Cyclopropanation of Terminal Alkenes through Sequential Atom-Transfer Radical Addition/1,3-Elimination

Article abstract of DOI:10.1002/anie.201907962

An operationally simple method to affect an atom-transfer radical addition of commercially available ICH₂Bpin to terminal alkenes has been developed. The intermediate iodide can be transformed in a one-pot process into the corresponding cyclopropane upon treatment with a fluoride source. This method is highly selective for the cyclopropanation of unactivated terminal alkenes over non-terminal alkenes and electron-deficient alkenes. Due to the mildness of the procedure, a wide range of functional groups such as esters, amides, alcohols, ketones, and vinylic cyclopropanes are well tolerated.

Full text of DOI:10.1002/anie.201907962

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Accepted Article
Title: Cyclopropanation of Terminal Alkenes via Sequential Atom
Transfer Radical Addition/1,3-Elimination
Authors: Philippe Renaud, Nicholas D. C. Tappin, Weronika Michalska,
and Simon Rohrbach
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201907962
Angew. Chem. 10.1002/ange.201907962
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10.1002/anie.201907962
Angewandte Chemie International Edition
COMMUNICATION
Cyclopropanation of Terminal Alkenes via Sequential Atom
Transfer Radical Addition/1,3-Elimination
Nicholas D. C. Tappin, Weronika Michalska, Simon Rohrbach, Philippe Renaud*[a]
Abstract: An operationally simple protocol to affect an atom transfer
radical addition of commercially available ICH2Bpin to terminal
alkenes has been developed. The intermediate iodide can be
1, B). Based on these simple considerations, it is expected that
iodine atom transfer between 1-iodoalkylboronic esters and
alkenes should be possible – but still challenging – due to
moderate thermodynamic and polar effects.[42] Recently, Zard and
co-workers rationalized the inefficiency of the xanthate transfer
mediated addition of electrophilic radicals to pinacol vinylboronate
by the lack of favorable thermodynamic and polar effects.[43–45]
transformed in
a
one-pot process into the corresponding
cyclopropane upon treatment with a fluoride source. This method is
highly selective for the cyclopropanation of unactivated terminal
alkenes over non-terminal alkenes and electron deficient alkenes.
Due to the mildness of the procedure, a wide range of functional
groups such as esters, amides, alcohols, ketones, and vinylic
cyclopropanes are well tolerated.
Decreasing RSEs disfavor ATRA
A
Me
Me
Me
MeO
MeO
B
B
B
MeO
Due to their stability and ease of handling, alkylboronic esters are
extremely useful and attractive synthetic intermediates for a broad
range of transformations[1] involving carbon–heteroatom[2] and
carbon–carbon[3–6] bond formation. Boronic esters have also been
involved in a variety of radical reactions.[7–11] They are prepared
either via hydroboration,[12,13] via reactions of organometallic
species with borate esters and related reagents,[14] via C—H
activation process[15] and more recently via radical borylation
reactions.[16] The nature of the alkyl chain at boron can be easily
modified with a high level of stereocontrol by homologation
reactions upon treatment with carbenoid type reagents.[17–19]
Our long-standing interest in developing mild methods for
the functionalization of alkenes via radical pathway[20–32] incited us
to investigate the iodoalkylation involving a 1-borylated alkyl
radicals leading to γ-iodoalkylboronates. Based on EPR studies
and calculations, Walton, Carboni, and co-workers reported that
1-borylated radicals are stabilized when the boron is sp2-
hybridized, however the extent of stabilization is smaller for
radicals substituted by a boronic ester substituent relative to the
corresponding borinic ester or borane (Figure 1, A).[33,34] This
stabilization is the first key feature to design an iodine atom
transfer process according to the pioneering work of Kharasch
and Curran.[35–41] Matching the philicities of the radicals and
alkenes involved in the process is the second key feature for the
success of the reaction. Strong polar effects favor an efficient and
selective iodine atom transfer process over an oligomerization
reaction. The resonance hybrids of the 1-borylalkyl radical
suggest that the oxygen lone pairs reduce electrophilicity by the
same mechanism that they decrease radical stabilization (Figure
6.7 kcal mol–1
8.2 kcal mol–1
10.4 kcal mol–1
B
Radical electrophilicity favors ATRA
MeO
MeO
MeO
MeO
B
B
B
B
OMe
OMe
OMe
OMe
resonance hybrids forms
showing reduced electrophilicity
(disfavor ATRA)
Figure 1. Radical stabilization energies (RSEs) of 1-borylated radicals and
resonance hybrids of boronic esters derived radicals.[34]
α-Haloboronic esters have been used in tin-mediated (Scheme 1,
C)[46–49] and metal-catalyzed radical processes.[50–52] Chen
reported the Pd(0) catalyzed cyclopropanation of norbornene
using potassium iodomethyltrifluoroborate.[53] Interestingly,
pinacol iodomethylboronic ester could also be used for this
transformation (Scheme 1, D).
A mechanism involving a
palladocyclobutane intermediate was proposed. Finally, 1-
borylated alkyl radicals were involved in the elegant nickel-
catalyzed alkylation and arylation of α-haloboronic esters
developed by Fu[54] and Martin,[55] respectively. 1-Borylated alkyl
radicals have also been generated from Barton esters[56] and
xanthates[45] as well as through radical addition to
vinylboronates.[43,44,46,57–61]
and
to
ate
complexes
of
vinylboronates.[62–64] To the best of our knowledge no halogen
ATRA process involving 1-haloalkylboronates have been reported.
This reaction would be highly attractive since it opens a way to
prepare in a straightforward manner 3-haloalkylboronates that are
potential precursors of cyclopropanes via a 1,3-elimination
process.[65–68] The stable boronic ester was has not yet been used
for this transformation and this attractive 1,3-cyclization has been
limited to a few very simple unfunctionalized cyclopropanes since
the precursors were only available by hydroboration of allylic
halides. We report here, a study of the iodine atom transfer
reactions between pinacol iodomethylboronate 1 and non-
[a]
N. D. C. Tappin, W. Michalska, Dr. S. Rohrbach, Prof. Dr. P.
Renaud
Department of Chemistry and Biochemistry
University of Bern
Freiestrasse 3, CH-3012 Bern, Switzerland
E-mail: philippe.renaud@dcb.unibe.ch
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201907962
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimization of the cyclopropanation of undecene 2a with pinacol
iodomethylboronate 1.[a] DLP = dilauroyl peroxide; DTBHN = di-tert-butyl hyponitrite; TBAF
= tetra-n-butylammonium peroxide; DCE = 1,2-dichloroethane; EtOAc = ethyl acetate.
activated alkenes 2 (Scheme 1, E) that led to the development of
a metal-free cyclopropanation procedure.[69]
I
Lewis
base
initiator
solvent
+ ICH2Bpin
C9H19
2a
C Batey 1996
pinB
C9H19
C9H19
1
3a
4a
Bu3SnH
initiator
Bpin
X
Bpin
+
OBu
Bu
R
OBu
Entry Initiator
Solvent, T
CH2Cl2, rt
CH2Cl2, reflux NaOH
CH2Cl2, reflux LiOH
C6H6, reflux
C6H6, reflux
C6H6, reflux
C6H6, reflux
C6H6, reflux
Lewis base
NaOH
Yield[b]
28%
21%
35%
71%
75%
73%
40%
71%
74%
68%
74%[d]
71%
1
BEt3, air
D Chen 2014
2
3
4
5
6
7
8
9
BEt3, DTBHN
BEt3,[c] DTBHN
DLP (1 equiv)
DLP (1 equiv)
DLP (1 equiv)
DLP (0.2 equiv)
DLP (1.4 equiv)
DLP (1 equiv)
DLP (1 equiv)
DLP (1 equiv)
Pd(P(t-Bu)3)2 (cat.)
K2CO3, CsF
LiOH
LiOEt
TBAF
TBAF
TBAF
+
Bpin
I
DMF/H2O, 90 ºC
92% (GC)
E This work
Bpin
1) initiator
2) F–
ClC6H5, reflux TBAF
DCE, reflux
EtOAc, reflux
+
I
R
10
11
TBAF
TBAF
R
Scheme 1. Reaction of alkenes with 1-haloalkylboronic esters. DMF = N,N-
Dimethylformamide. Bpin = pinacolboryl
[a] Reactions were run using 2a (1 mmol), 1 (2 mmol) in dry benzene (3.3 mL) then the
nucleophilic solution was added and the reaction mixture stirred vigorously. [b] Yields
determined by GC using pentadecane as internal standard. [c] Syringe pump addition. [d]
NMR yield with 1,4-dimethoxybenzene as external standard.
Initial attempts to run the iodine atom transfer reaction
between ICH2Bpin
1 and 1-undecene 2a as a substrate
demonstrated that the 3-iodoalkylboronate 3a was decomposing
during purification on silica gel. Eventually, we decided not to
isolate 3a and to convert it immediately into the cyclopropane 4a.
Preliminary experiments with small amount of isolated boronic
ester 3a showed that the cyclopropane formation was possible
upon treatment with a variety of nucleophiles such as HO–, EtO–,
and F–. Having established that the cyclopropane formation was
possible, we started to optimize the whole process as outlined in
Table 1. Initiation with BEt3 and oxygen or DTBHN were
attempted first using either NaOH or LiOH to trigger the
cyclopropanation but yields remained low (Table 1, entries 1–3).
DLP was eventually identified as a superior initiating system and
the use of one equivalent was necessary to reach the best yields
(Table 1, entries 6–8).[70] The reagent used to induce the
cyclopropane formation was found to be less crucial. Good but
slightly irreproducible results were obtained with the biphasic
NaOH or LiOH system (Table 1, entries 3–4), higher yields and
reproducibility were achieved by using LiOEt or TBAF (Table 1,
entries 5, 6). The latter was finally selected for its mildness. The
role of the solvent was found to be less critical. Good yields were
obtained in benzene and chlorobenzene (Table 1, entries 6, 9).
The reaction works also well in DCE (Table 1, entry 10) and it was
found later that the reaction gave a similar yield when run in dry
EtOAc (Table 1, entry 11). For the purposes of this investigation
dry benzene was selected as the solvent of choice but one scale-
up experiment was run in EtOAc with a more polar alkene (see
below).
The scope of the reaction was investigated with a series of substrates
(Scheme 2). Simple terminal alkenes bearing a wide range of functional
group such as the electron rich aromatic ring of safrole (2c), the silyl ether
2d (using LiOEt instead of TBAF to avoid cleavage of the silyl group), the
ketone 2e, the unprotected primary and secondary alcohols 2f and 2g, the
acylated alcohols 2h and 2i, the benzyl ether 2j, the free carboxylic acid
2k, the esters 2l and 2m, and the secondary and tertiary amides 2o and 2p
gave the desired products in fair to good yields (39–80%). Interestingly, the
cyclopropanation of 2d involved a neopentylic iodide showing that the
cyclization mechanism is probably best described as a 1,3-elimination
process in analogy to the reaction of 3-haloalkylboranes where inversion of
the configuration at occurs at the halide and boron substituted carbon
atoms.[71,72] When 1,1-disubstituted alkenes were employed (such as 2q),
troubles were encountered with the stability of the intermediate iodides and
a 15% yield was obtained with DLP under thermal initiation. Initiation with
BEt3/air turned out to be best since it could be performed at room
temperature to give 4q in 38% yield. Reaction with the
methylenecyclobutane 2r afforded the slightly volatile 4r in a 45% yield.
Following Chen’s work,[53] we also cyclopropanated norbornene 2s to 4s in
53% yield. Next, the procedure was used on diverse dienes to test the
chemoselectivity. α,β-Unsaturated esters 2t and 2u reacted selectively at
the unactivated terminal alkene. Acylated prenol, citronellol, nopol, and
cholesterol 2w–2y were selectively cyclopropanated at the terminal non-
activated alkene to give 4w–4y in 48–62% yields. Finally, the
chrysanthemic ester 2z afforded 4z as a single isolated regioisomer without
any modification of the trans/cis 8:2 diastereomeric ratio demonstrating
further the mildness of the reaction conditions.
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10.1002/anie.201907962
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COMMUNICATION
ICH2Bpin (1) (2 equiv)
DLP (1 equiv)
benzene, reflux, 4 h
then TBAF (5 equiv), rt, 16 h
R
R
4a—z
2a—z
Alkenes
O
O
OH
OTBDMS
4d 58% (LiOEt)a
( )9
Ph
( )8
4f 70%
( )8
O
4b 60%
4a 77%
4e 69%
4c 39%
CO2Me
CO2H
CO2Et
OH
OBz
OBn
OAc
( )8
( )9
4i 74%
( )8
4k 69%
( )8
( )9
( )9
4j 61%
( )9
4g 75%
4m 76% (80%)b
4l 71%
4h 70%
Ph
O
O
CN
CO2Bn
( )8
( )8
4o 65%
( )8
4p 65%
NHEt
NEt2
4s 50%d (53%)c,d
4n 69%
4q 15% (38%)c
4r 45%c
Dienes
O
O
O
Ph
O
( )9
( )9
( )8
( )8
O
O
O
O
4t 53%
4u 56%
4v 54%
4w 48%
H
O
O
( )9
H
H
O
O
( )8
O
H
4z 56%, trans/cis 8:2e
( )8
O
4x 62%
4y 56%
Scheme 2. Scope of the cyclopropanation. Procedure: All reactions were run on 1 mmol scale with no special precautions to remove moisture or air. Alkene (1
mmol), ICH2Bpin (2 mmol), and DLP (1 mmol) were heated in refluxing benzene (0.3 M) under argon for 4 h; to the cooled reaction mixture was added TBAF solution
(5 equiv, 1.0 M in THF) and stirred for 16 h. Each yield was determined by 1H-NMR analysis of the crude product mixture after work-up using 1,4-dimethoxybenzene
as reference. a) LiOEt (1.0 M in EtOH) was used instead of TBAF. b) Reaction performed in EtOAc on a 5 mmol scale. c) Initiated with BEt3 (0.5—1.2 equiv) open
to air, rt. d) Yield estimated by GC analysis using 1,5-cyclooctadiene as reference. See SI for details. e) No erosion of the trans/cis ratio.
I
F–
The isolation of the pinacol γ-iodoalkylboronic esters 3 resulting
from the reaction of ICH2Bpin 1 over numerous alkenes was
challenging due to their instability during purification by silica gel
chromatography. Pinanediol boronic esters are known to be
thermodynamically more stable,[73,74] therefore we tested the
reaction of iodomethylboronic ester 5 with alkene 2g. ATRA
product 6g was stable to silica gel purification and was obtained
in 74% isolated yield (Scheme 3).
R
F
pinB
I
pinB
R
1
3
pinB
I
1,3-elimination
ATRA
R
pinB
R
pinB
R
4
2
I
Scheme 4. Mechanism of the cyclopropanation involving ATRA (= atom transfer
radical addition) and 1,3-elimination processes.
O
B
I
+
OH
( )9
O
B
OH
DLP (1 equiv)
( )9
O
O
benzene, reflux
In conclusion, we have reported here an unprecedented approach
for the formation of cyclopropanes relying on a one-pot iodine
atom transfer radical addition followed by an ionic intramolecular
substitution process (1,3-elimination). The whole sequence is
characterized by mild reaction conditions and excellent functional
group tolerance. Interestingly, the high regioselectivity observed
for terminal non-activated alkenes over non-terminal and electron
deficient alkenes cannot be achieved easily using classical
cyclopropanation methods.[69] Finally, the possible isolation of the
intermediate products of iodine atom transfer depicted in Scheme
3 open new opportunities for further synthetic applications.
5 (2 equiv)
2g
6g 74% (dr 1:1)
Scheme 3. Isolation of a pinanediol γ-iodoalkylboronic ester.
The mechanism of the cyclopropanation reaction is depicted in
Scheme 4 and corresponds to a classical radical iodine ATRA
coupled with
intramolecular nucleophilic substitution). The radical addition to
alkenes is controlled by polar and steric effects: the electron
withdrawing boryl group favors the addition to electron rich
alkenes and radical addition are much faster at the less hindered
position. These two effects rationalize well the observed
regioselectitvities reported in Scheme 2.
a Lewis base promoted 1,3-elimination (or
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10.1002/anie.201907962
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COMMUNICATION
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The
Swiss
National
Science
Foundation
(Project
200020_172621) and the University of Bern are gratefully
acknowledged for financial support.
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Keywords: radical reaction • organoboron • cyclopropanation •
alkenes • 1-borylated radical • iodine atom transfer • ATRA •
boronate complexes.
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This article is protected by copyright. All rights reserved.

10.1002/anie.201907962
Angewandte Chemie International Edition
COMMUNICATION
This article is protected by copyright. All rights reserved.

10.1002/anie.201907962
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Nicholas D. C. Tappin, Weronika
Michalska, Simon Rohrbach, Philippe
Renaud*
I
ICH2BPin, DLP
R
TBAF
R
EtOAc
pinB
R
50–80%
Page No. – Page No.
O
O
CO2Et
O
9
( )8
( )5
( )8
Cyclopropanation of Terminal
O
Alkenes via Sequential Atom Transfer
Radical Addition/1,3-Elimination
An operationally simple protocol for the cyclopropanation of alkenes with ICH2Bpin
via an iodine atom transfer radical addition followed by a fluoride promoted 1,3-
elimination reaction has been developed. This procedure requires no metal and
tolerates a broad range of reactive functional groups.
This article is protected by copyright. All rights reserved.