The Synthesis of Chiral Allyl Carbamates via Merger of Photoredox and Nickel Catalysis

Article abstract of DOI:10.1002/adsc.202000404

A mild, and versatile, organophotoredox/Ni-mediated protocol was developed for the direct preparation of diverse, enantioenriched allyl carbamates. The reported approach represents a significant departure from classical step-by-step synthesis of allyl carbamates. This dual photoredox/Ni based strategy offers unrivalled capacity for convergent unification of readily available alkyl halides and chiral carbamates derived from 1-bromo-alken-3-ols with high chemoselectivity and efficiency. The reported photoredox/Ni catalyzed cross-coupling reaction is not limited to carbamates, but also to other O-derivatives such as esters, ethers, acetals, carbonates or silyl ethers. To demonstrate the utility of the reported protocol, the resulting allyl carbamates were transformed into functionalized non-racemic allylamines through a sigmatropic rearrangement reaction in enantiospecific manner. This approach allowed for synthesis of enantiomeric allylamines by a simple control of the geometry of a double bond of allyl carbamates. (Figure presented.).

Full text of DOI:10.1002/adsc.202000404

Title: The synthesis of chiral allyl carbamates via a merger of
photoredox and nickel catalysis
Authors: Mateusz Garbacz and Sebastian Stecko
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10.1002/adsc.202000404
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
The Synthesis of Chiral Allyl Carbamates via Merger of
Photoredox and Nickel Catalysis
Mateusz Garbacz, and Sebastian Stecko*
a
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland, phone: +4822
343 3065; e-mail: sebastian.stecko@icho.edu.pl
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201
Abstract. A mild, and versatile, organophotoredox/Ni- To demonstrate the utility of the reported protocol, the
mediated protocol was developed for the direct preparation of resulting allyl carbamates were transformed into
diverse, enantioenriched allyl carbamates. The reported functionalized
non-racemic
allylamines
through
approach represents a significant departure from classical a sigmatropic rearrangement reaction in enantiospecific
step-by-step synthesis of allyl carbamates. This dual manner. This approach allowed for synthesis of enantiomeric
photoredox/Ni based strategy offers unrivalled capacity for allylamines by a simple control of the geometry of a double
convergent unification of readily available alkyl halides and bond of allyl carbamates.
chiral carbamates derived from 1-bromo-alken-3-ols with
high chemoselectivity and efficiency. The reported
photoredox/Ni catalyzed cross-coupling reaction is not
limited to carbamates, but also to other O-derivatives such as
esters, ethers, acetals, carbonates or silyl ethers.
Keywords: allyl carbamates; cross-couplings; photoredox;
nickel catalysis; sigmatropic rearrangements; allylamines
Introduction
Allyl carbamates 1 are an important class of
compounds, valuable as synthetic intermediates as
well as biologically active molecules.[1],[2],[3]
Particularly, they have been found as valuable starting
materials in the preparation of non-racemic allylamine
derivatives through [3,3]-sigmatropic rearrangement
reactions, i.e. the Ichikawa rearrangement (Scheme
1).[4],[5],[6] They are also suitable staring materials in
synthesis of amino alcohols (and other β-
functionalized amines) via aminohydroxylation,[7]
aminoetherification[8] or aziridination[9] followed by a
subsequent ring-opening with the corresponding
nucleophiles (Scheme 1).[1a, 9-10] The classical methods
for their preparation are based on the carbamoylation
of allyl alcohols 2 with suitable isocyanates (e.g.
Scheme 1. Examples of allyl carbamates
transformations.
trichloracetyl
isocyanate,[11]
chlorosulfonyl
isocyanate,[11a,
trimethylsilyl isocyanate[13]) or
12]
through a transcarbamoylation reaction of the
hydroxyl group with phenyl carbamate (Scheme
2a).[14] Of course, structural variation of allyl
carbamates is determined and limited by the
availability of various alcohols.
Scheme 2. Strategies for the preparation of allyl
carbamates
Although numerous strategies for the preparation of
allyl alcohols 2, including non-racemic ones, are
known,[15] the access to their certain types is still
limited, for instance multi-functionalized ones or
chiral allyl alcohols bearing tri- or tetra-substituted
1
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10.1002/adsc.202000404
Advanced Synthesis & Catalysis
Results and Discussion
double bond. In results, multi-step methods of their
preparation
are
require
(with
additional
protection/deprotection steps).[15] Another issue is the
synthesis of 1, and thus alcohols 2,[15] in high stereo-
purity, in a term of high enantio-enrichment, as well
as, a complete control of geometry of a double bond.
And although various strategies, including chiral pool,
asymmetric synthesis, kinetic resolution or
deracemization, are known, they often have
limitations, and are substrate structure dependent,
what results in lack of a generality.
Since, non-racemic allyl carbamates 1 are of our
intrest, we became interested in developing an
alternative synthetic strategy for their preparation. Our
goal was to develop protocol that will allow us to avoid
classic parallel step-by-step of synthesis of 1. The
concept adopted by us assumed the development of a
method that would allow the synthesis of a wide range
of carbamates 1 starting from simple, non-racemic
precursors. The idea was to provide diversification of
their structure at the late stage of synthesis to avoid
repeating the reaction sequences (as presented in
Scheme 2a) leading to subsequent alcohols 2 and then
carmabates 1. In addition, the method should exhibit
high functional group tolerance, enable full control of
double bond geometry, and did not provide any
erosion of enantiopurity of starting materials.
In order to investigate the feasibility of this proposal,
in the initial attempt, we probed a coupling reaction of
model vinyl bromide 4 with various radical precursors
(Scheme 3). Compound rac-4 was obtained from 3-
butyn-2-ol
via
bromination/reduction
and
carbamoylation reaction sequence (see ESI).
Decarboxylative approaches proceeded poorly and
were limited mainly to α-amino and α-hydroxy acids
as well as 2°/3° alkyl carboxylic acids which provide
more stabilized radicals (vide infra). Importantly,
unlike Pd-catalyzed couplings, Ni-catalyzed processes
showed excellent tolerance towards vinyl precursors
bearing a primary carbamate (rac-4 and rac-5). This
resulted in the possibility of late functionalization of
the core vinyl bromide, and introduction of the desired
substituents. An analogous strategy based on Baran’s
redox-active ester chemistry[30] was not a good choice
since organozinc reagents were not compatible with
the carbamate reagent, and complex mixtures of
products were observed. The same problem was
noticed in the case of light-induced Ni-catalyzed
Negishi cross-coupling under conditions reported by
Alcazar and co-workers.[31] Interestingly,
an
application of nickel-catalyzed reductive cross-
coupling[29d,e] of vinyl and alkyl bromides resulted in a
formation of significant amount of 1,3-diene side-
product arising from a homo-coupling reaction.
Inspired by MacMillan’s[29a] and König’s[32] works on
the alkylation of aryl bromides, we turned our attention
to an analogous transformation with vinyl bromides.
To our delight, under the reported conditions, vinyl
bromide 4, bearing a carbamate functionality, coupled
with ethyl 4-bromobutyrate in 72% yield (Scheme 3).
These features are particularly crucial in the case
when carbamates 1 are to be used in a sigmatropic
rearrangement, since enantiomeric enrichment of the
resulting products directly depends on both enantio-
and E/Z-purity of the starting alcohol.
We sought to investigate the preparation of
carbamates 1 via a cross-coupling strategy using
readily available precursors such as vinyl halides 3a,b
(Scheme 2b). In recent years, the development of
transition‐metal
mediated
cross‐coupling
transformations for carbon–carbon bond formation has
changed the way in which organic synthesis is carried
out.[16],[17],[18] This includes also the coupling reactions
of redox-active esters.[19] Unfortunately, most of them
use palladium complexes as catalysts, which are not
suitable for allyl carbamates since they can promote
unwanted cyclization reactions.[20] More recently, the
advent of dual‐catalysis approaches based on the
combination of organometallic catalysts and
photosensitizers has opened new avenues in
C(sp3)−C(sp2) bond formation.[21],[22],[23] Different α‐
heteroatom‐containing
carboxylic
acids,[24]
alkyl
Scheme 3. Initial studies on the synthesis of allyl
carbamates.
alkylborane
reagents,[25]
ammonium
silicates,[26] O‐benzyl
xanthates,[27] 1,4-
dihydropyridines,[28] and alkyl halides (including
reductive protocols)[29] have been used to promote the
formation of alkyl radicals. Herein, we envisioned a
photoredox/Ni-catalyzed cross-coupling of alkyl
halides with vinyl bromides 3a,b as coupling partners,
to construct non-racemic allyl carbamates 1 directly
(Scheme 2).
Encouraged by these preliminary results, we
initiated optimization studies of the coupling reaction.
Factors investigated included type of photocatalyst,
solvent, base, Ni source, and ligand choice (Scheme 4).
Typically used photocatalysts are based on expensive
metals, such as iridium (Scheme 4, ent. 3) or
ruthenium (ent. 4), rendering these procedures less
2
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10.1002/adsc.202000404
Advanced Synthesis & Catalysis
sustainable and less suitable in terms of scalability.
Therefore, we were interested if it was possible to
ethyl, propyl or phenethyl ones. When MeBr was
applied (generated in situ by mixing MeOTf and LiBr),
the desired product 6b was obtained, although with
lower yield. It should be stressed that the present
approach had additional advantages over the standard
synthetic protocols (see Scheme 2) based on
carbamoylation of the corresponding alcohol, since it
eliminated disadvantages related to the synthesis and
handling of volatile low molecular weight alcohols.
Secondary alkyl bromides are also coupled easily,
as exemplified by the formation of products 6u-6ad.
Despite their steric hindrance, also tertiary halides
were good partners for the coupling reaction. However,
in this case, higher loading of the Ni catalyst
(10 mol%) was required to ensure complete
conversion of the starting vinyl bromide, and yields of
the corresponding products are slightly lower, e.g.
59% for 6ae and 45% 6af. Further experiments
showed that in this case an efficiency of the coupling
with tertiary bromides can be enhances by
modification catalytic system. The replacement of
bipyridine by dicarbonyl ligand (TMHD), according to
Molender’s report,[34] resulted in increase the yield 6af
up to 69%.
replace
such
complexes
by
inexpensive
organophotocatalysts. Gratifyingly, when 4CzIPN[26b,
33]
was applied, the desired product rac-6a was
obtained in 81% yield by using 2 mol% loading only.
In the case of lower amount of the photocatalyst
(1 mol%, ent. 7), the model product rac-6a was
obtained in 63% yield after standard reaction time (12
h). When the reaction time was extended to 48 h, the
yield increased to 75% (100% conversion of rac-4). In
comparison,
other
typically
used
organic
photocatalysts, such as eosin Y or rose Bengal were
not effective (entries 5 and 6). The model coupling
reaction in the presence of a Ru-based photocatalyst
failed as well (Scheme 4, ent. 4)
Encouraged by the above studies, we extended
the strategy for the synthesis of highly valuable,
structurally diverse, and unique allyl carbamates. To
our delight, the investigated reaction proceeds
chemoselectively and various functional groups such
as ester (6a, 6l), nitrile (6f), chloride (6g), boronate
(6h), phosphonate (6j) or sulfone (6k) were tolerated.
The coupling reaction proceeded well also in the case
of halides bearing protected hydroxyl and amine
groups. Even sensitive groups, such as epoxide (6s),
acetal (6o), and electron-rich aryls (e.g. 6t), were
tolerated.
Additionally, an alkene moiety was also
acceptable functionality (6p-r), although the coupling
reaction with 6-bromohex-1-ene provided a 1:1
mixture of desired product 6r along with product 6w
arising from 6-endo-trig radical cyclisation of the
radical partner. No reaction proceeded for 4-
bromobut-1-yne, and a starting material was recovered
only. Fortunately, its TMS derivative coupled with 4
to provide product 6m in 53% yield.
In contrast to previous examples, the reaction of
4 with benzyl bromide, allyl bromide, propargyl
bromide, and ethyl bromoacetate failed. In these cases,
the formation of a homo-coupling product of the alkyl
bromide, e.g. 1,2-diphenylethane in the case of benzyl
bromide, was observed predominantly. This indicated
that for these activated halides an oxidative addition
reaction is more rapid than for the starting vinyl
bromide, thus, the formation of a homo-coupling
product is dominant. This limitation could be
overcome by a replacement of alkyl bromide by the
corresponding carboxylic acid, which would provide
Scheme 4. Optimization of photoredox/Ni-catalyzed
cross-coupling reaction of vinyl bromide 4.
The change of Ni source had a slight influence on
the efficiency of the coupling and comparable results
were obtained when NiCl2 was replaced by NiBr2.
(Scheme 4, ent. 1 and 3). On the other hand, the type
of applied ligand was crucial for the activity of the Ni
complex. The change of dtbbpy to dmbpy or bpy
resulted in a decrease of the coupling efficiency
(Scheme 4, ent. 1, 12, 13). DME was the optimal
solvent. Its replacement by DMF or THF decreased the
yield of model product rac-6a significantly. Na2CO3
was the most suitable base for the process (compare
ent. 1 vs. 10 and 11). Finally, two-fold excess of alkyl
bromide and a slight excess of TTMS (1.1 eq.) were
optimal.
With optimized conditions in hand, we first
evaluated the coupling reactions of enantioenriched
vinyl bromide 4 with simple primary, secondary, and
tertiary alkyl bromides (Scheme 5). The reaction
proceeded smoothly for simple alkyl bromides such as
3
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10.1002/adsc.202000404
Advanced Synthesis & Catalysis
the same radical species under decarboxylative
conditions (Scheme 6a). Now, under conditions
showed in Scheme 6a, the desired product 6an was
obtained in 80% yield. Also other carboxylic acids
were suitable precursors of radical partners. Thus, the
decarboxylative approach was successfully applied
also in the case of cross-coupling of vinyl bromide 4
with an N-Boc proline, and phenoxyacetic acid
(Scheme 6b).
presumably due to competitive addition of radical
species to styrene-type vinyl bromide. Such radical
addition to activated olefins, such as styrenes is known,
and results in a formation of a stabilized benzyl-type
radicals.[35] 1H NMR spectra of the crude reaction
mixture showed the presence of multiple side-products
when the mentioned vinyl bromide was applied,
however, we were not to abele to isolate and assign any
reasonable structure. Re-optimization of reaction
conditions in this case (by reduction of the amount of
TTMS to 1 eq. and alkyl bromide to 1.3 eq) afforded
6am in 37% yield along with recovery of starting
material (35%) after the standard 12 h.
Scheme 6. Decarboxylative photoredox/Ni-catalyzed cross-
coupling reactions.
Scheme 5. Scope of photoredox/Ni-catalyzed cross-
coupling of vinyl bromide 4.
Next, the set of vinyl bromides was extended.
Gratifyingly, the coupling reaction tolerated also
sterically more demanding starting materials bearing
n-butyl (6ai/6ag), cyclohexyl (6ah), and phenyl (6ai)
as the R1 group. Additional functional groups can be
also incorporated into vinyl bromide cross-coupling
partner structure, as indicated during the synthesis of
carbamates 6an-6ap. The cross-coupling reaction
proceeded efficiently also for (Z)-vinyl bromides to
provide the corresponding (Z)-carbamates 6ag and 6ai.
Also trisubstituted (E)- and (Z)-vinyl bromides
coupled smoothly to provide the isomeric carbamates
6ak and 6al. The access to these isomeric allyl
carbamates is of particularly high interest since their
sigmatropic rearrangements provides enantiomeric
products (vide infra). The synthesis of compound 6am,
bearing a phenyl ring conjugated with a double bond,
was more complicated, and provided it in lower yield,
Scheme 7. Cross-coupling with other vinyl bromide
substrates.
4
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10.1002/adsc.202000404
Advanced Synthesis & Catalysis
bromine from alkyl bromide (25) to provide
nucleophilic radical species 26 along with (TMS)3SiBr.
Independently, Ni0 complex can undergo oxidative
addition with vinyl bromide 4 to furnish intermediate
27. Next, facile oxidative capture of radical 26 should
provide alkyl-NiIII complex 28. Reductive elimination
from 28 would provide the C(sp3)-C(sp2) coupling
product, e.g. 6a, and NiI species 29. Finally, single-
electron transfer from the available 30 species to NiI
푟푒푑
complex 29 (퐸
= –1.24 V) can reduce the latter one
1/2
to Ni0 and regenerate the ground state of photocatalysts.
Scheme 8. Proposed mechanism for photocatalytic
alkenylation of vinyl bromides.
The successful results encouraged us to extend the
scope of the investigated process. Thus, a series of
vinyl bromides 4, 5 and 7-13 were prepared and all of
them were subjected to a model coupling reaction with
ethyl 4-bromobutyrate. As depicted in Scheme 7, the
cross-coupling reaction proceeded smoothly also in
the case of O-silylated (5), O-benzylated (8), and O-
acylated (15, 19), as well as acetal- (17), and
carbonate-type (20) vinyl bromides. Amino acid-
derived allylic ester 19 can serve as substrate for
synthesis of highly functionalized unnatural amino
acids via Claisen rearrangement.[36] Besides primary
carbamates (4), also tertiary ones, such as 18, can be
efficiently coupled with ethyl 4-bromobutyrate. It is
worth to underline that all of these products are
valuable building blocks. For instance, type 18
carbamates can serve as substrates for lithiation-
borylation reactions which have found numerous
applications in organic synthesis.[37] Allyl carbonates
such as 20 are valuable staring materials for various
types of Tsuji-Trost reactions.[38] In contrast to O-
protected vinyl bromides, the coupling of 13,
containing a free hydroxyl group, proceeded less
efficiently, and the desired product 21 was obtained in
49% yield only.
Scheme 9. [3,3]-Sigmatropic rearrangement of allyl
carbamates 6.
To demonstrate the utility of this mild
organophotoredox/Ni-mediated
method,
we
transformed compounds 6 into the corresponding
allylamines 33 through a sigmatropic rearrangement
reaction.[4-5, 14],[18],[40] Such 2° and 3° non-racemic N-
functionalized allylamines are important structural
motifs and versatile intermediates for the synthesis of
a variety of products, including α-, β-, and γ-amino
acids, amino alcohols, and other derivatives.[5b, 40-42]
Thus, the treatment of 6 with TFAA/Et3N provided
the corresponding allyl cyanates 31, which
spontaneously rearranged to allyl isocyanates 32. The
latter were directly trapped with a nucleophilic reagent,
such as BnOLi, to provide N-Cbz protected
allylamines 16 in high to excellent overall yields after
3 steps. These 3 steps are realized in a one-pot manner,
what increases the efficiency of the entire process. As
shown in Scheme 9, the rearrangement was
Based related reports, the mechanism of for the
cross coupling of alkyl bromides and vinyl bromides
was proposed (Scheme 8).[29a][32][39] Upon LED
irradiation, 4CzIPN absorbs photons to excitations to
표푥
1/2
the strongly oxidizing agent [4CzIPN]* (22)(퐸
=
+1.43 V[39]). This complex can oxidize bromide anion
to provide bromine radical (23)[29a] that should abstract
a hydrogen atom from (TMS)3SiH (퐸1표/푥2= +1.86 V[32]).
Subsequently, the resulting silyl radical (24) abstracts
5
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10.1002/adsc.202000404
Advanced Synthesis & Catalysis
chemoselective and displayed high functional group
tolerance.
access to enantiomeric allylamines just by a change in
the geometry of the double bond (Scheme 10). It is
worth to stress that all of these starting carbamates can
be easily prepared from the same substrate,
enantomerically enriched (e.e. >99%) propargyl
alcohol 34.
Scheme 12. Further transformations of selected cross-
coupling products.
To further demonstrate the utility of the
investigated method, we performed, under mild
conditions, a series of late modifications of selected
allylamines, carbamates and others to precursors of
medicinal agents or important structural scaffolds. As
shown in Scheme 11, acid-mediated epoxide
opening/cyclization of 33u allowed the synthesis of
pyrrolidines 35 in 65% yield. Such a structural motif
is present in numerous naturally occurring
alkaloids.[42] The ozonolysis/oxidation of 33t provided
compound 36 which is a precursor of NMDA receptor
inhibitor 37. Intramolecular N-alkylation of 33w
provided piperidine 38 in 84% yield, which can be
transformed directly to known toxin (S)-coniine 39. It
is worth to mention that under basic conditions, the
same substrate may provide piperidine derivatives
which can be transformed into 4-hydroxy pipecolic
acid.[43] Finally, in the presence of Grubbs 1st gen.
catalyst, diene 33ag was cyclized to provide
carbacyclic allyl amine 40 (Scheme 10). As mentioned
before not only type 4 carbamates but also other allyl
alcohol derivatives (e.g. 18-20) synthesized according
to our protocol, can serve as valuable starting materials
in an organic synthesis. It can be exemplified by
chelate enolate Claisen rearrangement[36] of allyl ester
19. Upon treatment with LDA in the presence of ZnCl2,
this compound rearranged to the corresponding amino
acid derivative. This class of compounds have found
applications in the synthesis of the matrix
metalloprotease MMP-2 and MMP-9 inhibitors.[44] It
was not isolated but directly treated with TMSCHN2
to provide amino ester 41 in 70% (Scheme 12). As
described at the introduction, allyl carbamates are also
suitable substrates for a preparations of amino alcohols.
Scheme 10. Stereodivergent synthesis of enantiomeric
allylamines.
Scheme 11. Further transformations of selected allylamines.
Moreover, the use of (E)- or (Z)-allyl carbamates,
such as 6af and 6ag, or 6ak and 6al, bearing the same
absolute configuration at the C-center, allowed for
control of the stereochemical outcome of the
rearrangement reaction. Thus, due to its
enantiospecificity and transfer of chiral information
from substrate to product, this method enables the
For
example,
in
the
presence
of
6
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10.1002/adsc.202000404
Advanced Synthesis & Catalysis
[10g]
Villalgordo, F. Carreaux, Eur. J. Org. Chem. 2017,
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Rh2(OAc)4/PhI(OAc)2
carbamate 6d underwent
tandem intramolecular aziridination followed by a
ring-opening process to provide amino diol derivative
42, predominantly, in 68% yield (Scheme 12).
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Conclusion
[9]
In summary,
a mild, versatile, and direct
organophotoredox/Ni mediated protocol was
developed for the preparation of diverse,
enantioenriched allyl carbamates starting from
commercially available non-racemic propargyl-type
alcohols. The reported radical approach represents a
significant departure from classical stepwise synthesis
of allyl carbamates often described in the literature.
This dual photoredox/Ni based strategy offers
unrivalled capacity for convergent unification of
readily available alkyl halides and chiral carbamates
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derived
from
1-bromo-1-alken-3-ols,
and
simultaneously high chemoselectivity and efficiency.
Moreover, as it was indicated, the reported
photoredox/Ni catalyzed cross-coupling reaction is not
limited to carbamates, but also viable for 1-bromo-1-
alken-3-ols and their O-derivatives such as esters,
ethers, acetals, carbonates or silyl ethers.
Customizable by design, the simplicity and efficiency
of this protocol should resonate with the organic and
medicinal chemist requiring rapid access to these
highly valuable and sought-after building blocks.
[11]
[12]
Experimental Section
Electronic supplementary information (ESI) available:
synthetic procedures, spectral characterization data.
[13]
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Acknowledgements
The authors are grateful to National Science Center of Poland for
financial support of the project (research grant OPUS
2016/23/B/ST5/03322).
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UPDATE
The synthesis of chiral allyl carbamates via a
merger of photoredox and nickel catalysis
Adv. Synth. Catal. Year, Volume, Page – Page
Mateusz Garbacz, Sebastian Stecko*
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