Preparation of homoallylic amines via a three-component coupling process

Article abstract of DOI:10.1039/C8OB01831F

A three-component synthesis of homoallylic amines is described. The allylboronic species were generated in situ by homologation of vinyl boroxines with trimethylsilyldiazomethane, then followed by trapping of the allylboron intermediate with imines. Twenty-seven compounds were successfully prepared in moderate to high yields. Imines bearing various functional groups were tolerated, including aliphatic, aromatic and heteroaromatic substituents. Further elaboration of some of the homoallylic amines to form azeditines is also reported.

Full text of DOI:10.1039/C8OB01831F

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: X. Ou, R. Labes, C.
Battilocchio and S. V. Ley, Org. Biomol. Chem., 2018, DOI: 10.1039/C8OB01831F.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 3
View Article Online
DOI: 10.1039/C8OB01831F
Journal Name
COMMUNICATION
Preparation of homoallylic amines via a three-component
coupling process†
Xiaoxu Ou,a Ricardo Labes,a Claudio Battilocchio,a,b* Steven V. Leya*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A three-component synthesis of homoallylic amines is described. prepared via a Pd-catalysed procedure.6 Despite the lack of
The allylboronic species were generated in situ by homologation of stability and the limited scope of the boroxine component, the
vinyl boroxines with trimethylsilyldiazomethane, then followed by method has broad imine scope.
trapping of the allylboron intermediate with imines. Twenty-seven
Concerning the allylation of imines to afford homoallylic
compounds were successfully prepared in moderate to high yields. amines, although there are many reported studies to show
Imines bearing various functional groups were tolerated, including applicability of the various methods, there is however a need
aliphatic, aromatic and heteroaromatic substituents. Further for a complementary, more general method which would result
elaboration of some of the homoallylic amines to form azeditines is in a broader scope of the boronic precursors.
also reported.
Recently we have described a metal-free route to afford
homoallylic alcohols via in situ generation of allyl boronic
Homoallylic amines occur as a structural feature in various
species,
which
are
initially
formed
from
alkaloids and anti-cancer agents (Figure 1).1 As a result, there is
interest in developing efficient strategies for the formation of
these particular entities.
(trimethylsilyl)diazomethane (TMSCHN2) and a vinyl boronic
acid, and trapped with aldehydes.7 In addition to this, recent
DFT studies8 have shed light on the role that boroxines play in
the reactivity of this system.
Based on this previous work, we explored the use of
boroxines as reactive species to afford a broad class of
homoallylic amines, via homologation with TMSCHN2 followed
by combination with a variety of substituted imines.
Of special merit for their preparation is the addition of
allylboronic derivatives to imines.2-5 The first diastereoselective
allylboration of acyclic imines by allylic boroxines under
anhydrous conditions was reported in 2014.2 In this particular
case, the authors selected three boroxines, which were
In Table 1, N-methyl benzaldimine
boroxine were selected as model substrates for initial studies.
The reaction was performed under anhydrous conditions, to
avoid hydrolysis of the boroxine, and 1:1 ratio of
2 and chloro-methylvinyl
1
a
trimethylsilyldiazomethane vs boroxine was initially
investigated. When 1 equivalent of imine and boroxine were
reacted with trimethylsilyldiazomethane in CH2Cl2 at room
temperature for 24 hrs (Table 1, entry 1), we could isolate the
homoallylic amine 3 as a single diastereomer, but only in 13%
yield, alongside unreacted starting material and homoallylic
alcohol byproduct 4.
A series of further experiments highlighted that the yield
and reaction rate were affected by the stoichiometry of the
boroxine (Table 1, entry 3-5), whereby increasing the equivalent
of boroxine to 1.5 drove the reaction to completion. Employing
strictly anhydrous conditions, at 85°C, it was possible to obtain
the product in 94% yield, over 6h (Entry 11).
Figure 1 Natural products containing the homoallylic amine motif.
a. Innovative Technology Centre, Department of Chemistry, University of Cambridge,
Lensfield Road, CB2 1EW, Cambridge, UK. E-mail: svl1000@cam.ac.uk
b. Current address: Syngenta Crop Protection, Process Research,
Schaffhauserstrasse 101, CH-4332, Switzerland.
†
Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx0000
Additional data is available from the University of Cambridge Data Repository Web
site: https://doi.org/10.17863/CAM.26332
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 3
COMMUNICATION
Journal Name
Table 1 Allylboration of arylimines with allylboroxines
Table 2 Continued
View Article Online
DOI: 10.1039/C8OB01831F
Entry
Eq. Monomeric
Boroxine
Solvent
Temp
Time(h)
Additive
Yield
3 (%)
1
2
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
rt
rt
24
48
48
48
48
48
48
48
12
12
6
-
13
17
20
29
30
55
0
1
-
3
1.3
1.5
2
rt
-
4
rt
-
5
rt
-
6
1.5
1.5
1.5
1.5
1.5
1.5
1.5
rt
-
7
rt
Et3N
8
rt
Na2SO4
73
86
87
94
43
9
85˚C
85˚C
85˚C
85˚C
Na2SO4
10
11
12
-
-
-
The examples demonstrate wide reaction scope tolerating
heterocycles, esters, alkenes, halides and anilines. In most
cases, the reactions are highly diastereoselective while in some
cases moderate d.r. were observed. Yields are generally good to
excellent.
This very general and mild protocol clearly sets the scene for
further product transformations. One can envisage various
cross-couplings, cross metathesis, deprotection and ring
forming reactions for example. Similarly, the vinyl trimethylsilyl
substituent can serve as a precursor for protodesilylation or
halodesilylation following known procedures.9-10
3
Next we explored and the scope of the method, initially
varying the boroxine component. Both electron-rich (Table
entry 4) and electron-deficient (Table 2, entry 5 and 6) all
reacted in high yields. Alkyl and vinyl boroxines were also
tolerated affording good yields of the corresponding products
2,
(Table 2, entries 7,13,15-18 and 21-23).
Table 2 Allylboration of arylimines with allylboroxines
By way of an illustration, we report three examples whereby
the chloromethylated precursors 3, 25 and 26 were readily
converted using triethylamine to the corresponding azetidines
29-31 in essentially quantitative yields (Table 3).
Table 3 Synthesis of azetidines from homoallylic amines
It is clear that this new three component coupling approach
rapidly builds molecular complexity and attractively leads to a
wide range of useful homoallylic amines, some of which
precursors for azetidine preparation. One can anticipate further
elaboration and in particular employing other reactive more
substituted diazo species.
We are grateful to Syngenta Crop Protection (CB) and the
EPSRC (SVL, grant
# EP/K009494/1, EP/M004120/1 and
EP/K039520/1) for financial support.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 3
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
COMMUNICATION
Conclusions
View Article Online
DOI: 10.1039/C8OB01831F
In conclusion, the method efficiently generates a wide range of
potentially useful homoallylic amines through a 3-component
coupling approach, involving the reaction with vinyl substituted
boroxines, which were homologated in situ with trimethylsilyl
diazomethane prior to being intercepted with various imines to
afford a range of useful building blocks including azetidines.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1
a) U. Schmidt and J. Schmidt, Synthesis, 1994, 300. b) R. M.
Borzilleri, X. Zheng, R. J. Schmidt, J. A. Johnson, S. H. Kim, J.
D. DiMarco, C. R. Fairchild, J. Z. Gougoutas, F. Y. F. Lee, B. H.
Long and G. D. Vite, J. Am. Chem. Soc., 2000, 122, 8890–
8897. c) A. M. Doherty, I. Sircar and B. E. Kornberg, J. Med.
Chem., 1992, 35, 2–14. d) D. L. Silverio, S. Torker, T.
Pilyugina, E. M. Vieira, M. L. Snapper, F. Haeffner and A. H.
Hoveyda, Nature, 2013, 494, 216–221.
2
3
4
5
6
7
8
9
R. Alam, A. Das, G. Huang, L. Eriksson, F. Himo and K. J. Szab.,
Chem. Sci., 2014, 5, 2732–2737.
S. Lou, P. N. Moquist and S. E. Schaus, J. Am. Chem. Soc.,
2007, 129, 15398–15404.
Y. Jiang and S. E. Schaus, Angew. Chem. Int. Ed., 2017, 129
,
1566–1570.
J. L. Y. Chen and V. K. Aggarwal, Angew. Chem. Int. Ed., 2014,
53, 10992–10996.
M. Raducan, R. Alam and K. J. Szabo., Angew. Chem. Int. Ed.,
2012, 51, 13050–13053.
J. S. Poh, S. H. Lau, I. G. Dykes, D. N. Tran, C. Battilocchio and
S. V. Ley, Chem. Sci., 2016, 7, 6803–6807.
C. Bomio, M. A. Kabeshov, A. R. Lit, S. H. Lau, J. Ehlert, C.
Battilocchio and S. V. Ley, Chem. Sci., 2017, , 6031-6075.
8
W. Adam, C. R. Saha-Möller and K. S. Schmid, J. Am. Chem.
Soc., 2011, 22, 7365-7371.
10 R. B. Miller and G. McGarvey, J. Org. Chem., 1978, 23, 4424-
4431.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins