Transition Metal Free C-N Bond Forming Dearomatizations and Aryl C-H Aminations by in Situ Release of a Hydroxylamine-Based Aminating Agent

Article abstract of DOI:10.1021/jacs.7b07830

We outline a simple protocol that accesses directly unprotected secondary amines by intramolecular C-N bond forming dearomatization or aryl C-H amination. The method is dependent on the generation of a potent electrophilic aminating agent released by in situ deprotection of O-Ts activated N-Boc hydroxylamines.

Full text of DOI:10.1021/jacs.7b07830

Communication
pubs.acs.org/JACS
Transition Metal Free C−N Bond Forming Dearomatizations and Aryl
C−H Aminations by in Situ Release of a Hydroxylamine-Based
Aminating Agent
Joshua J. Farndon, Xiaofeng Ma, and John F. Bower*
School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom
S
* Supporting Information
hydroxylamines 2, which, in turn, were accessed by in situ
deprotection of N-Boc precursors 1 (Scheme 1B).2d This
ABSTRACT: We outline a simple protocol that accesses
directly unprotected secondary amines by intramolecular
C−N bond forming dearomatization or aryl C−H
amination. The method is dependent on the generation
of a potent electrophilic aminating agent released by in situ
deprotection of O-Ts activated N-Boc hydroxylamines.
approach is notable because (a) it allows the direct preparation
of unprotected nitrogen ring systems by aryl C−H amination and
(b)precursors 1aredirectlyaccessiblebyMitsunobualkylationof
bifunctional amino-reagent 4.
As part of an ongoing program aimed at exploiting electrophilic
nitrogen sources for heterocycle synthesis,7 we considered
whether the Falck approach could be adapted to C−N bond
forming dearomatizations of phenols 5 (R = OH) (Scheme 1C).8
Such a process would allow the direct preparation of complex “3-
dimensional” heterocycles from simple precursors.9 Contrary to
our initial expectations, we disclose herein that hydroxylammo-
nium intermediates 6 are in fact sufficiently reactive that C−N
bond formation occurs efficiently in the absence of a rhodium
catalyst. The method can be used to promote both the envisaged
C−N bond forming dearomatizations as well as aryl C−H
aminations, with the former providing products equipped with
nucleophilic and electrophilic functionality that can be engaged
directly in further annulations. The processes are rather unusual,
apparently involving direct SEAr-like attack of the aromatic
moiety onto the activated hydroxylammonium unit (6), which is
generated in situ under mild conditions. The studies described
here suggest that intermediates of this type might have the
potential to facilitate a wide range of transition metal free C−N
bond formations.
eneral methods for intramolecular electrophilic C−H
1−5
Gamination of aromatic units are rare,
and very few of
these are transferable to C−N bond forming dearomatization
reactions.1c,d,f,g,6 Classically, the most powerful approach
harnesses the intermediacy of nitrenium electrophiles; however,
their high reactivity necessitates stabilizing functionality, with
efficient protocols restricted to the provision of lactams equipped
with specific N-protecting groups (Scheme 1A).1 To circumvent
these limitations, Falck and co-workers recently disclosed
intramolecular aryl C−H amination processes triggered by
rhodium nitrenoids 3; these were generated from activated
Scheme 1. Introduction
In initial studies, we examined the cyclization of a TFE solution
of phenolic system 5a,10 which was prepared in high yield by
Mitsunobu alkylation of 4 (see the SI). To our delight, in the
presence of TFA (2 equiv) and Rh2(esp)2 (2 mol %), spirocyclic
target 7a was generated in 88% NMR yield (Table 1). However,
further control experiments revealed that the rhodium catalyst
wasnotrequired, with7aformedin77%yieldinitsabsence. Upon
completionofthereaction, 7acouldbeisolatedasitsTsOHsaltin
sufficient purity for most purposes by simply removing volatile
components under reduced pressure. Alternatively, and despite
its obvious sensitivity, we established that chromatographic
purification of 7a is possible using Et3N washed silica. Fractions
containing the product were acidified with TFA to afford the TFA
salt of 7a;with thenitrogen protonated, the product was relatively
resistant to polymerization and other decomposition pathways
(vide infra). This purification procedure was used for other
sensitive products described later (see the SI).
Received: July 26, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b07830
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
can be performed with equal levels of efficiency from silyl
protected phenols. For example, we found that O-TBS system
silyl-5a (the precursor to 5a) generated 7a in 83% yield simply by
using an extra equivalent of TFA in the dearomatization reaction
(Scheme 2A). In certain cases, we observed the formation of
tetrahydroquinoline products in addition to the desired
spirocyclic targets. This competing process was most apparent
formethoxy-substituted system 5j, whichcyclizedtoprovidea1:2
mixture of spirocycle 7j and tetrahydroquinoline 8j (Scheme 2B).
C−H amination is likely facilitated by the electron donating
methoxy group, which activates the para-position (C5) of 5j. This
side process was observed to a lesser extent for other systems
possessing para-directing substituents at C2. Indeed, in addition
to spirocycles 7c−e, tetrahydroquinolines 8c−e were also
isolated in 19−35% yield. 7d was recovered unchanged when
resubjected to the reaction conditions, supporting the idea that
tetrahydroquinoline 8d arises via a direct aryl C−H amination
pathway rather than by rearrangement of 7d. Although side
products of this type were not observed for the other examples
studied in Table 1, we have found that in certain cases other
tetrahydroquinoline substitution patterns can be accessed via a
mechanistically distinct pathway. When the cyclization of 5g was
run using only 15 mol % TFA at 60 °C (vs 200 mol % at r.t. in
Table 1), 7g was not observed and, instead, tetrahydroquinoline
8g formed in 79% yield (Scheme 2C). Control experiments
indicate that initial spirocyclization does occur, but the lower
equivalents of acid mean that the amine of 7g is not fully
protonated and so its lone pair can trigger a thermally promoted
aza-dienone-phenol rearrangement to provide 8g.1c,d,2a,12,13 This
process was notreadily achieved forsystems without asubstituent
at C3, likely due to the lower migratory aptitude of the associated
C−C bond.14
Table 1. C−N Bond Forming Dearomatizations of para-
Phenols and Naphthols
a
b
Isolated as the TFA salt. Isolated as the free base.
Examination of the scope of the process revealed that it
tolerates a wide range of differentially substituted para-phenols,
such that 7b−f were all formed in synthetically useful yields
(Table 1). Spirocycle 7b exhibited good levels of stability as its
free base, and this allowed unambiguous confirmation of its
structure by single crystal X-ray diffraction. The process also
extended to para-naphthol system 5i, which provided 7i in 56%
NMR yield; purification of this product was challenging owing to
its high sensitivity and the modest isolated yield (30%) reflects
this. Systems with substitution on the pyrrolidine ring can also be
generated, as demonstrated by the efficient synthesis of 7g and
7h.11
The studies outlined in Table 1 provided further useful and
insightful observations, and these are summarized in Scheme 2. If
desired from a synthetic viewpoint, the dearomatization process
The C−N bond forming dearomatization method can be
extended to ortho-substituted phenols and naphthols (Table 2).
Spirocyclization of phenols 5k and 5l provided 7k and 7l in 91%
and 78% yield, respectively. Note that 7k formed cleanly, which
highlights the high efficiency of the process in favorable cases.
Naphthol systems 5m−q also participated smoothly to provide
targets 7m−q in generally good yield. In certain cases (e.g., 5q to
7q), the addition of CH2Cl2 cosolvent was necessary to mitigate
the low solubility of the substrate in TFE. Overall, the results in
Tables 1 and 2 show that the dearomatization method has a useful
level of scope with respect to the arene.
Scheme 2. Key Observations
The processes described here provide, for the first time, a direct
C−N bond forming dearomatization approach to unprotected
pyrrolidine derivatives, and so further manipulations can be
achieved by direct reaction at nitrogen. N-Acylation of 7a and 7g
with phenylacetyl chloride provided amides 9a and 9g, which,
upon treatment with LHMDS, cyclized to provide tricycles 10a
and 10g with good levels of efficiency (Scheme 3). The relative
stereochemistry ofthemajordiastereomerof10gwasdetermined
by single crystal X-ray diffraction and other assignments were
supported by NOE studies (see the SI). Reaction of 7g with
phenylisocyanateprovided directlytricyclicurea11gin75%yield
and 4:1 d.r. Similar processes were investigated on spirocycle 7k,
which was used without purification after the dearomatization
step. Here, N-acylation with phenylacetyl chloride was followed
by 1,2-addition of the lithium enolate onto the carbonyl to
generate product 12k in >15:1 d.r. Reaction of 7k with phenyl
isocyanate afforded urea 11k in 68% yield. The processes in
Scheme 3 validate simple and direct entries to complex natural
product-like structures.
a
1
Yield determined by H NMR analysis vs 1,3,5-trimethoxybenzene.
B
DOI: 10.1021/jacs.7b07830
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
under Rh-free conditions to generate 14b in 65% yield (vs 81%
with Rh2(esp)2). More electron deficient aromatic precursors 13c
and 13d cyclize efficiently in the presence of Rh2(esp)2 but do not
undergo aryl C−Haminationinitsabsence. Thus, twocompeting
aryl C−H amination pathways appear to be operative, with the
Rh-catalyzed protocol enabling aminations of less nucleophilic
arenes. Nevertheless, the ability to promote efficient metal free
aryl C−H aminations of electron neutral and electron rich
aromatic units is of high significance (Table 3).15
Table 2. C−N Bond Forming Dearomatizations of ortho-
Phenols and Naphthols
Table 3. Scope of the Metal Free C−H Amination Process
a
Yield reported by Falck and co-workers (see ref 2d).
At the present stage, our collective observations are consistent
with the reactionpathway outlined in Scheme 1C. TFA promoted
deprotection of 5 releases the protonated O-tosyl hydroxylam-
monium unit of 6, which may be attacked directly by the tethered
arene (SEAr) in the C−N bond forming step. This would account
for the requirement of a relatively nucleophilic aromatic partner
for C−N bond formation, although we are unaware of a direct
precedent for this type of attack of an arene onto an electrophilic
primary N(sp3)-center.15 Attempted spirocyclization of methyl
carbamate system 15 resulted in no reaction (eq 1), which
a
Isolated as the TsOH salt by concentration of the reaction mixture.
Isolated as the TFA salt. 30:1 TFE:CH2Cl2 was used as solvent. 5:1
b
c
d
TFE:CH2Cl2 was used as solvent.
Scheme 3. Derivatizations of the Dearomatization Products
supports the idea that N-Boc deprotection occurs prior to C−N
bond formation. We suggest that nitrogen is protonated during
the C−N bond forming step because this alleviates electronic
repulsion that would otherwise exist between the incoming arene
and the N-lone pair of the corresponding hydroxylamine (cf. 2).
The possibility that cyclization occurs via a nitrenium ion or a
(protonated) aminyl radical cannot be discounted.16 However, as
discussed earlier, it is well established that nitrenium ion triggered
cyclizations are not efficient in the absence of stabilizing
functionality.1 To ascertain whether a discrete N-centered radical
might be involved, alkenyl system 17 was exposed to the reaction
conditions in both the absence and presence of 1,4-cyclo-
hexadiene. In both cases only decomposition occurred and
pyrrolidine 18, the potential product of 5-exo cyclization of an N-
centered radical, was not observed (eq 2).16 Addition of either
TEMPO or BHT to the spirocyclization of 5a had an inhibitory
effect, but this was largely overridden using slightly elevated
reaction temperatures.17
The earlier observation of a competing aryl C−H amination
pathway(seeScheme2B)promptedustoexaminethelimitations
of this process with respect to the electronics of the aromatic unit.
In Falck’s original report a series of systems was investigated using
Rh2(esp)2 as catalyst, but control experiments where this
component was omitted were not disclosed.2d Accordingly, it
was unclear whether the Rh-catalyst isrequired for intramolecular
C−H amination. Indeed, in it absence, we found that cyclization
of methoxy-system 13a occurred in 80% yield (vs 86% with
Rh2(esp)2). Phenyl-based system 13b also cyclized efficiently
C
DOI: 10.1021/jacs.7b07830
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
S.; Hattori, G.; Narasaka, K. Chem. Lett. 2007, 36, 52. (c) Stokes, B. J.;
Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver, T. G. J. Am. Chem. Soc.
2007, 129, 7500. (d) Jana, S.; Clements, M. D.; Sharp, B. K.; Zheng, N.
Org. Lett. 2010, 12, 3736.
To conclude, we outline a conceptually simple, but highly
unusual method for achieving C−N bond forming dearomatiza-
tions and aryl C−H aminations. Upon treatment with acid, and
under metal free conditions, a potent electrophilic aminating
agent is generated, and this interacts efficiently with pendant
arenes in a process that resembles an SEAr amination. Although
C−C bond forming dearomatizations triggered byintramolecular
attack of phenols onto primary C(sp3)-sulfonates were first
reported 60 years ago,18 the studies described here are the first
aza-variants of this process. The method represents a step change
in efficiency vs conventional nitrenium ion mediated processes,
suggesting that a diverse range of new C−N bond formations
might be achievable by exploiting the untapped potential of
electrophilic intermediates related to 6.
(4) Intramolecular aryl C−H aminations can also be achieved under
oxidative (oftenmetal-catalyzed) conditions to provide specific classes of
heterocycles. Selected examples: (a) Tsang, W. C. P.; Zheng, N.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560. (b) Inamoto, K.;
Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org. Lett. 2007, 9, 2931.
(c) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932.
(d) Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.;
Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184. (e) Inamoto, K.; Saito,
T.; Hiroya, K.; Doi, T. J. Org. Chem. 2010, 75, 3900. (f) He, G.; Zhao, Y.;
Zhang, S.;Lu, C.;Chen, G. J. Am. Chem. Soc. 2012, 134, 3. (g)Takamatsu,
K.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2015, 80, 3242.
(h) Clagg, K.; Hou, H.; Weinstein, A. B.; Russell, D.; Stahl, S. S.; Koenig,
S. G. Org. Lett. 2016, 18, 3586.
(5) For a recent review on metal-catalyzed aryl C−H amination: Jiao, J.;
Murakami, K.; Itami, K. ACS Catal. 2016, 6, 610.
(6) Intramolecular indole dearomatizations using O-sulfonyl oximes:
Tanaka, K.; Mori, Y.; Narasaka, K. Chem. Lett. 2004, 33, 26.
(7) See: Race, N. J.; Hazelden, I. R.; Faulkner, A.; Bower, J. F. Chem. Sci.
2017, 8, 5248 and references cited therein.
(8) Existing C−N bond forming dearomatizations of phenols involve
oxidation of the arene to a carbocation in advance of trapping by an NH-
nucleophile. Thisnecessitatesspecificprotectinggroupsonnitrogen, and
oxidatively sensitive functionality can compromise reaction efficiency.
Leading references: (a) Braun, N. A.; Ousmer, M.; Bray, J. D.; Bouchu,
D.; Peters, K.;Peters, E.-M.; Ciufolini, M. A. J. Org. Chem. 2000, 65, 4397.
(b) Canesi, S.; Belmont, P.; Bouchu, D.; Rousset, L.; Ciufolini, M. A.
Tetrahedron Lett. 2002, 43, 5193. (c) Liang, H.; Ciufolini, M. A. Chem. -
Eur. J. 2010, 16, 13262. (d) Liang, H.; Ciufolini, M. A. Tetrahedron 2010,
66, 5884. In certain settings, secondary amines have been used as the
nucleophile: (e) Scheffler, G.; Seike, H.; Sorensen, E. J. Angew. Chem., Int.
Ed. 2000, 39, 4593. (f) Mizutani, H.; Takayama, J.; Soeda, Y.; Honda, T.
Tetrahedron Lett. 2002, 43, 2411.
ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/jacs.7b07830.
■
S
Experimental details, characterization data and crystallo-
graphic data (PDF)
Data for C11H15NO (CIF)
Data for C14H15NO (CIF)
Data for C19H21NO2 (CIF)
Data for C18H19NO2 (CIF)
AUTHOR INFORMATION
Corresponding Author
*john.bower@bris.ac.uk
■
ORCID
John F. Bower: 0000-0002-7551-8221
(9) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752.
(10) Other solvents were less efficient. For example, PhMe or CH2Cl2
provided 7a in 40% and 41% yield, respectively. 7a was not formed using
MeOH, THF, EtOAc, or dioxane as solvent.
(11) Higher reaction temperatures provide faster conversion of starting
material but lower yields of the dearomatization products. So far, we have
been unable to extend the method to the synthesis of spirocyclic
piperidines.
(12) (a) Dienone-phenol rearrangement: Arnold, R. T.; Buckley, J. S.;
Richter, J. J. Am. Chem. Soc. 1947, 69, 2322. (b) A similar aza-variant has
beeninvokedbutnotconfirmed:Kawase, M.;Kikugawa, Y. Chem.Pharm.
Bull. 1981, 29, 1615.
(13)Thefreebaseof7gwasheatedat60°CinTFEand8gwasobtained
in 57% yield after 25 h. 8g was obtained in 50% yield (+26% recovered
7g) using 15 mol% TFA in TFE at r.t. (48 h).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
WethanktheBristolChemicalSynthesisCDT,fundedbyEPSRC
(EP/G036764/1) for a studentship (J.J.F.), the Royal Society for
a URF (J.F.B.) and the European Research Council for financial
support (ERC grant 639594 CatHet).
REFERENCES
■
(1) Examples of aryl C−H amination and aryl dearomatization via
nitrenium ions: (a) Glover, S. A.; Goosen, A.; McCleland, C. W.;
Schoonraad, J. L. J. Chem. Soc., Perkin Trans. 1 1984, 2255. (b) Kikugawa,
Y.; Kawase, M. J. Am. Chem. Soc. 1984, 106, 5728. (c) Glover, S. A.;
Goosen, A.; McClei, C. V.; Schoonraad, J. L. Tetrahedron 1987, 43, 2577.
(d) Kawase, M.; Kitamura, T.; Kikugawa, Y. J. Org. Chem. 1989, 54, 3394.
Stabilizing substituents other than N-alkoxy groups can be used, and
(OC)NH(OR) precursors can be used under oxidative conditions. For
example, see: (e) Kikugawa, Y.; Kawase, M. Chem. Lett. 1990, 19, 581.
(f) Kikugawa, Y.; Nagashima, A.; Sakamoto, T.; Miyazawa, E.; Shiiya, M.
J. Org. Chem. 2003, 68, 6739. (g) Miyazawa, E.; Sakamoto, T.; Kikugawa,
Y. Heterocycles 2003, 59, 149. (h) Liang, D.; Yu, W.; Nguyen, N.;
Deschamps, J. R.; Imler, G. H.; Li, Y.; MacKerell, A. D., Jr.; Jiang, C.; Xue,
F. J. Org. Chem. 2017, 82, 3589.
(14) Marx, J. N.; Argyle, J. C.; Norman, L. R. J. Am. Chem. Soc. 1974, 96,
2121.
(15) A full study on the metal free C−H amination protocol will be
reported in due course. Metal free intramolecular aryl C−H aminations
using primary hydroxylamine derivatives have been reported previously,
but forcing conditions were required (see ref 12b).
(16) Stella, L. Angew. Chem., Int. Ed. Engl. 1983, 22, 337 Conventionally,
aminyl radicals are generated from N-chloroamines under either
photochemical or strongly acidic conditions. In general, primary N-
chloroamines, and therefore primary aminyl radicals, are difficult to
access because polychlorination of the amine precursor is problematic.
(17) Full details are given in the SI. The reaction is unaffected by the
presence or absence of light, and very similar results are obtained using
distilled or nondistilled TFA/TFE.
(2)ExamplesofredoxneutralintramoleculararylC−Haminationusing
electrophilic nitrogen sources: (a) Cherest, M.; Lusinchi, X. Tetrahedron
Lett. 1989, 30, 715. (b) Tan, Y. T.; Hartwig, J. F. J. Am. Chem. Soc. 2010,
132, 3676. (c) An, X.-D.; Yu, S. Org. Lett. 2015, 17, 2692. (d) Paudyal, M.
(18) (a) Winstein, S.; Baird, R. J. Am. Chem. Soc. 1957, 79, 756.
(b) Masamune, S. J. Am. Chem. Soc. 1961, 83, 1009.
P.; Adebesin, A. M.; Burt, S. R.; Ess, D. H.; Ma, Z.; Kurti, L.; Falck, J. R.
̈
Science 2016, 353, 1144. (e) Walton, J. C. Acc. Chem. Res. 2014, 47, 1406.
(3) Examples of intramolecular aryl C−H amination using nitrenes:
(a) Taber, D. F.; Tian, W. J. Am. Chem. Soc. 2006, 128, 1058. (b) Chiba,
D
DOI: 10.1021/jacs.7b07830
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX