Transition-Metal-Free Self-Hydrogen-Transferring Allylic Isomerization

Article abstract of DOI:10.1021/acs.orglett.5b03124

Phenanthroline and tert-butoxide have been established as powerful radical initiators in reactions such as the S_RN1-type coupling reactions due to the cooperation of large heteroarenes and a special feature of tert-butoxide. The first phenanthroline-tert-butoxide-catalyzed transition-metal-free allylic isomerization is described. The resulting ketones are key intermediates for indenes. The control experiments rule out the base-promoted allylic anion pathway. The radical pathway is supported by experimental evidence that includes kinetic study, kinetic isotope effect, isotope-labeling experiments, trapping experiments, and EPR experiments.

Full text of DOI:10.1021/acs.orglett.5b03124

Letter
pubs.acs.org/OrgLett
Transition-Metal-Free Self-Hydrogen-Transferring Allylic
Isomerization
Hong-Xing Zheng,† Zu-Feng Xiao,† Chuan-Zhi Yao,† Qiang-Qiang Li,† Xiao-Shan Ning,†
Yan-Biao Kang,*,† and Yong Tang†,‡
†Center of Advanced Nanocatalysis, Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026,
China
‡The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, 345 Lingling Lu, Shanghai
200032, China
S
* Supporting Information
ABSTRACT: Phenanthroline and tert-butoxide have been established as
powerful radical initiators in reactions such as the SRN1-type coupling
reactions due to the cooperation of large heteroarenes and a special feature
of tert-butoxide. The first phenanthroline-tert-butoxide-catalyzed transition-
metal-free allylic isomerization is described. The resulting ketones are key
intermediates for indenes. The control experiments rule out the base-promoted allylic anion pathway. The radical pathway is
supported by experimental evidence that includes kinetic study, kinetic isotope effect, isotope-labeling experiments, trapping
experiments, and EPR experiments.
a
Table 1. Reaction Conditions
ransition-metal-free radical reactions such as SRN1-type
reactions have experienced a revival in recent years.1−3
T
Besides SRN1-type reactions, other radical reactions have also
been reported.4 The self-hydrogen transferring rearrangement
and coupling reactions have already proven to be powerful
approaches in organic synthesis.5 Transition metals such as Rh,
Ru, Ir, and Pd have been found to be necessary as catalysts for
the allylic isomerization.6−11 To date, the radical transition-
metal-free isomerization of allylic alcohol has not yet been
reported.
b
entry
base (mol %)
3 (mol %)
temp (°C)
conv (%)
1
2
3
4
5
6
7
−
3a (5)
−
90
90
90
90
90
90
80
0
9
tBuONa (5)
tBuONa (5)
tBuONa (5)
tBuONa (5)
tBuONa (5)
tBuONa (10)
3a (5)
3b (5)
3c (5)
3d (5)
3a (10)
97
84
17
15
96
In the transition-metal-catalyzed isomerization of allylic
alcohols, bases were normally found to be essential. We
noted that a catalytic amount of 1,10-phenanthroline (3a) and
tBuONa could catalyze the isomerization of 1a to 2a (Table 1,
entries 1−3).12−14 1,10-Phenanthroline, which was normally
considered a ligand, is essential in this reaction (entries 2 and
3). However, large heteroaromatic rings such as 3a have proven
a
Reaction conditions: 1a (0.5 mmol), toluene (1 mL), argon.
b
1
Determined by H NMR.
2
t
to be good radical initiators in the presence of BuONa. By
screening the reaction conditions, 3a-tBuONa (10 mol %) at 80
°C was chosen as the catalyst for the standard conditions in
allylic isomerization (entry 7). The effect of transition metal
traces was ruled out by ICP-AES analysis.
were achieved. For example, pyridyl ketone 2s was obtained in
84% yield (entry 19), which is comparable to that of 2k.
Ketones 2 are precursors for indenes. For example, 1a was first
isomerized to intermediate 2a, followed by the annulation
promoted by TfOH to afford indene 5a in high yields (eq 1).
The isomerization of allylic amines has also been explored.15
Amines 4a−4c were subjected to the reaction conditions, and
the corresponding ketones were obtained in high yields
(Scheme 1). Imines were not observed in the reaction mixture.
After establishing standard reaction conditions, the scope of
this isomerization was investigated. First, various allylic alcohols
with internal CC bonds were examined. Several (hetero)aryl
allylic alcohols have been subjected to the isomerization
conditions, and generally high yields were obtained (Table
2). For example, allylic alcohols bearing styryl or 2-pyridyl
groups gave the corresponding products 2c or 2k in high yields
(entries 3 and 11). The 3-substitution on an allylic alcohol
resulted in reducing the reaction rate due to the steric
hindrance (entry 12). Next, various allylic alcohols bearing
terminal CC bonds were investigated. Generally, high yields
Received: October 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03124
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Isomerization of Allylic Alcohols
Scheme 2. Deuterium Labeling Experiments
obtained.13 In the cross deuteration experiments, 1a was
subjected to radical reaction conditions in the presence of 1
equiv of tBuOD and only 2a was obtained in 59% yield without
the observation of 2a-d3. When 1a was treated with 2 equiv of
tBuOK without 3a under allylic-anion conditions in the
t
presence of BuOD, the nearly 1:1 mixture of 2a and 2a-d3
was obtained. These findings directly show that the reaction
catalyzed by 3a-tBuONa is different from that promoted by a
stoichiometric base. The deuterium in the 3-position of 2a
under the former conditions thus should be transferred from 1a
a
b
c
Isolated yield. tBuONa (20 mol %), 3a (20 mol %). At 110 °C.
d
e
tBuONa (50 mol %), 3a (20 mol %). tBuONa (50 mol %), 3a (20
t
itself other than BuOH or the OH-group of 1a.
mol %).
Compared to the very low conversion obtained without 3a,
the reaction in the presence of 3a gave the isomerization
product 2a in excellent yield (Table 1, entries 2 and 3). To
explore the form of hydrogen in this isomerization, 1a-d was
subjected to the catalytic isomerization conditions in the
presence of PhCHO under isomerization conditions and an
almost 1:1 ratio of chalcone 6a and 7a-d was found, where 1a
and benzaldehyde worked as the hydride donor and acceptor,
respectively. In contrast, without 3a there was no 6a or 7a
found. This result suggests that the hydrogen atom should be
transferred via the form of a hydrogen atom or hydride other
than a proton. The hydrogen transfer between 1a and 6w
further proved this (Scheme 3).
Scheme 1. Isomerization of Allylic Amines to Ketones
In previous work, a dimer of 3a was discussed as the
catalytically active species.3b Actually, when 3b (both sides are
blocked by methyl groups) was used instead of 3a, the
isomerization of 1a still works very well. The treatment of 3a
A kinetic isotope effect of 5/1 was established (eq 2),
suggesting the C−H bond cleavage step probably to be the
t
with 1 equiv of BuONa and D2O gave no deuterated 3a
(Scheme 3). Similarly, after the catalytic isomerization of 1a, 3a
was quantitatively recovered as well. All of the above-
mentioned information shows that 3a itself other than its
dimer works as a necessary catalytically active species.
rate-determining step. The hydrides were relocated in either the
3- or 2-position in a ratio of 3.6:1, rather than only the 3-
position as what has been reported in the metal-catalyzed
version (Scheme 2). The deuteration experiments show that
only monodeuterated products (2a-d3 and 2a-d2) were
observed. If 2a-d2 generated from deprotonation−reprotona-
tion of product 2a, the dideuterated product [2a-d22,3] should
also been observed. However, when 1a-d was treated with 2
In the kinetic study, a first-order dependence of initial rate on
t
either BuONa or 3a was established, indicating that both
tBuONa and 3a are necessary to catalyze this isomerization
reaction (Figure 1A). The first-order dependence of initial rate
on 3a directly illustrates the participation of 3a in the catalysis
as a catalyst rather than a chelating reagent for the Na+ cation.
t
The first-order dependence of initial rate on BuONa shows
t
t
equiv of BuOK without 3a, a 1:1 mixture of 2a and 2a-d3 was
that BuO− is directly involved in the catalysis. The similar
B
DOI: 10.1021/acs.orglett.5b03124
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Hydrogen/Hydride v.s. Proton
Scheme 5. Working Model
In this working model, either the 2- and 3-position can be
deuterated, which is consistent with the deuterium-labeling
experiments.
Alternatively, a base-promoted working model via an allylic-
anion pathway might be proposed to explain the deuteration on
either the 2- or 3-position.12 In a few previous base-promoted
allylic isomerizations, an excess of strong bases must be
engaged and various reaction working models were proposed
with no experimental evidence.12−14 The catalytic amount of
tBuONa (normally 5−10 mol %) will first deprotonate the
more acidic OH-group of starting materials; thus, there is no
extra base to deprotonate the less acidic α-H of 1a. In fact, even
when an excess amount of tBuONa was added, only 1a-Na was
Figure 1. Kinetic study and EPR experiments. First-order dependence
of initial rate on BuONa and 3a, respectively.
t
t
slopes of 3a and BuONa in Figure 1A indicate that these two
species should work cooperatively.
Radical scavengers such as N-tBu phenyl nitrone 8 and
TEMPO inhibit the isomerization. TEMPO was recovered
1
observed by H NMR. The existence of 2a-d2 could be argued
t
without change in the presence of BuONa. A radical process
by a base-promoted deuterium−proton exchange reaction of
product 2a. The enolate of 2a cannot directly scrabble a proton
from the less acidic α-d of 1a-Na. In addition, the allylic-anion
pathway could not explain the essential catalytic role of 3a.
Therefore, the base-promoted model should be ruled out.
In conclusion, a highly efficient phenanthroline-tert-butoxide-
catalyzed transition-metal-free allylic isomerization of alcohols
and amines has been developed. On the basis of systematic
experimental study including kinetic study, EPR, deuterium-
labeling experiments, and control experiments, a plausible
reaction mechanism involving a radical pathway has been
proposed. This phenanthroline-tert-butoxide-catalyzed isomer-
ization provided a new approach for self-hydrogen transferring
isomerization of allylic alcohols and allylic amines using as low
as 5 mol % of 3a-tBuONa. We anticipate that this approach
could be applied in other organic transformations, especially in
a transition-metal-free process via a radical pathway.
was further confirmed by 1u bearing a cyclopropyl ring as a
radical clock, which decomposed in the presence of 3a-tBuONa
t
but remained unchanged in excess BuOK (Scheme 4). The
Scheme 4. Radical Trapping Experiments
existence of the radical species was further proven by the EPR
t
experiment (Figure 1B). The mixture of 3a and BuONa gave
radical signals (a and b) with substrate 1a, indicating 3a and
alkoxide can produce a radical.1,2 This radical could be trapped
by N-tBu phenyl nitrone (signal c).
ASSOCIATED CONTENT
* Supporting Information
Based on the systematic experimental evidence, a plausible
working model is proposed (Scheme 5). The deprotonation of
■
S
t
1 with BuONa affords intermediate A, followed by generation
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03124.
of radical anion B promoted by phenanthroline 3a. Radical
anion B further transforms to C by resonance. C and its
resonance structure C′ are both protonated with the hydroxyl
group of 1 to afford D and D′ with the regeneration of A. D
and D′ easily scrabble a hydrogen atom from A to regenerate B.
Experimental details and spectroscopic data for all
products (PDF)
C
DOI: 10.1021/acs.orglett.5b03124
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) Fe-catalyst: (a) Branchadell, V.; Crev
Eur. J. 2003, 9, 2062. (b) Emerson, G. F.; Pettit, R. J. Am. Chem. Soc.
1962, 84, 4591.
́
isy, C.; Gree,
́
R. Chem. -
AUTHOR INFORMATION
■
Corresponding Author
(12) For stoichiometric NaH-promoted isomerization of allylic
alcohols: (a) Johnston, A. J. S.; McLaughlin, M. G.; Reid, J. P.; Cook,
M. J. Org. Biomol. Chem. 2013, 11, 7662. (b) Wang, X.; Wang, D. Z.
Tetrahedron 2011, 67, 3406.
*E-mail: ybkang@ustc.edu.cn.
Notes
The authors declare no competing financial interest.
(13) Through [1,3]- or [1,2]-hydride shift: Schmid, G. A.;
Borschberg, H.−J. Helv. Chim. Acta 2001, 84, 401.
ACKNOWLEDGMENTS
(14) For AIBN initiated thiyl radical-mediated cleavage of allylic C−
N bonds: Escoubet, S.; Gastaldi, S.; Timokhin, V. I.; Bertrand, M. P.;
Siri, D. J. Am. Chem. Soc. 2004, 126, 12343.
■
We thank the National Natural Science Foundation of China
(NSFC 21404096, U1463202), the Fundamental Research
Funds for the Central Universities of China (WK2060190022,
WK2060190026, WK3430000001) for financial support.
(15) (a) Inoue, S.; Takaya, H.; Tani, K.; Otsuka, S.; Sato, T.; Noyori,
R. J. Am. Chem. Soc. 1990, 112, 4897. (b) Tani, K.; Yamagata, T.;
Otsuka, S.; Akutagawa, S.; Kumobayashi, H.; Taketomi, T.; Takaya,
H.; Miyashita, A.; Noyori, R. J. Chem. Soc., Chem. Commun. 1982, 600.
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A.; Thiagarajan, V. J. Org. Chem. 1980, 45, 2821. (e) Escoubet, S.;
Gastaldi, S.; Bertrand, M. Eur. J. Org. Chem. 2005, 2005, 3855.
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DOI: 10.1021/acs.orglett.5b03124
Org. Lett. XXXX, XXX, XXX−XXX