One-Pot Three-Component Synthesis of Vicinal Diamines via In Situ Aminal Formation and Carboamination

Article abstract of DOI:10.1002/anie.201607318

A synthesis of vicinal diamines via in situ aminal formation and carboamination of allyl amines is reported. Employing highly electron-poor trifluoromethyl aldimines in their stable hemiaminal form was key to enable both a fast and complete aminal formation as well as the palladium-catalyzed carboamination step. The conditions developed allow the introduction of a wide variety of alkynyl, vinyl, aryl, and hetereoaryl groups with complete regioselectivity and high diastereoselectivity. The reaction exhibits a high functional-group tolerance. Importantly, either nitrogen atom of the imidazolidine products can be selectively deprotected, while removal of the aminal tether can be achieved in a single step under mild conditions to reveal the free diamine. We expect that this work will promote the further use of mixed aminal tethers in organic synthesis.

Full text of DOI:10.1002/anie.201607318

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201607318
German Edition: DOI: 10.1002/ange.201607318
Multicomponent Reactions
One-Pot Three-Component Synthesis of Vicinal Diamines via In Situ
Aminal Formation and Carboamination
Ugo Orcel and Jerome Waser*
Abstract: A synthesis of vicinal diamines via in situ aminal
formation and carboamination of allyl amines is reported.
Employing highly electron-poor trifluoromethyl aldimines in
their stable hemiaminal form was key to enable both a fast and
complete aminal formation as well as the palladium-catalyzed
carboamination step. The conditions developed allow the
introduction of a wide variety of alkynyl, vinyl, aryl, and
hetereoaryl groups with complete regioselectivity and high
diastereoselectivity. The reaction exhibits a high functional-
group tolerance. Importantly, either nitrogen atom of the
imidazolidine products can be selectively deprotected, while
removal of the aminal tether can be achieved in a single step
under mild conditions to reveal the free diamine. We expect
that this work will promote the further use of mixed aminal
tethers in organic synthesis.
V
icinal diamines are of utmost importance in natural
products, agrochemicals, drugs, and as chiral ligands.[1]
Hence, tremendous efforts have been invested to develop
new methods to access them efficiently.[2] Olefins have been
widely used as simple and readily available substrates for the
preparation of diamines.[3] The intermolecular diamination of
À
alkenes through the formation of two new C N bonds for
example is one of the most-direct synthetic approaches.[2h,4]
However, this strategy is often limited in scope and leads
usually to identically substituted nitrogen atoms, thus ham-
pering their differentiation and further elaboration. Tethering
both nitrogen atoms to the olefin has been a successful
approach to meet this challenge. The diamine motif is then
accessed either via intramolecular diamination,[5] or through
Scheme 1. Syntheses of diamines using a tether approach.
reaction requires strong tert-butoxide bases at elevated
temperatures, and final cleavage of the sulfamide tether
occurs in the presence of HBr at 1308C for a prolonged period
of time. Such harsh conditions are highly detrimental for the
tolerance to functional groups and the scope of the reaction.
Therefore, we decided to focus on the use of aminals as
Csp3 tethers,[7] which have received much less attention than
the classical urea and sulfamide tethers. They offer the
precious advantage of being potentially more easily installed
and removed, and could still engage efficiently in olefin
functionalization processes. Furthermore, the obtained imid-
azolidine products provide a direct access to other highly
important nitrogen-containing heterocycles such as imidazo-
lines, imidazoles, and N-heterocyclic carbenes.[8] Among the
groups who reported employing aminals as tethers, only two
described the functionalization of nonactivated olefins
(Scheme 1, B and C).[9] The seminal contribution of Hiemstra
and co-workers describes the use of aminal tethers for Aza-
Wacker cyclizations starting from allyl amines. However,
tether installation and removal proved to be tedious, requir-
ing five separate steps (Scheme 1, B).[9a] More recently,
Beauchemin and co-workers reported a Cope-type hydro-
amination of simple allyl amines in one step (Scheme 1,
À
formation of one C N bond when starting from allyl amine
derivatives and forming a five-membered ring.[6] The latter
might be accompanied by the simultaneous formation of
another bond to the olefin. In particular, urea and sulfamide
derivatives have been widely used in both approaches due to
their robustness.[5,6] The use of palladium catalysis is partic-
ularly attractive, since it enables both the mono- and
difunctionalization of olefins.[5a,c,6e–k] For example, Wolfe and
co-workers described the use of classical sulfamide tethers for
carboamination reactions (Scheme 1, A).[6h,i] However, the
[*] U. Orcel, Prof. Dr. J. Waser
Institut des sciences et ingꢀnierie chimiques
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL SB ISIC LCSO, BCH 4306
1015 Lausanne (Switzerland)
E-mail: jerome.waser@epfl.ch
Homepage: http://lcso.epfl.ch/
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201607318.
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Table 1: Optimization of the tethered aminoalkynylation.[a]
C).[9b–f] While elegant, both works remain limited to a single
À
C N bond formation.
Recently, our group has demonstrated that vicinal amino
alcohols could be synthesized from allyl amines using an
acetal tether and a palladium catalyst to form simultaneously
[10a]
À
À
new C O and C C bonds.
We envisioned that an allyl
Entry
Changes from standard conditions[b]
Yield [%][c]
amine and an imine could in situ form an aminal, which would
undergo a Pd-catalyzed carboamination reaction to generate
1
2
3
4
5
6
7
8
none
2b instead of 2a
2c instead of 2a
2d instead of 2a
2e instead of 2a
2 f instead of 2a
2g instead of 2a
2h instead of 2a
99 (95)[d]
<3
15
36
5
À
À
an imidazolidine by formation of both a C N and a C C bond
followed by hydrolysis to give the free diamine (Scheme 1,
D).[11] All the reported mixed aminals employed for olefin
functionalization bear electron-withdrawing groups on both
nitrogen atoms, which greatly stabilize them. However, the
poor nucleophilicity of the amine precursor prevents their fast
synthesis.[7] We thought to use nucleophilic allyl amines to
solve this issue. Three challenging conditions had to be met to
ensure the success of the envisioned transformation:
1) formation of the aminal must be complete, fast, and
selective to avoid side reactions or catalyst deactivation;
2) the mixed aminal formed needs to be both stable and
suitable for the envisioned Pd-catalyzed carboamination;
3) the imidazolidine obtained must be stable under the
reaction conditions to avoid catalyst poisoning, but still be
amenable to a straightforward deprotection to free the
diamine.
35
45
5
9
2i instead of 2a
7
10
11
12
13
14
15
16
17
18
19
PPh3 (12 mol%) instead of P(2-furyl)3
PhDavePhos (11 mol%) instead of P(2-furyl)3
DavePhos (11 mol%) instead of P(2-furyl)3
BINAP (6 mol%) instead of P(2-furyl)3
DPEPhos (6 mol%) instead of P(2-furyl)3
XANTPhos (6 mol%) instead of P(2-furyl)3
CsHCO3 instead of Cs2CO3
K2CO3 instead of Cs2CO3
Benzyl allylcarbamate instead of 1
without [Pd2dba3] or P(2-furyl)3 or base
39
81
11
3
90
58
44
89
8
<3
[a] Reactions conditions: 0.10 mmol 1, 0.11 mmol 2a, 0.13 mmol 3,
0.33m in PhMe, 20 h. [b] DavePhos: 2-dicyclohexylphosphino-2’-(N,N-
dimethylamino)biphenyl; PhDavePhos: 2-diphenylphosphino-2’-(N,N-
dimethylamino)biphenyl; BINAP: (1,1’-binaphthalene-2,2’-diyl)bis(di-
phenylphosphine); DPEPhos: bis[(2-diphenylphosphino)phenyl] ether;
XANTPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; PMP: p-
methoxyphenyl. [c] Yield determined through NMR spectroscopy using
3,4,5-trichloropyridine as internal standard. [d] Yield of isolated product
on 0.30 mmol scale.
The efficient implementation of this approach is reported
herein, employing electron-rich allyl amines, carbamate-
protected trifluoroaldimines in their stable hemiaminal
form, and a bromide, in the presence of a commercially
available palladium source and phosphine ligands. The
developed conditions allowed for a broad scope in both
allyl amines and alkynyl, aryl, or vinyl bromides, as well as for
high stereo-, regio-, and diastereoselectivity.
We started our studies with allylbenzylamine (1) and silyl
acetylene 3 as efficient electrophilic partner in Pd0/PdII-
catalyzed olefin functionalization (Table 1).[10,12] We identi-
fied aldimine precursor 2a as efficient tethering reagent in
combination with [Pd2dba3] as palladium source, P(2-furyl)3
as ligand, and cesium carbonate as base. Under these
conditions, imidazolidine 4 was isolated in excellent yield
and diastereoselectivity (95%, d.r. > 20:1) (Table 1, entry 1).
Importantly, 2a is easily available on multigram scale,[13]
bench stable for months, and only a slight excess is required
to achieve complete conversion into 4. As anticipated, the
tether was of great importance for the reaction outcome.
Electron-neutral aldimine 2b was ineffective (entry 2), and
even more-activated analogues still suffered from poor
reactivity (entries 3 and 4). Various N-protected trifluorome-
thylaldimines or their precursors did provide some improve-
ment, but furnished inferior results to 2a (entries 5–9).
Changing the ligand had also a profound effect. While using
simple triphenylphosphine decreased the yield (entry 10),
bulky PhDavePhos afforded 4 in high yield (entry 11).
Electron-rich DavePhos was not efficient (entry 12). Regard-
ing bidentate phosphines, BINAP was not competent, DPE-
Phos yielded 90% of 4, and closely related XANTPhos only
58% (entries 13–15). Switching to cesium hydrogen carbon-
ate as base reduced the yield significantly but still afforded
a reasonable amount of 4, while potassium carbonate
provided 89% of the desired imidazolidine (entries 16 and
17). The use of such mild bases is very rare for Pd0/PdII-
catalyzed carboamination reactions, which often require
stronger alkoxides. Deactivating the allyl amine with a carba-
mate protecting group led to very low conversion (entry 18).
Finally, without palladium or ligand or base, 4 was not
observed (entry 19).
The scope of the reaction was then examined (Scheme 2).
We performed an assessment of functional-group tolerance
and electronic effects by varying the substitution on the
nitrogen atoms (Scheme 2, A). Use of a methyl carbamate
protected tether provided product 5 in excellent yield.
Modifying the benzyl group with electron-donating or -with-
drawing groups had only minor influence (products 5–10).
Both the useful aryl bromide (product 8) and chloride
(product 9) were preserved under these conditions. When
the reaction was performed on gram-scale, compound 10 was
obtained in quantitative yield. A simple allyl group was also
tolerated, with no Heck side reaction observed (product 11).
Imidazolidines bearing a furan heterocycle or a ferrocene
2
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Scheme 2. Scope of the tandem aminal-formation carboamination reaction. d.r. >20:1 unless otherwise noted; d.r. in parenthesis represents the
diastereoisomeric ratio in the crude reaction mixture if different from the one of the isolated compound. [a] P(2-furyl)3 (12 mol%) as ligand.
[b] PhDavePhos (15–20 mol%) as ligand. [c] P(2-furyl)3 (24 mol%) as ligand and cesium triflate as additive (1.2 equiv). [d] DPEPhos (12 mol%) as
ligand.
group were obtained in 92 and 89% yield, respectively
(products 12 and 13). The use of primary allyl amines was also
possible (product 14). Finally, replacing an aliphatic amine by
an aniline still furnished the desired imidazolidine (15) in high
yield.
Geminal substitution of the olefin was possible when
using PhDavePhos as ligand (Scheme 2, B). a-Tertiary amines
16 and 17 were formed in good to high yields and with high
diastereoselectivity (d.r. > 20:1).
Next, we investigated a-substituted allyl amines
(Scheme 2, C).[14] This class of substrates required the use of
cesium triflate as additive to ensure high conversions.[15]
Substitution by a methyl group furnished the desired imida-
zolidine 18 in high yield, albeit in low diastereoselectivity. A
bis-allylic amine delivered product 19 in good yield and
diastereoselectivity. Bicyclic and tricyclic imidazolidines 20,
21, and 22 were formed in high diastereoselectivity. These
results highlight the fast access to complex structures with
control on up to four stereocenters in a single step.
Then, the scope of organohalides was examined. Alkynes
derived from secondary and tertiary propargylic alcohols
underwent the desired transformation in good to excellent
yields (Scheme 2, D, products 23–26). Notably, both aliphatic
and aromatic substituents were tolerated at the propargylic
position. We then turned our attention to aryl bromides
(Schemes 2, E). This class of electrophiles could be used as
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long as they were slightly activated with an electron-with-
drawing group. While DPEPhos was a competent ligand in
certain cases, the combination of P(2-furyl)3 with cesium
triflate as additive was more general and reliable. Ortho and
para substitution were well tolerated (products 27–32). 1,2-
Dibromoaryl derivatives underwent the reaction smoothly to
afford brominated products 29 and 30, which open up
possibilities for further derivatization. Substitution at the
meta positions cleanly delivered the desired products 33 and
34 bearing an a-secondary and an a-tertiary amine, respec-
tively. Due to the importance of aromatic heterocycles in the
agrochemical and pharmaceutical industries, several hetero-
aryl bromides were then submitted to the reaction conditions
(Scheme 2, F). Gratifyingly, both fluoropyridine and chloro-
pyrimidine were introduced in good to excellent yields
(products 35 and 36, respectively). Imidazolidines 37 and 38
bearing either a furan or a thiophene ring could be obtained in
81 and 82% yield, respectively. Finally, aminoalkenylation
was also possible (Scheme 2, G). Trifluoromethyl-substituted
olefin 39 could be isolated in 87% yield.
reoselectivities under mild reactions conditions, a high func-
tional-group tolerance, and a broad scope. The versatility of
our method was demonstrated by the introduction of alkynyl,
aryl, heteroaryl, and vinyl groups into the allyl amines. Both
free amines could be obtained orthogonally, while complete
tether cleavage to give diamines was performed under mild
conditions. Based on our results, we expect that the use of
aminal tethers will find much broader application in the
future.
Acknowledgements
We thank EPFL and the Swiss National Science Foundation
(grant number 200021_159920) for financial support.
Keywords: alkenes · aminals · homogeneous catalysis ·
Pd catalysis · vicinal diamines
To highlight the synthetic potential of the obtained
building blocks, we synthesized either of the free amines
selectively (Scheme 3). Starting from 10, oxidative cleavage of
the PMB protecting group led to free amine 14 in high yield,
while heating under microwave irradiation cleanly removed
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the Boc group to access 40 in nearly quantitative yield.
Removal of SiiPr3 with TBAF yielded terminal alkyne 41 in
98% yield. Finally, cleavage of the aminal was performed.
Using HCl in methanol delivered diamine salt 42 in 89%
yield. Treatment of imidazolidines 20 or 34 with trifluoro-
acetic acid (TFA) followed by addition of methanol allowed
full removal of the tether in excellent yields, without any
further purification. The mild acidic conditions used are
routinely applied in peptide chemistry.
In conclusion, we have developed the first palladium-
catalyzed carboamination of allyl amines employing an in situ
installed Csp3 aminal tether for the synthesis of 1,2-diamines.
The use of carbamate-protected trifluoroaldimines in their
stable hemiaminal form allowed excellent regio- and diaste-
4
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Received: July 28, 2016
Published online: && &&, &&&&
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Communications
Multicomponent Reactions
U. Orcel, J. Waser*
&&&& — &&&&
One-Pot Three-Component Synthesis of
Vicinal Diamines via In Situ Aminal
Formation and Carboamination
Ideal combination: Vicinal diamines with
a wide variety of alkynyl, vinyl, aryl, and
hetereoaryl groups are obtained with
complete regioselectivity and high dia-
stereoselectivity via in situ aminal for-
mation and Pd-catalyzed carboamination
of allyl amines. Key to the reaction is the
use of carbamate-protected trifluoro-
methyl aldimines in their stable hemi-
aminal form. Cleavage of the aminal
tether was achieved under mild condi-
tions.
6
www.angewandte.org
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!