 1.0, CHCl ). H NMR (600 MHz, CDCl ): δ 4.11 (dd, J = 1.5 Hz,
1
1
5
3 3
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
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
.9 Hz, 4 H), 4.71 (s, 2 H), 5.78 (d, J = 17.5 Hz, 2 H), 6.63 (dt, J = 5.9 Hz, 17.5 Hz,
2 H), 6.98 (t, J = 8.7 Hz, 4 H), 7.08 (t, J = 8.5 Hz, 4 H), 7.19–7.24 (m, 4 H), 7.34–7.40
m, 4 H) ppm. 13C{ H} NMR (151 MHz, CDCl ): δ 46.1, 69.0, 80.4, 115.1 (d, J =
1
(
3
2
1.5 Hz), 116.3 (d, J = 21.5 Hz), 125.0, 126.7 (d, J = 8.1 Hz), 128.1 (d, J = 7.9 Hz),
137.6 (d, J = 3.2 Hz), 139.0 (d, J = 3.3 Hz), 146.3, 162.1 (d, J = 246.7 Hz), 162.4 (d, J
=
9
248.6 Hz) ppm. IR (ATR): 휈 1713, 1640, 1603, 1506, 1363, 1328, 1266, 1219, 1160,
–1
18
92, 832, 739, 702, 585, 567 cm . The analytics are in alignment with the literature.
(
4aR,8aR,1’E,1’’E)-2,6-Di(3-chloroprop-1-en-1-yl)-4,4,8,8-tetrakis[4-(trifluorome-
thyl)phenyl]tetrahydro[1,3,2]dioxaborinino[5,4-d][1,3,2]dioxaborinin [(R,R)-5c]
Yield: 93%, 2.2 g (2.5 mmol); white solid. R (n-pentane:Et O 90:10): 0.26. Mp: 108.1–
f
2
09.5 °C. [α]D20 +48 (c 1.1, CHCl ). H NMR (600 MHz, CDCl ): δ 4.12 (dd, J = 1.4 Hz,
1
1
5
3 3
.9 Hz, 4 H), 4.87 (s, 2 H), 5.79 (dd, J = 1.5 Hz, 17.5 Hz, 2 H), 6.64 (dt, J = 5.8 Hz,
17.5 Hz, 2 H), 7.43 (d, J = 8.2 Hz, 4 H), 7.53–7.60 (m, 8 H), 7.70 (d, J = 8.3 Hz, 4 H)
13
1
ppm. C{ H} NMR (151 MHz, CDCl ): δ 45.8, 68.7, 80.4, 124.1, 125.2, 125.3 (d, J =
3
3
.6 Hz), 126.4, 126.5 (d, J = 3.6 Hz), 127.7, 130.0 (q, J = 32.6 Hz), 131.0 (q, J =
33.0 Hz), 145.4 (d, J = 206.1 Hz), 146.8 ppm. IR (ATR): 휈 1641, 1616, 1461, 1321,
–1
1
220, 1209, 1166, 1122, 1069, 1017, 992, 908, 851, 821, 773, 733, 649, 597 cm .
+
HRMS: m/z [M + NH ] calcd. 884.1541 for C H B Cl F NO ; found 884.1537.
4
38 30
2
2
12
4
(4aR,8aR,1’E,1’’E)-2,6-Di(3-chloroprop-1-en-1-yl)-4,4,8,8-tetrakis(3,5-difluoro-
phenyl)tetrahydro[1,3,2]dioxaborinino[5,4-d][1,3,2]dioxaborinin [(R,R)-5d]
20
Yield: 43%, 0.33 g (0.45 mmol); white solid. R (n-pentane:Et O 90:10): 0.29. [α] +15
f
2
D
1
(c 1.0, CHCl ). H NMR (600 MHz, CDCl ): δ 4.13 (dd, J = 1.5 Hz, 5.8 Hz, 4 H), 4.69
3 3
(s, 2 H), 5.77 (dd, J = 1.5 Hz, 17.5 Hz, 2 H), 6.63 (dt, J = 5.8 Hz, 17.5 Hz, 2 H), 6.73
(tt, J = 2.4 Hz, 8.6 Hz, 2 H), 6.82 (dd, J = 2.2 Hz, 8.1 Hz 4 H), 6.87 (tt, J = 2.3 Hz,
13
1
8
.4 Hz, 2 H), 6.95 (dd, J = 2.2 Hz, 8.3 Hz, 4 H) ppm. C{ H} NMR (151 MHz, CDCl ):
3
δ 45.8, 68.6, 79.8, 103.49 (t, J = 25.2 Hz), 104.7 (t, J = 25.1 Hz), 108.1 (dd, J = 5.2 Hz,
27.6 Hz), 109.1 (dd, J = 5.8 Hz, 27.0 Hz), 144.4 (t, J = 8.9 Hz), 145.8 (t, J = 7.6 Hz),
1
47.3, 162.9 (dd, J = 12.8 Hz, 248.8 Hz), 163.6 (dd, J = 12.6 Hz, 252.2 Hz) ppm. IR
(ATR): 휈 1641, 1611, 1588, 1487, 1446, 1381, 1358, 1327, 1266, 1251, 1221, 1173,
2
1 / 37
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 37
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
–1
+
1
146, 1070, 989, 885, 862, 807, 774, 716, 681 cm . HRMS: m/z [M – C H BCl] calcd.
3 4
653.0943 for C H BClF O ; found 653.0943.
31
19
8
4
General procedure for the synthesis of allyl boronates 1a–c
Allyl chloride 5 (0.3 mmol, 1 equiv), copper(I) thiophene-2-carboxylate (9 µmol,
mol%) and either the (S)- or the (R)-enantiomer of N,N-bis(1-phenylethyl)dibenzo-
[d,f][1,3,2]dioxaphosphepin-6-amine (9 µmol, 3 mol%) are dissolved in dry CH Cl
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
3
2
2
(
20 mM). The solution is cooled to –90 °C and an ethyl magnesium chloride solution
0.65 mmol, 2.2 equiv, 3 M in Et O diluted to 0.5 M with CH Cl ) is added using a
(
2
2
2
syringe pump within 1 h at –90 °C. The solution is stirred for additional 2 h at –90 °C.
Subsequently, quenching is conducted by addition of sat. aq. NH Cl-solution. After
4
separation of the organic and aqueous layer, the latter is extracted three times with
CH Cl . The combined organic layers are dried over MgSO and the solvent is removed
2
2
4
under reduced pressure. The product is purified by column chromatography.
4aR,8aR,3’S,3’’S)-2,6-Di(pent-1-en-3-yl)-4,4,8,8-tetraphenyltetrahydro[1,3,2]di-
(
oxaborinino[5,4-d][1,3,2]dioxaborinine [(S,R,R,S)-1a]
Yield: quant., 0.98 g (1.7 mmol); white solid. R (n-pentane:Et O 90:10): 0.68. Mp:
f
2
158.3–159.4 °C. [α]D20 +13 (c 0.9, CHCl ). H NMR (600 MHz, CDCl ): δ 0.87 (t, J =
1
3
3
7
.4 Hz, 6 H), 1.42 (ddq, J = 7.5 Hz, 14.9 Hz, 2 H), 1.61 (ddq, J = 7.0 Hz, 14.0 Hz, 2 H),
.79 (ddd, J = 7.9 Hz, 2 H), 4.76 (s, 2 H), 4.91–5.00 (m, 4 H), 5.82 (dt, J = 9.5 Hz,
1
13
1
17.4 Hz, 2 H), 7.11–7.40 (m, 22 H) ppm. C{ H} NMR (151 MHz, CDCl ): δ 13.8, 23.1,
3
3
5.7, 69.1, 80.5, 113.4, 125.2, 126.4, 127.0, 127.8, 127.9, 129.0, 140.4, 142.4, 143.8
ppm. IR (ATR): 휈 2958, 1493, 1386, 1280, 1185, 1034, 1002, 901, 838, 747, 694, 651,
–1
24 cm . The analytics are in alignment with the literature.17
6
(4aR,8aR,3’S,3’’S)-2,6-Di(pent-1-en-3-yl)-4,4,8,8-tetrakis(4-fluorophenyl)tetra-
hydro[1,3,2]dioxaborinino[5,4-d][1,3,2]dioxaborinine [(S,R,R,S)-1b]
Yield: quant., 0.80 g (1.2 mmol); white solid. R (n-pentane:Et O 90:10): 0.79. Mp:
f
2
50.8–155.3 °C. [α]D20 +12 (c 0.8, CHCl ). H NMR (600 MHz, CDCl ): δ 0.87 (t, J =
1
1
3 3
7.4 Hz, 6 H), 1.36–1.46 (m, 2 H), 1.53–1.63 (m, 2 H), 1.75–1.83 (m, 2 H), 4.64 (s, 2 H),
4
.92–5.01 (m, 4 H), 5.78 (ddd, J = 8.8 Hz, 10.3 Hz, 17.1 Hz, 2 H), 6.94 (t, J = 8.7 Hz,
4
H), 7.07 (t, J = 8.6 Hz, 4 H), 7.23 (dd, J = 5.2 Hz, 8.8 Hz, 4 H), 7.32 (dd, J = 5.3 Hz,
8.9 Hz, 4 H) ppm. 13C{ H} NMR (151 MHz, CDCl ): δ 13.6, 22.9, 35.4, 68.8, 79.8,
1
3
1
13.7,.114.6 (d, J = 21.5 Hz), 116.0 (d, J = 21.5 Hz), 126.7 (d, J = 8.0 Hz), 128.1 (d, J
7.9 Hz), 137.7 (d, J = 3.3 Hz), 139.1 (d, J = 3.3 Hz), 139.9, 161.9 (d, J = 246.1 Hz),
=
2
2 / 37
ACS Paragon Plus Environment

Page 23 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
62.2 (d, J = 248.3 Hz) ppm. IR (ATR): 휈 2959, 1604, 1507, 1385, 1279, 1229, 1197,
–1
1160, 1015, 999, 903, 831, 765, 739, 675, 587, 568 cm . The analytics are in
alignment with the literature.18
(4aR,8aR,3’S,3’’S)-2,6-Di(pent-1-en-3-yl)-4,4,8,8-tetrakis[4-(trifluoromethyl)-
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
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
phenyl]tetrahydro[1,3,2]dioxaborinino[5,4-d][1,3,2]dioxaborinine [(S,R,R,S)-1c]
Yield: 96%, 1.0 g (1.2 mmol); white solid. R (n-pentane:Et O 90:10): 0.90. Mp: 167.2–
f
2
70.8 °C. [α]D20 +6 (c 1.2, CHCl ). [α]
20
of enantiomer –4 (c 1.0, CHCl ). H NMR
3
1
1
3
D
(600 MHz, CDCl ): δ 0.86 (t, J = 7.4 Hz, 6 H), 1.40 (dq, J = 6.8 Hz, 13.6 Hz, 2 H), 1.52–
3
1.60 (m, 4 H), 1.81 (q, J = 7.7 Hz, 2 H), 4.78 (s, 2 H), 4.97 (s, 2 H), 4.99 (d, J = 8.4 Hz,
2
7
8
H), 5.75 (dt, J = 9.6 Hz, 17.0 Hz, 2 H), 7.43 (d, J = 8.1 Hz, 4 H), 7.49–7.56 (m, 8 H),
13
1
.69 (d, J = 8.2 Hz, 4 H) ppm. C{ H} NMR (151 MHz, CDCl ): δ 13.7, 23.0, 35.4, 68.6,
3
0.2, 114.2, 122.9, 123.2, 124.7, 125.2 (q, J = 3.3 Hz), 125.5, 126.5 (m), 130.0 (q, J =
32.7 Hz), 131.1 (q, J = 32.6 Hz), 139.5, 145.8 (d, J = 210.4 Hz) ppm. IR (ATR): 휈 2962,
–1
1619, 1417, 1387, 1324, 1284, 1168, 1127, 1071, 1018, 906, 841, 768, 720 cm .
+
HRMS (ESI-TOF): m/z [M + NH ] calcd. 872.2946 for C H B F NO ; found
4
42 40
2
12
4
872.2948.
(4aR,8aR,3’R,3’’R)-2,6-Di(pent-1-en-3-yl)-4,4,8,8-tetrakis[4-(trifluoromethyl)-
phenyl]tetrahydro[1,3,2]dioxaborinino[5,4-d][1,3,2]dioxaborinine [(R,R,R,R)-1c]
Yield: quant., 0.68 g (0.80 mmol); white solid. R (n-pentane:Et O 90:10): 0.84. Mp:
f
2
189.2–191.3 °C. [α]D20 –32 (c 0.9, CHCl ). [α] of enantiomer –9 (c 1.1, CHCl ). H
20
1
3
D
3
NMR (600 MHz, CDCl ): δ 0.86 (t, J = 7.3 Hz, 6 H), 1.44 (dq, J = 7.3 Hz, 14.4 Hz, 2 H),
3
1
.59 (dq, J = 7.1 Hz, 14.0 H, 2 H), 1.79 (q, J = 7.8 Hz, 2 H), 4.77 (s, 2 H), 4.96 (d, J =
.6 Hz, 2 H), 4.98 (s, 2 H), 5.78 (dt, J = 9.1 Hz, 18.1 Hz, 2 H), 7.41 (d, J = 8.1 Hz, 4 H),
4
13
1
7.49–7.57 (m, 8 H), 7.69 (d, J = 8.1 Hz, 4 H) ppm. C{ H} NMR (151 MHz, CDCl ): δ
3
1
3.8, 23.0, 27.1, 68.6, 80.2, 114.1, 123.8, 125.2 (d, J = 3.83 Hz), 125.4, 126.5 (d, J =
.83 Hz), 129.8 (d, J = 32.5 Hz), 130.9 (d, J = 32.8 Hz), 139.5, 145.7 (q, J = 205.6 Hz)
3
ppm. IR (ATR): 휈 2961, 1619, 1417, 1324, 1284, 1169, 1128, 1071, 1018, 906, 850
–1
+
cm . HRMS (ESI-TOF): m/z [M + NH ] calcd. 872.2946 for C H B F NO ; found
4
42 40
2
12
4
872.2946.
General procedure for the synthesis of allyl boronates 1c’
Allyl chloride 5 (0.3 mmol, 1 equiv), copper(I) thiophene-2-carboxylate (9 µmol,
mol%) and either the (S)- or the (R)-enantiomer of N,N-bis(1-phenylethyl)dibenzo-
d,f][1,3,2]dioxaphosphepin-6-amine (9 µmol, 3 mol%) are dissolved in dry CH Cl
3
[
2
2
2
3 / 37
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 37
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
(
20 mM). The solution is cooled to –90 °C and a pentyl magnesium bromide solution
(0.65 mmol, 2.2 equiv, 2 M in Et O diluted to 0.5 M with CH Cl ) is added using a
2
2
2
syringe pump within 1 h at –90 °C. The solution is stirred for additional 2 h at –90 °C.
Subsequently, quenching is conducted by addition of sat. aq. NH Cl-solution. After
4
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
separation of the organic and aqueous layer, the latter is extracted three times with
CH Cl . The combined organic layers are dried over MgSO and the solvent is removed
2
2
4
under reduced pressure. The product is purified by column chromatography.
(
4aR,8aR,3’S,3’’S)-2,6-Di(oct-1-en-3-yl)-4,4,8,8-tetrakis[4-(trifluoromethyl)-
phenyl]tetrahydro[1,3,2]dioxaborinino[5,4-d][1,3,2]dioxaborinine [(R,S,S,R)-1c’]
Yield: quant., 0.28 g (0.30 mmol); white foam. R (n-pentane:Et O 90:10): 0.89. Mp:
f
2
82.2–186.1 °C. [α]D20 +32 (c 1.1, CHCl ). H NMR (600 MHz, CDCl ): δ 0.86 (t, J =
1
1
7
3 3
.2 Hz, 6 H), 1.13–1.52 (m, 12 H), 1.91 (q, J = 7.8 Hz, 2 H), 4.79 (s, 2 H), 4.94–5.04
(m, 4 H), 5.79 (dt, J = 9.5 Hz, 16.9 Hz, 2 H), 7.44 (d, J = 8.0 Hz, 4 H), 7.49–7.58 (m,
13
1
8
2
H), 7.70 (d, J = 8.2 Hz, 4 H) ppm. C{ H} NMR (151 MHz, CDCl ): δ 14.1, 22.6, 28.7,
3
9.7, 32.0, 68.4, 80.0, 113.8, 125.1 (d, J = 3.74 Hz), 125.3, 126.3 (m), 126.4, 129.8 (d,
J = 32.50 Hz), 130.9 (d, J = 32.88 Hz), 139.7, 145.7 (d, J = 199.63 Hz) ppm. IR (ATR):
–1
휈 2957, 2923, 2854, 1420, 1325, 1289, 1170, 1129, 1071, 1017, 840, 762 cm . HRMS
+
(ESI-TOF): m/z [M + NH ] calcd. 956.3885 for C H B F NO ; found 956.3888.
4
48 52
2
12
4
(4aR,8aR,3’R,3’’R)-2,6-Di(oct-1-en-3-yl)-4,4,8,8-tetrakis[4-(trifluoromethyl)-
phenyl]tetrahydro[1,3,2]dioxaborinino[5,4-d][1,3,2]dioxaborinine [(R,R,R,R)-1c’]
Yield: quant., 0.28 g (0.30 mmol); white foam. R (n-pentane:Et O 90:10): 0.88. Mp:
f
2
95.0–196.8 °C. [α]D20 –81 (c 1.5, CHCl ). H NMR (600 MHz, CDCl ): δ 0.84 (t, J =
1
1
7
3 3
.0 Hz, 6 H), 1.13–1.32 (m, 8 H), 1.34–1.43 (m, 2 H), 1.45–1.52 (m, 2 H), 1.87 (q, J =
7.8 Hz, 2 H), 4.77 (d, J = 4.7 Hz, 2 H), 4.95 (s, 2 H), 4.98 (d, J = 6.5 Hz, 2 H), 5.78 (dt,
J = 10.9 Hz, 16.9 Hz, 2 H), 7.42 (d, J = 8.3 Hz, 4 H), 7.49–7.57 (m, 8 H), 7.67–7.72 (m,
13
1
4
1
H) ppm. C{ H} NMR (151 MHz, CDCl ): δ 14.1, 22.5, 28.8, 29.7, 31.9, 68.4, 80.0,
3
13.8, 124.5, 125.1 (d, J = 3.29 Hz), 125.3 (d, J = 3.30 Hz), 126.4, 129.8 (d, J =
32.61 Hz), 130.9 (d, J = 33.31 Hz), 139.6, 145.7 (d, J = 199.56 Hz) ppm. IR (ATR): 휈
–1
2
957, 2929, 2854, 1414, 1325, 1284, 1169, 1128, 1071, 1018, 849, 648 cm . HRMS
+
(ESI-TOF): m/z [M + NH ] calcd. 956.3885 for C H B F NO ; found 956.3909.
4
48 52
2
12
4
2
4 / 37
ACS Paragon Plus Environment

Page 25 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Allylation of Indoles
General Procedure for the racemic allylation of indoles
An equimolar amount of the four stereoisomers of the allyl boronate 1c (0.14 mmol,
1
equiv) and the indole of choice 8 [0.6 mmol, 4.4 equiv are dissolved in dry CH Cl
2 2
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
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
(0.5 M)]. The reaction is overlayed with Argon and stirred for 40 h at 40 °C. After
completion the reaction is quenched with sat. aq. NaHCO -solution. After phase
3
separation, the aq. layer is extracted three times with CH Cl and the combined organic
2
2
layers are dried over MgSO . The solvent is removed under reduced pressure and the
4
crude product is purified via column chromatography.
General Procedure for the stereoselective allylation of indoles (9a–e)
Allyl boronate (S,R,R,S)-1c (0.14 mmol, 1 equiv) and the indole of choice 8 [0.6 mmol,
4.4 equiv are dissolved in dry CH Cl (0.5 M)]. The reaction is overlayed with Argon
2 2
and stirred for 40 h at 40 °C. After completion the reaction is quenched with sat. aq.
NaHCO -solution. After phase separation, the aq. layer is extracted three times with
3
CH Cl and the combined organic layers are dried with MgSO . The solvent is removed
2
2
4
under reduced pressure and the crude product purified via column chromatography.
For analytics, the resulting diastereomeric mixtures are separated by preparative
HPLC since traditional column chromatography is not successful.
2-(Pent-2-en-1-yl)indoline (9a)
Yield: 80%, 42 mg (0.22 mmol); colourless oil. R (n-pentane:Et O 90:10): 0.38. HPLC
f
2
–
1
(Chiracel OD-H, 250 × 4.6 mm, 25 °C, 5 µL, 0.5 mL min , UV 245 nm, n-heptane:i-
propanol 99:1): R (R,E) 15.0 min, R (R,Z) 16.6 min, R (S,E) 17.7 min, R (S,Z)
t
t
t
t
21.1 min.
(R,E)-2-(Pent-2-en-1-yl)indoline [(R,E)-9a]
5:5 dr; 5:95 er; [α]D20 +44 (c 0.7, CHCl ). H NMR (600 MHz, CDCl ): δ 0.99 (t, J =
1
9
7
1
1
7
3 3
.5 Hz, 3 H), 2.01–2.08 (m, 2 H), 2.24–2.29 (m, 2 H), 2.73 (dd, J = 6.9 Hz, 15.5 Hz,
H), 3.13 (dd, J = 8.6 Hz, 15.6 Hz, 1 H), 3.82–3.89 (m, 1 H), 5.41 (dq, J = 6.8 Hz,
5.2 Hz, 1 H), 5.58 (dt, J = 6.2 Hz, 15.3 Hz, 1 H), 6.64 (d, J = 7.8 Hz, 1 H), 6.71 (t, J =
.4 Hz, 1 H), 7.02 (t, J = 7.5 Hz, 1 H), 7.08 (d, J = 7.5 Hz, 1 H) ppm. 13C{ H} NMR
1
(
151 MHz, CDCl ): δ 14.0, 25.8, 35.7, 39.7, 59.3, 109.8, 119.0, 124.9, 125.3, 127.4,
3
129.0, 135.6, 150.3 ppm. IR (ATR): 휈 3371, 2962, 2934, 2849, 1726, 1613, 1488, 1471,
2
5 / 37
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 37
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
–1
+
1
397, 1318, 1255, 966, 751, 705 cm . HRMS: m/z [M + H] calcd. 188.1434 for
C H N; found 188.1433.
13
18
(
S,Z)-2-(Pent-2-en-1-yl)indoline [(S,Z)-9a]
:94 dr; 95:5 er; [α]D20 –22 (c 0.8, CHCl ). H NMR (600 MHz, CDCl ): δ 0.97 (t, J =
1
6
7
3 3
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
.5 Hz, 3 H), 2.01–2.07 (m, 2 H), 2.24–2.30 (m, 1 H), 2.37–2.43 (m, 1 H), 2.73 (dd, J
= 6.8 Hz, 15.5 Hz, 1 H), 3.14 (dd, J = 8.6 Hz, 15.5 Hz, 1 H), 3.83–3.89 (m, 1 H), 5.38
dq, J = 8.1 Hz, 9.5 Hz, 1 H), 5.56 (dt, J = 7.2 Hz, 10.8 Hz, 1 H), 6.63 (d, J = 7.8 Hz,
(
1
H), 6.71 (t, J = 6.8 Hz, 1 H), 7.02 (t, J = 7.2 Hz, 1 H), 7.09 (d, J = 7.2 Hz, 1 H) ppm.
13
1
C{ H} NMR (151 MHz, CDCl ): δ 14.4, 20.9, 34.1, 35.8, 59.5, 109.7, 119.1, 125.0,
3
1
1
1
25.0, 127.5, 128.9, 134.9, 150.2 ppm. IR (ATR): 휈 3376, 2961, 2934, 2866, 1732,
–1
+
610, 1485, 1465, 1403, 1289, 1247, 1017, 746, 705 cm . HRMS: m/z [M + H] calcd.
88.1434 for C H N; found 188.1434.
13
18
5-Methyl-2-(pent-2-en-1-yl)indoline (9b)
Yield: 40%, 29 mg (0.14 mmol); colourless oil. R (n-pentane:Et O 90:10): 0.37. HPLC
f
2
–1
(
Chiracel OD-H, 250 × 4.6 mm, 25 °C, 5 µL, 0.5 mL min , UV 248 nm, n-heptane:i-
propanol 99:1): R (R,E) 13.0 min, R (S,E) 14.2 min, R (R,Z) 16.2 min, R (S,Z)
t
t
t
t
19.6 min.
(
R,E)-5-Methyl-2-(pent-2-en-1-yl)indoline [(R,E)-9b]
99:1 dr; 6:94 er; [α]D20 +51 (c 1.0, CHCl ). H NMR (600 MHz, CDCl ): δ 0.99 (t, J =
1
>
3
3
7.5 Hz, 3 H), 2.01–2.07 (m, 2 H), 2.21–2.29 (m, 5 H), 2.69 (dd, J = 6.9 Hz, 15.6 Hz,
1
1
=
H), 3.09 (dd, J = 8.5 Hz, 15.6 Hz, 1 H), 3.78–3.88 (m, 2 H), 5.41 (dq, J = 6.9 Hz,
5.4 Hz, 1 H), 5.57 (dt, J = 6.1 Hz, 15.4 Hz, 1 H), 6.56 (d, J = 7.8 Hz, 2 H), 6.83 (d, J
13
1
7.7 Hz, 1 H), 6.91 (s, 1 H) ppm. C{ H} NMR (151 MHz, CDCl ): δ 14.0, 21.0, 26.0,
3
35.8, 39.6, 59.6, 109.8, 125.4, 125.7, 127.7, 128.5, 129.3, 135.5, 147.8 ppm. IR (ATR):
–1
+
휈 3365, 3013, 2962, 2923, 1618, 1495, 1250, 972, 807 cm . HRMS: m/z [M + H]
calcd. 202.1590 for C H N; found 202.1590.
14
20
(
S,Z)-5-Methyl-2-(pent-2-en-1-yl)indoline [(S,Z)-9b]
>1:99 dr; >99:1 er; [α]D20 –33 (c 0.7, CHCl ). H NMR (600 MHz, CDCl ): δ 0.96 (t, J =
1
3
3
7
.5 Hz, 3 H), 2.00–2.08 (m, 2 H), 2.22–2.29 (m, 4 H), 2.36–2.43 (m, 1 H), 2.69 (dd, J
6.8 Hz, 15.5 Hz, 1 H), 3.11 (dd, J = 8.5 Hz, 15.5 Hz, 1 H), 3.81–3.87 (m, 2 H), 5.38
=
(dq, J = 8.2 Hz, 10.6 Hz, 1 H), 5.55 (dt, J = 7.3 Hz, 10.7 Hz, 1 H), 6.56 (d, J = 7.8 Hz,
13
1
2
H), 6.83 (d, J = 7.4 Hz, 1 H), 6.92 (s, 1 H) ppm. C{ H} NMR (151 MHz, CDCl ): δ
3
2
6 / 37
ACS Paragon Plus Environment

Page 27 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
4.4, 20.9, 21.0, 34.0, 35.8, 59.8, 109.8, 125.0, 125.8, 127.8, 128.6, 129.3, 134.8,
–1
147.6 ppm. IR (ATR): 휈 3365, 3008, 2962, 2928, 2871, 1618, 1493, 1250, 807 cm .
+
HRMS: m/z [M + H] calcd. 202.1590 for C H N; found 202.1590.
14 20
5-Methoxy-2-(pent-2-en-1-yl)indoline (9c)
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
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
Yield: 53%, 32 mg (0.15 mmol); colourless oil. R (n-pentane:Et O 90:10): 0.15. HPLC
f
2
–1
(Chiracel OD-H, 250 × 4.6 mm, 25 °C, 5 µL, 0.5 mL min , UV 244 nm, n-heptane:i-
propanol 99:1): R (R,E) 20.9 min, R (S,E) 21.3 min, R (R,Z) 36.1 min, R (S,Z)
t
t
t
t
49.9 min.
(R,E)-5-Methoxy-2-(pent-2-en-1-yl)indoline [(R,E)-9c]
99:1 dr; 4:96 er; [α]D20 +38 (c 1.0, CHCl ). H NMR (600 MHz, CDCl ): δ 0.99 (t, J =
1
>
7
1
3
3
.5 Hz, 3 H), 2.01–2.07 (m, 2 H), 2.26–2.30 (m, 2 H), 2.71 (dd, J = 7.0 Hz, 15.7 Hz,
H), 3.11 (dd, J = 8.5 Hz, 15.7 Hz, 1 H), 3.74 (s, 3 H), 3.81–3.88 (m, 2 H), 5.40 (dq, J
= 7.0 Hz, 15.2 Hz, 1 H), 5.57 (dt, J = 6.3 Hz, 15.0 Hz, 1 H), 6.57–6.63 (m, 2 H), 6.70–
.73 (m, 1 H) ppm. 13C{ H} NMR (151 MHz, CDCl ): δ 14.0, 25.8, 36.2, 39.5, 56.1,
1
6
5
2
3
9.9, 110.7, 111.9, 112.4, 125.3, 130.9, 135.6, 143.6, 154.0 ppm. IR (ATR): 휈 3365,
962, 2928, 2877, 2843, 1720, 1624, 1590, 1490, 1459, 1442, 1289, 1216, 1142, 1034,
–1
+
972, 807 cm . HRMS: m/z [M + H] calcd. 218.1539 for C H ON; found 218.1539.
14
20
(S,Z)-5-Methoxy-2-(pent-2-en-1-yl)indoline [(S,Z)-9c]
:93 dr; >99:1 er; [α]D20 –3 (c 0.7, CHCl ). H NMR (600 MHz, CDCl ): δ 0.96 (t, J =
1
7
3
3
7.5 Hz, 3 H), 2.01–2.07 (m, 2 H), 2.26–2.32 (m, 1 H), 2.39–2.45 (m, 1 H), 2.72 (dd, J
6.9 Hz, 15.6 Hz, 1 H), 3.13 (dd, J = 8.4 Hz, 15.7 Hz, 1 H), 3.75 (s, 3 H), 3.83–3.90
m, 2 H), 5.37 (dq, J = 7.7 Hz, 9.9 Hz, 1 H), 5.55 (dt, J = 7.2 Hz, 11.1 Hz, 1 H), 6.59–
=
(
13
1
6.64 (m, 2 H), 6.72–6.74 (m, 1 H) ppm. C{ H} NMR (151 MHz, CDCl ): δ 14.4, 20.9,
3
33.8, 36.2, 56.1, 60.1, 111.0, 111.9, 112.4, 124.8, 131.0, 134.9, 143.1, 154.3 ppm. IR
(ATR): 휈 3371, 2959, 2928, 2877, 1732, 1596, 1491, 1454, 1374, 1284, 1233, 1136,
–1
+
1040 cm . HRMS: m/z [M + H] calcd. 218.1539 for C H ON; found 218.1539.
14 20
5-Fluoro-2-(pent-2-en-1-yl)indoline (9d)
Yield: 46%, 26 mg (0.13 mmol); colourless oil. R (n-pentane:Et O 95:5): 0.10. HPLC
f
2
–1
(Chiracel OD-H, 250 × 4.6 mm, 25 °C, 5 µL, 0.5 mL min , UV 241 nm, n-heptane:i-
propanol 99.8:0.2): R (R,E) 19.3 min, R (S,E) 20.6 min, R (R,Z) 28.9 min, R (S,Z)
t
t
t
t
40.0 min.
2
7 / 37
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 37
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
(
R,E)-5-Fluoro-2-(pent-2-en-1-yl)indoline [(R,E)-9d]
97:3 dr; 3:97 er; [α]D20 +19 (c 0.4, CHCl ). H NMR (600 MHz, CDCl ): δ 0.99 (t, J =
1
3
3
7
1
1
.5 Hz, 3 H), 2.00–2.07 (m, 2 H), 2.19–2.29 (m, 2 H), 2.69 (dd, J = 7.0 Hz, 15.8 Hz,
H), 3.10 (dd, J = 8.6 Hz, 15.8 Hz, 1 H), 3.73–3.87 (m, 2 H), 5.39 (dq, J = 6.9 Hz,
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
5.1 Hz, 1 H), 5.56 (dt, J = 6.3 Hz, 15.3 Hz, 1 H), 6.47–6.51 (m, 1 H), 6.66–6.71 (m,
1 H), 6.77–6.81 (m, 1 H) ppm. 13C{ H} NMR (151 MHz, CDCl ): δ 14.0, 25.8, 36.0,
1
3
3
9.7, 59.9, 109.4 (d, J = 8.3 Hz), 112.3 (d, J = 23.8 Hz), 113.2 (d, J = 23.2 Hz), 125.2,
30.5 (d, J = 8.3 Hz), 135.6, 146.8, 157.1 (d, J = 234.9 Hz) ppm. IR (ATR): 휈 3371,
1
–
1
+
2962, 2928, 1720, 1489, 1448, 1284, 1233, 1122, 972, 807 cm . HRMS: m/z [M + H]
calcd. 206.1340 for C H NF; found 206.1339.
13 17
(S,Z)-5-Fluoro-2-(pent-2-en-1-yl)indoline [(S,Z)-9d]
:96 dr; 95:5 er; [α]D20 –7 (c 0.4, CHCl ). H NMR (600 MHz, CDCl ): δ 0.96 (t, J =
1
4
3
3
7.5 Hz, 3 H), 1.99–2.07 (m, 2 H), 2.20–2.27 (m, 1 H), 2.32–2.40 (m, 1 H), 2.69 (dd, J
6.9 Hz, 15.8 Hz, 1 H), 3.11 (dd, J = 8.5 Hz, 15.8 Hz, 1 H), 3.69–3.88 (m, 2 H), 5.38
dq, J = 8.2 Hz, 9.0 Hz, 1 H), 5.56 (dt, J = 7.2 Hz, 10.9 Hz, 1 H), 6.45–6.51 (m, 1 H),
=
(
13
1
6
.66–6.73 (m, 1 H), 6.77–6.82 (m, 1 H) ppm. C{ H} NMR (151 MHz, CDCl ): δ 14.4,
3
20.9, 34.1, 36.1, 60.1, 109.3 (d, J = 8.3 Hz), 112.3 (d, J = 23.7 Hz), 113.3 (d, J =
3.2 Hz), 124.9, 130.4 (d, J = 8.0 Hz), 134.9, 146.8, 157.1 (d, J = 234.9 Hz) ppm. IR
ATR): 휈 3376, 2962, 2928, 1726, 1488, 1448, 1289, 1233, 1125, 938, 864, 807, 751
2
(
–1
+
cm . HRMS: m/z [M + H] calcd. 206.1340 for C H NF; found 206.1339.
13
17
5
-Bromo-2-(pent-2-en-1-yl)indoline (9e)
Yield: 43%, 25 mg (0.09 mmol); colourless oil. R (n-pentane:Et O 90:10): 0.40. HPLC
f
2
–1
(Chiracel OD-H, 250 × 4.6 mm, 15 °C, 5 µL, 0.5 mL min , UV 254 nm, n-heptane:i-
propanol 99.8:0.2): R (R,E) 23.7 min, R (S,E) 25.5 min, R (R,Z) 49.4 min, R (S,Z)
t
t
t
t
7
6.7 min.
(R,E)-5-Bromo-2-(pent-2-en-1-yl)indoline [(R,E)-9e]
99:1 dr; 4:96 er; [α]D20 +52 (c 0.7, CHCl ). H NMR (600 MHz, CDCl ): δ 0.98 (t, J =
1
>
3 3
7.5 Hz, 3 H), 2.00–2.08 (m, 2 H), 2.22–2.29 (m, 2 H), 2.72 (dd, J = 6.7 Hz, 15.9 Hz,
1
H), 3.11 (dd, J = 8.6 Hz, 15.8 Hz, 1 H), 3.83–3.91 (m, 1 H), 5.38 (dq, J = 6.4 Hz,
5.3 Hz, 1 H), 5.57 (dt, J = 6.3 Hz, 15.3 Hz, 1 H), 6.52 (d, J = 8.2 Hz, 2 H), 7.10 (d, J
1
13
1
= 8.2 Hz, 1 H), 7.17 (s, 1 H) ppm. C{ H} NMR (151 MHz, CDCl ): δ 13.9, 25.8, 35.5,
3
3
9.5, 59.7, 110.8, 111.1, 124.9, 127.9, 130.1, 131.5, 135.9, 149.0 ppm. IR (ATR): 휈
–1
3
382, 2961, 2928, 2843, 1601, 1479, 1420, 1248, 1057, 969, 881, 805 cm . HRMS:
8 / 37
2
ACS Paragon Plus Environment

Page 29 of 37
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
+
m/z [M + H] calcd. 266.0539 and 268.0518 for C H NBr; found 266.0539 and
13
17
268.0519.
(
S,Z)-5-Bromo-2-(pent-2-en-1-yl)indoline [(S,Z)-9e]
1
>
7
1:99 dr; 97:3 er; [α]D20 –41 (c 0.9, CHCl ). H NMR (600 MHz, CDCl ): δ 0.96 (t, J =
3
3
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
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
.5 Hz, 3 H), 1.99–2.06 (m, 2 H), 2.21–2.27 (m, 1 H), 2.34–2.40 (m, 1 H), 2.71 (dd, J
= 6.5 Hz, 15.8 Hz, 1 H), 3.12 (dd, J = 8.6 Hz, 15.8 Hz, 1 H), 3.83–3.90 (m, 1 H), 5.34
(
dq, J = 6.8 Hz, 10.4 Hz, 1 H), 5.56 (dt, J = 7.0 Hz, 10.7 Hz, 1 H), 6.49 (d, J = 8.2 Hz,
13
1
2
H), 7.10 (d, J = 8.2 Hz, 1 H), 7.17 (s, 1 H) ppm. C{ H} NMR (151 MHz, CDCl ): δ
3
14.4, 20.9, 34.0, 35.6, 59.8, 110.6, 110.9, 124.6, 127.9, 130.1, 131.4, 135.2, 149.2
–1
ppm. IR (ATR): 휈 3382, 2968, 2934, 1607, 1475, 1420, 1250, 807 cm . HRMS: m/z
+
[
M + H] calcd. 266.0539 and 268.0518 for C H NBr; found 266.0539 and 268.0519.
13
17
2
-(Oct-2-en-1-yl)indoline (9a’)
Yield: 45%, 29 mg (0.13 mmol); colourless oil. R (n-pentane:Et O 90:10): 0.30. HPLC
f
2
–1
(
Chiracel OD-H, 250 × 4.6 mm, 25 °C, 5 µL, 0.5 mL min , UV 300 nm, n-heptane:i-
propanol 99.8:0.2): R (R,E) 22.4 min, R (S,E) 25.4 min, R (R,Z) 27.7 min, R (S,Z)
t
t
t
t
33.3 min
(R,E)-2-(Oct-2-en-1-yl)indoline [(R,E)-9a’]
1
>
7
95:5 dr; 7:93 er; [α]D20 +79 (c 1.0, CHCl ). H NMR (600 MHz, CDCl ): δ 0.90 (t, J =
3 3
.1 Hz, 3 H), 1.41–1.24 (m, 6 H), 2.00–2.04 (m, 2 H), 2.24–2.26 (m, 2 H), 2.71 (dd, J
= 6.9 Hz, 15.5 Hz, 1 H), 3.12 (dd, J = 8.7 Hz, 15.6 Hz, 1 H), 3.83 (dt, J = 7.3 Hz,
1
1
1
4.5 Hz, 1 H), 3.91 (brs, 1 H), 5.41 (dq, J = 7.3 Hz, 15.4 Hz, 1 H), 5.52 (dt, J = 7.3 Hz,
5.4 Hz, 1 H), 6.60 (d, J = 7.7 Hz, 1 H), 6.68 (t, J = 7.3 Hz, 1 H), 7.00 (t, J = 7.6 Hz,
13
1
H), 7.07 (d, J = 7.2 Hz, 1 H) ppm. C{ H} NMR (151 MHz, CDCl ): δ 14.1, 22.6, 29.2,
3
31.4, 32.6, 35.6, 39.8, 59.1, 109.2, 118.5, 124.8, 126.3, 127.2, 128.6, 133.9, 150.7
ppm. IR (ATR): 휈 2957, 2926, 2857, 1721, 1610, 1485, 1466, 1408, 1268, 1248, 1117,
–1
+
1
102, 1019, 971, 745, 731 cm . HRMS: m/z [M + H] calcd. 230.1903 for C H N;
16 24
found 230.1905.
(S,Z)-2-(Oct-2-en-1-yl)indoline [(S,Z)-9a’]
1
>
7
5:95 dr; 80:20 er; [α]D20 –49 (c 0.9, CHCl ). H NMR (600 MHz, CDCl ): δ 0.89 (t, J =
3 3
.5 Hz, 3 H), 1.23–1.38 (m, 6 H), 1.99–2.04 (m, 2 H), 2.19–2.30 (m, 1 H), 2.33–2.42
(m, 1 H), 2.72 (dd, J = 6.8 Hz, 15.5 Hz, 1 H), 3.13 (dd, J = 8.8 Hz, 15.6 Hz, 1 H), 3.80–
.88 (m, 1 H), 3.91 (brs, 1 H), 5.41 (dq, J = 8.3 Hz, 9.4 Hz, 1 H), 5.53 (dt, J = 7.0 Hz,
3
2
9 / 37
ACS Paragon Plus Environment