Free radical-mediated chemoselective reduction of enones

Article abstract of DOI:10.1080/00397911.2013.804573

A novel methodology has been devised for the chemoselective reduction of enones involving the use of n^Bu3SnH and azobisisobutyronitrile. The 1,4-reduction of variously substituted ,β-unsaturated cyclic and acyclic enones has been successfully c

Full text of DOI:10.1080/00397911.2013.804573

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Free Radical–Mediated Chemoselective
Reduction of Enones
Aeysha Sultan a , Abdul Rauf Raza a & Muhammad Nawaz Tahir b
a Ibn e Sina Block, Department of Chemistry , University of
Sargodha , Sargodha , Pakistan
b Ibn e Haithem Block, Department of Physics , University of
Sargodha , Sargodha , Pakistan
Accepted author version posted online: 27 Aug 2013.Published
online: 29 Oct 2013.
To cite this article: Aeysha Sultan , Abdul Rauf Raza & Muhammad Nawaz Tahir (2014)
Free Radical–Mediated Chemoselective Reduction of Enones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:2, 267-274, DOI:
10.1080/00397911.2013.804573
To link to this article: http://dx.doi.org/10.1080/00397911.2013.804573
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Synthetic Communications1, 44: 267–274, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.804573
FREE RADICAL–MEDIATED CHEMOSELECTIVE
REDUCTION OF ENONES
Aeysha Sultan,1 Abdul Rauf Raza,1 and
Muhammad Nawaz Tahir2
1Ibn e Sina Block, Department of Chemistry, University of Sargodha,
Sargodha, Pakistan
2Ibn e Haithem Block, Department of Physics, University of Sargodha,
Sargodha, Pakistan
GRAPHICAL ABSTRACT
Abstract A novel methodology has been devised for the chemoselective reduction of enones
involving the use of nBu3SnH and azobisisobutyronitrile. The 1,4-reduction of variously
substituted a,b-unsaturated cyclic and acyclic enones has been successfully carried out
under free radical reaction conditions. The reaction has been determined to proceed via
single-electron transfer.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords AIBN; nBu3SnH; chemoselectivity; enone; reduction; SET mechanism
INTRODUCTION
Chemoselectivity is an important tool in organic synthesis that involves
reaction of a reagent at a particular functional group. The current trends in organic
synthesis focus on the development of methodologies that lead a reaction to take
place precisely on a particular reaction center. Chemoselective reactions have the
advantage of formation of the desired product in greater yields with minimal loss
of reactants, minimal efforts, and great economy in the purification of product(s).
Received March 26, 2013.
Address correspondence to Abdul Rauf Raza, Ibn e Sina Block, Department of Chemistry,
University of Sargodha, Sargodha 40100, Pakistan. E-mail: roofichemist2012@gmail.com
267

268
A. SULTAN, A. R. RAZA, AND M. N. TAHIR
a,b-Unsaturated enones are a basic component of many medicinal and phar-
maceutical products either synthetic or naturally occurring (e.g., chalcones, steroids,
phytoestrogens, coumarins, certain carotenones, etc.). The chemoselective reaction
on such a functional group has been a challenge for chemists for many years and
the same is still the case because in many reactions attack on one group also leads
to the transformation of other. Furthermore, both natural products and synthetic
compounds with a variety of functional groups are vulnerable to different reagents.
Thus, methodologies involving selective, mild, and neutral conditions are the
demanding factor to devise chemoselective reactions on enones.
The reduction of enones has been carried out under different conditions and
many efforts have been made to carry out chemoselective 1,2- and=or 1,4-reduction.
The previously reported methods mostly involve the use of metals (e.g., Pd, Zn, Rh,
Pt, Ni, Ir, Co) and their complexes,[1–3] but hydrides of Cu, Sn, Se, Te, and B,[4,5]
sodium dithionite,[6,7] and sodium borohydride[8] have also been reported to be
useful for the hydrogenation of a,b-unsaturated carbonyl compounds. Mostly these
reagents have their own limitations. Negishi et al. used KCuH2 for 1,4-reduction of
enones. This reagent also reduces ketones and other functional groups.[9] Churchill
and co-workers described Osborn complex [(Ph3P)CuH]6 under slight positive
pressure of hydrogen as efficient 1,4-reductant of enone.[10,11] Jian et al. reported
Zn=NH4Cl as a selective 1,4-enone reductant.[12]
n
The Bu3SnH is used along with azobisisobultyronitrile (AIBN, as a radical
initiator) in numerous C-C bond formation reactions through dehalogenation
n
process; however, Bu3SnH is also a very powerful carbonyl reducing agent when
used in the presence of a Lewis acid, Ph3PO, AIBN, or neat in boiling MeOH.[13]
n
Leusink et al. were the first to report the application of Bu3SnH for 1,4-reduction
of a,b-unsaturated enones under the influence of UV irradiation.[14] Later on, Hays
n
et al. utilized Bu3SnH-catalyzed silicon-mediated conjugate reduction of enones by
making use of (tBuO)2 under refluxing conditions.[15] Pattenden et al. reported the
nBu3SnH=AIBN-mediated reduction of estrone as an undesired minor product
during the synthesis of estrone skeleton.[16]
DISCUSSION
In an attempt toward the free radical–mediated construction of ring
D–annulated estrogens, the radical-mediated conjugate addition of d-chloro substi-
tuted enone 1 to methyl vinyl ketone (MVK) was tried. Interestingly, instead of the
desired cyclized product 2, a conjugate adduct 3 was isolated as a minor product
along with a reduced product 4 formed as major product (Fig. 1).
These unexpected results forced us to repeat the reaction under the same
=
conditions again, which led to the same results. The reduction of the C C bond
instead of dehalogenation was a surprising fact and more interestingly the b,c-
=
=
unsaturated C C bond was reduced rather than the a,b-unsaturated C C under
=
these conditions. The b,c-unsaturated C C is reduced preferentially because the
=
endocyclic C C are more reactive than exocyclic C C because of relief of angle
=
=
strain. Second, the endocyclic C C in this particular case is less substituted (less hin-
dered), thus making it more reactive under these reaction conditions. Third, the –I
=
effect of the NO2 group destabilizes the radical cation on the exocylic C C whereas

CHEMOSELECTIVE REDUCTION OF ENONES
269
Figure 1. Attempted synthesis of 2 carried out by refluxing 1 in the presence of AIBN (0.1 eq), nBu3SnH
(4 eq), and MVK (4 eq) in PhH for 18 h.
the radical cation on the endocyclic double bond is stabilized by fused benzene ring.
=
Furthermore, the C O group has no destabilization effect on the fused benzene ring.
n
These findings led us to explore the Bu3SnH as a potential candidate for selective
reduction of conjugated enones.
In the absence of MVK, with the rest of conditions being the same, the enone 4
was the exclusive product obtained. By varying the equivalents of AIBN and=or
n
nBu3SnH it appeared that reaction went smoothly when 2 equivalents of Bu3SnH
and 0.1 equivalents of AIBN were employed. Increasing the equivalents of AIBN
n
did not affect the yield; however, decreasing equivalents of Bu3SnH reduced the
yield. In the absence of AIBN no reaction was observed (Table 1). These findings
suggest that AIBN is catalyzing the reaction and hence the reduction is free radical
mediated.
The same reaction was applied to enones bearing d-chloro group (5a and 5h) with
=
a single conjugated C C bond. In this case again, the reduction of C C bond was
=
observed and the mass spectrum clearly indicated the presence of two peaks in 1:3, thus
confirming the chlorine atom is intact. The disappearance of 0a singlet corresponding to
0
H1 and the appearance of diastereotopy (by H3 and H1 ) indicated formation of
1,4-adduct. The 1,4-addition was also supported by the 13C NMR, which indicated
2
10
=
the presence of C O and appearance of two new aliphatic carbons (C and C ).
Varying the position of the chloro group in the enone also resulted in the for-
mation of a reduced product with the halogen atom intact. The reaction was tried by
varying the ring size of enones; however, no significant difference in yields was
observed. Interestingly, the yield was quite poor (21%) for enone 5d. The poor yield
in this case can be rationalized from the fact that the hydroxyl proton can be easily
substituted by nBu3SnH under free radical conditions. Because there is a competition
n
between the 1,4-addition and the substitution of hydroxyl proton with Bu3Sn, the
Table 1. Synthesis of 4 via Fig. 1
Equivalent to 1
Entry
AIBN
(BzO)2
nBu3SnH
Solvent (time)
Yield of 4 (%)
1
2
3
4
5
6
0.1
0.1
0.1
0.1
1
—
—
—
—
—
0.1
0.5
1
THF (16 h)
THF (16 h)
PhH (8 h)
PhH (18 h)
8 h
23
43
82
85
74
—
2
4
2
—
2
8 h

270
A. SULTAN, A. R. RAZA, AND M. N. TAHIR
effective available concentration of the nBu3Sn radical is reduced, which results in an
overall decrease in the yield of 1,4-reduced product.
The reduction of unsubstituted enone 5a afforded the ketone 6a in reasonable
=
yield. The enone 5e afforded product 5a with C-Br reduction instead of C C
reduction. The inability of radical to cause dehalogenation in the case of
chloro-substituted enone(s) was attributed to the stronger C-Cl bond, which was
not cleaved under free radical conditions, whereas the bromo-substituted enone 5e
followed the course as predicted for any alkyl and=or aryl halide along with forma-
tion of reduced ketone 6a as trace product. When furyl substituted enones (5g and 5i)
were employed, no reaction was observed at all (Fig. 2). It would be due to the for-
mation of a highly resonance stabilized radical cation at O of oxole ring.
After the successful studies on the reduction of cyclic enones, variously substi-
tuted acyclic enones were subjected to free radical–mediated reduction. The disap-
pearance of trans coupling and appearance of two sets of triplets (in most of the
cases) in the aliphatic region indicated the formation of a reduced product. The mass
spectra were in agreement with the expected product in all cases (Fig. 3).
The changes in the bond length of C8–C9 (C2–C1 ) observed in the x-ray
diffraction for 4, 8a, and 9a are represented in Table 2. See also Fig. 4.
0
The role of AIBN in the nBu3SnH-mediated reaction makes it obvious that the
reaction is free radical mediated. The reaction mixture was boiled (digested) in HCl,
Figure 2. Reduction of cyclic enones under free radical conditions by refluxing 5a–i with AIBN (0.1 eq)
and nBu3SnH (2 eq) in PhH for 8 h.

CHEMOSELECTIVE REDUCTION OF ENONES
271
Figure 3. Reduction of acyclic enones under free radical conditions by refluxing 8a–d with AIBN (0.1 eq)
and nBu3SnH (2 eq) in PhH for 4 h.
and Na2S was added to this solution. The resulting mixture was heated to boiling
to exclude excess of H2S. Upon cooling, dull brown precipitates were produced,
which indicated the presence of SnS, and greenish-yellow-colored filtrate upon
concentration afforded a dull yellow solid, which indicated the presence of SnS2.[17]
The presence of both Sn[II] and Sn[IV] ions favor the SET mechanism (Fig. 5).
EXPERIMENTAL
The thin-layer chromatography (TLC) was carried out on precoated silica
gel (0.25-mm-thick layer over Al sheet, Merck) with fluorescent indicator. The
spots were visualized under ultraviolet lamps (365 and 254 nm k) of 8 W power or
a KMnO4 dip upon heating. The compounds were purified either on a glass column
˚
packed with silica gel (0.6–0.2 mm, 60-A mesh size, Merck) or by crystallization.
All solutions were concentrated under reduced pressure (25 mm of Hg) on a rotary
evaporator (Laborota 4001, Heidolph) at 35–40 ꢀC. Melting points were determined
using a MF-8 (Gallenkamp) instrument and are reported uncorrected. The infrared
(IR)-spectra were recorded on Prestige 21 spectrophotometer (Shimadzu) as KBr
discs. The electrospray ionization mass spectrometry (ESI MS) and electron impact
1
mass spectrometry (LR EIMS) were carried out on a MAT312 machine. The H
and 13C NMR were recorded on a Bruker Avance DPX300 spectrometer using
tetramethylsilane (TMS) as internal standard. The x-ray data for the single crystal
˚
Table 2. Selected bond lengths of 4, 8a, and 9a A
Bond
4
8a
9a
O1–C7
C8–C9
1.222(3)
1.518(3)
1.215 (5)
1.406 (5)
1.218 (5)
1.461 (6)

272
A. SULTAN, A. R. RAZA, AND M. N. TAHIR
Figure 4. ORTEP diagram of reduced product 4 (top), acyclic enone 8a (bottom left), and ketone 9a
(bottom right). (Figure is provided in color online.)
were collected on a Bruker Kappa Apex II CCD diffractometer using graphite
˚
monochromated (kMoKa ¼ 0.7107 A) as radiation source.
Representative Procedure for the Synthesis of Enones
A solution of acetophenone (0.88 mL, 0.9 g, 7.53 mmol, 1 eq) and 2-chloro-
5-nitrobenzaldehyde (1.40 g, 7.53 mmol, 1 eq) in EtOH was added to a refluxing
solution of KOH (0.42 g, 7.53 mmol, 1eq) in EtOH (25 mL), and resulting reaction
Figure 5. Mechanism of radical-mediated enone reduction.

CHEMOSELECTIVE REDUCTION OF ENONES
273
mixture was refluxed for 3 h. After the completion of the reaction, the solvent
was evaporated under reduced pressure, and the concentrate was acidified with
aq. HCl (15 mL). The reaction mixture was partitioned between H2O (15 mL)
and CH2Cl2 (3 ꢁ 25mL), and the combined organic extract was dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure to afford the enone
8a as off-white crystalline solid (1.78 g, 82%).
Acetophenone (0.88 mL, 0.9 g); 2-chloro-5-nitrobenzaldehyde (1.4 g)
Off-white crystalline solid 8a (1.78 g, 82%); Rf: 0.59 (EtOAc=petrol 1:1); Mp:
173 ꢀC; IR (KBr): tmax (cmꢂ1) 1676 (C O), 1512 (N O), 682 (C-Cl); UV-vis
(CHCl3): kmax ¼ 346 nm (log e ¼ 4.68318 cmꢂ1 Mꢂ1); LR EIMS (m=z): 287, 289
[M]þ(23, 7%), 105 [PhCO]þ (78%), 77 [Ph]þ (100%); ESI HRMS (amu): 310.0954,
0
=
=
312.0926 [M þ Na]þ (found in 3:1) for 310.000 247, 312.0217; H NMR (300 MHz,
1
00
00
CDCl3): d (ppm) 7.58 (3H, t, J ¼ 7.2 Hz, H3 þ H4 ), 7.66–7.69 (2H, m, H2 ), 7.68
0
(1H, d, J ¼ 15.9 Hz, H2), 8.10 (1H, d, J ¼ 7.2 Hz, H3 ), 8.19 (1H, d, J ¼ 15.9 Hz,
0
0
H3), 8.23 (1H, dd, J ¼ 7.2, 2.4 Hz, H4 ), 8.65 (1H, d, J ¼ 2.4 Hz, H6 ); 13C NMR
0
00
00
(75 MHz, CDCl3): d (ppm) 122.6 (C3 ), 125.1 (C4 ), 127.0 (C2), 128.7 (2ꢁ, C2 or
00
00
00
00
0
C3 ), 128.9 (2ꢁ, C2 or C3 ), 131.3 (C3), 132.0 (C1 ), 133.5 (C3), 134.9 (C1 ), 137.0
0
0
0
(C2 ), 138.0 (C6 ), 146.8 (C5 ), 189.4 (C1).
Representative Procedure for Free Radical Mediated Reduction
of Enones
A solution of nBu3SnH (0.70 mL, 0.77 g, 2.66 mmol, 2 eq) in PhH (5 mL) was
added like drops over a period of 25 min to a refluxing solution of enone 8a (0.25 g,
1.33 mmol, 1 eq) and AIBN (0.025 g, 0.13 mmol, 0.1 eq) in PhH (10 mL).
The resulting solution was refluxed for 4 h under N2. The reaction was quenched
with saturated aq. solution of NH4Cl. The solvent was evaporated in vacuo, and
tributyltin salts were precipitated by the addition of brine to the concentrate
followed by addition of acetone. The salts were filtered off, and the resulting
solution was partitioned between H2O (25 mL) and CH2Cl2 (3 ꢁ 25 mL). The organic
extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure to afford the reduced product 9a as off-white crystalline solid (0.16 g, 64%).
Enone 8a (0.25 g)
Time 4 h; off-white crystalline solid 9a (0.16 g, 64%); Rf: 0.67 (EtOAc=petrol
1:1). Mp: 141 ꢀC; IR (KBr): tmax (cmꢂ1) 1685 (C O), 1538 (N O), 695 (C-Cl);
UV-vis (CHCl3): kmax ¼ 299.7 nm (log e ¼ 4.32599 L cmꢂ1 Mꢂ1); LR EIMS (m=z):
289, 301 [M]þ (4, 1), 105 [PhCOþ] (100%), 77 [Phþ] (92%); ESI HRMS (amu):
312.0479, 314.0432 [M þ Na] (found in 3:1) for 312.0412, 314.0382; 1H NMR
(300 MHz, CDCl3): d (ppm) 3.27 (2H, t, J ¼ 6.8 Hz, H3), 3.35 (2H, t, J ¼ 6.8 Hz,
0
=
=
00
00
0
H2), 7.45–7.63 (5H, m, H2 -H4 ), 7.95 (1H, d, J ¼ 7.2 Hz, H3 ), 8.15–8.21 (1H, m,
0
0
H4 ), 8.60 (1H, d, J ¼ 2.4 Hz, H6 ); 13C NMR (75 MHz, CDCl3): d (ppm) 17.8 (C3),
00
00
00
00
00
00
35.9 (C2), 122.1 (C1 ), 123.5 (C4 ) 126.4 (2ꢁ, C2 0or C3 ), 127.1 (2ꢁ, C2 or C3 ),
0
0
0
0
0
130.0 (C3 þ C1 ), 130.9 (C4 ), 135.0 (C6 ), 138.9 (C2 ), 142.9 (C5 ), 196.5 (C1).

274
A. SULTAN, A. R. RAZA, AND M. N. TAHIR
CONCLUSION
n
In conclusion, Bu3SnH has been evaluated as a potential candidate toward
chemoselective 1,4-reduction of enones. These findings suggest that the free radical–
mediated reduction can take place easily under neutral conditions. The combination
n
of Bu3SnH and AIBN makes this the reagent of choice for chemoselective 1,4-
reduction of enones with substituents sensitive to pH changes. Furthermore, the
chloro groups are not affected under these conditions, but the same cannot be
claimed for bromine.
ACKNOWLEDGMENTS
The authors are obliged to the Higher Education Commission, Government of
Pakistan, for generous support of a research project (HEC 20-809), a fellowship to
Aeysha Sultan (074-141-Ps4-435), IRSIP award and financial assistance for ESIMS,
EIMS, and NMR analyses. The authors are also grateful to the Department of
Physics, University of Sargodha for the single-crystal XRD facility.
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