Direct introduction of nitrogen and oxygen functionality with spatial control using copper catalysis

Article abstract of DOI:10.1039/c8sc03288b

Synthetic chemists have spent considerable effort optimizing the synthesis of nitrogen and oxygen containing compounds through a number of methods; however, direct introduction of N- and O-functionality remains challenging. Presented herein is a general method to allow for the simultaneous installation of N- and O-functionality to construct unexplored N-O heterocyclic and amino-alcohol scaffolds. This transformation uses earth abundant copper salts to facilitate the formation of a carbon-centered radical and subsequent carbon-nitrogen bond formation. The intermediate aminoxyl radical is terminated by an intramolecularly appended carbon-centered radical. We have exploited this methodology to also access amino-alcohols with a range of aliphatic and aromatic linkers.

Full text of DOI:10.1039/c8sc03288b

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Direct Introduction of Nitrogen and Oxygen Functionality with
Spatial Control Using Copper Catalysis
Received 00th January 20xx,
Accepted 00th January 20xx
James B. Shaum, David J. Fisher, Miranda M. Sroda, Luis Limon, Javier Read de Alaniz*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Synthetic chemists have spent considerable effort optimizing the
synthesis of nitrogen and oxygen containing compounds through a
number of methods, however, direct introduction of N– and O-
functionality remains challenging. Presented herein is a general
method to allow for the simultaneous installation of N– and O–
functionality to construct unexplored N–O heterocycle and
amino–alcohol scaffolds. This transformation uses earth abundant
copper salts to facilitate formation of a carbon–centered radical
and subsequent carbon–nitrogen bond formation. The
intermediate aminoxyl radical is terminated by an
intramolecularly appended carbon–centered radical. We have
exploited this methodology to also access amino-alcohols with a
range of aliphatic and aromatic linkers.
A) Previous Work: Synthesis of isoxazolines using nitrones
R3
R3
R2
–O
R3
R4
N
NH OH
R4
R2
N+
R1
[3+2]
[H]
O
R2
R1
R4
R1
olefin
syntheses that relied on this [3+2]
nitrone
isoxazoline
1,3–amino alcohol
Ph
Me
O
iPr
H
O
N
Me
OH
H
H
O
N
N
H
O
O
H
H
O
H
N
H
H
Me
O
O
H
Me
Me
Me
O
H
Ref. 3a
Ref. 3b
Ref. 3c
B) Previous Work: Synthesis of oxazines using nitrosos
R3
NH
R2
R2
R3
[H]
O
N
[4+2]
N
R1
OH
R2
O
R3
R1
R1
1,4–amino alcohol
diene
nitroso
oxazine
Historically, cycloaddition reactions have provided an
efficient strategy to build molecular complexity into
heterocycles by taking advantage of multiple bond formations
in a single step. Given the ubiquity of C–N and C–O bonds in
biologically active molecules, the ability of nitrones and nitroso
compounds to directly install nitrogen and oxygen
heteroatoms is of particular importance.[1] Moreover, due to
the labile nature of the N–O bond, these transformations have
also served as strategic approaches for the synthesis of amino
alcohols bearing a 1,3 or 1,4-relationship.[2] Despite the
prevalence of these transformations in organic synthesis, most
methods have been restricted to the construction of
isoxazoline (Scheme 1A)[3] and 1,2-oxazine (Scheme 1B)[4]
heterocyclic scaffolds and the corresponding amino alcohols
upon reduction. To date, there is no unified method for the
synthesis of N–O heterocycles with varying ring sizes (small to
large) or a direct approach to construct amino–alcohols with
spatial control without independently installing the N– and O–
O
syntheses that relied on this [4+2]
OCONH2
OH
O
OH
OH
HO
H
OH
HO
O
NH
N
OHC
N
O
N
H
OH
O
OH
Ref. 4c
Ref. 4a
Ref. 4b
C) This Work: Direct installation of N– and O– functionality
R
Earth
abundant
R
NH OH
Br
Br
O
N
N
O
[H]
FG
FG
FG
FG
FG
FG
R
CuI salts
n
n
n
n= 1–8
n= 1–15
representative examples
Ph
OH
Me
O
O
O
Cl
NH OH
Ph
Me
N
O
N
O
Me
Me
EtO
NH
O
Ph
Me
O
O
Ph
No olefins or cycloadditions Up to 19 membered cycles > 30 examples
nitrogen and oxygen heteroatoms and examples of biologically active products
that relied on these methods.
functionality in sequential steps.
Scheme 1. Examples of strategies that enable the direct installation of
Previously, in an effort to provide alternatives to
cycloaddition reactions or electrophilic functionalization of
carbonyls using nitroso compounds, we[5] and others[6]
described the use of radical transformations with nitroso
compounds to construct sterically hindered amines. This
process employs earth abundant copper salts, tolerates a
range of functional groups and employs widely available
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radical precursors. Here we report the development of a addition of 5 mol% copper (II) bromide relative to the copper
generalized method to construct N–O heterocycles and (I) bromide. CuII is known to have a strong effect on the
amino–alcohols of any size and distribution. These studies kinetics of atom transfer radical polymerization (ATRP)
demonstrate that bi-molecular reactions are not necessary to systems[9] and we hypothesizes that the addition of CuII
trap the in situ generated aminoxyl radical, despite the well- decreases the concentration of carbon-centered radical,
known challenges of forming larger macrocyclic rings.[7] In leading to a more controlled reaction. As expected when
addition and in contrast to our previous work, this method also forming larger macrocyclic ring systems, the stereoselectivity
increases the atom economy of the nitroso additions, of the transformation decreases as the spacer length
accessing products that incorporate both heteroatoms. increases. The five-membered ring
1 demonstrated a relatively
Previously, the C–O bond constructed during the radical high dr of 5:1 cis:trans, while the six- and seven-membered
transformation was treated as part of the waste stream and rings
2 and 3 demonstrated dr’s of 1.8:1 and 1.5:1,
discarded upon N–O bond cleavage. Combined, this radical- respectively.[10] Rings eight-membered and greater
based process provides efficient entry into many unexplored demonstrated no selectivity. Alkyl-nitroso compounds were
scaffolds (Scheme 1C).
used to create heterocycles with yields similar to their
was synthesized using
To begin our investigations, we examined the aromatic counterparts; compound
8
intramolecular reaction of the 1,3-dibromide scaffold. Initially, commercially available 2-methyl-2-nitrosopropane dimer. We
we were able to identify conditions inspired by our previous were pleased to find that the intramolecular reaction could be
work and others[8] (5 equiv of both CuI and Cu0, 2.5 equiv of extended to readily available
α
-bromo carbonyl-based
PMDTA, 2 equiv of nitrosobenzene, THF, 40 ºC) that afforded scaffolds. Impressively, as shown in Figure 1B, these scaffolds
the desired N–O heterocycle in 70% yield. We were further were found to cyclize very efficiently, creating up to 19-
encouraged to find that, in a two-step-one-pot approach, the membered heterocycles in great yield ( 14). Overall, these
1
9
–
heterocycle could be reduced to the corresponding amino– results open the door for efficient access to a series of
alcohol 15 (65% overall yield) by simply adding additional CuI unexplored N–O based heterocyclic scaffolds.
and ascorbic acid. Further, the heterocycle was formed in a 2:1
ratio of diastereomers (dr), favouring the cis isomer over the
trans, and the N–O bond reduction did not erode the
selectivity. Through optimization of the reaction parameters,
we found Cu0 could be removed entirely, CuI loading could be
reduced to 2 equivalents, and nitrosobenzene loading could be
lowered to 1.5 equivalents. These modifications increased the
yield of the desired product (1) to 85%. Unfortunately, we
discovered that reduction of the N–O heterocycle with CuI and
ascorbic acid was only useful for five-member ring
heterocycles, with incomplete reduction occurring when larger
rings were investigated.
A screen of various reducing
conditions revealed that stronger reducing agent such as zinc
in HCl and sodium-napthalenide afforded the desired amino
alcohol 15 in higher yield (67% isolated yield over two steps
using Zn/HCl conditions) and these methods proved general.
Notably during optimization studies, we discovered that
increasing the reaction temperature to 50 °C increased the dr
of this transformation to 5:1 favoring the cis-isomer. Finally, a
copper ligand screen was investigated; reactions run with the
more activating ligands such as Me6TREN provided yields very
similar to those run with PMDTA. However, using a less
activating ligand, such as 2,2’-bipyridyl resulted in limited or no
conversion of the starting material.
With optimized conditions established, we initially
explored the generality of this method to construct N–O
Figure 1. Scope of N–O heterocycle synthesis. A) Products derived from
benzyl dibromide scaffolds and nitrosobenzene. B) Products derived from
bromocarbonyl compounds and nitroso benzene or 2-methyl-2-nitrosopropane
dimer. a Yield established through internal standard. Isolated yield of
is 10%.
α
-
heterocycles with varying ring sizes (Figure 1A). Five (
) membered rings were synthesized in good yields with the
optimized conditions. The seven-membered ring ( ) required
1) and six
(
2
7
3
more dilute reaction conditions, as increasing amounts of
oligomers were observed by 1H-NMR spectroscopy,
presumably formed via a competitive intermolecular radical
We were intrigued by the large discrepancy in yields
between the glycol-linked 10 14 and the alkyl-linked 1 – 5
substrates, and considered a CuII templating effect was
responsible. CuII has been employed advantageously in a
number of similar cyclizations.[11] To test this hypothesis, we
–
termination. The larger 8-12 membered heterocycles (4 – 7
)
required the same dilute reaction conditions, as well as the
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synthesized the alkyl-linked 18-membered heterocycle that synthesized and subjected to the optimized conditions (Figure
cannot benefit from templating and subjected it to optimized 3a). With respect to the nitrosoarene coupling partner, the
conditions (see SI, S25). Compared to the closest derivatives, reaction was tolerant of electronic changes. Not surprisingly,
compound 13–14, the yield dropped from greater than 60% to the reaction tolerates halogenated compounds 26 and 28 that
32%. This direct comparison indicates that a templating effect allow for facile downstream functionalization. Of note, the
might be responsible for the increased yields observed with amine functional group (NH2) group in substrate 27 is derived
substrates 10
–
14
.
from the corresponding nitro group and was generated in situ
After demonstrating the construction of N–O heterocycles upon treatment with zinc and HCl conditions. Moreover,
with spatial control, we were now set to examine the scope of structural changes can be made to dibromide scaffold, either
our two-step-one-pot approach to construct amino–alcohols the methylene linker or the aromatic rings, affording the
of various distributions (Figure 2). We were pleased to find anticipated product in moderate to good yields (40% to 66%)
that many of the yields are actually higher to the amino-
(Figure 3b). Notably, the reaction efficiency decreased slightly
alcohols using the two-step-one-pot approach than those of when gem-dimethyl groups are introduced alpha to the
the corresponding N–O heterocycle. For example, synthesis of dibromide (30). This is not surprising considering the costly
an amino-alcohol (21) bearing a 1-10 relationship, which steric interactions of forming C–N and C–O bond adjacent to a
represents the direct installation of both N– and O– quaternary center. Interestingly, while most of the
functionality over 12 angstroms of space, afforded the desired modifications to the scaffold had limited effect on the
product in 48% overall yield. Notably, this is 20% higher than diastereomeric ratio of the products (~3:1 dr ratio was
the corresponding N–O heterocycle
(7, 20% yield). We observed for 29–31, 33), compound 32 was formed in a 10:1
speculate this is due to the in situ reduction of oligomers that dr, suggesting diastereoselectivity can be enhanced using
also afford the desired amino–alcohol product 21. Previously, substitution at the meta-position.
the oligomers were removed during the heterocycle
purification and isolation. For the in-situ reduction, the five-
membered heterocycle affording amino-alcohol 15 and 22 was
reduced using Zn/HCl conditions, but all others were reduced
using sodium-napthalenide.
Figure 2. Scope of amino–alcohols synthesized with a one-pot-two-step approach. A)
Products derived from benzyl dibromide scaffolds and nitrosobenzene. B) Products
Figure 3. Scope of scaffold modifications. A) Substrates derived from functionalized
derived from benzyl dibromide and 2-methyl-2-nitrosopropane dimer or α-
nitrosoarenes. B) Substrates derived from modified dibromide scaffolds
.
bromocarbonyl compounds and nitroso benzene.
Next, we explored how structural modifications to the
nitrosoarene and the dibromide architecture were tolerated.
Given the higher yields of amino-alcohol synthesis, the two-
step-one-pot approach was used for these studies. A small
library of both electron-rich and deficient nitrosoarenes was
To demonstrate the synthetic utility of this methodology
beyond symmetrical substrates, we investigated strategies to
construct N– and O– bonds on unsymmetrical scaffolds with
regioselective control. A common feature of radical reactions
with nitroso compounds is that the initial carbon centered
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radical reacts at nitrogen. Consequently, we hypothesized that appended radical. Moreover, we have shown that
radical initiation rates could be leveraged to control the regioselectivity of the installation of nitrogen and oxygen
regioselectivity. The success of this approach would also functionality can be predicted using well-documented ATRP
require the second intramolecular radical reaction with the rate constants for radical formation. The method reported
intermediate aminoxyl radical to outcompete the herein provides new versatile platform for the develop of N–O
intermolecular reaction. Despite the challenges of balancing heterocycles and the corresponding amino-alcohols, all with
the reaction rates of these highly reactive radical high atom economy and earth-abundant catalysts.
intermediates, we were encouraged by the wealth of literature
on activation rates for various initiators used for ATRP.[12]
Guided by these activation studies, we designed a mixed-
Acknowledgements
initiator scaffold containing both an α-bromoester and a
benzyl-bromide radical precursor which could be synthesized
We thank the National Science Foundation (CHE-1566614)
for financial support. Mass spectrometry instrumentation was
partially supported by the MRL Shared Experimental Facilities,
which are supported by the MRSEC Program of the NSF (DMR-
1121053). NMR instrumentation was supported by an NIH
Shared Instrumentation Grant (1S10OD012077-01A1). J.B.S. is
thankful for a Mellichamp Academic Initiative in Sustainability
Fellowship. M.M.S. is thankful for a FLAM Program Award from
the National Science Foundation (DMR-1460656). This project
was partially supported by the LSAMP program of the National
Science Foundation (DMR-1102531).
in one step from styrene and ethyl dibromopropanoate (Figure
4). The kact of the α-bromoester moiety is roughly an order of
magnitude greater than that of the benzyl bromide under
standard ATRP conditions.[13] Given this difference, we
predicted that the initial radical would predominately form at
the
α-bromoester, leading to carbon-nitrogen bond formation
to the ester and carbon-oxygen bond formation at the less
α
active benzyl site. To our gratification, subjection of the
asymmetric scaffold to the optimized reaction conditions
resulted in the N–O heterocycle with a 10:1 ratio of products
35 to 36 favouring the predicted major isomer. This result
indicates that the major regioselectivity can be predicted
through the relative kact of each radical precursor; moreover,
the approximate ratio of the regioisomers can be predicted
from the ratio of the kact of the initiators. Further studies are
underway to elucidate these factors in more detail and explore
the scope of unsymmetrical scaffolds.
Conflicts of interest
There are no conflicts to declare.
Notes and References
1
2
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Conclusions
In summary, we have developed a new method for the
direct installation of nitrogen and oxygen functionality where
the N–O heterocycles and amino–alcohol scaffold size is
unencumbered by traditional olefin couplings reactions. The
described method is general in terms of scope and provides an
efficient method capable of construction macrocycles up to
19-members in size and amino-alcohols with up to 12 Å
separating the N– and O– heteroatoms. The reaction is
catalysed by copper salts and leverages readily available
radical precursors and nitroso compounds to generate a new
C–N bond and an intermediate aminoxyl radical, which is
4
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