Reductive and brominative termination of alkenol cyclization in aerobic cobalt-catalyzed reactions

Article abstract of DOI:10.1021/ja904577c

(Chemical Equation Presented) Tetrahydrofur-2-ylmethyl radicals were stereoselectively generated from substituted pent-4-en-1-ols in aerobic cobalt(II)-catalyzed oxidations. Intermediates were trapped with cyclohexa -1,4-diene, γ-terpinene, BrCCl3, diethyl dibromomalonate, or electron-deficient olefins such as acrylonitrile or dimethyl fumarate to afford functionalized tetrahydrofurans in synthetically useful yields.

Full text of DOI:10.1021/ja904577c

Published on Web 08/20/2009
Reductive and Brominative Termination of Alkenol Cyclization in Aerobic
Cobalt-Catalyzed Reactions
Dominik Schuch, Patrick Fries, Maike Do¨nges, Ba´rbara Mene´ndez Pe´rez, and Jens Hartung*
Fachbereich Chemie, Organische Chemie, Technische UniVersita¨t Kaiserslautern, Erwin-Schro¨dinger-Strasse,
D-67663 Kaiserslautern, Germany
Received June 9, 2009; E-mail: hartung@chemie.uni-kl.de
Aerobic oxidations of substituted pent-4-en-1-ols (bishomoallylic
alcohols) occur with notable rates and diastereoselectivity, if
catalyzed with appropriate cobalt(II) chelates.1,2 The ring closure
furnishes substituted tetrahydrofuryl-2-methanols (Scheme 1, Y )
OH), which constitute valuable building blocks for natural product
synthesis.3,4 In an attempt to oxidize (E)- and (Z)-configured
substrates under such conditions, however, a loss of stereochemical
information associated with the olefinic π-bond was observed. This
finding was explained with the appearance of configurationaly labile
reactive intermediates.5 In the present report we provide evidence
that these intermediates are free carbon radicals that can be
converted with a variety of reagents into synthetically useful
functional groups. Since oxidative catalytic methods in carbon
radical chemistry so far were restricted to hydrocarbon oxyfunc-
tionalization,6 it was our aim in the present study to develop
methods for reductive, brominative, and alkylative termination of
aerobic cobalt catalyzed alkenol cyclizations.7
naturally occurring derivative γ-terpinene (isopropyl-4-methylcy-
clohexa-1,4-diene) was effective without a change in selectivity
(Table 1, entries 2, 6, and 9). Such reactions provided isopropyl-
4-methylbenzene and H2O as secondary products. This finding
pointed to an active role of applied dihydroarenes in H-atom transfer
reactions, for instance, Co(III)/Co(II) reduction for maintaining the
catalytic cycle, or completion of O2 conversion into H2O. The
stoichiometry of this redox chemistry is under current investigation.
Table 1. Reagent Guided Selectivity in Cobalt-Catalyzed Alkenol
Cyclizationsa
CoL2c
mol %
/
H2Xd/
equiv
Br-Y/
equiv
T/
°C
(()-2e/
%
(()-3e/
%
entry
1-3
Scheme 1. Proposed Catalytic Cycle for Aerobic Alkenol
Oxidationa
1
2
3
4
5
6
7
8
9
a
a
a
a
b
b
b
c
1
1.5
CHD/20
γ-Ter/12
CHD/30
CHD/30
CHD/20
γ-Ter/12
-
-
60
80
85
82
-
-
-
g
4 × 5
2 × 5
2 × 2
2 × 2
BrCCl3/10 60
85
82
-
DBMf/6
60
75
80
4
80
70
-
-
-
g
4 × 10 CHD/30
BrCCl3/10 75
-
87h
-
2 + 1
3 + 2
CHD/20
γ-Ter/12
-
-
75
80
88
81
76
c
c
-
10
3 × 10 CHD/30
BrCCl3/10 75
13h
a Quantitative conversion of 1a-c (tlc). b Toluene for brominations;
no additional solvent for reductions. c Portions of CoL2 were added in
3
h ) cyclohexa-1,4-diene, γ-Ter ) γ-terpinene
intervals. d CHD
a (H2X ) coreductant, R1 ) e.g. alkyl or aryl; Y ) OH, H; for Y ) Br,
(isopropyl-4-methylcyclohexa-1,4-diene). e cis/trans < 1/99 for 2a-b,
3a-c, cis/trans ) 3/97 for 2c (GC). f DBM ) diethyl dibromomalonate.
g Not detected (GC-MS and 1H NMR). h Two isomers isolated
(additional stereogenic center in side chain); dr ) 65:35 for 3b and
54:46 for 3c (determined by GC).
and alkyl and for CoL2, see text).
Reductive ring closures of chosen reporter substrates, i.e.
1-phenylpent-4-en-1-ols 1a-c, required heating (60-75 °C) in
solutions of cyclohexa-1,4-diene (CHD, 20 equiv) containing 1-4
mol % of {4-[3,5-bis(trifluoromethyl)-phenyl]-4-oxybut-3-en-2-
one}-cobalt(II) (CoL2). The reactions were run in an open flask
that was connected to a reflux condenser, to allow extensive contact
with air. This setup gave 2,5-trans-substituted tetrahydrofurans
2a-c (94 e de <99%) in 80-88% yields (Table 1, entries 1, 5,
and 8). No substrate turnover occurred in the absence of O2, CHD,
and CoL2 or by substituting cobalt(II) acetate or donor-substituted
cobalt(II)-diketonate complexes for CoL2. Tetrahydrofuryl-2-metha-
nols (Scheme 1, Y ) OH) were not formed in these runs as evident
from GC analysis in combination with a highly sensitive color test,
i.e. the absence of bluish staining with Ekkert’s reagent of developed
SiO2-coated tlc sheets at Rf ) 0.13 [petroleum ether/acetone, 5:1
(v/v)]. Formation of suspected alcohols became evident as CHD
concentrations fell below ∼3 M. Replacement of CHD with its
A change in selectivity from reductive termination to bromocy-
clization was attainable upon addition of BrCCl3 or diethyl
dibromomalonate (DBM) to standard reaction mixtures (Table 1,
entries 3, 4, 7).8,9 Toluene was added as cosolvent for improving
selectivity of the system. Diastereoselectivities of brominated
heterocycles 3a-b corresponded to values reported for tetrahy-
drofurans 2a-b in the absence of BrCCl3. Acceptor-substituted
alkenol 1c was the only substrate that resisted effective bromocy-
clization under such conditions (Table 1, entry 10), possibly for
reasons suggested in the mechanistic discussion below. The rates
of bromocyclizations were smaller than those of the reductions (i.e.,
formation of 2) and required larger amounts of CoL2.
To further explore the scope of the cobalt-method, additional
mono-, di-, and trisubstituted alkenols 1d-h were transformed with
O2/CoL2 in CHD into products of reductive ring closure (formation
9
12918 J. AM. CHEM. SOC. 2009, 131, 12918–12920
10.1021/ja904577c CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Synthesis of (-)-allo-Muscarine
of 2d-h). Conversion of the given substrates using O2/CoL2 as
oxidant in solutions of CHD, toluene, and BrCCl3 consistently
provided bromocyclized compounds 3d-h. Derived tetrahydrofur-
2-ylmethanols were not detected in any of these runs. Observed
cis/trans ratios of products 2d-h/3d-h (Table 2) agreed with
stereoselectivity reported for oxidative cyclizations of the reactants
in iPrOH in the same temperature range. The latter solvent is
particularly useful for tetrahydrofurylmethanol synthesis from pent-
4-en-1-ols in aerobic cobalt-catalyzed oxidations.2
oxygen, not shown) requires an adequate hydroxyl protecting
group13 to undergo 5-exo-trig cyclization and not a very effective
ꢀ-fragmentation. No 3-hydroxyl-protecting group was necessary in
the case of the cobalt-catalyzed bromocyclization.
Table 2. Products of Reductive and Brominative Alkenol
Cyclization in Aerobic Cobalt-Catalyzed Reactions (See the
Supporting Information)
The chemical nature of the reactive intermediate relevant for
explaining selectivity in the terminating step was scrutinized in
aerobic cobalt-catalyzed oxidations of cyclopropyl-substituted phe-
nylpentenol 1j. If conducted in CHD, the reaction furnished
exclusively butenyl-substituted, diastereomerically pure tetrahy-
drofurans 2k and 4k but no cyclopropyl-substituted derivatives (1H
NMR and GC-MS; Scheme 3). Formation of alcohol (()-4k under
such conditions was unexpected in view of the observations
summarized above (Tables 1-2). This product was not found in
reaction mixtures obtained from aerobic oxidations of 1j in the
presence of BrCCl3 (Scheme 3).
Scheme 3. Formation of Butenyl-Substituted Tetrahydrofurans
c
a 10 mol % of CoL2 b 4 × 5 mol % of CoL2. GC and H NMR.
1
a 1-5 mol % CoL2, 60-75 °C, 7-24 h, 20 equiv of CHD. b 15-40
mol % CoL2, 60-75 °C, 8-22 h, 30 equiv of CHD, 10 equiv of
BrCCl3. c Additional product: ∼36% of (2,4,5-trimethoxyphenyl)prop-
1-ene. Numbers in parentheses refer to yields and cis/trans ratios.
The third objective, i.e., alkylative trapping of cyclized alkenols,
was feasible starting from substrate 1a in solutions of toluene (60
°C) that contained a 3-5 M concentration of CHD and 2-4 M
levels of preferentially an electron-deficient alkene. The use of
acrylonitrile provided 41% of 1,1-adduct (()-5a, 36% of 1,2-
addition product (()-6a, and 16% of reduction product 2a (Scheme
4 and Supporting Information). Equimolar BrCCl3/acrylonitrile
mixtures afforded under otherwise identical conditions exclusively
bromocyclization product 3a (GC-MS; not shown). The use of
dimethyl fumarate and CHD gave 51% of 1,1-adduct (()-7a and
15% of trans-5-methyl-2-phenyltetrahydrofuran 2a (Scheme 4).
Formation of 1,2-addition products from alkenol 1a and dimethyl
fumarate was not observed.
From a mechanistic point of view, the results collected in the
current study provide strong evidence for an alkenol conversion
that occurs in two consecutive steps. The combination of CoL2/O2
thereby is assumed to serve as a one-electron oxidant for transfor-
mation of the olefin into a radical cation and subsequently into an
intermediate that is for the following reasons proposed to be a free
carbon radical (see also Scheme 1).2,16
Reductive cyclization of diastereomerically pure (1S*,2S*,3R*)-
1,3-bis[2,4,5-(trimethoxy)phenyl]-2-methylpent-4-en-1-ol (()-1h10
provided target compound (()-2h, i.e. the 5-epimer of naturally
occurring antiallergic lignane magnosalicine, in 84% yield.11 The
origin of a surprisingly low yield of 22% of bromocyclization
product (()-3h, in combination with an unsatisfactory mass balance,
even by taking formation of 36% of (2,4,5-trimethoxy)-phenylprop-
1-ene into account, certainly requires future attention.
The outstanding 2,5-trans diastereoselectivity of cobalt-catalyzed
bromocyclizations was applied in a concise synthesis of enantio-
merically pure (-)-allo-muscarine,12,13 one of the physiologically
active constituents of the fly agaric Amanita muscaria14 (Scheme
2). For practical reasons, bromocyclization of (2S,3R)-hex-5-en-
2,3-diol, (2S,3R)-(1i), was conducted in the presence of DBM as a
trapping reagent. This variation improved the yield from 65%
(BrCCl3) to 75%. It furthermore prevented consumption of substrate
(2S,3R)-1i by side reactions, such as BrCCl3 addition across the
olefinic double bond, and thus allowed more convenient purification
of product (2S,3R,5R)-3i from the reaction mixture.
(i) Formation of ω-bromobutenyl-substituted tetrahydrofuran (()-
3k from ω-cyclopropylphenylpentenol 1j requires an efficient ring-
opening process. Although it is not possible from the existing data
to distinguish whether the cycloaliphatic ring fragments prior or
after tetrahydrofuran formation, this type of reactivity restricts the
set of possible intermediates to radicals, radical cations, or
carbenium ions.17
If compared to other electrophile-induced ring closures, it is
worth noting that polar bromocyclizations of substrate (2S,3R)-1i
(nucleophilic oxygen), e.g., with Br2, affords a 40/60 mixture (20
°C) of (2S,3R,5R)-3i versus the undesired (2S,3R,5S)-isomer.15 The
(2R,3S)-3-hydroxy-hex-5-en-2-oxyl radical in turn (electrophilic
9
J. AM. CHEM. SOC. VOL. 131, NO. 36, 2009 12919

C O M M U N I C A T I O N S
Scheme 4. Alkylative Termination of Aerobic Cobalt-Catalyzed
Alkenol Ring Closure
displacement at CHD, polar effects are expected to be less relevant
for explaining relative transition state energies of intermediates
associated with carbon radical reductions.
The chemistry associated with the final step of cobalt-catalyzed
aerobic alkenol oxidation, in conclusion, is uncontradictively
explicable with the existence of free carbon radicals. If combinations
of XH-acidic nucleophiles (X ) e.g. O, N) and olefins other than
those described in the present report were able to provide free
carbon radicals, the new methodology would have the potential to
supplement existing well-established tin or silicon hydride based
methods for conducting carbon radical chemistry under reductive
conditions, however, on the basis of a catalytic reaction.27
Acknowledgment. Financial support was provided by the Fonds
der Chemischen Industrie, the state of Rheinland-Pfalz/NanoKat
(scholarships for D.S.), and the DAAD (scholarship for B.M.). This
paper is dedicated to Prof. Dr. Bernd Giese on the occasion of his
69th birthday.
a 50/50 mixture of diastereomers at CR.
(ii) 1,4-Dihydroarenes, BrCCl3, and DBM are efficient radical
trapping reagents18 but typically do not react with cations.19,20
(iii) The notable driving force for addition to electron-deficient
olefins revealed the nucleophilic behavior of cyclized intermediates.
Primary, secondary, and tertiary carbon radicals are nucleophilic
intermediates.21
Supporting Information Available: Experimental procedures,
spectral and analytical data of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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