Design and Scalable Synthesis of N-Alkylhydroxylamine Reagents for the Direct Iron-Catalyzed Installation of Medicinally Relevant Amines**

Article abstract of DOI:10.1002/anie.202008247

Secondary and tertiary alkylamines are privileged substance classes that are often found in pharmaceuticals and other biologically active small molecules. Herein, we report their direct synthesis from alkenes through an aminative difunctionalization reaction enabled by iron catalysis. A family of ten novel hydroxylamine-derived aminating reagents were designed for the installation of several medicinally relevant amine groups, such as methylamine, morpholine and piperazine, through the aminochlorination of alkenes. The method has excellent functional group tolerance and a broad scope of alkenes was converted to the corresponding products, including several drug-like molecules. Besides aminochlorination, the installation of other functionalities through aminoazidation, aminohydroxylation and even intramolecular carboamination reactions, was demonstrated, further highlighting the broad potential of these new reagents for the discovery of novel amination reactions.

Full text of DOI:10.1002/anie.202008247

A Journal of the Gesellschaft Deutscher Chemiker
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International Edition
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Accepted Article
Title: Design and scalable synthesis of novel N-alkyl-hydroxylamine
reagents for the direct, Fe-catalyzed installation of medicinally
relevant amines
Authors: Eric Falk, Szabolcs Makai, Tristan Delcaillau, Laura Gürtler,
and Bill Morandi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202008247
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10.1002/anie.202008247
Angewandte Chemie International Edition
RESEARCH ARTICLE
Design and Scalable Synthesis of N-Alkyl-Hydroxylamine
Reagents for the Direct, Iron-Catalyzed Installation of
Medicinally Relevant Amines
Eric Falk,[a] Szabolcs Makai,[a] Tristan Delcaillau,[a] Laura Gürtler,[a] and Bill Morandi*[a]
In memory of Kilian Muñiz
[a]
E. Falk, S. Makai, T. Delcaillau, L. Gürtler, Prof. Dr. B. Morandi
Laboratorium für Organische Chemie
ETH Zürich
Vladimir-Prelog-Weg 3, HCI, 8093 Zürich, Switzerland
E-mail: bill.morandi@org.chem.ethz.ch
Supporting information for this article is given via a link at the end of the document
Abstract: Secondary and tertiary alkylamines are privileged
substance classes which are often found in pharmaceuticals and
other biologically active small molecules. Herein, we report their direct
synthesis from alkenes through an aminative difunctionalization
alkylamines in medicinal chemistry,[7] the installation of further
functionalities via intermolecular aminofunctionalization reactions
remains a central goal in synthetic chemistry.
Methods which provide direct access to unprotected primary and
secondary alkylamines from simple alkenes are highly attractive
for the step-economical and protecting-group-free synthesis of
bioactive molecules.[8] Compared to the synthesis of unprotected
primary amines from unsaturated compounds, in which significant
advancement has been achieved over the recent
reaction enabled by iron catalysis.
A family of ten novel
hydroxylamine-derived aminating reagents were designed for the
installation of several medicinally relevant amine groups, such as
methylamine,
morpholine
and
piperazine,
through
the
aminochlorination of alkenes. The methodology displays an excellent
functional group tolerance, and a broad scope of alkenes was
converted to the corresponding products, including several drug-like
molecules. Besides aminochlorination, the installation of other
functionalities through aminoazidation, aminohydroxylation and even
intramolecular carboamination reactions, is demonstrated, further
highlighting the broad potential of these new reagents for the
discovery of novel amination reactions.
Introduction
Densely functionalized aliphatic amines are prevalent in natural
products, pharmaceuticals and other small molecules with
biological
functions
(Scheme
1a).[1]
Intermolecular
aminofunctionalizations of alkenes are powerful tools for the
synthesis of this privileged substance class from simple
hydrocarbon feedstocks.[2] However, the majority of the reported
aminofunctionalizations introduce the amine in a protected form
(e.g. tosyl, nosyl) because these methods often require an
electron-deficient nitrogen to enhance the electrophilicity of the
aminating species involved.[3] In contrast, and despite their
synthetic utility, electron-rich alkylamino sources are mostly
unreactive in those cases, often preventing the development of
efficient and useful intermolecular aminofunctionalization
reactions. In a notable exception, an umpolung approach which
features migratory insertion of alkenes into M−X bonds (M = Cu,
Ni, Zr; X = B, C, H), followed by a nucleophilic attack of this alkyl-
metal species on a hydroxylamine derivative, has led to
synthetically
attractive
examples
of
intermolecular
aminoboration,[4] hydroamination[5] and carboamination[6] of
unactivated olefins (Scheme 1b). Given the synthetic relevance of
Scheme 1. Context of this work. Piv = pivalate, trimethylacetyl. Tf = triflyl,
trifluoromethanesulfonyl.
1
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10.1002/anie.202008247
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RESEARCH ARTICLE
years,[9] the direct synthesis of unprotected secondary amines
to employ two robust and general 3-step sequences from
commercially available hydroxylamine derivatives for the
synthesis of N-alkyl aminating reagents (Scheme 2A).[19,20] The
synthetic methods are scalable, do not require specialized
equipment and would likely be applicable to the synthesis of a
much larger library of reagents. To prove the generality of this
approach, we prepared seven novel mono-alkylated reagents,
most of them on a gram scale. This includes the single-batch
preparation of 33 grams of the N−methyl reagent 1a. Additionally,
a series of tertiary alkyl amine reagents were also readily
synthesized through similar 3-step sequences starting from easily
accessible hydroxylamine derivatives (Scheme 2B).[19,20] The
morpholine reagent 2a was prepared on a 101 mmol (34 grams)
scale, further demonstrating the scalability of this synthetic route.
Due to the versatility of hydroxylamine-derived compounds in
organic synthesis, these new reagents have broad potential for
the development of new amination reactions, even beyond the
aminative difunctionalizations of alkenes reported in this work.[21]
from
simple
hydrocarbon
feedstocks
remains
underdeveloped.[5g,10-12] Broadly applicable, intermolecular
catalytic methods for the direct synthesis of unprotected
secondary amines from alkenes are limited to isolated examples
of hydroamination[5g,10] and aziridination.[11] It is important here to
note that secondary amines can also be challenging to access
using traditional synthetic routes, such as reductive amination and
alkylation, because an overreaction can be difficult to prevent.[13]
Considering that the majority of aliphatic amines present in
biologically active compounds are either secondary or tertiary, the
extension of the scope of intermolecular aminofunctionalizations
to unprotected secondary as well as tertiary amines is highly
desirable.[14]
The aminohalogenation of alkenes provides a complementary
approach to the synthesis of important amines. The resulting
products are versatile building blocks for the rapid synthesis of a
plethora of derivatives. Recently, we reported an iron-catalyzed
aminochlorination of alkenes delivering versatile unprotected
2-chloroamines which could be further derivatized to useful
functionalized primary amines (Scheme 1c).[15] Unfortunately, this
chemistry could not be readily extended to the synthesis of
secondary and tertiary amines because of the unavailability of the
corresponding reagents and the lack of suitable reaction
conditions (vide infra). Shortly after our report, a directed
intermolecular aminohalogenation of unactivated alkenes was
reported by Guan, Bi and Fu (Scheme 1d).[16] While this reaction
allows for the installation of highly functionalized tertiary
alkylamines employing mild reaction conditions, the requirement
for a suitably positioned directing group severely limits its
generality. Furthermore, unprotected secondary amines are not
accessible through this transformation. In light of these
limitations,[17] the development of a new family of bench-stable
hydroxylamine reagents bearing medicinally relevant alkyl groups
appears crucial to fill an important gap in this research area and
enable the development of a general, catalytic aminochlorination
of unbiased alkenes.
Herein, we report the scalable syntheses of ten novel, versatile
aminating reagents bearing medicinally relevant substitution
patterns. We present their application in an iron-catalyzed
intermolecular aminative difunctionalization of unactivated
alkenes to directly access unprotected secondary as well as
tertiary 2-chloro-N-alkylamines (Scheme 1e).[18] The broad
substrate scope includes unactivated mono- and disubstituted
alkenes bearing unprotected polar functional groups often found
in biologically active molecules. The versatility of these new
reagents is further demonstrated in three additional examples of
aminofunctionalizations, clearly showing their broad potential in
catalytic aminations.
Scheme 2. Synthesis of
Boc = tert-butyloxycarbonyl. Bz = benzyl. CBz = carboxybenzyl.
a
novel family of aminating reagents.
N-Alkylaminochlorination of alkenes
Based on our research interests in the synthesis of unprotected,
primary amino alcohols, 2-azidoamines and 2-chloroamines
under iron-catalysis,[15,22] and the general interest in radical
amination reactions,[23] we set out to investigate conditions for the
synthesis of unprotected secondary 2-chloro-N-alkylamines from
alkenes using this novel series of reagents. We identified two
potential challenges which could prevent the desired reactivity: (1)
The increased steric bulk of the required aminating reagents could
prevent a productive reactivity with the iron catalyst and (2) the
presence of electron-donating alkyl substituents significantly
increases the electron density at the nitrogen center which, in turn,
Results and Discussion
Design and scalable synthesis of novel aminating reagents
Our initial goal was to develop suitable aminating reagents which,
ideally, can be obtained from commercially available starting
materials in a minimal number of steps and are stable to ambient
conditions. We targeted the preparation of reagents bearing some
of the most common motifs found in bioactive compounds, such
as a N−Me, piperazine or morpholine. Gratifyingly, we were able
2
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10.1002/anie.202008247
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RESEARCH ARTICLE
simple extension of our previous procedure for the synthesis of
unprotected, primary 2-chloroamines[15] did not result in any
product formation (Table 1, entry 1), clearly highlighting the
challenges of developing this process. We thus started our
investigations by evaluating different iron catalysts, chloride salts
and solvents. Increasing the ratio of dichloromethane to methanol
allowed the N-methylaminochlorination of 1-dodecene (3) to
occur with low yield (Entry 2). Encouraged by numerous reports
discussing the unique properties of fluorinated alcohols,
especially their ability to increase the lifetime of radical cations,
we investigated their use as co-solvents in our reaction (Entries 3
& 4).[25] We were pleased to find that a combination of
dichloromethane and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP)
led to a significant improvement of the yield. Inspired by a report
of Newcomb, in which they demonstrated the beneficial effect of
Lewis acids (LA) on dialkylaminyl radical reactions, we also
evaluated different Lewis acids as additives in our reaction.[26]
Gratifyingly, the addition of Lewis acids did indeed reproducibly
increase the yield of our reaction (Entries 5 & 6). Sc(OTf)3 proved
to be optimal as the addition of 7.5 mol% Sc(OTf)3 significantly
increased the yield of the benchmark reaction. If a simpler
reaction setup is desired, the reaction can be performed under air
without the addition of a Lewis acid to afford 4 in moderate yield
(Entry 9).
Table 1. Selected optimization results[a]
Entry
Deviation from standard conditions
Yield[b]
1
2
3
4
5
6
7
8
9
CH2Cl2/MeOH 1:3, no LA
MeOH instead of HFIP, no LA
TFE instead of HFIP, no LA
No LA
0
26
4
50
62
60
0
None
AlCl3 instead of Sc(OTf)3
No Fe
Under air
28
51
No LA, under air
[a] Reaction conditions: 1-dodecene (0.20 mmol), 1a (0.50 mmol), Fe(acac)2 (5
mol%), Sc(OTf)3 (7.5 mol%), NaCl (0.21 mmol), CH2Cl2/HFIP 9:1 (0.20 mL) at
r.t., 16 h, inert atmosphere. [b] Yields in % obtained by 1H NMR using
We then investigated the alkene scope of the reaction (Scheme
3A). Sterically congested alkyl groups such as cyclohexyl (5),
isopropyl (7) or adamantyl (8) in close proximity to the alkene
were all tolerated. In products bearing an acidic C−H bond at the
β-position relative to the chloride, no elimination of HCl was
observed (9). Alkenyl halides, such as chlorides (13) and fluorides
(14) could undergo methylaminochlorination. Dienes (15) were
trichloroethylene
as
internal
standard.
acac
=
acetylacetonate.
TFE = 2,2,2-trifluoroethanol.
could decrease the electrophilicity of the aminating species.[24]
Due to its prevalence in biologically active molecules, we decided
to utilize the installation of N-methylamine as a benchmark
reaction for the optimization of the reaction conditions. Importantly,
Scheme 3. Substrate scope of the N-alkylaminochlorination reaction. Yields are of isolated products; diastereomeric ratio (dr) determined by NMR. Reaction
conditions: Alkene (0.50 mmol), 1 (1.25 mmol), Fe(acac)2 (5 mol%), Sc(OTf)3 (7.5 mol%), NaCl (0.525 mmol), CH2Cl2/HFIP 9:1 (0.50 mL) at r.t., 16 h, inert
atmosphere. [a] 40 hours reaction time. TBDPS = tert-butyldiphenylsilyl.
3
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RESEARCH ARTICLE
only mono-aminated, even though an excess of aminating
reagent was used, a result best explained by the precipitation of
the ammonium product after the initial amination. Free primary
alcohols (16) and acid labile groups such as silyl ethers (17) were
also suitable substrates. Synthetically relevant functional groups
like esters (18) further expanded the scope of this transformation.
Even a β-cholestanol derivative, which is poorly soluble in many
organic solvents, afforded the desired product (19). Borneol,
ibuprofen and menthol derivatives (20-22) were all converted to
their N-methylaminated analogs. Collectively, these substrates
show that the reaction could be used for late-stage
functionalization. Styrenes only afforded the product in low yields,
despite the fact that high conversion of the alkene starting
material could be observed. This behavior is probably caused by
undesired radical oligomer- and polymerization under the reaction
conditions. To demonstrate the robustness and applicability of the
new reaction on a preparative scale, we further showed that the
method can produce gram amounts of the 2-chloroamine 4 in a
similar yield under otherwise identical reaction conditions.
The applicability of the other new reagents 1b-1g was next
explored (Scheme 3B). All reagents were compatible with the
reaction, including the sterically demanding isopropylamine
reagent. A cyclopropyl in close proximity did not undergo ring-
opening and afforded the corresponding cyclopropylmethylamine
(25) in moderate yield. Remarkably, preliminary experiments
showed that allylamine can be installed (26) with no subsequent
amination of the double bond. This result, when combined with
the observation made above that monoamination selectively
Table 2. Selected optimization results[a]
Entry
Deviation from standard conditions
Yield[b]
1
2
3
4
5
6
7
8
CH2Cl2/HFIP 9:1, no LA
No LA
0
38
57
39
24
10
0
None
NaCl instead of LiCl
NaCl, 7.5 mol% Sc(OTf)3
No LiCl
No Fe
Under air
0
[a] Reaction conditions: 1-dodecene (0.20 mmol), 2a (0.50 mmol), Fe(acac)2 (5
mol%), AlCl3 (10 mol%), LiCl (0.21 mmol), CH2Cl2/nBuOH 1:1 (0.20 mL) at r.t.,
16 h, inert atmosphere. [b] Yields in % obtained by GC-FID using n-dodecane
as internal standard.
We then set out to investigate the generality of the reaction on a
range of alkenes (Scheme 4A). Aside from different carbon
scaffolds, a broad variety of functional groups was found to be
tolerated under the reaction conditions, such as ethers (32), free
alcohols (35-37), aliphatic (38, 39) as well as aryl halides (45, 47),
esters (40), amides (41, 42) and nitriles (44). Again, dienes were
selectively mono-aminated despite using an excess of aminating
reagent (31). Remarkably, an alkene with an alkyne in close
proximity reacted selectively, giving the 2-chloroamine 36 and
leaving the alkyne untouched. Furthermore, heterocycles such as
highly strained oxetanes (43) or pyridines (45) were compatible
with this process as well. Alkenes with electron-poor aryl
substituents (46, 47) as well as internal alkenes (48) were
converted to the desired products, thus further expanding the
scope of the transformation. Alkenes with more electron-rich aryl
substituents only gave the product in low yields, presumably due
to radical oligomer- and polymerization. Encouraged by the broad
functional group tolerance, we investigated more challenging
substrates of interest to medicinal chemistry. Several derivatives
of pharmaceuticals or natural products were converted in
moderate to good yields (49-56), highlighting the synthetic
potential of this methodology for late-stage amination. The
2-chloroamine 29 was obtained on gram-scale in an even slightly
higher yield than on small scale, demonstrating the preparative
value of the methodology.
occurred on
a diene substrate, suggests that aminated
compounds (products or reagents) are likely protonated under the
reaction conditions and thus are not soluble enough to react with
the active aminating species. This phenomenon leads to a high
chemoselectivity for the amination of double bonds located on
non-aminated compounds.
N,N-Dialkylaminochlorination of alkenes
Aminative difunctionalizations of alkenes installing tertiary amines
are better developed compared to the installation of unprotected
secondary amines.[4-6,16,23h-j] However, due to significant
limitations in alkene scope, the discovery of a broadly applicable
method remains desirable. Hence, we began to expand our
methodology to the installation of tertiary amines using the
reagents 2a-2c presented above. An investigation of iron
catalysts, additives, chloride salts and solvents revealed again a
strong dependence on the solvent mixture. Surprisingly, the use
of HFIP as co-solvent led to a complete shutdown of the reactivity
in this case (Table 2, entry 1). Instead, a combination of
dichloromethane and n-butanol was found to be ideal (Entry 2).
Lewis acids were again found to be beneficial for the reaction, of
which AlCl3 proved to be optimal (Entry 3). Furthermore,
substituting NaCl with LiCl increased the yield of the reaction
significantly (Entries 4 & 5). Without any alkali metal chloride salt,
the desired product was still obtained in 10% yield (Entry 6). AlCl3
can thus also serve as a chloride source for the reaction besides
its primary function as Lewis acid.[27]
We next investigated the reactivity of different aminating reagents
2a-2c. As shown in Scheme 4B, all new N,N-dialkylamine
reagents were compatible with this process. Medicinally important
cyclic amines, such as morpholine (29) and piperazine (57), could
be installed in good yields. The protected amino group was left
intact in these reactions (57, 58).
4
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10.1002/anie.202008247
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RESEARCH ARTICLE
Scheme 4. Substrate scope of the N,N-dialkylaminochlorination reaction. Yields are of isolated products; dr determined by NMR. Reaction conditions: alkene (0.50
mmol), 2 (1.25 mmol), Fe(acac)2 (5 mol%), AlCl3 (10 mol%), LiCl (0.525 mmol), CH2Cl2/nBuOH 1:1 (0.50 mL) at r.t., 16 h, inert atmosphere. [a] 24 hours reaction
time. [b] 40 hours reaction time. [c] dr determined by GC-FID.
A chlorinated fomocaine analog could be obtained in only 3 steps
from commercially available materials (Scheme 4C), further
highlighting the synthetic utility of this methodology. The chlorine
atom in β-position relative to the amine can potentially be used as
a functional handle to facilitate the access to a broad variety of
fomocaine analogs.
are well known to undergo ring-opening in the presence of a
carbon-centered radical,[28] there is also precedent for a cation-
driven ring-opening of 1,1-dichloro-2-vinylcyclopropane.[29] Thus,
we attempted to find stronger support for a radical mechanism.
When diallyl ether was submitted to the reaction conditions for
N,N-dialkylaminochlorination, the cyclized tetrahydrofuran
derivative 64 could be isolated as the major product. Furthermore,
during the aminochlorination of 3,3-dimethyl-1-butene, no 1,2-
alkyl shift could be observed. Collectively, when combined with
the carboamination reaction presented below (vide infra), these
results are best explained by a stepwise mechanism proceeding
via a carbon-centered radical intermediate.
Control experiments
In recent work, our group hypothesized that the aminoazidation
and aminochlorination of alkenes proceed via a carbon-centered
radical.[15,22c] We thus assumed that the novel methodologies
presented herein follow a similar mechanistic pathway. We
decided to investigate the mechanism by conducting initial control
experiments for the N,N-dialkylaminochlorination (Scheme 5).
When we submitted 1,1-dichloro-2-vinylcyclopropane (61) to the
standard aminochlorination conditions, we could obtain the ring-
opened, chloroaminated product 62. While vinylcyclopropanes
Versatile use of the new reagents in further
aminofunctionalization reactions
Despite the broad synthetic applicability of 2-haloamines,[15,16] the
direct installation of other functionalities beside chloride remains
5
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10.1002/anie.202008247
Angewandte Chemie International Edition
RESEARCH ARTICLE
good yield (Scheme 6C). This natural product could thus be
transformed in two steps (alkylation followed by carboamination)
into a highly functionalized, polycyclic derivative. This result
demonstrates the possibility to trap the carbon-centered radical in
an intramolecular fashion, thus opening new horizons for the
development of amination reactions using these novel reagents.
Overall, the wide range of possible aminofunctionalizations
demonstrated with these new reagents clearly highlights their
broad synthetic potential in the preparation of bioactive molecules.
Conclusion
In conclusion, we have developed reliable and scalable synthetic
routes to access a series of novel aminating reagents for the
installation of several amine groups, such as methylamine,
morpholine and piperazine, that are prevalent in pharmaceuticals
and other biologically active small molecules. The reagents were
employed in the direct synthesis of unprotected secondary as well
as tertiary 2-chloroamines starting from a broad variety of
unactivated, functionalized alkenes. The reactions proceed under
mild conditions and are highly chemo- and regioselective. A
benign and inexpensive iron salt serves as the catalyst. The
versatility of the new reagents was further demonstrated in N-
Scheme 5. Control reactions.
highly attractive in terms of atom and step economy. We thus set
out to examine, in preliminary experiments, whether our
methodology can be diverted to other aminofunctionalizations.
Based on our group’s development of a protocol for the synthesis
of unprotected, primary amino alcohols,[22a] we investigated the
use of the new reagents in the synthesis of amino alcohols. After
a minor re-optimization of the reaction conditions,[19] we were
pleased to find that 4-methoxystyrene could be converted to the
N-methylamino alcohol 68, an O-methylated derivative of the
naturally occurring synephrine, in moderate yield (Scheme 6A).
Recently, our group also developed an aminoazidation reaction of
alkenes to directly obtain primary, unprotected 2-azidoamines.[22c]
We hence sought to use the new reagents to directly access 2-
azidoamines. A preliminary, unoptimized result delivered the
desired product 70 in 51% yield (Scheme 6B).
alkylaminohydroxylation
and
-azidation,
as
well
as
carboamination of alkenes.
Acknowledgements
We thank the Swiss National Science Foundation (SNSF 184658)
for financial support as well as the NMR service, the Molecular
and Biomolecular Analysis Service (MoBiAS) and ETH Zürich for
technical assistance. We further thank Prof. J. Vermant for
sharing analytical equipment, K. Feldman for technical assistance
with the DSC analysis and our group for critical proofreading of
the manuscript.
Keywords: amination • alkenes • difunctionalization • iron
catalysis • protecting-group-free
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Scheme 6. Versatile use of the new reagents. Yields are of isolated products.
[a] 1H NMR yield.
Encouraged by those results, we began to investigate other
aminative difunctionalizations. We reasoned that the proposed
carbon-centered radical intermediate could possibly be trapped
by a heteroarene in a new type of carboamination reaction.[30]
Indeed, when we used an alkene substrate with a tethered
theophylline unit (71), the cyclized product 72 was obtained in
6
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RESEARCH ARTICLE
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RESEARCH ARTICLE
Entry for the Table of Contents
We report the direct synthesis of unprotected secondary and tertiary alkylamines from alkenes through an aminative difunctionalization
reaction enabled by iron catalysis. A family of ten hydroxylamine-derived aminating reagents was designed for the installation of several
medicinally relevant amine groups, such as methylamine, morpholine and piperazine, through the aminochlorination, -hydroxylation, -
azidation and carboamination of alkenes.
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