Dearomative dihydroxylation with arenophiles

Article abstract of DOI:10.1038/nchem.2594

Aromatic hydrocarbons are some of the most elementary feedstock chemicals, produced annually on a million metric ton scale, and are used in the production of polymers, paints, agrochemicals and pharmaceuticals. Dearomatization reactions convert simple, readily available arenes into more complex molecules with broader potential utility, however, despite substantial progress and achievements in this field, there are relatively few methods for the dearomatization of simple arenes that also selectively introduce functionality. Here we describe a new dearomatization process that involves visible-light activation of small heteroatom-containing organic molecules - arenophiles - that results in their para-cycloaddition with a variety of aromatic compounds. The approach uses N-N-arenophiles to enable dearomative dihydroxylation and diaminodihydroxylation of simple arenes. This strategy provides direct and selective access to highly functionalized cyclohexenes and cyclohexadienes and is orthogonal to existing chemical and biological dearomatization processes. Finally, we demonstrate the synthetic utility of this strategy with the concise synthesis of several biologically active compounds and natural products.

Full text of DOI:10.1038/nchem.2594

ARTICLES
PUBLISHED ONLINE: 22 AUGUST 2016 | DOI: 10.1038/NCHEM.2594
Dearomative dihydroxylation with arenophiles
Emma H. Southgate†, Jola Pospech†, Junkai Fu, Daniel R. Holycross and David Sarlah
*
Aromatic hydrocarbons are some of the most elementary feedstock chemicals, produced annually on a million metric ton
scale, and are used in the production of polymers, paints, agrochemicals and pharmaceuticals. Dearomatization reactions
convert simple, readily available arenes into more complex molecules with broader potential utility, however, despite
substantial progress and achievements in this field, there are relatively few methods for the dearomatization of simple
arenes that also selectively introduce functionality. Here we describe a new dearomatization process that involves visible-
light activation of small heteroatom-containing organic molecules—arenophiles—that results in their para-cycloaddition
with a variety of aromatic compounds. The approach uses N–N-arenophiles to enable dearomative dihydroxylation and
diaminodihydroxylation of simple arenes. This strategy provides direct and selective access to highly functionalized
cyclohexenes and cyclohexadienes and is orthogonal to existing chemical and biological dearomatization processes. Finally,
we demonstrate the synthetic utility of this strategy with the concise synthesis of several biologically active compounds
and natural products.
he dearomatization of aromatic compounds is a fundamental synthetic problem. The high resonance energy renders aromatic
synthetic strategy that provides direct and efficient access to a compounds particularly unreactive as starting materials, and reagents
T
wide range of valuable intermediates from simple and abun- that can overcome this chemical inertness preferentially react with
dant sources of hydrocarbons1–5. Numerous bioactive compounds, the more-reactive unsaturated dearomatized products. Ultimately,
natural products, and drugs, such as the analgesic morphine6–8
this problem leads to overreaction and decomposition of the starting
,
the broad-spectrum antibiotic doxycycline9 and the antiviral drug material. We envisioned dearomative functionalization as a two-
oseltamivir (Tamiflu)10–12, have been synthesized utilizing dearoma- stage process, and thus we avoided restrictive reactivity differences
tization as a key step. Despite their strategic and widespread use, between the starting arenes and partially unsaturated products.
most dearomative strategies do not result in the introduction of Key to the successful execution of this plan was the use of visible-
additional functionality. Indeed, the venerable dissolving-metal light photoactivable 2π components, for which we introduce the
reduction (Birch reduction)13, oxidative dearomatization of term ‘arenophiles’, in analogy to thermal cycloaddition processes.
phenols14, and arene–alkene photocycloadditions15 are exception- Specifically, using heteroatom-containing arenophiles that could
ally powerful synthetic transformations; however, most of the dear- formally react in a [4+2] fashion would significantly expand the
omatized products have to be subjected to further manipulations to toolbox of dearomative chemistry, as they would simultaneously
install the desired level of functionalization. To date, only certain induce dearomatization, introduce functionality, create stereogenic
stoichiometric reactions of transition-metal complexes based on centres and enable further functionalization. Subsequent retrocyclo-
Os, Ru, Re, Cr and Mn can enable more elaborate functionalizations addition or fragmentation of the arenophile moiety would then
of the corresponding metal-bound arenes (Fig. 1a, left)2,16–19. Both provide selective access to the corresponding dearomatized
η2- and η6-coordination modes greatly reduce the aromatic character products. Herein we report the realization of this concept in the
of arene ligands and, as a consequence, activate them towards development of a method for the dearomative dihydroxylation
reactions with electrophiles or nucleophiles. After additional func- and diaminodihydroxylation of simple arenes (Fig. 1a, bottom).
tionalization, oxidative decomplexation liberates the dearomatized By using an N–N-arenophile and osmium-catalysed dihydroxyla-
products. Although these methods provide rapid access to com- tion, a variety of aromatic hydrocarbon compounds were trans-
pounds that otherwise require long and tedious manipulations, formed selectively into the corresponding 3,4-dihydrodiols or
the toxicity and cost of the above-mentioned metal complexes diaminodihydrodiols. The synthetic value of this method was
have been significant deterrents to their widespread synthetic use. demonstrated through the synthesis of several highly functionalized
In addition to stoichiometric methods, a catalytic dearomative small organic molecules from readily available staring arenes (Fig. 1b).
polyhydroxylation of benzene is known and proceeds through
photoinduced charge-transfer osmylation20.
Results and discussion
Aside from chemical processes, microbial arene oxidation con- Design of arenophiles and reaction development. Cycloaddition
verts arenes into the corresponding cis-1,2-dihydroxycyclohexa- reactions that involve arenes encompass an important group of
3,5-dienes (2,3-dihydrodiols, Fig. 1a, right) with high levels of enan- dearomatization strategies23. Aromatic compounds, known for
tioselectivity21. Although exceptionally powerful and synthetically their stability in the ground state, become exceptionally reactive
useful22, this biotransformation often involves the use of specific upon photoexcitation and can undergo cycloaddition with a
bacterial strains or recombinant organisms to effect substrate-specific variety of alkenes15. For these processes, high-energy ultraviolet
transformations, and these can usually be obtained only from the light is usually required to access the relatively high π,π*-singlet
laboratories in which they were first cultured.
state of the aromatic nucleus to enable reactivity. The resulting meta-
The development of dearomative functionalization strategies for photocycloaddition is well documented in the literature and has been
arenes is intrinsically challenging and remains a largely unsolved used many times in organic synthesis24,25, whereas the ortho- and,
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, USA. †These authors contributed equally to this work.
e-mail: sarlah@illinois.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2594
ARTICLES
a
R
R
R
Nu
OH
[TM]
η6-arene
E
OH
–
+
Then Nu and E and
metal decomplexation
2,3-dihydrodiol
Arene dioxygenase
R
R
R
E
R = Me
Arene
R
HO
HO
R
OH
Nu
OH
NR´
NR´
3,4-dihydrodiol
This work
[TM]
η2-arene
R
O
Then arenophile
cycloreversion
or fragmentation
–
+
Then E and Nu and
metal decomplexation
NH2
R = OH
OH
H2N
E
OH
Nu
Diaminohydrodiol
b
OH
OH
OH
OH
OAc
OH
OH
OH
OH
OH
Br
OH
H2N
Me
Me
OH
Benzene
Benzyl acetate
Bromobenzene
OH
Conduramine A
MK7607
3-O-desmethyl phomentrioloxin
Figure 1 | Current strategies in dearomative functionalization of arenes, which include this work. a, Left, transition-metal complexation to arenes results in
significant distortions of the of the π-electron density and enables dearomative functionalization. Top right, arene dioxygenase (Protein Data Bank 3EN1) is a
key enzyme in microbial arene oxidation that converts monosubstituted mononuclear arenes into the corresponding optically pure 2,3-dihydrodiols. Bottom
right, visible-light activation of small organic molecules (arenophiles) with in situ dihydroxylation provides tetrafunctionalized bicyclic compounds (this work).
Subsequent retrocycloaddition or fragmentation delivers racemic 3,4-dihydrodiols or diaminodihydrodiols, respectively. b, Small, highly functionalized
molecules prepared using arenophile-based dihydroxylation. Conduramine synthesis was achieved via nitroso Diels–Alder cycloaddition and deprotection
from the benzene-derived dihydrodiol. MK7607 synthesis was accomplished via dihydroxylation and deprotection of the corresponding dihydrodiol derivative
of benzyl acetate. The synthesis of 3-O-desmethyl phomentrioloxin was completed via dihydroxylation and Sonogashira coupling of the bromobenzene-
derived dihydrodiol. TM, transition metal; Nu, nucleophile; E, electrophile.
particularly, the para-photocycloadditions have not received much several small organic molecules using benzene (1a) (HOMO = −9.9 eV)
attention, because both types rarely occur with olefins, and and naphthalene (2a) (HOMO = −8.4 eV) as benchmarks (Fig. 2b).
typically are low-yielding side reactions24.
Thus, a number of different 1,2,4-triazoline-3,5-diones, A1
A conceptually distinct approach towards dearomative cyclo- (HOMO = −11.2 eV, LUMO = −9.7 eV), A2 (HOMO = −10.8 eV,
addition involves photoexcitation of the other cycloaddend to LUMO = −9.7 eV), A4 (HOMO = −10.8 eV, LUMO = −9.3 eV) and
engage the arene in the ground state during the reaction (Fig. 2a). A5 (HOMO = −10.4 eV, LUMO = −8.9 eV), and certain symmetric
Ideally, this alternative activation mode would provide complimen- cyclic (Z)-diazo-containing compounds connected to electron-
tary periselectivity, as well as enable cycloaddition with partners other deficient groups, such as A3 (HOMO = −10.9 eV, LUMO = −9.5 eV)
than alkenes. In this context, we were intrigued by a report by and A6 (HOMO = −9.9 eV, LUMO = −8.8 eV), were found to meet
Hamrock and Sheridan26 that indicated the existence of arenophile- the electronic criteria to react with benzene (the complete list of com-
type reactivity with benzene; however, because of its transient pounds is given in Supplementary Information, page 67). Next, on
nature, the corresponding para-cycloadduct had not been isolated the visible-light irradiation of dichloromethane solutions that
or chemically explored. Furthermore, arene–arenophile photo- contain the potential arenophiles (A1–A6) in the presence of
cycloadditions are still mechanistically ambiguous and could benzene, we detected the formation of para-cycloadducts in
occur via multiple reaction trajectories, including photoinduced three different cases. Although A1, A2 and A4 all showed the
electron- or charge-transfer complexes between the arene and the desired reactivity, we decided to continue our investigations with
excited arenophile23. Nevertheless, the energy provided by visible 4-methyl-1,2,4-triazoline-3,5-dione (A2) because of the ease of its
light is sufficient to excite only the arenophile, because of its preparation and its stability.
much lower-lying and narrower HOMO–LUMO gap (HOMO,
highest occupied molecular orbital; LUMO, lowest unoccupied evaluating the optimal reaction parameters for the formation of the
molecular orbital) compared with that of an arene (Fig. 2a, inset). cycloadduct of benzene with A2 and its in situ trapping with
We commenced our studies on dearomative dihydroxylation by
A crucial electronic requirement for the photoreactivity of an osmium tetroxide. Although cycloaddition occurred readily at
arenophile is that both the HOMO and LUMO energies are within the −78 °C under the influence of visible light, as evidenced by the com-
range of the energy of the HOMO of the arene. To evaluate the viability plete disappearance of the characteristic magenta colour of A2
of potential N–N-arenophiles for the photocycloaddition chemistry, (Fig. 2c) and monitoring by 1H-NMR spectroscopy, the corres-
we performed a computational frontier molecular orbital analysis27 of ponding cycloadduct proved to be rather thermally unstable.
2
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ARTICLES
a
*
*
+
Visible
light
δ
Arene
and/
or
*
–
NR´
R´N NR´
+
R´N NR´
R
NR´
δ
+
R
R´N NR´
R
R
–
NR´
NR´
Exciplex:
[Arene–arenophile
adduct]
Arene
Arenophile
Excited
Exciplex:
arenophile
electron transfer
charge transfer
E
LUMO
SOMOarenophile
LUMO
HOMO
SOMOarene
HOMO
b
E
(eV)
–4
1a
2a
–5
–6
–7
–8
–9
–5.1
–5.2
F3C
CF3
Me Me
N
O
O
O
H
Me
O
N
O
O
S
N
O
O
N
N
N
N
N
O
O
O
O
–8.4
A6
N
N
A5
N
N
–8.8
–9.9
–8.9
N
N
N
N
A4
A3
–9.3
A1
A2
–9.5
–10.9
–9.7
–9.7
–9.9
–10
–11
–10.4
–10.8
–10.8
–11.2
c
Visible light
+
−78 °C
Dissolve in
CH2Cl2
Benzene (1a)
(10 equiv.)
MTAD (A2)
(0.1 M solution)
Figure 2 | Mechanistic considerations and necessary criteria for arenophile reactivity. a, Mechanistic rationale for the visible-light activation of an
arenophile in the presence of an arene. The excited state of the arenophile is capable of forming an electron- and/or charge-transfer-derived exciplex with
the ground-state arene. The resulting exciplex subsequently collapses to form an arene–arenophile cycloadduct. b, Mechanism-guided computational
(B3LYP/6-311+G(d,p)) discovery of potential arenophiles based on benzene (1a) and naphthalene (2a) as archetypical arenes. The requirements for
arenophile reactivity are: (1) the HOMO–LUMO gap of the arene is narrow enough to permit visible-light excitation and (2) the HOMO of the arene is within
the HOMO–LUMO gap of the arenophile. Three arenophiles (insets) showed the desired reactivity with benzene. c, Magenta colour of a solution of A2 and
benzene (1a, 10 equiv.) in dichloromethane before and after visible-light-mediated photocycloaddition. SOMO, singly occupied molecular orbital.
Cycloreversion occurred slowly at temperatures above −50 °C and the subsequent addition of osmium(VIII) oxide and a solution of
rapidly above −10 °C. Furthermore, we found that a 10:1 molar ratio 4-methylmorpholine N-oxide (NMO), water and p-toluenesulfona-
of arene to A2 proved optimal, although ratios as low as 2:1 often mide (p-TsNH2) delivered the dihydroxylated benzene cycloadduct
gave similar yields, albeit at the expense of longer reaction times. 3a in 56% yield. The addition of p-TsNH2 proved to be crucial for
In view of the low thermal stability of the intermediate product, the higher yields as it facilitated hydrolysis of the intermediate osmate
development of reaction conditionsforcold-temperature dihydroxyla- ester28. The second dihydroxylation process (conditions B), based
tion proved necessary. As a result, two different catalytic conditions on a modified Narasaka–Sharpless method29, was performed using
were identified for the in situ dihydroxylation of A2 cycloadducts dichloromethane as the solvent. Thus, after the disappearance of the
with mononuclear arenes. Under the first set of conditions (Table 1, magenta colour, the addition of osmium(VIII) oxide, NMO and
conditions A), the cycloaddition reaction was run in acetone, and n-butylboronic acid afforded the cyclic boronate ester 4a in 65% yield.
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2594
ARTICLES
Table 1 | Substrate scope of mononuclear arenes.
A2
Visible light
O
NMe
R
OH
OH
R
R
O
B-nBu
or
X
X
N
N
then
X
=
O
OsO4 (cat.), NMO,
conditions A or B
1
3
4
O
Conditions A
Conditions B
Me
Me
i Pr
t Bu
TMS
O
O
O
O
O
O
O
O
O
O
O
O
AcO
AcO
AcO
2
X
Y
Y
Y
Y
Y
Y
Y
X
X
X
X
X
X
O
O
3a: 56%
4a: 65%
3b: 39%
4b: 28%
3c: 70%
4c: 28%
3d: 63%
4d: 18%
3e: 48%
4e: 55%
3f: 57%
4f: 44%
3g: 35%
4g: 42%
OMe
OMe
Me
Me
MeO
Me
Me
MeO2C
Me
Cl
Br
O
O
O
O
O
O
Y
O
O
O
O
O
Cl
MeO
Y
Y
X
X
Y
X
Y
X
Y
X
X
O
3h: 23%
4h: 61%
3i: 58%
4i: 64%
3j: 67%
4j: 77%
3k: 59%
4k: 60%
3l: 44%
4l: 64%
3m: 24%
4m: 40%
Compounds 3, Y = 2H
Compounds 4, Y = B-nBu
Conditions A: arene (1, 10 equiv.), A2 (1.0 equiv.), visible-light-emitting diodes (VLEDs), CH2Cl2, −78 °C, 4 h; then OsO4 (5 mol%), NMO (1.2 equiv.), p-TsNH2 (1.2 equiv.), H2O (20 equiv.), acetone (0.1 M
based on A2), −78 °C to 0 °C. Conditions B: arene (1, 10 equiv.), A2 (1.0 equiv.), VLEDs, CH2Cl2 (0.1 M based on A2), −78 °C, 4 h; then OsO4 (5 mol%), NMO (1.2 equiv.), nBuB(OH)2 (1.2 equiv.), CH2Cl2,
−78 °C to 0°C. Isolated yields of the purified material based on A2. TMS, trimethylsilyl.
Table 2 | Cycloreversion or fragmentation of the arenophile moiety.
NHBz
1. N2H4 or KOH,
then BzCl
2. SmI2
R
R
R
O
O
O
O
O
O
N2H4 or KOH,
then CuCl2
X
5
6
7
NHBz
NHBz
NHBz
NHBz
NHBz
iPr
tBu
O
O
O
O
O
iPr
tBu
O
O
O
O
O
O
O
6a: 77%
6b: 77%
6e: 90%
6c: 93%
6f: 90%
NHBz
NHBz
Me
7a: 57%
7b: 72%
7c: 87%
Me
TMS
O
O
O
O
HO
HO
NHBz
NHBz
NHBz
O
O
Me
Me
HO
TMS
6d: 94%
O
O
O
O
O
O
HO
OMe
OMe
MeO
Me
NHBz
NHBz
NHBz
O
O
O
HO
MeO
2
7d: 55%
7e: 61%
7f: 74%
O
O
O
6g: 83%
6h: 55%
6i: 61%
NHBz
NHBz
NHBz
Br
O
O
O
O
Me
Me
HO
BzHN
2
Me
Me
Cl
Br
O
O
O
O
HO2C
O
O
O
O
NHBz
NHBz
NHBz
7m: 45%
6j: 91%
6k: 80%
6m: 77%
7g: 58%
7l: 63%
Conditions for the preparation of 6: N2H4 (10 equiv.), 100 °C, 12 h; or KOH (10 equiv.), iPrOH (0.1 M), 100 °C, 12 h; then CuCl2, NH4OH, 25 °C, 5 min. Conditions for the preparation of 7: (1) N2H4 (10 equiv.),
100 °C, 12 h; or KOH (10 equiv.), iPrOH (0.1 M), 100 °C, 12 h, then BzCl (5.0 equiv.); (2) SmI2 (3.0 equiv.), MeOH, 25 °C, 1 h. Isolated yields of the purified material based on the A2–arene cycloadduct 5.
Bz, benzoyl.
4
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Table 3 | Site-selective dearomative diaminodihydroxylation of polynuclear arenes.
Step 1:
Step 2:
NH2
O
A2
Visible light
R
R
R
OH
OH
OH
OH
N2H4
N
N
X
X
=
NMe
then
OsO4 (cat.),
NMO
then
Ni (cat.), H2
O
NH2
Cl
2
8
9
Me
NH2
NH2
NH2
Br
NH2
OH
NH2
NH2
NH2
NR
OH
OH
OH
Br
OH
OH
OH
OH
OH
OH
Br
NH2
NH2
NH2
9d
9a
9b
9c
Step 1: 82%
Step 2: 75%
Step 1: 71%
Step 2: 82%
Step 1: 57%
Step 2: 60%
Step 1: 57%
Step 2: 81%
Step 1: 81% (9e-Boc, R = Boc)
Step 2: 66% (9e, R = H)
MeO
MeO
Me
NH2
NH2
NH2
OH
NH2
NH2
OH
OH
OH
OH
OH
OH
OH
N
OH
N
OH
NH2
NH2
NH2
NH2
NH2
9f
9g
9h
9i
9j
Step 1: 81%
Step 2: 73%
Step 1: 35%
Step 2: 65%
Step 1: 53%
Step 2: 91%
Step 1: 51%
Step 2: 72%
Step 1: 50%
Step 2: 63%
Conditions for step 1: arene (2, 1.5 equiv.), A2 (1.0 equiv.), VLEDs, acetone, −78 °C, 3 h; then OsO4 (5 mol%), NMO (1.2 equiv.), p-TsNH2 (1.2 equiv.), H2O (20 equiv.), acetone (0.1 M based on A2), −78 °C to
0 °C. Conditions for step 2: N2H4 (10 equiv.), 100 °C, 12 h; then Raney-Ni (0.5 equiv.), H2, EtOH, 50 °C, 12 h. Isolated yields of purified material. Cat., catalyst.
Reaction generality. With the optimal conditions in hand, we began
With the dihydroxylated bicyclic adducts prepared, we turned
an exploration of the scope of this dearomative tetrafunctionalization our attention to the cycloreversion of the arenophile moiety to
by examining simple, mononuclear arenes (Table 1). In addition to liberate the desired dihydrodiols. Although similar unsaturated
benzene (1a), a variety of monosubstituted derivatives proved to be bicyclic urazoles are known to undergo thermal cycloreversion31,
suitable photocycloaddition partners. The tolerance of halogen no reaction was observed on heating cycloadducts 3 or 4 to tempera-
(1k, 1l and 1m) and benzylic heteroatom (1e, 1f, 1h, 1i and 1l) tures up to 250 °C. Therefore, we decided to examine a one-pot
substituents is interesting, as these type of substrates are not urazole hydrolysis/bicyclic hydrazine oxidation sequence that would
generally compatible with chemical-based dearomatizations. generate dihydrodiols via the extrusion of molecular dinitrogen.
Traditionally,
the
use
of
ultraviolet
irradiation
in Although the hydrolysis and oxidation sequence was expected to be
arene cycloaddition chemistry does not permit broader functional- reasonably straightforward, the lability of such dihydrodiols was
group incorporation15,23. In contrast, even benzyl chloride (1l) and potentially troublesome21,32. Indeed, this turned out to be the case,
bromobenzene (1m) underwent para-cycloaddition with A2. This as we observed significant amounts of phenol formation during the
dearomative protocol can be conducted on
a larger scale, oxidation step. However, on examination of a range of protecting
exemplified with a multigram conversion of benzene (1a) and groups and conditions, we eventually found that using the corre-
bromobenzene (1m) without significant erosions in yields sponding acetonides 5 in combination with neat hydrazine or KOH
(Supplementary Information, pages 7 and 21). In addition to in 2-propanol33, followed by CuCl2-mediated oxidation, successfully
cycloaddition, we also observed that the abstraction of benzylic generated protected dihydrodiols 6 as stable compounds. This one-
C–H bonds by photoexcited A2 was a competitive process with pot sequence proved to be highly efficient, as the corresponding
certain substrates, to give formal C–H amidation products diene diol products were prepared in high yields (Table 2, left side).
(limitations of the method are given in Supplementary Information, Most of the functional groups tested proved resistant to urazole
page 22)30. For example, amidation proved to be a major reaction hydrolysis and hydrazine oxidation, with the exception that esters
pathway with toluene (not shown) and a minor side process with were converted into the corresponding carboxylic acids (6j) and alco-
cumene (1b). Importantly, all the substrates reacted in a highly hols (6e, 6f and 6g). Importantly, under the reaction conditions
stereo- and regioselective manner; the resulting products were described, no potentially competitive re-aromatization process was
consistently obtained as
a single constitutional isomer and observed and all the acetonide-protected dihydrodiols were stable
diastereoisomer (an X-ray structure of the acetonide-protected 3a is to standard purification methods. Finally, all the substituted dihydro-
given in Supplementary Information, page 162). At present, there is diols were complementary constitutional isomers to those obtained
no conclusive explanation for the high observed regioselectivity of by microbial arene oxidation21.
the cycloaddition process; however, computational studies are
Next, we sought to investigate arenophile fragmentation to
currently ongoing to elucidate the origins of this selectivity. Finally, extend further the functional scope and utility of this method
at the current level of development, polysubstituted mononuclear (Table 2, right side). This manipulation was achieved in two steps
arenes are not suitable substrates for the dearomatization reaction using hydrolysis of the urazole moiety under the above-mentioned
we describe (Supplementary Information, page 23).
conditions, followed by benzoylation and reductive cleavage of
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2594
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OH
a
O
O
N2H4, 100 °C, 12 h;
then TrocNHOH (1.2 equiv.),
CuCl (1.0 equiv.), Py (2.0 equiv.)
OH
1. Zn (10 equiv.), AcOH, r.t., 2 h
2. TFA, THF/H2O, r.t., 1 h
X
O
O
O
OH
Open to air, THF, r.t., 5 h
83%
78% (over two steps)
NH2
NTroc
5a
11: Conduramine A
10
b
1. TBSCl (1.2 equiv.), imid. (2.0 equiv.),
CH2Cl2, r.t., 2 h
OH
OH
OTBS
OH
2. OsO4 (5 mol%), NMO (1.2 equiv.),
acetone/H2O, 0 °C, 2 h
O
O
O
O
TFA/H2O, r.t., 6 h
OH
HO
HO
94%
60% (over two steps)
OH
OH
12
6e
13: MK7607
Me
Me
1. 15, (2.0 equiv.), Pd(PPh3)2Cl2 (5 mol%),
CuI (10 mol%), Et2NH, 50 °C, 12 h
2. AcOH/H2O, 70 °C, 12 h
c
OsO4 (5 mol%),
Br
Br
O
O
O
NMO (1.2 equiv.)
Acetone/H2O,
0 °C to r.t., 12 h
89%
63% (over two steps)
Me
OH
OH
O
HO
OH
14
HO
OH
16: 3-O-desmethyl phomentrioloxin
6m
Me
15
Figure 3 | Synthetic applications of dearomative dihydroxylation. Further functionalization of the dihydroxylated A2–benzene cycloadduct 5a and benzyl-
alcohol- and bromobenzene-derived 3,4-dihydrodiols (6e and 6m) provides rapid access to conduramine A (11) (a), MK7607 (13) (b) and 3-O-desmethyl
phomentrioloxin (16) (c). imid., imidazole; Py, pyridine; r.t., room temperature; TBS, t-butyldimethylsilyl; TFA, trifluoroacetic acid; Troc, trichloroethoxycarbonyl.
the N–N bond with samarium diiodide34. A range of substituted reductive conditions, followed by acid-mediated deprotection of
cycloadducts was transformed into the respective unsaturated diami- the acetonide, furnished conduramine A (11). Next, the highly
nodiols 7. Moreover, vinyl bromide (7m) survived under these oxygenated cyclohexene herbicidal natural product MK7607 (13)
reductive conditions; only cycloadduct 5l, derived from benzyl (ref. 42) was expediently synthesized in three steps from benzyl-alcohol-
chloride, was converted into the corresponding amide 7l during derived dihydrodiol 6e via protection, dihydroxylation (6e → 12)
this reaction sequence. Importantly, this synthetic sequence provides and subsequent double deprotection. Similarly, bromodihydro-3,4-
direct and selective access to highly functionalized small molecules diol 6m was concisely converted into the 3-O-desmethylated
that are characterized by four contiguous heteroatom-containing analogue of the potent herbicidal agent phomentrioloxin (16)43
stereogenic centres. The arenophile-mediated dihydroxylation with through a stereoselective dihydroxylation, followed by Sonogashira
subsequent fragmentation was also applicable to site-selective dearoma- coupling between the resulting vinyl bromide 14 and acetylene 15,
tization of polynuclear arenes (Table 3)35–38. Thus, using a two-step followed by deprotection44.
protocol that involves A2 cycloaddition/dihydroxylation and urazole
hydrolysis/catalytic hydrogenation, a series of naphthalene deriva- Conclusion
tives was successfully converted into the corresponding diamino- In summary, we disclose here a dearomative functionalization of
diols. In addition to halogens 2b–2d, amide (2e) and benzylic simple arenes that provides access to dihydrodiols and diaminodihy-
ketal (2f) substituents survived under the reaction conditions.
drodiols. Significant features of this strategy include visible-light acti-
Moreover, this strategy proved suitable for trinuclear arenes, vation of the arenophile, in situ dihydroxylation of the corresponding
such as phenyl- and pyridine-containing naphthalenes (2g and 2h) arene–arenophile cycloadduct, and subsequent arenophile cyclorever-
and phenanthrene (2j). For 2g and 2h, the observed site selectivity sion or fragmentation. This method permits the use of substrates that
of dearomatization could be explained by the higher ionization poten- are normally not suitable for chemical-based dearomatizations, such
tials of phenyl and pyridine as compared with that of naphthalene39. as halogen- and benzylic-heteroatom-containing arenes, and provides
In all cases, a single constitutional isomer and diastereoisomer was products that are not obtained by microbial oxidation. In addition to
obtained (X-ray structures of 8a and tetra-acetylated Ac-9a are given engaging a broad range of monosubstituted benzene derivatives, this
in Supplementary Information, pages 163 and 164).
system was also found to be applicable to the site-selective dearoma-
tive diaminodihydroxylation of polynuclear arenes. Finally, we have
Applications of dearomative dihydroxylation. The presented showcased the utilityof arenophile-based dihydroxylation as a starting
dearomative dihydroxylation strategy can enable rapid access to small, point in the expedient preparation of highly functionalized small
highly functionalized organic molecules; three illustrative cases are organic molecules. The study and expansion of the arenophile dearo-
demonstrated in Fig. 3. For example, conduramine A (ref. 40) (11) mative platform to other areas, including the application of different
was prepared from the corresponding A2–benzene cycloadduct functionalization reactions and natural product synthesis, is currently
5a through a modified hydrolysis–oxidation sequence that installed underway and will be reported in due course.
an additional 1,4-syn-aminohydroxy functionality. Accordingly,
one-pot successive urazole hydrolysis, hydrazine/oxamic acid Data availability. Crystallographic data for this paper have been
oxidation41 and subsequent hetero Diels–Alder reaction delivered deposited at the Cambridge Crystallographic Data Centre under
the bicyclic product 10 in 83% yield. Concurrent N–O cleavage and deposition numbers CCDC 1455841–1455843. These data can be
deprotection of the trichloroethoxycarbonyl (Troc) group under obtained free of charge from www.ccdc.cam.ac.uk/data_request/cif.
6
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© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.2594
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Received 9 March 2016; accepted 12 July 2016;
published online 22 August 2016
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Acknowledgements
The authors acknowledge the University of Illinois for generous support of this work. E.H.S.
is a Springborn Graduate Fellow and J.P. is a Fellow of the German Research Foundation
(DFG). We thank S. E. Denmark and P. J. Hergenrother (University of Illinois) for critical
proofreading of this manuscript. We dedicate this article to K. C. Nicolaou on the occasion
of his 70th birthday.
Author contributions
E.H.S., J.P., J.F. and D.R.H. conducted the experiments, analysed the data and prepared the
Supplementary Information. E.H.S., J.P. and D.S. conceived and designed the project,
analysed the data and wrote the manuscript.
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Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be
addressed to D.S.
26. Hamrock, S. J. & Sheridan, R. S. Para photoaddition of N-methyltriazolinedione
to benzene. Synthesis of energy-rich azo compounds comprising benzene +
nitrogen. J. Am. Chem. Soc. 111, 9247–9249 (1989).
Competing financial interests
The authors declare no competing financial interests.
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