Tandem Oxidative Derivatization of Nitrene Insertion Products for the Highly Diastereoselective Synthesis of 1,3-aminoalcohols

Article abstract of DOI:10.1002/chem.201702038

Transition-metal-catalyzed nitrene insertion into tertiary C?H bonds located at stereogenic carbons often results in mixtures of diastereomeric products, especially if the reaction proceeds through a concerted pathway. In this communication, we report a s

Full text of DOI:10.1002/chem.201702038

A Journal of
Accepted Article
Title: Tandem Oxidative Derivatization of Nitrene Insertion Products for
the Highly Diastereoselective Synthesis of 1,3-aminoalcohols
Authors: Jennifer M. Schomaker and Juliet M. Alderson
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Chemistry - A European Journal
10.1002/chem.201702038
Tandem Oxidative Derivatization of Nitrene Insertion Products for
the Highly Diastereoselective Synthesis of 1,3-aminoalcohols
Juliet M. Alderson and Jennifer M. Schomaker*
Abstract: Transition metal-catalyzed nitrene insertion into tertiary
C–H bonds located at stereogenic carbons often results in mixtures
of diastereomeric products, especially if the reaction proceeds
through a concerted pathway. In this communication, we report a
solution to this problem that invokes a one-pot, silver-catalyzed C–H
nitrene transfer reaction. Nitrene insertion is followed by facile
oxidation of the amine to an imine and nucleophilic addition to
furnish α-tertiary amine 1,3-aminoalcohol products in high
diastereoselectivities. The silver catalyst, PhIO oxidant and TEMPO
additive are crucial to success in this unusual oxidation, which is
proposed to occur via hydrogen-atom abstraction from pre-activation
of the initial nitrene insertion product by additional oxidant.
Stereodefined acyclic 1,3-aminoalcohols are common and
important motifs in the synthetic lexicon that are found in a
variety of natural products, pharmaceuticals and precursors
[
1]
[2]
[
3]
for potent BACE1 inhibitors, as well as diverse chiral ligands
While a
[4]
for metal-catalyzed asymmetric transformations.
number of strategies have been developed for the synthesis of
these valuable building blocks, relatively few approaches enable
stereocontrolled access to products bearing a chiral α-tertiary
Scheme 1. Stereocontrol in nitrene transfer for 1,3-aminoalcohol synthesis.
[
5]
benzyl imine 6 (Scheme 1c) observed in our previous studies of
Ag-catalyzed nitrene insertion into the 2°benzylic C-H bonds in
precursors of the form 4. We reasoned that gaining a better
understanding of how to optimize this unexpected oxidation
amine.
In this communication, we report a one-pot and
modular Ag-catalyzed tandem process that transforms simple
precursors to highly substituted 1,3-aminoalcohols with excellent
levels of diastereocontrol.
process could result in
a tandem C–H functionalization/
The intramolecular insertion of an oxygen-tethered nitrogen
source, typically a carbamate or a sulfamate, into a C-H bond
via nitrene transfer is a powerful strategy to access certain
classes of 1,3-aminoalcohols. Transition metal complexes,
particularly those based on Rh, Ru, Cu, Co and Fe, have been
demonstrated to successfully catalyze nitrene transfer reactions
oxidation/nucleophilic addition sequence that solves the problem
of controlling dr in the installation of a C–N bond at a stereogenic
center bearing a 3° C–H bond. The ablation of the intermediate
amine stereocenter through oxidation to the imine 6 lends
flexibility in the scope of nucleophiles that can be introduced at
the benzylic carbon.
[
6-10]
into 2°and 3°C-H bonds;
however, intramolecular reactions
Initial studies were conducted with
8 (Table 1), where
catalyzed by these metals yield mixtures of products when the
substrates contain two stereogenic carbons, unless the starting
material itself is diastereopure. Indeed, in our own efforts
competing formation of the imine 11 was first noted. As the
benzyl imine comprised less than 10% of the total yield under
standard conditions (entry 1), efforts to increase its formation
were undertaken. Specifically, we were curious if the PhIO
oxidant used in the nitrene insertion could also be employed for
the amine oxidation step. Methods employing stoichiometric
quantities of hypervalent iodine reagents, including PhIO or
[
11a-c]
directed towards Ag-catalyzed nitrene transfer,
all attempts
to react 1:1 mixtures of diastereomers of a sulfamate such as 1
(
2
Scheme 1a), resulted in poor dr in the α-tertiary amine product
[
11a,12]
.
Du Bois and co-workers devised a clever solution to
increase the dr of α-secondary 1,3-aminoalcohols through a
sequence involving Rh-catalyzed nitrene insertion into a 2°
ethereal C–H bond, followed by nucleophilic addition to yield the
products with high site-selectivity and excellent dr (Scheme
2
PhI(OAc) , are known to promote the oxidation of alcohols and
[13]
amines in combination with nitroxyl radical co-oxidants.
Gratifyingly, addition of 10 mol % TEMPO (2,2,6,6-tetramethyl-
piperidin-1-yl)oxyl) to our nitrene insertions increased the yield of
imine 11 from 8% to 37% (entry 2). Increasing the amount of
TEMPO to 30 mol % (entry 3) improved the 11:10 ratio to 2:1,
but further increasing the amount of TEMPO or the reaction time
resulted in lower yields of 11 (entries 4-5). Performing the
reaction under either a oxygen (entry 6) or nitrogen (entry 7)
atmosphere resulted in better conversion to 11. However,
waiting until the nitrene insertion was complete before adding
the TEMPO (entry 8) was ideal and resulted in full conversion to
[
6b
1
b). ] While this strategy was not employed for the synthesis of
α-tertiary amines, it inspired us to think about other ways in
which the stereochemistry set by a silver-catalyzed nitrene
insertion into a 3° C-H bond might be solely controlled by the
stereochemistry of the alcohol-bearing C3 carbon in 1.
A potential strategy for gaining rapid access to complex,
stereodefined α-tertiary 1,3-aminoalcohols from simple starting
materials was suggested by the formation of small amounts of
11. It should be noted that modified nitroxyl radicals shown to
improve related oxidation reactions, including ABNO (9-
[a]
J. M. Alderson, Prof. J. M. Schomaker
azabicyclo[3.3.1]nonane
azabicyclo[3,3,1]nonan-3-one-9-oxyl)
N-oxyl),
ketoABNO
and AZADO
(9-
(2-
Department of Chemistry, University of Wisconsin-Madison
1
101 University Avenue, Madison, WI 53706 (USA)
E-mail: schomakerj@chem.wisc.edu
azaadamantane N-oxyl) did not perform as well in this chemistry
[14]
(
see the SI for further details). Thus, the conditions in entry 8
were chosen for further studies to assess the role of each
reagent in the amine oxidation step.
Supporting information for this article is given via a link at the end
of the document.
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Chemistry - A European Journal
10.1002/chem.201702038
Table 1. Initial optimization studies for imine formation.
of a nucleophile to the imine was investigated next (Scheme 2a).
MeMgBr was first added directly to the isolated imine 13 to
furnish 14a in high yield and excellent dr, providing proof-of-
concept. However, as 13 is rather unstable and decomposes
quickly, a direct addition of the nucleophile to the crude imine
was preferred. Fortunately, after a quick filtration to remove the
molecular sieves and insoluble oxidant, MeMgBr could be added
directly to the crude imine 13 to deliver 14a in good yield for the
three-step process and with excellent dr (Scheme 2b) that could
be easily verified by nOe. Due to the nature of the reaction,
setting the alcohol stereochemistry in the substrate will result in
transfer to the aminoalcohol product with excellent fidelty.
Further optimization, including screening of solvent, temperature,
and the identity of the halogen in the Grignard reagent were also
carried out (see SI for further details).
A
series of control experiments were performed on the
benzylic amine 12 to analyze the ratio of recovered 12 to imine
3 (Table 2). Under standard conditions and no effort to exclude
air (entry 1), good conversion to 13 was noted; exclusion of air
by running the reaction under N (entry 2) resulted in full
1
2
conversion of 12 to 13. As noted previously, the absence of
TEMPO (entry 3) gave minimal conversion to 13. Exclusion of
AgOTf, PhIO or mole sieves (MS, entries 4-6) from the standard
reaction conditions resulted in minimal formation of 13, while the
tris(2-pyridylmethyl)amine (tpa) ligand (entry 7) utilized for the
Ag-catalyzed nitrene transfer was not necessary for imine
formation. Background oxidation due solely to PhIO or
Scheme 2. Development of a one-pot protocol.
The scope of the one-pot, three-step process was explored
using a variety of substrates and nucleophiles (Table 3). The
electronics of the aryl group of 14-17 had little effect on either
the C-H insertion or the oxidation/MeMgBr addition to the imine,
giving the α-tertiary 1,3-aminoalcohol products 14a-17a in good
yields and excellent diastereoselectivities of >19:1, favouring a
syn relationship between the alcohol and amine substituents, as
atmospheric O
AgOTf with Sc(OTf)
2
was also ruled out (entries 8-9). Replacing
or Bi(OTf) (entries 10-11) gave full
conversion to 13, indicating that the role of AgOTf in the amine
3
3
oxidation is to serve as a Lewis acid to break down the insoluble
PhIO polymer into active monomer units.
[
13b,15]
Overall, these
control experiments established that AgOTf, PhIO, TEMPO, MS
and an inert atmosphere are ideal for the amine oxidation.
1
well as the R and Et groups in the initial substrate. Introducing
an ortho-Me into the aryl group of 18 resulted in a slower imine
oxidation step and a lower overall yield of 18a, suggesting the
oxidation step is sensitive to steric hindrance. A naphthalene
group in 19 worked well; however, the furan group of 20 was
sensitive to the oxidative conditions, resulting in a lower yield of
20a, albeit in excellent dr. Amines resulting from nitrene
insertion into allylic C-H bonds, as in 21, proved more difficult to
oxidize; refluxing temperatures and longer reaction times were
required to obtain the imines. The nucleophile scope was also
briefly examined. Surprisingly, there is little literature precedent
for the addition of nucleophiles to sulfamate-derived imines; thus,
nucleophiles known to add to tosyl-protected imines were first
With optimized conditions in hand for the tandem C–H
functionalization/amine oxidation reaction, subsequent addition
Table 2. Control experiments for imine formation conditions.
[
16]
[17]
examined, including Grignard reagents, various silanes and
to achieve Strecker-type reactions. A
[
18]
trimethylsilyl cyanide
variety of Grignard reagents worked well, resulting in good yield
and excellent diastereoselectivity. Benzyl and allyl Grignards
provided additional functional handles to allow for further
derivatization of these products (22, 23). A bulkier isobutyl group
could also be added to the sterically encumbered imine (24).
However, the nucleophile addition is sensitive to sterics, as
shown in the decreased yield for the addition of iPrMgBr to
furnish 25. Vinyl Grignard reagents proved difficult to employ in
the one-pot process; however, this problem could be solved by a
quick isolation of the imine intermediate to provide 26 in 65%
yield and >19:1 dr. The issue with the one-pot process was
traced to formation of 5 obtained due to β-hydride elimination of
the reagent. Unfortunately, weaker nucleophiles, including cyan-
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Chemistry - A European Journal
10.1002/chem.201702038
Table 3. Substrate scope for C-H amination/oxidation/nucleophilic addition
process (yields are over three steps).
Scheme 3. General TEMPO-based pathway under mildly acidic conditions.
gave only recovered starting material (entry 2). Adding 3.5
equivalents of PhIO in conjunction with Bobbitt’s salt provided
some conversion to imine 13 (entry 3), but full conversion was
only achieved when both AgOTf and PhIO were employed in the
presence of Bobbitt’s salt (entry 4). Interestingly, these results
suggest that AgOTf plays a role beyond catalyzing the nitrene
insertion reaction, while PhIO serves a function beyond that of
simple oxidization of TEMPO to the active oxoammonium
species. We hypothesize that PhIO may be necessary to
activate amine 12 for more facile oxidation to 13, as the
electron-withdrawing nature of the sulfamate group decreases
the nucleophilicity of the nitrogen. Recently, Moriyama and co-
workers have shown that tBuOCl is able to pre-activate an
electron-poor amine towards oxidation through the formation of
[
17b]
a N-chlorinated intermediate.
In our previous studies of Ag-
catalyzed nitrene transfer reactions utilizing PhIO as the oxidant,
we have shown that Ag(I) salts play a role in breaking up the
polymeric PhIO to furnish the activated monomeric species.
[
11c]
Table 4. Control experiments for imine formation using Bobbitt's salt.
ides and silanes, were not successful under the reaction
conditions. We proposed the recalcitrance of these nucleophiles
to react might be due to lessened electrophilicity of the
oxathiazinane-derived imines as compared to imines activated
with common sulfonyl groups. Regardless, this method still
expands the synthetic flexibility of catalyst-controlled nitrene
transfer chemistry to obtain highly stereodefined products that
would normally require a more involved and stereospecific
substrate synthesis.
With these insights in hand, a full mechanistic pathway was
proposed for the amine-to-imine oxidation (Scheme 4). First, the
polymeric PhIO is broken down by either AgOTf or Ag(tpa)OTf
acting as a Lewis acid to give activated monomers of the
general form A, explaining the requirement for either a Ag salt or
other Lewis acid to be present for successful amine oxidation.
Efforts to gain insight into the mechanism of this tandem
reaction and delineate the roles of PhIO, AgOTf and TEMPO in
the amine to imine oxidation were undertaken. Typically,
TEMPO-based oxidations require stoichiometric amounts of a
[
.
13,14]
terminal oxidant, such as PhI(OAc)
2
, Br , NaOCl or O
2
2
The
oxidant can play multiple roles, depending on the specific
reaction conditions. In our reaction, one possible pathway
(
Scheme 3) based on literature precedent would involve a
single-electron oxidation of TEMPO to produce highly
electrophilic oxoammonium species that serves as the oxidizing
a
[
14]
agent to convert 12 to 13.
Regeneration of the oxoammonium
species occurs through further oxidation and loss of water. To
test this hypothesis, a set of control reactions using Bobbitt’s salt
Scheme 4. Proposed mechanistic pathway.
(
4-(acetylamino)-2,2,6,6-tetramethyl-1-oxo-piperidinium*BF
commercially available oxoammonium reagent, were carried out
Table 4). Surprisingly, only amine 12 was recovered after being
subjected to Bobbitt’s salt (entry 1). The addition of AgOTf still
4
),
a
(
Lending support to this proposal is the identification of activated
iodine species similar to A by mass spec using KBr as the Lewis
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Chemistry - A European Journal
10.1002/chem.201702038
[
15f]
acid.
The
A
(or related species) activates 12 via N-
[5]
(a) H. Uno, T. Terakawa, H. Suzuki, Bulletin of the Chemical Society of
Japan, 1993, 66, 2730. (b) A. R. Minter, A. A. Fuller, A. K. Mapp, J. Am.
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halogenation to give B after proton transfer. One possible
pathway is H-atom abstraction by TEMPO to yield C and D; C
undergoes loss of PhI and a hydroxyl radical to form the imine
product 13. TEMPO is regenerated through loss of
2
H O,
explaining the necessity for mole sieves in the reaction. The
proposed pathway also accounts for the necessity of both AgOTf
and PhIO in the amine oxidation step; however, an
oxoammonium pathway similar to that shown in Scheme 3
cannot be completely ruled out at this point. In addition, the HO
radical could abstract H-atoms from either substrate or product,
perhaps accounting for the modest yields.
[6]
For selected examples of Rh-catalyzed C–H amination, see: (a) C. G.
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6
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Lescot, B. Darses, C. Collet, P. Retailleau, P. Dauban, J. Org. Chem.
In conclusion,
a
convenient one-pot protocol for the
preparation of diastereomerically pure 1,3-aminoalcohols
bearing an α-tertiary amine functionality has been developed.
Silver-catalyzed nitrene transfer into activated benzylic and
allylic C-H bonds is followed by oxidation to an imine simply
through addition of a catalytic amount of TEMPO. Subsequent
reaction with a Grignard reagent results in the syn aminoalcohol
in >19:1 dr. This three-step method features simplified substrate
preparation and offers greater flexibility in the range of groups
that can be introduced into the product. Preliminary mechanistic
studies suggest that an oxoammonium pathway is not likely and
that PhIO plays a role in activating the nitrene insertion product
before oxidation can occur.
2
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1
This work was funded by the Wisconsin Alumni Research
Foundation to JMS. The 400 MHz NMR at UW-Madison was
funded by the NSF CHE-1048642; 500 MHz spectrometers were
provided through a generous gift from Paul J. and Margaret M.
Bender. The Chemistry Instrumentation Center’s Q Exactive Plus
Orbi Mass Spectrometer is funded by the NIH (1S10OD020022-1).
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7
Keywords: amine oxidation • heterocycles • silver catalysis •
diastereoselective • one-pot process
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Chemistry - A European Journal
10.1002/chem.201702038
Layout 2:
COMMUNICATION
Juliet M. Alderson, Jennifer M.
Schomaker*
Page No. – Page No.
Tandem Oxidative Derivatization of
Nitrene Insertion Products for the
Highly Diastereoselective Synthesis
of 1,3-aminoalcohols
A simple one-pot, silver-catalyzed C–H nitrene transfer/oxidation/nucleophilic
addition sequence converts simple sulfamates into α-tertiary amine 1,3-
aminoalcohols in >19:1 dr with flexibility in the choice of R . This unusual oxidation,
3
which is proposed to occur via hydrogen-atom abstraction from pre-activation of the
amine resulting from Ag-catalyzed C-H insertion with additional PhIO.
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