A Practical and Chemoselective Ammonia-Free Birch Reduction

Article abstract of DOI:10.1021/acs.orglett.8b00891

A novel protocol for a significantly improved, practical, and chemoselective ammonia-free Birch reduction mediated by bench-stable sodium dispersions and recoverable 15-crown-5 ether is reported. A broad range of aromatic and heteroaromatic compounds is reduced with excellent yields.

Full text of DOI:10.1021/acs.orglett.8b00891

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Practical and Chemoselective Ammonia-Free Birch Reduction
Peng Lei,‡ Yuxuan Ding,‡ Xiaohe Zhang, Adila Adijiang, Hengzhao Li, Yun Ling, and Jie An*
College of Science, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China
S
* Supporting Information
ABSTRACT: A novel protocol for a significantly improved,
practical, and chemoselective ammonia-free Birch reduction
mediated by bench-stable sodium dispersions and recoverable 15-
crown-5 ether is reported. A broad range of aromatic and
heteroaromatic compounds is reduced with excellent yields.
he reduction and dearomatization of aromatic compounds
to produce unconjugated cyclohexadienes is a key
synthetic transformation in organic synthesis, with wide
application and scope. Despite being developed over 70 years
ago, the classic Birch reduction, involving dissolving metal in
liquid ammonia, is still the most common method available1
(Scheme 1, eq 1). Recently, the venerable Birch reduction has
tem developed by Donohoe,6 SmI2/Et3N/H2O7 complexes,
etc., have provided better alternatives for ammonia-free
dearomatization processes. However, the reduction of benzene
and electron-rich benzenoid aromatic compounds under
ammonia and amine-free conditions is still a formidable
challenge.
Herein, we address this challenge and report the develop-
ment of a new electride-based Birch reduction that is practical,
green, and wide in scope. This ammonia-free system is
amenable to scale-up, using only bench-stable and commercially
available sodium dispersions, recoverable 15-crown-5, and
iPrOH (Scheme 1, eq 3).
T
Scheme 1. Single Electron Reduction of Benzenoid
Compounds
Dye demonstrated that crown ethers and cryptand improve
the solubility of alkali metals in organic solvents, affording
solutions of electride salts.8 This discovery has attracted
significant interest from organic chemists.9 However, to the
best of our knowledge, aromatic compound reduction mediated
by Na/crown ether remains unknown.
Electride salts are typically prepared using freshly distilled
sodium, a potassium mirror or highly pyrophoric potassium−
sodium alloy, and a suitable complexant under rigorous oxygen-
and moisture-free conditions.8a,9 The reaction between a freshly
prepared sodium lump and a complexant is extremely slow.
Undoubtedly, the tedious procedures required for the
preparation of electride salts have restricted their application
in organic synthesis.
Recently, bench-stable sodium dispersions with high specific
surface area have been developed as useful deprotonating
reagents, and we have previously demonstrated the application
of such reagents as a practical electron transfer reagent.10
In this study, we found that sodium dispersions (particle size
5−10 μm) react rapidly with 15-crown-5 at room temperature
to form the corresponding electride salt, even without the use
of rigorously dried reagents and Schlenk conditions (Scheme
2).
been applied in the functionalization of carbon-based materials,
such as graphene and carbon nanotubes.2 Nevertheless, the use
of liquid ammonia, poor chemoselectivity, and tedious
experimental procedures are obvious disadvantages of this
classic reaction. In a typical Birch reduction, careful purification
of ammonia and all starting materials is critical. Dilute
conditions (0.1−0.5 g/100 mL ammonia) are often required,
which makes the scaleup nontrivial.1
Although liquid ammonia can be replaced by low molecular
weight amines (Benkeser reduction), over-reduced byproducts
are always formed under these conditions (Scheme 1, eq 2).3
Catalytic hydrogenation of aromatic rings is challenging and
typically leads to more saturated products with low
predictability.4 Recent advances in single electron transfer
reductants, including alkali metals and alloys in silica gel (Na-
SG(I) and Na2K-SG(I)) developed by Dye,5 a lithium di-tert-
butylbiphenyl (LiDBB)/bis(methoxyethyl)amine (BMEA) sys-
Given the preferred outer sphere reduction mechanism of the
electride, we hypothesized that this reagent might be suitable
for the challenging reduction of unactivated aromatics. To test
our hypothesis, we chose 1a as model, since it comprises both a
Received: March 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00891
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
suitable for this reaction, although, as expected, the yield is
sensitive to the size of the crown ether. A higher yield was
achieved with 15-crown-5, which is the most complementary
crown ether to the sodium cation. Aza-analogs of crown ethers
(3e, 3f, and 3h) are much less effective for this reaction,8b while
the alkylated aza-crown ether 3g afforded a similar result.
Acyclic polyether 3j and primary amine 3k were determined to
be unsuitable complexants for this reaction. While it is
noteworthy that the reaction with cryptand 3i afforded the
highest yield of 2b, given the high price of 3i, 15-crown-5 3c is
still recommended as the complexant of choice. Importantly,
15-crown-5 is not consumed under our conditions, and about
95% of the crown ether can be recovered using a simple
protocol (see the SI).
Scheme 2. Formation of Electride Salt
phenyl ring and alkyl amide. Upon exposure of 1a to the Na/
15-crown-5/iPrOH system at 0 °C, the corresponding
dearomatized product 2a was obtained in 68% yield (Scheme
3). It is worth noting that the aliphatic tertiary amide that is
Scheme 3. Reduction via Inner or Outer Sphere Electron
Transfer Process
Next, the substrate scope was investigated. In general, this
method is amenable to a broad range of benzenoid aromatic
and heteroaromatic compounds, with excellent regioselectivity
and yields (Tables 1 and 2). Benzene derivatives with electron-
donating substituents (1b, 1h, 1p) are reduced using 9.0 equiv
of Na/15-crown-5/iPrOH, indicating that the reducing power
of Na/15-crown-5/iPrOH is comparable to that of sodium in
liquid ammonia. In the case of aryl ethers 1h and 1p, partial loss
of the alkoxy or methyl groups was not observed.12
Furthermore, when polyconjugated aromatic compounds 1c
are used, the formation of the over-reduced byproducts was
cleanly controlled by using 3.0 equiv of Na/15-crown-5/iPrOH,
giving reducible dihydro derivatives in nearly quantitative yield.
By contrast, mixtures of products at different stages of the
reduction are commonly obtained under the classic Birch
conditions.1a Alkenes and alkynes conjugated to aromatic rings
(1d, 1f, 1g) were selectively reduced without any detectable
reduction of aromatic rings. Tetrahydro derivatives can also be
obtained in high yields by using 9.0 equiv Na/15-crown-5/
iPrOH (1e, 1o). Even aliphatic tertiary amides 1j−1o are stable
under these conditions, which represents a rare example of
benzene reduction in the presence of an unconjugated tertiary
amide. The reduction of σ-bonded functional groups, such as
the cleavage of halides 1k−1n and the removal of benzylic
protecting groups from alcohol 1q and amine 1r, can also be
achieved. Interestingly, the position of the electron-withdrawing
fluoride substituents has no influence on the regioselectivity of
this reaction (1k, 1l, 1m). Furthermore, scaling up the reaction
from 0.5 to 5.0 mmol did not have a detrimental effect on the
product yield (1b) (Table 1). However, the reduction reactions
of 1-phenylbutan-1-one, methyl benzoate, and N,N-dimethyl-
benzamide resulted in lower yields and the formation of
complicated byproducts.
readily reduced by Na/NH3 is stable under these conditions.11
As expected, the control reaction without crown ether afforded
only alcohol 2a′ (Scheme 3). The above results demonstrate
that crown ether can effectively switch the electron transfer
mediated by sodium from an inner to an outer sphere electron
transfer process.7a−c
After careful investigation of the reaction (see the Supporting
Information (SI)), a 91% yield of 2a was obtained by using 6
equiv of Na/iPrOH/15-crown-5 in THF at 0 °C.
A stable and strong complexant for the sodium cations is the
key to generating the electride; therefore, different complexants
were screened (Scheme 4). Cyclic polyethers are in general
a
Scheme 4. Evaluation of Different Complexants
Regarding heteroaromatic compounds, acridines 1s, quino-
lines 1t and 1v, isoquinolines 1u, and N-alkylated indoles 1w,
were readily reduced (Table 2). Dimerization and over-reduced
byproducts were not observed in our reactions.13 Reduction of
benzofuran 1y afforded a significant amount of the C−O
cleavage ring-opening product 2y′, while furan is not reduced
under these conditions, as is often the case in the traditional
Birch reduction. Interestingly, free O−H phenol 1i and free N−
H indole 1x were not reduced by Na/15-crown-5/iPrOH,
indicating the high chemoselectivity of this protocol.
A series of competition studies were performed in order to
assess the chemoselectivity of the reaction (Table 3). The
results demonstrate that electron-deficient aromatic com-
pounds like 1k (Table 3, entry 1), polynuclear aromatics
such as 1c (Table 3, entry 2), conjugated alkenes such as 1d
(Table 3, entry 4), and heteroaromatic compounds such as 1s
a
Conditions: 1b (0.50 mmol, 1.0 equiv), Na (6.0 equiv), iPrOH (6.0
equiv), ligand (6.0 equiv), THF (3.0 mL), 0 °C, 15 min. Yield of 2b
determined by H NMR.
1
B
DOI: 10.1021/acs.orglett.8b00891
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Reduction of Aromatic Substrates Using Na/15-
crown-5/iPrOH
Table 2. Reduction of Heteroaromatic Substrates Using Na/
15-crown-5/iPrOH
a
a
a
Conditions: 1 (0.50 mmol, 1.0 equiv), Na/iPrOH/15-crown- (3.0−
b
6.0 equiv), THF (3.0 mL), 0 °C. Isolated yield.
Table 3. Competition Reactions
Na/iPrOH/
15-crown-5
conversion A/B
entry substrate A substrate B
(%)
1
2
3
4
5
1b
1b
1b
1b
1i
1k
1c
1s
9.0 equiv
3.0 equiv
6.0 equiv
3.0 equiv
9.0 equiv
<5:60
<5:62
<5:84
<5:51
<5:>95
1d
1h
reagents, and impractical low reaction temperatures are not
required. The high chemoselectivity of this method will
potentially expand the application of the Birch reduction in
the construction of complex molecules. Most importantly, this
new practical method to prepare electride salts provides a
general strategy for the application to other Na/NH3 mediated
reactions.
a
Conditions: 1 (0.50 mmol, 1.0 equiv), Na/iPrOH/15-crown-5 (3.0−
b
c
9.0 equiv), THF (3.0 mL), 0 °C. Isolated yield. 1 (5.0 mmol).
(Table 3, entry 3) can be selectively reduced in the presence of
unactivated benzenoids such as 1b. Furthermore, selective
reduction of phenol ether 1h in the presence of the
corresponding phenol 1i can also be readily achieved (Table
3, entry 5).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00891.
In summary, a practical and highly chemoselective ammonia-
free Birch reduction mediated by Na/15-crown-5/iPrOH has
been developed. The key to the success is the use of chelating
15-crown-5, which switches the electron transfer mediated by
sodium from an inner to an outer sphere electron transfer.
Critical from a practical standpoint, the reaction requires only
inexpensive, air- and moisture-stable reagents. Excellent yields
were obtained across a broad range of aromatic and
heteroaromatic substrates. In general, the substrate scope and
regioselectivity compare well with the classic Birch reduction;
however, this new method is operationally trivial and gives
much higher chemoselectivity. Rigorous purification of
reagents, a strictly inert atmosphere, hazardous flammable
Experimental procedures and compound characterization
data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jie_an@cau.edu.cn.
ORCID
Peng Lei: 0000-0003-1685-9517
Jie An: 0000-0002-1521-009X
C
DOI: 10.1021/acs.orglett.8b00891
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Yang, R.; Ma, X.; Ling, Y.; An, J. Tetrahedron Lett. 2017, 58, 2757.
(c) Han, M.; Ding, Y.; Yan, Y.; Li, H.; Luo, S.; Adijiang, A.; Ling, Y.;
An, J. Org. Lett. 2018, 20, 3010. (d) Zhang, B.; Li, H.; Ding, Y.; Yan,
Y.; An, J. J. Org. Chem. 2018, DOI: 10.1021/acs.joc.8b00617.
(11) Although primary and secondary amides are relatively stable
under Birch conditions, tertiary amides can be reduced to form
alcohols using the Na/NH3/ROH system; see: Barrett, A. G. M. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 8, pp 236−281.
(12) Demethylation of methoxybenzene derivatives mediated by the
K/crown ether system was achieved in toluene without the reduction
of the aromatic ring; see: Ohsawa, T.; Hatano, K.; Kayoh, K.; Kotabe,
J.; Oishi, T. Tetrahedron Lett. 1992, 33, 5555.
Author Contributions
‡P.L. and Y.D. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21602248, 21711530213) and Chinese Universities
Scientific Fund for financial support. We thank Dr. Ross
Denton from the University of Nottingham, Prof. Michal
Szostak from Rutgers University, and Prof. John Moses from La
Trobe University for useful discussions.
(13) Keay, J. G. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 8, pp 579−602.
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DOI: 10.1021/acs.orglett.8b00891
Org. Lett. XXXX, XXX, XXX−XXX