Catalytic Metal-free Allylic C?H Amination of Terpenoids

Article abstract of DOI:10.1021/jacs.0c06997

The selective replacement of C?H bonds in complex molecules, especially natural products like terpenoids, is a highly efficient way to introduce new functionality and/or couple fragments. Here, we report the development of a new metal-free allylic amination of alkenes that allows the introduction of a wide range of nitrogen functionality at the allylic position of alkenes with unique regioselectivity and no allylic transposition. This reaction employs catalytic amounts of selenium in the form of phosphine selenides or selenoureas. Simple sulfonamides and sulfamates can be used directly in the reaction without the need to prepare isolated nitrenoid precursors. We demonstrate the utility of this transformation by aminating a large set of terpenoids in high yield and regioselectivity.

Full text of DOI:10.1021/jacs.0c06997

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Article
Catalytic Metal-free Allylic C-H Amination of Terpenoids
Wei Pin Teh, Derek C Obenschain, Blaise M. Black, and Forrest E. Michael
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c06997 • Publication Date (Web): 10 Sep 2020
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Catalytic Metal-free Allylic C-H Amination of Terpenoids
Wei Pin Teh, Derek C. Obenschain, Blaise M. Black and Forrest E. Michael*
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Department of Chemistry, University of Washington, Box 351700, Seattle, Washington 98195-1700
ABSTRACT The selective replacement of C–H bonds in complex molecules, especially natural products like terpenoids, is a high-
ly efficient way to introduce new functionality and/or couple fragments. Here, we report the development of a new metal-free al-
lylic amination of alkenes that allows the introduction of a wide range of nitrogen functionality at the allylic position of alkenes
with unique regioselectivity and no allylic transposition. This reaction employs catalytic amounts of selenium in the form of phos-
phine selenides or selenoureas. Simple sulfonamides and sulfamates can be used directly in the reaction without the need to prepare
isolated nitrenoid precursors. We demonstrate the utility of this transformation by aminating a large set of terpenoids in high yield
and
regioselectivity.
INTRODUCTION
Scheme 1. C-H Amination of Terpenoids.
The selective replacement of C–H bonds in complex organic
molecules is a powerful tool for the efficient construction of
new molecular species. As such, this important problem has
received significant attention over the last century, resulting in
many new methods for the formation of new C–O, C–N, and
C–C bonds.1-6 Considering the well-documented importance of
nitrogen in biologically active compounds, the formation of
new C–N bonds via C–H amination reactions is a particularly
promising application of this technology.7-14
Inspired by nature, we were drawn to a particular synthetic
challenge: can new classes of potentially bioactive nitrogen-
containing compounds be generated by combining the natural-
ly-occurring structural complexity of terpenes with a general
allylic C–H amination method (Scheme 1A)? In synthesizing
terpenoid natural products, organisms generate structural
complexity in the carbon backbone by cyclizing acyclic iso-
prenoid precursors.15 They then add functional complexity
using C–H oxidation reactions of exquisite selectivity to intro-
duce new C–O bonds in well-defined locations, often in allylic
positions.16 This approach has been successfully mimicked in
the laboratory by several groups carrying out total syntheses of
natural products and late-stage functionalizations.17-20 We im-
agined that an analogous allylic C-H amination reaction could
enable the synthesis of a wide variety of previously unknown
nitrogen-containing bioactive compounds using the pre-
existing structural diversity of terpenoids. Furthermore, such a
method would also allow the selective labeling of terpenoids
with functional reagents via the extra valence on the nitrogen
atom.
The primary challenge in C–H amination of complex sub-
strates is achieving predictable site selectivity, as highlighted
by recent attempts to use C–H amination to selectively label
complex biologically active molecules.9,13,14 In this context,
the presence of carbon-carbon double bonds in terpenoids
presents both a prime underexplored opportunity and a diffi-
cult problem. As a consequence of the weakened C–H bond in
the allylic positions, alkenes ought to provide a convenient
reactive handle for introducing new functionality.21 However,
the high reactivity of the C–C  bond itself poses special
challenges for known C–H amination methods (Scheme 1B).
Existing nitrenoid-11-14,22,23 or radical-based8-10,24-29 approaches
to C–H amination result in competing aziridination and/or
alkene addition reactions rather than allylic amination. Meth-
ods that involve the formation of -allyl complexes30-38 avoid
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Scheme 2. Terminal alkene substrate scope.
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aziridination but are prone to problems with alkene transposi-
tion and regioselectivity, and are thus often limited to a narrow
range of alkene substitution patterns. Furthermore, each of
these systems are optimized to introduce only a single nitrogen
substituent, or require special pre-made nitrogen sources,
hampering their use as a means of introducing new functional-
ity.
pensive PhI(OAc)2, would allow maximum flexibility in di-
rectly introducing a wide variety of nitrogen substituents. In
the process, we discovered that introduction of a ligand for
selenium was critical for high reactivity of the selenium cata-
lyst.
RESULTS AND DISCUSSION
We started by treating a test alkene (4-phenyl-1-butene, 1)
with PhI(OAc)2 and 4-nitrobenzenesulfonamide (NsNH2) in
the presence of catalytic Se powder. Disappointingly, no cou-
pling product was formed under these conditions. At this
stage, we reckoned that the use of a selenium source bearing
an appropriate ligand would be more effective. In transition
metal catalysis, phosphine and N-heterocyclic carbene (NHC)
ligands are commonly used to improve the solubility and sta-
bility of the active metal center and to control its reactivity. In
a similar manner, analogous complexes of these ligands with
selenium, i.e. phosphine selenides and selenoureas, which are
trivial to generate from the corresponding phosphines and
imidazolium salts, might also serve as more effective catalysts.
Indeed, we and others have recently shown that these com-
plexes can be used to control the selectivity of selenium-
catalyzed reactions.46-48 Gratifyingly, phosphine selenide cata-
lysts did afford the desired allylic amination product, with 15
mol % tricyclohexylphosphine selenide (Cy3PSe) proving to
be the most convenient and effective catalyst. The quantity of
catalyst could be reduced further to 5 mol % with only a mod-
erate drop in yield. No trace of any alkene transposition prod-
ucts was detected, nor was any competing amination of the
benzylic position observed. The procedure is operationally
simple, requiring only addition of the selenium catalyst and
the stoichiometric oxidant to a mixture of the alkene and sul-
fonamide or sulfamate to be coupled.
To achieve our goal of selective terpenoid amination, we
needed to develop a new, more versatile solution to the gen-
eral problem of allylic C–H amination; one that gives good
reactivity and predictable regioselectivity for all alkene substi-
tution patterns without alkene transposition and that allows the
introduction of a wide range of functional groups via the ni-
trogen substituent (Scheme 1C). This new method would serve
as
a
selective coupling reaction between sulfona-
mides/sulfamates and alkenes via the adjacent C–H bond.
In 1976, Sharpless and coworkers determined that a stoichi-
ometric selenium reagent derived from anhydrous TsNClNa
(Chloramine-T) could achieve highly selective allylic C–H
amination of a range of simple alkenes.39-41 Unfortunately,
development and application of this exciting reaction has re-
mained largely dormant (with the notable exception of an en-
antioselective sulfur variant)42-45 since this initial report due to
its moderate yields, the need for an inconvenient and potential-
ly explosive nitrogen source, and the use of stoichiometric
quantities of selenium. We reasoned that we could solve these
problems by using a catalytic quantity of a selenium catalyst
and regenerating the active selenium bis(imide) in situ with a
milder, more convenient nitrenoid source, thereby greatly ex-
panding the utility of this underexplored reaction. For this
purpose, we targeted the use of simple sulfonamides and sul-
famates as nitrogen sources, which in combination with inex-
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Scheme 3. Alkene labeling with functional sulfonamides/sulfamates.
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We tested a variety of terminal and 1,1-disubstituted alkenes
(Scheme 2) and found that a wide range of functional groups,
including esters, protected alcohols and amines, electron-rich
aromatics, aryl boronates, and alkyl and aryl halides were
well-tolerated. Amination of protected homoallylic alcohol
and homoallylic amine groups generates synthetically im-
portant 1,2-aminoalcohols and 1,2-diamines. Importantly,
primary, secondary, and tertiary C–H bonds could all be effec-
tively aminated using this procedure. The reaction can be easi-
ly run on large scale with no diminution of yield; at 5 mol %
catalyst loading 4.39 grams of product 1a can be generated
using less than 80 mg of elemental selenium (Scheme 2). No-
tably, two of the most conveniently removed protecting groups
for amines, the 4-nitrobenzenesulfonyl (Ns) and 2,2,2-
trichloroethoxysulfonyl (Tces) groups, generally gave high
yields.
were generally orthogonal: IMeSe gave high yields for more
electron rich alkenes whereas Cy3PSe was required for less
electron rich alkenes.
Having successfully developed a broadly applicable allylic
C–H amination reaction, we returned to the original question
of whether this method could be used to generate new nitro-
gen-containing compounds based on terpenoid scaffolds. A
variety of terpenoid natural products were subjected to the
optimum reaction conditions (Scheme 4). We were able to
obtain good yields of allylic amination products for every al-
kene substitution pattern from monosubstituted to tetrasubsti-
tuted, and in most cases a single regioisomer was formed.
Acyclic trisubstituted alkenes, e.g. those derived from
uncyclized terpenoids like citronellol and geraniol, reliably
gave amination at the more substituted end of the alkene, trans
to the third substituent, giving a single alkene stereoisomer
(23a-29a). Mycophenolic acid, for example, was preferentially
aminated beta to the ester according to this rule, rather than at
the weaker benzylic/allylic C-H bond. In compounds with
multiple C=C bonds, the most electron-rich alkene reacted
preferentially.
To illustrate the full potential of this reaction as a labeling
method, a wide range of sulfonamides and sulfamates were
coupled with our test alkene (Scheme 3). Several types of syn-
thetically useful amine protecting groups were introduced in
high yields, including groups that are cleaved using mild nu-
cleophilic substitution (Ns), Zn reduction (Tces), hydrolysis
(Tfes), and photolysis (Nbos). Groups that can undergo further
coupling reactions can also be reliably introduced, including
aryl halides and boronates for cross-coupling (1e, 1f) and al-
kynes and azides for Cu-catalyzed cycloaddition (1g, 1h). The
polarity and/or solubility of the alkene substrate can be modi-
fied by appropriate choice of amination partner, including
groups with strongly acidic N–H bonds (TfNH, pKa ~ 7 in
H2O), long hydrocarbon chains for hydrophobicity (1j), and
perfluorocarbon chains for fluorous separation (1k). This cou-
pling procedure could also be used to label substrates with
fluorescent groups (1l).
Exploration of cyclic substrates revealed that trisubstituted
alkenes typically provided endocyclic substitution products
(32a-34a), most notably at the highly sterically hindered ter-
tiary position in -ionone. If the endocyclic site was blocked,
as in cholesterol, theaspirane, nerol, and pinene, exocyclic
substitution took place instead (31a, 35a-38a). High diastere-
oselectivity was usually observed in cyclic alkene substrates,
with amination occurring at the stereoelectronically required
axial C–H bond (32a, 34a, 35a, 40a, 41a). Interestingly, the
1,2-disubstituted alkenes methyl jasmonate and -damascone
reacted regioselectively (39a, 40a), as did 1,1-disubstituted
alkene caryophyllene oxide (41a). The most challenging sub-
strates were those bearing an exocyclic isopropenyl group
(42b-45a). Although these gave high overall yields of prod-
ucts, selectivity between a CH3 group and a CH group was
sometimes low. It is important to note that in almost all cases,
the regioselectivity observed in this selenium-catalyzed proto-
col was different from that observed in nitrenoid, radical, and
We then tested our allylic amination procedure on more
highly substituted alkenes and found that these gave disap-
pointing yields with the Cy3PSe catalyst. However, a screen of
ligands revealed that simply changing the catalyst to the N-
heterocyclic carbene-derived selenourea IMeSe gave us high
yields for these more active substrates. These two catalysts
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Scheme 4. Amination of terpenoids and tagging of biologically active sulfonamides and sulfamates.
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To demonstrate the ability of this reaction to easily couple
complex partners, a collection of sulfamates and sulfonamides
derived from biologically active compounds was reacted with
-allyl amination reactions, which usually aminate on the less-
substituted end of the alkene, providing unique access to these
amination products.
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several different alkene partners (Scheme 4). Sulfamates were
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easily prepared in a single step from biologically active alco-
hols like the antifungal paclobutrazol, antibiotics triclosan and
metronidazole, as well as a glucofuranose derivative. These
sulfamates were then coupled to a range of alkenes in good
yields, generating alkene/drug conjugates (46-49). The sulfon-
amide analgesic celecoxib (50) and the fluorescent group dan-
syl amide (51) also could be coupled to terpenoids in good
yields.
The observed regio- and stereoselectivities are consistent
with the sequential ene reaction/[2,3]-sigmatropic rearrange-
ment mechanism originally proposed by Sharpless (Scheme
5D) and are similar to those observed in the stoichiometric
reactions of sulfur and selenium bis(imide)s. Specifically,
steric and electronic bias in the initial ene reaction generally
determines the observed product. Similar to SeO2 oxidations,49
development of partial positive charge at the internal carbon
explains why amination at the more substituted end of the
most electron rich alkene is observed. A complex interplay
between steric and electronic effects is responsible for the
observed order of substitution pattern reactivity (CH2 > CH ~
CH3). More substituted C-H bonds result in a more exothermic
ene reaction because they give more substituted alkene prod-
ucts, but steric hinderance at more substituted C-H bonds in-
hibits activation of highly substituted methine centers. The
observed preference for activation of the axial hydrogen is due
to the fact that only the axial hydrogen has proper stereoelec-
tronic overlap with the pi system to undergo the ene reaction.
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To test the role of the ligand, several mechanistic experi-
ments were performed (Scheme 5A). Neither commercial Se
powder nor Cy3P alone gives any product. Adding Se and
Cy3P to the reaction mixture separately does give the desired
product, but these two reagents also react with each other to
generate Cy3PSe under these conditions. Indeed, pre-mixing of
Se and Cy3P for just 5 minutes before adding the other rea-
gents results in yields that are nearly the same as using pre-
made Cy3PSe, indicating that in situ formation of the phos-
phine selenide is a viable alternate protocol.
In situ 31P NMR spectroscopy of the catalytic reaction mix-
ture revealed the immediate disappearance of the signal for
Cy3PSe with concomitant formation of two new species
(Scheme 5B, see Supporting Information for details). Both
new species persisted for the duration of the catalytic reaction,
and the same NMR spectrum was obtained in the presence or
absence of alkene 1. One new resonance at 68 ppm had clear
satellites from coupling to 77Se, whose coupling constant (JP-Se
~ 425 Hz) is substantially smaller than that of Cy3PSe. The
downfield shift and reduced coupling constant of this species
are both consistent with substantial weakening of the P-Se
bond via coordination at Se. Similar values have been ob-
served for metal complexes of Cy3PSe.50 The other resonance
at 56 ppm is somewhat broad and has no 77Se satellites. Addi-
tion of an authentic sample established that this resonance is
due to Cy3PO, but its downfield shift relative to free phosphine
oxide (~56 vs 49 ppm) is consistent with coordination of the
oxygen to a Lewis acid and/or hydrogen bond donor.51,52 Un-
fortunately, further NMR investigations did not allow conclu-
sive identification of the exact species to which Cy3PO and
Cy3PSe are coordinated.
Isolation or characterization of the putative selenium
bis(imide) has not been reported, frustrating our efforts to es-
tablish it as a key intermediate. Instead, we focused our study
on the active aminating reagent previously prepared by Sharp-
less from SeCl4 and TsNH2 in the presence of Et3N (Scheme
5C).39 This mixture was then treated with an equivalent of
Cy3P, Cy3PSe or Cy3PO and a 31P NMR spectrum was ob-
tained. Then, 1 equiv of alkene 1 was added to each of these
mixtures and allowed to react for 24 h. Addition of Cy3P re-
sulted in three new 31P NMR resonances, none of which corre-
sponds to free Cy3P. We can assign these as Cy3PNTs (38
ppm), Cy3PO (49 ppm) and Cy3PSe (58 ppm), indicating that
free phosphine is rapidly oxidized by the putative selenium
bis(imide) and unlikely to persist under the reaction condi-
tions. Addition of Cy3PSe to selenium bis(imide) resulted in
no change in the 31P NMR for Cy3PSe. However, addition of
Cy3PO to this mixture resulted in a significant change in the
1H NMR resonances of the tosyl substitutents, accompanied by
a shift of the Cy3PO 31P NMR resonance to 52 ppm. Notably,
conversion of alkene 1 to amination product 1m was only
moderate for the putative free selenium bis(imide), as well as
for the mixtures with Cy3P and Cy3PSe added. However, addi-
tion of Cy3PO resulted in a substantial increase in conversion
Scheme 5. Mechanistic experiments and proposed catalytic
cycle
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to 51%. This is identical to the yield of 1m under our standard
catalytic conditions (51%).
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We propose that selenium bis(imide) is generated by oxida-
tion of the phosphine selenide by PhI(OAc)2/RSO2NH2 and
that phosphine oxide formed in the process (and possibly
phosphine selenide) may coordinate to the bis(imide) under
the reaction conditions (Scheme 5D).52 Coordination of phos-
phine oxide to the selenium bis(imide) is predicted to be mod-
erately exergonic by DFT calculations (G ~ -10 kcal/mol, see
Supporting Information for details) and may help stabilize the
selenium bis(imide) and/or promote its regeneration. Further-
more, these calculations identify a transition state (Gǂ = +18
kcal/mol) for the ene reaction to take place on the adduct A
with simultaneous displacement of the phosphine oxide. We
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Allylic Amination versus Allylic Oxidation: A Mechanistic Dichoto-
my. Organometallics 2005, 24, 1747-1755.
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CONCLUSIONS
In conclusion, we have developed a new broadly applicable
selenium-catalyzed allylic C–H amination of alkenes. Alkene
substitution patterns from mono- to tetrasubstituted can be
directly coupled with a wide range of sulfonamides and sulfa-
mates with high, predictable regioselectivity in an operational-
ly simple, metal-free reaction. This reaction has been used to
introduce new C–N bonds in an assortment of terpenoid natu-
ral products, thereby generating a new class of potentially
bioactive products.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, spectral characterizations, and addition-
al data. (PDF)
AUTHOR INFORMATION
Corresponding Author
* Forrest Michael – michael@chem.washington.edu.
ACKNOWLEDGMENT
We thank the University of Washington and the National Science
Foundation (CHE-1764450) for funding.
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